Northern California Institute For Research And Education Inc

ALZHEIMER'S DISEASE NEUROIMAGING INITIATIVE

ALZHEIMER'S DISEASE NEUROIMAGING INITIATIVE

AMYLOID IMAGING, VMCI, AND ANALYSIS FOR ADNI

EFFECTS OF TRAUMATIC BRAIN INJURY (TBI) AND POST TRAUMATIC STRESS DISORDER (PTSD) ON ALZHEIMER'S DISEASE (AD) IN VETERANS USING IMAGING AND BIOMARKERS IN THE AD NEUROIMAGING INITIATIVE (ADNI)"

PHYSICAL AND NEUROPSYCHIATRIC TRAUMA - WOUND HEALING AND TISSUE PREVENTION

U.S. DEPRESCRIBING RESEARCH NETWORK

THE AGING KIDNEY IN HIV-INFECTION: BIOMARKERS FOR EARLY DETECTION OF INJURY

NON-ALCOHOLIC FATTY LIVER DISEASE AND CARDIOVASCULAR DISEASE IN HISPANICS/LATINOS

IMPLEMENTATION OF A PRAGMATIC TRIAL OF WHOLE HEALTH TEAM VS. PRIMARY CARE GROUP EDUCATION TO PROMOTE NON-PHARMACOLOGICAL STRATEGIES TO IMPROVE PAIN, FUNCTION AND QUALITY OF LIFE IN VETERANS

STRUCTURE/FUNCTION OF COMPLEX LL OXIDOREDUCTASES

A CONTROLLED TRIAL OF TOPIRAMATE TREATMENT FOR ALCOHOL DEPENDENCE IN VERTERANS WITH PTSD

DOES KIDNEY FUNCTION DETERMINE AGING SUCCESS

EFFECTS OF TRAUMATIC BRAIN INJURY AND POSTTRAUMATIC STRESS DISORDER ON ALZHEIMERS DISEASE

RESOURCE FOR MRI OF NEURODEGENERATIVE DISORDERS

PHYSICAL AND NEUROPSYCHIATRIC TRAUMA - WOUND HEALING AND TISSUE PREVENTION

MAGNETIC RESONANCE AND SPECTROSCOPY OF THE HUMAN BRAIN IN GULF WAR

EFFECTS OF TRAUMATIC BRAIN INJURY AND POST TRAUMATIC STRESS DISORDER AND ALZHEIMER'S DISEASE ON BRAIN TAU IN VIETNAM VETERANS USING ADNI

EFFECT OF A HYPOCRETIN/OREXIN ANTAGONIST ON NEUROCOGNITIVE PERFORMANCE

COROLLARY DISCHARGE DYSFUNCTION IN SCHIZOPHRENIA: ERPS AND EEG

QUANTITATIVE ANALYSIS OF LEFT VENTRICULPLASTY--CHF

PHYSICAL AND NEUROPSYCHIATRIC TRAUMA - WOUNT HEALING AND TISSUE PREVENTION

THE BIOLOGICAL BASIS OF ALCOHOL-AND SMOKING-INDUCED BRAIN INJURY

PREDICTION OF COGNITIVE DECLINE WITH MRI AND MRS

STIMULANT AND POLYSUBSTANCE USE, INFLAMMATION AND SEX EFFECTS ON MYOCARDIAL DISEASE IN HIV (SPISE) - PROJECT SUMMARY/ABSTRACT HEART FAILURE (HF) AND OTHER CARDIOVASCULAR DISEASES (CVDS) CONSTITUTE A LEADING CAUSE OF DEATH IN PEOPLE WITH HIV (PWH). COMPARED TO PEOPLE WITHOUT HIV, PWH HAVE GREATER HF RISK AND WE HAVE SHOWN THAT THE DIFFERENCE IN RISK MAY BE GREATER IN WOMEN THAN MEN. HOWEVER, TRADITIONAL HIV AND CVD RISK FACTORS DO NOT FULLY EXPLAIN THE HIGHER HF RISK. NOTABLY, SYMPTOMATIC HF IS OFTEN PRECEDED BY SUBCLINICAL CHANGES IN LEFT VENTRICULAR STRUCTURE AND FUNCTION DETECTABLE BY ECHOCARDIOGRAPHY (ECHO), AND EVEN SOONER BY CARDIAC MAGNETIC RESONANCE IMAGING (CMR). RECOGNIZING MYOCARDIAL DISEASE DETERMINANTS AND THE MECHANISTIC CONTRIBUTORS EARLY IN THE DISEASE PROCESS IS IMPERATIVE TO IDENTIFY TARGETS FOR HF PREVENTION AND TREATMENT IN PWH. CONTROLLED STIMULANTS LIKE COCAINE AND METHAMPHETAMINE ARE KNOWN CARDIOTOXINS, BUT THEIR ROLE IN MYOCARDIAL REMODELING AMONG PWH IS UNCLEAR. STIMULANT USE IS HIGHER AMONG PWH THAN THE GENERAL POPULATION, YET STIMULANT USE IS POORLY ASSESSED IN LARGE HIV AND CVD STUDIES. IT IS EITHER POOLED WITH OTHER SUBSTANCES OR LACKS DETAILS ABOUT PATTERNS OF USE, LEVEL OF EXPOSURE, AND SYNERGISTIC INFLUENCES WITH OTHER SUBSTANCES – HAMPERING OUR ABILITY TO UNDERSTAND THE POTENTIALLY OUTSIZED ROLE OF STIMULANT USE IN THE PATHOGENESIS OF HIV AND MYOCARDIAL DISEASE IN PWH. WE PROPOSE “STIMULANT AND POLYSUBSTANCE USE, INFLAMMATION, AND SEX EFFECTS ON MYOCARDIAL DISEASE IN HIV (SPISE)” A RESEARCH PROGRAM WITHIN THE MULTICENTER AIDS COHORT STUDY (MACS)/WOMEN’S INTERAGENCY HIV STUDY (WIHS) COMBINED COHORT STUDY. OUR FINDINGS FROM WIHS SUGGEST THAT SUSTAINED (AND NOT ANY) SELF-REPORTED SUBSTANCE USE IS ASSOCIATED WITH CARDIAC DYSFUNCTION, AND SUSTAINED CANNABIS MAY HAVE A PROTECTIVE EFFECT, EMPHASIZING A NEED TO ASSESS SUBSTANCE USE PATTERNS AND DIFFERENT INFLUENCES OF MULTIPLE SUBSTANCES. FURTHERMORE, WOMEN WITH HIV WHO REPORTED PRIOR COCAINE USE MAY HAVE A LARGER HIV-1 RESERVOIR THAN NEVER USERS, EVEN AFTER ADJUSTING FOR ART ADHERENCE, WHICH COULD EXPLAIN PERSISTENT VIREMIA IN SOME WOMEN WITH IMPLICATIONS TO INFLAMMATION AND EPIGENETIC MALADAPTATION. SPISE’S OVERARCHING RESEARCH GOAL IS TO RIGOROUSLY CHARACTERIZE SUBSTANCE USE PATTERNS (USING SERIAL URINE DRUG TOXICOLOGY MEASURES AND SELF-REPORT) AND DETERMINE ITS EFFECT ON STRUCTURAL HEART DISEASE AND MYOCARDIAL DISEASE THROUGH THE LONGITUDINAL SPICE-ECHO AND PROSPECTIVE SPICE-CMR STUDIES, RESPECTIVELY; WHETHER DNA METHYLATION AND THE INFLAMMATORY PROTEOME MEDIATES THESE EFFECTS; AND HOW HIV AND SEX INFLUENCE THE PATHWAYS. SPISE WILL ESTABLISH A TRANSDISCIPLINARY INFRASTRUCTURE TO COMPREHENSIVELY INVESTIGATE THE BIOLOGICAL BASIS OF SUBSTANCE-ASSOCIATED MYOCARDIAL DISEASE AT MULTIPLE POINTS OF THE MECHANISTIC PATHWAY. OUR FINDINGS WILL BE SHARED WITH THE SCIENTIFIC COMMUNITY TO STIMULATE AND SUSTAIN RESEARCH IN SUBSTANCE USE AND HIV. SPISE HAS THE POTENTIAL TO TRANSFORM CURRENT RESEARCH PARADIGMS THAT DO NOT CONSIDER INDEPENDENT STIMULANT USE EFFECTS, PROMOTE NEW APPROACHES FOR IMPLEMENTATION RESEARCH THAT ACKNOWLEDGE THE IMPORTANCE OF SUBSTANCE USE PATTERNS, INFORM BIOMEDICAL AND BEHAVIORAL INTERVENTIONS THAT ARE SEX-SPECIFIC, AND DIRECT RESOURCE-INTENSIVE RISK REDUCTION STRATEGIES TO THOSE PWH WHO USE SUBSTANCES AND ARE AT HIGHEST CVD RISK.

ALPHA-1 ADRENERGIC RECEPTOR SUBTYPES IN CARDIAC GROWTH

NOVEL SINGLE GENOME APPROACHES TO DETERMINE THE MECHANISMS OF HIV LATENT INFECTION IN BLOOD, GUT, AND LYMPH NODES

9/9-PREDICTORS AND MECHANISMS OF CONVERSION TO PSYCHOSIS

INDIVIDUAL VARIATION IN EFFECTS OF TRAUMATIC STRESS ON GRAY MATTER MYELIN

ROLE OF STREPTOCOCCAL-PLATELET BINDING IN ENDOCARDITIS

ADVANCED KIDNEY HEALTH MONITORING IN PERSONS HOSPITALIZED WITH HEART FAILURE - PROJECT SUMMARY HEART FAILURE LEADS TO >1.4 MILLION HOSPITALIZATIONS ANNUALLY IN THE U.S. DURING THESE ACUTE DECOMPENSATED HEART FAILURE (ADHF) HOSPITALIZATIONS, THE KIDNEYS’ HEALTH INFLUENCES ALMOST EVERY ASPECT OF MANAGEMENT, INCLUDING INITIAL DIURETIC DOSING, TREATMENT INTENSIFICATION, AND DISCHARGE PLANNING. HOWEVER, CLINICAL RELIANCE ON SERUM CREATININE, AN INSENSITIVE, NONSPECIFIC AND OFTEN MISLEADING KIDNEY BIOMARKER, SUBSTANTIALLY CONTRIBUTES TO SUBOPTIMAL ADHF TREATMENT. ALTHOUGH GUIDELINES SUGGEST THAT CLINICIANS USE THE PATIENT’S KIDNEY FUNCTION AS AN INDICATOR FOR THE INITIAL DIURETIC DOSE, THE CREATININE IS ACTUALLY A POOR PREDICTOR OF DIURETIC RESPONSE AND CLINICIANS MUST RESORT TO “TRIAL AND ERROR” IN SEARCHING FOR EACH PATIENT’S OPTIMAL DOSE. FURTHER, ALTHOUGH CREATININE ELEVATIONS DURING TREATMENT COMMONLY REFLECT BENEFICIAL EFFECTS, CLINICIANS TYPICALLY DE-ESCALATE DIURESIS FROM FEAR OF WORSENING KIDNEY DAMAGE. DURING DISCHARGE PLANNING, THIS FEAR ALSO DRIVES CLINICIANS TO PRESCRIBE AN ORAL DIURETIC DOSE THAT IS TOO LOW, AND TO AVOID BENEFICIAL THERAPIES. THESE OBSTACLES TO IDEAL CARE CULMINATE IN DELAYED SYMPTOM RELIEF, PROLONGED HOSPITALIZATION, FREQUENT READMISSIONS, AND HIGH MORTALITY RISK. GIVEN THE KIDNEY TUBULES’ CENTRAL ROLE IN DETERMINING THE EFFECTIVENESS AND SAFETY OF ADHF PHARMACOLOGICAL TREATMENT, CLINICIANS NEED TOOLS THAT CAPTURE KIDNEY TUBULE HEALTH TO OPTIMIZE DIURETIC STRATEGIES, IMPROVE DELIVERY OF GUIDELINE-DIRECTED MEDICAL THERAPY, AND MINIMIZE THE RISK FOR TRUE KIDNEY DAMAGE. IN AMBULATORY SETTINGS, OUR TEAM HAS DEMONSTRATED THE REMARKABLE ABILITY OF TUBULE HEALTH MEASURES TO DETECT KIDNEY DAMAGE EARLY, TO REFLECT THE KIDNEYS’ RESPONSE TO TREATMENT MORE ACCURATELY THAT CREATININE, AND TO PREDICT LONG-TERM OUTCOMES. EARLY STUDIES OF A FEW TUBULE MARKERS IN ADHF SHOW THAT THEY IMPROVE IN PROPORTION TO DIURETIC RESPONSE AND HAVE TREMENDOUS POTENTIAL TO CHANGE HOW KIDNEY HEALTH IS MONITORED DURING ADHF TREATMENT. GIVEN THE CENTRAL ROLE OF KIDNEY HEALTH IN ADHF TREATMENT AND PROGNOSIS, OUR OVERALL GOALS ARE TO FUNDAMENTALLY CHANGE HOW CLINICIANS APPROACH KIDNEY HEALTH MONITORING AND CLINICAL DECISION-MAKING DURING ADHF TREATMENT. TO ACHIEVE THESE GOALS, WE WILL CAPITALIZE ON THE WELL-CHARACTERIZED MECHANISMS OF DIURETIC RESISTANCE (MDR) STUDY, A COHORT OF PATIENTS HOSPITALIZED FOR ADHF WHO HAVE UNDERGONE SERIAL BIOSPECIMEN COLLECTIONS TIMED TO DIURETIC TREATMENT THROUGHOUT HOSPITALIZATION WITH LONGITUDINAL FOLLOW-UP FOR KEY CLINICAL OUTCOMES. WE WILL MEASURE A BROAD PANEL OF KIDNEY BIOMARKERS THAT REFLECT TUBULE REABSORPTIVE AND SECRETORY FUNCTIONS, INJURY, SYNTHETIC AND REPARATIVE CAPACITY, AND TUBULOINTERSTITIAL INFLAMMATION AND FIBROSIS. WE WILL IDENTIFY WHICH TUBULE HEALTH MEASURES MOST EFFECTIVELY: 1) PREDICT TREATMENT RESPONSE TO INITIAL LOOP DIURETIC DOSING AND ADJUNCTIVE DIURETIC THERAPY (AIM 1); 2) DISCERN PSEUDO- FROM INTRINSIC KIDNEY DAMAGE AMONG PATIENTS WITH CREATININE ELEVATIONS DURING TREATMENT (AIM 2); AND 3) IDENTIFY PATIENTS APPROPRIATE FOR DISCHARGE AND DISTINGUISH THEIR RISKS FOR SUBSEQUENT ADVERSE EVENTS (AIM 3). THIS PROJECT WILL LAY THE NECESSARY GROUNDWORK FOR A CLINICAL TRIAL TO TEST A KIDNEY BIOMARKER-GUIDED ADHF TREATMENT STRATEGY.

