Wake Forest University Health Sciences

EVALUATING NEW NICOTINE STANDARDS FOR CIGARETTES

ARMED FORCES INSTITUTE OF REGENERATIVE MEDICINE

WAKE FOREST NCORP RESEARCH BASE

COMPREHENSIVE CANCER CENTER OF WAKE FOREST UNIVERSITY

SUBCLINICAL VASCULAR CONTRIBUTIONS TO ALZHEIMER'S DISEASE: THE MULTI ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) MULTISITE STUDYOF AD

LOOK AHEAD: ACTION FOR HEALTH IN DIABETES

WAKE FOREST CLINICAL AND TRANSLATIONAL SCIENCE AWARD

NSF ENGINES: PIEDMONT TRIAD REGENERATIVE MEDICINE ENGINE -THE PIEDMONT TRIAD REGENERATIVE MEDICINE ENGINE (THE PIEDMONT TRIAD ENGINE) IS WORKING TO BUILD AN ECOSYSTEM AROUND STRONG ASSETS IN THE FIELD OF REGENERATIVE MEDICINE (RM) BASED AT THE WAKE FOREST INSTITUTE FOR REGENERATIVE MEDICINE (WFIRM) IN COLLABORATION WITH ITS EXTENSIVE NETWORK OF PARTNERS. LOCATED IN THE PIEDMONT TRIAD REGION OF CENTRAL NORTH CAROLINA, THE ENGINE WILL PROVIDE THE RESOURCES TO ACCELERATE TRANSITION OF USE-INSPIRED RM TECHNOLOGIES INTO COMMERCIAL PRODUCTS, CREATING AN ECONOMIC DRIVER FOR THE REGION AND ITS DIVERSE COMMUNITIES. THIS GROWTH IN THE RM INDUSTRY HELPS TO ADDRESS LONG-TERM REGIONAL CHALLENGES RELATED TO RETRAINING AND UPSKILLING OF AN UNDEREMPLOYED LOCAL WORKFORCE LEFT BEHIND BY THE LOSS OF TOBACCO, TEXTILES AND FURNITURE JOBS THROUGHOUT THE REGION OF SERVICE. THE PROJECT PRIORITIZES BUILDING A TECHNICAL INFRASTRUCTURE FOR HISTORICALLY BLACK COLLEGES AND UNIVERSITIES (HBCUS) IN THE REGION TO REDUCE DISPARITIES FOR UNDERREPRESENTED GROUPS IN STEM FIELDS. REGENERATIVE MEDICINE PROMISES TO OFFER PERMANENT CURES RATHER THAN RELIEF FROM SYMPTOMS, WHICH IS AN IMPORTANT ADVANCE GIVEN RISING HEALTHCARE COSTS. THE GOAL IS TO BREAK THE CYCLE OF DEPENDENCE ON LIFELONG MAINTENANCE DRUGS AND THERAPIES. AREAS OF TECHNICAL FOCUS INCLUDE STANDARDIZED MATERIALS AND PROCESSES FOR THE PRODUCTION OF RM PRODUCTS THAT CAN BE BROUGHT TO MARKET. INDUSTRY PARTNERS AND COMMUNITY STAKEHOLDERS WILL DRIVE THE DIRECTION OF THE TECHNOLOGY DEVELOPMENT, WHILE ALLOWING FOR CREATIVE INNOVATION THROUGH THE ACADEMIC RESEARCH ENVIRONMENT. TECHNOLOGIES BORN FROM THE PIEDMONT TRIAD ENGINE WILL BE COMMERCIALIZED THROUGH A ROBUST BUSINESS DEVELOPMENT SYSTEM, GIVING RISE TO NEW COMPANIES AND INCREASED WORKFORCE DEMAND THAT WILL BE MET BY THE PIEDMONT TRIAD ENGINE?S PARTNERS INCLUDING TWO-YEAR COMMUNITY AND TECHNICAL COLLEGES. THIS NSF ENGINE WILL BE BUILT UPON INDUSTRY USE-INSPIRED AND GUIDED RESEARCH SPANNING PRODUCT IDEATION AND DEVELOPMENT, TRANSLATIONAL SCIENCE, BIOMANUFACTURING, AND NEXT GENERATION STRATEGIES, INCLUDING IN-SPACE RM TECHNOLOGIES. AN INNOVATION, TRANSLATION, & EDUCATION CORE SYSTEM WILL BE DEVELOPED ACROSS PARTNERING ACADEMIC INSTITUTIONS, INCLUDING AT HBCUS AND TECHNICAL COLLEGES IN THE REGION OF SERVICE, THAT COMBINES MULTIPLE AREAS OF SCIENTIFIC EXPERTISE TO ADDRESS CHALLENGES IN THE MULTIDISCIPLINARY FIELD OF RM. THE RESOURCES PROVIDED BY THE PIEDMONT TRIAD ENGINE WILL INCREASE THE REGION?S COMPETITIVE ADVANTAGE AND LEVERAGE ITS NATIONAL REPUTATION AS A HUB FOR THE RM INDUSTRY, ATTRACTING MORE CAPITAL AND NEW COMPANIES TO THE REGION. THE PIEDMONT TRIAD ENGINE WILL HAVE TRANSFORMATIVE IMPACT ON THE REGION BY CREATING A NEW TRAINED RM WORKFORCE THAT WILL GIVE THE U.S. A COMPETITIVE EDGE IN THE DEVELOPMENT AND MANUFACTURE OF NEXT-GENERATION RM THERAPIES WITH POTENTIAL TO IMPACT MILLIONS OF INDIVIDUALS WORLDWIDE. RM BUSINESSES THAT EMERGE FROM TECHNICAL INNOVATIONS WILL BE ECONOMIC DRIVERS, ATTRACTING INVESTMENT FROM STAKEHOLDERS ACROSS THE NATION. CREATION OF NEW RM PRODUCTS AND BUSINESSES WILL CREATE SELF-SUSTAINING REGIONAL PROSPERITY WITH ECONOMIC IMPACT FOR MANY COMMUNITIES IN THE REGION, INCLUDING HISTORICALLY DISADVANTAGED BLACK COMMUNITIES IN THE PIEDMONT TRIAD REGION. THIS NSF ENGINE PROJECT IS BUILT ON A STRONG RESEARCH AND DEVELOPMENT PORTFOLIO AT WFIRM AND EMPHASIZES THE TRANSLATION TO PRACTICE AND COMMERCIALIZATION STEPS OF BUILDING AN INNOVATION ECOSYSTEM IN PARTNERSHIP WITH STRONG WORKFORCE DEVELOPMENT ORGANIZATIONS ALREADY IN THE REGION OF SERVICE. BIOMEDICAL TECHNOLOGIES AND THE RM INDUSTRY SHOW STRONG ALIGNMENT WITH THE PRIORITIES OF THE REGION OF SERVICE, WHICH WAS REINFORCED BY THE STRONG SHOWING OF ENTHUSIASTIC PARTNERS WHO ENGAGED WITH THE SITE VISIT TEAM. THE LEADERSHIP IS READY TO UTILIZE THE NSF ENGINE RESOURCES TO BRIDGE THE GAP BETWEEN THE RESEARCH LAB AND THE COMMERCIAL MARKET WITHOUT LEAVING THE LOCAL COMMUNITY BEHIND. COMMUNITY ENGAGEMENT AND WORKFORCE TRAINING WILL BE KEY TO THE SUCCESS OF THE PIEDMONT TRIAD ENGINE. 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.- SUBAWARDS ARE PLANNED FOR THIS AWARD.

MOTRPAC CONSORTIUM COORDINATING CENTER

CLAUDE D. PEPPER OLDER AMERICANS INDEPENDENCE CENTER AND COORDINATING CENTER

PHYSICAL REHABILITATION FOR OLDER PATIENTS WITH ACUTE HFPEF-THE REHAB-HFPEF TRIAL - ACUTE DECOMPENSATED HEART FAILURE (ADHF) IS THE LEADING CAUSE OF HOSPITALIZATION IN OLDER PERSONS, AND IS ASSOCIATED WITH MARKED PHYSICAL DISABILITY, POOR HEALTH-RELATED QUALITY OF LIFE (HRQOL), FREQUENT REHOSPITALIZATIONS, LOSS OF INDEPENDENCE, HIGH MORTALITY, AND ENORMOUS HEALTH CARE COSTS. HOWEVER, MOST OF THE TRIALS TESTING A WIDE RANGE OF MEDICATIONS AND STRATEGIES IN ADHF HAVE BEEN NEUTRAL. IN OUR RECENTLY COMPLETED NIA-FUNDED PHASE 2 TRIAL (REHAB-HF), AN INNOVATIVE, EARLY, TRANSITIONAL, TAILORED, AND PROGRESSIVE MULTI-DOMAIN PHYSICAL REHABILITATION INTERVENTION PRODUCED A LARGE IMPROVEMENT IN THE PRIMARY OUTCOME OF SHORT PHYSICAL PERFORMANCE BATTERY (+1.5 POINTS) IN OLDER PATIENTS WITH ADHF. AT BASELINE, THE PARTICIPANTS (53%) WITH HF WITH PRESERVED EJECTION FRACTION (HFPEF), HAD SIGNIFICANTLY WORSE IMPAIRMENTS IN PHYSICAL FUNCTION, FRAILTY, HRQOL, AND DEPRESSION THAN THOSE WITH HF WITH REDUCED EF. THEY ALSO APPEARED TO DERIVE GREATER BENEFIT FROM THE INTERVENTION, WITH ~50% LARGER EFFECT SIZES IN PHYSICAL FUNCTION, FRAILTY, HRQOL, AND DEPRESSION. PATIENTS WITH HFPEF ALSO APPEARED TO HAVE MUCH GREATER REDUCTIONS IN REHOSPITALIZATIONS AND DEATH AND POTENTIAL FOR REDUCED MEDICAL RESOURCE USE. THE FINDING OF POTENTIALLY GREATER BENEFIT IN HFPEF IS NOTEWORTHY AS HFPEF IS HIGHLY RELEVANT TO OLDER PERSONS AND HAS THE MOST URGENT NEED FOR NEW TREATMENTS SINCE IT IS: 1) THE MOST COMMON FORM OF HF, NEARLY UNIQUE TO OLDER PERSONS, AND DISPROPORTIONATELY AFFECTS OLDER WOMEN AND BLACK PERSONS; 2) INCREASING IN PREVALENCE; 3) ACCEPTED AS A GERIATRIC SYNDROME; 4) ASSOCIATED WITH MARKED IMPAIRMENTS IN PHYSICAL FUNCTION AND HRQOL AND HIGH RATES OF FRAILTY; 5) HAS HIGH MORBIDITY AND MORTALITY WHICH ARE WORSENING OVER TIME; AND 6) HAS LIMITED EVIDENCE-BASED TREATMENTS. THE PHASE 3 REHAB- HFPEF TRIAL WILL FOCUS ON THIS LARGE, GROWING, VULNERABLE, UNDERSERVED POPULATION. THE 5-YEAR, RANDOMIZED, ATTENTION-CONTROLLED, SINGLE-BLINDED TRIAL WILL ENROLL 880 OLDER ADULTS AGE >60 YEARS WITH ADHF AND HFPEF ACROSS 20 GEOGRAPHICALLY DISPERSED CLINICAL CENTERS. WE WILL TEST THE HYPOTHESIS THAT THE INNOVATIVE REHAB-HF INTERVENTION WILL IMPROVE THE CLINICALLY COMPELLING COMBINED PRIMARY ENDPOINT OF ALL-CAUSE REHOSPITALIZATIONS AND MORTALITY DURING 6-MONTH FOLLOW-UP, THE MOST VULNERABLE TIME PERIOD FOLLOWING ADHF HOSPITALIZATION (AIM 1) AND THE SECONDARY ENDPOINT OF PREVALENCE OF MAJOR MOBILITY DISABILITY, A CLINICALLY MEANINGFUL OUTCOME IN TRIALS OF OLDER ADULTS, AT 6-MONTHS (AIM 2). WE WILL ALSO ASSESS THE INTERVENTION’S IMPACT ON HRQOL, FRAILTY, DEPRESSION, PHYSICAL ACTIVITY, AND HEALTH CARE COSTS. OUR DIVERSE, COHESIVE, MULTI-DISCIPLINARY TEAM AND EXPERIENCE FROM THE PHASE 2 TRIAL WILL ENSURE EFFICIENT AND EFFECTIVE EXECUTION AND DISSEMINATION. REHAB-HFPEF DIRECTLY ADDRESSES THE KEY RECOMMENDATIONS OF SEVERAL RECENT NIA AND NHLBI SPONSORED WORKSHOPS. ITS RESULTS COULD IMPROVE KEY OUTCOMES THAT ARE MEANINGFUL TO PATIENTS, CAREGIVERS, HEALTH SYSTEMS, AND PAYERS. THE TRIAL HAS STRONG POTENTIAL TO CHANGE CLINICAL GUIDELINES, REDUCE HEALTH CARE COSTS, AND INFLUENCE NATIONAL COVERAGE DECISIONS FOR THE LARGE, GROWING, UNDERSERVED, HIGH-RISK POPULATION OF OLDER PATIENTS WITH ACUTE HFPEF.

THE WAKE FOREST NONHUMAN PRIMATE RADIATION SURVIVOR COHORT

VASODEPRESSOR MECHANISMS IN HYPERTENSION

AFIRM II (ARMED FORCES INSTITUTE OF REGENERATIVE MEDICINE) CONSORTIUM. THIS AWARD IS FOR THE GENITOURINARY/LOWER ABDOMEN RECONSTRUCTION (GU) FOCUS A

CENTER THE NEUROBIOLOGICAL INVESTIGATION OF DRUG ABUSE

GENOMIC AND PROTEOMIC ARCHITECTURE OF ATHEROSCLEROSIS

CLINICAL REGISTRY OF DENTAL OUTCOMES IN HEAD AND NECK CANCER PATIENTS

ALZHEIMER'S DISEASE RESEARCH CENTER - OVERALL – PROJECT SUMMARY THE ALZHEIMER’S DISEASE RESEARCH CENTER (ADRC) WAS FOUNDED AT WAKE FOREST SCHOOL OF MEDICINE (WFSM) IN 2016 TO PROVIDE A COMPREHENSIVE INFRASTRUCTURE FOR RESEARCH ON THE PATHOPHYSIOLOGY, PREVENTION, AND TREATMENT OF AD AND RELATED DISORDERS (ADRD). THE THEME OF OUR ADRC IS TO BETTER UNDERSTAND EARLY TRANSITIONS FROM NORMAL AGING TO MCI AND DEMENTIA, AND TO ELUCIDATE THE ROLE THAT METABOLIC AND VASCULAR FACTORS PLAY IN THESE TRANSITIONS, THROUGH COORDINATED RESEARCH ACTIVITIES SPANNING THE TRANSLATIONAL SPECTRUM. NO CURRENT THERAPIES EFFECTIVELY PREVENT OR TREAT THE SYMPTOMS OF AD. THIS CHASM HIGHLIGHTS THE NEED TO IDENTIFY ANTECEDENT BIOMARKERS AND RISK FACTORS THAT PREDICT LATER-LIFE VULNERABILITY OR RESILIENCE, IN ORDER TO DEVELOP STRATEGIES FOR PREVENTION AND EARLY INTERVENTION. METABOLIC AND VASCULAR DISORDERS ARE POWERFUL MODIFIABLE FACTORS THAT MAY CONTRIBUTE TO THE TRANSITIONS FROM NORMAL AGING TO MCI AND ADRD. SUCH DISORDERS ARE EPIDEMIC IN THE SOUTHEASTERN REGION SURROUNDING THE WF ADRC; MORE THAN 70% OF ADULTS OVER THE AGE OF 50 HAVE PREDIABETES, DIABETES, OR HYPERTENSION. THESE DISORDERS INCREASE THE RISK OF COGNITIVE IMPAIRMENT AND DEMENTIA THROUGH COMPLEX INTERACTIONS THAT ARE POORLY UNDERSTOOD. THE WF ADRC SEEKS TO PROVIDE RESOURCES TO BETTER UNDERSTAND THESE INTERACTIONS. WE ALSO SEEK TO ELUCIDATE THE MULTI-DIMENSIONAL ROLE THAT HEALTH DISPARITIES PLAY IN INFLUENCING RISK FOR AD. WE EMPHASIZE ENGAGEMENT OF AFRICAN AMERICANS AND OTHER UNDERREPRESENTED GROUPS, WHO ARE TWICE AS LIKELY TO DEVELOP DEMENTIA, AND HAVE HIGH RATES OF DIABETES AND VASCULAR DISEASE. TO PROMOTE INNOVATIVE RESEARCH ON METABOLIC/VASCULAR RISK AND HEALTH DISPARITIES, OUR OUTREACH, RECRUITMENT AND ENGAGEMENT AND CLINICAL CORES HAVE PARTNERED TO ENROLL AND FOLLOW ~600 PARTICIPANTS, CAREFULLY CHARACTERIZING THEIR VASCULAR AND GLYCEMIC STATUS. PARTICIPANTS RECEIVE MAGNETIC RESONANCE IMAGING AND AMYLOID AND TAU POSITRON EMISSION TOMOGRAPHY OVERSEEN BY THE IMAGING BIOMARKER CORE. VALUABLE SAMPLES AND DATA FROM THIS COHORT ARE MADE WIDELY AVAILABLE TO THE NATIONAL ALZHEIMER’S COORDINATING CENTER, THE NATIONAL CENTRALIZED REPOSITORY FOR AD AND OTHER INVESTIGATORS BY THE DATA MANAGEMENT AND STATISTICAL ANALYSIS AND NEUROPATHOLOGY CORES, PROVIDING INVALUABLE RESOURCES TO ADDRESS NUMEROUS NATIONAL ALZHEIMER’S PROJECT ACT MILESTONES. THE NEUROPATHOLOGY CORE HAS ALSO CHARACTERIZED NOVEL NONHUMAN PRIMATE MODELS WITH METHODS THAT PARALLEL THE ADRC’S HUMAN COHORT TO PROMOTE TRANSLATIONAL RESEARCH. FINALLY, THE ADRC AND ITS RESEARCH EDUCATION COMPONENT PROVIDE TRAINING RELATING TO AD, METABOLIC/ VASCULAR FACTORS AND HEALTH DISPARITIES TO A DIVERSE CADRE OF NEW RESEARCHERS, AND EDUCATION FOR PATIENTS AND FAMILIES, HEALTH PROFESSIONALS, AND THE COMMUNITY. THE PREVALENCE OF METABOLIC AND VASCULAR RISK FACTORS, THEIR ROLE IN ONSET, PROGRESSION, AND HETEROGENEITY OF ADRDS, AND THE STRENGTHS OF THE WF ADRC IN THESE RESEARCH AREAS, ENSURE THAT WE WILL MAKE HIGH-IMPACT CONTRIBUTIONS TO THE SEARCH FOR STRATEGIES TO TREAT AND PREVENT AD.

AFIRM II CF

LIMITED COMPETITION FOR THE CONTINUATION OF THE SEARCH FOR DIABETES IN YOUTH COHORT STUDY (UC4)SEARCH FOR DIABETES IN YOUTH COHORT STUDY

WAKE FOREST TRANSLATIONAL ALCOHOL RESEARCH CENTER (WF-TARC)

AFIRM II ER FOCUS AREA

SKIN REGENERATION

VERVET RESEARCH COLONY AS A BIOMEDICAL RESOURCE

COMPOSITE TISSUE ALLOTRANSPLANTATION AND IMMUNOMODULATION

HE WAKE FOREST INSTITUTE FOR REGENERATIVE MEDICINE (WFIRM) HAS OVER TWO DECADES OF EXPERIENCE USING A VARIETY OF 3D PRINTING MODALITIES TO DEVELOP IMPLANTABLE HUMAN TISSUE CONSTRUCTS. OVER TIME THE CELLULAR COMPOSITIONS AND IMPLANT DIMENSIONS RELEVANT TO CLINICAL APPLICATIONS HAVE INCREASED REQUIRING AN INTEGRATED VASCULAR SYSTEM THAT ALLOWS PERFUSION OF THE ENTIRE CONSTRUCT. THESE BIOPRINTED VASCULARIZED TISSUE CONSTRUCTS OPEN THE POSSIBILITY OF SUPPORTING A FUNCTIONAL MICROANATOMY THAT CAN PERFORM NUANCED ORGAN SPECIFIC FUNCTIONS. THE OVERALL STRATEGY WILL INCLUDE A PROTOCOL FOR COST EFFECTIVE CLINICAL MANUFACTURING OF A SUFFICIENT NUMBER OF AUTOLOGOUS RENAL CELLS FROM A SMALL SURGICAL SAMPLE OR TISSUE BIOPSY. THESE CELLS WILL BE COMBINED WITH A FUNCTIONALIZED HYDROGEL BIOINK THAT BOTH SUPPORTS THE LONG TERM VIABILITY OF THE EMBEDDED CELLS AND PROMOTES THE ACTIVATION OF ENDOGENOUS DEVELOPMENTAL PATHWAYS THAT GUIDE THE FORMATION OF A FUNCTIONAL CELLULAR MICROANATOMY. CUTTING EDGE MULTIPHYSICS MODELING WILL BE APPLIED TO NATIVE RENAL TISSUE TO ESTABLISH A BLUEPRINT THAT APPROXIMATES RENAL TISSUE ARCHITECTURE AT A RESOLUTION OF 50 UM. SOFTWARE WILL ALSO BE DEVELOPED TO TRANSLATE THIS BLUEPRINT INTO A PRINTABLE CODE THAT WILL GUIDE THE RAPID PRODUCTION OF RUDIMENTARY RENAL TISSUE. THESE CONSTRUCTS WILL BE FURTHER ENHANCED THROUGH MATURATION IN A SPECIALIZED PERFUSION BIOREACTOR WITH AN INTEGRATED SENSOR SUITE THAT MONITORS TISSUE FUNCTION. STRATEGIES WILL ALSO BE DEVELOPED USING SMALL AND LARGE PRECLINICAL ANIMAL MODELS TO PROMOTE FURTHER REMODELING OF BIOPRINTED RENAL TISSUE FOLLOWING IMPLANTATION. THE OVERARCHING GOAL IS THE PRODUCTION OF BIOPRINTED VASCULARIZED AUTOLOGOUS RENAL TISSUE TO AUGMENT RENAL FUNCTION IN PATIENTS SUFFERING FROM KIDNEY DISEASE. THIS TISSUE THERAPY WILL BE QUALIFIED USING IND ENABLING PRECLINICAL ANIMALS IN PARALLEL WITH A COMMERCIALIZATION PLAN TO MAKE THIS A COST EFFICIENT SOLUTION TO THE NATIONS GROWING DONOR ORGAN SHORTAGE.

WOMB TO TOMB: DEVELOPMENTAL PROGRAMMING AND AGING INTERACTIONS IN PRIMATES

THERAPEUTIC EFFECT OF INTRANASAL INSULIN ON COGNITION, FUNCTION, AND AD BIOMARKER

WAKE FOREST ALZHEIMER'S DISEASE CORE CENTER

COMPREHENSIVE CANCER CENTER OF WAKE FOREST UNIVERSITY CCOP RESEARCH BASE

THE WAKE FOREST AND HARVARD CENTER FOR BOTANICAL LIPIDS

GENERAL CLINICAL RESEARCH CENTER

MULTICENTER CLINICAL TRIAL OF KERATIN BIOMATERIALS FOR PERIPHERAL NERVE REGENERATION

THE POINTER NEUROVASCULAR ANCILLARY STUDY

PRENATAL EVENTS-POSTNATAL CONSEQUENCES

LONG-TERM FOLLOW-UP OF THE DELAYED EFFECTS OF ACUTE RADIATION EXPOSURE IN PRIMATES

THE SPRINT ALZHEIMER'S, SENIORS AND KIDNEY STUDY (SPRINT ASK)

LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS

OXYTOCIN: A PAIN DISEASE-MODIFYING AGENT IN THE NERVOUS SYSTEM AFTER INJURY - THIS P01 WILL ADDRESS FUNDAMENTAL GAPS IN KNOWLEDGE THAT CURRENTLY IMPEDE TRANSLATION OF FINDINGS IN THE PRECLINICAL LITERATURE TO IMPROVED CLINICAL PRACTICE REGARDING THE UTILITY OF OXYTOCIN AS A PAIN THERAPEUTIC AND POTENTIAL DISEASE-MODIFYING AGENT TO PREVENT THE TRANSITION FROM ACUTE TO CHRONIC PAIN. OXYTOCIN ITSELF IS THE ONLY CLINICALLY AVAILABLE TOOL FOR TRANSLATIONAL STUDIES IN MANY AREAS – NEUROPROTECTION, ANXIETY, SLEEP, SOCIAL BEHAVIORS, ADDICTION, AND PAIN. MOST RODENT AND HUMAN STUDIES OF OXYTOCIN LACK STRONG SCIENTIFIC RIGOR, WITH ONLY HALF OF THE CLINICAL STUDIES EXAMINING PAIN DEMONSTRATING EFFICACY, AND WE HAVE MINIMAL ABILITY TO UNDERSTAND OXYTOCIN EFFECTS WITHIN AND ACROSS SPECIES. SINCE CHRONIC PAIN IS USUALLY REDUCED ACUTELY BY PERIPHERAL NERVE BLOCK, PERIPHERAL INPUT IS NECESSARY, BUT MOST RESEARCH ASSUMES THAT INPUT IS NORMAL AND PAIN REFLECTS ONGOING CENTRAL SENSITIZATION. WE AND OTHERS CHALLENGE THESE IDEAS, SHOWING THAT LTMRS ARE DESENSITIZED AFTER INJURY WHEREAS FAST HIGH THRESHOLD MECHANORECEPTORS (A-HTMRS) ARE SENSITIZED AND BEHAVIORAL RECOVERY COINCIDES WITH RETURN TO NORMAL FUNCTION OF BOTH AFFERENT SUBTYPES. IMPORTANTLY, OXYTOCIN ACUTELY MOVES LTMR AND A-HTMR DYSFUNCTION AFTER INJURY TOWARDS NORMAL. PAIN RESOLVES QUICKER IN WOMEN AFTER CESAREAN DELIVERY THAN OTHER PELVIC SURGERIES, AND HYPERSENSITIVITY RESOLVES QUICKER IN RODENTS WHEN NEUROPATHIC INJURY IS PERFORMED AFTER DELIVERY, AN EFFECT BLOCKED BY INHIBITION OF OXYTOCIN ACTION. THESE DATA SUGGEST THAT OXYTOCIN MAY ALTER THE PROCESS OF CHRONIC PAIN DEVELOPMENT AFTER INJURY OR SURGERY, AND HAS THE POTENTIAL TO BE NOT JUST AN ACUTE ANALGESIC, BUT A DISEASE-MODIFYING THERAPEUTIC. OXYTOCIN HAS PROSOCIAL, ANXIOLYTIC, AND TRUST ENHANCING EFFECTS ACCORDING TO SMALL STUDIES IN RODENTS AND HUMANS, BUT THE CIRCUITRY AND ROLE OF THESE CENTRAL ACTIONS ON SPEEDING RECOVERY FROM PAIN AND DISABILITY AFTER INJURY ARE UNEXPLORED. THIS P01 WILL ADDRESS THESE GAPS AND ADVANCE THE FIELD OF PAIN RESEARCH THROUGH THE COORDINATED INTERACTIONS BETWEEN THE PRECLINICAL AND CLINICAL PROJECTS ACROSS 3 SPECIFIC AREAS. THE FIRST IS EXTRAPOLATION OF THE PHARMACOKINETICS OF OXYTOCIN ACROSS SPECIES, SUCH THAT DRUG EXPOSURE IN RELEVANT COMPARTMENTS WITH TIME ARE BEING STUDIED IN A COORDINATED MANNER THAT PERMITS INTERPRETATION OF PHYSIOLOGICAL OR BEHAVIORAL EFFECTS BETWEEN RATS AND HUMANS SECOND IS THE STUDY OF PRIMARY SENSORY AFFERENT PHYSIOLOGY ACROSS SPECIES THAT DETERMINES HOW OXYTOCIN ALTERS SPECIFIC NERVE FIBER TYPES AND THE KEY ELECTRICAL PROPERTIES RELATED TO PAIN TRANSMISSION, INCLUDING MULTIPLE MODES OF NOCICEPTIVE STIMULATION AND THEIR INTERACTION. THIRD, WE STUDY PAIN BEHAVIORS BEYOND REFLEXIVE RESPONSES OR VERBAL REPORT IN ANIMALS AND HUMANS, RESPECTIVELY, WHICH MAY OFFER GREATER TRANSLATIONAL VALUE. COLLECTIVELY, THE COORDINATED AND SYNERGISTIC NATURE OF THESE STUDIES WILL HOPEFULLY PROVIDE CLARITY ON THE POTENTIAL OF OXYTOCIN TO MITIGATE CHRONIC PAIN DEVELOPMENT AFTER INJURY, AND THE CONTEXT WITHIN SUCH EFFECTS OCCUR.

