Rector & Visitors Of The University Of Virginia

CANCER CENTER SUPPORT GRANT

MULTIMODAL DEVELOPMENTAL NEUROGENETICS OF FEMALES WITH ASD

CARES ACT HIGHER ED EMERGENCY RELIEF FUND PART 2 FOR THE UNIVERSITY OF VIRGINIA

CARES ACT GRANT US DEPT OF EDUCATION FOR THE UNIVERSITY OF VIRGINIA

PANNEXIN CHANNELS IN VASCULAR PHYSIOLOGY & INFLAMMATION

DOPAMINE/ANGIOSTENSIN RECEPTORS IN GENETIC HYPERTENSION

THE STROKE HYPERGLYCEMIA INSULIN NETWORK EFFORT (SHINE) TRIAL

CARES ACT - RADFORD UNIVERSITY

CELL MIGRATION CONSORTIUM

PROVISION OF CLINICAL DATA TO SUPPORT A NATIONWIDE COVID-19 COHORT COLLABORATIVE

DESCRIPTION:THIS AGREEMENT PROVIDES FUNDING UNDER THE INFLATION REDUCTION ACT (IRA) TO THE UNIVERSITY OF VIRGINIA. SPECIFICALLY, THE PROJECT WILL ALLOW THE UNIVERSITY OF VIRGINIA, WORKING IN UTQIAGVIK, AK, TO IMPROVE STORM- AND MELT-WATER INFRASTRUCTURE AND MANAGEMENT; PRESERVE INUPIAT TRADITIONS AND CULTURAL SITES; ENHANCE BARROW LOCAL UTILITIES' READINESS AND PREPAREDNESS, AND STRENGTHEN LOCAL CAPACITY; IMPROVE RESIDENTIAL SANITATION BY CONNECTING UNSERVICED HOMES TO MODERN WATER/SEWER SYSTEMS; AND PROTECT THE COMMUNITY'S DRINKING WATER LAGOON. ACTIVITIES:THE ACTIVITIES INCLUDE A COMPREHENSIVE DRAINAGE STUDY OF THE CITY TO INFORM INFRASTRUCTURE UPGRADES AND SUSTAINABLE WATER, SNOW AND PERMAFROST MANAGEMENT, AND IMPLEMENTING IDENTIFIED UPGRADES TO BETTER RESPOND TO INCREASED PRECIPITATION, FLOODING AND ASSOCIATED PERMAFROST DEGRADATION; INSTALLING THERMOSIPHONS IN TRADITIONAL ICE CELLARS WITH UPGRADED DRILLING EQUIPMENT, AND INSTALLING AND IMPROVING DRAINAGE AND RESTORING DISTURBED TUNDRA VEGETATION TO REDUCE FLOODING AT THE COMMUNITY'S CEMETERY; UPGRADING OR EXPANDING CRITICAL HEAVY-DUTY MAINTENANCE VEHICLES THAT ARE BETTER EQUIPPED FOR THE ARCTIC CONDITIONS TO ENHANCE THE LOCAL UTILITY'S READINESS AND PREPAREDNESS, AND STRENGTHENING LOCAL WORKFORCE CAPACITY WHILE REDUCING GREENHOUSE GAS EMISSIONS AND OCCUPATIONAL HAZARDS, AND CREATING AND EXPANDING PROGRAMS THAT BUILD KNOWLEDGE AND JOBS IN SUSTAINABLE WATER, SNOW AND PERMAFROST MANAGEMENT; CONNECTING UNSERVICED HOMES TO MODERN WATER/SEWER SYSTEMS, ELIMINATING OR REDUCING THE USE OF HONEY BUCKETS, HUMAN WASTE SPILLAGE, AND ASSOCIATED ENVIRONMENTAL AND HUMAN HEALTH RISKS; AND PROTECTING THE COMMUNITY'S DRINKING WATER LAGOON BY CONDUCTING COMPREHENSIVE FEASIBILITY STUDIES FOR PER-AND POLYFLUOROALKYL (PFAS) SUBSTANCES REMEDIATION/REMOVAL AND ALGAE BLOOM MITIGATION. SUBRECIPIENT:THE SUBAWARD WITH BARROW UTILITIES AND ELECTRIC COOPERATIVE, INC. (BUECI) WILL COVER WATER AND SEWER CONNECTIONS FOR UNSERVICED HOMES, UPGRADE OF HEAVY-DUTY VEHICLES TO IMPROVE READINESS AND REDUCE GREENHOUSE GAS EMISSIONS AND OCCUPATIONAL HAZARDS, FEASIBILITY STUDIES FOR PER- AND POLYFLUOROALKYL SUBSTANCES (PFAS) AND ALGAL GROWTH MITIGATION IN THE COMMUNITY DRINKING WATER LAGOON, MATERIAL COSTS TO STABILIZE SUBSIDING BUECI STRUCTURES DUE TO PERMAFROST DEGRADATION, AND CONTINUING EDUCATION FOR BUECI LEADERSHIP AND MEMBERS. THE SUBAWARD WITH NORTH SLOPE BOROUGH (NSB) WILL COVER IMPROVEMENTS TO DRAINAGE INFRASTRUCTURE AND COVER MATERIALS, AND CIVIL WORKS TO STABILIZE PERMAFROST AND REDUCE MELTWATER FLOODING, IMPROVE PUMPING OPERATION OF NEWLY ADDED SEWER TANKS, CONDUCT A COMMUNITY-WIDE DRAINAGE ASSESSMENT AND PRODUCE AN ACTION PLAN FOR STORMWATER/MELTWATER MANAGEMENT, CONTINUING EDUCATION FOR NSB LEADERSHIP AND PUBLIC WORKS OPERATORS, AND INTERNSHIPS / APPRENTICESHIPS BETWEEN DEPARTMENT OF PUBLIC WORKS AND I#7735;ISA#289;VIK COLLEGE'S WORKFORCE DEVELOPMENT PROGRAM. THE SUBAWARD WITH THE CITY OF UTQIA#289;IVK (COU) WILL ALLOW FOR IMPROVEMENTS TO THE CULTURAL SITE OF IMAIQSAUN CEMETERY AND COVER DRAINAGE DESIGN, DRAINAGE INSTALLATION AND EXPANSION, IMPROVED SNOW AND MELTWATER MANAGEMENT, GRAVESITE REVEGETATION, AND REPATRIATION OF GRAVESITES INCLUDING NEW COFFINS AND CULTURAL RE-BURIAL CEREMONY. THE SUBAWARD WITH THE INUPIAT COMMUNITY OF ARCTIC SLOPE (ICAS) WILL COVER THE PURCHASE AND SHIPPING OF THERMOSIPHONS AND AN AUGER DRILL TO BE USED FOR THEIR ICE CELLAR PRESERVATION PROJECT. THE SUBAWARD WITH THE ARCTIC INFRASTRUCTURE DEVELOPMENT CENTER AT THE UNIVERSITY OF ALASKA FAIRBANKS WILL ALLOW THE AIDC TO PROVIDE ON-SITE ASSESSMENTS, AND REVIEW AND CONSULTATION ON FEASIBILITY STUDIES AND ICE CELLAR PRESERVATION. OUTCOMES:THE ANTICIPATED DELIVERABLES INCLUDE INCLUDE A STORM(MELT)WATER INFRASTRUCTURE AND MANAGEMENT STUDY/ACTION PLAN, AND IMPLEMENTATION OF THE RECOMMENDATIONS IDENTIFIED IN THE PLAN; ACQUISITION OF THERMOSIPHON INSTALLATION EQUIPMENT AND INSTALLATION OF THERMOSIP