COMPARATIVE EFFECTIVENESS OF CAROTID ARTERY REVASCULARIZATION VS MEDICAL THERAPY

HEPATITIS C DRIVES NEUROPATHOGENESIS IN HIV/HCV COINFECTION PATIENTS

INTEGRIN REGULATION OF IGF-1 RESPONSIVENESS IN BONE DURING MECHANICAL LOADING

BIOMARKERS OF KIDNEY INJURY TO PREDICT AKI ONSET AND PROGRESSION IN HIV INFECTION

MECHANISMS FOR LIGAND BINDING BY SERINE-RICH ADHESINS OF GRAM-POSITIVE PATHOGENS

LONG-TERM OCULAR SEQUELAE AND BIOLOGICAL DETERMINANTS OF POST-ACUTE EBOLA VIRUS DISEASE - PROJECT SUMMARY/ABSTRACT. OCULAR POST-ACUTE SEQUELAE OF EBOLA VIRUS DISEASE (EVD) (PASE) CAN BE DEFINED ACCORDING TO SYMPTOMS OR SIGNS ATTRIBUTED TO EVD WHICH PERSIST OR MANIFEST AFTER EVD IN UP TO 34% OF SURVIVORS. UVEITIS, RETINAL SCARS, AND DECREASED INTRAOCULAR PRESSURE ARE AMONG THE FINDINGS ASSOCIATED WITH OCULAR PASE OVER THE 5-YEAR POST-EVD PERIOD (TERMED “EARLY PASE”). AFTER 5 YEARS, THERE IS EVIDENCE OF ONGOING AND INCIDENT OCULAR PASE (TERMED “LATE PASE”), BUT THE TRAJECTORY IS UNKNOWN. IN ADDITION TO UVEITIS AND OTHER KNOWN PASE, EVD SURVIVORS CAN DEVELOP OTHER OCULAR PASE—SOME OF WHICH ARE VISION-THREATENING AND PREVENTABLE WITH MEDICAL THERAPY (E.G., CYSTOID MACULAR EDEMA), OR SURGICALLY REVERSIBLE (E.G., CATARACTS). ACUTE EVD CAN CAUSE VIRAL PERSISTENCE, INFLAMMATION, AND AUTOIMMUNITY, 3 INTER-RELATED BIOLOGICAL MECHANISMS THAT MAY PLAY A ROLE IN EARLY PASE PATHOGENESIS. VIRAL PERSISTENCE HAS BEEN FOUND IN THE EYES, SPINAL CORD, AND TESTES (OFTEN CONCURRENTLY) FOR AS LONG AS 2 YEARS POST-EVD AND MAY ALSO CONTRIBUTE TO SUBSEQUENT AUTOIMMUNITY AND INFLAMMATION. IN 2014, THE NIH-FUNDED PARTNERSHIP FOR RESEARCH ON VACCINES AND INFECTIOUS DISEASES IN LIBERIA (PREVAIL) LAUNCHED THE LARGEST LONGITUDINAL COHORT STUDY (P3) (2015-21) TO DATE OF EVD SURVIVORS (N=966) AND UNINFECTED COMPARATORS (N=2,784) TO INVESTIGATE PASE FOR UP TO 5 YEARS AFTER ACUTE EVD. THE P3 COHORT OFFERS A UNIQUE AND LARGE SAMPLING FRAME WITH DETAILED CHARACTERIZATIONS OF PASE AND ACCESS TO A BIOREPOSITORY OF BLOOD AND SEMEN SAMPLES. THE OVERACHING OBJECTIVE OF THIS R01 PROPOSAL IS TO ASSESS THE PREVALENCE AND BIOLOGICAL DETERMINANTS OF OCULAR PASE. CENTRAL HYPOTHESIS: VIRAL PERSISTENCE, INFLAMMATION, AND AUTOIMMUNITY ARE PART OF A BIOLOGICAL CASCADE THAT CAUSES EARLY OCULAR PASE, AND FOLLOWING VIRAL CONTROL, LATE OCULAR PASE CAN OCCUR EITHER DUE TO POST-VIRAL MECHANISMS (E.G., AUTOIMMUNITY) OR AS COMPLICATIONS OF EARLY OCULAR PASE. WE WILL TEST THIS WITH 2 SPECIFIC AIMS: AIM 1. TO ESTIMATE EXCESS PREVALENCE OF LATE OCULAR PASE AT 9-13 YEARS POST- EVD; AIM 2: TO ASSESS THE BIOLOGICAL DETERMINANTS OF OCULAR PASE. LEVERAGING THE P3 COHORT AND EXISTING RESEARCH INFRASTRUCTURE, WE WILL LAUNCH A NEW 4-YEAR FOLLOW-UP PERIOD, RE-SAMPLING THE EYE (OCULAR) COHORT, MANY OF WHOM DONATED SEMEN FOR VIRAL RNA TESTING. USING PROSPECTIVELY COLLECTED AND PREVIOUSLY BANKED SAMPLES AND EXISTING P3 DATA, WE WILL INVESTIGATE BIOLOGICAL MECHANISMS OF OCULAR PASE. THE STUDY TEAM HAS A STRONG HISTORY OF SUCCESSFUL COLLABORATION WITH OPHTHALMOLOGIC EXPERTISE IN NATURAL HISTORY STUDIES AND POST- ACUTE SEQUELAE OF EVD, METHODOLOGICAL EXPERTISE IN EPIDEMIOLOGY, DETAILED KNOWLEDGE OF THE P3 DATASET AND ANALYTICAL APPROACH, AND UNDERSTANDING OF LIBERIAN CULTURE. THIS R01 WILL YIELD INSIGHTS INTO BIOLOGIC TARGETS FOR INTERVENTIONS WHILE IDENTIFYING LATE OCULAR PASE THAT COULD BE PREVENTABLE OR REVERSIBLE.

HIV, HCV AND THE MENOPAUSAL TRANSITION: EFFECTS ON STEATOSIS AND FIBROSIS PROGRESSION

PATHOGENESIS AND THERAPY OF ICHTHYOSIS IN DISORDERS OF LIPID METABOLISM

AN EVALUATION OF NOVEL DOMAINS FOR PREDICTING 30-DAY READMISSION

MITOCHONDRIAL HEALTH, CARDIOVASCULAR RISK, AND BLOOD PRESSURE TARGETS IN HYPERTENSIVE ADULTS - PROJECT SUMMARY THE SYSTOLIC BLOOD PRESSURE INTERVENTION TRIAL (SPRINT) DEMONSTRATED THAT INTENSIVE BLOOD PRESSURE (BP) TARGETS SIGNIFICANTLY REDUCED RISKS OF CARDIOVASCULAR DISEASE (CVD) AND MORTALITY, LEADING TO NEW GUIDELINES RECOMMENDING A LOWER BP TARGET OF <130/80 MM HG. HOWEVER, INTENSIVE BP TARGETS MAY INCREASE THE RISK OF ADVERSE EVENTS FROM ANTIHYPERTENSIVE THERAPY. WITH WIDESPREAD ADOPTION OF THE NEW BP GUIDELINES, THERE IS AN URGENT NEED TO EVALUATE WHETHER THERE ARE SUBGROUPS OF PATIENTS WHO MAY HAVE AN UNFAVORABLE BALANCE OF BENEFITS AND HARMS FROM INTENSIVE BP LOWERING. WE PROPOSE AN INNOVATIVE APPROACH TO RISK STRATIFICATION THAT INTEGRATES TRADITIONAL RISK FACTORS WITH NOVEL INFORMATION GLEANED FROM MITOCHONDRIAL DNA (MTDNA). MITOCHONDRIA ARE INTRACELLULAR ORGANELLES THAT ARE ESSENTIAL FOR ENERGY METABOLISM AND STRESS ADAPTATION. IN ANIMAL MODELS, MITOCHONDRIAL DYSFUNCTION PLAYS A FUNDAMENTAL ROLE IN AGING, CVD, AND NEURODEGENERATIVE DISEASES. BECAUSE MITOCHONDRIAL METABOLISM IS VITAL TO ADAPT POSITIVELY TO BIOENERGETIC STRESSORS SUCH AS BP LOWERING, MEASURES OF MITOCHONDRIAL HEALTH MAY HELP TO PREDICT BENEFICIAL AND ADVERSE OUTCOMES AMONG ADULTS UNDERGOING INTENSIVE TREATMENT FOR HYPERTENSION. RECENT OBSERVATIONAL STUDIES HAVE LINKED NOVEL MTDNA MEASURES WITH SEVERAL AGE-RELATED OUTCOMES, INCLUDING RISKS OF CVD, HYPERTENSION, DEATH, DEMENTIA, AND REDUCED FUNCTIONAL STATUS. HOWEVER, THE OPTIMAL METHODS FOR INTEGRATING DATA ACROSS THE MITOCHONDRIAL GENOME HAVE NOT BEEN ESTABLISHED, NOR HAVE PRIOR STUDIES INVESTIGATED THE UTILITY OF MTDNA MEASURES FOR IDENTIFICATION OF SUBGROUPS WHO MAY DERIVE GREATEST BENEFITS OR HARMS FROM INTENSIVE BP TARGETS. THIS PROPOSAL WILL LEVERAGE NEXT-GEN SEQUENCING TECHNOLOGY AND MACHINE LEARNING ANALYTICS TO DEVELOP AND VALIDATE MTDNA RISK SCORES THAT PREDICT CVD RISK, MORTALITY RISK, AND LONGITUDINAL CHANGES IN COGNITIVE AND PHYSICAL FUNCTION IN OLDER ADULTS. OUR FIRST AIM WILL IMPLEMENT A BIOLOGICALLY-INFORMED NEURAL NETWORK AMONG PARTICIPANTS OF THE HEALTH, AGING, AND BODY COMPOSITION STUDY (HEALTH ABC; N=3,075) AND THE LIFESTYLE INTERVENTIONS AND INDEPENDENCE FOR ELDERS STUDY (LIFE; N=1,755) TO DEVELOP TWO MTDNA RISK SCORES FOR PREDICTION OF CVD AND COGNITIVE AND PHYSICAL FUNCTION OUTCOMES, WHILE ACCOUNTING FOR THE COMPETING RISK OF DEATH. OUR SECOND AND THIRD AIMS WILL VALIDATE THESE MTDNA RISK SCORES IN TWO LANDMARK TRIALS THAT EVALUATED THE IMPACT OF INTENSIVE VS STANDARD BP TARGETS ON CARDIOVASCULAR OUTCOMES: SPRINT (N=9,361) AND ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES (ACCORD; N=2,488). WE WILL THEN EXAMINE WHETHER MITOCHONDRIAL RISK, ASSESSED BY THESE MTDNA SCORES, MODIFIES THE EFFICACY OR SAFETY OF THE BP INTERVENTIONS. THIS WORK WILL: 1) DEVELOP INNOVATIVE METHODS FOR ANALYSIS OF MITOCHONDRIAL GENOMIC DATA; 2) PROVIDE NOVEL HYPOTHESES REGARDING PATHWAYS LINKING MITOCHONDRIAL HEALTH, CVD RISK AND FUNCTIONAL STATUS; AND 3) EXPLORE THE POTENTIAL OF MTDNA MEASURES FOR PERSONALIZED HEALTH INTERVENTIONS IN OLDER ADULTS.

IMPROVING ADVANCE CARE PLANNING BY PREPARING DIVERSE SENIORS FOR DECISION MAKING

COGNITIVE DECLINE IN CHRONIC RENAL INSUFFICIENCY

COGNITIVE REMEDIATION IN SCHIZOPHRENIA

PILOT CLINICAL TRIAL OF DEEP BRAIN STIMULATION FOR TINNITUS

EVALUATION OF HIV-ASSOCIATED CARDIAC DYSFUNCTION IN WOMEN

PROGNOSTIC INDICES FOR HOSPITALIZED OLDER ADULTS WITH AND WITHOUT ALZHEIMER?S DISEASE AND RELATED DEMENTIAS - PROJECT SUMMARY/ABSTRACT WE WILL DEVELOP AND EXTERNALLY VALIDATE ELECTRONIC HEALTH RECORD (EHR)-BASED PROGNOSTIC INDICES TO IMPROVE HEALTHCARE QUALITY FOR HOSPITALIZED OLDER ADULTS BY IDENTIFYING PATIENTS MOST LIKELY TO QUALIFY FOR (AND BENEFIT FROM) SPECIFIC HEALTH SERVICES. OUR INDICES WILL PREDICT: 1) 6-MONTH MORTALITY TO GUIDE HOSPICE REFERRAL DECISIONS; AND 2) 2-YEAR MORTALITY TO GUIDE OUTPATIENT PALLIATIVE CARE REFERRALS AND INFORM MEDICATION DEPRESCRIBING. WE WILL DEVELOP EACH OF THESE INDICES FOR PATIENTS WITH AND WITHOUT ALZHEIMER’S DISEASE AND RELATED DEMENTIAS, SINCE PREVIOUS STUDIES SUGGEST THAT THE TRAJECTORY OF DECLINE DIFFERS BETWEEN OLDER ADULTS WITH AND WITHOUT ALZHEIMER’S DISEASE AND RELATED DEMENTIAS. FUNCTION IS CRITICALLY IMPORTANT TO PREDICTION IN OLDER ADULTS, PARTICULARLY THOSE WITH ALZHEIMER’S DISEASE AND RELATED DEMENTIAS, AND WE HAVE SHOWN THAT THE PROGNOSTIC POWER OF FUNCTION INCREASES WITH AGE. A MAJOR LIMITATION THAT HAS HINDERED THE EFFECTIVENESS OF PREDICTIVE INDICES FOR HOSPITALIZED OLDER ADULTS HAS BEEN THE LACK OF FUNCTIONAL DATA IN THE EHR. RECENTLY, RECOGNIZING THE CRITICAL ROLE OF FUNCTION IN PROVIDING HIGH QUALITY HEALTHCARE TO OLDER ADULTS, HOSPITAL SYSTEMS HAVE STARTED TO ROUTINELY ASSESS AND DOCUMENT FUNCTIONAL STATUS. THIS DEVELOPMENT FACILITATES OUR PROPOSAL SINCE WE NOW HAVE ACCESS TO ROUTINE FUNCTIONAL DATA FROM SEVERAL HOSPITALS, ALLOWING US TO INCORPORATE THESE DATA INTO PROGNOSTIC INDICES. WITH EHRS BECOMING UBIQUITOUS IN HEALTHCARE SYSTEMS, OUR EXTERNALLY VALIDATED INDICES COULD BE INTEGRATED INTO THE EHR IN MOST HOSPITALS. TO FACILITATE USE IN HOSPITALS WITHOUT EHR INTEGRATION, WE WILL DEVELOP PARSIMONIOUS INDICES (ALSO FOR ADRD AND NON-ADRD PATIENTS) AVAILABLE ON EPROGNOSIS, OUR FREE AND WIDELY USED ONLINE COMPENDIUM OF GERIATRIC PREDICTION INDICES. WE WILL SET A NEW STANDARD FOR EQUITY-CONSCIOUS PROGNOSTIC MODEL BUILDING BY “BAKING EQUITY” INTO MODEL SELECTION AND INCORPORATING NEIGHBORHOOD DISADVANTAGE AS PREDICTOR REPRESENTING SOCIAL DETERMINANTS OF HEALTH. WE HAVE ESTABLISHED A 4 SITE COLLABORATORY, WHICH ALL ROUTINELY COLLECT PHYSICAL FUNCTION DATA, CLINICAL DIAGNOSES, STANDARDIZED DELIRIUM ASSESSMENTS, LABORATORY VALUES, AND PHYSIOLOGIC MEASURES: UCSF & CLEVELAND CLINIC (DEVELOPMENT COHORT); AND BETH ISRAEL DEACONESS MEDICAL CENTER & JOHNS HOPKINS (EXTERNAL VALIDATION COHORT). WE PROPOSE TO: (1) DEVELOP FULL PROGNOSTIC INDICES DESIGNED TO BE EMBEDDED IN EHRS FOR 6-MONTH AND 2-YEAR MORTALITY FOR HOSPITALIZED OLDER ADULTS WITH AND WITHOUT ALZHEIMER’S DISEASE AND RELATED DEMENTIAS; (2) DEVELOP PARSIMONIOUS WEB-BASED PROGNOSTIC INDICES DESIGNED TO BE ACCESSED THROUGH EPROGNOSIS FOR 6-MONTH AND 2-YEAR MORTALITY FOR OLDER ADULTS WITH AND WITHOUT ALZHEIMER’S DISEASE AND RELATED DEMENTIAS; (3) TO INTERNALLY VALIDATE THE EFFECTIVENESS OF THESE PROGNOSTIC INDICES; AND (4) TO EXTERNALLY VALIDATE THESE INDICES. THESE INDICES WILL HELP CLINICIANS IMPROVE HEALTHCARE QUALITY FOR OLDER ADULTS BY PROMPTING ALIGNMENT OF PATIENT PROGNOSIS WITH HEALTH SERVICES (I.E. HOSPICE AND PALLIATIVE CARE REFERRALS) AND DEPRESCRIBING DECISIONS.

IMPROVING DELIVERY OF GERMLINE TESTING IN VETERANS WITH ADVANCED PROSTATE CANCER

LIFECOURSE CVD RISK AND MIDLIFE COGNITIVE TRAJECTORIES AND BRAIN AGING: IMPLICATIONS FOR ALZHEIMER'S AND DEMENTIA PREVENTION

WNT ANTAGONIST GENES IN KIDNEY TUMOR PROGRESSION AND METASTASIS

MINIMALLY INVASIVE VENTRICULAR POLYMERIC INJECTION FOR TREATMENT OF HEART FAILURE

MARIJUANA USE IN OLDER ADULTS: HEALTH, FUNCTION AND FALL-RELATED INJURY

PLASMA NEURONAL-DERIVED EXOSOMES ARE BIOMARKERS OF HIV COGNITIVE IMPAIRMENT

SUVOREXANT: TARGETING OREXIN TO AUGMENT EXPOSURE THERAPY IN VETERANS WITH PTSD AND INSOMNIA

OPTIMIZING COGNITIVE REMEDIATION OUTCOMES IN SCHIZOPHRENIA

PHONE-BASED INTERVENTIONS UNDER NURSE GUIDANCE AFTER STROKE II (PINGS II)

A RADOMIZED, DOUBLE-BLIND, PLACEBO-CONROLLED TRIAL OF DOXAZOSIN FOR NIGHTMARES, SLEEP DISTURBANCE, AND NON-NIGHTMARE CLINICAL SYMPTOMS IN POST-TRAUMA