LOOK AHEAD SLEEP: SLEEP-DISORDERED BREATHING, CIRCADIAN REST/ACTIVITY RHYTHMS, AND THE RISK OF ALZHEIMER'S DISEASE AND RELATED DEMENTIAS IN LOOK AHEAD - PROJECT SUMMARY SLEEP DISORDERED BREATHING (SDB) AND ALTERED CIRCADIAN REST/ACTIVITY RHYTHMS (CRARS) ARE INCREASINGLY RECOGNIZED AS RISK FACTORS FOR ALZHEIMER’S DISEASE AND RELATED DEMENTIAS. OBESITY AND TYPE 2 DIABETES (T2D) ARE LEADING LIFESTYLE RISK FACTORS FOR POOR COGNITIVE OUTCOMES, AND ARE CLOSELY LINKED TO SDB AND CIRCADIAN ALTERATIONS. THE ROLES OF SDB AND ALTERED CRARS IN THE PROMOTION OF COGNITIVE DECLINE AND DEMENTIA RISK, HOWEVER, HAVE NOT BEEN WELL STUDIED IN OLDER OVERWEIGHT OR OBESE INDIVIDUALS WITH T2D, WHO ARE ALREADY VULNERABLE TO COGNITIVE DECLINE. THE PROPOSED ANCILLARY INVESTIGATION TO THE LOOK AHEAD STUDY WILL QUANTIFY SDB AND CRARS (THROUGH HOME SLEEP TESTING AND WRIST ACTIGRAPHY) AND WILL USE A VALIDATED TELEPHONE COGNITIVE ASSESSMENT PROTOCOL IN 1,500 LOOK AHEAD PARTICIPANTS, TO EVALUATE THE LINKS OF SDB AND ALTERED CRARS WITH COGNITIVE DECLINE AND ADJUDICATED CLINICAL CONDITIONS: MILD COGNITIVE IMPAIRMENT, ALZHEIMER’S DISEASE, AND ALZHEIMER’S DISEASE RELATED DISORDERS, IN THIS COHORT. WE WILL INVESTIGATE ~20-YEAR DIABETES CONTROL AND WEIGHT TRAJECTORIES, AND APOE E4 CARRIER STATUS AS POTENTIAL EFFECT MODIFIERS, AND EXPLORE BLOOD BASED BIOMARKERS OF ALZHEIMER’S DISEASE (ASS42/ASS40, TOTAL TAU, PTAU181, AND NFL). FINALLY, WE WILL LEVERAGE LOOK AHEAD’S RANDOMIZED CONTROLLED TRIAL DESIGN TO EXAMINE WHETHER PARTICIPANTS WHO WERE RANDOMIZED TO AN INTENSIVE LIFESTYLE INTERVENTION (ILI) THAT TARGETED DIET AND PHYSICAL ACTIVITY (VS. A DIABETES SUPPORT AND EDUCATION (DSE) CONTROL CONDITION) EXHIBIT LOWER RATES OF SDB AND MORE ROBUST, LESS PHASE-DELAYED CRARS IN LATER LIFE. WE WILL DETERMINE WHETHER DIFFERENCES IN THESE SDB/CIRCADIAN CHARACTERISTICS ARE ASSOCIATED WITH MAINTENANCE OF COGNITIVE FUNCTION IN OLDER ADULTHOOD. RESULTS OF THIS STUDY—CONDUCTED BY A TEAM OF INVESTIGATORS WITH EXPERTISE IN AGING, SLEEP, DIABETES, AND COGNITIVE DECLINE AND ALZHEIMER’S DISEASE—WILL ADVANCE OUR UNDERSTANDING OF HOW SDB AND ALTERED CRARS AFFECT BRAIN HEALTH AMONG OLDER ADULTS WITH T2D AND OVERWEIGHT/OBESITY, AND WHETHER A LIFESTYLE INTERVENTION PRODUCES DURABLE EFFECTS ON SLEEP/CIRCADIAN HEALTH THAT TRANSLATE INTO SUSTAINED BRAIN HEALTH IN THIS AT-RISK POPULATION.

MAXIMIZING LOCAL ACCESS TO THERAPEUTIC DELIVERIES IN GLIOBLASTOMA

CHRONIC STRESS AND COCAINE ABUSE IN FEMALE MONKEYS

LONG-TERM IMPACT OF RANDOM ASSIGNMENT TO INTENSIVE LIFESTYLE INTERVENTION ON ALZHEIMERS DISEASE AND RELATED DEMENTIAS: THE ACTION FOR HEALTH IN DIABETES ADRD STUDY (LOOK AHEAD-MIND)

COMMUNITY PARTICIPATORY APPROACH TO MEASURING FARMWORKER PESTICIDE EXPOSURES: PAC

MULTI-DISCIPLINARY TRAINING IN THE BIOLOGY OF ALCOHOLISM

RECOVERY FROM PAIN AND DISABILITY AFTER SURGERY

CTSA UM1 PROGRAM AT WAKE FOREST - PROJECT SUMMARY/ABSTRACT THE EMERGENCE OF LARGE INTEGRATED HEALTH SYSTEMS LINKED BY COMMON INFORMATICS PLATFORMS OFFERS AN UNPRECEDENTED OPPORTUNITY TO STUDY THE IMPACT OF NEW THERAPIES, HEALTHCARE DELIVERY MODELS, AND STRATEGIES TO MITIGATE HEALTH DISPARITIES IN REAL WORLD SETTINGS. SUCH INTEGRATED SYSTEMS ALSO OFFER OPPORTUNITIES TO TEST APPROACHES TO IMPLEMENT AND SCALE EVIDENCE-BASED PRACTICES, TO ADDRESS GAPS IN TRANSLATIONAL SCIENCE, AND TO BECOME LEARNING HEALTH SYSTEMS (LHS). THE WAKE FOREST (WF) CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE (CTSI) HAS PIONEERED THE INTEGRATION OF THE ACADEMIC MISSION INTO THE LHS FRAMEWORK INCLUDING T0-T4 TRANSLATION, SCHOLARSHIP, AND EDUCATION WHILE ALSO ADDRESSING THE SOCIAL DETERMINANTS OF HEALTH AND PROMOTING THE VITALITY OF THE COMMUNITIES SERVED. WF LEADS AS THE ACADEMIC CORE OF ADVOCATE HEALTH – THE NATION’S FIFTH LARGEST NOT-FOR-PROFIT HEALTH SYSTEM SERVING NEARLY 6 MILLION PATIENTS ACROSS THE SOUTHEAST AND MIDWEST UNITED SATES. THE ALHS IS ADVOCATE HEALTH’S GUIDING VISION, AND THE WF CTSI IS ITS CENTRAL RESOURCE FOR SUPPORTING TRANSLATIONAL SCIENCE ACROSS THE ENTIRE SYSTEM. THE SIZE OF THE HEALTH SYSTEM OFFERS A UNIQUE OPPORTUNITY TO DEVELOP, DEMONSTRATE, AND DISSEMINATE NOVEL CARE MODELS IN A WIDE RANGE OF SETTINGS. WITH THIS FUNDING, THE WF CTSI WILL DRIVE THE REALIZATION OF THE FULL POTENTIAL OF AN ALHS AND CREATE A MODEL FOR ADVANCING TRANSLATIONAL SCIENCE IN A LARGE ACADEMIC HEALTH SYSTEM. THE NEED FOR SUCH A MODEL IS URGENT, GIVEN THE ONGOING CONSOLIDATION OF ACADEMIC AND NON-ACADEMIC HEALTH SYSTEMS IN THE UNITED STATES AND THE CHALLENGES IN CONDUCTING RESEARCH IN BUSY PRACTICE SETTINGS. ALL ACTIVITIES AND INITIATIVES TO ADVANCE TRANSLATIONAL SCIENCE WILL BE GROUNDED IN A CULTURE OF ACCOUNTABILITY FOR ENHANCING DIVERSITY, EQUITY, AND INCLUSION. WF CTSI’S VISION WILL BE ACHIEVED THROUGH THE FOUR SPECIFIC AIMS: 1) SUPPORT AN INCLUSIVE AND HIGHLY EFFECTIVE GOVERNANCE STRUCTURE THAT PROMOTES A CULTURE OF CONTINUOUS QUALITY IMPROVEMENT, ENABLES TIMELY RESPONSE TO REGIONAL AND NATIONAL HEALTH EMERGENCIES, SUPPORTS PROACTIVE DISSEMINATION AND IMPLEMENTATION, AND ENABLES ACTIVE PARTICIPATION IN CTSA-SPONSORED TRIALS; 2) RECRUIT AND TRAIN A HIGHLY COMPETENT AND DIVERSE ALHS WORKFORCE AND ENGAGE THE FULL RANGE OF PATIENT AND COMMUNITY STAKEHOLDERS WHO ARE ESSENTIAL TO IMPROVING HEALTH AND MITIGATING HEALTH DISPARITIES; 3) PROVIDE RESOURCES TO PROMOTE INNOVATIVE PRAGMATIC STUDY DESIGNS, SUPPORT PILOT STUDIES THAT ADDRESS KEY TRANSLATIONAL ROADBLOCKS, AND SATISFY THE NEEDS OF THE ALHS RESEARCH COMMUNITY FOR TIMELY ACCESS TO DATA FROM ELECTRONIC HEALTH RECORDS, POPULATION SURVEYS, OMICS ANALYSES, AND OTHER SOURCES; AND 4) ENHANCE TRANSLATIONAL EFFICIENCY THROUGH PROJECTS TESTING NOVEL METHODS (E.G., RESPONDENT DRIVEN SAMPLING TO IMPROVE PATIENT RECRUITMENT, INTEGRATING PATIENT GENERATED DATA INTO THE EHR). INNOVATIONS MADE IN ACHIEVING THESE AIMS WILL BE SHARED THROUGH AND BEYOND THE CTSA NATIONAL NETWORK.

NORTH CAROLINA DIABETES RESEARCH CENTER

WAKE FOREST APOLLO SCIENTIFIC AND DATA RESEARCH CENTER

DEVELOPING AN NIA RESEARCH CENTERS COLLABORATIVE NETWORK (RCCN)

1/2, CLINICAL COORDINATING CENTER FOR THE LONG-TERM EFFECTIVENESS OF THE ANTI-OBESITY MEDICATION PHENTERMINE: THE LEAP TRIAL - PROJECT SUMMARY/ABSTRACT OVER ONE-THIRD OF ADULTS IN THE US HAVE OBESITY, MANY WITH COMORBIDITIES INCLUDING HYPERTENSION AND DIABETES. COMPREHENSIVE LIFESTYLE CHANGE IS THE FIRST-LINE APPROACH TO TREATING OBESITY, BUT AS MANY AS HALF OF PATIENTS ARE NON-RESPONSIVE TO BEHAVIOR CHANGE INTERVENTIONS, AND THE MAJORITY OF INITIAL RESPONDERS GO ON TO REGAIN LOST WEIGHT WITHIN 2 YEARS. PAIRING LIFESTYLE INTERVENTION WITH AN ANTIOBESITY MEDICATION (AOM) CAN ENHANCE WEIGHT LOSS AND PROMOTE WEIGHT LOSS MAINTENANCE. HOWEVER, DESPITE THE RECENT AVAILABILITY OF SEVERAL AOMS IN THE US, THESE MEDICATIONS ARE RARELY PRESCRIBED. AMONG THE SMALL SUBSET OF PATIENTS WHO DO RECEIVE AN AOM PRESCRIPTION, THE GENERIC MEDICATION PHENTERMINE ACCOUNTS FOR 76% OF FILLS. PHENTERMINE IS ONLY APPROVED FOR SHORT-TERM USE, WHILE CURRENT GUIDELINES FOR TREATMENT OF OBESITY RECOMMEND LONG-TERM AOM PRESCRIBING. CONCERNS ABOUT LONGER-TERM USE OF PHENTERMINE STEM FROM THE FACT THAT IT CAN INCREASE HEART RATE AND BLOOD PRESSURE, THEORETICALLY INCREASING RISK OF INCIDENT CARDIOVASCULAR DISEASE. DESPITE THESE CONCERNS, AND DESPITE THE PRESSING NEED FOR AFFORDABLE AND EFFECTIVE LONG-TERM OBESITY PHARMACOTHERAPY, THERE HAVE BEEN NO HIGH-QUALITY, RANDOMIZED CONTROLLED TRIALS OF PHENTERMINE MONOTHERAPY TO EXAMINE ITS EFFICACY, IMPACT ON RISK FACTORS, OR POTENTIAL ADVERSE EVENTS IF USED LONG-TERM. AT 5 CENTERS ACROSS THE UNITED STATES, WE WILL CONDUCT THE LONG-TERM EFFECTIVENESS OF THE ANTI-OBESITY MEDICATION PHENTERMINE (LEAP) TRIAL—A PLACEBO-CONTROLLED, RANDOMIZED TRIAL, ENROLLING 1,000 ADULTS WITH BMI 27-44.9KG/M2. IN AN INTENT-TO-TREAT FASHION, WITH ALL PARTICIPANTS PROVIDED WITH AN EVIDENCE-BASED ONLINE LIFESTYLE INTERVENTION, WE WILL COMPARE PARTICIPANTS RECEIVING 24 MG/DAY OF PHENTERMINE VS. PLACEBO FOR UP TO 24 MONTHS. WE WILL EXAMINE CO-PRIMARY OUTCOMES OF PERCENT WEIGHT LOSS AND CHANGE IN SYSTOLIC BLOOD PRESSURE AT 24 MONTHS. ADDITIONALLY, WE WILL COMPARE BETWEEN GROUPS CHANGES IN DRIVERS OF ENERGY BALANCE, INCLUDING RESTING METABOLIC RATE, CALORIC INTAKE, PHYSICAL ACTIVITY AND DIETARY COMPOSITION. BECAUSE WEIGHT LOSS CAN IMPROVE CARDIOMETABOLIC HEALTH, WE WILL ALSO COMPARE CHANGES IN HEART RATE, HEMOGLOBIN A1C, LIPIDS, WAIST CIRCUMFERENCE, ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (ASCVD) RISK SCORE, AND NOVEL ECG MARKERS OF CARDIAC STRAIN. FINALLY, WE WILL EXAMINE OVERALL ADVERSE EVENT AND SERIOUS ADVERSE EVENT RATE, INCLUDING RATES OF INCIDENT CARDIOVASCULAR DISEASE OR DEATH. THE POTENTIAL IMPACT OF OUR FINDINGS IS LARGE REGARDLESS OF WHETHER THEY ARE POSITIVE OR NEGATIVE. IF PHENTERMINE WERE SHOWN TO BE SAFE AND EFFECTIVE FOR LONG-TERM USE IN PATIENTS WITH OBESITY, IT COULD PROVIDE AN IMMEDIATELY AVAILABLE LOW-COST OPTION FOR WEIGHT MANAGEMENT. IN CONTRAST, IF SHOWN INEFFECTIVE, THE TRIAL COULD REDUCE OFF-LABEL PRESCRIBING OF THE MEDICATION AND PROMOTE A SHIFT TO DRUGS WITH PROVEN, ALBEIT COSTLY, LONG-TERM EFFECTIVENESS.

MARVEL: A MULTIDISCIPLINARY ASSESSMENT OF RISKS FROM VAPING DURING EARLY LIFE - ABSTRACT – OVERALL THE PROPOSED PROGRAM PROJECT, A MULTIDISCIPLINARY ASSESSMENT OF RISKS OF VAPING IN EARLY LIFE (PROJECT MARVEL), TAKES AN INTEGRATED APPROACH TO ASSESSING VAPING BEHAVIOR AND THE EMERGENCE OF DEPENDENCE; ELUCIDATING THE IMPACT OF VAPING ON ADOLESCENT HEALTH; AND GENERATING EMPIRICALLY-TESTED MESSAGES TO REDUCE ADOLESCENT VAPING. IN 2020, 19.6% OF HIGH SCHOOL STUDENTS, REPRESENTING OVER 3 MILLION ADOLESCENTS, REPORTED PAST MONTH VAPING. MOREOVER, THE PROPORTION OF HIGH SCHOOL STUDENTS WHO REPORT FREQUENT VAPING HAS INCREASED SUBSTANTIALLY. SIGNIFICANT GAPS EXIST IN UNDERSTANDING CURRENT PATTERNS OF YOUTH VAPING, THE RELATIONSHIP BETWEEN VAPING AND DEPENDENCE, THE IMPACT OF VAPING ON HEALTH, AND HOW BEST TO STEM THE SURGE IN ADOLESCENT VAPING. THE OVERARCHING AIMS OF THIS PROGRAM PROJECT ARE TO: (1) ASSESS THE USE OF NICOTINE-CONTAINING VAPING PRODUCTS AND THE RELATIONSHIP BETWEEN VAPING AND THE EMERGENCE OF SYMPTOMS OF DEPENDENCE, INCLUDING INDIVIDUAL, INTERPERSONAL, AND ENVIRONMENTAL FACTORS THAT MAY MODERATE THE IMPACT OF VAPING; (2) DETERMINE HOW VAPING DISRUPTS HEALTH AND WELL-BEING THROUGH ITS IMPACT ON KEY PHYSIOLOGICAL AND PSYCHOLOGICAL SYSTEMS THAT ARE STILL DEVELOPING DURING ADOLESCENCE; AND (3) EVALUATE THE POTENTIAL IMPACT OF VAPING PREVENTION MESSAGES, DEVELOPED BASED ON EMERGING EVIDENCE OF HEALTH HARMS FROM PROJECT MARVEL AND FOCUSED ON THE WAYS IN WHICH VAPING AFFECTS ADOLESCENTS’ BODIES AND LIVES. FOUR PROJECTS ARE PROPOSED, SUPPORTED BY FOUR CORES. PROJECT 1 WILL ASSESS THE RELATIONSHIP BETWEEN VAPING AND THE EMERGENCE OF DEPENDENCE, DESCRIBE HOW VAPING IMPACTS THE DEVELOPMENT OF ADOLESCENT WELL-BEING, AND DETERMINE HOW ADOLESCENTS PERCEIVE THE IMPACT OF VAPING ON THEIR DAILY LIVES. PROJECT 2 WILL EXAMINE THE ASSOCIATION BETWEEN VAPING, NEURODEVELOPMENT, AUTONOMIC REGULATION, AND COGNITIVE/PSYCHOLOGICAL SKILLS. PROJECT 3 WILL DETERMINE HOW VAPING IMPACTS RESPIRATORY HEALTH BY EXAMINING SYMPTOMS, FUNCTION, AND EARLY MOLECULAR ALTERATIONS IN AIRWAYS. PROJECT 4 WILL DEVELOP, OPTIMIZE, AND EVALUATE MESSAGES ABOUT NOVEL HEALTH HARMS OF VAPING, IDENTIFIED IN PROJECTS 1-3 AND THE EXTANT LITERATURE, THAT RESONATE WITH HIGH SCHOOL STUDENTS. THE ADMINISTRATIVE CORE WILL MANAGE OPERATIONS FOR PROJECT MARVEL, FACILITATE INTERACTIONS BETWEEN PROJECTS, AND COORDINATE STUDY PARTICIPATION. THE BIOSTATISTICS CORE WILL ENSURE OUR DESIGNS AND ANALYSES MAXIMIZE VALIDITY, GENERALIZABILITY, AND EFFICIENCY. THE ADOLESCENT RESEARCH SUPPORT CORE WILL ADDRESS THE UNIQUE CHALLENGES OF CONDUCTING RESEARCH WITH A LARGE NUMBER OF ADOLESCENTS FROM MULTIPLE SCHOOLS, FACILITATE RECRUITMENT AND RETENTION, ENSURE PROTECTION OF HUMAN SUBJECTS, AND MAINTAIN AND LEVERAGE COMMUNITY PARTNERSHIPS. FINALLY, THE BIOMARKER AND PRODUCT EVALUATION CORE WILL CHARACTERIZE THE MOST COMMONLY USED PRODUCTS AND PROVIDE OBJECTIVE MARKERS OF EXPOSURE AND BIOLOGICAL EFFECT. PROJECT MARVEL HAS THE POTENTIAL TO GREATLY IMPROVE OUR UNDERSTANDING OF HOW VAPING IMPACTS ADOLESCENT HEALTH AND HOW BEST TO INTERVENE TO REDUCE VAPING DURING THIS CRITICAL DEVELOPMENTAL PERIOD.

