An improved method of preserving the flavor in a food product, such as a low calorie food bar, is characterized by stabilizing the flavoring by plating the flavoring on synthetic amorphous silica. An improved flavoring system for a food product contains aspertame and/or proteinaceous material in combination with a flavoring plated on synthetic amorphous silica.

Numerous studies that have evaluated effects of excessive body weight on mortality suggest that mortality increases with increasing weight. The mortality ratio (the actual number of deaths as a percent of expected deaths for a population) increases with degree and duration of obesity from 110 among persons 5 to 15 percent overweight to 227 among those 55 to 65 percent overweight. Morbid obesity (100 percent over desirable weight) has been associated with a mortality ratio of 1200.
Relative body weights above 100 to 109 percent of desirable weight are associated with increased incidence of morbidity from cardiovascular diseases, cancer, diabetes, and digestive diseases. The greater the relative weight, the greater the risk for these conditions. Many other potentially serious conditions such as sleep apnea, gallbladder disease, osteoarthritis, and other bone and joint disorders are associated with obesity. In the United States alone, studies have shown that over 34,000,000 individuals could be classified as being overweight.
Weight loss and subsequent weight maintenance reduce the health risks associated with obesity. A variety of approaches including reducing caloric intake, exercise, behavior modification, drug therapy, surgery, and combinations of these methods are currently practiced. Some approaches are more "aggressive" than others.
An "aggressive" approach to weight management is not new. Prolonged total fasting under hospital supervision became an accepted approach for treating morbid obesity in the early 1960's. Total fasting (starvation) is characterized physiologically by decreases in serum insulin and glucose concentrations and increases in serum free fatty acids (from body fat) and ketone concentrations (substrate from body fat).
Additionally, total fasting results in the excretion of higher than normal concentrations of potassium (with related electrolyte imbalances) and loss of lean body mass (i.e., nitrogen--protein--losses from skeletal muscle and organ tissue). The increase in serum ketones occurring during fasting is important in decreasing body protein losses as the ketones substitute for protein-derived glucose. Although body protein losses are reduced, they remain significant and seriously detrimental. While weight loss and rate of weight loss was significant with total fasting regimens, health- and life-threatening physiologic complications such as significant loss of lean body mass, electrolyte imbalances, and nutrient deficiencies associated with this treatment limited their use.
Information obtained from early experiences with total fasting led to the development of safer and more effective dietary regimens such as the protein-sparing diet of the very-low-calorie type, (PSD/VLC), also referred to as a protein-sparing modified fast. Currently, this relatively "aggressive" approach to weight loss and management is considered an accepted treatment for obesity when used as part of a medically supervised, comprehensive program.
The goal of a PSD/VLC diet is to achieve weight loss of body fat comparable to that of fasting, while sparing lean body mass and avoiding electrolyte imbalances and nutrient deficiencies. The administration of exogenous protein (i.e., from diet) of high quality promotes improved body protein-sparing over fasting alone. Studies suggest that providing a level of protein of 1.2 to 1.5 g/kg body weight facilitates protein-sparing, thus making the PSD/VLC diet a safer regimen. PSD/VLC regimens, therefore, must contain relatively high levels of protein and very low levels of carbohydrate when compared with a "typical" diet to be safe and efficacious.
The recommended percent distribution of total calories provided by protein, fat, and carbohydrate for a "typical" diet is 15 to 20%, less than 30%, and 50 to 55%, respectively. In a "typical" diet providing as few as 800 calories (a number representative of a very-low-calorie diet), 50 to 55% of the calories as carbohydrate is approximately 100 to 110 grams. The maximum amount of carbohydrate per day that will facilitate ketone production is 50 grams. Therefore, low levels of carbohydrate (less than 50 grams per day) and high levels of protein are essential to the effectiveness of a PSD/VLC diet as they facilitate body fat utilization for energy (ketosis and free fatty acid production) and spare body protein.
PSD/VLC type diets must also provide vitamins and minerals, especially electrolytes, at levels that meet an individual's needs for maintaining nutritional status, as well as the increased needs resulting from the physiologic response to the fasting regimen. Ideally, all nutrients needed for nutritional safety should be contained in the meal replacement product to reduce the need for vitamin/mineral/electrolyte supplementation and the inherent risk of non-compliance with supplementation regimens.
Typically, individuals who respond favorably to a PSD/VLC diet may be kept on the regimen until their goal weight is obtained. Therefore, they may be on the regimen for months, usually more than 3 months and sometimes over a year. While most PSD/VLC beverages are well-tolerated, individuals often complain that they miss the action and associated sensations of chewing food while on the diet regimen. Currently, no solid food form is available that meets accepted formulation criteria for such a regimen. There is provided by the present invention a solid food form (bar) that may replace a serving of the beverage due to its similar nutritional profile. The development of a bar acceptable from organoleptic and textural properties was a challenge due to the unique nutritional profile of a bar required to accommodate the physiologic response to the PSD/VLC regimen and to make this product safe for use with such a diet regimen.
In any attempt to produce a meal replacement bar for use in conjunction with a PSD/VLC diet, it is necessary to overcome a number of inter-related problems. First, the bar must be of a palatable texture. This problem is particularly acute in attempting to design a low carbohydrate, high protein, nutrient-dense, solid food product since the high concentration of protein tends to facilitate tight bonding, such that the food product becomes rubbery or brick-like in as little as a few days. Thus, prior attempts have had problems creating a solid food product which had a reasonable shelf life with respect to a palatable texture.
The second problem, and one which has applications far beyond the creation of a high protein solid food product, is the inherent problem of flavor system having stability in high protein, low carbohydrate solid products. There are two sources to this problem, and the fact that these two sources are interrelated exacerbates the problem. The first source is the fact that carbohydrates and, to a far greater degree, proteins are known to bind flavors. Furthermore, the high level of protein present in PSD/VLC foods increases any tendency for the protein to react with the flavoring components. This problem is compounded further by the need to compensate for undesirable flavors introduced by vitamins and minerals in concentrations required by this dietary regimen.
The second source of the problem is the desired presence of the sweetener, aspartame. Aspartame is well known for reacting with flavors. The problem caused by the high level of proteins and the presence of aspartame in a PSD/VLC food product normally culminates in one of two results. The first is a food product which over time experiences a change in flavor, such that the taste becomes one which is totally undesirable. The other possible result is for the reaction of the protein and aspartame with the flavor component to cause a significant loss in flavor over a relatively short period of time. Additionally, it is extremely difficult to predict how various proteins, aspartame and flavoring components will react in a given food product.
Although problems related to the obtaining of a palatable texture and a stable flavor are the primary concerns in manufacturing such a food product, it also must be kept in mind that problems can exist in the initial selection of a flavoring component. Regardless of the theoretical stability of flavoring, any given flavor may initially react differently with a food product composition. Therefore, just because a flavoring component has been successfully used before or in conjunction with a certain food product formulation is no guarantee that the flavor will respond similarly with a different list of ingredients. There is a fair amount of prior art related to the solving of this or a similar problem. Perhaps the most pertinent are U.S. Pat. No. 4,900,566 for a confectionery product and process for producing the same; Patent WO 92/02149 for a reduced-calorie low-moisture absorbing bulking agent compositions and methods for preparing same; and Japanese Patent No. Hei 4-158744-A for a low-calorie chocolate preparation.
The U.S. Patent concerns a process and confectionery product wherein the proteinaceous material and carbohydrate material are present in a relative ratio of from about 1:1 to 1:10. In addition, the sweetening agents do not include aspartame. The patent on bulking agent compositions pertains to products which can be incorporated into chewing gum or confections similar to nougat. The Japanese patent pertains to a low-calorie chocolate preparation involving dough, however no mention is made of protein content, suitability of use in a PSD/VLC, or manufacture in food bar form.
It is thus apparent that a need exists for a solid food product such as a food bar, which provides a high level of protein, a low level of carbohydrates and is nutrient-dense and does so having both a palatable texture and a stable flavor delivery system.
It is apparent that a need exists for a flavor system which has good shelf life when used in conjunction with aspartame and/or high levels of protein.


