A non-adhesive matrix for use as a dosage form in the transdermal administration of a medicament to a mammal comprises a porous, non-adhesive, absorbent perforate solid support having absorbed thereon a mixture comprising a medicament adapted for transdermal administration and a pharmaceutically acceptable carrier for the medicament. The carrier consists essentially of at least one compound selected from esters of C.sub.8-24 fatty acids, pharmaceutically acceptable aliphatic polyhydroxy compounds and non-volatile paraffins.

The present invention relates to a matrix incorporating medicaments for transdermal administration, particularly but not exclusively in the field of animal husbandry and to apparatus and techniques for administering veterinary medicaments transdermally.
Various techniques and devices are known for administering medicaments through the skin, particularly for veterinary use. One example of such a technique is described in U.S. Pat. No. 4,026,290, which suggests attachment of a device to the ears or tail of the animal for applying motion sickness mitigators, anti-migraine compounds, analgesics, anthelmintics, antiprotozoal compounds and systemic insecticides, miticide and acaricides.
Transdermal drug delivery in veterinary applications is discussed in an article entitled "Topical Drug Delivery to Cattle and Sheep" by Ian H. Pitman and Susan J. Rostas, in Journal of Pharmaceutical Sciences, Vol. 70, No. 11, November, 1981, pp. 1181-1193 and in an article by the same authors entitled "A Comparison of Frozen and Reconstituted Cattle and Human Skin as Barriers to Drug Penetration", in Journal of Pharmaceutical Sciences, Vol. 71, No. 4, April, 1982, pp 427-430. Transdermal drug delivery has been proposed for administering prophylactic medicaments in veterinary contexts but, to the best of the knowledge of the inventors, has not had any practical application of significance in veterinary practice.
Growth radiators and growth promoters, here collectively termed "growth promoters", are commonly used in veterinary applications and are often applied using implants which cannot be conveniently removed prior to slaughter. Hormones for synchronization in mammals are generally administered vaginally, a technique which requires skill and involves potential damage to the animal and could result in infertility.
In U.S. Pat. No. 4,638,043 (Szycher et al), there is disclosed a polyurethane matrix for dispensing drugs dispersed therein, primarily for incorporation in a medical patch comprised of successive layers of a substrate, a pressure sensitive adhesive, the drug dispensing matrix and optionally a second layer of adhesive. The matrix may also include (e.g.) polypropylene glycol, polyethylene glycol or glycerine, to soften layer softer and to aid the transport of the drug out of the matrix and into the skin.
As acknowledged in U.S. Pat. No. 4,767,402 (Kost et al), which discloses the use of ultrasound for enhancing transdermal drug delivery, relatively few drugs are known to be deliverable transdermally, insofar as the majority of drugs will not penetrate the skin at rates sufficiently high for therapeutic efficacy.
U.S. Pat. No. 4,792,450 (Kydonieus et al) discloses a transdermal drug delivery device which comprises a vinyl gel layer comprising PVC and a drug uniformly dispersed therein, the vinyl gel layer comprising a primary plasticizer for the PVC and an organic nonvolatile gel forming additive in an amount sufficient to form a gel. Examples of such additives are isopropyl palmirate, isopropyl myristate, soybean oil, castor oil, linseed oil, olive oil, mineral oil, petrolatum, caprylic/capric triglyceride and non-ionic surfactants.
In U.S. Pat. No. 4,818,540 (Chien et al), there is disclosed essentially a transdermal fertility-controlling polymer matrix dosage unit comprising an impervious backing layer, a polymer matrix disc layer adhered thereto containing microdispersed fertility-controlling estrogen and progestin hormones, and an adhesive layer for securing the dosage unit to the subject. The device may contain, preferably in the adhesive layer, but alternatively or additionally in the matrix layer, a skin permeation enhancing agent, in particular a fatty acid CH.sub.3 (CH.sub.2).sub.n COOH, where n is 2-16, isopropyl myristate or decyl methyl sulfoxide.
U.S. Pat. No. 4,820,525 (Leonard et al) discloses the use of a foamed polyethylene having specified properties, as a drug reservoir in a transdermal/transmucosal pharmaceutical delivery system. Thus, fertility hormones and albuterol were applied transdermally from such reservoirs attached to adhesive tape across nude mouse skin or cadaver skin, using menthol as penetration enhancer.
In U.S. Pat. No. 4,822,617 (Panoz), there is disclosed a device for the transdermal administration of skin-permable drugs (e.g. nitroglycerin, clonidin, methadone and scopolamine) in an ointment, cream or jelly-like carrier, comprising a laminar applicator adapted to receive a predetermined quantity of the drug on a skin-contacting surface thereof, the latter being overlaid by a drug-impervious layer to ensure a unidirectional transfer of the drug to the skin surface. In an exemplified embodiment, the applicator is loaded with a predetermined amount of ointment containing 2% nitroglycerin and lactose in an absorptive lanolin and white petrolatum base formulated to provide controlled release of the active ingredient. The entire contents of all of the foregoing U.S. patents are incorporated by reference herein.
It will be appreciated that adhesive patches, by means of which drugs are conventionally administered transdermally to humans, can result in skin irritation and sensitization with prolonged use. Shaving the hair from a suitable area may also be necessary. Adhesive patches would be quite unsuitable for animals, partly because of the great quantity of body hair in comparison with humans, and partly because adhesive patches would be liable to be rubbed off. By contrast, the present matrices can conveniently be used for transdermal administration to animals, by means of the devices described herein. Moreover, persons skilled in the art can readily appreciate that these matrices could also be readily adapted for human use, e.g. by securing to the arm or leg by a bandage which is impervious to the drug/carrier combination.
It may further be noted that the sense of the most of the prior art in relation to transdermal administration to humans is that only a restricted number of drugs are inherently suitable for this form of administration. It is believed that the present invention offers a means of transdermal delivery of a wider spectrum of drugs than has heretofore been made generally available, particularly to animals, but also to humans.
As indicated above, adhesive plasters incorporating medicaments for transdermal administration, which are known for application to humans, would be generally inappropriate for veterinary use.

Systems for transdermal administration of medicaments


A kit, system, and associated methods are provided to facilitate wireless printing. In one embodiment, the system comprises a platform having a processor circuit having a processor and a memory. The system also includes a wireless printing logic stored in the memory and executable by the processor. The wireless printing logic comprises an application capable of a print operation and a number of hidden objects that encapsulate a number of wireless printing tasks associated with a wireless printing operation for the application. The wireless printing logic also includes at least one application programming interface (API) object that provides an interface between the application and the hidden objects, and, at least one platform specific object that encapsulates a number of adaptive wireless printing tasks that are configured for operation on the platform.

Existing print frameworks typically employ a printer driver architecture that converts a high-level page description language to a raster image that is suitable for printing by a destination printer. Such a printer driver architecture often requires intimate knowledge of a single page description language and a printer control language. Unfortunately, such a printer driver architecture also requires more resources then are available in many resource-limited platforms that suffer from a lack of printing capability. For example, in the Microsoft Windows environment, Graphic Device Interface (GDI) commands are often converted to a Printer Control Language such as PCL3 or other such language to send print output to printers. This causes resource intensive rendering to occur in the rendering platform. A resource-limited platform may not be able to perform such rendering tasks.
This printing approach also has other drawbacks. For example, to print according to a printer driver architecture, the user must use a printer driver that is specific to the platform and the printer. This can be problematic where a printer is available to print to, but the needed printer driver is unavailable. Another drawback is that the driver consumes a lot of computer processing power and memory resources.

Wireless printing interface kit and method

Hewlett-Packard Development Company, L.P.


A multicasting authorization system comprises a streaming server, an authorization server, a user system and a distribution server. The distribution server provides a multicast data stream over multicast channels. A user system requests and receives an authorization code from an authorization server to receive the multicast data stream, and provides the authorization code to a streaming server. A streaming server, coupled to both an authorization server and a user system sends start up information for accessing the multicast data stream to the user system upon validation of the authorization code. The multicast datastream is encrypted and the user system maintains a connection with the authorization server which provides a cryptographic key for use in decrypting the encrypted multicast datastream.