WAKE FOREST PRECLINICAL IMAGING AND IRRADIATION FACILITY

ALZHEIMER DIAGNOSIS IN OLDER ADULTS WITH CHRONIC CONDITIONS ADACC NETWORK - PROJECT SUMMARY / ABSTRACT APPROXIMATELY 60% OF OLDER ADULTS WITH ALZHEIMER’S DISEASE OR A RELATED DEMENTIA (ADRD) HAVE THREE OR MORE CHRONIC CONDITIONS. MULTIPLE CHRONIC CONDITIONS (MCCS) AND FRAILTY ARE ALSO RISK FACTORS FOR ADRD AND CAN AFFECT THE EXPRESSION OF AD PATHOLOGY WITH REGARDS TO COGNITIVE FUNCTION, DISEASE STAGE, AND NEUROPATHOLOGICAL BURDEN. UTILIZING BIOMARKERS TO DIAGNOSIS ADRD MAY PROVIDE A MORE ACCURATE AND COST-EFFECTIVE ASSESSMENT OF THE UNDERLYING ETIOLOGY CONTRIBUTING TO THE COGNITIVE IMPAIRMENT AND MAY GUIDE TREATMENTS AND COUNSELING ABOUT INDIVIDUALIZED CARE PATHWAYS. HOWEVER, WIDESPREAD INCORPORATION OF THESE BIOMARKERS INTO ROUTINE CLINICAL CARE AND POPULATION SCREENING PROGRAMS FOR OLDER ADULTS WITH MULTIPLE MCCS AND COGNITIVE IMPAIRMENT HAS NOT OCCURRED. BLOOD-BASED BIOMARKERS ARE NOW CLINICALLY AVAILABLE TO AID IN THE DIAGNOSIS OF ADRD AND ARE MORE FEASIBLE, ESPECIALLY FOR OLDER ADULTS WITH MCCS, AND LESS COSTLY AND INVASIVE THAN CSF OR PET-BASED BIOMARKERS. HOWEVER, NO RESEARCH HAS EXAMINED THESE BLOOD BIOMARKERS FOR THE DIAGNOSIS AND PROGNOSIS OF ADRD IN PRIMARY CARE, ESPECIALLY AMONG DIVERSE POPULATIONS. IT IS UNKNOWN HOW AND WHEN THESE BLOOD BIOMARKERS SHOULD BE USED, PARTICULARLY FOR DIAGNOSIS AND PROGNOSIS AMONG OLDER ADULTS WITH MCCS AND/OR LIMITED LIFE EXPECTANCY. MOREOVER, THE EFFECT OF MCCS ON LEVELS OF THE BIOMARKERS ARE NOT WELL UNDERSTOOD. NUMEROUS OTHER QUESTIONS REMAIN, SUCH AS: 1) WHETHER THE ADRD BIOMARKERS ENHANCE PROGNOSIS AMONG OLDER ADULTS WITH MCCS AND COGNITIVE IMPAIRMENT; 2) FOR WHOM IT IS MOST BENEFICIAL TO OBTAIN ADRD BIOMARKERS INCLUDING BLOOD, CSF OR IMAGING; 3) HOW THE BIOMARKERS CAN BE IMPLEMENTED IN A PRIMARY CLINICAL HEALTHCARE DELIVERY MODEL; 4) WHETHER THERE ARE SUBGROUP DIFFERENCES (E.G. RACE/ETHNICITY, SEX, MCCS) THAT AFFECT THE INTERPRETATION OF THE BIOMARKERS; 5) ASSESSMENT OF COST ESTIMATES AND RISK/BENEFIT RATIOS FOR REIMBURSEMENT; 6) HOW BEST TO COMMUNICATE THE RESULTS TO PATIENTS AND THEIR CAREGIVERS; AND 7) THE ETHICAL ASPECTS OF BIOMARKER COLLECTION AND POTENTIAL FOR INCIDENTAL FINDINGS DUE TO MIXED PATHOLOGIES, ESPECIALLY AMONG OLDER ADULTS. THE OVERALL GOAL OF THIS APPLICATION IS TO ESTABLISH A NATIONAL CONSORTIUM, THE ALZHEIMER’S DIAGNOSIS IN OLDER ADULTS WITH CHRONIC CONDITIONS (ADACC) NETWORK, CONSISTING OF MULTI-DISCIPLINARY INVESTIGATORS THAT WILL ADDRESS THESE AND OTHER QUESTIONS, AND DEVELOP EVIDENCE-BACKED STRATEGIES AND GUIDELINES FOR THE USE AND IMPLEMENTATION OF BIOMARKERS FOR ADRD DIAGNOSIS IN OLDER PATIENTS WITH MCCS AND COGNITIVE IMPAIRMENT. THE CONSORTIUM WILL HAVE AN EXECUTIVE COMMITTEE, STEERING COMMITTEE, AND DATA COORDINATING CENTER. IT WILL FUND THREE PILOT PROJECTS EACH YEAR AND CONVENE AN ANNUAL MEETING. WORKING GROUPS WILL BE DEVELOPED TO FOCUS ON THE QUESTIONS LISTED ABOVE AND OTHERS. SUCCESSFUL COMPLETION OF THE GRANT AIMS WILL ADVANCE THE DIAGNOSIS AND CARE OF OLDER ADULTS WITH MCCS AND COGNITIVE IMPAIRMENT BY INCREASING UNDERSTANDING OF HOW AND WHEN TO IMPLEMENT ADRD BIOMARKERS.

LA-AGING DIVERSITY SUPPLEMENT - PROJECT SUMMARY/ABSTRACT OVERALL – PROJECT SUMMARY OBESITY AND TYPE 2 DIABETES ARE DESCRIBED AS ACCELERATORS AGING. THERE HAVE BEEN NUMEROUS ATTEMPTS ACROSS DECADES TO DEVELOP AND VALIDATE MEASUREABLE CONSTRUCTS FOR ACCELERATED AGING. WE HAVE CONDUCTED RESEARCH SUPPORTED BY TWO PRIOR SUCCESSFUL NIDDK-FUNDED DIVERSITY SUPPLEMENTS TO DEVELOP AND APPLY DEFICIT ACCUMULATION FRAILTY INDICES TO THE FIRST 8 YEARS OF FOLLOW-UP IN THE LOOK AHEAD COHORT, THE SPAN OF TIME WHEN ALL PARTICIPANTS WERE ASSIGNED TO ACTIVE INTERVENTIONS. THIS HAS BEEN A PRODUCTIVE ENTERPRISE. WE HAVE PUBLISHED THAT: THE LOOK AHEAD INTENSIVE LIFESTYLE INTERVENTION (ILI) CREATED A BUFFER AGAINST INCREASES IN FI, ROUGHLY PROPORTIONAL TO ONE YEAR OF AGING IN THE CONTROL GROUP AMONG PARTICIPANTS WITH RELATIVELY LOW FI AT BASELINE, THE ILI RESULTED IN LOWER INCIDENCE OF MAJOR CARDIOVASCULAR DISEASE EVENTS, HOWEVER AMONG PARTICIPANTS WITH THE HIGHEST FI SCORES AT BASELINE, THE ILI WAS ASSOCIATED WITH AN INCREASED INCIDENCE OF CARDIOVASCULAR EVENTS THE LOOK AHEAD ILI WAS EQUALLY INEFFECTUAL IN PRESERVING COGNITIVE FUNCTION ACROSS THE FULL RANGE OF BASELINE FI GREATER INCREASES IN FI ACROSS 8 YEARS WAS ASSOCIATED WITH SUBSEQUENT INCREASED RISK FOR MORTALITY AND POORER TRAJECTORIES OF PHYSICAL AND COGNITIVE FUNCTION WE PROPOSE TO CONDUCT A SERIES OF SECONDARY DATA ANALYSES, USING THE EXTENSIVE DATA RESOURCES PROVIDED BY THE LOOK AHEAD COHORT, 1) TO EXTEND THE DEFICIT ACCUMULATION FI ORIGINALLY DEVELOPED BY LOOK AHEAD THROUGH YEAR 8 TO THE CLOSE-OUT OF THE LOOK AHEAD EXTENSION (YEAR 18), PRODUCING FIE; 2) TO DEVELOP A STATISTICAL BRIDGE LINKING THIS FI WITH ONE BEING DEVELOPED BY THE PARENT GRANT (LA-AGING) FOR YEARS 19-23 OF FOLLOW-UP (FIA); AND 3) TO EXAMINE HOW TRAJECTORIES OF FIE ARE RELATED TO THE PREVALENCE OF GERIATRIC SYNDROMES IN THE LOOK AHEAD AGING STUDY. IF SUCCESSFUL, THIS PROJECT WILL PROVIDE A VALIDATED MARKER OF LONG-TERM BIOLOGICAL AGING THAT CAN SERVE AS AN OUTCOME MEASURE IN CLINICAL TRIALS AND A TOOL FOR IDENTIFYING FACTORS THAT SLOW AGING AMONG OLDER ADULTS WITH TYPE 2 DIABETES AND OBESITY. A COMPLEMENTARY GOAL OF THIS PROJECT IS TO FURTHER THE DEVELOPMENT OF JOHNATHAN ROSS, A PROMISING UNDERGRADUATE STUDENT AT WINSTON-SALEM STATE UNIVERSITY, A HISTORICALLY BLACK PUBLIC RESEARCH UNIVERSITY. HIS PRIMARY MENTOR WILL BE DR. MARK ESPELAND, WHO IS EXPERIENCED AND WELL-SUITED FOR THIS ROLE. WE RESPOND TO PA- 21-071 RESEARCH SUPPLEMENTS TO PROMOTE DIVERSITY IN HEALTH-RELATED RESEARCH. SUMMARY OF PLANNED CONTRIBUTIONS TO THE LOOK AHEAD PROGRAM. THIS REQUEST IS ATTACHED TO 1U01AG073697-01: ACTION FOR HEALTH IN DIABETES (LOOK AHEAD) EXTENDED FOLLOW-UP (LA-AGING) MARK A. ESPELAND, PHD, DUAL PRINCIPAL INVESTIGATOR.

SMOKELESS TOBACCO USE IN COLLEGE STUDENTS

GENETIC & EPIDEMIOLOGIC PREDICTORS OF GLUCOSE HOMEOSTASIS MEASURES IN HISPANICS

CVD EPIDEMIOLOGY TRAINING PROGRAM

REHAB-HF: A TRIAL OF REHABILITATION THERAPY IN OLDER ACUTE HEART FAILURE PATIENTS

ETHANOL, STRESS AND DOPAMINE

VALIDATION OF VIDEO ADMINISTRATION OF A MODIFIED UDSV3 COGNITIVE BATTERY - PROJECT SUMMARY THIS MULTI-SITE R01 AIMS TO VALIDATE VIDEO-ADMINISTERED COGNITIVE ASSESSMENTS FOR USE BY THE ALZHEIMER’S DISEASE RESEARCH CENTERS (ADRCS) AND OTHER RESEARCH PROGRAMS WHOSE ACTIVITIES HAVE BEEN INTERRUPTED BY THE COVID-19 PANDEMIC, AS WELL AS FOR USE IN FUTURE INITIATIVES WHEN REMOTE TESTING WILL ENHANCE ACHIEVEMENT OF SCIENTIFIC GOALS. WHILE FACE-TO-FACE ADMINISTRATION IS THE GOLD STANDARD FOR COGNITIVE ASSESSMENTS, CONDITIONS OFTEN ARISE THAT PREVENT PARTICIPANTS FROM ATTENDING IN-PERSON VISITS. THESE BARRIERS INCLUDE TRANSPORTATION CHALLENGES, LIMITED MOBILITY, AND FINANCIAL HARDSHIP. THERE IS ALSO EVIDENCE THAT UNDERSERVED POPULATIONS, INCLUDING RURAL POPULATIONS AND RACIAL/ETHNIC MINORITIES, ARE LESS LIKELY TO ENROLL IN STUDIES THAT REQUIRE TRAVEL TO AN ACADEMIC MEDICAL CENTER FOR FACE-TO-FACE TESTING. THE PROPOSED STUDY WILL ADDRESS THESE CHALLENGES BY UTILIZING A VIDEO-ADAPTED BATTERY INCORPORATING THE UNIFORM DATA SET VERSION 3 (UDSV3) MEASURES WITH ADDITIONAL MEASURES THAT MAY SERVE AS ALTERNATIVES FOR UDSV3 MEASURES NOT ADAPTABLE TO VIDEO ADMINISTRATION. WE PROPOSE TO FULLY VALIDATE THESE ASSESSMENT TOOLS FOR REMOTE ADMINISTRATION IN PARTNERSHIP WITH THE NIA AND THE NATIONAL ALZHEIMER’S COORDINATING CENTER (NACC), AND CARRIED OUT BY A CONSORTIUM OF 12 ADRCS. PILOT DATA WAS GATHERED FROM 88 WAKE FOREST ADRC PARTICIPANTS, DEEMED BY IN-PERSON TESTING AND ADJUDICATION TO HAVE NORMAL COGNITION, MCI, OR DEMENTIA, WHO WERE TESTED EITHER BY PHONE OR VIDEO. DATA SHOW HIGH PARTICIPANT RATINGS OF TOLERABILITY, FEASIBILITY, AND PREFERENCE FOR VIDEO VERSUS TELEPHONE ASSESSMENT. THERE IS ALSO HIGH CONCORDANCE BETWEEN VIDEO-ADMINISTERED AND IN- PERSON TEST SCORES. BASED ON THIS COLLECTIVE DATA, WE PLAN TO FULLY VALIDATE A VIDEO-VERSION OF THE UDSV3 BATTERY IN A RANGE OF COGNITIVELY, ETHNICALLY, AND GEOGRAPHICALLY DIVERSE PARTICIPANTS. WE PROPOSE TO ADMINISTER REMOTE VIDEO COGNITIVE ASSESSMENTS, PAIRED ALONGSIDE ANNUAL IN-PERSON COGNITIVE ASSESSMENTS, IN COUNTERBALANCED ORDER, TO 500 EXISTING PARTICIPANTS FROM 12 ADRCS UTILIZING A COMPUTER TABLET DEVICE, INCLUDING THOSE PREVIOUSLY ADJUDICATED AS HAVING NORMAL COGNITION, MCI AND DEMENTIA. PARTICIPANTS’ RATINGS OF SATISFACTION WITH TEST CONDITION AND PREFERENCE OF TEST MODALITY WILL BE OBTAINED, IN ADDITION TO THE PSYCHOMETRIC CHARACTERISTICS OF THE VIDEO BATTERY RELATIVE TO FACE-TO-FACE ADMINISTRATION, INCLUDING CONCURRENT VALIDITY, AND ESTIMATES OF RELATIVE BIAS OVERALL AND ACROSS IMPORTANT SUBGROUPS (AGE, ETHNICITY, COGNITIVE STATUS) AND MODE OF ADMINISTRATION OF INDIVIDUAL TESTS. CONCORDANCE BETWEEN ADJUDICATION OUTCOMES WILL ALSO BE EXAMINED TO ASSESS THE ABILITY OF THE BATTERY TO DISTINGUISH NORMAL COGNITION, MCI AND DEMENTIA. WE WILL ASSESS THE SENSITIVITY OF THE VIDEO BATTERY TO DETECT LONGITUDINAL CHANGE IN COGNITION IN ADRC PARTICIPANTS BY REPEATING COUNTERBALANCED, IN-PERSON AND REMOTE ASSESSMENTS 2 YEARS FOLLOWING INITIAL EVALUATION. COMPLETION OF THIS PROJECT IS CRITICAL TO THE ONGOING SUCCESS OF COGNITIVE ASSESSMENT IN THE ADRC NETWORK.

WOMEN'S HEALTH INITIATIVE SLEEP HYPOXIA EFFECTS ON RESILIENCE (WHISPER)

GASTROPARESIS GASTRIC DYSRHYTHMIAS AND DYSPEPSIA SYMP*

MODERATION OF AGING TRAJECTORIES OF COGNITION AND NEUROPATHOLOGY BY DIET COMPOSITION IN MIDDLE-AGED NONHUMAN PRIMATES - PROJECT SUMMARY DIET COMPOSITION POTENTLY MODULATES TRAJECTORIES OF BRAIN AGING. INTAKE OF A MEDITERRANEAN DIET INCLUDING FRUIT AND VEGETABLES, FISH, AND HEALTHY FATS IS ASSOCIATED WITH REDUCED RISK OF ALZHEIMER'S DISEASE AND RELATED DEMENTIAS INCLUDING VASCULAR DEMENTIA. INTAKE OF A WESTERN DIET HIGH IN SIMPLE SUGARS AND SATURATED FAT IS ASSOCIATED WITH INCREASED RISK OF THESE CONDITIONS. NONHUMAN PRIMATE MODELS OF DIET COMPOSITION EFFECTS ON BRAIN HEALTH ARE CRITICAL FOR PROVIDING INSIGHT INTO MECHANISMS OF DIET EFFECTS ON THE BRAIN, BECAUSE OF CHALLENGES ASSOCIATED WITH LONG-TERM STUDIES OF DIET MANIPULATIONS IN HUMANS. OUR PREVIOUS WORK SHOWED WESTERN DIET CONSUMPTION (COMPARED TO MEDITERRANEAN) INCREASED SOCIAL ISOLATION AND ANXIETY-RELATED BEHAVIORS, INCREASED GRAY MATTER VOLUME IN AN ALZHEIMER'S-RELATED TEMPORAL-PARIETAL CORTEX META-REGION OF INTEREST, REDUCED WHITE MATTER VOLUME, AND RESULTED IN LATERAL TEMPORAL TRANSCRIPTIONAL PROFILES ASSOCIATED WITH INFLAMMATION IN MIDDLE- AGED FEMALE CYNOMOGLUS MONKEYS. HOWEVER, BECAUSE COGNITIVE FUNCTION WAS NOT ASSESSED IN THESE MONKEYS, THE INTERPRETATION OF CHANGES IN BIOMARKERS AS REFLECTING A NASCENT PATHOLOGICAL PROCESS OR, ALTERNATIVELY, A RESILIENT ADAPTATION REMAINS UNCLEAR. FOR EXAMPLE, ELEVATED GRAY MATTER VOLUME IN MONKEYS CONSUMING THE WESTERN DIET MAY REFLECT IMPAIRED FUNCTION ASSOCIATED WITH INFLAMMATION, OR A REACTIVE CHANGE TO PRESERVE FUNCTION AND PROMOTE RESILIENCE IN THE FACE OF A POOR DIET. FURTHERMORE, MALES WERE NOT STUDIED IN OUR PREVIOUS WORK. TO ADDRESS THESE CRITICAL BARRIERS TO PROGRESS IN THE FIELD, WE PROPOSE TO TEST THE IMPACT OF MEDITERRANEAN VS. WESTERN DIET ON COGNITIVE FUNCTION AND TRANSLATIONAL IMAGING AND FLUID BIOMARKERS OF ALZHEIMER'S DISEASE RISK, NEUROINFLAMMATION, AND NEURODEGENERATION IN MIDDLE-AGED MALE AND FEMALE CYNOMOLGUS MONKEYS, IN A LONGITUDINAL DESIGN SPANNING 32 MONTHS OF DIET TREATMENT, CORRESPONDING TO ~9.5 HUMAN YEARS. OUR OVERARCHING HYPOTHESIS IS THAT CONSUMPTION OF WESTERN DIET INTERACTS WITH AGING TRAJECTORIES TO EXACERBATE COGNITIVE IMPAIRMENT WITH AGING AND PRODUCE PATHOLOGICAL BRAIN AGING, WHEREAS MEDITERRANEAN DIET PROMOTES RESILIENT AGING, PRESERVED COGNITIVE FUNCTION, AND REDUCTION OF MARKERS OF ALZHEIMER'S DISEASE RISK, INCLUDING FLUID BIOMARKERS OF NEURODEGENERATION AND NEUROINFLAMMATION, AND PET IMAGING MEASURES OF MICROTUBULE STABILITY AND NEUROINFLAMMATION. WE EXPECT THAT WITHIN AND ACROSS DIET TREATMENT GROUPS AND SEXES THAT ELEVATED MARKERS OF NEUROPATHOLOGY WILL PREDICT COGNITIVE DECLINE. THIS PROJECT SPECIFICALLY EXAMINES VULNERABILITY OF MIDDLE-AGED MONKEYS, A TIME IN THE LIFESPAN WHERE TRAJECTORIES OF AGING TAKE A TURN TOWARDS SUCCESSFUL AGING OR GREATER RISK OF NEURODEGENERATIVE DISEASE, WITH IMMENSE TRANSLATIONAL SIGNIFICANCE.

GENOME WIDE ASSOCIATION FOR ASTHMA AND LUNG FUNCTION

COORDINATING CENTER OF THE CLAUDE D. PEPPER OLDER AMERICANS INDEPENDENCE CENTERS

MIRHIQL RESOURCE CENTER FOR IMPROVING QUALITY OF LIFE WITH CHRONIC PAIN (MRC) - PROJECT SUMMARY DESPITE ACKNOWLEDGING THE CHALLENGES OF LONG-TERM OPIOID USE (LTOT) IN CLINICAL AND RESEARCH STUDIES, THERE IS NO CONSENSUS ON CLINICALLY DEFINING OPIOID MISUSE. IN CLINICAL PRACTICE, SCREENING AND RISK/BENEFIT CALCULATIONS REMAIN DIFFICULT BECAUSE WHILE OPIOID USE CAN BE PROBLEMATIC, IT MAY BE BENEFICIAL IN CERTAIN SUBPOPULATIONS. THE COMBINATION OF VARIABLES THAT COULD BE USED CLINICALLY TO ASSESS THE RISK OF HARMS VERSUS QUALITY OF LIFE FOR PEOPLE ON LTOT HAS NOT BEEN ESTABLISHED. IT MAY BE POSSIBLE TO DECREASE SOME OF THE TENSION BETWEEN PRESCRIBERS AND PATIENTS IF CLINICAL PROVIDERS HAVE A WORKING CLINICAL DEFINITION AND IMPROVED WAYS OF ASSESSING WHETHER A PATIENT IS A CANDIDATE FOR LTOT. THE MIRHIQL RESOURCE CENTER'S (MRC) LONG-TERM GOAL IS TO UNDERSTAND HOW CHRONIC PAIN (CP) AND RELATED FACTORS INFLUENCE THE PROGRESSION OF LTOT BEHAVIORS. THE OBJECTIVE OF MRC CENTER IS TO CREATE A RESEARCH COMMUNITY THAT CONNECTS THE MIRHIQL NETWORK TO IMPOWR RESEARCH CENTERS AND LARGER HEAL NETWORK TO TRANSLATE FINDINGS WHILE DEVELOPING A KEY OPIOID MISUSE AND LTOT INFRASTRUCTURE. WE HYPOTHESIZE THAT DEFINING OPIOID MISUSE AND THE LTOT BENEFIT/RISK FRAMEWORK WILL REQUIRE INTEGRATED PATIENT-CENTERED CLINICAL APPROACHES THAT ADDRESS THE SYSTEMIC ISSUES AFFECTING HEALTHCARE DELIVERY AND THE PATIENT-PROVIDER INTERACTION, LEADING TO A FUNDAMENTAL SHIFT IN HOW HEALTHCARE PROVIDERS AND THE PUBLIC ARE EDUCATED. THESE GOALS WILL BE ACHIEVED THROUGH THE FOLLOWING SPECIFIC AIMS: (1) THE MRC WILL HARMONIZE DATA COLLECTION AND COMMON DATA ELEMENTS FOR THE MIRHIQL NETWORK, PROVIDING COORDINATED SUPPORT FOR NETWORK ACTIVITIES WHILE CONNECTING TO THE IMPOWR NETWORK AND LARGER HEAL ECOSYSTEM VIA OUR IMPOWR CC, (2) THE MRC WILL CLINICALLY DEFINE OPIOID MISUSE WITH ASSOCIATED RISKS/BENEFITS USING AN INTERCONNECTED STRATEGY INCLUDING MULTI-SOCIETY EXPERT DELPHI, QUALITATIVE INTERVIEWING OF PRESCRIBERS AND PEOPLE WITH LIVED PAIN EXPERIENCE, AND PHENOTYPING AND VALIDATING COHORT DEFINITIONS IN ELECTRONIC HEALTH AND ADMINISTRATIVE CLAIMS DATA, AND (3) THE MRC WILL PERFORM ANALYTICAL AND CLINICAL VALIDATION OF SCREENING AND BENEFIT/RISK TOOLS FOR LTOT AND DEFINITION OF OPIOID MISUSE IN A COHORT TRIAL COMPARING DIFFERENT COMBINATIONS OF RELEVANT OM VARIABLES. USABILITY (SYSTEM/PROVIDER INPUT) AND USER EXPERIENCE (PROVIDER/PATIENT INPUT) WILL EVALUATED FOR CLINICAL UTILITY IN REAL-WORLD CLINICAL SETTINGS. THESE AIMS WILL PROVIDE A COORDINATED INTEGRATION OF SYSTEMATIC REVIEW, QUALITATIVE INTERVIEWING, EHR AND CLAIMS DATA, AND EXPERT DELPHI TASKFORCE TO IDENTIFY AND TEST CANDIDATE VARIABLES FOR A CLINICAL DEFINITION OF OPIOID MISUSE AND DEVELOP SCREENING AND RISK/BENEFIT TOOLS FOR CLINICAL CARE. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE WE WILL BE ABLE TO LEVERAGE THE LARGE-SCALE CLAIMS (CMS AND PRIVATE PAYER) AND EHR DATA TO BUILD A FRAMEWORK FOR LTOT CARE ON A RAPID TIMELINE. THESE RESULTS WILL SUPPORT FUTURE RESEARCH BUT WILL ALSO HAVE DIRECT CLINICAL IMPACT, ALIGNING WITH NIH HEAL'S MISSION.