The application relates to methods for the diagnosis, treatment, and prevention of autoimmune and/or inflammatory disease such as systemic lupus erythematosus (SLE), lupus nephritis, IgA nephropathy, other types of glomerulonephritis.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which the immune system makes antibodies to cells and molecules in the body, leading to widespread inflammation and tissue damage. The causes of SLE are believed linked to genetic and to hormonal factors, as well as environmental factors that remain poorly understood.
Although most epidemiologic studies have focused on genetic factors, environmental influences may be inferred in results from a recent large survey of over 23 million individuals, representing nearly the entire population of Taiwan (1). As expected, homozygotic twins showed a relative risk (RR) of over 300 for disease concordance, while those with an affected first-degree relative (FDR) had an overall RR of Lupus over 17-fold. Strikingly, spouses "without genetic similarity" had a 4-fold RR (2.38-8.30). By contrast, individual disease-associated SNPs and genetic intervals generally convey a less than 1.4-fold RR (2).
SLE family members, including spouses, are reported to more commonly have serum Lupus autoantibodies (3, 4). Laboratory workers that handle blood from SLE patients are reported to also have significantly higher rates of serum anti-DNA antibodies (5). Notably, family members are known to more commonly share many of the taxa in their intestinal microbiomes (6, 7). Together, this suggests a new hypothesis regarding a different type of candidate transmissible agent(s) in Lupus pathogenesis.
The disease concordance in genetically dissimilar spouses implicates shared close personal environmental exposures. It is postulated that the community of bacterial commensals that we all carry within us may provide the largest environmental exposure. In health, this microbiome may include species that can be major determinants of host immune activation thresholds. In susceptible hosts, some of these commensals may also contribute to autoimmune pathogenesis.
Accelerating advances are illuminating how intestinal microbial communities prime our immune systems and then set overall activation levels (11). Intestinal colonization is required for B-cell development, and the secretion of IgA into the gut lumen (12). In turn this secretory IgA affects the properties and even representation of specific gut bacterial taxa. Notably, some commensal species have been implicated in the pathogenesis of inflammatory and autoimmune diseases, and been termed pathogenic symbionts or pathobionts. In the mouse, Segmented Filamentous Bacteria (SFB) represents the archetypic example of a common colonizer of the small intestine that aids physiologic immune maturation and development of host immune defenses to pathogens (13, 14). However, in predisposed murine strains, SFB colonization can trigger the onset of a range of autoimmune diseases (11). In humans, GI tract colonization with Helicobacter pylori is generally innocuous, and it may protect from esophageal cancer (15). Yet this common commensal species can cause peptic ulcer disease, which at one time was the most common indication for abdominal surgery. H. pylori infections also contributes to the development of some cases of marginal zone lymphoma (16), which remits with antibiotic treatment.
Advances in culture-independent surveys now enable massive high-throughput 16S ribosomal gene sequence determinations (17, 18). Studies in inflammatory bowel disease (IBD) patients have detected lower microbial diversity and greater temporal instability compared to controls (19), which reflects imbalances (or dysbioses) in their gut microbiomes (20), but this might be expected as the bowel itself is diseased.
In clinical rheumatology, intestinal blooms of the anaerobe, Prevotella copri, have been reported at onset of symptomatic seropositive rheumatoid arthritis (RA) (21). There is, however, sparse literature on the microbiome in human Lupus. Although, there are reports on a cohort of 20 female SLE patients (22), but these women were without active disease at the time of sampling. Thus, conceptually, this may be like looking for a disease-associated microbiome in a twin who has never had SLE disease.
SLE affects an estimated 1.5 million Americans (80). Yet all too often treatment options are inadequate to arrest disease progression, and, in general these treatments are highly immunosuppressive and are responsible for high frequencies of serious and often fatal infections (81). Moreover, SLE can lead to complications such as lupus nephritis, which is an immune mediated inflammatory disease of the kidneys. Lupus nephritis can be life-threatening and/or result in renal failure. Definitive diagnosis may require a renal biopsy, which is expensive and associated with defined morbidity and complications. Moreover, delays in Lupus nephritis diagnosis puts the patient at further risk for progression of renal disease, and the associated morbidity, complicating illnesses and premature mortality. There are financial costs that are associated with this increased morbidity, disability, and premature death. These affect individuals, families, communities, and our society in general. Thus, there remains a need for methods for earlier and more accurate diagnosing, treating, and preventing conditions such as SLE and/or lupus nephritis, such as methods and treatments based on or related to the gut microbiome, including associated antigens.

Methods and compositions for treating and diagnosing autoimmune diseases


Circuitry for and method of power efficient operation of, and energy recovery from, tissue-stimulating electrodes having high charge capacities. Post-stimulation energy is recovered from the electrodes through a variety of techniques into circuit elements such as other electrodes, an intermediate distribution system, a power supply or any other elements, through the use of sequential switching. Energy is also recoverable from the intermediate distribution system, which preferably is comprised of one or more storage capacitors operating a different voltages. Efficient power transfer among circuit elements is effected by transferring energy while limiting element-element voltage differences and/or voltage differences between the elements and the capacitances of the electrodes.

Devices for electrically stimulating tissue, including cochlear implants, pacemakers, muscle and spinal cord stimulators, have been in use for decades. Retinal prostheses that might assist some of the estimated 10 million people worldwide who are blind as a result of degenerative retinal diseases, such as age-related macular degeneration and retinitis pigmentosa, are under development based on the concept of replacing photoreceptor function with an electronic nerve-stimulating device.
Many tissue-stimulating prostheses provide electrical signals to an implanted section, which then generates excitation signals to excite the tissue of a patient by means of appropriately positioned stimulation electrodes or arrays of electrodes. Common in some tissue stimulators is a two-part design, wherein an external section transmits RF energy that is inductively coupled by a transcutaneous RF link to the implanted section. The energy of the coupled RF electrical signals is rectified and stored by a power supply located in the internal section. It is that power supply that provides the energy required to power the internal section and to generate the stimulus signals.
To increase patient safety, to minimize the power requirements of a tissue stimulator, and because power dissipation losses are in proportion to the square of the voltage, it is desirable to operate the tissue stimulator at low voltages that are no greater than required. This is especially true in implantable stimulator electronics. During stimulation, the electrodes of tissue stimulating devices are typically driven by a constant current source to a prescribed level of charge, resulting in storage of that charge, and therefore storage of energy, within the electrodes. To ensure charge balancing to avoid electroplating the electrodes, the same amount of charge is then driven in the opposite direction (changing polarity) until the electrodes are left uncharged. Typical circuit techniques are very inefficient when driving this type of electrode, often using more than twice the necessary energy during the first phase of current drive, and even more during the second phase.
U.S. Pat. No. 5,522,865 to Schulman, et al., entitled "Voltage/Current Control System for a Human Tissue Stimulator" discloses a human tissue stimulating system that comprises an audio responsive system for artificially stimulating a cochlea to improve hearing for the hearing impaired. The implanted stimulator includes a power supply that extracts raw power from a data signal, a voltage downconverter for providing a number of output voltages from the extracted raw power signal, and a storage capacitor that serves as the power source for portions of the stimulator. One of the output voltages is applied to isolated refresh voltage capacitors, where it controls a voltage controlled current source that supplies output to the electrodes through a complex switch matrix. Energy is conserved by turning off and on various subsystems within a control processor, and by optimizing power dissipation of a conventional input switching regulator by controlling the RF power transmitted from an external source to the implanted stimulator based on a telemetered voltage drop across the regulator, indicating what power is required to be transmitted for just sufficient stimulator operation.
U.S. Pat. No. 5,876,425 to Gord, et al., entitled "Power Control Loop for Implantable Tissue Stimulator" also describes a feedback power control loop utilizing back telemetry from the implantable device. The voltage level of a tank capacitor utilized as an internal rechargeable power source is transmitted to an external power supply processor for computation and delivery of an appropriate amount of power to maintain normal operation, while minimizing transmission of extra energy that might otherwise be dissipated.
U.S. Pat. No. 6,415,186 to Siu-Chor Chim, et al., entitled "Active Feed Forward Power Control Loop" discloses a feed forward power control loop for providing power to the implanted part of a tissue stimulator. Power consumption is similarly kept low by transmitting across a wireless transcutaneous transmission link only the amount of power required by the implanted device, as predicted by the power control loop processor. The reference discloses the use of intermittent telemetry and predictive modeling to determine the appropriate amount of power to transmit.
Each of the references cited above approaches power transfer optimization by using tank capacitor voltage telemetry to determine power transmission. They address power consumption efficiency of the implanted circuitry, to a greater or lesser extent, by turning on and off circuit components, and otherwise treat conventionally the transfer of energy from the power supply to the electrodes. None address recovering energy from the electrodes and other components after stimulation has occurred.
U.S. Pat. No. 6,181,969 to Gord, entitled "Programmable Current Output Stimulus Stage for Implantable Device" discloses a programmable output current source for use within an implantable tissue or nerve stimulator. Each electrode node has parallel-connected P-FET current source sets permanently connected between it and a positive voltage rail, and parallel-connected N-FET current source sets permanently connected between it and a negative voltage rail. The higher power requirement of the PFET and NFET current sources is kept to a minimum by avoiding physically or electrically "switching" the electrode nodes between one or more circuit locations, or to different sides of a current or voltage source so as to change the polarity of the current flowing through the node. Rather, the P-FET sources "source" current to the node, and the N-FET sources receive, or "sink", current from the node. Such a non-switching approach is achieved at the cost of more circuit components.
Accordingly, there is a continuing need for greater power utilization and delivery efficiency in tissue stimulating devices. The present invention satisfies such needs.

System for and method of power efficient electrical tissue stimulation


A die package having an adhesive flow restriction area. In a first embodiment, the adhesive flow restriction area is formed as a trench in a transparent element. A second embodiment has a transparent element with an adhesive flow restriction area formed as a plurality of trenches that extend from one edge of the transparent element to the other edge. A third embodiment has a transparent element with an adhesive flow restriction area formed as a plurality of trenches. A fourth embodiment has a transparent element with an adhesive flow restriction area formed as a protuberance. A fifth embodiment comprises a trench in the die. A sixth embodiment has a die with a plurality of trenches in the die as an adhesive flow restriction area. A seventh embodiment has a die with a protuberance.