SKELETAL HEALTH IN TYPE 1 DIABETES AND THE ROLE OF DIABETIC KIDNEY DISEASE

NEUROPSYCHOBIOLOGY IN POLYSUBSTANCE ABUSERS DURING ABSTINENCE

NON-STEROIDAL IMPACT ON KIDNEY DISEASE STUDY (NSAIDS) - ABSTRACT THE PREVALENCE OF CHRONIC PAIN AMONG ADULTS IN THE UNITED STATES NOW EXCEEDS 20% AND IS EVEN HIGHER AMONG OLDER ADULTS AND THOSE WITH MULTIPLE COMORBID CONDITIONS. AS CLINICIANS HAVE INCREASINGLY LEARNED TO AVOID OPIATES FOR CHRONIC PAIN, NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) HAVE AN ESSENTIAL ROLE AS EFFECTIVE ANALGESICS. UNFORTUNATELY, THE THREAT OF KIDNEY TOXICITY FROM NSAIDS LIMITS THEIR USE FOR PAIN CONTROL, AND THERE ARE NO OPTIONS AVAILABLE TO MITIGATE THAT RISK DURING TREATMENT. AS A RESULT, CLINICIANS LARGELY AVOID USING NSAIDS IN PERSONS WHO EITHER HAVE CHRONIC KIDNEY DISEASE (CKD) OR ARE AT HIGH RISK FOR DEVELOPING CKD, REGARDLESS OF THEIR SEVERITY OF PAIN. THE PREMISE OF THIS PROPOSAL IS THAT NSAID EFFECTS ON THE KIDNEYS CAN BE MONITORED THROUGH A BIOMARKER GUIDED STRATEGY, AND THAT NEPHROTOXICITY CAN BE DETECTED EARLY AMONG THE SUBSET WHO WOULD EXPERIENCE DELETERIOUS IMPACT ON THEIR KIDNEYS. THE PRIMARY OBJECTIVE OF THIS PROPOSAL WILL BE TO BUILD AN NSAID KIDNEY MONITORING PANEL FROM URINE AND BLOOD BIOMARKERS OF KIDNEY TUBULE HEALTH THAT WILL IDENTIFY THE SPECIFIC SITES OF NSAID TOXICITY, DISTINGUISH NSAID-INDUCED CHANGES ON THE KIDNEY, AND FORECAST THE IMPACT ON SUBSEQUENT KIDNEY FUNCTION DECLINES. CURRENT MONITORING FOR NSAID-RELATED KIDNEY TOXICITY STILL RELIES ON SERUM CREATININE (SCR), WHICH IS INSENSITIVE FOR EARLY DETECTION, LACKS SPECIFICITY FOR TRUE KIDNEY INJURY, AND DOES NOT MEASURE TUBULOINTERSTITIAL HEALTH, THE MAJOR SITE OF NSAID ACTION AND INJURY. WITHOUT A BETTER STRATEGY, CLINICIANS WILL CONTINUE WITHHOLDING NSAIDS FROM PATIENTS IN CHRONIC PAIN. OUR RESEARCH TEAM HAS EXPERIENCE IN DEPLOYING A BROAD PANEL OF URINE AND BLOOD BIOMARKERS OF KIDNEY TUBULAR FUNCTION, INJURY AND TUBULOINTERSTITIAL INFLAMMATION THAT ENABLES BOTH THE SENSITIVITY TO DETECT EARLY KIDNEY DAMAGE AND THE SPECIFICITY TO DISTINGUISH PATTERNS THAT ARE MOST CONSISTENT WITH A DISTINCT MEDICATION EFFECT. WE WILL APPLY THIS STRATEGY AMONG TWO POPULATIONS AT HIGH RISK FOR DEVELOPING NSAID NEPHROTOXICITY. TO BEST CHARACTERIZE THE IMPACT OF HIGH-DOSE NSAID USE, WE WILL EVALUATE THE UCSF AXIAL SPONDYLOARTHRITIS COHORT (AIM 1), AS PATIENTS WITH THIS CONDITION HAVE FEW OTHER TREATMENT OPTIONS AND ARE ALSO LARGELY FREE OF OTHER KIDNEY RISK FACTORS. SECOND, WE WILL COLLABORATE WITH THE CHRONIC RENAL INSUFFICIENCY COHORT (CRIC) TO DETERMINE THE EFFECTS OF NSAID INITIATION AND DISCONTINUATION ON KIDNEY HEALTH IN THIS VERY HIGH-RISK GROUP WITH MODERATE-TO-SEVERE CKD (AIM 2). IN AIM 3, WE WILL INTEGRATE THE FINDINGS FROM EACH SETTING TO DETERMINE THE SET OF BIOMARKERS THAT BEST CAPTURES CHRONIC NSAID EXPOSURE, DYNAMIC CHANGES IN LONGITUDINAL NSAID USE, AND RISKS FOR LONGITUDINAL KIDNEY FUNCTION TRAJECTORIES. THIS RESEARCH WILL UNQUESTIONABLY YIELD TREMENDOUS INSIGHTS INTO THE INCIDENCE AND PATTERNS OF KIDNEY TUBULOINTERSTITIAL INJURY FROM NSAID USE IN THESE TWO DISTINCT POPULATIONS. WE ARE OPTIMISTIC THAT OUR FINDINGS WILL GUIDE FUTURE DEVELOPMENT OF AN NSAID KIDNEY MONITORING PANEL THAT WILL IMPROVE THE SAFE AND EFFECTIVE TREATMENT OF PAIN ACROSS THE SPECTRUM OF KIDNEY DISEASE RISK.

IMPACT OF MARIJUANA ON ADHERENCE, RISK FACTOR CONTROL AND CARDIOVASCULAR EVENTS

ATP2A2-REGULATED KERATINOCYTE CA2+ SIGNALING MECHANISMS

MOTION MOVING ONLINE TOGETHER INVESTIGATION OF NEUROCOGNITION

SURGERY FOR ISCHEMIC MITRAL REGURGITATION

THE U.S. DEPRESCRIBING RESEARCH NETWORK - MODIFIED PROJECT SUMMARY/ABSTRACT SECTION DEPRESCRIBING IS AN ESSENTIAL COMPONENT OF SAFE AND EFFECTIVE HEALTH CARE FOR OLDER ADULTS, WITH PARTICULAR RELEVANCE TO OLDER ADULTS WITH VULNERABILITIES SUCH AS MULTIMORBIDITY AND ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) THAT PLACE THEM AT HIGH RISK OF ADVERSE CONSEQUENCES FROM UNNECESSARY, HARMFUL, AND GOAL-DISCORDANT MEDICATION USE. YET, DEPRESCRIBING IS MUCH EASIER SAID THAN DONE. THERE IS A PAUCITY OF RESEARCH ABOUT HOW TO SAFELY AND EFFECTIVELY STOP MEDICATIONS AMONG OLDER ADULTS, INCLUDING THOSE WITH ADRD AND OTHER FORMS OF VULNERABILITY, AND THE MEDICAL RESEARCH PARADIGM IS BASED ON TESTING AND IMPLEMENTING NEW TREATMENTS RATHER THAN THE REMOVAL OF TREATMENTS. SUPPLEMENTING THE EXISTING PARADIGM WITH A NEW WAY OF THINKING REQUIRES NEW METHODS, NEW COLLABORATIONS, AND A NEW GENERATION OF INVESTIGATORS. TO ADDRESS THIS CHALLENGE, IN 2019 NIA FUNDED THE U.S. DEPRESCRIBING RESEARCH NETWORK (USDEN), A NATIONAL RESEARCH NETWORK WHOSE MISSION IS TO EXPAND THE QUALITY, QUANTITY, AND TRANSLATIONAL IMPACT OF RESEARCH ON DEPRESCRIBING FOR OLDER ADULTS, PARTICULARLY THOSE WITH HEIGHTENED VULNERABILITIES SUCH AS ADRD AND MULTIMORBIDITY. TO DATE, USDEN HAS BEEN REMARKABLY SUCCESSFUL. EDUCATIONAL AND COMMUNITY-BUILDING PROGRAMS HAVE ENGAGED HUNDREDS OF INTERPROFESSIONAL INVESTIGATORS IN COLLABORATIVE RESEARCH. MULTIPLE PILOT RESEARCH PROJECTS HAVE CATALYZED NEW SCHOLARSHIP AND FUTURE GRANT-SUPPORTED RESEARCH, PARTICULARLY IN POPULATIONS WITH DEMENTIA, MULTIMORBIDITY, AND OTHER VULNERABILITIES. WORKING GROUPS AND A DATA HARMONIZATION INITIATIVE HAVE DEVELOPED RESOURCES AND ESTABLISHED EVIDENCE-BASED BEST PRACTICES ON FOUNDATIONAL TOPICS IN DEPRESCRIBING SCIENCE. YET, MUCH ESSENTIAL WORK REMAINS TO BE DONE. THIS PROPOSAL SEEKS TO FUND THE NEXT PHASE OF THE US DEPRESCRIBING RESEARCH NETWORK, EXTENDING OUR PAST SUCCESSES AND LAUNCHING NEW INITIATIVES THAT WILL ADVANCE THE FIELD. THROUGH A SERIES OF CORES AND PROGRAMS, WE SEEK TO GROW AND SUPPORT A NATIONAL COMMUNITY OF DEPRESCRIBING INVESTIGATORS, AID EARLY-CAREER RESEARCHERS WITH A SPECIAL FOCUS ON HELPING THEM OBTAIN GRANTS TO ADVANCE THEIR DEPRESCRIBING SCIENCE AND CAREERS, ADVANCE HIGH-PRIORITY SCIENCE THROUGH TARGETED PILOT AWARDS AND PROJECTS, AND DO THIS ALL WITH INPUT FROM KEY STAKEHOLDERS AND SPECIAL ATTENTION TO OLDER ADULTS WITH ADRD AND OTHER FORMS OF HEIGHTENED VULNERABILITY. OUR AIMS ARE TO: (1) GROW AND SUPPORT A NATIONAL, INTERPROFESSIONAL COMMUNITY OF RESEARCHERS FOCUSED ON DEPRESCRIBING FOR OLDER ADULTS, WITH PARTICULAR FOCUS ON THOSE WITH HEIGHTENED VULNERABILITY SUCH AS ADRD; (2) ENHANCE THE RESEARCH AND CAREER DEVELOPMENT OF EARLY-CAREER INVESTIGATORS IN DEPRESCRIBING SCIENCE; (3) SUPPORT HIGH-VALUE RESEARCH INITIATIVES INCLUDING PILOT GRANTS AND PROJECTS THAT WILL ADVANCE DEPRESCRIBING SCIENCE; AND (4) ENGAGE STAKEHOLDERS AND PARTNER ORGANIZATIONS TO MAXIMIZE THE RELEVANCE, SUSTAINABILITY, AND TRANSLATIONAL POTENTIAL OF DEPRESCRIBING RESEARCH. TOGETHER, THESE ACTIVITIES WILL ADVANCE THE SCIENCE AND TRANSLATIONAL IMPACT OF DEPRESCRIBING IN OLDER ADULTS WHILE ELEVATING THE CAREER DEVELOPMENT OF INVESTIGATORS WHO WILL LEAD THE NEXT GENERATION OF SCHOLARSHIP IN THIS FIELD.

TRAINING IN RESEARCH FOR ACADEMIC NEUROLOGISTS TO SUSTAIN CAREERS AND ENHANCE THE NUMBERS OF DIVERSE SCHOLARS (TRANSCENDS)

PROGRAM TO AVOID CEREBROVASCULAR EVENTS THROUGH SYSTEMATIC ELECTRONIC TRACKING AND TAILORING OF AN EMINENT RISK-FACTOR (PACESETTER)

TBI REHABILITATION AND ACTIVATION IN VETERANS (TRAIN-VETS)

EFFECTS OF SLEEVE GASTRECTOMY ON CALCIUM METABOLISM AND THE SKELETON

NEUROSCIENCE-GUIDED COGNITIVE REMEDIATION IN ADOLESCENTS AT RISK FOR PSYCHOSIS

ROLE FOR THE INTERLEUKIN-2 RECEPTOR IN SIGNAL TRAN SDUCTION & GRAVI-SENSING THRESHOLD OF T LYMPH

SUPPRESSION OF THE IMMUNE RESPONSE IN SPACEFLIGHT AND AGING

ALZHEIMER?S DISEASE AND RELATED DEMENTIAS IN THE MOST INCARCERATED GENERATION: AN UNDERSTUDIED POPULATION WITH HEALTH DISPARITIES - THE PROPOSED PROJECT, WHICH RESPONDS TO NOT-AG-21-033 (HEALTH DISPARITIES AND ALZHEIMER’S DISEASE), IS THE FIRST LONGITUDINAL AND EPIDEMIOLOGICAL EXAMINATION OF JUSTICE-INVOLVEMENT AND DEMENTIA. AMERICANS WHO EXPERIENCE JUSTICE-INVOLVEMENT, MOVING FROM THE COMMUNITY TO INCARCERATION AND FROM INCARCERATION BACK TO THE COMMUNITY, ARE AGING RAPIDLY. MOREOVER, JUSTICE-INVOLVEMENT DISPROPORTIONATELY IMPACTS PERSONS OF COLOR AND OF LOW SOCIOECONOMIC STATUS, WHO ARE ALSO AT HIGH RISK FOR ALL FORMS OF DEMENTIA YET ARE FREQUENTLY EXCLUDED FROM DEMENTIA-RELATED RESEARCH. THIS STUDY WILL CONTRIBUTE TO OUR UNDERSTANDING OF HEALTH DISPARITIES IN DEMENTIA BY EVALUATING THE INTER-RELATIONSHIP AMONG INCARCERATION, DEMENTIA, AND A NUMBER OF IMPORTANT SOCIAL RISK FACTORS AND MULTI-MORBIDITY FACTORS OVER TIME IN A NATIONAL SAMPLE. WE WILL OPTIMIZE THE VETERANS HEALTH ADMINISTRATION’S (VHA) CAPACITY TO ACCESS INCARCERATION HISTORY FILES FROM THE CENTERS FOR MEDICARE AND MEDICAID SERVICES (CMS). WE PROPOSE TO LEVERAGE A LONGITUDINAL “PRISON RELEASE” COHORT WHICH WE CREATED FOR A DIFFERENT NIH-FUNDED STUDY AND SUPPLEMENT (R01 MH117604 AND S1). THIS COHORT INCLUDES >30,000 INDIVIDUALS ENROLLED IN BOTH MEDICARE AND VHA, WHO REENTERED THE COMMUNITY AT AGE =50 (BETWEEN 2008-2018) FOLLOWING AN INCARCERATION. WE WILL ENHANCE THIS COHORT TO INCLUDE ALL VETERANS WHO WERE AGE =50 BETWEEN 2008 TO 2022, INCLUDING THOSE INCARCERATED AT ANY POINT DURING THAT TIMEFRAME AND WHO WERE RELEASED, THOSE WHO REMAINED INCARCERATED (NO COMMUNITY REENTRY), AND THOSE NEVER INCARCERATED, FOR A TOTAL OF MORE THAN 46,000 JUSTICE-INVOLVED VETERANS AMONG 10.5 MILLION VETERANS. USING THIS RICH, LONGITUDINAL DATASET, WE HAVE THE UNPRECEDENTED OPPORTUNITY TO DEVELOP SOCIAL RISK FACTOR PROFILES AND MULTI-MORBIDITY PROFILES ASSOCIATED WITH RISK OF INCARCERATION AMONG THOSE WITH DEMENTIA (AIM 1) AND RISK OF DEMENTIA AMONG THOSE RELEASED FROM INCARCERATION (AIM 2). ACCESS TO VA AND MEDICARE DATA PROVIDES MORE COMPLETE OUTCOME ASCERTAINMENT, THUS INCREASING THE OPPORTUNITY TO DETERMINE IF THESE PROFILES DIFFER ACCORDING TO DEMENTIA SUBTYPES (E.G., ALZHEIMER’S DISEASE, VASCULAR, FRONTOTEMPORAL, MILD COGNITIVE IMPAIRMENT (MCI)). WE WILL ALSO MAKE NOVEL USE OF TRANSITION MODELS TO EVALUATE PROBABILITIES OF EXPERIENCING DISTINCT PATHWAYS (E.G., PATHWAY TO ENTERING INCARCERATION, TO BEING RELEASED FROM INCARCERATION, TO DEVELOPING DEMENTIA) AND DETERMINE PRECURSORS THAT PREDICT THESE PATHWAYS (AIM 3). WE WILL EVALUATE ALL AIMS WITHIN HEALTH DISPARITY POPULATIONS SUCH AS NON- HISPANIC BLACK, HISPANIC, NATIVE/INDIGENOUS GROUPS AND THOSE EXPERIENCING INDICATORS OF POVERTY (E.G., HOMELESSNESS AND SOCIOECONOMIC DISADVANTAGE). THIS STUDY HAS SUBSTANTIAL PUBLIC HEALTH SIGNIFICANCE. IT WILL INFORM STRATEGIES TO MITIGATE RISK OF PATIENTS WITH DEMENTIA ENTERING INCARCERATION, WILL DELINEATE THOSE AT HIGHEST RISK OF DEVELOPING DEMENTIA AFTER INCARCERATION SO AS TO INFORM PRISON-TO-COMMUNITY TRANSITIONAL CARE PLANNING, AND WILL IDENTIFY PRIME INTERVENTION POINTS WHERE OPTIMIZING DEMENTIA CARE COULD REDUCE HEALTH DISPARITIES BETWEEN THOSE WITH AND WITHOUT JUSTICE-INVOLVEMENT AND EVEN WITHIN THE JUSTICE-INVOLVED.