DETERMINING THE FUNDAMENTAL DIFFERENCES AMONG TISSUE ORGANOIDS FROM DIFFERENT SPECIES FOR MODELING THE EFFECTS OF BIOCHEMICAL WARFARE AGENTS AND DEVE

THE MAYA ANGELOU CENTER FOR HEALTH EQUITY

TRANSITION FROM RISK FACTORS TO EARLY HF: PREVALENCE, PATHOGENESIS, AND PHENOMICS

ARIC NEUROCOGNITIVE STUDY (ARIC-NCS)

INTEGRATED OMICS ANALYSIS OF PAIN: OMICS DATA GENERATION CENTER

POINTER-ZZZ: SLEEP ANCILLARY TO U.S. STUDY TO PROTECT BRAIN HEALTH THROUGH LIFESTYLE INTERVENTION TO REDUCE RISK OF ALZHEIMER'S DISEASE

DEVELOPMENT OF AN INNOVATIVE VERVET (CHLOROCEBUS AETHIOPS SABAEUS) MODEL OF EARLY ALZHEIMER'S-LIKE NEUROPATHOLOGY AND SYMPTOMATOLOGY - THIS APPLICATION IS IN RESPONSE TO RFA-AG-21-003: NEW/UNCONVENTIONAL ANIMAL MODELS OF ALZHEIMER’S DISEASE (AD). CURRENTLY AVAILABLE ANIMAL MODELS OF AD MOSTLY MODEL THE LESS COMMON EARLY-ONSET FAMILIAL AD AND HAVE POOR PREDICTIVE VALUE IN CLINICAL TRIALS. HOWEVER, NONHUMAN PRIMATES ARE USEFUL FOR STUDYING CHARACTERISTICS OF THE MORE CLINICALLY RELEVANT LATE-ONSET SPORADIC AD BECAUSE OF THEIR PHYLOGENETIC SIMILARITY TO HUMANS IN BRAIN STRUCTURE AND FUNCTION; COMPLEX ENDOCRINE, SOCIAL, AND COGNITIVE CHARACTERISTICS; LARGE SIZE FAVORABLE FOR IMAGING STUDIES AND CEREBROSPINAL FLUID COLLECTION; AND SEQUENCE HOMOLOGY WITH HUMANS FOR BOTH TAU AND ASS BETA-AMYLOID (ASS). VERVETS SHOW AGE-RELATED BRAIN CHANGES SIMILAR TO HUMANS, INCLUDING INCREASED ASS PLAQUE BURDEN, COGNITIVE AND MOTOR DEFICITS, INCREASED AD BIOMARKERS IN CEREBROSPINAL FLUID, PAIRED HELICAL FILAMENT TAU (PHF-TAU) FORMATION, DECREASED BRAIN VOLUMES, DECREASED CEREBRAL GLUCOSE UTILIZATION, AND ALTERED CORTICAL TRANSCRIPTION PROFILES. NHPS REQUIRE FURTHER STUDY TO UNDERSTAND THEIR APPARENT RESISTANCE TO DEVELOPING EXTENSIVE NEUROFIBRILLARY TANGLES WHICH MAY PROVIDE INSIGHT INTO MECHANISMS UNDERLYING RESILIENCE, TO CHARACTERIZE CENTRAL NERVOUS SYSTEM TAU SPECIES, AND TO DEVELOP PET TRACERS FOR ASS AND OTHER TARGETS ASSOCIATED WITH AD AND DEMENTIA .MODIFIABLE RISK FACTORS THAT ARE POTENTIAL TARGETS FOR EARLY INTERVENTION IN HUMANS INCLUDE OBESITY, HYPERTENSION, PHYSICAL ACTIVITY, IMPAIRED GLUCOSE TOLERANCE, PSYCHOSOCIAL STRESS, AND POOR SLEEP. VERVETS RESPOND TO STRESS LIKE HUMANS AND MAY BECOME OBESE. AGE INCREASES THEIR RATES OF HYPERTENSION AND IMPAIRED GLUCOSE TOLERANCE ACCOMPANIED BY DECREASED ASS42/ASS40 IN CEREBROSPINAL FLUID. THUS, VERVETS MAY PROVIDE OPPORTUNITIES FOR TRANSLATIONAL AND MECHANISTIC RESEARCH HIGHLY RELEVANT TO LATE-ONSET SPORADIC AD. THE PREMISE OF THE PROPOSED RESEARCH IS THAT VERVETS ARE A PROMISING MODEL OF LATE-ONSET SPORADIC AD IN WHICH AD-RELATED DISEASE PROGRESSION COULD BE CHARACTERIZED AND ALTERED BY EARLY INTERVENTION ON MODIFIABLE RISK FACTORS. THE OVERARCHING GOAL IS TO FURTHER DEVELOP, CHARACTERIZE, AND VALIDATE THE VERVET MODEL OF NEUROPATHOLOGY AND COGNITIVE DECLINE, WHILE IDENTIFYING NOVEL TARGETS FOR EARLY INTERVENTION FOR AD CHARACTERISTICS. OUR SPECIFIC AIMS ARE TO DETERMINE AGE-RELATED CHANGES IN COGNITIVE AND PHYSICAL FUNCTION, CEREBROSPINAL FLUID AND IMAGING BIOMARKERS; IDENTIFY TARGETS FOR EARLY INTERVENTION BY CHARACTERIZING MODIFIABLE RISK FACTORS FOR LATE-ONSET SPORADIC AD; AND ASSESS THE PREDICTIVE VALIDITY OF THESE RISK FACTORS FOR NEUROPATHOLOGY IN 30 VERVETS FROM OUR VERVET RESEARCH COLONY (FROM 10 TO 30 YEARS OLD) WHICH COMPRISE THE AGING VERVET COHORT. UNIQUE RESOURCES AT WAKE FOREST THAT WILL ASSURE RAPID PROGRESS TOWARD OUR GOAL INCLUDE OUR ALZHEIMER’S DISEASE RESEARCH CENTER; AGING VERVET COHORT, EXTENSIVE BIOSPECIMEN, DATA AND IMAGE REPOSITORY, UNIQUE NONHUMAN PRIMATE IMAGING CAPABILITIES, EXPERTISE IN NONHUMAN PRIMATE RESEARCH, AND CLOSE COLLABORATION WITH OUR CLAUDE D. PEPPER OLDER AMERICANS INDEPENDENCE CENTER.

A NEW PATHOGENIC MECHANISM FOR DIABETIC RETINOPATHY

A RANDOMIZED TRIAL OF FISTULA VS. GRAFT ARTERIOVENOUS VASCULAR ACCESS IN OLDER ADULTS WITH END-STAGE KIDNEY DISEASE ON HEMODIALYSIS: THE AV ACCESS TRIAL - ABSTRACT END-STAGE KIDNEY DISEASE IS A DISEASE OF AGING, EXACERBATED BY MULTIPLE COEXISTING HEALTH CONDITIONS. NEARLY 50% OF PATIENTS INITIATING CHRONIC HEMODIALYSIS FOR TREATMENT OF END-STAGE KIDNEY DISEASE ARE 65 YEARS OR OLDER. PATIENTS WHO USE CENTRAL VENOUS CATHETERS FOR HEMODIALYSIS ACCESS TYPICALLY UNDERGO SURGICAL PLACEMENT OF AN ARTERIOVENOUS ACCESS—EITHER A FISTULA OR A GRAFT—TO REDUCE THE RISKS OF INFECTION, VASCULAR COMPLICATIONS AND DEATH ASSOCIATED WITH CATHETER USE. ARTERIOVENOUS FISTULAS HAVE LONG BEEN CONSIDERED FIRST-LINE VASCULAR ACCESS OPTION, WITH GRAFTS AS SECOND BEST. HOWEVER, SEVERAL RECENT STUDIES SUGGEST THAT GRAFTS MAY BE A BETTER STRATEGY THAN FISTULAS FOR HEMODIALYSIS ACCESS IN OLDER ADULTS. WITHOUT EVIDENCE FROM WELL-POWERED RANDOMIZED CLINICAL TRIALS, THESE STUDIES CANNOT BE INTEGRATED INTO PRACTICE. WE CONDUCTED THE FIRST PILOT TRIAL (N=46) THAT REVEALED THE FEASIBILITY OF ENROLLING AND RANDOMIZING OLDER ADULTS TO SURGICAL FISTULA OR GRAFT PLACEMENT, WITH 89% (20 OF 22) OF THOSE ASSIGNED TO FISTULA AND 79% (19 OF 24) OF THOSE ASSIGNED TO GRAFT PLACEMENT UNDERGOING THE ASSIGNED INTERVENTION. BUILDING ON THIS SUCCESSFUL PILOT, WE PROPOSE A PRAGMATIC MULTICENTER RANDOMIZED CLINICAL TRIAL IN 262 ADULTS, 65 YEARS OF AGE AND OLDER, RECEIVING HEMODIALYSIS VIA CATHETERS. UNBIASED, COMPARATIVE CHARACTERIZATION OF CLINICAL OUTCOMES AND PATIENT VIEWS BETWEEN ALTERNATIVE ACCESS STRATEGIES WILL ADVANCE THE FIELD, FOR THE FIRST TIME, TO EVIDENCE-BASED VASCULAR ACCESS CARE. OUR LONG-TERM GOALS ARE TO OPTIMIZE CLINICAL DECISIONS BASED ON OBJECTIVE, AGE-SPECIFIC DATA WHILE INCORPORATING GOALS OF CARE AND PATIENT PREFERENCE FOR VASCULAR ACCESS TYPE. THE OBJECTIVE OF THIS PROPOSAL IS TO DELINEATE VASCULAR ACCESS EFFECTS ON DISEASE-SPECIFIC AND PATIENT-REPORTED OUTCOMES, USING A RANDOMIZED INTERVENTION, AT 6 NATIONAL SITES, OF SURGICAL FISTULA VERSUS GRAFT PLACEMENT IN OLDER ADULTS WHO HAVE END-STAGE KIDNEY DISEASE AND COEXISTING CORONARY ARTERY DISEASE, PERIPHERAL ARTERIAL DISEASE, AND/OR DIABETES MELLITUS. THE OVERARCHING HYPOTHESIS IS THAT GRAFT PLACEMENT STRATEGY WILL YIELD MORE DIALYSIS CATHETER-FREE DAYS, LOWER COST, AND BETTER PATIENT SATISFACTION. OUR SPECIFIC AIMS WILL DETERMINE THE EFFECTS OF FISTULA VERSUS GRAFT VASCULAR ACCESS STRATEGY ON RATES OF CATHETER-FREE DIALYSIS DAYS AND ACCESS-RELATED INFECTIONS AND DEATH (PRIMARY AIM), COSTS ASSOCIATED WITH VASCULAR ACCESS CARE (SECONDARY AIM), AND PATIENT-REPORTED SATISFACTION WITH ACCESS-RELATED OUTCOMES (TERTIARY AIM). WE WILL ALSO INVESTIGATE THE RELATIONSHIP BETWEEN PREOPERATIVE OBJECTIVE AND SUBJECTIVE MEASURES OF PHYSICAL FUNCTION AND FAILURE OF FISTULA OR GRAFT MATURATION (EXPLORATORY AIM). RESULTS FROM THIS TRIAL COULD TRANSFORM THE CLINICAL PRACTICE BY PROVIDING HIGH-QUALITY EVIDENCE TO GUIDE COMMON CLINICAL DECISIONS ON DIALYSIS VASCULAR ACCESS IN OLDER ADULTS—A GROWING POPULATION WHOSE CARE IS COMPLEX AND COSTLY.

MECHANISMS OF ALCOHOL WITHDRAWAL

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

DEPRESSION AND CORONARY ARTERY ATHEROSCLEROSIS IN PREMENOPAUSAL

WAKE FOREST CLINICAL AND TRANSLATIONAL SCIENCE AWARD

CANNABINOID RECEPTORS AND ASSOCIATED PROTEINS

MODIFIED KETOGENIC DIET EFFECTS ON ALZHEIMER'S DISEASE BIOMARKERS AND COGNITION IN MILD COGNITIVE IMPAIRMENT

CASCADE: A NORTH CAROLINA COHORT TO ADDRESS THE CASCADING EFFECTS OF THE HIV AND SUBSTANCE USE SYNDEMIC - THE US DEEP SOUTH BEARS THE HIGHEST BURDEN OF HIV, AND THE SOUTH IS LAGGING BEHIND IN ACHIEVING ENDING THE HIV EPIDEMIC (EHE) GOALS. PEOPLE WHO USE DRUGS (PWUD) LIKE COCAINE, METH, HEROIN, AND FENTANYL, ARE MORE LIKELY TO FALL OUT AT EACH STEP OF THE HIV CARE CASCADE. CONTEXTUAL FACTORS CONTRIBUTE TO POORER HIV AND SUBSTANCE USE OUTCOMES, NEUROIMMUNE DYSFUNCTION, AND RELATED CHRONIC ILLNESS. THE OVERARCHING GOAL OF CASCADE (CAROLINA ADDICTION SCIENCE COALITION FOR ACCELERATING DISCOVERY AND ENGAGEMENT) IS TO INVESTIGATE THE IMPACTS OF ESTABLISHED AND EMERGING DRUG USE PATTERNS AND ADDICTION TREATMENT ON THE HIV PREVENTION/CARE CASCADE IN THE SOUTH. AS A COMMUNITY-ACADEMIC-HEALTH SYSTEM PARTNERSHIP, THIS PROPOSAL IS A COLLABORATION BETWEEN WAKE FOREST UNIVERSITY HEALTH SCIENCES IN WINSTON-SALEM AND CHARLOTTE AND MULTIPLE COMMUNITY ORGANIZATIONS THROUGHOUT CENTRAL AND WESTERN NORTH CAROLINA. LEVERAGING THE ROBUST INFRASTRUCTURE OF ATRIUM HEALTH, ONE OF THE LARGEST NONPROFIT HEALTH SYSTEMS IN THE SOUTH, ALONG WITH HIV AND SUBSTANCE USE SERVICE PROGRAMS, WE WILL ENROLL A STATUS-NEUTRAL COHORT OF 1,000 PERSONS WHO USE STIMULANT AND/OR OPIOID DRUGS – 500 PEOPLE WITH HIV (PWH) AND 500 PEOPLE AT RISK FOR HIV. USING AN OBSERVATIONAL-IMPLEMENTATION HYBRID APPROACH, OUR AIMS ARE TO: (1) RECRUIT AND RETAIN THE CASCADE COHORT TO COLLECT MULTILEVEL DATA HARMONIZED WITH OTHER NIDA-FUNDED HIV COHORTS FOR EMERGING AND HIGH-PRIORITY RESEARCH; (2) USING A SOCIAL-ECOLOGICAL FRAMEWORK, EXAMINE THE EFFECTS OF INDIVIDUAL, COMMUNITY, AND CONTEXTUAL FACTORS ON STATUS-NEUTRAL HIV AND SUBSTANCE USE OUTCOMES OVER TIME, INVESTIGATE THE NEUROIMMUNE MECHANISMS THROUGH WHICH PSYCHOSOCIAL STRESS AFFECTS NEUROPSYCHIATRIC OUTCOMES, AND IDENTIFY STRUCTURAL MODIFIERS (E.G., RURAL/URBAN SETTING) AND POTENTIAL RESILIENCY FACTORS (E.G., COPING); AND (3) CONDUCT MIXED-METHODS ASSESSMENTS USING IMPLEMENTATION MAPPING TO IDENTIFY STRUCTURAL FACTORS, ORGANIZATIONAL PRACTICES, AND OTHER CONTEXTUAL FACTORS THAT INFLUENCE THE UPTAKE OF EVIDENCE-BASED HIV AND SUBSTANCE USE TREATMENTS IN HEALTHCARE SETTINGS, AND CO-CREATE AND DISSEMINATE A SET OF MULTILEVEL STRATEGIES INFORMED BY USER-CENTERED DESIGN TO IMPROVE SERVICE DELIVERY. THROUGH OUR APPLICATION OF CUTTING-EDGE BIOSTATISTICS AND DATA SCIENCE METHODOLOGIES, OUR FINDINGS WILL YIELD NOVEL INSIGHTS TO ACCELERATE SCIENTIFIC DISCOVERIES WHILE ALSO ENHANCING TRANSLATION TO CLINICAL CARE AND FACILITATING RAPID DISSEMINATION. AS THE FIRST NIDA HIV COHORT IN THE SOUTH, WE WILL PARTNER WITH OUR COMMUNITY AND SCIENTIFIC ADVISORY BOARD, CONSISTING OF MEMBERS FROM COMMUNITY ORGANIZATIONS, HEALTH SYSTEM ADMINISTRATORS, PUBLIC HEALTH OFFICIALS, SCIENTIFIC LEADERS, AND PERSONS WITH LIVED EXPERIENCES, TO INFORM GUIDELINES AND PRACTICES IN THE CAROLINAS AND BEYOND. CASCADE ALIGNS WITH NATIONAL PRIORITIES BY ADDRESSING THE GROWING BURDEN OF CHRONIC ILLNESS AND SUBSTANCE USE THROUGH A PRAGMATIC, SCIENCE-BASED APPROACH.

RANDOMIZED TRIAL OF NON-SURGICAL THERAPY AND ORAL HYGIENE INSTRUCTION TO REDUCE RISK OF INFECTIVE ENDOCARDITIS - PROJECT SUMMARY INFECTIVE ENDOCARDITIS (IE) HAS HIGH MORBIDITY AND MORTALITY. UPWARDS OF 30% OF CASES OF IE ARE CAUSED BY ORAL BACTERIAL SPECIES THAT ENTER THE BLOODSTREAM AND COLONIZE HEART VALVES. FREQUENT EPISODES OF BACTEREMIA FROM DENTAL BIOFILM (PLAQUE) ARE LIKELY TO BE SIGNIFICANT RISK FACTORS FOR DEVELOPMENT OF IE. OUR PRIOR WORK DEMONSTRATES THAT: 1) THERE ARE ONLY INFORMAL GUIDELINES FOR PREVENTION IN 90% OF PEOPLE AT RISK FOR IE; 2) TOOTH BRUSHING RESULTS IN A HIGH INCIDENCE OF BACTEREMIA OF IE-CAUSING SPECIES; 3) THE RISK OF SUCH BACTEREMIA INCREASES WITH THE LEVEL OF DENTAL PLAQUE AND CALCULUS PRESENT; AND 4) PATIENTS WITH IE HAVE A HIGHER BURDEN OF DENTAL PLAQUE AND CALCULUS THAN MATCHED NON-IE CONTROLS. ALTHOUGH MILLIONS OF PEOPLE IN THE U.S. ARE AT RISK FOR IE BECAUSE OF PRE-EXISTING CARDIAC CONDITIONS, THERE ARE NO PROSPECTIVE STUDIES OR SOLID EVIDENCE TO SHOW THAT IMPROVING ORAL HYGIENE REDUCES BACTEREMIA FROM ROUTINE DAILY ACTIVITIES (E.G., TOOTHBRUSHING). EVIDENCE DOES SHOW, HOWEVER, THAT BACTEREMIA IS A STRONG SURROGATE MARKER FOR RISK OF IE. THE LACK OF SUPPORTING DATA MEANS THAT LONGSTANDING SPECULATION ABOUT THE IMPORTANCE OF ORAL HYGIENE AND GINGIVAL INFLAMMATION AS RISK FACTORS FOR IE HAVE HAD TOO LITTLE IMPACT ON PRACTICE GUIDELINES ON PREVENTION, CLINICAL PRACTICE, OR FUNDING FOR PREVENTIVE CARE. THE NEXT STEP IS TO DETERMINE IF PROFESSIONAL SCALING AND ORAL HYGIENE INSTRUCTION SIGNIFICANTLY REDUCE THE INCIDENCE AND DURATION OF IE-CAUSING BACTEREMIA FROM TOOTHBRUSHING. WE PLAN TO ENROLL 320 PEOPLE AT RISK FOR IE INTO A CLINICAL TRIAL. ENROLLEES WILL BE RANDOMIZED TO PROFESSIONAL SCALING AND ORAL HYGIENE INSTRUCTION VERSUS ROUTINE ORAL CARE. WE WILL TEST THE STEPS IN THE HYPOTHESIZED CAUSAL PATHWAY FROM IMPROVED ORAL HYGIENE TO DECREASED BACTEREMIA FROM IE-CAUSING SPECIES BY: 1) DETERMINING THE IMPACT OF PROFESSIONAL SCALING AND ORAL HYGIENE INSTRUCTION ON THE INCIDENCE AND DURATION OF BACTEREMIA WITH IE-CAUSING SPECIES DURING AND FOLLOWING TOOTHBRUSHING; 2) COMPARING ORAL HYGIENE AND GINGIVAL HEALTH MEASURES BETWEEN RANDOMIZED TREATMENT GROUPS AND TESTING WHETHER IMPROVEMENT IN THESE MEASURES IS ASSOCIATED WITH REDUCED INCIDENCE AND DURATION OF BACTEREMIA FROM TOOTHBRUSHING; AND 3) DETERMINING THE DEGREE TO WHICH REDUCTION IN BACTEREMIA INCIDENCE AND DURATION, AND IMPROVEMENT IN ORAL HYGIENE AND GINGIVAL INFLAMMATION SCORES, ARE MAINTAINED FOLLOWING THE INTERVENTION. THIS STUDY WILL PROVIDE NOVEL, IMPORTANT DATA TO INFORM THE HEALTHCARE COMMUNITY, GUIDELINE COMMITTEES, AND HEALTH FUNDING AGENCIES OF THE IMPORTANCE OF IMPROVING ORAL HYGIENE AND REDUCING GINGIVAL INFLAMMATION AS PRIMARY PREVENTIVE MEASURES FOR ALL PEOPLE AT RISK OF IE.

EXOME SEQUENCING TO IDENTIFY CVD RISK VARIANTS IN HISPANICS & AFRICAN AMERICANS

THE ETHANOL - ANXIETY INTERACTION: CELLULAR MECHANISMS

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

WFUSM MACACA FASCICULARIS SPF BREEDING COLONY

TISSUE ENGINEERING

TRANSLATING RESEARCH INTO PREVENTION OF DIABETES (TRIP DIABETES)

ATLANTIC COAST CONSORTIUM FOR ASTHMA (ACC-A) ASTHMANET CLINICAL SITE

REGENERATION OF THE LOWER URINARY TRACT IN NONHUMAN PRIMATES

WF DISC: NAVIGATING DATA SOLUTIONS FOR CHRONIC PAIN AND OPIOID USE DISORDER - PROJECT SUMMARY THE MULTIDIMENSIONAL CHALLENGE OF OPIOID OVERDOSE PREVENTION REQUIRES SOLUTIONS LARGER THAN A SINGLE NETWORK PROJECT. WHILE THE HHS AND NIH ARE FOCUSING ON DEVELOPING PREVENTION STRATEGIES FROM NUMEROUS PERSPECTIVES, BLENDING THESE DATA WILL REQUIRE COMPLEX DATA SOLUTIONS TO MOVE BEYOND SILOES. WHILE WE DO NOT KNOW YET HOW BRINGING THE ELEMENTS OF OPIOID OVERDOSE DATA TOGETHER WILL BE MOST EFFECTIVE, COLLECTING THESE DATA IN WAYS THAT ALLOW FOR FAIR (FINDABLE, ACCESSIBLE, INTEROPERABLE, REUSABLE) FORMATTING BUILDS TOWARD THAT POTENTIAL. THE GOAL OF THE HEAL D2A PROGRAM IS TO DEVELOP OPIOID OVERDOSE SURVEILLANCE IN REAL TIME, BUT IT GOING TO TAKE SIGNIFICANT COMBINED CLINICAL AND INFORMATICS KNOWLEDGE TO BRING THIS SYSTEM TOGETHER. TO ACCOMPLISH THIS GOAL, OUR PROPOSAL IS RESPONSIVE TO RFA-DA-22-052 TO DESIGN FLEXIBLE AND CREATIVE INFORMATICS SOLUTIONS FOR THE HEAL DATA2ACTION PROGRAM (HD2A) NETWORK. THE WF DATA INFRASTRUCTURE SUPPORT CENTER (DISC)'S HIGHLY QUALIFIED CLINICAL INFORMATICS TEAM WILL PROVIDE DIRECT SUPPORT, GUIDANCE, AND ASSISTANCE TO ENSURE THAT DATA INFRASTRUCTURES OF THE HIGHEST QUALITY ARE PRODUCED IN THE SHORTEST POSSIBLE TIME FOR THE HEAL D2A INNOVATION PROJECTS. OUR OVERALL GOAL AS A U24 DATA CENTER IS TO IDENTIFY AND ELIMINATE DATA INFRASTRUCTURE BARRIERS (KNOWLEDGE AND TECHNICAL) TO ALLOW SUCCESSFUL COMPLETION OF THE HD2A PROJECTS. THE OBJECTIVE OF THIS PROPOSAL IS TO NAVIGATE THE EXPECTED AND UNEXPECTED DATA CHALLENGES FOR THE HD2A NETWORK, ENCOMPASSING THE INNOVATION PROJECTS TO IDENTIFY TOOLS, PROVIDE DATA SUPPORT, AND DELIVER TRAINING ASSISTANCE. WE WILL ACCOMPLISH THIS OBJECTIVE THROUGH SUCCESSFUL COMPLETION OF THESE PHASED AIMS. TO SUPPORT THE OVERALL HYPOTHESIS OF THE HEAL D2A NETWORK, IN AIM 1, THE WF DISC'S STUDY START-UP CORE WILL IDENTIFY AND DEVELOP DATA INFRASTRUCTURE SUPPORT AND TOOLS. IN AIM 2, WF DISC'S STUDY CONDUCT CORE WILL WORK WITH THE HD2A RASC AND MERC PROVIDE DATA MEASUREMENT, ANALYTICAL, AND VISUALIZATION SUPPORT AND COORDINATION. IN AIM 3, THE WF DISC'S STUDY DISSEMINATION CORE WILL DEVELOP AND PROVIDE DATA TRAINING AND RESOURCES. IN AIM 4, WE WILL IDENTIFY RAPID DATA INFRASTRUCTURE MODERNIZATION SUPPORT (RAPID DIMS) NEEDS AND PROVIDE PROGRAMMATIC RESOURCES. AT THE SUCCESSFUL COMPLETION OF THE PROPOSED RESEARCH, THE EXPECTED OUTCOMES ARE CENTRALIZED SUPPORT, RESOURCES, AND COORDINATION OF ALL DATA-RELATED NEEDS FOR THE HEAL HD2A INNOVATION PROJECTS. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE ADAPTATION OF OUR TEAM'S EXPERIENCE WILL BRIDGE CLINICAL RESEARCH AND INFORMATICS INFRASTRUCTURE TO PROVIDE LOGISTICAL, SCIENTIFIC, OVERSIGHT, AND TECHNICAL SUPPORT FOR DATA COLLECTION, CURATION, REPORTING, AND MANAGEMENT BY THE HD2A INNOVATION PROJECTS. THESE RESULTS WILL PROVIDE A STRONG BASIS FOR FURTHER/FUTURE DEVELOPMENT OF OPIOID OVERDOSE PREVENTION SURVEILLANCE, WHICH IS EXPECTED TO HAVE A SIGNIFICANT IMPACT ON OVERDOSE BY ALLOWING FOR RAPID INTERVENTION AND PIVOTING OF RESOURCES. THIS RESEARCH ALIGNS WITH NIH NIDA AND HEAL'S GOALS TO PREVENT AND MITIGATE THE IMPACT OF THE OUD EPIDEMIC.

