Submission of proposals
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| PHASE I: Develop overall system design document, to include a high level hardware firmware/software, power budget, integrate a multi-node thermoregulatory model, PC support software interface, and smart sensor/network integration requirements. Phase I may also include initial proof-of-concept hardware and software prototypes detailing prediction model algorithms.
PHASE II: Build no more that 10 working prototypes and supporting hardware/software interfaces suitable for full scale performance evaluations in the laboratory or field. The working prototypes must have a simple thermoregulatory model allowing output of simulated water requirements, work/rest cycles and maximum work times from the given environmental sensor sweeps, clothing system menu, and activity level. The end point is to merge with WPSM product technology integration for a facile, near real-time deployable environmental sensor suite capable of simulation of soldier performance. PHASE III DUAL USE APPLICATIONS: The system would have significant potential for use in real-time physiological response monitoring of HAZMAT and firefighting applications, for evaluating micro-environments for individual firefighters exposed to warm environments, and for judging relative risks associated with diverse activities, environments, and clothing challenges. The system may also have commercial applications in the bus or truck driving industries, bomb disposal, and helicopter cockpit environmental assessment. KEYWORDS: Environmental sensor suite, algorithms, ASICS, physiologic prediction models, cold stress, heat stress, micro scale environment A03-170 TITLE: Patient Safety Perioperative Readiness Support System TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA, MRMC OBJECTIVE: Develop an interactive PC based system for employment in the perioperative environment; capable of providing explicit patient tracking, monitoring of physiological data of all patients and readiness status of all relevant medical personnel and support systems. Seven key components should assist in providing a focus for this research agenda. The intent is to develop new knowledge by building on extent knowledge related to human factors and error reduction strategies. DESCRIPTION: Background of the Problem Clinicians caring for surgical patients strive to ensure patient safety while providing quality care. However, existing evidence suggests that both medical and surgical errors are excessive in the current health care system. A particular concern is the fact that “surgical errors often appear the worse…The end points in surgery are often more concrete and immediate than in medicine – survival or death, cure or failure” (Hettiaratchy, 2001, p. 887). Limited information exists regarding the exact incidence and nature of surgical errors and adverse events, and even less is known about actions and interventions that promote and ensure patient safety. PHASE I: Provide appropriate research and analysis to facilitate a definitive understanding of the true nature and incidence of adverse events in Operating Rooms/Surgical settings, building on extensive knowledge related to human factors and error reduction strategies. Assess adverse events in the perioperative environment (space utilization); system failures, team-work, communications and leadership. Provide a detailed illustrative report that identifies safer and more effective clinical processes resulting from the initial research and analytical findings. PHASE II: Design, develop and demonstrate a functional prototype of a full performance PC based interactive system for employment in the perioperative environment. The system will be capable of explicit patient tracking, monitoring of physiological data of all patients and readiness status of all relevant medical personnel and perioperative support systems. The system will have the ability to provide virtual perioperative readiness support system updates on an interactive ‘white board’ that is accessible to all personnel in the perioperative environment. PHASE III DUAL USE COMMERCIALIZATION: The value of this research will be to provide new knowledge and understanding to clinicians in military and civilian surgical settings, as well as to provide the perioperative team with an interactive monitoring system that will help and assist in managing the operating room. The ultimate goals are to facilitate and enhance perioperative team awareness, patient safety and logistical preparedness. REFERENCES: 1. Gawande, A. A., Thomas, E. J., Zinner, M. J., & Brennan, T. A. (1999). The incidence and nature of surgical adverse events in Colorado and Utah in 1992. Surgery, 126(1), 66-75. 2. Grazer, F. M. & de Jong, R. H. (2000). Fatal outcomes from liposuction: Census survey of cosmetic surgeons. Plastic and Reconstructive Surgery, 105, 436-445. 