TARGETED SPHINGOLIPID METABOLISM FOR TREATMENT OF AML

DESCRIPTION:THIS AGREEMENT PROVIDES FUNDING UNDER THE INFLATION REDUCTION ACT (IRA) TO RECTOR AND VISITORS OF THE UNIVERSITY OF VIRGINIA (UVA). SPECIFICALLY, THE PROJECT WILL IMPLEMENT CLIMATE RESILIENCE PLANNING IN TEN COMMUNITIES THROUGH SOUTHWEST (APPALACHIAN) VIRGINIA AND ADVANCE PROJECTS THAT REDUCE POLLUTION AND CARBON EMISSIONS WHILE SIMULTANEOUSLY ADVANCING CRITICAL COMMUNITY NEEDS: CLIMATE-RESILIENT AFFORDABLE HOUSING, ENERGY-EFFICIENT AND CARBON-NEUTRAL CHILDCARE AND WORKFORCE TRAINING, AND CLIMATE-RESILIENT GATHERING SPACES THAT DOUBLE AS COMMUNITY CAPACITY BUILDING SPACES AND HEALTHCARE ACCESS POINTS. ACTIVITIES:THE ACTIVITIES INCLUDE 1) PARTNER WITH UNITED WAY OF SOUTHWEST VIRGINIA/ENDLESS OPPORTUNITIES (UW/EO), BUCHANAN COUNTY, AND DICKENSON COUNTY TO SUPPORT ELECTRIC VEHICLE TRANSPORTATION OPTIONS AS WELL AS EV CHARGING UNITS; 2) PARTNER WITH BUCHANAN COUNTY AND THE SOUTHERN GAP DEVELOPMENT AREA TO BUILD ENERGY-EFFICIENT, HEALTHY AND CLIMATE-RESILIENT WORKFORCE HOUSING; 3) PARTNER WITH UW/EO TO INCREASE THE ENERGY EFFICIENCIES OF THEIR WORKFORCE AND CHILDCARE CENTERS; 4) PARTNER WITH THE UW/EO TO SUPPORT THE INSTALLATION OF COMMUNITY SOLAR ON THEIR AFFILIATED WORKFORCE DEVELOPMENT AND CHILDCARE CENTERS; 5) PARTNER WITH DICKENSON COUNTY AND THE TOWN OF HAYSI TO DEVELOP A COMMUNITY RESILIENCE HUB THAT CAN ALSO BE A CENTER FOR COMMUNITY ENGAGEMENT AND CAPACITY; 6) PARTNER WITH HEALTHY APPALACHIA INSTITUTE TO RENOVATE 10 LOCATIONS TO DOUBLE AS COMMUNITY RESILIENCE HUBS AND HEALTHCARE OUTPOSTS; 7) CONDUCT FEASIBILITY STUDIES OF ADVANCING MIXED RENEWABLE ENERGY DEVELOPMENTS ON BROWNFIELD SITES IN BUCHANAN AND DICKENSON COUNTIES; AND 8) PARTNER WITH JAMES MADISON UNIVERSITY'S CENTER FOR THE ADVANCEMENT OF SUSTAINABLE ENERGY AND THE NETWORK OF LOCAL COMMUNITY COLLEGES TO ADVANCE CLEAN ENERGY CAREER DEVELOPMENT. SUBRECIPIENT:SUBAWARD OF $4,594,245 TO UNITED WAY (FORMERLY EO) FOR THE DECARBONIZATION AND CARBON MITIGATION OF CHILDCARE CENTERS. THIS PROJECT INCLUDES SOLAR INSTALLATION AND ENERGY EFFICIENCY UPGRADES TO CHILDCARE FACILITIES, OUTDOOR CLASSROOMS, AND BUILDING OUT PROGRAMMING FOR THE RENEWABLE ENERGY SECTOR WORKFORCE. SUBAWARD OF $1,757,708 TO DICKENSON COUNTY FOR BUILDING A CLIMATE RESILIENCE HUB IN THE TOWN OF HAYSI OUTSIDE OF THE FLOODPLAIN. THIS PROJECT INCLUDES ENGINEERING AND ARCHITECTURAL DESIGN AND PERMITS, CONSTRUCTION OF THE FACILITY, AND INSTALLATION OF EV FAST CHARGER. SUBAWARD OF $4,847,841 TO BUCHANAN COUNTY FOR THE BUILDING OF CLIMATE RESILIENT HOUSING IN SOUTHERN GAP OUTSIDE OF THE FLOODPLAIN. THIS PROJECT INCLUDES CONSTRUCTION EXTENSION OF INFRASTRUCTURE (WATER, SEWER, POWER AND TELCOM) TO SUBDIVISION LOTS, CONSTRUCTION OF INTERIOR ROADWAYS AND WALKWAYS, CONSTRUCTION OF TWO SINGLE FAMILY DWELLING UNITS, CONSTRUCTION OF MULTI-FAMILY TOWN HOUSE RENTAL UNITS, AND AN EV CHARGING STATION AT THE REGIONAL OFFICE PARK OFFICE BUILDING. SUBAWARD OF $132,000 TO VIRGINIA TECH FOR A COMMUNITY ENGAGEMENT PROJECT ON CLIMATE RESILIENCE STRATEGIC PLANNING. THIS COMMUNITY-BASED CLIMATE RESILIENCE PLANNING PROCESS INVOLVES THE RAFT (RESILIENCE ADAPTATION FEASIBILITY TOOL). SUBAWARD OF $1,973,797 TO JAMES MADISON UNIVERSITY (JMU) CENTER FOR THE ADVANCEMENT OF SUSTAINABLE ENERGY FOR DEVELOPING CLEAN ENERGY CAREERS. THIS PROJECT INCLUDES BUILDING OR EXPANDING A REGIONAL ENERGY WORKFORCE HUB IN ABINGDON IN PARTNERSHIP WITH VIRGINIA HIGHLANDS COMMUNITY COLLEGE (VHCC) AND NEW RIVER COMMUNITY COLLEGE (NRCC) TO DEVELOP GREEN JOBS PIPELINE, FROM ENTRY LEVEL INSTALLATION, TO PROJECT MANAGEMENT, TO ADVANCED MANAGERIAL AND LEADERSHIP IN RENEWABLE ENERGY CAREERS. PROGRAMS SUPPORTED AT THE REGIONAL HUB WILL ADDRESS RENEWABLE ENERGY SKILL DEVELOPMENT FOR K-12 STUDENTS, TEACHER TRAININGS FOR K-12 FACULTY, RENEWABLE ENERGY KIT AND CURRICULUM DISTRIBUTION, SUMMER CAMPS, AND SUPPORT FOR KIDWIND CHALLENGE TEAMS. OUTCOMES:THE ANTICIPATED DELIVERABLES INCLUDE SOLAR INSTALLATION, ENERGY EFFICIENCY UPGRADES,

NEW: CENTER FOR CATALYTIC HYDROCARBON FUNCTIONALIZATION -- EFRC; PI - BRENT GUNNOE

ESTABLISHED STATUS EPILEPTICUS TREATMENT TRIAL (ESETT)