VITAMIN D RECEPTOR COACTIVATORS IN KERATINOCYTES

CHEMO-DIETARY PREVENTION, MIRNAS, EPIGENETIC AND PROSTATE CANCER

THE IMPACT OF MUSIC ON WELL-BEING AFTER DIAGNOSIS WITH ALZHEIMER'S DISEASE OR ITS RELATED DEMENTIAS - PROJECT SUMMARY/ABSTRACT NEARLY HALF A MILLION PEOPLE IN THE UNITED STATES DEVELOP ALZHEIMER’S DISEASE AND RELATED DEMENTIAS EACH YEAR. PEOPLE NEWLY DIAGNOSED AND THEIR FAMILY AND FRIENDS (CARE PARTNERS), REPORT THAT THESE DIAGNOSES CAN BE TERRIFYING AND LIFE-CHANGING, EVEN REPRESENTING A FORM OF SOCIAL DEATH. BUT RESPONSES TO DIAGNOSIS CAN ALSO BE POSITIVE AND CREATIVE. AFTER PEOPLE ARE DIAGNOSED WITH A FORM OF DEMENTIA, THEY AND THEIR CARE PARTNERS TURN TO COMMUNITY-BASED AND ONLINE RESOURCES FOR SUPPORT. SMALL QUALITATIVE STUDIES SHOW THAT THEY ENGAGE IN MUSIC, PREFERRED ACTIVITIES, AND SOCIAL NETWORKS TO SUPPORT PERSONAL IDENTITY AND SOCIAL RELATIONSHIPS. AMONG THESE RESPONSES, MUSIC ENGAGEMENT, DEFINED AS THE TOTALITY OF LISTENING, DANCING AND PARTICIPATING IN PREFERRED MUSIC ACTIVITIES, CREATES MOMENTS OF JOY DESPITE DEMENTIA-RELATED COGNITIVE DECLINE AND FUNCTIONAL IMPAIRMENT. MUSIC IS WELL STUDIED IN MODERATE AND SEVERE DEMENTIA, BUT WE LACK STUDIES ABOUT IMPACT OF MUSIC ON WELL-BEING IN THE MONTHS FOLLOWING A DEMENTIA DIAGNOSIS, WHEN IT MIGHT BE MOST HELPFUL AS A SUPPORT. AFTER DIAGNOSIS, MUSIC IS PROMISING NOT ONLY BECAUSE OF ITS ROLE IN WELL-BEING IN LATER STAGE DEMENTIA, BUT BECAUSE MUSIC SUPPORTS IDENTITY AND SOCIAL RELATIONSHIPS IN MOMENTS OF IDENTITY TRANSFORMATION, SUCH AS MARRIAGE OR DEATH. IN THIS STUDY, WE EXAMINE THE WAYS IN WHICH MUSIC IMPACTS WELL-BEING IMMEDIATELY AFTER A DEMENTIA DIAGNOSIS, AND THE WAYS IN WHICH POSITIVE EFFECTS PERSIST OVER TIME. WE DO THIS BY LOOKING AT WELL-BEING AT THREE LEVELS, PERSONAL, RELATIONSHIP, AND COMMUNITY, PLACING THESE IN THE CONTEXT OF LARGER SOCIAL AND SOCIETAL FORCES INCLUDING STIGMA AND DISCRIMINATION. WE WILL EXAMINE HOW MUSIC IMPACTS PERSONAL WELL-BEING AFTER DEMENTIA DIAGNOSIS, FOLLOWING 100 PEOPLE NEWLY DIAGNOSED AND 100 IDENTIFIED CARE PARTNERS (DYADS) FOR SIX MONTHS USING MIXED-METHODS, INCLUDING QUANTITATIVE MEASURES AND QUALITATIVE INTERVIEWS (AIM 1). DYADS WILL BE RECRUITED TO ENSURE DIVERSITY OF MUSIC ENGAGEMENT, FROM NO MUSIC TO EVERYDAY MUSIC ENGAGEMENT. AIM 1 FINDINGS ARE USED TO IDENTIFY POSITIVE IMPACTS OF MUSIC ON WELL-BEING THAT CAN BE STUDIED OVER TIME AND A DIVERSE SUB-SAMPLE OF DYADS WHO HAVE WIDELY DIFFERENT WAYS OF ENGAGING IN MUSIC. WE WILL IDENTIFY REPRODUCIBLE MUSIC BEHAVIORS THAT SUPPORT WELL- BEING IN RELATIONSHIPS AS DEMENTIA PROGRESSES, IN A LONGITUDINAL ETHNOGRAPHY OF 50 DYADS FOR UP TO TWO YEARS IN THE HOME, USING INTERVIEWS, OBSERVATIONS, AND ENGAGEMENT IN USUAL MUSIC ACTIVITIES (AIM 2). WE PLACE THESE FINDINGS IN THE CONTEXT OF ONLINE AND COMMUNITY-BASED ORGANIZATION SUPPORT, INCLUDING ON-LINE RESOURCES THAT INCORPORATE MUSIC AND PARTICIPANT OBSERVATION IN PUBLIC EVENTS SUCH AS THE WALK TO END ALZHEIMER’S AND PUBLICLY AVAILABLE ONLINE PROGRAMS USING MUSIC (AIM 3). THE FINDINGS FROM THESE THREE AIMS WILL BE USED TO IDENTIFY BEST PRACTICES THAT WE CAN BRING BACK TO THE COMMUNITY-BASED ORGANIZATIONS THAT SERVE PEOPLE LIVING WITH DEMENTIA AND CARE PARTNERS. THE FINDINGS WILL BE SYNTHESIZED TO IDENTIFY THE KEY FEATURES NECESSARY FOR THE DESIGN AND TESTING OF NEW MUSIC-FOCUSED INTERVENTIONS TO SUPPORT PEOPLE NEWLY DIAGNOSED WITH DEMENTIA AND THEIR CARE PARTNERS.

INVESTIGATING MECHANISMS OF HIV PERSISTENCE IN THE GUT

REGULATION OF PARATHYROID FUNCTIONS BY G-PROTEIN COUPLED RECEPTORS

LONG-TERM NEUROPSYCHIATRIC SEQUELAE OF SARS-COV-2 INFECTION IN LATE LIFE - THE PSYCHOLOGICAL AND SOCIAL IMPACT OF THE PANDEMIC HAVE BEEN SEVERE AND LIKELY WILL HAVE SIGNIFICANT MENTAL EFFECTS OVER THE LONG TERM. THERE IS ALSO EMERGING EVIDENCE THAT SUGGESTS THAT COVID-19 MAY HAVE DIRECT EFFECTS ON THE BRAIN OR TRIGGER IMMUNE RESPONSES THAT HAVE ADDITIONAL ADVERSE CONSEQUENCES ON BRAIN FUNCTION AND MENTAL HEALTH IN PATIENTS WITH COVID-19. COVID-19 HAS DISPROPORTIONATELY IMPACTED OLDER ADULTS, WITH THOSE 65 YEARS AND OLDER AT HEIGHTENED RISK OF SEVERE ILLNESS. IN FACT, MOST OLDER ADULTS WITH COVID-19 SURVIVE INITIAL INFECTION AND ENTER A CLINICAL RECOVERY PHASE FOR MONTHS OR LONGER, WHICH IS OFTEN MARKED BY PERSISTENT SYMPTOMS AND ADVERSE HEALTH OUTCOMES. THUS, THERE IS AN URGENT NEED TO UNDERSTAND THE NEUROPSYCHIATRIC SEQUELAE OF COVID-19, ESPECIALLY IN OLDER ADULTS. THE PRIMARY GOAL OF THE PROPOSED RESEARCH IS TO DETERMINE WHETHER COVID-19 IS ASSOCIATED WITH INCREASED INCIDENCE OF DEMENTIA (ALZHEIMER’S DISEASE AND RELATED DEMENTIAS) AND NEW OR REEMERGENCE OF PSYCHIATRIC DISORDERS IN A NATIONAL SAMPLE OF PATIENTS 65 YEARS AND OLDER, WITH COMPLETE OUTCOME ASCERTAINMENT FROM VETERANS HEALTH ADMINISTRATION AND MEDICARE DATA. THE SECONDARY AIM IS TO EXAMINE RISK FACTORS ASSOCIATED WITH DEVELOPMENT OF THESE NEUROPSYCHIATRIC DISORDERS (I.E., ALZHEIMER’S DISEASE AND RELATED DEMENTIAS [AD/ADRD], MOOD DISORDERS, ANXIETY DISORDERS, AND PSYCHOSIS) AMONG OLDER ADULTS WITH HISTORY OF COVID-19. THE INTENT OF THE CURRENT PROPOSAL ISN’T TO BE DETERMINISTIC ABOUT THE MECHANISMS OF THESE ASSOCIATIONS, BUT TO MOVE THE FIELD FORWARD INFORMING CURRENT KNOWLEDGE GAPS ABOUT COVID-19 AS A RISK FACTOR FOR NEUROPSYCHIATRIC DISORDERS IN LATE LIFE. THE CURRENT PROPOSAL WILL SUBSTANTIATE THE EARLY REPORTS OF NEUROPSYCHIATRIC EFFECTS FROM COVID-19 IN SMALL STUDIES IN A LARGE GEOGRAPHICALLY AND RACIALLY DIVERSE NATIONAL SAMPLE USING COMPREHENSIVE DATA SOURCES AND ADVANCED STATISTICAL METHODS AND WILL IMPROVE OUR UNDERSTANDING OF WHETHER COVID-19 IS A RISK FACTOR FOR THE DEVELOPMENT OF AD/ADRD AND PSYCHIATRIC DISORDERS (AIM 1). FURTHERMORE, THIS STUDY WILL IDENTIFY THE BASELINE RISK FACTORS FOR DEVELOPMENT OF AD/ADRD AND PSYCHIATRIC DISORDERS AMONG INDIVIDUALS WITH COVID-19 (AIM 2) AND DETERMINE WHETHER CERTAIN ACUTE AND POST- ACUTE SYMPTOMS ARE INDICATIVE OF A HIGHER RISK FOR DEVELOPING AD/ADRD (AIM 3). GIVEN THAT OVER 79 MILLION AMERICANS HAVE BEEN DIAGNOSED WITH COVID-19, EVEN SMALL INCREASES IN RISK OF AD/ADRD AND PSYCHIATRIC DISORDERS MAY HAVE SIGNIFICANT CONSEQUENCES FOR PATIENTS, THEIR CAREGIVERS, AND THE U.S. HEALTH CARE SYSTEM. IT IS LIKELY THAT THE PROPOSED RESEARCH WILL HELP TO IDENTIFY INDIVIDUALS THAT MAY BE AT HIGHER RISK AND SUPPORT ENGAGEMENT IN EARLY INTERVENTION STRATEGIES THAT WILL LEAD TO MITIGATION OF AD AND RELATED DISEASES AND LATE-LIFE MENTAL HEALTH DISORDERS.

UTILIZING BEIGE FAT TO IMPROVE MUSCLE FUNCTION AFTER ROTATOR CUFF REPAIR

IMPACT OF EXERCISE ON KIDNEY FUNCTION AND INJURY AMONG ELDERS IN THE LIFE TRIAL

TRANSLATION OF COGNITIVE NEUROSCIENCE TO REHABILITATION FOR PATIENTS WITH TBI

ENVIRONMENTAL METAL TOXICITY AND KIDNEY TUBULE MEASURES IN DIVERSE POPULATIONS - PROJECT SUMMARY / ABSTRACT THERE IS A HIGH BURDEN OF ENVIRONMENTAL METAL EXPOSURE IN THE U.S. IN RURAL COMMUNITIES, THIS IS OFTEN FROM CONTAMINATION OF GROUNDWATER FROM MINING AND NATURAL SOURCES AND USE OF WELL WATER FOR COOKING AND DRINKING. IN URBAN SETTINGS, RECENT WATER CONTAMINATION EVENTS IN FLINT, MICHIGAN AND JACKSON, MISSISSIPPI, AMONG OTHER COMMUNITIES, HAVE HIGHLIGHTED VULNERABILITIES TO FAILURES IN WATER SAFETY. METAL EXPOSURE REMAINS DISPROPORTIONATELY HIGH AMONG MINORITIZED POPULATIONS AND THOSE WITH LOWER SOCIOECONOMIC STATUS IN BOTH RURAL OR URBAN SETTINGS. ACROSS A BROAD PANEL OF DIFFERENT METALS, INCLUDING ARSENIC, CADMIUM, LEAD, AND URANIUM, HIGH LEVELS OF EXPOSURE ARE KNOWN TO DAMAGE KIDNEY TUBULES. YET, THE HEALTH CONSEQUENCES OF LOWER LEVELS OF METAL EXPOSURE HAVE NOT BEEN ELUCIDATED, PRINCIPALLY BECAUSE SENSITIVE MARKERS OF KIDNEY TUBULE DAMAGE HAD BEEN LACKING. RECENTLY, METHODS FOR ASSESSING METAL LEVELS IN BIOSPECIMENS AND IN THE WATER SUPPLY, HAVE MARKEDLY PROGRESSED, INCLUDING SENSITIVE METHODS TO DETECT KIDNEY TUBULE DAMAGE NON-INVASIVELY. OUR ULTIMATE GOAL IS TO DEVELOP A KIDNEY MONITORING PANEL THAT CAN DETECT AND QUANTIFY DAMAGE TO THE KIDNEY FROM ANY OF THE METAL EXPOSURES THAT HAVE

INVESTIGATING FEAR SYSTEM MYELINATION IN PTSD USING IN VIVO AND POST MORTEM DATA - PROJECT SUMMARY/ABSTRACT THIS PROPOSAL WILL EXAMINE MALADAPTIVE GRAY MATTER (GM) MYELINATION AS A CANDIDATE MECHANISM UNDERPINNING TWO FUNCTIONAL BRAIN ABNORMALITIES WELL ESTABLISHED IN POSTTRAUMATIC STRESS DISORDER (PTSD): HYPER- CONNECTEDNESS OF THE THREAT RESPONSE NETWORK (TRN: DEFINED AS HIPPOCAMPUS (HIP), AMYGDALA (AMYG), ANTERIOR INSULA (INS), AND DORSAL ANTERIOR CINGULATE CORTEX (DACC)), AND DISRUPTION OF THE DEFAULT MODE NETWORK (DMN). EXPERIENCE- AND ACTIVITY-DEPENDENT GM MYELINATION HAVE BEEN OBSERVED IN MANY BRAIN REGIONS AND HAVE BROAD RELEVANCE TO PSYCHIATRIC DISORDERS. WHILE EXPERIENCE-DEPENDENT MYELINATION EVOLVED TO ACCELERATE NERVE CONDUCTION, MYELINATION IN GM HAS BEEN SHOWN TO REDUCE SYNAPTIC DENSITY AND SYNAPSE-BASED NEUROPLASTICITY IN ANIMAL MODELS. OUR MODEL PROPOSES THAT EXCESS GM MYELINATION IN THE TRN IN PTSD RESULTS IN A HYPERCONNECTED SALIENCE NETWORK (SN; WHICH INCLUDES AMYG, DACC, AND INS BUT NOT HIP. SEE “BRIDGING FRAMEWORKS” SECTION) AND A POORLY CONNECTED AND HYPOACTIVE DMN. GIVEN THAT MYELIN DEVELOPMENT AND RE- MYELINATION IN BOTH CORTICAL AND SUBCORTICAL GM ARE RESPONSIVE TO THERAPEUTIC AGENTS, CONFIRMING OUR MODEL COULD LEAD TO NOVEL TARGETS FOR TREATMENT OF PTSD, A CONDITION THAT HAS RESISTED PHARMACOTHERAPEUTIC INTERVENTION. OUR PROPOSED MODEL YIELDS A CANDIDATE MECHANISM UNDERPINNING THE “SYNAPTIC DISCONNECTION” SYNDROME PROPOSED BY KRYSTAL AND COLLEAGUES TO EXPLAIN IMPAIRED FUNCTIONAL BRAIN CONNECTIVITY IN PTSD. IT IS ALSO NOTEWORTHY THAT RECENT EVIDENCE SUGGESTS THAT DMN DYSCONNECTIVITY IN PTSD IS NOT ASSOCIATED WITH THE DISRUPTION OF LARGE FRONTAL WHITE MATTER TRACKS. AS SUCH, EXCESS GM MYELINATION IN KEY STRUCTURES MAY SUPPLY AN EXPLANATION FOR THIS PHENOMENON. USING A COMBINATION OF POSTMORTEM NEUROPATHOLOGY IN PTSD CASES VERSUS BRAIN BANK CONTROLS, AND IN VIVO NEUROIMAGING AT 3T IN A MATCHED CASE CONTROL DESIGN, WE WILL EXAMINE IF PTSD IS ASSOCIATED WITH INCREASED MYELIN CONTENT AND DECREASED SYNAPTIC AND NEURITE DENSITY IN THE TRN STRUCTURES. FINALLY, WE WILL TEST IF INCREASED GM MYELIN AND DECREASED NEURITE DENSITY IN TRN ACCOUNT FOR INCREASED RESTING STATE (RS) CONNECTIVITY WITHIN THE SN AND DECREASED RS CONNECTIVITY WITHIN THE DMN IN THE SAME LIVING SUBJECTS. INTEGRATION OF POSTMORTEM NEUROPATHOLOGY, AFFORDED BY THE NATIONAL PTSD BRAIN BANK, AND IN VIVO NEUROIMAGING WILL ENABLE A HIGHLY NOVEL BUT BROADLY TESTABLE EXPLORATION OF GM MYELINATION AND ITS CONSEQUENCES IN THE HUMAN BRAIN AS MODIFIED BY PTSD.

