Boston Medical Center Corporation

MASSHEAL - REDUCING OVERDOSE DEATHS BY 40% (2019-2023)

BOSTON OBESITY RESEARCH CENTER

NEONATAL BIOMARKERS IN EXTREMELY PRETERM BABIES PREDICT CHILDHOOD BRAIN DISORDERS

EXCEPTIONAL SURVIVAL AND LONGEVITY IN NEW ENGLAND

OXIDATIVE STRESS, AMPK & DIABETIC CARDIOVASCULAR DISEASE

TRANSLATING RESEARCH INTO PRACTICE: A REGIONAL COLLABORATIVE TO REDUCE DISPARITIES IN BREAST CANCER CARE

GROUP-BASED MINDFULNESS FOR PATIENTS WITH CHRONIC LOW BACK PAIN IN THE PRIMARY CARE

CHAMPS NATIONAL - BACKGROUND: US BREASTFEEDING RATES ARE LOWEST AMONG BLACK INFANTS DUE TO INSTITUTIONAL RACISM AND POOR PERINATAL CARE. BREASTFEEDING-SUPPORTIVE, EVIDENCE-BASED PRACTICES EQUITABLY APPLIED INCREASE HOSPITAL BREASTFEEDING RATES, ESPECIALLY IN POPULATIONS AT HIGHEST RISK OF NOT BREASTFEEDING. COMMUNITIES AND HOSPITALS ADVANCING MATERNITY PRACTICES (CHAMPS) HAS A TRACK RECORD OF IMPROVING BREASTFEEDING RATES AND IS THE ONLY LARGE US PROGRAM TO HAVE SIGNIFICANTLY DECREASED RACIAL INEQUITIES IN HOSPITAL BREASTFEEDING RATES. CHAMPS NATIONAL HAS SUBSTANTIAL SUPPORT FROM NATIONAL AND REGIONAL COLLABORATORS, AND WILL ACTIVATE A DIVERSE TEAM OF INTERDISCIPLINARY US EXPERTS TO INCREASE SAFE, EQUITABLE, HOSPITAL COMPLIANCE WITH THE 2018 TEN STEPS TO SUCCESSFUL BREASTFEEDING, USING INNOVATIVE APPROACHES AND PARTNERSHIPS WITH EXTERNAL QUALITY ASSURANCE AND REGULATING ENTITIES. PURPOSE CHAMPS NATIONAL WILL ENROLL, TRAIN, AND SUPPORT 100 US HOSPITALS TO IMPLEMENT AND SUSTAIN SAFE COMPLIANCE WITH THE TEN STEPS USING THE IHI BREAKTHROUGH SERIES MODEL FOR IMPROVEMENT. THE PROGRAM WILL INTEGRATE ORGANIZATIONS REPRESENTING INDIVIDUALS OF COLOR AT ALL LEVELS. SHORT TERM OUTCOMES - 100 HOSPITALS WILL BE ENROLLED. AT 50% OF HOSPITALS, AT LEAST 36% OF BIRTHS WILL BE TO AFRICAN AMERICANS - CLINICIANS WILL BE TRAINED TO PROVIDE SAFE, EVIDENCE-BASED, BREASTFEEDING-SUPPORTIVE PRENATAL AND MATERNITY CARE WITH CULTURAL HUMILITY - CLINICIANS WILL BE TRAINED ON QI METHODOLOGY INTERMEDIATE OUTCOMES ENROLLED HOSPITALS WILL ACHIEVE: - AN INCREASE OF AT LEAST 60 PERCENTAGE POINTS IN RATES OF SKIN-TO-SKIN CARE - AN INCREASE OF AT LEAST 60 PERCENTAGE POINTS IN ROOMING IN RATES LONG TERM OUTCOMES ENROLLED HOSPITALS WILL ACHIEVE: - AN INCREASE OF AT LEAST 10 PERCENTAGE POINTS IN BREASTFEEDING INITIATION - A DECREASE IN THE RATE OF SUPPLEMENTAL FORMULA FEEDING OF AT LEAST 11 PERCENTAGE POINTS - A DECREASE IN THE GAP IN BREASTFEEDING INITIATION BETWEEN BLACK AND WHITE DYADS OF AT LEAST 15 PERCENTAGE POINTS STRATEGIES AND ACTIVITIES WE WILL IDENTIFY TARGET HOSPITALS AND REGIONS BY REVIEWING NATIONAL DATASETS, AND WITH HELP FROM OUR COLLABORATORS. A SIMPLE APPLICATION FORM WILL ASSESS CANDIDATE HOSPITALS AND PROVIDE DEMOGRAPHICS AND BASELINE DATA. WE WILL RETAIN HOSPITALS AND COLLABORATORS THROUGH A DYNAMIC NETWORK OF TRAINING AND EVENTS, AND WILL NURTURE FIVE ORGANICALLY RELATED HUBS (ORBS) TO REPRESENT SPHERES OF INFLUENCE, PERSPECTIVE, AND INCLUSION. WE WILL TRAIN CLINICIANS USING EVIDENCE-BASED CHAMPS TRAININGS LED BY EXPERIENCED TRAINERS WITH A FOCUS ON SAFELY MEETING THE TEN STEPS, DELIVERED VIA IN A WAY THAT INCORPORATES PRINCIPLES OF ADULT LEARNING. WE WILL TRAIN CLINICIANS IN QI METHODOLOGY. TRAININGS WILL ALWAYS INCLUDE TRAINERS OF COLOR. THE CURRICULUM WILL COVER THE WHO’S 16 COMPETENCIES AS WELL AS SAFETY AND QI. EVALUATION WE WILL COLLECT HOSPITAL POPULATION BASELINE DATA EARLY IN THE PROCESS AND ANNUALLY. BASED ON SUCCESSFUL PRIOR EXPERIENCE, WE WILL COLLECT DATA ON BREASTFEEDING INITIATION AND EXCLUSIVITY, SKIN-TO-SKIN CARE IN THE FIRST HOUR OF LIFE, AND ROOMING IN RATES, FROM THE MEDICAL RECORD. WE WILL COLLECT COMPLIANCE DATA ON ALL TEN STEPS USING A MATERNAL QUESTIONNAIRE BEFORE DISCHARGE. HOSPITALS WILL SUBMIT DE-IDENTIFIED, AGGREGATE DATA MONTHLY OVERALL AND BY RACE/ETHNICITY, AND CHAMPS WILL ANALYZE ALL DATA PROJECT-WIDE AND AT SPECIFIC SITES USING RUN CHARTS. THESE DATA WILL BE SHARED WITH HOSPITAL TEAMS AND THE CDC. CONCLUSION CHAMPS IS THE ONLY LARGE SCALE US PROGRAM TO HAVE SIGNIFICANTLY DECREASED RACIAL INEQUITIES IN HOSPITAL BREASTFEEDING RATES. WE HAVE COUNTLESS ALLIES, SUPPORTERS, AND COLLABORATORS, AND OUR SUCCESS HAS INSPIRED ADMIRATION AND COMMITMENT FROM A NATIONAL FOLLOWING IN ALL SECTORS. CDC FUNDING WILL ALLOW US TO MAKE A NATIONAL MARK, NOT ONLY ON INCREASING BREASTFEEDING RATES AND DECREASING DISPARITIES, BUT IN SHAPING THE COURSE OF TEN STEPS COMPLIANCE IN THE US FOR DECADES TO COME.

THE INTERNATIONAL UGANDA RUSSIA BOSTON ALCOHOL NETWORK FOR ALCOHOL RESEARCH COLLABORATION ON HIV/AIDS (URBAN ARCH) CENTER - ABSTRACT ONE QUARTER OF THE GLOBAL POPULATION IS INFECTED WITH THE BACILLUS MYCOBACTERIUM TUBERCULOSIS AND IS AT RISK OF DEVELOPING ACTIVE TUBERCULOSIS (TB) DISEASE AND DEATH, ESPECIALLY PERSONS LIVING WITH HIV (PLWH). ALCOHOL USE IS INCREASINGLY BEING RECOGNIZED AS A DRIVER OF THE TB EPIDEMIC, AND MAY BE A VITAL MEANS TO MITIGATE HIV/TB MORBIDITY AND MORTALITY. TB PREVENTIVE THERAPY (TPT) IS AN IMPORTANT APPROACH IN PREVENTING THE PROGRESSION OF LATENT TB INFECTION TO ACTIVE TB DISEASE. HOWEVER, TPT DOES NOT PREVENT NEW OR REPEAT TB INFECTION, THUS PLWH WHO DRINK ALCOHOL MAY REMAIN AT INCREASED RISK FOR TB ACQUISITION, EVEN AFTER RECEIPT OF TPT. HEAVY ALCOHOL USE IS COMMON AMONG PERSONS LIVING WITH HIV (PLWH). WHILE THE INCREASED RISK FOR ACTIVE TB IS ATTRIBUTED TO ALCOHOL-RELATED IMMUNOSUPPRESSION LEADING TO LATENT TB RE-ACTIVATION, THE ROLE OF ALCOHOL USE IN ACQUIRING NEW OR REPEAT TB INFECTION AND PROGRESSION TO ACTIVE TB DISEASE AFTER TPT HAS NOT BEEN EXTENSIVELY EXAMINED, INCLUDING AMONG PLWH. THOSE WHO COMPLETE TB TREATMENT HAVE EXTENSIVE POST-TB MORBIDITY AND ALMOST A 4-FOLD HIGHER RISK OF MORTALITY. THE ROLE OF BOTH HEAVY ALCOHOL USE AND HIV IN PROMOTING LUNG DISEASE AFTER TB TREATMENT IS NOT CLEAR. THE CENTRAL GOAL OF THE INTERNATIONAL UGANDA RUSSIA BOSTON ALCOHOL NETWORK FOR ALCOHOL RESEARCH COLLABORATION ON HIV/AIDS (URBAN ARCH) CENTER IS TO EXAMINE THE ROLE OF ALCOHOL USE ON NEW TB ACQUISITION, OCCURRENCE OF ACTIVE TB DISEASE AFTER TPT, AND POST-TB LUNG DISEASE AMONG PLWH. THIS NEW KNOWLEDGE WILL ENABLE FUTURE DEVELOPMENT OF INTERVENTIONS THAT CAN REDUCE ALCOHOL’S IMPACT ON TB- RELATED MORBIDITY AND MORTALITY AMONG PLWH. THE CENTER WILL BE COMPRISED OF 4 COMPONENTS (ADMINISTRATIVE CORE, BIOSTATISTICS AND DATA MANAGEMENT [BDM] CORE, UGANDA PROJECT, RUSSIA PROJECT) THAT WILL WORK SYNERGISTICALLY TO ACCOMPLISH THE FOLLOWING PRIMARY OBJECTIVES: 1) EXAMINE THE ROLE OF ALCOHOL USE IN DRIVING THE ACQUISITION OF NEW TB INFECTION AND THE OCCURRENCE OF ACTIVE TB DISEASE AFTER TPT IN PLWH IN UGANDA (UGANDA PROJECT). THIS NEW KNOWLEDGE WILL INFORM POTENTIAL NEW INTERVENTIONS TO REDUCE RISK OF TB ACQUISITION AND ACTIVE DISEASE; 2) DETERMINE THE RELATIONSHIP BETWEEN ALCOHOL USE AND LUNG DISEASE AFTER TREATMENT FOR ACTIVE TB DISEASE AMONG PLWH AND QUALITATIVELY EVALUATE FACTORS TO TAILOR ALCOHOL AND SMOKING INTERVENTIONS IN THE SETTING OF TB TREATMENT IN PLWH (RUSSIA PROJECT); 3) CONDUCT HIGH QUALITY DATA MANAGEMENT AND STATISTICAL ANALYSES FOR HIV/ALCOHOL RESEARCH (BDM CORE); 4) FOSTER MULTIDISCIPLINARY INTERNATIONAL COLLABORATIONS TO PROMOTE INNOVATIVE AND RIGOROUS HIV/ALCOHOL RESEARCH (ADMINISTRATIVE CORE); AND 5) PROVIDE ONGOING TRAINING AND MENTORING TO DEVELOP JUNIOR AND MID-CAREER INVESTIGATORS INTO FUTURE LEADERS IN HIV/ALCOHOL RESEARCH (ADMINISTRATIVE CORE). THE STRUCTURE OF THE INTERNATIONAL URBAN ARCH CENTER WILL ENSURE EFFECTIVE ADMINISTRATIVE AND SCIENTIFIC INTEGRATION OF A BROAD RANGE OF ACTIVITIES DESIGNED TO SYNERGISTICALLY GROW THE FIELD OF HIV/ALCOHOL/TB PREVENTION AND TREATMENT.

RESEARCHING EFFECTIVE STRATEGIES TO PREVENT OPIOID DEATH (RESPOND)

CLINICAL ADDICTION RESEARCH AND EDUCATION (CARE) PROGRAM

NEISSERIAL PORINS AND ANTIGEN PRESENTING CELLS

CATEGORY B - COMMUNITIES PUTTING PREVENTION TO WORK

GERIATRIC TRAINING PROGRAM FOR PHYSICIANS, DENTISTS, AND BEHAVIORAL AND MENTAL HEALTH PROFESSIONS

THE MASSACHUSETTS ALLIANCE FOR COMPLEX CARE (MACC)

BU CLINICAL HIV/AIDS RESEARCH TRAINING PROGRAM

CENTER FOR HEALTH INSURANCE REFORM, CARDIOVASCULAR OUTCOMES, AND DISPARITIES

EFFICACY/EFFECTIVENESS OF UNHEALTHY DRUG USE SCREENING/BRIEF INTERVENTION MODELS

IMPROVING PHYSICIAN OPIOID PRESCRIBING FOR CHRONIC PAIN IN HIV-INFECTED PERSONS

PRENATAL COCAINE EXPOSURE: ADOLESCENT FOLLOW-UP

COLLECTIN-MEDIATED DEFENSE AGAINST INFLUENZA

GONOCOCCAL VACCINE EVALUATION IN A HUMANIZED MOUSE MODEL

ALCOHOL & ZINC IMPACT ON INFLAMMATORY MARKERS IN HIV DISEASE - RUSSIA ARCH COHORT

PREP AND MOUD RAPID ACCESS FOR PERSONS WHO INJECT DRUGS: THE CHORUS+ STUDY - PROJECT SUMMARY / ABSTRACT THE US OPIOID OVERDOSE EPIDEMIC HAS BEEN ACCOMPANIED BY AN INCREASE IN HUMAN IMMUNODEFICIENCY (HIV) AMONG PERSONS WHO INJECT DRUGS. THE CO-OCCURRENCE OF HIV AND OPIOID USE DISORDER (OUD) SUGGESTS THAT A COMPREHENSIVE APPROACH TO OUD AND ITS INFECTIOUS COMPLICATIONS HAS THE POTENTIAL TO IMPROVE OUTCOMES. HIV PRE-EXPOSURE PROPHYLAXIS (PREP) AND MEDICATION FOR OPIOID USE DISORDER (MOUD) ARE EVIDENCE-BASED APPROACHES THAT ARE RECOMMENDED FOR PERSONS WHO INJECT DRUGS. UNFORTUNATELY, THESE MEASURES HAVE NOT BEEN WIDELY ADOPTED IN REAL-WORLD SETTINGS OR ACCESSED BY PERSONS AT-RISK. FOUNDATION FOR THE PROPOSAL: THE CHORUS INTERVENTION (COMPREHENSIVE HIV AND OPIOID USE DISORDER RESPONSE TO THE UNADDRESSED SYNDEMIC) IS INFORMED BY PRELIMINARY RESEARCH, INCLUDING: (A) QUANTITATIVE AND QUALITATIVE RESEARCH WITH PERSONS WITH SUBSTANCE USE DISORDER, (B) A RANDOMIZED CONTROLLED TRIAL OF A PEER-DELIVERED MOTIVATIONAL INTERVENTION DEMONSTRATING EFFECTIVENESS IN REDUCING HEROIN AND/OR COCAINE USE, AND (C) PRELIMINARY STUDIES DEMONSTRATING THE FEASIBILITY AND ACCEPTABILITY OF PEER-DELIVERED MOTIVATIONAL INTERVENTIONS IN NON-TRADITIONAL SETTINGS. DURING THE CHORUS PILOT PHASE, WE UNCOVERED THAT PREP WAS INITIATED LATE IN THE INTERVENTION. THEREFORE, WE ARE ATTEMPTING TO ACCELERATE PREP INITIATION BY PROVIDING HIV SELF-TESTING (CHORUS +) AT BASELINE. THE CHORUS+ INTERVENTION INCLUDES HIV SELF-TESTING, RAPID INITIATION OF PREP AND MOUD, AND A 6-MONTH PEER RECOVERY COACH TO SUPPORT ADHERENCE TO THESE MEDICATIONS. CONCEPTUAL MODEL: CHORUS+ IS A THEORY-BASED, PEER-DELIVERED, MOBILE PHONE-SUPPORTED INTERVENTION FOCUSED ON ENHANCING UPTAKE AND ADHERENCE TO HIV PREP (PRIMARY OUTCOME), AND RECEIPT OF MOUD (SECONDARY OUTCOME) AMONG PERSONS WHO INJECT OPIOIDS. CHORUS+ AIMS TO IMPROVE BEHAVIORAL SKILLS AND SELF-EFFICACY WHILE ADDRESSING STRUCTURAL BARRIERS. SUMMARY: THE CURRENT PROPOSAL SEEKS TO DETERMINE THE EFFICACY OF A NOVEL INTERVENTION TO INCREASE THE UPTAKE OF EVIDENCE-BASED MEASURES TO PREVENT HIV AND TREAT OPIOID USE DISORDER. WE WILL COMPARE THE CHORUS+ INTERVENTION TO USUAL CARE (PASSIVE REFERRAL) AMONG PERSONS WHO INJECT OPIOIDS (AIM 1). IN ADDITION, WE WILL EXAMINE STUDY IMPLEMENTATION TO FACILITATE POTENTIAL FUTURE DISSEMINATION USING A MIXED-METHODS PROCESS EVALUATION OF CHORUS+ (AIM 2). THE STUDY WILL BE PERFORMED AT BOSTON MEDICAL CENTER’S FASTER PATHS CLINIC, A LOW-BARRIER SUBSTANCE USE DISORDER BRIDGE CLINIC, AND THROUGH VICTORY PROGRAMS, WHICH UTILIZES A MOBILE OUTREACH VAN. THE PROPOSED INTERVENTION WILL RECRUIT FROM NON-TRADITIONAL SETTINGS IN ORDER TO REACH PARTICIPANTS WHO MIGHT NOT BE COMFORTABLE IN OFFICE- BASED CLINICS. THIS PROJECT SPECIFICALLY ADDRESSES NIDA’S MISSION OF DEVELOPING EFFECTIVE SOCIO-BEHAVIORAL INTERVENTIONS TO INCREASE UPTAKE OF HIV PREVENTION STRATEGIES, AND ACCELERATING THE ADOPTION OF EVIDENCE-BASED INTERVENTIONS TO ADDRESS SUBSTANCE USE AND ITS INFECTIOUS COMPLICATIONS.

ELUCIDATING MECHANISTIC CONNECTIONS BETWEEN GUIDANCE SIGNALING, MICROTUBULE REGULATION, AND GROWTH CONE STEERING

ADVANCING CLINICAL RESEARCH TRAINING WITHIN ADDICTION RESIDENCY PROGRAMS

TRAINING IN HEALTH SERVICES RESEARCH FOR VULNERABLE POPULATIONS

SPECTRAL MARKERS FOR EARLY DETECTION OF COLON NEOPLASIA

METABOLIC SIGNAL TRANSDUCTION IN ADIPOCYTES

OPTIMIZING A PARAPROFESSIONAL, FAMILY PARTNER NAVIGATION MODEL FOR CHILDREN

LONG-TERM SURVIVORSHIP IN OLDER WOMEN WITH EARLY STAGE BREAST CANCER

IMPACT OF SMOKING AND ITS CESSATION ON SYSTEMIC AND AIRWAY IMMUNE ACTIVATION

YOGA VS. PHYSICAL THERAPY FOR CHRONIC LOW BACK PAIN IN MINORITY POPULATIONS

SUPPORT FOR FETAL ALCOHOL SPECTRUM DISORDERS (FASD) PREVENTION, IDENTIFICATION, AND INTERVENTION

US-BRAZIL RESEARCH COLLABORATION ON STRAIN VARIATION IN TB

AFFORDABLE CARE ACT: PRIMARY CARE RESIDENCY EXPANSION

ADDICTION MEDICINE FELLOWSHIP

PERSISTENT HIV-1 EXPRESSION AND MICROGLIA DYSFUNCTION - ABSTRACT/PROJECT SUMMARY MICROGLIA ARE LONG-LIVED CENTRAL NERVOUS SYSTEM (CNS)-RESIDENT INNATE IMMUNE CELLS THAT HAVE CRITICAL IMMUNE SURVEILLANCE FUNCTIONS AND HOMEOSTATIC FUNCTIONS IN THE BRAIN INCLUDING CLEARANCE OF PATHOGENS AND MAINTAINING INTEGRITY OF NEURONAL SYNAPSES. MICROGLIA ARE TARGETED BY HIV, HAVE BEEN PROPOSED TO BE A RESERVOIR FOR HIV PERSISTENT INFECTION AND ARE MEDIATORS OF HIV-ASSOCIATED INFLAMMATION AND NEUROPATHOGENESIS. IMPORTANTLY, MICROGLIA DYSFUNCTION IS PROPOSED TO CONTRIBUTE TO HIV ASSOCIATED NEURODEGENERATION AND INFLAMMATION EVEN WHEN HIV REPLICATION IS SUPPRESSED DURING ANTIRETROVIRAL TREATMENTS. THE MECHANISMS, DIRECT OR INDIRECT, THAT DRIVE MICROGLIA TO PROMOTE INFLAMMATION DURING HIV INFECTION HAVE NOT BEEN ELUCIDATED. IN THIS STUDY, WE WILL UTILIZE A PRIMARY MICROGLIA-NEURON COCULTURE MODEL DERIVED FROM PLURIPOTENT STEM CELLS TO TEST THE HYPOTHESIS THAT HIV IN MICROGLIA ESTABLISHES PERSISTENTLY INFECTED MICROGLIA THAT EXPRESS ABERRANT VIRAL RNAS, INCLUDING THOSE THAT RETAIN INTRONIC SEQUENCES, WHICH MEDIATE INFLAMMASOME ACTIVATION TO DRIVE MICROGLIA DYSFUNCTION, CNS INFLAMMATION AND NEURONAL INJURY. OUR PRELIMINARY DATA SUPPORTING OUR HYPOTHESIS INCLUDES RESULTS DEMONSTRATING THAT PRIMARY MACROPHAGES HARBOR DEFECTIVE HIV PROVIRUSES AND, DESPITE HARBORING DELETIONS AND MUTATIONS THAT ATTENUATE VIRUS PRODUCTION, GENERATE HIV RNAS. FURTHERMORE, OUR PREVIOUS WORK ESTABLISHED THE POTENTIAL ROLE OF HIV INTRON CONTAINING RNA IN ACTIVATING INFLAMMATORY ACTIVITIES IN MACROPHAGES AND MICROGLIA. SPECIFIC QUESTIONS ADDRESSED IN THIS PROPOSAL INCLUDE: 1) WHAT IS THE STATUS OF PROVIRUSES IN HIV INFECTED MICROGLIA; 2) WHAT MECHANISMS DRIVE PERSISTENT EXPRESSION OF HIV RNA IN MICROGLIA; AND 3) WHAT ARE THE MECHANISMS THAT TRIGGER INFLAMMASOME ACTIVATION IN HIV-ACTIVATED MACROPHAGES? COMPLETION OF THIS PROJECT WILL PROVIDE GENERAL INSIGHTS INTO THE IMPACT OF HIV-1 PERSISTENCE AND EXPRESSION IN THE CONTEXT OF MICROGLIA. IMPORTANTLY, THESE STUDIES WILL PROVIDE INSIGHTS INTO MECHANISMS THAT CONTRIBUTE TO HIV-1 CNS COMORBIDITIES WHICH PERSIST EVEN WITH ART AND COULD LEAD TO NEW TARGETS AND STRATEGIES FOR TREATMENTS THAT WILL IMPROVE THE LIVES OF PEOPLE LIVING WITH HIV.

LINKING RUSSIAN NARCOLOGY AND HIV CARE TO ENHANCE TREATMENT, RETENTION AND OUTCOMES PART II

WOMEN IN CONTROL: A VIRTUAL WORLD STUDY OF DIABETES SELF-MANAGEMENT

VALIDATION OF LIGHT SCATTERING SPECTROSCOPY FOR INTRA-OPERATIVE MARGIN GUIDANCE DURING ORAL CANCER RESECTION

MASSACHUSETTS HEALTH DISPARITIES MONITORING SYSTEM

UNDERSTANDING AND ADDRESSING THE SOCIAL DETERMINANTS OF HEALTH FOR FAMILIES OF CHILDREN WITH SICKLE CELL ANEMIA WITHIN PEDIATRIC HEMATOLOGY DIVERSITY SUPPLEMENT

TRANSMISSION OF TUBERCULOSIS AMONG ILLICIT DRUG USE LINKAGES (TOTAL)

INDUCED PLURIPOTENT STEM CELL-DERIVED ENDOTHELIAL CELL THERAPY FOR LIVER DISEASE - ABSTRACT LIVER TRANSPLANTATION IS THE ONLY CURATIVE TREATMENT FOR END-STAGE AND ACUTE LIVER DISEASE; HOWEVER, THE SCARCITY OF DONOR ORGANS UNDERSCORES THE URGENT NEED FOR ALTERNATIVE THERAPIES. HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSC) COULD PROVIDE AN UNLIMITED SUPPLY OF PATIENT-SPECIFIC LIVER CELLS FOR CELL-REPLACEMENT THERAPY. ALTHOUGH HEPATOCYTES, THE PRIMARY FUNCTIONAL CELLS OF THE LIVER, ARE THE MOST DESIRABLE CELL TYPE TO TRANSPLANT, A MAJOR LIMITATION IS THE INCOMPLETE MATURATION OF HIPSC-DERIVED HEPATOCYTES, WHICH REDUCES THEIR THERAPEUTIC EFFECTIVENESS, PARTICULARLY IN ACUTE LIVER DISEASES THAT REQUIRE RAPID RESTORATION OF FUNCTIONAL CELLS. TO OVERCOME THIS LIMITATION, THIS APPLICATION PROPOSES TRANSPLANTING SUPPORTIVE CELLS THAT ENHANCE THE PROLIFERATION AND FUNCTION OF THE REMAINING HEPATOCYTES. WE WILL LEVERAGE THE WELL-ESTABLISHED SUPPORTIVE ROLE OF LIVER ENDOTHELIAL CELLS (EC), WHICH PROMOTE HEPATOCYTE PROLIFERATION AND FUNCTION THROUGH PARACRINE SIGNALING DURING LIVER REPAIR. THE GOAL OF THIS PROPOSAL IS TO EVALUATE THE THERAPEUTIC POTENTIAL OF IPSC-DERIVED EC (IEC) THERAPY FOR PROMOTING LIVER REGENERATION. ENGRAFTMENT OF HEALTHY ECS IS EXPECTED NOT ONLY TO RESTORE FUNCTIONAL LIVER VASCULATURE BUT ALSO TO RECONSTRUCT THE SUPPORTIVE CELLULAR NICHE REQUIRED FOR THE PROLIFERATION AND FUNCTION OF THE REMAINING HEPATOCYTES, ULTIMATELY ALLEVIATING LIVER DISEASE. THIS APPROACH BUILDS ON OUR LONG-STANDING EXPERTISE IN THE SUPPORTIVE INTERACTIONS BETWEEN HEPATOCYTES AND ECS DURING LIVER DEVELOPMENT. WE PREVIOUSLY OBSERVED THAT ECS FUNCTION AS A NICHE THAT REPRESSES WNT AND NOTCH SIGNALING TO PROMOTE HEPATOCYTE GENERATION FROM PSCS, AND THAT THIS SUPPORT DEPENDS ON ACTIVATION OF VEGFR2. CONSISTENT WITH OUR FINDINGS, OTHERS HAVE SHOWN THAT THE VEGFA/VEGFR2 AXIS ACTIVATES ECS IN INJURED MOUSE LIVERS, INDUCING THE EXPRESSION OF FACTORS SUCH AS WNT2 AND HGF THAT STIMULATE HEPATOCYTE PROLIFERATION. SIMILARLY, WNT2 AND WNT9B SECRETED BY ECS HAVE BEEN SHOWN TO DRIVE HEPATOCYTE PROLIFERATION FOLLOWING PARTIAL HEPATECTOMY. TO SUPPORT OUR PROPOSAL, WE PRODUCED KEY PRELIMINARY DATA DEMONSTRATING THE ROBUST GENERATION OF IECS THAT CONSISTENTLY ENGRAFT IN A MURINE ACUTE LIVER INJURY MODEL INDUCED BY MONOCROTALINE (MCT), AND THAT ENGRAFTMENT WAS SIGNIFICANTLY ENHANCED WHEN MICE WERE TREATED WITH VEGFA MRNA FORMULATED IN LIPID NANOPARTICLES (MRNA-LNP). THIS PROPOSAL WILL THUS TEST THE HYPOTHESIS THAT IEC THERAPY WILL NOT ONLY RESTORE DAMAGED LIVER VASCULATURE BUT ALSO ALLEVIATE THE LIVER DYSFUNCTION BY PROMOTING THE PROLIFERATION AND FUNCTION OF REMAINING MATURE HEPATOCYTES THROUGH ENDOTHELIAL-DERIVED FACTORS. AIM 1 WILL DEVELOP STRATEGIES TO FURTHER PROMOTE VEGFA-MEDIATED IEC ENGRAFTMENT TO REGENERATE A FUNCTIONAL HYBRID HOST VASCULATURE IN THE ACUTE MCT MODEL. AIM 2 WILL DETERMINE THE PRE-CLINICAL THERAPEUTIC BENEFIT OF VEGFA MRNA-LNP-ENHANCED IEC ENGRAFTMENT IN MITIGATING ACUTE AND CHRONIC LIVER DISEASE FEATURES. AIM 3 WILL DEFINE THE CELLULAR AND MOLECULAR MECHANISMS UNDERLYING VEGFA-DRIVEN IEC THERAPY. ALTOGETHER, THIS PROPOSAL WILL PROVIDE CRITICAL INSIGHTS INTO THE PRECLINICAL THERAPEUTIC POTENTIAL OF VEGFA MRNA-LNP-MEDIATED IEC THERAPY AND ELUCIDATE THE ASSOCIATED CELLULAR AND MOLECULAR MECHANISMS FOR TREATING ACUTE AND CHRONIC LIVER DISEASES.

ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY AND HIV-1 MOTHER TO CHILD TRANSMISSION - PROJECT SUMMARY OVER 150,000 INFANTS ACQUIRE HIV-1 FROM THEIR INFECTED MOTHERS PRIMARILY BECAUSE COMBINATION ANTIRETROVIRAL TREATMENT (CART) REMAINS INACCESSIBLE IN SOME POPULATIONS. SURPRISINGLY EVEN IN THE ABSENCE CART, ONLY AROUND 20 – 30% OF INFANTS GET HIV-1 FROM THEIR MOTHER ALTHOUGH THEY ARE CONSTANTLY EXPOSED TO THE VIRUS DURING GESTATION, BIRTH AND BREAST FEEDING. IMMUNE FACTORS, SUCH AS MATERNAL ANTIBODIES, LIKELY PREVENT TRANSMISSION. MOTHER TO CHILD TRANSMISSION (MTCT) COHORTS ARE AN IDEAL WAY TO EXAMINE THE IMPACT OF PRE- EXISTING ANTIBODIES IN PREVENTING HIV-1 TRANSMISSION IN A NATURAL SETTING BECAUSE: 1) INFANTS ARE RELIABLY EXPOSED TO THE VIRUS; 2) MOTHERS PASS THEIR ANTIBODIES TO THE INFANT; AND 3) SAMPLES CAN BE OBTAINED FROM BOTH THE MOTHER AND THE INFANT PRIOR TO AND AFTER TRANSMISSION. UNDERSTANDING THE ROLE OF AND THE TYPES OF ANTIBODIES THAT CAN PREVENT HIV-1 TRANSMISSION REMAINS ONE OF THE HIGHEST PRIORITIES ESPECIALLY FOR VACCINE EFFORTS. IN CONTRAST TO ALL ANIMAL MODELS, MTCT INVESTIGATIONS AND ANTIBODY PASSIVE INFUSION CLINICAL TRIALS DEMONSTRATE THAT PRE-EXISTING NEUTRALIZING ANTIBODIES (NABS) DO NOT PROVIDE SIGNIFICANT PROTECTION AGAINST HIV-1 TRANSMISSION. THE MAJOR DIFFERENCE AMONG ANIMAL MODELS AND HIV-1 TRANSMISSION IS THAT HUMANS ARE EXPOSED TO A DIVERSE SWARM OF HIV-1 VARIANTS, AND SOME OF THE STRAINS ARE NEUTRALIZATION RESISTANT. IN SETTING WHERE THE EXPOSED INDIVIDUAL ALREADY POSSESSES NABS, THEY ACQUIRE NEUTRALIZATION RESISTANT VARIANTS. IN CONTRAST, WE SHOW THAT INFANTS WITH PRE-EXISTING ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY (ADCC) AGAINST THEIR MOTHER’S NEUTRALIZATION RESISTANT STRAINS ARE LESS LIKELY TO ACQUIRE HIV-1, AND THEY HAVE LOWER MORBIDITY UP TO 1 YEAR AFTER BIRTH IN THE ABSENCE OF CART. WE HAVE FURTHER OBSERVED THAT TRANSMISSION DEPENDS ON BOTH THE PREEXISTING ADCC BREADTH AND POTENCY IN THE NAÏVE EXPOSED INFANT AND THE ADCC SENSITIVITY OF THE VARIANTS CIRCULATING IN THE MATERNAL VARIANTS (EXPOSURE STRAINS). WE PROPOSE TO PROVIDE MORE DEFINITIVE SUPPORT FOR THE IMPORTANCE OF ADCC DURING MTCT BY EXPLORING IF NEWLY INFECTED INFANTS ACQUIRE ADCC RESISTANT STRAINS. WE WILL FURTHER IDENTIFY HOST FACTORS AND VIRUS CHARACTERISTICS THAT INFLUENCE ADCC BREADTH AND POTENCY AND ADCC SUSCEPTIBILITY. WE FURTHER HYPOTHESIZE THAT ADCC PRESENT IN INFECTED INFANTS CAN ELIMINATE CELLS WITH INFECTIOUS VIRUS THAT CAN PRODUCE VIRUS. INFANTS WITH HIGHER ADCC AGAINST THEIR AUTOLOGOUS VIRUS HAVE A LOWER NUMBER OF RESIDUAL INFECTED CELLS. A SMALLER NUMBER OF INFECTED CELLS RESULTS IN LOWER VIREMIA AND PLASMA INFLAMMATION, WHICH DECREASES MORBIDITY AND MORTALITY IN THE ABSENCE OF CART. FINALLY, WE WILL USE STATE OF THE ART TECHNIQUES TO ISOLATE AND CHARACTERIZE BROAD AND POTENT ADCC ANTIBODIES. THESE STUDIES WILL PROVIDE INSIGHTS ABOUT THE CHARACTERISTICS OF THESE ANTIBODIES AND THE POTENTIAL NOVEL WAYS TO ELICIT THEM USING STATE OF THE ART VACCINE METHODOLOGIES. THE PROPOSED STUDIES WILL PROVIDE CLARITY ABOUT THE SELECTION PRESSURE ADCC EXERTS DURING TRANSMISSION, HIGHLIGHT HOW PRE-EXISTING ADCC DECREASES MORTALITY, AND LEAD TO THE GENERATION OF NOVEL PROTECTIVE ANTIBODIES. CUMULATIVELY, THIS WORK WILL PROVIDE NEW STRATEGIES FOR DEVELOPING AN EFFECTIVE HIV-1 VACCINE.

BOSTON CHRONIC KIDNEY DISEASE RESEARCH BIOPSY CENTER - PROJECT SUMMARY CHRONIC KIDNEY DISEASE (CKD) AFFECTS 37 MILLION AMERICANS, COSTS TENS OF BILLIONS OF DOLLARS ANNUALLY, AND CAN LEAD TO KIDNEY FAILURE, CARDIOVASCULAR DISEASE (CVD), AND EARLY MORTALITY. CKD IS NOT A SINGLE ENTITY BUT RATHER A HETEROGENEOUS CONDITION WITH A WIDE SPECTRUM OF UNDERLYING CAUSES, PATHOLOGIC AND CLINICAL MANIFESTATIONS, AND VARYING RATES OF LOSS OF KIDNEY FUNCTION. BECAUSE OF THE PAUCITY OF KIDNEY BIOPSY SAMPLES FROM PATIENTS WITH COMMON FORMS OF CKD AND THE ACKNOWLEDGED LIMITATIONS OF ANIMAL MODELS, OUR UNDERSTANDING OF THE PATHOLOGY AND MOLECULAR MECHANISMS OF CKD IS LIMITED. IMPROVED UNDERSTANDING OF HUMAN CKD DUE TO HYPERTENSION AND DIABETES WILL REQUIRE INVESTIGATION OF KIDNEY TISSUE FROM PATIENTS WITH CKD, USING RAPIDLY EVOLVING TECHNIQUES IN MOLECULAR PATHOLOGY. WE ARE RESPONDING TO RFA-DK-20-026 TO CONTINUE AS A MULTICENTER CKD RECRUITMENT SITE FOR THE KIDNEY PRECISION MEDICINE PROJECT (KPMP) THAT BUILDS UPON THE ACCOMPLISHMENTS OF OUR ESTABLISHED MULTIDISCIPLINARY RESEARCH GROUP IN THE UG3/UH3 PHASE. WE PROPOSE TO CONTINUE TO PARTICIPATE AS A SUCCESSFUL CKD RECRUITMENT SITE IN BOSTON, MA INCLUDING FOUR CLINICAL SITES: JOSLIN DIABETES CENTER, BETH ISRAEL DEACONESS MEDICAL CENTER, BRIGHAM AND WOMEN’S HOSPITAL, AND BOSTON MEDICAL CENTER. THE PROPOSAL BUILDS UPON AN ESTABLISHED INFRASTRUCTURE AND OUR EXPERIENCE RECRUITING AND RETAINING KPMP PARTICIPANTS. IN ADDITION, OUR SITE HAS AN OUTSTANDING SAFETY RECORD FOR PARTICIPANTS WITH NO MAJOR POST-BIOPSY COMPLICATIONS AS WELL AS EXCEEDING THE QUALITY BIOSPECIMEN METRICS. FOR THE U01 PHASE WE PROPOSE TO OBTAIN REPEAT KIDNEY BIOPSIES IN SELECTED INDIVIDUALS AS WELL AS INCREASE THE FOCUS ON SOCIAL DETERMINANTS OF HEALTH. WE ALSO WILL CONTINUE TO BIOPSY INDIVIDUALS WITH LONGSTANDING TYPE 1 DIABETES MELLITUS WITH NO EVIDENCE OF KIDNEY PATHOLOGY (‘RESISTORS') TO IDENTIFY MOLECULAR UNDERPINNINGS OF PROTECTION AGAINST DIABETIC KIDNEY DISEASE. WE ARE COMMITTED TO CONTINUED COLLABORATIVE PROTOCOL DEVELOPMENT, SHARING BEST PRACTICES, AND TEAM SCIENCE TO ACHIEVE THE KPMP’S OBJECTIVES OF ADVANCING PRECISION MEDICINE TO IMPROVE THE LIVES OF OUR PATIENTS WITH AND AT RISK FOR CKD. THE PROPOSED RESEARCH PLAN, BY IMPROVING OUR UNDERSTANDING OF CKD PATHOPHYSIOLOGY, HAS THE POTENTIAL TO DRAMATICALLY IMPACT PUBLIC HEALTH.

DEVELOPING NOVEL THERAPEUTICS FOR NEPHROTIC SYNDROME

ADMINISTRATIVE COORDINATING CORE - URBAN ARCH CONSORTIUM

NATIONAL RESEARCH SERVICE AWARD

LINKING RUSSIAN NARCOLOGY & HIV CARE TO ENHANCE TREATMENT, RETENTION, & OUTCOMES

OXIDATIVE STRESS IN MYOCARDIAL REMODELING AND FAILURE

ASSOCIATION OF MATERNAL, FETAL AND PLACENTAL BIOMARKERS WITH NEONATAL NEUROIMAGING AND DEVELOPMENT FOLLOWING IN-UTERO OPIOID EXPOSURE - ABSTRACT PRENATAL OPIOID EXPOSURE CAN INFLUENCE THE INTEGRITY AND HEALTH OF THE PLACENTA AND THE DEVELOPING FETAL BRAIN. THESE MODIFICATIONS AT CRITICAL TIME POINTS CAN HAVE LASTING EFFECTS ON PREGNANCY OUTCOMES AND SUBSEQUENT INFANT NEURODEVELOPMENT. THE MECHANISMS BY WHICH OPIOIDS MODIFY THE PLACENTA AND FETAL BRAIN, CRITICAL TIME POINTS FOR THESE MODIFICATIONS, AND WHETHER THERE ARE USEFUL BIOMARKERS THAT CAN BE TRACKED THROUGHOUT THE PREGNANCY ARE UNKNOWN. TWO HYPOTHESIS DRIVEN MECHANISMS ARE 1) GENE EXPRESSION CHANGES, AND 2) INTRAUTERINE INFLAMMATION, BOTH KNOWN TO OCCUR AFTER EXPOSURE TO OPIOIDS. THESE CAN BE MEASURED USING BIOMARKERS FROM MATERNAL PLASMA AND PLACENTAL TISSUE, SPECIFICALLY MICRORNAS AND MATERNAL-INFANT INFLAMMATORY CYTOKINE PROFILES. WE PROPOSE A PROSPECTIVE COHORT STUDY COMPARING 100 OPIOID-EXPOSED TO 50 NON-EXPOSED CONTROL PREGNANCIES TO FILL THESE GAPS IN KNOWLEDGE. THE SPECIFIC AIMS OF THIS PROPOSAL ARE: 1) COMPARE SERIAL MIRNA SIGNATURES IN OPIOID-EXPOSED AND CONTROL PREGNANCIES. IN 100 OPIOID AND 50 CONTROL PARTICIPANTS, WE WILL COLLECT SERIAL MATERNAL PLASMA SAMPLES IN THE 2ND TRIMESTER, 3RD TRIMESTER, AND DELIVERY, AS WELL AS PLACENTAL TISSUE AT DELIVERY. MATERNAL EXOSOMAL MIRNA EXPRESSION LEVELS WILL BE COMPARED BETWEEN GROUPS WITH A FOCUS ON PLACENTA-DERIVED MIRNA. TOP MIRNA ASSOCIATIONS WITH PRENATAL OPIOID EXPOSURE WILL BE IDENTIFIED. 2) COMPARE SERIAL INFLAMMATORY CYTOKINES IN OPIOID- EXPOSED AND CONTROL PREGNANCIES. IN THE 100 OPIOID AND 50 CONTROL PARTICIPANTS, WE WILL COLLECT SERIAL MATERNAL PLASMA SAMPLES, PLACENTAL TISSUE, AND CORD BLOOD FOR ANALYSIS WITH A MULTIPLEX INFLAMMATORY CYTOKINE PANEL. CYTOKINE LEVELS WILL BE COMPARED BETWEEN GROUPS AT EACH TIME POINT, AND TOP ASSOCIATIONS IDENTIFIED. 3) NEURODEVELOPMENT: ASSOCIATION OF TOP MIRNAS AND CYTOKINES WITH PLACENTAL HEALTH, INFANT NEUROIMAGING AND DEVELOPMENTAL OUTCOMES IN OPIOID-EXPOSED PREGNANCIES. TOP MIRNAS AND CYTOKINES IDENTIFIED THROUGH AIMS 1 AND 2 WILL BE ANALYZED FOR ASSOCIATION WITH INFANT NEURODEVELOPMENT IN THE OPIOID COHORT. 3A) PLACENTAL HEALTH: WE WILL EVALUATE ASSOCIATIONS OF TOP BIOMARKERS WITH PLACENTAL HEALTH MEASURES (IUGR, PRE-ECLAMPSIA, PRETERM BIRTH, PLACENTAL EFFICIENCY SCORES). 3B) NEUROIMAGING: ULTRASOUND IMAGING WILL BE OBTAINED IN THE 2ND TRIMESTER, 3RD TRIMESTER, AND 1-MONTH CORRECTED GESTATIONAL AGE, AND ASSOCIATIONS EVALUATED FOR TOP BIOMARKERS. 3C) NEURODEVELOPMENT: INFANTS WILL UNDERGO A 12-MONTH BAYLEY DEVELOPMENT EXAMINATION. IN OUR FINAL REGRESSION MODEL, WE WILL EXAMINE ASSOCIATIONS BETWEEN TOP MIRNAS AND CYTOKINES WITH NEURODEVELOPMENT WITH CONSIDERATION OF PLACENTAL HEALTH (3A) AND BRAIN MEASUREMENTS (3B) AS INTERMEDIATES IN THE PATHWAY. THIS STUDY WILL HELP US TO GAIN INSIGHT INTO MECHANISMS AND DEVELOPMENTAL TIMING OF HOW PRENATAL OPIOID EXPOSURE SHAPES BOTH PLACENTAL AND FETAL BRAIN DEVELOPMENT, AND ULTIMATELY INFANT NEURODEVELOPMENTAL OUTCOMES.

GABAPENTIN TO REDUCE ALCOHOL AND IMPROVE VIRAL LOAD SUPPRESSION - PROMOTING "TREATMENT AS PREVENTION" - PROJECT SUMMARY / ABSTRACT ENDING THE HIV EPIDEMIC REQUIRES ACHIEVING HIV VIRAL LOAD (HVL) SUPPRESSION FOR KEY POPULATIONS. UNHEALTHY ALCOHOL USE BY PEOPLE WITH HIV (PWH) IS A BARRIER TO REACHING HVL SUPPRESSION AT MULTIPLE STAGES OF THE HIV CARE CASCADE. ALCOHOL USE IS COMMON AMONG PWH AND RESULTS IN LOWER ANTIRETROVIRAL THERAPY (ART) ADHERENCE AND HVL SUPPRESSION, MITIGATING THE EFFECTIVENESS OF TREATMENT AS PREVENTION (TASP), A KEY STRATEGY FOR PREVENTING HIV TRANSMISSION. TREATING ALCOHOL USE IS THEREFORE A MECHANISM TO SUPPORT PWH WITH UNHEALTHY ALCOHOL USE ALONG THE HIV CARE CASCADE. IN FACT, PRIOR STUDIES DEMONSTRATE THAT INTERVENTIONS TO REDUCE ALCOHOL USE POSITIVELY IMPACT HIV OUTCOMES. GABAPENTIN IS EFFICACIOUS FOR DECREASING ALCOHOL CONSUMPTION AND MAY BE AN EFFECTIVE TREATMENT FOR PAINFUL CONDITIONS, SUCH AS HIV-ASSOCIATED SENSORY NEUROPATHIES. HOWEVER, GABAPENTIN’S ROLE IN ACHIEVING HVL SUPPRESSION IN THIS POPULATION HAS NOT BEEN ESTABLISHED. OUR HYPOTHESIS IS THAT EFFECTIVE PHARMACOLOGICAL ALCOHOL TREATMENT (I.E., GABAPENTIN) WILL HELP PWH ENGAGE IN HIV CARE, ADHERE TO ART, AND ACHIEVE HVL SUPPRESSION. WE PROPOSE THE GABAPENTIN TO REDUCE ALCOHOL AND IMPROVE VIRAL LOAD SUPPRESSION (GRAIL) RANDOMIZED, DOUBLE-BLINDED, PLACEBO-CONTROLLED CLINICAL TRIAL TO EVALUATE THE EFFICACY OF GABAPENTIN VS. PLACEBO TO ACHIEVE HVL SUPPRESSION AMONG PWH. THE STUDY POPULATION WILL BE HEAVY DRINKERS WITH HIV WHO HAD A DETECTABLE VIRAL LOAD IN THE PAST YEAR, DESPITE HAVING BEEN PRESCRIBED ART. PARTICIPANTS (N=300) WILL BE RANDOMIZED 1:1 TO RECEIVE EITHER GABAPENTIN (1800MG/DAY TARGET DOSE) OR PLACEBO FOR 3 MONTHS; BOTH ARMS WILL EMPLOY A ONE-TIME BRIEF INTERVENTION TO REDUCE ALCOHOL USE. GRAIL AIMS TO 1) TEST THE EFFICACY OF GABAPENTIN VERSUS PLACEBO TO ACHIEVE UNDETECTABLE HVL AT 3 MONTHS (PRIMARY OUTCOME) AND AT 6 & 12 MONTHS (SECONDARY OUTCOMES); AND 2) TO ASSESS THE IMPACT OF GABAPENTIN COMPARED TO PLACEBO ON: A) ALCOHOL CONSUMPTION, B) PAIN SEVERITY, C) SELF-REPORTED ART ADHERENCE, AND D) ENGAGEMENT IN HIV CARE, IN ORDER TO EXPLORE POTENTIAL MECHANISMS BY WHICH GABAPENTIN MAY LEAD TO HVL SUPPRESSION. THIS STUDY WILL TAKE PLACE IN RUSSIA, IN A CONTEXT OF SYNDEMIC UNHEALTHY ALCOHOL USE, DRUG USE, AND HIV. OUR MULTI-DISCIPLINARY TEAM HAS AN EXTENSIVE TRACK RECORD OF SUCCESSFULLY CONDUCTING RANDOMIZED CLINICAL TRIALS IN RUSSIA, INCLUDING PHARMACOLOGICAL TRIALS (E.G., GABAPENTIN) IN PWH. RUSSIA, A SETTING IN WHICH HIV AND HEAVY ALCOHOL USE ARE MORE PREVALENT THAN IN THE US, WILL ENABLE EFFICIENT STUDY OF INTERVENING ON ALCOHOL USE AMONG PWH. THE KNOWLEDGE GAINED WILL BE APPLICABLE TO POPULATIONS LIVING WITH HIV IN THE US AND GLOBALLY. THE PROPOSED TRIAL OF GABAPENTIN IS SIGNIFICANT AS IT EMPLOYS A TASP APPROACH TO PREVENT TRANSMISSION OF HIV BY TARGETING ALCOHOL USE AND ACHIEVING HVL SUPPRESSION. IF SHOWN TO BE EFFECTIVE, THIS HIGHLY GENERALIZABLE PRAGMATIC APPROACH TO TASP CAN BE IMPLEMENTED IN A VARIETY OF CLINICAL SETTINGS, THUS MAKING IT A PRACTICAL ADDITION TO THE HIV PREVENTION TOOLKIT.

SAFETY, PHARMACOKINETICS AND EFFICACY OF EXTENDED-RELEASE NALTREXONE IN PREGNANT WOMEN WITH OPIOID USE DISORDER

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

SCALABLE SOFTWARE ENGINEERING AND METHODS FOR LARGE-SCALE SUBCELLULAR SPATIAL OMICS - PROJECT SUMMARY / ABSTRACT EMERGING SPATIAL SUBCELLULAR TRANSCRIPTOMICS TECHNOLOGIES REPRESENT A MAJOR ADVANCEMENT IN BIOLOGICAL RESEARCH, OFFERING TO STUDY THE RELATIONSHIP OF GENE EXPRESSION AND TISSUE ARCHITECTURE AT UNPRECEDENTED RESOLUTION AND SCALE. THESE TECHNOLOGIES PROMISE TO TRANSFORM FIELDS ACROSS THE BIOMEDICAL RESEARCH BY PROVIDING DETAILED INSIGHTS INTO CELLULAR BEHAVIOR AND TISSUE ARCHITECTURE IN HEALTH AND DISEASE. HOWEVER, DESPITE THEIR TRANSFORMATIVE POTENTIAL, THE ABILITY TO FULLY LEVERAGE THESE NEW TECHNOLOGIES IS CURRENTLY LIMITED BY SEVERAL CRITICAL BARRIERS. FIRST, NO SCALABLE COMPUTATIONAL TOOLS EXIST THAT FACILITATE AN INTERACTIVE AND EFFICIENT ANALYSIS OF THE MASSIVE DATASETS GENERATED BY THESE PLATFORMS, MAKING IT DIFFICULT FOR RESEARCHERS TO EXPLORE AND EXTRACT MEANINGFUL INSIGHTS. SECOND, THE CURRENT ANALYTICAL APPROACHES ARE LARGELY FOCUSED ON SINGLE-CELL RESOLUTION AND FAIL TO UTILIZE THE RICH TRANSCRIPT-LEVEL INFORMATION THAT IS ENCODED IN THE DATA, LIMITING OUR ABILITY TO UNDERSTAND COMPLEX TISSUE ORGANIZATION AND THE MOLECULAR UNDERPINNINGS OF BIOLOGICAL PROCESSES AND MORPHOLOGY. FINALLY, THERE IS A PRESSING NEED FOR SYSTEMATIC METHODS THAT INTEGRATE AND ANALYZE SPATIAL DATA ACROSS MULTIPLE SAMPLES, WHICH WOULD ENABLE ROBUST STATISTICAL ANALYSES AND LINK SPATIAL GENE EXPRESSION PATTERNS TO CLINICAL OR EXPERIMENTAL OUTCOMES. THIS PROJECT WILL DIRECTLY ADDRESS THESE CHALLENGES BY DEVELOPING A COMPREHENSIVE SUITE OF COMPUTATIONAL TOOLS DESIGNED TO UNLOCK THE FULL POTENTIAL OF SPATIAL SUBCELLULAR DATA. 1) WE WILL CREATE A SCALABLE AND EXTENSIBLE DATABASE INFRASTRUCTURE THAT SUPPORTS INTERACTIVE ANALYSIS OF LARGE DATASETS ON STANDARD COMPUTING SYSTEMS, REMOVING THE NEED FOR SPECIALIZED HIGH-PERFORMANCE COMPUTING RESOURCES. ADDITIONALLY, 2) WE WILL DEVELOP NOVEL METHODS THAT FULLY HARNESS THE HIGH-RESOLUTION TRANSCRIPT SPATIAL DISTRIBUTION INFORMATION TO IMPROVE THE IDENTIFICATION OF CELLS, BOUNDARIES, AND SPATIAL DOMAINS WITHIN TISSUES. THESE METHODS WILL ALSO EXTEND TO 3D DATASETS, ALLOWING FOR MORE ACCURATE MODELING OF COMPLEX TISSUE STRUCTURES. FINALLY, 3) WE WILL BUILD A ROBUST STATISTICAL FRAMEWORK THAT INTEGRATES SPATIAL DATA FROM MULTIPLE SAMPLES, ENABLING RESEARCHERS TO ASSOCIATE DETAILED SPATIAL GENE EXPRESSION PATTERNS WITH CLINICAL FEATURES OR EXPERIMENTAL OUTCOMES. THESE TOOLS WILL BE AVAILABLE AS STANDALONE TOOLS AND INTEGRATED INTO THE WIDELY USED GIOTTO SUITE, THEREBY DEMOCRATIZING ACCESS TO ADVANCED SPATIAL DATA ANALYSIS AND FACILITATING NOVEL DISCOVERIES IN BOTH BASIC AND CLINICAL RESEARCH.

CONVERSATIONAL AGENTS TO IMPROVE QUALITY OF LIFE IN PALLIATIVE CARE

METABOLISM, ENDOCRINOLOGY AND OBESITY TRAINING GRANT

THE MB-CCOP AT BOSTON MEDICAL CENTER

THE IMPACT OF ALCOHOL CONSUMPTION ON TB TREATMENT OUTCOMES

ZINC FOR HIV DISEASE AMONG ALCOHOL USERS -AN RCT IN THE RUSSIA ARCH COHORT

MASSACHUSETTS HIV AND JUSTICE-INVOLVED POPULATIONS RESEARCH NETWORK - PROJECT SUMMARY A MAJOR DRIVER OF THE U.S. HIV EPIDEMIC IS INADEQUATE ACCESS TO HIV PREVENTION AND CARE IN THE CRIMINAL LEGAL SYSTEM. THE END HIV EPIDEMIC (EHE) TOOLKIT RECOMMENDS THAT JAILS OFFER LOW-BARRIER ACCESS TO HIV TESTING, TREATMENT, AND PREVENTION TO PEOPLE WHO INJECT OPIOIDS, BUT MANY JUSTICE-INVOLVED PEOPLE WITH OPIOID USE DISORDER (OUD) DO NOT KNOW THEIR HIV STATUS AND FEW ACCESS MEDICATIONS TO PREVENT HIV (PRE-EXPOSURE PROPHYLAXIS, PREP). SUFFOLK COUNTY, THE ONLY EHE-DESIGNATED JURISDICTION IN MASSACHUSETTS (MA), HAD A RECENT HIV OUTBREAK, OCCURRING IN FORMERLY INCARCERATED PEOPLE WITH OUD, THAT DISPROPORTIONATELY IMPACTED THREE GEOGRAPHICALLY AND RACIALLY DISTINCT COMMUNITIES (BOSTON, CHELSEA, REVERE). IMPROVEMENTS WERE MADE TO INCREASE CARCERAL HIV PREVENTION AND CARE, BUT ONE YEAR INTO IMPLEMENTATION ONLY ABOUT 10% WERE HIV TESTED AND FEW WERE INITIATED ON PREP. MA MEDICAID NOW AUTHORIZES COVERAGE OF HIV CARE BEFORE, UPON, AND FOLLOWING RELEASE FROM INCARCERATION, BUT HIV CARE IS NOT WELL-INTEGRATED WITH THE JAILS’ EXISTING MEDICATIONS FOR OPIOID USE DISORDER (MOUD) PROGRAM AND THERE ARE GAPS BETWEEN JAILS AND COMMUNITY HEALTHCARE. THE MASSACHUSETTS HIV/JUSTICE RESEARCH NETWORK PROPOSES TO PARTNER WITH THE SUFFOLK JAIL SYSTEM AND COMMUNITY TREATMENT PARTNERS TO CONDUCT A FORMATIVE EVALUATION AND PILOT (R61, AIM 1) AND TYPE 2 HYBRID IMPLEMENTATION- EFFECTIVENESS STUDY (R33, AIMS 2-4) OF A MULTI-PRONGED INTERVENTION TO INCREASE HIV TESTING AND PREP LINKAGE CALLED ID-TOUCH (ID TESTING OUTREACH IN CARCERAL HUBS). WE WILL (1) PERFORM A FORMATIVE EVALUATION OF HIV CARE GAPS AND OPPORTUNITIES IN SUFFOLK JAILS, USING (1A) STAKEHOLDER ENGAGEMENT TO CO-DESIGN ID-TOUCH, (1B) EXISTING ADMINISTRATIVE DATA TO IDENTIFY TOUCHPOINTS FOR HIV CARE, FOCUSING ON DIFFERENTIAL BARRIERS AMONG INCARCERATED PEOPLE WHO WERE AND WERE NOT TREATED WITH MOUD, AND (1C) A PILOT-TRIAL OF ID-TOUCH, MEASURING CHANGES IN HIV TESTING, FEASIBILITY AND ACCEPTABILITY, AND SELF-REPORTED PATIENT OUTCOMES. (2) CONDUCT A LONGITUDINAL TREATMENT OUTCOME STUDY COMPARING OUTCOMES OF INDIVIDUALS RELEASED FROM SUFFOLK JAILS (A) DURING ID-TOUCH IMPLEMENTATION, (B) BEFORE IMPLEMENTATION, AND (C) IN RELATION TO A NEARBY COMPARABLE JAIL SYSTEM (CONTEMPORANEOUS CONTROL SITE) USING THE MA PUBLIC HEALTH DATA WAREHOUSE, A COLLECTION OF TWO DOZEN LINKED STATE ADMINISTRATIVE DATA SETS, TO EXAMINE HIV TESTING AND POST-RELEASE LINKAGE TO PREP OR HIV TREATMENT. (3) CONDUCT AN IMPLEMENTATION STUDY OF ID-TOUCH TO UNDERSTAND CONTEXTUAL FACTORS THAT FACILITATE AND IMPEDE DELIVERY OF HIV CARE IN JAIL AND COMMUNITY CARE COORDINATION, AND BEST PRACTICE STRATEGIES THAT OPTIMIZE HIV CARE. (4) ESTIMATE THE COST OF IMPLEMENTING AND SUSTAINING ID-TOUCH, AND ASSESS ITS ECONOMIC VALUE, RELATIVE TO USUAL CARE, FROM HEALTHCARE SECTOR, STATE-POLICYMAKER, AND SOCIETAL PERSPECTIVES. THE MASSACHUSETTS HIV/JUSTICE RESEARCH NETWORK, WITH THE MA DEPARTMENT OF PUBLIC HEALTH, SUFFOLK JAILS, AND COMMUNITY TREATMENT PARTNERS, HAS THE EXPERIENCE AND EXPERTISE TO FULFILL THE STUDY AIMS. THIS STUDY’S INSIGHTS WILL INFORM THE DEVELOPMENT OF NEW TREATMENT OPTIONS TO END THE HIV EPIDEMIC IN JAIL POPULATIONS.