Efficient network security enables successful digital multimedia transmissions. Network authentication protocol designed to provide authentication for client/server applications by using secret-key cryptography exists in today's technology. Used with a communications protocol, network authentication protocols provide secure delivery of data between two parties.
Secure socket layer (SSL) is the leading security protocol on the Internet. SSL is widely used to validate the identity of a Web site and to provide authentication and encryption in order to send sensitive data such as credit card and other personal data to a vendor. Successful authentication proves the identity of the user or client machine attempting to log on. The authenticated user is granted access to specific resources based on predefined policies and the permission level assigned to the user or user group.
The process of authenticating a user involves verifying the integrity of a transmitted message between two parties. When users log onto a network, their identities must be verified and an authentication method is used to prove the identity of each specific user. When a user logs on, the network access server (NAS), wireless access point or authentication server creates a "challenge," which is typically a random number sent to the client machine.
An authentication token is a security device provided to authorize users who keep them in their possession. To log onto the network, the security "card" or "token" may be read directly like a credit card, or it may display a changing number that is typed in as a password. The latter has also been implemented entirely in software.
Challenge/response systems may also work with an authentication token, which is a smart card or credit-card sized card that users have in their possession. When users log on, they respond to the challenge by either inserting their smart card into a reader or typing in the password displayed on the card's readout. In this example, either the network access server or the authentication server generates a random number and sends it to the client as the challenge. The client uses a hash algorithm to combine the challenge and password and send the result back. The originating component performs the same hash step and compares it to the client's results. If they match, the system knows the client has the correct password.
Another widely used form of network security is cryptography. Cryptography is the creation, distribution and maintenance of a secret key. Cryptography determines how secret keys are generated and made available to both parties. A secret key is a binary number that is typically from 40 to 256 bits in length. The greater the number of bits in the key (cipher strength), the more possible key combinations and the longer it would take to break the code. Data is encrypted by combining the bits in the key mathematically with the data bits. At the receiving end, the key is used to unlock the code and restore the original data. Public key systems are widely used for exchanges. If session keys are used, key management is responsible for generating them and determining when they should be renewed.
Passwords, digital signatures, and smart cards can also be used to prove the identity of the client to the network. The client software uses its password or a secret key to encrypt the identity via an encryption algorithm or a one-way hash function and sends the result back to the network. The authentication system also performs the same cryptographic process on the challenge and compares its result to the response from the client. If they match, the authentication system has verified that the user has the correct password. While passwords are widely used to identify a user, they only verify that a user knows the password. Digital signatures guarantee that information has not been modified. The two major applications of digital signatures are for setting up a secure connection to a Web site and verifying the integrity of files transmitted. Smart cards function similarly to digital signatures. Smart cards, however, verify that users have a physical token in their possession.
Kerberos is an access control system designed to operate in both small companies and large enterprises with multiple domains and authentication servers. The Kerberos concept uses a "master ticket" obtained at logon, which is used to obtain additional "service tickets" when a particular resource is required. When users log on to a Kerberos system, their password is encrypted and sent to the authentication server in the Key Distribution Center (KDC). If successfully authenticated, the KDC creates a master ticket that is sent back to the user's machine. Each time the user wants access to a service, the master ticket is presented to the KDC in order to obtain a service ticket for that service. The master-service ticket method keeps the password more secure by sending it only once at logon. From then on, service tickets are used, which function like session keys.
In a typical multimedia system, a server responds to connection requests made by clients across a data network. Each client is subject to conventional access control to authorize reception of multimedia information across the same connection. The system can authorize clients, but is bandwidth intensive. Therefore, there is a need to streamline the authorization process in multimedia systems responding to client requests.
In a typical multimedia streaming system, a streaming server provides multicast data streams over multicast channels. A user system requests and receives an authorization code from an authorization server to receive the multicast data stream, and provides the authorization code to a streaming server. The streaming server, coupled to both an authorization server and a user system, sends the multicast data stream information to the user system upon validation of the authorization code.
To reduce the bandwidth needs of a streaming system, some streaming servers respond to stream-oriented connection requests made across the network by streaming clients differently. Instead of receiving a copy of the multimedia stream, the clients receive information detailing a multicast group where the stream data can be found. The clients then receive multimedia streams by subscribing to the specified multicast group. Once clients have subscribed to a multicast group, they are no longer subject to access control. The system is less secure and security credentials can be shared among multiple subscribers, but it is less bandwidth intensive in the event the system serves a relatively large number of clients who are viewing relatively few multimedia streams.
Large businesses with streaming systems deployed across a wide and heterogeneous network have strong fiscal incentive to utilize the more bandwidth efficient multicast system. However, such businesses also have obligations to secure the content they broadcast. Thus, large businesses need systems that offer a way to authorize client reception for the entire duration of a multicast group subscription.

Method and system for authorizing multimedia multicasting


Integrated circuit IC package with one or more IC dies including solder features that are thermally coupled to the IC. The thermally coupled solder features (e.g., bumps) may be electrically insulated from solder features electrically coupled to the IC, but interconnected with each other by one or more metallization layers within a plane of the IC package. An in-plane interconnected network of thermal solder features may improve lateral heat transfer, for example spreading heat from one or more hotspots on the IC die. An under-bump metallization (UBM) may interconnect two or more thermal solder features. A through-substrate via (TSV) metallization may interconnect two or more thermal solder features. A stack of IC dies may include thermal solder features interconnected by metallization within one or more planes of the stack.

In electronics manufacturing, integrated circuit (IC) packaging is a stage of semiconductor device fabrication, in which an IC that has been fabricated on a die (or chip) comprising a semiconducting material is encapsulated in a supporting case or "package" that can protect the IC from physical damage and support electrical contacts that connect the IC to a host circuit board or another package. In the IC industry, the process of fabricating a package is often referred to as packaging, or assembly.
3D packaging architectures integrate multiple components (e.g., IC die) vertically within a single package assembly. Within a 3D packaging architecture, IC die may be assembled in various manners. For example, a first IC die may include a ball grid array (BGA) or land grid array (LGA) of solder features, while a second IC die stacked on the first may be connected to the first IC die through additional BGA/LGA connections that may for example interface with through-substrate vias (TSVs). As another example, one or more of the IC dies may be in a flip-chip BGA (e.g., FCBGA) architecture while a back side of one of the dies may be connected to another IC die, interposer, or package substrate through another means, such as TSVs, or wire bonds.
3D packaging brings new challenges in thermal management, and as such, heat dissipation is now one of the primary areas of research in the assembly industry. To date much work has emphasized improving heat transfer between different planes of a package assembly (i.e., die-to-die heat transfer). Such work has often neglected, or even hindered, the heat transfer within planes of a package assembly (i.e., lateral heat transfer across a die). However, in-plane heat transfer is very important for package assemblies where one or more IC die are not in close thermal contact with a dedicated heat spreader.

Thermal bump networks for integrated circuit device assemblies


A multilayered, white, biaxially-oriented polypropylene film is disclosed. The film has an at least three-layered build-up and has a base layer comprised of propylene polymers comprising up to 2% by weight of calcium carbonate having an average particle size of not more than 2.0 .mu.m and 0 to 25% be weight of titanium dioxide, an intermediate layer comprised of propylene polymers comprising 0 to 25% by weight of titanium dioxide, relative to the total weight of the intermediate layer; and a top layer comprised of a sealable raw material. The base layer and/or the intermediate layer of the film contain a total of at least 2% by weight of titanium dioxide.

The present invention relates to a biaxially-oriented opaque polypropylene film.
Biaxially-oriented, transparent or opaque polypropylene films are widely used in the packaging industry. Goods wrapped in opaque films, in particular chocolate bars or cookies, are protected against the influence of light to a far higher degree than goods wrapped in transparent films, which is of advantage in view of the desired long-term storability of the respective goods. Opaque films are films possessing vacuoles and are well-known in the art.
Disadvantages arise when opaque films are to be processed into bags or similar containers on high-speed automatic packaging machines. Usually, machines of this type are designed so that the film is guided, by exerting a tensile force, over an appropriately shaped forming tool to produce a tubing with overlapping edges from the flat film. Further process steps including sealing, filling of the tubing with the goods to be packaged and severing of the filled tubing sections, result in the individual bags.
When opaque, vacuole-containing films are guided over a forming tool in order to shape them into tubings, it is frequently observed that stripe-like markings of varying intensity appear in the longitudinal direction of the film or tubing. This adversely affects the optical appearance of the package. Text printed in the area of these undesired markings can only be read with difficulty, and industrial users that employ such films for packaging their quality products do not accept them, because an impression of inferior quality might be given to the end consumer. The markings are obviously a result of the compressibility of vacuole-containing opaque films, which is strongly increased as compared to transparent films. In the case of transparent films markings of the described type are not visible.


The subject oscillation frequency generating section generates a subject oscillation frequency in response to the capacitance of subject when the subject contacts the measurement electrode. The subject recognition signal generating section generates a subject recognition signal corresponding to the subject oscillation frequency. The reference signal setting section previously sets a reference signal used to determine whether the subject is an animate body. The animate body detection control section compares the subject recognition signal and the reference signal to determine whether the subject is an animate body.

1. Field of the Invention
The present invention relates to an animate body detector and, more specifically, to an animate body detector for determining whether a subject to be checked is an animate body.
2. Description of Related Art
Technologies on security of information processing systems are developing with the progression of computerization society. For example, it has been conventional to use ID cards to control entry to a computer room, but they tend to be lost or stolen. For this reason, ID cards are being replaced by an individual validation system which checks individuals to enter the room by consulting individuals' fingerprints or the like previously registered.
In such an individual validation system, a check is sometimes passed by creating a replica of a registered fingerprint. Accordingly, an individual validation system must determine whether subjects to be checked are animate bodies, besides making fingerprint comparisons.
The technique for determining whether subjects to be checked are animate bodies is disclosed in Japanese Patent Laid-Open No. Hei 3-38621 that detects animate bodies by animate body detection means exploiting skin pressure dependence.
General animate body detectors exploiting capacitance detect an animate body by using a sine wave voltage to measure the capacitance of a contacting subject to be checked.
However, the above-mentioned prior art has a problem that many parts including a light source are required and circuit configuration is complicated because an animate body is detected in a way that irradiates light to a subject to be checked and measures the reflection factor of its reflected light.
The prior art of using capacitance described later also has a problem that it is difficult to miniaturize an animate body detector because a sine wave voltage generator is required to measure capacitance.


A skiing simulator is provided which includes a load adjusting mechanism controlled by a control console for adjusting the resistance exerted by the load adjusting mechanism on a belt drive system disposed about a pair of guide tracks. A pair of foot pedals slidably mounted on the guide tracks, and a tension adjusting mechanism for adjusting the slack in the belt drive system is further provided. The control console is positioned on the skiing simulator to allow the user to change the resistance of the load adjusting mechanism without interrupting an exercise routine being performed.