STROKE MINIMIZATION THROUGH ADDITIVE ANTI-ATHEROSCLEROTIC AGENTS IN ROUTINE TREATMENT II STUDY - GLOBAL ESTIMATES SUGGEST THAT SUB-SAHARAN AFRICA (SSA) NOW HAS THE HIGHEST INCIDENCE AND PREVALENCE OF STROKE AND THE WORST SURVIVAL OUTCOMES FROM STROKE IN THE WORLD. CURRENT PROJECTIONS ARE THAT THE ALREADY OVERWHELMING BURDEN OF STROKES AND OTHER CARDIOVASCULAR DISEASES (CVDS) IN AFRICA WILL CONTINUE TO ESCALATE OVER THE COMING DECADES AS TRADITIONAL VASCULAR RISK FACTORS BURGEON IN THESE POPULATIONS. INDEED, HYPERTENSION AND DYSLIPIDEMIA ARE THE TOP 2 MODIFIABLE RISK FACTORS FOR STROKE IN AFRICA WITH POPULATION ATTRIBUTABLE FRACTIONS OF 90.2% AND 35.8%, RESPECTIVELY, POSITIONING THEM AS PRIME TARGETS FOR SECONDARY RISK REDUCTION AFTER STROKE. IDENTIFYING STRATEGIES TO REDUCE VASCULAR RISK IN LOW-AND MIDDLE-INCOME COUNTRIES (LMICS) WILL MEET A GLOBAL GOAL OF REDUCING CHRONIC DISEASE DEATH RATES BY AN ADDITIONAL 2% PER YEAR, WITH ONLY A MODERATE RISE IN HEALTH EXPENDITURES. GHANA IS A LMIC IN SSA WITH A PROFOUND LACK OF HUMAN RESOURCES FOR HEALTH CARE COORDINATION FOR STROKE SURVIVORS, ESPECIALLY IN THE IMPLEMENTATION OF EVIDENCE-BASED SECONDARY PREVENTION THERAPIES. FIXED-DOSE COMBINATION PILLS, ALSO KNOWN AS “POLYPILLS”, CONTAINING GENERIC DRUGS: ASPIRIN, A STATIN, AND BLOOD PRESSURE (BP) LOWERING MEDICATION(S), MAY BE A VIABLE LOW-COST AVENUE TO BROADLY IMPROVE MEDICATION ADHERENCE AND CONSEQUENTLY REDUCE FURTHER DISABILITY OR DEATH ON A LARGE SCALE AMONG STROKE SURVIVORS IN SSA. THEREFORE, THE OVERALL OBJECTIVE OF STROKE MINIMIZATION THROUGH ADDITIVE ANTI-ATHEROSCLEROTIC AGENTS IN ROUTINE TREATMENT II (SMAART-II) STUDY IS TO DEPLOY A HYBRID STUDY DESIGN TO 1) DEMONSTRATE THE EFFICACY OF A POLYPILL (POLYCAP ®) CONTAINING FIXED DOSES OF ANTIHYPERTENSIVES, A STATIN, AND ANTIPLATELET THERAPY TAKEN AS TWO CAPSULES, ONCE DAILY ORALLY IN REDUCING COMPOSITE VASCULAR RISK OVER 24 MONTHS VS. USUAL CARE AMONG 500 RECENT STROKE PATIENTS ENCOUNTERED AT 12 HOSPITALS IN GHANA; 2) DEVELOP AN IMPLEMENTATION STRATEGY FOR ROUTINE INTEGRATION AND POLICY ADOPTION OF POLYPILL FOR POST-STROKE CARDIOVASCULAR RISK REDUCTION IN AN UNDER-RESOURCED SYSTEM BURDENED BY SUBOPTIMAL CARE AND OUTCOMES. SMAART-II IS PREMISED ON THE FEASIBILITY AND RELATIVE SAFETY OF THE POLYCAP ® FOR ISCHEMIC STROKE AMONG GHANAIANS IN A SINGLE CENTER TRIAL (SMAART-I) CONDUCTED WITH THE SUPPORT OF AN R21 GRANT (NS103752) FROM THE NIH GLOBAL BRAIN DISORDERS PROGRAM. WE NOW SEEK TO TEST THE DEFINITIVE EFFICACY AND SAFETY OF THE POLYPILL TO IMPROVE MEANINGFUL POST-STROKE GLOBAL RISK FACTOR CONTROL IN A LARGER SAMPLE, ACROSS SEVERAL SITES, ACROSS DIVERSE HEALTH CARE SETTINGS, BEYOND TERTIARY LEVEL CARE, AND OVER A LONGER PERIOD. IN ADDITION TO ASSESSING CLINICAL OUTCOMES, SMAART II WILL ASSESS IMPLEMENTATION OUTCOMES SUCH AS ADOPTION, ACCEPTABILITY, COST, PERTINENT TO UPTAKE OF THE POLYPILL STRATEGY IN GHANA TO INFORM POLICY. REGARDLESS OF ITS OUTCOME, FINDINGS FROM SMAART-II WILL CONTRIBUTE MEANINGFUL INFORMATION FROM THE AFRICAN PERSPECTIVE TO INFORM THE FORMULATION OF GUIDELINES FOR GLOBAL ADOPTION OF POLYPILLS INTO ROUTINE CARE FOR SECONDARY CVD RISK PREVENTION BY INTERNATIONAL BODIES SUCH AS THE WORLD HEALTH ORGANIZATION.

VISCERAL ADIPOSITY HIV AND HCV: BIOLOGIC MEDIATORS OF HEPATIC STEATOSIS

INFLAMMATORY MECHANISMS IN CEREBRAL ISCHEMIA

INFLAMMATORY CHALLENGE AND FEAR EXTINCTION: A MODEL TO ENHANCE UNDERSTANDING OF POSTTRAUMATIC STRESS DISORDER - PROJECT SUMMARY POSTTRAUMATIC STRESS DISORDER (PTSD) IS A CHRONIC DISORDER AFFECTING MORE THAN 8% OF THE GENERAL POPULATION AND TWO-THREE TIMES AS MANY WOMEN AS MEN. DEFICITS IN FEAR EXTINCTION, WHICH REFERS TO THE LEARNED INHIBITION OF FEAR RESPONSES, AND FEAR EXTINCTION RECALL, WHICH REFERS TO THE RETENTION OF THIS LEARNED INHIBITION OVER TIME, PLAY A CRITICAL ROLE IN PTSD. INTERVENTIONS THAT TARGET FEAR EXTINCTION LEARNING ARE FIRST-LINE TREATMENTS FOR PTSD, BUT THEY ARE ONLY PARTIALLY EFFECTIVE. TO DEVELOP NEW AND ENHANCED INTERVENTIONS, WE NEED A BETTER UNDERSTANDING OF THE FACTORS THAT INFLUENCE FEAR EXTINCTION PROCESSES IN PTSD IN BOTH FEMALES AND MALES. ONE SUCH FACTOR IS INFLAMMATION, WHICH IS ELEVATED IN RESPONSE TO ACUTE PSYCHOLOGICAL STRESS AND IN PTSD. PRECLINICAL MODELS INDICATE THAT ELEVATED INFLAMMATION IN GENERAL, AND ELEVATED LEVELS OF THE PRO-INFLAMMATORY CYTOKINE INTERLEUKIN- 6 (IL-6) IN PARTICULAR, CAN IMPAIR FEAR EXTINCTION. PEOPLE WITH PTSD AND WOMEN MAY BE MORE SENSITIVE TO THE EFFECTS OF INFLAMMATORY ACTIVITY ON FEAR EXTINCTION. OUR LONG-TERM GOAL IS TO UNCOVER THE MECHANISTIC ROLE THAT INFLAMMATION PLAYS IN PTSD IN ORDER TO IDENTIFY EFFECTIVE PRIMARY AND ADJUNCTIVE ANTI-INFLAMMATORY INTERVENTIONS. OUR OBJECTIVE IN THIS PROPOSAL IS TO DETERMINE THE EFFECTS OF ACUTE INFLAMMATORY CHALLENGE ON FEAR EXTINCTION PROCESSES IN TRAUMA-EXPOSED WOMEN AND MEN WITH AND WITHOUT PTSD. OUR CENTRAL HYPOTHESIS IS THAT ACUTE INFLAMMATORY CHALLENGE WILL IMPAIR FEAR EXTINCTION PROCESSES, WITH PARTICULARLY STRONG EFFECTS IN PEOPLE WITH CHRONIC PTSD AND WOMEN. OUR AIMS ARE TO: 1) DETERMINE THE EFFECTS OF ACUTE INFLAMMATORY CHALLENGE ON FEAR EXTINCTION PROCESSES IN INDIVIDUALS WITH AND WITHOUT PTSD; 2) EXAMINE IF INCREASES IN INFLAMMATORY ACTIVITY MEDIATE ASSOCIATIONS BETWEEN ACUTE INFLAMMATORY CHALLENGE AND FEAR EXTINCTION PROCESSES; AND 3) ELUCIDATE SEX DIFFERENCES IN THE EFFECTS OF ACUTE INFLAMMATORY CHALLENGE ON FEAR EXTINCTION PROCESSES. IN OUR PROPOSED STUDY, WE WILL USE POLYSACCHARIDE TYPHOID VACCINE, WHICH OUR PRELIMINARY DATA SUPPORT AS A ROBUST ACUTE INFLAMMATORY CHALLENGE, AND A FEAR-CONDITIONING PARADIGM THAT WE HAVE USED IN >200 PEOPLE WITH PTSD. PARTICIPANTS WILL FIRST UNDERGO FEAR ACQUISITION (I.E., FEAR LEARNING). THEN, THREE DAYS LATER, FOLLOWING CONSOLIDATION, THEY WILL RECEIVE EITHER VACCINE OR PLACEBO; 4.5 HOURS LATER, WHEN INFLAMMATORY ACTIVITY IS ROBUSTLY INCREASED, PARTICIPANTS WILL GO THROUGH THE FEAR EXTINCTION PHASE OF THE PROTOCOL, AND ONE WEEK LATER, THE EXTINCTION RECALL PHASE, WITH OUTCOMES INDEXED BY THE SKIN CONDUCTANCE RESPONSE (SCR). INFLAMMATORY MARKERS WILL BE MEASURED AT BASELINE PRIOR TO FEAR ACQUISITION, PRE- AND 4.5 HOURS POST VACCINE/PLACEBO PRIOR TO FEAR EXTINCTION, AND PRIOR TO EXTINCTION RECALL. THIS PROPOSAL IS SIGNIFICANT AND INNOVATIVE BECAUSE IT WOULD BE THE FIRST STUDY TO EXAMINE THE EFFECTS OF ACUTE INFLAMMATORY ACTIVITY ON FEAR EXTINCTION PROCESSES IN TRAUMA-EXPOSED INDIVIDUALS WITH AND WITHOUT PTSD, AND IT HAS POTENTIAL TO ELUCIDATE BIOLOGICAL MECHANISMS OF IMPAIRED FEAR EXTINCTION, UNCOVER SEX DIFFERENCES, AND POINT US IN THE DIRECTION OF NOVEL INTERVENTIONS TO TREAT PTSD.

MECHANISTIC LINKS BETWEEN PARP, NAD AND BRAIN INFLAMMATION AFTER TBI

FUNCTIONAL BRAIN ABNORMALITIES IN THE SCHIZOPHRENIA PRODROME

PRECURSORS OF SUICIDE IN OLDER ADULTS TRANSITIONING FROM PRISON TO COMMUNITY

ROLE OF PRES2 MUTANTS IN PATHOGENESIS OF CHRONIC HEPATITIS B

MICRORNAS IN FREQUENTLY DELETED LOCI REGULATE PROSTATE CANCER EMT AND METASTASIS

REGULATION OF ALVEOLAR EPITHELIAL BARRIER FUNCTION BY CLAUDINS

UNDERSTANDING HIV LATENCY REVERSAL AND CLEARANCE OF INFECTED CELLS IN VIVO

INTEGRATING PATHOGENIC MECHANISMS IN PARKINSON'S DISEASE

ROLE OF APOLIPOPROTEIN E4 IN THE PROGRESSION AND REGRESSION OF ATHEROSCLEROSIS

USING AN AMBULATORY TECHNOLOGY APPROACH TO UNDERSTAND NIGHTMARES, NIGHTMARE ENACTMENT, AND SLEEP-RELATED VIOLENT BEHAVIOR: TOWARD PRECISION DIAGNOSIS IN PTSD

EPIDEMIOLOGY OF DEPRESSION AND HEART FAILURE IN AGING

MRI OF STRUCTURE AND FUNCTION IN ASSESSING HEMODYNAMIC IMPACT ON AAA EVOLUTION

REGULATORY CONTROL OF GLUTAMATE - INDUCED SUPEROXIDE PRODUCTION

PROSTATE-SPECIFIC ANTIGEN PRACTICES AND OUTCOMES IN THE ELDERLY

GENISTEIN AND CHEMOTHERAPY OF KIDNEY CANCER

DEVELOPING PROGNOSTIC MODELS FOR LIFE EXPECTANCY AND GERIATRIC OUTCOMES

MOLECULAR BIOMARKERS FOR KIDNEY CANCER PROGNOSIS USING NON-CODING RNAS

RISK FACTORS AND SUSCEPTIBILITY IN GONOCOCCAL INFECTION

NATURE OF MAMALIAN CUTANEOUS PERMEABLILTY BARRIER

COMBINED PTH AND CALCIMIMETIC THERAPY AND ITS MECHANISMS FOR OSTEOANABOLISM

OUTCOMES OF BETA BLOCKERS AFTER MYOCARDIAL INFARCTION IN NURSING HOME RESIDENTS

INTEGRATING ENVIRONMENTAL, GENOMIC, AND FUNCTIONAL DATA TO CHARACTERIZE INDIVIDUAL RISK FOR PARKINSON'S DISEASE. NEW AWARD.

CONDITIONAL KNOCKOUT OF CALCIUM RECEPTORS IN BONE CELLS

INFLAMMATORY MECHANISMS IN CEREBRAL ISCHEMIA

PILOT TEST OF APNEA AND INSOMNIA RELIEF FOR VETERANS WITH GULF WAR ILLNESS.

DEACETYLATION OF MITOCHONDRIAL PROTEINS PROTECT NEURONS FROM ISCHEMIC INJURY

S1P-MEDIATED STIMULATION OF ANTIMICROBIAL DEFENSE

NEUROPLASTICITY AFTER EXPERIMENTAL STROKE

EFFECTS OF HIGH VERSUS LOW AUTONOMY ON SPACE CREWMEMBER PERFORMANCE

STROKE IN FEMALES WITH METABOLIC SYNDROME, A VASCULAR PERSPECTIVE

CALCIUM-SENSING RECEPTOR AND KERATINOCYTE DIFFERENTIATION

GENETIC FACTORS FOR RACE RELATED PROSTATE CANCER.

AUTOPSY-INFORMED INTEGRATED CLINICAL AND IMAGING MODELS FOR PREDICTION OF NON-AD CO-PATHOLOGIES IN AD - THE OVERALL GOAL OF THIS PROJECT IS TO USE GOLD-STANDARD AUTOPSY-CONFIRMED DATASETS TO BUILD COMPUTATIONAL MODELS WITH WHICH WIDELY AVAILABLE NEUROIMAGING AND COGNITIVE ASSESSMENTS CAN BE USED TO PREDICT PRESENCE OF NON- ALZHEIMER’S DISEASE NEUROPATHOLOGICAL CHANGES (NON-ADNC) IN INDIVIDUALS WITH ADNC. FAR FROM A RARE PROBLEM, ESTIMATES OF RATES OF NEURODEGENERATIVE CO-PATHOLOGY IN PATIENTS WITH ADNC RANGE FROM 50% TO 100%. THESE CO-PATHOLOGIES HAVE BEEN SHOWN TO INFLUENCE THE CLINICAL PROGRESSION OF AD SYMPTOMS. YET, BIOMARKERS REMAIN MOSTLY UNAVAILABLE FOR NON-ADNC, INCLUDING LEWY BODY DISEASE (LBD), TRANSACTIVE RESPONSE DNA-BINDING PROTEIN 43 (TDP-43) PROTEINOPATHY, AND CEREBRAL AMYLOID ANGIOPATHY (CAA). WITHOUT BIOMARKERS TO RECOGNIZE THE PRESENCE AND SEVERITY OF THESE CO-PATHOLOGIES IN INDIVIDUALS WITH AD, EVERY CLINICAL TRIAL DESIGNED TO SHOW THE EFFECTIVENESS OF AN AD TREATMENT WILL CONTINUE TO SYSTEMATICALLY UNDERESTIMATE THE MAXIMUM THERAPEUTIC EFFECT OF THE DRUG. BETTER BIOMARKERS TO DETECT CO-PATHOLOGIES IN ADNC CASES ARE AN ESSENTIAL PRECURSOR TO OPTIMALLY TREATING AD. WE WILL PURSUE THE FOLLOWING SPECIFIC AIMS: AIM 1: DEVELOP PRECISE MACHINE-LEARNING BASED COMPUTATIONAL MODELS THAT PREDICT THE PRESENCE OF THREE MAJOR FORMS OF NON-ADNCS (LBD, TDP-43, CAA) IN INDIVIDUALS WITH ADNC USING A SINGLE TIMEPOINT OF IN VIVO MULTIMODAL NEUROIMAGING AND CLINICAL DATA ON A DISCOVERY COHORT OF N=530 FROM THE UNIVERSITY OF CALIFORNIA SAN FRANCISCO (UCSF) ADRC, THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI), AND RELIGIOUS ORDERS STUDY / RUSH MEMORY AND AGING PROJECT (ROS/MAP) BY LEVERAGING EFFORT OF THE ALZHEIMER'S DISEASE SEQUENCING PROJECT PHENOTYPE HARMONIZATION CONSORTIUM (ADSP-PHC). AIM 2: INCREASE MODEL PRECISION BY ADDING CLINICAL PROGRESSION FEATURES FROM DISCOVERY COHORT LONGITUDINAL NEUROIMAGING AND CLINICAL ASSESSMENTS TO PREDICT NON-ADNC IN INDIVIDUALS WITH ADNC. THE MODELS WILL BE OPTIMIZED FOR REAL-WORLD IMPLEMENTATION BY CLINICAL RESEARCHERS VIA PERFORMANCE TESTING AGAINST A SUBSET OF NACC PARTICIPANTS (N=365) AND A NON-AUTOPSY COHORT OF 2000+ ADNI AND DIAN PARTICIPANTS (VALIDATION COHORT). WE WILL EXAMINE TO WHAT EXTENT CLINICAL STAGE, TIMING OF DATA COLLECTION, AND MISSING DATA AFFECT THE ACCURACY OF MODEL PREDICTIONS, AND CREATE AND DISSEMINATE TOOLS BASED ON THESE MODELS FOR ALL RESEARCHERS TO USE. THESE MODELS WILL RELY HEAVILY ON THE MACROSTRUCTURAL BRAIN CHANGES SEEN ON MRI, AND WILL INTEGRATE MULTIMODAL MRI SEQUENCES (T1, FLAIR) AND FDG-PET, CROSS-SECTIONAL AND LONGITUDINAL TIMEPOINTS, AND CLINICAL DATA, INCLUDING NEUROPSYCHOLOGICAL TESTING AND NEUROPSYCHIATRY. BECAUSE BIOMARKER DEVELOPMENT REQUIRES VALIDATION AGAINST GROUND-TRUTH DATA, KEY TO THIS PROPOSAL IS THE HARMONIZATION OF THREE HIGHLY DETAILED AND COMPREHENSIVE AUTOPSY-CONFIRMED COHORTS (DISCOVERY COHORT) WITH ENRICHED NEUROPATHOLOGY, NEUROIMAGING, AND CLINICAL DATA. AT THE CONCLUSION OF THIS STUDY, WE WILL HAVE FOR THE FIRST TIME ESTABLISHED CLINICALLY TRANSLATABLE COMPUTATIONAL MODELS TO PREDICT THE PRESENCE OF TDP-43, LBD, AND CAA CO-PATHOLOGIES AT THE SINGLE CASE LEVEL IN INDIVIDUALS WITH ADNC FROM IMAGING AND CLINICAL DATA.