HEALTH AGING & LATER-LIFE OUTCOMES PLANNING (HALLO-P) - THE HEALTH, AGING AND LATER-LIFE OUTCOMES PLANNING GRANT (HALLO-P) IS SUBMITTED IN RESPONSE TO RFA-AG-21-016. COLLECTIVELY, HALLO-P AFFILIATED INVESTIGATORS HAVE LED 17 CLINICAL TRIALS OF CALORIC RESTRICTION (CR; 3 ONGOING), ENROLLING 2,773 ADULTS (AGES 55-91) WITH BMIS = 27 KG/M2, SHOWING MULTIPLE BENEFICIAL PHYSIOLOGIC CHANGES ASSOCIATED WITH LOWER DISEASE AND DISABILITY RISK. WHETHER THIS TRANSLATES TO ACTUAL REDUCTIONS IN DISEASE AND DISABILITY IS UNCLEAR. A LARGE MULTI-YEAR TRIAL WITH DEFINITIVE CLINICAL OUTCOMES IS NEEDED TO FILL THIS EVIDENCE GAP. TIME RESTRICTED FEEDING (TRF) COULD BE AN ATTRACTIVE ALTERNATIVE TO CR IF IT PRODUCED SIMILAR HEALTH BENEFITS, WAS MORE EASILY SUSTAINED, AND MITIGATED CR’S UNDESIRABLE LOSS OF MUSCLE AND BONE. THE OVERALL GOAL OF THIS 3-YEAR HALLO PLANNING GRANT IS TO DEVELOP A PROTOCOL FOR A RIGOROUS, MULTI-SITE, RANDOMIZED CLINICAL TRIAL (RCT) COMPARING CLINICALLY-RELEVANT HEALTH OUTCOMES IN OLDER PERSONS RANDOMIZED TO DAILY CR, A TRF REGIMEN, OR A NON-DIETARY ATTENTION CONTROL GROUP EMPLOYING INNOVATIVE MHEALTH TOOLS TO PROMOTE ADHERENCE. WE WILL COMPLETE A 12-MONTH PILOT STUDY ENROLLING 120 OLDER ADULTS (AGE =60 YEARS; 50% WOMEN; =23% MINORITY) TO PROVIDE CRITICAL INFORMATION ON FEASIBILITY, INTERVENTION DELIVERY, AND DATA INFORMING EFFECT SIZE DETERMINATION. HALLO-P’S OBJECTIVES ARE TO: 1. ESTABLISH A SCIENTIFIC ADVISORY BOARD AND OTHER STRUCTURES TO GUIDE PLANNING ACTIVITIES AND THE DESIGN OF A FULL- SCALE RCT THAT ENGAGE A WIDE RANGE OF STAKEHOLDERS AND BUILD A NATIONAL CONSTITUENCY FOR THE PROJECT. 2. REFINE OUR MHEALTH BEHAVIOR-CHANGE AND ADHERENCE TRACKING PLATFORM—THE HALLO-P COMPANION APP—TO OPTIMIZE DELIVERY OF BOTH THE CR AND TRF INTERVENTIONS. 3. CONDUCT FOCUS GROUPS AND A 12-MONTH PILOT RCT OF: 1) 20% CR DELIVERED IN-PERSON; 2) 20% CR DELIVERED REMOTELY VIA VIDEO CONFERENCING; AND 3) TRF (8-10 HOURS) WITH AD LIBITUM CALORIC INTAKE. PILOT DATA WILL HELP REFINE RECRUITMENT CRITERIA, ESTIMATE RECRUITMENT YIELDS, AND REFINE INTERVENTION APPROACHES. WE WILL USE DOUBLY- LABELED WATER TO MEASURE ACHIEVED CR AND CONTINUOUS GLUCOSE MONITORING TO ASSESS ADHERENCE TO TRF. 4. MODEL AGING BIOMARKER CHANGES FOR DIFFERING CR DOSES USING WF OAIC REPOSITORIES AND THE HALLO-P PILOT. EXISTING EPIDEMIOLOGICAL DATABASES WILL BE USED TO ESTIMATE THE ANTICIPATED EFFECT OF THESE BIOMARKER CHANGES ON CLINICAL OUTCOMES AND TO DERIVE KEY DESIGN METRICS RELATED TO INCLUSION/EXCLUSION CRITERIA, AND EVENT RATES RELATED TO MULTI-MORBIDITY, HEALTH DEFICIT ACCUMULATION, AND FUNCTIONAL DECLINE/DISABILITY; AND 5. INTEGRATE NEW DATA, THE SCIENTIFIC LITERATURE .AND EXPERT ADVICE TO PREPARE A PROTOCOL, AND DEVELOP INFORMED CONSENT FORMS, MANUALS OF OPERATION, STUDY FORMS, AND RELATED SYSTEMS TO PERMIT THE RAPID LAUNCH OF THE LARGER TRIAL UPON COMPLETION OF THE PILOT ACTIVITIES IN COORDINATION WITH THE OTHER U01 PROJECT FUNDED BY THIS MECHANISM.

ESTABLISHING THE OPTIMAL FREQUENCY OF DANCE MOVEMENT FOR NEUROCOGNITIVE AND PHYSICAL OUTCOMES IN PEOPLE AT RISK OF ALZHEIMER'S DISEASE - PROJECT SUMMARY DANCE MOVEMENT IS A FORM OF PHYSICAL ACTIVITY THAT MAY BENEFIT THE BRAIN AS MUCH OR MORE THAN STRUCTURED AEROBIC EXERCISE. DESPITE THE POTENTIAL OF DANCE AS AN INTERVENTION TO PROMOTE NEUROCOGNITIVE HEALTH, GAPS IN KNOWLEDGE ABOUT ESSENTIAL INTERVENTION COMPONENTS ARE A BARRIER TO DEFINITIVE TRIALS, SPECIFICALLY:1) A LACK OF SPECIFICITY ON KEY PRESCRIPTION PARAMETERS INCLUDING HOW MANY TIMES A WEEK DANCE CLASSES SHOULD BE TAUGHT, 2) NEED FOR BETTER ESTIMATES OF HOW LARGE AN EFFECT DANCE HAS ON FITNESS AND THE BRAIN, AND 3) LITTLE UNDERSTANDING OF THE EXPECTED TIME COURSE FOR CHANGE IN FITNESS AND THE BRAIN IN RESPONSE TO DANCE. THE PRIMARY AIM OF THIS PROPOSAL IS TO TEST WHETHER WEEKLY DANCE FREQUENCY DIFFERENTIALLY MODIFIES KEY OUTCOMES, AND FROM THIS TO TEST EFFECT SIZES TO DETERMINE SUFFICIENT SAMPLE SIZES FOR A LARGER-SCALE TRIAL. PHYSICAL ACTIVITY PROMOTING INTERVENTIONS TESTED IN OLDER ADULTS HAVE TRADITIONALLY FOCUSED ON EXERCISE, I.E., STRUCTURED PHYSICAL ACTIVITY OF AT LEAST MODERATE INTENSITY WITH THE EXPRESS PURPOSE OF IMPROVING HEALTH OR FITNESS. HOWEVER, IN 2003, EPIDEMIOLOGICAL EVIDENCE SHOWED THAT SOCIAL DANCE WAS THE ONLY LEISURE TIME PHYSICAL ACTIVITY ASSOCIATED WITH LOWER ALZHEIMER’S DISEASE RISK. SINCE THEN, MULTIPLE SMALLER STUDIES HAVE SHOWN BENEFITS OF DANCE MOVEMENT AND DANCE THERAPY ON MOBILITY AND NEUROCOGNITIVE HEALTH IN OLDER ADULTS, INCLUDING CARDIORESPIRATORY FITNESS, BALANCE, WHITE MATTER HEALTH, AND COGNITION. DANCE MOVEMENT INHERENTLY INVOLVES SIMULTANEOUS COGNITIVE STIMULATION THROUGH MOTOR LEARNING AND DUAL-TASKING; SOCIAL INTERACTIONS; AEROBIC PHYSICAL ACTIVITY THAT ELEVATES HEART RATE AND IMPROVES CARDIORESPIRATORY FITNESS; AND IMPROVES BALANCE AND REDUCES FALL RISK. DANCE ALSO SATISFIES KEY ANTECEDENTS OF LASTING BEHAVIOR CHANGE OUTLINED IN CONTEMPORARY BEHAVIORAL THEORIES INCLUDING SELF-EFFICACY, INTRINSIC MOTIVATION, AUTONOMY, AND RELATEDNESS. DANCE IS ALSO CULTURALLY RELEVANT AND HAS BEEN PRACTICED SPONTANEOUSLY FOR THOUSANDS OF YEARS. THIS MEANS DANCE MAY RESULT IN BETTER LONG-TERM ADHERENCE THAN MORE COMMONLY STUDIED FORMS OF AEROBIC EXERCISE LIKE BRISK WALKING, WHERE DATA FROM OUR GROUP AND OTHERS SHOWS THAT ADHERENCE DROPS SIGNIFICANTLY AFTER INTERVENTION ENDS. THIS PROPOSAL PLANS TO ASSESS OUTCOMES OF 1X/WEEKLY, 2X/WEEKLY, AND 3X/WEEKLY DANCE MOVEMENT CLASSES AND 1X/WEEK MUSIC APPRECIATION CLASS CONTROL AT 4 TIME-POINTS OVER 6 MONTHS TO DETERMINE THE TIME COURSE OF CHANGES IN CARDIORESPIRATORY FITNESS, COGNITION, AND KEY SECONDARY OUTCOMES IN 160 ADULTS = 65 YEARS OLD AT RISK FOR ALZHEIMER’S DISEASE DUE TO SUBJECTIVE COGNITIVE DECLINE. 1X/WEEKLY IS COMMON FOR COMMUNITY CLASSES AND HAS BEEN TESTED IN MULTIPLE DANCE STUDIES; 2X/WEEKLY IS MOST COMMON IN DANCE RESEARCH; AND 3X/WEEKLY IS MOST COMMON FOR AEROBIC EXERCISE INTERVENTIONS LIKE TREADMILL WALKING THAT TARGET CRF. WE AIM TO DETERMINE THE OPTIMAL FREQUENCY OF DANCE MOVEMENT INTERVENTION FOR A PHASE III TRIAL THAT WILL EFFECT CHANGE IN RELEVANT OUTCOMES WHILE MAINTAINING ATTENDANCE.

LABORATORY ANIMAL & COMPARATIVE MEDICINE TRAINING

MODELING THE EFFECTS OF CHRONIC MARIJUANA USE ON NEUROINFLAMMATION AND HIV-RELATED NEURONAL INJURY

VERVET RESEARCH COLONY AS A BIOMEDICAL RESOURCE

BRAIN NETWORKS AND MOBILITY FUNCTION: B-NET

PREVENTING ANTHRACYCLINE CARDIOVASCULAR TOXICITY WITH STATINS

INTERLEUKIN-6 AND RETINAL GANGLION CELL DEGENERATION IN GLAUCOMA

INTENTIONAL WEIGHT REDUCTION AND PHYSICAL AND COGNITIVE FUNCTION

IDENTIFYING NICOTINE WITHDRAWAL MECHANISMS HIDDEN WITHIN HABENULAR COMPLEXITY

CELL-SPECIFIC GENOMIC FEATURES OF ALZHEIMER'S DISEASE PROGRESSION

CLINICAL VALIDITY AND UTILITY OF GENOMIC TARGETED CHEMOPREVENTION OF PCA

HL146818-URIC ACID, KLOTHO AND SALT SENSITIVITY IN YOUNG ADULTS BORN PRETERM

THE ROLE OF HEPATOCYTE ABCA1 IN LIPID MOBILIZATION AND TRANSPORT

STUDIES OF RPE65

SUBCLINICAL CVD IN AFRICAN AMERICAN TYPE 2 DIABETICS

PAIN RESPONSE EVALUATION OF A COMBINED INTERVENTION TO COPE EFFECTIVELY (PRECICE)

IRON AND METABOLISM: ALTERED FUEL OXIDATION AND MITOCHONDRIAL DYSFUNCTION

REGION 4 PREVENTION TECHNOLOGY TRANSFER CENTER

IDAPT: IMPLEMENTATION AND INFORMATICS - DEVELOPING ADAPTABLE PROCESSES AND TECHNOLOGIES FOR CANCER CONTROL

COCOA SUPPLEMENT AND MULTIVITAMIN OUTCOMES STUDY IN THE MIND (COSMOS-MIND)

GENETIC ANALYSIS OF AFRICAN AMERICAN HYPERTENSIVE END-STAGE RENAL DISEASE

THE MACROVASCULAR AND MICROVASCULAR CONTRIBUTIONS TO ALZHEIMER'S DISEASE: MESA VASCAD

GLUCOSE REGULATION AND MEMORY IN ALZHEIMER'S DISEASE

BLOOD BASE BIOENERGETIC PROFILING: A NOVEL APPROACH FOR IDENTIFYING ALZHEIMER'S DISEASE RISK AND PATHOLOGY

INTERVENING ON SEDENTARY BEHAVIOR TO PREVENT WEIGHT REGAIN IN OLDER ADULTS

LONGITUDINAL PHENOMICS AND GENETICS OF SEVERE ASTHMA

METABOLOMICS OF NEUROCOGNITIVE RISK FOR DEMENTIA IN DIABETES

NICOTINIC ACETYLCHOLINE RECEPTOR FUNCTION IN THE MESOLIMBIC DOPAMINE SYSTEM

SPATIO-TEMPORAL METHODS FOR SURVEILLANCE OF THE OPIOID SYNDEMIC - PROJECT SUMMARY/ABSTRACT THE UNITED STATES IS IN THE MIDST OF A PUBLIC HEALTH CRISIS DUE TO THE ONGOING OPIOID SYNDEMIC. THE OPIOID SYNDEMIC CONSISTS OF THE INTER-RELATED EPIDEMICS OF OPIOID MISUSE, FATAL AND NON-FATAL OVERDOSE, HUMAN IMMUNODECIENCY VIRUS (HIV), AND HEPATITIS C (HCV). THE CONSEQUENCES OF OPIOID MISUSE ARE PARTICULARLY SEVERE IN OHIO AS THE STATE HAS EXPERIENCED OVERDOSE RATES THAT ARE DOUBLE THE NATIONAL AVERAGE AS WELL AS ELEVATED RISK FOR EPIDEMIC LEVELS OF HIV AND HCV. A KEY NEED FOR ADDRESSING THE SYNDEMIC IS TO IMPROVE SURVEILLANCE SCIENCE METHODOLOGY TO BETTER MEASURE COMMUNITY-LEVELS OF OPIOID MISUSE AND BE ABLE TO IDENTIFY AND TARGET AREAS OF EMERGING RISK WITH RESOURCES. HOWEVER, NO SINGLE DATA SOURCE CURRENTLY OBSERVED BY THE PUBLIC HEALTH SURVEILLANCE SYSTEM FULLY CHARACTERIZES OPIOID MISUSE AT RELEVANT SPATIAL AND TEMPORAL SUPPORTS. NOVEL STATISTICAL METHODS ARE NEEDED TO BETTER LEVERAGE EXISTING DATA AND APPROPRIATELY INTEGRATE MULTIPLE IMPERFECT SURVEILLANCE OUTCOMES ACROSS DIFFERENT SPATIAL SCALES TO COMPREHENSIVELY ESTIMATE LEVELS OF OPIOID MISUSE AND MODEL THE SYNDEMIC OVER SPACE AND TIME. DOING SO WILL ENABLE ESTIMATION AND INFERENCE AT SMALL AREAS THAT ARE RELEVANT TO LOCAL POLICYMAKERS AND PUBLIC HEALTH OFCIALS WHILE ACCOUNTING FOR MEASUREMENT ERROR. THERE ARE SEVERAL METHODOLOGICAL CHALLENGES THAT WILL BE OVERCOME WITH ACHIEVEMENT OF THE FOLLOWING AIMS: 1) DEVELOP AND ASSESS A SPATIO-TEMPORAL FACTOR MODEL THAT ESTIMATES A FACTOR THAT CAN BE MEANINGFULLY INTERPRETED LONGITUDINALLY, 2) DEVELOP AND ASSESS A SPATIAL FACTOR MODEL THAT ALLOWS FOR OUTCOMES TO HAVE DIFFERENT SPATIAL SUPPORTS, AND 3) DEVELOP AND ASSESS A MULTIVARIATE SPATIO- TEMPORAL MODEL TO ESTIMATE AREAL PREVALENCE OF LATENT OPIOID MISUSE. SUCCESSFUL DEVELOPMENT OF A COMPREHENSIVE MODEL OF THE OPIOID SYNDEMIC WILL ADVANCE SURVEILLANCE SCIENCE AND WILL PRODUCE ESTIMATES OF OPIOID MISUSE THAT ADVANCE EPIDEMIOLOGICAL UNDERSTANDING AND PROVIDE VALUABLE INFORMATION TO POLICYMAKERS AND PUBLIC HEALTH OFCIALS.

RECEPTOR SELECTIVE SPINAL ANALGESIA

EXERCISE INTOLERANCE IN OLDER HFPEF PATIENTS

SNPS AND EXTENT OF ATHEROSCLEROSIS (SEA) STUDY

NF-KB AND CHROMATIN CHANGES IN HUMAN SEPSIS

COMMON STEM CELL OF ORIGIN FOR JUNCTIONAL AND GASTRIC ADENOCARCINOMA - SUMMARY DESPITE THEIR EMERGENCE FROM DISTAL ESOPHAGUS AND DISTAL STOMACH, RESPECTIVELY, ESOPHAGEAL ADENOCARCINOMA (EAC) AND INTESTINAL GASTRIC CANCER (IGC) SHARE THE NATURAL HISTORIES AND MOLECULE GENETICS OF A SINGLE DISEASE. HISTORICALLY, EAC AND IGC WERE AMONG THE FIRST CANCERS TO BE LINKED TO THE PRIOR PRESENCE OF DISCRETE, PRE- CANCEROUS LESIONS THAT CAN PROGRESS TO DYSPLASIA AND THEN INVASIVE DISEASE OVER A TWO-DECADE INTERVAL. IN BOTH CASES THE EARLIEST PRECANCEROUS LESION WAS AN ODD "INTESTINAL METAPLASIA; IM" KNOWN AS "BARRETT'S ESOPHAGUS (BE)" FOR EAC AND "GASTRIC INTESTINAL METAPLASIA (GIM)" FOR IGC. THESE COMMON EVOLUTIONARY FEATURES HAVE BEEN EXTENDED BY CANCER GENETICS BREAKTHROUGHS THAT PLACE EAC AND IGC INTO SINGLE CLUSTER DISTINCT FROM OTHER GASTRIC AND ESOPHAGEAL CANCERS. WHILE IT WAS WIDELY ANTICIPATED THAT ADVANCES IN ENDOSCOPIC AND ABLATIVE TECHNOLOGIES APPLIED TO PRECURSOR LESIONS WOULD SPELL THE END OF EAC AND IGC, RATES OF EAC AND IGC HAVE NOT APPRECIABLY DECREASED AND MOST PATIENTS STILL PRESENT WITH ADVANCED DISEASE AND POOR FIVE-YEAR SURVIVAL. THIS DIRE CLINICAL REALITY HAS PREDICATED A BROAD EFFORT TO UNDERSTAND THE CELL-OF-ORIGIN OF THESE DISEASES, THEIR EARLIEST EMERGENCE TOWARDS PATHOLOGY, AS WELL AS THEIR DETECTION AND PHARMACEUTICAL ELIMINATION. A HIGHLY COLLABORATIVE TEAM CONSISTING OF UPPER GASTROINTESTINAL ONCOLOGISTS, STEM CELL AND MOLECULAR BIOLOGISTS, EXPERTS IN MURINE CANCER MODELING, AND PROTEOMICS SPECIALISTS HAS EMPLOYED ADVANCED STEM CELL CLONING TECHNOLOGIES TO CAPTURE PATIENT-MATCHED STEM CELLS IN EACH OF THE SUCCESSIVE LESIONS IN PATIENTS WITH EAC AND IGC. IN ADDITION TO THE HIGH-RESOLUTION PHYLOGENETICS AFFORDED BY THESE STEM CELLS, THIS ANALYSIS HAS REVEALED THE BE AND GIM STEM CELLS ARE INDISTINGUISHABLE AT THE LEVEL OF WHOLE GENOME EXPRESSION PROFILING DOWN TO THE LEVEL OF HOMEOTIC TRANSCRIPTION FACTORS THAT DEFINE CELLULAR IDENTITY. COMMON CELL SURFACE MARKERS OF BE AND GIM STEM CELLS IDENTIFY A DISCRETE POPULATION OF CELLS AT BOTH THE GASTROESOPHAGEAL (GE) JUNCTION AND IN THE DISTAL STOMACH OF NORMAL MICE WHICH WE HYPOTHESIZE ARE THE INTRINSIC SOURCE OF THE IM FOR EAC AND IGC RESPECTIVELY. THESE MARKERS HAVE ALSO ENABLED THE CLONING OF THE CORRESPONDING SITE-SPECIFIC STEM CELLS, WHICH WE FIND TO BE INDISTINGUISHABLE GENE EXPRESSION PROFILES AND TO BE COMMITTED TO IM UPON IN VITRO DIFFERENTIATION. IN THREE AIMS, WE WILL 1) USE SIMILAR METHODS TO CLONE THE INTRINSIC IM STEM CELLS FROM HUMAN FETAL AND ADULT GE JUNCTIONS AND GASTRIC MUCOSA; 2) ENGINEER MOUSE MODELS FOR CONDITIONAL EXPRESSION OF ONCOGENIC FACTORS IN INTRINSIC IM CELLS; AND 3) IDENTIFY SMALL MOLECULES THAT SELECTIVELY TARGET INTRINSIC IM STEM CELLS AS LEADS FOR THERAPEUTICS TO PREVENT EAC AND IGC. WE ANTICIPATE THAT THE STUDIES PROPOSED HEREIN WILL PROVIDE NEW INSIGHTS INTO THE BIOLOGY AND ORIGIN OF THESE REMARKABLY SIMILAR AND WIDESPREAD CANCERS, PROVIDE DATASETS ESSENTIAL FOR PROSPECTIVE EARLY DETECTION SCREENS, AND YIELD HIGHLY SELECTIVE THERAPEUTICS THAT ELIMINATE THE NASCENT LESIONS ESSENTIAL FOR THE EVOLUTION OF THESE CANCERS.

POSTDOCTORAL TRAINING IN CANCER CONTROL RESEARCH

CMR-IMPACT

POPULATION-BASED DIABETES YOUTH REGISTRY

A PARTNERSHIP APPROACH TO REDUCING HIV DISPARITIES AMONG LATINO MEN

IMPROVING NEUROLOGIC OUTCOMES IN DIABETICS UNDERGOING CARDIAC SURGERY

EPIGENOME-WIDE ASSOCIATION STUDY OF DNA METHYLATION AND ATHEROSCLEROSIS

TRAINING PROGRAM IN GERONTOLOGICAL AND GERIATRIC MEDICINE

CRCNS INVESTIGATING PERCEPTUAL PROCESSING SPEED AND ITS IMPACT ON CHOICE BEHAVIOR

RYAN WHITE TITLE IV WOMEN, INFANTS, CHILDREN, YOUTH AND AFFECTED FAMILY MEMBERS AIDS HEALTHCARE

LINKING GENETICS, GENOMICS AND PHENOMICS TO BETTER UNDERSTAND ASTHMA SEVERITY

EXPLORING THE CONSEQUENCES OF FOOD INSECURITY AND HARNESSING THE POWER OF PEER NAVIGATION AND MHEALTH TO REDUCE FOOD INSECURITY AND CARDIOMETABOLIC COMORBIDITIES AMONG PERSONS WITH HIV - UP TO 50% OF PEOPLE WITH HIV (PWH) IN THE US ARE FOOD INSECURE. PWH WHO ARE FOOD INSECURE ARE MORE LIKELY TO HAVE LOWER ANTIRETROVIRAL ADHERENCE, DECREASED VIRAL SUPPRESSION, AND INCREASED INCIDENCE OF SERIOUS ILLNESS. INCREASING RESEARCH SUGGESTS THAT HIV ALSO LEADS TO THE DEVELOPMENT OF CARDIOMETABOLIC COMORBIDITIES, BUT LITTLE IS KNOWN ABOUT HOW FOOD INSECURITY (FI) AFFECTS THE DEVELOPMENT OF THESE COMORBIDITIES AMONG PWH. THE OBJECTIVES OF THIS STUDY ARE TO BETTER UNDERSTAND HOW FI CONTRIBUTES TO THE DEVELOPMENT OF CARDIOMETABOLIC COMORBIDITIES AMONG PWH AND TO TEST A NOVEL BILINGUAL FI INTERVENTION DESIGNED TO REDUCE THESE COMORBIDITIES AMONG FOOD INSECURE PWH. WE WILL CONDUCT THIS STUDY IN PARTNERSHIP WITH THE WAKE FOREST INFECTIOUS DISEASES SPECIALTY CLINIC, ONE OF THE LARGEST RYAN WHITE-FUNDED CLINICS IN NORTH CAROLINA, WHICH SERVES MORE THAN 2,000 PWH ANNUALLY FROM A PREDOMINANTLY RURAL CATCHMENT AREA THAT INCLUDES SOUTH CENTRAL APPALACHIA. THIS AREA HAS HIGH RATES OF BOTH FI AND HIV. IN AIM 1, WE WILL COLLECT LONGITUDINAL DATA FROM EACH PATIENT YEARLY FOR UP TO 3 YEARS DURING THEIR ROUTINE HIV CARE VISITS. USING THESE DATA, WE WILL COMPARE THE PREVALENCE AND INCIDENCE OF CARDIOMETABOLIC COMORBIDITIES BETWEEN FOOD SECURE AND INSECURE PWH. WE HYPOTHESIZE THAT FOOD INSECURE PWH WILL BE MORE LIKELY TO HAVE CARDIOMETABOLIC COMORBIDITIES, INCLUDING PREDIABETES AND T2DM THAN FOOD SECURE PWH AT BASELINE. WE ALSO HYPOTHESIZE THAT THOSE WHO ARE FI WILL HAVE A HIGHER INCIDENCE OF PREDIABETES AND T2DM THAN THOSE WHO ARE FOOD SECURE OVER TIME. IN AIM 2, USING A RANDOMIZED CONTROLLED TRIAL DESIGN, WE WILL TEST WECARE/SECURE, A REFINED VERSION OF A BILINGUAL EVIDENCE-BASED INTERVENTION THAT INTEGRATES PEER NAVIGATION AND MHEALTH, TO DETERMINE THE IMPACT OF THE INTERVENTION ON INSULIN SENSITIVITY AMONG FOOD INSECURE PWH WITH PREDIABETES OR T2DM. IN AIM 3, WE WILL EXPLORE INTERVENTION EFFECTS THOUGH SEMI-STRUCTURED INDIVIDUAL IN-DEPTH INTERVIEWS. THE PROPOSED RESEARCH COMPLEMENTS THE RFA’S FOCUS BY ADVANCING OUR UNDERSTANDING OF HOW “FI IMPACTS THE DEVELOPMENT OF COMORBIDITIES” AMONG PWH AND TESTING “HOW INTERVENTIONS FOR FI ALLEVIATE NIDDK- RELEVANT COMORBIDITIES.” THIS WILL BE ONE OF THE FIRST STUDIES TO EVALUATE HOW FI LEADS TO THE DEVELOPMENT OF CARDIOMETABOLIC COMORBIDITIES AMONG PWH. ADDITIONALLY, WE WILL TEST A NOVEL BILINGUAL INTERVENTION TO IMPROVE INSULIN SENSITIVITY AMONG PWH BY REDUCING FI. GIVEN THE GROWING INTEREST AMONG HEALTH SYSTEMS IN ADDRESSING FI AS A ROUTINE PART OF CLINICAL PRACTICE, IF THE INTERVENTION IS FOUND TO BE EFFICACIOUS, IT COULD BE BROADLY DISSEMINATED ACROSS HIV CLINICAL CARE SETTINGS. OUR TEAM OF ESTABLISHED INVESTIGATORS HAS A PROVEN RECORD OF SUCCESS CONDUCTING RANDOMIZED TRIALS AMONG PWH, HAS SUCCESSFULLY USED METHODS PROPOSED IN THIS APPLICATION, AND HAS THE FULL SUPPORT OF THE CLINICAL SITE WHERE THE STUDY WILL OCCUR.

