Hennepin Healthcare Research Institute

ASPIRIN IN REDUCING EVENTS IN THE ELDERLY

ASPIRIN IN REDUCING EVENTS IN THE ELDERLY - EXTENSION

NORTHSTAR NODE OF THE CLINICAL TRIALS NETWORK

HYPERBARIC OXYGEN BRAIN INJURY TREATMENT (HOBIT) TRIAL - CCC

VACCINES FOR PRESCRIPTION OPIOID AND HEROIN ABUSE

ASPIRIN IN REDUCING EVENTS IN THE ELDERLY

EARLY INTERVENTION SERVICES

SEX-SPECIFIC RISK FACTORS AND TRAJECTORIES OF BLOOD BIOMARKERS FOR ALZHEIMER'S DISEASE AND RELATED DEMENTIAS - PROJECT SUMMARY / ABSTRACT LATE-LIFE ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) ARE DEVASTATING MULTIFACTORIAL CONDITIONS AND THE MAJOR CONTRIBUTORS TO LOSS OF INDEPENDENCE IN OLDER AGE. THERE IS A CRITICAL UNMET NEED TO IDENTIFY WHICH INDIVIDUALS ARE AT THE GREAT RISK OF THESE CONDITIONS, THUS PERMITTING ACCURATE PROGNOSIS AND TIMELY PREVENTATIVE INTERVENTIONS TO REDUCE THE BURDEN. YET, WHILE A NUMBER OF RISK FACTORS HAVE BEEN IDENTIFIED FOR THESE CONDITIONS, SEX DIFFERENCES IN THESE ASSOCIATIONS HAVE RARELY BEEN CONSIDERED. FURTHERMORE, EXCITING RECENT ADVANCES IN BLOOD AMYLOID, TAU AND NEURODEGENERATION (AT(N)) BIOMARKERS FOR ADRD MEANS THAT THEY COULD SOON BE USED AS POWERFUL CLINICAL DIAGNOSTIC AND PROGNOSTIC TOOLS IN A PERSONALIZED MEDICINE APPROACH. HOWEVER, A NUMBER OF CRITICAL KNOWLEDGE GAPS REMAIN. IMPORTANTLY, 1) THESE BIOMARKERS HAVE NOT BEEN SUFFICIENTLY EXAMINED IN LONGITUDINAL STUDIES OF OLDER COMMUNITY- BASED POPULATIONS WITHOUT DIAGNOSED DEMENTIA; 2) IT IS UNCLEAR HOW PARTICIPANT CHARACTERISTICS SUCH AS COMORBIDITIES AFFECT THE CLINICAL INTERPRETATION OF THESE BIOMARKERS; AND 3) HOW THEIR INTERPRETATION MAY DIFFER BETWEEN MEN AND WOMEN. TOGETHER, THESE LARGE KNOWLEDGE GAPS HIGHLIGHT A CRUCIAL NEED TO DEVELOP THE FIRST SEX-SPECIFIC RISK SCORE FOR ADRD THAT INCORPORATES BLOOD AT(N) BIOMARKERS AND ADRD RISK FACTORS. OUR OVERARCHING HYPOTHESIS IS THAT AT(N) PLASMA BIOMARKERS WILL BE PREDICTIVE OF ADRD IN INITIALLY HEALTHY COMMUNITY-DWELLING OLDER INDIVIDUALS, BEYOND KNOWN RISK FACTORS (INCLUDING AGE, EDUCATION, LIVING ALONE, DIABETES, HYPERTENSION, SMOKING, ALCOHOL CONSUMPTION, PHYSICAL ACTIVITY), AND THAT THESE ASSOCIATIONS WILL VARY BY SEX. THIS PROJECT PROVIDES AN UNPRECEDENTED OPPORTUNITY TO ADDRESS THIS IMPORTANT QUESTION WITHIN THE CONTEXT OF A RIGOROUS, LARGE-SCALE STUDY OF INITIALLY HEALTHY INDIVIDUALS AGED 65-98 YEARS FROM THE US AND AUSTRALIA (12,716 WHITES, 412 BLACKS, 339 OTHER MINORITIES) WITH COMPREHENSIVE ANNUAL IN-PERSON COGNITIVE ASSESSMENTS, ADJUDICATED CLINICAL OUTCOMES, DETAILED DATA ON SOCIO-ECONOMIC STATUS, LIFESTYLE AND HEALTH FACTORS COLLECTED OVER A MEDIAN 9+ YEARS, AND EXISTING GENETIC DATA (APOE4, DEMENTIA POLYGENIC RISK SCORES). LEVERAGING UNIQUE BLOOD SAMPLES AVAILABLE AT TWO TIME-POINTS (N=13,435 AT BASELINE, AND ~8000 AT 7 TO 10 YEARS), AT(N) BIOMARKERS WILL BE MEASURED LONGITUDINALLY. THIS PROPOSAL IS A UNIQUE, HIGHLY COST-EFFICIENT OPPORTUNITY TO ADDRESS GAPS IN OUR ABILITY TO ACCURATELY DETERMINE WHO IS AT THE GREATEST RISK OF ADRD, INDIVIDUALLY FOR WOMEN AND MEN. WE WILL ADDRESS CRITICAL GAPS IN IDENTIFYING WHICH FACTORS INFLUENCE BLOOD BIOMARKER LEVELS AND MUST BE CONSIDERED WHEN ESTABLISHING THEIR CLINICAL REFERENCE RANGES. THE SEX-SPECIFIC RISK SCORE RESULTING FROM THIS PROJECT WILL PROVIDE A POWERFUL NEW TOOL FOR PRACTITIONERS TO PREDICT RISK OF COGNITIVE DECLINE AND ADRD THAT CONSIDERS COMMON COMORBIDITIES, SOCIAL, LIFESTYLE, AND GENOMIC RISK FACTORS, TOGETHER WITH THE UNIQUE PREDICTIVE STRENGTH OF THE PLASMA AT(N) BIOMARKERS.

COMPARATIVE NEUROBEHAVIORAL PHARMACOLOGY OF COMBUSTED AND NON-COMBUSTED TOBACCO PRODUCTS

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

THE NATURAL HISTORY OF COGNITIVE DECLINE IN CHRONIC KIDNEY DISEASE: RENAL, VASCULAR AND ALZHEIMER'S DISEASE CONTRIBUTIONS

EVALUATION OF THE DIAGNOSTIC AND THERAPEUTIC VALUE OF TISSUE ULTRAFILTRATION IN PATIENTS AT RISK OF ACUTE COMPARTMENT SYNDROME (ACS). NEW AWARD.

