Rhode Island Hospital

THE DEVELOPING BRAIN: INFLUENCES AND OUTCOMES

COBRE CENTER ON OPIOIDS AND OVERDOSE

THE DEVELOPING BRAIN: INFLUENCES AND OUTCOMES

RHODE ISLAND HOSPITAL INJURY CONTROL CENTER FOR BIOMEDICAL RESEARCH EXCELLENCE (COBRE) - PROJECT SUMMARY (OVERALL) INJURY IS THE LEADING CAUSE OF DEATH FOR INDIVIDUALS 1-44 YEARS OF AGE AND CONTRIBUTES TO OVER 30 MILLION EMERGENCY DEPARTMENT VISITS ANNUALLY1. THERE IS A TREMENDOUS NEED FOR GREATER SCIENTIFIC UNDERSTANDING AND STRATEGIES TO COMBAT THE INJURY EPIDEMIC YET INJURY CONTROL RESEARCH IS UNDERFUNDED COMPARED TO OTHER LEADING CAUSES OF DEATH2,3. WE PROPOSE TO ESTABLISH THE RHODE ISLAND HOSPITAL INJURY CONTROL CENTER FOR BIOMEDICAL RESEARCH EXCELLENCE (COBRE). THE PROPOSED CENTER WOULD BE THE FIRST AND ONLY NIH-FUNDED COBRE RESEARCH CENTER TO FOCUS SOLELY ON INJURY CONTROL. THE OBJECTIVE OF THIS PROPOSAL IS TO ESTABLISH AND BUILD A COBRE CENTER TO SUPPORT THE RESEARCH ACTIVITIES OF PROJECT RESEARCH LEADERS TO ENSURE THEIR TRANSITION TO INDEPENDENTLY FUNDED SCIENTISTS. THIS OBJECTIVE WILL BE MET THROUGH THE FOLLOWING SPECIFIC AIMS: 1) ESTABLISH THE CORES (ADMINISTRATIVE CORE, INJURY CONTROL DIGITAL INNOVATION CORE & INJURY CONTROL RESEARCH TO PRACTICE AND POLICY CORE) NEEDED TO DEVELOP AND SUSTAIN A THEMATIC MULTIDISCIPLINARY CENTER OF RESEARCH EXCELLENCE ON INJURY CONTROL AND TO 2) SUPPORT THE SELECTION, MENTORSHIP, AND CAREER DEVELOPMENT OF EARLY CAREER FACULTY THROUGH THE COBRE’S RESEARCH STUDIES AND A PILOT STUDY PROGRAM. THE RIH INJURY CONTROL COBRE RESEARCH STUDIES WILL TARGET THE ENTIRE SPECTRUM OF INJURY PREVENTION (PRIMARY, SECONDARY, TERTIARY) WITH INDIVIDUALS ACROSS THE LIFECYCLE (CHILDREN, EMERGING ADULTS AND OLDER ADULTS). THE THREE INITIAL RPLS ARE THREE WOMEN JUNIOR FACULTY WITH OUTSTANDING POTENTIAL TO MAKE SIGNIFICANT CONTRIBUTION TO INJURY SCIENCE RESEARCH: LESLIE BRICK, PHD, ELIZABETH GOLDBERG, MD, SCM AND STEPHANIE RUEST, MD, MPH. IN ADDITION, A PILOT PROJECT PROGRAM WILL SUPPORT RESEARCH PROPOSALS FOR FUTURE JUNIOR INVESTIGATORS TO CONTINUE THE GROWTH OF INDEPENDENT RESEARCHERS. THIS MENTORED PILOT PROGRAM WILL ALLOW EARLY WORK TO COMMENCE ON IMPORTANT INJURY CONTROL TOPICS WITH INNOVATIVE RESEARCH AND ALLOW THOSE PROJECTS TO PROCEED AND BECOME LATER RESEARCH PROJECTS WITHIN THE COBRE OR TO PROGRESS DIRECTLY TO INDEPENDENT FUNDING. RIH HAS A STRONG CORE OF SENIOR RESEARCHERS IN THE FIELD OF INJURY CONTROL SCIENCE; HOWEVER, OUR PIPELINE OF RESEARCHERS WILL RUN DRY IF WE DO NOT EXPAND AND REPLENISH RESEARCHERS CAPABLE OF INJURY CONTROL RESEARCH EXCELLENCE. THE RIH INJURY CONTROL COBRE WILL BRING TOGETHER JUNIOR INVESTIGATORS, SENIOR FACULTY AND ADVISORY COMMITTEE MEMBERS TO BUILD A CENTER WHICH PRODUCES HIGH LEVEL, INDEPENDENT RESEARCHERS EQUIPPED TO ADDRESS AND IMPROVE THE SUBSTANTIAL BURDEN INJURY HAS ON POPULATION HEALTH. IT WILL BE CONTINUOUSLY AND RIGOROUSLY EVALUATED ALLOWING FOR CONSTANT IMPROVEMENT AND PREPARING OUR INSTITUTION TO ACCELERATE ITS PRODUCTION OF HIGH-QUALITY INNOVATIVE INJURY CONTROL RESEARCH AND RESEARCHERS.

COBRE FOR SKELETAL HEALTH AND REPAIR

FOLIC ACID FOR VASCULAR OUTCOME REDUCTION IN TRANSPLANTATION (FAVORIT) TRIAL

STEM CELLS AND AGING

COBRE FOR SKELETAL HEALTH AND REPAIR

RHODE ISLAND ASTHMA INTEGRATED RESPONSE PROGRAM (RI-AIR)

A MULTI-SCALE APPROACH TO CARDIAC ARRHYTHMIA: FROM THE MOLECULE TO THE ORGAN

THUMB CMC BIOMECHANICS AND EARLY OA PROGRESSION

STEM CELL BIOLOGY: NEW DIRECTIONS IN CLINICAL AND BASIC RESEARCH

COBRE CENTER FOR CANCER RESEARCH DEVELOPMENT

COBRE CENTER FOR CANCER RESEARCH DEVELOPMENT

MECHANISMS OF IMMUNE DYSFUNCTION AND MORBID OUTCOME IN RESPONSE TO SHOCK/SEPSIS

CARDIOPLEGIA AND CORONARY MICROVASCULAR REACTIVITY

COBRE FOR SKELETAL HEALTH & REPAIR

TRAINING IN CHILD/ADOLESCENT BIOBEHAVIORAL HIV RESEARCH

RESEARCH TRAINING IN CHILD MENTAL HEALTH

BIOLOGICALLY ENHANCED HEALING OF AUTOGRAFT ACL RECONSTRUCTION.

VASCULAR DYSFUNCTION IN MYOCARDIAL ISCHEMIA AND METABOLIC SYNDROME

REGULATION OF FETAL HEPATIC GROWTH

PERSONALIZED INTEGRATED CHRONOTHERAPY FOR PERINATAL DEPRESSION

CLAUDICATION: EXERCISE VS. ENDOLUMINAL REVASCULARIZATION

STEM CELL BIOLOGY: NEW DIRECTIONS IN CLINICAL AND BASIC RESEARCH

COBRE CENTER FOR CANCER RESEARCH DEVELOPMENT

MECHANISM AND ACTIVITY OF BETA-LACTAM RESISTANT ENZYMES IN E. FAECIUM AND E. FAECALIS

RHODE ISLAND CHILD CLINICAL TRIALS COLLABORATIVE

BLOOD-BRAIN BARRIER DISRUPTION AS A BIOMARKER FOR PERIOPERATIVE NEUROCOGNITIVE DISORDER:COGNITIVE RECOVERY AFTER ELECTIVE SURGERY

SCARRING AND ARRHYTHMIA IN INFARCTED AGED HEARTS: ROLE OF SENESCENT FIBROBLASTS

IMPACT OF SLEEP DURATION ON IMMUNE BALANCE IN URBAN CHILDREN WITH ASTHMA - PROJECT SUMMARY / ABSTRACT URBAN CHILDREN WITH ASTHMA ARE AT HIGH RISK FOR SHORT SLEEP, DUE TO AN ENVIRONMENT THAT JEOPARDIZES SLEEP AND ASTHMA MANAGEMENT. FURTHER, THIS GROUP SUFFERS FROM ALTERED IMMUNE BALANCE, A KEY BIOLOGICAL PROCESS CONTRIBUTING TO INDIVIDUAL DIFFERENCES IN ASTHMA MORBIDITY AND SLEEP HEALTH. ALLERGIC ASTHMA IS A CHRONIC INFLAMMATORY DISORDER DRIVEN PRIMARILY BY DISTURBED T HELPER 1 (TH1)/ 2 (TH2) CYTOKINE BALANCE MARKED BY TH2 CYTOKINE (IL-4, IL-5 AND/OR IL-13) PREDOMINANCE. EXPERIMENTAL FINDINGS IN HEALTHY ADULTS SHOW THAT SHORTENED SLEEP INCREASES INFLAMMATORY CYTOKINE (E.G., IL-6) AND CERTAIN TH2 CYTOKINE LEVELS AND THAT RECOVERY SLEEP FOLLOWING SLEEP RESTRICTION PROMOTES A RETURN TO IMMUNE BALANCE. WHETHER SLEEP DURATION PLAYS A KEY ROLE IN IMMUNE FUNCTION AND ASSOCIATED ASTHMA ACTIVITY IN URBAN CHILDREN WITH ASTHMA REMAINS A SCIENTIFIC GAP. WE WILL USE AN EXPERIMENTAL DESIGN THAT TARGETS SLEEP DURATION, BECAUSE (1) THE URBAN ENVIRONMENT AND ASTHMA SYMPTOMS INTERACT TO SHORTEN SLEEP, (2) SLEEP DURATION IS A MODIFIABLE BEHAVIOR OVERLOOKED IN CLINICAL CARE OF URBAN CHILDREN WITH ASTHMA, AND (3) EXPERIMENTAL DATA ARE CRITICAL TO TEST A CAUSAL LINK FOR SLEEP DURATION AS A MECHANISM UNDERLYING IMMUNE BALANCE AND ASTHMA. WE WILL ENROLL URBAN CHILDREN (N=204; AGES 8-9 YEARS) WITH PERSISTENT ALLERGIC ASTHMA AND ADEQUATE SLEEP DURATION (9-11 H) WHO WILL COMPLETE A 4-WEEK WITHIN-SUBJECTS PROTOCOL THAT INCLUDES 3 SCHEDULED EXPERIMENTAL SLEEP CONDITIONS: (1) 1 WEEK STABILIZED SLEEP (INDIVIDUALIZED; 9-11 H TIME IN BED), (2) 1 WEEK SHORTENED SLEEP (1.5 H DECREASE IN TIME IN BED), AND (3) 2 WEEKS RECOVERY SLEEP (1.5 H INCREASE IN TIME IN BED). WE WILL MONITOR SLEEP DURATION (ACTIGRAPHY) AND LUNG FUNCTION (HOME SPIROMETRY) DAILY AND ASSESS IMMUNE BIOMARKERS WEEKLY AND AT THE MIDPOINT OF SHORTENED SLEEP. TO CONTROL TIME-IN-STUDY EFFECTS, 1/3 OF OUR SAMPLE WILL RECEIVE ONLY THE STABILIZED SLEEP SCHEDULE ACROSS THE 4-WEEK PROTOCOL. IN THIS PROJECT, WE WILL STUDY ONLY URBAN CHILDREN WITH ALLERGIC ASTHMA WHO OBTAIN SUFFICIENT SLEEP (9-11 H, WITHIN NATIONAL GUIDELINES). OUR SHORTENED SLEEP PROTOCOL WILL MODEL THE SLEEP LOSS THAT URBAN CHILDREN WITH ASTHMA CAN EXPERIENCE DUE TO ASTHMA AND/OR URBAN CONTEXT. ADDITIONALLY, OUR RECOVERY SLEEP PROTOCOL SIMULATES A SLEEP OPTIMIZATION INTERVENTION FOLLOWING SHORTENED SLEEP IN A WELL-CONTROLLED APPROACH. THE FIRST AIM OF THE STUDY IS TO EXAMINE THE EFFECTS OF SHORTENED SLEEP ON IMMUNE BALANCE [E.G., TH1 (INTERFERON-IFN)/TH2 (INTERLEUKIN-IL-4, IL-5, IL-13)R AND PLASMA IL-6 LEVELS]. THE SECOND AIM INVOLVES DETERMINING THE EFFECTS OF RECOVERY SLEEP ON IMMUNE BALANCE. THE THIRD AIM INVOLVES EXAMINING THE EXTENT TO WHICH CHANGES IN IMMUNE BALANCE ARE ASSOCIATED WITH CHANGES IN ASTHMA-RELATED LUNG FUNCTION (CHANGES IN FEV1) UNDER CONDITIONS OF SHORTENED AND RECOVERY SLEEP. RESULTS FROM THIS STUDY ULTIMATELY WILL SUPPORT THE DEVELOPMENT FEASIBLE, ECOLOGICALLY VALID, AND CLINICALLY MEANINGFUL INTERVENTIONS TO OPTIMIZE SLEEP DURATION, IMMUNE BALANCE, AND ASTHMA IN THIS AT-RISK GROUP.

PEER-ADMINISTERED ASTHMA SELF-MANAGEMENT INTERVENTION IN URBAN MIDDLE SCHOOLS

DISPARITIES IN SLEEP, ASTHMA, AND THE SLEEP CONTEXT IN URBAN CHILDREN

LEADERSHIP EDUCATION IN NEURODEVELOPMENTAL AND RELATED DISORDERS TRAINING PROGRAM

SELECTIVE MODULATION OF NEUTROPHILS IN CRITICAL ILLNESS

EFFECTS OF DHEA IN PULMONARY HYPERTENSION (DIPH)

STEM CELLS AND AGING - OVERALL ABSTRACT THE LONG-TERM GOAL OF THE CENTER OF BIOMEDICAL RESEARCH EXCELLENCE (COBRE) FOR STEM CELLS AND AGING IS TO DEVELOP A MULTIDISCIPLINARY TRANSLATIONAL CENTER FOR STEM CELLS AND AGING BIOLOGY AND THERAPEUTICS, FOCUSING ON THE UNDERLYING MECHANISMS AND THERAPEUTIC POTENTIALS IN THE STEM CELL AND AGING FIELDS. THE TWO AREAS OF ENDEAVOR OVERLAP EXTENSIVELY, ONE HOLDING THE PROMISE OF TISSUE RESTORATION IN A WIDE VARIETY OF DISORDERS WHILE THE OTHER UNDERLIES DISEASES THAT IMPACT EVERYONE AND LEADS TO DEATH. SINCE THE START OF THE COBRE NINE YEARS AGO 17 JUNIOR INVESTIGATORS HAVE RECEIVED EITHER FULL PROJECTS OR PILOTS, WITH 369 RESEARCH ARTICLES AND CUMULATIVE EXTRAMURAL FUNDING OF OVER $20,000,000 LARGELY FROM NIH. SEVEN OF THESE INDIVIDUALS ARE STILL FUNDED WHILE 13 HAVE SUSTAINED OR ADVANCED IN THEIR ACADEMIC FIELDS, WITH THREE ENTERING THE BIOTECHNOLOGY FIELD. SINCE THEIR COBRE FUNDING, 5 HAVE RECEIVED PROMOTIONS AT BROWN UNIVERSITY. THE MAIN OBJECTIVE OF THE PHASE 3 COBRE IS TO STRENGTHEN AND TRANSITION THE COBRE RESEARCH INFRASTRUCTURE INTO A COMPETITIVE, INDEPENDENT AND SELF- SUSTAINING ACADEMIC CENTER OF EXCELLENCE- THE CENTER FOR STEM CELLS AND AGING BIOLOGY AND THERAPEUTICS IN 5 YEARS. TO ACHIEVE THIS MAIN OBJECTIVE FOUR SPECIFIC AIMS ARE PROPOSED AS FOLLOWS. 1) TO PROVIDE STRONG LEADERSHIP, STRUCTURE AND SUPPORT TO ENHANCE TRANSLATIONAL STEM CELL AND AGING RESEARCH, BY PROVIDING CRITICAL EQUIPMENT AND UNIQUE EXPERTISE IN FLOW CYTOMETRY, VIRAL CONSTRUCTION AND EXTRACELLULAR ISOLATION AND CHARACTERIZATION. 2) TO FACILITATE AND DEVELOP THE FLOW CYTOMETRY, LENTIVIRUS CONSTRUCT, AND THE EXTRACELLULAR VESICLE CORES, BY EVALUATING AND FOCUSING THE PERFORMANCE OF THE CORES TOWARD THE GOAL OF LONG-TERM INDEPENDENCE, SUSTAINABILITY, AND REGIONAL GROWTH. 3) TO GUIDE THE PILOT PROJECT PROGRAM IN TRANSLATIONAL STEM CELL AND AGING RELATED RESEARCH, TOWARD EXTRAMURAL FUNDING, WITH EXPERT MENTORSHIP FROM SUCCESSFUL LOCAL FACULTY THROUGH SUPPORT OF THE ADMINISTRATIVE CORE. 4) ENHANCE TRANSLATIONAL RESEARCH IN THE RHODE ISLAND COMMUNITY BY ENCOURAGING AND ENABLING COLLABORATIONS BETWEEN CLINICIANS AND BASIC RESEARCHERS AT THE JUNIOR AND SENIOR INVESTIGATOR LEVELS. OUR VISION IS BY SUSTAINING AND TRANSITIONING THE ESTABLISHED HIGH CALIBER RESEARCH INFRASTRUCTURE, WE WILL ENABLE CLINICIANS WORKING SIDE-BY-SIDE WITH BASIC RESEARCH SCIENTISTS, JUNIOR INVESTIGATORS AND SENIOR INVESTIGATORS, TO DEVELOP INSIGHTS INTO DISEASES AND DISORDERS OF STEM CELLS AND AGING, LEADING IN TURN TO EFFECTIVE CLINICAL THERAPEUTIC APPROACHES.

CONTINUITY OF CARE FOR DRUG-ADDICTED OFFENDERS IN RI

FACILITATING HIV/AIDS AND HIV TESTING LITERACY FOR EMERGENCY DEPARTMENT PATIENTS

MHEALTH FACILITATED INTERVENTION TO IMPROVE MEDICATION ADHERENCE AMONG PERSONS LIVING WITH HIV - THERE ARE MORE THAN A MILLION PERSONS LIVING WITH HIV IN THE UNITED STATES. DESPITE THE EFFECTIVENESS OF ANTIRETROVIRAL THERAPY (ART), VIRAL SUPPRESSION, PARTICULARLY DURABLE VIRAL SUPPRESSION, CAN BE DIFFICULT TO ACHIEVE. SUBOPTIMAL ART ADHERENCE PLAYS A SIGNIFICANT ROLE IN UNSUCCESSFUL VIRAL SUPPRESSION, WHICH INCREASES THE RISK OF DISEASE PROGRESSION, A SHORTENED LIFESPAN, TRANSMISSION TO OTHERS, AND THE DEVELOPMENT OF TREATMENT RESISTANT STRAINS OF HIV. AS A RESULT, INTERVENTIONS TARGETING ADHERENCE HAVE BEEN DEVELOPED. THERE HAVE BEEN SOME SIGNS OF SUCCESS, PARTICULARLY WITH MORE INTENSIVE INTERVENTIONS. HOWEVER, THERE IS A NEED TO DEVELOP EFFICACIOUS ART ADHERENCE INTERVENTIONS THAT ARE READILY DISSEMINABLE AND MAKE EFFICIENT USE OF AVAILABLE RESOURCES. TO THAT END, PI RAMSEY DEVELOPED AND TESTED AN MHEALTH FACILITATED ART ADHERENCE INTERVENTION THAT INCLUDES A SINGLE FACE-TO-FACE ART ADHERENCE SESSION DELIVERED BY A HEALTH COACH, FOLLOWED BY 12 MONTHS OF ACCESS TO AN APP AND HEALTH COACHING DELIVERED VIA THE APP. THE APP GENERATES A PUSH NOTIFICATION MEDICATION REMINDER, AND ADHERENCE DATA ARE AVAILABLE TO THE HEALTH COACH VIA A “DASHBOARD,” ALLOWING THE HEALTH COACH TO MONITOR ADHERENCE IN REAL TIME AND PROVIDE SUPPORT. THE HEALTH COACH USES A TWO-WAY SECURE MESSAGING FEATURE ON THE APP TO MESSAGE PARTICIPANTS AND TO PROVIDE SUPPORT, ENCOURAGEMENT, AND RESOURCES, INCLUDING LINKS AND ATTACHMENTS, IN RESPONSE TO ADHERENCE LAPSES AND IN RESPONSE TO PARTICIPANT-GENERATED MESSAGES. THE COMBINATION OF A FACE-TO-FACE INTERVENTION COMPONENT FOLLOWED BY APP FACILITATED HEALTH COACHING REPRESENTS A NOVEL COMBINATION THAT AFFORDS PARTICIPANTS WITH A PERSONAL CONNECTION TO A HEALTH COACH WHILE MINIMIZING THE RESOURCES NEEDED TO DELIVER THE INTERVENTION AND MAXIMIZING TIMELY RESPONSIVENESS TO ADHERENCE LAPSES AND OTHER PARTICIPANT NEEDS. A PRELIMINARY RANDOMIZED CONTROLLED TRIAL (RCT) COMPARED THE INTERVENTION TO A CONTROL CONDITION IN WHICH PARTICIPANTS RECEIVED THE SINGLE FACE-TO-FACE ART ADHERENCE SESSION ALONE. BASED ON PILOT DATA, THE PROTOCOL AND INTERVENTION ARE HIGHLY FEASIBLE AND ACCEPTABLE, AND RESULTS ARE CONSISTENT WITH PRELIMINARY EFFICACY OF THE INTERVENTION ON OBJECTIVE MEASURES OF ART ADHERENCE. THE PROPOSED STUDY WILL EXPAND ON THIS PRELIMINARY TEST OF THE INTERVENTION USING A FULLY POWERED RCT (N=400) ACROSS TWO SITES (PROVIDENCE, RI AND ATLANTA, GA). THE LONG-TERM GOAL OF THIS LINE OF RESEARCH IS TO DISSEMINATE AN EFFICACIOUS, MHEALTH FACILITATED ART ADHERENCE INTERVENTION THAT CAN BE READILY INTEGRATED INTO CLINICAL CARE. THE PRESENT PROPOSAL WILL EXAMINE THE IMPACT OF THE INTERVENTION, RELATIVE TO CONTROL, ON ELECTRONIC PILLBOX ART ADHERENCE AND VIRAL LOAD DATA. IN ADDITION, WE WILL EXPLORE THE ROLE OF THEORETICALLY SUPPORTED VARIABLES IN THE MEDIATION AND MODERATION OF INTERVENTION EFFECTS. INTERVIEWS WILL BE CONDUCTED AT BASELINE, 1, 3, 6, AND 12 MONTHS. A SUBSET OF PARTICIPANTS WILL ALSO COMPLETE INTERVIEWS AT 18 AND 24 MONTHS TO EXPLORE SUSTAINED INTERVENTION EFFECTS. IF FOUND EFFICACIOUS, THE INTERVENTION COULD BE BROADLY INTEGRATED INTO CLINICAL CARE FOR HIV, REDUCING MORBIDITY AND MORTALITY AMONG PLWH IN A MANNER THAT MAKES EFFICIENT USE OF AVAILABLE RESOURCES.

RESPIRATORY SINUS ARRHYTHMIA AS A PREDICTOR OF SUBSTANCE USE AMONG EARLY ADOLESCENTS - RESPIRATORY SINUS ARRHYTHMIA AS A PREDICTOR OF SUBSTANCE USE AMONG EARLY ADOLESCENTS RISK BEHAVIORS THAT CAUSE NEGATIVE HEALTH OUTCOMES, SUCH AS SUBSTANCE USE OR SEXUAL RISK BEHAVIORS, TYPICALLY BEGIN IN ADOLESCENCE. IDENTIFYING THOSE MOST AT RISK IN EARLY ADOLESCENCE IS CRITICAL FOR PREVENTION INTERVENTIONS. EMOTION REGULATION PLAYS AN IMPORTANT ROLE IN REDUCING ADOLESCENT RISK BUT DETECTING THOSE WHO ARE VULNERABLE BECAUSE OF DEFICITS IN EMOTION REGULATION DURING EARLY ADOLESCENCE IS CHALLENGING DUE TO POOR ADOLESCENT INSIGHT INTO THESE STILL-DEVELOPING EMOTIONAL PROCESSES. RESPIRATORY SINUS ARRHYTHMIA (RSA), AN INDEX OF HEART RATE VARIABILITY THAT IS INFLUENCED BY THE PARASYMPATHETIC NERVOUS SYSTEM, IS AN ESTABLISHED MARKER OF EMOTION REGULATION PROCESSES. RSA DOES NOT RELY ON SELF-REPORT AND MAY BE USEFUL FOR EARLY IDENTIFICATION OF RISK. OUR TEAM HAS DEVELOPED A NOVEL VIRTUAL REALITY PARTY TASK WITH WHICH TO ASSESS EMOTION REGULATION PATTERNS IN ADOLESCENTS. PILOT DATA IN OUR LABORATORY USING THIS TASK SUGGEST THAT ADOLESCENTS WITH A HISTORY OF SUBSTANCE USE EXHIBIT SLOWER RETURN TO BASELINE RSA (MEASURED AT REST) AFTER EXPOSURE TO A CHALLENGING SITUATION (REFERRED TO AS RECOVERY RSA) COMPARED TO NON-USING PEERS. THIS MAY SUGGEST THAT RECOVERY RSA IS A RELEVANT INDEX OF EMOTION REGULATION RELATED TO RISK BEHAVIORS, AS EMOTIONAL TRIGGERS OFTEN OCCUR IN RAPID SUCCESSION IN REAL-WORLD RISK SITUATIONS. THE PROPOSED STUDY WILL PROSPECTIVELY EXAMINE RSA'S UTILITY IN PREDICTING ADOLESCENT RISK BEHAVIORS (SUBSTANCE USE AND SEXUAL RISK) AMONG A SAMPLE OF 280 EARLY ADOLESCENTS (AGES 12.0-12.5 YEARS) FOR A PERIOD OF 24 MONTHS. WE WILL ALSO EVALUATE WHETHER EMOTION REGULATION IN THE CONTEXT OF A SUBSTANCE USE AND SEXUAL RISK-TAKING SITUATION (THE VIRTUAL REALITY PARTY) IS MORE USEFUL IN PREDICTING RISK BEHAVIOR THAN A COMPUTER RISK-TAKING TASK (THE BALLOON ANALOGUE RISK TASK). WE ALSO WILL EXAMINE STRATEGIES FOR DEFINING RECOVERY RSA, GIVEN INCONSISTENCIES IN THE CURRENT LITERATURE. THE CURRENT PROPOSAL ADVANCES THE FIELD BY COMBINING VIRTUAL REALITY AND RSA COLLECTION TO ASSESS EMOTION REGULATION WITH THE AIM OF IDENTIFYING MARKERS OF THOSE MOST VULNERABLE TO ENGAGING IN RISK BEHAVIORS AT AN EARLY AGE, THUS INNOVATING THE SCIENCE OF PREVENTION.