3. Hettiaratchy, S. (2001). Uses of error: Surgical mistakes. Lancet, 358, 887. Institute of Medicine. (1999). To error is human Building a safer health system. Washington, DC: National Academy Press. 4. JCAHO. (2001, December 5). A follow-up review of wrong site surgery. Sentinel Event Alert, 24. Safety-Centered Solutions. (2001, March 21). Surgical errors most frequent and costly medical errors. http:www.sccare.com/news/articles/pr-03-21-01.html (accessed 11/19/01). 5. Wanzel, K. R., Jamieson, C. G., & Bohnen, J. M. A. (2000). Complications on a general surgery service: Incidence and reporting. Canadian Journal Of Surgery, 43, (2), 113-117. KEYWORDS: Patient Safety, Surgical Settings, Adverse Events, Surgical Errors, Inpatient Surgery, Post Operative, Governance/Leadership, Process Implementation, Learning Environment A03-171 TITLE: Multimeric Protein Malaria Vaccine TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA, MRMC Objective: Design, create and test platforms that create multimeric proteins to improve the immunogenicity of the E.coli expressed protein vaccine candidate PfMSP1-42(FVO). Description: Malaria remains one of the most widespread of human pathogenic diseases in Africa, South America and Southeast Asia. Not only does this disease have a heavy impact on endemic populations, killing more than 1 million children annually, it also strongly affects US military peacekeeping and humanitarian missions in these areas. Apart from these needs, businessmen and tourists traveling to malaria endemic areas would also benefit from an antimalarial vaccine. The 42 kDa C-terminal fragment from Plasmodium falciparum Merozoite Surface Protein 1, known as PfMSP1-42 expressed in E. coli is safe and immunogenic, and when administered in conjunction with Freund’s adjuvant, it induces the strongest protective effect measured to date in an Aotus monkey challenge trial (manuscript in preparation). In one such trial four of six animals self-resolved their infections, and two suppressed parasitemia but required treatment for anemia. This result contrasts with another vaccine tested in the same trial based on the same protein produced in a baculovirus expression system (1). In this later group, only one of five animals self-resolved infection, two were treated for uncontrolled parasitemia, and the other two were treated for anemia. The reduced efficacy of the baculovirus-expressed antigen is probably due to protein glycosylation (1), which suppresses induction of immunity by this antigen. Other adjuvants did not induce protective immunity in our trial. MSP1 may physically exist in a multimeric state rather than a monomeric state on the merozoite surface, and thus an optimal vaccine may have to replicate this structure. This hypothesis has not been addressed in the peer reviewed literature, but it is supported by our observation that functional mAbs have increased binding strength to aggregated antigen compared to monomeric antigen, and that during chromatography the E. coli MSP1-42 (FVO) antigen appears to behave as a multimer. The current effort would develop multimeric PfMSP1-42 (FVO strain) expressed in E. coli, with the objective of improving immunogenicity and protection against malaria parasite infection. Improved immunogenicity would be measured by increased induction of functional antibodies that inhibit parasite growth (2) or inhibit proteolytic processing of malaria merozoite derived PfMSP1-42 in vitro (3), and would provide increased protection in the Aotus challenge model. Such antibodies would be induced by vaccination of animals with Freund’s adjuvant but more importantly with adjuvants that have strong potential for human use. Phase I: Develop a prototype of the biochemical components of the multimeric PfMSP1-42(FVO) vaccine. As a proof of principle of the biochemical part of the project, perform the initial characterization of the multimeric protein, and show that multimerization does not disrupt or make inaccessible the conformational “inhibitory” epitopes on MSP1-42 (FVO). Additionally provide a theoretical justification as to why this approach and compatible adjuvants might be considered safe for human use by the FDA. Phase II: Complete the development of the biochemical components of the multimeric PfMSP1-42(FVO) vaccine, and show that functional monoclonal antibodies that react with conformational epitopes on MSP1-42 (FVO) bind to the multimer with affinity that is at least equal to that of binding to monomer. Compare immunogenicity of monomeric and multimeric MSP1-42 given with Freund’s adjuvant and adjuvants that are suitable for human use. Success will be significant increases in induction of functional antibodies by multimeric antigen compared to monomeric antigen. The best performing