SECONDARY PREVENTION FOLLOWING ACUTE CORONARY SYNDROME USING INTEGRATED SMOKING CESSATION AND MOOD MANAGEMENT

PRECLINICAL STUDIES OF A HEROIN/MORPHINE VACCINE FOR OPIATE ADDICTION

IMMUNIZATION TO BLOCK THE EFFECTS OF NICOTINE

STROKE AND COGNITIVE IMPAIRMENT IN AGING CHRONIC KIDNEY DISEASE PATIENTS

TREATMENT TO REDUCE INFLAMMATION AND IMPROVE IMMUNE RECOVERY AMONG OLDER HIV PTS

TARGETED ANTICOAGULANT THERAPY TO REDUCE INFLAMMATION IN TREATED HIV DISEASE

MULTIVALENT VACCINE FOR OPIATE ADDICTION

CLINICAL AND IMMUNOLOGIC FACTORS UNDERLYING HEART FAILURE WITH PRESERVED EJECTION FRACTION AMONG PERSONS WITH HIV IN SOUTH AFRICA - PREMISE: HIV ASSOCIATED CVD IS A SIGNIFICANT CAUSE OF CLINICAL MORBIDITY AND A BARRIER TO SUCCESSFUL AGING AMONG PERSONS LIVING WITH HIV (PWH). TO DATE, HIV-CVD RESEARCH HAS EMPHASIZED ISCHEMIC CORONARY HEART DISEASE. HOWEVER, NEARLY 80% OF THE GLOBAL CVD BURDEN EXISTS IN DEVELOPING NATIONS AND 70% OF THE HIV EPIDEMIC EXISTS IN SUB-SAHARAN AFRICA (SSA) WHERE HEART FAILURE (HF) IS THE PREDOMINANT CVD MANIFESTATION. DATA FROM HIGH INCOME COUNTRIES (HIC) HAS ESTABLISHED THAT CHRONIC HIV DISEASE CONTRIBUTES TO INCREASED RISK FOR VENTRICULAR DYSFUNCTION AND CLINICAL HF. WE HAVE SHOWN THAT ASYMPTOMATIC PWH IN SOUTH AFRICA (SA) HAVE GREATER DIFFUSE MYOCARDIAL FIBROSIS BY CMR, WHEN COMPARED TO UNINFECTED CONTROLS, REPRESENTING STRUCTURAL CHANGES THAT MAY INCREASE RISK FOR HF WITH PRESERVED EJECTION FRACTION (HFPEF). THESE FINDINGS SUPPORT OUR HYPOTHESIS THAT RISK FOR HF WILL BE INCREASED AMONG PWH TAKING ART IN SA, AND WILL MANIFEST PREDOMINANTLY AS HFPEF. UNIFYING MECHANISTIC FEATURES OF HFPEF HAVE BEEN PROPOSED BUT THE PATHOGENESIS IS HEAVILY INFLUENCED BY THE PRESENCE OF CO-MORBID END-ORGAN DISEASES. THIS HAS MOTIVATED ATTEMPTS TO CHARACTERIZE CLINICAL `PHENOGROUPS' OF HFPEF BASED ON THE PROFILE OF COMORBID CONDITIONS. WHEN COMPARED TO HICS, THE RELATIVE FREQUENCIES OF CO-MORBID CONDITIONS (E.G., OBESITY, HYPERTENSION) AND OTHER RISK FACTORS (E.G., MTB, SUBSTANCE USE) DIFFERS IN LOW-TO-MIDDLE INCOME COUNTRIES LIKE SA. THE UNIQUE RISK FACTOR PROFILES OF PWH IN SA WILL THEN RESULT IN DISTINCT HFPEF PHENOGROUPS AND CHANGES TO UNDERLYING CARDIAC STRUCTURE. APPROACH: WE PROPOSE TO ENROLL PWH AND UNINFECTED CONTROLS, UTILIZE ECHOCARDIOGRAPHY TO ADJUDICATE HF SUBGROUPS, AND THEN IDENTIFY A COHORT OF PWH WITH HFPEF TO STUDY CLINICAL AND BIOLOGIC FACTORS IN GREATER DETAIL. THE TARGET POPULATION INCLUDES PATIENTS LIVING IN KHAYELITSHA TOWNSHIP, OUTSIDE OF CAPE TOWN, SA, WHO ARE AGE =40 YEARS AND ON ART WITH VIRAL SUPPRESSION (IF LIVING WITH HIV). STANDARDIZED CLINICAL ECHOCARDIOGRAM (ECHO) WILL BE USED TO ADJUDICATE HF STATUS AND CARDIAC MAGNETIC RESONANCE (CMR) WILL BE USED TO CHARACTERIZE THE INJURY PATTERN OF CARDIAC FIBROSIS AMONG THOSE WITH HF. OUR PROPOSAL INCLUDES FOLLOWING SPECIFIC AIMS: AIM 1: ESTIMATE THE PREVALENCE OF HF DUE TO VENTRICULAR DYSFUNCTION IN SA, AS WELL AS THE EFFECT OF TREATED-HIV. AIM 2: DETERMINE THE CLINICAL PHENOGROUP(S) THAT DEFINE HFPEF AMONG PWH ON ART, AGE =40, IN SA. AIM 3: EXPLORE IMMUNOLOGIC FACTORS THAT MAY CONTRIBUTE TO MYOCARDIAL FIBROSIS AND HFPEF RISK IN PWH. RESEARCH AND HEALTH IMPLICATIONS: THIS PROPOSAL TARGETS A LARGE UNMET NEED IN THE HIV-CVD FIELD. HIV ASSOCIATED HF IS A CLINICALLY SIGNIFICANT CHALLENGE, AND DATA FROM HIC DO NOT ADEQUATELY REPRESENT LMIC LIKE SA. IN ADDITION, HFPEF CAN RESULT FROM HETEROGENEOUS PATHOLOGIES, AND HIV DISEASE MAY INFLUENCE HFPEF RISK THROUGH MULTIPLE PATHWAYS DEPENDING ON UNDERLYING RISK. OUR PROPOSAL WILL DETERMINE THE BURDEN OF HFPEF AMONG PWH, DEVELOP POC APPROACHES FOR IDENTIFYING THOSE AT RISK, AND IDENTIFY CLINICAL AND BIOLOGIC FEATURES THAT MAY BE TARGETED IN HIV-CVD CLINICAL TRIALS WITHIN A GLOBAL REGION WHERE MOST OF THE HIV EPIDEMIC RESIDES.

EFFECTIVENESS OF NICOTINE REPLACEMENT THERAPY SAMPLING IN DENTAL PRACTICES - CIGARETTE SMOKING HAS PROFOUND NEGATIVE EFFECTS ON ORAL HEALTH. SMOKING CESSATION DECREASES THE INCIDENCE AND PROGRESSION OF ORAL HEALTH PROBLEMS. MOST SMOKERS ATTEMPT TO QUIT, BUT THE MAJORITY OF QUIT ATTEMPTS ARE UNAIDED BY SMOKING CESSATION MEDICATIONS AND END IN RELAPSE. THE AMERICAN DENTAL HYGIENISTS ASSOCIATION RECOMMENDS THAT ALL ORAL HEALTH PROFESSIONALS ASK PATIENTS IF THEY SMOKE, ADVISE SMOKERS TO QUIT, AND REFER SMOKERS TO QUITLINES FOR COUNSELING (ASK-ADVISE-REFER; AAR). AAR CONNECTS PATIENTS DIRECTLY TO COUNSELING BUT NOT TO MEDICATION, WHICH CAN DOUBLE CESSATION RATES INDEPENDENT OF COUNSELING. INDEED, FEW DENTISTS PRESCRIBE CESSATION MEDICATIONS. FAILURE TO CONNECT SMOKERS TO MEDICATION IS A CRITICAL MISSED OPPORTUNITY TO PREVENT DISEASE AND SAVE LIVES. NICOTINE REPLACEMENT THERAPY SAMPLING (NRTS) REFERS TO PROVIDING ALL SMOKERS, REGARDLESS OF CURRENT INTEREST IN QUITTING, WITH FREE SAMPLES OF OVER-THE-COUNTER NRT PRODUCTS AND BRIEF USE INSTRUCTIONS. NRTS HAS BEEN SHOWN TO INCREASE QUIT ATTEMPTS AND SMOKING ABSTINENCE RATES. DENTAL SETTINGS ARE AN IDEAL FIT FOR NRTS BECAUSE NRTS COULD EASILY BE COMBINED WITH AAR AND PROVIDING SAMPLES OF ORAL CARE PRODUCTS IS ROUTINE AND UNIVERSAL IN DENTAL CARE SETTINGS. THE PROPOSED UG3/UH3 PROJECT WILL TEST THE EFFECTIVENESS OF NRTS IN DENTAL PRACTICES. IN THE 2-YEAR CLINICAL TRIAL PLANNING PHASE (UG3), WE WILL COMPLETE ALL REQUIRED MILESTONES TO ESTABLISH FEASIBILITY AND ACCEPTABILITY OF STUDY PROTOCOLS AND PREPARE FOR THE 3-YEAR CLINICAL TRIAL IMPLEMENTATION PHASE (UH3). UG3 ACTIVITIES WILL INCLUDE STAKEHOLDER INTERVIEWS TO EVALUATE INITIAL ACCEPTABILITY AND FEASIBILITY OF PROPOSED STUDY INTERVENTIONS AND PROCEDURES, PILOT TESTING, PROTOCOL REFINEMENT, AND RECRUITMENT OF PRACTITIONERS FOR THE UH3 TRIAL. IN THE UH3 TRIAL, WE PROPOSE TO CONDUCT A CLUSTER RANDOMIZED, HYBRID TYPE 1 IMPLEMENTATION-EFFECTIVENESS TRIAL COMPARING AAR + NRTS (NRTS) TO ENHANCED USUAL CARE (ET; AAR + ELECTRIC TOOTHBRUSH; N = 50 PRACTITIONERS, LIMITED TO 1 PER PRACTICE; N = 1200 PATIENTS) RECRUITED FROM THE NORTHEAST AND MIDWEST REGIONS OF THE NATIONAL DENTAL PRACTICE-BASED RESEARCH NETWORK. STUDY INTERVENTIONS WILL BE DELIVERED WITHIN THE PRACTICES BY TRAINED PRACTICE STAFF. OUR CENTRAL HYPOTHESIS IS THAT NRTS WILL PRODUCE GREATER ABSTINENCE RATES THAN ET. OUR PRIMARY OUTCOME WILL BE BIOLOGICALLY VERIFIED, 7-DAY POINT PREVALENCE ABSTINENCE AT 6-MONTHS POST-INTERVENTION. WE ALSO PREDICT THAT COMPARED TO ET, NRTS WILL INCREASE RATES OF QUIT ATTEMPTS, REDUCE SMOKING HEAVINESS, AND INCREASE NRT UTILIZATION. WE WILL CONDUCT A MULTI-STAKEHOLDER PROCESS EVALUATION OF THE FEASIBILITY AND ACCEPTABILITY OF THE NRTS INTERVENTION AND A COST-EFFECTIVENESS ANALYSIS TO AID FUTURE IMPLEMENTATION EFFORTS. OVERALL, WE EXPECT THAT, AS A RESULT OF THIS PROJECT, WE WILL ESTABLISH THE FEASIBILITY, ACCEPTABILITY, AND EFFECTIVENESS OF NRTS IN DENTAL PRACTICES AND DETERMINE THAT NRTS HAS HIGH POTENTIAL FOR TRANSLATION TO CLINICAL PRACTICE.