MECHANISMS OF PARP AND PARG MEDIATED CELL DEATH

CALCIUM-SENSING RECEPTORS AND GROWTH PLATE DEVELOPMENT

SIMULATION OF CORONARY ARTERY BYPASS GRAFT AND SURGICAL VENTRICULAR RESTORATION

SPHINGOSINE 1-PHOSPHATE AND CARDIOPROTECTION

BIOMECHANICAL UNDERSTANDING OF ASCENDING THORACIC AORTIC ANEURYSMS

PROGNOSTIC CALCULATORS FOR PATIENTS WITH ALZHEIMERS DISEASE AND RELATED DEMENTIAS

HYPERGLYCEMIA AND MICRORNA DYSREGULATION OF INFLAMMATION IN ATHEROSCLEROSIS

AGING STRATUM CORNEUM PH AND BARRIER FUNCTION

NEEDS AND OUTCOMES OF ELDERS WITH HIP FRACTURE: SUPPORTIVE, FUNCTIONAL, PALLIATIV

P.R.I.S.M: PURIFICATION OF EXRNA BY IMMUNO-CAPTURE AND SORTING USING MICROFLUIDIC - SUMMARY EXTRACELLULAR RNAS (EXRNAS), PROTECTED FROM DEGRADATION IN BIOFLUIDS BY A DIVERSE SET OF CARRIERS, ARE CURRENTLY CONSIDERED AS PROMISING BIOMARKERS. INDEED, IT WAS SHOWN THAT DURING DISEASE PROGRESSION, IMPACTED CELLS/TISSUES MODIFY THEIR REGISTRIES OF SECRETED EXRNAS, CARRIED BY ONE OR SEVERAL PROTEIN OR VESICULAR CARRIERS, WHICH THEN PARTICIPATE IN A MODIFICATION OF THE GLOBAL EXRNAS PROFILE IN RELATED BIOFLUIDS. HOWEVER, THE CLINICALLY- RELEVANT EXRNA MODIFICATIONS OFTEN REPRESENT A SMALL FRACTION OF THE CIRCULATING EXRNA WITHIN A GIVEN BIOFLUID, AND COULD THEN REMAIN UNDETECTABLE WHEN EXAMINING TOTAL BIOFLUIDS EXRNAS PROFILES. AS SUCH, ESTABLISHING EFFICIENT AND SPECIFIC EXRNAS-CARRIER ISOLATION METHODS, AND DOWNSTREAM ASSOCIATED EXRNAS REFERENCE PROFILES IN NORMAL AND DISEASE SITUATIONS, REPRESENTS A PREREQUISITE TOWARDS IMPLEMENTATION OF BIOFLUID EXRNAS PROFILING AS A ROUTINE DIAGNOSTIC TOOL. THE OBJECTIVE OF THE P.R.I.S.M PROJECT (PURIFICATION OF EXRNA BY IMMUNO-CAPTURE AND SORTING USING MICROFLUIDICS), IS TO COMBINE VISCOLEASTIC EXTRACELLULAR NANOVESICLE SORTING WITH PROTEIN-AFFINITY CAPTURE METHODS, USING DIFFERENT MICROFLUIDIC CHIP DEVICE, IN ORDER TO ISOLATE DISTINCT EXRNA CARRIERS (VESICLES, LIPOPROTEINS, OR RNA-BINDING PROTEINS) FROM A SINGLE SAMPLE OF HUMAN BIOFLUIDS (PLASMA, CSF, URINE, MILK), PRIOR TO RNA PROFILING. THIS PROJECT WILL NOT ONLY ESTABLISH ESSENTIAL CARRIER-SPECIFIC EXRNA REFERENCE PROFILES FOR DIFFERENT HUMAN BIOFLUIDS, BUT SHOULD ALSO DRAMATICALLY IMPROVE THE REPRODUCIBILITY, SPEED, SENSITIVITY AND SPECIFICITY OF EXRNA-BASED DIAGNOSTIC ASSAYS COMPARED TO THE CURRENT STATE-OF-THE-ART IN THE FIELD. RELEVANCE CIRCULATING EXTRACELLULAR RNA (EXRNAS) IN BIOFLUIDS, PROTECTED BY DISTINCT PROTEINS AND VESICULAR CARRIERS, ARE CURRENTLY CONSIDERED AS PROMISING BIOMARKERS IN DISEASES, SUCH A CANCER. HOWEVER, ONLY A SMALL PERCENTAGE OF THE TOTAL EXRNAS, CLUSTERED IN SOME SPECIFIC EXRNA CARRIERS, CONTAIN THE CLINICALLY RELEVANT INFORMATION. OUR PROJECT AIMS AT DEVELOPING MICROFLUIDIC METHODS FOR FRACTIONATING BIOFLUID INTO ITS MOST RELEVANT EXRNAS CARRIER COMPONENTS, FROM A SINGLE LOW VOLUME OF BIOFLUID SAMPLE BEFORE CHARACTERIZING THEIR EXRNA CONTENT. UPON CONCLUSION, WE EXPECT TO REACH A DRAMATIC IMPROVEMENT IN THE SPECIFICITY AND SENSITIVITY OF EXRNA DIAGNOSTIC STRATEGIES.

IMPLEMENTATION OF A PRAGMATIC TRIAL OF WHOLE HEALTH TEAM VS. PRIMARY CARE GROUP EDUCATION TO PROMOTE NON-PHARMACOLOGICAL STRATEGIES TO IMPROVE PAIN, FUNCTIONING, AND QUALITY OF LIFE IN VETERANS

THE IMPRINT OF PSYCHOGENIC NON-EPILEPTIC SEIZURES ON THE BRAIN: A NEW MODEL AND IMAGING BIOMARKER

EFFECTS OF ANTIRETROVIRAL DRUGS ON METABOLISM

A NEW PARADIGM FOR HYPERTENSION IN THE ELDERLY- BEYOND AGE

EVALUATING HIV EXPRESSION AND LATENCY IN BLOOD AND TISSUES AT THE SINGLE CELL LEVEL

INTERFERON-A DRIVES PERIPHERAL ACTIVATION AND BRAIN INJURY IN CHRONIC HIV

IGF-1 MEDIATES THE ANABOLIC EFFECTS OF PTH ON BONE

BIOMECHANICAL COMPUTED TOMOGRAPHY FACILITATES THE DIAGNOSIS OF OSTEOPOROSIS AND FRACTURE PREDICTION IN PATIENTS WITH HIGH-RISK PROSTATE CANCER

BACTERIAL STI AND INNATE IMMUNITY IN HIV SUSCEPTIBILITY

PSYCHOBIOLOGICAL ASSESSMENT AND ENHANCEMENT OF TEAM COHESION AND PSYCHOLOGICAL RESILIENCE IN ROTC CADETS USING A VIRTUAL-REALITY TEAM COHESION TEST

INVESTIGATING FEAR SYSTEM MYELINATION IN PTSD USING IN VIVO AND POST MORTEM DATA - PROJECT SUMMARY/ABSTRACT THIS PROPOSAL WILL EXAMINE MALADAPTIVE GRAY MATTER (GM) MYELINATION AS A CANDIDATE MECHANISM UNDERPINNING TWO FUNCTIONAL BRAIN ABNORMALITIES WELL ESTABLISHED IN POSTTRAUMATIC STRESS DISORDER (PTSD): HYPER- CONNECTEDNESS OF THE THREAT RESPONSE NETWORK (TRN: DEFINED AS HIPPOCAMPUS (HIP), AMYGDALA (AMYG), ANTERIOR INSULA (INS), AND DORSAL ANTERIOR CINGULATE CORTEX (DACC)), AND DISRUPTION OF THE DEFAULT MODE NETWORK (DMN). EXPERIENCE- AND ACTIVITY-DEPENDENT GM MYELINATION HAVE BEEN OBSERVED IN MANY BRAIN REGIONS AND HAVE BROAD RELEVANCE TO PSYCHIATRIC DISORDERS. WHILE EXPERIENCE-DEPENDENT MYELINATION EVOLVED TO ACCELERATE NERVE CONDUCTION, MYELINATION IN GM HAS BEEN SHOWN TO REDUCE SYNAPTIC DENSITY AND SYNAPSE-BASED NEUROPLASTICITY IN ANIMAL MODELS. OUR MODEL PROPOSES THAT EXCESS GM MYELINATION IN THE TRN IN PTSD RESULTS IN A HYPERCONNECTED SALIENCE NETWORK (SN; WHICH INCLUDES AMYG, DACC, AND INS BUT NOT HIP. SEE “BRIDGING FRAMEWORKS” SECTION) AND A POORLY CONNECTED AND HYPOACTIVE DMN. GIVEN THAT MYELIN DEVELOPMENT AND RE- MYELINATION IN BOTH CORTICAL AND SUBCORTICAL GM ARE RESPONSIVE TO THERAPEUTIC AGENTS, CONFIRMING OUR MODEL COULD LEAD TO NOVEL TARGETS FOR TREATMENT OF PTSD, A CONDITION THAT HAS RESISTED PHARMACOTHERAPEUTIC INTERVENTION. OUR PROPOSED MODEL YIELDS A CANDIDATE MECHANISM UNDERPINNING THE “SYNAPTIC DISCONNECTION” SYNDROME PROPOSED BY KRYSTAL AND COLLEAGUES TO EXPLAIN IMPAIRED FUNCTIONAL BRAIN CONNECTIVITY IN PTSD. IT IS ALSO NOTEWORTHY THAT RECENT EVIDENCE SUGGESTS THAT DMN DYSCONNECTIVITY IN PTSD IS NOT ASSOCIATED WITH THE DISRUPTION OF LARGE FRONTAL WHITE MATTER TRACKS. AS SUCH, EXCESS GM MYELINATION IN KEY STRUCTURES MAY SUPPLY AN EXPLANATION FOR THIS PHENOMENON. USING A COMBINATION OF POSTMORTEM NEUROPATHOLOGY IN PTSD CASES VERSUS BRAIN BANK CONTROLS, AND IN VIVO NEUROIMAGING AT 3T IN A MATCHED CASE CONTROL DESIGN, WE WILL EXAMINE IF PTSD IS ASSOCIATED WITH INCREASED MYELIN CONTENT AND DECREASED SYNAPTIC AND NEURITE DENSITY IN THE TRN STRUCTURES. FINALLY, WE WILL TEST IF INCREASED GM MYELIN AND DECREASED NEURITE DENSITY IN TRN ACCOUNT FOR INCREASED RESTING STATE (RS) CONNECTIVITY WITHIN THE SN AND DECREASED RS CONNECTIVITY WITHIN THE DMN IN THE SAME LIVING SUBJECTS. INTEGRATION OF POSTMORTEM NEUROPATHOLOGY, AFFORDED BY THE NATIONAL PTSD BRAIN BANK, AND IN VIVO NEUROIMAGING WILL ENABLE A HIGHLY NOVEL BUT BROADLY TESTABLE EXPLORATION OF GM MYELINATION AND ITS CONSEQUENCES IN THE HUMAN BRAIN AS MODIFIED BY PTSD.

GENETICS, COMORBIDITIES, AND ETHNICITY: EFFECTS OF TBI ON DEMENTIA

NEUROIMAGING ENDOPHENOTYPES AND PREDICTORS OF POST-TRAUMATIC BRAIN INJURY DEMENTIA IN A NATIONWIDE COHORT OF VETERANS.

MELANOCYTE-KERATINOCYTE CROSS-TALK IN RELATION TO BARRIER FUNCTION

A CONTROLLED TRIAL OF CBT FOR MS INFLAMMATION

IMPROVING IDENTIFICATION OF OBSTRUCTIVE SLEEP APNEA IN WOMEN - : OBSTRUCTIVE SLEEP APNEA IS ASSOCIATED WITH NEGATIVE IMPACTS ON HEALTH, FUNCTIONING, AND QUALITY OF LIFE. HISTORICALLY BELIEVED TO BE A “DISEASE OF MALES”, OBSTRUCTIVE SLEEP APNEA IS NOW ESTIMATED TO IMPACT OVER 25% OF ADULT WOMEN IN THE US. IT IS ALSO ESTIMATED THAT OVER 98% OF WOMEN WITH OBSTRUCTIVE SLEEP APNEA REMAIN UNDIAGNOSED, IN PART BECAUSE EXISTING SCREENING QUESTIONNAIRES RELY ON THE COMMON SYMPTOMS PRESENTED BY MALES WITH THE DISEASE, SUCH AS LOUD SNORING, WITNESSED APNEAS, AND EXCESSIVE DAYTIME SLEEPINESS. HOWEVER, WOMEN WITH OBSTRUCTIVE SLEEP APNEA TEND TO HAVE A DIFFERENT CONSTELLATION OF SYMPTOMS, SUCH AS INSOMNIA, DEPRESSION, AND FATIGUE. WOMEN OFTEN ARE NOT DIAGNOSED UNTIL THE DISEASE BECOMES SEVERE AND MORE CLOSELY MIMICS THE CLINICAL PRESENTATION OF MEN, AT WHICH POINT NEGATIVE HEALTH IMPACTS ASSOCIATED WITH OBSTRUCTIVE SLEEP APNEA APPEAR TO BE WORSE THAN THOSE SEEN IN MEN. THERE IS THEREFORE A CRITICAL NEED TO IMPROVE THE UNDERSTANDING, IDENTIFICATION, AND DIAGNOSIS OF OBSTRUCTIVE SLEEP APNEA IN WOMEN. THE PROPOSED PROJECT AIMS TO (1) IDENTIFY HEALTH FACTORS ASSOCIATED WITH OBSTRUCTIVE SLEEP APNEA IN WOMEN VIA (A) ELECTRONIC HEALTH RECORDS (ESTIMATED N=600,000) AND (B) SURVEY DATA COLLECTION (FOR PATIENT-CENTERED SELF-REPORT MEASURES NOT RELIABLY OR MEANINGFULLY AVAILABLE IN ELECTRONIC HEALTH RECORDS; TARGET N=400) AMONG WOMEN VETERANS WITH AND WITHOUT DIAGNOSED OBSTRUCTIVE SLEEP APNEA ENROLLED IN THE VETERANS HEALTH ADMINISTRATION, (2) DEVELOP A NOVEL, SEX-TAILORED SCREENING INSTRUMENT TO IDENTIFY WOMEN WITH OBSTRUCTIVE SLEEP APNEA USING BEST PRACTICE METHODS (PROMIS SCIENTIFIC STANDARDS FOR INSTRUMENT DEVELOPMENT AND VALIDATION, INCLUDING FOCUS GROUPS AND COGNITIVE INTERVIEWS), AND (3) TEST THE ACCURACY OF THE NEW SCREENING INSTRUMENT IN A NATIONAL SAMPLE OF ADULT WOMEN, VALIDATED AGAINST HOME SLEEP APNEA TESTING. THE DEVELOPMENT OF A NEW SCREENING QUESTIONNAIRE WILL PROMOTE BETTER DETECTION OF OBSTRUCTIVE SLEEP APNEA IN WOMEN BY CREATING A MORE ACCURATE AND FACE VALID MEASURE OF THE COMMON SYMPTOMS OF THIS DISEASE IN WOMEN. IT WILL ALSO TAKE INTO ACCOUNT THE IMPACT OF SEX IN THE PRESENTATION OF OBSTRUCTIVE SLEEP APNEA AND USE THIS INFORMATION TO CREATE AN INNOVATIVE DELIVERABLE THAT CAN BE USED IN STANDARD HEALTHCARE SCREENING, AS RECOMMENDED BY THE AMERICAN ACADEMY OF SLEEP MEDICINE.