BASIC CARDIOVASCULAR RESEARCH TRAINING GRANT

STRUCTURAL DYNAMICS OF PRESYNAPTIC MEMBRANE FUSION

HCMR NOVEL MARKERS OF PROGNOSIS IN HYPERTROPHIC CARDIOMYOPATHY

GENERAL CLINICAL RESEARCH CENTER

ELECTRON INTERACTIONS WITH NUCLEI

APPALACHIAN SUPPORT FOR SPECIALIZED EDUCATION TRAINING (ASSET)

KIDNEY DEVELOPMENT CELL FATE AND PRECURSORS OF DISEASE IN THE YOUNG AND ADULT

CLINICAL ACCEPTANCE OF THE ARTIFICIAL PANCREAS: THE INTERNATIONAL DIABETES CLOSED LOOP (IDCL) TRIAL

SIGNALING AND PROGRESSION IN PROSTATE CANCER

IMMUNOBIOLOGY OF TRANSFUSION

PROTEIN SEQUENCING BY TANDEM MASS SPECTROMETRY

SYSTEMS ANALYSIS OF STRESS-ADAPTED CANCER ORGANELLES (SASCO) CENTER - PROJECT SUMMARY/ABSTRACT ONCOGENE ACTIVATION IS MODULATED BY NORMAL SUBCELLULAR COMPARTMENTS THAT EXECUTE SPECIALIZED FUNCTIONS RELATED TO HALLMARK CANCER PHENOTYPES. THESE ORGANELLES MUST ADAPT TO ONCOGENIC STRESS IN ORDER FOR TUMORS TO INITIATE AND PROGRESS, BUT THERE IS LITTLE TO NO SYSTEMS-LEVEL UNDERSTANDING OF HOW SUCH ADAPTATIONS OCCUR AND WHAT VULNERABILITIES MIGHT BE CREATED. THE SYSTEMS ANALYSIS OF STRESS-ADAPTED CANCER ORGANELLES (SASCO) CENTER AT THE UNIVERSITY OF VIRGINIA WILL ADDRESS THIS CHALLENGE BY MECHANISTIC MODELING OF ORGANELLAR PROCESSES THAT ITERATES WITH QUANTITATIVE EXPERIMENTS IN DISEASE-RELEVANT CELL CULTURES AND PRIMARY TUMORS. THE WORKING SASCO CENTER HYPOTHESIS IS THAT ORGANELLE-SPECIFIC ADAPTATION TO ONCOGENIC STRESS OCCURS THROUGH A FEW CRITICAL BOTTLENECKS, WHICH BECOME IDENTIFIABLE ONCE THE RELEVANT SIGNALING, METABOLIC, AND TRANSPORT PATHWAYS HAVE BEEN PROPERLY INTEGRATED. THE CENTER BRINGS TOGETHER 14 INVESTIGATORS WITH PRIMARY AND COLLABORATIVE TRACK RECORDS IN CANCER BIOLOGY, SYSTEMS BIOLOGY, GENETICALLY ENGINEERED MOUSE MODELS OF CANCER, AND CLINICAL PRACTICE. THREE RESEARCH PROJECTS AND ONE SHARED RESEARCH CORE WILL PURSUE A COMMON RESEARCH STRATEGY, WHICH LEVERAGES MECHANISTIC MODELS TO TEST COMPETING ALTERNATIVE HYPOTHESES ABOUT HOW ORGANELLES ADAPT TO STRESSES FROM PROXIMAL ONCOGENES THAT DRIVE SPECIFIC TYPES OF CANCER. THE PROJECTS ARE ORGANIZED HIERARCHICALLY AS ORGANELLE STRESSES DOWNSTREAM OF PROLIFERATION-INDUCING ONCOGENES. PROJECT 1 WILL EXAMINE THE CHROMOSOME PASSENGER COMPLEX AND ITS REGULATED PHASE SEPARATION DURING METAPHASE AS AN ORGANELLE THAT SENSES AND REPAIRS SPINDLE DEFECTS TO SUPPRESS BREAST CANCER ANEUPLOIDY DRIVEN BY MITOTIC TRANSCRIPTION FACTORS. PROJECT 2 WILL EVALUATE THE METABOLIC CONSEQUENCES OF CHRONIC MITOCHONDRIAL FRAGMENTATION CAUSED BY MUTANT KRAS IN PRIMARY COLORECTAL CANCERS AND SECONDARY LIVER METASTASES. PROJECT 3 WILL INVESTIGATE LOCALIZED SIGNAL-TRANSDUCTION REBALANCING AS A MECHANISM FOR ALLEVIATING PLASMA-MEMBRANE STRESS CAUSED BY EGFR AMPLIFICATION IN GLIOBLASTOMA. ALL RESEARCH PROJECTS WILL RELY ON THE HIGH-CONTENT IMAGING & ANALYSIS CORE TO OBTAIN ITERATIVE MULTICHANNEL IMMUNOFLUORESCENCE DATA WITH ORGANELLE-LEVEL RESOLUTION AND QUANTIFICATION. THE SASCO OUTREACH CORE AMPLIFIES ONGOING PROGRAMS AT THE UNIVERSITY OF VIRGINIA TO PROVIDE SUMMER RESEARCH EXPERIENCES FOR UNDERGRADUATES AND FACULTY SCHOLARS FROM HISTORICALLY UNDERREPRESENTED BACKGROUNDS AS WELL AS INTRODUCTORY SYSTEMS BIOLOGY MODELING MATERIALS FOR CLINICIANS ACROSS THE COMMONWEALTH OF VIRGINIA. THE SASCO CENTER WILL THUS CREATE A NATIONAL HEADQUARTERS FOR SUBCELLULAR CANCER SYSTEMS BIOLOGY WITHIN THE BROADER CANCER SYSTEMS BIOLOGY CONSORTIUM.

INFECTIOUS DISEASES TRAINING PROGRAM

EPIDEMIOLOGY OF OVARIAN CANCER IN AFRICAN-AMERICAN WOMEN

MODULAR BIO-BEHAVIORAL CLOSED-LOOP CONTROL OF TYPE 1 DIABETES

CELEBRATING THE 250TH ANNIVERSARY OF THE UNITED STATES OF AMERICA: CREATING AND SUSTAINING ACCESS TO FOUNDING ERA / EARLY REP [THE COLLABORATIVE PROJECT, CELEBRATING THE 250TH ANNIVERSARY OF THE UNITED STATES OF AMERICA: CREATING AND SUSTAINING ACCESS TO FOUNDING ERA / EARLY REPUBLIC PRIMARY SOURCES, REPRESENTS A TIMELY AND TRANSFORMATIVE INVESTMENT IN RESEARCHING, EDITING, PUBLISHING, AND PROMOTING THE DOCUMENTARY HERITAGE OF THE FOUNDING ERA AND EARLY REPUBLIC. WITH SUPPORT FROM THIS GRANT, THE UNIVERSITY OF VIRGINIA AND ITS PARTNERS WILL ACHIEVE FOUR CRITICAL OUTCOMES: INCREASING OUR UNDERSTANDING OF THE FOUNDING ERA AND EARLY REPUBLIC; REFINING AND STRENGTHENING THE TECHNICAL AND INSTITUTIONAL INFRASTRUCTURE; CREATING A DYNAMIC, FREELY-ACCESSIBLE WEBSITE; AND PROVIDING HANDS-ON TRAINING AND KNOWLEDGE-SHARING OPPORTUNITIES. BY UNITING EDITORIAL EXPERTISE, TECHNOLOGICAL INNOVATION, AND PUBLIC OUTREACH, THIS INITIATIVE ENSURES THAT THE IDEAS, VOICES, AND EXPERIENCES THAT SHAPED THE FOUNDING OF THE UNITED STATES OF AMERICA REMAIN AVAILABLE, UNDERSTANDABLE, AND ENDURING FOR FUTURE GENERATIONS.]