BOSTON UNIVERSITY MEDICAL CENTER LEADERSHIP PROGRAM IN VASCULAR MEDICINE

IMPROVING PRETERM OUTCOMES BY SAFEGUARDING MATERNAL MENTAL HEALTH

RESEARCH ETHICS AND SAFETY PROMOTED BY EMBODIED CONVERSATIONAL TECHNOLOGY

PRIMARY CARE TRAINING AND ENHANCEMENT-COMMUNITY PREVENTION AND MATERNAL HEALTH

NATIONAL RESEARCH SERVICE AWARD

MITOCHONDRIAL DYNAMICS IN BETA CELL FUNCTION AND DYSFUNCTION

INVESTIGATION OF THE ROLE OF VEGFA IN HARNESSING CHOLANGIOCYTE-DRIVEN LIVER REGENERATION - PROJECT SUMMARY / ABSTRACT LIVER DISEASE AFFECTS HUNDREDS OF MILLIONS OF PEOPLE WORLDWIDE. LIVER TRANSPLANTATION REMAINS THE ONLY TREATMENT FOR END STAGE LIVER DISEASE (ESLD); HOWEVER, TRANSPLANTATION FACES A MAJOR BURDEN DUE TO A SHORTAGE OF LIVER DONORS. THE LIVER IS KNOWN FOR A REMARKABLE REGENERATIVE ABILITY THROUGH HEPATOCYTE-DRIVEN REGENERATION, THE PROLIFERATION OF THE MAIN FUNCTIONAL LIVER CELL TYPE, THE HEPATOCYTE. HOWEVER, IN ESLD, HEPATOCYTE PROLIFERATION BECOMES EXHAUSTED. AN ALTERNATIVE STRATEGY TO TREAT ESLD WOULD BE TO PROMOTE LIVER REGENERATION THROUGH BILIARY EPITHELIAL CELL (BEC)-DRIVEN REGENERATION AS A NOVEL MECHANISM THAT COULD BE EXPLOITED AS A THERAPEUTIC TARGET. BEC-DRIVEN LIVER REGENERATION IS A PROCESS BY WHICH BECS PROLIFERATE, TRANSITION TO A LIVER PROGENITOR CELL (LPC) STAGE, A PROCESS DEFINED AS DUCTULAR REACTION (DR), AND DIFFERENTIATE INTO FUNCTIONAL HEPATOCYTES AND RESTORE LIVER FUNCTION. BEC-DRIVEN REGENERATION HAS BEEN EXPERIMENTALLY DEMONSTRATED IN MOUSE MODELS IN WHICH HEPATOCYTE PROLIFERATION WAS COMPROMISED AND IN OUR ZEBRAFISH MODELS AFTER NEAR COMPLETE ABLATION OF HEPATOCYTES. OBSERVATION OF DR IN VIRTUALLY ALL CHRONIC AND ACUTE HUMAN LIVER DISEASES AND OF BUDDING HEPATOCYTES FROM BECS IN HUMAN CIRRHOTIC LIVERS SUGGESTS THAT BEC-DRIVEN REPAIR OCCURS IN HUMAN, YET DIFFERENTIATION INTO HEPATOCYTES IS INSUFFICIENT TO ALLEVIATE THE LIVER DISEASE. OUR GOAL IS THEREFORE TO IDENTIFY AND TEST A DRUGGABLE PATHWAY THAT TRIGGERS BEC-TO-HEPATOCYTE CONVERSION FOR THE EFFICIENT THERAPEUTIC USE OF BECS TO TREAT LIVER DISEASES. WE PROPOSE THAT VEGFA PROMOTES BEC-TO-HEPATOCYTE CONVERSION AND RESCUES LIVER FUNCTION IN COMPLEMENTARY MOUSE AND ZEBRAFISH LIVER INJURY MODELS. OUR PRELIMINARY DATA DEMONSTRATE THAT DELIVERY OF VEGFA IN INJURED MOUSE LIVERS VIA THE NON-INTEGRATIVE AND SAFE NUCLEOSIDE-MODIFIED MRNA COMPLEXED WITH LIPID NANOPARTICLES (MRNA-LNP) INDUCES ROBUST BEC-TO-HEPATOCYTE CONVERSION AND REVERSION OF STEATOSIS AND FIBROSIS. MOREOVER, BLOCKING VEGFR2, THE MAIN RECEPTOR FOR VEGFA, OR DOWNSTREAM MEDIATORS PI3K/AKT ABROGATES BEC-DRIVEN LIVER REGENERATION IN ZEBRAFISH, SUGGESTING THE KEY CONTRIBUTION OF THE VEGFR2/PI3K/AKT AXIS. PREVIOUS STUDIES SHOWED THAT VEGFA PROMOTES LIVER REPAIR IN RODENTS BY STIMULATING VEGFR2 ON ENDOTHELIAL CELLS (ECS) THAT INDUCE THE SECRETION OF HEPATOCYTE MITOGENS AND THUS DRIVES HEPATOCYTE-DRIVEN REPAIR. HOWEVER, IT HAS NOT BEEN REPORTED THAT VEGFA DIRECTLY AFFECTS BECS FOR BEC-DRIVEN REPAIR, WHICH IS SUGGESTED BY OUR PRELIMINARY DATA SHOWING VEGFR2 INDUCTION IN A SUBSET OF BECS IN INJURED MOUSE LIVERS, AN OBSERVATION ALSO REPORTED BY OTHERS IN INJURED RATS. THEREFORE, OUR FINDINGS COMBINED WITH STUDIES FROM OTHERS LEAD US TO TEST 2 HYPOTHESES USING THE COMPLEMENTARY MOUSE AND ZEBRAFISH LIVER INJURY MODELS: (AIM 1) VEGFA DELIVERY IN VIVO TRIGGERS BEC-TO- HEPATOCYTE CONVERSION TO REPLENISH THE LOST CELL MASS AND RESTORE LIVER FUNCTIONS, AND THAT (AIM 2) VEGFA ACTS DIRECTLY ON BECS AND/OR INDIRECTLY ON ECS THAT EXPRESS VEGFR2. THIS STUDY MAY HAVE KEY CLINICAL SIGNIFICANCE BY ESTABLISHING A TREATMENT TO PREVENT PROGRESSION OF THE LIVER DISEASE, BY EXPLOITING THE ALTERNATIVE INTRINSIC REGENERATIVE ABILITY OF THE LIVER VIA BEC-DRIVEN LIVER REGENERATION USING CLINICALLY SAFE MRNA-LNPS.

EFFECTIVENESS AND SAFETY OF ANTITHROMBOTIC STRATEGIES AFTER JOINT REPLACEMENT

SUPPORTING FETAL ALCOHOL SPECTRUM DISORDERS (FASD) SCREENING AND INTERVENTION - BOSTON MEDICAL CENTER AND PROOF ALLIANCE HAVE PARTNERED TO CREATE THE SAFEST (SBIRT AND FASD EDUCATION, SUPPORT AND TECHNICAL ASSISTANCE) CHOICE NATIONAL LEARNING COLLABORATIVE (SAFEST CHOICE NATIONAL), WHICH IS AN EXPANSION AND ENHANCEMENT OF THE CURRENT HRSA-FUNDED REGIONAL SAFEST CHOICE. THE CURRENT PROGRAM, IN ITS FOURTH AND FINAL YEAR, SUCCESSFULLY TRAINED APPROXIMATELY 300 PARTICIPANTS FROM 70 PRACTICES IN 18 STATES. THIS NEW PROPOSED PROGRAM WILL INCLUDE MANY OF THE STRATEGIES USED IN THE CURRENT REGIONAL PROGRAM ALONG WITH INNOVATIONS BASED ON LESSONS LEARNED. ONE PRIMARY INNOVATION IS TO OFFER A SECOND TYPE OF LONGITUDINAL LEARNING TO ACCOMMODATE A WIDER RANGE OF PRACTICES WITH DIFFERING CAPACITIES TO ENGAGE IN LONGITUDINAL LEARNING. THE PROPOSED PROGRAM HAS TWO MAIN GOALS: 1) TO IMPROVE THE ABILITY OF PRIMARY CARE PROVIDERS (PCPS) AND THEIR TEAMS TO SCREEN FOR ALCOHOL USE PRIOR TO, AND DURING PREGNANCY, PROVIDE EVIDENCE-BASED BRIEF INTERVENTIONS TO PREVENT PRENATAL ALCOHOL EXPOSURE (PAE), AND FACILITATE REFERRAL OF HIGH-RISK PEOPLE TO SPECIALTY CARE; AND 2) TO IMPROVE THE ABILITY OF PCPS AND THEIR TEAMS SERVING CHILDREN AND ADOLESCENTS TO SCREEN FOR PAE AND MANAGE AND FACILITATE REFERRALS TO NECESSARY SERVICES FOR THOSE AT RISK FOR, AND IDENTIFIED WITH, A FETAL ALCOHOL SPECTRUM DISORDER (FASD). THE PRIMARY PROGRAM OBJECTIVES ARE 1) AT LEAST 90% OF PCPS EDUCATED THROUGH THIS PROGRAM WILL HAVE MORE KNOWLEDGE ABOUT THE HAZARDS OF PAE, AND ABOUT OPTIONS FOR SCREENING FOR ALCOHOL USE AND PAE AMONG CHILDREN AND ADOLESCENTS SUSPECTED OF HAVING A FASD; 2) AT LEAST 75% OF PCPS EDUCATED THROUGH THIS PROGRAM WILL HAVE APPLIED THIS KNOWLEDGE AND WILL HAVE USED A RECOMMENDED APPROACH OF SCREENING, BRIEF INTERVENTION, AND REFERRAL TO SERVICES. SAFEST CHOICE NATIONAL WILL ACHIEVE THE ABOVE-STATED GOALS AND OBJECTIVES BY ENROLLING 80-100 PRACTICES WITH A FOCUS ON THOSE CARING FOR UNDERSERVED, RURAL, AND TRIBAL COMMUNITIES TO PARTICIPATE IN ONE OF TWO TYPES OF FASD LEARNING COLLABORATIVES AND TECHNICAL ASSISTANCE (TA): 1) FASD ECHO TRAINING: 5-MONTH PROGRAM THAT INCLUDES A FOUNDATIONAL WEBINAR FOLLOWED BY 10 ECHO® (EXTENSION FOR COMMUNITY HEALTHCARE OUTCOMES) SESSIONS; AND 2) FASD INTENSIVE TRAINING: 2-MONTH PROGRAM THAT INCLUDES 2 DAYS OF LIVE IMMERSION TRAINING FOLLOWED BY 3 VIRTUAL CASE DISCUSSION SESSIONS. THERE ARE 6 CORE LEARNING COMPETENCIES IN BOTH THE PEDIATRIC AND PRENATAL TRAININGS. THE TA WILL INCLUDE A MENU OF OPTIONS THAT ARE EITHER GROUP SKILLS-BASED OR PERSONALIZED PRACTICE-BASED. RECRUITMENT OF PRACTICES WILL FOCUS ON STATES AND COUNTIES WITH UNDERSERVED AND RURAL COMMUNITIES WITH HIGH RATES OF RISKY ALCOHOL USE THROUGHOUT THE U.S. PARTICIPANTS WILL BE RECRUITED THROUGH STRATEGIC PARTNERSHIPS WITH NATIONAL AREA HEALTH EDUCATION CENTERS ORGANIZATION, NATIONAL RURAL HEALTH ASSOCIATION, NATIONAL ASSOCIATION OF COMMUNITY HEALTH CENTERS, TALEM HEALTH RURAL MEDICAL EDUCATION, AND JOHNS HOPKINS CENTER FOR INDIGENOUS HEALTH. A PROGRAM ADVISORY BOARD WHICH WILL MEET TWICE YEARLY, WILL BE COMPRISED OF EXPERTS IN RELATED FIELDS AND PEOPLE WITH LIVING EXPERIENCE. IT WILL GUIDE ACTIVITIES AND ADVISE ON ALL PHASES OF THE PROGRAM. TO EXAMINE THE EFFECTIVENESS OF SAFEST CHOICE NATIONAL, A MIXED-METHOD PROCESS AND OUTCOME EVALUATION WILL BE CONDUCTED. THE PROCESS EVALUATION WILL BE USED TO IMPROVE PROGRAM ACTIVITIES. THE OUTCOME EVALUATION WILL USE A PRE, POST, FOLLOW-UP DESIGN TO MEASURE CHANGES IN KNOWLEDGE, CONFIDENCE, AND PRACTICE CHANGE. BASED ON THE SUCCESSFUL IMPLEMENTATION OF OUR REGIONAL SAFEST CHOICE PROGRAM AND OUR MANY PROPOSED ENHANCEMENTS OF OUR TRAINING OFFERINGS, PRACTICE RECRUITMENT AND ENGAGEMENT STRATEGIES, NEW COLLABORATIONS WITH NATIONAL ORGANIZATIONS SERVING RURAL AND UNDERSERVED COMMUNITIES, AND ADDITIONS TO OUR CORE FACULTY AND ADVISORY BOARD, WE ARE WELL-POSITIONED TO SUCCESSFULLY ACHIEVE THE GOALS AND OBJECTIVES OF OUR SAFEST CHOICE NATIONAL PROGRAM.

PREVENTING MATERNAL DEPRESSION IN HEAD START

TEEN PREVENTION PROGRAM - TIER 2

NUCLEOPHOSMIN CENTERED DIAGNOSTICS AND TREATMENT OF ISCHEMIC ACUTE KIDNEY INJURY

NATIONAL INSTITUTE ON DISABILITY AND REHABILITATION RESEARCH - SPINAL CORD INJURY MODEL DEMONSTRATIONS

TRANSFORMING COLORECTAL CANCER SCREENING THROUGH MULTIMODAL SPECTRAL MARKERS

DIAGNOSTIC AND THERAPEUTIC CANCER CARE EQUIPMENT

MOUD COMPARATIVE EFFECTIVENESS STUDY - PROJECT SUMMARY OPIOID OVERDOSE DEATHS REMAIN AT CRISIS LEVELS; HOWEVER, INCREASING AVAILABILITY OF EFFECTIVE MEDICATIONS FOR OPIOID USE DISORDER (MOUD) ARE ONE REASON FOR OPTIMISM. UNFORTUNATELY, MOUD ARE UNDERUTILIZED. REAL-WORLD DATA HAVE IDENTIFIED LOW MOUD RETENTION RATES IN CONTRAST WITH HIGHER RETENTION RATES OBSERVED IN RANDOMIZED CONTROLLED TRIALS (RCTS). WHILE COMPARATIVE EFFECTIVENESS RCTS FOUND THAT BUPRENORPHINE-NALOXONE AND EXTENDED-RELEASE NALTREXONE HAVE SIMILAR RETENTION AND ILLICIT OPIOID USE, OBSERVATIONAL STUDIES IDENTIFY LOWER RATES OF FATAL OPIOID OVERDOSE AND IMPROVED RETENTION WITH BUPRENORPHINE-NALOXONE. WHILE RCTS ARE CONSIDERED THE GOLD STANDARD FOR STUDYING CAUSAL RELATIONSHIPS, EXTERNAL GENERALIZABILITY IS LIMITED, AND RCTS HAVE LIMITED POWER TO STUDY RELATIVELY RARE OUTCOMES SUCH AS FATAL OR NONFATAL OPIOID OVERDOSE. THE MASSACHUSETTS PUBLIC HEALTH DATA WAREHOUSE (PHD) IS A NOVEL NEAR POPULATION-LEVEL DATABASE LINKING MORE THAN 20 STATE-BASED DATASETS AT THE INDIVIDUAL LEVEL. THE PHD OFFERS AN UNPARALLELED ABILITY TO STUDY A BREADTH AND DEPTH OF OPIOID-RELATED EXPOSURES AND OUTCOMES, INCLUDING OPIOID OVERDOSE. THE CURRENT PROPOSAL SEEKS TO USE PHD TO EMULATE TARGET COMPARATIVE EFFECTIVENESS TRIALS OF A RAPIDLY EXPANDING ARRAY OF BUPRENORPHINE AND NALTREXONE FORMULATIONS. WE WILL EXAMINE MOUD INITIATION FOLLOWING OPIOID DETOXIFICATION, A COMMON TREATMENT ENTRY POINT FOR INDIVIDUALS AT HIGH-RISK FOR SUBSEQUENT OPIOID OVERDOSE. TO ADVANCE UNDERSTANDING OF THE DIFFERENCES BETWEEN OBSERVATIONAL STUDIES AND RCTS WE WILL DIRECTLY COMPARE EFFECT ESTIMATES OF TREATMENT RETENTION FROM AN EMULATED TRIAL IN PHD WITH A REANALYSIS OF THE TARGET X:BOT RCT THAT COMPARED SUBLINGUAL BUPRENORPHINE-NALOXONE AND EXTENDED-RELEASE NALTREXONE. USING THE PHD, WE WILL EXAMINE ADDITIONAL OUTCOMES, INCLUDING FATAL AND NONFATAL OPIOID OVERDOSE. WE WILL LEVERAGE THE EMULATED TRIAL FRAMEWORK DEVELOPED TO STUDY ADDITIONAL HIGH PRIORITY COMPARATIVE EFFECTIVENESS QUESTIONS. WE WILL COMPARE OUTCOMES FROM INITIATION OF SUBLINGUAL BUPRENORPHINE-NALOXONE VERSUS BUPRENORPHINE EXTENDED-RELEASE FORMULATIONS FOLLOWING OPIOID DETOXIFICATION. FINALLY, WHILE LONG-TERM MOUD TREATMENT IS THE STANDARD OF CARE, MANY PATIENTS PREFER TO STOP TREATMENT. WE WILL ASSESS THE IMPACT OF TAPERING SUBLINGUAL BUPRENORPHINE-NALOXONE AFTER 3 OR 6 MONTHS OF TREATMENT COMPARED WITH CONTINUED USE. THE FINDINGS OF THESE COMPARATIVE EFFECTIVENESS ANALYSES WILL INFORM POLICY AND PRACTICE ON THE COVERAGE AND USE OF AN EXPANDING ARRAY OF MOUD FORMULATIONS.

ROLE OF CHLAMYDIA SPECIES IN PRETERM BIRTH AND PLACENTAL DYSFUNCTION

CHARACTERIZATION OF HIV-1 IGA BNABS AND ADCP FUNCTION - PROJECT SUMMARY HIV-1 SPREADS MAINLY THROUGH MUCOSAL EXPOSURES. DOMINANT IN MUCOSAL SECRETIONS, IGA HAS LONG BEEN THE CLASS OF ANTIBODIES DESIRED AT THE PORTAL OF ENTRANCE TO BLOCK INFECTION. HOWEVER, DUE TO A PAUCITY OF IGA RESPONSES TO HIV-1, COMPARED TO IGG, PREVIOUS ANTIBODY ISOLATION EFFORTS AND ANTIBODY REPERTOIRE ANALYSES HAVE FOCUSED ON IGG+ B CELLS AND MISSED IGA+ B CELLS. WITH A NOVEL VESICULAR STOMATITIS VIRUS (VSV)-BASED PLATFORM, WE DISPLAYED THE MEMBRANE-EMBEDDED HIV-1 ENVELOPE (ENV) TRIMER TO PROBE ENV-SPECIFIC MEMORY B CELLS AND ISOLATE HIV-1 BROADLY NEUTRALIZING ANTIBODIES (BNABS) FROM INFECTED INDIVIDUALS. DURING THIS PROCESS, WE INCLUDED IGA ANTIBODY REPERTOIRE ANALYSES AND IDENTIFIED TWO HIV-1 BNAB LINEAGES THAT CLASS-SWITCHED TO BOTH IGG AND IGA, THUS FOR THE FIRST TIME IDENTIFIED BONA FIDE IGA BNABS PRODUCED DURING HIV-1 NATURAL INFECTION. ADDITIONALLY, WE HAVE ISOLATED TWO ENV-DIRECTED IGA MONOCLONAL ANTIBODIES (MABS) THAT EXHIBITED PARTIAL VIRUS NEUTRALIZATION AND POTENT ANTIBODY-DEPENDENT CELLULAR PHAGOCYTOSIS (ADCP) FUNCTION TO ELIMINATE HIV-1-INFECTED CELLS. AS RECENT VRC01 PREVENTION TRIALS SHOWED NO OVERALL EFFICACY AND ONLY 75% EFFICACY TO VRC01-SENSITIVE STRAINS, IT CALLS FOR IMPROVED BNAB-MEDIATED PREVENTION. GIVEN THE UNIQUE PROPERTIES OF MUCOSAL SIGA, SUCH AS DIMERIZATION, HIGH STABILITY, AND RESISTANCE TO ENZYMATIC DEGRADATION, WE AIM TO TEST WHETHER IGA (DIMER) BNAB PASSIVE INFUSION IS BETTER THAN IGG TO BLOCK INFECTION. SUPPORTED BY THESE SCIENTIFIC PREMISES AND THE NEED TO IMPROVE BNAB- MEDIATED PREVENTION, WE PROPOSE TO IDENTIFY ADDITIONAL HIV-1 IGA BNABS AND ADCP IGA MABS FROM PERIPHERAL BLOOD OF CLADE-B AND NON-CLADE-B INFECTED INDIVIDUALS, INCLUDING THOSE FOLLOWED LONGITUDINALLY, AND FROM BREAST MILK CELLS OF HIV CLADE C INFECTED MOTHERS FROM THE BAN COHORT (AIM 1), THEN STRUCTURALLY DEFINE AND CHARACTERIZE THE IGA TARGETED EPITOPES (AIM 2), AND FINALLY TEST A REPRESENTATIVE IGA BNAB AND ADCP IGA, USING AN IGG BNAB AS BENCHMARK, FOR PROTECTION EFFICACY IN A RHESUS MACAQUE SHIV MUCOSAL CHALLENGE MODEL (AIM 3). WE AIM TO TEST THE HYPOTHESIS THAT 1) SIGNIFICANT IGA BNABS AND ADCP RESPONSES ARE ELICITED IN SYSTEMIC AND MUCOSAL COMPARTMENTS DURING HIV-1 INFECTION; 2) IGA BNABS AND ADCP IGAS MAY TARGET EPITOPES DISTINCT FROM THOSE OF PREVIOUSLY KNOWN IGG BNABS; 3) IGA BNAB IS COMPARABLE TO OR BETTER THAN ITS IGG BNAB COUNTERPART TO PROTECT AGAINST SHIV MUCOSAL CHALLENGE, AND ADCP IGA MAY ALSO PROTECT FROM SHIV MUCOSAL CHALLENGE. IF SUCCESSFUL, THE PROJECT WILL UNVEIL AND VALIDATE THE POTENTIAL ANTIVIRAL FUNCTIONS OF IGA TO FIGHT AGAINST HIV-1.

DISEASE-SPECIFIC RISK FACTORS FOR THROMBOSIS FOLLOWING VASCULAR INTERVENTIONS - ABSTRACT VASCULO-THROMBOSIS AND ALTERED HEMOSTASIS ARE ASSOCIATED WITH SEVERAL ORGAN PATHOLOGIES, THE DISEASE- SPECIFIC MEDIATORS OF WHICH REMAIN POORLY UNDERSTOOD. THIS ASPECT IS PARTICULARLY RELEVANT IN CHRONIC KIDNEY DISEASE (CKD), WHICH AFFECTS 30 MILLION AMERICANS. PATIENTS WITH CKD SUFFER FROM HIGH CARDIOVASCULAR DISEASE BURDEN, MAKING CKD PATIENTS IN NEED OF FREQUENT VASCULAR INTERVENTIONS, SUCH AS ENDOVASCULAR PROCEDURES OR VASCULAR SURGERY. A CKD MILIEU (UREMIA) IS A STRONG AND INDEPENDENT RISK FACTOR FOR THROMBOSIS AFTER SUCH PROCEDURES. GIVEN THE UPWARD TREND OF CKD IN GENERAL, AND HIGH FREQUENCY OF INTERVENTIONAL PROCEDURES IN THEM, INVESTIGATING SUCH POST-INTERVENTIONAL COMPLICATIONS AND MEANS TO CONTROL THEM IS A WORTHY PURSUIT. CKD IS CHARACTERIZED BY RETENTION OF A HOST OF UREMIC SOLUTES. ALTHOUGH STUDIES IN HUMANS AND ANIMAL MODELS IMPLICATE THE UREMIC SOLUTES INDOXYL SULFATE AND KYNURENINE AS CKD-SPECIFIC RISK FACTORS AND ARE, THEREFORE, PERCEIVED AS TANTALIZING THERAPEUTIC TARGETS FOR CARDIOVASCULAR DISEASE, THEIR EXACT MECHANISM OF ACTIONS REMAINS POORLY UNDERSTOOD. THIS UNDERPINNING WILL BE ADDRESSED IN THE CURRENT PROPOSAL. OUR WORK IN RECENT YEARS ELUCIDATED PROTHROMBOTIC PROPENSITIES OF INDOLIC UREMIC TOXINS, PARTIALLY MEDIATING THEIR TOXICITY THROUGH UPREGULATION OF TISSUE FACTOR IN VSMCS. HERE, BUILDING ON NEW DATA, WE PROPOSE AN INTEGRATIVE APPROACH TO STUDY NEWLY IDENTIFIED CONVERGING PATHWAYS THAT AUGMENT THROMBOSIS IN CKD, CONSISTING OF INDOLEAMINE 2,3- DIOXYGENASE-1 (IDO1), A KEY ENZYME IN KYNURENINE PRODUCTION, AND LYSYL OXIDASE (LOX), A KEY ENZYME REGULATOR OF EXTRACELLULAR MATRIX REMODELING AND THROMBOSIS. AIM 1 EXAMINES A NOVEL REGULATION OF IDO1 LEVEL AND ACTIVITY BY INDOXYL SULFATE AND/OR KYNURENINE, AND ITS CONTRIBUTION TO UREMIC THROMBOSIS, USING GENETIC AND PHARMACOLOGICAL MANIPULATION OF IDO1 IN A CKD MOUSE MODEL. AIM 2 BUILDS ON OUR NEW FINDINGS SUGGESTING LOX EXPRESSION AS A TARGET OF INDOXYL SULFATE AND KYNURENINE, THEREBY CONTRIBUTING TO UREMIA-INDUCED VASCULO- THROMBOSIS. THIS AIM EMPLOYS MOLECULAR AND GENE KNOCKOUT APPROACHES TO UNDERSTAND THE CONTROL OF LOX BIOGENESIS IN VSMCS IN A UREMIC MILIEU, AND ITS CONTRIBUTION TO THROMBOSIS IN CONTEXT OF CKD. BOTH AIMS OF RESEARCH WILL UTILIZE ARTERIAL AND VENOUS THROMBOSIS MODELS IN CKD MICE. SUCCESSFUL COMPLETION OF THIS PROPOSAL WILL DEFINE CKD-ASSOCIATED COMMON MEDIATORS OF THROMBOSIS. ALONG WITH MECHANISTIC ADVANCES, OUR PROPOSED INVESTIGATIONS MIGHT PAVE WAYS TO REPURPOSING ADVANCED CLINICAL COMPOUNDS FOR THE MANAGEMENT OF VASCULAR OCCLUSION IN CKD PATIENTS.