1. Field of the Invention
This invention relates to a skiing simulator. In particular, this invention pertains to a skiing simulator having a load adjusting mechanism which increases or decreases the resistance exerted on a belt mechanism of the ski simulator. The load adjusting mechanism is controlled by a computer control console positioned on the skiing simulator to allow the user to change the resistance of the load adjusting mechanism without interrupting any exercise routine being performed.
2. Prior Art
Skiing simulator devices are known in the art and have been widely accepted and used in Europe and North America since they provide the benefits of skiing in an indoor setting. Skiing simulators are known which include a user adjustable load device to allow the user to set a load (resistance) that is appropriate for his or her physical condition. In prior art skiing simulators, as shown in FIG. 7, the load device is adjusted by setting the tension of the braking wires by moving the braking disk b relative to another disk. The structure of such prior art skiing simulators prevents the user from setting and retaining a suitable resistance for an exercise routine. It has been found that changing the resistance on prior art skiing simulators is time consuming and cannot be accomplished without interrupting the user's exercise routine. Generally, the user changes the resistance during an exercise routine to simulate skiing downhill or uphill. As in actual skiing, when using the skiing simulator, both of the user's hands and legs are moving. In order to change the resistance of the prior art skiing simulator, the user must first stop the exercise routine, adjust the resistance to a desired level, and then restart the exercise routine, thereby interrupting the exercise routine and reducing the beneficial effects of the exercise routine.


The present invention relates to a semi-automatic pencil sharpener comprising a sharpening body and a blade; the sharpening body has a conical bore with a throughslot for allowing shavings to go out; and the blade is disposed outside the sharpening body on one side of the shavings throughslot; an external housing is disposed outside the sharpening body; the external housing comprises a pencil fixation casing and a rotation casing which can rotate opposite to each other; the pencil fixation casing and the rotation casing are removably engaged with each other. The present pencil sharpener can be operated with one hand. It is convenient to use in comparison with available products and has a high degree of automation. Pencil shavings produced from pencil sharpening using the present invention can be stored in the pencil sharpener without falling out affecting hygiene. The present invention is therefore relatively easy to clean up and is environmental friendly. It also has the advantages of being small in size, easy to carry around and good for application.

The present invention relates to stationery and more particularly pertains to a semi-automatic pencil sharpener in the field of implements for writing or drawing.
The pencil sharpeners available in the marketplace are relatively simple in construction. They mainly comprise a sharpening body which has a conical bore with a throughslot for allowing shavings to go out, and onto which a blade is connected. To operate, the user inserts a pencil into the conical bore and makes the pencil to rotate opposite to the sharpening body, thereby making the blade to sharpen the pencil. This kind of pencil sharpeners is convenient to use, but has a relatively low degree of automation. Further, in the sharpening process pencil shavings easily drop and it is not easy to clean up.


A system for molding a non-pneumatic tire includes a lower mold portion including a lower backing plate, a plurality of lower projections extending from the lower backing plate, and a plurality of lower sleeves configured to at least partially cover the lower projections. The system further includes at least one lower retention plate configured to be positioned proximate the lower backing plate and retain the lower sleeves on the lower projections. The system also includes an upper mold portion configured to be associated with the lower mold portion. The system further includes an upper backing plate, a plurality of upper projections extending from the upper backing plate, and a plurality of upper sleeves configured to at least partially cover the upper projections. The system also includes at least one upper retention plate configured to be positioned proximate the upper backing plate and retain the upper sleeves on the upper projections.

When forming parts by molding, it is sometimes desirable to be able to form relatively small or intricate features in the part being molded. However, such features may result in difficulty separating portions of the mold from the molded part following curing of the molding material inside the mold. This difficulty may be particularly pronounced if the features extend relatively deeply into the molded part or if the molded part is particularly large. In such cases, it may be necessary to design the mold so that it has relatively large draft angles to facilitate removal of the molded part from the mold following curing of the molding material. However, large draft angles may be inconsistent with the desired design of the molded part.
For example, non-pneumatic tires may be formed by molding. However, some molded non-pneumatic tires may be typically less compressible than similar-sized pneumatic tires. This reduced compressibility may render the non-pneumatic tires unsuitable for some desired uses. However, it is possible to increase the compressibility of some non-pneumatic tires by creating axially-extending cavities in the tires between the tread and the hub. As a result, it may be desirable to provide a mold for forming tires having cavities between the tread and hub. However, it may be difficult to remove a molded tire from a mold having structures for forming the cavities in the tires as a result of the increased surface area of contact between the mold and the molded tire, particularly when the tire is large or there are a relatively large number of cavities having a relatively small cross-section compared to the length of the cavities. As a result, it may be difficult to mold such a tire.
An example of a mold and method for forming a non-pneumatic tire is disclosed in U.S. Patent Application Publication No. US 2012/0038206 A1 to Chadwick et al. ("the '206 publication"). In particular, the '206 publication discloses fabricating a non-pneumatic tire and wheel assembly by casting with a pour molding process. An outer mold element is received within a preformed tread. The outer mold element extends from a flat plate and incorporates struts corresponding to spoke locations in the tire body element and includes apertures to receive rubber mold blocks. An inner mold element is concentrically received over the tread and incorporates struts and apertures symmetrical with the outer mold element. Rubber casting blocks are inserted through the apertures in the inner mold element and received in corresponding apertures in the outer mold element to complete the casting mold. Sizing of the struts and apertures in the outer and inner mold elements and the rubber casting blocks provides corresponding sizing of the spokes in the cast tire body element. Elastomeric material is introduced through fill tubes to completely fill the interstitial spaces between the rubber mold blocks, is allowed to cure, and the rubber mold blocks and inner and outer mold elements are removed.
Although the mold and method disclosed in the '206 publication permits spokes to be molded into a molded tire, the mold and method may suffer from a number of possible drawbacks. For example, the method may be undesirably complex and lack efficiency due to the need to manually insert the rubber mold blocks into the inner and outer mold elements. In addition, the use of the rubber mold blocks may limit the ability to mold certain desired features into the molded tire.
The systems and methods disclosed herein may be directed to mitigating or overcoming one or more of the possible drawbacks set forth above.


A recombinant vector having an expression cassette is provided which comprises a modified human low density lipoprotein receptor (hLDLR) gene is provided, wherein said hLDLR gene encodes a modified hLDLR comprising (a) one or more of the following amino acid substitutions: L318H, N295D, H306D, V307D, N309A, D310N, L318H, and/or L318D; or (b) an amino acid substitution of any of (a) in combination with one or more of the following amino acid substitutions: K796, K809R and/or C818A. Also provided are pharmaceutical compositions containing this vector and uses therefor in lowering cholesterol and/or treating familial hypercholesterolemia.

Familial Hypercholesterolemia (FH) is an autosomal co-dominant disorder characterized by absence of the receptor for low-density lipoproteins (LDLR); a single chain glycoprotein containing 839 amino acids in its mature form. Hussain M M, et al, Annu Rev Nutr. 1999; 19:141-172. Patients with one abnormal allele, heterozygous FH (heFH) have moderate elevations in plasma LDL and suffer from premature coronary artery disease (CAD), whereas homozygous FH patients (hoFH) have high serum cholesterol (LDL-C>24 mmol/L) that often results in the early onset of life-threatening cardio vascular disease (CVD). Marais A D, Clin Biochem Rev. 2004; 25:49-68. Current treatment options to reduce excess serum cholesterol include LDL apheresis [McGowan M P. J Clin Lipidol. 2013; 7:521-26] and treatment with cholesterol lowering drugs. Hovingh G K, et al, Eur Heart J. 2013; 34:962-971. Orthotopic liver transplantation can lead to long term correction [Raal F J, 2012; 223:262-268], although, it is associated with substantial treatment related morbidity and mortality.
Liver-directed gene therapy using adeno-associated viral vectors (AAV) has been demonstrated in preclinical models to stably correct several metabolic disorders and is currently being pursued in clinical trials for treatment of hemophilia A and B, ornithine transcarbamylase deficiency (OTC) and alpha1-antitrypsin (A1AT) deficiency. Wang L, et al, Mol Genet Metab. 2012; 105:203-211; Brantly M L, et al, Proc Natl Acad Sci USA. 2009; 106:16363-16368; Nathwani A C, et al., N Engl J Med. 2011; 365:2357-2365; Ward N J, et al, Blood. 2011; 117:798-807]. Recently, the effectiveness of AAV mediated gene therapy in correcting serum cholesterol levels in humanized mouse models of FH has been demonstrated. Kassim S H, et al, PLoS One. 2010; 5:e13424. In these mice, systemic administration of AAV8 expressing human LDLR (AAV8.hLDLR) led to a lowering of cholesterol to normal levels by day 7 which was sustained for over a year and led to regression of pre-existing atherosclerosis. However, AAV8.LDLR transduction was dose dependent and statistically significant correction was only achieved at a vector dose of 1.5×1011 GC/kg or above. For clinical gene therapy, minimizing the vector dose is critical for many reasons, including vector injection volume, toxicity, immune response and manufacturing and cost of goods constraints.
Hepatic LDLR expression is modulated by multiple pathways within the cell: LDLR transcription is regulated by the sterol response element binding proteins (SREBPs), and HMGcoA reductase inhibitors (statins) activate SREBPs by inhibiting cholesterol synthesis within hepatocytes [Blumenthal R S, Am Heart J. 2000; 139:577-583].
A second pathway of LDLR regulation, involving pro-protein convertase subtilisin kexin 9 (PCSK9), was discovered based on human genetics gain-of-function mutations that caused high LDL-C levels [Abifadel M, et al., Nat Genet. 2003; 34:154-156] and loss-of-function mutations that caused low LDL-C levels [Cohen J, et al., Nat Genet. 2005; 37:161-1653]. The loss of PCSK9 function was associated with an 88% reduction in cardiovascular disease and has led to the development of a new class of cholesterol lowering drugs based on the inhibition of PCSK9 [Fitzgerald K, et al, Lancet. 2014; 383:60-68; Giugliano R P, et al, Lancet. 2012; 380:2007-2017]. Patients with FH have significantly higher plasma levels of PCSK9 [Raal F, et al., J Am Heart Assoc. 2013; 2:e000028].
A third pathway of LDLR regulation was discovered by Zelcher et al, [Zelcher N, et al., Science. 2009; 325:100-104] who demonstrated the degradation of LDLR by IDOL (inducible degrader of LDLR). An E3 ubiquitin ligase, IDOL was induced following activation of liver X receptors (LXRs) and subsequently interacted with the cytoplasmic tail of LDLR in mediating receptor ubiquitination and degradation. Furthermore, screening of subjects with low LDL-C identified loss-of-function mutations in IDOL that prevented degradation of LDLR [Sorrentino V, et al., Eur Heart J. 2013; 34:1292-1297].
Compositions useful for effectively lowering cholesterol in subjects, particularly those having familial hypercholesterolemia, are needed.