HISTONE DEACETYLASE INHIBITION: A NOVEL APPROACH TO CARDIOPROTECTION

ETHANOL INSULIN/IGF SIGNALING AND NEURONAL MIGRATION

BRIEF INTERVENTION FOR DRUG MISUSE FOR THE EMERGENCY DEPARTMENT (BIDMED)

INTEGRATED MENTAL HEALTH TREATMENT & HIV PREVENTION FOR COURT-INVOLVED YOUTH

IAMSBIRT: IMPLEMENTING ALCOHOL MISUSE SBIRT IN A NATIONAL COHORT OF PEDIATRIC TRAUMA CENTERS

INTERVENTION TO PREVENT PEER VIOLENCE & DEPRESSIVE SYMPTOMS AMONG AT-RISK ADOLESCENTS

TEEN ALCOHOL SCREENING IN THE PEDIATRIC EMERGENCY CARE APPLIED RESEARCH NETWORK

FROM COURT TO THE COMMUNITY: IMPROVING ACCESS TO EVIDENCE-BASED TREATMENT FOR UNDERSERVED JUSTICE-INVOLVED YOUTH AT-RISK FOR SUICIDE - PROJECT SUMMARY JUSTICE-INVOLVED YOUTH (JIY) LIVING IN THE COMMUNITY EXPERIENCE DISPROPORTIONATELY HIGH RATES OF SUICIDAL THOUGHTS AND BEHAVIOR (STB) AND NON-SUICIDAL SELF-INJURY (NSSI) COMPARED TO ADOLESCENTS IN THE GENERAL POPULATION. MANY JIY LACK ACCESS TO EVIDENCE-BASED TREATMENT SPECIFICALLY DESIGNED TO TREAT NNSI AND STB, THEREBY INCREASING THE OVERALL RISK OF SUICIDE IN THIS POPULATION. FURTHER, EVEN WHEN JIY DO HAVE ACCESS TO EVIDENCE-BASED TREATMENT, TREATMENT INITIATION IN THIS POPULATION IS LOW. THE CURRENT PROPOSAL AIMS TO REDUCE STB AND NSSI AMONG JIY, AND THUS REDUCE MENTAL HEALTH DISPARITIES IN THIS VULNERABLE AND UNDERSERVED YOUTH POPULATION. OUR PRIMARY AIM IS TO IMPLEMENT A SYSTEMS-LEVEL INTERVENTION DESIGNED TO INCREASE ACCESS TO EVIDENCE-BASED TREATMENT STRATEGIES SPECIFICALLY DESIGNED TO TREAT STB AND NSSI BEHAVIORS FOR JIY REFERRED TO OUTPATIENT CARE BY THE RHODE ISLAND FAMILY COURT. WE WILL CONDUCT A CLUSTER RANDOMIZED STEPPED WEDGE TRIAL IN WHICH 9 DISTINCT COMMUNITY MENTAL HEALTH AGENCIES (CMHA) WHO SERVE JIY IN THE STATE OF RHODE ISLAND WILL BE RANDOMIZED TO RECEIVE A STANDARDIZED TRAINING PROGRAM. A SELECT NUMBER OF CHMA ADMINISTRATORS AND PROVIDERS WILL COMPLETE SEMI-STRUCTURED QUALITATIVE INTERVIEWS PRE-IMPLEMENTATION TO ASSESS AGENCY/SYSTEM-LEVEL AND PROVIDER-LEVEL FACTORS THAT MAY PROMOTE OR HINDER THE UPTAKE OF EVIDENCED-BASED TREATMENT STRATEGIES FOR STB AND NSSI IN CMHAS SERVING JIY LIVING IN THE COMMUNITY. QUANTITATIVE DATA WILL ASSESS ORGANIZATIONAL, PROVIDER, AND YOUTH CHARACTERISTICS AND WILL BE COLLECTED THROUGH QUESTIONNAIRES CMHA PROVIDERS COMPLETE AND FROM THE ELECTRONIC MEDICAL RECORD PRE- IMPLEMENTATION, IMMEDIATELY POST-IMPLEMENTATION, AND 9-MONTHS INTO SUSTAINMENT. IT IS HYPOTHESIZED THAT AT THE SYSTEMS LEVEL, THE TRAINING PROGRAM WILL BE SUSTAINED FOR AT LEAST ONE YEAR AND UP TO 3 YEARS BY CMHA ADMINISTRATORS. AT THE PROVIDER LEVEL, IT IS HYPOTHESIZED THAT TRAINING IN THE USE OF EVIDENCE-BASED TREATMENT STRATEGIES FOR STB AND NSSI WILL SIGNIFICANTLY INCREASE BOTH THE USE OF THESE STRATEGIES AND THE QUALITY OF THEIR DELIVERY OVER A YEAR’S FOLLOW-UP PERIOD. AT THE PATIENT LEVEL, WE HYPOTHESIZE THAT THE TRAINING PROGRAM WILL IMPROVE PARENTAL ADHERENCE TO OUTPATIENT TREATMENT AND REDUCE RATES OF ADOLESCENT STB AND NSSI THAT REQUIRE EMERGENCY MEDICAL/PSYCHIATRIC CARE IN OUR HEALTHCARE SYSTEM. OUR SECONDARY AIM IS TO EXAMINE FACTORS THAT INFLUENCE TREATMENT INITIATION AMONG JIY LIVING IN THE COMMUNITY. WE WILL ENROLL 180 CAREGIVERS OF JIY YOUTH WHO SCREEN POSITIVE FOR RECENT NSSI/STB TO TEST THE HYPOTHESIS THAT JIY WHOSE CAREGIVERS ARE RANDOMIZED TO THE PSYCHOEDUCATION/ACTION PLAN CONDITION, COMPARED TO AN EDUCATIONAL VIDEO, WILL BE SIGNIFICANTLY MORE LIKELY TO INITIATE TREATMENT AT A CMHA. CAREGIVERS WILL COMPLETE FOLLOW-UP ASSESSMENTS AT 3- AND 6-MONTHS POST-BASELINE TO ASSESS WHETHER THEIR ADOLESCENT INITIATED TREATMENT AND HOW MANY SESSIONS THE ADOLESCENT ATTENDED. THIS APPLICATION HAS STRONGLY ALIGNS WITH NIMH’S STRATEGIC OBJECTIVE 3.3: “TEST INTERVENTIONS FOR EFFECTIVENESS IN COMMUNITY PRACTICE SETTINGS,” AND THE GOALS OF THE RFA-MH-21-187 TO TEST EFFECTIVE “SYSTEMS-LEVEL STRATEGIES FOR THE DETECTION AND PREVENTION OF SIB AND/OR NSSI SPECIFICALLY AMONG UNDERSERVED CHILDREN AND ADOLESCENTS.”

ASTHMA AND ACADEMIC PERFORMANCE IN URBAN CHILDREN

S.JAPONICUM AND PREGNANCY OUTCOMES: AN RCT

REDIAL: A TELEPHONE BRIEF INTERVENTION FOR INJURED EMERGENCY DEPARTMENT PATIENTS

DATING VIOLENCE PREVENTION PROGRAM FOCUSING ON MIDDLE SCHOOL BOYS

ASSESSMENT OF IMPLEMENTATION METHODS IN SEPSIS AND RESPIRATORY FAILURE - PROJECT SUMMARY SEPSIS IS THE LEADING CAUSE OF ADMISSION TO INTENSIVE CARE UNITS (ICUS) IN THE U.S., AND THE LEADING CAUSE OF RESPIRATORY FAILURE AND DEATH IN ICUS. THE MAJORITY OF ICU PATIENTS WITH SEPSIS OR SEPTIC SHOCK HAVE EITHER RESPIRATORY INFECTION AS THE SOURCE OF SEPSIS, OR HAVE RESPIRATORY FAILURE REQUIRING MECHANICAL VENTILATION. IN RECOGNITION OF THE BURDEN OF SEPSIS IN THE U.S., SEPSIS “BUNDLES” WERE INTRODUCED TO FACILITATE GUIDELINE IMPLEMENTATION IN CLINICAL PRACTICE (KNOWN AS THE 3-HOUR BUNDLE). SINCE THE INTRODUCTION OF SEPSIS BUNDLES, MULTIPLE OBSERVATIONAL STUDIES HAVE DEMONSTRATED A CONSISTENT, STRONG ASSOCIATION BETWEEN IMPLEMENTATION OF SEPSIS BUNDLES AND IMPROVED SURVIVAL. THESE DATA LED TO THE NEW YORK STATE (NYS) SEPSIS INITIATIVE, WHICH DEMONSTRATED A SIGNIFICANT ASSOCIATION BETWEEN ADHERENCE WITH SEPSIS BUNDLES AND IMPROVED SURVIVAL, AND THE CENTERS FOR MEDICARE AND MEDICAID SERVICES (CMS) MANDATED PUBLIC REPORTING OF SEPSIS MEASURES (SEP-1). ANALYSIS OF THE NYS DATABASE HAS REVEALED THAT COMPLETION OF THE 3-HOUR BUNDLE IN PATIENTS WITH RESPIRATORY FAILURE WAS ASSOCIATED WITH AN 8.6% ABSOLUTE REDUCTION IN MORTALITY (18.5 RRR). FOR THOSE PATIENTS WHO COMPLETED THE 3-HOUR BUNDLE WITHIN 1 HOUR, THE MORTALITY REDUCTION WAS EVEN HIGHER, 9.8% (RRR 21.7%). IN 2018, THE HOUR-1 BUNDLE WAS PUBLISHED TO UNDERSCORE THE NEED FOR URGENCY IN THE TREATMENT OF SEPTIC PATIENTS. WE BELIEVE THAT THE PRIMARY BENEFICIAL EFFECT OF BOTH THE HOUR-1 AND 3-HOUR BUNDLE IS IN PATIENTS WITH RESPIRATORY FAILURE. IT IS NOT KNOWN IF IMPLEMENTATION OF THE HOUR-1 BUNDLE REDUCES MORTALITY MORE THAN THE 3 HOUR BUNDLE. ALTHOUGH ADHERENCE WITH THE 3-HOUR BUNDLE (SEP-1) IS MANDATED BY CMS, COMPLIANCE IS MODERATE (60%), SUGGESTING AN ACTIVE IMPLEMENTATION PROCESS FOR THE 3-HOUR BUNDLE IS NECESSARY TO COMPARE THE HOUR-1 BUNDLE TO THE 3-HOUR BUNDLE. THE CURRENT PROPOSAL IS A PRAGMATIC, CLUSTER-RANDOMIZED CLINICAL TRIAL USING A HYBRID TYPE 2 EFFECTIVENESS-IMPLEMENTATION APPROACH TO EVALUATE MORTALITY AND RESPIRATORY FAILURE-BASED OUTCOMES AND BUNDLE ADHERENCE, IN EMERGENCY ROOM PATIENTS WITH SEPSIS. WE WILL COMPARE THE HOUR-1 BUNDLE TO THE 3-HOUR BUNDLE. THE OUTCOME MEASURES INCLUDE HOSPITAL MORTALITY, HOSPITAL LENGTH OF STAY, VENTILATOR-FREE DAYS, AND INCIDENCE OF RESPIRATORY FAILURE. THE EFFECTIVENESS OF A CLINICAL INTERVENTION (HOUR-1 BUNDLE) IS IMPLEMENTED USING A RIGOROUS IMPLEMENTATION STRATEGY (THE EXPLORATION, ADOPTION/PREPARATION, IMPLEMENTATION, SUSTAINMENT – EPIS – MULTI-LEVEL CONCEPTUAL MODEL) FOR BOTH THE 1- AND 3-HOUR BUNDLES. WE WILL ALSO EVALUATE A POSSIBLE PRECISION-BASED APPROACH IN THIS STUDY. ROUTINE CLINICAL INFORMATION AVAILABLE AT HOSPITAL PRESENTATION WILL IDENTIFY 4 DISCRETE, SEPSIS PHENOTYPES AND WE HYPOTHESIZE THAT 2 OF THESE IDENTIFY PATIENTS WHO ARE SIGNIFICANTLY MORE LIKELY TO BENEFIT FROM THE 1-HOUR BUNDLE IN FUTURE STUDIES. OUR TEAM HAS EXTENSIVE EXPERIENCE CONDUCTING MULTI-CENTER TRIALS IN SEPSIS GUIDED BY EFFECTIVE MODELS OF IMPLEMENTATION SCIENCE. WE HAVE DEVELOPED AUTOMATED SCREENING TOOLS TO IDENTIFY PATIENTS WITH SEPSIS AND HAVE GUIDED STATE-WIDE IMPLEMENTATION OF SEPSIS PERFORMANCE MEASURES. WE HAVE ALSO USED AUTOMATED EHR METHODS TO SCREEN FOR AND ENROLL SEPTIC PATIENTS INTO THESE STUDIES. THIS NOVEL, HYBRID TYPE 2 EFFECTIVENESS-IMPLEMENTATION APPROACH ADDRESSES KEY GAPS TO FACILITATE THE IMPLEMENTATION OF EVIDENCE-BASED STRATEGIES TO IMPROVE PATIENT OUTCOMES FROM SEPSIS AND ACUTE RESPIRATORY FAILURE.

CELL SENESCENCE REGULATING OSTEOARTHRITIS PROGRESSION: SEX-DEPENDENT MECHANISMS - OSTEOARTHRITIS (OA), A LEADING CAUSE OF DISABILITY IN THE ELDERLY (AGING OA), IS A COMPLEX DEGENERATIVE JOINT DISEASE INVOLVING ARTICULAR CARTILAGE DEGRADATION, CHRONIC INFLAMMATION, AND BONE REMODELING. IN ADDITION, JOINT INJURY CAN TRIGGER POST-TRAUMATIC OSTEOARTHRITIS (PTOA). THE PREVALENCE AND SEVERITY OF KNEE OA ARE HIGHER IN WOMEN THAN MEN DURING AGING, ALTHOUGH FEMALE MICE ARE MORE RESISTANT TO OA PROGRESSION AFTER INJURY. THE SCIENTIFIC CHALLENGE IS THE INCOMPLETE UNDERSTANDING OF THE SEX-SPECIFIC MECHANISMS REGULATING OA PROGRESSION, WHICH HAMPERS THE DEVELOPMENT OF DISEASE-MODIFYING OSTEOARTHRITIS DRUGS THAT CAN TARGET THE PROCESS. THE SCIENTIFIC GOAL OF THIS PROJECT IS TO DETERMINE THE MOLECULAR MECHANISMS UNDERLYING SEX-DIFFERENCE IN OA PROGRESSION. WE DISCOVERED THAT RETROTRANSPOSON LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1, OR L1), A NOVEL MARKER OF CELL SENESCENCE, IS CLOSELY ASSOCIATED WITH OA LESIONS IN BOTH HUMAN AND MICE. FURTHER, L1 ACTIVATION MECHANISM IS SEX DEPENDENT. ACTIVATION OF STRESS-INDUCIBLE MIR-365 STIMULATES L1 AND OA PROGRESSION IN FEMALE BUT NOT IN MALE DURING AGING. FURTHERMORE, SENOSTATICS THAT TARGET CELL SENESCENCE INHIBIT OA PROGRESSION BY INHIBITING L1, WHICH IS REPRESSED IN CHONDROCYTES BUT DE-REPRESSED IN SENESCENT MSCS IN THE JOINT. THESE DATA SUGGEST THAT SENESCENT MSCS CAN BE A KEY TARGET FOR EFFECTIVE TREATMENT OF OA. THE INNOVATIVE HYPOTHESIS IS THAT FEMALES ARE MORE SUSCEPTIBLE TO EARLY-ONSET AND PROGRESSION OF OA DURING AGING BECAUSE STRESS SIGNALS STIMULATE L1, WHICH LEADS TO MSC SENESCENCE, SASP INFLAMMATION, AND JOINT DEGENERATION IN FEMALE. ON THE OTHER HAND, AFTER OA ONSET IS TRIGGERED BY INJURY, MALES ARE MORE SUSCEPTIBLE TO OA PROGRESSION BECAUSE OF THE HIGHER BASAL LEVELS OF L1 AND IL-1SS IN MALE. IF SO, INTERVENTION OF AGING-OA PROGRESSION IN FEMALE AND PTOA PROGRESSION IN MALE CAN BE ACHIEVED BY REPRESSING L1 USING FDA-APPROVED ANTI-VIRAL DRUG NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NRTI). THIS HYPOTHESIS WILL BE TESTED THROUGH THREE AIMS. FIRST, WE WILL DEFINE ACTIVATION PATTERNS OF L1 AND CELL SENESCENCE IN OA CARTILAGE LESIONS OF MALE AND FEMALE PATIENTS. SECOND, WE WILL DETERMINE SEX-SPECIFIC MECHANISMS REGULATING OA PROGRESSION IN AGING OA AND PTOA USING THE SEX-SPECIFIC OA PROGRESSION MOUSE MODELS. THIRD, WE WILL DEVELOP SEX-SPECIFIC INTERVENTION FOR NRTIS TO INHIBIT OA PROGRESSION. THIS STUDY HAS HIGH IMPACT BECAUSE IT UNCOVERS FUNDAMENTAL MECHANISMS OF OA DISEASE DISPARITY BETWEEN MEN AND WOMEN. IT IS INNOVATIVE BECAUSE IT REPRESENTS A NEW AND DISTINCT DIRECTION FOR THE FIELD BY REVEALING SEX-SPECIFIC REGULATION OF OA PROGRESSION THROUGH ADDRESSING A PREVIOUSLY UNSUSPECTED ROLE OF RETROTRANSPOSONS IN THESE PROCESSES. IT HAS SIGNIFICANT CLINICAL AND TRANSLATIONAL VALUES. IF SUCCESSFUL, NRTIS, WHICH ARE SAFE AND READILY AVAILABLE, CAN BE RE-PURPOSED FOR OA TREATMENT IN HUMAN. IT WILL NOT ONLY CHANGE THE CONCEPTS THAT DRIVE THE OA RESEARCH FIELD, BUT ALSO GREATLY IMPACT THE CLINICAL PRACTICE OF HOW WE TREAT OA PATIENTS.

PUERTO RICO ASTHMA INTEGRATED RESPONSE PROGRAM (PR-AIR) - PROJECT SUMMARY/ABSTRACT CHILDREN OF PUERTO RICAN (PR) DESCENT HAVE HIGHER RATES OF ASTHMA PREVALENCE AND MORBIDITY THAN CHILDREN FROM ANY OTHER ETHNIC GROUP. CHILDREN RESIDING ON THE ISLAND OF PR HAVE EVEN HIGHER ASTHMA PREVALENCE THAN MAINLAND PR CHILDREN. WE PROPOSE TO IMPLEMENT AND EVALUATE THE PUERTO RICO-ASTHMA INTEGRATED RESPONSE PROGRAM (PR-AIR) TO ADDRESS PEDIATRIC ASTHMA DISPARITIES IN SAN JUAN, PR, AN AREA OF HIGH ASTHMA BURDEN. PR-AIR INTEGRATES EVIDENCE-BASED INTERVENTIONS IN HOME AND SCHOOL SETTINGS, AND ENHANCES COMMUNICATION BETWEEN FAMILIES, SCHOOLS, AND HEALTH CARE PROVIDERS. DURING PHASE 1, WE WILL CONVENE A COMMUNITY COLLABORATIVE OF STAKEHOLDERS THAT WILL PROVIDE INPUT THROUGHOUT THE PROJECT, AND USE IN-DEPTH INTERVIEWS TO IDENTIFY COMMUNITY NEEDS, BARRIERS, AND FACILITATORS TO ENABLE PR-AIR IMPLEMENTATION. WE WILL IDENTIFY WHICH CHARACTERISTICS OF OUR EXISTING EVIDENCE-BASED VIRTUAL AND IN-PERSON INTERVENTIONS IN HOME AND SCHOOL SETTINGS REQUIRE FIDELITY-CONSISTENT MODIFICATIONS AND USE STAKEHOLDER INPUT AND MATCHING OF BARRIERS TO IMPLEMENTATION STRATEGY SELECTION TO IDENTIFY METHODS TO ENHANCE PR-AIR UPTAKE. DURING PHASE 2, WE WILL USE A HYBRID TYPE III EFFECTIVENESS-IMPLEMENTATION DESIGN, EVALUATING LOW-INTENSITY (VIRTUAL) AND HIGH-INTENSITY (IN-PERSON) METHODS OF IMPLEMENTATION OF PR-AIR. WE WILL PROVIDE PR-AIR SEQUENTIALLY TO 12 COMMUNITIES IDENTIFIED WITH HIGH ASTHMA BURDEN THROUGH GEOSPATIAL MAPPING USING A CLUSTER RANDOMIZED, STEPPED WEDGE TRIAL DESIGN, DELIVERING PR-AIR TO 400 CHILDREN WITH ASTHMA AGES 2-12. WE WILL USE A MIXED-METHODS APPROACH TO ASSESS THE IMPACT OF OUR IMPLEMENTATION STRATEGIES ON PR-AIR REACH, ADOPTION, IMPLEMENTATION, AND MAINTENANCE, AND EVALUATE EFFECTIVENESS OF PR-AIR ON INDIVIDUAL-LEVEL (ASTHMA CONTROL, QUALITY OF LIFE) AND COMMUNITY-LEVEL (HEALTH CARE UTILIZATION, SCHOOL ABSENCES) OUTCOMES. PR-AIR BUILDS ON A 20-YEAR COLLABORATION BETWEEN OUR RESEARCH TEAMS IN RI AND PR, WITH AN INVESTMENT IN ADVANCING KNOWLEDGE OF MULTI-LEVEL FACTORS AFFECTING PEDIATRIC ASTHMA DISPARITIES AND REDUCING MORBIDITY IN CHILDREN THROUGH EVIDENCE- BASED, SUSTAINABLE INTERVENTIONS.

PEDIATRIC EMERGENCY CARE APPLIED RESEARCH NETWORK (PECARN)

HISTONE DEACETYLASES AS NOVEL THERAPEUTIC TARGETS FOR KIDNEY FIBROSIS

SEXUAL ASSAULT PREVENTION FOR MEN IN THE MILITARY

ENHANCING THE HEMONC KNOWLEDGEBASE OF CHEMOTHERAPY DRUGS AND REGIMENS - PROJECT SUMMARY SYSTEMIC CANCER TREATMENTS HAVE TRANSFORMED THE LANDSCAPE FOR MANY PATIENTS WITH CANCER, YET ARE TOXIC AND OFTEN GIVEN IN COMPLICATED COMBINATIONS AND PROTOCOLS. IN 2011, WE BEGAN TO BUILD THE HEMONC.ORG WEBSITE AS A FREE AND OPEN RESOURCE FOR HEMATOLOGY AND ONCOLOGY HEALTHCARE PROFESSIONALS. HEMONC.ORG CONTAINS GRANULAR INFORMATION ON ANTI-CANCER DRUGS, REGIMENS, AND GUIDELINES, AND IS NOW THE LARGEST RESOURCE OF ITS KIND. IN 2020, THERE WERE >250,000 UNIQUE VISITORS AND >1,000,000 PAGEVIEWS FROM 181 COUNTRIES. USERS ARE PRIMARILY SPLIT BETWEEN CLINICIANS AND PHARMACISTS, WITH UTILIZATION BY TRAINEES AS WELL AS EXPERIENCED PRACTITIONERS. TRANSLATIONAL RESEARCHERS ALSO UTILIZE THE SITE AS A SOURCE OF DOMAIN KNOWLEDGE. BEGINNING IN 2017, WE FORMALIZED THE STRUCTURE OF MUCH OF THE CONTENT ON HEMONC.ORG, ENABLING ITS TRANSFORMATION INTO A STRUCTURED VOCABULARY, HEMONC. AS OF JANUARY 2021, HEMONC COMPRISES 83,879 CONCEPTS ACROSS 30 CONCEPT CLASSES, AND 223,039 RELATIONSHIPS ACROSS 45 RELATIONSHIP TYPES. EXPLICIT MAPPINGS EXIST BETWEEN HEMONC AND RXNORM, CANMED, SNOMED-CT, ONCOTREE, AND THE NCI THESAURUS. SEVERAL ORGANIZATIONS AND PROJECTS ACTIVELY UTILIZE OR ARE EVALUATING HEMONC, INCLUDING AACR PROJECT GENIE, THE ITCR-FUNDED DEEPPHE PROJECT, THE VARIANT INTERPRETATION FOR CANCER CONSORTIUM, AND CBIOPORTAL. IN ADDITION TO MAINTAINING THE STEADY GROWTH IN CONTENT THAT HAS TAKEN PLACE OVER THE PAST NINE YEARS, WE AIM TO ENHANCE THE HEMONC.ORG WEBSITE AND HEMONC ONTOLOGY THROUGH THE FOLLOWING FIVE SPECIFIC AIMS: 1) PRESENT INTERACTIVE RANKED REGIMEN GRAPHS ON THE WEBSITE; 2) ALLOW FOR DYNAMIC TEMPORAL EXPLORATION OF REGIMENS, STUDIES, AND AUTHORS WITH AN INTERACTIVE REGIMEN BROWSER; 3) GROW AND REFINE THE HEMONC ONTOLOGY; 4) BUILD STRUCTURED SUMMARIES AND NARRATIVE SYNOPSES FOR THE MOST IMPORTANT ANTICANCER REGIMENS, INCLUDING IDENTIFICATION OF REGIMENS SPECIFICALLY EVALUATED IN UNDERREPRESENTED POPULATIONS; 5) CULTIVATE A ROBUST USER COMMUNITY. THIS WORK WILL BE UNDERTAKEN BY AN ACCOMPLISHED TEAM OF CLINICIANS AND TRANSLATIONAL RESEARCHERS.

PRENATAL TOBACCO EXPOSURE: EFFECTS ON NEUROPSYCHOLOGICAL OUTCOMES AND ADHD

PREVENTING HIV THROUGH AFFECT MANAGEMENT FOR HIGH-RISK EARLY ADOLESCENTS

HEART AND MUSCLE K+ CHANNELS: ASSEMBLY AND REGULATION

TRAUMA AND INFLAMMATION RESEARCH TRAINING

A NOVEL CYCLIC PEPTIDE-BASED TREATMENT FOR TBI

MULTI-MODAL TRACKING OF IN VIVO SKELETAL STRUCTURES AND IMPLANTS - ABSTRACT THE GOAL OF THIS R01 APPLICATION IS TO DEVELOP STATE-OF-THE-ART, OPEN-SOURCE SOFTWARE FOR IMAGE-BASED ANALYSIS OF SKELETAL KINEMATICS. WORLDWIDE, OVER 250 MILLION PEOPLE ARE AFFECTED BY MUSCULOSKELETAL DISORDERS, INCLUDING ARTHRITIS, TRAUMA, OSTEOPOROSIS, AND SPINE PATHOLOGY, A NUMBER THAT IS PROJECTED TO INCREASE AS THE POPULATION AGES. THE IN-DEPTH UNDERSTANDING OF NORMAL JOINT FUNCTION AND THE CHANGES ASSOCIATED WITH AGING, INJURY AND DISEASE REQUIRES THE ABILITY TO QUANTITATIVELY MEASURE SKELETAL KINEMATICS. THE CURRENT STATE-OF-THE ART FOR QUANTIFYING SKELETAL KINEMATICS – ESPECIALLY THE COMPLEX MOTION AT THE JOINT SURFACE, CALLED ARTHROKINEMATICS – IS IMAGE-BASED OBJECT TRACKING PERFORMED WITH DATASETS FROM BIPLANE VIDEORADIOGRAPHY (BVR), AND STATIC AND DYNAMIC COMPUTED TOMOGRAPHY (3DCT AND 4DCT, RESPECTIVELY). REGARDLESS OF THE IMAGING MODALITY, IMAGE- BASED SKELETAL TRACKING INVOLVES IMAGE SEGMENTATION AND BONE MODEL GENERATION, BONE IMAGE REGISTRATION, COORDINATE SYSTEM SELECTION, AND DATA PRESENTATION. SOFTWARE AND COMPUTING INFRASTRUCTURE ARE CRITICAL FOR ACCURACY AND EFFICIENCY. THE LACK OF “INDUSTRY-STANDARD” SOFTWARE OR TEMPLATES FOR WORKFLOW ARE MAJOR OBSTACLES TO PROGRESS IN THE FIELD. LABORATORIES USE THEIR OWN COMBINATION OF COMMERCIAL, PUBLIC-DOMAIN, AND CUSTOM- WRITTEN CODE. THE CURRENT INDIVIDUALIZED IMPLEMENTATION MODEL IS INEFFICIENT, DUPLICATES EFFORT, AND IMPEDES COLLABORATION, AND, IMPORTANTLY, THE SHARING OF SOFTWARE AND TECHNICAL ADVANCES. RECENT FOCUS WORKSHOPS AND SURVEYS DEMONSTRATE CLEAR INTEREST IN BETTER SOLUTIONS. ACCORDINGLY, BASED ON OUR LONGSTANDING EXPERTISE IN IMAGE-BASED TRACKING, WE WILL DEVELOP AN OPEN SOURCE PROGRAM FOR IMAGE-BASED SKELETAL MOTION TRACKING CAPABLE OF ACCEPTING AS INPUT ALL OF THE COMMONLY USED IMAGING MODALITIES (VIDEORADIOGRAPHY, 3DCT, AND 4DCT). OUR LONG-TERM OBJECTIVE IS TO BUILD A WORLD-WIDE USER BASE OF COLLABORATORS AND CONTRIBUTORS TO FOSTER INNOVATION AND INQUIRY IN MUSCULOSKELETAL RESEARCH. IN OUR FIRST AIM WE WILL PARTNER WITH KITWARE, INC. AN EXPERIENCED AND SUCCESSFUL OPEN-SOURCE SOFTWARE DEVELOPMENT COMPANY, TO REFINE AND ENHANCE AUTOSCOPER, AND INTEGRATE IT INTO THE 3D SLICER PLATFORM TO YIELD SLICERAUTOSCOPERM (SAM). AUTOSCOPER IS AN EXISTING BVR SOFTWARE PROGRAM DEVELOPED AT BROWN UNIVERSITY TO SEMI-AUTOMATICALLY ALIGN SKELETAL STRUCTURES (BONES AND IMPLANTS) TO X-RAY VIDEOS. SAM WILL BE REFINED WITH INPUT FROM THE PROJECT’S CO-INVESTIGATORS AND AN ESTABLISHED CORE USER BASE. IN AIM 2 WE WILL DETERMINE THE AGREEMENT AND ACCURACY OF SAM BY COMPARING ITS OUTPUTS TO THOSE OF OBTAINED USING LEGACY METHODS, USING DATA FROM EXISTING STUDIES PERFORMED IN FOUR INDEPENDENT LABORATORIES. FINALLY, IN AIM 3 WE WILL USE A SYNTHETIC MODEL TO EVALUATE THE ACCURACY OF SAM IN ROUND-ROBIN TESTING IN FOUR LABS (BROWN, CLEVELAND CLINIC, MAYO CLINIC, AND QUEENS UNIVERSIYT) USING IMAGE DATA FROM 3DCT, 4DCT AND BVR. THE WORK OUTLINED IN THIS PROPOSAL WILL YIELD A STATE-OF-THE-ART, OPEN-SOURCE SOFTWARE SOLUTION THAT WILL ACCEPT DATASETS FROM MULTIPLE IMAGING MODALITIES. SAM WILL SIMPLIFY AND IMPROVE IMAGE-BASED SKELETAL TRACKING, FACILITATE THE SHARING OF NOVEL ANALYSIS ALGORITHMS, METHODOLOGIES, AND DATA, AND HASTEN THE TRANSLATION TO CLINICAL IMPLEMENTATION.