adjuvants will be selected for an additional comparative study conducted in Aotus monkeys with P. falciparum challenge and will include Freund’s Adjuvant groups as the reference standard. Phase III: A successful malaria vaccine will have important application not only meeting DOD objectives, but also as vaccine strategies for residences of malaria endemic areas, as well as for business travelers and tourists. References: Stowers, AW, et. al. A recombinant vaccine expressed in the milk of transgenic mice protects Aotus monkeys from a lethat challenge with Plasmodium falciparum. Proc Natl Acad Sci 2002;99;339-44. [2] Haynes JD, Moch JK & Smoot DS. Erythrocytic malaria growth or invasion inhibition assays with emphasis on suspension culture GIA. Methods Mol Med 2002;72:535-54. [3] Blackman MJ. Purification of Plasmodium falciparum merozoites for analysis of the processing of merozoite surface protein-1. Methods Cell Biol 1994;45:213-20. KEYWORDS: Plasmodium falciparum, malaria, vaccine, Merozoite Surface Protein, Adjuvant, human use A03-172 TITLE: Angiogenesis Targeted Drug Development TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA,MRMC OBJECTIVE: Develop Novel Therapeutic Strategies for Pharmacological Intervention of Angiogenesis DESCRIPTION: Angiogenesis, the process by which new blood vessels are formed, is a complex sequence of events that is fundamental to many physiologic and pathologic processes such as tumor growth, and vascular and chronic inflammatory diseases. Generation of new blood vessels plays dual but opposing roles in biology. While stimulating angiogenesis may be beneficial in the treatment and healing of battlefield injuries, surgical wounds and ulcers (1), inhibiting excessive blood vessel growth may be critical to delaying or halting the progression of diseases such as cancer (2), diabetes retinopathy, rheumatoid arthritis and inflammatory bowel disease. With the identification of a number of proangiogenic molecules such as the vascular endothelial cell growth factor (VEGF), the fibroblast growth factors (FGF) and other inhibitors of angiogenesis such as angiostatin and endostatin, it is recognized that therapeutic intervention with vasculature formation offers unique drug targeting opportunities for the treatment of cancer, heart and vascular diseases, and chronic inflammation (3). Agents/drugs that stimulate angiogenesis may also find immediate military application in the treatment of injuries by reducing the morbidity and facilitating a shorter course of rehabilitation for soldiers deployed in the battlefield. The challenge remains with identifying specific molecular targets in the angiogenesis process and applying technologies to design and develop various agent/drug candidates directed toward those molecular targets. Agents/drugs that either stimulate or inhibit angiogenesis may serve as important pharmacological tools for intervening during the healing process or disease progression, respectively (3). The goal of this solicitation is to develop new agent/rug candidates using the knowledge of molecular targets involved in the angiogenesis process. Applying new technologies such as phase display, serial analysis of gene expression (SAGE), and systematic evolution of ligands by exponential enrichment (SELEX) may be useful in this endeavor. Phase I: Identify several new agent/drug candidates targeted toward angiogenesis. The methodology to identify molecular targets, and the rationale for designing the effector molecular entities such as small molecules, peptides, oligonucleotides, ribozymes, antibodies, drug conjugates, immunological agents etc, should be elaborated. Phase II: Initiate evaluation of several agent/drug candidates in biological assays and preclinical animal models. Phase III: Perform additional experiments with the lead targeted agent(s)/drug(s) to prepare for FDA review, and approval, and subsequent commercialization. The molecular-targeted agent/drugs identified and the technologies developed should yield many advances important not only to the civilian but also to the military community. Identifying and developing agents/drugs that stimulate new blood vessel formation and enhance the oxygenation of damaged tissues should have an enormous impact on wound healing and the treatment of injuries such as surgical wounds and fractures. REFERENCES: 1. Wynendale, W, van Oosterom AT, Pawinski, A, de Bruijn, EA, and Maes, RA. 1998. Angiogenesis: Possibilities for Therapeutic Interventions. Pharm World Sci 20(6): 225-35. 2. Folkman, J. 2002. Role of Angiogenesis in Tumor Growth and Metastasis. Sem Oncol, Dec;29 (6 Suppl 16):15-18. 