MEDICAL SCIENTIST TRAINING PROGRAM

CANCER RESEARCH TRAINING IN MOLECULAR BIOLOGY

KETAMINE ADD-ON FOR ESTABLISHED STATUS EPILEPTICUS TREATMENT TRIAL (KESETT) - THE KETAMINE ADD-ON THERAPY FOR ESTABLISHED STATUS EPILEPTICUS TREATMENT TRIAL (KESETT) IS A PHASE III RANDOMIZED, DOUBLE-BLIND CLINICAL TRIAL TO TEST WHETHER KETAMINE (KET) (1 OR 3 MG/KG) ADDED TO THE STANDARD THERAPY, LEVETIRACETAM (LEV), IS MORE EFFECTIVE THAN LEVETIRACETAM (60 MG/KG) ALONE IN TREATING STATUS EPILEPTICUS AFTER BENZODIAZEPINES HAVE FAILED. GENERALIZED CONVULSIVE STATUS EPILEPTICUS (SE) IS A DANGEROUS BUT COMMON NEUROLOGIC EMERGENCY; IT CAN CAUSE RESPIRATORY DEPRESSION AND PERMANENT BRAIN DAMAGE. BENZODIAZEPINES ARE AN EFFECTIVE FIRST-LINE THERAPY, BUT APPROXIMATELY ONE-THIRD OF CHILDREN AND 40% OF ADULTS DO NOT RESPOND. PATIENTS WHO FAIL BENZODIAZEPINES ARE IN ESTABLISHED STATUS EPILEPTICUS. THEY ARE TREATED WITH SECOND-LINE AGENTS SUCH AS LEVETIRACETAM, WHICH SUCCESSFULLY TERMINATES STATUS EPILEPTICUS IN ONLY 47% OF SUBJECTS. WE PROPOSE THAT ADDING KETAMINE TO LEVETIRACETAM WILL INCREASE EFFICACY TO 62%. PRECLINICAL AND CLINICAL EVIDENCE SUPPORTS THIS TRIAL. KETAMINE, AN NMDA RECEPTOR ANTAGONIST, TERMINATES BENZODIAZEPINE REFRACTORY SE IN EXPERIMENTAL ANIMALS. NMDA RECEPTOR ACTIVATION TRIGGERS SELF-REINFORCING SEIZURE MECHANISMS UNDERLYING SE. IT ABROGATES INHIBITORY PLASTICITY, PREVENTS EXCITOTOXICITY AND NEURONAL DEATH, AND PREVENTS EPILEPTOGENESIS ACCOMPANYING SE IN EXPERIMENTAL ANIMALS. RECENT CLINICAL STUDIES IN CHILDREN AND ADULTS SHOWED THAT KETAMINE TERMINATED ESTABLISHED STATUS EPILEPTICUS IN 23 OF 24 SUBJECTS. KETAMINE IS USED EXTENSIVELY IN EMERGENCY SETTINGS FOR SEDATION, INTUBATION, AGITATION, AND PAIN MANAGEMENT; IT IS ON THE WHO ESSENTIAL MEDICATIONS LIST BECAUSE IT IS SAFELY USED EXTENSIVELY. CLINICIANS USE IT EFFECTIVELY TO TREAT REFRACTORY AND SUPER-REFRACTORY SE, AND MANY EXPERTS RECOMMEND IT. ED PHYSICIANS HAVE USED IT FOR DECADES FOR PROCEDURAL SEDATION. WE PROPOSE TO TEST 1 AND 3 MG/KG KETAMINE DOSES BASED ON RECENT HUMAN STUDIES, EXTENSIVE PHARMACOKINETIC MODELING, ANIMAL-TO-HUMAN DOSE CONVERSION AS SUGGESTED BY THE FDA, AND DATA ON THE SAFETY OF KETAMINE. OUR OVERALL HYPOTHESIS IS THAT KETAMINE ADDED TO LEV WILL IMPROVE THE OUTCOME OF ESTABLISHED STATUS EPILEPTICUS COMPARED TO TREATMENT WITH LEVETIRACETAM ALONE BY CLINICALLY MEANINGFUL 15%. WE WILL TEST THIS HYPOTHESIS BY ACCOMPLISHING THE FOLLOWING SPECIFIC AIMS IN A BAYESIAN-ADAPTIVE RANDOMIZED CLINICAL TRIAL: AIM 1: DETERMINE WHETHER PARTICIPANTS RANDOMIZED TO LEVETIRACETAM +3 MG/KG KETAMINE OR LEVETIRACETAM +1 MG/KG KETAMINE WILL HAVE MORE DESIRABLE OUTCOMES THAN THOSE RECEIVING LEVETIRACETAM +PLACEBO. WE RANK THE OUTCOMES ON A SCALE RANGING FROM 1 TO 5. AIM 2: TO ENSURE THAT THE TRIAL IS INFORMATIVE FOR TREATING ESTABLISHED STATUS EPILEPTICUS IN CHILDREN BY DESCRIBING THE EFFECTIVENESS AND RATE OF ADVERSE REACTIONS OF THESE DRUGS. AIM 3: MEASURE DIFFERENCES BETWEEN TREATMENT ARMS IN SECONDARY OUTCOMES. THIS TRIAL CAN CHANGE THE TREATMENT PARADIGM FOR SE BY SUPPLEMENTING CURRENT SECOND-LINE AGENTS WITH KETAMINE TO IMPROVE THE TIMELINESS OF SEIZURE TERMINATION.