Integrated circuits, including dies, for example, imager dies such as charge-coupled-devices (CCD) and complementary metal oxide semiconductor (CMOS) dies, have commonly been used in photo-imaging applications. Such dies typically contain thousands of pixel cells in a pixel array on a single chip. Pixel cells convert light into an electrical signal that can then be stored and recalled by an electrical device such as, for example, a processor.
Dies are typically packaged and inserted into imaging devices such as, for example, a digital camera. FIG. 1 illustrates a cross-sectional view of one conventional die package 100. The die package 100 includes a die 14 positioned on a substrate 10. The die 14 includes an array of pixels 16. The die 14 typically has a transparent element 18 attached to a surface containing the array of pixels 16 by an adhesive material 24.
In operation, light radiation enters the transparent element 18 of the die package 100. The transparent element 18 filters out IR radiation that can cause color shifts due to cross talk between pixels in the array of pixels 16. Light radiation is then adsorbed, and image signals are created by the array of pixels 16, which converts the photons from light radiation to electrical signals. Wire bonds 13 conduct electrical output signals from the die 14 to wiring on the substrate 10, which, in turn, connects to external circuitry (not shown). The external circuitry may include processing circuits for storing, compressing, manipulating, or displaying an acquired image.
The FIG. 1 die package 100 is formed by placing the die 14 on the substrate 10, applying adhesive material 24 on the periphery of the die 14, and finally placing the transparent element 18 over the die 14. The adhesive material 24 ensures that the transparent element 18 remains attached to the die 14.
While the package illustrated in FIG. 1 works well, the adhesive material 24 often interferes with the array of pixels 16. During the process of attaching the transparent element 18 to the die 14, adhesive material 24 often covers the edge pixels of the array of pixels 16, as illustrated in FIG. 1. As the transparent element 18 is placed over the die 14, capillary action, as well as the force pushing down on the adhesive material 24, may force the adhesive material 24 onto the array of pixels 16, thus interfering with the operation of the die 14. This can lower the yield of packaged products and may affect the performance of packaged products which pass yield tests.
The problem may also be present in packaged dies fabricated to have display pixels, rather than pixels used to receive an image and convert it to electrical signals, resulting in poor visual quality.

Die package having an adhesive flow restriction area


Techniques for data transmission including receiving, at a geostationary earth orbiting satellite, forward-direction user data via a forward optical link; transmitting, by the geostationary earth orbiting satellite via multiple radio frequency (RF) spot beams, the forward-direction user data received via the forward optical link; receiving, at a stratospheric high-altitude communication device, forward-direction user data via multiple concurrent forward RF feeder links; transmitting, by the stratospheric high-altitude communication device via the forward optical link, the forward-direction user data received via the forward RF feeder links; transmitting, by each of multiple ground-based feeder RF terminals at a same RF feeder site, a respective one of the forward RF feeder links. At least 95% of forward feeder data throughput for all of the forward RF service link transmissions by the satellite is carried via the forward optical link and the forward RF feeder links.

Individual high-throughput satellites in geosynchronous earth orbit (GEO) over time offer increasing aggregate end-user data throughput. For example, the EchoStar 19 satellite, launched in 2016, offers a data throughput in excess of 200 gigabits per second (Gbps). One limit to achieving terabit per second (Tbps) forward data throughput (also referred to as "data capacity" or "capacity") from a single GEO satellite is available forward feeder link bandwidth for delivering data to the satellite. With radio frequency (RF) communications, including various "millimeter wave" bands, such rates are generally impractical and expensive. RF feeder links must comply with regulatory constraints and also not conflict with user RF links (the co-siting problem), which makes the following RF bands undesirable:                27.5-28.35 GHz has geographical limitations due to conflicts with 5G cellular communications technology efforts.        28.6-29.1 GHz is utilized by NGSO (non-geostationary orbit) communication satellites, placing the band at risk from various LEO satellite constellation plans.        License-exempt V-band (50-75 GHz) guarantees 4 GHz of bandwidth, with a likely additional 2 GHz, another 2 GHz hopeful, and another 2 GHz in the distant future.
Plus, at this time, the W-band (75-110 GHz), although it offers 10 GHz, requires further technical development for this purpose for use in GEO RF feeder links. Additionally, even with a spectral efficiency of 2.5 bps/Hz, 400 GHz of total RF bandwidth is required to reach 1 Tbps data capacity, so combined use of the available bands would require about 19 gateways (GWs), plus many additional gateways for diversity. For GEO satellites with data throughput in only a few hundreds of gigabits per second, ground segment costs (construction, operation, and maintenance) for feeder links are already a significant percentage of overall network system cost. For 1 Tbps or greater data throughput, and the resulting increase in the number of gateways, ground segment costs become even more significant. Also, although it may be possible to fit the needed number of gateways in the United States, a very favorable satellite location would still be needed. Thus, in view of significant technology challenges and regulatory uncertainty, use of RF feeders between the Earth's surface and a GEO satellite to achieve terabit per second or higher data throughput is a difficult, uncertain, and expensive architecture.

Systems and methods for high-altitude radio/optical hybrid platform


A system, computer-readable medium, and method for automatically determining if an applicant is qualified to perform a task are provided. In the method, an application including applicant identifier information identifying an applicant is received by a computing device. The applicant identifier information is extracted from the received application. A query to a database including the extracted applicant identifier information is created and sent to a database system using a network. The database system stores data associated with the extracted applicant identifier information. A response to the query is received from the database system using the network. The response includes data associated with the applicant's qualification to perform a task. Whether or not the applicant is qualified to perform the task is determined by comparing the data associated with the applicant's qualification to a predetermined qualification criterion.

The transportation industry in the United States is a highly regulated and complex industry in which various tasks must be performed by multiple parties to ensure the safe, cost effective, precise, and timely delivery of goods. Hiring and on-boarding truck drivers is the process of coordinating recruiters and sellers to hire the most qualified applicants from a pool of drivers to ensure the safety of the public and the continuation of the carrier or trucking company. Various data must be collected from the driver applicant, as well as from criminal databases, credit reports, driving records, and previous employers to determine if the applicant is qualified depending on the driver status such as student, interstate, or hazardous material. Different requirements are placed upon the carrier to hire the appropriate driver with specific endorsements, experience, and criminal behavior. Therefore, the eligibility of the driver must be evaluated against the standards set by the carrier's requirements for a particular driving task.
Finally, many documents, certifications, and agreements must be either signed or verified to qualify a driver or a carrier to carry a shipment. Often the pressure on recruiters to fill trucks with drivers, or an agent for a logistics company's motivation to sell freight and increase commissions compels them to cut corners and not follow established policies. Timeliness also plays a key role in transportation because the first offer for employment or acceptance of a shipment often receives the contract. As a result, "best practices" have been difficult to enforce because there was no system that required that a process be followed or gave management visibility to those who ignored policies. In addition, there was no way to communicate and make automated the decision process between disparate systems and content contained on paper.
In the conventional process, a carrier of goods manually collects information from the driver, from governmental and other third party databases regarding licensure, previous employers, and other applicable information. After the collection of this disparate data, the carrier manually reviews the information and determines whether the driver is eligible or otherwise suitable to transport freight. If the driver is deemed eligible, the carrier manually creates the appropriate contracts and documentation and sends it to the driver for acceptance and signature, usually via the United States Postal Service or facsimile. The carrier waits until the driver returns all of the documentation and manually analyzes the returned documents to determine if the driver properly executed and returned the necessary forms. The carrier manually creates an orientation date and documents and enters data for driver information into the dispatching system to facilitate dispatches. A particular carrier may have its own requirements for all drivers transporting goods that differ from the requirements of other transportation carriers.
Drivers may become ineligible to transport freight due to a change in the driver's safety, health, criminal activity, financial, or certification status. There is currently no efficient way to determine and communicate the current status of a previously approved driver or remove the driver from the active eligible driver pool if the driver no longer meets the qualifying requirements for the transportation task.
Logistics management is the process of coordinating and facilitating the pickup, shipment, and delivery of goods. Depending on the type of goods shipped, requirements are placed upon the carrier or trucking company. For example, some carriers and their equipment may not be suitable for the delivery of milk, but may be suitable for the delivery of clothing. Different shippers also screen their carriers based upon safety and security by checking the carrier's driving record, insurance status, driving experience, etc. Additionally, various trucking companies or individual carriers qualify for the shipment of certain goods, along certain routes, but do not qualify to ship the same goods on other routes. Therefore, an evaluation of the eligibility of the carrier or their trucking company is evaluated against the shipment load, route, and requirements for a particular shipment. Thus, similar to a driver's eligibility to work for a carrier, a carrier may be selected by a manufacturer to support shipment of the manufacturer's goods to various customers.


Electrode foils suitable for use in electrolytic capacitors, including those having multiple configurations, have improved strength, reduced brittleness, and increased capacitance compared to conventional anode foils for electrolytic capacitors. Exemplary methods of manufacturing an anode foil suitable for use in an electrolytic capacitor include forming a pattern of etch resist on a surface of a substrate; etching a first area of the surface substantially enclosed by the pattern and a second area in intervals between the pattern to form tunnels in first and second areas of the surface; and removing the resist material revealing a non-etched frame. The resist material may be deposited, for example, by ink-jet printing, stamping or screen printing. Additionally, an etch resist pattern may be used to form strength lines on the substrate surface.