INVESTIGATING STRUCTURAL MATERNAL HEALTH INEQUITIES AMONG BLACK REPRODUCTIVE AGED WOMEN IN GEORGIA: A MIXED METHODS AND MULTI-LEVEL APPROACH - PROJECT SUMMARY/ABSTRACT RACIAL INJUSTICE AND OPPRESSION ARE PREVALENT AND DEVASTATING CAUSES OF HEALTH DISPARITIES. BLACK WOMEN ARE 2- 3 TIMES MORE LIKELY THAN WHITE WOMEN TO EXPERIENCE SEVERE MATERNAL MORBIDITY (SMM) AND TO DIE FROM PREGNANCY-RELATED CAUSES. THE MATERNAL HEALTH CRISIS IS PARTICULARLY PROFOUND IN GEORGIA, WHERE BLACK WOMEN ACCOUNT FOR 35% OF ALL BIRTHS AND THE PREGNANCY-RELATED MORTALITY RATIO IS 1.5 TIMES HIGHER THAN NATIONAL ESTIMATES. RESEARCH THAT EXAMINES DISPARITIES IN MATERNAL HEALTH OFTEN FOCUS ON INDIVIDUAL-LEVEL BEHAVIORS WHEN THE ROOT OF THE ISSUES ARE BETTER CONCEPTUALIZED AS BEING WITHIN STRUCTURES AND SYSTEMS THAT PERPETUATE INJUSTICE INTERGENERATIONALLY AND OVER THE LIFE COURSE. THIS STUDY WILL ADDRESS THREE MAJOR GAPS IN THE LITERATURE TO DATE. FIRST, TRADITIONAL MEASURES OF STRUCTURAL RACIAL DISCRIMINATION (SRD) OFTEN FAIL TO CAPTURE THE FULL RANGE OF HISTORICAL OPPRESSION, AND RESEARCH IS NEEDED TO EXPLORE AN ARRAY OF MEASURES TO BETTER UNDERSTAND AND ADDRESS THE CONTEMPORARY EFFECTS OF HISTORICALLY UNJUST PRACTICES, POLICIES, AND STRUCTURES. SECOND, IT IS UNCLEAR WHAT MULTI-LEVEL STRATEGIES COULD MITIGATE THE IMPACT OF SRD ON SMM AND PROMOTE RESILIENCE FOR BLACK WOMEN. THIRD, WITH RESEARCH SEEKING TO ADDRESS MULTI-LEVEL INEQUITIES, IT IS IMPORTANT TO INTEGRATE QUALITATIVE METHODS THAT CENTER THE EXPERIENCES OF BLACK WOMEN WITHIN SRD IN ORDER TO APPROACH SOLUTIONS. THE OBJECTIVE OF THIS PROPOSAL IS TO ASCERTAIN NEW INFORMATION FROM DIVERSE PERSPECTIVES USING A ROBUST MIXED-METHODS APPROACH TO UNDERSTAND HOW SRD AFFECTS BLACK MATERNAL HEALTH OUTCOMES AT THE POPULATION, HEALTH SYSTEM, AND INDIVIDUAL LEVEL. AT THE POPULATION LEVEL, WE WILL CONDUCT A SECONDARY DATA ANALYSIS TO ESTIMATE COUNTY-LEVEL ASSOCIATIONS BETWEEN MEASURES OF SRD AND BLACK-WHITE SMM DISPARITIES (AIM 1). RECOGNIZING THAT PROVIDER PRACTICES ARE INFLUENCED BY INDIVIDUAL BIASES AND INSTITUTIONAL STRUCTURES, WE WILL USE A CAUSAL ATTRIBUTION FRAMEWORK TO CHARACTERIZE PHYSICIAN PERCEPTIONS REGARDING THE UNDERLYING CAUSES OF BLACK-WHITE MATERNAL HEALTH DISPARITIES AND THE RACIAL CLIMATE OF THE ORGANIZATIONS IN WHICH THEY PRACTICE. (AIM 2). LASTLY, WE WILL ASSESS BLACK WOMEN’S LIVED EXPERIENCES OF OBSTETRIC AND INSTITUTIONAL RACISM AND HOW THESE EXPERIENCES INFLUENCE ACCESS TO CARE AND HEALTH STATUS BEFORE, DURING, AND AFTER PREGNANCY, USING A FRAMEWORK OF RADICAL HEALING FOR COMMUNITIES OF COLOR TO IDENTIFY RISK AND RESILIENCE COPING PROCESSES. (AIM 3). THIS MULTI-LEVEL AND MIXED-METHODS STUDY WILL ALLOW US TO CONTEXTUALIZE BLACK MATERNAL OUTCOMES AND CAPTURE STRUCTURAL INTERSECTIONALITY CONSTRUCTS THAT HAVE YET TO BE STUDIED. OUR FINDINGS WILL PROVIDE CRITICAL INSIGHT ON POTENTIALLY MODIFIABLE FACTORS FOR ADDRESSING THE CURRENT MATERNAL HEALTH CRISIS IN A SOUTHERN STATE WHERE THE LEGACY OF SLAVERY AND OPPRESSION LINGERS.

THE LINK INTERVENTION: USING INFORMATICS AND IMPLEMENTATION SCIENCE TO REDUCE MISSED OPPORTUNITIES TO PREVENT OPIOID OVERDOSE AND HIV INFECTION - PROJECT SUMMARY / ABSTRACT OPIOID USE DISORDER (OUD) IS A KEY DRIVER OF OPIOID OVERDOSE (OOD) AND HIV INCIDENCE. MEDICATIONS FOR OUD (MOUD) AND PRE-EXPOSURE PROPHYLAXIS FOR HIV (PREP) REDUCE RISK OF OOD AND HIV BY 50% AND >70%, RESPECTIVELY. YET TREATMENT INITIATION RATES ARE LOW AND RETENTION IS POOR. OPTIMIZING MOUD AND PREP USE IS CRUCIAL TO IMPROVING OOD AND HIV PREVENTION. HEALTH SYSTEMS HAVE AN OPPORTUNITY TO CLOSE THIS TREATMENT GAP USING BIOMEDICAL INFORMATICS AND IMPLEMENTATION SCIENCE. THIS PROPOSAL INTRODUCES LINK, A SYSTEM-WIDE PACKAGED STRATEGY TO OPTIMIZE MOUD AND PREP UTILIZATION VIA 1) CENTRALIZED TELEMEDICINE OUTREACH TO PATIENTS TO INCREASE MOUD AND PREP INITIATION (LINK2CARE), AND 2) ACADEMIC DETAILING FOR PROVIDERS TO IMPROVE MOUD AND PREP PRESCRIBING (LINK2EDU). AN INFORMATICS-ENABLED PATIENT REGISTRY UNDERPINS LINK. THIS REGISTRY SUMMARIZES UP-TO-DATE MOUD AND PREP UTILIZATION DATA ENABLING REAL-TIME LINK2CARE OUTREACH TO PATIENTS AND REAL-TIME LINK2EDU PERFORMANCE FEEDBACK FOR PROVIDERS. THUS, LINK USES EHR INFORMATICS TO IMPLEMENT A SYSTEM-WIDE “NO WRONG DOOR” APPROACH TO IMPROVED OPIOID-RELATED CARE THEREBY REDUCING MISSED OPPORTUNITIES TO PREVENT OOD AND HIV. LINK’S DESIGN IS BASED ON AN INTEGRATED MOUD/PREP CARE CASCADE CYCLE THAT RECOGNIZES THE IMPORTANCE OF INITIATION, ENGAGEMENT AND RE-INITIATION FOR IMPROVED MOUD AND PREP RETENTION. WHILE LINK2CARE ENHANCES MEDICATION (RE)INITIATION, LINK2EDU ENHANCES ENGAGEMENT AND RETENTION. THE LINK REGISTRY UNITES THESE COMPONENTS BY TRACKING UTILIZATION ACROSS THE FULL CASCADE CYCLE PROMPTING OUTREACH WHEN PATIENTS EXHIBIT TREATMENT GAPS TO SUPPORT (RE)INITIATION, ENGAGEMENT AND RETENTION. THIS HIGH-RISK, HIGH-REWARD PROPOSAL TRANSFORMS HEALTH CARE FOR PATIENTS WHO USE OPIOIDS BY USING INFORMATICS TO PAIR SYSTEM-WIDE PATIENT IDENTIFICATION WITH PROACTIVE OUTREACH TO OFFER INTEGRATED MOUD AND PREP SERVICES TO UNTREATED PATIENTS. THOUGH LACKING PILOT DATA, THIS COMPREHENSIVE GROUNDBREAKING APPROACH CARRIES HIGH REWARD POTENTIAL TO EXPAND AND OPTIMIZE MOUD AND PREP UTILIZATION THEREBY IMPROVING OOD AND HIV PREVENTION. BY LEVERAGING EHR INFORMATICS, LINK ENSURES HIGH TRANSLATABILITY TO OTHER HEALTH CARE SYSTEMS INCLUDING THOSE WITHOUT ROBUST ADDICTION SERVICES. I AM A DUAL BOARD-CERTIFIED FAMILY AND ADDICTION MEDICINE PHYSICIAN-SCIENTIST WITH A PHD IN POPULATION HEALTH COMMITTED TO USING DATA SCIENCE AND COMMUNITY-BASED CARE TO IMPROVE OOD AND HIV PREVENTION. MY TRAJECTORY DEMONSTRATES MY ABILITY TO PAVE INNOVATIVE PATHS, DEVELOP NEW COLLABORATIONS AND SKILLFULLY EXECUTE RESEARCH STUDIES. THIS APPLICATION MARKS A MAJOR STEP IN MY CAREER BY PROPOSING A NOVEL STRATEGY WITH POTENTIAL TO TRANSFORM HEALTHCARE DELIVERY FOR PEOPLE WHO USE OPIOIDS AND, IN TURN, STRENGTHEN OOD AND HIV PREVENTION NATIONWIDE. AS SUCH, THIS AWARD WILL BRING US CLOSER TO ENDING THE OOD AND HIV EPIDEMICS IN THE UNITED STATES.

IMPLEMENTING OPIOID RISK REDUCTION STRATEGIES INTO PRIMARY CARE PRACTICE

NUTRIENT AND HORMONAL REGULATIONS OF AMPK AND MALONYL COA

METABOLIC REGULATION OF INSULIN SECRETION

THE ROLE OF INTERFERON REGULATORY FACTOR 5 IN THE PATHOGENESIS OF SLE

HIV/AIDS, SEVERE MENTAL ILLNESS AND HOMELESSNESS

EFFECTIVENESS TRIAL TO SUPPORT ADOPTION OF HYBRID CLOSED LOOP THERAPY IN UNDERSERVED ADULTS WITH TYPE 1 DIABETES: IMPACT OF SYSTEM FUNCTIONALITY AND FEATURES ON LIVED EXPERIENCE - PROJECT SUMMARY/ABSTRACT MINORITIZED INDIVIDUALS WITH TYPE 1 DIABETES (T1D) HAVE APPROXIMATELY 2% HIGHER AVERAGE A1C LEVELS AND TWICE THE RATE OF HOSPITALIZATIONS, COMPLICATIONS, AND MORTALITY AS THEIR WHITE COUNTERPARTS. HOWEVER, THE EFFICACY TRIALS ESTABLISHING THE BENEFITS OF HYBRID CLOSED LOOP (HCL) PUMP THERAPY IN T1D HAVE BEEN IN MORE SOCIALLY ADVANTAGED AND PREDOMINANTLY NON-HISPANIC WHITE PATIENTS. USE OF THIS TRANSFORMATIVE TECHNOLOGY BY INDIVIDUALS WITH T1D FROM UNDERSERVED COMMUNITIES REMAINS VERY LOW. WE PLAN TO CONDUCT A RANDOMIZED EFFECTIVENESS TRIAL - WITH BROADER ELIGIBILITY CRITERIA (INCLUDING MARKEDLY ELEVATED A1C) AND LONGER (9 MONTH) FOLLOW UP THAN THE PIVOTAL HCL EFFICACY TRIALS - TO EVALUATE THE BENEFITS, SAFETY RISKS AND TREATMENT COMPLICATIONS OF HCL USE IN UNDERSERVED ADULTS WITH T1D (SPECIFIC AIM 1). PRIMARY OUTCOME WILL BE % TIME-IN-RANGE 70-180 MG/DL, AND SECONDARY OUTCOMES WILL INCLUDE % TIME < 70 MG/DL, DKA EVENTS AND BODY WEIGHT. THE HCL ARM IN THE TRIAL WILL INCLUDE THREE HCL SYSTEMS (BETABIONICS ILET, INSULET OP 5, TANDEM CONTROL IQ) THAT VARY IN DEGREE OF AUTOMATION AND USER INPUT REQUIRED FOR OPERATION. MORE AUTOMATED SYSTEMS COULD POTENTIALLY BETTER MATCH THE NEEDS OF UNDERSERVED INDIVIDUALS WITH COMPETING LIFE DEMANDS THAT LIMIT DIABETES SELF-CARE; HOWEVER, THE POTENTIAL BENEFITS OF AUTOMATION ARE AT THE COST OF LESS PERSONAL CONTROL OF THE SYSTEM, INCLUDING ADJUSTMENTS FOR WORK-SHIFT CHANGES AND ACTIVITY. SPECIFIC AIM 2 INCORPORATES THE NOVEL APPLICATION OF ECOLOGICAL MOMENTARY ASSESSMENT TO EXAMINE THE LIVED EXPERIENCE WITH HCL (INCLUDING BENEFITS AND BURDENS, THE IMPACT OF LIFE STRESSORS IMPACT ON HCL USE, AND HOW THE MATCH BETWEEN HCL SYSTEM FUNCTIONALITY AND THE INDIVIDUAL’S NEEDS AND EXPECTATIONS IMPACTS ON USER EXPERIENCE). IN SPECIFIC AIM 3, IN COLLABORATION WITH A USER-CENTERED DESIGNER, WE WILL APPLY THE LEARNINGS FROM THE STUDY TO DEVELOP: 1) IMPROVED HCL PATIENT EDUCATION AND CLINICIAN SUPPORT TOOLS; AND 2) DECISION-AIDS TO GUIDE PATIENT SELECTION OF THE HCL SYSTEM THAT IS MOST ALIGNED WITH PERSONAL PREFERENCES AND NEEDS. THESE OPTIMIZED TRAINING MATERIALS AND DECISION-AIDS WILL SET THE STAGE FOR THE TRANSLATION OF OUR RESEARCH FINDINGS INTO INCREASED ADOPTION OF HCL IN UNDERSERVED COMMUNITIES AND IMPROVED SHARED DECISION-MAKING BY PATIENTS AND CLINICIANS IN THE SELECTION OF HCL SYSTEMS.

CYTOPROTECTIVE ROLE OF HSP72 IN RENAL CELL INJURY

MOLECULAR PATHOGENESIS OF VESICOURETERAL REFLUX

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

IMPACT OF MARIJUANA POLICIES ON ALCOHOL USE AND ALCOHOL-RELATED MORTALITY

TESTOSTERONE SUPPLEMENTATION FOR MEN WITH SARCOPENIA

REDUCING HOSPITAL READMISSION AMONG MEDICAL PATIENTS WITH DEPRESSIVE SYMPTOMS

BOSTON BASIC AND TRANSLATIONAL RESEARCH PROGRAM

ARRA - TRAINING IN PRIMARY CARE MEDICINE AND DENTISTRY: PHYSICIAN FACULTY DEVELOPMENT IN PRIMARY CA

THE MOVING FORWARD INITIATIVE FOR SURVIVORS OF TORTURE AND THEIR FAMILIES

EFFICACY OF TELECONSULTATION TO IMPROVE PREHOSPITAL PATIENT SAFETY FOR CRITICALLY ILL INFANTS AND CHILDREN - A MULTICENTER, SIMULATION-BASED RANDOMIZED CONTROL TRIAL - ABSTRACT THE EMERGENCY MEDICAL SERVICES (EMS) 2050 AGENDA FOR FUTURE SYSTEMS ENVISIONS THAT TELEHEALTH TOOLS COULD MAKE PREHOSPITAL CARE SAFER AND MORE EFFECTIVE, BUT FEW EMS SYSTEMS USE VIDEO TECHNOLOGY. TELECONSULTATION WITH PEDIATRIC EXPERTS REDUCES IN-HOSPITAL ERRORS IN CHILDREN, BUT WHETHER IT PREVENTS PREHOSPITAL HARM—A NATIONAL PRIORITY—IS UNKNOWN. TO GUIDE EMS SYSTEMS, WE NEED PREHOSPITAL TRIALS DEMONSTRATING PATIENT SAFETY BENEFITS FOR CRITICALLY ILL INFANTS AND CHILDREN, A HIGH RISK GROUP FOR PREHOSPITAL ERROR. VIDEO USE COULD ALSO HELP EMS SYSTEMS TRACK AND MEASURE INTERVENTION EFFECTS AS THE MOST COMMON METHOD, CHART REVIEW, UNDERESTIMATES SAFETY EVENT (CARE COULD/DID CAUSE HARM) PREVALENCE AND MAY LACK SENSITIVITY TO MEASURE CHANGES IN CARE SAFETY AND QUALITY WITH REAL-WORLD USE. THE R01 OBJECTIVE IS TO TEST THE EFFICACY OF TELECONSULTATION TO REDUCE HARM IN A CONTROLLED PREHOSPITAL SETTING USING IN SITU SIMULATION, AN INNOVATIVE TECHNIQUE TO TEST EARLY STAGE INTERVENTION EFFECTS ON CLINICAL PROCESSES WITH REAL MULTIDISCIPLINARY TEAMS IN ACTUAL PREHOSPITAL ENVIRONMENTS. IN PRIOR KL2/K23 AWARDS, WE DESIGNED A PROTOTYPE PLATFORM USING SCALABLE LOW-COST TECHNOLOGY, VALIDATED A SIMULATION MODEL AND TOOL-KIT TO STUDY SAFETY EVENTS IN CRITICAL PEDIATRIC TRANSPORTS, AND DEMONSTRATED INTERVENTION ACCEPTABILITY AND FEASIBILITY IN A PILOT SIMULATION RANDOMIZED CONTROLLED TRIAL (RCT). NOW, WE WILL TEST INTERVENTION EFFICACY (AIM 1) AND COMPARE SAFETY SURVEILLANCE METHODS (AIM 2) TO TARGET TWO CRITICAL GAPS. IN AIM 1, WE WILL TEST THE EFFICACY OF TELECONSULTATION WITH PEDIATRIC EMERGENCY PHYSICIANS USING VIDEO (INTERVENTION) VERSUS USUAL CARE PHYSICIANS USING AUDIO (CONTROL) COMMUNICATION WITH EMS TEAMS TO REDUCE SERIOUS SAFETY EVENTS (CAUSE MODERATE-SEVERE HARM/DEATH, PRIMARY OUTCOME) IN THE SIMULATION MODEL. IN AIM 2, WE WILL COMPARE THE FREQUENCY, TYPE, AND REASONS FOR DIFFERENCES IN SERIOUS SAFETY EVENT DETECTION (PRIMARY OUTCOME) WHEN USING VIDEO REVIEW VERSUS CHART REVIEW METHODS. WE WILL CONDUCT A MULTICENTER, SINGLE-BLIND, PARALLEL-ARM, SIMULATION RCT IN THE PEDIATRIC EMERGENCY CARE APPLIED RESEARCH NETWORK (PECARN) AND ITS EMS AFFILIATES TO ENROLL A DIVERSE COHORT AND LEVERAGE EMS COLLABORATIONS AND RESEARCH INFRASTRUCTURE FOR HIGH-QUALITY GENERALIZABLE RESULTS. WE WILL RANDOMIZE REAL-WORLD EMS-PHYSICIAN TEAMS TO TELECONSULTATION OR CONTROL ARMS. EACH TEAM WILL COMPLETE 4 STANDARDIZED, VIDEO-RECORDED, SIMULATED TRANSPORTS IN REAL AMBULANCES. EMS PROVIDERS WILL DOCUMENT CARE IN A SIMULATED EMS MEDICAL RECORD TO CREATE A UNIQUE DATASET OF PAIRED VIDEO AND CHART RECORDS. IN AIM 1, WE WILL MEASURE BETWEEN GROUP DIFFERENCES AFTER BLINDED RATERS USE VIDEO REVIEW TO SCORE SERIOUS SAFETY EVENTS ON THE SIMULATION TOOL-KIT CHECKLIST. IN AIM 2, RATERS WILL USE AN EMS CHART REVIEW TOOL TO IDENTIFY SERIOUS SAFETY EVENTS IN PAIRED VIDEO AND CHART RECORDS USING BOTH REVIEW METHODS IN A RANDOMIZED CROSSOVER DESIGN. THIS R01 WILL GENERATE THE FIRST EFFICACY EVIDENCE FOR TELECONSULTATION AS AN INNOVATIVE PREHOSPITAL INTERVENTION FOR CHILDREN BY DEMONSTRATING REDUCED HARM IN HIGH- RISK PREHOSPITAL SETTINGS AND ILLUMINATING PATIENT SAFETY BLIND SPOTS IN SURVEILLANCE METHODS. WE WILL ADVANCE THE FIELD BY PROVIDING THE SCIENTIFIC BASIS FOR EMS SYSTEMS TO ADOPT NEW MODELS OF CARE TO ACHIEVE EMS 2050 GOALS.

DEFECTIVE HIV PROVIRUSES AND PERSISTENT INNATE IMMUNE ACTIVATION - ABSTRACT/SUMMARY CD4+ T CELLS AND MACROPHAGES ARE INFECTED BY HIV AND THIS INFECTION CORRELATES TO MORE PROINFLAMMATORY ACTIVITIES THAT DRIVE HIV COMORBIDITIES AND END ORGAN DISEASES. MECHANISMS THAT BIAS INNATE IMMUNE FUNCTIONS IN HIV-INFECTED CELLS TOWARDS CHRONIC INFLAMMATION ARE POORLY UNDERSTOOD. WE HAVE DEMONSTRATED INFECTED PRIMARY RESTING CD4+ T CELLS AND MACROPHAGES HARBOR DEFECTIVE HIV-1 PROVIRUSES THAT, DESPITE HAVING DELETIONS AND MUTATIONS WHICH ATTENUATE PROVIRUS TRANSCRIPTION, GENERATE HIV-1 RNAS. THE IMMUNOPATHOLOGICAL CONSEQUENCES OF PERSISTENT ABERRANT VIRAL RNA EXPRESSION HAVE NOT BEEN ADDRESSED. WE HYPOTHESIZE THAT HIV INFECTION OF CD4+ T CELLS AND MACROPHAGES ESTABLISHES A DEFECTIVE BUT TRANSCRIPTIONALLY COMPETENT PROVIRAL RESERVOIR THAT EXPRESSES ABERRANT VIRAL RNAS WHICH PERPETUATE PERSISTENT INFLAMMATION. WE WILL ADDRESS THIS HYPOTHESIS IN THREE SPECIFIC AIMS: 1) DETERMINE IF PERSISTENT EXPRESSION OF CRYPTIC HIV-1 RNAS PROMOTE INNATE IMMUNE ACTIVITIES; 2) EXAMINE WHETHER HIV-1 AND HIV-2 HAVE DIFFERENT PROPENSITIES FOR GENERATING INTACT PROVIRAL GENOMES AND WHETHER THIS INFLUENCES IMMUNE ACTIVATION; AND 3) DETERMINE IF DNA DAMAGE RESPONSE MECHANISMS LEAD TO ESTABLISHMENT OF DEFECTIVE PROVIRUSES. SUCCESSFUL COMPLETION OF THESE STUDIES WILL PROVIDE GENERAL INSIGHTS INTO THE IMPACT OF HIV-1 PERSISTENCE AND EXPRESSION IN THE CONTEXT OF CD4+ T CELLS AND MACROPHAGES. IMPORTANTLY, THESE STUDIES WILL PROVIDE AN UNDERSTANDING INTO MECHANISMS THAT CONTRIBUTE TO HIV-1 COMORBIDITIES WHICH PERSIST EVEN WITH ANTIRETROVIRAL TREATMENTS AND COULD LEAD TO NEW TARGETS AND STRATEGIES FOR TREATMENTS TO IMPROVE THE LIVES OF PEOPLE LIVING WITH HIV.

TARGETING ENERGETICS TO IMPROVE OUTCOMES IN HYPERTROPHIC CARDIOMYOPATHY - PROJECT SUMMARY DESPITE RECENT EXPONENTIAL GROWTH OF THE FIELD OF CARDIOVASCULAR GENETICS LEADING TO IDENTIFICATION OF HUNDREDS OF MUTATIONS RESPONSIBLE FOR HYPERTROPHIC CARDIOMYOPATHY (HCM), THE MECHANISM LINKING SARCOMERIC MUTATIONS TO THE DISEASE PROGRESSION TO HEART FAILURE (HF) REMAINS UNCLEAR. CLINICAL FEATURES OF HCM ARE SEVERE LEFT VENTRICULAR HYPERTROPHY (LVH), DIASTOLIC DYSFUNCTION, AND AN INCREASED RISK OF ARRHYTHMIAS. GIVEN SUCCESS IN SUDDEN DEATH PREVENTION, THE PREDOMINANT CAUSE OF HCM-RELATED MORBIDITY AND MORTALITY IS HF. IMPORTANTLY, RECENT REPORTS SHOW PROFOUND STRUCTURAL MITOCHONDRIAL DAMAGE IN PATIENTS WITH HCM. THE GOAL OF THIS PROPOSAL IS TO IMPROVE MITOCHONDRIAL FUNCTION TO DELAY OR REVERSE THE PROGRESSION OF HCM. THIS PROPOSAL CONSIDERS WORSENED MYOCARDIAL ENERGETICS AS THE INITIAL SHARED STIMULUS THAT, WHEN TRIGGERED BY A SARCOMERIC MUTATION, LEADS TO THE DEVELOPMENT OF THE CLINICAL PHENOTYPE. HCM MUTATIONS INEFFICIENTLY INCREASE POWER OUTPUT OF THE SARCOMERE, RESULTING IN SEVERAL-FOLD INCREASED ATP DEMAND. MITOCHONDRIA MEET THE EXCESSIVE ATP DEMAND, ALBEIT AT A COST OF ACCUMULATION OF ADP, A PRODUCT OF ATP HYDROLYSIS. ELEVATED ADP, IN TURN, LIMITS THE AMOUNT OF CHEMICAL ENERGY EXTRACTABLE FROM ATP TO PUMP SODIUM AND CALCIUM IONS. THIS LEADS TO SLOWER REMOVAL OF CALCIUM DURING RELAXATION OF THE HEART RESULTING IN DIASTOLIC DYSFUNCTION. MOREOVER, ELEVATED INTRACELLULAR SODIUM FURTHER IMPAIRS MITOCHONDRIAL ATP SYNTHESIS AND INCREASES REACTIVE OXYGEN SPECIES (ROS) PRODUCTION. EXCESSIVE ROS, IN TURN, OXIDATIVELY INHIBIT MITOCHONDRIAL PROTEINS AND ATP SYNTHESIS. CONTINUOUS EXCESSIVE DEMAND CAUSES MITOCHONDRIA TO SWITCH THEIR FUEL PREFERENCE TOWARDS GLUCOSE OXIDATION. SUCH SHIFT IS INITIALLY BENEFICIAL, BUT OVER TIME SUPPORTS LVH AND DEPLETES MITOCHONDRIA OF IMPORTANT METABOLITES. THUS, EVEN THOUGH THE PRIMARY DEFECT IS IN THE INEFFICIENT SARCOMERE, SEVERE MITOCHONDRIAL DAMAGE ENSUES. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT INTERVENTIONS THAT IMPROVE ENERGY BALANCE HAVE THE CAPACITY TO REVERSE MITOCHONDRIAL DAMAGE IN HCM. WE WILL RESTORE ENERGY BALANCE BY DECREASING ATP DEMAND AND INCREASING ATP SUPPLY. PHOSPHORUS AND CARBON MAGNETIC RESONANCE SPECTROSCOPY AND IMAGING WILL DETERMINE WHETHER IMPROVEMENTS IN FUEL PREFERENCE AND ROS PRODUCTION REVERSE MITOCHONDRIAL DAMAGE AND HYPERTROPHY IN MURINE MODELS OF HCM. IN MICE BEARING TWO OF THE MOST LETHAL HCM MUTATIONS, R403Q IN MYOSIN AND R92L IN TROPONIN T, WE WILL PURSUE THE FOLLOWING THREE SPECIFIC AIMS: 1) TO DETERMINE THE EXTENT TO WHICH TREATMENT WITH CK-274, INHIBITOR OF THE ENGINE OF THE SARCOMERE - MYOSIN, IMPROVES MITOCHONDRIAL FUNCTION AND STRUCTURE IN HCM MICE. 2) TO TEST THE HYPOTHESIS THAT SUPPRESSING EXCESSIVE MITOCHONDRIAL ROS BY OVEREXPRESSING MITOCHONDRIAL CATALASE INCREASES ATP SYNTHESIS AND PREVENTS MITOCHONDRIAL DAMAGE AND HYPERTROPHY IN HCM. 3) TO DETERMINE WHETHER EMPAGLIFLOZIN, CLINICALLY USED ANTIDIABETIC MEDICATION, REVERSES THE MALADAPTIVE CARDIAC SUBSTRATE PREFERENCE, MITOCHONDRIAL DAMAGE AND LVH IN HCM. THESE RESULTS WILL PROVIDE IMMEDIATELY TRANSLATABLE TOOLS TO MODIFY THE DISEASE PROCESS IN HCM AND OTHER MITOCHONDRIA-BASED CARDIOVASCULAR CONDITIONS.