3. Molema, G. 2002. Tumor Vasculature Directed Drug Targeting: Applying New Technologies and Knowledge to the Development of Clinically Relevant Therapies. Pharm. Res. 19 (9), 1251-1258. KEYWORDS: Angiogenesis, drug targeting, vascularization, wound healing. A03-173 TITLE: Amplification of Proteins in Body Fluids for Early Detection of Biological Warfare Exposure TECHNOLOGY AREAS: Chemical/Bio Defense ACQUISITION PROGRAM: DSA, MRMC OBJECTIVE: The overall objective is to detect very low levels of multiple pathogen- specific proteins (or perhaps host responses) very quickly after exposure. In the case of B. anthracis exposure, various proteins (lethal factor, edema factor, etc) are released but the quantity is low until onset of serious disease consequences. Proteins studied should be associated with a BW agent from the CDC "A" list. DESCRIPTION: Effective prophylaxis and treatment for infections caused by biological threat agents rely upon early diagnosis and rapid initiation of therapy. However, most methods for identifying pathogens or infectious agents in body fluids and tissues require that the pathogen proliferate to a detectable level, which might take days to weeks, thereby delaying diagnosis and treatment and putting the patient at increased risk of morbidity and mortality. In an effort to detect such exposure more rapidly (within hours), during the prodromal or even prepatent stages, we found that certain gene expression patterns were unique to each pathogen and that other gene changes occurred in response to multiple agents, perhaps relating to the eventual course of illness. Although gene expression patterns can serve as diagnostic markers for predicting the course of impending illness and may lead to new stage-specific therapeutic strategies to ameliorate the devastating effects of exposure to biological threat agents, it may be useful to identify either pathogen or host-specific proteins as early markers of exposure. PHASE I: Identify specific binding entities (aptamers, antibodies, etc) to 3 very low level proteins. Develop a method to encorporate distinguishing amplifiable material (such as DNA) into the binding entities, specifically amplify only the tagged entities bound to the proteins of interest, standardize appropriate amplification methods of those proteins. Our laboratory will provide body fluids from animals studies of exposure to selected biological threat agents. PHASE II: Utilizing the technology developed in Phase I, apply the principle for development of a multiplex/high throughput assay to be able to differentiate among ~20 proteins in a single mix, to include those proteins that can provide even greater certainty that exposure was due to the biothreat agent rather than to a "common" infectious agent. Our laboratory could provide body fluids from animal studies of exposure to selected biological threat agents in order to further expand the range of proteins that encompass the prodromal period through the early stages of illness. Selection of specific proteins will be justified by bioinformatics and will be submitted for approval. Qualifications: a) The contractor will have the expertise to develop protocols for constructing and attaching discriminating tags (such as DNA) to the aptamers/antibodies, etc, that will bind specifically to protein moieties. b) Amplification of the protein-aptamer/antibody-TAG complex will have to be optimized, and turned into highthroughput assays. c) Scientists at the company/contractor will have vast experience in the fields of molecular biology, multiplexing/highthroughput technology and proteomics. d) Bioinformatics knowledge and capabilities will also contribute to the project’s challenges. PHASE-III: DUAL USE APPLICATIONS: The information heavily relies on identification of proteins that will discriminate biothreat from "common" illnesses and therefore is not restricted to exposure of biological agents but is applicable to any infectious or common illnesses. The information obtained from these studies will be used to design a diagnostic tool for detection of infectious diseases, common inflammatory illnesses and exposure to biological threat agents. This type of a rapid and sensitive diagnostic tool is much needed in today's world and will be of great value commercially to both the defense and civilian community. REFERENCES: 1. Das, R., Mendis, C., Yan, Z., Neill, R., Boyle, T. and Jett, M. (1998) Alterations in Gene Expression show unique patterns in response to toxic agents. In Proceeding of the 21st Army Science Conference, F-P9. 2. Ionin, B., Foley, J., Lee, D., Das, R., and Jett, M. (1999). Differential gene expression pattern induced by staphylococcal enterotoxin B in human kidney cells. Abstract #443. FASEB Journal 13:A1407. 