BASIC AND TRANSLATIONAL MECHANISMS OF ALLOIMMUNIZATION TO RBC TRANSFUSION - ALLOIMMUNIZATION TO TRANSFUSED RBCS REMAINS A MAJOR PROBLEM FOR THE LARGE NUMBER OF PATIENTS WHO REQUIRE TRANSFUSION (APPROXIMATELY 1 OUT OF 70 PEOPLE (~5,000,000 PATIENTS) ANNUALLY IN THE USA ALONE). ALTHOUGH A BARRIER TO TRANSFUSION IN MULTIPLE SETTINGS, ALLOIMMUNIZATION IS PARTICULARLY PROBLEMATIC FOR PATIENTS WITH SICKLE CELL DISEASE (SCD) DUE TO 1) THE INCREASED RATE OF ALLOIMMUNIZATION (UP TO 30%), 2) THE NEED FOR CHRONIC TRANSFUSION, AND 3) THE RISK OF UNDETECTED (OR NEW) ALLOANTIBODIES CAUSING POTENTIALLY CATASTROPHIC HYPERHEMOLYSIS. THERE ARE VERY FEW EFFECTIVE THERAPEUTIC INTERVENTIONS TO PREVENT RBC ALLOIMMUNIZATION (E.G., EXTENSIVE ANTIGEN MATCHING). FOR ALL TRANSFUSION INDICATIONS, PATIENTS TEND TO BE EITHER “RESPONDERS” THAT DEVELOP ALLOANTIBODIES OVER TIME WITH ONGOING TRANSFUSION OR “NON-RESPONDERS” WITH NO DETECTABLE ALLOANTIBODIES EVEN AFTER MANY TRANSFUSIONS. CURRENTLY, WE CANNOT PREDICT WHICH PATIENTS ARE LIKELY TO BE RESPONDERS AND BECOME ALLOIMMUNIZED. THIS P01 FOCUSES ON ADDRESSING THE PERSISTENT PROBLEM OF RBC ALLOIMMUNIZATION FOR THE LARGE NUMBER OF PATIENTS WHO REQUIRE TRANSFUSIONS AND ARE AT RISK FOR ALLOIMMUNIZATION. THE PROGRAM IS STRUCTURED AROUND A CENTRAL CORE (CORE A) THAT WILL COLLECT LONGITUDINAL SAMPLES FROM A COHORT OF 2000 PATIENTS WITH SCD (AT STEADY STATE, AT TIME OF TRANSFUSION, AND ONE-MONTH POST-TRANSFUSION) LINKED TO DETAILED CLINICAL INFORMATION, INCLUDING RBC ALLOIMMUNIZATION. PROJECTS 1-3 COMBINE NOVEL TRANSLATIONAL MURINE MODELS WITH CLINICAL SAMPLES FROM CORE A WHILE PROJECT 4 USES SAMPLES FROM CORE A TO TEST HYPOTHESES THROUGH AN OMICS-BASED APPROACH AND GENERATES DATA ON PATHWAYS STUDIED IN PROJECTS 1-3. IN THIS WAY, THE PROPOSED PROGRAM CREATES A SYNERGY OF APPROACHES WITH THE ABILITY TO TRANSLATE MURINE FINDINGS INTO HUMANS AND MODEL HUMAN FINDINGS IN MICE. USING THE SAMPLES FROM CORE A AS A COMMON RESOURCE, FOUR PROJECTS ARE PROPOSED. PROJECT 1 BUILDS ON A NOVEL OBSERVATION THAT A MOUSE MODEL OF SLE RECAPITULATES INCREASED RBC ALLOIMMUNIZATION OBSERVED IN HUMANS WITH SLE AND UTILIZES THE MODEL AND SAMPLES FROM CORE A TO TEST THE MECHANISTIC ROLE OF TLR7, TLR9 AND ANTI-NUCLEIC ACID ANTIBODIES IN RBC ALLOIMMUNIZATION. PROJECT 2 BUILDS ON OUR NOVEL OBSERVATION THAT MULTIPLE PURINERGIC SIGNALING PATHWAYS REGULATE RBC ALLOIMMUNIZATION IN MICE AND UTILIZES MOUSE MODELS AND SAMPLES FORM CORE A TO TEST THE MECHANISTIC ROLE OF CD73, AMP, ADORA1, ADENOSINE AND ADORA2B IN RBC ALLOIMMUNIZATION. PROJECT 3 PROPOSES MECHANISTICALLY DRIVEN STUDIES IN PRE-CLINICAL MODELS AND HUMAN STUDIES TO EXPAND UPON OUR NOVEL FINDING THAT RETICULOCYTES (IN DONOR RBC UNITS OR IN TRANSFUSION RECIPIENTS) ARE A RISK FACTOR FOR RBC ALLOIMMUNIZATION. PROJECT 4 WILL INVESTIGATE THE UNDERLYING GENETIC RISK FACTORS THAT PREDISPOSE A GIVEN PATIENT WITH SCD THROUGH ANALYSIS OF WHOLE GENOME SEQUENCING AND THE SPECIFIC MOLECULAR DRIVERS OF ALLOIMMUNIZATION TO A GIVEN TRANSFUSION THROUGH ANALYSIS OF SINGLE CELL RNASEQ DATA. THIS P01 IS DESIGNED TO HAVE NEAR-TERM BENEFITS OF GUIDING CLINICAL PRACTICE BY DISCOVERING PREDICTORS OF RESPONDER/NON-RESPONDER PATIENTS AND LONGER-TERM BENEFITS OF ELUCIDATING MECHANISMS OF RBC ALLOIMMUNIZATION TO ALLOW RATIONAL TARGETS FOR THERAPY DEVELOPMENT.

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP) -THE NATIONAL SCIENCE FOUNDATION (NSF) GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP) IS A HIGHLY COMPETITIVE, FEDERAL FELLOWSHIP PROGRAM. GRFP HELPS ENSURE THE VITALITY AND DIVERSITY OF THE SCIENTIFIC AND ENGINEERING WORKFORCE OF THE UNITED STATES. THE PROGRAM RECOGNIZES AND SUPPORTS OUTSTANDING GRADUATE STUDENTS WHO ARE PURSUING RESEARCH-BASED MASTER'S AND DOCTORAL DEGREES IN SCIENCE, TECHNOLOGY, ENGINEERING, AND MATHEMATICS (STEM) AND IN STEM EDUCATION. THE GRFP PROVIDES THREE YEARS OF FINANCIAL SUPPORT FOR THE GRADUATE EDUCATION OF INDIVIDUALS WHO HAVE DEMONSTRATED THEIR POTENTIAL FOR SIGNIFICANT RESEARCH ACHIEVEMENTS IN STEM AND STEM EDUCATION. THIS AWARD SUPPORTS THE NSF GRADUATE FELLOWS PURSUING GRADUATE EDUCATION AT THIS GRFP INSTITUTION. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

THE UNIVERSITY OF VIRGINIA EXPERIMENTAL HIGH ENERGY PHYSICS AT THE ENERGY FRONTIER

MEDIUM ENERGY SPIN PHYSICS WITH LASERS

CLINICAL AND BASIC STUDIES IN POLYCYSTIC OVARIAN SYNDROME

CLINICAL & BASIC STUDIES IN POLYCYSTIC OVARIAN SYNDROME

"CENTER FOR HYPERSONIC COMBINED CYCLE FLOW PHYSICS"

FUNCTIONAL ANALYSIS OF GENOME WIDE ASSOCIATIONS IN COLORECTAL CANCER

HIGH ENERGY PHYSICS

IMMUNE REGULATION OF VIRUS CLEARANCE AND TISSUE INJURY AT SITES OF INFECTION

PROJECT ENGAGE: THE IMPACT OF CARE FOR TEACHERS ON STUDENTS' SUCCESS

UNIVERSITY TRANSPORTATION CENTER

PREDICTIVE INFORMATICS MONITORING IN THE NEONATAL INTENSIVE CARE UNIT

COMPREHENSIVE MAGNETIC RESONANCE IN PAD

IGE ANTIBODIES TO THE MAMMALIAN OLIGOSACCHARIDE GALACTOSE-ALPHA-1, 3-GALACTOSE (ALPHA-GAL): IMMUNOLOGY, EPIDEMIOLOGY AND RELEVANCE TO ALLERGIC AND INFLAMMATORY DISEASE

AN INTERDISCIPLINARY TRAINING PROGRAM IN IMMMUNOLOGY

THE PURPOSE OF THIS AGREEMENT IS TO FUND RESEARCH SUPPORTING THE DEFENSE ADVANCED RESEARCH PROJECTS AGENCY DARPA DEFENSE SCIENCES OFFICE DSO MULTIOBJECTIVE ENGINEERING AND TESTING OF ALLOY STRUCTURES METALS PROGRAM. THIS EFFORT SHALL BE CARRIED OUT GENERALLY AS SET FORTH IN EXHIBIT B, RESEARCH DESCRIPTION DOCUMENT, DATED JANUARY 30, 2024, AND IN THE RECIPIENTS REVISED PROPOSAL TITLED, OPTIMAL MULTI MATERIAL DESIGN VIA TOMOGRAPHIC CHARACTERIZATION AND DATA DRIVEN MODELS, DATED JUNE 8, 2023, COPIES OF WHICH ARE IN THE POSSESSION OF BOTH PARTIES.