LDLR variants and their use in compositions for reducing cholesterol levels

The Trustees of the University of Pennsylvania


A Triac and a phase-locked loop are used to control the amplitude of reciprocation of an AC linear motor. The phase locked loop generates a square wave that is synchronized with an AC power source but is substantially isolated from electrical noise on the power source. The phase of the square wave is varied with an amplitude control signal, and Triac firing pulses are generated at the transitions of the square wave.

The invention is in the general field of electric motor control. Specifically, the invention uses a Triac and a phase locked loop to control the amplitude of reciprocation of a linear motion AC motor, in such a way that pulses of power line noise have little effect on amplitude or phase of reciprocation.
Triac controllers (Ref. 2) offer an inexpensive means of controlling reciprocation amplitude of linear motion AC motors (Ref. 1), but in prior art have the disadvantage of responding to pulses of electrical noise on the AC power line if peak pulse voltage is high enough to cause the power line voltage to cross zero volts. A spurious zero crossing is treated by the prior art control as a normal zero crossing, and, since prior art Triac control generates Triac firing pulses that are timed relative to zero crossings of power line voltage, the result of a pulse of line noise can be generation of a spurious Triac firing pulse. If the linear motor drives a free piston machine such as a Stirling refrigerator, incorrectly timed Triac firing can cause damage to the machine and/or loss of amplitude control. Electrical filtering of line voltage can attenuate line noise, but suppression by filtering of pulses of line noise occurring very near normal zero crossings, to the point where a spurious zero crossing cannot occur, is impractical.
The invention uses a Triac and a phase locked loop to control the amplitude of reciprocation of a linear motor with substantial isolation from disturbance by line noise pulses. Amplitude control in the invention is achieved, as in prior art, by connecting the series combination of the motor and a Triac across an AC power source, and varying the phase of Triac firing pulses relative to the power source voltage. The invention departs from prior art in that firing pulses are generated at transitions of the square wave output of a Voltage Controlled Oscillator (VCO) that is part of a phase locked loop (PLL). The VCO is synchronized in frequency with the AC power source by the PLL, but is practically isolated from power line noise pulses. In the invention, the phase of the VCO output and therefore of the Triac firing pulses, relative to line voltage, is varied with a control voltage that is proportional to the difference between a first voltage proportional to an xe2x80x9camplitude set-pointxe2x80x9d voltage and a second voltage that is proportional to a measured value of reciprocation amplitude. A decrease in measured amplitude causes a leading phase shift of firing pulses, which constitutes negative feedback that acts to hold the amplitude of reciprocation of the motor at a preset value determined by the amplitude set point voltage.
In one form of the invention, a voltage proportional to the amplitude of reciprocation of the linear motor is derived by analog or digital computation based on the equivalent circuit of the linear motor, thus obviating the cost and complexity of a position sensor.
The basic components of the phase locked loop used in the invention can be elements of a single integrated circuit (e.g., type 4046, see Ref 4).

Linear motor control with triac and phase locked loop


An integrated circuit package system comprising: forming leads adjacent a die paddle having a die pad extension; forming a region having one of the leads depopulated for the die pad extension; and connecting an integrated circuit die to the die pad extension.

Most if not all electronic products benefit from increasing including functions and performance in integrated circuit chips particularly in a smaller (or at least not larger) overall physical size or form factor. These needs for more, faster, and smaller are often very visible with the many consumer electronic products including but not limited to personal portable devices such as cellular phones, digital cameras, and music players.
The demands for smaller yet higher performing semiconductor devices have motivated the development of new techniques for producing smaller and less expensive semiconductor devices. One of these technologies involves packaging the integrated circuit chip in as small a form factor as possible in addition to manufacturing the integrated circuit chip as efficiently as possible.
Usually, many individual devices are constructed on a semiconductor wafer. When the devices are separated into individual rectangular units, each takes the form of an integrated circuit chip. In order to interface a chip with other circuitry, it is common to mount it with leads and individually connect pads on the chip to the leads of a package using extremely fine wires or similar electrical connectors. The assemblies are then packaged by individually encapsulating them in molded plastic or ceramic bodies.
Integrated circuit packaging technology has shown an increase in the number of chips mounted on a single circuit board or substrate that parallels the reduction in the number of components needed for a circuit. This results in packaging designs that are more compact, in the physical size and shape of a device, and provide a significant increase in overall integrated circuit density. However, integrated circuit density continues to be limited by the area available for mounting chips on a substrate.
To condense the packaging of individual devices, packages have been developed in which the integrated circuit package is not much larger than the integrated circuit(s) within. Each package site is a structure that provides mechanical support for the individual integrated circuit device(s). The package also provides one or more layers of interconnect lines that enable the devices to be connected electrically to surrounding circuitry.
In some cases, multi-chip devices can be fabricated faster and more cheaply than a corresponding single integrated circuit chip, that incorporates all the same functions. Some multi-chip modules have been found to increase circuit density and miniaturization, improve signal propagation speed, reduce overall device size, improve performance, and lower costs.
However, such multi-chip modules can be bulky. Package density is determined by the area required to mount a chip or module on a circuit board. One method for reducing the board size of multi-chip modules and thereby increase their effective density is to stack the chips vertically within the module or package. Such designs are improvements over prior packages that combined several chips and associated passive components side by side in a single, horizontal layer.
In any case, electrical connections and the leads can be very closely spaced even with a single integrated circuit chip. The close spacing of the electrical connections results in several problems in manufacturing as well as assembly of the integrated circuit package and the circuit board. One such problem involves a lack of space to supply a ground level voltage to the integrated circuit chip(s). This is particularly critical as the integrated circuit chip(s) cannot operate without a ground level voltage supply.
Despite the advantages of recent developments in semiconductor fabrication and packaging techniques, there is a continuing need for improving integrated circuit package form factors, numbers of integrated circuit package signal connections, and integrated circuit connections to a ground level supply.
Thus, a need still remains for an integrated circuit package system to provide improved compactness, functions, efficiency, and performance. In view of the increasing demand for improved density of integrated circuits and particularly portable electronic products, it is increasingly critical that answers be found to these problems.
Solutions to these problems have been long sought but prior developments have not taught or suggested any solutions and, thus, solutions to these problems have long eluded those skilled in the art.

Integrated circuit package system with ground bonds


A fan-out wafer level package is provided. The fan-out wafer level package includes a semiconductor element, a molding compound, a first fan-out structure, a conductive heat spreader, and a plurality of solder balls. The semiconductor element includes a plurality of bonding pads. The molding compound covers the semiconductor element. The first fan-out structure is formed on the semiconductor element, wherein the first fan-out structure has a plurality of fan-out contacts electrically connected to the bonding pads. The conductive heat spreader is formed on the first fan-out structure, wherein the conductive heat spreader has a plurality of through holes filled with a conductive material. The solder balls are formed on the conductive heat spreader, wherein the solder balls are electrically connected to the first fan-out structure via the through holes filled with the conductive material.

1. Technical Field
The disclosure relates in general to a fan-out wafer level package, and more particularly to a fan-out wafer level package having excellent heat dissipation effects.
2. Description of the Related Art
Recently, fan-out wafer level packages (FOWLP) have been popularly applied in making semiconductor chips due to the high performance and low cost requirements provided therefrom. For example, 28 nm node wafers have utilized FOWLP technology as a solution for mobile products.
However, there are still some issues, such as heat dissipation and structural delamination; therefore, there is always a continuing need to provide an improved FOWLP with reliable performances.


Cryptographic equipment is used with a number of user identification cards which are distributed to various authorized users, each user identification card being a non-volatile memory which can be overwritten in which a user-associated external crypto-ignition key is stored. Insertion of the user identification card in the cryptographic equipment releases the cryptovariable code by cooperation with an internal crypto-ignition key stored internal in a sub-memory of the cryptographic equipment for every authorized user. The cryptovariable required for setting and controlling the cryptosequence generator is stored in encoded form in another sub-memory of the variable memory, and is capable of being decoded with the cryptovariable code.