FROSTBITE MULTICENTER OBSERVATIONAL TRIAL (FROST)

POPULATION PHARMACOKINETICS: METHADONE-ANTIRETROVIRAL INTERACTIONS IN VIETNAM

PREDICTORS AND OUTCOMES OF FRAILTY IN DIALYSIS PATIENTS

THE HEMODIALYSIS OPIOID PRESCRIPTION EFFORT CONSORTIUM

DETERMINANTS OF NICOTINE REINFORCEMENT THRESHOLDS AND DEMAND ELASTICITY IN RATS

FAILURE MECHANISMS OF JOINT REPLACEMENT

TARGETED TOBACCO REGULATORY SCIENCE: NICOTINE DOSE EFFECTS IN ANIMAL MODELS OF SMOKING INITIATION IN VULNERABLE ADOLESCENT SUBPOPULATIONS

EFFECTS OF MATERNAL E-CIGARETTE AEROSOL EXPOSURE ON NICOTINE'S ADDICTION-RELATED BEHAVIORAL AND NEUROBIOLOGICAL EFFECTS IN OFFSPRING - SUMMARY/ABSTRACT THE GOAL OF THIS PROJECT IS TO USE ANIMAL MODELS TO UNDERSTAND HOW MATERNAL EXPOSURE TO ELECTRONIC NICOTINE DELIVERY SYSTEM (ENDS) AEROSOLS DURING PREGNANCY ADVERSELY IMPACTS ADDICTION-RELATED BEHAVIORS AND REINFORCEMENT-RELATED NEUROCIRCUITRY IN OFFSPRING. AN INCREASING NUMBER (UP TO 15%) OF PREGNANT WOMEN ARE USING ENDS, EXPOSING SEVERAL HUNDRED THOUSAND FETUSES PER YEAR IN THE U.S. ALONE. COMBUSTIBLE CIGARETTES HAVE LONG-TERM DEVELOPMENTAL CONSEQUENCES IN OFFSPRING INCLUDING INCREASED RISK OF IMPULSIVITY-RELATED DISORDERS SUCH AS ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD) AND ADDICTION TO TOBACCO. THESE ADVERSE EFFECTS ARE GENERALLY ATTRIBUTABLE TO NICOTINE, BUT OTHER TOXICANTS IN TOBACCO SMOKE MAY ALSO PLAY A ROLE. ALTHOUGH ENDS CONTAIN LOWER LEVELS OF MANY OF THOSE TOXICANTS, ENDS CAN DELIVER AS MUCH OR MORE NICOTINE AS COMBUSTIBLE CIGARETTES, AND CONTAIN ADDITIONAL CHEMICALS (E.G., PROPYLENE GLYCOL, ETHANOL, UNIQUE FLAVORANTS, TOXIC BYPRODUCTS) THAT ARE NOT PRESENT IN TOBACCO OR TOBACCO SMOKE. THUS, ENDS USE MAY POSE NOT ONLY MANY OF THE SAME RISKS TO PREGNANT WOMEN AND THEIR CHILDREN AS SMOKING, BUT UNIQUE RISKS AS WELL. THESE ISSUES HAVE RECEIVED ONLY LIMITED ATTENTION, LEAVING THE ADVERSE EFFECTS OF ENDS USE DURING PREGNANCY LARGELY UNKNOWN. RESEARCH TO DATE SHOWS THAT PRENATAL ENDS EXPOSURE IN RODENTS HAS ADVERSE EFFECTS ON SEVERAL BEHAVIORAL AND GENETIC OUTCOMES IN OFFSPRING THAT ARE ATTRIBUTABLE TO NICOTINE AND/OR NON-NICOTINE CONSTITUENTS IN ENDS. HOWEVER, NO STUDIES HAVE EXAMINED OTHER POTENTIAL ADVERSE OUTCOMES, SUCH AS INCREASED IMPULSIVITY OR ABUSE LIABILITY OF NICOTINE AND ASSOCIATED ADAPTATIONS IN REINFORCEMENT-RELATED CIRCUITRY. TO ADDRESS THIS ISSUE, THIS PROJECT WILL EXAMINE THE EFFECTS OF MATERNAL INHALATIONAL EXPOSURE TO COMMERCIAL ENDS AEROSOLS (FRUIT- AND TOBACCO-FLAVOR) ON THESE OUTCOMES IN RAT OFFSPRING. ENDPOINTS WILL INCLUDE MEASURES OF IMPULSIVE ACTION AND IMPULSIVE CHOICE (AIM 1), NICOTINE ABUSE LIABILITY IN NICOTINE SELF-ADMINISTRATION MODELS (AIM 2), AND FUNCTION OF REINFORCEMENT-RELATED NEUROCIRCUITRY FOLLOWING ACUTE OR CHRONIC NICOTINE IN INTRACRANIAL SELF-STIMULATION MODELS (AIM 3). CELL-SPECIFIC CHANGES IN GENE EXPRESSION AND CHROMATIN ACCESSIBILITY, AS WELL AS DEGREE OF NACHR UPREGULATION, IN KEY REINFORCEMENT-RELATED MESOCORTICOLIMBIC AREAS (NAC, PFC), WILL ALSO BE ANALYZED TO EXAMINE POTENTIAL NEUROBIOLOGICAL MECHANISMS MEDIATING BEHAVIORAL EFFECTS IN THESE AND OTHER STUDIES AND GENERATE HYPOTHESES FOR FUTURE STUDIES (AIM 4). INCLUSION OF NICOTINE-FREE ENDS AEROSOL AND AEROSOLIZED NICOTINE ALONE WILL ALLOW US TO ASSESS THE RELATIVE CONTRIBUTION OF NICOTINE VERSUS OTHER CONSTITUENTS IN THE EFFECTS OF NICOTINE-CONTAINING ENDS AEROSOL. GIVEN THE ABILITY OF CERTAIN NON-NICOTINE CONSTITUENTS IN ENDS AEROSOL TO ENHANCE THE EFFECTS OF NICOTINE OR PRODUCE ADVERSE PRENATAL EFFECTS OF THEIR OWN, OUR OVERALL HYPOTHESIS IS THAT PRENATAL EXPOSURE TO NICOTINE- CONTAINING ENDS AEROSOL WILL PRODUCE GREATER ADVERSE EFFECTS THAN THE OTHER EXPOSURE CONDITIONS. FINDINGS WILL PROVIDE NEW INFORMATION TO THE PUBLIC AND THE FDA ON THE POTENTIAL RISKS OF ENDS USE DURING PREGNANCY AND SUGGEST NEURAL MECHANISMS OF INTEREST FOR FUTURE PRECLINICAL STUDIES AND BRAIN IMAGING STUDIES IN HUMANS.