CRYO-EM OF HELICAL PROTEIN AND NUCLEOPROTEIN POLYMERS AT NEAR ATOMIC RESOLUTION

LTER: CLIMATE DRIVERS, DYNAMICS, AND CONSEQUENCES OF ECOSYSTEM STATE CHANGE IN COASTAL BARRIER SYSTEMS

RESEARCH IN THE INTENSITY FRONTIER: NOVA AND MU2E

A MICRO-CELLULAR SOLIDS APPROACH TO THERMO-STRUCTURAL MATERIALS WITH CONTROLLED ARCHITECTURES

ROLE OF TH17 IN SEVERE AND RECURRENT C. DIFFICILE INFECTION

AN INTEGRATED CELLUAR MATERIALS APPROACH TO FORCE PROTECTION (TOPIC# 7)

SYSTEM-LEVEL APPROACH FOR MULTI-PHASE, NANOTECHNOLOGY-ENHANCED COOLING OF HIGH-POWER MICROELECTRONIC SYSTEMS

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

NETWORK FOR CARDIOTHORACIC SURGICAL INVESTIGATIONS IN CARDIOVASCULAR MEDICINE

EXPRESSION AND PROTEOMIC CHARACTERIZATION OF RISK LOCI IN TYPE 1 DIABETES

TO FOCUS ON DEVELOPMENT AND DEMONSTRATION OF MODELING/SIMULATION TECHNOLOGIES AND METHODOLOGIES THROUGH THE STRUCTURE OF MULTIDISCIPLINARY SIMULATION CENTERS, SINGLE-DISCIPLINE CENTERS, AND FOCUS INVESTIGATORY CENTERS TO SOLVE OPEN SCIENCE AND ENGINEERING PROBLEMS RELEVANT TO NNSA DEFENSE PROGRAM MISSIONS; TO PROMOTE AND SUSTAIN SCIENTIFIC INTERACTIONS BETWEEN THE ACADEMIC COMMUNITY AND SCIENTISTS AT THE DOE NNSA LABORATORIES; AND TO TRAIN FUTURE SCIENTISTS IN SPECIFIC AREAS OF LONG-TERM RESEARCH RELEVANT TO NNSA STOCKPILE STEWARDSHIP.

BIOSPECIMEN PROCUREMENT AND TISSUE MICROARRAY MANUFACTURE FOR THE CHTN

TOWARDS A MISSION CONFIGURABLE STEALTH UNDERWATER BATOID

BIO-BEHAVIORAL FEEDBACK AND CONTROL OF TYPE 1 DIABETES

CELLULAR/MOLECULAR MECHANISMS OF RESPIRATORY NEURONAL CHEMOSENSITIVITY

GENOMIC ARCHITECTURE OF LGL LEUKEMIA

IGE ANTIBODY RESPONSES TO THE OLIGOSACCHARIDE GALACTOSE-ALPHA-1,3-GALACTOSE (ALPHA-GAL) IN MURINE AND HUMAN ATHEROSCLEROSIS - PROJECT ABSTRACT INCREASED TOTAL SERUM IGE LEVELS ARE ASSOCIATED WITH CORONARY ARTERY DISEASE (CAD). HOWEVER, THE CAUSAL ROLE OF ANTIGEN-SPECIFIC IGE IN CAD REMAINS LARGELY UNEXPLORED. RECENT WORK FROM OUR GROUP AND OTHERS PROVIDE EVIDENCE THAT HUMANS WITH IGE SENSITIZATION TO THE MAMMALIAN OLIGOSACCHARIDE ALLERGEN A-GAL HAVE LARGER CORONARY ARTERY PLAQUES AND UNSTABLE PLAQUE FEATURES SIGNIFYING INCREASED CAD COMPARED TO THOSE WITHOUT IGE TO A-GAL. YET, WHETHER IGE TO A-GAL DIRECTLY PROMOTES ATHEROSCLEROTIC PLAQUE DEVELOPMENT AND THE MOLECULAR AND CELLULAR MECHANISMS MEDIATING IGE SENSITIZATION TO A-GAL LINKED TO ATHEROSCLEROSIS FORMATION ARE UNKNOWN. BITES FROM THE LONE STAR TICK INDUCE IGE SENSITIZATION TO A-GAL AND A SUBSEQUENT SEVERE ALLERGIC RESPONSE WHEN THE SUBJECT INGESTS A-GAL-CONTAINING FOODS SUCH AS RED MEAT. HOWEVER, THE VAST MAJORITY OF INDIVIDUALS WITH IGE TO A-GAL DO NOT MANIFEST WITH DELAYED ANAPHYLAXIS AND FREQUENTLY HAVE NO OUTWARD IDENTIFYING SYMPTOMS. AS SUCH, THEY CONTINUE TO CONSUME A-GAL-CONTAINING FOOD PRODUCTS (MEAT, DAIRY, ETC.) WHICH HAVE THE CAPACITY TO CONTINUE TO STIMULATE IGE RESPONSES AND INFLAMMATION IN THE VESSEL WALL. PRELIMINARY DATA PROVIDE THE FIRST EVIDENCE THAT HUMANS WITH IGE SENSITIZATION TO A-GAL HAD A HIGHER FREQUENCY OF CCR6+ SWITCHED MEMORY (SWM) B CELLS. NOTABLY, CONSISTENT WITH THE ASSOCIATION OF THE IGE SENSITIZATION TO A-GAL AND CAD, THE AMOUNT OF CCR6 ON SWM B CELLS WAS ASSOCIATED WITH CAD SEVERITY. TRANSCRIPTOMIC ANALYSIS DEMONSTRATED THAT CCR6+ SWM B CELLS EXPRESSED HIGHER IL-4R AND STAT6 IN SUBJECTS THAT WERE IGE A-GAL+ COMPARED TO IGE A- GAL-. INTERESTINGLY, IL-4 AND STAT6 ARE IMPORTANT FOR B CELL CLASS SWITCH RECOMBINATION TO IGE, SUGGESTING THAT CELLS THAT MAKE IL-4 MAY BE IMPORTANT IN IGE A-GAL PRODUCTION. STUDYING IGE SENSITIZATION TO A-GAL IN CONVENTIONAL MURINE MODELS OF ATHEROSCLEROSIS IS NOT FEASIBLE AS MICE, LIKE ALL LOWER MAMMALS BUT UNLIKE HUMANS, EXPRESS THE ENZYME GALACTOSYLTRANSFERASE, PRODUCE A-GAL AND DO NOT DEVELOP AN IGE RESPONSE TO A- GAL. WE HAVE OBTAINED A NOVEL A-GAL-/- MOUSE THAT MIMICS THE HUMAN CONDITION TO STUDY THE ROLE OF IGE SENSITIZATION TO A-GAL IN ATHEROSCLEROSIS. COMPARING A-GAL-/- MICE TO MICE WILDTYPE (WT) FOR A-GAL, WE SHOW A SIGNIFICANT INDUCTION OF IGE TO A-GAL AFTER EXPOSURE TO LONE STAR TICK-DERIVED LIPIDS IN THE A-GAL-/- BUT NOT THE WT MOUSE. MOREOVER, PRELIMINARY DATA FROM MICE DEFICIENT IN NKT CELLS IMPLICATES INKT CELLS IN THE REGULATION OF IGE ANTIBODY PRODUCTION TO LIPIDS FROM LONE STAR TICKS. BASED ON THESE HUMAN AND MURINE DATA, THE OVERARCHING OBJECTIVE OF THIS PROPOSAL IS TO INVESTIGATE WHETHER THESE FACTORS AND CELLS PLAY A CAUSAL ROLE IN ATHEROSCLEROSIS DEVELOPMENT DUE TO IGE SENSITIZATION TO A-GAL. WE WILL USE LOSS AND GAIN OF FUNCTION STUDIES IN MURINE ATHEROSCLEROSIS MODELS TO DEFINE NOVEL MECHANISMS OF A-GAL IGE PRODUCTION AND THE IMPACT OF TICK-INDUCED A- GAL SENSITIZATION ON DIET-INDUCED ATHEROSCLEROSIS, AND TEST A LARGER COHORT OF HUMANS WITH CAD QUALITATIVELY AND QUANTITATIVELY BY INTRAVASCULAR ULTRASOUND VIRTUAL HISTOLOGY (IVUS-VH), ALLOWING FOR MORE ROBUST MULTIVARIATE ANALYSIS AND DEEPER INTERROGATION OF IMMUNE CELL PHENOTYPES THAT MARK THOSE AT GREATEST RISK.