SYNAPTIC CORRELATES OF VULNERABILITY AND RESILIENCE TO ALCOHOL USE DISORDERS

ACTION FOR HEALTH IN DIABETES BRAIN MAGNETIC RESONANCE IMAGING ANCILLARY STUDY

TIP60 IN P38 AND PRAK MEDIATED ONCOGENE-INDUCED SENESCENCE AND TUMOR SUPPRESSION

RYAN WHITE TITLE IV WOMEN, INFANTS, CHILDREN, YOUTH AND AFFECTED FAMILY MEMBERS AIDS HEALTHCARE

BIASED KAPPA OPIOID AGONISTS AS NON-ADDICTIVE ANALGESICS

PRIMARY CARE IMPLEMENTATION AND EVALUATION OF COACH MCLUNGS? AN ASTHMA SHARED DECISION-MAKING INTERVENTION, ACROSS A LARGE HEALTHCARE SYSTEM - PROJECT SUMMARY / ABSTRACT (30 LINES) CHANGING BEHAVIOR OF HEALTH PROVIDERS CAN BE CHALLENGING, AND SIGNIFICANT GAPS EXIST IN OUR KNOWLEDGE OF HOW TO BEST IMPLEMENT NEW MEDICAL EVIDENCE INTO EVERYDAY PRACTICE. NUMEROUS INDIVIDUAL- AND SYSTEM-LEVEL FACTORS CONTRIBUTE TO POOR ASTHMA OUTCOMES WHICH PERSIST DUE TO THE LACK OF A COMPREHENSIVE APPROACH FOR ASTHMA CARE THAT IS SCALABLE, SUSTAINABLE, AND WIDELY DISSEMINATED. IMPROVED ASTHMA OUTCOMES ARE ASSOCIATED WITH EFFECTIVE COMMUNICATION STRATEGIES BETWEEN THE PATIENT AND PROVIDER. SHARED DECISION MAKING (SDM) IS A PATIENT-CENTERED PROCESS IN WHICH PATIENTS AND PROVIDERS WORK TOGETHER TO MAKE DECISIONS AND SELECT TESTS, TREATMENTS, AND CARE PLANS BASED ON EVIDENCE THAT BALANCES RISKS WITH PATIENT PREFERENCES AND VALUES. PREVIOUS STUDIES, INCLUDING OUR PCORI-FUNDED DISSEMINATION STUDY, HAVE SHOWN THAT SDM IS ASSOCIATED WITH IMPROVED OUTCOMES FOR ASTHMA PATIENTS IN PRIMARY CARE. HERE WE WILL EVALUATE THE IMPLEMENTATION OF COACH MCLUNGSSM, A VIRTUAL EVIDENCE-BASED ASTHMA SDM INTERVENTION WITH BUILT-IN ASTHMA EDUCATION AND CLINICAL DECISION SUPPORT, INTO PRIMARY CARE PRACTICES ACROSS A LARGE HEALTHCARE SYSTEM. ATRIUM HEALTH, THE 2ND LARGEST VIRTUALLY INTEGRATED HEALTHCARE SYSTEM IN THE NATION, WITH OVER 14 MILLION PATIENT VISITS PER YEAR AND THE REGION'S LARGEST PRIMARY CARE NETWORK, PROVIDES AN IDEAL VENUE TO EVALUATE IMPLEMENTATION INTO PRIMARY CARE. COACH MCLUNGSSM WILL BE FULLY INTEGRATED INTO THE ELECTRONIC MEDICAL RECORD AT ALL PRIMARY CARE PRACTICES. ALL ASTHMA PATIENTS AGED 5-17 WHO ATTEND THESE PRACTICES WILL BE ASSESSED FOR UNCONTROLLED ASTHMA. THE GOAL OF THIS STUDY WILL BE TO EVALUATE THE IMPLEMENTATION OF THE COACH MCLUNGSSM SDM INTERVENTION INTO PRIMARY CARE. IMPLEMENTATION WILL BE GUIDED USING THE EXPERT RECOMMENDATIONS FOR IMPLEMENTING CHANGE (ERIC), A COMPILATION OF IMPLEMENTATION STRATEGIES, AND EVALUATED USING THE RE-AIM (REACH EFFECTIVENESS, ADOPTION, IMPLEMENTATION, MAINTENANCE) FRAMEWORK. RESEARCH QUESTIONS ARE: HOW BEST CAN WE IMPLEMENT THE COACH MCLUNGSSM SDM ASTHMA INTERVENTION INTO PRIMARY CARE? WILL USE OF COACH MCLUNGSSM IN PRIMARY CARE IMPROVE OUTCOMES FOR PATIENTS WITH UNCONTROLLED ASTHMA? AFTER CONVENING A STAKEHOLDER ADVISORY COMMITTEE (SAC) COMPOSED OF PROVIDERS, RESEARCHERS, PATIENTS, STAKEHOLDERS WITH EXPERTISE IN IMPLEMENTATION SCIENCE, ASTHMA RESEARCH AND ADVOCACY, WE WILL IMPLEMENT THE COACH MCLUNGSSM SDM INTERVENTION INTO PRIMARY CARE PRACTICES USING A STEPPED WEDGE RANDOMIZED CONTROL STUDY DESIGN. PROVIDERS AND STAFF WILL BE TRAINED IN SDM COMMUNICATION AND USE OF THE COACH MCLUNGSSM TOOL. WE WILL MEASURE CHANGES IN EMERGENCY DEPARTMENT VISITS, HOSPITALIZATIONS, AND ORAL STEROID USE, WHICH SERVE AS SURROGATE MEASURES FOR PATIENT-CENTERED ASTHMA OUTCOMES. THE SAC WILL USE AN ITERATIVE PROCESS IMPROVEMENT METHOD AND GIVE BEST PRACTICE RECOMMENDATIONS BACK TO THE PRACTICES FOR IMPLEMENTATION IMPROVEMENT. WE WILL DISSEMINATE FINDINGS THROUGH LOCAL STAKEHOLDERS, PRACTICE-BASED RESEARCH NETWORKS, ASTHMA ADVOCACY NATIONAL ORGANIZATIONS, AND ACADEMIC RESEARCH MEETINGS FOR HEALTHCARE, PRIMARY CARE, AND ASTHMA.

TRIAL OF VITAMIN D SUPPLEMENTATION AND NEUROMUSCULAR FUNCTIOIN IN OLDER ADULTS

RANDOMIZED CONTROLLED TRIAL OF A NOVEL SMOKING CESSATION APPLICATION TAILORED TO INDIVIDUALS WITH SERIOUS MENTAL ILLNESS

A GERMLINE- AND PROMOTER-INDEPENDENT STRATEGY TO GAIN ACCESS TO ALL CELL TYPES IN THE BRAIN - PROJECT SUMMARY THE HETEROGENEITY FROM THE VAST NUMBER OF CELL TYPES IN THE BRAIN PRESENTS A MAJOR CHALLENGE IN OUR UNDERSTANDING OF HOW BRAIN WORKS AND IN OUR TREATMENT OF NEUROLOGICAL DISORDERS. WITH THE AMAZING ADVANCES IN HIGH THROUGHPUT SEQUENCING TECHNOLOGY, OUR KNOWLEDGE ON THE MOLECULAR MAKEUP OF THE MYRIAD CELL TYPES IN THE BRAIN HAS REACHED AN UNPRECEDENTED LEVEL. HOWEVER, TOOLS THAT ALLOW US TO EASILY STUDY THE FUNCTIONS OF ANY CELL TYPES OF OUR CHOICE ARE LAGGING. THE GOAL OF OUR PROPOSED RESEARCH IS TO DEVELOP TECHNOLOGY TO GENERATE SUCH TOOLS. IN ORDER TO TARGET A SPECIFIC CELL TYPE, CURRENT APPROACHES TYPICALLY DEPEND ON GENETICALLY MODIFIED ANIMAL MODELS, WHICH IS LABORIOUS, COSTLY, AND LOW THROUGHPUT, OR WELL-DEFINED AND SMALL CELL-TYPE-SPECIFIC PROMOTERS, WHICH STILL REMAIN TO BE DIFFICULT TO ISOLATE. HERE WE PROPOSE TO DEVELOP AN AAV-BASED CELL-TYPE-SPECIFIC TARGETING (ACTSTAR) SYSTEM TO ENABLE EASY ACCESS TO ANY CELL TYPE IN THE BRAIN IN ANY SPECIES THAT IS INDEPENDENT OF GERMLINE MODIFICATION AND PROMOTER ISOLATION AND CHARACTERIZATION. WE PLAN TO GENERATE A LIBRARY OF ACTSTAR DRIVERS TO TARGET 50 DIFFERENT BRAIN CELL TYPES IN THE MOUSE AND MARMOSET. IN ADDITION, TO REDUCE OFF-TARGET INTEGRATION AND NEUROINFLAMMATION ASSOCIATED WITH LONG-TERM CAS9 EXPRESSION, ESPECIALLY IN LONG-TERM EXPERIMENTS IN PRIMATES, WE WILL DEVELOP A NOVEL AAV-CAPSID MEDIATED CAS9 MRNA DELIVERY SYSTEM FOR TRANSIENT CAS9 EXPRESSION. THIS PROJECT WILL GENERATE THE MUCH-NEEDED TOOLS FOR EASY ACCESS TO ANY BRAIN CELL TYPES IN MULTIPLE SPECIES. OUR RESEARCH GOAL WILL BE FACILITATED BY THE COMPLEMENTARY EXPERTISE OF THE MPI TEAM IN GENOME EDITING AND DEVELOPING SAFE CAS9 DELIVERY METHODS (LU), NEURAL CIRCUIT FUNCTIONS OF THE MOUSE BRAIN (LIN), AND VISUAL FUNCTIONS USING NON-HUMAN PRIMATES (HU).

PROCESSING VISUAL AND MULTISENSORY INFORMATION

SOCIAL STRESS: VULNERABILITY TO COCAINE ABUSE IN MONKEYS

GENETIC DETERMINANTS OF VISCERAL ADIPOSITY

EVALUATING COMMUNITY DRIVEN STRATEGIES TO PREVENT UNDERAGE DRINKING PARTIES

LONGITUDINAL INVESTIGATION OF TMS AS A TOOL TO IMPROVE ALCOHOL TREATMENT OUTCOMES

EFFECT OF FAT LOSS ON FUNCTIONAL AND CARDIOVASCULAR BENEFITS OF AEROBIC EXERCISE

MAPPING GENES FOR NIDDM NEPHROPATHY IN AFRICAN AMERICANS

WAKE FOREST IMPOWR DISSEMINATION EDUCATION AND COORDINATION CENTER (IDEA-CC) - PROJECT SUMMARY PEOPLE WITH CHRONIC PAIN (CP) AND OPIOID USE DISORDER (OUD) EXPERIENCE SILOED CLINICAL PATHWAYS THAT UNDERMINE TREATMENT FOR BOTH CONDITIONS. RECOGNIZING THAT CLINICAL AND RESEARCH SEPARATE CP AND OUD LEAVES PATIENTS AT RISK FOR UNDERTREATED PAIN AND DETRIMENTAL OUD OUTCOMES, NIH NIDA AND THE HEAL INITIATIVE ARE FOCUSED ON DEVELOPING INTEGRATED ASSESSMENT AND TREATMENT PATHWAYS. IN ORDER TO EFFECTIVELY ENCOMPASS THE PRAGMATIC CLINICAL INITIATIVES DEVELOPING THOUGH THE IMPOWR PROGRAM, THIS PROPOSAL ANSWERS THE CALL FOR A CP AND OUD FOCUSED DISSEMINATION AND COORDINATION CENTER. THE IMPOWR DISSEMINATION, EDUCATION, AND COORDINATION CENTER (IDEA-CC) WILL DEVELOP A CP AND OUD FOCUSED INFRASTRUCTURE SUPPORT TO AMPLIFY, AND CREATE MOMENTUM FOR THE FINDINGS OF IMPOWR AND OTHER LINKED RESEARCH NETWORKS. BUILDING ON EXISTING WORK, OUR PROPOSAL WILL DEVELOP THE INFRASTRUCTURE FOR THE IMPOWR NETWORK THROUGH SEVERAL KEY DOMAINS: 1) RAPIDLY DEPLOY A COMMUNICATION FRAMEWORK TO LINK IMPOWR CLINICAL SITES WITH EACH OTHER AND THE LARGER HEAL RESEARCH FRAMEWORK; 2) DEVELOP AN EDUCATIONAL INFRASTRUCTURE ADDRESSING STIGMA AND HEALTH DISPARITIES IN PATIENTS WITH CO-MORBID CP AND OUD; AND 3) EFFECTIVELY DISSEMINATE RESEARCH FINDINGS TO TARGETED AUDIENCES. THE RATIONALE FOR THE PROPOSED RESEARCH IS THAT UNDERSTANDING THE RELATIONSHIP BETWEEN CO-MORBID CP AND OUD IS CRITICAL TO DESIGNING THE MOST EFFECTIVE INTERVENTIONS. THE OBJECTIVE OF THE IDEA-CC IS TO CREATE A RESEARCH COMMUNITY THAT CONNECTS IMPOWR CENTERS TO TRANSLATE FINDINGS AND DEVELOP A KEY CP-OUD RESEARCH AND EDUCATION INFRASTRUCTURE. OUR CENTRAL HYPOTHESIS IS THAT IMPROVING CO-MORBID CP AND OUD TREATMENT WILL INVOLVE INTEGRATED CLINICAL APPROACHES, AND A FUNDAMENTAL SHIFT IN HOW WE EDUCATE HEALTHCARE PROVIDERS AND THE COMMUNITY. WE WILL ACHIEVE THIS THROUGH SEVERAL AIMS. AIM 1: HARMONIZE PROCESSES FOR DATA COLLECTION AND COMMON DATA ELEMENTS OF CP AND OUD MEASURES ACROSS THE IMPOWR RESEARCH CENTER, PROVIDING A COORDINATED PLATFORM FOR GATHERING DATA FROM THESE STUDIES. AIM 2: BIDIRECTIONALLY DISSEMINATE INFORMATION REGARDING NETWORK RESEARCH AND DATA SHARING OPPORTUNITIES TO THE LARGER SCIENTIFIC COMMUNITY AND COMMUNITY PARTNERS IN THE FIELDS OF PAIN, ADDICTION, AND MENTAL HEALTH. AIM 3: SUPPORT IMPOWR NETWORK DEVELOPMENT AND THE VALIDATION OF KEY INSTRUMENTS/MEASURES OF COMPOSITE CP AND OUD MEASURES. AIM 4: DEVELOP AN EDUCATIONAL INFRASTRUCTURE THAT ADDRESSES STIGMA AND HEALTH DISPARITIES FOR CO-MORBID CP AND OUD. THIS WORK IS INNOVATIVE BECAUSE OF THE ABILITY TO DESIGN MEASURES SUPPORTED BY PROMIS EXPERTISE AND MAP VALIDATED DATA TO LARGER RESEARCH FRAMEWORKS. THE WAKE FOREST IDEA-CC WILL CREATE A SHARED RESEARCH PLATFORM TO AMPLIFY AND ACCELERATE INVESTIGATIONS AT THE INTERFACE OF CP AND OUD. THIS RESEARCH WILL SUPPORT NIH NIDA'S GOAL TO ENHANCE THE CLINICAL IMPACT OF EXISTING TREATMENTS AT THE CRITICAL INTERSECTION OF OUD AND CP CONDITIONS, WHILE ACTIVELY WORKING TO DESTIGMATIZE TREATMENT IN A WAY THAT PROMOTES HEALTH EQUITY.

THE MOVEMENT OF INFLUENZA VIRUS IN HUMAN POPULATION

PSYCHOSOCIAL STRESS EFFECTS ON REGENERATIVE MEDICINE THERAPIES FOR LOWER URINARY TRACT DISORDERS IN NONHUMAN PRIMATES

GENETIC AND EPIDEMIOLOGICAL PREDICTORS OF GLUCOSE HOMEOSTASIS MEASURES

A SEPSIS TRANSITION PROGRAM TO REDUCE MORBIDITY AND MORTALITY IN HIGH RISK INDIVIDUALS

ITAKL: IMAGING TELEMETRY AND KINEMATIC MODELING IN YOUTH FOOTBALL

DIETARY EFFECTS ON IMAGING AND FLUID-BASED BIOMARKERS OF THE ADIPOSE-BRAIN AXIS IN ALZHEIMERS DISEASE

ROLE OF MONOAMINE OXIDASE A AND DIET-INDUCED MONOCYTE DYSFUNCTION, MACROPHAGE REPROGRAMMING, AND ATHEROSCLEROSIS - MONOCYTES AND MACROPHAGES ARE ESSENTIAL FOR TISSUE HOMEOSTASIS, BUT IN THE CONTEXT OF METABOLIC DISORDERS THEY BECOME DYSFUNCTIONAL AND PROMOTE CHRONIC INFLAMMATORY DISEASES, INCLUDING ATHEROSCLEROSIS. HOWEVER, THE UNDERLYING MECHANISMS ARE NOT WELL-UNDERSTOOD. WE SHOWED THAT CHRONIC EXPOSURE OF BLOOD MONOCYTES TO NUTRIENT STRESS INDUCED BY A “WESTERN”-STYLE HIGH-CALORIE DIET (HCD) STIMULATES THE FORMATION OF REACTIVE OXYGEN SPECIES (ROS) AND PROMOTES PROTEIN THIOL OXIDATION, RESULTING IN MONOCYTE DYSFUNCTION AND THE REPROGRAMMING OF BLOOD MONOCYTES INTO A PRO-INFLAMMATORY, PRO-ATHEROGENIC PHENOTYPE, HYPER-SENSITIVE TO CHEMOATTRACTANTS. THESE METABOLICALLY “PRIMED” BLOOD MONOCYTES GIVE RISE TO REPROGRAMMED AND DYSFUNCTIONAL MACROPHAGES, SENSITIVE TO OXYSTEROL-INDUCED CELL DEATH, WITH DEFECTIVE AUTOPHAGY AND DYSREGULATED ACTIVATION PROFILES. MONOCYTE PRIMING BY NUTRIENT STRESS IS MEDIATED BY THE H2O2-DEPENDENT S-GLUTATHIONYLATION, INACTIVATION AND DEGRADATION OF MITOGEN-ACTIVATED PROTEIN KINASE PHOSPHATASE 1 (MKP-1), A MASTER REGULATOR OF BOTH MONOCYTE ADHESION AND MIGRATION AND MACROPHAGE FUNCTION AND PLASTICITY. HOWEVER, THE SOURCE OF HCD-INDUCED H2O2 AND “OXIDATIVE STRESS” IN “PRIMED” BLOOD MONOCYTES IS NOT KNOWN. WE HAVE NOW IDENTIFIED MONOAMINE OXIDASE A (MAO A) AND NADPH OXIDASE 4 (NOX4) AS NOVEL SOURCES OF H2O2 INDUCED BY NUTRIENT STRESS IN MONOCYTES AND MACROPHAGES AND AS MEDIATORS OF NUTRIENT STRESS-INDUCED MONOCYTE PRIMING AND DYSFUNCTION. WE HYPOTHESIZE THAT THE INDUCTION OF MAO A IN MONOCYTES IN RESPONSE TO A HCD ACCELERATES ATHEROGENESIS BY PROMOTING H2O2 PRODUCTION AND THE INACTIVATION OF MKP-1, RESULTING IN MONOCYTE PRIMING AND REPROGRAMMING, AND GIVING RISE TO DYSFUNCTIONAL, HYPER-INFLAMMATORY AND PRO-ATHEROGENIC MONOCYTE-DERIVED MACROPHAGES WITH IMPAIRED INFLAMMATION RESOLVING CAPABILITIES. FURTHERMORE, WE PROPOSE THAT BY INACTIVATING THE THIOL TRANSFERASE GLUTAREDOXIN 1 (GRX1) AND DISRUPTING THIOL REDOX HOMEOSTASIS, MAO A-DERIVED H2O2 PROMOTES THE INDUCTION OF NOX4, AMPLIFYING THE OXIDATIVE STRESS RESPONSE TRIGGERED BY HCD. TO TEST THESE HYPOTHESES AND TO ELUCIDATE THE UNDERLYING MECHANISMS, WE PROPOSE THE FOLLOWING SPECIFIC AIMS: SPECIFIC AIM 1: DETERMINE THE MECHANISMS BY WHICH HIGH-CALORIE DIET-TRIGGERED INDUCTION OF MAO A PROMOTES MONOCYTE DYSFUNCTION, DYSREGULATES MACROPHAGE PLASTICITY, AND ACCELERATES ATHEROGENESIS. SPECIFIC AIM 2: DETERMINE THE CONTRIBUTION OF NOX4 TO HIGH-CALORIE DIET-INDUCED MONOCYTE PRIMING, MACROPHAGE DYSFUNCTION, AND ATHEROGENESIS. SPECIFIC AIM 3: DETERMINE THE MOLECULAR MECHANISMS BY WHICH HIGH-CALORIE DIETS TRIGGER MONOCYTE PRIMING AND REPROGRAMMING IN METABOLICALLY HEALTHY HUMAN SUBJECTS AND WHETHER AND TO WHAT EXTENT THESE MECHANISMS DIFFER FROM MICE.

ASSESSING EFFICACY AND IMPLEMENTATION OF AN EHR TOOL TO ASSESS HEART HEALTH AMONG SURVIVORS

MITOCHONDRIAL PROTECTION TO PREVENT NEUROBEHAVIORAL CHANGES AFTER POSTNATAL ANESTHESIA

ADIPOSE MITOCHONDIAL QUALITY CONTROL AND CARDIOVASCULAR FUNCTION IN METABOLICALLY HEALTHY AND UNHEALTHY OBESE MONKEYS

HIGH-GRADE ASTROCYTOMA-SPECIFIC MOLECULAR TARGETING

AGING BIOMARKERS: INTEGRATING OMIC PROFILES WITH MECHANISTIC MEASURES

NEUROIMMUNE PATHWAYS LINKING CHRONIC PSYCHOSOCIAL STRESS TO CO-OCCURRING STIMULANT USE AND DEPRESSION IN HIV DISEASE: A MECHANISTIC CLINICAL TRIAL - PEOPLE WITH HIV (PWH) WHO USE STIMULANTS EXPERIENCE PROFOUND INTERSECTIONAL STIGMA AND DISCRIMINATION THAT CAN CAUSE CONSIDERABLE PSYCHOSOCIAL STRESS. AN OVERACTIVE, UNRESOLVED STRESS RESPONSE FUELS SYSTEMIC INFLAMMATION, WHICH MAY BE A COMMON PATHWAY LINKING PSYCHOSOCIAL STRESSORS TO COMPLEX NEUROPATHOLOGY IN HIV. CHRONIC STRESS CAN DISRUPT CENTRAL NERVOUS SYSTEM FUNCTIONS THAT REGULATE REWARD PROCESSING. OUR TEAM AND OTHERS HAVE SHOWN THAT THESE PATHOPHYSIOLOGIC ALTERATIONS ARE AMPLIFIED BY STIMULANT USE AND POTENTIATE NEUROPSYCHIATRIC SYMPTOMS. HOWEVER, THE INFLAMMATORY MECHANISMS THROUGH WHICH STRESS AFFECTS BRAIN NETWORKS THAT SUBSERVE SUBSTANCE USE AND PSYCHIATRIC MULTI-MORBIDITY IN HIV REMAIN UNKNOWN. THE OVERARCHING GOAL OF THIS PROPOSAL IS TO IDENTIFY NEUROIMMUNE MECHANISMS THAT UNDERLIE THE INTERSECTION OF SOCIAL STIGMA, ANHEDONIA, AND ALTERED REWARD PROCESSING IN PWH WHO USE STIMULANTS (E.G., COCAINE, METHAMPHETAMINE). EMBRACING THE EXPERIMENTAL RIGOR OF A RANDOMIZED CONTROLLED TRIAL (RCT) DESIGN, WE WILL LEVERAGE AN EVIDENCE-BASED POSITIVE AFFECT INTERVENTION (ARTEMIS) AS A MECHANISTIC PROBE TO ELUCIDATE THE NEURAL AND IMMUNOLOGIC SUBSTRATES LINKING PSYCHOSOCIAL STRESS TO SUBSTANCE USE AND DEPRESSION IN PWH. WITH THIS TRANSLATIONAL APPROACH, WE AIM TO: (1) INVESTIGATE THE CAUSAL LINK BETWEEN ARTEMIS-INDUCED IMPROVEMENTS IN ANHEDONIA AND NEURAL FUNCTIONING IN REWARD CIRCUITRY USING RESTING-STATE AND TASK-BASED FUNCTIONAL MRI; (2) EVALUATE THE EFFECTS OF ARTEMIS ON TRANSCRIPTIONAL CONTROL PATHWAYS AND DOWNSTREAM MARKERS OF PERIPHERAL INFLAMMATION; AND (3) TEST WHETHER REDUCTIONS IN PROINFLAMMATORY MARKERS HAVE POSITIVE FEEDBACK ON REWARD FUNCTIONING AND STIMULANT USE. TO ACHIEVE THESE SPECIFIC AIMS, WE WILL ENROLL 189 PWH WHO CURRENTLY USE STIMULANTS AND HAVE SUPPRESSED HIV VIRAL LOAD. PARTICIPANTS WILL BE RANDOMLY ASSIGNED ON A 2:1 RATIO TO RECEIVE ARTEMIS OR A WAIT-LIST CONTROL. TO SUPPORT DURABLE HIV VIRAL SUPPRESSION THROUGHOUT THE TRIAL, ALL PARTICIPANTS WILL RECEIVE SMARTPHONE-BASED CONTINGENCY MANAGEMENT FOR ART ADHERENCE. ASSESSMENTS AT 3- AND 6-MONTH FOLLOW-UPS WILL CHARACTERIZE CHANGES IN NEURAL FUNCTIONING AND LEUKOCYTE SIGNALING AS PLAUSIBLE MEDIATORS OF ARTEMIS EFFECTS ON BEHAVIORAL OUTCOMES. OUR INNOVATIVE AND CLINICALLY IMPORTANT PROPOSAL IS HIGHLY RESPONSIVE TO RFA-DA-24-005 AND WILL ADVANCE OUR BASIC UNDERSTANDING OF THE NEUROIMMUNE PATHWAYS UNDERLYING PSYCHOLOGICAL RESILIENCE TO SOCIAL STRESS THAT MAY MITIGATE SUBSTANCE USE AND DEPRESSION IN PWH. THIS PROPOSAL PROVIDES A SCIENTIFICALLY RIGOROUS MODEL FOR EXAMINING THE CAUSAL ASSOCIATIONS AMONGST THESE PREVALENT COMORBIDITIES IN A POPULATION THAT IS CRITICAL TO ENDING THE HIV EPIDEMIC, WHILE ALSO PROVIDING PARTICIPANTS WITH THE BENEFIT OF AN EVIDENCE-BASED INTERVENTION WITH A TRANSDIAGNOSTIC TARGET. THE RESULTS OF THIS MECHANISTIC TRIAL WILL IDENTIFY PRECLINICAL TARGETS FOR NOVEL PHARMACOTHERAPIES LINKED TO REWARD CIRCUITRY.