GENETICS OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)

CREATING A BETTER INDEX FOR MEASURING MULTIMORBIDITY IN OLDER ADULTS

TYPE 2 DIABETES INDUCED CHRONIC INFLAMMATION ON STROKE OUTCOME - TYPE 2 DIABETES (T2DM) NOT ONLY INCREASES THE RISK OF STROKE, BUT ALSO WORSENS THE STROKE OUTCOME. POOR BLOOD PERFUSION, HYPERCOAGULABILITY AND CHRONIC INFLAMMATION ARE KNOWN TO BE CONTRIBUTING FACTORS. COMPLEMENT ACTIVATION PRODUCTS, ESPECIALLY C3 OPSONINS AND THE C3A/C5A ANAPHYLAXIS, HAVE BEEN IMPLICATED IN PROMOTING SECONDARY INJURY FOLLOWING CEREBRAL ISCHEMIC/REPERFUSION. THE INVOLVEMENT OF COMPLEMENT IN THE PATHOGENESIS OF INSULIN RESISTANCE AND COMPLICATIONS ASSOCIATED WITH TYPE 2 DIABETES IS ALSO WELL DOCUMENTED. HOWEVER, HOW COMPLEMENT PREDISPOSES THE BRAIN TO EXACERBATED ISCHEMIC INJURY AND FUNCTIONAL IMPAIRMENT IS NOT WELL UNDERSTOOD, LET ALONE WHICH CELL TYPES ARE INVOLVED IN PROPAGATING COMPLEMENT- MEDIATED INFLAMMATION. VIA SINGLE CELL TRANSCRIPTOMICS WE DETECTED ELEVATED EXPRESSION OF COMPLEMENT GENES IN THE BRAIN MYELOID CELLS OF MICE WITH T2DM PRIOR TO THE ONSET OF STROKE, INCLUDING COMPONENTS OF THE CLASSICAL PATHWAY (C1QA-C), THE ANAPHYLATOXIN RECEPTORS (C3AR AND C5AR), AND COMPLEMENT RECEPTOR 3 (CR3, ITGAM), AS WELL AS A NUMBER OF CHEMOTAXIS-RELATED MOLECULES. MULTIPHOTON IMAGING CONFIRMED THAT T2DM MICE EXHIBITED POOR COLLATERAL FLOW, ACCOMPANIED BY INCREASED WBC-PLATELET AGGREGATES IN CEREBRAL VESSELS TOGETHER WITH INCREASED LEUKOCYTE ROLLING, RESULTING IN INCREASED INFILTRATION OF NEUTROPHILS INTO BRAIN PARENCHYMA. WE HERE PROPOSE TO INVESTIGATE THE ROLE OF COMPLEMENT IN PROMOTING WORSE STROKE OUTCOMES IN T2DM MICE. OUR FIRST AIM WILL DETERMINE THE FUNCTIONAL ROLE OF P-SELECTIN AND THE ANAPHYLATOXIN RECEPTORS C3AR AND C5AR IN T2DM PROMOTED TRANSMIGRATION OF PERIPHERAL MYELOID CELLS INTO BRAIN AFTER STROKE. AIM 2 WILL DETERMINE THE SPATIAL AND TEMPORAL EXPRESSION OF COMPLEMENT C3 IN BRAINS AFTER STROKE, AND EXPERIMENTS WILL ALSO DELINEATE THE FUNCTIONAL EFFECT OF C3 FROM INFILTRATING VERSUS BRAIN RESIDENT GLIA CELLS ON NEURONAL LOSS AND STROKE OUTCOME. AIM 3 WILL INVESTIGATE THE ROLE OF MICROGLIA SPECIFIC COMPLEMENT RECEPTOR 3 (CR3) IN ABERRANT NEURONAL/SYNAPTIC LOSS AND THE FUNCTIONAL ROLE OF THIS RECEPTOR IN DETERMINING OUTCOMES IN T2DM AND CONTROL MICE. WITH COMPREHENSIVE AND EFFECTIVE APPROACHES INCORPORATING MULTIDISCIPLINARY TECHNIQUES, THIS PROJECT WILL PROVIDE SIGNIFICANT INSIGHT INTO THE MECHANISMS UNDERLYING T2DM-MEDIATED INFLAMMATION IN THE CONTEXT OF STROKE.

RESOURCE FOR MRI OF NEURODEGENERATIVE DISORDERS

DOES EVIDENCE-BASED PTS TREATING REDUCE PTS SYMPTOMS AND SUICIDE IN IRAQ AND AFGHANISTAN VETERANS SEEKING VA CARE?

FROM HERE TO ETERNITY: GUT MICROBIAL RESPONSE TO DRUG THERAPY AND INFLAMMATION - ABSTRACT THE GENOMIC REVOLUTION HAS PROVIDED US WITH AN “EMBARRASSMENT OF RICHES” WITH RESPECT TO OUR UNDERSTANDING OF THE COMPOSITION OF GUT MICROBIAL COMMUNITIES IN DISEASE, BUT WE ARE STILL FAR FROM UNDERSTANDING HOW MICROBIAL GENES AND PATHWAYS IMPACT HOST HEALTH. WHILE A WEALTH OF STUDIES SHOW THAT THE MICROBIOME IS ASSOCIATED WITH DISEASE STATES, WE KNOW LITTLE ABOUT THE MICROBIAL GENES THAT RESPOND TO DISEASE-ASSOCIATED PERTURBATIONS, SUCH AS INFLAMMATION OR DRUG THERAPY, AND HOW THESE MICROBIAL RESPONSES CONTRIBUTE TO DISEASE AND DRUG RESPONSE. LACK OF KNOWLEDGE OF HOW MICROBIAL GENES RESPOND AND CONTRIBUTE TO DISEASE-ASSOCIATED PERTURBATIONS LIMITS OUR ABILITY TO RATIONALLY DESIGN MICROBIOME-TARGETED THERAPIES, SUCH AS FECAL MICROBIOTA TRANSPLANT, LIVE BIOTHERAPEUTICS, AND SMALL MOLECULE MICROBIAL INHIBITORS. MY LAB’S LONG-TERM GOAL IS TO UNDERSTAND HOW THE MICROBIOME CONTRIBUTES TO THE RESOLUTION OF SYSTEMIC INFLAMMATION. THE OVERALL OBJECTIVE OF THIS R35 NIGMS MIRA GRANT IS TO SUPPORT THE ASPECT OF MY RESEARCH PROGRAM FOCUSED ON DECIPHERING THE MICROBIAL GENETIC DETERMINANTS OF RESPONSES TO INFLAMMATION AND DRUG THERAPY AND HOW THESE IMPACT THE HOST. WITH THE SUPPORT OF THE R35 MIRA GRANT, OVER THE NEXT 5 YEARS, I AIM TO ESTABLISH A UNIQUE AND PRODUCTIVE NICHE AT THE INTERSECTION OF MICROBIOLOGY, GENETICS, AND SYSTEMIC INFLAMMATORY DISEASE BY INVESTIGATING THE FOLLOWING KEY QUESTIONS / THEMES: (1) WHICH MICROBIAL GENES ARE IMPORTANT FOR RESPONDING TO HOST INFLAMMATION AND DRUG TREATMENT, (2) HOW DO THESE MICROBIAL GENES SUBSEQUENTLY CONTRIBUTE TO HOST INFLAMMATION, AND (3) CAN DRUGS TARGETING SPECIFIC MICROBIAL GENES IMPACT GUT MICROBIAL ECOLOGY AND EVOLUTION IN THE SETTING OF HOST INFLAMMATION. THE PROPOSED RESEARCH PROGRAM SEEKS TO FILL THESE KNOWLEDGE GAPS BY HARNESSING CUTTING-EDGE TECHNOLOGIES AND MY UNIQUE BACKGROUNDS IN COMPUTER SCIENCE, GENOMICS, MICROBIOLOGY, CLINICAL IMMUNOLOGY, AND GNOTOBIOLOGY. THE HUMAN GUT MICROBIOME IS WITH US “FROM HERE TO ETERNITY” BUT WE ARE JUST BEGINNING TO UNCOVER THE POWERFUL FORCES IN VIVO THAT SHAPE THE MICROBIAL COMMUNITY AND ITS EVOLUTION. THE MICROBIAL GENETIC BASIS OF THESE SHIFTS IN THE SETTING OF INFLAMMATION AND DRUG THERAPY IS NOT COMMONLY STUDIED; FILLING THIS FUNDAMENTAL KNOWLEDGE GAP WILL PAY DIVIDENDS IN THE FUTURE BY IMPROVING THE EFFICACY OF THERAPEUTIC STRATEGIES THAT ARE CURRENTLY UNDERWAY IN PATIENTS WITH INFLAMMATORY DISEASE.

CILOSTAZOL FOR PREVENTION OF RECURRENT STROKE IN AFRICA (CLARITY-AFRICA) - PROJECT SUMMARY GLOBAL ESTIMATES SUGGEST THAT SUB-SAHARAN AFRICA (SSA) NOW HAS THE HIGHEST INCIDENCE, PREVALENCE, AND WORST SURVIVAL OUTCOMES OF STROKE. WITH AN ESTIMATED 1.4 MILLION STROKE SURVIVORS, OUTCOMES OF STROKE IN SSA ARE ABYSMAL WITH 1-MONTH CASE FATALITY AT 30% AND 3-YEAR MORTALITY RATE OF 84%. STROKE SURVIVORS IN AFRICA ARE AT AN INORDINATELY HIGH (AND WORSENING) RISK OF ADVERSE OUTCOMES INCLUDING RECURRENT STROKE AND CARDIAC EVENTS OVER THE MEDIUM- TO LONG-TERM. GIVEN THE PAUCITY OF RESOURCES IN THE REGION, TESTING OF THERAPIES, WHICH ARE POTENTIALLY HIGHLY CLINICALLY EFFICACIOUS AND COST-EFFECTIVE, WHILE DEVELOPING LOCAL STROKE RESEARCH CAPACITY AND CONTRIBUTING TO THE GLOBAL SECONDARY STROKE PREVENTION EVIDENCE BASE, IS URGENTLY NEEDED. CILOSTAZOL, A PHOSPHODIESTERASE 3 INHIBITOR, HAS SHOWN PROMISING EFFICACY AND SAFETY MAINLY AMONG AN ASIAN POPULATION BY CUTTING RISK OF MAJOR ADVERSE CARDIOVASCULAR EVENTS INCLUDING STROKE, IN HALF, WHEN ADDED TO ASPIRIN OR CLOPIDOGREL (8% VS. 4%, HR 0.52, 95% CI 0.35-0.77), WITH NO INCREASED RISK IN BLEEDING OR SERIOUS ADVERSE EVENTS. CILOSTAZOL’S POTENTIALLY STRONG EFFICACY, PRESUMED PLEIOTROPIC EFFECTS, AND RELATIVELY LOW COST, MAKE IT A HIGHLY APPEALING AGENT FOR USE IN STROKE-PRONE, LOW-RESOURCE SETTINGS. THEREFORE, THE OVERALL OBJECTIVE OF THE CILOSTAZOL FOR PREVENTION OF RECURRENT STROKE IN AFRICA (CLARITY-AFRICA) STUDY IS TO DEPLOY A HYBRID STUDY DESIGN TO DEMONSTRATE THE EFFICACY AND SAFETY OF CILOSTAZOL TWICE DAILY IN REDUCING MACE OVER 24 MONTHS VS. PLACEBO AMONG 800 RECENT STROKE PATIENTS ENCOUNTERED AT 12 HOSPITALS IN GHANA. SECONDLY, CLARITY-AFRICA ALSO SEEKS TO DEVELOP AN IMPLEMENTATION STRATEGY FOR ROUTINE INTEGRATION AND POLICY ADOPTION OF CILOSTAZOL FOR POST-STROKE CARDIOVASCULAR RISK REDUCTION IN AN UNDER-RESOURCED SYSTEM. GIVEN ITS COMPELLING EFFICACY AMONG A PREDOMINANTLY ASIAN POPULATION, THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) IS POISED TO FUND A US-BASED CLINICAL TRIAL TO ASSESS THE LONGER-TERM EFFICACY AND SAFETY OF CILOSTAZOL IN A STUDY TITLED CILOSTAZOL FOR PREVENTION OF RECURRENT STROKE (CLARITY). WE ARE ALSO AWARE THAT EUROPEAN AND AUSTRALIAN FUNDING AGENCIES ARE CONSIDERING STROKE TRIALS OF CILOSTAZOL. A CONCURRENTLY EXECUTED CLARITY-AFRICA TRIAL WOULD ALLOW RECRUITMENT OF A HISTORICALLY UNDER- REPRESENTED AND HIGH-RISK GROUP (AFRICANS), TEST A THERAPY THAT IF EFFICACIOUS COULD BE AFFORDABLE FOR BROADER REGIONAL IMPLEMENTATION, PERMIT TRANSCONTINENTAL MENTORSHIP/COLLABORATIONS, AND LEVERAGE NINDS IMPENDING INVESTMENT. CLARITY-AFRICA WILL ASSESS IMPLEMENTATION OUTCOMES SUCH AS ADOPTION, ACCEPTABILITY, COST, PERTINENT TO UPTAKE OF CILOSTAZOL IN GHANA TO INFORM POLICY. REGARDLESS OF ITS OUTCOME, FINDINGS FROM CLARITY- AFRICA WILL CONTRIBUTE MEANINGFUL INFORMATION FROM THE AFRICAN PERSPECTIVE TO INFORM THE FORMULATION OF GUIDELINES FOR GLOBAL ADOPTION OF CILOSTAZOL INTO ROUTINE CARE FOR SECONDARY CVD RISK PREVENTION BY INTERNATIONAL BODIES SUCH AS THE WORLD HEALTH ORGANIZATION.

PRESCRIPTION EXERCISE FOR OLDER MEN WITH URINARY DISEASE (PROUD) PILOT STUDY - PROJECT SUMMARY/ABSTRACT ONE IN 3 AMERICAN MEN WILL DEVELOP BOTHERSOME LOWER URINARY TRACT SYMPTOMS IN THEIR LIFETIME, AND THE MAJORITY WILL BE ATTRIBUTED TO BENIGN PROSTATIC HYPERPLASIA (LUTS/BPH). OLDER MEN WITH LUTS/BPH HAVE INCREASED RISK OF DEVELOPING NEW MOBILITY LIMITATIONS, FALLS, FRACTURES, DISABILITY, AND DEATH. UNFORTUNATELY, CURRENT LUTS/BPH MEDICATIONS TARGETING PROSTATE-CENTRIC MECHANISMS LIKELY FURTHER INCREASE RISK OF SOME OF THESE ADVERSE CLINICAL OUTCOMES, HAVE MODEST EFFICACY, AND POOR ADHERENCE. FRAILTY-RELATED MECHANISMS ARE NOVEL LUTS/BPH INTERVENTION TARGETS THAT MAY BE PREVENTABLE OR MODIFIABLE VIA AN EXERCISE INTERVENTION. OUR TEAM HAS PREVIOUSLY CREATED AN INDIVIDUALIZED, REMOTELY-MONITORED, AND HOME-BASED EXERCISE PROGRAM BASED ON WELL- KNOWN BEHAVIORAL CHANGE PRINCIPLES AND PRIORITIZATION OF SCALABLE INTERVENTIONS REQUIRING MINIMAL EQUIPMENT FOR OLDER MEN WITH PROSTATE CANCER. HOWEVER, A PILOT STUDY IS REQUIRED TO DETERMINE THE FEASIBILITY AND OPTIMAL TRIAL DESIGN FOR TESTING THIS EXERCISE INTERVENTION IN PHYSICALLY INACTIVE OLDER MEN WITH LUTS/BPH. WE THEREFORE PROPOSE A SINGLE-CENTER PILOT RANDOMIZED CONTROLLED TRIAL AMONG 68 PHYSICALLY INACTIVE OLDER MEN WITH LUTS/BPH OF A 12-WEEK MULTICOMPONENT EXERCISE INTERVENTION VERSUS HEALTH EDUCATION CONTROL. THE EXERCISE INTERVENTION INCLUDES PERSONALIZED WRITTEN AND PICTORIAL INSTRUCTIONS ON AEROBIC AND RESISTANCE EXERCISES, SUPPORTED BY WEEKLY ONE-ON-ONE COACHING BY PHONE OR VIDEO CALL, ALONG WITH HEART RATE MONITOR BIOFEEDBACK AND THE PROVISION OF LIMITED EQUIPMENT. THE FOLLOWING AIMS MUST BE ADDRESSED PRIOR TO CONDUCTING AN ADEQUATELY POWERED EFFICACY TRIAL: AIM 1: EVALUATE THE FEASIBILITY, ACCEPTABILITY, FIDELITY, AND SAFETY OF A REMOTE EXERCISE INTERVENTION AND HEALTH EDUCATION CONTROL AMONG PHYSICALLY INACTIVE OLDER MEN WITH LUTS/BPH (N=68 TOTAL) 34/ARM); AIM 2: ASSESS THE MAGNITUDE, VARIABILITY, AND DURABILITY OF CHANGES IN LUTS, UROLOGIC AND PHYSICAL FUNCTION, AND ACTIGRAPHY MEASURES AFTER A 12-WEEK EXERCISE INTERVENTION OR HEALTH EDUCATION CONTROL; AND AIM 3: ASSESS THE FEASIBILITY OF DETECTING EXERCISE-INDUCED CHANGE IN NOVEL FRAILTY-RELATED MECHANISTIC MEASURES (TOTAL MUSCLE MASS, MITOCHONDRIAL FUNCTION, URINE A1-MICROGLOBULIN). THIS PROJECT IS INNOVATIVE BECAUSE IT LEVERAGES A REMOTE EXERCISE INTERVENTION WITH PLEOTROPIC AND SYSTEMIC EFFECTS ACROSS MULTIPLE ORGAN SYSTEMS, IN CONTRAST TO EXISTING PROSTATE-CENTRIC PHARMACOLOGICAL AND SURGICAL THERAPIES WITH SIDE EFFECTS THAT ARE CRITICAL TO AVOID IN OLDER MEN. OUR PROJECT WILL ACCOMPLISH THE EXTENSIVE FEASIBILITY WORK THAT IS REQUIRED FOR BOTH A FUTURE EFFICACY TRIAL AND THE FRAILTY-RELATED MECHANISTIC BIOMARKER MEASUREMENTS. THIS PILOT STUDY IS AN IMPORTANT STEP TOWARDS AN EXTENDED, FULLY-POWERED EFFICACY TRIAL WITH A SECONDARY FOCUS ON FRAILTY-RELATED MECHANISMS OF AN EXERCISE INTERVENTION FOR TREATING LUTS/BPH. THIS FUTURE EFFICACY TRIAL HAS THE POTENTIAL TO TRANSFORM BOTH THE CLINICAL CARE FOR PHYSICALLY INACTIVE OLDER MEN WITH LUTS/BPH WHILE SIMULTANEOUSLY INCREASING OUR UNDERSTANDING OF HOW EXERCISE AFFECTS FRAILTY-RELATED LUTS/BPH MECHANISMS.