THE ROLE OF COPY NUMBER VARIANTS (CNV) IN TYPE 1 DIABETES

DEVELOPMENTAL ORIGINS AND HOMEOSTATIC MECHANISMS UNDERLYING ADULT PHENOTYPES

FIELD STUDIES OF HUMAN IMMUNITY TO AMEBIASIS IN BANGLADESH

URINE COLORIMETRY FOR TUBERCULOSIS PHARMACOKINETICS EVALUATION IN CHILDREN AND ADULTS

NEW START GRANT

SOCIAL RELATIONSHIP QUALITIES AS PREDICTORS OF HEALTH & AGING FROM ADOLESCENCE THROUGH EARLY MIDLIFE

CELLULAR AND GENETIC BASIS OF SYSTEMIC LUPUS

STUDY OF THE NUCLEON STRUCTURE AT JEFFERSON LAB HALL A

CARDIOVASCULAR SURGERY RESEARCH TRAINING GRANT

DOPAMINERGIC AND GLUTAMATERGIC MECHANISMS OF COCAINE ADDICTION: SEX DIFFERENCES

ONTOGENY OF CENTRAL NEURAL TASTE RESPONSES

LTER: DRIVERS, DYNAMICS AND CONSEQUENCES OF NON-LINEAR CHANGE IN COASTAL BARRIER SYSTEMS

CRITICAL PERIOD PLASTICITY AND BINOCULAR MATCHING IN THE VISUAL CORTEX

MOLECULAR MECHANISMS OF MEMBRANE TRANSPORT

REAL-TIME MEASUREMENTS OF NEUROTRANSMISSION IN DROSOPHILA MELANOGASTER

TARGETED CEU IMAGING OF ATHEROSCLEROSIS AND ANGIOGENESIS

HERCULES: HARDWARE-ENHANCED RESILIENT COMPARTMENTALIZATION AND PROGRAM ANALYSIS FOR UPGRADED LEGACY ENVIRONMENT SECURITY

BFGF LOW AFFINITY RECEPTORS AND HIVAN

MINIMALLY INVASIVE CEREBRAL BLOOD FLOW AND OXYGENATION MONITORING FOR INTRACRANIAL HYPERTENSION - ABSTRACT/PROJECT SUMMARY TRAUMATIC BRAIN INJURY, ACUTE ISCHEMIC STROKE, AND INTRACEREBRAL HEMORRHAGE ARE FREQUENTLY COMPLICATED BY INTRACRANIAL HYPERTENSION LEADING TO PROGRESSIVE ISCHEMIA AND SECONDARY BRAIN INJURY. RECENT EFFORTS FOCUSED ON IMPROVING OUTCOMES HAVE THEREFORE BEEN FOCUSED UPON IMPROVING CEREBRAL OXYGENATION AND THE DEVELOPMENT OF MONITORING DEVICES TO GUIDE THERAPY. CURRENT DEVICES DESIGNED TO MEASURE TISSUE OXYGENATION ARE, HOWEVER, SEVERELY LIMITED IN THEIR SCOPE OF SURVEILLANCE AND ACCURACY. SURFACE OXIMETRY MONITORS INTERROGATE ONLY SUPERFICIAL BRAIN TISSUE, WITH CONTAMINATION FROM INTERVENING SKIN AND SKULL. INTRAPARENCHYMAL BRAIN TISSUE OXYGEN PROBES SURVEY RELATIVELY METABOLICALLY LESS ACTIVE WHITE MATTER (COMPARED TO GRAY MATTER), A VOLUME OF LESS THAN 3 MM3, AND AT A SINGLE LOCATION. LASTLY, INTRAPARENCHYMAL TISSUE OXYGEN MONITORS ARE BULKY, INCOMPATIBLE WITH MAGNETIC RESONANCE IMAGING, AND HAVE YET TO DEMONSTRATE CLINICAL EFFICACY. TO FILL THIS NEED, WE WILL FINALIZE THE DEVELOPMENT OF A BRAIN-SPECIFIC, MINIMALLY INVASIVE, OPTICAL BLOOD FLOW AND OXYGENATION MONITORING SYSTEM (FLOXBR), THEN TRANSLATE THIS DEVICE TO HUMANS. THE FLOXBR, EMPLOYING DIFFUSE OPTICAL AND CORRELATION SPECTROSCOPIES VIA A BRAIN SURFACE PROBE, MAY OFFER IMPROVED SENSITIVITY AND SPECIFICITY COMPARED TO NON-INVASIVE PROBES AND WILL PROBE LARGER VOLUMES THAN CURRENTLY AVAILABLE INVASIVE PROBES, SUCH AS THE LICOXTM TISSUE PO2 PROBE. UNLIKE INTRAPARENCHYMAL PROBES, THIS DEVICE CAN LIE ABOVE OR BELOW THE DURA AND WILL BE MORE SENSITIVE TO HIGHLY METABOLICALLY ACTIVE GRAY MATTER. ITS SMALL SIZE AND FLEXIBILITY WILL PERMIT MULTIPLE PROBES TO BE PLACED THROUGH A SINGLE BURR HOLE, THUS ALLOWING FOR THE MONITORING OF REGIONAL DIFFERENCES IN FLOW AND OXYGENATION. UNLIKE SURFACE OXIMETRY, THE FLOXBR IS NOT IMPACTED BY SUPERFICIAL TRAUMA OR EDEMA, IMPROVING RELIABILITY AND SENSITIVITY. CONTINUOUS, EASILY INTERPRETED, AND RELIABLE MINIMALLY INVASIVE MONITORING OF CEREBRAL OXYGEN DELIVERY MAY ENHANCE MANAGEMENT AND OUTCOMES IN PATIENTS SUFFERING FROM INTRACRANIAL HYPERTENSION. OUR AIMS ARE SUCCINCTLY SUMMARIZED BELOW. AIM 1) FINALIZE DEVELOPMENT & MANUFACTURE THE FLOXBR BRAIN FLOW AND OXIMETRY MONITORING DEVICE. AIM 2) PRE-CLINICAL DEVICE EVALUATION, MEASUREMENT VALIDATION, AND SAFETY TESTING OF FLOXBR. AIM 3) COMPLETE REGULATORY AND SAFETY REQUIREMENTS TO SUPPORT FLOXBR FIRST-IN-HUMANS FEASIBILITY TESTING. AIM 4) CONDUCT FIRST-IN-HUMANS FEASIBILITY TESTING.