UNDERSTANDING AND PREDICTING FATIGUE, CV DECLINE & EVENTS AFTER BREAST CA TREATMENT

EFFECT OF CALORIC RESTRICTION ON AGING BIOMARKERS, FRAILTY, AND MULTIMORBIDITY IN OLDER ADULTS - PROJECT SUMMARY/ABSTRACT OBESITY IS ASSOCIATED WITH POOR QUALITY OF LIFE AND REDUCED LIFESPAN AND HEALTHSPAN – THE PERIOD OF TIME FREE OF MULTIPLE CHRONIC DISEASES AND DISABILITY. GIVEN THAT OVER ONE-THIRD OF OLDER ADULTS ARE OBESE, IDENTIFYING EFFECTIVE THERAPIES THAT PREVENT OBESITY-RELATED DECLINES IN HEALTHSPAN AND LIFESPAN IN OLDER ADULTS ARE URGENTLY NEEDED. CLINICAL TRIALS BY OUR GROUP AND OTHERS SHOW THAT CALORIC RESTRICTION IMPROVES PHYSICAL AND METABOLIC FUNCTION OVER THE SHORT-TERM IN OLDER ADULTS WITH OBESITY. HOWEVER, THE LONG-TERM BENEFITS OF CALORIC RESTRICTION IN THIS POPULATION REMAIN CONTROVERSIAL AND WEIGHT LOSS IS OFTEN NOT RECOMMENDED BECAUSE OF UNCERTAINTY OF WHETHER THE BENEFITS OUTWEIGH THE RISKS (E.G., LOSS OF MUSCLE MASS AND BONE). THE FIELD OF GEROSCIENCE AIMS TO ADDRESS BIOLOGICAL AGING BY TARGETING THE FUNDAMENTAL BIOLOGY SHARED BY THE AGING PROCESS TO PREVENT OR DELAY COMMON AGE-RELATED CHRONIC DISEASES IN HOPES OF EXTENDING HEALTHSPAN AND LIFESPAN. CALORIC RESTRICTION IS ONE SUCH INTERVENTION KNOWN TO ALTER AGING BIOLOGY TO EXTEND HEALTHSPAN AND LIFESPAN IN MULTIPLE SPECIES, INCLUDING NON-HUMAN PRIMATES; HOWEVER, THE EFFECTS OF CALORIC RESTRICTION IN EXTENDING HEALTHSPAN AND LIFESPAN IN HUMANS REMAINS UNKNOWN. THE OVERALL GOALS OF THE PROPOSED STUDY ARE TO DETERMINE IF SHORT-TERM CALORIC RESTRICTION IN OLDER ADULTS WITH OBESITY AFFECTS BIOMARKERS OF BIOLOGICAL AGING AND WHETHER THESE BIOMARKERS OF BIOLOGICAL AGING ARE CORRELATED WITH HEALTHSPAN. WE WILL DETERMINE THE EFFECTS OF RANDOMIZATION TO CALORIC RESTRICTION ON A CONSENSUS DERIVED BLOOD-BASED BIOMARKER INDEX (IL-6, TNFΑR1, GDF-15, CYSTATIN C, CRP, AND INSULIN; PRIMARY AIM) AND MULTIMORBIDITY AND DEFICIT ACCUMULATION FRAILTY INDICES (SECONDARY AIM) AN AVERAGE OF 10 YEARS AFTER THE COMPLETION OF A CALORIC RESTRICTION INTERVENTION. OUR PRIMARY HYPOTHESIS IS THAT RANDOMIZATION TO CALORIC RESTRICTION WILL RESULT IN IMPROVED BIOMARKERS OF BIOLOGICAL AGING COMPARED TO A CONTROL CONDITION IN OLDER ADULTS WITH OBESITY AND THIS IMPROVEMENT WILL BE REFLECTED IN BETTER HEALTHSPAN. WE WILL LEVERAGE BIOSPECIMENS AND DATA FROM 5 NIH-SUPPORTED RANDOMIZED CONTROLLED TRIALS CONDUCTED UNDER THE AUSPICES OF THE WAKE FOREST PEPPER CENTER THAT ENROLLED OLDER ADULTS (MEAN AGE AT RANDOMIZATION, 67.3 YEARS) WITH OVERWEIGHT OR OBESITY (BMI≥27 KG/M2) AND RANDOMIZED THEM TO CALORIC RESTRICTION (N=520) OR NO CALORIC RESTRICTION (N=446) FROM 2005 TO 2014 TO CONDUCT AN INDIVIDUAL PARTICIPANT-LEVEL META-ANALYSIS WITH SUFFICIENT SAMPLE SIZE TO DEFINITIVELY EVALUATE THE EFFECT OF CALORIC RESTRICTION ON BIOLOGICAL AGING. WE WILL ALSO EXPLORE THE EFFECTS OF RANDOMIZATION TO CALORIC RESTRICTION ON CELLULAR SENESCENCE AND PROTEOMIC BIOMARKERS AND THE UNDERLYING MOLECULAR MECHANISMS OF CALORIC RESTRICTION, AS WELL AS THE ASSOCIATIONS BETWEEN CELLULAR SENESCENCE AND PROTEOMIC BIOMARKERS ON MULTIMORBIDITY AND A DEFICIT ACCUMULATION FRAILTY INDEX. THE PROPOSED STUDY BUILDS ON THE WAKE FOREST’S PEPPER CENTER’S COLLABORATIVE RESEARCH FOCUS IN GERIATRIC OBESITY TREATMENT TO ANSWER COMPELLING AND CLINICALLY IMPORTANT QUESTIONS REGARDING THE EFFICACY OF CALORIC RESTRICTION TO SLOW BIOLOGICAL AGING AND INCREASE HEALTHSPAN IN OLDER ADULTS WITH OBESITY IN AN EFFICIENT AND COST-EFFECTIVE MANNER.

ITAKL:IMAGING TELEMETRY AND KINEMATIC MODELING IN YOUTH FOOTBALL-HIGH SCHOOL

TRAINING PROGRAM IN IMMUNOLOGY AND PATHOGENESIS

ROLE OF CANNABIS ON HIV-RELATED COGNITIVE IMPAIRMENT: A BRAIN CONNECTOMICS STUDY

EPIGENETICS OF WEIGHT LOSS AND GLYCEMIC IMPROVEMENT

SINGLE SKELETAL MUSCLE FIBER IMPAIRMENT WITH AGING

THE PREVENTABLE PHYSICAL PERFORMANCE ANCILLARY STUDY - PROJECT SUMMARY/ABSTRACT AGING IS ASSOCIATED WITH SIGNIFICANT DECLINES IN MUSCLE MASS, STRENGTH, AND PHYSICAL PERFORMANCE, WHICH OFTEN LEAD TO DISABILITY, LOSS OF INDEPENDENCE, AND ADVERSE CLINICAL OUTCOMES INCLUDING MULTIMORBIDITY AND MORTALITY. AT PRESENT, HEALTH CARE PROVIDERS HAVE NO THERAPEUTIC OPTIONS TO OFFER THEIR PATIENTS TO SLOW AGING-RELATED DECLINES IN PHYSICAL FUNCTION. IMPORTANTLY, EVIDENCE IS EMERGING THAT STATINS COULD BE AN EFFECTIVE TREATMENT FOR PRESERVING PHYSICAL FUNCTION BY PREVENTING DISABLING EVENTS SUCH AS STROKE, HEART FAILURE, OR MYOCARDIAL INFARCTION. IN ADDITION, STATINS HAVE PLEIOTROPIC PROPERTIES INCLUDING ANTI-INFLAMMATORY, ANTI-OXIDANT, AND IMMUNO- MODULATORY EFFECTS, WHICH MAY SLOW OR PREVENT AGING-RELATED DECLINES IN PHYSICAL FUNCTION. HOWEVER, REPORTS OF MUSCLE PAIN AND WEAKNESS IN PATIENTS ON STATINS HAS LED TO A SIGNIFICANT NUMBER OF PATIENTS DISCONTINUING STATINS. THUS, THE PROPOSED STUDY IS CRITICAL TO ESTABLISH WHETHER STATINS MAY HELP TO PRESERVE PHYSICAL FUNCTION AND INDEPENDENCE IN OLDER ADULTS, OR WHETHER STATIN-ASSOCIATED MUSCLE SYMPTOMS PORTEND A STATIN-RELATED DECLINE IN PHYSICAL FUNCTION. THE PREVENTABLE TRIAL (U19 AG065188) PROVIDES AN IDEAL OPPORTUNITY TO DEFINITIVELY DETERMINE THE EFFECT OF STATINS AS A TREATMENT FOR AGING-RELATED DECLINES IN PHYSICAL FUNCTION. PREVENTABLE IS A PLACEBO-CONTROLLED PRAGMATIC CLINICAL TRIAL DESIGNED TO INVESTIGATE WHETHER RANDOMIZATION TO A STATIN CAN PREVENT DEMENTIA AND PROLONG DISABILITY-FREE SURVIVAL IN 20,000 PARTICIPANTS AGED 75+ YEARS WITHOUT CLINICALLY EVIDENT CORONARY HEART DISEASE. WHILE THE PREVENTABLE TRIAL WILL HELP CLARIFY THE EFFECTS OF STATINS ON SELF-REPORTED DISABILITY, THE PROPOSED ANCILLARY STUDY WILL EXTEND AND VALIDATE THE PHYSICAL DISABILITY DATA BY INVESTIGATING THE EFFECTS OF STATINS ON CHANGES IN PHYSICAL PERFORMANCE, WHICH ARE TYPICALLY OBSERVED EARLIER IN THE TRAJECTORY OF FUNCTIONAL DECLINE AND MAY BE A MORE SENSITIVE MARKER FOR THE EFFECTS OF STATIN. TO DETERMINE IF STATINS AFFECT LONGITUDINAL CHANGE IN PHYSICAL PERFORMANCE, THE PROPOSED ANCILLARY WILL ADD THE SHORT PHYSICAL PERFORMANCE BATTERY (SPPB), A VALIDATED MEASURE OF LOWER-EXTREMITY PERFORMANCE COMPRISED OF BALANCE TASKS, A 4-M WALK, AND REPEATED CHAIR STAND TEST, OVER 3 YEARS OF FOLLOW-UP IN 2,500 PREVENTABLE PARTICIPANTS (1,250 PER INTERVENTION ARM). SELF-REPORTED INFORMATION ON PATIENT-CENTERED OUTCOMES RELEVANT TO PHYSICAL FUNCTION INCLUDING STATIN-ASSOCIATED MUSCLE SYMPTOMS, FATIGUE, AND PAIN WILL ALSO BE COLLECTED. THE SPECIFIC AIMS OF THIS ANCILLARY STUDY ARE TO: 1) DETERMINE WHETHER RANDOMIZATION TO STATIN SLOWS THE AGING- RELATED DECLINE IN USUAL GAIT SPEED; 2) DETERMINE WHETHER RANDOMIZATION TO STATIN SLOWS AGING-RELATED DECLINES IN LOWER-EXTREMITY FUNCTION (SPPB SCORE) AND STRENGTH (CHAIR RISE TIME); AND 3) EXPLORE WHETHER RANDOMIZATION TO STATIN IS ASSOCIATED WITH SELF-REPORTED STATIN-ASSOCIATED MUSCLE SYMPTOMS, FATIGUE, AND PAIN. BY LEVERAGING THE RICH RESOURCES AND INFRASTRUCTURE OF PREVENTABLE, THIS TIMELY AND COST-EFFECTIVE STUDY PROVIDES A UNIQUE OPPORTUNITY TO SIGNIFICANTLY EXPAND THE SCOPE AND IMPACT OF THE PARENT TRIAL ON SELF-REPORTED PHYSICAL DISABILITY BY DETERMINING THE THERAPEUTIC POTENTIAL OF STATINS TO SLOW AGING-RELATED DECLINES IN PHYSICAL PERFORMANCE.

GENETIC EPIDEMIOLOGY OF CEREBROVASCULAR DISEASE AND COGNITION IN DIABETES

HIRED LATINO YOUTH FARMWORKERS: WORK ORGANIZATION, SAFETY, HAZARDS, AND HEALTH

TRAINING PROGRAM IN CANCER BIOLOGY

MECHANISM OF FISH OIL SUPPLEMENTS IN PREVENTION OF CANCER

COMPUTED TOMOGRAPHY MUSCLE SIZE AND COMPOSITION ASSOCIATIONS WITH HIP AND SPINE BONE STRENGTH OVER 4 YEARS: SOMMA-CT - PROJECT SUMMARY OSTEOPOROTIC FRACTURES ARE ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY, AND THEIR U.S. ECONOMIC BURDEN IS PROJECTED TO REACH $20 BILLION BY 2025. AGING ACCELERATES THE DECLINE OF BOTH MUSCLE AND BONE, INCREASING FRACTURE RISK. UNDERSTANDING HOW MUSCLE AND BONE INTERACT ANATOMICALLY, MECHANICALLY, AND BIOCHEMICALLY TO REDUCE BONE STRENGTH COULD PROFOUNDLY ADVANCE FRACTURE PREVENTION BY IDENTIFYING NEW FRACTURE RISK SCREENING AND INTERVENTION TARGETS TO DIAGNOSE AND TREAT AGE-RELATED MUSCULOSKELETAL DECLINE. COMPUTED TOMOGRAPHY (CT) SCANS HOLD GREAT PROMISE FOR ASSESSING REGIONAL MUSCLE AND BONE PHENOTYPES TO IDENTIFY OLDER ADULTS AT HIGH RISK OF FRACTURE. SPECIFICALLY, BONE STRENGTH – A CT AND FINITE ELEMENT MODELING ASSESSMENT OF 3D BONE MORPHOLOGY, BONE MINERAL DENSITY (BMD), AND CORTICAL THICKNESS – IS A STRONGER PREDICTOR OF FRACTURE RISK THAN BMD ALONE. BUILDING ON THE STUDY OF MUSCLE, MOBILITY & AGING (SOMMA), THE PROPOSED SOMMA-CT ANCILLARY STUDY IS UNIQUELY POSITIONED TO EXPLORE HOW THIGH AND TRUNK MUSCLE PROPERTIES FROM CT (VIA AUTOMATED AND RADIOMIC ANALYSIS), D3CR MUSCLE MASS (D3-CREATINE DILUTION), MUSCLE PERFORMANCE, AS WELL AS CIRCULATING MUSCLE- BONE CROSSTALK BIOMARKERS, RELATE TO CHANGES IN BONE STRENGTH AT THE HIP AND SPINE (2 CLINICALLY-RELEVANT FRACTURE SITES). SOMMA IS A PROSPECTIVE STUDY EXAMINING AGING-RELATED MUSCLE BIOLOGY CONTRIBUTIONS TO MOBILITY DISABILITY (R01 AG059416). THIS ANCILLARY STUDY IN 360 SOMMA OLDER MEN AND WOMEN (AGES 70-94) WILL EMPLOY AN EFFICIENT AND COST-EFFECTIVE LONGITUDINAL DESIGN THAT ADDS: 1) A 4TH-YEAR FOLLOW-UP CT SCAN AND BLOOD DRAW, AND 2) ADVANCED PROCESSING OF BASELINE AND 4-YEAR CT SCANS AND BLOOD SAMPLES TO EXTRACT NEW LONGITUDINAL MUSCLE AND BONE PHENOTYPES. SPECIFIC AIMS ARE TO: 1) DETERMINE IF MUSCLE QUANTITY AND COMPOSITION (CT- DERIVED THIGH AND TRUNK MUSCLE AREA, MUSCLE DENSITY, INTERMUSCULAR FAT, AND RADIOMIC TEXTURE FEATURES OF MUSCLE HETEROGENEITY; D3CR MUSCLE MASS) ARE ASSOCIATED WITH CHANGES IN HIP AND SPINE BONE STRENGTH OVER 4 YEARS OF AGING. 2) DETERMINE IF MUSCLE PERFORMANCE (LEG EXTENSOR SPECIFIC POWER; 4-M GAIT SPEED; TIME TO COMPLETE 5 CHAIR STANDS) IS ASSOCIATED WITH CHANGE IN HIP AND SPINE BONE STRENGTH OVER 4 YEARS OF AGING. WE WILL ALSO EXPLORE HOW BIOMARKERS OF MUSCLE-BONE CROSSTALK (MYOKINES: AMINOBUTYRIC ACIDS; OSTEOKINES: CTX-1, P1NP) RELATE TO BONE STRENGTH BOTH CROSS-SECTIONALLY AND LONGITUDINALLY, AND TEST IF THESE BIOMARKERS MEDIATE THE MUSCLE-BONE ASSOCIATIONS IN AIMS 1-2. THE SCIENTIFIC PREMISE IS THAT THIGH AND TRUNK MUSCLE DEGENERATION WILL BE ASSOCIATED WITH DECLINING HIP AND SPINE BONE STRENGTH, AND THAT CIRCULATING BIOMARKERS WILL OFFER MECHANISTIC INSIGHTS ON MUSCLE-BONE CROSSTALK CONTRIBUTORS TO BONE STRENGTH. THIS INVESTIGATION IN AN AGING COHORT WILL INCREASE OUR KNOWLEDGE OF THE DYNAMIC INTERRELATIONSHIPS AND CROSSTALK BETWEEN MUSCLE AND BONE. NEW DISCOVERIES IN THIS AREA COULD IMPACT OVER 158 MILLION OLDER ADULTS WORLDWIDE WHO ARE AT HIGH RISK OF OSTEOPOROTIC FRACTURE. THIS WORK HAS STRONG POTENTIAL TO SHIFT CLINICAL PRACTICE PARADIGMS BY IMPROVING PREDICTIVE POWER IN FRACTURE RISK SCREENING AND IDENTIFYING NEW PHENOTYPES IN MUSCLE AND/OR BONE WHICH COULD BE TARGETED TO PREVENT FRACTURE.

LONG-TERM EFFECTS OF WEIGHT LOSS AND SUPPLEMENTAL PROTEIN ON PHYSICAL FUNCTION

EPIGENETIC ROLES IN REGULATION OF CHOLESTEROL METABOLISM AND CVD RISK

USING RURAL COMMUNITY PARAMEDICINE TO ENGAGE LOWER-MOTIVATED SMOKERS: SPREADING AN EFFECTIVE MHEALTH-ASSISTED INTERVENTION TO MOTIVATE CESSATION - 7. PROJECT SUMMARY/ABSTRACT WE WILL CONDUCT A MULTI-LEVEL “HYBRID TYPE 2” STUDY (I.E.: IMPLEMENTATION AND EFFECTIVENESS OUTCOMES) TO TEST 1) A NOVEL IMPLEMENTATION PROGRAM IN RURAL COUNTIES AND 2) A MHEALTH (MOBILE HEALTH)-ASSISTED BRIEF ABSTINENCE EXPERIENCE (TAKE A BREAK, TAB) FOR RURAL ADULTS WHO SMOKE AND ARE NOT-YET-READY TO QUIT. IN OUR NETWORK OF RURAL COUNTIES, THE IMPLEMENTATION TRIAL WILL USE A NOVEL, MULTI-STRATEGY IMPLEMENTATION PROGRAM CENTERED ON COUNTY EMPLOYEES ENGAGED IN ‘COMMUNITY PARAMEDICINE.’ EMERGENCY MEDICAL SERVICES PERSONNEL (EMS) ARE EVOLVING INTO THIS MORE EXPANSIVE ROLE (E.G.: NON-EMERGENT HEALTHCARE DELIVERY, MONITORING OF CHRONIC DISEASE, AND PREVENTIVE MEDICINE). TO TEST THE IMPLEMENTATION, WE WILL RANDOMIZE RURAL COUNTIES WITH EMS SERVING GEOGRAPHICALLY COMPLEX AND ETHNICALLY VARIED AREAS (THE MOUNTAINOUS REGION OF APPALACHIA AND PLAINS OF EASTERN NORTH CAROLINA). THESE COUNTIES HAVE SOME OF THE HIGHEST SMOKING RATES IN THE U.S. WE WILL COMPARE A WELL- TESTED (STANDARD) IMPLEMENTATION PROGRAM VERSUS A NOVEL ENHANCED PROGRAM. THE STANDARD PROGRAM USES EVIDENCE-BASED EXTERNAL FACILITATION – PROVIDING TRAINING AND TECHNICAL SUPPORT TO EMS SERVICES TO SUPPORT THE INTEGRATION OF ENHANCED TOBACCO CONTROL PRACTICES (INCLUDING RECOMMENDING AND REFERRING PEOPLE WHO SMOKE AND NOT-YET-READY-TO-QUIT TO THE MHEALTH-ASSISTED POPULATION HEALTH INTERVENTION. THE NOVEL ENHANCED IMPLEMENTATION PROGRAM WILL INCLUDE THE STANDARD PROGRAM AN EMS CHAMPION PROGRAM. EMS WHO CURRENTLY SMOKE WILL BE OFFERED PARTICIPATION IN TAB THEMSELVES. THOSE WHO PARTICIPATE, CHAMPIONS, WILL THEN USE THEIR TAB EXPERIENCE TO SUPPORT IMPLEMENTATION AS INTERNAL FACILITATORS. THEY WILL ENCOURAGE OTHER EMS TO EXPERIENCE TAB, LONGITUDINALLY ENCOURAGE USE OF THE TOBACCO CONTROL PRACTICES IN ROUTINE WORKFLOW FOR ALL EMS, AND WILL BE ABLE TO USE THEIR PERSONAL EXPERIENCE WITH TAB TO ENGAGE IN A RICHER DIALOG WITH PATIENTS WHO SMOKE. USING THESE STRATEGIES, WE SEEK TO ENGAGE INDIVIDUALS LIVING IN HARDER-TO-REACH RURAL AREAS WITH LESS ACCESS TO CLINICAL SERVICES. ENGAGING THESE INDIVIDUALS IS POSSIBLE WITH BRIEF, LOW INTENSITY, PALATABLE INTERVENTIONS THAT TARGET SELF-EFFICACY AND FACILITATE SKILLS BUILDING TO SUPPORT FUTURE ABSTINENCE. THE TAB INTERVENTION ADDRESSES THE CHALLENGE OF ENGAGING LOWER MOTIVATED INDIVIDUALS USING A NOVEL FORMAT, A BRIEF ABSTINENCE GAME, SUPPORTED USING MHEALTH AND BUILDING UPON 10 YEARS OF RESEARCH. WE RECENTLY PUBLISHED THE FIRST TAB EFFECTIVENESS TRIAL IN JAMA INTERNAL MEDICINE. THIS PRELIMINARY DATA SUPPORTS THE CURRENT APPLICATION AND DOES NOT INCLUDE A LARGE NUMBER OF INDIVIDUALS LIVING IN RURAL AREAS. IN THIS PROJECT, WE WILL RANDOMIZE TO TAB VERSUS AN ACTIVE COMPARISON DESIGNED TO ISOLATE THE EFFECT OF TAB AND BALANCE THE PARTICIPANT CONTACT ACROSS THE TWO GROUPS. IN ADDITION TO EVALUATING IMPLEMENTATION SUCCESS AND EFFECTIVENESS OUTCOMES, WE WILL STUDY PATHWAYS TO CESSATION. TO INFORM SUSTAINMENT AND DISSEMINATION, WE WILL COLLECT DATA ON IMPLEMENTATION FIDELITY, COUNTY-LEVEL ADAPTATIONS, VARIATIONS IN REFERRALS, AND PATIENT-LEVEL ENGAGEMENT ACROSS THE COUNTIES, AND AT THE EMS AND PATIENT-LEVEL. TO EVALUATE BUDGET IMPACT, WE WILL TRACK THE COST OF THE IMPLEMENTATION STRATEGIES AND THE INTERVENTION.