1. Field of the Invention
The present invention is directed to cryptographic equipment for encoding information to be transmitted, including an encoder stage and a cryptovariable processing stage.
2. Description of the Prior Art
In the transmission of information, particularly voice and data, it is sometimes necessary to ensure that the information to be transmitted is accessible only to authorized personnel. If high secrecy demands are made on the information to be transmitted, it is known, for example, from German OS 21 60 132 to transmit the information in digital form and to encode the information for transmission in a suitable manner with a cryptosignal sequence. At the receiver, the incoming encoded information must then be then decoded with the same cryptosignal sequence in order to regain the original information.
If the secrecy of the information to be transmitted is to be guaranteed, the cryptographic equipment for encoding at the transmission side and for decoding at the reception side must be protected against misuse. It must be ensured that such cryptographic equipment is only accessible to authorized personnel. As soon as the cryptovariable is entered, cryptographic information supplied with such cryptovariables (codes) via a cryptovariable input must be classified for a secrecy level associated with the cryptovariable. When this secrecy level is"Confidential" or higher, the cryptographic equipment must be appropriately secured to prevent access by unauthorized personnel. For example, the equipment may be stored locked in a safe. The use of cryptographic equipment by authorized users is thus made difficult.


Each of a plurality of acoustic sensors (acoustically coupled to a structure for monitoring) is connected to a network bus system via a preamplifier for capturing, processing and reporting acoustic events in a structure, for example aircraft structures. Each of the preamplifiers processes the acoustic event signals received from the sensors when an acoustic emission resulting from an acoustic event (defect in a structure, impact on the structure etc), and passes digital processed signal data relating to the detected acoustic event to a Remote Data Concentrator over the network for collation. The collated data is then stored and/or further processed (at a later time or in near real-time) to determine the source and/or location of detected acoustic emissions in the structure.

The present invention generally relates to a system and method for monitoring for structural defects in structures or impacts on structures on the basis of acoustic emission from such defects or impacts.
Stress corrosion and fatigue in structures causes crack growth. This is due to the metal slowly becoming brittle when there is a concentration of stress within a short distance of the crack tip. The crack then advances to a zone boundary in a series of discrete microfracture events, where the microfractures can take place either intergranularly or transgranularly. Tougher undamaged material at the zone boundary stops the crack advancing. The cycle of cracking is then repeated, starting again with a concentration of stress at or near the crack tip.
Under normal operating conditions, damage such as cracking in a structure develops slowly over time. However, if the structure is operating outside its normal range, a large amount of damage may occur within a short time. In addition, damage caused by stress to a structure is not limited to cracking and may also include fretting, pitting and rubbing. It is therefore essential that structures be monitored regularly so that damage may be detected and repaired, or further damage prevented if the damage is not advanced.
Cracking and fracturing is known to cause particular problems in aircraft, pressure vessels and oilrigs, as well as in large structures such as bridges. As cracking occurs, the cracks produce bursts of acoustic energy as wideband ultrasonic emissions in the structure where the cracking is taking place, known as acoustic emissions. The properties of the waveform of the acoustic emissions, such as frequency, amplitude, rise time etc, along with the exact times that bursts of acoustic energy are received at different locations, are dependent on the size of the crack, the location of the crack and how rapidly it propagates through the structure. Therefore cracks can be identified by their acoustic emission signature, which can be detected using acoustic sensors as acoustic emission sensors.
US 2003/0140701, the disclosure of which is hereby incorporated by reference, discloses a method of detecting and monitoring damage in a structure by receiving electrical signals continuously over a period of time as pulses representing a burst of acoustic energy from a plurality of acoustic sensors carried by the structure. The bursts of acoustic energy represent emissions from sites of damage. The burst is processed to obtain a smoothed envelope waveform. Wave-shape information and time information is determined and stored for each burst. If a burst is detected at three or more sensors, the difference in the time of arrival of the bursts at the sensors is determined as Δt values. The Δt values are then used to accumulate the bursts to determine if a threshold for the bursts is exceeded. If so, the burst data is stored to represent structural damage together with non-acoustic parameters.
A limitation in this system is that, when the health of a structure and structural damage is monitored by acoustic emission techniques, errors can occur in the analysis of the data using the system due to the assumption that the speed of sound in structures is uniform in all directions and there is a single mode of acoustic propagation though the structure. However, the speed of sound varies with the thickness and type of material through which the sound is propagating. The speed of propagation of acoustic waves will therefore vary as they propagate through an inhomogeneous structure.
Our previous application, WO2008107668, the disclosure of which is hereby incorporated by reference, addressed this problem by introducing a model of the effect of acoustic paths in a structure in the processing path of the acoustic event data. The model is built by inducing a plurality of types of acoustic emissions at many positions in the structure and by detecting the acoustic emissions using a plurality of acoustic emission sensors that are arranged on the structure. The model takes into account inhomogeneities of the structure, as well as differences in acoustic propagation modes in the structure, so that errors in the location of the damage sites can be reduced.
Referring to FIG. 1, this shows a schematic diagram of an arrangement for locating a site of damage on a typical aircraft structure by detecting acoustic emissions from the site of damage. The aircraft wing has an upper spar cap 101, a lower spar cap 102, a front spar 103, and cross-sectional stiffeners 104. The front spar 103 has reinforcing ribs 107 running vertically at spaced intervals. A fuel aperture 105 is provided on the inside of the front spar 100 and acoustic emission sensors 106 are acoustically coupled to the front spar 103 at several positions.
The illustrated part of the wing 100 is the section of the aircraft wing between the aircraft fuselage and the first engine. The vertical strut 103 supports the upper spar cap 101 and the lower spar cap 102 and the cross-sectional stiffeners 104 add stiffness to the structure of the wing and provide added strength to the front spar 103. The acoustic emission sensors 106 detect acoustic emissions originating from the source of damage on the front spar 103. The acoustic emission sensors are piezoelectric transducers with a resonant frequency in the range of the resonant frequency of the structure under investigation. In aluminium structures, transducers with resonant frequencies of around 200-300 kHz are suitable. The sensors 106 are attached to the structure of the front spar 103 by means of cable ties and self-adhesive bases. In addition, a sealant is used as a joining compound between the base of the sensor and the structure in order to provide a low attenuation acoustic coupling.
Differences in the time of arrival (Δt) of features, such as the leading edges of acoustic emission signals from sources of damage on the structure of the front spar 103 at the sensors 106 or the times of the peak signals from each sensor are used by a triangulation algorithm in analysis software to locate the source of the acoustic emission and therefore the damage. Although the surfaces of modern aircraft structures tend to be substantially homogeneous, discontinuities in the structure result from components in the interior of the structures, for example the vertical struts 103, the cross-sectional stiffeners 104 and the fuel aperture 105. Older aircraft also have surface discontinuities, since their structures consist primarily of riveted and bolted extruded or machined aluminium sections and plates.
For example, the discontinuities and inhomogeneities in the structure of the front spar 100 will cause an acoustic path from point A to point B shown in FIG. 1 to be non-uniform, as the acoustic transmission speed will change as it propagates through the structure. This leads to errors in Δt in the triangulation algorithm, which in turn leads to errors in the location of the site of damage on the aircraft structure. As mentioned above, this problem was addressed by our previous application, WO2008107668.
A schematic diagram of a system 110 for detecting and acquiring acoustic emission data from a structure is shown in FIG. 2. This system is known in the art and a similar system is described in US 2003/0140701. A sensor 111 is coupled to a preamplifier 112, which is connected to a data acquisition unit 113. The data acquisition unit 113 comprises a logarithmic amplifier 114 and a pulse processor unit 115. The data acquisition unit 113 is connected to a computer 116.
Acoustic emissions from sites of damage on the structure are detected by sensors 111, which comprise the acoustic emission sensors 106 placed on an aircraft structure as shown in FIG. 1. The sensors 111 are acoustically coupled to the aircraft structure and can be, for example, a piezoelectric sensor with a resonant frequency in the range from 20 kHz to 2 MHz. Any damage such as cracking on an aircraft structure will emit acoustic waves with a fundamental frequency equal to the resonant frequency of the structures. The resonant frequency of the sensor should therefore be the same as that of the structure being investigated. Typically aluminium aircraft structures have a resonant frequency in the region of 300 kHz, so this is the preferred frequency of sensor to use for detecting acoustic emissions from an aircraft structure. In practice the sensors generally have a bandwidth of a few hundred kHz and sample acoustic data at 15 MHz.
The preamplifier 112 is located in the vicinity of the sensor. There is an array of sensors and preamplifiers having N channels, each channel having one sensor 111 and one preamplifier 112. When calculating the Δt values of acoustic emissions, at least three sensors are required for triangulation. The sensors are acoustically coupled to the structure in spaced apart locations. Each sensor 111 is connected to the data acquisition unit 113 for acquiring and processing acoustic emission data from acoustic emission pulses.
The sensors 111 and preamplifiers 112 are connected to the data acquisition unit 113. The distance between the sensors 111 and the data acquisition unit 113 is installation dependant. In practice, when detection of acoustic emissions takes place from an aircraft structure, the data acquisition unit 113 is located within the avionics bay of the aircraft and is powered from the aircraft's power supply.
There will be background noise from sources such as the aircraft engines that will interfere with acoustic emission signals from the aircraft structure. The data acquisition unit 113 conditions the acoustic emission signals received at the sensor 111 and performs real time filtering and signal processing to isolate acoustic emissions from background noise and produce acoustic emission data that can be used to locate a source of damage on the aircraft structure. The signal received at the sensor takes the form of a wave packet. In each channel the logarithmic amplifier 114 rectifies the signal received from the preamplifier 112. The rectified signal then enters the pulse processor unit 115, which converts the acoustic emission signals received at the sensor 111 to digital signals, filters the digital signals and isolates the digital signals in order to distinguish acoustic emissions received from damage on the structure from background noise.
The digital signals from each channel take the form of pulses, which are analysed by a computer 116 using a triangulation algorithm. Each sensor 111 is generally at a different distance from the site of damage, which means that acoustic emission signals from the damage will reach each sensor at a different time. The location of the damage can be identified by measuring the difference in times of arrival between sensors (Δt) and using acoustic velocity information for each sensor 111. This process is known as triangulation. However, triangulation assumes a homogeneous structure and a uniform speed of sound in all directions in the structure, so there will be errors in the location of the damage as calculated by this method.
As can be seen from the above discussion, prior art systems may have long, and differing, runs of cables between the preamplifiers (local to each sensor) and the data acquisition unit, which can introduce noise in the received signal, and can cause errors to be introduced into the triangulation of the detected acoustic event due to errors in the timing data.