PREVENTIVE MEDICINE RESIDENCIES

ROLE OF INTRAVENOUS ULTRASOUND (IVUS) IN ARTERIOVENOUS HEMODIALYSIS ACCESS DYSFUNCTION - PROJECT SUMMARY ALMOST 600,000 PATIENTS WITH END-STAGE KIDNEY DISEASE (ESKD) ARE ON HEMODIALYSIS (HD) IN THE UNITED STATES. AN ARTERIOVENOUS (AV) ACCESS IS THE PREFERABLE ACCESS FOR HD. DYSFUNCTION OF AV ACCESS IS COMMON AND PREDOMINANTLY OCCURS DUE TO STENOSIS IN THE AV ACCESS, WHICH IS TYPICALLY MANAGED BY A CROSS-DISCIPLINARY TEAM OF VASCULAR SURGEONS, INTERVENTIONISTS, AND NEPHROLOGISTS. BASED ON MEDICARE DATA ANALYSIS, ~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

A RISK PREDICTION MODEL FOR COLORECTAL CANCER SCREENING

CD1A VAGINAL DENDRITIC CELLS AND HIV-1 ACQUISITION IN THE FEMALE GENITAL TRACT

SIGNALS THAT ESTABLISH AND MAINTAIN HIV LATENCY

"PATIENT NAVIGATION IN THE SAFETYNET: CONNECTEDD"

ROLE OF ABNORMAL LYSYL OXIDASE IN THE PATHOGENESIS OF DIABETIC RETINOPATHY

KNOCK AND TALK: PUBLIC HEALTH-PUBLIC SAFETY PARTNERSHIPS FOR POST-OVERDOSE OUTREACH AND PREVENTION

ION CHANNELS AND CA REGULATION IN VASCULAR SMC FUNCTION

A MULTI-MODULAR APPROACH FOR HUMAN PLURIPOTENT STEM CELL-BASED LIVER REGENERATION

NATIONAL ESTIMATES FOR INPATIENT CARE, OUTCOMES & HOSPITAL EFFECT AMONG HISPANICS

THE ROLE OF PTDINS-5-P IN CELL FUNCTION AND SIGNALING

ROLE OF INTERCELLULAR COMMUNICATION IN PATHOGENESIS OF DIABETIC RETINOPATHY

AMPK AND MECHANISMS OF GLUCOSE TOXICITY

RESEARCH TRAINING IN NEPHROLOGY

AWARENESS AND ACCESS TO CARE FOR CHILDREN AND YOUTH WITH EPILEPSY

VHL AND FGFR SIGNALING IN ANGIOGENESIS

SIMULATION MODELING TO IMPROVE HIV/HCV SCREENING, TREATMENT AND CARE

IDENTIFICATION OF A MECHANOSENSOR IN JUXTAGLOMERULAR CELLS FOR THE REGULATION OF RENIN SYNTHESIS AND SECRETION - PROJECT SUMMARY JUXTAGLOMERULAR (JG) CELLS ARE A CLUSTER OF SPECIALIZED VASCULAR SMOOTH MUSCLE (VSM) CELLS LOCATED IN THE WALL OF EACH AFFERENT ARTERIOLE (AF-ART) AT THE ENTRANCE TO THE GLOMERULUS. ON ONE HAND, JG CELLS PRESERVE MOST OF THE CHARACTERISTICS OF VSM CELLS, BUT ON THE OTHER HAND, THEY ARE DISTINGUISHED FROM VSM CELLS BY THEIR UNIQUE ENDOCRINE CHARACTERISTICS, SPECIFICALLY THE SYNTHESIS AND SECRETION OF RENIN. RENIN RELEASED FROM JG CELLS INTO THE CIRCULATION CATALYZES THE CONVERSION OF ANGIOTENSINOGEN TO ANGIOTENSIN I, THE FIRST AND RATE-LIMITING STEP OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) CASCADE. COMMENSURATE WITH THE CENTRAL ROLE OF RAAS IN FLUID AND ELECTROLYTE HOMEOSTASIS, RENIN SYNTHESIS AND SECRETION BY JG CELLS IS REGULATED BY MULTIPLE INPUTS THAT GENERALLY REFLECT THE STATUS OF EXTRACELLULAR FLUID VOLUME. THE MOST IMPORTANT AMONG THE CONTROL MECHANISMS OF RENIN RELEASE IS A PRESSURE-SENSING MECHANISM, DENOMINATED AS THE INTRARENAL BARORECEPTOR. IT IS BELIEVED THAT JG CELLS CAN DETECT SLIGHT CHANGES IN PERFUSION PRESSURE THROUGH THE AF-ART AND RESPOND WITH PRECISE AMOUNTS OF RENIN SYNTHESIZED AND SECRETED TO THE CIRCULATION IN SYNC, THEREFORE FUNCTIONING AS A MECHANO-SENSITIVE RHEOSTAT TO MAINTAIN A STEADY-STATE LEVEL OF AF-ART PERFUSION PRESSURE AND THUS SYSTEMIC BLOOD PRESSURE. HOWEVER, THE NATURE OF THE INTRARENAL BARORECEPTOR AND IN PARTICULAR, THE CENTRAL QUESTIONS ABOUT THIS PRESSURE-SENSING MECHANISM: WHAT THE EXACT MECHANO-SENSOR IS IN JG CELLS AND HOW IT CONTROLS RENIN SYNTHESIS AND SECRETION, REMAIN ELUSIVE. A NOVEL TECHNIQUE, SINGLE-CELL RNA SEQUENCING (SCRNA-SEQ), PROVIDES A NEW TOOL TO FURTHER UNDERSTAND THE GENETIC AND MOLECULAR BASIS OF THE INTRARENAL BARORECEPTOR IN JG CELLS. OUR PRELIMINARY STUDIES OF SCRNA-SEQ ANALYSIS HAVE REVEALED THAT A GENE SDC1 IS NOT ONLY HIGHLY AND DIFFERENTIALLY EXPRESSED IN JG CELLS VS. VSM CELLS, BUT ALSO POSITIVELY CORRELATED WITH REN1 EXPRESSION. SDC1 ENCODES SYNDECAN-1, A TRANSMEMBRANE PROTEOGLYCAN, WHICH ALLOWS FOR THE TRANSFER OF INFORMATION ABOUT EXTRACELLULAR ENVIRONMENT CHANGES INTO THE CELL THAT CONSEQUENTLY AFFECTS INTRACELLULAR ACTIVITIES. THUS, IN THIS PROJECT, WE AIM TO DETERMINE WHETHER SYNDECAN-1 IS A KEY MECHANO-SENSOR OF THE INTRARENAL BARORECEPTOR MECHANISM IN JG CELLS THAT CONTROLS RENIN SYNTHESIS AND SECRETION, REGULATES THE CIRCULATING RAAS, AND THUS CONTRIBUTES TO THE MAINTENANCE OF FLUID AND ELECTROLYTE HOMEOSTASIS AND BLOOD PRESSURE. SPECIFICALLY, IN AIM 1, WE WILL DETERMINE THE EXPRESSION OF SYNDECAN-1 IN THE KIDNEY, ESPECIALLY IN JG CELLS; MOREOVER, WE WILL EXAMINE THE EFFECTS OF DIFFERENT PERFUSION PRESSURES ON THE RENIN MRNA AND PROTEIN EXPRESSION LEVELS IN JG CELLS WITH THE IN VITRO MODEL OF ISOLATED/PERFUSED JUXTAGLOMERULAR APPARATUS AND IN VIVO MODEL OF AORTIC COARCTATION IN WILD-TYPE (WT), GLOBAL SDC1 KNOCKOUT (KO), AND JG CELL- SPECIFIC SDC1KO MICE. IN AIM 2, WE WILL EXAMINE THE VOLUME DEPLETION (LOW PERFUSION PRESSURE) OR VOLUME EXPANSION (HIGH PERFUSION PRESSURE)-INDUCED CHANGES IN THE RENIN EXPRESSION LEVELS IN JG CELLS, CIRCULATING LEVELS OF RAAS, RENAL VASCULAR RESISTANCE, URINARY SODIUM EXCRETION, AND BLOOD PRESSURE IN WT, GLOBAL SDC1KO, AND JG CELL-SPECIFIC SDC1KO MICE.

PREP-TALK: TRANSFORMING HOSPITALIZATION INTO A PREP ENGAGEMENT OPPORTUNITY FOR PEOPLE WHO USE DRUGS - PROJECT SUMMARY PEOPLE WHO USE DRUGS (PWUD), SUCH AS OPIOIDS AND STIMULANTS, ARE AT INCREASED RISK FOR HIV. PRE-EXPOSURE PROPHYLAXIS (PREP) IS A HIGHLY EFFECTIVE AND SAFE MEDICATION AVAILABLE IN PILLS OR LONG-ACTING INJECTABLE FORM WHICH REDUCES THE RISK OF HIV. HOWEVER, CURRENT NORMS CONFINE PREP PRESCRIBING TO OUTPATIENT SETTINGS. THIS CREATES A GAP IN CARE FOR PWUD WHO HAVE LOW UPTAKE OF PREP AND ARE OFTEN DISCONNECTED FROM OUTPATIENT HEALTHCARE SYSTEMS. HOSPITALIZATION HAS EMERGED AS A CRITICAL TOUCHPOINT TO ENGAGE PWUD IN MULTIPLE ASPECTS OF PREVENTATIVE HEALTHCARE BUT HAS NOT BEEN PREVIOUSLY EXAMINED AS AN ACCESS POINT FOR PREP. SUCCESSFULLY INTEGRATING PREP INTO INPATIENT CARE REQUIRES SYSTEMATIC IMPLEMENTATION STRATEGIES THAT ADDRESS MULTILEVEL BARRIERS AND FACILITATORS WITHIN HOSPITAL SYSTEMS. THERE IS AN URGENT NEED TO DEVELOP, IMPLEMENT AND TEST SYSTEMS FOR INTEGRATING PREP PRESCRIPTIONS INTO HOSPITAL WORKFLOWS, DISCHARGE PLANNING, AND LINKAGE TO COMMUNITY RESOURCES FOR LONG-TERM FOLLOW-UP. IN RESPONSE TO RM1 FUNDING OPPORTUNITY DA-25-060, OUR TEAM OF SIX MPIS WILL LEVERAGE FOUR GEOGRAPHICALLY AND DEMOGRAPHICALLY DIVERSE HOSPITAL SITES IN BOSTON, ST. LOUIS, CHAPEL HILL AND SAN FRANCISCO TO SHIFT THE PARADIGM OF HIV PREVENTION FOR PWUD BY MOVING PREP FROM A PURELY OUTPATIENT CONSIDERATION TO A ROUTINE PART OF INPATIENT CARE. WE WILL USE A CONSOLIDATED FRAMEWORK FOR IMPLEMENTATION RESEARCH TO METHODICALLY INTRODUCE ACADEMIC DETAILING, AN EVIDENCE-BASED EDUCATIONAL STRATEGY THAT USES TRAINED HEALTH PROFESSIONALS TO DELIVER TARGETED OUTREACH TO CLINICIANS, TO SUPPORT THE UPTAKE OF PREP PRESCRIBING BEST PRACTICES. WE HYPOTHESIZE THAT AN ACADEMIC DETAILING TOOLKIT, INFORMED BY COMMUNITY PREFERENCES AND OPTIMIZED THROUGH HUMAN-CENTERED DESIGN CAN SHIFT THE PARADIGM OF HIV PREVENTION FOR PWUD BY LEVERAGING THE STRATEGIC POSITIONING OF THE HOSPITAL AS AN ACCESSIBLE HEALTHCARE NODE TO SCREEN FOR HIV AND INITIATE PREP, INCREASING RETENTION IN PREP CARE. IN AIM 1, WE WILL DEVELOP, REFINE AND PILOT AN INPATIENT PREP ACADEMIC DETAILING TOOLKIT ENTITLED PREP-TALK. WE WILL UTILIZE PARTICIPATORY HUMAN-CENTERED DESIGN WORKSHOPS WITH A MULTI-TIERED COMMUNITY ADVISORY BOARD (CAB) COMPRISING CLINICIANS AND PWUD TO CO-CREATE TOOLKIT COMPONENTS, INCLUDING ACADEMIC DETAILING TRAINING, CLINICIAN AND PEER EDUCATION, AND PATIENT-FACING MATERIALS. IN AIM 2 WE WILL EVALUATE THE EFFECTIVENESS OF PREP-TALK ON PREP UPTAKE AMONG HOSPITALIZED PWUD, AND IN AIM 3 WE WILL EVALUATE IMPLEMENTATION OUTCOMES OF PREP-TALK. OUR FINDINGS HAVE THE POTENTIAL TO IDENTIFY A NOVEL INTERVENTION AND METHODOLOGY TO INCREASE PREP UPTAKE AND RETENTION IN A POPULATION WHERE NEED REMAINS HIGH, PROVIDING A SCALABLE, EVIDENCE-BASED PATHWAY TO END THE HIV EPIDEMIC.

EFFICACY OF ELECTRICAL STIMULATION FOR DYSPHAGIA IN HEAD & NECK CANCER PATIENTS

ENHANCED LINKAGE OF DRUG ABUSERS TO PRIMARY MEDICAL CARE

VHL, JADE-1 AND PROTEIN STABILITY IN RENAL CANCER

INTEGRATING RESPONSES TO STIMULANT OVERDOSE AMONG POST-OVERDOSE PROGRAMS

YOUTH DRINKING: THE EFFECTS OF ALCOHOL CONTROL POLICIES AND ADULT DRINKING PATTE

REDUCING SOCIOECONOMIC DISPARITIES IN HEALTH AT PEDIATRIC VISITS

IMPLEMENTING TELEMEDICINE TO IMPROVE APPROPRIATE ANTIBIOTIC PRESCRIBING FOR ACUTE RESPIRATORY TRACT INFECTIONS - PROJECT SUMMARY INAPPROPRIATE ANTIBIOTIC USE FOR THE MANAGEMENT OF ACUTE RESPIRATORY TRACT INFECTIONS (ARTIS) IN AMBULATORY CARE IS A MAJOR DRIVER OF ANTIBIOTIC RESISTANCE AND AN URGENT PUBLIC HEALTH THREAT. DESPITE DECADES OF RESEARCH AND INTERVENTIONS TO INCREASE EVIDENCE-BASED CARE FOR ARTIS, LIMITED PROGRESS HAS BEEN MADE. TELEHEALTH VISITS (THVS) HAVE THE POTENTIAL TO IMPROVE ARTI MANAGEMENT AND ANTIBIOTIC PRESCRIBING BY ADDRESSING FACTORS THAT INFLUENCE INAPPROPRIATE CARE AND BY IMPLEMENTING AN APPROACH THAT OPTIMIZES OUTCOMES ACROSS POPULATIONS. THE SHIFT TO CARE VIA THVS NECESSITATED DURING THE PEAK OF THE COVID-19 PANDEMIC HAS CREATED A CLIMATE OF INCREASED ACCEPTABILITY FOR TELEMEDICINE AND AN IMPORTANT OPPORTUNITY TO ADDRESS THIS QUESTION. WE PROPOSE TO LEVERAGE THE CURRENT INNOVATIVE LANDSCAPE OF EXPANDED USE OF TELEHEALTH TO TEST WHETHER THV APPROACHES FOR ARTIS CAN ADDRESS DRIVERS OF INAPPROPRIATE CARE AND IMPROVE MANAGEMENT. WE SEEK TO CONDUCT A RIGOROUS IMPLEMENTATION STUDY USING A MIXED METHODS APPROACH TO DEVELOP AND EVALUATE A MULTISITE INTERVENTION DESIGNED TO IMPROVE ARTI CARE. WE WILL CONDUCT THE STUDY IN AMBULATORY HEALTHCARE SETTINGS FROM THREE DIVERSE HEALTHCARE SYSTEMS WITH PATIENTS OF A WIDE RANGE OF RACIAL AND ETHNIC BACKGROUNDS, THOSE FOR WHOM ENGLISH IS NOT THEIR PRIMARY LANGUAGE, AND THOSE WITH DISPARITIES RELATED TO SOCIAL DETERMINANTS OF HEALTH. OUR STUDY WILL FIRST CONSTRUCT A PREDICTION TOOL USING RETROSPECTIVE DATA FOR ARTI ENCOUNTERS (ACUTE SINUSITIS, PHARYNGITIS, BRONCHITIS, AND VIRAL UPPER RESPIRATORY TRACT INFECTIONS) AT THE THREE SITES. THE PREDICTION TOOL WILL BE USED TO IDENTIFY CANDIDATES FOR ARTI MANAGEMENT VIA THV WHO ARE AT LOW RISK FOR POOR OUTCOMES. WE WILL INCORPORATE THE TOOL INTO THE WORKFLOW OF AMBULATORY CARE TO OPTIMIZE APPROPRIATE TRIAGE TO THVS. SECOND, WE WILL USE PRIOR RESEARCH BY OUR TEAM AND OTHER PUBLISHED DATA TO DEFINE FACTORS IDENTIFIED AS BARRIERS AND FACILITATORS FOR INAPPROPRIATE PRESCRIBING FOR ARTIS. USING THAT BACKGROUND, MATERIALS WILL BE DEVELOPED TO FACILITATE APPROPRIATE MANAGEMENT AND TO EDUCATE PATIENTS. THOSE MATERIALS WILL BE CREATED VIA CO-PRODUCTION WITH PROVIDERS AND COMMUNITY MEMBERS. PATIENT MATERIALS WILL BE TRANSLATED IN LANGUAGES REFLECTIVE OF THE PATIENT POPULATIONS SERVED AND BE CULTURALLY SENSITIVE. WE WILL NEXT CONDUCT OPEN PILOT TESTING AT HOSPITAL-BASED CLINICS AT EACH OF THE THREE PARTICIPATING HEALTHCARE SYSTEMS TO REFINE THE PROCESS AND MATERIALS AND GET FEEDBACK FROM BOTH PATIENTS AND PROVIDERS FOR ADAPTATION AND IMPROVEMENT. FINALLY, WE WILL IMPLEMENT THE APPROACH ACROSS SIX SITES – THE SITES WHERE THE THREE OPEN PILOTS WERE CONDUCTED AND THREE AFFILIATED COMMUNITY PRACTICES. WE WILL STUDY OUTCOMES INCLUDING ANTIBIOTIC PRESCRIBING, NEED FOR FOLLOW-UP VISITS AND ENCOUNTERS, AND PATIENT AND PROVIDER SATISFACTION WITH THE THV, THE PROCESS, AND THE MEDICAL CARE. BASED ON OUR ASSESSMENT OF OUTCOMES, INCLUDING FEASIBILITY AND SUSTAINABILITY, FINAL MATERIALS WILL BE ORGANIZED INTO A TOOLKIT FOR OTHER SITES TO IMPLEMENT.

BOSTON HEALTH EQUITY & COMMUNITY-ALIGNED LEARNING HEALTH SYSTEM (BOSTON-HEALHS) - PROJECT SUMMARY - OVERALL THE BOSTON HEALTH EQUITY & COMMUNITY-ALIGNED LEARNING HEALTH SYSTEM (BOSTON HEALHS) E-STAR PROPOSAL WILL EXPAND EXISTING LEARNING HEALTH SYSTEM (LHS) CAPACITY IN A COMBINED ACADEMIC-SAFETY NET SYSTEM TO CREATE A ROBUST AND INNOVATIVE PROGRAM OF RESEARCH AND TRAINING IN LHS SCIENCE. THE INTEGRATED EFFORTS OF THREE DISTINCT CORES WILL BE MANAGED BY AN EXPERIENCED TEAM OF RESEARCHERS AND HEALTH SYSTEM LEADERS, WORKING CLOSELY WITH AND INFORMED BY A NETWORK OF PATIENTS, COMMUNITY GROUPS, CLINICIANS, EDUCATORS, AND OTHER LOCAL STAKEHOLDERS TO ENSURE THAT THE LHS RESEARCH AND TRAINING ARE COMMUNITY-ENGAGED, PATIENT-CENTERED, AND OF THE HIGHEST QUALITY, AND THAT FINDINGS FROM LHS RESEARCH ARE RAPIDLY EMPLOYED TO IMPROVE CARE DELIVERY. THE ADMINISTRATIVE (ADMIN) CORE WILL COORDINATE THE OVERALL ACTIVITIES OF BOSTON HEALHS, CREATING AN ORGANIZATIONAL STRUCTURE THAT PROVIDE EFFICIENT, RESPONSIVE, AND INCLUSIVE GOVERNANCE, WITH A PARTICULAR FOCUS ON ENGAGING COMMUNITY, PATIENT, AND HEALTH SYSTEM STAKEHOLDERS IN COLLABORATIVE DECISION-MAKING. THE ADMIN CORE WILL OVERSEE THE RECRUITMENT AND RETENTION OF LHS SCIENTISTS PARTICIPATING IN THE TRAINING PROGRAM, CENTERING DIVERSITY AND EQUITY AT ALL STAGES, FROM JOB DESCRIPTIONS AND INITIAL OUTREACH, THROUGH CANDIDATE SELECTION, TO LONG-TERM PROFESSIONAL DEVELOPMENT AND RETENTION. THE ADMIN CORE WILL CONDUCT A DATA-INFORMED, COMMUNITY- ENGAGED PROCESS TO IDENTIFY PRIORITY TOPICS FOR EMBEDDED LHS RESEARCH, SELECTING THOSE FOR WHICH RAPID-CYCLE RESEARCH RESULTS WILL HAVE A MEANINGFUL IMPACT ON CLINICAL OPERATIONS AND PATIENT OUTCOMES. THE RESEARCH EDUCATION CORE (REC) WILL IMPLEMENT THE LHS SCIENTIST RECRUITMENT, TRAINING, AND RETENTION. REC LEADERSHIP WILL FULLY DEVELOP THE RECRUITMENT PLANS, DRAWING ON MULTIPLE EXISTING PROGRAMS IN OUR ACADEMIC- SAFETY NET PARTNERSHIP THAT PROMOTE EQUITY. THE LHS SCIENTISTS MATRICULATING IN THE PROGRAM WILL BE LINKED WITH MENTORSHIP TEAMS INCLUDING BOTH EXPERIENCED RESEARCHERS AND HEALTH SYSTEM LEADERS AND WILL WORK WITH THEM ON DETAILED INDIVIDUAL DEVELOPMENT PLANS THAT WILL BE CONTINUOUSLY UPDATED DURING AND BEYOND THE TRAINING PERIOD. THE REC INCLUDES A LARGE GROUP OF EXPERTS IN THE AHRQ-DEFINED LHS COMPETENCY DOMAINS WHO WILL PROVIDE THE LHS SCIENTISTS WITH THE TOOLS TO MASTER THESE COMPETENCIES, AND THE CURRICULUM TEAM WILL WORK WITH SCIENTISTS TO IDENTIFY DIDACTIC TRAINING OPPORTUNITIES IN THE PCORI METHODOLOGY STANDARDS. THE RESEARCH AND DATA ANALYSIS CORE (RDAC) WILL CONNECT LHS SCIENTISTS PARTICIPATING IN THE TRAINING PROGRAM, AS WELL AS EMBEDDED LHS RESEARCHERS ACROSS THE INSTITUTION, WITH LINKED DATA RESOURCES IDEALLY SUITED FOR RAPID-CYCLE, CLINICALLY IMPACTFUL RESEARCH. THE RDAC WILL EMPLOY COMMUNITY-ENGAGED PARTICIPATORY RESEARCH PRINCIPLES TO INFORM THE SELECTION OF PRIORITY RESEARCH TOPICS, WHILE SIMULTANEOUSLY DEVELOPING INNOVATIVE METHODS FOR THE RIGOROUS CONDUCT OF COMPARATIVE EFFECTIVENESS AND PATIENT-CENTERED OUTCOMES RESEARCH IN A SAFETY-NET SETTING.

MAXIMIZING OPPORTUNITY - HIV PREVENTION IN HOSPITALIZED RUSSIAN DRINKERS

USING INNOVATIVE COMMUNICATION TECHNOLOGY TO IMPROVE THE HEALTH OF YOUNG AFRICAN

COMPONENT A; OPIOID USE DISORDER IN PREGNANCY AND NEONATAL OPIOID WITHDRAWAL SYNDROME LONGITUDINAL SURVEILLANCE PROJECT

ADDRESSING AN INHERENT BIAS IN NEUROPROGNOSTICATION: A COLLABORATION BETWEEN THE US AND BRAZIL TO REDUCE THE IMPACT OF SELF-FULFILLING PROPHECY IN CARDIAC ARREST (SPARE) - PROJECT ABSTRACT HYPOXIC-ISCHEMIC BRAIN INJURY IN CARDIAC ARREST SURVIVORS RANGES IN SEVERITY FROM MILD COGNITIVE IMPAIRMENT TO PER- SISTENT VEGETATIVE STATE. PRECISE ESTIMATION OF NEUROLOGIC OUTCOME (NEUROPROGNOSTICATION) IN THIS SETTING IS CRUCIAL TO GUIDE FAMILIES AND PHYSICIANS IN GOALS-OF-CARE DECISIONS AND TO IMPROVE ALLOCATION OF CRITICAL CARE RESOURCES. OUTCOME PREDICTION TOOLS INCLUDE NEUROLOGIC EXAMINATION, NEUROIMAGING, BIOCHEMICAL MARKERS, AND ELECTROPHYSI- OLOGIC STUDIES. ACCURATE NEUROPROGNOSTICATION REMAINS CHALLENGING, AS PREVIOUS STUDIES ASSESSING THE PROGNOSTIC ACCURACY OF THESE TOOLS HAVE BEEN AFFECTED BY WITHDRAWAL OF LIFE SUPPORT DUE TO PERCEIVED POOR NEUROLOGIC PROG- NOSIS (WLS-N), AND THUS SUBJECT TO SELF-FULFILLING PROPHECY BIAS. THIS BIAS, ALONG WITH EARLY PESSIMISTIC PROGNOSTI- CATION, MOST OFTEN LEADS TO PREMATURE DEATH OF THOSE DEPENDENT ON LIFE SUPPORT, INCLUDING SOME WITH POTENTIAL FOR GOOD NEUROLOGIC RECOVERY. CONSEQUENTLY, THE NATURAL HISTORY OF HYPOXIC-ISCHEMIC BRAIN INJURY UNBIASED BY THE EFFECT OF WLS-N HAS NOT BEEN ADEQUATELY INVESTIGATED. IN BRAZIL, THE SEVERITY OF HYPOXIC-ISCHEMIC BRAIN INJURY IS ASSESSED BY PROGNOSTIC TOOLS SIMILAR TO THOSE USED IN THE US; HOWEVER, LIFE-SUSTAINING THERAPIES ARE MAINTAINED FOR PROLONGED PERIODS DUE TO CULTURAL NORMS. THIS DIFFERENCE IN PRACTICE, UNBIASED BY WLS-N, ALLOWS FOR A UNIQUE OPPORTUNITY TO OBSERVE THE NATURAL HISTORY OF HYPOXIC-ISCHEMIC BRAIN INJURY, AND TO IDENTIFY TRUE PREDICTORS OF POOR OUTCOME. THE ELUCIDATION OF THE IMPACT OF WLS-N ON THE PERFORMANCE OF NEUROPROGNOSTIC TOOLS IS A VITAL STEP TOWARD MORE ACCURATE OUTCOME PREDICTION. THIS WILL BE THE FIRST STUDY TO COMBINE THE ADVANCED EXPERTISE FROM LEADING INTERNATIONAL SITES ANALYZING NEUROIMAGING AND ELECTROPHYSIOLOGIC DATA APPLIED TO A POPULATION UNBIASED BY WLS-N, AND TO UNVEIL THE IMPACT OF SELF-FULFILLING PROPHECY BIAS ON THE NATURAL HISTORY OF HYPOXIC-ISCHEMIC BRAIN INJURY AND ON THE PREDICTION PERFORMANCE OF GUIDELINE-RECOMMENDED NEUROPROGNOSTIC TOOLS. WE WILL PROSPECTIVELY COLLECT DATA ON DEMOGRAPHICS, PREMORBID CHARACTERISTICS, DETAILS OF CARDIAC ARREST AND RESUSCITATION, POST-CARDIAC ARREST CARE, DETAILED NEUROLOGICAL EXAMINATION FINDINGS, ELECTROPHYSIOLOGIC STUDIES AND NEUROIMAGING AT STANDARD- IZED TIME POINTS, AND ASSESS FUNCTIONAL OUTCOMES AT DISCHARGE AND AT 3, 6 AND 12 MONTHS. OUR GOALS ARE TO: 1) DETERMINE THE INDEPENDENT EFFECT OF WLS-N ON MORTALITY AND OVERALL OUTCOMES, AND 2) DEMONSTRATE THE PROGNOSTIC ACCURACY OF CURRENT GUIDELINE-RECOMMENDED TOOLS IN AN UNCENSORED POPULATION. AS AN EX- PLORATORY AIM, WE WILL ALSO DEVELOP INDEPENDENT, BLINDED MULTIMODAL NEUROPROGNOSTIC MODELS FOR THE US AND BRAZIL COHORTS, AND COMPARE THEIR PERFORMANCE. BY COMPLETING THIS INNOVATIVE PROJECT, WE WILL UNDERSTAND THE IMPACT OF WLS-N ON THE NATURAL HISTORY OF HYPOXIC-ISCHEMIC BRAIN INJURY AND BETTER CHARACTERIZE THE TIMING OF RECOVERY AFTER CARDIAC ARREST. THESE DATA WILL INFLUENCE FUTURE NEUROPROGNOSTICATION STUDIES AND TRIALS OF NEURO- THERAPEUTICS, AS WELL AS OPTIMIZE THE USE OF CRITICAL CARE RESOURCES. THIS STUDY IS THE STEPPING STONE TO STRENGTH- ENING DATA ON NEUROPROGNOSTICATION BY IMPROVING THEIR RELIABILITY, THEREBY ULTIMATELY EASING UNDUE PATIENT AND FAMILY SUFFERING FROM PROGNOSTIC UNCERTAINTY, AND DIRECTING MEDICAL RESOURCES MOST EFFICIENTLY.