LONG TERM DEPRESSIVE SYMPTOM COURSE & ADVERSE HEALTH OUTCOMES AMONG OLDER WOMEN

EPIDEMIOLOGY OF SUICIDAL BEHAVIOR IN RACIALLY/ETHNICALLY DIVERSE OLDER AMERICANS

MIDLIFE RISK FACTORS AND RISK SCORE DEVELOPMENT FOR AD/ADRD AMONG MALE AND FEMALE VETERANS

ADRD RISK AND RESILIENCE FACTORS AMONG AMERICAN INDIAN AND ALASKAN NATIVE VETERANS: IMPLICATIONS FOR PREVENTION

THE ROLE OF MICROGLIAL SUBSETS IN REGULATING TRAUMATIC BRAIN INJURY

DEPRESSIVE SYMPTOMS, AGING, DISABILITY AND HEALTH OUTCOMES

DIABETES ERECTILE DYSFUNCTION AND APOPTOSIS OF CAVERNOUS TISSUES

INCIDENCE OF MILD COGNITIVE IMPAIRMENT IN GULF WAR VETERANS.

GENISTEIN AND PROSTATE CANCER

BREAKING THE BARRIERS TO MICROSCALE FMRI

BRAIN MR SPECTROSCOPY BIOMARKERS IN A CLINICAL TRIAL OF PTS PATIENTS

DEVELOPMENT AND VALIDATION OF THE EMR RISK OF ALZHEIMER'S AND DEMENTIA ASSESSMENT RULE (ERADAR)

RISK FACTORS FOR ECZEMA VACCINATUM IN ATOPIC DERMATITIS

IMPROVING FRONTAL EMOTION REGULATION IN PTSD BY TARGETING SLEEP

MILITARY RISK FACTORS AND DEMENTIA IN VETERANS: THE IMPACT OF RACE AND SOCIAL DETERMINANTS OF HEALTH

BASIC DESCRIPTION THIS IS AWARDED AS A SINGLE YEAR AWARD WITH YEAR 2&3 AS OPTIONS TO APPROVE&ADD PER THE NRA #01-OBPR-03 AND THE SELECTION LETTER ON

A MENINGOCOCCAL LOS VACCINE

P.R.I.S.M: PURIFICATION OF EXRNA BY IMMUNO-CAPTURE AND SORTING USING MICROFLUIDIC

"REMOTELY DEPLOYED TRAINING FOR COGNITITIVE IMPAIRMENTS ASSOCIATED WITH TBI"

CD44/VARIANT CYTOSKELETON IN BREAST CANCER PROGRESSION

INTEGRATING ENVIRONMENTAL, GENOMIC, AND FUNCTIONAL DATA TO CHARACTERIZE INDIVIDUAL RISK FOR PARKINSON'S DISEASE. NEW AWARD.

HIV-1 ADAPTATION IN THE CENTRAL NERVOUS SYSTEM

USING MULTIMODAL IMAGING TO EXAMINE THE NEURAL MECHANISMS OF AN INTEGRATIVE EXERCISE PROGRAM FOR INDIVIDUALS WITH DEMENTIA

IMPROVING CARDIAC AND DIAPHRAGM FUNCTION WITH BETA-3 ADRENERGIC RECEPTOR AGONIST IN DUCHENNE MUSCULAR DYSTROPHY

RISK THRESHOLDS OF ALCOHOL AND POLYSUBSTANCE USE AMONG OLDER ADULTS - ALCOHOL USE AND BINGE DRINKING ARE INCREASING AMONG OLDER ADULTS, AS IS THE NEED FOR TAILORED, AGE-SPECIFIC STRATEGIES TO IDENTIFY AND TREAT UNHEALTHY ALCOHOL USE. CURRENT ALCOHOL GUIDELINES AND RISK THRESHOLDS FOR BINGE DRINKING WERE NOT DEVELOPED FOR OLDER ADULTS, AND IT IS NOT KNOWN WHETHER ALCOHOL USE CONSISTENT WITH THESE GUIDELINES IS SAFE FOR OLDER ADULTS, PARTICULARLY WOMEN. IT IS ALSO NOT KNOWN WHETHER ANY LEVEL OF ALCOHOL USE IS SAFE FOR OLDER ADULTS WHO USE CANNABIS OR OTHER PSYCHOACTIVE DRUGS (OPIOIDS OR BENZODIAZEPINES) OR HAVE FUNCTIONAL IMPAIRMENT OR COMORBIDITY. ALCOHOL USE, ALONE OR COMBINED WITH OTHER DRUGS, IS A RISK FACTOR FOR FALLS, INJURIES, OVERDOSE, HOSPITALIZATION, AND DEATH, BUT RISK THRESHOLDS FOR OLDER ADULTS HAVE NOT BEEN ESTABLISHED. TO ADDRESS THE GAP IN THE LITERATURE ON THE RISKS OF ALCOHOL AND POLYSUBSTANCE USE AMONG OLDER ADULTS, WE PROPOSE TO CONSTRUCT A COHORT OF PATIENTS 65 AND OLDER WITH A RECENT CLINICAL ALCOHOL SCREEN IN A VETERANS HEALTH ADMINISTRATION (VA) FACILITY USING MERGED NATIONAL VA AND MEDICARE DATA. WE WILL STRATIFY OUR SAMPLING FRAME BY CLINICAL ALCOHOL SCREENING SCORE AND THE PRESENCE OF A CANNABIS NOTE IN THE HEALTH RECORD (BOTH AVAILABLE FROM VA DATA) AND WILL RECRUIT A COHORT OF 4500 OLDER PATIENTS (30% WOMEN). WE WILL CONDUCT A TELEPHONE INTERVIEW TO ASSESS EXPOSURE HISTORY (E.G., PAST-MONTH ALCOHOL USE) AND WILL QUANTIFY THE ASSOCIATION BETWEEN ALCOHOL USE (CATEGORY OF USE OR BINGE DRINKING) AND ADVERSE EVENTS (HOSPITALIZATION OR ALL-CAUSE MORTALITY, AND AS SECONDARY OUTCOMES, FALLS, INJURIES, OVERDOSE, AND HOSPITALIZATION FOR CARDIAC, RENAL, HEPATIC, OR MENTAL HEALTH CONDITIONS). WE WILL ALSO EXAMINE HOW THE EFFECTS OF ALCOHOL DIFFER FOR OLDER PATIENTS WHO USE CANNABIS. FINALLY, WE WILL EXPLORE WHETHER THE EFFECTS OF ALCOHOL ARE GREATER AMONG HIGHER RISK OLDER ADULTS (WOMEN, OLDER ADULTS WITH FUNCTIONAL IMPAIRMENT/COMORBIDITY, OR WHO USE OTHER PSYCHOACTIVE DRUGS SUCH AS OPIOIDS OR BENZODIAZEPINES. THE GOALS OF THIS PROPOSAL ARE TO EXAMINE: 1) WHETHER, AFTER ACCOUNTING FOR BASELINE DIFFERENCES IN PATIENT CHARACTERISTICS, HIGHER LEVELS OF ALCOHOL USE ARE ASSOCIATED WITH INCREASED RISK FOR ADVERSE EVENT; 2) WHETHER BINGE DRINKING IS ASSOCIATED WITH INCREASED RISK FOR ADVERSE EVENTS; AND 3) WHETHER ASSOCIATIONS BETWEEN ALCOHOL USE AND ADVERSE EVENTS VARY FOR PATIENTS WHO USE CANNABIS. WE WILL ALSO ASSESS THE EFFECT OF ALCOHOL USE ON ADVERSE EVENTS AMONG HIGH-RISK PATIENTS. WE WILL USE PROPENSITY SCORE METHODS TO CONTROL CONFOUNDING. THERE IS CURRENTLY INSUFFICIENT EVIDENCE TO ESTABLISH SAFE DRINKING GUIDELINES FOR OLDER ADULTS. THIS PROJECT WILL DEVELOP THE FOUNDATIONAL EVIDENCE BASE NEEDED TO CREATE BETTER ALCOHOL GUIDANCE, IMPROVE ALCOHOL ASSESSMENT TOOLS, AND DEVELOP MORE PATIENT-CENTERED RISK COMMUNICATION STRATEGIES FOR OLDER ADULTS.

FEASIBILITY OF TELE-SINGING AT HOME FOR OLDER ADULTS WITH MILD COGNITIVE DECLINE - ABSTRACT AN ESTIMATED 6 MILLION ADULTS AGED 60 AND OVER IN THE UNITED STATES HAVE ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (AD/ADRD) AT A COST OF $345 BILLION PER YEAR. OLDER ADULTS WITH MILD COGNITIVE IMPAIRMENT (MCI), AN INTERMEDIATE STAGE BETWEEN TYPICAL AGING AND DEMENTIA, ARE 3-5 TIMES MORE LIKELY TO PROGRESS TO AD THAN THOSE WITH NORMAL COGNITION. ALTHOUGH NEW PHARMACOLOGICAL INTERVENTIONS FOR DEMENTIA APPEAR TO SLOW DISEASE PROGRESSION BY ABOUT 6 MONTHS, THEY DO NOT CURE THE DISEASE OR IMPROVE QUALITY OF LIFE, AND ARE OFTEN CONTRAINDICATED OR DISCONTINUED DUE TO SIGNIFICANT SIDE EFFECTS. THUS, THERE IS A COMPELLING NEED TO CONTINUE TESTING NON-PHARMACOLOGICAL ALTERNATIVES FOR SLOWING DISEASE PROGRESSION. LATE-LIFE ENGAGEMENT IN COGNITIVELY CHALLENGING ACTIVITIES HAS BEEN ASSOCIATED WITH DECREASED RISK OF COGNITIVE DECLINE; HOWEVER, NOT ALL OLDER ADULTS, PARTICULARLY THOSE WITH MCI, REMAIN COGNITIVELY ACTIVE. MUSIC-BASED INTERVENTIONS (MBIS) ARE A PROMISING STRATEGY FOR ADDRESSING COGNITIVE INACTIVITY IN LATE-LIFE. GROUP SINGING, IN PARTICULAR, IS AN APPEALING APPROACH BECAUSE IT IS A MULTI-DOMAIN PROCESS THAT INVOLVES THE COMPLEX INTERPLAY OF NUMEROUS BRAIN REGIONS. RESEARCH HAS SHOWN THAT GROUP SINGING FACILITATES SOCIAL BONDING AND BENEFITS HEALTH AND COGNITION IN COMMUNITY- DWELLING ELDERS AS WELL AS IN PATIENTS WITH DEMENTIA. HOWEVER, FEW STUDIES TO DATE HAVE INVESTIGATED THE EFFECTS OF GROUP SINGING FOR OLDER ADULTS WITH MCI. BECAUSE INTERNET-BASED INTERVENTIONS CAN IMPROVE QUALITY OF LIFE AND DECREASE SOCIAL ISOLATION AND DEPRESSION IN OLDER ADULTS, INCLUDING OLDER ADULTS WITH MCI, THE PROPOSED PROJECT WILL DEVELOP, REFINE, AND TEST THE EFFECTS OF AN ONLINE GROUP SINGING INTERVENTION FOR OLDER ADULTS WITH MCI IN TWO PHASES. IN PHASE 1, WE WILL DEVELOP AND REFINE AN ONLINE GROUP SINGING INTERVENTION THAT USES THE JACKTRIPTM VIRTUAL STUDIO, A PLATFORM THAT PROVIDES AN AUDIO-VISUAL SETUP SIMILAR TO ZOOM BUT WITH MINIMAL LATENCY DELAYS ALLOW SINGERS TO ACHIEVE THE “SAME ROOM” EXPERIENCE. WE WILL AIM TO TEST THE FEASIBILITY OF THE MBI TOOLKIT PRINCIPLES AND AFFECT ALL THREE SCIENCE OF BEHAVIOR CHANGE (SOBC) TARGETS (I.E., INTERPERSONAL AND SOCIAL PROCESSES, STRESS REACTIVITY, AND SELF-REGULATION) WITH THE INTERVENTION. IN PHASE 2, WE WILL CONDUCT A 2-ARM RANDOMIZED PILOT TRIAL TO EXAMINE THE FEASIBILITY AND ACCEPTABILITY OF THE ONLINE GROUP SINGING INTERVENTION VERSUS AN ATTENTION CONTROL CONDITION ACCORDING TO THE NIH MBI TOOLKIT PRINCIPLES AND GUIDELINES. WE WILL ALSO EXAMINE THE FEASIBILITY OF ADMINISTERING THE ASSESSMENTS OF THE PROPOSED SOBC TARGETS OF OUR ONLINE GROUP SINGING INTERVENTION. THE SUCCESSFUL COMPLETION OF THIS STUDY WILL SUPPORT A SUBSEQUENT, LARGER RANDOMIZED EFFECTIVENESS TRIAL THAT WILL RIGOROUSLY EVALUATE OUR ONLINE GROUP SINGING INTERVENTION VERSUS AN ACTIVE ATTENTION CONTROL AS A VIABLE INTERVENTION FOR MCI AND OTHER BRAIN DISORDERS OF AGING.

CHARACTERIZATION OF EPIDERMAL STEM CELLS

LOWERING BLOOD PRESSURE AMONG HYPERTENSIVES WITH SCREEN-DETECTED KIDNEY DISEASE

THE PARKINSON'S REGISTRY INVESTIGATION OF DIAGNOSIS AND ETIOLOGY (PRIDE) STUDY

IMPROVING OPIOID SAFTEY IN VETERANS USING COLLABORATIVE CARE AND DECISION SUPPORT

G PROTEIN SIGNALING IN OSTEOBLASTS

PATHOLOGY OF RENAL MATRIX METABOLISM

ROLE OF GUT ASSOCIATED LYMPHOID TISSUE IN HIV PERSISTENCE

RISK AND RESILIENCY FOR DEMENTIA: COMPARISON OF MALE AND FEMALE VETERANS

COGNITIVE BEHAVIORAL TREATMENT OF INSOMNIA IN POSTTRAUMATIC STRESS DISORDER

THE GENETIC BASIS OF SEX DIFFERENCES IN LIVER CANCER

BLOOD BIOMARKER PROFILE OF TBI-ASSOCIATED COGNITIVE IMPAIRMENT AMONG OLD AND YOUNG VETERANS

CAN NEURAL NETWORK INSTABILITY IN SCHIZOPHRENIA BE IMPROVED WITH A VERY LOW CARBOHYDRATE KETOGENIC DIET? - PROJECT SUMMARY/ABSTRACT THIS DIVERSITY SUPPLEMENT WILL SIGNIFICANTLY ENHANCE THE RESEARCH POTENTIAL OF MS. ZANIB NAEEM AND MAKE HER COMPETITIVE FOR TOP-TIER PHD PROGRAMS. MS. NAEEM WILL BE INVOLVED IN A TEAM PROJECT THAT FOCUSES ON THE BENEFITS OF A KETOGENIC DIET IN OVERWEIGHT PEOPLE WITH SCHIZOPHRENIA. SHE WILL BECOME FAMILIAR WITH AN ARRAY OF TOOLS WE USE IN OUR STUDIES OF THE PATHOPHYSIOLOGY OF SCHIZOPHRENIA: STRUCTURAL AND FUNCTIONAL MRI, NEUROPSYCHOLOGY, AND CLINICAL INTERVIEWS. SHE WILL ALSO PARTICIPATE IN THE POST-BAC PROGRAM FOR EQUITY AND LEARNING (PROPEL) CURRICULUM ACTIVITIES, ON WHICH THE PI (DR. FORD) SERVES AS A MENTOR. THROUGH THE PROPEL PROGRAM, MS. NAEEM WILL BOTH PARTICIPATE IN BIOMEDICAL SEMINARS AND HAVE ACCESS TO CAREER DEVELOPMENT OPPORTUNITIES, SUCH AS GRANT WRITING WORKSHOPS AND MOCK INTERVIEWS.

PREVALENCE AND PROGNOSIS OF BLOOD PRESSURE MEDICATION DEINTENSIFICATION AMONG OLDER VA NURSING HOME RESIDENTS

EPIDERMAL MECHANISMS OPPOSING CERAMIDE-INDUCED APOPTOSIS

SIGNALING PATHWAYS OF HIPK2 IN NEURONAL APOPTOSIS

DIAGNOSIS OF COMPARTMENT SYNDROME BASED ON TISSUE OXYGENATION

ANTIGEN-SPECIFIC CD4+ T CELL PRIMING AND MEMORY RESPONSE DURING SPACEFLIGHT: SPACEFLIGHT IMMUNOSUPPRESSION IS A SIGNIFICANT OBSTACLE TO LONG-TERM HUM

TISSUE RESERVOIRS OF HIV IN VICTIMS OF SUDDEN DEATH

ASSESSING MOLECULAR PATHWAYS DRIVING CONJUNCTIVAL MELANOMA

A TRIPLE MARKER APPROACH TO OPTIMIZE CKD DETECTION AMONG BLACK AND WHITE ADULTS