THE PURPOSE OF THIS AGREEMENT IS TO FUND RESEARCH SUPPORTING THE DEFENSE ADVANCED RESEARCH PROJECTS AGENCY DARPA MICROSYSTEMS TECHNOLOGY OFFICE MTO FOR THE INTENSITY SQUEEZED PHOTONIC INTEGRATION FOR REVOLUTIONARY DETECTORS INSPIRED PROGRAM. THIS EFFORT SHALL BE CARRIED OUT GENERALLY AS SET FORTH IN EXHIBIT B, RESEARCH DESCRIPTION DOCUMENT, DATED JUNE 12, 2024, AND IN THE RECIPIENTS PROPOSAL TITLED, SQUEEZED INTEGRATED NITRIDE TECHNOLOGY SQUINT, DATED DECEMBER 17, 2023, COPIES OF WHICH ARE IN THE POSSESSION OF BOTH PARTIES.

KETAMINE ADD-ON FOR ESTABLISHED STATUS EPILEPTICUS TREATMENT TRIAL (KESETT) - THE KETAMINE ADD-ON THERAPY FOR ESTABLISHED STATUS EPILEPTICUS TREATMENT TRIAL (KESETT) IS A PHASE III RANDOMIZED, DOUBLE-BLIND CLINICAL TRIAL TO TEST WHETHER KETAMINE (KET) (1 OR 3 MG/KG) ADDED TO THE STANDARD THERAPY, LEVETIRACETAM (LEV), IS MORE EFFECTIVE THAN LEVETIRACETAM (60 MG/KG) ALONE IN TREATING STATUS EPILEPTICUS AFTER BENZODIAZEPINES HAVE FAILED. GENERALIZED CONVULSIVE STATUS EPILEPTICUS (SE) IS A DANGEROUS BUT COMMON NEUROLOGIC EMERGENCY; IT CAN CAUSE RESPIRATORY DEPRESSION AND PERMANENT BRAIN DAMAGE. BENZODIAZEPINES ARE AN EFFECTIVE FIRST-LINE THERAPY, BUT APPROXIMATELY ONE-THIRD OF CHILDREN AND 40% OF ADULTS DO NOT RESPOND. PATIENTS WHO FAIL BENZODIAZEPINES ARE IN ESTABLISHED STATUS EPILEPTICUS. THEY ARE TREATED WITH SECOND-LINE AGENTS SUCH AS LEVETIRACETAM, WHICH SUCCESSFULLY TERMINATES STATUS EPILEPTICUS IN ONLY 47% OF SUBJECTS. WE PROPOSE THAT ADDING KETAMINE TO LEVETIRACETAM WILL INCREASE EFFICACY TO 62%. PRECLINICAL AND CLINICAL EVIDENCE SUPPORTS THIS TRIAL. KETAMINE, AN NMDA RECEPTOR ANTAGONIST, TERMINATES BENZODIAZEPINE REFRACTORY SE IN EXPERIMENTAL ANIMALS. NMDA RECEPTOR ACTIVATION TRIGGERS SELF-REINFORCING SEIZURE MECHANISMS UNDERLYING SE. IT ABROGATES INHIBITORY PLASTICITY, PREVENTS EXCITOTOXICITY AND NEURONAL DEATH, AND PREVENTS EPILEPTOGENESIS ACCOMPANYING SE IN EXPERIMENTAL ANIMALS. RECENT CLINICAL STUDIES IN CHILDREN AND ADULTS SHOWED THAT KETAMINE TERMINATED ESTABLISHED STATUS EPILEPTICUS IN 23 OF 24 SUBJECTS. KETAMINE IS USED EXTENSIVELY IN EMERGENCY SETTINGS FOR SEDATION, INTUBATION, AGITATION, AND PAIN MANAGEMENT; IT IS ON THE WHO ESSENTIAL MEDICATIONS LIST BECAUSE IT IS SAFELY USED EXTENSIVELY. CLINICIANS USE IT EFFECTIVELY TO TREAT REFRACTORY AND SUPER-REFRACTORY SE, AND MANY EXPERTS RECOMMEND IT. ED PHYSICIANS HAVE USED IT FOR DECADES FOR PROCEDURAL SEDATION. WE PROPOSE TO TEST 1 AND 3 MG/KG KETAMINE DOSES BASED ON RECENT HUMAN STUDIES, EXTENSIVE PHARMACOKINETIC MODELING, ANIMAL-TO-HUMAN DOSE CONVERSION AS SUGGESTED BY THE FDA, AND DATA ON THE SAFETY OF KETAMINE. OUR OVERALL HYPOTHESIS IS THAT KETAMINE ADDED TO LEV WILL IMPROVE THE OUTCOME OF ESTABLISHED STATUS EPILEPTICUS COMPARED TO TREATMENT WITH LEVETIRACETAM ALONE BY CLINICALLY MEANINGFUL 15%. WE WILL TEST THIS HYPOTHESIS BY ACCOMPLISHING THE FOLLOWING SPECIFIC AIMS IN A BAYESIAN-ADAPTIVE RANDOMIZED CLINICAL TRIAL: AIM 1: DETERMINE WHETHER PARTICIPANTS RANDOMIZED TO LEVETIRACETAM +3 MG/KG KETAMINE OR LEVETIRACETAM +1 MG/KG KETAMINE WILL HAVE MORE DESIRABLE OUTCOMES THAN THOSE RECEIVING LEVETIRACETAM +PLACEBO. WE RANK THE OUTCOMES ON A SCALE RANGING FROM 1 TO 5. AIM 2: TO ENSURE THAT THE TRIAL IS INFORMATIVE FOR TREATING ESTABLISHED STATUS EPILEPTICUS IN CHILDREN BY DESCRIBING THE EFFECTIVENESS AND RATE OF ADVERSE REACTIONS OF THESE DRUGS. AIM 3: MEASURE DIFFERENCES BETWEEN TREATMENT ARMS IN SECONDARY OUTCOMES. THIS TRIAL CAN CHANGE THE TREATMENT PARADIGM FOR SE BY SUPPLEMENTING CURRENT SECOND-LINE AGENTS WITH KETAMINE TO IMPROVE THE TIMELINESS OF SEIZURE TERMINATION.

LONG-TERM DRIVERS, STATE CHANGE AND DISTURBANCE ON THE VIRGINIA COAST RESERVE: LTER V

FOCUSED ULTRASOUND INTERVENTIONS FOR NONINVASIVE PRECISION THERAPY IN PRIMARY AND METASTATIC BREAST CANCERS

TRAINING IN CELL AND MOLECULAR BIOLOGY

AUGMENTATION OF TISSUE PERFUSION IN PAD WITH ULTRASOUND-MEDIATED CAVITATION

THE ROLE OF ION TRANSPORT IN GLIOMA MIGRATION, PROLIFERATION, AND APOPTOSIS

ROLE OF EOSINOPHILS IN INNATE PROTECTION FROM C. DIFFICILE

GROWTH AND REGENERATION IN THE INNER EAR

MOLECULAR MECHANISMS OF VIRAL MEMBRANE FUSION

MOLECULAR MECHANISMS OF RHOA-MEDIATED CA2+SENSITIZATION IN VASCULAR SMOOTH MUSCLE

ELECTRON INTERACTIONS WITH NUCLEI

ADOLESCENT PEER AND FAMILY PRECURSORS OF ADULT PSYCHOSOCIAL FUNCTIONING