VACCINE IMMUNITY AND INFLAMMATION IN THE AGING PERSON LIVING WITH HIV - PERSONS LIVING WITH HIV (PLWH) ARE AT INCREASED RISK OF CHRONIC INFLAMMATION AND THE ASSOCIATED ADVERSE HEALTH OUTCOMES. THERE IS CONSIDERABLE EVIDENCE THAT CHRONIC INFLAMMATORY CONDITIONS LIKE METABOLIC DISEASE AND AUTOIMMUNE DISORDERS ARE ASSOCIATED WITH WEAKENED VACCINE RESPONSES AND EXISTING VACCINE STUDIES IN PLWH DO NOT ADEQUATELY SAMPLE OLDER INDIVIDUALS WHO ARE DISPROPORTIONATELY AFFECTED BY THIS “INFLAMMAGING.” WE HYPOTHESIZE THE EFFECT OF AGE ON POOR VACCINE RESPONSES IS GREATER AMONG PLWH GIVEN THE ADDITIONAL BURDENS OF HIV DRIVEN INFLAMMATION. THE OVERALL PROJECT GOAL IS TO EXAMINE THIS PREMISE BY MEASURING THE IMPACT OF HIV STATUS, AGE, AND CHRONIC IMMUNE ACTIVATION ON CONJUGATE PNEUMOCOCCAL VACCINE RESPONSES. WE WILL STUDY ACUTE (30 DAY) AND LONGER-TERM (2 YEAR) IMMUNE RESPONSES FOLLOWING PCV20 VACCINATION, AMONG A COHORT OF PARTICIPANTS INCLUDING 4 GROUPS: A) OLDER PLWH, AGE ≥50 (N=100), B) OLDER HIV UNINFECTED CONTROLS, AGE ≥50 (N=50), C) YOUNGER PLWH, AGE <50 (N=50), D) YOUNGER HIV UNINFECTED CONTROLS, AGE <50 (N=50). WITH THESE COHORTS, WE WILL 1) COMPREHENSIVELY CHARACTERIZE THE IMPACT OF HIV AND AGE ON THE IMMUNOGENICITY OF CONJUGATE PNEUMOCOCCAL VACCINATION BY LONGITUDINALLY TRACKING ADAPTIVE VACCINE- SPECIFIC ANTIBODY, B CELL AND CD4 T CELL RESPONSES. WE WILL COMPARE THESE RESPONSES BY AGE AND HIV STATUS. WE WILL ALSO 2) DETERMINE THE INFLUENCE OF CHRONIC INFLAMMATION ON VACCINE-SPECIFIC IMMUNITY AMONG PLWH ACROSS THE ADULT LIFESPAN BY MEASURING THE ASSOCIATE BETWEEN VACCINE IMMUNITY AND BIOMARKERS OF CHRONIC INFLAMMATION. THIS PROJECT WILL PROVIDE VALUABLE KNOWLEDGE ON HOW HIV AND AGE INFLUENCE VACCINE IMMUNE RESPONSES WITH THE HOPE OF INFORMING VACCINE DEVELOPMENT AND SCHEDULE TO OPTIMIZE THE LONG-TERM HEALTH OF PERSONS LIVING WITH HIV.

PREVALENCE AND IMPACT OF FRAILTY AMONG DIALYSIS PATIENTS

ANIMAL MODELS TO INFORM FDA TOBACCO REGULATION: ASSESSING THE RELATIVE ABUSE LIABILITY OF DIFFERENT CLASSES OF TOBACCO PRODUCTS

CREATING A PATIENT-CENTERED REPORT CARD FOR SOLID ORGAN TRANSPLANT CANDIDATES

OVC FY09 SART CONFERENCE 2011

EFFECTIVENESS OF THE DIABETES HOMELESS MEDICATION SUPPORT (D-HOMES) PROGRAM ON DIABETES MANAGEMENT - PROJECT SUMMARY/ABSTRACT AMONG THE MILLIONS OF AMERICANS WHO EXPERIENCE HOMELESSNESS YEARLY, THOUSANDS DIE PREMATURELY FROM DIABETES. THEY DO SO AT A RATE THAT IS 3 TO 6 TIMES HIGHER THAN THE GENERAL POPULATION. THE FEDERAL DEFINITIONS OF HOMELESSNESS INCLUDE PEOPLE STAYING IN SHELTERS OR SUBSIDIZED HOUSING, SLEEPING OUTSIDE, OR “DOUBLED UP” IN SHARED HOUSING WITHOUT BEING NAMED ON THE LEASE. ALTHOUGH DIABETES PREVALENCE IS SIMILAR TO THEIR STABLY HOUSED PEERS, RATES OF GLYCEMIC CONTROL ARE LOWER AND OUTCOMES ARE WORSE AMONG THOSE LIVING WITH TYPE 2 DIABETES WHO HAVE EXPERIENCED HOMELESSNESS. OUR TEAM IDENTIFIED KEY INDIVIDUAL AND STRUCTURAL BARRIERS TO GLYCEMIC CONTROL FOR PEOPLE EXPERIENCING HOMELESSNESS INCLUDING MEDICATION ACCESS AND ADHERENCE, PSYCHOLOGICAL DISTRESS, AND COMPETING DEMANDS (E.G., SHELTER, SAFETY, AND FOOD). MEDICATION ADHERENCE IS A KEY MODIFIABLE HEALTH BEHAVIOR THAT CAN RAPIDLY IMPROVE GLYCEMIC CONTROL. USING THE ORBIT MODEL OF BEHAVIORAL TREATMENT DEVELOPMENT, OUR RESEARCH TEAM (INCLUDING PEOPLE WITH RELEVANT LIVED EXPERIENCE) HAS DEVELOPED AND PILOT TESTED THE DIABETES HOMELESS MEDICATION SUPPORT (D-HOMES) PROGRAM, A TAILORED PROGRAM OF BEHAVIORAL SUPPORT FOR ENGLISH AND SPANISH-SPEAKING PEOPLE LIVING WITH TYPE 2 DIABETES WHO HAVE EXPERIENCED HOMELESSNESS. D-HOMES OFFERS UP TO 10 ONE-ON-ONE SESSIONS WEEKLY OVER 3 MONTHS WITH A HEALTH COACH USING BEHAVIORAL ACTIVATION TO IMPROVE DIABETES MEDICATION ADHERENCE AND PSYCHOLOGICAL WELLNESS. COACHES ALSO REFER PARTICIPANTS TO LOCAL HOUSING, FOOD, BEHAVIORAL HEALTH, AND RELATED RESOURCES. OUR TEAM’S LONG-TERM GOAL IS TO REDUCE PREMATURE DIABETES-RELATED MORTALITY AMONG PEOPLE WHO HAVE EXPERIENCED HOMELESSNESS. IN THIS STUDY WE NOW PROPOSE THE NEXT STEP OF THE ORBIT MODEL, A TYPE 1 HYBRID EFFECTIVENESS/IMPLEMENTATION RANDOMIZED TRIAL FULLY POWERED ON GLYCEMIC CONTROL WITH 256 PARTICIPANTS. AIM 1 (PRIMARY OUTCOME) WILL TEST THE EFFECTIVENESS OF D-HOMES VS. ENHANCED USUAL CARE ([EUC], A SINGLE BRIEF DIABETES EDUCATIONAL SESSION) ON GLYCEMIC CONTROL AMONG ADULTS LIVING WITH TYPE 2 DIABETES WHO HAVE EXPERIENCED HOMELESSNESS. AIM 2 (SECONDARY OUTCOMES) WILL TEST THE EFFECTIVENESS OF D-HOMES VS. EUC ON LONG-TERM GLYCEMIC CONTROL, MEDICATION ADHERENCE, PSYCHOLOGICAL WELLNESS, AND DIABETES DISTRESS AND EXPLORE MODERATORS OF TREATMENT EFFECTIVENESS. AIM 3 WILL COMPLETE AN EQUITY-FOCUSED MIXED METHODS EVALUATION USING THE RE-AIM MODEL TO ASSESS THE IMPLEMENTATION-RELEVANT FEATURES OF D-HOMES (E.G., REACH, ADOPTION, IMPLEMENTATION) FOR FUTURE SCALABILITY. IF EFFECTIVE FOR IMPROVING GLYCEMIC CONTROL, D-HOMES COULD DIRECTLY IMPACT PUBLIC HEALTH THROUGH SCALING WITHIN THE HRSA-FUNDED NATIONAL NETWORK OF HEALTH CARE FOR THE HOMELESS PROGRAMS. FURTHERMORE, D- HOMES CAN INFORM ADAPTATION OF OTHER EVIDENCED-BASED PRACTICES TO MEET THE NEEDS OF OTHER POPULATIONS WITH ACCESS BARRIERS AND/OR OTHER CHRONIC HEALTH CONDITIONS AMONG PEOPLE WHO EXPERIENCE HOMELESSNESS.