1. Field of the Invention
The present invention generally relates to electrode foils and, more particularly, to a method for making electrode foils suitable for use as anodes in electrolytic capacitors.
2. Related Art
Electrolytic capacitors are compact, high voltage energy storage devices used in a variety of applications including, for example, in implantable medical devices (IMDs) such as implantable cardioverter defibrillators (ICDs). An ICD is a medical device that is implanted in a patient to monitor electrical activity of the patient's heart and to deliver appropriate electrical and/or drug therapy, as required. ICDs include, for example, pacemakers, cardioverters, defibrillators, and the like.
ICDs conventionally use electrolytic capacitors because such capacitors have a high energy density and can withstand a relatively high voltage. ICDs typically use two electrolytic capacitors in series to achieve the desired high voltage for shock delivery. For example, an ICD can utilize two 250 to 500 volt electrolytic capacitors in series to achieve a voltage of 500 to 1,000 volts.
One type of electrolytic capacitor includes an etched aluminum foil anode, an aluminum foil or film cathode, and an interposed kraft paper or fabric gauze separator impregnated with a solvent-based liquid electrolyte. The electrolyte impregnated in the separator functions as the cathode in continuity with the cathode foil, while an oxide layer on the anode foil functions as the dielectric. The entire laminate may be rolled up into the form of a substantially cylindrical body, or wound roll that is held together with adhesive tape and is encased, with the aid of suitable insulation, in an aluminum tube or canister. Connections to the anode and the cathode are made via tabs. Alternative flat constructions for aluminum electrolytic capacitors are also known, composing a planar, layered, stack structure of electrode materials with separators interposed therebetween.
Such capacitors used in ICD applications must typically be able to store a relatively large amount of energy (e.g., approximately 10-100 joules). Because the capacitance of an electrolytic capacitor increases with the surface area of its electrodes, one way to increase capacitance is to increase electrode (e.g., anode) surface area. But smaller size devices are desired for implantable devices such as ICDs. So the challenge is to increase surface area of the electrodes without increasing the physical size of the resulting capacitor.
In ICDs, as in other applications where space is a critical design element, it is desirable to use capacitors with the greatest possible capacitance per unit volume. By electrolytically etching the foils that are used to form the anodes and cathodes of a capacitor, surface area can be increased without enlargement of the overall capacitor. As a result of this enlargement of the surface area, electrolytic capacitors can obtain a given capacity with a smaller volume than an electrolytic capacitor which utilizes a foil with a non-etched surface. Likewise, etched-foil capacitors of a given volume can obtain a higher capacitance compared to non-etched foil capacitors. Etching the foil increases the surface area of the foil by pitting an otherwise flat surface.
In a conventional electrolytic etching process, the surface area of a foil is increased by removing portions of the foil to create etch tunnels. The foil used for such etching is typically an etchable aluminum strip of high cubicity. The etch initiation and hence the gain or capacitance of the foil is the result of several variables, such as foil cubicity, thermal oxide on the foil, and the electrochemical reaction. As tunnel density (i.e., the number of tunnels per square centimeter) is increased, a corresponding enlargement of the overall surface area will occur. Larger surface area results in higher overall capacitance.
But etching comes at the cost of increased brittleness of the foil itself. In order to obtain high capacitance, foil material must be removed during the etching process to create the tunnels and increase the surface area. Additionally, a widening process may be used to open the tunnels to prevent clogging during later oxide formation. Both the etching and widening processes can remove as much as 50 to 60% of the foil material (e.g., aluminum) to create a desired etch degree of greater than 30 million tunnels per cm2. After formation of oxide during an aging process, the foil becomes even more brittle. This creates problems during further processing of the foil and assembly of the capacitor.
For example, a series of etched anode foils may be formed from a single aluminum sheet. After etching and otherwise processing the sheet, each anode is punched out by use of a mechanical die into an anode shape to conform to the geometry of the capacitor case. The more aluminum that is removed during etching and widening, the more difficult the foil is to punch from the sheet without creating cracks and loose particles.
After the anodes are punched by the mechanical die, the anodes are interleaved with paper and cathode layers and are assembled into stacks. But the edges of the brittle anodes can contain burrs and attached particles. And the burrs and particles can penetrate the paper layers and cause short circuits between the anode and cathode foils, compromising the quality and life of the capacitor. High potential tests performed to check the stacks for short circuit conditions prior to final assembly have shown that failures (i.e., short circuits) can occur in as many as 5 to 10% of the capacitor stacks depending on the brittleness of the anode foil.
Additionally after the punching process, the newly created edges of the anodes has exposed aluminum without a high-quality oxide formed thereon. After the assembly of the anodes, paper, and cathodes into a case, the capacitor case is sealed and filled with an electrolyte. Next, the capacitors are put through an aging process that reforms oxide on the edges and on any exposed cracks in the anodes. The oxide formed from the aging process is not as high quality as the oxide formed during the formation process. And the higher the ratio of edge surface to anode surface, the higher the potential is for increased leakage current.
In fabricating anode foils for use in an electrolytic capacitor having a multiple anode stack configuration, a tab extending from each anode foil is connected to tabs of adjacent anode foils of the stack to electrically connect the anodes together in parallel. To facilitate the electrical connection (e.g., by welding), the tabs are left un-etched. This can be accomplished using a mechanical mask to mask the tabs, and any other areas where etching is not desired during the etching process. For example, U.S. Pat. No. 5,660,737 to Elias et al. discloses use of a mechanical mask. Without the non-etched tab areas, welds will not appropriately form the connections between the anodes in a stack configuration. But the foils are susceptible to cracking along the etch/non-etch transition edge during the welding process. This can result in a tab detaching in the event of extreme crack propagation.
Another problem with using a mechanical mask in manufacturing anode foils for electrolytic capacitors is that the process is tedious, requiring operator involvement for mask alignment. This leads to production inefficiency. Further, since different capacitor products have different anode shapes, unique tab etch masks must be maintained for each particular product model, and current density must be optimized for each etch mask. This again leads to cost inefficiency and recurring costs as new products with different anode shapes are introduced.
What is needed is a high capacity anode foil and method of making such anode foil that overcomes deficiencies of known systems and methods.

Method for making electrode foils having reduced particle detachment and reduced leakage current


A jointing structure comprising multiple steps provided face to face at the coaxially built traveling path ends with an expansion gap between, multiple elastic members respectively mounted inside the multiple steps, and a joint block mounted on the multiple elastic members across the expansion gap. Multiple supporting blocks and one or more than one intermediate joint block are mounted inside the multiple steps with the joint block between. The multiple supporting blocks, the joint block and the one or more than one intermediate joint block are of concrete. The elastic members are joined together across the expansion gap. The elastic member on one side is fixed to the inside of the step on one side and then subjected to deformation toward the bridge girder axis, and thereafter, the elastic member on the other side is fixed to the inside of the step on the other side.

1. Field of the Invention
This invention relates to a jointing structure in vehicle traveling path joints and the like having an expansion function and also to a method of mounting an elastic member therein, and is useful in applications mainly to vehicle traveling path joints in new transit systems, monorails and the like and besides, to road bed plate joints in road bridges, footbridges and the like.
2. Description of the Related Arts
One well-known urban traffic means is a new transit system which makes use of rubber tires to provide traveling on an exclusive vehicle traveling path using a motor, with power fed via a feeder line laid parallel to the traveling path.
This type of traffic means is such that a vehicle traveling path is built continuously in a belt-like form with concrete on a bridge girder and has an expansion gap in the same position as a bridge girder joint in order to absorb bridge girder expansion or contraction caused by temperature changes or the like.
With this type of traffic means, a traveling path joint is especially fitted with a rubber or steel expansion joint to prevent the occurrence of tire fallen-in, stuck-in and/or like situations so that the increased riding quality as well as the maintainability of in-traveling safety are provided.
Regarding an expansion joint applied to an expansion gap and having an elastic function with respect to the bridge girder expansion or contraction, the patent document 1, for instance, describes an expansion joint having a top-plate reinforcing material laid over the expansion gap, side-plate reinforcing materials respectively fixed to the traveling path ends, and chloroprene rubber or the like adapted to join the top-plate reinforcing material and both the side-plate reinforcing materials together.

Jointing structure of vehicle traveling path joints having expansion function and method of mounting elastic member therein


A vehicle Active Roll Control System having a two stage spool valve that provides hydraulic fluid at different pressures to front and rear actuators for varying the torque applied to associated roll bars.