WAR OF ATTRITION: PREDICTING DROPOUT FROM PEDIATRIC WEIGHT MANAGEMENT

GENETIC DETERMINANTS OF ADIPOSITY IN AFRICAN AMERICANS

DEVELOPMENT OF VACCINE APPROACHES TO ELICIT BROADLY PROTECTIVE INFLUENZA-SPECIFIC IMMUNE RESPONSES IN INFANTS

FUNGAL TRANSLOCATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE - PROJECT SUMMARY ALTHOUGH SMOKING IS A LEADING RISK FACTOR FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), OTHER FACTORS LIKELY CONTRIBUTE TO DISEASE PATHOGENESIS SINCE ONLY A SUBSET OF SMOKERS DEVELOP COPD. TISSUE HYPOXIA RELATED TO ACUTE EXACERBATIONS OR PHYSICAL ACTIVITY IMPAIRS GUT EPITHELIAL BARRIER FUNCTION IN COPD AND MAY RESULT IN MICROBIAL TRANSLOCATION, OR MOVEMENT OF MICROBES OR MICROBIAL PRODUCTS ACROSS THE INTESTINAL MUCOSA. ONCE IN CIRCULATION, THESE MICROBIAL PRODUCTS MAY CAUSE IMMUNE CELL ACTIVATION OR DIRECT LUNG INJURY, AUGMENTING INFLAMMATION AND LUNG FUNCTION DECLINE IN PATIENTS WITH COPD. ALTHOUGH STUDIES OF MICROBIAL TRANSLOCATION HAVE LARGELY FOCUSED ON THE TRANSLOCATION OF BACTERIA, WE HAVE PRELIMINARY DATA SUGGESTING THAT FUNGAL TRANSLOCATION OCCURS IN SMOKERS AND MAY CONTRIBUTE TO COPD PATHOGENESIS. WE SHOW THAT 1,3 BETA-D-GLUCAN (BDG), A PATTERN ASSOCIATED MOLECULAR PATTERN THAT IS A MAJOR POLYSACCHARIDE COMPONENT OF THE FUNGAL CELL WALL, IS ELEVATED IN COPD PATIENTS IN THE ABSENCE OF INVASIVE FUNGAL INFECTION AND CORRELATES WITH LUNG FUNCTION, SYMPTOMS, AND EXACERBATIONS. IN VITRO, BDG INCREASES LUNG EPITHELIAL CELL EXPRESSION OF INFLAMMATORY CYTOKINES INVOLVED IN THE PATHOGENESIS OF COPD. WITH THIS PROJECT, WE WILL TEST THE OVERARCHING HYPOTHESIS THAT IMPAIRED GUT EPITHELIAL BARRIER INTEGRITY IN COPD PATIENTS LEADS TO FUNGAL MICROBIAL TRANSLOCATION THAT CONTRIBUTES TO LUNG FUNCTION DECLINE AND WORSE RESPIRATORY MORBIDITY THROUGH HEIGHTENED IMMUNE CELL ACTIVATION AND DIRECT LUNG PATHOGENIC EFFECTS. AIM 1 WILL ASSESS THE RELATIONSHIP BETWEEN GUT EPITHELIAL BARRIER INTEGRITY MEASURED BY THE LACTULOSE/MANNITOL DIFFERENTIAL SUGAR ABSORPTION TEST, LUNG FUNCTION, RESPIRATORY MORBIDITY (SYMPTOMS, EXACERBATIONS), AND CIRCULATING BDG LEVELS IN A COHORT OF CURRENT AND FORMER SMOKERS WITH COPD. AIM 2 WILL DETERMINE THE ASSOCIATION BETWEEN CIRCULATING BDG LEVELS, IMMUNE CELL ACTIVATION, PROSPECTIVE EXACERBATIONS, AND TWO-YEAR CHANGE IN LUNG FUNCTION, SYMPTOMS, AND CT INDICES OF EMPHYSEMA AND AIRWAYS IN COPD. AIM 3 WILL DETERMINE WHETHER BDG INCREASES CYTOKINE EXPRESSION AND SECRETED PROTEIN LEVELS BY BINDING TO THE LUNG EPITHELIAL CELL PATTERN RECOGNITION RECEPTORS DECTIN- 1 AND EPHA2 IN HUMAN BRONCHIAL EPITHELIAL CELLS IN VITRO, AND IF THIS EFFECT IS POTENTIATED BY CO-EXPOSURE TO CIGARETTE SMOKE. AIM 3 WILL ALSO INVESTIGATE IF BDG EFFECTS ON CYTOKINE EXPRESSION AND SECRETED PROTEIN LEVELS ARE ATTENUATED BY TREATMENT WITH METFORMIN. AT THE COMPLETION OF THIS PROJECT, WE WILL HAVE GAINED CRITICAL INSIGHT INTO THE ROLE OF MICROBIAL TRANSLOCATION IN COPD PATHOGENESIS AND WILL HAVE BUILT THE FOUNDATION FOR FUTURE CLINICAL TRIALS TARGETING THE GUT-LUNG AXIS BY EITHER IMPROVING GUT EPITHELIAL BARRIER FUNCTION, BLOCKING BDG’S ACTIONS, OR MODULATING BDG’S DOWNSTREAM EFFECTS AS A NOVEL APPROACH TO THERAPY IN COPD.

CHROMATIN MOBILITY IN RESPONSE TO DNA DAMAGE

BYTES TO BEDSIDE: COLLABORATIVE DEVELOPMENT FOR TRANSLATIONAL CLINICAL DECISION SUPPORT - PROJECT SUMMARY CLINICAL DECISION SUPPORT (CDS) SYSTEMS WERE DEVELOPED TO IMPROVE THE QUALITY AND SAFETY OF MEDICAL PRACTICE. AT PRESENT, HOWEVER, THESE SYSTEMS ARE GENERALLY NOT TIED TO CLINICAL OUTCOMES, DECREASING THEIR EFFECTIVENESS. ADDITIONALLY, CDS IS OFTEN BUILT ONE INSTITUTION AT A TIME, SO EFFECTIVE CDS DOES NOT SCALE AND ACHIEVE ITS POTENTIAL. OUR PROPOSED STUDY AIMS TO EXPAND EXISTING CDS METRICS AND DATA SHARING INFRASTRUCTURE ACROSS SIX CTSA HUBS. IN DOING SO, THIS STUDY SEEKS TO FULLY REALIZE THE EFFECTIVENESS OF CDS SYSTEMS THROUGH THE LEVERAGING OF ELECTRONIC HEALTH RECORD (EHR) DATA AND ULTIMATELY REDUCING THE BARRIERS TO HIGHLY EFFICIENT DATA INTEROPERABILITY. OUR HYPOTHESIS IS THAT THE DEVELOPMENT OF TRANSLATIONAL METRICS AND DATA SHARING INFRASTRUCTURE ACROSS MULTIPLE INSTITUTIONS WILL ADDRESS BOTH TRANSLATIONAL SCIENCE AND RESEARCH BARRIERS, INCREASING THE EFFICIENCY AND EFFECTIVENESS OF CDS, AND IMPROVING CLINICAL OUTCOMES. THROUGH THIS STUDY, WE WILL CREATE A CENTRALIZED AND HIGHLY EFFICIENT DATA-SHARING INFRASTRUCTURE TO SUPPORT TRANSLATIONAL CLINICAL DECISION SUPPORT ANALYSIS AND BENCHMARKING OF PERFORMANCE ACROSS SITES. WE WILL GROUND OUR WORK IN THE EPIS FRAMEWORK, WHICH CONSISTS OF EXPLORATORY, PREPARATION, IMPLEMENTATION, AND SUSTAINMENT PHASES. THE EPIS CONCEPTUAL FRAMEWORK IS WELL-KNOWN, RELIABLE, EFFICIENT, AND SCIENTIFICALLY VALID FOR OUR APPROACH. WE WILL GROUND THE WORK FROM ALL FIVE AIMS (ACROSS BOTH THE UG3 AND UH3 PHASES) IN THIS FRAMEWORK, TESTING OUR APPROACH FOR GAINS IN EFFICIENCY, COLLABORATIVE PERFORMANCE, AND TRANSLATIONAL OUTCOMES. IN THE UG3 PHASE (AIMS 1-3) WE WILL CREATE THE PROCESSES AND GOVERNANCE FOR THE TRANSLATIONAL CDS COLLABORATIVE, BUILD THE ANALYTICAL INFRASTRUCTURE AND TEST ITS PERFORMANCE, AND ESTABLISH FEASIBILITY OF THE COLLABORATIVE BEYOND THE INITIAL STUDY SITES. AFTER REACHING OUR MILESTONE GOALS, WE WILL PROGRESS INTO THE UH3 PHASE (AIMS 4-5), WHICH WILL EVALUATE THE IMPACT OF THE COLLABORATIVE ON CLINICAL OUTCOMES AND EXPAND THE CAPABILITIES AND IMPACT OF THE INFRASTRUCTURE. THE PROPOSED WORK WILL SET THE FOUNDATION FOR EFFICIENTLY AND EFFECTIVELY CREATING, DISSEMINATING, IMPLEMENTING, AND EVALUATING ELECTRONIC CDS. WE WILL CREATE A CENTRALIZED COLLABORATIVE LEARNING PLATFORM AND SHAREABLE RESOURCES FOR CTSI SITES, ACTING AS AN INNOVATION NIDUS FOR THE ENTIRE INFORMATICS AND CLINICAL RESEARCH COMMUNITY, ENABLING DATA-DRIVEN CDS DESIGN RECOMMENDATIONS AND FRAMEWORKS. THIS CTSA-SPONSORED PROJECT WILL AGGREGATE THE EXPERTISE, TALENT, AND RESOURCES WE HAVE AT OUR INDIVIDUAL SITES INTO A COLLECTIVE PROGRAM THAT IS DESIGNED TO REFRAME CDS AS A TRANSLATIONAL CATALYST AND ENABLER. THE MULTI-SITE FOUNDATION WE PROPOSE WILL SERVE AS THE STARTING POINT FOR THE DEVELOPMENT OF NEXT-GENERATION ANALYSIS OF CDS DATA, THE EFFECTIVE DESIGN OF IMPACTFUL CDS-BASED INTERVENTIONS, AND INNOVATIVE APPROACHES TO SOLVING SOME OF THE LARGEST CHALLENGES IN MODERN INFORMATICS AND CLINICAL PRACTICE.

ROLE OF CENTRAL AUTONOMIC RELAYS IN AGING SARCOPENIA - SUMMARY: SNS FAILURE IS COMMON IN OLD AGE AND NEURODEGENERATIVE DISEASES THAT IMPAIR ADAPTATION TO COMMON PHYSIOLOGICAL STRESSORS. WE AND OTHERS FOUND THAT SYMPATHETIC AXONS INNERVATE SKELETAL MUSCLE FIBERS AND MAINTAIN THE INTEGRITY OF SKELETAL MUSCLE COMPOSITION AND FUNCTION AT THE PRESYNAPTIC AND POSTSYNAPTIC NEUROMUSCULAR JUNCTION (NMJ) IN HEALTH AND DISEASE. WE ALSO DEMONSTRATED THAT (A) SNS IMPAIRMENT LEADS TO SKELETAL MUSCLE MOTOR DENERVATION; (B) BOTH THE SNS AND SYMPATHOMIMETICS REGULATE MOTONEURON SYNAPTIC VESICLE RELEASE AND POSTSYNAPTIC MOLECULAR COMPOSITION; AND (C) AGING BLUNTS THE INFLUENCE OF THE SNS ON NMJ TRANSMISSION. THESE DATA SUPPORT THE STRONG INFLUENCE OF THE SNS ON MOTONEURON AND MYOFIBER MOLECULAR COMPOSITION AND FUNCTION. PROBING DEEPER, WE FOUND THAT THE SNS AND SYMPATHOMIMETICS REGULATE MOTONEURON SYNAPTIC VESICLE RELEASE VIA EXTRACELLULAR CA2+ AND SUCH MOLECULAR TARGETS, AS TRPV1 AND P/Q- AND N-TYPE VOLTAGE-ACTIVATED CA2+ CHANNELS. RECENTLY, WE DEMONSTRATED THAT ?1-ADRENOCEPTOR IS EXPRESSED IN MOTONEURONS AND DECLINES SIGNIFICANTLY WITH AGING. THESE STUDIES UNVEIL THE MOLECULAR SUBSTRATE THAT ACCOUNTS FOR THE INFLUENCE OF PERIPHERAL SYMPATHETIC NEURONS ON NMJ TRANSMISSION IN YOUNG MICE AND ITS DECLINE WITH AGING. HOWEVER, WE DO NOT KNOW WHETHER AND HOW THE CENTRAL AUTONOMIC RELAYS (CARS)—PARTICULARLY THE PONTINE A5 NUCLEUS, WHICH PROJECTS TO THE SPINAL CORD INTERMEDIOLATERAL (IML) COLUMN—REGULATE SKELETAL MUSCLE MASS, STRENGTH, INNERVATION, AND NMJ TRANSMISSION AND WHETHER THIS INFLUENCE DECLINES OVER TIME. OPTOGENETICS COMBINED WITH NEURON RETROGRADE LABELING PROVIDES A UNIQUE OPPORTUNITY TO DETERMINE THE PRECISE ROLE OF A5 NUCLEUS IN LIVING MICE. BASED ON OUR PUBLISHED AND PRELIMINARY DATA, WE PROPOSE THAT AGING IMPAIRS A5 NUCLEUS REGULATION OF THE PERIPHERAL SNS, INCREASING SKELETAL MUSCLE SYMPATHETIC AND MOTOR DENERVATION AND LOSS OF MASS AND STRENGTH. THE FOLLOWING SPECIFIC AIMS ARE DESIGNED TO TEST THIS HYPOTHESIS: AIM 1 DEFINE THE ROLE OF A5 SYMPATHETIC NEURONS PROJECTING TO HINDLIMB MUSCLES (SNPHLM) IN MUSCLE MOTONEURON DENERVATION, IMPAIRED NMJ TRANSMISSION, AND SARCOPENIA WITH AGING, AND AIM 2 WILL DETERMINE WHETHER SUSTAINED EXPRESSION OF THE MASTER SYMPATHETIC TRANSCRIPTION FACTOR PHOX-2B IN A5 SNPHLM ATTENUATES SKELETAL MUSCLE SYMPATHETIC AND MOTOR DENERVATION WITH AGING. THIS PROJECT WILL BE THE FIRST TO DEFINE CARS’ ROLE IN NMJ TRANSMISSION AND MUSCLE SYMPATHETIC AND MOTOR INNERVATION. IT WILL ELUCIDATE UPPER LEVEL CONTROL OF THE MOTOR UNIT TO ACHIEVE AN INTEGRATED, COMPREHENSIVE UNDERSTANDING OF AGING SARCOPENIA. SUCCESSFUL RESULTS WILL SHIFT THE TREATMENT TARGET FOR SARCOPENIA FROM THE SKELETAL MUSCLE TO THE CENTRAL SYMPATHETIC NEURON.

DISTINGUISHING PREEXISTENT AND INDUCED EPIGENETIC RISK FOR ALCOHOL USE DISORDERS

IN SPACE MANUFACTURING OF ENGINEERED LIVER TISSUE

AN INFORMAL LEARNING MODEL OF GENETIC AND GENOMIC EDUCATION FOR ADULT, BILINGUAL LEARNERS

THE IMPACT OF PRODUCT PACKAGING ON APPEAL, KNOWLEDGE AND RISK PERCEPTIONS OF CANNABIS EDIBLES - PROJECT SUMMARY THE RATE OF CANNABIS LEGALIZATION IN THE U.S. HAS INCREASED RAPIDLY IN RECENT YEARS. THIS HAS LED TO THE PROLIFERATION OF NON-COMBUSTIBLE CANNABIS PRODUCTS, LIKE EDIBLES (CANNABIS-INFUSED FOOD PRODUCTS), THAT DO NOT INVOLVE INHALING TOXIC SMOKE, CAN BE USED WITH DISCRETION, AND HAVE NO SMELL. WHILE POPULAR IN RECREATIONAL STATES, THESE PRODUCTS POSE UNIQUE PUBLIC HEALTH CHALLENGES. ALTHOUGH EDIBLES ARE PACKAGED AS APPEALING FOOD PRODUCTS AND ARE PERCEIVED TO BE LESS HARMFUL THAN OTHER CANNABIS PRODUCTS, THERE IS AN INCREASED RISK FOR THE OVERCONSUMPTION OF TETRAHYDROCANNABINOL (THC), THE PSYCHOACTIVE COMPONENT IN CANNABIS. WHILE SMOKING CANNABIS RESULTS IN AN IMMEDIATE HIGH, INTOXICATION FROM CONSUMING EDIBLES CAN BE DELAYED UP TO TWO HOURS OR MORE AND LAST UP TO 12 HOURS. THIS CAN LEAD TO CONSUMING MORE THAN THE RECOMMENDED SERVING, WHICH CAN RESULT IN UNEXPECTED, STRONGER, AND LONGER-LASTING HIGHS AS WELL AS SEVERE INTOXICATION, CARDIOVASCULAR EFFECTS, AND PSYCHOTIC EPISODES. SINCE CANNABIS IS REGULATED ON A STATE-BY-STATE BASIS, THERE IS SUBSTANTIAL VARIATION IN THE REGULATION OF PRODUCT PACKAGING AND WARNINGS THAT INFORM CONSUMERS. FURTHERMORE, LITTLE RESEARCH HAS BEEN CONDUCTED ON EDIBLES, RESULTING IN SIGNIFICANT GAPS IN UNDERSTANDING HOW PACKAGING AND WARNINGS IMPACT PRODUCT APPEAL, KNOWLEDGE, HARM PERCEPTIONS AND WILLINGNESS TO TRY EDIBLES. THIS R01 WILL ADDRESS THESE GAPS BY TESTING THE IMPACT OF CANNABIS EDIBLES PRODUCT PACKAGING AND WARNINGS USING CONTROLLED, EXPERIMENTAL DESIGNS. FIRST, WE WILL CONTENT ANALYZE TEXT AND VISUAL PACKAGING ELEMENTS OF A SAMPLE OF PRODUCTS MARKETED ONLINE. WE WILL CONDUCT TWO EXPERIMENTS TO EVALUATE THE IMPACT OF THESE ELEMENTS ON PRODUCT APPEAL AND HARM PERCEPTIONS (AIM 1). NEXT, WE WILL CONVENE AN EXPERT PANEL THAT WILL EVALUATE EXISTING EDIBLES WARNINGS AND DEVELOP AN EXPANDED WARNING TO CONVEY ADDITIONAL INFORMATION ABOUT DOSING AND ACUTE CONSEQUENCES. THIS WARNING WILL BE PAIRED WITH AN ICON TO INCREASE ATTENTION. WARNINGS WILL BE TESTED IN AN EXPERIMENT TO EVALUATE THEIR IMPACT ON COMMUNICATING KNOWLEDGE (AIM 2). FINALLY, IN A COMBINED EXPERIMENT, WE WILL TEST THE IMPACT OF THE EDIBLE WARNING DEVELOPED IN AIM 2 IN THE CONTEXT OF PACKAGE MARKETING (IDENTIFIED IN AIM 1) ON APPEAL, KNOWLEDGE, HARM PERCEPTIONS AND WILLINGNESS TO TRY EDIBLES IN A NATIONALLY REPRESENTATIVE SAMPLE (AIM 3). GIVEN THE RAPID PACE OF LEGALIZATION, COUPLED WITH THE RESPONSIBILITY OF INFORMING CONSUMERS ABOUT SAFE CONSUMPTION AND THE RISKS OF USE, THE SCIENTIFIC EVIDENCE GENERATED FROM THIS STUDY WILL BE TIMELY AND IS URGENTLY NEEDED BY STATE POLICYMAKERS AS THEY DEVELOP INFORMED REGULATIONS, INCLUDING BEST PRACTICES FOR COMMUNICATING KNOWLEDGE TO MINIMIZE HARMS. THIS APPLICATION IS DIRECTLY RESPONSIVE TO NIDA’S RESEARCH PRIORITY AREAS OUTLINED IN NOT-DA-19-065 (PUBLIC HEALTH RESEARCH ON CANNABIS), INCLUDING THE IMPACT OF CANNABIS INDUSTRY PRACTICES LIKE MARKETING AND WARNINGS ON CANNABIS USE AND OUTCOMES.

ILLUMINATING THE PATH(OPHYSIOLOGY) TO DEVELOPMENT OF YOUTH-ONSET TYPE 2 DIABETES (PATH-NC) - ABSTRACT ESTIMATES SUGGEST THAT ACROSS A PERIOD OF JUST 16 YEARS (2001-2017), PREVALENCE OF T2D IN YOUTH HAS DOUBLED, FROM AN ESTIMATED PREVALENCE OF 0.34 PER 1000 YOUTHS TO 0.67 PER 1000 YOUTHS. THROUGH OUR WORK ON THE SEARCH FOR DIABETES IN YOUTH STUDY (SEARCH) WE HAVE REPORTED THAT THE INCIDENCE OF T2D IS DISPROPORTIONATELY EXPERIENCED IN MARGINALIZED RACIAL AND ETHNIC MINORITY GROUPS, WITH AMERICAN INDIAN AND NON-HISPANIC BLACK YOUTH EXPERIENCING THE GREATEST BURDEN OF T2D. WE HAVE DEMONSTRATED THAT THE WELL- KNOWN COMPLICATIONS AND COMORBIDITIES OF ADULT-ONSET T2D, INCLUDING DIABETIC NEPHROPATHY, RETINOPATHY, PERIPHERAL NEUROPATHY, ARTERIAL STIFFNESS, AND HYPERTENSION, HAVE AN ACCELERATED ONSET IN YOUTH ONSET T2D. WHILE IT HAS BEEN WELL-ESTABLISHED THAT OVERWEIGHT AND OBESITY, TOGETHER WITH FAMILY HISTORY, ARE ASSOCIATED WITH INCREASED RISK FOR DEVELOPMENT OF YOUTH ONSET T2D, THE MAJORITY OF YOUTH WITH THESE RISK FACTORS DO NOT DEVELOP T2D. T2D RARELY OCCURS PRIOR TO THE ONSET OF PUBERTY AND IT IS WELL-ESTABLISHED THAT PUBERTY IS ASSOCIATED WITH A DECREASE IN INSULIN SENSITIVITY, WITH NADIR EXPERIENCED TYPICALLY AT TANNER STAGE III, BEFORE RETURNING TO PRE- PUBERTAL LEVELS BY TANNER STAGE V IN THE HEALTHY ADOLESCENT. YOUTH APPEAR TO BE AT GREATEST RISK FOR DEVELOPMENT OF T2D AS THEY PROGRESS TOWARD THE LATTER STAGES OF PUBERTY. WE PROPOSE A LONGITUDINAL COHORT STUDY DESIGNED TO PROVIDE DEEP PHENOTYPING OF PATHOPHYSIOLOGIC MARKERS ACROSS THE PUBERTAL TRANSITION FOR HIGH-RISK YOUTH WITH OBESITY, ASSESSING THESE FACTORS IN RELATION TO UNDEREXPLORED SOCIAL, BEHAVIORAL, AND EARLY LIFE RISK FACTORS FOR DEVELOPMENT OF T2D IN YOUTH. AS ONE OF MANY CLINICAL SITES SUPPORTING THIS CONSORTIUM, WE ARE PREPARED TO ENROLL 504 YOUTH, FROM A HIGHLY DIVERSE POPULATION OF YOUTH WITH OBESITY AND IN EARLY TO MID- PUBERTY (TANNER STAGE II OR III). OPERATIONAL AIMS INCLUDE RECRUITING AND RETAINING A DIVERSE COHORT OF AT-RISK YOUTH (OA1), SUSTAINING STAKEHOLDER ENGAGEMENT TO INFORM THE STUDY THROUGHOUT STUDY PLANNING, IMPLEMENTATION, AND DISSEMINATION (OA2), AND ESTABLISHING A BIOBANK OF PARTICIPANT SPECIMENS AND SAMPLES FROM WHICH FUTURE ANCILLARY STUDIES CAN BE CONDUCTED (OA3). THE SCIENTIFIC AIMS SUPPORTED BY THESE OPERATIONAL AIMS ADDRESS THE OVERARCHING OBJECTIVES OF CONDUCTING DEEP PHENOTYPIC CHARACTERIZATION OF YOUTH- ONSET T2D, INCLUDING ASSESSMENT OF PHYSIOLOGIC MARKERS ACROSS THE PUBERTAL TRANSITION (SA 1.), ESTABLISHING SOCIAL AND BEHAVIORAL RISK FACTORS FOR AND PROTECTIVE FACTORS AGAINST DEVELOPMENT OF YOUTH ONSET T2D, BEYOND THAT WHICH HAS ALREADY BEEN ESTABLISHED (SA 2.), AND EVALUATING GENETIC AND EPIGENETIC DATA TO FURTHER MECHANISTIC UNDERSTANDING OF DISEASE PATHOGENESIS IN YOUTH (SA 3.). ULTIMATELY, THIS WORK WILL SUPPORT INCREASED UNDERSTANDING OF WHICH INDIVIDUALS ARE AT RISK FOR DEVELOPING YOUTH-ONSET T2D AND ALLOW IDENTIFICATION OF DETERMINANTS OF PROGRESSION FROM PREDIABETES TO T2D, WHICH WILL SUPPORT GROUNDBREAKING FUTURE PREVENTION APPROACHES THAT, ONCE EVALUATED, COULD BE TAILORED TO INDIVIDUAL RISK.

SYSTEMS GENETICS TO IDENTIFY NEURONAL GENES FOR DIET-INDUCED OBESITY

A PERSONALIZED DIGITAL OUTREACH INTERVENTION FOR LUNG CANCER SCREENING

ISOFORM-SPECIFIC ROLES OF AMPK IN SYNAPTIC FAILURE AND MEMORY DEFICIT IN ALZHEIMER'S DISEASE