IMPROVING MEDICATION ADHERENCE AMONG PEOPLE WITH DIABETES WHO ARE HOMELESS

MEMORY T FOLLICULAR HELPER CELL KINETICS AND LOCALIZATION DURING RECALL IMMUNE RESPONSES TO TETANUS VACCINATION

AN EVALUATION OF BETA-NICOTYRINE AS A POTENTIAL CONTRIBUTOR TO THE ABUSE LIABILITY OF E-CIGARETTES - PROJECT SUMMARY/ABSTRACT ADDICTION TO ENDS PRODUCTS IS A NEWLY EMERGING FORM OF NICOTINE ADDICTION. UNDERSTANDING THE PRODUCT CHARACTERISTICS AND THE HARMFUL AND POTENTIALLY HARMFUL CONSTITUENTS (HPHCS) THAT CONTRIBUTE TO ENDS ADDICTION IS VITAL FOR EFFECTIVE FDA CTP REGULATION. THIS HPHC LIST, HOWEVER, WAS LAST UPDATED IN 2012, JUST PRIOR TO THE RISE IN ENDS POPULARITY. SINCE TWO OF THE FIVE ADDICTION-RELATED HPHCS ARE TOBACCO-RELATED MINOR ALKALOIDS (E.G., NORNICOTINE), THEN IT SUGGESTS RESEARCH ON ENDS-SPECIFIC MINOR ALKALOIDS IS WARRANTED. ONE UNIQUELY PREVALENT MINOR ALKALOID IN ENDS IS SS-NICOTYRINE, WHICH IS FORMED BY AGING AND/OR AEROSOLIZING E-LIQUIDS AND CAN REACH 25% OF NICOTINE LEVELS WHEN VAPED. OUR PILOT WORK FOUND THAT SS-NICOTYRINE APPROXIMATELY DOUBLES THE HALF-LIFE OF NICOTINE AND THAT IT FUNCTIONS AS A NICOTINIC ACETYLCHOLINE RECEPTOR (NACHR) AGONIST WITH FUNCTIONAL EFFICACY AT A4SS2 NICOTINIC-ACHRS SIMILAR TO NORNICOTINE. GIVEN ITS A) ABUNDANCE IN ENDS AEROSOLS, B) SIMILARITIES TO NORNICOTINE, AND C) ABILITY TO INHIBIT NICOTINE METABOLISM, SS-NICOTYRINE MAY CONTRIBUTE TO THE ADDICTION-RELEVANT EFFECTS OF ENDS AND REPRESENT A NOVEL HPHC. IF WE FIND SS-NICOTYRINE HAS ABUSE LIABILITY OR INCREASES THE ABUSE LIABILITY OF NICOTINE, IT SUGGESTS THE CTP SHOULD CONSIDER IT A HPHC GIVEN THAT THE FDA CONSIDERS OTHER LESS PREVALENT MINOR ALKALOIDS AS HPHCS. THE PRESENT PROJECT WILL INITIALLY CHARACTERIZE THE PHARMACOKINETICS OF SS- NICOTYRINE AND ITS INTERACTION WITH NICOTINE METABOLISM, AND THEN SUBSEQUENTLY DETERMINE ITS EFFECTS IN FDA- RECOMMENDED ANIMAL MODELS OF ABUSE LIABILITY, INCLUDING DRUG DISCRIMINATION, INTRACRANIAL SELF-STIMULATION (ICSS) AND DRUG SELF-ADMINISTRATION. THIS PROJECT IS INNOVATIVE BECAUSE: 1) IT EXTENDS RESEARCH ON MINOR ALKALOIDS, A CLASS OF CONSTITUENTS THAT INCLUDES HPHCS WITH ESTABLISHED ABUSE LIABILITY, 2) IT WILL BE THE FIRST TO EXAMINE THE ABUSE LIABILITY OF SS-NICOTYRINE AND ITS ABILITY TO ALTER THE ABUSE LIABILITY OF NICOTINE, INCLUDING AT VAPING RELEVANT CONCENTRATIONS, AND 3) IT WILL BE THE FIRST TO CHARACTERIZE THE PK OF SS-NICOTYRINE AND HOW IT ALTERS NICOTINE PK. IN SO DOING, THIS PROJECT COULD ELUCIDATE NOVEL MECHANISMS MEDIATING ENDS ADDICTION AND TEST THE PROPOSED SS- NICOTYRINE HYPOTHESIS.

UNDERSTANDING STI AND HIV PREVENTION ADHERENCE AMONG KENYAN WOMEN

METHADONE POPULATION PHARMACOKINETICS: TREATMENT OUTCOME IN HMONG AND NON-HMONG

THE MINNESOTA HEART FAILURE CONSORTIUM: A REGIONAL CLINICAL CENTER

FACTORS ASSOCIATED WITH WARFARIN USE IN DIALYSIS PATIENTS W/ ATRIAL FIBRILLATION

CREATING HEALTHY WORKPLACES: IMPROVING OUTCOMES FOR PROVIDERS AND PATIENTS

VIRTUAL COACHING FOR POTENTIAL KIDNEY TRANSPLANT CANDIDATES AND THEIR SOCIAL SUPPORT NETWORKS - PROJECT SUMMARY / ABSTRACT KIDNEY TRANSPLANT COMPARED TO DIALYSIS DRAMATICALLY IMPROVES SURVIVAL AND QUALITY OF LIFE FOR PATIENTS WITH END STAGE KIDNEY DISEASE (ESKD), BUT OF THE ~500,000 PATIENTS WITH ESKD IN THE US ON DIALYSIS, LESS THAN 1/5 ARE LISTED FOR TRANSPLANT. DESPITE WIDESPREAD RECOGNITION OF THE NEED TO IMPROVE ACCESS TO TRANSPLANT, RATES OF WAITLISTING AND TRANSPLANT ARE SUBSTANTIALLY LOWER IN PATIENTS IN UNDERSERVED COMMUNITIES, INCLUDING INDIVIDUALS WITH LOW SOCIOECONOMIC STATUS AND THOSE IN UNDERREPRESENTED RACIAL/ETHNIC GROUPS. THE CURRENT SYSTEM FOR EDUCATING PATIENTS IS OVERWHELMING AND IS DESIGNED TO OPTIMIZE CLINICAL EFFICIENCY. POTENTIAL TRANSPLANT CANDIDATES MUST COMPLETE A LENGTHY EVALUATION PROCESS, OFTEN WITH ADDITIONAL APPOINTMENTS AND REQUIREMENTS DEPENDING ON COMORBIDITIES, WHILE ALSO MANAGING A SEVERE CHRONIC ILLNESS WITH HIGH TREATMENT BURDEN. THUS, IT IS NOT SURPRISING THAT A HIGH PROPORTION OF PATIENTS NEVER ACCESS THE WAITLIST OR LIVING DONOR TRANSPLANT, AND THAT THE SYSTEM INADVERTENTLY FAVORS PATIENTS WITH HIGH HEALTH LITERACY AND SOCIOECONOMIC STATUS. WHILE THE BARRIERS TO TRANSPLANT ARE COMPLEX, MODIFIABLE INDIVIDUAL-LEVEL BARRIERS CONTRIBUTE SIGNIFICANTLY TO LOW TRANSPLANT ACCESS. PRIOR RESEARCH SUPPORTS AN INTERVENTION PROVIDED TO BOTH PATIENTS AND THEIR SOCIAL SUPPORT NETWORKS (SN) BUT MANY EFFICACIOUS INTERVENTIONS ARE TOO RESOURCE INTENSIVE TO IMPLEMENT IN PRACTICE. THERE IS A CRITICAL NEED TO IDENTIFY FEASIBLE, EFFICACIOUS INTERVENTIONS SUPPORTING UNDERSERVED PATIENTS AND SNS TO IMPROVE ACCESS TO KIDNEY TRANSPLANT. THIS PROPOSAL SEEKS TO CONDUCT A PILOT RANDOMIZED CONTROLLED TRIAL (RCT) OF JOURNEY TO TRANSPLANT (JTT), A VIRTUAL COUNSELING SESSION WITH THE POTENTIAL CANDIDATE ALONG WITH THEIR SN VERSUS USUAL PRE- TRANSPLANT EDUCATION IN A SAFETY NET HOSPITAL SETTING (AIM 1). THE STUDY WILL EVALUATE THE EFFECT OF JTT ON INTENTION TO PURSUE TRANSPLANT AND ON THE DETERMINANTS OF BEHAVIORAL CHANGE THAT ARE IMPACTED BY THE INTERVENTION. IN ADDITION, THE PROPOSAL WILL ASSESS MULTISITE RCT IMPLEMENTATION OUTCOMES, INCLUDING ENROLLMENT RATES AND SURVEY COMPLETION RATES, AS WELL AS QUALITATIVE INTERVIEWS WITH PATIENTS AND PROVIDERS ON THE BARRIERS TO IMPLEMENTING THE PROTOCOL IN OTHER SAFETY NET HOSPITAL SETTINGS (AIM 2). THIS PROPOSAL IS IN RESPONSE TO PAS- 20-160: SMALL R01S FOR CLINICAL TRIALS TARGETING DISEASES WITHIN THE MISSION OF NIDDK, THAT DOES NOT REQUIRE PRELIMINARY EFFICACY DATA, AND WILL FACILITATE A FUTURE MULTISITE, FULLY POWERED RCT TO EVALUATE THE EFFECT OF JTT ON IMPROVING TRANSPLANT ACCESS IN UNDERSERVED POPULATIONS. THIS RESEARCH AGENDA IS AIMED AT TRANSFORMING THE PARADIGM OF PRE-TRANSPLANT COUNSELING, EMPOWERING UNDERSERVED PATIENTS AND THEIR SUPPORT NETWORKS TO IMPROVE CRITICAL LIFE-ALTERING DECISIONS SURROUNDING KIDNEY TRANSPLANTATION.