Acoustic structural integrity monitoring system and method


A method and apparatus for automatic determination of a pacemaker patient's pacing stimulation threshold. Circuitry is provided in a pacemaker for obtaining a signal reflecting cardiac impedance, which is known to reliably reflect certain aspects of cardiac function. Circuitry is also provided for monitoring the cardiac impedance waveform during a predetermined capture detect window following delivery of stimulating pulses. One or more values are derived which characterize the morphology of the impedance waveform during the capture detect window associated with each stimulation pulse delivered. These values are compared to predetermined control values in order to assess whether a stimulation pulse has achieved cardiac capture. The assessment of whether cardiac capture has been achieved is also based partly upon the conventional sensing of atrial and/or ventricular cardiac signals occurring during the capture detect window. In one embodiment of the invention, the control values against which impedance waveform characterization values are compared are obtained by delivering a series of stimulation pulses having sufficient energy to ensure that capture is achieved, and by monitoring the impedance waveform during delivery of these pulses.

In general, cardiac pacemakers are electrical devices used to supplant some or all of an abnormal heart's natural pacing function. Pacemakers typically operate to deliver appropriately timed electrical stimulation signals, sometimes called pacing pulses, designed to cause the myocardium to contract or "beat." For state-of-the-art pacemakers, the rate at which stimulation signals are delivered may be variable, and such variation may occur automatically in response to detected changes in a patient's level of physical activity. Such rate- or activity-responsive pacemakers depend on physiologically-based signals, such as signals from sensors measuring the pressure inside the patient's ventricle, for determining a patient's activity level. One popular method for measuring a patient's activity level, and hence the patient's demand for oxygenated blood, is to measure the physical activity of the patient by means of a piezoelectric transducer. Such a pacemaker is disclosed in U.S. Pat. No. 4,485,813 to Anderson et al.
In typical prior art rate-responsive pacemakers, the pacing rate is determined according to the output from an activity sensor. The pacing rate is variable between a predetermined maximum and minimum level, which may be selectable by a physician from among a plurality of programmable upper and lower rate limit settings. When the activity sensor output indicates that the patient's activity level has increased, the pacing rate is increased from the programmed lower rate by an incremental amount which is determined as a function of the output of the activity sensor. That is, the rate-responsive or "target" pacing rate in a rate-responsive pacemaker is determined as follows: EQU Target Rate=Programmed Lower Rate+f(sensor output)
where f is typically a linear or monotonic function of the sensor output. As long as patient activity continues to be indicated, the pacing rate is periodically increased by incremental amounts until the rate computed according to the above formula is reached (or until the programmed upper rate limit is reached, whichever is lower). In this way, an elevated pacing rate (i.e., one higher than the programmed lower rate limit) may be sustained during periods of patient activity. When patient activity ceases, the pacing rate is gradually reduced, until the programmed lower rate limit is reached.
For any of the known rate-responsive pacemakers, it is clearly desirable that the sensor output correlate to as high a degree as possible with the actual metabolic and physiologic needs of the patient, so that the resulting rate-responsive pacing rate may be adjusted to appropriate levels. A piezoelectric activity sensor can only be used to indirectly determine the metabolic need. The physical activity sensed can be influenced by upper body motion. Therefore, an exercise that involves arm motion may provide signals that are inappropriately greater than the metabolic need. Conversely, exercises that stimulate the lower body only, such as bicycle riding, may provide a low indication of metabolic need while the actual requirement is very high.
To address these perceived disadvantages in the prior art, other physiologically-based parameters have been utilized to assess a patient's metabolic demand. Among these parameters are cardiac pressure, blood oxygen saturation, and minute ventilation (V.sub.e), each of which having been demonstrated clinically to be parameters that correlates well with the actual metabolic and physiologic needs of the patient.
Minute ventilation, which has been found to be a very good indicator of a patient's metabolic demand, is defined by the equation: EQU V.sub.e =RR.times.VT
where RR=respiration rate in breaths per minute (bpm), and VT=tidal volume in liters. Clinically, the measurement of V.sub.e is performed by having the patient breathe directly into a device that measures the exchange of air and computes the total volume per minute. The direct measurement of V.sub.e is not practical with an implanted device. However, measurement of the impedance changes of the thoracic cavity can be implemented with an implanted pacemaker. Such a pacemaker is disclosed in U.S. Pat. No. 4,702,253 issued to Nappholz et al. on Oct. 27, 1987. The magnitude of the change of the impedance signal corresponds to the tidal volume and the frequency of change corresponds to respiration rate. Thus, measurement of cardiac impedance can be used as one method for obtaining V.sub.e data.
In practice, cardiac impedance can be measured through assessment of the impedance present between two or more cardiac electrodes, such as the electrodes otherwise used for pacing and/or sensing in connection with a cardiac pacemaker. In particular, it has been shown that cardiac impedance can be measured by delivering constant-current excitation pulses between two "source" electrodes, such that the current is conducted through some region of cardiac tissue. The voltage differential between two "recording" electrodes can then be measured to ascertain the impedance as reflected by the voltage differential arising from the conduction of the excitation current pulses through the tissue. Such an impedance measuring technique has proven to be practicable in connection with implantable devices, such as cardiac pacemakers.
In U.S. Pat. No. 4,721,110 to Lampadius, there is described a rheographic arrangement for a cardiac pacemaker in which the base pacing rate of the pacemaker is determined, in part, by a rheographically derived respiration rate signal.
Correlation of breathing and intrathoracic pressure fluctuations with impedance of blood in the heart is also recognized in U.S. Pat. No. 4,884,576 to Alt, which describes the measurement of impedance between two electrodes. According to the Alt '576 patent, low-pass filtering of the impedance signal yields a signal from which the patient's respiratory rate can be derived, while high-pass filtering of the same signal yields a signal from which the patient's cardiac function can be observed.
There are currently several commercially-available implantable devices which employ rheographic techniques to adjust the pacing rate in response to metabolic needs. For example, the Biorate device manufactured by Biotec International, Bologna, Italy, uses a bipolar rheographic arrangement to monitor the patient's respiration rate. The Meta-MV device manufactured by Telectronics, Inc., Englewood, Colo., uses a tripolar rheographic arrangement to monitor the patient's metabolic demand for oxygenated blood. The Precept device manufactured by CPI, St. Paul, Minn., uses a tetrapolar rheographic configuration to monitor the patient's pre-ejection interval (PEI), stroke volume, and heart tissue contractility.
The Legend Plus.TM. pulse generator, manufactured by Medtronic, Inc., Minneapolis, Minn. and currently undergoing clinical trials in the United States, is another example of an implantable pacemaker which employs rheography in support of its activity-response function. The Legend Plus.TM. delivers a biphasic excitation signal between the pulse generator's canister (serving as an indifferent electrode) and a ring electrode of a transvenous pacing/sensing lead. Impedance sensing in the Legend Plus.TM. carried out between the lead's tip electrode and the pulse generator canister. The Legend Plus.TM. impedance measuring circuitry generates an impedance waveform in which both respiration and cardiac systole are reflected. This waveform is used by the pacemaker's circuitry to derive a minute ventilation value V.sub.e, as defined above. The Legend Plus.TM. periodically assesses a patient's V.sub.e, and adjusts its base pacing rate up or down in accordance with the metabolic demand reflected in the V.sub.e value. (Various aspects of the Legend Plus.TM. device are described in U.S. Pat. No. 5,271,395 to Wahlstrand et al. entitled "Method and Apparatus for Rate-Responsive Cardiac Pacing," which patent is hereby incorporated by reference herein in its entirety.)
Another disclosure which relates to the use of rheography in connection with an implanted device can be found in co-pending U.S. patent application Ser. No. 08/233,901 filed on Apr. 28, 1994 in the name of Wahlstrand et al. entitled "Method and Apparatus for Sensing of Cardiac Function", which proposes a method and apparatus for obtaining an impedance waveform. The Wahlstrand et al., disclosure, which relates to the use of a specialized lead for improving the quality of an impedance waveform like that utilized in the aforementioned Legend Plus.TM., is hereby incorporated by reference herein in its entirety.
Yet another disclosure relating to the use of rheography in connection with implantable devices can be found in co-pending U.S. patent application Ser. No. 08/277,051 filed on Jul. 19, 1994 in the name of Gianni Plicchi et al. entitled "Time-Sharing Multi-Polar Rheography".
In an effort to minimize patient problems and to prolong or extend the useful life of an implanted pacemaker, it has become common practice to provide numerous programmable parameters in order to permit the physician to select and/or periodically adjust the desired parameters or to match or optimize the pacing system to the patient's physiologic requirements. The physician may adjust the output energy settings to maximize pacemaker battery longevity while ensuring an adequate patient safety margin. Additionally, the physician may adjust the sensing threshold to ensure adequate sensing of intrinsic depolarization of cardiac tissue, while preventing oversensing of unwanted events such as myopotential interference or electromagnetic interference (EMI). Also, programmable parameters are typically required to enable and to optimize a pacemaker rate response function as described above. Among the pacemakers manufactured by the assignee of the present invention are those that are multiprogrammable and rate-responsive, having numerous programmable parameters, including pacing mode, sensitivity, refractory period, pulse amplitude, pulse width, lower and upper rate limits, rate response gain, and activity threshold.
Those of ordinary skill in the art will appreciate that whether or not a pacemaker operates in a rate-responsive mode, the energy of stimulating pulses it delivers, i.e., the strength (amplitude) and duration (pulse width) of stimulation signals, must be of sufficient magnitude to achieve capture. (As used herein, the term "capture" will be used to refer to the occurrence of a cardiac contraction in direct response to the application of an electrical stimulation signal; to achieve capture is to evoke a cardiac response to delivery of a stimulation signal.) It is imperative that capture be maintained in order to prevent serious complications or even death, especially for those patient's who are partially or wholly dependent upon their pacemakers. At the same time, however, it is desirable for pacemaker stimulation signal energy levels to not be unnecessarily high, as this tends to decrease the useful life of the implanted device due to battery depletion, and can also have undesirable physiological side effects. In recognition of this trade-off between maintaining capture and maximizing device longevity, it has been common practice in the prior art to first determine the minimum energy level necessary to achieve capture in a patient (the patient's "pacing threshold"), and then to pace a patient's heart with pulses having an energy level that is a predetermined safety margin greater than the patient's pacing threshold.
Chief among the problems of ensuring that the safety margin between the energy level of stimulation pulses and a patient's pacing threshold is that stimulation thresholds necessary for maintaining capture often fluctuate in the short term, and can gradually change over the long term. It has been clinically observed that a lower threshold is typically exhibited immediately after implantation of the pacemaker (the so-called "acute threshold"). Inflammation in the tissue around the stimulating electrode generally drives the pacing threshold up sharply to its "peak threshold" level during the first two to six weeks after implant. Over the long term, some of this inflammation reduces, lowering the threshold from its peak to a "chronic threshold" level. The chronic threshold may not reduce to the acute level, however, since some permanent fibrous tissue will develop around the stimulating site, so that greater energy is required than for non-fibrous acute tissue.
In the short term, thresholds may decrease with exercise, for example, and may increase with other activities, including sleep.
Since patient's pacing thresholds vary over time, periodic assessments of a patient's threshold must be made, so that the energy level of stimulation pulses can be adjusted accordingly. One early proposal relating to the assessment of stimulating thresholds and adjusting stimulating levels in response to detected threshold levels can be found in U.S. Pat. No. 3,920,024 to Bowers, entitled "Threshold Tracking System and Method for Stimulating a Physiological System."
Another prior art arrangement for assessing stimulating thresholds is disclosed in U.S. Pat. No. 4,250,884 to Hartlaub et al., entitled "Apparatus For and Method Of Programming the Minimum Energy Threshold for Pacing Pulses to be Applied to a Patient's Heart." The Hartlaub et al. '884 patent is assigned to the assignee of the present invention and is hereby incorporated by reference herein in its entirety.
According to the Hartlaub '884 patent, a pacemaker and programmer are operable to function in a so-called "autothreshold" mode, wherein the pacemaker delivers a series of progressively lower energy level stimulation pulses to the patient's heart. While the pacemaker and programmer are operating in the autothreshold mode, the physician or clinician who initiated the autothreshold function monitors the patient's EKG on a strip-chart or display screen. The physician or clinician takes note of which pulse among the sequence first fails to achieve capture, and in response immediately discontinues the autothreshold test. This identifies to the programmer that the patient's pacing threshold lies between the energy levels of the two most recently delivered pulse, and the programmer can then adjust the level of pacing pulse energy to be at a level which includes at least a predetermined safety margin above the patient's threshold.
Although the method and apparatus disclosed in the Hartlaub '884 reference provides a means for determining a patient's pacing threshold so that battery depletion is minimized and patient safety is ensured, the Hartlaub '884 system requires the presence of a trained physician or clinician to perform the autothreshold procedure, and the autothreshold adjustment must be carried out in a clinical setting. This can be inconvenient and expensive for the patient. To address these issues, attempts have been made in the prior art to provide implantable pulse generators with a more fully automatic threshold detection feature, so that capture can be maintained without the need for clinical or patient intervention. Such IPGs typically rely upon electrical sensors similar to pacing leads to sense the presence of capture in response to the delivery of stimulation signals. However, the function and accuracy of these sensors have been shown to be adversely affected by one or more factors, including (but not limited to): myopotentials (electrical signals which are the product of muscle movement), electromagnetic interference (EMI), problems with sensor sensitivity (either too sensitive or not sensitive enough), and variations in the sense electrical signals as a function of changes in thoracic pressure (for example, due to changes in respiration rate, coughing, or sneezing).
Another difficulty with reliance upon electrical sensing to detect the presence or absence of capture without the necessity of physician intervention is that the sensing circuitry typically is not capable of discriminating between an intrinsic beat which would have occurred even if no stimulation pulse had been delivered, and an actual captured beat.
The above-mentioned and other difficulties associated with automating the procedure for determining a patient's pacing threshold and adjusting the stimulation pulse energy level can be generally described as involving either lack of sensitivity or lack of specificity in capture detection. (As used herein, "sensitivity" in capture detection is used to refer to the ability to avoid false negative capture detection--not recognizing when capture actually occurs--quantified as the number of loss-of-capture beats identified as such divided by the actual number of loss-of-capture beats, over a given time. On the other hand, "specificity" in capture detection refers to the ability avoid false positive capture detection--indicating that capture has occurred when it actually has not--quantified as the number of capture beats identified as such divided by the actual number of capture beats, over a given time.)