ASPH TARGETED THERAPY FOR CHONDROSARCOMA - PROJECT SUMMARY/ABSTRACT THE LONG-TERM OBJECTIVE OF THIS APPLICATION IS TO IMPROVE THE SURVIVAL AND QUALITY OF LIFE FOR PATIENTS WITH CHONDROSARCOMA, A PRIMARY MALIGNANT BONE TUMOR DESPERATELY IN NEED OF MORE EFFECTIVE TREATMENTS. THE FIVE- YEAR SURVIVAL FOR CHONDROSARCOMA, THE MOST COMMON BONE SARCOMA IN ADULTS, IS AN ABYSMAL 10-25%, WITH MOST PATIENTS SUCCUMBING TO PULMONARY METASTASES. CONVENTIONAL CYTOTOXIC CHEMOTHERAPY HAS NO EFFECT ON CHONDROSARCOMA, SO THE CURRENT STANDARD OF CARE IS SURGICAL RESECTION. THERE HAS BEEN NO IMPROVEMENT IN THE CURE RATE FOR CHONDROSARCOMA IN THE LAST SEVERAL DECADES. THE GOAL OF THIS PROPOSAL IS TO SYSTEMATICALLY EVALUATE PROMISING NEW TREATMENT STRATEGIES THAT TARGET ASPARTATE SS-HYDROXYLASE (ASPH), A TRANSMEMBRANE PROTEIN THAT IS NORMALLY EXPRESSED DURING EMBRYONIC DEVELOPMENT, BUT NOT AFTER BIRTH. WE HAVE FOUND THAT ASPH IS RE- EXPRESSED IN CHONDROSARCOMA. IN SOME CARCINOMAS, ASPH SIGNALS THROUGH THE NOTCH PATHWAY TO INFLUENCE THE EXPRESSION OF MATRIX METALLOPROTEINASES (MMPS) AND VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), WHICH SUPPORT CELL PROLIFERATION, INVASION, AND METASTASIS. WE HAVE DATA SUGGESTING THAT ASPH FUNCTIONS SIMILARLY IN CHONDROSARCOMA. ASPH IS HIGHLY EXPRESSED IN >90% OF CHONDROSARCOMAS, AS ARE ACTIVATED NOTCH AND MULTIPLE MMPS, AND HIGH ASPH EXPRESSION CORRELATES POSITIVELY WITH TUMOR GRADE AND POOR LONG-TERM SURVIVAL. INHIBITION OF NOTCH IS A LONG SOUGHT AFTER BUT, AS OF YET, UNACHIEVED GOAL IN CANCER TREATMENT. THE WORK IN THIS PROPOSAL WILL ADVANCE ASPH AS A POTENTIAL THERAPEUTIC TARGET BY DETERMINING THE RELATIONSHIP BETWEEN ASPH AND NOTCH IN CHONDROSARCOMA. FIRST, ASPH LEVELS IN HUMAN CHONDROSARCOMA CELL LINES WILL BE MODULATED USING CRISPR-CAS9 GENE EDITING, FOLLOWED BY TREATMENT WITH A PROVEN SMALL MOLECULE INHIBITOR (SMI) OF ASPH. CHANGES IN PROLIFERATION, INVASION, APOPTOSIS, AND NOTCH SIGNALING WILL BE USED AS MECHANISTIC READOUTS OF ASPH SIGNALING IN VITRO. NOTCH SIGNALING WILL BE MANIPULATED IN THESE ASPH-MODULATED CELL LINES WITH GAIN AND LOSS OF FUNCTION APPROACHES TO EVALUATE THE ROLE OF NOTCH IN ASPH SIGNALING (AIM 1). SECOND, THE ROLE OF ASPH AND NOTCH IN CHEMOTHERAPY RESISTANCE WILL BE EVALUATED IN HUMAN CHONDROSARCOMA CELL LINES, AND THE ABILITY OF THE SMI AND AN ASPH-TARGETED ANTIBODY-DRUG CONJUGATE (ADC) TO ENHANCE DOXORUBICIN EFFICACY WILL BE TESTED (AIM 2). FINALLY, THREE DIFFERENT APPROACHES TO TARGETING ASPH WILL BE EVALUATED IN VIVO USING MOUSE CHONDROSARCOMA MODELS: SMI INHIBITION OF ASPH, SMI + DOXORUBICIN, AND AN ANTIBODY-DRUG CONJUGATE TARGETING ASPH LINKED TO EMTANSINE (AIM 3). THE COMPLETION OF THESE AIMS WILL PROVIDE IMPORTANT INSIGHT INTO THE BIOLOGY OF CHONDROSARCOMA AND DETERMINE WHETHER THE THERAPEUTIC TARGETING OF ASPH HAS POTENTIAL AS AN EFFECTIVE STRATEGY FOR THE TREATMENT OF THESE MALIGNANCIES. THE RESULTS MAY ALSO HAVE WIDER IMPACT AND BE APPLICABLE TO PATIENTS WITH OTHER TYPES OF BONE AND SOFT TISSUE SARCOMAS.

EARLY BRAIN DEVELOPMENT AND CHILDHOOD OBESITY

TRANSLATIONAL APPROACHES FOR PATHOGENS OF HUMAN SIGNIFICANCE - THE OVERARCHING GOAL OF THIS PROPOSAL IS TO ESTABLISH A CENTER FOR BIOMEDICAL RESEARCH EXCELLENCE (COBRE) AT RHODE ISLAND HOSPITAL’S (RIH) CENTER FOR INTERNATIONAL HEALTH RESEARCH IN PARTNERSHIP WITH KEY COLLABORATORS ACROSS RHODE ISLAND. THE PROPOSED COBRE, TRANSLATIONAL APPROACHES FOR PATHOGENS OF HUMAN SIGNIFICANCE (“PATHOGENS”), EMPLOYS INTERDISCIPLINARY APPROACHES TO MITIGATE THE SIGNIFICANT MORBIDITY AND MORTALITY CAUSED BY PATHOGENS THAT ARE HIGHLY PREVALENT AMONG HUMAN POPULATIONS. THE DISEASES INITIALLY TARGETED BY THIS PHASE I COBRE PROPOSAL (MALARIA, TUBERCULOSIS, SCHISTOSOMIASIS, EBOLA) ARE HIGHLY PREVALENT AND COLLECTIVELY CAUSE 2 MILLION DEATHS ANNUALLY WITH ROUGHLY HALF OCCURRING IN CHILDREN. THESE INFECTIONS ARE FURTHER RESPONSIBLE FOR A SIGNIFICANT BURDEN OF DISEASE THAT IS DRIVEN BY THE MORBIDITY THEY CAUSE AMONG INFECTED INDIVIDUALS. THE PATHOGENS COBRE WILL SUPPORT AND FORTIFY THE CAREERS OF OUTSTANDING RESEARCH PROJECT LEADERS (RPLS) WHO WILL DEDICATE THEIR CAREERS TO REDUCE THE BURDEN OF DISEASE DUE TO THESE PATHOGENS WHILE ESTABLISHING A CENTER OF EXCELLENCE IN THIS CRUCIAL AREA OF RESEARCH. THE SCIENTIFIC AND MENTORING HUB FOR THE PATHOGENS COBRE WILL BE THE CENTER FOR INTERNATIONAL HEALTH RESEARCH (CIHR) AT RHODE ISLAND HOSPITAL (RIH). CIHR WAS ESTABLISHED BY RIH IN 2005 WITH TWO FACULTY MEMBERS AND HAS GROWN TO INCLUDE TEN FULL TIME AND MANY AFFILIATED FACULTY. CIHR, AND THE PROPOSED PATHOGENS COBRE, EMPLOY A “TEAM SCIENCE” APPROACH TO CONDUCT CUTTING EDGE TRANSLATIONAL RESEARCH, MORE EFFICIENTLY PROPELLING APPLICATION TO HUMAN POPULATIONS. THIS APPROACH ENGENDERS AND EMPHASIZES FLUENCY ACROSS SCIENTIFIC DISCIPLINES SPANNING THE CONTINUUM FROM MOLECULAR BIOLOGY TO POPULATION SCIENCE. WITH THE GROWING SCALE AND COMPLEXITY OF SCIENTIFIC RESEARCH, THIS APPROACH IS CRUCIAL TO THE ULTIMATE SUCCESS OF OUR RPLS WHO WILL LEARN WITHIN OUR HIGHLY SUCCESSFUL MODEL. THE LONG-TERM GOAL OF THE PATHOGENS COBRE IS TO DEVELOP, SUSTAIN, AND RECRUIT A CRITICAL MASS OF INVESTIGATORS AND ESTABLISH KEY CORES WITH A FOCUS ON SOME OF THE MOST SIGNIFICANT PATHOGENS IMPACTING HUMAN HEALTH. THE OBJECTIVES OF THIS PHASE I PROPOSAL ARE TO ESTABLISH AND BUILD A CENTER WITH AN EXPERIENCED TEAM OF MENTORS AND OUTSTANDING INITIAL RPLS IN SUPPORT OF THEIR TRANSITION TO RESEARCH INDEPENDENCE WHILE ALSO EXPANDING AND CONSOLIDATING THE POOL OF INVESTIGATORS STUDYING PATHOGENS AT RIH AND THE BROADER RI SCIENTIFIC COMMUNITY. THE SUCCESSFUL ESTABLISHMENT OF THE PATHOGENS COBRE WILL SUPPORT THE TRANSITION OF FOUR OUTSTANDING RPLS TO RESEARCH INDEPENDENCE AND BUILD AND SUSTAIN THE PATHOGENS CENTER, WHICH WILL APPLY TRANSDISCIPLINARY APPROACHES TO ACCELERATE THE DELIVERY OF THERAPEUTICS FOR SOME OF HUMANITY’S MOST DEADLY PATHOGENS.

BIOMARKERS TO IDENTIFY INDIVIDUALS AT RISK FOR PROGRESSION OF S. JAPONICUM ASSOCIATED HEPATIC FIBROSIS WITH POINT OF CARE TEST DEVELOPMENT - PROJECT SUMMARY THE OVERALL GOALS OF THIS TROPICAL MEDICINE RESEARCH CENTER (TMRC), PROPOSED FOR THE RESEARCH INSTITUTE OF TROPICAL MEDICINE (RITM) IN THE PHILIPPINES, ARE TO A) EXECUTE THE KEY SCIENTIFIC AIMS OF THIS STUDY, B) BUILD RESEARCH CAPACITY AT RITM, AND C) BUILD RESEARCH CAPACITY AND SUPPORT THE DEVELOPMENT OF JUNIOR INVESTIGATORS AT ALL TMRCS IN PARTNERSHIP WITH THE TMRC COORDINATING CENTER’S “OPPORTUNITY FUNDS” AND OTHER INITIATIVES CURRENTLY, PREVENTATIVE CHEMOTHERAPY STRATEGIES WITH PRAZIQUANTEL (PZQ) ARE THE MAINSTAY OF TREATMENT FOR SCHISTOSOMIASIS, WITH “MASS DRUG ADMINISTRATION” (MDA) DELIVERED ANNUALLY OR BI-ANNUALLY. THE PRIMARY CAUSE OF SEVERE MORBIDITY AND DEATH DUE TO INTESTINAL SCHISTOSOMIASIS IS PORTAL FIBROSIS SECONDARY TO INTRA-HEPATIC EGG DEPOSITION WITH CONSEQUENT PORTAL HYPERTENSION AND ESOPHAGEAL VARICES WITH HIGH RISK OF HEMORRHAGE. IMPORTANTLY, THERE ARE NO CURRENT RECOMMENDATIONS TO IDENTIFY AND MORE AGGRESSIVELY TREAT INDIVIDUALS WITH HEPATIC FIBROSIS IN MOST REGIONS, INCLUDING THE PHILIPPINES, LEAVING INDIVIDUALS TO RECEIVE INFREQUENT, IF ANY, TREATMENT. CURRENTLY, LITTLE IS KNOWN WITH RESPECT TO RISK FACTORS FOR PROGRESSION TO HIGHER GRADE PORTAL FIBROSIS, INCLUDING BIOMARKERS TO IDENTIFY RISK. THIS IS A LOST OPPORTUNITY TO MITIGATE THIS RISK THROUGH MORE FREQUENT TREATMENT, WHICH HAS BEEN SHOWN TO HALT AND EVEN REVERSE FIBROSIS IF IDENTIFIED EARLY. OUR GROUPS HAVE DEVELOPED A MULTIPLEXED “FIBROPLEX_V2” ASSAY THAT NOW CAPTURES 38 KEY ANALYTES INVOLVED IN FIBRO-PROLIFERATION OR DEGRADATION. WE WILL EMPLOY THIS TO ADDRESS THE SCIENTIFIC GOALS OF THE STUDY WHICH ARE TO: 1) EVALUATE BIOMARKERS THAT WILL IDENTIFY INDIVIDUALS WITH S. JAPONICUM ASSOCIATED HEPATIC FIBROSIS AS DIAGNOSED BY ULTRASOUND (US) AT BASELINE AS WELL AS BIOMARKERS THAT IDENTIFY RISK OF PROGRESSION FROM MILD-MODERATE TO HIGHER GRADES AS ASSESSED BY US ANNUALLY FOR THREE YEARS 2) TO DEVELOP DIAGNOSTIC TESTS TO FACILITATE IDENTIFICATION OF HIGH-RISK INDIVIDUALS IN THE FIELD WHO WOULD ULTIMATELY BENEFIT FROM MORE FREQUENT TREATMENT WITH PZQ OR OTHER TREATMENT APPROACHES. WE EXPECT MANY ANALYTES WILL PREDICT PROGRESSION AND THESE WILL BE DEVELOPED SINGLY OR IN COMBINATION AS LATERAL FLOW-BASED ASSAYS THAT CAN ULTIMATELY BE DEVELOPED AS POCTS FOR USE WITH MDA. THE AVAILABILITY OF POTENTIAL TREATMENT APPROACHES TO HALT PROGRESSION, THE LACK OF APPROACHES TO REVERSE HIGHER GRADE PERIPORTAL FIBROSIS ONCE ESTABLISHED, AND SUB-OPTIMAL INTERVENTIONS FOR ADDRESSING PORTAL HYPERTENSION AND ITS HIGH MORTALITY RATE ONCE ESTABLISHED, MAKE THIS AN IDEAL SCREENING TARGET. BIOMARKERS THAT LONGITUDINALLY PREDICT RISK OF PROGRESSION TO LESS REVERSIBLE GRADES ARE A CRUCIAL FIRST STEP. THE SUCCESSFUL EXECUTION OF THESE AIMS WILL ALSO BUILD RESEARCH CAPACITY AT RITM AND PROVIDE OUTSTANDING OPPORTUNITIES FOR RELATED STUDIES THROUGH TMRC “OPPORTUNITY FUNDS” AS WELL AS FUTURE GRANTS TO EVALUATE DIFFERENT TREATMENT STRATEGIES FOR INDIVIDUALS AT RISK FOR FIBROSIS PROGRESSION WITH DEFINITIVE RANDOMIZED CONTROLLED TRIALS.

ADOLESCENTS' SOCIAL MEDIA USE AND INTERNALIZING SYMPTOMS: MECHANISMS OF RISK AND RESILIENCE - PROJECT SUMMARY/ABSTRACT RATES OF INTERNALIZING SYMPTOMS (DEPRESSION, ANXIETY) AMONG YOUTH HAVE INCREASED SIGNIFICANTLY OVER THE PAST DECADE. DURING THIS SAME TIME PERIOD, THE USE OF SOCIAL MEDIA (E.G., TIKTOK, SNAPCHAT) HAS BECOME NEARLY UBIQUITOUS, WITH 97% OF ADOLESCENTS USING AT LEAST ONE PLATFORM. DESPITE GROWING PUBLIC CONCERN THAT SOCIAL MEDIA HAS CONTRIBUTED TO THE YOUTH MENTAL HEALTH CRISIS, LITTLE IS KNOWN ABOUT HOW AND FOR WHOM SOCIAL MEDIA USE CONTRIBUTES RISK FOR INTERNALIZING PROBLEMS AMONG ADOLESCENTS. THIS STUDY AIMS TO IDENTIFY SPECIFIC MECHANISMS OF RISK IN THE CONTEXT OF SOCIAL MEDIA ENGAGEMENT, INCLUDING YOUTHS’ USES OF, BELIEFS ABOUT, AND EMOTIONAL RESPONSES TO SOCIAL MEDIA. WE WILL RECRUIT A DIVERSE SAMPLE OF 200 YOUTH (AGES 13-16) WITH A FULL RANGE OF INTERNALIZING SYMPTOMS FOR A FOUR-WAVE, LONGITUDINAL STUDY WITH ASSESSMENTS AT BASELINE, 6-, 12-, AND 18-MONTH FOLLOW-UP. PARTICIPANTS WILL ENGAGE IN AN INNOVATIVE, ONLINE EXPERIMENTAL EYE-TRACKING TASK THAT SIMULATES PEER INTERACTIONS IN A SOCIAL MEDIA ENVIRONMENT. AT EACH TIME POINT, A REAL-TIME, COLLABORATIVE SOCIAL MEDIA DATA COLLECTION PROCEDURE WILL BE USED AND DIMENSIONAL MEASURES OF INTERNALIZING SYMPTOMS COLLECTED. WE WILL ALSO CONVENE A YOUTH ADVISORY BOARD TO PROVIDE ONGOING FEEDBACK AND INSIGHT. THE PRIMARY AIMS OF THIS STUDY ARE TO: (1) IDENTIFY SOCIAL MEDIA EXPERIENCES THAT INCREASE ADOLESCENTS’ RISK FOR SUBSEQUENT INTERNALIZING SYMPTOMS, USING AN EXPERIMENTAL, EYE-TRACKING PARADIGM; (2) TEST A LONGITUDINAL MEDIATION MODEL WHEREBY ADOLESCENTS’ BELIEFS ABOUT SOCIAL MEDIA PREDICT HIGH-RISK SOCIAL MEDIA ENGAGEMENT AND SUBSEQUENT INTERNALIZING SYMPTOMS; AND (3) EXAMINE MODERATION EFFECTS BY GENDER AND AGE IN THE ASSOCIATIONS AMONG BELIEFS ABOUT SOCIAL MEDIA, SOCIAL MEDIA USE, AND INTERNALIZING SYMPTOMS (EXPLORATORY AIM). THIS RESEARCH WILL OFFER NEW INSIGHTS INTO THE MECHANISMS OF SOCIAL MEDIA’S INFLUENCE ON ADOLESCENT INTERNALIZING SYMPTOMS. IT WILL IDENTIFY NOVEL, POTENTIALLY-MODIFIABLE TARGETS FOR FUTURE CLINICAL, EDUCATION, AND PUBLIC HEALTH INTERVENTIONS, AND WILL HAVE IMMEDIATE RELEVANCE FOR SUPPORTING YOUTH IN USING SOCIAL MEDIA IN HEALTHIER WAYS.

DIFFERENTIAL EFFECTS OF SEPSIS ON IMMUNE CELL FUNCTION

ETHANOL, IRS-1 SIGNALING AND NEURONAL MIGRATION

TARGETED VACCINE DEVELOPMENT FOR PEDIATRIC FALCIPARUM MALARIA

HIV PREVENTION FOR YOUTH WITH SEVERE MENTAL ILLNESS

GENE THERAPY FOR LONG QT SYNDROME TYPE 2 - ABSTRACT THERE ARE >500 PATHOLOGIC VARIANTS WITHIN 17 GENES CAUSING CONGENITAL LONG QT SYNDROME, WHICH LEADS TO POLYMORPHIC VENTRICULAR TACHYCARDIA (PVT) AND SUDDEN CARDIAC DEATH (SCD). ABOUT 30% OF THE MUTATIONS ARE CONCENTRATED IN THE KCNH2 GENE RESULTING IN LOSS-OF-FUNCTION OF THE RAPIDLY ACTIVATING DELAYED RECTIFIER POTASSIUM CURRENT IKR CAUSING PROLONGATION OF THE ACTION POTENTIAL DURATION AND QT INTERVAL (LQT2). WE DEVELOPED A TRANSGENIC RABBIT MODEL FOR LQT2 THAT RECAPITULATE THE HUMAN PHENOTYPE. THIS APPLICATION IS AIMED AT DEVELOPING GENE THERAPY FOR LQT2 USING OUR RABBIT MODEL AND AN AAV9-MEDIATED MOSAIC GENE EXPRESSION OF HERG. AIM 1 TO RESCUE THE PHENOTYPE OF LQT2G BY DELIVERING AAV9-ENCODED SHRNA THAT WILL ABOLISH EXPRESSION OF BOTH THE HUMAN PORE MUTANT TRANSGENE AND ENDOGENOUS RERG WITH AN SHRNA-RESISTANT HERG (HERG*) UNDER THE CONTROL OF THE CMV PROMOTER AT DOSES OF 6E13VG/KG AND 2E14VG/KG AS COMPARED TO VEHICLE CONTROL. THE AIM ALSO PROPOSES TO STUDY THE CELLULAR PHENOTYPE OF THE TREATED RABBITS AS COMPARED TO VEHICLE CONTROL. AIM 2 PROPOSES TO MONITOR ANT TEST THE TWO GROUPS FOR SPONTANEOUS AND INDUCIBLE ARRHYTHMIAS. THIS APPLICATION OUTLINES THE ROADMAP FOR GENE THERAPY OF ALL VARIANTS CAUSING HUMAN LQT2 SYNDROME AND HAS THE POTENTIAL TO REVOLUTIONIZE THE THERAPY OF THIS SYNDROME.

PHASE II PK/PD DRIVEN DOSE FINDING TRIAL OF PRAZIQUANTEL IN CHILDREN UNDER FOUR

CARDIAC UBIQUITIN LIGASES: REGULATION AND ROLE IN MODULATING CARDIAC EXCITATION.

SEX HORMONES AND CARDIAC ARRHYTHMIA IN TRANSGENIC LQT2 RABBITS

REPRODUCTIVE HORMONES AND THEIR IMPACT ON HIV-1 ACQUISITION

IMPLEMENTING STATEWIDE EMERGENCY DEPARTMENT CARE PATHWAYS FOR ADDICTION RECOVERY AFTER OPIOID OVERDOSE

BRIEF ALCOHOL INTERVENTION TO REDUCE AT-RISK DRINKING AMONG TYPE 2 DIABETES

EFFECTS OF INITIAL GRAFT TENSION ON ACL RECONSTRUCTION

BROWN CARDIOPULMONARY RESEARCH TRAINING PROGRAM

NON-TRIBOLOGIC BIOACTIVITY OF LUBRICIN

IMPROVING SEPSIS CARE WITH DEEP RNA SEQUENCING DATA - PROJECT SUMMARY/ABSTRACT SEPSIS IS RESPONSIBLE FOR ONE OUT OF EVERY FIVE DEATHS WORLDWIDE. IT IS THEREFORE ESSENTIAL TO BETTER UNDERSTAND BETTER DIAGNOSE AND TREAT SEPSIS. WE PROPOSE TO USE DEEP RNA SEQUENCING OF THE WHOLE BLOOD OF SEPSIS PATIENTS TO BETTER IDENTIFY THE PATHOGEN CAUSING THE DISEASE, TRIAGE THE APPROPRIATE RESOURCES, PREDICT OUTCOMES, AND IDENTIFY NOVEL THERAPEUTIC TARGETS. UTILIZING NOVEL METHODS OF COMPUTATIONAL ANALYSIS OF DEEP RNA SEQUENCING DATA WE WILL ASSESS MICROBIAL POPULATIONS, RNA BIOLOGY (SPECIFICALLY RNA SPLICING ENTROPY AND RNA LARIATS) AND IDENTIFY NOVEL TREATMENT TARGETS/IDENTIFY PATIENTS LIKELY TO BENEFIT. SOME RNA SEQUENCING DATA THAT DOES NOT MATCH THE SPECIES IT CAME FROM (HUMAN) IS TYPICALLY DISCARDED. WE WILL LOOK AT THIS TYPICALLY DISCARDED DATA FOR MICROBIAL (BACTERIA AND VIRUSES) POPULATIONS TO IMPROVE DIAGNOSTIC ABILITY. TO ASSESS THE HOST RESPONSE WE WILL STUDY RNA BIOLOGY. RNA SPLICING IS A BASIC MOLECULAR FUNCTION THAT OCCURS IN ALL CELLS DIRECTLY AFTER RNA TRANSCRIPTION, BUT BEFORE PROTEIN TRANSLATION IN WHICH INTRONS ARE REMOVED AND EXONS ARE JOINED TOGETHER. OVER 90% OF HUMAN GENES WITH MULTIPLE EXONS HAVE ALTERNATIVE SPLICING EVENTS. WE HOPE TO ASSESS IF RNA SPLICING ENTROPY COULD BE A POTENTIAL BIOMARKER IN SEPSIS. INTRONS ARE TYPICALLY DEGRADED RAPIDLY AFTER REMOVAL DURING SPLICING, HOWEVER, THE PRESENCE OF THESE LARIATS COULD SIGNIFY RNA METABOLISM DYSFUNCTION AND WE WILL CORRELATE THIS TO OUTCOMES. RNA SEQUENCING DATA WILL ALSO ALLOW FOR APPLICATION OF NOVEL INTERVENTIONS, SUCH AS PD-1 ANTIBODIES, TO PATIENTS MOST LIKELY TO BENEFIT; ESSENTIALLY APPLYING PRECISION MEDICINE TO A CRITICALLY ILL PATIENT. WE WILL UTILIZE WHOLE BLOOD FROM HUMANS WITH SEPSIS AND COMPARE TO CONTROL PATIENTS IN THE INTENSIVE CARE UNIT WITHOUT SEPSIS. SAMPLES WILL BE COLLECTED SERIALLY OVER THE COURSE OF THE STAY IN THE INTENSIVE CARE UNIT. WE HYPOTHESIZE THAT DATA FROM DEEP RNA SEQUENCING OBTAINED DURING SEPSIS CAN BE QUANTIFIED AND IMPROVE CARE.