3. Das et al (2002) Host gene expression profiles in peripheral blood mononuclear cells: Detection of exposure to biological Threat Agents. In Proceedings of the 23rd Army Science Conference, KO-04. KEYWORDS: proteomics, aptamers, amplification methods, host response profiles A03-174 TITLE: Advancing Training Techniques of Non-Invasive 3-Dimensional Ultrasound Sound Technologies for both Diagnostic and Therapeutic Applications TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA, MRMC OBJECTIVE: Currently, technology advancements are focused on reducing the cube and weight of current ultrasound devices providing easy to use high frame rate ultrasound scanners through improved transducer array designs that offer for both three-dimensional diagnostic imaging and therapeutic applications in diagnosing and treating blunt and/or ballistic trauma. These efforts have taken into consideration the infrastructure necessary to provide both ruggedization, as well as configuration to military field sites. However, the human-machine interface on the battlefield has not been explored sufficiently to best determine ultrasound’s potential impact as a force multiplier providing tertiary level health care across the echelons of care. Therefore, this proposal is to develop training techniques for using ultrasound imagers due to the difficulty of reading diagnostic ultrasound scans and thus its limited utility in far-forward conditions in which lower-skilled medics would have to acquire and transmit these scans to higher-skilled clinicians. DESCRIPTION: It is desired to have a visual anatomic guidance system that will provide military personnel expert assistance in performing diagnostic and therapeutic medical ultrasound in injured or sick personnel in forward echelons. The recent availability of hand-held diagnostic ultrasound devices have limited utility because the difficulty of training medics to obtain and interpret images of diagnostic quality. A goal of this solicitation is to mitigate the training requirement by providing active computer assistance that visually displays to the medic how the image plane moves toward the specified anatomic location as s/he manipulates the ultrasound probe over the combatant's body. The system should also enable experts in a remote telemedicine facility who are reviewing the initial images to direct the medic in acquiring additional images in specified anatomical locations to facilitate diagnosis and triage. The same display could also be used to guide therapeutic ultrasound for hemostasis. PHASE I: The proposal for Phase I should focus on a Research and Development Design Plan to include commercial viability and whether a completely new device or a modification of current technology will be most cost effective. Conduct a thorough technology search to to determine availablity of commercial devices/products requiring modification versus the need to develop an entirely new product prototype. During Phase I, any requirement for the use of animal and/or human models will be identified and local IRB and government RCQ protocol approvals will be granted prior to any clinincal trials. PHASE II: In this phase an actual prototype would be developed at the breadboard or work bench level. PHASE III DUAL-USE COMMERCIALIZATION: This phase will pertain to completion of a prototype at the beta level and a commercialization plan for a commercially viable product to include FDA clearance and cost/benefit analysis. Cost sharing between the government and the commercial sector will only maximize funding and viability of this effort. REFERENCES: 1) Sapin P M, Schroeder K M, Gopal A S, Smith MD, King D L. Three-dimensional echocardiography: Limitations of apical biplane imaging for measurement of left ventricular volume. J Am Soc Echocardiogr 1995;8:576-584. 2) King D L, Harrison M R, King D L, Jr, Gopal A S, Martin R P, DeMaria A N. Improved reproducibility of left atrial and left ventricular measurements by guided three-dimensional echocardiography. J Am Coll Cardiol 1992;20:1238-1245. 3) Martin R W, Vaezy S, Kackowski P, Keilman G, Carter S, Caps M, et al. Hemostasis of punctured vessels using Doppler-guided high-intensity ultrasound. Ultrasound Med Biol 1999;25:985-990. KEYWORDS: ultrasonography, non-invasive, diagnostic imaging, therapeutic, hemostasis, transcranial ultrasound, hand-held A03-175 TITLE: Portable Test for Detection of Viruses in Arthropod Vectors TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA, MRMC STO: STO IV.ME.2000.08 Replacement of the Standard Military Insect Repellent OBJECTIVE: To produce a device for rapid, portable, and cheap detection of dengue and other viruses in arthropod vectors. DESCRIPTION: A membrane-bound wicking assay requiring no refrigeration that produces accurate (sensitivity > 95%; specificity > 95%) identification of dengue (either serotype specific or not) in individual or pooled (at least 10) vector mosquitoes. Application of similiar technology in separate assays for Japanese encephalitis, Ross River virus, Rift Valley fever virus. 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