SHARED DECISION MAKING FOR KIDNEY TRANSPLANT CANDIDATES TO PLAN FOR AN ORGAN OFFER DECISION - PROJECT SUMMARY/ABSTRACT THE CURRENT PROCESS TO ALLOCATE KIDNEY DONOR ORGANS TO CANDIDATES WHO ARE WAITING FOR A TRANSPLANT RESULTS IN HIGH NUMBERS OF DISCARDED DONOR ORGANS, AN INCREASED COST AND BURDEN OF CARE, AND HIGH MORTALITY WHILE ON THE WAITING LIST. THIS SYSTEM IS CHARACTERIZED BY HIGH RATES OF OFFERS DECLINED BY EITHER CLINICIANS AT TRANSPLANT CENTERS OR PATIENTS. PATIENTS RECEIVE EDUCATION ABOUT DONOR OFFERS DURING THEIR TRANSPLANT EVALUATION, AND THIS EVALUATION IS KNOWN TO BE AN OVERWHELMING EXPERIENCE. PATIENTS WHO ARE ACCEPTED ONTO THE WAITLIST MAY THEN WAIT SEVERAL YEARS BEFORE RECEIVING A CALL ABOUT AN OFFER, WHICH MAY COME LATE AT NIGHT WHILE PATIENTS ARE SLEEPING AND REQUIRES A DECISION WITHIN 30 MINUTES. RETENTION OF EDUCATION FROM YEARS AGO IS LOW, AND PATIENTS WHO ARE OFFERED A DONOR WITH POTENTIAL RISK FACTORS, SUCH AS AN EXPOSURE TO INFECTIOUS DISEASE, MAY DECLINE THE OFFER DUE TO RISK AVERSION, ANXIETY, AND FEAR. PATIENTS ARE FREE TO DECLINE OFFERS WITHOUT PENALTY; HOWEVER, EVIDENCE CONSISTENTLY SHOWS THAT ACCEPTING AN OFFER PROVIDES A SURVIVAL BENEFIT IN NEARLY ALL CASES. AMONG CANDIDATES WHO HAVE RECEIVED AT LEAST ONE DONOR OFFER, OVER 30% OF PATIENTS DIE ON THE LIST AFTER OFFERS TO THEM ARE DECLINED. SHARED DECISION MAKING (SDM) IS A METHOD FOR HELPING PATIENTS THINK, TALK, AND FEEL THROUGH HOW TO HANDLE THE PATIENT’S UNIQUE SITUATION. SDM IS CONDUCTED IN CONVERSATIONS BETWEEN PATIENTS, FAMILY, AND CLINICIANS WITH THE PURPOSE OF DEVELOPING A MEDICALLY, PRACTICALLY, AND EMOTIONALLY DESIRABLE PLAN. OPTIMAL SDM SHOULD HELP PATIENTS DEVELOP A PLAN IN ADVANCE OF THE ACTUAL ORGAN OFFER, DURING THE PERIOD OF TIME PATIENTS ARE WAITING. THE STUDY WILL USE AN ONLINE TOOL, DONOR PLAN DONOR CALL (DPDC), WHICH IS COMPLETED BY PATIENTS AFTER BEING PLACED ON THE WAITING LIST BUT IN ADVANCE OF AN OFFER. THE ONLINE TOOL IS PREPARATION FOR A VIRTUAL OR IN- PERSON SDM SESSION WITH THEIR TRANSPLANT PROVIDER. THE DPDC TOOL WAS INFORMED BY BEHAVIOR CHANGE THEORY AND WAS DEVELOPED FOLLOWING A HUMAN-CENTERED DESIGN PROCESS OVER MULTIPLE ITERATIONS WITH USER FEEDBACK. THIS PATIENT-CENTERED TOOL WAS DEVELOPED USING A SYSTEMS APPROACH TO COMPLEMENT OTHER INTERVENTIONS TO SUPPORT OFFER DECISIONS MADE BY CLINICIANS. THE PROPOSED RESEARCH WILL PROVIDE PILOT DATA USING A RANDOMIZED TRIAL OF USUAL CARE COMPARED TO THE SDM INTERVENTION USING THE DPDC TOOL WITH PATIENTS AND PROVIDERS AT 2 SITES. THE PILOT RANDOMIZED TRIAL WILL DETERMINE THE IMPACT AND QUALITY OF SDM FOR PATIENTS TO PLAN FOR AN ORGAN OFFER (AIM 1). THE PRIMARY OUTCOME WILL BE WILLINGNESS TO ACCEPT DONOR ORGANS AT INCREASED RISK OF DISCARD. SECONDARY ANALYSES WILL INCLUDE CHANGES IN DECISIONAL CONFLICT, KNOWLEDGE, PATIENT HOPE AND DISTRESS, AND DURATION OF TIME SPENT MAKING A DECISION. THE STUDY WILL EVALUATE THE ACCEPTABILITY OF SDM WITH DPDC, BARRIERS TO ADOPTION OF THE INTERVENTION, AND OTHER LEADING INDICATIONS OF IMPLEMENTATION SUCCESS WITH PATIENTS AND PROVIDERS (AIM 2). THIS RESEARCH WILL ALLOW US TO REFINE THE INTERVENTION AND IMPLEMENTATION TO FACILITATE A FULLY POWERED MULTI-CENTER RANDOMIZED TRIAL. THIS PROPOSAL FILLS A CRITICAL NEED TO IMPROVE DONOR OFFER DECISIONS TO REDUCE PATIENT MORTALITY, THE NEGATIVE HEALTH EFFECTS FROM TIME ON DIALYSIS, AND DISCARDS OF VIABLE DONOR KIDNEYS.