TRIBOSUPPLEMENTATION WITH LUBRICIN IN PREVENTION OF POST-TRAUMATIC ARTHRITIS

AMPICILLIN RESISTANCE MECHANISMS IN E. FAECIUM

A RANDOMIZED CONTROLLED TRIAL OF FAMILY-BASED HIV PREVENTION FOR LATINO YOUTH

USE OF BIOMIMICRY TO DETERMINE THE EFFECT OF SEPSIS ON NEUTROPHIL TRACTION

NON-INVASIVE ASSESSMENT OF LIGAMENT HEALING IN VIVO

IDENTIFICATION OF A DAMAGING SUBSET OF NEUTROPHILS THAT ARISES IN SEPTIC PATIENTS

DEVELOPMENTAL-BEHAVIORAL PEDIATRICS TRAINING PROGRAM

ENDOTHELIAL PLASTICITY IN HUMAN DISEASE

EFFECTS OF ETHANOL ON INSULIN SIGNALING IN THE BRAIN

ADVANCING HEMIARTHROPLASTY: PREDICTING IN VIVO PERFORMANCE OF CARTILAGE BEARING SYSTEMS THROUGH BENCHTOP AND EX VIVO TESTING. - ABSTRACT THE ULTIMATE GOAL OF THIS RESEARCH PROGRAM IS TO ADVANCE HEMIARTHROPLASTY PERFORMANCE. HEMIARTHROPLASTY INVOLVES REPLACEMENT OF ONE OF THE ARTICULAR JOINT SURFACES WITH AN ARTIFICIAL BEARING SURFACE. IT OFFERS A CLEAR BENEFIT IN PATIENTS WITH LOCALIZED CARTILAGE DAMAGE, PRESERVING THE HEALTHY BONE AND CARTILAGE IN THE JOINT TO MAXIMIZE FUTURE TREATMENT OPTIONS. AND HEMIARTHROPLASTY IS INHERENT IN THE REPLACEMENT OF INDIVIDUALLY DISEASED CARPAL (WRIST) OR TARSAL (FOOT) BONES, WHICH HAVE MULTIPLE ARTICULATIONS WITH NEIGHBORING BONES. CURRENTLY, HEMIARTHROPLASTY OUTCOMES VARY DRAMATICALLY BY THE JOINT INVOLVED AND BY THE TYPE OF BEARING SURFACE USED TO ARTICULATE WITH THE OPPOSING CARTILAGE. FAILURE MOST OFTEN OCCURS BY DEGENERATION OF THE OPPOSING ARTICULAR SURFACE. A CRITICAL CHALLENGE IN ADVANCING HEMIARTHROPLASTY PERFORMANCE IS THE ABILITY TO IDENTIFY BEARING SURFACES THAT WILL MAINTAIN HEALTHY CARTILAGE. THERE ARE NUMEROUS CANDIDATE BIOMATERIALS THAT MIGHT BE SUITABLE FOR USE AS HEMIARTHROPLASTY BEARING SURFACES, INCLUDING METALS, CERAMICS, AND POLYMERS, AS WELL AS SPECIALIZED COATINGS, SUCH AS TITANIUM NITRIDE AND PYROLYTIC CARBON. HOWEVER, THE PERFORMANCE OF THESE MATERIALS HAS BEEN MIXED, DUE IN LARGE PART TO THE LACK OF STANDARDIZED AND VALIDATED TESTING METHODOLOGIES. ACCORDINGLY, THE SPECIFIC OBJECTIVE OF THIS PROJECT IS TO DEVELOP A MODEL WHERE BENCHTOP AND EX VIVO TESTING CAN PREDICT THE CARTILAGE RESPONSE TO HEMIARTHROPLASTY BEARING SYSTEM WEAR IN A FIT-FOR-PURPOSE LARGE ANIMAL MODEL. THIS GOAL WILL BE ACHIEVED BY COMPLETING THREE SPECIFIC AIMS. IN THE FIRST, WE WILL CHARACTERIZE THE MATERIAL AND MECHANICAL PROPERTIES OF EIGHT CANDIDATE HEMIARTHROPLASTY BEARING SURFACES (2 METALS, 4 POLYMERS, 1 CERAMIC, AND 1 PYROLYTIC CARBON) USING STANDARD BENCHTOP MECHANICAL TESTS (ROUGHNESS, WETTABILITY, MODULUS, HARDNESS, AND WEAR TESTING AGAINST CORTICAL BONE). IN THE SECOND, WE WILL CHARACTERIZE THE CARTILAGE BEARING PERFORMANCE OF EACH OF THE CANDIDATE BIOMATERIALS BY WEAR TESTING THEM AGAINST BOVINE CARTILAGE PLUGS IN A JOINT MOTION-SIMULATING BIOTRIBOMETER, USING PROTEOGLYCAN/GLYCOSAMINOGLYCAN (PG/GAG) AND HYDROXYPROLINE AS MEASURES OF CARTILAGE MATRIX DEGRADATION AND LIVE/DEAD ASSAYS AS A MEASURE OF CELL DAMAGE. IN THE THIRD, WE WILL TEST FOUR OF THE 8 MATERIALS FROM AIMS 1 & 2 AS BEARING SURFACES IN A NOVEL UNICOMPARTMENTAL TIBIAL HEMIARTHROPLASTY MODEL IN THE YUCATAN MINIPIG, MEASURING CARTILAGE DAMAGE (MACRO- AND MICROSCOPIC), SYNOVIAL INFLAMMATION, CARTILAGE THICKNESS, AND OSTEOPHYTE BONE FORMATION AT 52 WEEKS. AND FINALLY, WE WILL DEVELOP A STATISTICAL MODEL WHERE THE DATA FROM AIMS 1 AND 2 CAN BE USED TO PREDICT THE OUTCOME IN AIM 3. THE WORK OUTLINED IN THIS PROPOSAL WILL YIELD A MODEL WHERE BENCHTOP AND EX VIVO TESTING CAN PREDICT THE CARTILAGE RESPONSE TO HEMIARTHROPLASTY. THIS PROJECT WILL PROVIDE A CRUCIAL TOOL NEEDED TO ACCELERATE THE DESIGN, DEVELOPMENT, AND FDA CLEARANCE OF NEW HEMIARTHROPLASTY BEARING SURFACES, RESULTING IN A SIGNIFICANT BENEFIT FOR MILLIONS OF PATIENTS AFFLICTED WITH DEGENERATIVE JOINT DISEASE.

THE ROLE OF ABELSON INTERACTOR 1 (ABI-1) IN HEMATOPOIETIC STEM CELL SELF-RENEWAL AND MALIGNANT TRANSFORMATION: DIVERSITY SUPPLEMENT

REGULATION OF GQ SIGNALING IN CARDIAC FIBROBLASTS AND ITS ROLE IN CARDIAC REMODEL

REDUCING DRIVING OFFENSES OF ADOLESCENT DRINKERS

SKCA/IKCA CHANNEL ACTIVATION AND ENDOTHELIAL PROTECTION DURING CARDIAC SURGERY

INTRA-ARTICULAR INJECTION OF ALPHA-2 MACROGLOBULIN PREVENTS POST-TRAUMATIC OSTEOARTHRITIS

THE ROLE OF DYNAMIC CHANGES IN REPOLARIZATION AND CALCIUM TRANSIENTS IN LONG QT R

DEVELOPMENTAL-BEHAVIORAL PEDIATRICS TRAINING PROGRAM

TREATMENT STUDY USING DEPOT NALTREXONE(2/6)RHODE ISLAND PROTOCOL TREATMENT SITE

HEPATITIS B VIRUS VACCINE ESCAPE MUTANTS

THERAPEUTIC TARGETING OF GSK3BETA: A NOVEL APPROACH FOR PODOCYTE PROTECTION

ROLE OF PTPN11 IN CARTILAGE STEM CELLS AND TUMORIGENESIS

PREVENTING SEXUAL AGGRESSION AMONG HIGH SCHOOL BOYS

PATHOGENESIS OF EARLY- VERSUS LATE-STAGE ALCOHOL-MEDIATED WHITE MATTER DEGENERATION - CHRONIC HEAVY OR BINGE ALCOHOL CONSUMPTION DAMAGES THE STRUCTURAL AND FUNCTIONAL INTEGRITY OF THE BRAIN. ETHANOL’S NEUROTOXIC AND DEGENERATIVE EFFECTS TARGET WHITE MATTER (WM) ACROSS THE LIFESPAN, RESULTING IN LOSS OF MYELIN, IMPAIRED MYELIN MAINTENANCE, AND DEGENERATION OF AXONS. SINCE WM INTEGRITY IS CRITICAL TO MANY CNS FUNCTIONS, BETTER UNDERSTANDING OF HOW ETHANOL EXERTS ITS ADVERSE EFFECTS ON WM IS NEEDED TO PREVENT OR REMEDIATE THE ASSOCIATED NEUROBEHAVIORAL AND COGNITIVE DEFICITS. OLIGODENDROCYTE DYSFUNCTION IS AT THE CORE OF WM DEGENERATION SINCE OLIGODENDROGLIA ARE RESPONSIBLE FOR SYNTHESIZING AND MAINTAINING MYELIN. MYELIN IS NEEDED TO SUPPORT AND PROTECT AXONS AND ENSURE EFFICIENT NEURONAL CONDUCTIVITY. WE HYPOTHESIZE THAT ALCOHOL- RELATED BRAIN DEGENERATION (ARBD) INVOLVING WM COULD BE DIVIDED INTO: 1) AN EARLY, REVERSIBLE STAGE THAT IS MAINLY ASSOCIATED WITH MYELIN LOSS AND MEDIATED BY OXIDATIVE STRESS, INFLAMMATION, AND NEUROTOXIC CERAMIDE ACCUMULATION VIA MYELIN BREAKDOWN AND DYSREGULATION OF LIPID METABOLISM; AND 2) A LATER STAGE MARKED BY IMPAIRED INSULIN/IGF-1 SIGNALING THROUGH PI3K-AKT-MTOR-MTORC. CONSEQUENCES OF THE LATTER INCLUDE LOSS OF MATURE OLIGODENDROCYTES AND COMPACT MYELIN, IMPAIRED MATURATION OF OLIGODENDROGLIA, AXONAL DAMAGE, AND FURTHER PROGRESSIVE DYSREGULATED SPHINGOLIPID METABOLISM WITH CERAMIDE ACCUMULATION AND SULFATIDE DEPLETION. WE ANTICIPATE THAT ABSTINENCE WILL BE SUFFICIENT TO REMEDIATE EARLY STAGES OF WM ARBD, WHEREAS ACTIVE INTERVENTIONS, SUCH AS INSULIN SENSITIZER TREATMENTS, WILL BE REQUIRED TO REVERSE WM DAMAGE SUSTAINED BY LONG PERIODS OF HEAVY ALCOHOL EXPOSURE. HOWEVER, BOTH EARLY AND LATE STAGES OF ARBD WILL LIKELY RESPOND TO CERAMIDE INHIBITORS SUCH AS MYRIOCIN. AIM 1 WILL CHARACTERIZE THE STRUCTURAL, BIOCHEMICAL AND MOLECULAR PATHOLOGIES OF EARLY-STAGE WM ARBD IN AN ESTABLISHED RAT MODEL OF CHRONIC ETHANOL EXPOSURE. AIM 2 WILL UTILIZE A RAT MODEL AND HUMAN POSTMORTEM BRAINS TO ASSESS THE ROLES OF IMPAIRED INSULIN/IGF-1 SIGNALING THROUGH PI3K-AKT-MTOR AND MTORC1 VERSUS MTORC2 AS DRIVERS OF OLIGODENDROCYTE DYSFUNCTION AND ALTERED SPHINGOLIPID METABOLISM IN THE LATER STAGES OF WM ARBD. AIM 3 WILL EVALUATE THE EFFECTIVENESS OF ABSTINENCE, CERAMIDE INHIBITOR, AND INSULIN SENSITIZER TREATMENTS IN REMEDIATING OLIGODENDROCYTE DYSFUNCTION AND ASSOCIATED ALTERATIONS IN MYELIN SPHINGOLIPID COMPOSITION IN EARLY VERSUS LATE STAGES OF WM ARBD. IN ADDITION, A NOVEL SUB-AIM WILL DETERMINE THE DEGREE TO WHICH ETHANOL-INDUCED CNS WM MYELIN SPHINGOLIPID ABNORMALITIES AND THEIR RESPONSES TO TREATMENT CAN BE DETECTED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS). OUR UNDERLYING HYPOTHESES ARE ADDRESSED THROUGH THE USE OF QUANTITATIVE IMMUNOHISTOCHEMISTRY, ELECTRON MICROSCOPY, MULTIPLEX ELISAS, MRNA STUDIES, AND MATRIX-ASSISTED LASER DESORPTION/IONIZATION-IMAGING MASS SPECTROMETRY. THE RESEARCH PLAN IS NOVEL, MECHANISTIC, ROBUST, TRANSPARENT, AND INCLUSIVE OF BOTH SEXES, HUMAN VALIDATION STUDIES, PROSPECTS FOR STRATIFYING TREATMENT ACCORDING TO ARBD STAGE, AND APPROACHES FOR POTENTIALLY MONITORING ARBD-ASSOCIATED WM BIOCHEMICAL PATHOLOGY AND RESPONSES TO TREATMENT WITH NON-INVASIVE PBMC ASSAYS.

MICROBIAL TRANSLOCATION, INFLAMMATION, AND ADVERSE PREGNANCY OUTCOMES IN HUMANS

PROMOTING UTILIZATION AND SAFETY OF HYDROXYUREA USING PRECISION IN AFRICA - PROJECT SUMMARY/ABSTRACT SICKLE CELL ANEMIA (SCA) IS AMONG THE WORLD’S MOST COMMON AND DEVASTATING BLOOD DISORDERS, AFFECTING MORE THAN 300,000 NEWBORNS PER YEAR. THE MAJORITY OF INFANTS WITH SCA ARE BORN IN THE LOW-RESOURCE SETTINGS OF SUB- SAHARAN AFRICA, WHERE AN ESTIMATED 50-90% WILL DIE BEFORE 5 YEARS OF AGE DUE TO LACK OF EARLY DIAGNOSIS AND APPROPRIATE CARE. HYDROXYUREA IS A ONCE-DAILY ORAL MEDICATION THAT HAS BECOME THE STANDARD OF CARE FOR THE TREATMENT OF CHILDREN WITH SCA IN HIGH-RESOURCE SETTINGS. THERE IS NOW A GROWING BODY OF EVIDENCE TO SUPPORT THE SAFETY AND CLINICAL BENEFITS OF HYDROXYUREA FOR THE TREATMENT OF SCA IN SUB-SAHARAN AFRICA. THE REQUIREMENT FOR FREQUENT LABORATORY MONITORING AND THE CONCERN FOR HEMATOLOGIC LABORATORY TOXICITIES, HOWEVER, WILL LIMIT WIDESPREAD HYDROXYUREA UTILIZATION. WE HAVE RECENTLY DEVELOPED AND PROSPECTIVELY EVALUATED AN INDIVIDUALIZED, PHARMACOKINETICS-GUIDED HYDROXYUREA DOSING STRATEGY FOR CHILDREN WITH SCA THAT HAS DEMONSTRATED OPTIMAL CLINICAL AND LABORATORY BENEFITS WITH MINIMAL TOXICITY. IN THIS PROPOSAL, WE AIM TO EXTEND THIS PRECISION MEDICINE APPROACH TO AFRICA. THIS PROPOSAL INCLUDES A PROSPECTIVE, RANDOMIZED CLINICAL TRIAL OF HYDROXYUREA FOR CHILDREN WITH SCA AT TWO CLINICAL SITES IN SUB-SAHARAN AFRICAN (LUANDA, ANGOLA AND MWANZA, TANZANIA). THE STUDY WILL BE THE FIRST TO BRING PRECISION MEDICINE TO CHILDREN WITH SCA THROUGH SEVERAL NOVEL FEATURES INCLUDING MEASUREMENT OF HYDROXYUREA USING A BATTERY-POWERED HPLC MACHINE AND INDIVIDUALIZED DOSE CALCULATIONS USING AN AUTOMATED COMPUTER-BASED ALGORITHM. THE FIRST PHASE OF THE STUDY WILL COMPARE DOSING STRATEGIES AND DETERMINE THE OPTIMAL DOSING STRATEGY, AND THE SECOND PHASE WILL IMPORTANTLY ADDRESS THE SAFETY OF HYDROXYUREA THERAPY WITH LIMITED LABORATORY MONITORING. THE PRIMARY OBJECTIVES ARE TO ESTABLISH THE FEASIBILITY AND EVALUATE THE CLINICAL BENEFITS OF PK-GUIDED HYDROXYUREA FOR CHILDREN WITH SCA IN AFRICA AND TO PROVIDE EVIDENCE TO SUPPORT MINIMAL LABORATORY MONITORING WITH HYDROXYUREA THERAPY IN THESE SETTINGS. WE WILL ACCOMPLISH THESE OBJECTIVES THROUGH THE FOLLOWING SPECIFIC AIMS: SPECIFIC AIM 1: TO COMPARE THE CLINICAL BENEFITS OF TWO HYDROXYUREA DOSING STRATEGIES FOR TREATMENT OF SCA IN SUB-SAHARAN AFRICA: A NOVEL INDIVIDUALIZED, PK-GUIDED INITIAL DOSE WITHOUT SUBSEQUENT ESCALATION AND A WEIGHT-BASED DOSE WITH SUBSEQUENT DOSE ESCALATION. WE HYPOTHESIZE THAT THE PK- GUIDED ARM WILL HAVE A REDUCTION IN SICKLE-RELATED ADVERSE EVENTS COMPARED TO THE WEIGHT-BASED ARM. SPECIFIC AIM 2: TO EVALUATE THE SAFETY OF HYDROXYUREA FOR CHILDREN WITH SCA IN SUB-SAHARAN AFRICA WITH LIMITED LABORATORY MONITORING. WE HYPOTHESIZE THAT THERE WILL BE NO DIFFERENCE IN THE FREQUENCY OF ADVERSE EVENTS (GRADE = 3) UNRELATED TO SCA DURING THE PERIOD OF HYDROXYUREA TREATMENT WITH LIMITED MONITORING COMPARED TO THE NO TREATMENT RUN-IN PERIOD. EXPLORATORY AIM 3: TO EVALUATE THE UTILITY AND VALIDITY OF TWO ESTABLISHED MEASURES OF HEALTH-RELATED QUALITY OF LIFE (HRQOL) FOR PATIENTS AND FAMILIES AFFECTED BY SCA IN ANGOLA AND TANZANIA BEFORE AND AFTER HYDROXYUREA TREATMENT. WE HYPOTHESIZE THAT BASELINE HRQOL MEASURES WILL BE LOW FOR BOTH MEASURES AND WILL IMPROVE SIGNIFICANTLY WITH HYDROXYUREA TREATMENT.

MAP KINASE PHOSPHATASE 3 (MKP-3) AND OBESITY-RELATED GLUCONEOGENESIS

SIRNA MICROBICIDES

A NOVEL PROTECTIVE MECHANISM IN HEMORRHAGIC SHOCK - THE ASSESSMENT OF MYOCARDIAL FUNCTION IN VIVO FOLLOWING TRAUMA AND HEMORRHAGE IS IMPLICATED AS ONE OF THE MOST CRITICAL APPROACHES TO DECIPHERING PHYSIOLOGICAL MECHANISM AND DESIGNING A THERAPEUTIC STRATEGY. THE PRECISE AND ACCURATE DETERMINATION OF THE PHYSIOLOGICAL FUNCTION IN PRECLINICAL ANIMAL MODELS WILL PROVIDE IMPORTANT EVIDENCE FOR DEVELOPING AN EFFECTIVELY THERAPY AND UNRAVELLING THE DEEP MECHANISM(S) ATTRIBUTABLE FOR PATHOLOGICAL DISORDERS AND THERAPEUTIC INTERVENTION. IN VIVO NON-INVASIVE APPROACHES HAVE SERVED AS A POWERFUL TECHNOLOGY TO ELUCIDATE THESE PHYSIOLOGICAL FUNCTIONS. WE AND OTHERS HAVE EXTENSIVELY USED IN VITRO AND INVASIVE METHODS TO DETERMINE CARDIAC FUNCTIONING IN SMALL ANIMAL STUDIES, PROVIDING CRUCIAL ANALYSIS OF CARDIAC PERFORMANCE IN EXPERIMENTAL DESIGN. HOWEVER, THOSE APPROACHES AND METHODOLOGICAL TOOLS WITH IN VITRO AND INVASIVE TECHNIQUES WERE DESIGNED TO BE PERFORMED AT THE END STAGE OF THE STUDY AND AT THE EXPENSE OF EUTHANIZING ANIMALS IN THE STUDIES, WHICH LIMITS OBTAINING THE IN VIVO ASSESSMENT OF CARDIAC PERFORMANCE IN A SERIAL MANNER TO MONITOR THE PROGRESS OF EXPERIMENTAL STUDIES. THE DEFICIENCIES INCLUDE THE LIMITATION OF MEASUREMENTS AND THE LACK OF REAL TIME MONITORING. IN THIS PARENT R01 GRANT, WE WILL DETERMINE CARDIAC FUNCTION OF MICE THAT ARE SUBJECTED TO HEMORRHAGE AND RESUSCITATION, IN VIVO MEASUREMENT OF CARDIAC FUNCTION BY ECHOCARDIOGRAPHIC ASSESSMENT WILL BE CONDUCTED IN REAL TIME AND IN A NON-INVASIVE MANNER. WE HAVE EMPLOYED ECHOCARDIOGRAPHIC ANALYSIS OF MYOCARDIAL PERFORMANCE IN MOUSE USING THE CONVENTIONAL ULTRASOUND FOR ACQUISITION OF DATA, HOWEVER, FALSE NEGATIVE AND POSITIVE SIGNALS, HIGH BACKGROUND NOISE OF IMAGING MEASUREMENT FREQUENTLY OCCUR DUE TO THE LIMITATION OF THE LOW FREQUENCY OF TRANSDUCER. IN ORDER TO ENSURE THE RIGOROUSNESS AND SOLIDITY OF OUR STUDY, WE WILL REQUEST TO INCLUDE THE MOST ADVANCED TECHNOLOGY BY IMPLEMENTING A HIGH- RESOLUTION MICRO-ULTRASOUND THE VEVO® 3100 LT IMAGING SYSTEM THAT IS SPECIFICALLY DESIGNED FOR SMALL ANIMALS TO DETERMINE IN VIVO CARDIAC FUNCTION. THE ADVANTAGES WITH EMPLOYMENT OF THE HIGH RESOLUTION ULTRASOUND TECHNOLOGY THE VEVO® 3100 LT IMAGING SYSTEMIN OUR RESEARCH NOT ONLY PROVIDE A COMPREHENSIVE ARRAY OF ACCURATE AND SERIAL ANALYSES OF CARDIOVASCULAR FUNCTION FOR THE PROPOSED STUDIES, BUT IT WILL ALSO IMPACT OUR LONG- STANDING FOCUS ON STUDYING PHYSIOLOGICAL FUNCTION IN SMALL ANIMALS BY STRENGTHENING OUR ONGOING SUPPORT, IMPROVING THE KNOWLEDGE OF TRAINEES, AND BENEFITING THE GREATER RESEARCH COMMUNITY AND NIH-FUNDED RESEARCH.

SOX17/RUNX1 AXIS REGULATES ENDOTHELIAL CELL FATE IN THE PATHOGENESIS OF PULMONARY ARTERIAL HYPERTENSION - PROJECT SUMMARY/ABSTRACT: PULMONARY ARTERIAL HYPERTENSION (PAH) IS A PROGRESSIVE DISEASE CHARACTERIZED BY AN OBLITERATIVE VASCULOPATHY OF THE DISTAL PULMONARY CIRCULATION. ADVERSE STRUCTURAL REMODELING AND INCREASED PULMONARY VASCULAR RESISTANCE RESULT IN CARDIAC HYPERTROPHY AND ULTIMATELY FAILURE OF THE RIGHT VENTRICLE, WITH ANNUAL MORTALITY AVERAGING 10%. CURRENT THERAPIES CAN IMPROVE SYMPTOMS AND DELAY DISEASE PROGRESSION, BUT THERE IS NO CURE. THERE IS A CRITICAL NEED TO DEVELOP NEW THERAPIES THAT EFFECTIVELY HALT AND REVERSE THE DISEASE BY TARGETING THE CELLULAR AND MOLECULAR MECHANISMS UNDERLYING THE PATHOPHYSIOLOGY OF PAH. IN SOX17 MUTANT PAH PATIENTS, WE POSTULATE THAT LOSS-OF-FUNCTION MUTATIONS IN THE SOX17 GENE RESULT IN INSUFFICIENT UPREGULATION OF SOX17 DURING NORMAL REPARATIVE RESPONSES TO VASCULAR INJURY ALLOWING INCREASED RUNX1 SIGNALING TO DRIVE ABERRANT ANGIOGENESIS. THUS, OUR CENTRAL HYPOTHESIS IS THAT LOSS OF REPRESSION OF RUNX1 BY ENDOTHELIAL SOX17 PREDISPOSES TO THE DEVELOPMENT OF PAH THROUGH IMPAIRED ARTERIAL ENDOTHELIAL DIFFERENTIATION AND ABERRANT ANGIOGENESIS. TO TEST OUR HYPOTHESIS, WE PLAN THE FOLLOWING SPECIFIC AIMS: AIM 1. DETERMINE IF ENDOTHELIAL SOX17 DEFICIENCY LEADS TO HIGHER SUSCEPTIBILITY OF DEVELOPING PAH. AIM 2. DETERMINE IF SOX17/RUNX1 IMBALANCE LEADS TO IMPAIRED ARTERIAL DIFFERENTIATION AND ABERRANT ANGIOGENESIS FOLLOWING SUHX-PH INDUCTION. AIM 3: DETERMINE IF SOX17 MUTANT PAH PATIENT IPSC-DERIVED ECS HAVE IMPAIRED ARTERIAL DIFFERENTIATION AND DEFECTIVE ANGIOGENIC CAPABILITY.

SCHISTOSOME VACCINES

SURGICAL INTRAMYOCARDIAL ANGIOGENESIS IN A SWINE MODEL OF ENDOTHELIAL DYSFUNCTION

SNRK(SUCROSE NON-FERMENTING RELATED KINASE)AND ADIPOSE ENERGY HOMEOSTASIS

SUB-CELLULAR TARGETING OF ENDOTHELIAL ROS IN MYOCARDIAL ISCHEMIA

COMMUNITY-LEVEL PRIMARY PREVENTION OF DATING AND SEXUAL VIOLENCE IN MIDDLE SCHOOLS

METABOLIC REGULATION OF SODIUM CHANNELS

MECHANOTRANSDUCTION IN HEART DEVELOPMENT AND REGENERATION

IMPROVING THE TREATMENT OF DEPRESSION AMONG YOUTH WITH HIV - PROJECT SUMMARY/ABSTRACT DEPRESSION IS A COMMON PSYCHIATRIC CONDITION AMONG YOUTH WITH HIV (YWH), WITH PREVALENCE AS HIGH AS 25% IN THE UNITED STATES. IT HAS BEEN SHOWN TO REDUCE ADHERENCE TO ANTIRETROVIRAL TREATMENT (ART), INCREASE RISK OF DISEASE PROGRESSION, INCREASE CAREGIVER BURDEN, INCREASE HEALTHCARE COSTS, AND DECREASE QUALITY OF LIFE. FORTUNATELY, THERE IS AN EFFICACIOUS TREATMENT. PRACTICE GUIDELINES AND SUBSTANTIAL RESEARCH (INCLUDING FOR THOSE WITH HIV), INDICATE THAT MEASURED-CARE TREATMENT (CARE DECISIONS GUIDED BY MEASURES OF SYMPTOMATOLOGY) USING COMBINATION OF A MEDICATION MANAGEMENT ALGORITHM AND COGNITIVE BEHAVIORAL THERAPY (CBT) THAT IS TAILORED TO THE POPULATION IS VERY EFFECTIVE AT REDUCING DEPRESSION. IN TWO PRIOR STUDIES WITH YWH, WE HAVE SUCCESSFULLY TRAINED CLINICIANS IN THIS TAILORED, MEASURED-CARE, CBT, AND MEDICATION MANAGEMENT APPROACH (COMB) AND THE OUTCOMES HAVE BEEN IMPRESSIVE. FOR EXAMPLE, OUR CLUSTER-RANDOMIZED RCT AT 13 HIV CARE SITES FOUND THAT THE PROPORTION OF YOUTH WITH A TREATMENT RESPONSE (SYMPTOM DECREASE > 50% FROM BASELINE) WAS SIGNIFICANTLY GREATER AT COMB SITES COMPARED TO TREATMENT AS USUAL (TAU) SITES (62% VS. 18%, P <0.001) AT WEEK 24. WE WERE ATTENTIVE TO PROCESSES IMPORTANT TO IMPLEMENTATION, AND USED FOUR EXPERT RECOMMENDATION FOR IMPLEMENTING CHANGE (ERIC) STRATEGIES: PROMOTING ADAPTABILITY, DEVELOPING EDUCATIONAL RESOURCES, PROVIDING CLINICAL SUPERVISION, AND CHANGING THE RECORD SYSTEM. DESPITE OUR USE OF THESE IMPLEMENTATION STRATEGIES, BY WEEK 48 DEPRESSION RATES IN COMB HAD NOT CONTINUED TO IMPROVE INDICATING A “VOLTAGE DROP” OF COMB’S IMPACT AND PROGRAM “DRIFT.” BECAUSE OF THE NEED TO ENHANCE SUSTAINABILITY, WE PROPOSE TESTING COMBEX (COMB WITH ADDITIONAL IMPLEMENTATION STRATEGIES TO THOSE PREVIOUSLY USED) COMPARED TO COMB IN A HYBRID TYPE 2 CLUSTER RANDOMIZED TRIAL. GUIDED BY THE CONSOLIDATED FRAMEWORK FOR SUSTAINABILITY CONSTRUCTS IN HEALTHCARE, COMBEX WILL BE ENHANCED BY USING FIVE ADDITIONAL ERIC STRATEGIES: 1) FACILITATING THE RELAY OF CLINICAL DATA TO PROVIDERS; 2) REEXAMINING CLINICAL PRACTICES; 3) PROVIDING EDUCATIONAL MATERIAL IN REAL TIME USING SUSTAINABLE TECHNOLOGY; 4) PROVIDING SUPERVISION TO ENHANCE FIDELITY; 5) REMINDING CLINICIANS ABOUT ADHERENCE WITH PROMPTS. THE TRIAL WILL ALSO TEST THE REAL-WORLD EFFECTIVENESS OF COMBEX IN REDUCING INDICES OF DEPRESSION COMPARED TO COMB. TO OUR KNOWLEDGE, THIS WILL BE THE FIRST PROJECT TO EXAMINE IMPLEMENTATION OUTCOMES IN DEPRESSION TREATMENT AMONG YWH AND AMONG THE FEW TO TEST THE EFFECTIVENESS OF TREATMENT OF DEPRESSION IN IMPROVING VIRAL LOAD (VL) SUPPRESSION FOR YWH.