BEHAVIORAL HEALTH WORKFORCE EDUCATION AND TRAINING PROGRAM- AMERICAN RESCUE PLAN

ROLE OF PLA2R AND ANTI-PLA2R IN IDIOPATHIC MEMBRANOUS NEPHROPATHY

COMPUTER AGENTS TO PROMOTE WALKING IN OLDER ADULTS WITH LOW HEALTH LITERACY

BOSTON SERVICES FOR TRAUMA AND RESOURCES FOR FAMILIES (BOSTON STAR) - THE POPULATION OF FOCUS FOR THE PROJECT, BOSTON SERVICES FOR TRAUMA AND RESOURCES FOR FAMILIES (BOSTON STAR), CONSISTS OF CHILDREN FROM BIRTH TO 17 YEARS OF AGE AND THEIR FAMILIES WHO HAVE EXPERIENCED TRAUMATIC EVENTS AND WHO ACCESS PRIMARY CARE AT BOSTON MEDICAL CENTER (BMC) OR ITS 12 AFFILIATED COMMUNITY HEALTH CENTERS (CHCS). OUR GEOGRAPHIC CATCHMENT AREA IS SUFFOLK COUNTY, MA, HOME TO BOSTON, WHERE BMC AND THE CHCS FORM THE BACKBONE OF BOSTON’S SAFETY NET HEALTH CARE SYSTEM. BMC AND BHN SERVE DISPROPORTIONATE NUMBERS OF LOW-INCOME AND RACIAL AND ETHNIC MINORITY RESIDENTS. HALF OF OUR PATIENTS HAVE INCOMES AT OR BELOW FEDERAL POVERTY, AND 70% ARE RACIAL AND ETHNIC MINORITIES. UP TO 56,692 CHILDREN IN SUFFOLK COUNTY HAVE TRAUMA EXPOSURES, AND AS MANY AS 5,953 SUFFER FROM POST-TRAUMATIC STRESS DISORDER (PTSD). THE CHILDREN WE SERVE WITHIN BMC AND THE CHCS ARE AT INCREASED RISK OF EXPERIENCING EXTREME POVERTY, CHILD ABUSE AND NEGLECT, DOMESTIC VIOLENCE, COMMUNITY VIOLENCE, AND OTHER FORMS OF TRAUMA; YET SERVICES TO THIS POPULATION ARE SEVERELY LIMITED BY THE LACK OF NCTSN LEVEL III PROVIDERS IN BOSTON (GAP 1). FURTHER, FEW PEDIATRICIANS POSSESS THE KNOWLEDGE OR SKILL TO SYSTEMATICALLY SCREEN FOR AND ADDRESS TRAUMA SYMPTOMS IN PRIMARY CARE (GAP 2), AND NO CAPACITY EXISTS TO REACH OUT TO AND ENGAGE TRAUMATIZED CHILDREN AND FAMILIES IN CARE ONCE THEY HAVE BEEN IDENTIFIED (GAP 3). TO FILL THESE GAPS, BOSTON STAR WILL PURSUE THREE GOALS. GOAL 1: INCREASE BY 35% FROM BASELINE (156 TO 210) THE NUMBER OF INFANTS, CHILDREN, AND ADOLESCENTS ACCESSING OUTPATIENT TRAUMA CARE AT BMC. OBJECTIVES: 1.1 BY 11/30/21, EDUCATE AND TRAIN PEDIATRIC PRIMARY CARE TEAMS WITHIN BMC AND OUR AFFILIATED COMMUNITY HEALTH CENTERS TO SCREEN FOR AND ADDRESS TRAUMA SYMPTOMS, REFERRING PATIENTS AS APPROPRIATE TO BOSTON STAR. 1.2 BY 12/31/21, HIRE AND TRAIN NEW STAFF (1.5 FTE LICSWS AND 1.0 FTE FAMILY NAVIGATOR). 1.3 BEGINNING 1/1/22, INITIATE OUTREACH, NAVIGATION, INTAKE ASSESSMENT, AND ENROLLMENT OF SIX NEW PATIENTS/FAMILIES PER MONTH UP TO ACHIEVE A CASELOAD OF 210 PATIENTS. 1.4 BEGINNING 1/1/22, PLAN AND CONDUCT QUARTERLY INFORMATIONAL WEBINARS TO ADVERTISE THE AVAILABILITY OF BOSTON STAR SERVICES. GOAL 2: INCREASE THE EXPERTISE OF PEDIATRIC PRIMARY CARE PROVIDERS IN MANAGING LESS COMPLEX TRAUMA EXPOSURES. OBJECTIVES: 2.1 BEGINNING 1/1/22, PROVIDE 10 CASE CONSULTATIONS PER MONTH TO PEDIATRIC PRIMARY CARE PROVIDERS THROUGHOUT BMC AND ITS AFFILIATED CHCS. 2.2 NO LATER THAN MARCH 31, 2021, INITIATE QUARTERLY, CASE-BASED TRAINING ON-LINE TRAININGS FOR PEDIATRIC PRIMARY CARE PROVIDERS. GOAL 3: MANAGE, EVALUATE, SUSTAIN AND DISSEMINATE BOSTON STAR. OBJECTIVES. 3.1 BEGINNING 1/1/22, INITIATE QUARTERLY AND ANNUAL EVALUATION OF PROJECT PROCESSES AND OUTCOMES. 3.2 BEGINNING 1/1/22, INITIATE QUARTERLY AND ANNUAL EVALUATION OF PROJECT PROCESSES AND OUTCOMES. OVER THE PROJECT PERIOD, WE WILL SERVE A TOTAL OF 342 PATIENTS (OVER BASELINE) ENROLLED IN BOSTON STAR. BOSTON STAR’S CORE SERVICES INCLUDE CHILD-PARENT PSYCHOTHERAPY, TRAUMA-FOCUSED COGNITIVE/BEHAVIORAL THERAPY, AND FAMILY NAVIGATION. THE PROJECT DIRECTOR IS KRISTIN PARENT, LMHC, FROM THE DEPARTMENT OF PSYCHIATRY AT BMC.

FACILITATED ACCESS TO SUBSTANCE ABUSE TREATMENT WITH PREVENTION AND TREATMENT OF HIV (FAST PATH)

IMPROVING DIETARY BEHAVIOR THROUGH TAILORED MESSAGES

ENDOGENOUS RNA LIGANDS FOR TOLL-LIKE RECEPTORS IN IMMUNE-COMPLEX NEPHRITIS

RESPECT (RECOVERY, EMPOWERMENT, SOCIAL SERVICES, PRENATAL CARE, EDUCATION, AND COMMUNITY TREATMENT)-PLUS

ROLE OF C-CBL IN COLON CANCER

ADAPTIVE INTERVENTIONS TO IMPROVE POSTTRAUMATIC STRESS (PTSD) TREATMENT ACCESS, ENGAGEMENT, AND EFFECTIVENESS IN ROUTINE CARE - PROJECT ABSTRACT/SUMMARY POSTTRAUMATIC STRESS DISORDER (PTSD) PREVALENCE CAN BE AS HIGH AS 50% IN RESOURCE-CONSTRICTED PRIMARY CARE CLINICS, WHEREIN ONLY 13% OF PEOPLE WITH PTSD RECEIVE ANY TREATMENT. THE U.S. BEHAVIORAL HEALTH SYSTEM’S STRUGGLE TO PROVIDE ACCESS TO HIGH QUALITY SERVICES AND ENSURE GOOD HEALTH OUTCOMES FOR ALL POPULATIONS HAS LED TO LARGE TREATMENT AND HEALTH OUTCOME GAPS. THE LOW AVAILABILITY OF FIRST LINE TREATMENTS FOR PTSD IN ROUTINE CARE IS DUE TO HIGH TREATMENT DEMAND, LOW AVAILABILITY OF TRAINED SPECIALISTS, AND HIGH RESOURCE BURDENS ASSOCIATED WITH THE DELIVERY OF INTENSIVE PTSD THERAPIES IN HEALTHCARE SYSTEMS. ADDITIONALLY, LOW TREATMENT EXPECTATIONS, MEDICAL MISTRUST, AND BEHAVIORAL HEALTH STIGMA IMPACT TREATMENT INITIATION AND RETENTION. INNOVATIVE TREATMENT APPROACHES FOR PTSD ARE NEEDED TO BROADEN ACCESS TO TREATMENT IN ROUTINE CARE. LEADERS IN HEALTH CARE HAVE CALLED FOR A RESEARCH AGENDA FOCUSED ON INCREASING ACCESS IN HIGHLY CONSTRAINED RESOURCE SETTINGS, SEQUENCING TREATMENTS ALONG CARE PATHWAYS, AND PERSONALIZING TREATMENTS. ADAPTIVE (STEPPED) INTERVENTIONS HOLD PROMISE IN ADVANCING THIS RESEARCH AGENDA YET HAVE NOT BEEN DEVELOPED FOR PTSD. THIS STUDY EXTENDS A PROGRAM OF RESEARCH FOCUSED ON DEVELOPING ADAPTIVE INTERVENTIONS FOR PTSD. OUR ADAPTIVE INTERVENTION SEQUENCES A DIGITAL BEHAVIORAL HEALTH INTERVENTION AND BRIEF TRAUMA- AND SKILLS-FOCUSED TREATMENTS FOR PTSD. THE SELECTED TREATMENTS ARE BRIEF AND SCALABLE, LESS BURDENSOME TO SYSTEMS OF CARE, AND HIGHLY ACCEPTABLE TO PATIENTS AND CARE SETTINGS. TREATMENTS CAN BE TAILORED TO INDIVIDUAL NEEDS BY THEIR CLINICIAN, AND TAILORING IS SUPPORTED BY CASE CONSULTATION THAT PERMITS FIDELITY-CONSISTENT MODIFICATIONS. THESE TREATMENTS ARE: WEB-ADMINISTERED SKILLS TRAINING IN AFFECTIVE AND INTERPERSONAL REGULATION (WEBSTAIR), BRIEF STAIR, AND WRITTEN EXPOSURE THERAPY (WET). SELECTED IMPLEMENTATION STRATEGIES INCLUDE FACILITATION AND ENHANCING ENGAGEMENT VIA WEB-ADMINISTRATION AND COMMUNITY HEALTH WORKER [CHW] SUPPORT. OUR OVERALL APPROACH IS INFORMED BY THE LATEST TREATMENT OUTCOME RESEARCH, FORMATIVE EVALUATIONS IN THE LOCAL SETTING, AND PILOT DATA FROM DR. VALENTINE’S K23 TRIAL WHICH OPTIMIZED WEB- AND BRIEF STAIR FOR PRIMARY CARE. IN THE PROPOSED STUDY, PRIMARY CARE PATIENTS WILL RECEIVE RAPID ACCESS TO WEBSTAIR FOLLOWING A POSITIVE PTSD SCREEN. USING A SEQUENTIAL MULTIPLE ASSIGNMENT RANDOMIZED TRIAL (SMART) DESIGN, NONRESPONDERS AT 4 WEEKS WILL BE RANDOMIZED TO STAGE 1 TREATMENTS: WEBSTAIR V. WEBSTAIR + CHW COACHING. INITIAL AND STAGE 1 TREATMENTS ARE OFFERED WHILE PATIENTS REMAIN ON BEHAVIORAL HEALTH CLINICIAN WAITLISTS. AT 8 WEEKS, NONRESPONDERS WILL BE RE-RANDOMIZED TO CLINICIAN-ADMINISTERED STAGE 2 TREATMENTS: BRIEF STAIR V. WET. THIS STUDY WILL (AIM 1) TEST ONE WAY TO SEQUENCE BRIEF, SCALABLE, VARIED INTENSITY PTSD TREATMENTS ACROSS SETTINGS, AND WILL PROVIDE DATA ON (AIM 2) MECHANISMS OF CHANGE FOR ENGAGEMENT AND EFFECTIVENESS, (AIM 3) PATIENT-LEVEL MODERATORS OF ADAPTIVE INTERVENTIONS, AND (AIM 4) IMPLEMENTATION OUTCOMES AND FACILITATION STRATEGIES.

HUMAN IMMUNODEFICIENCY VIRUS(HIV) PREVENTION PROJECTS FOR COMMUNITY BASED ORGS

SIR2 REGULATES AMPK AND LIPID METABOLISM IN DIABETES

REDEFINING MEMBRANOUS NEPHROPATHY BY AUTOANTIBODY-SPECIFIC SUBCLASSIFICATION

THROMBOTIC COMPLICATION OF UREMIA: ROLE OF PROTHROMBOTIC UREMIC SOLUTES

MECHANISMS OF CIS-ACTING HBF REGULATION IN SICKLE CELL ANEMIA

RISK FACTORS FOR BARRETT'S ESOPHAGUS

TRANSCRIPTION MECHANISMS THAT CONTRIBUTE TO HIV-1 LATENCY

STORE-OPERATED CA ENTRY AND IPLA2 IN VASCULAR SMC

LINKAGE OF ALCOHOL ABUSERS TO PRIMARY CARE

PRIMARY CARE TRAINING AND ENHANCEMENT

BOSTON MEDICAL CENTER''S VIOLENCE INTERVENTION ADVOCACY PROGRAM: SUPPORTING MALE SURVIVORS OF VIOLENCE

BOSTON CENTER FOR REFUGEE HEALTH AND HUMAN RIGHTS: LIVING WITH PURPOSE

ADDICTION MEDICINE FELLOWSHIP - APPLICANT ORGANIZATION: BOSTON MEDICAL CENTER CORPORATION PROJECT DIRECTOR: ALYSSA PETERKIN, MD PROJECT CONTACT: 617-414-6900; ALYSSA.PETERKIN@BMC.ORG FUNDS REQUESTED: $3,997,395 REQUESTING FUNDING PRIORITY 3 AND FUNDING PREFERENCE 1, 2 OVERVIEW. THE PURPOSE OF THE PROPOSED PROJECT IS TO PROVIDE EVIDENCE-BASED, HIGH-QUALITY PREVENTION AND TREATMENT SERVICES FOR PEOPLE WITH SUBSTANCE USE DISORDERS (SUDS) AT RISK OF HEALTH DISPARITIES BY DEVELOPING, EXPANDING AND EVALUATING AN INTERDISCIPLINARY ADDICTION FELLOWSHIP PROGRAM THAT WILL TRAIN PHYSICIANS TO BE CLINICAL AND ACADEMIC LEADERS IN ADDICTION MEDICINE AND ADDICTION PSYCHIATRY. THE PROGRAM BASED AT BOSTON MEDICAL CENTER (BMC), NEW ENGLAND’S LARGEST SAFETY-NET HOSPITAL, MASSACHUSETTS’S LARGEST MEDICAID ACCOUNTABLE CARE ORGANIZATION AND THE PRIMARY TEACHING AFFILIATE FOR BOSTON UNIVERSITY CHOBANIAN AND AVEDISIAN SCHOOL OF MEDICINE (SOM), THE RURAL-SERVING BRIEN CENTER, BOSTON HEALTH CARE FOR THE HOMELESS, CODMAN SQUARE AND NEIGHBORHEALTH SOUTH END HEALTH CENTERS IN MEDICALLY UNDERSERVED COMMUNITIES (MUCS). OUR COLLABORATIVE PROPOSAL WILL LEVERAGE OUR NATIONALLY RECOGNIZED ADDICTION FELLOWSHIP TRAINING PROGRAMS FROM BMC’S DEPARTMENTS OF MEDICINE AND PSYCHIATRY. THE LEAD APPLICANT PROGRAM IS OUR ADDICTION MEDICINE FELLOWSHIP PROGRAM. WE WILL RECRUIT AND TRAIN HIGHLY QUALIFIED PHYSICIANS WHO HAVE COMPLETED AN ACGME-ACCREDITED RESIDENCY PROGRAM AND ARE BOARD-ELIGIBLE OR BOARD-CERTIFIED IN: INTERNAL MEDICINE, FAMILY MEDICINE, OBSTETRICS AND GYNECOLOGY, EMERGENCY MEDICINE, PEDIATRICS, PREVENTIVE MEDICINE, OR PSYCHIATRY. WE HAVE BASED OUR PROPOSED PROGRAM ON OUR EXTENSIVE EXPERIENCE AND THE PREMISES THAT TRAINING THE NEXT GENERATION OF ADDICTION MEDICINE AND ADDICTION PSYCHIATRY LEADERS TO IMPROVE HEALTH OUTCOMES FOR AT RISK PATIENTS REQUIRES KNOWLEDGE AND EXPERIENCE IN: (1) POPULATION-BASED CARE DELIVERY AND RESEARCH; (2) PUBLIC HEALTH PRACTICE FOCUSED ON HEALTH DISPARITIES IN BOTH RURAL AND URBAN POPULATIONS; (3) MEDICAL EDUCATION, INCLUDING PATIENT CARE AND CLINICAL PREVENTIVE MEDICINE; AND (4) IMPLEMENTATION, EVALUATION, AND IMPROVEMENT OF SYSTEM-LEVEL CHANGES TO PREVENT DISEASE BURDEN AND IMPROVE HEALTH OUTCOMES ACROSS POPULATIONS. OUR PROGRAM GOAL IS TO INCREASE THE NUMBER OF BOARD-CERTIFIED PHYSICIANS IN ADDICTION MEDICINE AND ADDICTION PSYCHIATRY WHO SERVE IN MEDICALLY UNDERSERVED COMMUNITY-BASED AND RURAL SETTINGS. OUR CONFIDENCE THAT WE CAN ACHIEVE THIS GOAL IS BASED ON OUR WELL-ESTABLISHED RECORD OF TRAINING ADDICTION SPECIALISTS THAT ARE ALREADY WORKING IN HIGH-NEED COMMUNITIES. FUTURE FUNDING WILL ENSURE THAT WE CONTINUE TO BUILD AND EXPAND OUR PRIOR SUCCESS. TO ACCOMPLISH THIS GOAL WE WILL (1) INCREASE THE NUMBER OF ADDICTION TRAINED PHYSICIANS TO PRACTICE IN MEDICALLY UNDERSERVED COMMUNITY-BASED SETTINGS AND INTEGRATE PRIMARY CARE WITH MENTAL HEALTH AND SUD PREVENTION AND TREATMENT SERVICES; (2) INCREASE FELLOWS’ KNOWLEDGE TO ASSIST THEIR PATIENTS TO NAVIGATE LEGAL AND SOCIAL SYSTEMS RELATED TO PATIENTS’ CLINICAL NEEDS (3) INCREASE AWARENESS OF ADDICTION MEDICINE AS A SUB-SPECIALTY AND REDUCE PROVIDER STIGMA TO INCREASE THE NUMBER OF PHYSICIANS INTERESTED IN PURSUING CAREERS IN ADDICTION MEDICINE AND ADDICTION PSYCHIATRY THROUGH THE PROVISION OF CLINICAL ROTATIONS THAT EXPOSE MEDICAL STUDENTS AND RESIDENTS TO PRACTICE IN THESE SPECIALTIES AND THROUGH EDUCATION AND CONSULTATION. WE WILL CONDUCT FIVE ITERATIONS OF THE FULL CURRICULUM DURING THE PROJECT PERIOD, DELIVERING TO A TOTAL OF 25 FELLOWS (15 ADDICTION MEDICINE AND 10 ADDICTION PSYCHIATRY FELLOWS). THE PROGRAM WILL BE LED BY ALYSSA PETERKIN, MD, A GENERAL INTERNIST AND ADDICTION MEDICINE SPECIALIST, AND MICHAEL DAWES, MD, ADDICTION PSYCHIATRY FELLOWSHIP DIRECTOR. ALSO SERVING IN LEADERSHIP ROLES WILL BE ALEXANDER WALLEY MD, MSC, AND ZOE WEINSTEIN, MD, MS.

SIGNIFICANCE OF TUBULOGLOMERULAR FEEDBACK IN SGLT1 AND SGLT2 INHIBITION IN DIABETIC KIDNEY DISEASE - INCREASED GLOMERULAR FILTRATION RATE (GFR), ALSO KNOWN AS GLOMERULAR HYPERFILTRATION, IS A COMMON OBSERVATION IN THE EARLY STAGE OF DIABETES AND IS CONSIDERED A KEY RISK FACTOR FOR THE LATER DEVELOPMENT OF DIABETIC KIDNEY DISEASE (DKD). ALTHOUGH THE PATHOPHYSIOLOGICAL MECHANISMS OF GLOMERULAR HYPERFILTRATION IN DIABETES HAVE NOT BEEN FULLY UNDERSTOOD, THE TUBULOGLOMERULAR FEEDBACK (TGF) HAS BEEN IMPLICATED. IN PARTICULAR, THE “TUBULAR HYPOTHESIS” IS NOW WIDELY RECOGNIZED. IT DESCRIBES THAT PROXIMAL TUBULAR REABSORPTION OF SODIUM AND GLUCOSE VIA THE SODIUM- GLUCOSE COTRANSPORTER 2 (SGLT2) IS UPREGULATED IN THE DIABETIC KIDNEY, THEREBY REDUCING THE NACL DELIVERY TO THE MACULA DENSA, WHICH DECREASES THE TGF ACTIVITY AND INCREASES THE SINGLE-NEPHRON GFR IN AN EFFORT TO NORMALIZE NACL EXCRETION (SGLT2-NACL-TGF PATHWAY). WE HAVE RECENTLY IDENTIFIED A NEW AND COMPLEMENTING MECHANISM THAT INCREASES GFR IN THE DIABETIC KIDNEY: THE INCREASED TUBULAR GLUCOSE LOAD AT THE MACULA DENSA IS SENSED THROUGH THE APICAL SODIUM-GLUCOSE COTRANSPORTER 1 (SGLT1) AND ENHANCES THE NEURONAL NITRIC OXIDE SYNTHASE (NOS1)-DERIVED NITRIC OXIDE (NO) GENERATION, WHICH BLUNTS TGF RESPONSIVENESS AND LIKEWISE INCREASES THE SINGLE-NEPHRON GFR (SGLT1-NOS1-TGF PATHWAY). SGLT2 INHIBITION IS CURRENTLY CHANGING THE PERSPECTIVES OF ANTIDIABETIC THERAPY WITH SIGNIFICANT RENOPROTECTIVE EFFECTS. THE BENEFITS OF SGLT2 INHIBITION IN THE DIABETIC KIDNEY HAVE BEEN PROPOSED TO BE LARGELY INDEPENDENT OF ITS BLOOD GLUCOSE-LOWERING EFFECT AND MAINLY BASED ON THE CENTRAL ROLE OF THIS TRANSPORTER IN THE “TUBULAR HYPOTHESIS” OF DIABETIC GLOMERULAR HYPERFILTRATION AND NEPHROPATHY. IN ACCORDANCE WITH THE “TUBULAR HYPOTHESIS”, INHIBITION OF SGLT2 INCREASES THE MACULA DENSA NACL DELIVERY AND REDUCES DIABETIC HYPERFILTRATION AND THEREBY PROTECTS THE DIABETIC KIDNEY. HOWEVER, INHIBITION OF SGLT2 ALSO INCREASES GLUCOSE DELIVERY TO THE MACULA DENSA, WHICH IS EXPECTED TO DECREASE THE TGF RESPONSIVENESS THROUGH THE MACULA DENSA SGLT1-NOS1-TGF PATHWAY, AND THEREBY LIMIT BOTH THE GFR-LOWERING EFFECT OF SGLT2 INHIBITION AND ITS PROTECTIVE EFFECTS ON KIDNEY. THEREFORE, IN THE PRESENT PROPOSAL, WE WILL EXAMINE THE EFFECTS OF SGLT2 INHIBITION ON THE TUBULAR GLUCOSE LOAD AT THE MACULA DENSA, THE MACULA DENSA NOS1/NO LEVELS, AND TGF RESPONSIVENESS IN DIABETIC MICE, AND THEN DETERMINE THE SIGNIFICANCE OF THE MACULA DENSA SGLT1-NOS1 PATHWAY IN THE SGLT2 INHIBITION-INDUCED ALTERATIONS IN TGF AND GFR BY USING MOUSE MODELS WITH SGLT1 KNOCKOUT OR MACULA DENSA-SPECIFIC NOS1 KNOCKOUT; MOREOVER, WE WILL COMPARE THE EFFECTS OF DUAL SGLT1/SGLT2 INHIBITION AND SELECTIVE SGLT2 INHIBITION ON TGF ACTIVITY, GFR AND KIDNEY INJURY IN DIABETIC MICE, AND FURTHER DETERMINE THE SIGNIFICANCE OF THE TGF MECHANISM IN THESE EFFECTS BY USING A MOUSE MODEL THAT LACKS TGF DUE TO MACULA DENSA-SPECIFIC NKCC2 KNOCKOUT. SUCCESSFUL COMPLETION OF THIS PROPOSAL WILL ESTABLISH THE OPPOSING ROLE OF THE MACULA DENSA SGLT1-NOS1-TGF PATHWAY IN THE PROTECTIVE EFFECTS OF SGLT2 INHIBITION ON DIABETIC GLOMERULAR HYPERFILTRATION AND KIDNEY INJURY, AND THUS PROVIDE SUPPORTIVE AND MECHANISTIC EVIDENCE FOR THE USE OF DUAL SGLT1/SGLT2 INHIBITION IN THE TREATMENT OF DKD.

PREVENTIVE MEDICINE RESIDENCY

THE BOSTON SUSTAINABLE MODELS FOR UNHEALTHY ALCOHOL USE REDUCTION (B SMART) PROGRAM

BOSTON AREA TRAVEL MEDICINE NETWORK (BATMN)

THRIVE-DM: IMPROVING DIABETES CARE WITH STRATEGIES FOR ADDRESSING HEALTH-RELATED SOCIAL NEEDS AND COMMUNITY PARTNERSHIPS - PROJECT SUMMARY/ABSTRACT WE PROPOSE TO IMPLEMENT AND ASSESS THRIVE-DM, AN EXPANSION OF OUR EXISTING THRIVE HEALTH-RELATED SOCIAL NEEDS (HRSN) SCREENING AND REFERRAL PROGRAM, WITH THE AIM OF MAXIMIZING THE PROPORTION OF T2DM PATIENTS WITH HRSN WHO CONNECT TO SOCIAL SERVICES AND USE THESE SERVICES TO ADDRESS HRSN AND IMPROVE THEIR T2DM OUTCOMES. THIS WILL BE ACHIEVED THROUGH DEVELOPING, IMPLEMENTING, AND EVALUATING THE THRIVE-DM INTERVENTION, WHICH ENHANCES THRIVE IN 3 KEY WAYS: 1) A COMMUNITY HEALTH WORKER-LED REFERRAL SUPPORT PROTOCOL; 2) A COMMUNITY-ENGAGED AND PATIENT-CENTERED CASE MANAGEMENT WORKING GROUP; AND 3) A DATA- DRIVEN TRIAGE TOOL TO IDENTIFY PATIENTS WHO ARE WELL-SUITED FOR A LOW VERSUS HIGH SUPPORT STRATEGY TO CONNECT WITH SOCIAL SERVICES. TOGETHER THESE INNOVATIONS AIM TO INCREASE PATIENTS’ ABILITY TO RECEIVE SERVICES THAT MITIGATE OR EVEN RESOLVE THEIR HRSN, WHILE ALSO ENSURING HIGH ACCEPTABILITY AMONG BOTH PATIENTS AND SOCIAL SERVICE PROVIDERS. WE WILL CONDUCT A HYBRID TYPE 3 IMPLEMENTATION-EFFECTIVENESS TRIAL TO ASSESS THE FEASIBILITY AND PRELIMINARY EFFECTIVENESS OF THE THRIVE-DM INTERVENTION. THE RATIONALE UNDERLYING THIS PROPOSAL ENCOMPASSES TWO KEY FOUNDATIONS. FIRST, IT RECOGNIZES THAT HRSN SCREENING AND REFERRAL INITIATIVES, WHILE VALUABLE, TEND TO FAVOR INDIVIDUALS WITH A STRONGER LOCUS OF CONTROL, GREATER SOCIOECONOMIC RESOURCES, SUPERIOR HEALTH STATUS, AND ENHANCED SOCIAL CAPITAL, FACILITATING THEIR SUCCESSFUL NAVIGATION OF REFERRALS AND PARTICIPATION IN SUBSEQUENT PROGRAMS. WHEREAS, INDIVIDUALS WHO LACK THESE ADVANTAGES ACHIEVE LOWER LEVELS OF SUCCESS. SECOND, IT ACKNOWLEDGES THE CHALLENGE OF EFFECTIVELY ALLOCATING HEALTH SYSTEM-BASED RESOURCES TO EFFECTIVELY IMPLEMENT CLOSED-LOOP HRSN SERVICE REFERRAL LINKAGES BASED ON INDIVIDUAL PATIENT CHARACTERISTICS. CONSEQUENTLY, PATIENTS WITH T2DM EXHIBITING GREATER OR MORE SEVERE HRSN MAY ENCOUNTER BARRIERS TO ACCESSING SOCIAL SERVICES DUE TO THESE VERY SAME SOCIAL NEEDS. MOREOVER, THESE PATIENTS MAY ALSO EXPERIENCE DIFFICULTIES IN MANAGING THEIR T2DM, PARTLY AS A RESULT OF THESE UNADDRESSED SOCIAL NEEDS. THUS, ENHANCED HRSN SCREENING AND REFERRAL PROTOCOLS, COMPLEMENTED BY COMMUNITY-ENGAGED CASE MANAGEMENT BASED ON THE COMPLEXITY OF HRSN, BUILD UPON OUR EXISTING PROGRAM TO FACILITATE MORE SUCCESSFUL CONNECTIONS BETWEEN PATIENTS AND SOCIAL SERVICES. SUCCESSFULLY ALLEVIATING HRSN THAT DIRECTLY AFFECT PATIENTS' ABILITY TO MANAGE T2DM IS A MECHANISM BY WHICH, AT SCALE, WE CAN REDUCE INEQUITIES IN T2DM MANAGEMENT. HOWEVER, COMMUNITY-LEVEL INTERVENTIONS ADDRESSING THE ROOT CAUSES OF HRSN MUST OCCUR SIMULTANEOUSLY TO ELIMINATE THESE INEQUITIES. THE PROPOSED WORK WILL PILOT THE IMPLEMENTATION OF ENHANCED, TIERED, CASE MANAGEMENT HRSN SCREENING AND REFERRAL PROTOCOLS FOR PATIENTS WITH UNCONTROLLED T2DM. WE WILL ASSESS THE FEASIBILITY OF DATA COLLECTION ON KEY PERSON-CENTERED CLINICAL OUTCOME MEASURES TO EVALUATE THE EFFECTIVENESS OF THIS ENHANCED PROTOCOL IN MITIGATING SELF-IDENTIFIED HRSN AMONG T2DM PATIENTS AND ITS IMPACT ON CONNECTIONS WITH SOCIAL SERVICES, AND HEMOGLOBIN A1C LEVELS.