This invention relates in general to active vehicle suspensions and in particular to a multi-channel hydraulic control unit for such a suspension.
Vehicle suspension systems control chassis motion during operation of the vehicle in order to isolate the vehicle load from irregularities in the terrain over which the vehicle travels. One such chassis motion, that is controlled by know suspension systems, is chassis roll. A vehicle experiences chassis roll during a turning maneuver. During chassis roll, the chassis tilts or "rolls" about the vehicle's fore-to-aft axis toward an outside direction of the turn.
In the past, vehicles have been provided with passive suspension systems that normally include a spring and damper connected in parallel between sprung and unsprung portions of the vehicle. Accordingly, a spring and damper is typically provided for each vehicle wheel. Passive suspension systems are generally self-contained and only react to loads applied to them.
More recently, active suspension systems have been developed that apply positive reactions to applied loads. Active suspension systems typically include hydraulic or pneumatic actuators that are coupled to the passive suspension system components. A typical prior art active suspension system with a hydraulically actuated active roll control system 10 is illustrated in FIG. 1. The roll control system 10 includes an Electronic Control Unit (ECU) 12 that is in electrical communication with at least one wheel speed sensor 14, a lateral accelerometer 16 and a steering angle detector 18 that together provide a means for sensing forces that cause the vehicle to roll.
The active roll control system 10 also includes a front anti-roll, or stabilizer, bar 20 and a front hydraulic actuator 22 associated with a pair of vehicle front wheels 24. Similarly, a rear anti-roll, or stabilizer, bar 26 and a rear hydraulic actuator 28 are associated with a pair of rear vehicle wheels 30. As illustrated in FIG. 1, both the front and rear hydraulic actuators comprise a piston and cylinder assembly. The front anti-roll bar 20 is mounted upon the vehicle body (not shown) with a first end connected via the front hydraulic actuator 22 and a front actuator strut 32 to one of a pair of front suspension arms 34. A second end of the front anti-roll bar 20 is connected via a front suspension strut 36 to the other of the front suspension arms 34. Similarly, the rear anti-roll bar 26 also is mounted upon the vehicle body (not shown) with a first end connected via hydraulic actuator 28 and a rear actuator strut 38 to one of a pair of rear suspension arms 40. A second end of the rear anti-roll bar 26 is connected via a rear suspension strut 42 to the other of the rear suspension arms 40.
The roll control system 10 further includes a pump 44 having an intake port connected by a first hydraulic fluid line 46 to a hydraulic fluid reservoir 48 and a discharge port connected by a second hydraulic fluid line 50 to a suspension fluid control device 52. A hydraulic fluid supply line 54 connects the suspension fluid control device 52 to a power steering valve assembly 56 while a hydraulic fluid discharge line 57 connects the power steering valve assembly 56 to the hydraulic fluid reservoir 48. The suspension fluid control device 52 is connected by front hydraulic supply lines 58 and 60 to the front and rear hydraulic actuators 22 and 28, respectively. The front and rear actuators 22 and 28 are also connected to the suspension control device 52 by hydraulic return lines 62 and 64, respectively, while the control device 52 is connected to the fluid reservoir 48 by a discharge line 66.
A fluid schematic drawing for the roll control system 10 is shown in FIG. 2 where components that are similar to components shown in FIG. 1 have the same numerical designators. Because so many vehicles are equipped with power steering, the power steering pump 44 is typically used to supply pressurized hydraulic fluid to both the power steering valve assembly 56 and the roll control system 10, as shown in FIG. 2. The roll control system 10 includes a three-position four-way directional control valve 72 for controlling the flow of hydraulic fluid to the front and rear cylinder and piston assemblies 22 and 26. A slidable spindle within the control valve is 72 moved axially by first and second pilot valves 72a and 72b, respectively, that are located in the ends of the directional valve. The first pilot valve 72a of the directional control valve 72 is connected to an normally closed digital solenoid valve 73a and a normally open digital solenoid valve 74a. Similarly, the second pilot valve 72b also is connected to an normally closed digital solenoid valve 73b and a normally open digital solenoid valve 74b. The directional control valve 72 is connected by a drain line 66 to the fluid reservoir 48 and by a feed line 75 to a priority valve 76. The priority valve 76 receives pressurized hydraulic fluid from the power steering pump 44 and divides the pump fluid flow between the power steering valve assembly 54 and the directional control valve 72. Typically, the power steering pump 44 is oversized by approximately 50 percent to provide flow for both the power steering and the roll control system 10. The pressure within the roll control system 10 is controlled by a two stage proportional pressure relief valve 77 having a main stage 78a controlled by a pilot stage 78b. As shown in FIG. 2, the pressure relief valve 77 is connected between the feed line 75 supplying pressurized hydraulic fluid to the directional control valve 72 and the reservoir 48. When there is no flow demand from the actuators 22 and 26, all of the fluid flow in line 75 for the roll control system 10 is diverted to the reservoir 48. Otherwise, the pressure of the hydraulic fluid supplied to the directional control valve 72 is controlled by the pressure relief valve 77 reducing the diverted flow to the reservoir 48. The roll control system 10 also includes a pair of pressure sensors 79 that monitor the hydraulic fluid pressure being supplied to the front and rear cylinder and piston assemblies 22 and 26 at the outlet ports A and B.
The roll control system 10 shown in FIG. 2 allows small valves to control large flows. Flow is supplied by a hydraulic pump which is powered in some fashion by the motor vehicle and directed to the actuators 22 and 26 by a three-position-four-way valve 72 that is controlled by two pairs of small ABS style solenoid valves 73 and 74. This allows for a minimum of power to be supplied by the vehicle to operate the system 10. Also, this valve arrangement allows a desirable failure mode where hydraulic fluid is locked into the hydraulic actuators 22 and 26, there by locking in the anti-roll bar in case of a system failure. If electrical power is not or can not be supplied to the small digital valves 73 and 74, the three-position-four-way valve 72 will maintain a center position locking fluid into the actuators 22 and 26 and causing the anti-roll bar to act as in a conventional suspension system. Fluid pressure is determined by a valve that supplies pressure proportional to an applied current. The use of a piloted operated pressure control valve 77 allows a small valve 78a to control large flows without large pressure drops added to the system.
During operation of the vehicle, the ECU 12 receives input signals from the wheel speed sensor 14, the lateral accelerometer 16 and the steering angle detector 18. The ECU 12 processes the input signals to determine any roll of the vehicle relative to the front and rear wheels 24 and 30. Based upon the roll determination, the ECU 12 activates the fluid control device 52 to supply pressurized hydraulic fluid to one end of the hydraulic actuators 22 and 28. In response, both of the pistons move axially within the cylinders to input a torque through the anti-roll bars 20 and 26 to cancel the roll of the vehicle. For example, when the spool in the valve 72 is shifted in a downward direction in FIG. 2, both of the pistons are urged in a downward axial direction. Conversely, when the valve shuttle is shifted to the left in FIG. 2, both of the pistons are urged in an upward direction.
Additional details of the active roll control system 10 shown in FIGS. 1 and 2 are included in U.S. patent application Ser. No. 11/000,319, which is incorporated herein by reference.

Multi-channel hydraulic control unit for an active vehicle suspension


A lock ring (6), which comprises a core part (61) and a twisted wire part (62) around it. The lock ring (6) comprises shape memory alloy or bimetal, whereby the lock ring is arranged to deform as the temperature changes to a predetermined value.

The invention relates to a lock ring.
The invention generally relates to retainer means, particularly lock rings.
Shape memory alloy parts are known which deform in a certain training temperature. It is typical for the shape memory alloy parts that they are extremely elastic i.e. ductile at least in a untrained position, whereby they are not suitable as such to be used as lock rings which are required rigidity in all situations. Furthermore, wires comprising shape memory alloy are typically quite thin of their diameter, whereby they are not suitable for targets in which the ring part of the lock ring is required adequate thickness in the target, e.g. due to quite large tolerances of the target of use. When using thicker shape memory alloy wires/bars, a problem is again their slower response to a change in temperature, whereby deformation occurs too slowly for some targets of application.
An object of this invention is to provide a totally novel arrangement into connection with lock rings, in which a lock ring can be made to deform based on temperature. Another object is to provide a lock ring which deforms based on temperature, by means of which disadvantages of known prior art are avoided.

This patent is subject to a terminal disclaimer.


The present invention relates to the use of a histone H1 binding agent for detecting, isolating and/or purifying cell free nucleosomes of tumor origin from a biological sample. The invention also describes methods of negative or positive selection using histone H1 binding agents, in order to enrich a sample for cell free nucleosomes of tumor origin.