2/2-CBT VERSUS SUPPORTIVE PSYCHOTHERAPY FOR BODY DYSMORPHIC DISORDER

REGULATORY MECHANISMS OF ACUTE LUNG INJURY

HISTONE DEACETYLATION REGULATES GROWTH PLATE DEVELOPMENT

A PILOT GAMING ADHERENCE PROGRAM FOR YOUTH LIVING WITH HIV

METABOLIC REGULATION OF SKCA/IKCA CHANNELS AND ENDOTHELIAL FUNCTION

COMPARING MEDICATION MAINTENANCE IN COMPREHENSIVE COMMUNITY AND PHARMACY SETTINGS TO ENHANCE ENGAGEMENT

EFFECT OF NEUTROPHIL PRIMING ON CHEMOTAXIS AND SIGNALING

GENETIC INFORMATION TRANSFER TO HEMATOPOIETIC CELLS: ROLE OF MICROVESICLES

THE INFECTADO STUDY: INFECTIONS ACQUIRED BY PERSONS ON MAINTENANCE HEMODIALYSIS DURING HOSPITALIZATIONS - ABSTRACT MORE THAN 500,000 PERSONS REQUIRE MAINTENANCE HEMODIALYSIS (PMHD) PER YEAR IN THE UNITED STATES, DISPROPORTIONATELY AFFECTING PERSONS WHO ARE BLACK OR HISPANIC. PMHD ARE AN AGENCY OF HEALTHCARE RESEARCH AND QUALITY PRIORITY POPULATION. INFECTIONS ARE THE SECOND MOST COMMON CAUSE OF MORTALITY AMONG PMHD DUE TO A UREMIA-INDUCED IMMUNOCOMPROMISED STATE AND MULTIPLE CO-MORBIDITIES. PMHD ARE ALSO AT SUBSTANTIAL RISK OF HOSPITAL-ACQUIRED INFECTIONS (HAI) AS THEY ARE ADMITTED TO THE HOSPITAL ON AVERAGE TWICE PER YEAR. COMPARED TO THE GENERAL HOSPITALIZED POPULATION, PMHD HAVE A 2.4-FOLD HIGHER RISK OF DEVELOPING AN HAI. THERE IS A TREMENDOUS PAUCITY OF DATA PERTAINING TO THE EPIDEMIOLOGY OF HAI AMONG PMHD, INCLUDING POTENTIAL RACIAL AND ETHNIC DISPARITIES. IN THIS PROPOSAL, ENTITLED “THE INFECTADO STUDY: INFECTIONS ACQUIRED BY PERSONS ON MAINTENANCE HEMODIALYSIS DURING HOSPITALIZATIONS”, WE WILL QUANTIFY AND CHARACTERIZE THE EPIDEMIOLOGY OF HAI AMONG PMHD. THIS PROPOSAL WILL THEREFORE GENERATE IMPORTANT INFORMATION AS HOW TO BEST IMPROVE CURRENT PREVENTION STRATEGIES AIMED AT REDUCING HAI IN PMHD. UNDER AIMS 1 AND 2, WE WILL USE THE UNITES STATES RENAL DATA SYSTEM (USRDS), A NATIONWIDE-MEDICARE DATABASE, TO ANALYZE PREVALENCE, RISK FACTORS AND OUTCOMES OF HAI OVER AN 8-YEAR STUDY PERIOD (~360,000 PMHD PER YEAR). ANALYSES WILL ALSO FOCUS ON MHD MODALITY TYPE, RACE/ETHNICITY AND SOCIAL DETERMINANTS OF HEALTH. UNDER AIM 3, WE WILL USE THE CENTERS FOR DISEASE CONTROL AND PREVENTION’S NATIONAL HEALTHCARE SAFETY NETWORK-BASED ACTIVE SURVEILLANCE DATA FROM 31 HOSPITALS WITHIN THE UNIVERSITY OF PITTSBURGH MEDICAL CENTER HOSPITAL NETWORK OVER AN 8-YEAR PERIOD (~4,777 PMHD PER YEAR), TO FURTHER CHARACTERIZE HAI EPIDEMIOLOGY, INCLUDING CAUSATIVE PATHOGENS AND ANTIMICROBIAL RESISTANCE PROFILES. BY USING TWO DIFFERENT DATA SOURCES, A COMPLETE CHARACTERIZATION OF HAI EPIDEMIOLOGY AMONG PMHD WILL BE OBTAINED, SINCE EACH DATA SOURCE PROVIDES SUPPLEMENTARY DATA, AS OUTLINED IN THE PROPOSAL. THE INTERDISCIPLINARY TEAM IS COMPRISED OF INVESTIGATORS WHO HAVE PRODUCED AN ABUNDANCE OF SCHOLARLY END-STAGE RENAL DISEASE RESEARCH EFFORTS OVER THE LAST 2-DECADES AND HAVE EXPERTISE IN INFECTIONS AMONG PMHD, DATA ANALYSES USING THE USRDS AND HAI ACTIVE SURVEILLANCE METHODOLOGIES. A SUMMARY OF SPECIFIC AIMS ARE 1] AIMS 1 AND 2: TO QUANTIFY AND CHARACTERIZE HAI PREVALENCE, RISK FACTORS AND OUTCOMES AMONG ALL PMHD WITH AND WITHOUT HAI, AND BETWEEN: A] IN-CENTER VS HOME MHD, B] BLACK PERSONS VS PERSONS OF OTHER RACES ON MHD AND C] HISPANIC VS NON-HISPANIC PERSONS ON MHD, USING THE USRDS DATABASE AND 2] AIM 3: TO QUANTIFY AND CHARACTERIZE HAI EPIDEMIOLOGY AMONG PMHD WITH AN HAI COMPARED TO HOSPITALIZED PERSONS WITH AN HAI, INCLUDING CAUSATIVE PATHOGENS AND ANTIMICROBIAL RESISTANCE PROFILES, USING ACTIVE INFECTION SURVEILLANCE. THIS PROPOSAL WILL RESULT IN AN INCREASED UNDERSTANDING OF HAI EPIDEMIOLOGY AMONG THE HIGH-RISK GROUP OF PMHD AND HEALTH DISPARITIES WITHIN THIS POPULATION, AND WILL PROVIDE IMPORTANT INFORMATION TO GUIDE FUTURE PREVENTION STRATEGIES AIMED AT REDUCING HAI AND IMPROVING PATIENT OUTCOMES.

ADVANCED NURSING EDUCATION - SEXUAL ASSAULT NURSE EXAMINERS PROGRAM - RHODE ISLAND HOSPITAL (RIH) PROPOSES TO IMPLEMENT THE RHODE ISLAND SEXUAL ASSAULT NURSE EXAMINERS (RI SANE) ENHANCED TRAINING PROJECT TO INCREASE THE NUMBER OF TRAINED SANES, ESTABLISH A SANE PRECEPTOR PROGRAM, AND LAUNCH AN EMERGENCY DEPARTMENT (ED) LIAISON INITIATIVE AND COLLABORATIONS WITH COMMUNITY-BASED HEALTH CENTERS TO FURTHER FOSTER A CULTURE OF TRAUMA-INFORMED CARE IN HEALTHCARE SETTINGS, RECRUIT A DIVERSE GROUP OF SANES, AND EXPAND ACCESS TO SEXUAL ASSAULT SERVICES THROUGHOUT THE STATE. IN 2022, RIH IMPLEMENTED THE STATE’S FIRST SEXUAL ASSAULT FORENSIC EXAMINERS PROGRAM. THROUGH THE PROPOSED PROJECT, RIH WILL FURTHER ENHANCE ITS TRAINING PROGRAM, DEVELOP A STANDARDIZED CURRICULUM AND SANE CERTIFICATION, AND ESTABLISH CONTINUING EDUCATION FOR MAINTENANCE OF CERTIFICATION MODELED AFTER OTHER STATES THAT FOLLOW NATIONAL BEST PRACTICES. THE PROJECT INCLUDES A MULTIDISCIPLINARY TEAM FOR EXPERTISE AND TECHNICAL ASSISTANCE, INCLUDING FROM WOMEN & INFANTS HOSPITAL, SANE PROGRAMS IN MASSACHUSETTS AND MAINE, COMMUNITY ADVOCACY GROUPS, AND SUBJECT MATTER EXPERTS. DESPITE INCREASES IN SERVICES, SUBSTANTIAL GAPS BETWEEN THOSE SEEKING ASSISTANCE AND MEDICAL CARE CONTINUE TO EXIST: IN 2022 ONLY 63 OF THE 451 (14%) CALLERS SOUGHT FORENSIC CARE AND IN 2023 ONLY 89 OF THE 456 (20%) CALLERS DID (BLACKSTONE VALLEY ADVOCACY CENTER CRIME VICTIM HELPLINE DATA). WHILE 40% OF ALL 2023 CALLS CAME FROM PROVIDENCE, VICTIMS FROM 30 COMMUNITIES REACHED OUT AND 13% DID NOT DISCLOSE THEIR LOCATION. RIH RECOGNIZES THAT EXISTING SERVICES DO NOT YET MEET STATEWIDE NEEDS. THE PROJECT WILL ADDRESS THE FOUR HRSA GOALS WITH SPECIFIC PROJECT OBJECTIVES TO: -STANDARDIZE, FORMALIZE, AND IMPLEMENT AN ACCESSIBLE STATEWIDE SANE TRAINING CURRICULUM THAT BECOMES A STATE-CERTIFIED SANE MODEL PROGRAM BASED ON NATIONAL BEST PRACTICE -RECRUIT NURSES, PARTICULARLY THOSE WHO MIRROR THE SURVIVOR POPULATION AND FROM HEALTHCARE SETTINGS WHERE SERVICES ARE PROVIDED, TO INCREASE THE N UMBER OF SANES WORKING IN RHODE ISLAND AND IMPROVE ED PREPAREDNESS AND SUPPORT TO CARE FOR VICTIMS OF SEXUAL VIOLENCE -DEVELOP A SANE PRECEPTOR TRAINING PROGRAM TO DEVELOP A GEOGRAPHICALLY DIVERSE GROUP OF MENTORS THAT PROVIDE DIRECT SUPPORT TO SANES, ASSURE ADHERENCE TO BEST PRACTICE CARE, AND HELP PROMOTE SANE SUPPORT AND WELLNESS -DEVELOP A COMMUNITY SANE ECHO FACILITATED BY EXPERTS IN TRAUMA CARE TO SUPPORT SANE EXPERIENCES AND PROMOTE SUSTAINMENT AND WELLNESS -INCREASE ACCESS TO SERVICES FOR PATIENTS BY ESTABLISHING SANE PRESENCES IN LIAISON ROLES IN EDS AND OTHER HEALTHCARE SETTINGS (E.G. FQHCS, COLLEGE CAMPUSES, TRIBAL HEALTH CENTERS, AND URGENT CARES) ACROSS THE STATE THE PROJECT ADDRESSES THE NEEDS OF VICTIMS WHO FACE DISPARITIES IN CARE BY RECRUITING NURSES AS SANES WHO WORK AND LIVE IN UNDERSERVED COMMUNITIES OR PROVIDE CARE IN HEALTHCARE SETTINGS THAT SERVE POPULATIONS WITH IDENTIFIED RISKS FOR VICTIMIZATION FROM SEXUAL VIOLENCE, INCLUDING THOSE WITH PHYSICAL AND MENTAL HEALTH DISABILITIES, CHRONIC MEDICAL PROBLEMS, HOMELESSNESS, SUBSTANCE ABUSE, IMMIGRATION AND LEGAL STATUS, GENDER IDENTITY ISSUES, COLLEGE STUDENTS, AND ADOLESCENTS AND YOUNG ADULTS. INTENDED TRAINING NUMBERS ARE: 30 SANES AND 6 PRECEPTORS (Y1); 15 SANES, 30 SANE RECERTIFICATIONS, AND 8 PRECEPTORS (Y2); AND 20 SANES, 45 SANE RECERTIFICATIONS, AND 12 PRECEPTORS (Y3). ADDITIONALLY, RIH WILL SEEK TO ESTABLISH AT LEAST 10 SANE LIAISONS AND CHAMPIONS DURING THE PROJECT PERIOD, AS WELL AS PROVIDE MATERIALS AND TRAINING, IN EVERY ED IN THE STATE TO FURTHER SUPPORT THE PROVISION OF TRAUMA-INFORMED CARE FOR VICTIMS OF SEXUAL ASSAULT.

POLICE PATHWAYS TO ADDICTION TREATMENT, HEALTH, AND SAFETY: THE POLICE PATHS STUDY - PROJECT SUMMARY IN THE U.S., POLICE OFFICERS ENCOUNTER PEOPLE WHO USE DRUGS (PWUD) MILLIONS OF TIMES PER YEAR. OFTEN, THESE ENCOUNTERS ARISE FROM UNLAWFUL BEHAVIOR ASSOCIATED WITH PROBLEMATIC SUBSTANCE USE, RESULTING IN ARRESTS THAT INCREASE SUBSEQUENT OVERDOSE RISK AND DIMINISH OTHER HEALTH OUTCOMES. AS AN ALTERNATIVE TO ARREST ON MISDEMEANOR CHARGES, POLICE-ASSISTED DIVERSION (PAD) LINKS PWUD WITH TREATMENT AND SERVICES, ESPECIALLY MEDICATIONS FOR OPIOID USE DISORDER, OFFERING THE POTENTIAL TO REDUCE OVERDOSE, PROTECT HEALTH, AND ADDRESS THE ADDICTION-RELATED PROBLEMS THAT CAN MOTIVATE UNLAWFUL BEHAVIOR. TO LEVERAGE THIS POTENTIAL, POLICE AGENCIES ACROSS THE NATION HAVE IMPLEMENTED PAD, WHILE OPIOID SETTLEMENT FUNDS PROVIDE THE OPPORTUNITY FOR PAD’S EXPANSION. YET, GAPS IN OUR KNOWLEDGE ABOUT PAD PREVENT AGENCIES FROM MAXIMIZING ITS IMPACT. AS THERE HAS YET TO BE A RIGOROUS STUDY OF ITS EFFECT ON HEALTH OUTCOMES, JURISDICTIONS CANNOT BE SURE HOW ITS COSTS COMPARE TO ARREST AS USUAL, AND THERE IS LITTLE UNDERSTANDING OF HOW TO EFFECTIVELY IMPLEMENT THE INTERVENTION. THIS PROJECT WILL INVESTIGATE THOSE GAPS IN TWO LARGE U.S. CITIES FACING ESPECIALLY ACUTE AND PERSISTENT OVERDOSE CRISES: PHILADELPHIA, WHERE PAD HAS OPERATED SINCE 2017, AND BALTIMORE, WHERE IT FACED IMPLEMENTATION CHALLENGES THAT MADE IT UNSUSTAINABLE. EMPLOYING THE EXPLORATION, PREPARATION, IMPLEMENTATION, SUSTAINMENT FRAMEWORK, AIM 1 WILL USE SEMI-STRUCTURED INTERVIEWS OF BALTIMORE AND PHILADELPHIA POLICE (N=25 IN EACH CITY), AND PHILADELPHIA PAD CLIENTS (N=25) AND PROVIDERS (N=25) TO CONSTRUCT RETROSPECTIVE IMPLEMENTATION RESEARCH LOGIC MODELS FOR EACH SITE. THE MODELS WILL ARRAY THE CAUSAL PATHWAYS—AND EXPOSE THE CAUSAL GAPS—THAT LINK IMPLEMENTATION DETERMINANTS, DE-FACTO STRATEGIES, AND MECHANISMS TO OUTCOMES INCLUDING FEASIBILITY, ACCEPTABILITY, APPROPRIATENESS, FIDELITY, AND SUSTAINABILITY. AIM 2 WILL EVALUATE THE CAUSAL EFFECTS OF PAD IN PHILADELPHIA ON ACCESS TO MEDICATIONS FOR OPIOID USE DISORDER AND ITS HEALTH OUTCOMES (E.G., OVERDOSE, HOSPITALIZATION FOR INJECTION-RELATED INFECTIONS) USING A QUASI-EXPERIMENTAL ANALYSIS OF LINKED ADMINISTRATIVE DATA FROM THOUSANDS OF PWUD WHO DID AND DID NOT RECEIVE PAD. AIM 3 WILL ASSESS THE COST-EFFECTIVENESS OF PAD COMPARED TO CRIMINAL JUSTICE PROCESSING AS USUAL BY USING DATA FROM PAD AND NON-PAD INDIVIDUALS TO PARAMETERIZE AN ECONOMIC MODEL AND ESTIMATE THE MEAN INCREMENTAL COST EFFECTIVENESS RATIO OF PAD. THE PROJECT WILL YIELD A COMPREHENSIVE UNDERSTANDING OF PAD, AND PROVIDE NOVEL DATA ABOUT THE DECOMPOSITION OF A PUBLIC HEALTH INTERVENTION IN BALTIMORE’S CHALLENGING SETTING. IT WILL IMPROVE PAD IN PHILADELPHIA AND ASSIST BALTIMORE IN AN ANTICIPATED RE-IMPLEMENTATION. THE LAW ENFORCEMENT ASSISTED DIVERSION NATIONAL SUPPORT BUREAU WILL ENSURE THE PROJECT’S FINDINGS ARE USED BY PRACTITIONERS TO IMPLEMENT AND SUSTAIN PAD ACROSS THE U.S., AND THE PROJECT’S LOGIC MODEL WILL PROVIDE THE MEANS FOR POLICE AND RESEARCHERS TO CONDUCT PAD IMPLEMENTATION IN A RIGOROUS AND METHODICAL WAY. RESULTS WILL ALSO PROVIDE THE BASIS FOR IMPLEMENTATION AND EFFECTIVENESS TRIALS OF PAD IN OTHER SETTINGS THAT TEST THE DETERMINANTS AND STRATEGIES OBSERVED TO HAVE HAD THE GREATEST IMPACT IN THE CITIES HERE. THIS STUDY IS PART OF THE NIH’S HELPING TO END ADDICTION LONG-TERM (HEAL) INITIATIVE TO SPEED SCIENTIFIC SOLUTIONS TO THE NATIONAL OPIOID PUBLIC HEALTH CRISIS. THE NIH HEAL INITIATIVE BOLSTERS RESEARCH ACROSS NIH TO IMPROVE TREATMENT FOR OPIOID MISUSE AND ADDICTION.

SHP2'S REGULATION OF THE BONE MARROW STROMA AND HEMATOPOIETIC CROSSTALK - (PLEASE KEEP IN WORD, DO NOT PDF) (ENTER THE TEXT HERE THAT IS THE NEW ABSTRACT INFORMATION FOR YOUR APPLICATION. THIS SECTION MUST BE NO LONGER THAN 30 LINES OF TEXT.) IT HAS BEEN REPORTED THAT DEPLETION OF RUNX21 OR LEPR2 IN MESENCHYMAL STEM/PROGENITOR CELLS (MSPCS) REDUCES BONE MASS AND INCREASES BONE MARROW (BM) ADIPOCYTES (BMA), AND THAT PDGFRΒ ACTIVATION DRIVES MSPC EXPANSION AND BM VASCULOGENESIS, FINALLY INFLUENCING HEMATOPOIESIS3. OUR PRELIMINARY DATA SHOW THAT MICE LACKING SHP2 IN THE OSTERIX+ STROMAL PROGENITOR CELLS (O+SPCS) HAVE SIMILARLY INCREASED BMA AND BM VASCULATURE AND SKEWED LYMPHOPOIESIS. WE HAVE NOT YET DETERMINED THE MOLECULAR MECHANISM(S) BY WHICH SHP2 EXERTS ITS INFLUENCE ON O+SPCS AND HEMATOPOIETIC CELLS. HOWEVER, THE PHENOTYPIC SIMILARITY OF MICE LACKING SHP2, RUNX2, LEPR, OR PDGFR IN O+SPCS LEADS US TO HYPOTHESIZE THAT SHP2 INFLUENCES THE OSTEOGENIC, ADIPOGENIC AND/OR STROMOGENIC FATE OF O+SPCS BY MODIFYING THE TRANSCRIPTION ACTIVITY OF RUNX2 AND THE KINASE ACTIVITY OF PDGFR, AND THAT ALTERED BM O+SPCS CHANGE THE CELLULAR AND MOLECULAR CONSTITUENTS OF THE BM NICHE AND SUBSEQUENTLY HEMATOPOIESIS. TO TEST THIS NOVEL HYPOTHESIS, WE WILL COMPLETE TWO SPECIFIC AIMS. IN AIM 1 WE WILL INTERROGATE THE IMPACT OF SHP2 DEPLETION ON RUNX2 TRANSCRIPTIONAL ACTIVITY IN O+SPCS, WHILE IN AIM 2 WE WILL DETERMINE THE EFFECT OF SHP2 DEPLETION ON STROMOGENIC DIFFERENTIATION OF O+SPCS AND HEMATOPOISIS IN VITRO AND IN VIVO. O+SPCS PARTICIPATE IN BM HEMATOPOIETIC NICHE CONSTRUCTION AND MAINTENANCE, AND BOTH SHP2 AND RUNX2 INFLUENCE O+SPCS. THIS INNOVATIVE STUDY WILL YIELD FOUNDATIONAL INFORMATION REGARDING SHP2’S REGULATORY ROLE IN O+SPCS AND ITS CONSEQUENT ROLE IN HEMATOPOIESIS AND BM VASCULOGENESIS. THIS INFORMATION WILL SIGNIFICANTLY ADVANCE OUR UNDERSTANDING OF THE EFFECT AND IMPORTANCE OF CROSSTALK BETWEEN BM STROMAL CELLS AND HEMATOPOIETIC CELLS, AND HEMATOPOIETIC MALIGNANCY.

PSYCHOSOCIAL TELEPHONE INTERVENTION FOR DEMENTIA CAREGIVERS

ROLE OF HISTONE METHYLTRANSFERASE EZH2 IN ACUTE AND CHRONIC RENAL INJURY

HYPOTHALAMIC SIRT1 AND ENERGY BALANCE

HCV IN ALCOHOLICS

THE COVID-19 AND CANCER CONSORTIUM (CCC19) REGISTRY - PROJECT SUMMARY PEOPLE WITH CANCER HAVE A HIGHER RISK OF INFECTIONS IN GENERAL BECAUSE OF VULNERABILITIES ARISING FROM THEIR CANCER AND ITS TREATMENTS. THIS IS ESPECIALLY TRUE FOR THE NOVEL CORONAVIRUS, SARS-COV- 2. PEOPLE WITH CANCER ARE TWICE AS LIKELY TO DIE FROM COVID-19 COMPARED TO THE GENERAL POPULATION, WITH SOME SUBGROUPS APPEARING TO FARE MUCH WORSE. THE PANDEMIC HAS ALSO LED TO SIGNIFICANT DISRUPTION IN CANCER SCREENING, DIAGNOSIS, AND TREATMENT, WHICH IS ANTICIPATED TO LEAD TO AN INDIRECT INCREASE IN MORBIDITY AND MORTALITY IN THIS POPULATION. THUS, STUDYING COVID-19 IN PEOPLE WITH CANCER IS HIGHLY WARRANTED. IN THIS U01 PROJECT, “THE COVID-19 AND CANCER CONSORTIUM (CCC19) REGISTRY”, WE LEVERAGE THE ESTABLISHED CCC19 REGISTRY (NCT04354701), WHICH IS THE LARGEST REGISTRY OF ADULTS WITH COVID-19 AND CANCER IN NORTH AMERICA, TO ANSWER A NUMBER OF IMPORTANT SCIENTIFIC QUESTIONS. IN AIM 1, WE EVALUATE HOW ANTICANCER TREATMENTS, ANTI- COVID-19 TREATMENTS, VACCINATION, AND, IMPORTANTLY, THEIR INTERACTIONS MODIFY SHORT- AND LONG- TERM COMPLICATIONS. WE WILL EXPLORE WHETHER RACE, ETHNICITY, AND SOCIODEMOGRAPHIC FACTORS (E.G., INSURANCE, ACCESS TO TREATMENT) ARE ASSOCIATED WITH OUTCOMES. WE WILL EXPLORE WHETHER DATA- DRIVEN FEATURE SELECTION WITH MACHINE-LEARNING ALGORITHMS REVEALS UNRECOGNIZED ASSOCIATIONS. IN AIM 2, WE HYPOTHESIZE THAT THERE WILL BE MEASURABLE CHANGES IN CANCER RECURRENCE AND PROGRESSION IN PATIENTS WHO SURVIVE COVID-19. WE WILL ALSO INVESTIGATE WHETHER ANTICANCER TREATMENT MODIFICATIONS, WHICH WE HAVE OBSERVED IN 40% OF PATIENTS WHO WERE ON ANTICANCER THERAPY AT THE TIME OF INFECTION, WILL AFFECT LONGER-TERM PROGNOSIS. IN AIM 3, WE WILL DEVELOP METHODS TO MEASURE ASCERTAINMENT AND COLLIDER BIASES, WHICH ARE SOME OF THE MOST IMPORTANT SOURCES OF BIAS IN REGISTRY-BASED STUDY DESIGNS. ALONG WITH THESE AIMS, WE WILL CONTINUE TO SUPPORT AND MAINTAIN THE CCC19 REGISTRY AND PROMOTE ITS USE BY THE GENERAL COMMUNITY, FOLLOWING THE FAIR PRINCIPLES.