IMPLEMENTATION AND DISSEMINATION OF 'GABBY,' A HEALTH INFORMATION TECHNOLOGY (HIT) SYSTEM FOR YOUNG WOMEN, INTO COMMUNITY-BASED CLINICAL SITES

EFFECT OF STATINS AND MODIFIABLE FACTORS ON STROKE OUTCOME IN ATRIAL FIBRILLATION

THE MASSACHUSETTS MODEL OF MAT FOR PATIENTS WITH CO-OCCURRING MENTAL DISORDERS (4MD)

SUBSTANCE USE PREVENTION FOR RECENTLY DISPLACED ADULTS (SUPRA) - PROJECT SUMMARY THE WAR IN UKRAINE HAS PROVOKED THE WORLD’S CURRENT LARGEST HUMANITARIAN DISPLACEMENT: SINCE FEBRUARY 2022, OVER 13 MILLION PEOPLE, I.E., ONE-THIRD OF UKRAINIANS, HAVE BEEN FORCED TO LEAVE THEIR HOMES, RESULTING IN NEARLY 6 MILLION INTERNALLY DISPLACED PERSONS (IDPS). WAR AND HUMANITARIAN EMERGENCIES MAY EXACERBATE SUBSTANCE USE, BUT THE INCIDENCE AND PREVALENCE OF UNHEALTHY SUBSTANCE USE IN HUMANITARIAN SETTINGS, INCLUDING UKRAINE, ARE CURRENTLY LARGELY UNKNOWN. THIS LACK OF DATA LIMITS THE ABILITY TO TAILOR TARGETED, EFFECTIVE PREVENTIVE SUBSTANCE USE INTERVENTIONS FOR THESE MOBILE POPULATIONS. ADDRESSING THIS KNOWLEDGE GAP IS AN IMMENSE PRIORITY FOR UKRAINE, WHERE RATES OF SUBSTANCE USE WERE HIGH EVEN PRIOR TO THE RUSSIAN INVASION IN FEBRUARY 2022, AND IN OTHER SETTINGS HOSTING LARGE POPULATIONS OF IDPS, INCLUDING THE UNITED STATES. WE PROPOSE TO CONDUCT AN EPIDEMIOLOGICAL SUBSTANCE USE SURVEY AMONG IDPS IN UKRAINE DURING THE R61 PHASE, FOLLOWED BY R33-SUPPORTED DEVELOPMENT AND EVALUATION IN A RANDOMIZED CONTROLLED TRIAL OF A SUBSTANCE USE PREVENTION INTERVENTION FOR THIS POPULATION. DUE TO BURGEONING EVIDENCE AND OUR OWN PRELIMINARY DATA, WE ANTICIPATE ADAPTING AN ACCEPTANCE AND COMMITMENT THERAPY (ACT)-INFORMED INTERVENTION, THOUGH FINAL INTERVENTION DECISIONS WILL BE RESPONSIVE TO THE NEEDS IDENTIFIED IN THE EPIDEMIOLOGICAL PHASE. ACT FOR SUBSTANCE USE PREVENTION WILL USE ACCEPTANCE, MINDFULNESS, AND BEHAVIOR CHANGE PROCESSES TO IMPROVE PSYCHOLOGICAL FLEXIBILITY AND THUS SUPPORT PEOPLE IN REFRAINING FROM USE. OUR TRANSNATIONAL, MULTIDISCIPLINARY TEAM OF COMMUNITY PARTNERS, MENTAL HEALTH EXPERTS, AND BEHAVIORAL CLINICAL TRIAL SCIENTISTS HAS CONDUCTED STUDIES WITH WAR-AFFECTED POPULATIONS IN UKRAINE AND SUCCESSFULLY USED ACT TO IMPROVE HEALTH BEHAVIORS AMONG DISADVANTAGED POPULATIONS IN EASTERN EUROPE. WE WILL WORK CLOSELY WITH OUR COMMUNITY PARTNER, THE ALLIANCE FOR PUBLIC HEALTH (“ALLIANCE,” A LEADING NON-GOVERNMENTAL ORGANIZATION IN UKRAINE) AND ACADEMIC EXPERTS IN UKRAINE. IN THE R61 PHASE OF THE GRANT, WE WILL CONDUCT AN EPIDEMIOLOGICAL SURVEY (N=577) EVALUATING SUBSTANCE USE PATTERNS AND RISK FACTORS AMONG IDPS SEEKING MEDICAL SERVICES AT MOBILE MEDICAL POINTS ESTABLISHED BY THE ALLIANCE. DIRECTLY INFORMED BY FINDINGS FROM THE EPIDEMIOLOGY STUDY, WE WILL TRANSITION TO THE R33 PHASE AND WILL ENGAGE COMMUNITY MEMBERS TO CO-DESIGN THE MOST APPROPRIATE PREVENTION INTERVENTION. WE WILL ADAPT THE INTERVENTION USING QUALITATIVE METHODS (FOCUS GROUPS AND STAKEHOLDER INTERVIEWS) AND CONDUCT A PILOT RANDOMIZED CONTROLLED TRIAL (N=144) EVALUATING THE INTERVENTION ON PREVENTING THE DEVELOPMENT OF SUBSTANCE USE DISORDERS AMONG IDPS, WITH PRIMARY OUTCOMES INCLUDING FEASIBILITY AND ACCEPTABILITY. THE EXPECTED OUTCOME OF THIS AWARD IS A POTENTIALLY EFFECTIVE AND SCALABLE INTERVENTION THAT COULD PREVENT AT SCALE THE DEVELOPMENT OF SUBSTANCE USE DISORDERS AMONG IDPS AFFECTED BY HUMANITARIAN CRISES. THE KEY INNOVATION IS THAT THIS STUDY WILL EXPAND ON LIMITED EPIDEMIOLOGICAL DATA SPECIFIC TO SUBSTANCE USE IN HUMANITARIAN SETTINGS AND BE AMONG THE FIRST TO DEMONSTRATE THE EFFECTIVENESS OF AN INTERVENTION TO PREVENT SUBSTANCE USE DISORDERS IN HUMANITARIAN CONTEXTS.

MITOCHONDRIAL FRAGMENTATION AND DYSFUNCTION IN DIABETIC RETINOPATHY

DEVELOPMENT OF SYSTEMS AND EDUCATION FOR CERVICAL CANCER PREVENTION (DOSE-CC) - PROJECT SUMMARY / ABSTRACT CERVICAL CANCER DISPROPORTIONATELY AFFECTS BLACK, HISPANIC, AND LOW-INCOME AMERICANS. UNIVERSAL SCREENING HAS THE POTENTIAL TO DECREASE THE OVERALL BURDEN OF CERVICAL CANCER AND TO REDUCE RACIAL AND ETHNIC DISPARITIES IN THIS DISEASE. HOWEVER, MORE THAN HALF OF THE INDIVIDUALS WHO DEVELOP CERVICAL CANCER HAVE NOT BEEN SCREENED IN MORE THAN 5 YEARS, AND 20% DID NOT FOLLOW-UP AFTER AN ABNORMAL RESULT. TO ADDRESS THIS PROBLEM, WE AIM TO ADAPT AND TEST AN INTERVENTION TO IMPROVE CERVICAL SCREENING AND FOLLOW-UP IN THREE DIVERSE, UNDERSERVED POPULATIONS: URBAN INNER CITY BLACKS/HAITIANS (BOSTON), HISPANIC IMMIGRANTS (FLORIDA), AND HAWAIIAN NATIVES/PACIFIC ISLANDERS (HAWAII). OUR RESEARCH GROUP PREVIOUSLY DEVELOPED A SUCCESSFUL INTERVENTION TO IMPROVE HPV VACCINATION RATES, WHICH WE PLAN TO ADAPT FOR CERVICAL CANCER SCREENING. THE INTERVENTION COMBINES EDUCATION AND QUALITY IMPROVEMENT METHODS USING A MECHANISM CALLED PERFORMANCE IMPROVEMENT CONTINUING MEDICAL EDUCATION. THIS TYPE OF INTERVENTION IS ATTRACTIVE TO CLINICIANS BECAUSE THEY ARE ABLE TO IMPROVE THEIR CANCER PREVENTION PRACTICES WHILE FULFILLING REQUIREMENTS FOR MAINTAINING BOARD CERTIFICATION. WHEN APPLIED TO HPV VACCINATION, THE INTERVENTION IMPROVED RATES BY OVER 10 PERCENTAGE POINTS, AND GAINS CONTINUED FOR OVER 4 YEARS AFTER THE INTERVENTION CONCLUDED. THE GOAL OF THE PROPOSED RESEARCH IS TO ADAPT THE INTERVENTION TO CERVICAL CANCER SCREENING, AND TO EVALUATE ITS EFFECTIVENESS IN IMPROVING SCREENING AND FOLLOW-UP AFTER ABNORMAL RESULTS. FIRST, WE WILL ADAPT OUR SUCCESSFUL HPV VACCINE INTERVENTION TO ADDRESS CERVICAL CANCER SCREENING (DOSE-CC). WE WILL INTERVIEW KEY STAKEHOLDERS TO EXPLORE FACILITATORS AND BARRIERS TO SCREENING AND FOLLOW-UP AT THE PATIENT, CLINICIAN, AND HEALTHCARE SETTING LEVELS AND USE THESE FINDINGS AND ADVISORY BOARD INPUT TO DEVELOP THE DOSE-CC INTERVENTION. SECOND, WE WILL VALIDATE DOSE-CC USING A HYBRID TYPE 1 EFFECTIVENESS-IMPLEMENTATION, STEPPED-WEDGE RANDOMIZED CONTROLLED TRIAL DESIGN OF THE 6-MONTH INTERVENTION, REACHING OVER 40,000 PATIENTS. THIRD, GUIDED BY THE RE-AIM QUEST FRAMEWORK, WE WILL CONDUCT SEMI- STRUCTURED INTERVIEWS OF KEY STAKEHOLDERS TO EXAMINE INTERVENTION REACH, ADOPTION, IMPLEMENTATION, MAINTENANCE AND SUSTAINABILITY, AND BARRIERS AND FACILITATORS OF INTERVENTION SUCCESS. THE PROPOSED INTERVENTION REPRESENTS AN INNOVATIVE AND SCALABLE MODEL FOR PROMOTING CANCER PREVENTION AND SCREENING ACTIVITIES BY CLINICIANS. UNLIKE PROGRAMS THAT INCREASE ADMINISTRATIVE BURDENS ON BUSY CLINICIANS, THE PROPOSED INTERVENTION ALLOWS CLINICIANS TO IMPROVE CANCER PREVENTION PRACTICES WHILE SIMULTANEOUSLY FULFILLING REQUIREMENTS TO MAINTAIN THEIR BOARD CERTIFICATION AND IMPROVING THE QUALITY OF CANCER PREVENTION CARE. IT THEREFORE HAS GREAT POTENTIAL FOR WIDESPREAD DISSEMINATION.

MACROPHAGE-MUSCLE PRECURSOR CELL INTERACTION IN THE CONTEXT OF HIV INFECTION

NICHE-SPECIFIC ENDOTHELIAL MECHANISMS REGULATING THE EXTRAVASATION OF HEMATOPOIETIC STEM CELLS - PROJECT SUMMARY HEMATOPOIETIC STEM CELL (HSC) TRANSPLANTATION IS A POTENTIALLY CURATIVE TREATMENT FOR NUMEROUS BLOOD AND IMMUNE DISORDERS. THE PROCESS ITSELF, HOWEVER, IS INEFFICIENT AND CAN LEAVE PATIENTS IMMUNOCOMPROMISED AND VULNERABLE TO LIFE-THREATENING INFECTIONS FOR UP TO A YEAR POST-TRANSPLANTATION. ONLY ONCE DONOR HSCS ENGRAFT IN THE RECIPIENT’S BONE MARROW NICHES CAN THE STEM CELLS REGENERATE A NEW IMMUNE SYSTEM. IN THIS PROPOSAL, WE AIM TO ELUCIDATE THE KEY ENDOTHELIAL MECHANISMS THAT DIRECT CIRCULATING HSCS ACROSS THE BLOOD VESSEL WALL AND INTO THEIR NICHE. OUR STUDIES WILL PAVE THE WAY FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS TO ACCELERATE POST- TRANSPLANT IMMUNE RECOVERY BY ENHANCING THE NICHE MIGRATION OF HSCS. IN MAMMALS, THE TRANS-ENDOTHELIAL MIGRATION OF HSCS OCCURS DEEP INSIDE OPAQUE BONES, WHICH ARE LARGELY INACCESSIBLE TO IMAGING AND EXPERIMENTATION IN LIVE ANIMALS. THE TRANSPARENT ZEBRAFISH EMBRYO, BY CONTRAST, WHICH HAS A BLOOD AND VASCULAR SYSTEM HIGHLY SIMILAR TO THAT OF HUMANS, ENABLES DIRECT VISUALIZATION OF HSC MIGRATION WITH UNPRECEDENTED SUB-CELLULAR RESOLUTION. WE PREVIOUSLY IDENTIFIED A CONSERVED GENE EXPRESSION SIGNATURE FOR HSC NICHE ENDOTHELIAL CELLS, WHICH INCLUDES MOLECULES WITH CELL ADHESION AND ENDOCYTOSIS/VESICLE TRAFFICKING FUNCTIONS. CONSISTENT WITH THIS, INTRAVENOUS INJECTION OF FLUORESCENT ENDOCYTOSIS REPORTERS REVEALED A HIGH LEVEL OF ENDOCYTOSIS ACTIVITY, WITH EACH NICHE ENDOTHELIAL CELL HARBORING A DISCRETE CLUSTER OF ENDOCYTIC ACTIVITY. USING HIGH-RESOLUTION TIME-LAPSE MICROSCOPY, WE OBSERVED ADHERENT HSCS INITIATING TRANS-ENDOTHELIAL MIGRATION INTO THE NICHE SPECIFICALLY THROUGH THESE ENDOCYTIC CLUSTERS. IN PRELIMINARY STUDIES, WE DISRUPTED CANDIDATE FACTORS FROM OUR NICHE ENDOTHELIAL SIGNATURE, WHICH BLOCKED ENDOCYTOSIS IN THE NICHE ENDOTHELIUM AND IMPAIRED HSC MIGRATION. TOGETHER, OUR DATA SUGGEST THAT A COMBINATION OF SPECIFIC CELL ADHESION AND ENDOCYTOSIS/VESICLE TRAFFICKING MACHINERY WITHIN THE ENDOTHELIUM FACILITATE THE EXTRAVASATION OF HSCS INTO THEIR NICHE, A HYPOTHESIS WE WILL TEST IN OUR PROPOSED AIMS. IN AIM 1, WE EMPLOY HIGH-RESOLUTION LIVE CELL IMAGING IN COMBINATION WITH STRUCTURE-FUNCTION STUDIES AND IN VIVO PROXIMITY-DEPENDENT BIOTINYLATION IN ZEBRAFISH, TO DEFINE THE ENDOTHELIAL RECEPTOR DOMAINS AND BINDING PARTNERS THAT MEDIATE THE ADHESION AND TRANS-ENDOTHELIAL MIGRATION OF HSCS. IN AIM 2, WE USE LOSS-OF-FUNCTION CHEMICAL AND GENETIC TOOLS IN COMBINATION WITH OVEREXPRESSION STUDIES, BOTH IN THE ZEBRAFISH AND A BIOMIMETIC HUMAN BLOOD VESSEL MODEL, TO DETERMINE THE CONSERVED VASCULAR ENDOCYTOSIS AND MEMBRANE TRAFFICKING MACHINERY THAT IS NECESSARY AND SUFFICIENT TO TRIGGER HSC EXTRAVASATION. TOGETHER, OUR STUDIES WILL PROVIDE NOVEL MOLECULAR TARGETS FOR THE DESIGN OF NEW ENDOTHELIAL-FOCUSED THERAPEUTICS AIMED AT MORE EFFICIENTLY GUIDING HSCS INTO THE BONE MARROW, WHICH COULD ACCELERATE IMMUNE SYSTEM RECOVERY FOLLOWING HSC TRANSPLANTATION.

BOSTON UNIVERSITY MEDICAL CAMPUS-MASSACHUSETTS GENERAL HOSPITAL GLOBAL PSYCHIATRIC CLINICAL RESEARCH TRAINING PROGRAM

POPULATION-BASED REFERENCE RANGES FOR TESTOSTERONE

H+-ATPASE AND AQP2: REGULATION OF TARGETING AND RECYCLING IN IMCD CELLS

CE25-149 - ENGAGING OVERDOSE SURVIVORS WITH THE SAFESPOT HOTLINE FOR SECONDARY OVERDOSE PREVENTION

SICKLE CELL

A RCT TO REDUCE CARDIOPULMONARY REHOSPITALIZATIONS

TRANSITION FOR YOUTH WITH AUTISM AND/OR EPILEPSY DEMONSTRATION PROJECTS - A COMMUNITY-CENTERED, STRATEGIC APPROACH FOR ENHANCING THE WELLBEING OF YOUTH WITH EPILEPSY AND DEVELOPMENTAL DISABILITIES AND THEIR CAREGIVERS DURING THE TRANSITION TO ADULT-SERVING SYSTEMS. BOSTON MEDICAL CENTER PEDIATRIC RESEARCH BUILDING, 801 ALBANY ST, ROXBURY, MA 02119-3791 LAURIE M DOUGLASS, MD; 617-899-1025 (CELL); 617-414-4590 (OFFICE); 617-414-4841 (FAX) EMAIL: LAURIE.DOUGLASS@BMC.ORG WEBSITE: HTTPS://WWW.BMC.ORG/PEDIATRICS-NEUROLOGY PROGRAM FUNDS REQUEST: $2,248,780 BOSTON MEDICAL CENTER’S PROJECT, A COMMUNITY-CENTERED, STRATEGIC APPROACH FOR ENHANCING THE WELLBEING OF YOUTH WITH EPILEPSY AND DEVELOPMENTAL DISABILITIES AND THEIR CAREGIVERS DURING THE TRANSITION TO ADULT-SERVING SYSTEMS, WILL DEVELOP, IMPLEMENT, EVALUATE, AND SCALE UP FIVE INNOVATIVE STRATEGIES THAT WILL BROADLY IMPROVE OUTCOMES FOR YOUTH WITH EPILEPSY (YWE) AS THEY TRANSITION FROM CHILD- TO ADULT-SERVING SYSTEMS. BOSTON MEDICAL CENTER (BMC) AND THE EPILEPSY FOUNDATION NEW ENGLAND (EFNE) ARE UNIQUELY POSITIONED TO MOBILIZE A CROSS-DISCIPLINARY NETWORK IN ORDER TO SUPPORT 9,066 YWE BETWEEN 13 AND 26 YEARS OF AGE AND THEIR FAMILIES WHO LIVE IN FIVE NEW ENGLAND STATES (MASSACHUSETTS, NEW HAMPSHIRE, MAINE, RHODE ISLAND, AND VERMONT). THE PROPOSED CONSORTIUM WOULD PRIORITIZE THE NEEDS OF AN ESTIMATED 4,502 YWE WHO HAVE A CO-OCCURRING DIAGNOSIS OF AUTISM SPECTRUM DISORDER (ASD), INTELLECTUAL/DEVELOPMENTAL DISABILITY (IDD), OR BOTH WITHIN THE PROJECT CATCHMENT AREA, HEREAFTER REFERRED TO AS YEDD. SINCE 2016, BMC’S TELEHEALTH EPILEPSY CARE COLLABORATIVE (TECC) HAS ENABLED OVER 3,000 UNIQUE YWE TO OVERCOME BARRIERS AND ACCESS HOLISTIC SPECIALTY CARE THROUGH ITS HRSA-FUNDED INITIATIVES. AS COLLABORATORS UNDER TECC, BOTH BMC AND THE EFNE HAVE ACCUMULATED THE INSTITUTIONAL CAPACITY, EXPERTISE, AND COMMUNITY CONNECTIONS NEEDED TO OVERCOME REMAINING BARRIERS IN OUR CATCHMENT AREA. WE USED EXTENSIVE INTERVIEW, FOCUS GROUP, AND SURVEY DATA PROVIDED BY YWE, THEIR SUPPORTERS AND SER VICE PROVIDERS OVER THE PAST TWO YEARS TO INFORM THIS PROPOSAL. WE WILL CONTINUE TO ENGAGE YWE/YEDD AND THEIR CAREGIVERS AT EVERY STAGE OF EVERY INNOVATIVE STRATEGY, AND PRIORITIZE THE PURSUIT OF TOTAL HEALTH EQUITY. OVER THE NEXT FIVE YEARS, THIS PROJECT WILL ADDRESS ALL THREE HRSA-24-042 OBJECTIVES BY IMPROVING UPON TRANSITION SUPPORT CAPACITY DEVELOPED THROUGH PREVIOUS CYCLES OF HRSA FUNDING. EACH PROPOSED STRATEGY WILL INCORPORATE IMPLEMENTATION SCIENCE, CONTINUOUS QUALITY IMPROVEMENT (QI), HEALTHCARE TRANSITION FRAMEWORKS AND CORE PRINCIPLES FROM THE HRSA/MCHB BLUEPRINT FOR CHANGE. SPECIFIC AREAS OF INNOVATIONS UNDER THIS PROJECT WILL INCLUDE: A NOVEL APPROACH TO SCREENING YWE/YEDD FOR OVERALL TRANSITION READINESS, THE EXPANSION OF TWO TRANSITION NAVIGATION PROGRAMS THAT SERVE PATIENTS AND FAMILIES AT ZERO COST, A NEW COACHING PROGRAM FOR CAREGIVERS, AND THE CREATION OF SEVERAL NEW TARGETED EDUCATION, ADVOCACY, AND SOCIAL GROUPS THAT RESPOND SPECIFICALLY TO THE NEEDS OF YEDD AND THEIR FAMILIES. WITH THE HELP OF A LARGE, CROSS-DISCIPLINARY PARTNERS NETWORK AND ADVISORY COUNCIL MEMBERS WITH DIVERSE LIVED EXPERIENCE, WE WILL ALSO GENERATE REGIONAL KNOWLEDGE, PERFORM A SOPHISTICATED NEED AND NETWORK ANALYSIS, DEVELOP A VIRTUAL RESOURCE HUB FOR YEDD/CAREGIVERS, AND STRENGTHEN CROSS-AGENCY COLLABORATION FOR VARIOUS YEDD-SERVING COMMUNITY GROUPS. PROJECT SUCCESS WILL BE EVALUATED THROUGH A MIXED METHODS APPROACH THAT INCORPORATES QUANTITATIVE AND QUALITATIVE DATA COLLECTION METHODS. LONGITUDINAL DATA COLLECTED ACROSS THE ENTIRE PROJECT PERIOD WILL BE USED TO ESTIMATE THE CONSORTIUM’S EFFORTS IMPACT ON HEALTH EQUITY, COMMUNITY CONNECTIVITY PATTERNS, THE NUMBER OF UNIQUE YEDD WHO SUCCESSFULLY TRANSFER INTO ADULT-ORIENTED SERVICES OVER TIME, THE BROAD ADOPTION OF SUPPORTED DECISION MAKING STRATEGIES, AND THE GENERAL WELLNESS AND PERCEIVED SELF-EFFICACY SCORES REPORTED BY CAREGIVERS.

BREAKING THE CYCLE OF INTERGENERATIONAL FAMILY VIOLENCE AND TRAUMA: INNOVATING, EXPANDING AND SUSTAINING TREATMENT FOR CAREGIVERS AND VERY YOUNG CHIL

SURVIVORS OF TORTURE AND SEVERE TRAUMA

FROM SURVIVING TO THRIVING

ADVANCING PATIENT SAFETY IMPLEMENTATION THROUGH PHARMACY-BASED OPIOID MEDICATION USE RESEARCH

MASSACHUSETTS HIV AND JUSTICE-INVOLVED POPULATIONS RESEARCH NETWORK - PROJECT SUMMARY A MAJOR DRIVER OF THE U.S. HIV EPIDEMIC IS INADEQUATE ACCESS TO HIV PREVENTION AND CARE IN THE CRIMINAL LEGAL SYSTEM. THE END HIV EPIDEMIC (EHE) TOOLKIT RECOMMENDS THAT JAILS OFFER LOW-BARRIER ACCESS TO HIV TESTING, TREATMENT, AND PREVENTION TO PEOPLE WHO INJECT OPIOIDS, BUT MANY JUSTICE-INVOLVED PEOPLE WITH OPIOID USE DISORDER (OUD) DO NOT KNOW THEIR HIV STATUS AND FEW ACCESS MEDICATIONS TO PREVENT HIV (PRE-EXPOSURE PROPHYLAXIS, PREP). SUFFOLK COUNTY, THE ONLY EHE-DESIGNATED JURISDICTION IN MASSACHUSETTS (MA), HAD A RECENT HIV OUTBREAK, OCCURRING IN FORMERLY INCARCERATED PEOPLE WITH OUD, THAT DISPROPORTIONATELY IMPACTED THREE GEOGRAPHICALLY AND RACIALLY DISTINCT COMMUNITIES (BOSTON, CHELSEA, REVERE). IMPROVEMENTS WERE MADE TO INCREASE CARCERAL HIV PREVENTION AND CARE, BUT ONE YEAR INTO IMPLEMENTATION ONLY ABOUT 10% WERE HIV TESTED AND FEW WERE INITIATED ON PREP. MA MEDICAID NOW AUTHORIZES COVERAGE OF HIV CARE BEFORE, UPON, AND FOLLOWING RELEASE FROM INCARCERATION, BUT HIV CARE IS NOT WELL-INTEGRATED WITH THE JAILS’ EXISTING MEDICATIONS FOR OPIOID USE DISORDER (MOUD) PROGRAM AND THERE ARE GAPS BETWEEN JAILS AND COMMUNITY HEALTHCARE. THE MASSACHUSETTS HIV/JUSTICE RESEARCH NETWORK PROPOSES TO PARTNER WITH THE SUFFOLK JAIL SYSTEM AND COMMUNITY TREATMENT PARTNERS TO CONDUCT A FORMATIVE EVALUATION AND PILOT (R61, AIM 1) AND TYPE 2 HYBRID IMPLEMENTATION- EFFECTIVENESS STUDY (R33, AIMS 2-4) OF A MULTI-PRONGED INTERVENTION TO INCREASE HIV TESTING AND PREP LINKAGE CALLED ID-TOUCH (ID TESTING OUTREACH IN CARCERAL HUBS). WE WILL (1) PERFORM A FORMATIVE EVALUATION OF HIV CARE GAPS AND OPPORTUNITIES IN SUFFOLK JAILS, USING (1A) STAKEHOLDER ENGAGEMENT TO CO-DESIGN ID-TOUCH, (1B) EXISTING ADMINISTRATIVE DATA TO IDENTIFY TOUCHPOINTS FOR HIV CARE, FOCUSING ON DIFFERENTIAL BARRIERS AMONG INCARCERATED PEOPLE WHO WERE AND WERE NOT TREATED WITH MOUD, AND (1C) A PILOT-TRIAL OF ID-TOUCH, MEASURING CHANGES IN HIV TESTING, FEASIBILITY AND ACCEPTABILITY, AND SELF-REPORTED PATIENT OUTCOMES. (2) CONDUCT A LONGITUDINAL TREATMENT OUTCOME STUDY COMPARING OUTCOMES OF INDIVIDUALS RELEASED FROM SUFFOLK JAILS (A) DURING ID-TOUCH IMPLEMENTATION, (B) BEFORE IMPLEMENTATION, AND (C) IN RELATION TO A NEARBY COMPARABLE JAIL SYSTEM (CONTEMPORANEOUS CONTROL SITE) USING THE MA PUBLIC HEALTH DATA WAREHOUSE, A COLLECTION OF TWO DOZEN LINKED STATE ADMINISTRATIVE DATA SETS, TO EXAMINE HIV TESTING AND POST-RELEASE LINKAGE TO PREP OR HIV TREATMENT. (3) CONDUCT AN IMPLEMENTATION STUDY OF ID-TOUCH TO UNDERSTAND CONTEXTUAL FACTORS THAT FACILITATE AND IMPEDE DELIVERY OF HIV CARE IN JAIL AND COMMUNITY CARE COORDINATION, AND BEST PRACTICE STRATEGIES THAT OPTIMIZE HIV CARE. (4) ESTIMATE THE COST OF IMPLEMENTING AND SUSTAINING ID-TOUCH, AND ASSESS ITS ECONOMIC VALUE, RELATIVE TO USUAL CARE, FROM HEALTHCARE SECTOR, STATE-POLICYMAKER, AND SOCIETAL PERSPECTIVES. THE MASSACHUSETTS HIV/JUSTICE RESEARCH NETWORK, WITH THE MA DEPARTMENT OF PUBLIC HEALTH, SUFFOLK JAILS, AND COMMUNITY TREATMENT PARTNERS, HAS THE EXPERIENCE AND EXPERTISE TO FULFILL THE STUDY AIMS. THIS STUDY’S INSIGHTS WILL INFORM THE DEVELOPMENT OF NEW TREATMENT OPTIONS TO END THE HIV EPIDEMIC IN JAIL POPULATIONS.