Cellular DNA exists as a protein-nucleic acid complex called chromatin. The nucleosome is the basic unit of chromatin structure and consists of double stranded DNA (dsDNA) wound around a protein complex. The DNA is wound around consecutive nucleosomes in a structure often said to resemble "beads on a string" and this forms the basic structure of open or euchromatin. In compacted or heterochromatin this string is coiled and super coiled in a closed and complex structure.
Each nucleosome in chromatin consists of a protein complex of eight highly conserved core histones (comprising of a pair of each of the histones H2A, H2B, H3, and H4). Around this complex are wrapped approximately 146 base pairs (bp) of DNA. Another histone, H1 or H5, which is located on the nucleosome outside of the core histones, acts as a linker and is involved in chromatin compaction. Cell free nucleosomes are reported to comprise predominantly mono-nucleosomes together with associated DNA produced as chromatin fragments by digestion of chromatin on cell death.
Normal cell turnover in adult humans involves the creation by cell division of some 1011 cells daily and the death of a similar number, mainly by apoptosis. During the process of apoptosis chromatin is broken down into mononucleosomes and oligonucleosomes some of which may be found in the circulation. Under normal conditions the level of circulating nucleosomes found in healthy subjects is reported to be low. Elevated levels are found in subjects with a variety of conditions including many cancers, auto-immune diseases, inflammatory conditions, stroke and myocardial infarction (Holdenreider & Stieber, 2009). Nucleosomes from dead cells may also be shed into other body fluids such as urine, feces, or sputum.
DNA abnormalities are characteristic of all cancer diseases. The DNA of cancer cells differs from that of healthy cells in many ways including, but not limited to, point mutations, translocations, gene copy number, micro-satellite abnormalities, DNA strand integrity and nucleotide modifications (for example methylation of cytosine at position 5). These tumor associated alterations in DNA structure or sequence are investigated routinely in cancer cells or tissue removed at biopsy or surgery for clinical diagnostic, prognostic and treatment selection purposes. Tumor genetic and epigenetic characteristics vary between different tumor types and between different patients with the same tumor disease. Moreover, these characteristics vary over time within the same cancer of the same patient with the progression of the disease and in the development of acquired resistance to drug or other therapies. Thus serial investigation of tumor DNA in cells removed at surgery or biopsy may help the clinician to monitor disease progression and detect any relapse or acquired treatment resistance at an early stage (possibly many months earlier than radiological detection) and allow potentially successful changes in treatment courses.
However, tissue DNA tests have limitations as invasive biopsy procedures cannot be performed repeatedly on patients for monitoring purposes. For some patients, biopsy may not be used at all. Biopsy is expensive to perform, uncomfortable for the patient, poses patient risk, and may lead to surgical complications. Moreover, a tumor in a patient may consist of multiple tumoral clones located within different areas of the same tumor or within different metastases (in metastatic cancer) not all of which may be sampled on biopsy. A tissue biopsy DNA investigation therefore provides a snap-shot of the tumor, both in time and in space, amongst different tumor clones located within different areas of a tumor at a particular moment in time.
The blood of cancer patients contains circulating tumor DNA (ctDNA) which is thought to originate from the release of chromatin fragments or nucleosomes into the circulation from dying or dead cancer cells. Investigation of matched blood and tissue samples from cancer patients shows that cancer associated mutations, present in a patient's tumor (but not in his/her healthy cells) are also present in ctDNA in blood samples taken from the same patient (Newman et al, 2014). Similarly, DNA sequences that are differentially methylated (epigenetically altered by methylation of cytosine residues) in cancer cells can also be detected as methylated sequences in ctDNA in the circulation. In addition, the proportion of cell-free circulating DNA (cfDNA) that is comprised of ctDNA is related to tumor burden so disease progression may be monitored both quantitatively by the proportion of ctDNA present and qualitatively by its genetic and/or epigenetic composition. Analysis of ctDNA can produce highly useful and clinically accurate data pertaining to DNA originating from all or many different clones within the tumor and which hence integrates the tumor clones spatially. Moreover, repeated sampling over time is a much more practical and economic option. Analysis of (ctDNA) has the potential to revolutionize the detection and monitoring of tumors, as well as the detection of relapse and acquired drug resistance at an early stage for selection of treatments for tumors through the investigation of tumor DNA without invasive tissue biopsy procedures. Such ctDNA tests may be used to investigate all types of cancer associated DNA abnormalities (e.g.; point mutations, nucleotide modification status, translocations, gene copy number, micro-satellite abnormalities and DNA strand integrity) and would have applicability for routine cancer screening, regular and more frequent monitoring and regular checking of optimal treatment regimens (Zhou et al, 2012).
Blood, plasma or serum may be used as a substrate for ctDNA assays and any DNA analysis method may be employed including, without limitation, DNA sequencing, epigenetic DNA sequencing analysis (e.g., for sequences containing 5-methylcytosine), PCR, BEAMing, NGS (targeted or whole genome), digital PCR, cold PCR (co-amplification at lower denaturation temperature-PCR), MAP (MIDI-Activated Pyrophosphorolysis), PARE (personalized analysis of rearranged ends) and Mass Spectrometry.
As DNA abnormalities are characteristic of all cancer diseases and ctDNA has been observed for all cancer diseases in which it has been investigated, ctDNA tests have applicability in all cancer diseases. Cancers investigated include, without limitation, cancer of the bladder, breast, colorectal, melanoma, ovary, prostate, lung liver, endometrial, ovarian, lymphoma, oral, leukaemias, head and neck, and osteosarcoma (Crowley et al, 2013; Zhou et al, 2012; Jung et al, 2010). The nature of ctDNA tests will now be illustrated by outlining three (non-limiting) example approaches.
The first example involves the detection of a cancer associated gene sequence mutation in ctDNA. Blood tests involving the detection of a single gene mutation in ctDNA generally have low clinical sensitivity. There are two reasons for this. Firstly, although all cancers have mutations, the frequency of any particular mutation in a particular cancer disease is usually low. For example, although K-ras and p53 mutations are regarded as two of the more frequent cancer mutations and have been studied in a wide range of cancers including bladder, breast, colon, lung, liver, pancreas, endometrial and ovarian cancers, they were detected in 23%-64% and 17%-54% of cancer tissue samples respectively. Secondly, even if the cancer tissue of a patient does contain the mutation, the level or concentration of mutated ctDNA present in the blood of the patient may be low and difficult to detect. For example, K-ras and p53 mutations could be detected in the ctDNA of 0%-75% of K-ras and p53 tissue positive patients. The sum of these two effects meant that K-ras or p53 mutations were detected in the blood of less than 40% of cancer patients (Jung et al, 2010).
The second example involves the detection of multiple cancer associated gene sequence mutations in ctDNA. Although mutations of any particular gene such as K-ras or p53 may be present in only a minority of cancers, all cancers contain mutations so study of a sufficiently large panel of mutations should in principle, facilitate the detection of most or even all tumors. One way to increase the clinical sensitivity of such tests is therefore to test for a wide range of mutations in many genes. Newman et al have taken this approach for non-small cell lung cancer (NSCLC) and investigated 521 exons and 13 intron sequences from 139 recurrently mutated genes. The mutations studied encompassed multiple classes of cancer associated genetic alterations, including single nucleotide variation (SNV) and fusion genes. In this way the authors reported the detection of more than 95% of stage II-IV tumors and 50% of stage I tumors with 96% specificity in ctDNA blood tests (Newman et al, 2014).
The third example involves the detection of cancer associated epigenetic alterations to particular gene sequences in ctDNA. This approach can be applied to any DNA or nucleotide modification. A prime example of this approach is the detection of genes which are differentially methylated at cytosine residues in certain cancers. A large number of genes have been investigated for this purpose in a variety of cancers. A few of these are SEPTIN-9, APC, DAPK, GSTP1, MGMT, p16, RASSF1A, T1G1, BRCA1, ERα, PRB, TMS1, MLH1, HLTF, CDKN2A, SOCS1, SOCS2, PAXS, PGR, PTGS2 and RARβ2 investigated in bladder, breast, colorectal, melanoma, ovarian and prostate cancers. An illustrative example of this approach is the detection of methylated SEPTIN-9 in ctDNA for the detection of ColoRectal Cancer (CRC) which was reported to detect 68% of CRC cases with a clinical specificity of 89% (Grutzmann et al, 2008).
The tumor derived ctDNA fraction of cfDNA circulates as small DNA fragments less than 200 bp in length consistent with that expected for DNA fragments circulating in the form of mono-nucleosomes (Newman et al, 2014). Cancer patients are reported to have higher cfDNA levels than healthy subjects. Workers in the field have reported ranges of 0-100 ng/ml (mean 30 ng/ml) cfDNA for healthy subjects and 0-1000 ng/ml (mean 180 ng/ml) cfDNA for subjects with cancer (Schwarzenbach et al, 2011). Circulating cfDNA consists of DNA molecules of various sizes up to 20,000 base pairs in length (Zhou et al, 2012). In agreement with the hypothesis that ctDNA circulates predominantly as mono-nucleosomes, measured levels of cell free nucleosomes in the circulation are, like DNA levels, higher in cancer patients than in healthy subjects (Holdenrieder et al, 2001). However, raised levels of circulating nucleosomes per se are not used clinically as biomarkers of cancer as nucleosomes are a non-specific product of cell death and raised levels are observed for many conditions involving elevated cell death including acute trauma (Holdenrieder and Stieber, 2009). As a product of cell death, circulating nucleosome levels can rise markedly on treatment with cytotoxic drugs or radiotherapy. However, nucleosomes are also cleared from the circulation so levels may spike with treatment and then fall (Holdenrieder et al, 2001).
Although the level of circulating cell free nucleosomes per se has not been used in clinical practice as a blood based biomarker in cancer, the epigenetic composition of circulating cell free nucleosomes in terms of their histone modification, histone variant, DNA modification and adduct content have been investigated as blood based biomarkers in cancer (WO 2005/019826; WO 2013/030577; WO 2013/030579; WO 2013/084002).
The biological origin of cfDNA is not well understood. Fragmentation of chromatin to produce mononucleosomes and oligonucleosomes is a feature of apoptotic cell death. Necrotic cells are thought to produce larger DNA molecules of thousands of base pairs in length, but DNA fragmentation may also occur in some cases of necrosis. Further, common DNA repeat sequences (e.g.; ALU or LINE1 sequences) may be released as 200-400 base pair DNA fragments from cells undergoing non-apoptotic or necrotic cell death (Schwarzenbach et al, 2011). DNA fragments may also be secreted by cells as a form of inter-cellular communication. The origin of ctDNA is thought to be related to the death of cancer cells. DNA fragments may be released as nucleosomes from necrotic and/or apoptotic tumor cells. However, necrotic and apoptotic cells are usually phagocytosed by macrophages or other scavenger cells and DNA may be released by macrophages that have engulfed necrotic or apoptotic cells (Schwarzenbach et al, 2011).
There are a variety of methods available for extracting cfDNA from blood, serum or plasma and these have been compared for yield of extracted DNA and for their efficiency of extraction of DNA fragments of different lengths. Phenol-chloroform and sodium iodide extraction methods provide the highest yield and extract small DNA fragments of less than 200 bp in length. Other methods tested (including commercially available methods) are reported to have lower DNA extraction yields and to fail to extract small DNA fragments of less than 200 bp in length (Fong et al, 2009).
Extraction of cfDNA from blood, serum or plasma for analysis of ctDNA is usually performed using commercially available DNA extraction products. Such extraction methods claim high recoveries of circulating DNA (>50%) and some products (for example; the QIAamp Circulating Nucleic Acid Kit produced by Qiagen) are claimed to extract DNA fragments of small size. Typical sample volumes used are in the range 1-5 mL of serum or plasma.
There are currently no ctDNA based tests in routine use for clinical oncology purposes due to a number of limitations. A major methodological limitation is a requirement for high quality DNA. Current ctDNA sampling methods produce poor quality ctDNA samples due to the nature of the sample. The main difficulty lies in the presence of large amounts of non-tumor cfDNA in the circulation which complicates any analysis of ctDNA. Estimates from different workers vary but the fraction of ctDNA present in the circulation can be too low to detect or above 50% of cfDNA. However, for most cancer patients the ctDNA fraction is a small part of cfDNA. For example, recent studies report that the ctDNA fraction increases with tumor size in pre-treatment lung cancer patients. The highest level found was 3.2% in a patient with a large tumor burden but most patients were found to have ctDNA fractions below 0.1% (Newman et al, 2014). This means that for many patient samples, a very low level of ctDNA must be analysed in the presence of a much higher level of non-tumor derived DNA. Moreover, this DNA is from the same subject and hence of similar sequence and will interfere in any method for the quantification or analysis of ctDNA.
A similar problem occurs for the measurement of circulating cell free nucleosomes and/or the epigenetic composition of circulating nucleosomes as biomarkers for cancer because nucleosomes per se are a non-specific indicator of cell death and are released as part of the normal cell turnover process of the body as well as in conditions associated with elevated levels of cell death such as autoimmune diseases, stroke, sepsis, post trauma, burns, myocardial infarction, cerebral stroke, during graft rejection after organ transplantation and after severe exercise. Thus nucleosomes of tumor origin circulate together with other non-tumor nucleosomes of various cellular and tissue origins. These non-tumor nucleosomes will interfere in any method for the quantification or epigenetic analysis of nucleosomes of tumor origin. A similar effect may occur in other body fluids. Feces, for example, may contain nucleosomes and associated DNA of colorectal cancer cell origin together with nucleosomes originating in healthy colon or rectal cells. Sputum may contain nucleosomes and associated DNA of lung cancer cell origin together with nucleosomes originating in healthy lung cells. Similar effects will occur in other body fluids.
There is therefore a great need for a method for the enrichment of nucleosomes and DNA of tumor origin from blood, serum or plasma samples and other body fluid samples. Similarly, there is a need for analytical methods for circulating cell free nucleosomes which are able to distinguish those nucleosomes of tumor and non-tumor origin for improved detection of cancer disease states.