ANTIMICROBIAL USE IN DIALYSIS UNITS

GENESIS OF LIVER CARCINOMAS WITH OVAL CELL TRAITS

THE FETAL HEPATOCYTE PHENOTYPE AND CELL-BASED THERAPY FOR LIVER DISEASE

ENGINEERING REPLACEMENT TISSUES WITH AMNIOTIC STEM CELLS

NADPH OXIDASE-ASSOCIATED TRANSITION FROM BARRETT'S ESOPHAGUS TO ADENOCARCINOMA

TARGETING CXCR4 AND MICRORNA AS THERAPY FOR CHONDROSARCOMA

EFFECT OF ADRENAL AND GONADAL HORMONES ON BONE MARROW AND APPENDICULAR BMD

A SLEEP HYGIENE INTERVENTION TO IMPROVE SLEEP HEALTH IN URBAN, LATINO MIDDLE SCHOOL CHILDREN - PROJECT SUMMARY/ABSTRACT: SLEEP IS ESSENTIAL FOR OPTIMAL HEALTH AND DEVELOPMENT. POOR SLEEP IS ASSOCIATED WITH IMPAIRED FUNCTIONING AND ACADEMIC PERFORMANCE, AND WORSE HEALTH OUTCOMES IN CHILDREN. LATINO CHILDREN ARE DISPROPORTIONATELY PRESENT IN URBAN SETTINGS, AND DUE TO THEIR EXPOSURE TO HIGHER LEVELS OF URBAN AND CULTURAL STRESSORS, ARE AT GREATER RISK FOR POOR SLEEP HYGIENE AND QUALITY. OVER THE PAST 3 YEARS, WE HAVE DEMONSTRATED THE ACCEPTABILITY, FEASIBILITY AND PRELIMINARY EFFICACY OF A NOVEL SLEEP HYGIENE INTERVENTION, SIESTA (SCHOOL INTERVENTION TO ENHANCE LATINO STUDENTS’ TIME ASLEEP) FOR IMPROVING SLEEP HYGIENE AND SLEEP DURATION IN URBAN LATINO MIDDLE SCHOOLERS IN TWO GEOGRAPHIC AREAS WITH A HIGH PROPORTION OF URBAN LATINO CHILDREN AT INCREASED RISK FOR POOR SLEEP HEALTH: PROVIDENCE, RHODE ISLAND, AND SAN JUAN, PUERTO RICO. SIESTA INVOLVES 4 GROUP SESSIONS ADMINISTERED IN SCHOOL TO LATINO MIDDLE SCHOOLERS (6TH-8TH GRADE) AND TWO CHILD-CAREGIVER SESSIONS ADMINISTERED REMOTELY BY A BILINGUAL (ENGLISH/SPANISH) TRAINED FACILITATOR FROM THE COMMUNITY. THE GOAL OF THIS APPLICATION IS TO ADMINISTER A TWO-SITE HYBRID TYPE 1 EFFECTIVENESS-IMPLEMENTATION DESIGN TO EVALUATE SIESTA’S EFFECTS ON A LARGER-SCALE- FOR ADDRESSING LATINO MIDDLE SCHOOLER’S SLEEP HEALTH, WHILE ALSO ASSESSING IMPLEMENTATION DETERMINANTS. THE FIRST AIM OF THE PROPOSED WORK IS TO EVALUATE SIESTA THROUGH A LARGE-SCALE RCT WITH URBAN MIDDLE SCHOOL STUDENTS IN PROVIDENCE, RI AND SAN JUAN, PUERTO RICO. WE WILL ENROLL 150 LATINO CHILDREN PER SITE (N=300), AND RANDOMLY ASSIGN THEM EITHER TO THE SIESTA INTERVENTION, OR TO THE SLEEP EDUCATION PLUS CHILD HEALTH ATTENTION-CONTROL CONDITION (9 GROUPS OF EACH OF THE TWO CONDITIONS, PER SITE; 8-9 STUDENTS PER GROUP). WE WILL EVALUATE TREATMENT EFFECTS ON PRIMARY SLEEP OUTCOMES SUCH AS SLEEP DURATION, EFFICIENCY AND SLEEP ONSET LATENCY AND ON SECONDARY SLEEP OUTCOMES INVOLVING SLEEP HYGIENE BEHAVIORS, THE SLEEP ENVIRONMENT AND SLEEP-RELATED DISTURBANCES AND IMPAIRMENT. ASSESSMENTS WILL OCCUR PRIOR TO, IMMEDIATELY FOLLOWING, AND AT 4, 8, AND 12 MONTHS AFTER THE INTERVENTION. OVER 1 YEAR, WE EXPECT SIESTA PARTICIPANTS WILL HAVE IMPROVED SLEEP OUTCOMES, SLEEP HYGIENE BEHAVIORS AND LESS SLEEP-RELATED IMPAIRMENT THAN CONTROLS. THE SECOND AIM IS TO IDENTIFY IMPLEMENTATION DETERMINANTS AND PRELIMINARY IMPLEMENTATION OUTCOMES OF SIESTA TO PREPARE FOR FUTURE LARGE-SCALE IMPLEMENTATION IN OTHER URBAN SCHOOL SETTINGS. WE WILL CONDUCT A MIXED METHODS PROCESS EVALUATION WITH INPUT FROM COMMUNITY PARTNERS USING THE RE-AIM FRAMEWORK THROUGHOUT AND FOLLOWING ADMINISTRATION OF THE RCT. THE PROPOSED WORK BUILDS ON A 20-YEAR COLLABORATION BETWEEN OUR RESEARCH TEAMS IN RI AND PR, AND AN INVESTMENT IN ADVANCING KNOWLEDGE OF MULTI-LEVEL FACTORS AFFECTING PEDIATRIC HEALTH DISPARITIES IN CHILDREN THROUGH EVIDENCE-BASED, SUSTAINABLE INTERVENTIONS. SIESTA HAS THE POTENTIAL TO IMPROVE SLEEP OUTCOMES IN URBAN LATINO CHILDREN AND THEIR DAYTIME FUNCTIONING, AND TO ADDRESS A CRITICAL GAP OF THE NEED FOR TAILORED AND EFFECTIVE SLEEP HYGIENE INTERVENTIONS FOR CHILDREN AT GREATER RISK FOR POOR SLEEP HEALTH.

LEADERSHIP EDUCATION IN NEURODEVELOPMENTAL AND RELATED DISORDERS TRAINING PROGRAM

INFLAMMATION AND SIGNAL TRANSDUCTION IN ESOPHAGITIS

PULMONARY ARTERY ENDOTHELIAL CELL ENDOTYPES AND THE ROLE OF ANOIKIS RESISTANCE IN PULMONARY HYPERTENSION - ABSTRACT PULMONARY ARTERIAL HYPERTENSION (PAH) IS A DEVASTATING DISEASE MARKED BY ENDOTHELIAL CELL (EC) DYSFUNCTION. WHILE EC DYSFUNCTION IS AT THE CORE OF PAH PATHOBIOLOGY, EC PHENOTYPES ARE INCOMPLETELY CHARACTERIZED AND REMAIN CONTROVERSIAL. CURRENT METHODS TO STUDY THIS GAP SOURCE CELLS FROM END-STAGE PATIENTS, NON-DISEASED CELL LINES, OR OUTSIDE OF THE PULMONARY VASCULATURE. RIGHT HEART CATHETERIZATION IS THE FUNDAMENTAL DIAGNOSTIC PROCEDURE IN PAH AND IS REPEATED THROUGHOUT THE DISEASE COURSE. WE HAVE SHOWN THAT ECS FROM THE BALLOONS OF PULMONARY ARTERY CATHETERS CAN BE HARVESTED, PROPAGATED EX VIVO AND CHARACTERIZED TO ELUCIDATE MOLECULAR MECHANISMS OF EC DYSFUNCTION. WE CONTEND THAT ECS IN PAH DISPLAY ABNORMAL PROGRAMMED CELL DEATH TRIGGERED BY CELL DETACHMENT FROM THE VESSEL WALL, KNOWN AS ANOIKIS RESISTANCE. THIS PROPOSAL WILL LEVERAGE OUR “CELL BIOPSY” METHOD TO DEFINE EC DYSFUNCTION IN HUMAN PAH AND PATIENT, TIME AND BIOMECHANICAL FACTORS THAT INFLUENCE EC ENDOPHENOTYPES. OUR CENTRAL HYPOTHESIS IS THAT ANOIKIS RESISTANCE IS A CENTRAL PARADIGM IN PROGRESSIVE PAH AND THAT ECS FROM PATIENTS WITH ADVANCED PAH WILL DEMONSTRATE DYSREGULATED ANOIKIS AS COMPARED TO THOSE WITH LESS SEVERE DISEASE AND OTHER PULMONARY HYPERTENSION SUBTYPES. WE WILL DETERMINE THE ANOIKIS MEDIATORS (E.G., SYNDECAN-4, AND PLAC8) THAT PROMOTE THIS PATHOPHENOTYPE AND THE EXTENT TO WHICH TARGETING THEM CAN REVERSE ANOIKIS RESISTANCE. WE WILL CHARACTERIZE SAMPLE MICROHETEROGENEITY WITH SINGLE-CELL SEQUENCING OF PRIMARY ECS AND SINGE-CELL CLONING OF PROPAGATED CELLS TO STUDY ANOIKIS RESISTANT SUBPOPULATIONS AND THEIR ADHESIVE PROPERTIES. TRANSCRIPTOMICS WILL BE INTEGRATED IN SILICO TO IDENTIFY ADDITIONAL THERAPIES VIA A DRUG REPOSITIONING STRATEGY TO RESCUE ANOIKIS RESISTANCE IN VITRO. OUR EXPERIMENTS WILL INCLUDE ECS FROM PATIENTS WITH DIFFERENT FORMS OF PULMONARY VASCULAR DISEASE, DISEASED CONTROLS, AND BIOLOGICAL REPLICATES FROM THE SAME PATIENTS OVER TIME. WE WILL COMPARE THE SIGNATURES FROM OUR MORE CENTRAL PULMONARY ARTERY ECS TO THAT OF ESTABLISHED MICROVASCULAR PAH ECS. TOGETHER, THESE AIMS WILL INFORM NEW MECHANISTIC TARGETS TO REVERSE ANOIKIS RESISTANCE IN PAH AS WELL AS A PERSONALIZED DRUG SCREENING APPROACH OVER THE COURSE OF PULMONARY VASCULAR DISEASE.

NATRIURETIC PEPTIDES IN PULMONARY ENDOTHELIAL CELL BARRIER FUNCTION

SAVE KIDNEYS IN CISPLATIN CHEMOTHERAPY BY BLOCKING HDAC6 - PROJECT SUMMARY CISPLATIN AND ITS DERIVATIVES ARE THE MOST WIDELY USED CHEMOTHERAPEUTIC AGENTS FOR TREATING SOLID TUMORS. HOWEVER, CISPLATIN INDUCES KIDNEY INJURY DURING ITS USE IN CANCER THERAPY. CURRENTLY, NO TREATMENT IS AVAILABLE FOR CISPLATIN-INDUCED KIDNEY INJURY EXCEPT SUPPORTIVE CARE. THE GOAL OF THIS PROJECT IS TO ELUCIDATE THE ROLE AND MECHANISM OF HISTONE DEACETYLASE 6 (HDAC6) IN CISPLATIN-INDUCED KIDNEY INJURY, FIBROSIS AND CHRONIC KIDNEY DISEASE (CKD), AND TO IDENTIFY HDAC6 INHIBITION AS A NOVEL APPROACH FOR RENOPROTECTION DURING CANCER TREATMENT. IN OUR PRELIMINARY STUDIES, HDAC6 WAS UP-REGULATED IN ACUTE KIDNEY INJURY (AKI) INDUCED BY A SINGLE HIGH-DOSE OF CISPLATIN IN MICE AND PHARMACOLOGICAL INHIBITION OF HDAC6 ATTENUATED RENAL TUBULAR APOPTOSIS AND AKI. HDAC6 WAS ALSO HIGHLY INDUCED BY REPEATED LOW-DOSE CISPLATIN (RLDC) TREATMENT, WHICH WAS ACCOMPANIED BY RENAL INTERSTITIAL FIBROSIS, PERSISTENT ACTIVATION OF EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AND AUTOPHAGY, AND DEACETYLATION OF Α-TUBULIN, A KEY PROCESS IN CILIUM DISASSEMBLY. IMPORTANTLY, PHARMACOLOGICAL AND GENETIC BLOCKADE OF HDAC6 REDUCED RLDC-INDUCED RENAL FIBROSIS. MOREOVER, CISPLATIN TREATMENT INDUCED SHORTENING OF PRIMARY CILIUM IN CULTURED RENAL EPITHELIAL CELLS, AND THE CELLS WITH SHORTER CILIA WERE MORE SENSITIVE TO CISPLATIN-INDUCED INJURY. THESE DATA, TOGETHER WITH A KNOWN CANCER-PROMOTING ROLE OF HDAC6 IN TUMORS, HAVE LED TO OUR HYPOTHESIS THAT BLOCKADE OF HDAC6 MAY PROTECT KIDNEYS DURING CISPLATIN CHEMOTHERAPY WHILE ENHANCING ITS ANTI-CANCER EFFICACY IN TUMORS. MECHANISTICALLY, HDAC6 MAY CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC KIDNEY PROBLEMS AFTER CISPLATIN TREATMENT THROUGH THE ACTIVATION OF EGFR AND AUTOPHAGY, AND DISASSEMBLY OF PRIMARY CILIUM IN RENAL TUBULAR CELLS. WE PROPOSE THREE SPECIFIC AIMS TO (1) TEST THE HYPOTHESIS THAT HDAC6 CAN PROTECT KIDNEYS DURING CISPLATIN TREATMENT WHILE ENHANCING THE CHEMOTHERAPY EFFECTS IN TUMORS; (2) TEST THE HYPOTHESIS THAT HDAC6 CONTRIBUTES TO CISPLATIN-INDUCED RENAL INJURY, FIBROSIS AND CKD BY PERSISTENT ACTIVATION OF EGFR AND AUTOPHAGY; AND (3) TEST THE HYPOTHESIS THAT HDAC6-MEDIATED CILIARY DISASSEMBLY AGGRAVATES KIDNEY INJURY, FIBROSIS AND CKD FOLLOWING CISPLATIN TREATMENT. SUCCESSFUL COMPLETION OF THE PROPOSED STUDIES WILL DEFINE THE THERAPEUTIC EFFECT OF HDAC6 INHIBITION ON CISPLATIN-INDUCED RENAL DAMAGE AND FIBROSIS, ELUCIDATE THE UNDERLYING MECHANISMS, AND IDENTIFY A NOVEL STRATEGY FOR KIDNEY PROTECTION WHILE ENHANCING CHEMOTHERAPEUTIC EFFICACY.

CORONARY VASCULAR RESILIENCE BY MODULATION OF MITOCHONDRIAL ROS IN ENDOTHELIUM - THE MAIN OBJECTIVE OF THIS STUDY IS TO ELUCIDATE MOLECULAR MECHANISMS BY WHICH CORONARY ENDOTHELIAL CELLS (EC) CAN SURVIVE AND PROLIFERATE IN ISCHEMIC (LOW OXYGEN, LOW GLUCOSE) CONDITIONS AND HELP IMPROVE CARDIAC THIS PROPOSAL IS BASED ON OUR RECENT REPORT THAT REDUCTION IN MITOCHONDRIAL (MITO)-ROS, USING EC-SPECIFIC TRANSGENIC OVEREXPRESSION OF MITO-ANTIOXIDANT MNSOD (SOD-OE) OR USING MITO-SPECIFIC ANTIOXIDANT NANOPARTICLE JP4-039, IMPROVES SURVIVAL AND PROLIFERATION OF CORONARY EC, AND HELP RECOVER CARDIAC FUNCTION IN A POST-MYOCARDIAL INFARCT (MI) ANIMAL MODEL. CORONARY ECS FROM SOD-OE DEMONSTRATED 50% REDUCTION IN MITO-ROS (BY MITO-ROGFP), SIGNIFICANT INCREASE IN MITOCHONDRIAL COMPLEXES I AND IV BIOGENESIS (PROTEOMIC DATA), SUPER-COMPLEX FORMATION, AND OXIDATIVE PHOSPHORYLATION (OX-PHOS). THE SHIFT FROM LESS-EFFICIENT ENERGY PRODUCTION SYSTEM GLYCOLYSIS (2 ATP/GLUCOSE MOLECULE), TO A MORE EFFICIENT OX-PHOS (32 ATP/GLUCOSE) MAY PROVIDE CRITICAL ENERGY SUPPORT TO EC NEEDED DURING ISCHEMIA (LOW GLUCOSE, OXYGEN). HOWEVER, TWO MAJOR CONCERNS ABOUT THESE COUNTERINTUITIVE FINDINGS OF INCREASED OXPHOS IN ISCHEMIC EC SHOULD BE ADDRESSED: (1) OXPHOS REQUIRES OXYGEN BUT ISCHEMIC EC HAS LOW OXYGEN AND HIGH ROS, AND (2) IN ISCHEMIA, GLUCOSE IS CATALYZED TO LACTATE BUT NOT PYRUVATE THAT IS REQUIRED FOR OXPHOS. INDEED, STUDIES REPORTED LACTATE ACCUMULATION DURING ISCHEMIA INDUCED ENDOTHELIAL-TO-MESENCHYMAL TRANSITION (EMT) AND CARDIAC REMODELING. HERE, WE HYPOTHESIZE THAT REDUCTION OF EXCESS MITO-ROS BY MNSOD DURING ISCHEMIA RESULTS IN RECYCLING OF ENDOTHELIAL MITO-SUPEROXIDE TO MOLECULAR OXYGEN (O2- TO H2O2 BY MNSOD, AND O2 BY GPX4) TO BE UTILIZED BY MITO-COMPLEXES (E.G. COMPLEX IV) FOR EFFICIENT ELECTRON TRANSPORT CHAIN (ETC) IN EC SUPER-COMPLEXES. IN ADDITION, GLYCOLYTIC PRODUCT LACTATE IS CATALYZED TO PYRUVATE FOR THE TCA CYCLE IN EC MITOCHONDRIA. WE PROPOSE 3 AIMS: FUNCTION BY RENDERING CORONARY VESSELS RESILIENT IN ISCHEMIA. SPECIFIC AIM 1: ELUCIDATE THE MOLECULAR MECHANISMS BY WHICH MITOCHONDRIAL MNSOD PROTECT CORONARY EC BY INDUCING MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION AND CORONARY ANGIOGENESIS IN ISCHEMIC MYOCARDIUM. WE HYPOTHESIZE THAT REDUCTION IN EC-MITO-ROS BY MNSOD RESULTING IN INCREASED OXPHOS DEPENDS ON GPX4-MEDIATED CONVERSION OF MITOCHONDRIAL H2O2 TO OXYGEN AS ELECTRON ACCEPTOR AT ETC. SPECIFIC AIM 2: ELUCIDATE THE MECHANISMS BY WHICH CORONARY ENDOTHELIAL TCA CYCLE OF OXPHOS RECEIVE PYRUVATE/AC-COA DURING ISCHEMIA THAT FAVORS LACTATE ACCUMULATION. SPECIFIC AIM 3: DETERMINE WHETHER MITOCHONDRIA-SPECIFIC ANTIOXIDANT NANOPARTICLES JP4-039 AND XJB-5-131 INDUCE POST-MI RECOVERY OF CARDIAC FUNCTION IN LARGE ANIMALS (SWINE) IN VIVO AND INCREASE OXPHOS AND ANGIOGENIC SPROUTING IN HUMAN ATRIAL TISSUE EX VIVO.

PROGRAMMED CELL DEATH: ROLE IN SEPTIC IMMUNE DYSFUNCTION

KNEE ARTHROSIS AFTER ACL RECONSTRUCTION: A LONG-TERM COHORT STUDY WITH MATCHED CONTROLS

NEUROMUSCULAR RESPONSE TO COMPETING ACL SURGERIES - ABSTRACT THE OVERALL PROJECT OBJECTIVE IS TO LEVERAGE PATIENTS ENROLLED IN THE BEAR-MOON TRIAL TO EVALUATE A NEUROMUSCULAR MECHANISM THAT MAY EXPLAIN DIFFERENCES IN FUNCTIONAL OUTCOMES BETWEEN THE NOVEL BRIDGE-ENHANCED ANTERIOR CRUCIATE LIGAMENT RESTORATION (BEAR) AND THE STANDARD OF CARE, ANTERIOR CRUCIATE LIGAMENT RECONSTRUCTION SURGERY (ACLR). WHEREAS ACLR REQUIRES REMOVAL OF THE INJURED LIGAMENT AND THE BONY INSERTION SITES TO IMPLANT A TENDON GRAFT, BEAR USES A SCAFFOLD TO PROMOTE HEALING OF THE INJURED ACL. THEREFORE, THE ACL NEURAL STRUCTURES AND BONY INSERTIONS REMAIN INTACT WITH BEAR, WHILE THEY ARE SEVERED AND REMOVED DURING ACLR. EARLY CLINICAL STUDIES HAVE SHOWN THAT MUSCLE STRENGTH IS RESTORED FOLLOWING BEAR, BUT NOT AFTER ACLR AT 2-YEAR FOLLOW-UP. WE HAVE DATA TO SHOW THAT JOINT MOTION ABNORMALITIES SIMILARLY PERSIST OVER A DECADE AFTER ACLR, WHICH ARE THOUGHT TO BE A RISK FACTOR FOR POSTTRAUMATIC OSTEOARTHRITIS. THEREFORE, WE POSTULATE THAT DIFFERENCES IN MUSCLE RECOVERY AND JOINT MOTION ARE DUE TO THE PRESERVATION OF NEUROMUSCULAR FUNCTION WITH BEAR. THE BEAR-MOON TRIAL (THE PARENT STUDY) IS A MULTICENTER, RANDOMIZED CONTROL TRIAL COMPARING 2-YEAR OUTCOMES OF BEAR TO THOSE OF ACLR. WHILE THE PARENT STUDY WILL ESTABLISH WHETHER DIFFERENCES EXIST BETWEEN PROCEDURES, IT WAS NOT DESIGNED TO DETERMINE THE MECHANISM BEHIND THOSE DIFFERENCES. THEREFORE, THE OVERARCHING ANCILLARY STUDY HYPOTHESIS IS THAT BEAR PRESERVES THE NEUROMUSCULAR ACTIVATION PATTERNS ABOUT THE KNEE THAT, IN TURN, PROMOTE NORMAL HOP LANDING JOINT MOTION COMPARED TO ACLR AT 2 YEARS POST-SURGERY. THE ANCILLARY STUDY ADDRESSES THREE AIMS: 1) TO APPLY OUR INNOVATIVE MACHINE LEARNING APPROACH TO CLASSIFY NEUROMUSCULAR ACTIVITY PATTERNS AS BELONGING TO ACLR, BEAR OR HEALTHY CONTROL SUBJECTS (CONTROLS); 2) TO COMPARE KNEE POSITION BETWEEN ACLR, BEAR, AND CONTROLS AT GROUND CONTACT WHEN LANDING FROM A 1-LEG HOP; AND 3) TO DETERMINE THE RELATIONSHIP BETWEEN NEUROMUSCULAR ACTIVITY PATTERNS AND JOINT MOTION ABNORMALITIES. TWENTY-SIX SUBJECTS ENROLLED IN THE BEAR-MOON TRIAL AT RHODE ISLAND HOSPITAL WILL BE RECRUITED INTO THE ANCILLARY STUDY AT THEIR 2-YEAR PARENT STUDY FOLLOW-UP VISIT. AN AGE- AND SEX-MATCHED CONTROL GROUP WILL BE RECRUITED FROM THE COMMUNITY. ALL 39 SUBJECTS WILL PERFORM A 1-LEG HOP-FOR-DISTANCE ACTIVITY WHILE SURFACE ELECTROMYOGRAPHY IS RECORDED TO ASSESS NEUROMUSCULAR FUNCTION (AIM 1), AND BIPLANE VIDEORADIOGRAPHY WILL BE PERFORMED TO EVALUATE PRECISE TIBIOFEMORAL MOTION (AIM 2). REGRESSION ANALYSIS WILL BE USED TO RELATE NEUROMUSCULAR ACTIVATION PATTERNS WITH TIBIOFEMORAL POSITION (AIM 3). THE ANCILLARY STUDY DOVETAILS WELL WITH THE PARENT STUDY, WHICH IS NOW IN ITS FINAL YEAR OF RECRUITMENT. IF THE HYPOTHESES OF THE ANCILLARY STUDY ARE SUPPORTED, THE RESULTS WILL DEMONSTRATE THAT ACL MECHANORECEPTOR CONTINUITY IS THE MECHANISM GOVERNING NEUROMUSCULAR FUNCTION, AND THAT ITS LOSS WITH ACLR IS A DRIVER OF JOINT MOTION DYSFUNCTION AND POSSIBLE DOWNSTREAM JOINT ARTHROSIS THAT CAN BE EXPLORED IN FUTURE LONGITUDINAL STUDIES.

BIOACTIVE INJECTABLE CELL SCAFFOLD FOR MENISCUS INJURY REPAIR IN A LARGE ANIMAL MODEL - SUMMARY ABSTRACT MENISCAL TEARING IS A SIGNIFICANT RISK FACTOR FOR THE DEVELOPMENT OF POSTTRAUMATIC OSTEOARTHRITIS (PTOA). THE LONG- TERM GOAL OF THIS PROJECT IS TO DEVELOP AN INNOVATIVE BIOLOGIC THERAPY TO IMPROVE MENISCUS TEAR HEALING FOR THE PREVENTION OF PTOA. OUR LABORATORY HAS DEMONSTRATED THE EFFICACY OF UTILIZING CARTILAGE-DERIVED PROGENITOR CELLS (CPCS) TO STIMULATE HEALING OF MENISCAL TEARS IN A SMALL ANIMAL MODEL. IN EFFORTS TO TRANSLATE OUR SUCCESS IN SMALL ANIMALS TO A CLINICALLY RELEVANT LARGE ANIMAL MODEL, WE WILL OPTIMIZE AND IMPLEMENT A BIOACTIVE TEAR INTERFACING FIBRIN HYDROGEL (FIBROGEL) THAT IS LADEN WITH CPCS AND INFUSED WITH THE CHEMOKINE STROMAL CELL DERIVED FACTOR- 1 (SDF-1) AND THE SMALL MOLECULE KARTOGENIN (KGN), WHICH COLLECTIVELY INCREASES CPC RETENTION AT THE TEAR SITE AND INCREASES THEIR CHONDROGENIC MATRIX SYNTHESIS, RESPECTIVELY. THE OBJECTIVES OF THE PROPOSED STUDY ARE: TO OPTIMIZE FIBROGEL AS A NOVEL BIOLOGIC THERAPY FOR MENISCUS TEAR REPAIR; (2) TO DETERMINE ITS EFFICACY FOR STIMULATING TEAR REUNIFICATION AND REDUCTION OF PTOA SEVERITY; AND (3) TO COLLECT BIOCOMPATIBILITY DATA THROUGHOUT THE STUDY TO AID IN CLINICAL TRANSLATION OF THIS TECHNOLOGY. THERE ARE THREE INDEPENDENT SPECIFIC AIMS: (I) OPTIMIZE CELLULAR AND BIOACTIVE COMPONENTS OF FIBROGEL TO PRODUCE ROBUST FIBROCARTILAGE MATRIX RE-SYNTHESIS TO BRIDGE AND REUNIFY MENISCUS TEARS; (II) EVALUATE THE EFFICACY OF USING FIBROGEL FOR IMPROVING MENISCAL FIBROCARTILAGE HEALING IN A PRECLINICAL LARGE ANIMAL MODEL; AND (III) DETERMINE THE EFFICACY OF FIBROGEL-AUGMENTED MENISCUS REPAIR IN ATTENUATING PTOA IN THE KNEE. THE RESEARCH DESIGN WILL EMPLOY A MENISCUS TISSUE EXPLANT MODEL TO OPTIMIZE FIBROGEL IN ORDER TO MAXIMIZE CELL RETENTION AND CHONDROGENIC MATRIX RE-SYNTHESIS AT THE TEAR SITE, AS WELL AS INCREASE THE STRENGTH OF TISSUE REINTEGRATION/REUNION AT THE TEAR SITE. A PORCINE MODEL OF MENISCAL INJURY WILL BE USED TO EXAMINE THE SHORT- AND LONG-TERM EFFICACY AND BIOCOMPATIBILITY OF FIBROGEL. OUTCOME ASSESSMENTS WILL INCLUDE EVALUATION OF MENISCUS TEAR HEALING, EVALUATION OF PTOA SEVERITY AS DETERMINED BY BIOMARKER ANALYSIS, GAIT ASYMMETRY ANALYSIS, AND MACROSCOPIC/MICROSCOPIC ASSESSMENT OF THE ARTICULAR CARTILAGE AND SYNOVIUM FOLLOWING FIBROGEL TREATMENT. SUCCESSFUL COMPLETION WILL HAVE A POSITIVE IMPACT BY FACILITATING THE DEVELOPMENT AND TRANSLATION OF A NEW STRATEGY TO STIMULATE MENISCUS INJURY REPAIR THROUGH THE USE OF CELLULAR BIOLOGICS. THIS PROJECT IS RELEVANT TO THE MISSION OF NIAMS BECAUSE IT SEEKS TO FIND INNOVATIVE WAYS TO TREAT MUSCULOSKELETAL INJURIES AND PREVENT ARTHRITIS.