GENETIC VARIANTS ASSOCIATED WITH TACROLIMUS METABOLISM IN KIDNEY TRANSPLANT RECIPIENTS

PLATELET ACTIVATION IN SEPTIC SHOCK

A CLINICAL DECISION SUPPORT TOOL TO UNDERSTAND THE SURVIVAL BENEFIT OF KIDNEY TRANSPLANTATION IN CANDIDATES WITH A HISTORY OF CANCER - PROJECT SUMMARY / ABSTRACT: SURVIVAL WITH END-STAGE KIDNEY DISEASE (ESKD) HAS IMPROVED IN THE LAST DECADE ALONGSIDE THE TREND OF AN AGING POPULATION WITH GREATER RISKS, INCLUDING CANCER. THEREFORE, OPTIMAL MANAGEMENT FOR PATIENTS WITH BOTH ESKD AND CANCER (AFFECTING AT LEAST 7% OF THE > 130,000 ANNUAL INCIDENT ESKD PATIENTS) IS OF INCREASING PUBLIC HEALTH IMPORTANCE. KIDNEY TRANSPLANTATION CONFERS SUBSTANTIAL SURVIVAL BENEFIT OVER DIALYSIS FOR PATIENTS WITH ESKD, BUT THE IMMUNOSUPPRESSION DOUBLES THE RISK OF CANCER COMPARED TO THE GENERAL POPULATION. NEPHROLOGISTS FACE A DILEMMA TO WHEN EVALUATING TRANSPLANT CANDIDATES WHO HAVE A PREVIOUS HISTORY OF CANCER, BECAUSE WHILE MOST ACTIVE MALIGNANCIES ARE CONSIDERED A CONTRAINDICATION TO TRANSPLANTATION DUE TO HIGH MORTALITY RISK, THE RECOMMENDED WAITING TIME TO TRANSPLANT FOR PATIENTS IN REMISSION IS BASED LARGELY ON EXPERT OPINION AND LOW-GRADE EVIDENCE. THE RESULTING UNCERTAINTY IN THE CONTEXT OF THE CURRENT ORGAN SHORTAGE MAKES PROVIDERS RELUCTANT TO TRANSPLANT KIDNEY PATIENTS WITH A HISTORY OF CANCER. YET, FOR MANY OF THESE PATIENTS, THE RISK OF DYING WHILE ON DIALYSIS LIKELY EXCEEDS THE RISK CONFERRED BY THEIR CANCER RECURRENCE. THERE ARE LITTLE DATA AVAILABLE TO TRANSPLANT CENTERS TO GUIDE DECISIONS ABOUT LISTING PATIENTS WITH KIDNEY FAILURE IN REMISSION FROM CANCER, AND NEPHROLOGISTS FACE A CRITICAL NEED TO BETTER SERVE PATIENTS WITH ESKD BY IMPROVING PREDICTIONS OF PRE- AND POST-TRANSPLANT OUTCOMES. THIS PROPOSAL WILL PROVIDE PERSONALIZED RISK ESTIMATES TO NEPHROLOGISTS IN A CLINICALLY USEFUL, PUBLICLY AVAILABLE FORMAT. MODELS WILL ESTIMATE THE “TIPPING POINT” FOR AN INDIVIDUAL, WHEN THE RISK OF WAITING LONGER FOR SURVEILLANCE EXCEEDS THE RISK OF IMMUNOSUPPRESSION. THESE ESTIMATES WILL BE COMMUNICATED IN A FREE, USER-FRIENDLY, ONLINE TOOL FOR USE BY TRANSPLANT PROGRAMS TO PRECISELY GUIDE DECISIONS ABOUT LISTING KIDNEY TRANSPLANT CANDIDATES WITH A HISTORY OF CANCER. MULTIPLE DATA SOURCES WITH BE USED TO ADDRESS POTENTIAL BIAS: THE UNITED STATES RENAL DATA SYSTEM (USRDS), TRANSPLANT CANCER MATCH (TCM) STUDY, AND US CANCER REGISTRIES. AIM 1 WILL ESTIMATE MORTALITY RISK IN WAITLISTED KIDNEY TRANSPLANT CANDIDATES WITH A HISTORY OF CANCER, COMPARING THOSE WHO ARE TRANSPLANTED VS. NOT YET TRANSPLANTED USING DATA FROM THE TCM STUDY. AIM 2 WILL ESTIMATE MORTALITY RISK IN ESKD PATIENTS WITH A HISTORY OF CANCER WHO ARE NOT YET LISTED FOR TRANSPLANT, COMPARED TO PATIENTS IN THE TCM STUDY WHO WERE TRANSPLANTED, USING A NOVEL LINKAGE BETWEEN THE USRDS DATABASE AND US CANCER REGISTRIES. AIM 3 WILL DEVELOP A CLINICIAN DECISION SUPPORT WEBSITE THAT INCORPORATES THE MORTALITY ESTIMATES DEVELOPED IN AIMS 1 AND 2 INTO A FREE USER-FRIENDLY, ONLINE INTERFACE FOR NEPHROLOGISTS TO USE IN TRANSPLANT CANDIDATE WAITLISTING DECISIONS. THIS PROPOSAL FILLS AN IMMEDIATE NEED TO INFORM DECISIONS THAT BALANCE THE RISK OF DEATH ON DIALYSIS WITH THE RISK OF CANCER RECURRENCE AFTER TRANSPLANT. THE NOVEL DATABASE LINKAGE ALSO CREATES WIDE-RANGING POTENTIAL FOR FUTURE INVESTIGATIONS INTO THE ASSOCIATION BETWEEN ESKD AND CANCER. THUS, THIS PROPOSAL ALIGNS WELL WITH THE NIDDK MISSION TO IMPROVE THE LIVES OF PATIENTS WITH CHRONIC KIDNEY DISEASE, AND WILL EXTEND THE SCIENTIFIC REACH OF THE USRDS.

ENHANCING T AND B CELL RESPONSES TO PLASMODIUM VIA IL-15 - PROJECT SUMMARY/ABSTRACT MALARIA, WHICH RESULTS FROM INFECTION WITH PLASMODIUM PARASITES, IS A SIGNIFICANT GLOBAL HEALTH PROBLEM WITH NEARLY 250 MILLION CLINICAL CASES AND OVER 600,000 DEATHS ANNUALLY WORLDWIDE. WITH GROWING ANTI-MALARIAL DRUG AND INSECTICIDE RESISTANCE, NEW THERAPEUTIC STRATEGIES AND HIGHLY EFFECTIVE VACCINES ARE URGENTLY NEEDED. PROTECTION AGAINST SYMPTOMATIC DISEASE DEVELOPS AFTER YEARS OF REPEATED EXPOSURES TO PLASMODIUM PARASITES. HOWEVER, THERE IS NO DEFINITIVE EVIDENCE OF LONG-LIVED, STERILIZING IMMUNITY IN HUMANS FOLLOWING REPEATED EXPOSURE TO PLASMODIUM PARASITES, AND CLINICAL IMMUNITY TO MALARIA RAPIDLY WANES IN THE ABSENCE OF RE- INFECTION. SIMILARLY, THE LIMITED PROTECTION OFFERED BY THE TWO CURRENTLY LICENSED MALARIA VACCINES LOSE EFFICACY QUICKLY IN MALARIA ENDEMIC AREAS. DYSREGULATED INFLAMMATION IS THOUGHT TO CONTRIBUTE TO THE SHORT-LIVED RESPONSE TO PLASMODIUM. THE CELLULAR PROCESSES IMPAIRING THE ACQUISITION AND MAINTENANCE OF CELLULAR AND HUMORAL IMMUNITY TO PLASMODIUM ARE NOT KNOWN. THERAPIES THAT BOOST THE ROBUSTNESS AND DURABILITY OF THE IMMUNE RESPONSE COULD BE TRANSFORMATIVE IN VACCINE DEVELOPMENT. THIS PROJECT CENTERS ON INVESTIGATING AN IL- 15 CYTOKINE-BASED THERAPY THAT ENHANCES THE IMMUNE RESPONSE TO PLASMODIUM INFECTION AND VACCINATION. THE PROPOSED STUDIES WILL UTILIZE NOVEL PEPTIDE:MHC CLASS II AND B CELL TETRAMERS IN EXPERIMENTAL PLASMODIUM INFECTION AND VACCINATION MOUSE MODELS. WE FOUND THAT IN THE CONTEXT OF PLASMODIUM INFECTION IN MICE, IL-15 THERAPY PROMOTES THE DIFFERENTIATION OF T FOLLICULAR HELPER (TFH) CELLS, WHICH ARE CRITICAL FOR PROMOTING LONG-LIVED AND HIGH-QUALITY ANTIBODY RESPONSES. IN THE CONTEXT OF WHOLE SPOROZOITE PLASMODIUM VACCINATION, IL- 15 THERAPY INCREASES THE NUMBER OF LIVER-RESIDENT MEMORY T (TRM) CELLS AND ANTIBODY LEVELS, SUGGESTING THAT IL-15 COULD BE HARNESSED AS AN IMMUNOTHERAPY TO ENHANCE PLASMODIUM VACCINE IMMUNOGENICITY AND EFFICACY. IN THIS PROPOSAL, WE WILL DEFINE THE MECHANISM BY WHICH IL-15 THERAPY PROMOTES TFH DIFFERENTIATION AS WELL AS GERMINAL CENTER FORMATION AND ANTIBODY GENERATION IN THE CONTEXT OF PLASMODIUM INFECTION USING NOVEL CONDITIONAL KNOCKOUT MOUSE MODELS AND OUR NOVEL TETRAMER REAGENTS (AIM 1). WE WILL ALSO DEFINE THE IMPACT OF IL-15 AS A VACCINE IMMUNOTHERAPY TO ENHANCE TRM CELLS AS WELL B CELL AND ANTIBODY RESPONSES TO A WHOLE SPOROZOITE PLASMODIUM VACCINE (AIM 2). THESE STUDIES WILL DEFINE THE MECHANISTIC PATHWAYS INDUCED BY IL-15 TREATMENT THAT ENHANCE PLASMODIUM CONTROL TO BOTH UNDERSTAND THE DISEASE MORE COMPLETELY AND DEVELOP THERAPIES THAT EXPLOIT THESE PATHWAYS. OVERALL, THESE STUDIES WILL DELIVER FOUNDATIONAL KNOWLEDGE ON THE NATURALLY-ACQUIRED AND VACCINE-ELICITED IMMUNE RESPONSE TO PLASMODIUM. THIS INFORMATION WILL BE LEVERAGED FOR THE RATIONAL DESIGN OF VACCINATION STRATEGIES TO IMPROVE ANTI-PLASMODIUM IMMUNITY.