Method for the enrichment of cell free nucleosomes


A tab is cut into a sheet of transparent material. The tab has a free end and a fixed end. A source of light is attached to the tab and the tab and the sheet are displaced along the z-axis of the sheet to direct light from the source into an edge of the sheet. The tab can include conductive traces for electrical connection to the light source or other electrical devices on the sheet. A variable display device adjacent the sheet is viewed through the sheet and the sheet with attached light source provides front lighting for the variable display device.

Edge lit sheets have long been known in the art; e.g. U.S. Pat. No. 3,027,669 (Hardesty) and U.S. Pat. No. 3,356,839 (Mehess et al.). Edge lit keypads are also known in the art. For example, U.S. Pat. No. 3,892,959 (Pulles) discloses peripheral cavities for receiving light emitting diodes (LEDs); U.S. Pat. No. 4,177,501 (Karlin) discloses peripheral cavities for receiving light sources; U.S. Pat. No. 4,247,747 (Swatten) discloses LEDs optically coupled to a polyester sheet having a thickness of seven mils (0.18 mm); and U.S. Pat. No. 5,975,711 (Parker et al.) discloses a light conductive panel coupled to a light source.
U.S. Pat. No. 3,998,525 (Giglia) discloses a front lit electrochromic display, wherein the display is on the "back" side of a glass substrate (the side opposite the viewing side). Light is directed into an edge of the substrate. Several sources of light are disclosed.
As used herein, "transparent" does not imply a particular level of light transmission. The amount of light transmission that is suitable depends, among other factors, upon the thickness of the light guide. "Transparent" does imply a sufficient clarity that an image, such as text, is legible or recognizable when viewed through the light guide.
As used herein, "deform" and its cognates are generic to elastic deformation, wherein an article springs back into its original shape when stress is removed, and to plastic deformation, wherein an article is permanently changed in shape.
As portable electronic devices become more common, they are also becoming thinner, which places a premium on reducing the thickness of components. A substrate, light guide, light source, power source, electronics, and display all have finite thicknesses, herein referring to a measurement along the z-axis. The length and width of a device, measured along the x-axis and the y-axis, can have any desired dimension, typically fitting within a pocket on ones clothes. Thickness is typically considerably smaller than the other two dimensions and the desire is for the thickness to be even smaller.
In view of the foregoing, it is therefore an object of the invention to provide a light guide having an integral light source.
It is another object of the invention to provide a light guide having an integral light source, wherein the light guide is also a substrate for conductive traces interconnecting electrical devices.


A new approach is proposed that contemplates systems and methods to support distributed stream media transcoding and sharing in real time. Under the approach, a host associated with a sender generates a high quality stream of media content that is to be shared with a plurality of viewers over a communication network. The hosting devices associated with the plurality of viewers are evaluated for their capability to process and/or transcode the high quality media stream. Based on the evaluation, the host of the sender encodes and transmits the high quality media stream to at least one selected host associated a viewer. Besides decoding the received high quality media stream and displaying it for its own consumption, the selected host of the sender further transcodes the media stream by re-encoding the high quality media steam into a different, probably lower quality media stream, and transmits the re-encoded media stream to a mobile device associated with another viewer, which then decodes and displays the lower quality media stream on the mobile device.

Increasingly, stream media content, which in addition to textual images (such as simple text), static images (such as solid background and continuous-tone images), may contain one or more media streams, including but not limited to audio clips, video clips, animation or simulation applications, real-time screensharing of content rendered on a screen, and any media that is dynamic in nature and changes constantly over time. Such stream media content can be generated by a sender and shared with a plurality of viewers over a communication network, where each of the sender and the viewers is associated with a hosting device (host) that is capable of transmitting, receiving, processing, and displaying the stream media content in real time.
In certain scenarios, the hosting devices involved in media streaming are homogenous, having roughly comparable capabilities such as CPU speed, memory, screen resolution, bandwidth. For example, when the hosting devices are desktop computers or laptops, they have roughly comparable capabilities. In such a situation, the sender can generate a single (high-quality/resolution) media stream and all viewers would be capable of receiving it and displaying it. For example, for streaming of videos, this could mean 30 frames per second at 1920×1080 resolution encoded at 10 Megabits per second of bandwidth. With the recent rapid proliferation of mobile phones and other less powerful computing devices, however, there is a need to support heterogeneous systems where hosting devices of some of the viewers have much weaker capabilities and are unable to receive and display the same high-quality media stream as the hosting devices of more powerful viewers can. On the other hand, hosting devices running web-based applications written in JavaScript or Adobe Flash® inside a browser are much slower than native application written in C++ and are another example of slow "devices". Such slow hosting devices may have limited CPU power, limited memory, limited bandwidth, limited screen resolution, limited battery life, or limited set of supported media codecs that restrict them, for a non-limiting example, to be only able to display a video media stream at 15 frames per second and 320×240 resolution encoded at 100 Kilobits per second of bandwidth.
One approach to supporting two (or more) classes of hosting devices would be to use the least common denominator and have the sender produce the lowest-quality media stream that even the least powerful viewer hosting device can consume. However, a better approach is to find a way to deliver two (or more) media streams for the same content—a high-quality media stream for the powerful viewer hosting devices and a lower-quality media stream to the slower viewer hosting devices.
There are several potential approaches to providing two media streams. Probably the most obvious approach is to utilize a transcoding server between the sender's device and the viewer's devices. The sender's device produces a single high quality media stream suitable for the fast viewer devices (e.g., desktop viewers) and sends it to a transcoding server. The transcoding server decodes the high-quality media stream and then re-encodes it to produce a low quality media stream suitable for the slow viewer devices (e.g., mobile phones). This is a natural approach since one-to-many media streaming solutions typically already require a communication server that receives the media stream from the one sender and retransmits it to the many viewers (relying on the sender to directly deliver the media stream to the viewers does not scale since it puts very heave bandwidth requirements on the sender's bandwidth). One disadvantage of such an approach is that it requires a powerful server capable of carrying out the transcoding work. A much bigger fundamental disadvantage, however, is that it requires the transcoding server to be able to manipulate the media stream. This does not work when the sender and the viewers encrypt all communications among themselves (end-to-end encryption) and for security reasons do not trust any intermediate server to decode the media stream. This is an important issue for Software-as-a-Service (SaaS) products, where the servers are operated by the SaaS provider and for maximum security should not be capable of seeing (spying on) the media stream which may contain confidential information of their customers.
A second approach that works with end-to-end encryption is for the sender's device itself to produce both the high-quality media stream and the low-quality media stream. Such an approach, however, requires extra processing power and extra outgoing bandwidth which may not be available at the sender's device, and this problem gets worse if there are three or more classes of devices. A third approach is to adopt a layered codec to generate a base media stream and an enhanced media stream for the media content, wherein only the base stream is sent to the mobile phone viewer, while the enhanced media stream is also sent to the desktop viewers. The base stream can then be integrated with the enhanced stream for desktop viewers capable of handling high quality media streams. Such layered codec can alleviate the issues of the first approach, however, it does not eliminate them since it also requires extra processing power and extra bandwidth from sender's device, just to a smaller degree that the second approach.
Besides discrepancies in processing capacity and/or bandwidth, the sender's device and the viewer's devices may support different types of codecs for encoding and decoding of the media streams. For a non-limiting example, Adobe Flash® supports only specific audio and video codecs that may be either suboptimal or unsupported for the desktop viewers.
The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent upon a reading of the specification and a study of the drawings.