THE ROLE OF NPR-C IN MODULATION OF ACUTE LUNG INJURY

TELEMEDICINE FOR PREP THROUGHOUT MISSISSIPPI (TELE-PREP-MS)

THE VIRA PLATFORM: A CONTEXTUALLY TRIGGERED JUST-IN-TIME ADAPTIVE INTERVENTION FOR OPIOID USE DISORDER - ABSTRACT ALTHOUGH BUPRENORPHINE IS A FIRST-LINE INTERVENTION FOR OPIOID USE DISORDER (OUD), MAINTAINING ADHERENCE TO AND RETENTION IN TREATMENT IS A SIGNIFICANT CHALLENGE. A SUBSTANTIAL PORTION OF PATIENTS RECEIVING BUPRENORPHINE DISCONTINUE TREATMENT PREMATURELY AND/OR RETURN TO ILLICIT OPIOID USE PLACING THEM AT INCREASED RISK FOR OVERDOSE AND DEATH. CONVERGING LINES OF EVIDENCE IMPLICATE NEGATIVE AFFECT, SLEEP DEFICIENCY AND ANHEDONIA AS IMPORTANT RISK FACTORS THAT ARE ASSOCIATED WITH INCREASED DRUG CRAVING AND A REOCCURRENCE OF OPIOID USE. IN TURN, GREATER CRAVING, AND SUBSEQUENT OPIOID USE, ARE POSITED TO BE MECHANISMS UNDERLYING BUPRENORPHINE DISCONTINUATION. THERE IS A CRITICAL NEED TO DEVELOP INNOVATIVE, SCALABLE, SOLUTIONS THAT MODIFY AND ADDRESS THESE RISK FACTORS TO SUPPORT RETENTION IN LIVE SAVING MEDICATIONS SUCH AS BUPRENORPHINE. THE VIRA HEALTHCARE PLATFORM IS A DIGITALLY ENHANCED BEHAVIOR CHANGE TECHNOLOGY THAT HAS PRIMARILY BEEN USED IN THE MANAGEMENT OF MENTAL HEALTH SYMPTOMS. IT CONSISTS OF A PATIENT SMARTPHONE APPLICATION THAT UTILIZES MOBILE SENSING TO GARNER INSIGHT ABOUT PATTERNS OF BEHAVIOR AS WELL AS PROVIDE TAILORED JUST-IN-TIME INTERVENTIONS TO SUPPORT BEHAVIOR CHANGE. IT IS ACCOMPANIED BY AN ASSOCIATED PRACTITIONER PORTAL WHICH ALLOWS CLINICIANS OR COACHES TO SCHEDULE CUSTOMIZED NOTIFICATIONS WITH SKILLS, TIPS, AND TOOLS TO SUPPORT PATIENTS. THE PLATFORM UTILIZES WELL-ESTABLISHED PRINCIPLES FROM EVIDENCE-BASED THERAPY (BEHAVIORAL ACTIVATION) TO PROVIDE USERS WITH THE INSIGHTS TO SUSTAIN WELLBEING AND BETTER MANAGE OPIOID-RELATED RISK FACTORS. THE OVERARCHING OBJECTIVE OF THIS PROPOSAL IS TO MODIFY AND EXTEND THE VIRA PLATFORM, AUGMENTED BY COACHING SUPPORT FROM CERTIFIED PEER RECOVERY SUPPORT SPECIALISTS (PRSS), TO IMPROVE PATIENT OUTCOMES FOR OUD BY DELIVERING A DIGITAL THERAPEUTIC THAT INTEGRATES SENSORS TO PROVIDE JUST-IN-TIME INTERVENTIONS TO ADDRESS RISK FACTORS ASSOCIATED WITH POOR TREATMENT RESPONSE – NEGATIVE AFFECT, SLEEP DEFICIENCY, AND ANHEDONIA. SPECIFICALLY, THIS PROPOSAL SEEKS TO OBTAIN FDA AUTHORIZATION FOR THE VIRA PLATFORM AS A PRESCRIPTION DIGITAL THERAPEUTIC INTENDED TO EXTEND THE EFFICACY OF BUPRENORPHINE. THE STUDY WILL BE ACCOMPLISHED THROUGH TWO PRIMARY AIMS: (1) UG3 - USING A USER-CENTERED DESIGN, ADAPT AND REFINE THE VIRA PLATFORM TO INCREASE RELEVANCE AND USABILITY FOR INDIVIDUALS WITH OUD AND CONDUCT A PILOT FEASIBILITY TRIAL; AND (2) UH3 – CONDUCT A PRAGMATIC 2-ARM RANDOMIZED CLINICAL TRIAL AMONG 340 PATIENTS WITH OUD, ENGAGED IN OUTPATIENT BUPRENORPHINE CARE, TO EVALUATE THE EFFECTIVENESS OF THE VIRA PLATFORM PLUS TREATMENT-AS-USUAL (TAU), RELATIVE TO TAU ALONE, IN TERMS OF RETENTION IN BUPRENORPHINE (PRIMARY ENDPOINT), ENGAGEMENT IN SUBSTANCE USE TREATMENT (SECONDARY ENDPOINT), AND OPIOID USE, CRAVING, NEGATIVE AFFECT, SLEEP, ANHEDONIA, WELLBEING / QUALITY OF LIFE, AND INCIDENCE OF ADVERSE EVENTS (SECONDARY OUTCOMES). GO/NO-GO CRITERIA TO ADVANCE FROM THE UG3 TO UH3 PHASE INCLUDE: A) COMPLETE FEASIBILITY TRIAL BY SUCCESSFULLY ENROLLING PROPOSED SAMPLE SIZE AND B) FILE Q-SUBMISSION/RECEIVE FDA FEEDBACK. IF SUCCESSFUL, THIS STUDY WILL DEMONSTRATE THE EFFICACY AND SAFETY OF A SIMPLE, SCALABLE, INTERVENTION THAT MAY EASILY AUGMENT STANDARD OUD CARE THROUGH A PRESCRIPTION DIGITAL THERAPEUTIC.

MECHANOTRANSDUCTION MECHANISMS OF CARDIAC GROWTH AND REGENERATION - PROJECT SUMMARY MORE THAN A MILLION AMERICANS EXPERIENCE A HEART ATTACK EACH YEAR CAUSING IRREVERSIBLE DAMAGE TO THEIR HEART MUSCLE. CURRENT THERAPIES PROLONG SURVIVAL BY PROTECTING REMAINING CARDIOMYOCYTES BUT ARE UNABLE TO OVERCOME THE FUNDAMENTAL PROBLEM OF REPLACING LOST CARDIOMYOCYTES. THUS, UNDERSTANDING WHICH MOLECULAR PATHWAYS GOVERN CARDIOMYOCYTE PROLIFERATION IS A HIGH PRIORITY IN THE EFFORT TO EXPLORE NEW TREATMENTS FOR HEART FAILURE. THE TRANSITION FROM HYPERPLASTIC TO HYPERTROPHIC GROWTH IN THE POSTNATAL HEART IS ACCOMPANIED BY DYNAMIC REMODELING OF CELL-CELL AND CELL-EXTRACELLULAR MATRIX (ECM) ADHESION STRUCTURES, SUGGESTING THAT CELL ADHESION/CYTOSKELETAL CHANGES PLAY A CRITICAL ROLE IN MYOCARDIAL GROWTH CONTROL. IN SUPPORT OF THIS IDEA OUR LAB FOUND THAT MODIFYING THE CONNECTION BETWEEN N-CADHERIN AND THE ACTIN CYTOSKELETON LEADS TO ACCUMULATION OF YAP IN THE NUCLEUS, INCREASE CARDIOMYOCYTE PROLIFERATION, AND IMPROVED CARDIAC FUNCTION FOLLOWING MYOCARDIAL INFARCTION IN MICE. THE OVERALL GOAL OF THIS NEW PROJECT IS TO ELUCIDATE THE MOLECULAR MECHANISMS REGULATING THE DYNAMIC NATURE AND INTERPLAY BETWEEN MYOCARDIAL CELL-CELL AND CELL-ECM INTERACTIONS AND THE ENSUING DOWNSTREAM SIGNALS THAT ULTIMATELY CONTROL CARDIOMYOCYTE PROLIFERATION. AIM 1 WILL DETERMINE THE REQUIREMENT FOR POST-TRANSLATIONAL MODIFICATION OF A CYTOSKELETAL ADAPTOR PROTEIN IN JUNCTION MATURATION, CARDIOMYOCYTE DIFFERENTIATION AND CELL CYCLE ARREST IN THE NEONATAL HEART, AIM 2 WILL DETERMINE WHETHER INHIBITING PHOSPHORYLATION OF THIS CYTOSKELETAL ADAPTOR PROTEIN, EITHER GENETICALLY OR PHARMACOLOGICALLY, WILL PROMOTE HEART MUSCLE REGENERATION FOLLOWING MYOCARDIAL INFARCTION, AND AIM 3 WILL ELUCIDATE MECHANICAL CONSEQUENCES OF ALTERING VCL FUNCTION IN HUMAN IPSC-DERIVED CARDIOMYOCYTES. COMPLETION OF THESE PRECLINICAL PROOF-OF-CONCEPT STUDIES WILL DETERMINE WHETHER TARGETING CELL ADHESION/CYTOSKELETAL LINKAGE REPRESENTS A NOVEL STRATEGY TO STIMULATE CARDIOMYOCYTE PROLIFERATION FOLLOWING ISCHEMIC INJURY.

CARDIOVASCULAR SURGERY RESEARCH TRAINING - PROJECT SUMMARY THE CARDIOVASCULAR SURGERY RESEARCH TRAINING PROGRAM’S MAIN OBJECTIVE IS TO PREPARE FULL-TIME ACADEMIC CARDIOVASCULAR SURGEONS, CLINICIANS AND SCIENTISTS IN CARDIAC AND VASCULAR BASIC AND TRANSLATIONAL RESEARCH. THIS OBJECTIVE WILL BE ACCOMPLISHED BY AN OUTSTANDING MENTORED RESEARCH EXPERIENCE AND RIGOROUS PROGRAMS OF DIDACTIC AND CAREER DEVELOPMENT TRAINING IN A MULTIDISCIPLINARY SETTING. THE OVERALL GOAL IS TO TRAIN 4 POSTDOCTORAL MD, PHD, AND MD/PHD FELLOWS PER YEAR IN CARDIOVASCULAR DISEASE (CVD) RESEARCH WHERE TRAINEES AND FACULTY WILL INTERACT CLOSELY. THIS TRAINING PROGRAM IS DESIGNED TO TRAIN AND PREPARE THE TRAINEES TO CONDUCT RESEARCH USING STATE-OF-THE-ART METHODS, CONCEPTUALIZE RESEARCH PROBLEMS, AND PUBLISH RESEARCH FINDINGS FOR SUCCESSFUL ACADEMIC CAREERS AS INDEPENDENT INVESTIGATORS. THE FUNDAMENTAL NEED FOR RESEARCH TRAINING IN CARDIOVASCULAR SURGERY IS HIGHLIGHTED BY STUDIES SHOWING THAT THE NUMBER OF CLINICIAN/SURGEONS AND PHD SCIENTISTS IN TRANSLATIONAL CVD RESEARCH CONTINUES TO DECLINE. FURTHERMORE, RESEARCH FINDINGS DEMONSTRATE THAT CLINICIAN-SCIENTISTS WHO ARE MOST SUCCESSFUL TO DATE ARE THE ONES WHO HAVE UNDERGONE A PERIOD OF INTENSE RESEARCH TRAINING FOR TWO OR MORE YEARS AS AN INTEGRAL PART OF THEIR TRAINING. ONE- TO TWO-YEAR TRAINING OF PHD SCIENTISTS DURING THEIR EARLY POSTDOCTORAL TRAINING PERIOD WILL CERTAINLY HELP BUILD A SOLID KNOWLEDGE- AND EXPERIENCE-BASED FOUNDATION TO BECOME EXCELLENT CARDIOVASCULAR RESEARCHERS IN THE COMING DAYS. UPON COMPLETION OF THIS TRAINING PROGRAM THE CARDIAC AND VASCULAR SURGEONS AND THE CARDIOLOGISTS WILL BE ABLE TO BETTER INTEGRATE INTO THE RAPIDLY EXPANDING AND CHANGING FIELDS OF SPECIALIZED CARDIOVASCULAR MEDICINE AND SURGERY. IN PARALLEL, IN ADDITION TO HAVING STATE- OF-THE-ART CARDIOVASCULAR RESEARCH EXPERIENCE, THE POSTDOCTORAL PHD SCIENTISTS WILL BE WELL-TRAINED TO ADDRESS THE MAJOR CARDIOVASCULAR HEALTH ISSUES, RESEARCH QUESTIONS AND CHALLENGES OF THE DAY. WHILE THERE ARE A FEW GOOD TRAINING PROGRAMS IN CARDIAC MEDICINE AND SURGICAL RESEARCH, THEY TEND TO BE LIMITED IN FOCUS TO CERTAIN SPECIFIC ISSUES SUCH AS TRANSPLANTATION, VENTRICULAR MECHANICS, AND GENE AND CELL-BASED THERAPIES. THE PROPOSED TRAINING PROGRAM HAS BEEN BUILT UPON AN INTEGRATED APPROACH TO THE TRAINING OF A NEW GENERATION ACADEMIC CARDIOVASCULAR SURGEONS AND SCIENTISTS, WHICH IN TURN WILL RESULT IN EXCELLENT QUALITY OF TEACHING, SUCCESS OF RESEARCH FUNDING, AND PUBLICATION OF HIGH QUALITY BASIC AND TRANSLATIONAL RESEARCH FINDINGS IN THE FIELD OF CARDIOVASCULAR RESEARCH.

NAVIGATING THE FENTANYL AGE WITH COMMUNITY DRUG CHECKING - PROJECT SUMMARY THE DRUG SUPPLY IS IN ENORMOUS FLUX WITH ILLICITLY MANUFACTURED FENTANYL (IMF) AND ANALOGS CREATING A DEADLY ENVIRONMENT FOR PEOPLE WHO USE DRUGS (PWUD). CLAIMING 93,311 LIVES IN 2020, IMF IS THE UNDERLYING DRIVER OF THE CURRENT CRISIS. ITS FAST ONSET LEAVES LITTLE TIME FOR EMERGENCY INTERVENTION AND ITS PRESENCE AS THE DOMINANT OPIOID IN CIRCULATION UNDERMINES EVIDENCE-BASED TREATMENTS. RHODE ISLAND (RI) IS A SITE OF EARLY IMF DEVASTATION, SUBJECT OF MUCH EPIDEMIOLOGIC INVESTIGATION ABOUT IMF, AND AN INNOVATION HUB FOR EXPANDED ACCESS TO LIFESAVING NALOXONE AND MEDICATIONS FOR OPIOID USE DISORDER (MOUD) AND STRUCTURES TO BETTER PROVIDE THEM. TWO RECENT INNOVATIONS SHOW PROMISE EVEN WITH IMF’S ENDEMICITY AND THE COVID-19 PANDEMIC BECAUSE THEY ADDRESS THE ILLICIT DRUG SUPPLY HEAD-ON: NON-TRADITIONAL MOUD INDUCTION PATHWAYS AND COMMUNITY DRUG CHECKING. BUT TREATMENT SUCCESS MAY BE UNDERMINED BY THE ILLICIT DRUG SUPPLY UNLESS WE LEARN HOW TO NAVIGATE IT. ONE NOVEL APPROACH TO DOING SO IS WITH COMMUNITY DRUG CHECKING. DRUG CHECKING GIVES INSIGHTS INTO WHAT DRUGS PEOPLE USE, ENGAGES PWUD IN RELEVANT EXCHANGE OF HEALTH INFORMATION, AND GENERATES DATA THAT COULD INFORM TREATMENT. APPLICATION OF THESE DATA FOR EPIDEMIOLOGIC RESEARCH TO HELP BETTER UNDERSTAND EXPOSURE, IDENTIFY RISK, MEASURE CONSEQUENCE AND CONSIDERATION OF THEIR ROLE IN A CLINICAL SETTING TO INFORM TREATMENT HAVE NOT BEEN EXAMINED. WE PROPOSE AN OBSERVATIONAL STUDY THAT LEVERAGES RECENTLY ACQUIRED DEVICES AND CAPACITIES TO CARRY OUT RESEARCH ON DRUG CHECKING, MULTIPLE LINKABLE INDIVIDUAL LEVEL DATASETS, AND STATE LAW AND PUBLIC HEALTH LEADERSHIP SUPPORTIVE OF DRUG CHECKING. CONSISTENT WITH THE RFA, WE SEEK TO UNCOVER HOW CHARACTERISTICS OF IMF IN THE DRUG SUPPLY INFLUENCE TREATMENT REGIMENS AND ONGOING DRUG USE AND RISK IN PEOPLE INTENTIONALLY OR UNWITTINGLY USING POLYSUBSTANCES (TOPICS 2 AND 4). SPECIFIC AIMS ARE TO: AIM 1) EXAMINE THE ANATOMY OF THE ILLICIT DRUG SUPPLY BY ESTABLISHING A COMMUNITY DRUG CHECKING COHORT (N=600) TO LEARN HOW: A) IMF’S PRESENCE, FORM (I.E., POWDER, COUNTERFEIT PILL), AND POTENCY IN THE OPIOID SUPPLY AFFECT ONGOING USE AND OVERDOSE RISK; B) IMF’S PRESENCE IN NON-OPIOID DRUGS LIKE STIMULANTS AFFECTS USE, OVERDOSE RISK AND CLINICAL SEVERITY OF HEALTH CONSEQUENCES; AND C) USE OF DRUG CHECKING AFFECTS UPTAKE OF MOUD. [UG3 AND UH3]. AIM 2) DOCUMENT CLINICIANS’ PERCEPTIONS ABOUT DRUG CHECKING, AND THEIR EXPERIENCES, INNOVATIONS, BARRIERS AND FACILITATORS OF INDUCTION OF PATIENTS ONTO MOUD, INCLUDING MICRO- AND MACRO-DOSING, IN RI. [UH3] AIM 3) ASSESS AMONG COMMUNITY DRUG CHECKING COHORT MEMBERS A) WHICH DRUG SUPPLY CHARACTERISTICS ARE ASSOCIATED WITH ONGOING DRUG USE, OVERDOSE AND MOUD INTEREST; B) WHAT DRUG SUPPLY FACTORS IMPACT INCIDENCE OF INDUCTION PROBLEMS LIKE PRECIPITATED WITHDRAWAL AND SUCCESSFUL RETENTION IN BUPRENORPHINE CARE USING ADMINISTRATIVE DATA. [UH3] FINDINGS WILL HELP INFORM PREVENTION AND INTERVENTION APPROACHES TO THE DRUG SUPPLY IN IMF ENDEMIC AREAS, DETERMINE ENGAGEMENT IN AND CLINICAL UTILITY OF COMMUNITY DRUG CHECKING, AND HELP IDENTIFY FACTORS INFLUENCING POOR TREATMENT EXPERIENCE AND BETTER RETENTION.

EMOTION REGULATION INTERVENTION TO PREVENT SUBSTANCE USE AMONG YOUTH IN THE CHILD WELFARE SYSTEM - PROJECT SUMMARY/ABSTRACT CHILDHOOD MALTREATMENT IS A MAJOR PUBLIC HEALTH PROBLEM THAT IS A RISK FACTOR FOR SUBSTANCE USE ACROSS THE LIFESPAN. EMOTION REGULATION (ER) IS A MODIFIABLE MECHANISM UNDERLYING THE IMPACT OF MALTREATMENT ON SUBSTANCE USE BUT IS OFTEN IMPAIRED IN YOUTH WITH A MALTREATMENT HISTORY DUE TO THE NEUROTOXIC EFFECTS OF EARLY TRAUMA AND/OR NEGLECT. INTERVENTIONS TO SUPPORT THE DEVELOPMENT OF ADAPTIVE ER IN YOUTH WITH A MALTREATMENT HISTORY HAVE THE POTENTIAL TO INTERRUPT TRAJECTORIES OF RISK AND ENHANCE HEALTH OUTCOMES, YET THIS POPULATION IS OFTEN DIFFICULT TO REACH AND FREQUENTLY FACES STRUCTURAL AND PSYCHOSOCIAL BARRIERS TO ENGAGEMENT IN INTERVENTION. FURTHERMORE, THE CHILD WELFARE SYSTEM, WHICH IS DESIGNED TO PROTECT AND SUPPORT YOUTH WITH MALTREATMENT HISTORIES, IS UNDER RESOURCED AND OFTEN UNABLE TO MEET THE CRITICAL NEEDS FOR PREVENTION IN THIS POPULATION. INTERVENTIONS TARGETING SUBSTANCE USE WITH THIS POPULATION MUST BE ACCEPTABLE, EASILY ACCESSIBLE, AND LOW RESOURCE FOR THE CHILD WELFARE SYSTEM. ITRAC IS A TABLET-BASED ER SKILLS TRAINING INTERVENTION FOR EARLY ADOLESCENTS THAT PREVIOUSLY DEMONSTRATED GOOD FEASIBILITY AND ACCEPTABILITY, AS WELL AS INCREASES IN EMOTIONAL SELF-EFFICACY, EMOTIONAL AWARENESS, AND USE OF ER STRATEGIES WITH COMMUNITY SAMPLES OF URBAN ADOLESCENTS. ITRAC’S APPROACH OF DELIVERING ER CONTENT THROUGH A TECHNOLOGICAL PLATFORM MAY EFFECTIVELY ENGAGE AND PROMOTE ER AND PREVENT SUBSTANCE USE AMONG YOUTH WITH MALTREATMENT HISTORIES. THIS TABLET-BASED APPROACH MAY ALSO BE MORE SUSTAINABLE IN CHILD WELFARE SETTINGS THAN APPROACHES THAT REQUIRE A TRAINED CLINICIAN. HOWEVER, NO PRIOR WORK HAS EXAMINED ITRAC WITH THIS VULNERABLE POPULATION. IN COLLABORATION WITH THE RHODE ISLAND DEPARTMENT OF CHILDREN, YOUTH, AND FAMILIES, THE PROPOSED RESEARCH WILL INNOVATE AND ENHANCE THE EXISTING ITRAC INTERVENTION TO INTEGRATE SUBSTANCE USE CONTENT WITH THE GOAL OF REDUCING SUBSTANCE USE AMONG CHILD WELFARE INVOLVED YOUTH. THIS WORK WILL OCCUR IN TWO PHASES. DURING THE PLANNING AND INTERVENTION ENHANCEMENT PHASE (PHASE I), WE WILL INTERVIEW ADOLESCENTS, CAREGIVERS, AND CHILD WELFARE PROFESSIONALS TO OBTAIN THEIR DIVERSE PERSPECTIVES REGARDING THE INTEGRATION OF ER AND SUBSTANCE USE. WE WILL SUBSEQUENTLY CREATE AND PROGRAM THIS CONTENT WITHIN THE ITRAC FRAMEWORK, FOLLOWED BY ACCEPTABILITY TESTING TO ENSURE USABILITY AND UNDERSTANDING. UPON COMPLETION OF PHASE I, WE WILL BEGIN PHASE II, DURING WHICH A REAL-WORLD EFFICACY (HYBRID EFFICACY-EFFECTIVENESS) TRIAL OF YOUTH WITH MALTREATMENT HISTORIES WILL TEST THE IMPACT OF THE ITRAC FOR SUBSTANCE USE (ITRAC-SU) INTERVENTION OVER AN 8-MONTH FOLLOW-UP PERIOD. WE WILL ALSO ASSESS THE FEASIBILITY, ACCEPTABILITY, UPTAKE, AND COSTS OF THIS APPROACH. TRIAL RESULTS, AND QUALITIVE INTERVIEWS WITH CHILD WELFARE PROFESSIONALS AT THE END OF THE PROJECT, WILL INFORM SUSTAINABILITY PLANNING BEYOND THE PROJECT PERIOD.

"NATURALISTIC ASSESSMENT OF THE DRIVING ABILITY OF COGNITIVELY IMPAIRED ELDERS

DEVELOPMENT OF A MOBILE HEALTH PERSONALIZED PHYSIOLOGIC ANALYTICS TOOL FOR PEDIATRIC PATIENTS WITH SEPSIS - PROJECT SUMMARY SEPSIS IS A LIFE-THREATENING CONDITION CAUSED BY AN IMBALANCED IMMUNE RESPONSE TO INFECTION, LEADING TO ORGAN FAILURE AND DEATH IF UNTREATED. LOW- AND MIDDLE-INCOME COUNTRIES (LMICS) BEAR A DISPROPORTIONATE BURDEN OF CHILDHOOD DEATHS DUE TO SEPSIS RESULTING FROM ACUTE INFECTIONS LIKE PNEUMONIA, DIARRHEA, AND MALARIA. TIMELY RECOGNITION AND TREATMENT OF SEPSIS IN CHILDREN ARE CRUCIAL FOR ALTERING THE DISEASE COURSE AND PREVENTING MORTALITY. THERE IS IMMENSE POTENTIAL FOR NOVEL CLINICAL TOOLS THAT CAN EXPEDITE THE IDENTIFICATION OF SEVERE SEPSIS, MULTIPLE ORGAN DYSFUNCTION SYNDROME (MODS), AND PREDICT THE HIGHEST MORTALITY RISK. THESE TOOLS CAN ALSO EFFECTIVELY MONITOR TREATMENT RESPONSES, DECREASING THE NEED FOR EXPENSIVE LABORATORY DIAGNOSTICS AND CRITICAL CARE MONITORING EQUIPMENT USED IN HIGH-RESOURCE SETTINGS. WHILE EARLY INITIATION OF ANTIMICROBIAL DRUGS IS WELL-ESTABLISHED IN SEPSIS TREATMENT, THE GUIDANCE FOR ADMINISTRATION OF INTRAVENOUS FLUIDS (IVF) FOR TREATMENT OF SEVERE SEPSIS CAN VARY DEPENDING ON THE GEOGRAPHICAL REGION AND EVEN NUTRITION STATUS. THE 2020 SURVIVING SEPSIS CAMPAIGN ADVISES THAT CHILDREN WHO RESIDE IN AREAS WITH RESOURCE-LIMITED HEALTHCARE SYSTEMS RECEIVE LOWER INITIAL FLUID VOLUMES BASED FOR SEPSIS TREATMENT BASED ON A STUDY WITH NARROW GENERALIZABILITY THAT DEMONSTRATED INCREASED MORTALITY RATES AMONG PEDIATRIC PATIENTS WHO RECEIVED NORMAL SALINE BOLUSES FOR SEVERE SEPSIS. CHILDREN WITH MALNUTRITION AND SEVERE SEPSIS ARE ALSO FLUID RESTRICTED. THIS PROJECT AIMS TO LEVERAGE PREDICTIVE MODELING AND MOBILE HEALTH (MHEALTH) TOOLS TO EVALUATE THE IMPACT OF IVF ADMINISTRATION ON SEPSIS SEVERITY IN PEDIATRIC PATIENTS. BY UTILIZING MACHINE LEARNING MODELS DEVELOPED UNDER THE PARENT AWARD, REAL-TIME ANALYSIS OF IVF EFFECTS ON SEPSIS SEVERITY CAN BE PERFORMED IN LMIC SETTINGS. UTILIZING CONTINUOUS VITAL SIGN PARAMETERS TRANSMITTED FROM A WEARABLE DEVICE TO A MOBILE PHONE, REAL-TIME MEASUREMENT OF IVF IMPACT ON SEPSIS SEVERITY CAN BE DETERMINED. THIS RESEARCH CAN SHED LIGHT ON THE BENEFITS OR HARMS OF FLUID ADMINISTRATION IN LMIC CHILDREN WITH SEVERE SEPSIS, INCLUDING SPECIFIC POPULATIONS LIKE MALNOURISHED CHILDREN. GIVEN THE LIMITED STUDIES ON APPROPRIATE FLUID VOLUMES FOR THIS SUBGROUP, THIS RESEARCH OFFERS AN OPPORTUNITY TO DETERMINE SAFE AND OPTIMAL FLUID ADMINISTRATION PRACTICES. THROUGH THIS RESEARCH, WE AIM TO CONTRIBUTE TO THE UNDERSTANDING OF IVF ADMINISTRATION EFFECTS ON SEPSIS SEVERITY IN CHILDREN, PARTICULARLY IN LMIC SETTINGS. THE FINDINGS CAN GUIDE FLUID MANAGEMENT PRACTICES, INFORM TAILORED TREATMENT STRATEGIES FOR MALNOURISHED PATIENTS, AND IMPROVE OUTCOMES FOR PEDIATRIC SEPSIS PATIENTS WORLDWIDE.