Method and apparatus for detecting cardiac capture


The invention relates to a two-stroke engine in a portable handheld work apparatus such as a motor chain saw. A combustion chamber (3) is formed in a cylinder (2) and is delimited by a piston (5). The piston (5) drives a crankshaft (7) via a connecting rod (6). The crankshaft is journalled in a crankcase (4). Air is supplied to the combustion chamber (3) via a first outlet-near transfer channel (15); whereas, the air/fuel mixture, which is needed for operation, flows in via a second outlet-remote transfer channel (12) from the crankcase (4). The constructive volume of the outlet-near transfer channel (15) is designed to be approximately 20% to 60% of the volumetric total air input of the engine (1) in order to achieve a complete charge of the combustion chamber while having low scavenging losses.

The invention relates to a two-stroke engine such as a drive engine in a portable handheld work apparatus including a motor chain saw, brushcutter, cutoff machine or the like.
In known two-stroke engines, the air/fuel mixture needed for operation as well as clean air are supplied to the crankcase. The air flows in via channels close to the outlet. The entry openings of the transfer channels in the crankcase housing are arranged at different spatial locations in order to ensure that air or a low-fuel mixture enters the combustion chamber from the crankcase via the outlet-near transfer channel and that only a rich air/fuel mixture enters via the outlet-remote channel. This requires a complex channel arrangement and ensures that only air is supplied via the outlet-near channel at the start of the scavenging cycle. After a first introduction of air, a low-fuel mixture flows from the crankcase which escapes in considerable amounts via the outlet because of the outlet-near position of the transfer channels. This leads to an excellent charge of the combustion chamber but causes high hydrocarbon emissions in the exhaust gas because of the energy-rich scavenging losses which is unacceptable in view of a need to provide a high measure of environmental compatibility.
It is an object of the invention to provide a two-stroke engine which is improved so that, on the one hand, a complete charge of the combustion chamber with a mixture is ensured while, on the other hand, the mixture component, which escapes via the outlet, is held as small as possible.
The two-stroke engine of the invention includes a two-stroke engine in a portable handheld work apparatus. The two-stroke engine includes: a cylinder having a cylinder wall; a piston mounted in the cylinder to undergo a reciprocating movement along a stroke path between top dead center and bottom dead center during operation of the engine; the cylinder and the piston conjointly delimiting a combustion chamber; a crankcase connected to the cylinder; a crankshaft rotatably mounted in the crankcase; a connecting rod connecting the piston to the crankshaft to permit the piston to drive the crankshaft as the piston reciprocates in the cylinder; a carburetor for supplying an air/fuel mixture and the carburetor having an intake channel; an inlet channel connected to the intake channel and leading to the crankcase for conducting the air/fuel mixture into the crankcase; the cylinder having a discharge outlet formed therein for conducting exhaust gases away from the combustion chamber; an outlet-near transfer channel connecting the crankcase to the combustion chamber; the outlet-near transfer channel having a first end defining a transfer window opening into the combustion chamber and a second end defining inflow opening open to the crankcase; an air channel connected to transfer channel between the first and second ends thereof for supplying an essentially fuel-free gas flow to the transfer channel; an outlet-remote transfer channel connecting the crankcase to the combustion chamber; the outlet-remote transfer channel having a first end defining a transfer window opening into the combustion chamber and a second end defining and inflow opening open to the crankcase; and, a sum of the constructive volumes of the outlet-near transfer channel between the transfer window and the inflow opening being approximately 20% to 60% of the volumetric total air input of the engine at rated engine speed.
The dimensions of the outlet-near transfer channels (that is, the constructive volumes between the transfer windows of the channels to the combustion chamber and their inflow openings from the crankcase) are so predetermined that the sum of these constructive volumes corresponds to approximately 20% to 60% of the total volumetric air input of the engine at rated engine speed rpm. In this way, a significant part of the total air of the engine is supplied as pure air via the outlet-near transfer channels. The mixture, which flows in from the crankcase, is designed to be correspondingly rich so that, after closing the outlet, the remaining air and the rich mixture define an air/fuel ratio which ensures a substantially complete combustion for a ready power development. The air quantity, which flows in via the outlet-near transfer windows corresponding to the provided constructive volume, provides an air curtain, which shields the outlet over the long duration of the scavenging cycle. This air curtain prevents an escape of the rich air/fuel mixture. Preferably, toward the end of the scavenging phase, the air/fuel mixture, which is inducted into the crankcase, can follow on also via the outlet-near transfer channels. For this reason, an advantageous change of the charge stratification results for the next combustion.
The outlet-near transfer channel is configured so as to be closed to the piston in order to easily make available the constructive volume of the outlet-near transfer channel. In this way, a wall is formed between a transfer channel and the cylinder bore and the thickness of the cylinder wall is between 2 mm and 6.5 mm. This thickness ensures an adequate shielding of the transfer channel from the hot interior of the cylinder whereby an excessive heating of the advanced air in the outlet-near transfer channel is prevented.
The outlet-remote transfer channels have the exclusive function of transfer. For this reason, these outlet-remote transfer channels are configured in a simple manner to be open toward the cylinder bore and this reduces manufacturing complexity. It is practical to also configure the outlet-remote transfer channels as closed toward the cylinder bore.
The two-stroke engine of the invention is advantageously so operated that approximately 30% to 70% (preferably approximately 35% to 45%) of the volumetric total air input of the engine is supplied via the outlet-near transfer channel at rated rpm of the engine. The volume design for the outlet-near transfer channels is provided in such a manner that the stratified charge, which is formed in the combustion chamber, is maintained over approximately 65% to 95% (preferably approximately 75%) of the duration of the scavenging operation.