Systems and methods for distributed media stream transcoding and sharing


Methods and apparatus are provided for non-invasively treating patent foramen ovale using an ultrasound imaging system and a high intensity focused ultrasound system to selectively target high intensity ultrasound energy on either or both of a patient's septum primum or septum secundum.

Up until the 1980s, there was dramatic growth in the creation of new surgical methods for treating a wide variety of previously untreated conditions. Over the past twenty years there has been a clear trend towards the invention of devices and methods that enable less-invasive treatment of such diseases, moving from invasive surgery, and then to less-invasive surgery, and to interventional techniques. Ultimately, it is desirable to move to totally non-invasive therapies.
Patent foramen ovale (PFO) is characterized by a persistent fetal opening between the left and right atria of the heart that allows blood to bypass the lungs. In most people, this opening permanently closes during the first few months after birth. However, a PFO is present in up to 15 percent of adults.
PFO may be associated with various heart conditions including paradoxical embolus, in which an embolus arising in venous circulation gains access to the arterial circulation through the PFO, thereby resulting in stroke or transient ischemic attack. Closure of PFO using a transcatheter approach may be medically necessary for patients with a history of cryptogenic stroke that are not candidates for anticoagulant therapy. Implantable devices, such as those of AGA Medical Corporation (Golden Valley, Minn.) and NMT Medical, Inc. (Boston, Mass.) are used to close PFOS.
It would be desirable to develop methods of treating PFO that are even less invasive than transvascular interventional techniques, thereby eliminating the need for catheters.
The following devices pertain to the use of high intensity focused ultrasound (HIFU) energy to weld the tissues of a PFO closed. Each device is used for application of energy to the tissues to be sealed. Heating of the tissues of the PFO by the HIFU causes a healing response which causes the formerly separate tissues of the PFO to heal together. In some embodiments, the energy denatures the collagen of the tissues of the different portions of the PFO, and the tissues are caused to remain in close apposition in order to allow the collagen to bond while the tissue return to normal body temperature.
By way of example, WO 99/18871 and 99/18870 to Laufer, et al. (now abandoned) describe the heating of the tissue of a PFO to induce closure through natural wound healing. These, however are invasive devices which require entering and crossing the PFO. Additionally, U.S. Pat. No. 6,562,037 to Paton et al. describes in detail methods and considerations for the rejoining of two tissue sections through the precise application of energy in a two-stage algorithm, wherein all voltage levels used are empirically derived and pre-programmed into the energy delivery control system. Again, however, all devices described would need to be in contact with the tissues to be joined. Relevant articles from the clinical literature include "High-burst-strength, feedback-controlled bipolar vessel sealing", Kennedy et al., Surg Endosc (1998) 12:876-878. This article describes the development of a system for use in open or laparoscopic surgical procedures for achieving hemostasis in large-diameter arteries through the use of RF welding.
A wide variety of energy modes have been used to create lesions using epicardial or intracardiac probes. Radio-frequency electrical energy, microwaves, cryothermia probes, alcohol injection, laser light, and ultrasound energy are just a few of the technologies that have been pursued.
Separately, several groups have developed focused ultrasound devices with both imaging and therapeutic capabilities. These efforts began perhaps with lithotripsy, in which a high power focused ultrasound system developed by Dornier Medizintechnik, Germany, was used to break up kidney stones in the body. The kidney stones generally are located within the body at a significant depth from the skin. One ultrasound imaging system is used to aim the system at the kidney stones, and then a second, high energy ultrasound system delivers energy that breaks up the stones so they can be passed.
More recently, Therus Corp of Seattle, Wash., has developed a system to seal blood vessels after the vessels have been punctured to insert sheaths and catheters. The Therus system shrinks and seals femoral artery punctures at a depth of approximately 5 cm.
In addition, Timi-3 Systems, Inc., Santa Clara, Calif., has developed and is testing a trans-thoracic ultrasound energy delivery system to accelerate the thrombolysis process for patients suffering an acute myocardial infarction. This system delivers energy at a frequency intended to accelerate thrombolysis without damaging the myocardium or vasculature of the heart.
Epicor Medical, Inc. of Sunnyvale, Calif., has developed a localized high intensity focused ultrasound ("HIFU") device to create lesions in the atrial walls. The Epicor device is a hand-held intraoperative surgical device, and is configured to be held directly against the epicardium or outside wall of the heart. When energized, the device creates full-thickness lesions through the atrial wall of the heart, and has demonstrated that ultrasound energy may be safely and effectively used to create atrial lesions, despite presence of blood flow past the interior wall of the atrium.
In addition, Transurgical, Inc., Setauket, N.Y. has been actively developing HIFU devices. However, while the Epicor Medical devices are placed in close approximation against the outside of the heart, the Transurgical devices are directed to intravascular catheters for heating or ablating tissue in the heart and require that the catheter be brought into close approximation with the targeted tissue.
In view of the aforementioned limitations or previously-known devices and methods, it would be desirable to provide methods and apparatus for treating PFO by heating or ablating tissue at a distance from that tissue, so that the procedure may be performed non-invasively.
It also would be desirable to provide methods and apparatus for treating PFO by applying energy from outside the body or from organs, such as the esophagus, that are easily accessible via natural body openings.

Methods and apparatus for non-invasively treating atrial fibrillation using high intensity focused ultrasound


A method for wear control of vehicle tires, includes: detecting deformation of an inner surface of a first tire by means of a first sensor; determining a first level of wear of the first tire; detecting a deformation of an inner surface of a second tire by means of a second sensor; determining a second level of wear of the second tire; comparing the first and second levels of wear with each other; and generating a notification signal representative of the comparison. Also disclosed is a system for wear control of vehicle tires, a method of determining the wear of a tire and a system for determining the wear of a tire.

1. Field of the Invention
The present invention relates to a method and a system for wear control of vehicle tyres.
The present invention also relates to a method and a system for determining the wear in a tyre.
2. Description of the Related Art
Tyres are subject to wear in use; it is therefore important to have the conditions of each tyre monitored, since the tyre performance varies depending on the wear. In fact, a too worn tyre becomes very dangerous because it can give rise to a reduction in the vehicle's roadholding, an increase in the braking distances, etc.
The European patent application EP 1759891 discloses a wear detecting system in a tyre involving use of a detecting unit adapted to detect the acceleration to which a wear bar positioned in a groove of the tyre tread is submitted. When the tyre is not yet too worn, the bar does not come into contact with the ground and the acceleration detected by the detecting unit is contained within limits. As a result of the tyre wear, the bar comes into contact with the ground at each wheel revolution, causing an important increase in the acceleration detected by the detecting unit.

Method and system for wear control of vehicle tyres


A method and apparatus for dynamic integration of a covert namespace are provided. A Software-Defined Networking (SDN) controller is configured to send a request for workload transfer to an endpoint where the endpoint is connected to a virtual switch. The SDN controller determines that a connection between the endpoint and the virtual switch is secure based on a tenant-specific policy associated with the endpoint. A first covert namespace is configured to be connected between the endpoint and the virtual switch to communicate to the endpoint and the virtual switch directly. The operations of the virtual switch are executed using the first covert namespace according to the tenant-specific policy. A workload is caused to be transmitted to the endpoint through the first covert namespace.

The approaches described in this section are approaches that could be pursued, but not necessarily approaches that have been previously conceived or pursued. Therefore, unless otherwise indicated, it should not be assumed that any of the approaches described in this section qualify as prior art merely by virtue of their inclusion in this section.
Computer application programs executed in cloud environments are now widely used to deploy large-scale services for large numbers of client computers. As the number of client computers increases and the type of services varies, clouds are becoming ever more diversified. For example, environments that use different hardware, virtual switches, public cloud resources, private cloud resources and different vendors are expected to interoperate. In these multi-cloud deployments, however, implementing policies for virtual switches may change from one cloud to another cloud and maintaining consistent enforcement at endpoints becomes difficult. Thus, for more consistent and secure cloud connectivity, allowing workload mobility across the cloud computing platforms while maintaining adherence to client-specific policies becomes more important in multi-cloud deployments.

Enforcing network endpoint policies in a cloud-based environment using a covert namespace


A failure analysis apparatus obtains information associated with an operational status of a data center, determines information regarding fault repair work for the data center, based on the information associated with the operational status, and transmits the information regarding the fault repair work to a head mounted display (HMD). The HMD synthesizes and presents computer graphics image data for providing guidance for a method of the fault repair work, with an image of real space, based on the information regarding the fault repair work. After the fault repair work according to the guidance presented by the HMD, if the information associated with the operational status of the data center is newly obtained, the failure analysis apparatus newly determines the information regarding the fault repair work for the data center based on the information associated with the operational status, and transmits the information to the HMD.

If a fault occurs in a device or the like, a fault point is specified and fault repair work is performed by a worker. For example, as disclosed in Patent Literature 1, there is known a technique for using Augmented Reality (hereinafter, AR) to simplify a removal operation for a paper jam in a copying machine. Specifically, when a paper sheet is not detected by a predetermined sensor within a predetermined time, it is assumed that a paper jam has occurred, and a video of the inside of the copying machine, which has been previously prepared corresponding to a paper jam occurrence position, and an operation procedure are displayed in a superimposed manner. Thereby, a paper jam occurrence point in the copying machine can be easily recognized, and guidance for the removal operation can be easily provided. It should be noted that the AR is a technique for displaying data managed in a computer (hereinafter, computer graphics image data), such as characters, figures, still images or moving images, into a real environment in a superimposed manner to give supplementary information.

Information processing system, information processing method and program for synthesizing and displaying an image