CONTROL OF EMBRYONIC DEVELOPMENT BY CK2: CK2 AS A CORE WNT/BETA-CATENIN COMPONENT

THE ALCOHOL POLICY ENVIRONMENT AND LEADING CAUSES OF ALCOHOL RELATED MORTALITY

A UNIVERSAL PRIMARY CARE BASED INTERVENTION TO REDUCE YOUTH OVERDOSE RISK - PROJECT SUMMARY/ABSTRACT BETWEEN 2015 AND 2019, OVERDOSE DEATHS TRANSLATED TO 1.25 MILLION YEARS OF LIFE LOST AMONG ADOLESCENTS AND YOUNG ADULTS (“YOUTH”), AND THE PERCENT CHANGE IN FATAL OVERDOSE DEATH RATES AMONG ADOLESCENTS WAS HIGHER THAN ADULTS BETWEEN 2019 AND 2020. SIMILAR TO ADULTS, ILLICITLY MANUFACTURED FENTANYL (IMF) IS THE MAJOR DRIVER OF DRUG OVERDOSE DEATHS IN YOUTH. UNLIKE ADULTS, YOUTH ARE MORE COMMONLY EXPOSED TO IMF THROUGH COUNTERFEIT PILLS, AND SOME YOUTH ARE UNAWARE THAT THEY ARE USING A PILL THAT IS COUNTERFEIT AND THUS UNINTENTIONALLY EXPOSED TO IMF. UNFORTUNATELY, ANY YOUTH WHO USES A COUNTERFEIT PILL OR OTHER DRUG IS AT RISK FOR AN OVERDOSE, EVEN AFTER FIRST USE. THERE IS AN URGENT NEED FOR EVIDENCE-BASED OVERDOSE PREVENTION INTERVENTIONS FOR YOUTH. WITHIN THE HEALTHCARE SETTING, YOUTH PRIMARY CARE PROVIDERS ROUTINELY PROVIDE INJURY PREVENTION ANTICIPATORY GUIDANCE AS PART OF ANNUAL COMPREHENSIVE PHYSICAL EXAMS AND ARE WELL POSITIONED TO PROVIDE ANTICIPATORY GUIDANCE FOR OVERDOSE PREVENTION. THROUGH THIS R61/R33 MECHANISM WE PROPOSE TO DEVELOP AND EVALUATE THE EFFICACY OF AN UNIVERSAL OVERDOSE PREVENTION INTERVENTION THAT WILL INCREASE: (1) AWARENESS OF THE RISKS OF FENTANYL AND OTHER EMERGING DRUGS IN THE DRUG SUPPLY, (2) KNOWLEDGE OF STRATEGIES TO REDUCE OVERDOSE RISK, AND (3) RECOGNITION AND RESPONSE TO OVERDOSE. IN THE R61, IN COLLABORATION WITH OUR EXISTING YOUTH COMMUNITY ADVISORY BOARD, WE PROPOSED TO USE THE INFORMATIONAL-MOTIVATIONAL-BEHAVIORAL SKILLS MODEL TO DEVELOP AN OVERDOSE PREVENTION INTERVENTION TO BE DELIVERED IN PRIMARY CARE SETTING. WE WILL PILOT THE INTERVENTION IN TWO PRIMARY CARE SETTINGS AT BOSTON MEDICAL CENTER, PEDIATRIC PRIMARY CARE AND FAMILY MEDICINE, TO ASSESS ACCEPTABILITY AND FEASIBILITY FOR PROVIDERS AND YOUTH AGES 13 TO 26 YEARS WHO ARE BEING SEEN FOR AN ANNUAL COMPREHENSIVE PHYSICAL EXAM. WE WILL DO THIS THROUGH A PILOT TWO-ARM CLUSTER RANDOMIZED CONTROLLED TRIAL (RCT) THAT IS RANDOMIZED AT THE PROVIDER LEVEL. DURING THE PILOT TRIAL, WE WILL SHARE PRELIMINARY DATA WITH THE COMMUNITY ADVISORY BOARD TO INFORM ANY NEEDED ADAPTATIONS TO THE INTERVENTION. IF THE INTERVENTION IS ACCEPTABLE AND FEASIBLE TO PROVIDERS WE WILL TRANSITION TO EVALUATING THE INTERVENTION’S EFFICACY IN A LARGER RCT DURING THE R33. IN THE R33, WE WILL AGAIN CONDUCT A TWO-ARM CLUSTER RCT RANDOMIZED AT THE PROVIDER LEVEL USING THE SAME INCLUSION/EXCLUSION CRITERIA, PROCEDURES, AND STUDY MEASURES AS THE R61. YOUTH OUTCOMES WILL BE EVALUATED AT ONE-YEAR FOLLOW UP AND THE PRIMARY OUTCOME WILL BE YOUTH KNOWLEDGE OF THE RISK ASSOCIATED WITH FENTANYL AND OTHER EMERGING DRUGS IN THE DRUG SUPPLY. SECONDARY OUTCOMES WILL INCLUDE YOUTH KNOWLEDGE OF STRATEGIES TO REDUCE OVERDOSE RISK, RECOGNIZE AND RESPOND TO AN OVERDOSE. IF THE UNIVERSAL YOUTH OVERDOSE PREVENTION INTERVENTION IS EFFECTIVE THIS WILL BENEFIT YOUTH AND PUBLIC HEALTH GENERALLY AS YOUTH WILL BE BETTER PREPARED TO DECREASE THEIR RISK FOR OVERDOSE, AND RECOGNIZE AND RESPOND TO OTHERS WHO HAVE AN OVERDOSE.

AWARENESS AND ACCESS TO CARE FOR CHILDREN AND YOUTH WITH EPILEPSY

A LONGITUDINAL TELEPHONE AND MULTIPLE DISEASE MANAGEMENT SYSTEM TO IMPROVE AMBULA

BEHAVIORAL HEALTH WORKFORCE EDUCATION AND TRAINING PROGRAM - DISCIPLINES: PSYCHOLOGY PRE-DOCTORAL INTERNS, POSTDOCTORAL FELLOWS, AND MA STUDENTS IN MENTAL HEALTH COUNSELING. REQUESTED FUNDING AMOUNT: $ 2,399,244. BRIEF OVERVIEW: THE PURPOSE OF CONTINUATION OF THE PREVIOUSLY PROPOSED TRAINING PROGRAM, BUILDING THE PIPELINE OF MULTICULTURAL CHILD AND ADOLESCENT BEHAVIORAL HEALTH PROFESSIONALS (MULTICULTURAL CAP, OR MCAP), IS TO CONTINUE PREPARING A NEW GENERATION OF INTERDISCIPLINARY, TRAUMA-INFORMED, AND CULTURALLY ATTUNED BH PROFESSIONALS TO UNDERTAKE CAREERS SERVING DIVERSE CHILDREN, ADOLESCENTS AND TRANSITIONAL-AGE YOUTH (TAY) AGES 3 TO 25 YEARS IN MENTAL HEALTH PROFESSIONAL SHORTAGE AREAS (HPSAS). CONCURRENTLY, WE INTEND TO FILL THE GAPS IN PEDIATRIC BH SERVICES IN FOUR PARTNERING COMMUNITY HEALTH CENTERS (CHCS) WITH TRAINEES WHOSE IDENTITIES AND BACKGROUNDS REFLECT THE DIVERSITY OF THE CHCS. OUR TARGET POPULATION CONSISTS OF CHILDREN, ADOLESCENTS, AND TAY SERVED BY THE FOUR CHCS. TRAINEES WILL INCLUDE FIVE PSYCHOLOGY PREDOCTORAL INTERNS, TWO PSYCHOLOGY POST-DOCTORAL FELLOWS, AND TWO MENTAL HEALTH COUNSELING MASTER’S LEVEL GRADUATE STUDENTS EACH YEAR. OVER FOUR YEARS, WE WILL PROVIDE PLACEMENTS TO 36 TRAINEES WHO WILL PROVIDE 13,344 HOURS OF ON-SITE CLINICAL WORK PER YEAR IN THE CHCS—EQUAL TO 6.5 FTES. GOALS. THE GOALS OF THE M-CAP PROGRAM, AS HAVE BEEN ACHIEVED IN THE PREVIOUS ITERATION, WILL CONTINUE IN A REVISED FORM TO BE: 1) TO DEVELOP NINE NEW YEAR-LONG TRAINING POSITIONS ON INTERDISCIPLINARY PEDIATRIC PRIMARY CARE TEAMS IN FOUR CHC; 2) TO DEVELOP A MULTI-LEVEL, EVIDENCE-BASED 12-MONTH CURRICULUM IN CHILD, ADOLESCENT AND TAY BH; 3) TO RECRUIT/MATCH, PLACE, AND TRAIN 20 DIVERSE PRE-DOCTORAL PSYCHOLOGY INTERNS, 8 PSYCHOLOGY POST-DOCTORAL FELLOWS, AND 8 MENTAL HEALTH COUNSELING STUDENTS OVER THE COURSE OF FOUR YEARS; AND 4) TO DEVISE AND IMPLEMENT SYSTEMS FOR ONGOING PROGRAM MANAGEMENT, DATA COLLECTION, QUARTERLY AND ANNUAL EVALUATION, QUALITY IMPROVEMENT AND REGIONAL AND NATIONAL DISSEMINATION OF M-CAP. HOW THE PROJECT WILL BE ACCOMPLISHED. THE PROJECT WAS AND WILL CONTINUE TO BE LED BY THE CENTER FOR MULTICULTURAL TRAINING IN PSYCHOLOGY AT BOSTON MEDICAL CENTER (BMC). THE OLDEST MULTICULTURAL PSYCHOLOGY TRAINING PROGRAM IN THE NATION (52 YEARS), CTMP HAS BEEN ACCREDITED BY THE AMERICAN PSYCHOLOGICAL ASSOCIATION (APA) SINCE 1986. TO DATE, 87% OF CMTP TRAINEES HAVE BEEN RACIAL AND/OR ETHNIC MINORITIES. SHAMAILA KHAN, PHD, DIRECTOR OF THE CTMP, WILL SERVE AS .2 FTE PROJECT DIRECTOR. FACULTY WILL BE DRAWN BOTH FROM CTMP AND THE BMC DEPT. OF PSYCHIATRY. M-CAP WILL COLLABORATE WITH THE CHCS TO ASSESS THEIR NEEDS, DESIGN EXPERIENTIAL PLACEMENTS, AND ENSURE THAT THE MULTI-LEVEL M-CAP CURRICULUM ADDRESSES THE NEEDS OF THE TARGET POPULATION. ALL TRAINEES WILL BE MENTORED AND SUPERVISED BY BMC FACULTY AND ALSO HAVE ON-SITE SUPERVISION. A .2 FTE PROJECT COORDINATOR AND .2 FTE PROJECT EVALUATOR WILL ASSEMBLE A REDCAP DATABASE, ENSURE THAT ALL DATA COLLECTION AND REPORTING REQUIREMENTS ARE MET, AND EVALUATE M-CAP PROCESSES AND OUTCOMES. BMC’S TELEHEALTH PLATFORMS WILL CONTINUE TO BE USED FOR SOME ON-LINE TRAINING, MENTORING /SUPERVISION, AND THE DELIVERY OF TELEHEALTH SERVICES. SPECIFIC MEASURABLE OBJECTIVES: 1.1 NO LATER THAN 3/31/2025, COMPLETE ASSESSMENT OF CHC INTEGRATED BH WORKFLOWS AND UNMET BH NEEDS; 1.2 NO LATER THAN 6/30/2025, COMPLETE DESIGN OF EXPERIENTIAL PLACEMENTS; 2.1 NO LATER THAN 5/31/2025, DEVELOP CURRICULUM OUTLINES; 2.2 NO LATER THAN 8/31/2025, FINALIZE MULTI-LEVEL CURRICULUM; 3.1 NO LATER THAN 9/1/2025, PLACE FIRST COHORT OF NINE BH TRAINEES IN CHCS; 3.2 NO LATER THAN 8/31/2029, COMPLETE FOUR ITERATIONS OF M-CAP PROGRAM; 4.1 NO LATER THAN 9/1/25, IMPLEMENT SYSTEMS FOR DATA COLLECTION, PROGRAM MANAGEMENT AND QUALITY IMPROVEMENT.4.2 NO LATER THAN 9/1/25, IMPLEMENT QUARTERLY AND ANNUAL EVALUATIONS OF M-CAP PROGRAM; 4.3 NO LATER THAN 8/31/29, DISSEMINATE M-CAP PROGRAM THROUGH PROFESSIONAL ASSOCIATIONS, NATIONAL CONFERENCES AND SCHOLARLY PUBLICATIONS. FUNDING PRIORITY: YES.

BOSTON UNIVERSITY MEDICAL CAMPUS- MASSACHUSETTS GENERAL HOSPITAL GLOBAL PSYCHIATRIC CLINICAL RESEARCH TRAINING PROGRAM - PROJECT ABSTRACT THE OBJECTIVE OF THE BOSTON UNIVERSITY MEDICAL CAMPUS-MASSACHUSETTS GENERAL HOSPITAL GLOBAL PSYCHIATRY CLINICAL RESEARCH TRAINING PROGRAM (BUMC-MGH GPCRTP) IS TO DEVELOP INDEPENDENT CLINICAL SCIENTISTS WHO CAN ADDRESS THE MOST PRESSING GLOBAL MENTAL HEALTH CHALLENGES. POSTDOCTORAL FELLOWS WILL BE PREPARED TO WORK COLLABORATIVELY ACROSS DISCIPLINES AND CULTURES IN ORDER TO RESPOND TO THE SUBSTANTIAL BURDEN OF MENTAL HEALTH RELATED DISEASES IN LOW- TO MIDDLE-INCOME COUNTRIES AND RESOURCE-LIMITED AREAS, AND TO DEVELOP STRATEGIES THAT ADVANCE GLOBAL DELIVERY AND SCALE-UP OF MENTAL HEALTH SERVICES, IMPROVE GENERAL WELLBEING, AND FOSTER OVERALL COUNTRY DEVELOPMENT. THE PROPOSED POSTDOCTORAL FELLOWSHIP IS A THREE-YEAR CLINICAL RESEARCH TRAINING PROGRAM THAT WILL BE ADMINISTERED BY BOSTON MEDICAL CENTER (BMC) AND COMBINES RIGOROUS DIDACTIC INSTRUCTION, CLINICAL RESEARCH METHODS TRAINING FROM BOSTON UNIVERSITY AND HARVARD UNIVERSITY, PRACTICE IN WORKING EFFECTIVELY WITH DISADVANTAGED COMMUNITIES, AND IMMERSIVE, MENTORED CLINICAL RESEARCH EXPERIENCES IN GLOBAL SETTINGS. FOUR FELLOWS WILL BE DRAWN FROM A DEEP POOL OF TALENT AND WILL BE MENTORED BY A DIVERSE GROUP OF FACULTY WHO ARE RECOGNIZED LEADERS IN MAJOR PSYCHIATRIC SUBSPECIALTIES AS WELL AS CLINICAL RESEARCH APPROACHES. EACH FELLOW WILL HAVE AT LEAST ONE SENIOR MENTOR AT THEIR PRIMARY TRAINING SITE (BUMC OR MGH), AN ONSITE MENTOR AT THE INTERNATIONAL SITE, AND AN ADDITIONAL MENTOR SPECIALIZING IN RESEARCH METHODS DEPENDING ON INDIVIDUAL NEEDS AND EXPERIENCE. FELLOWS WILL COMPLETE A MENTORED RESEARCH PROJECT AT AN INTERNATIONAL TRAINING SITE IN BARBADOS, ETHIOPIA, PERU, SOUTH AFRICA, UGANDA OR UKRAINE ON TOPICS SUCH AS ADDICTIONS, MOOD DISORDERS, PSYCHOTIC DISORDERS, PTSD/TRAUMA/COMPLEX EMERGENCY, HIV MENTAL HEALTH, WOMEN’S MENTAL HEALTH, AND CHILDHOOD MENTAL DISORDERS. THEY WILL UTILIZE A VARIETY OF RESEARCH SKILLS AND TECHNIQUES TO UNDERSTAND THE SCOPE OF A PROBLEM, AND TO DEVELOP INNOVATIVE INTERVENTIONS THAT ARE FEASIBLE AND CULTURALLY AND CLINICALLY RELEVANT TO THE SPECIFIC ENVIRONMENTS AND POPULATIONS. FELLOWS ARE EXPECTED TO BE WELL SITUATED FOR A NIH OR EQUIVALENT K AWARD APPLICATION BY THE END OF THE THIRD YEAR OF THE PROGRAM. WITH HEAVILY CIRCUMSCRIBED CLINICAL RESPONSIBILITIES, TRAINEES WILL FOCUS ON THE REFINEMENT OF THEIR RESEARCH PROJECTS, DEVELOPING INTERNATIONAL COLLABORATIONS, AND STRENGTHENING THEIR CLINICAL RESEARCH SKILLS.

FREEDOM THROUGH WELLNESS

REFINING CONCEPTUAL MODELS FOR THE ROLE OF HEALTH LITERACY IN HEALTH OUTCOMES

EDUCATION IN BEHAVIORAL PEDIATRICS

RECORDS FOR ALCOHOL CARE ENHANCEMENT (RACE) - PROJECT SUMMARY UNHEALTHY ALCOHOL USE (THE SPECTRUM FROM RISKY CONSUMPTION THROUGH ALCOHOL USE DISORDER, AUD) IS A LEADING CAUSE OF PREVENTABLE DEATH, AND ALCOHOL-RELATED HEALTH HARMS (E.G. AUD ITSELF, CIRRHOSIS) ARE INCREASING. MOST PEOPLE WITH UNHEALTHY USE RECEIVE NO EFFECTIVE INTERVENTIONS DESPITE THE HIGH FREQUENCY OF CONTACT WITH MEDICAL CARE. ELECTRONIC HEALTH RECORDS (EHRS) CAN BE LEVERAGED TO IMPROVE THE IDENTIFICATION AND EFFECTIVE TREATMENT OF AUD. SOME INTEGRATED HEALTH SYSTEMS HAVE LEVERAGED EHRS BUT EXAMPLES NOT SUPPORTED BY SUCH SUBSTANTIAL INFRASTRUCTURE ARE UNCOMMON, AND THE FULL POTENTIAL TO MANAGE POPULATIONS IN ACCOUNTABLE CARE ORGANIZATIONS BEYOND SCREENING AND BRIEF PREVENTIVE COUNSELING HAS NOT BEEN REALIZED. THIS RESEARCH IS AIMED AT IMPROVING SERVICES FOR AUD BY USING EHRS TO SUPPORT INDIVIDUAL CARE AND POPULATION HEALTH MANAGEMENT IN URBAN PRIMARY CARE BASED AT A HOSPITAL WITH AN ACCOUNTABLE CARE ORGANIZATION (ACO) IN A DIVERSE UNDERSERVED COMMUNITY. THE OVER-ARCHING GOAL OF THE PROPOSED PROJECT (RACE-RECORDS FOR ALCOHOL CARE ENHANCEMENT) IS TO USE DATA ALREADY BEING COLLECTED IN ROUTINE CLINICAL PRACTICE IN EHRS TO IMPROVE CLINICAL IDENTIFICATION AND MANAGEMENT OF PEOPLE WITH AUDS. TO ACHIEVE THAT GOAL WE WILL, IN THE FIRST PHASE OF THIS PROJECT, 1) CREATE A CLINICALLY USEFUL LIVE DATABASE OF PATIENTS WITH UNHEALTHY ALCOHOL USE AND IMPLEMENT PROMPTS AND DECISION SUPPORT (“BEST PRACTICE ADVISORY” OR ALERT, BPA) AND PRACTICE LEVEL MONITORING IN AN URBAN UNDERSERVED COMMUNITY ACO, 2) ACCESS AND AUTOMATE LINKAGE OF INPATIENT AND OUTPATIENT (INCLUDING EMERGENCY DEPARTMENT VISIT) EHR DATA AND PRIMARY CARE IN-PERSON-COLLECTED ALCOHOL SCREENING DATA, 3) CREATE A USABLE REGISTRY OF PRIMARY CARE PATIENTS WITH ALCOHOL USE DISORDER FROM THE LINKED EHR AND SCREENING DATA, 4) ADAPT THE EHR TO CREATE A BEST PRACTICE ADVISORY TO ALERT CLINICIANS OF THEIR PATIENTS’ UNHEALTHY ALCOHOL USE AND PROVIDE GUIDANCE FOR CLINICAL ACTION, AND THEN 5) CREATE A DATA COLLECTION AND CAPTURE METHOD TO MONITOR AND REPORT ON ALCOHOL USE AND ALCOHOL CONSEQUENCE-RELATED HEALTHCARE VISITS FOR THE PANEL OF PATIENTS IN THE REGISTRY AT THE INDIVIDUAL AND PRACTICE LEVELS BEFORE AND AFTER IMPLEMENTATION OF THE EHR CHANGES. IN THE SECOND PHASE OF THE PROJECT, WE WILL TEST FEASIBILITY AND OBTAIN PRELIMINARY EFFECTIVENESS ESTIMATES IN A 4-ARM RANDOMIZED TRIAL COMPARING EHR 1) CLINICIAN PROMPTING AND DECISION SUPPORT BEST PRACTICE ADVISORY ALONE (BPA), 2) BPA PLUS POPULATION HEALTH MANAGEMENT (BPA+PHM), 3) BPA PLUS CLINICAL CARE MANAGEMENT (BPA+CCM) AND 4) ALL THREE (BPA+PHM+CCM), TO IMPROVE AUD CARE. WE HYPOTHESIZE THAT COMPARED TO BPA ALONE (ARM 1), PHM (ARM 2) AND CCM (ARM 3) SEPARATELY AND ALL 3 TOGETHER (ARM 4) WILL IMPROVE ENGAGEMENT (A NATIONAL QUALITY OF CARE MEASURE), RECEIPT OF AUD MEDICATION, AUD COUNSELING, AND SPECIALTY AUD CARE BY REFERRAL. THE STUDY WILL DEMONSTRATE THE FEASIBILITY OF LEVERAGING EHRS IN WIDESPREAD USE, AND WILL INFORM LIKELY EFFECTIVENESS FOR IMPROVING CARE THAT COULD LEAD TO BETTER CLINICAL OUTCOMES FROM LESS HEAVY DRINKING TO FEWER EMERGENCY DEPARTMENT VISITS FOR ALCOHOL-RELATED CARE, THEREBY REDUCING ALCOHOL-RELATED MORBIDITY AND MORTALITY IN THE US.

ORAL MACROPHAGE FUNCTION IN THE CONTEXT OF PERIODONTAL DISEASE AND HIV INFECTION

A UNIVERSAL PRIMARY CARE BASED INTERVENTION TO REDUCE YOUTH OVERDOSE RISK - PROJECT SUMMARY/ABSTRACT BETWEEN 2015 AND 2019, OVERDOSE DEATHS TRANSLATED TO 1.25 MILLION YEARS OF LIFE LOST AMONG ADOLESCENTS AND YOUNG ADULTS (“YOUTH”), AND THE PERCENT CHANGE IN FATAL OVERDOSE DEATH RATES AMONG ADOLESCENTS WAS HIGHER THAN ADULTS BETWEEN 2019 AND 2020. SIMILAR TO ADULTS, ILLICITLY MANUFACTURED FENTANYL (IMF) IS THE MAJOR DRIVER OF DRUG OVERDOSE DEATHS IN YOUTH. UNLIKE ADULTS, YOUTH ARE MORE COMMONLY EXPOSED TO IMF THROUGH COUNTERFEIT PILLS, AND SOME YOUTH ARE UNAWARE THAT THEY ARE USING A PILL THAT IS COUNTERFEIT AND THUS UNINTENTIONALLY EXPOSED TO IMF. UNFORTUNATELY, ANY YOUTH WHO USES A COUNTERFEIT PILL OR OTHER DRUG IS AT RISK FOR AN OVERDOSE, EVEN AFTER FIRST USE. THERE IS AN URGENT NEED FOR EVIDENCE-BASED OVERDOSE PREVENTION INTERVENTIONS FOR YOUTH. WITHIN THE HEALTHCARE SETTING, YOUTH PRIMARY CARE PROVIDERS ROUTINELY PROVIDE INJURY PREVENTION ANTICIPATORY GUIDANCE AS PART OF ANNUAL COMPREHENSIVE PHYSICAL EXAMS AND ARE WELL POSITIONED TO PROVIDE ANTICIPATORY GUIDANCE FOR OVERDOSE PREVENTION. THROUGH THIS R61/R33 MECHANISM WE PROPOSE TO DEVELOP AND EVALUATE THE EFFICACY OF AN UNIVERSAL OVERDOSE PREVENTION INTERVENTION THAT WILL INCREASE: (1) AWARENESS OF THE RISKS OF FENTANYL AND OTHER EMERGING DRUGS IN THE DRUG SUPPLY, (2) KNOWLEDGE OF STRATEGIES TO REDUCE OVERDOSE RISK, AND (3) RECOGNITION AND RESPONSE TO OVERDOSE. IN THE R61, IN COLLABORATION WITH OUR EXISTING YOUTH COMMUNITY ADVISORY BOARD, WE PROPOSED TO USE THE INFORMATIONAL-MOTIVATIONAL-BEHAVIORAL SKILLS MODEL TO DEVELOP AN OVERDOSE PREVENTION INTERVENTION TO BE DELIVERED IN PRIMARY CARE SETTING. WE WILL PILOT THE INTERVENTION IN TWO PRIMARY CARE SETTINGS AT BOSTON MEDICAL CENTER, PEDIATRIC PRIMARY CARE AND FAMILY MEDICINE, TO ASSESS ACCEPTABILITY AND FEASIBILITY FOR PROVIDERS AND YOUTH AGES 13 TO 26 YEARS WHO ARE BEING SEEN FOR AN ANNUAL COMPREHENSIVE PHYSICAL EXAM. WE WILL DO THIS THROUGH A PILOT TWO-ARM CLUSTER RANDOMIZED CONTROLLED TRIAL (RCT) THAT IS RANDOMIZED AT THE PROVIDER LEVEL. DURING THE PILOT TRIAL, WE WILL SHARE PRELIMINARY DATA WITH THE COMMUNITY ADVISORY BOARD TO INFORM ANY NEEDED ADAPTATIONS TO THE INTERVENTION. IF THE INTERVENTION IS ACCEPTABLE AND FEASIBLE TO PROVIDERS WE WILL TRANSITION TO EVALUATING THE INTERVENTION’S EFFICACY IN A LARGER RCT DURING THE R33. IN THE R33, WE WILL AGAIN CONDUCT A TWO-ARM CLUSTER RCT RANDOMIZED AT THE PROVIDER LEVEL USING THE SAME INCLUSION/EXCLUSION CRITERIA, PROCEDURES, AND STUDY MEASURES AS THE R61. YOUTH OUTCOMES WILL BE EVALUATED AT ONE-YEAR FOLLOW UP AND THE PRIMARY OUTCOME WILL BE YOUTH KNOWLEDGE OF THE RISK ASSOCIATED WITH FENTANYL AND OTHER EMERGING DRUGS IN THE DRUG SUPPLY. SECONDARY OUTCOMES WILL INCLUDE YOUTH KNOWLEDGE OF STRATEGIES TO REDUCE OVERDOSE RISK, RECOGNIZE AND RESPOND TO AN OVERDOSE. IF THE UNIVERSAL YOUTH OVERDOSE PREVENTION INTERVENTION IS EFFECTIVE THIS WILL BENEFIT YOUTH AND PUBLIC HEALTH GENERALLY AS YOUTH WILL BE BETTER PREPARED TO DECREASE THEIR RISK FOR OVERDOSE, AND RECOGNIZE AND RESPOND TO OTHERS WHO HAVE AN OVERDOSE.

RESEARCH GRANTS TO IDENTIFY EFFECTIVE STRATEGIES FOR OPIOID OVERDOSE PREVENTION

TARGETING PGC-1A FOR THE TREATMENT OF SICKLE CELL DISEASE - ABSTRACT SICKLE CELL DISEASE (SCD) AND -THALASSEMIA ARE GENETIC DISORDERS AFFECTING THE STRUCTURE OR PRODUCTION OF HEMOGLOBIN. THEY ARE GROWING GLOBAL HEALTH BURDEN AFFLICTING MILLIONS AROUND THE WORLD. SUFFICIENT FETAL HEMOGLOBIN (HBF) INDUCTION CAN REDUCE MORBIDITY AND MORTALITY IN SCD. THE SAME IS TRUE FOR -THALASSEMIA. THE STANDARD CURRENT THERAPY FOR HBF INDUCTION IN SCD HYDROXYUREA (HU) WHICH IN ADULTS, DOES NOT USUALLY AMELIORATE SUFFICIENTLY EITHER SICKLE VASO-OCCLUSION OR HEMOLYSIS. THEREFORE, THE SEARCH FOR MORE EFFECTIVE AND SAFER SMALL MOLECULE HBF INDUCERS IS A KEY UNMET NEED IN THE MANAGEMENT OF SCD. WE RECENTLY DISCOVERED THAT THE PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR-1 (PGC-1) IS INVOLVED IN THE REGULATION OF THE GLOBIN GENES. UPREGULATION OF PGC-1A BY LENTIVIRUS INFECTION OR BY A SMALL MOLECULE COMPOUND ZLN005 IN HUMAN PRIMARY ERYTHROID PROGENITOR CD34+ CELLS INDUCED HBF EXPRESSION AND INCREASED THE PERCENT OF F-CELLS WITHOUT AFFECTING CELL PROLIFERATION AND DIFFERENTIATION. ACTIVATION OF PGC-1A BY ZLN005 MIGHT PROVIDE A NEW PATH INTO HEMOGLOBIN REGULATION WITH A PROMISING THERAPEUTIC BENEFIT IN SCD. WE INTEND TO TEST FOR IN VIVO THERAPEUTIC EFFECTS OF ZLN005 IN SICKLE CELL MICE. THE FINDINGS FROM THESE PRECLINICAL STUDIES COULD PROVIDE INITIAL PROOF OF PRINCIPLE FOR DEVELOPING SAFER, MORE BENEFICIAL SMALL MOLECULE THERAPEUTICS FOR SCD TREATMENT AND LEAD TO EARLY- PHASE CLINICAL TRIALS.

A MEDICAL HOME-BASED INTERVENTION TO PREVENT CHILD NEGLECT IN HIGH-RISK FAMILIES

PEPTIDE ACTIVATORS OF DIPHTHERIA TOXIN REPRESSOR(DTXR)

PROJECT RECOVER (REFERRAL, ENGAGEMENT, CASE MANAGEMENT AND OVERDOSE PREVENTION EDUCATION IN RECOVERY)