The present invention is directed towards instruments and methods for discharging an anesthetic drug on a continuous basis for use as a nerve block. In accordance with the present invention, a catheter assembly is provided that comprises an electrically conductive wire, a protective sheath and an inflatable balloon. The inflatable balloon is at the distal end of the catheter capable of being inflated and deflated. A balloon channel terminates within the inflatable balloon at the distal end of the catheter and extends proximally along the length of the catheter to the proximal end of the catheter. The balloon channel has a balloon channel opening at a distal end of the balloon channel within the inflatable balloon, capable of releasing an injected substance into the inflatable balloon. The balloon channel further has a balloon channel injection opening at a proximal end of the balloon channel, capable of receiving an injected substance.

Regional anesthesia refers to anesthetizing only a region of the body, usually in the region where surgery is performed or where acute or chronic pain from any other cause is present. A nerve block accomplishes this task, by administering a local anesthetic agent, such as novocaine, bupivacaine or lidocaine, to the plexus of a nerve. Traditionally, a nerve block was administered using a needle to locate the target nerve and to then insert the anesthetic agent through the needle in order to make contact with the nerve, commonly referred to as a single injection nerve block or single-shot nerve block. One of the major disadvantages of single injection nerve blocks was that the duration of acute pain would be longer than the duration of the single injection nerve block.
As a result, continuous nerve blocks emerged, which utilized an epidural catheter that was threaded through a needle once the needle was properly placed adjacent to the target nerve, and used to deliver variable amounts of the anesthetic agent to the target nerve. In order to properly position the needle on or near the target nerve, a nerve stimulator, such as an electrical current, would be used. Later advances utilized a nerve stimulator on the epidural catheter as well, in order to properly position the epidural catheter on or near the target nerve.
More recently, continuous nerve blocks have been utilized where a needle is properly placed adjacent to the target nerve using ultrasound technology, instead of a nerve stimulator. Subsequent to the proper placement of the needle, an epidural catheter is threaded through the needle and positioned on or near the nerve using a nerve stimulator. However, the major disadvantage to this existing technique is that the catheter is not reliably visible using ultrasound technology, which in turn prevents the epidural catheter to be optimally positioned on or near the target nerve. For example, the current technique requires that the catheter be advanced far down along the nerve to ensure that it is positioned on the nerve for the duration of the continuous block, which in turn may result in coiling of the catheter around the nerve, potentially causing damage to the nerve upon removal of the catheter. In addition, coiling of the catheter is not visible using ultrasound technology, as such technology only allows for a two dimensional view. Furthermore, the current technique requires tunneling of the catheters in order to avoid any dislodgment of the catheters, which also leads to potential damage to the nerves from broken or leaking catheters, as well as infections.
Therefore, there exists a need for a catheter instrument that is visible on an ultrasound image, which would allow for the catheter to be optimally positioned on or near a target nerve and avoid any potential damage from coiling or tunneling of the catheter.

Instrument for continuous discharge of anesthetic drug


A calibration circuit block includes a first resistor network, a second resistor network, and a feedback loop. The first resistor network includes a set of transistors and receives a constant current from a constant current source. The second resistor network receives a tracking current from a tracking current source. The impedance of the second resistor network changes with temperature and process variations on the integrated circuit. The tracking current source compensates for variations in the impedance of the second resistor network that are caused by process and temperature variations to maintain a constant reference voltage at the second resistor network. The feedback loop generates calibration control signals for controlling the conductive states of the transistors in the first resistor network. The feedback loop adjusts the calibration control signals to maintain a constant impedance in the first resistor network.

The present invention relates to electronic circuits, and more particularly, to techniques for calibrating on-chip termination impedances for transmitters and receivers to terminate transmission lines.
Signal reflection can occur on transmission lines when there is a mismatch between the characteristic impedance of the transmission line and the impedance of the transmitter and/or receiver. The reflected signal can interfere with the transmitted signal, causing distortion and degrading signal integrity.
To solve this problem, transmission lines are resistively terminated by a matching impedance to minimize or eliminate signal reflection. Input/output (I/O) pins on an integrated circuit package can be terminated by coupling external termination resistors to the appropriate I/O pins. However, many integrated circuit packages require a large number of termination resistors, because they have a large number of I/O pins. Therefore, it is becoming more common to resistively terminate transmission lines using on-chip termination (OCT) circuits to reduce the number of external components and to conserve board area.
On-chip termination circuits can be implemented with on-chip termination resistors. However, the impedance of on-chip resistors varies as the temperature of the integrated circuit changes. Also, process variations between integrated circuit die can cause on-chip resistors to have different impedances. When the impedance of an on-chip termination circuit is not equal to the characteristic impedance of the transmission line, signal reflection typically increases, causing increased signal distortion.
Because un-calibrated on-chip termination circuits can have impedances with undesirably large tolerance ranges, calibration circuits are often used to improve the accuracy of an on-chip termination (OCT) circuit. However, many prior art on-chip termination calibration circuits do not provide a high enough accuracy for some applications. Therefore, it would be desirable to provide on-chip termination calibration circuits that can provide highly accurate on-chip termination impedances.

Techniques for calibrating on-chip termination impedances


Systems and methods of adjusting zone associated risks of a coverage zone covered by one or more sensors of an autonomous driving vehicle (ADV) operating in real-time are disclosed. As an example, the method includes defining a performance limit detection window associated with a first sensor based on a mean time between failure (MTBF) lower limit of the first sensor and a MTBF upper limit of the first sensor. The method further includes determining whether an operating time of the ADV operating in autonomous driving (AD) mode is within the performance limit detection window associated with the first sensor. The method further includes in response to determining that the operating time of the ADV operating in AD mode is within the performance limit detection window of the first sensor, adjusting a zone associated risk of the coverage zone to a performance risk of a second sensor.

Vehicles operating in an autonomous mode (e.g., driverless) can relieve occupants, especially the driver, from some driving-related responsibilities. When operating in an autonomous mode, the vehicle can navigate to various locations using onboard sensors, allowing the vehicle to travel with minimal human interaction or in some cases without any passengers.
Motion planning and control are critical operations in autonomous driving. As companies race to deploy SAE (Society of Automotive Engineers) Level 4 (L4) autonomous vehicles (e.g., robotaxi) within a geofenced operational design domain (ODD), one of the challenges involved is to define sensor system capabilities with associated risks for a given geofenced ODD, so that an autonomous vehicle operation can be planned with acceptable risks. Herein, an L4 autonomous vehicle refers to a fully autonomous vehicle. L4 vehicles are designed to perform all safety-critical driving functions and monitor roadway conditions for an entire trip. However, it is important to note that this is limited to the ODD of the vehicle—meaning it does not cover every driving scenario.
With respect to defining the sensor system capabilities with associated risks, one common approach is to use simulation, verification, and validation to ensure that an autonomous vehicle has a sufficient handle of most scenarios within an ODD. However, the dynamic performance of the autonomous vehicle's sensor system is yet to be addressed.
That is, current industrial approaches for L4 autonomous vehicles focus on improving the performance with redundant and diversified sensors, hardware, and algorithms. Unfortunately, very little has been reported about dynamic performance and associated risk distribution of a sensor system to define sensor system capabilities.

Systems and methods to enhance early detection of performance induced risks for an autonomous driving vehicle