ENGINEERED NEUTROPHILS FOR INTRATUMORAL DELIVERY AND TARGETING

RGS REGULATION OF CARDIAC SIGNALING AND HYPERTROPHY

REGULATION OF RENAL AND BONE MARROW INJURY BY EXTRACELLULAR VESICLE NON-CODING RN

INJECTABLE EXTENDED-RELEASE BUPRENORPHINE (XR-B) IN A CORRECTIONAL SETTING: A PILOT RANDOMIZED CONTROLLED TRIAL - PROJECT SUMMARY THIS K23 APPLICATION PROPOSES NOVEL RESEARCH IN OPIOID USE DISORDER (OUD) TREATMENT IN A CORRECTIONAL HEALTHCARE SETTING AND A ROBUST TRAINING PLAN TO SUPPORT THE SUCCESSFUL TRANSITION OF THE DR. JUSTIN BERK, MD MPH MBA (PI) TO INDEPENDENT CLINICIAN-SCIENTIST. HIS BACKGROUND IN PUBLIC HEALTH, HEALTH MANAGEMENT, AND CLINICAL MEDICINE CREATES A STRONG FOUNDATION FOR FURTHER DEVELOPMENT AS AN EXPERT SCIENTIST. HE HAS ASSEMBLED A HIGHLY ACCOMPLISHED AND DIVERSE TEAM OF NATIONALLY RECOGNIZED MENTORS AND ADVISORS WITH COMPLEMENTARY EXPERTISE IN CLINICAL TRIALS AND OTHER RESEARCH AMONG VULNERABLE POPULATIONS INCLUDING QUALITATIVE METHODOLOGIES AND IMPLEMENTATION SCIENCE. THE PROPOSED RESEARCH WORK WILL PROVIDE HANDS-ON EXPERIENCE INSTRUMENTAL TO DR. BERK’S CAREER PROGRESSION AS A CLINICAL TRIALIST PRELIMINARY DATA FOR A FUTURE MULTI-SITE R01 APPLICATION. THE RHODE ISLAND DEPARTMENT OF CORRECTIONS (RIDOC) IS AN IDEAL SETTING FOR THIS TYPE OF PILOT STUDY. MEDICATIONS FOR OPIOID USE DISORDER (MOUD) ARE AN EFFECTIVE TREATMENT IN THE COMMUNITY AND AMONG INCARCERATED INDIVIDUALS. GIVEN THE HIGH PREVALENCE OUD IN JAILS AND PRISONS AND THE HIGH RISK OF OPIOID OVERDOSE UPON RELEASE, THE CRIMINAL JUSTICE (CJ) SYSTEM OFFERS A TARGETED OPPORTUNITY TO ENGAGE INDIVIDUALS IN TREATMENT INITIATION. DESPITE THE STRONG EVIDENCE-BASE FOR MOUD, FEW CORRECTIONAL FACILITIES OFFER THESE LIFE- SAVING MEDICATIONS. A SHIFTING POLICY LANDSCAPE IN LEGISLATION AND COURT RULINGS WILL LEAD TO MORE FACILITIES OFFERING MOUD TREATMENT. DELIVERY BARRIERS, HOWEVER, STILL EXIST. A NEW INJECTABLE EXTENDED-RELEASE FORM OF BUPRENORPHINE (XR-B) CAN HELP OVERCOME THESE BARRIERS, THOUGH THERE IS NO PUBLISHED LITERATURE ON ITS EFFECTIVENESS OR IMPLEMENTATION IN A CJ SETTING. THIS K23 PROPOSES A RANDOMIZED CONTROLLED TRIAL (RCT) TO DEMONSTRATE PRELIMINARY EFFECTIVENESS, ACCEPTABILITY, AND FEASIBILITY OF XR-B AND USES A CONCOMITANT PROCESS EVALUATION, WITH FRAMEWORKS FREQUENTLY USED IN IMPLEMENTATION SCIENCE, TO INVESTIGATE HOW THIS NOVEL TREATMENT MODALITY MAY BE USED IN A CJ SETTING TO PREVENT OPIOID OVERDOSE IN THE HIGH-RISK TIME OF RE-ENTRY TO THE COMMUNITY. THE SPECIFIC AIMS OF THIS K23 PROPOSAL INCLUDE: (AIM 1) COMPARE XR-B INITIATION TO TREATMENT-AS-USUAL SUBLINGUAL BUPRENORPHINE AMONG INCARCERATED INDIVIDUALS ON TREATMENT ENGAGEMENT, RE-INCARCERATION, OVERDOSE, BUPRENORPHINE ADHERENCE, AND ILLICIT OPIOID USE. (AIM 2) CONDUCT A PROCESS EVALUATION USING THE RE- AIM EVALUATIVE FRAMEWORK AND IPARIHS IMPLEMENTATION SCIENCE FRAMEWORK TO ASSESS THE IMPLEMENTATION OF XR-B INITIATION AND IDENTIFY FACILITATORS TO AND BARRIERS OF MOUD TREATMENT IN A CJ SETTING. IN ORDER TO ACHIEVE THESE AIMS AND MOVE TOWARDS RESEARCH INDEPENDENCE, DR. BERK WILL RECEIVE TRAINING AND EXPERIENCE IN CLINICAL TRIAL RESEARCH, INCLUDING SUPPORTING QUALITATIVE METHODOLOGIES AND IMPLEMENTATION SCIENCE, AND BUILD A CAREER TO CONDUCT HIGH-IMPACT AND ETHICAL RESEARCH IN A MARGINALIZED POPULATION.

REPURPOSING PROPRANOLOL TO TREAT SICKLE CELL CARDIOMYOPATHY AND VENTRICULAR ARRHYTHMIAS: ROLE OF NONADRENERGIC SIGNALING

SOCIAL MEDIA USE AND MECHANISMS OF SUICIDE RISK IN ADOLESCENTS

PROMOTING CHILD AND ADOLESCENT RESEARCH DURING TRAINING - PSYCHIATRIC DISORDERS ARE COMMON IN CHILDHOOD AND CAUSE SIGNIFICANT MORBIDITY, MORTALITY AND DISABILITY. THERE IS A CRITICAL SHORTAGE OF PHYSICIAN-SCIENTISTS IN CHILD AND ADOLESCENT PSYCHIATRY (CAP) TO ADDRESS THIS SIGNIFICANT PROBLEM. UNFORTUNATELY, THERE ARE A DEARTH OF PROGRAMS THAT PROVIDE SIGNIFICANT RESEARCH TRAINING, FORCING CAP FELLOWS WHO DESIRE A RESEARCH CAREER TO COMMIT TO AN ADDITIONAL 2-3 YEARS OF POSTGRADUATE RESEARCH TRAINING BEYOND THEIR CAP FELLOWSHIP. THIS PROPOSED R25-FUNDED CHILD AND ADOLESCENT PSYCHIATRY RESEARCH TRAINING TRACK (CAP-RTT) WILL FILL THIS CRITICAL TRAINING GAP AND NATIONAL NEED. IT WILL TRAIN THE NEXT GENERATION OF PHYSICIAN- SCIENTISTS IN CAP RESEARCH AND ACCELERATE THEIR TRAJECTORIES TO INDEPENDENT, PRODUCTIVE RESEARCH CAREERS. THIS TWO YEAR PROGRAM, WITH AN OPTIONAL THIRD YEAR, WILL PAIR SUBSTANTIAL DEDICATED RESEARCH TIME WITH EXCELLENT CLINICAL TRAINING IN OUR CAP FELLOWSHIP. OUR DIVISION PROVIDES AN IDEAL SETTING TO COMBINE SUPERB RESEARCH AND CLINICAL TRAINING. OUR CAP FELLOWSHIP AND TRIPLE BOARD PROGRAM HAVE A LONG HISTORY OF ATTRACTING EXCELLENT TRAINEES PROVIDING UNPARALLELED TRAINING. WE HAVE A POOL OF POTENTIAL CAP RESEARCHERS FOR THE CAP-RTT. THE NUMBER OF RESEARCH-ORIENTED RESIDENTS POTENTIALLY AVAILABLE TO OUR PROGRAM, STIMULATED THIS APPLICATION. IN 2019, THE DIVISION RECEIVED MORE THAN $15 MILLION FOR ACTIVE GRANTS (REPRESENTING OVER $38 MILLION IN ALL YEARS OF FUNDING FOR THOSE PROJECTS). THE DIVISION'S PIONEERING RESEARCH IN PSYCHOPATHOLOGY, CHILDREN'S SLEEP, INFANT DEVELOPMENT, PSYCHOPHYSIOLOGY, AND HIV CLINICAL INTERVENTIONS HAS TRANSLATED INTO NEW AND EFFECTIVE TREATMENTS FOR CHILDREN AND THEIR FAMILIES. OTHER AREAS OF INTEREST INCLUDE NEUROSCIENCE, GENETICS, SOCIAL SCIENCE, PREVENTION, HEALTH DISPARITIES, AND HEALTH SERVICES RESEARCH. OUR FACULTY ARE SKILLED MENTORS IN THE DIVISION'S TWO NIMH T32 PROGRAMS AND PARTICIPATE IN MANY OTHER RESEARCH TRAINING PROGRAMS AT BROWN. OUR PROGRAM WILL COMBINE AN INTENSIVE LONGITUDINAL MENTORED RESEARCH EXPERIENCE WITH AN INDIVIDUALIZED RESEARCH DIDACTIC CURRICULUM AND CAREER DEVELOPMENT ACTIVITIES IN A RICH, MULTIDISCIPLINARY ENVIRONMENT. THE PROGRAM WILL CONTAIN SUBSTANTIAL PROTECTED RESEARCH TIME, INDIVIDUALIZED MENTORED RESEARCH TRAINING, A SPECIALIZED DIDACTIC RESEARCH CURRICULUM, CAREER DEVELOPMENT EXPERIENCES FOR TRAINEES, AND A COMPREHENSIVE EVALUATION COMPONENT OF THE FELLOWS AND THE PROGRAM.

SHORT-TERM TRAINING FOR MINORITY STUDENTS

AN INTERVENTION TO IMPROVE HIV PRE-EXPOSURE PROPHYLAXIS INITIATION, ADHERENCE AND LINKAGE TO CARE FOR RECENTLY INCARCERATED MEN WHO INJECT DRUGS. - PROJECT SUMMARY THIS K23 APPLICATION OUTLINES A NOVEL AREA OF CLINICAL RESEARCH THAT MEETS A GROWING PUBLIC HEALTH NEED AS PEOPLE WHO INJECT DRUGS (PWID) REPRESENT A DISPROPORTIONATE NUMBER OF NEW HIV CASES WITH LIMITED KNOWLEDGE ABOUT THE PROGRAMMING AND LINKAGE TO CARE NEEDED TO SUPPORT PRE-EXPOSURE PROPHYLAXIS (PREP) USAGE AMONG THIS POPULATION. THE RESEARCH AIMS ARE DESIGNED TO ENSURE DR. MATTHEW MURPHY'S (PI) FUTURE RESEARCH INDEPENDENCE IN HIV PREVENTION AND PREP USE FOR THOSE WITH SUBSTANCE USE DISORDERS (SUD) AT THE GREATEST RISK OF HIV INFECTION BY PROVIDING PRELIMINARY DATA FOR A FUTURE R01 APPLICATION. THE SPECIFIC AIMS OF THE K23 PROPOSAL ARE TO 1) CONDUCT QUALITATIVE INTERVIEWS WITH 20 CJ-INVOLVED MALE PWID TO EVALUATE BARRIERS AND FACILITATORS TO PREP INITIATION, ADHERENCE, AND LINKAGE TO CARE AFTER RELEASE FROM INCARCERATION; 2) DEVELOP A “PREPARE-FOR-RELEASE” INTERVENTION AND CONDUCT AN OPEN LABEL PILOT INTERVENTION WITH 15 MALE PWID WHO ARE BEING RELEASED FROM INCARCERATION AND 3) CONDUCT AN RCT OF THE “PREPARE-FOR-RELEASE” INTERVENTION AMONG 100 MALE PWID WHO ARE BEING RELEASED FROM INCARCERATION. IN ORDER TO BOTH ACHIEVE THOSE AIMS AND ATTAIN RESEARCH INDEPENDENCE, DR. MURPHY WILL RECEIVE TRAINING IN HIV PREVENTION APPROACHES FOR THOSE WITH SUD WITHIN THE CRIMINAL JUSTICE (CJ) SYSTEM, QUALITATIVE RESEARCH METHODOLOGY USED TO IDENTIFY BARRIERS AND FACILITATORS TO HIV PREVENTION CARE, APPROACHES TO BEHAVIORAL INTERVENTION DEVELOPMENT AND EVALUATION AS WELL AS TRAINING IN THE RESPONSIBLE CONDUCT OF RESEARCH. THE MENTORSHIP TEAM, MADE UP OF LEADING EXPERTS IN RELATED FIELDS OF CLINICAL AND PUBLIC HEALTH RESEARCH FROM BOTH BROWN UNIVERSITY AND NEARBY YALE UNIVERSITY, ARE INCREDIBLY WELL SUITED TO ENSURE BOTH SUCCESSFUL ATTAINMENT OF THE RESEARCH AIMS AS WELL AS FUTURE RESEARCH INDEPENDENCE FOR THE PI. DR. PHILIP A CHAN (PRIMARY MENTOR), AS A LEADER IN THE FIELD OF PREP CLINICAL RESEARCH, WILL BE A KEY EXPERT ON THE SUCCESSFUL IMPLEMENTATION OF THE PREP CARE CONTINUUM FOR THIS POPULATION AND CONDUCTING TRIALS EVALUATING INTERVENTIONS TO IMPROVE ITS USE. ADDITIONAL MENTORSHIP FOR THIS PROPOSAL INCLUDES DR. JOSIAH RICH (CO-MENTOR), A GLOBAL LEADER ON INTERVENTION DEVELOPMENT TO IMPROVE SUD MANAGEMENT AND HIV INFECTION RISK DURING THE PERIOD OF TRANSITION FROM INCARCERATION TO THE COMMUNITY, DR. AMY NUNN (CO- MENTOR), A LEADING EXPERT ON QUALITATIVE METHODOLOGY RELATED TO PREP CARE AND HEALTH INEQUALITIES WITH SIGNIFICANT PRIOR EXPERIENCE WORKING WITH CJ-INVOLVED POPULATIONS, DR. TRACE KERSHAW (CO-MENTOR), A GLOBAL LEADER ON BEHAVIORAL INTERVENTION DEVELOPMENT TO REDUCE HIV INFECTION RISK IN POPULATIONS WITH SUDS, AND DR. CHRISTOPHER SCHMID (CO-MENTOR), FORMER CHAIR OF BIOSTATISTICS AT BROWN'S SCHOOL OF PUBLIC HEALTH WITH SIGNIFICANT EXPERIENCE IN CLINICAL TRIAL DESIGN AND AN EXPERT IN QUANTITATIVE METHODOLOGY.

BIOMARKER FOR HEPATOCELLULAR CARCINOMA

HIV IN INJURY: EVALUATION OF SELF-TESTING IN AFRICAN EMERGENCY CARE FOR THE INJURED (HIV AECI)

AN ACCEPTANCE BASED PREP INTERVENTION TO ENGAGE YOUNG BLACK MSM IN THE SOUTH - PROJECT SUMMARY/ABSTRACT YOUNG BLACK MEN WHO HAVE SEX WITH MEN (YBMSM) HAVE A HIGH INCIDENCE OF HIV, PARTICULARLY IN THE SOUTH. THUS, INTERVENTIONS TAILORED TO YBMSM TO ENHANCE ENGAGEMENT IN PREVENTION SERVICES ARE URGENTLY NEEDED. ENGAGEMENT IN PREP CARE AMONG YBMSM IS LESS THEN OPTIMAL. THE MODIFIED SOCIAL ECOLOGICAL MODEL (MSEM) DEFINES THE MULTI-LEVEL DOMAINS OF HIV INFECTION RISK AMONG KEY POPULATIONS. BARRIERS TO PREP USE AMONG YBMSM OCCUR AT EACH LEVEL: 1) INDIVIDUAL, 2) SOCIAL AND SEXUAL NETWORK, 3) COMMUNITY, 4) POLICY, AND 5) STAGE OF THE HIV EPIDEMIC. EXAMPLES INCLUDE INDIVIDUAL (E.G. PERCEPTION OF HIV RISK), SOCIAL AND SEXUAL NETWORK (E.G. STIGMA), COMMUNITY (E.G. LACK OF MEDICAL SERVICES), AND PUBLIC POLICY (E.G. COST OF CARE). THE BOUNDARY BETWEEN EACH LEVEL IS PERMEABLE, THUS EACH IS CONSIDERED IN THE PROPOSED STUDY. UTILIZING COMPONENTS OF ACCEPTANCE AND COMMITMENT THERAPY (ACT), WE WILL DESIGN AN INTERVENTION TO IMPROVE PREP UPTAKE, PERSISTENCE, AND ADHERENCE. WE WILL USE A GENERALIZED FRAMEWORK FOR THE ADAPTATION OF EBIS TO INFORM THE DEVELOPMENT OF A BRIEF INTERVENTION FOR PREP TAILORED TO YBMSM, NAMED ACTPREP. ACT ADDRESSES BARRIERS BY PROMOTING: 1) PRESENT MOMENT AWARENESS, 2) ACCEPTANCE OF INTERNAL AND EXTERNAL EXPERIENCES, AND 3) ENGAGEMENT IN BEHAVIORS THAT ARE CONSISTENT WITH VALUES. TO MAXIMIZE UTILITY, ACTPREP WILL BE DELIVERED BY A PREP NAVIGATOR. CANDIDATE: DR. ARNOLD IS A MEDICAL CLINICAL PSYCHOLOGIST/SCIENTIST WITH A RESEARCH BACKGROUND IN HIV RELATED STUDIES IN THE SOUTH. HER CAREER HAS FOCUSED ON HIV INTERVENTION AND PREVENTION. BUILDING ON PRIOR RESEARCH, SHE IS APPLYING FOR A FIVE-YEAR K23 CAREER DEVELOPMENT AWARD. MENTORING: AN EXCEPTIONAL TEAM OF SENIOR INVESTIGATORS SERVE AS MENTORS. DR. BROWN IS THE PRIMARY MENTOR AND HAS EXPERTISE IN THE DESIGNING AND IMPLEMENTING OF PREP INTERVENTIONS. FOUR CO-MENTORS BRING COMPLEMENTARY EXPERTISE IN PREP DELIVERY FOR YBMSM IN THE SOUTH AND ADHERENCE MONITORING (DR. MENA); ADAPTING BEHAVIOR CHANGE INTERVENTIONS (DR. GAUDIANO); IMPLEMENTATION SCIENCE (DR. ELWY); AND QUANTITATIVE DATA ANALYSES (DR. JONES). RESEARCH: THE PROPOSED AIMS ARE 1) GATHER DATA FROM YBMSM (N = 20) AND CLINIC STAFF (N = 10) THROUGH IN- DEPTH INTERVIEWS TO ASSESS MEASURES, INTERVENTION DESIGN, AND BARRIERS; 2) DEVELOP ACTPREP UTILIZING AIM 1 DATA AND WORKING ITERATIVELY WITH EXPERTS; AND 3) EVALUATE ACTPREP FEASIBILITY AND ACCEPTABILITY THROUGH A RANDOMIZED CONTROL TRIAL (N=66) AND COMPARE ACTPREP VS. ENHANCED STANDARD OF CARE ON UPTAKE, ADHERENCE, AND PREP PERSISTENCE. TRAININGS: DR. ARNOLD WILL RECEIVE SPECIFIC TRAINING IN DESIGNING, ADAPTING, AND TESTING THEORY-BASED INTERVENTIONS, ADDRESSING HEALTH DISPARITIES WITH RACIAL AND SEXUAL MINORITIES, IMPLEMENTATION SCIENCE, AND QUANTITATIVE ANALYSES THROUGH COURSEWORK, SEMINARS, WORKSHOPS, DIRECTED READINGS, AND MENTORED RESEARCH. THESE TRAINING AND RESEARCH EXPERIENCES WILL ESTABLISH THE CANDIDATE’S CAREER AS AN EXPERT IN CLINICALLY INFORMED BEHAVIOR CHANGE INTERVENTIONS. THE CANDIDATE IS SUPPORTED BY RHODE ISLAND HOSPITAL.

AGE-RELATED DECREASE IN A-BETA PEPTIDE CLEARANCE PATHWAYS: CSF AND BBB

FAMILY BASED TREATMENT OF EARLY CHILDHOOD OCD

REPRESSING RETROTRANSPOSON LINE-1: NEW CONCEPTS FOR OSTEOARTHRITIS TREATMENT - ABSTRACT OSTEOARTHRITIS (OA) IS A DEGENERATIVE JOINT DISEASE INVOLVING ARTICULAR CARTILAGE DEGRADATION, CHRONIC INFLAMMATION, AND BONE REMODELING. ALTHOUGH IT IS A LEADING CAUSE OF DISABILITY IN THE ELDERLY, THERE IS NO FDA APPROVED DISEASE MODIFYING OSTEOARTHRITIS DRUGS (DMOADS) CURRENTLY. THE SCIENTIFIC CHALLENGE IS THE INCOMPLETE UNDERSTANDING OF MECHANISMS TRIGGERING INFLAMMATION AND DEGENERATION IN THE JOINT DURING AGING OR AFTER INJURY, WHICH HAMPERS THE DEVELOPMENT OF DMOADS THAT CAN TARGET THESE PROCESSES. THE SCIENTIFIC GOAL OF THIS PROJECT IS TO DETERMINE WHETHER RETROTRANSPOSON LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1, OR L1), WHICH IS REPRESSED IN NORMAL SOMATIC CELLS BUT DE-REPRESSED IN SENESCENT CELLS DURING AGING OR AFTER TRAUMATIC INJURY, CONTRIBUTE TO AGING-ASSOCIATED OR POST-TRAUMATIC OA (PTOA). WE FOUND THAT L1 LEVELS ARE SIGNIFICANTLY ELEVATED IN HUMAN OA CARTILAGE LESIONS AND IN CARTILAGE JOINT OF BOTH AGING-ASSOCIATED OA AND PTOA MOUSE MODELS. THE INNOVATIVE HYPOTHESIS IS THAT, DURING AGING AND/OR INJURY-ASSOCIATED OA, THE CELLULAR CONTENT OF L1 RETROTRANSPOSONS IS 1) SIGNIFICANTLY INCREASED IN THE JOINT AND 2) RESPONSIBLE FOR STIMULATION OF SASP AND INFLAMMATION THAT LEAD TO JOINT DESTRUCTION. IF SO, OA PATHOGENESIS CAN BE INHIBITED BY REPRESSING L1 USING FDA- APPROVED ANTI-VIRAL DRUG NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIS). THIS HYPOTHESIS WILL BE TESTED THROUGH TWO AIMS IN THE R61 PHASE. THE FIRST AIM IS TO CHARACTERIZE AGING AND INJURY INDUCED L1 DE-REPRESSION IN THE COL2A1-CREERT2; MIR-365 MICE CAPABLE OF INDUCING EARLY ONSET-OA AND/OR PTOA. IT WILL ESTABLISH WHETHER AGING, INJURY, OR BOTH WOULD RESULT IN DE-REPRESSION OF THE L1 LEVELS IN MOUSE JOINT DURING OA. THE SECOND AIM IS TO DETERMINE WHETHER NRTIS INHIBIT OA PATHOGENESIS BY REPRESSING L1 LEVELS IN OA ANIMAL MODELS IN VIVO. NRTI NUCLEOSIDE CYTIDINE ANALOGUE LAMIVUDINE WILL BE TESTED FOR ITS ABILITY OF INHIBITING OA/PTOA IN CREERT2; MIR-365 MICE. IT WILL ESTABLISH THE EFFICACY AND THE WINDOW OF INTERVENTION FOR NRTI TO MODIFY CARTILAGE DEGENERATION, BONE REMODELING, SASP GENE EXPRESSION, AND MOVEMENT DEFICIENCY IN OA ANIMAL MODELS IN VIVO. IF THE HYPOTHESIS IS UNAMBIGUOUSLY SUPPORTED BY THE EXPERIMENTS IN R61 PHASE, IT WILL BE FURTHER EXPLORED, THROUGH A MECHANISTIC AIM IN THE R33 PHASE, TO DETERMINE THE MOLECULAR PATHWAYS BY WHICH L1 ACTIVATES OA PATHOGENESIS IN OA MOUSE MODELS AND HUMAN OA TISSUES. IT WILL ESTABLISH THE MOLECULAR PATHWAYS OF L1 DE-REPRESSION INDUCED OA MARKER GENES AND SASP EXPRESSION AT THE CELLULAR LEVEL. THIS PROJECT REPRESENTS A NEW AND DISTINCT DIRECTION FOR THE FIELD BECAUSE IT ADDRESSES THE ROLE OF RETROTRANSPOSONS IN OA PATHOGENESIS FOR THE VERY FIRST TIME. IF SUCCESSFUL, NRTIS, WHICH ARE SAFE AND READILY AVAILABLE, CAN BE RE-PURPOSED FOR OA TREATMENT IN HUMAN. IT WILL NOT ONLY CHANGE THE CONCEPTS THAT DRIVE THE OA RESEARCH FIELD, BUT ALSO GREATLY IMPACT THE CLINICAL PRACTICE OF HOW WE TREAT OA PATIENTS.

HEMATOLOGY POST DOCTORAL TRAINING

STOP STROKE: SEX-SPECIFIC PREVENTION OF STROKE THROUGH REPRODUCTIVE RISK FACTORS AND SEX HORMONE EFFECTS

IMPROVING PEDIATRIC RESUSCITATION: A SIMULATION PROGRAM FOR THE COMMUNITY ED

CBT FOR PEDIATRIC OCD: EFFECTIVE THERAPIST BEHAVIORS AND COMMUNITY TRAINING PILOT

A MULTILEVEL HIV-PREVENTION STRATEGY FOR HIGH-RISK YOUTH

ANGIOGENESIS IN A MODEL OF DIABETES AND ENDOTHELIAL DYSFUNCTION

TEXT-MESSAGE-BASED DEPRESSION PREVENTION FOR HIGH-RISK YOUTH IN THE ED

CO-INHIBITORY MOLECULES AND THE PATHOLOGY OF INDIRECT-ACUTE LUNG INJURY

HARNESSING PLACEBO ANALGESIA TO ADDRESS THE OPIOID EPIDEMIC

A COMPUTER-BASED INTERVENTION FOR WOMEN WITH SUBSTANCE USE AND IPV IN THE ED

INTEGRATED DIGITAL HEALTH INTERVENTION TO PROMOTE ENGAGEMENT IN AND ADHERENCE TO MEDICATION-ASSISTED TREATMENT

A TEXT-BASED ADHERENCE GAME FOR YOUNG PEOPLE LIVING WITH HIV IN GHANA

MIDCAREER INVESTIGATOR AWARD IN PATIENT-ORIENTED RESEARCH

CELLULAR AND MOLECULAR BIOLOGY OF INFLAMMATION AND REPAIR

STUDY OF GPR30: A NOVEL ESTROGEN RECEPTOR LINKED TO BREAST CANCER.

BASIC ASPECTS OF HEMATOPOIETIC STEM CELLS AND AGING

NOVEL NEUROCOGNITIVE MARKERS OF RISK FOR AND RESILIENCE TO COGNITIVE DECLINE IN PRECLINICAL ALZHEIMER'S DISEASE

SYSTEM GENETICS OF ALCOHOLISM: NETWORK-BASED APPROACHES FOR GENETIC ASSOCIATION