OVC FY 06 SART CONFERENCE

IMPLEMENTATION OF CESSATION TREATMENT IN COMMUNITY BASED MENTAL HEALTH CENTERS

A LEARNING HEALTH SYSTEM TO INCREASE ORGAN DONATION AND EQUITY IN POPULATIONS EXPERIENCING HEALTH DISPARITIES - PROJECT SUMMARY/ABSTRACT ORGAN TRANSPLANTATION IS THE BEST THERAPEUTIC OPTION TO IMPROVE QUALITY OF LIFE AND MORTALITY FOR MANY PATIENTS SUFFERING FROM ORGAN FAILURE. UNFORTUNATELY, OVER 10,000 DIE OR BECOME TOO SICK EACH YEAR WHILE ON THE WAITLIST DUE TO AN EXTREME ORGAN SHORTAGE. NATIVE AMERICANS (NA) AND OTHER MINORITIES ARE LESS LIKELY TO RECEIVE AN ORGAN TRANSPLANT AND ARE ALSO LESS LIKELY TO BECOME AN ORGAN DONOR. INCREASING ORGAN DONATION IS A CRITICAL STRATEGY TO REDUCE DISPARITIES IN ACCESS TO TRANSPLANT. DESPITE NUMEROUS RESEARCH INTERVENTIONS TO INCREASE ORGAN DONATION, RATES OF WAITLISTING AND TRANSPLANT HAVE NOT INCREASED IN THE UNITED STATES IN THE PAST TWO DECADES. ORGAN PROCUREMENT ORGANIZATIONS (OPOS) ARE A PRIMARY DRIVER OF THE DECEASED DONATION PROCESS AND PROVIDE LOCAL SERVICE AREAS WITH EDUCATION AND FAMILY SUPPORT. OPOS ARE A CRITICAL RESOURCE TO DISSEMINATE INTERVENTIONS ACROSS THE US THROUGH LOCAL COMMUNITY RELATIONSHIPS. THE TALKDONATION CAMPAIGN TO INCREASE NA ORGAN DONATION WAS DEVELOPED AND PILOTED IN URBAN MINNEAPOLIS BY LIFESOURCE, AN OPO SERVING MINNESOTA AND SURROUNDING STATES. HOWEVER, OPOS FACE A BARRIER TO CONTINUOUSLY IMPROVE AND SCALE INTERVENTIONS BECAUSE THE NATIONAL TRANSPLANT SYSTEM DOES NOT PROVIDE A FEEDBACK LOOP TO IDENTIFY WHAT INTERVENTIONS ARE EFFECTIVE IN INDIVIDUAL COMMUNITIES. A LEARNING HEALTH SYSTEM (LHS) MODEL WITH A FOCUS ON EMBEDDED RESEARCH, SYSTEMS THINKING, AND INTEGRATION OF OUTCOMES DATA INTO PRACTICE CAN PROVIDE A SUSTAINABLE NATIONAL SYSTEM FOR MONITORING ORGAN DONATION OUTCOMES USING PUBLICLY AVAILABLE DATA. THE LHS FOR ORGAN DONATION WILL USE THE TALKDONATION PROGRAM TO DEVELOP AND EVALUATE ORGAN DONATION EQUITY-FOCUSED DATA TOOLS THAT ARE ADAPTABLE ACROSS GEOGRAPHIES AND INTERVENTIONS TO MONITOR AND GUIDE COMMUNITY-LEVEL INTERVENTIONS ACROSS THE US. THE PROPOSED ORGAN DONATION DATA TOOLS WILL DESCRIBE ORGAN DONATION AT COUNTY, RACE, AND ETHNICITY LEVELS TO MONITOR DISPARITIES IN ORGAN DONATION (AIM 1). WE WILL EXPAND TALKDONATION IMPLEMENTATION THROUGH MULTI- PHASED ENGAGEMENT WITH TRIBAL COMMUNITIES IN MINNESOTA, SOUTH DAKOTA, AND NORTH DAKOTA TO INCREASE SUPPORT FOR ORGAN DONATION. WE WILL CONDUCT PARTICIPATORY WORKSHOPS TO UNDERSTAND COMMUNITY PERSPECTIVES AND TAILOR MATERIALS FOR UNIQUE NEEDS IN NORTHERN GREAT PLAINS NATIVE AMERICAN COMMUNITIES. (AIM 2). WE WILL USE SURVEYS AND IN-DEPTH INTERVIEWS TO ASSESS THE USE OF A LEARNING HEALTH SYSTEM MODEL FOLLOWING THE IMPLEMENTATION OF THE TALKDONATION CAMPAIGN AND MONITORING WITH THE EQUITY DATA TOOLS. WE WILL USE THE RE- AIM (REACH, EFFECTIVENESS, ADOPTION, IMPLEMENTATION, AND MAINTENANCE) IMPLEMENTATION FRAMEWORK AND IDENTIFY IMPLEMENTATION OUTCOMES TO FACILITATE SCALING AND SUSTAINABILITY (AIM 3). THIS RESEARCH WILL ALLOW US TO DEVELOP A SYSTEMATIC OUTCOMES FEEDBACK LOOP TO INFORM INTERVENTIONS ACROSS OTHER POPULATIONS EXPERIENCING HEALTH DISPARITIES AND OTHER SOLID ORGAN TRANSPLANT FIELDS AS WELL AS TISSUE DONATION. IN ADDITION, THE PROPOSED RESEARCH WILL INCREASE AWARENESS AND TRANSPARENCY OF THE ORGAN DONATION SYSTEM, POTENTIALLY IMPROVING COMMUNITY TRUST IN THE TRANSPLANT SYSTEM AND REDUCING PERSISTENT DISPARITIES.

SEX-SPECIFIC RISK FACTORS AND TRAJECTORIES OF BLOOD BIOMARKERS FOR ALZHEIMER'S DISEASE AND RELATED DEMENTIAS - PROJECT SUMMARY / ABSTRACT LATE-LIFE ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) ARE DEVASTATING MULTIFACTORIAL CONDITIONS AND THE MAJOR CONTRIBUTORS TO LOSS OF INDEPENDENCE IN OLDER AGE. THERE IS A CRITICAL UNMET NEED TO IDENTIFY WHICH INDIVIDUALS ARE AT THE GREAT RISK OF THESE CONDITIONS, THUS PERMITTING ACCURATE PROGNOSIS AND TIMELY PREVENTATIVE INTERVENTIONS TO REDUCE THE BURDEN. YET, WHILE A NUMBER OF RISK FACTORS HAVE BEEN IDENTIFIED FOR THESE CONDITIONS, SEX DIFFERENCES IN THESE ASSOCIATIONS HAVE RARELY BEEN CONSIDERED. FURTHERMORE, EXCITING RECENT ADVANCES IN BLOOD AMYLOID, TAU AND NEURODEGENERATION (AT(N)) BIOMARKERS FOR ADRD MEANS THAT THEY COULD SOON BE USED AS POWERFUL CLINICAL DIAGNOSTIC AND PROGNOSTIC TOOLS IN A PERSONALIZED MEDICINE APPROACH. HOWEVER, A NUMBER OF CRITICAL KNOWLEDGE GAPS REMAIN. IMPORTANTLY, 1) THESE BIOMARKERS HAVE NOT BEEN SUFFICIENTLY EXAMINED IN LONGITUDINAL STUDIES OF OLDER COMMUNITY- BASED POPULATIONS WITHOUT DIAGNOSED DEMENTIA; 2) IT IS UNCLEAR HOW PARTICIPANT CHARACTERISTICS SUCH AS COMORBIDITIES AFFECT THE CLINICAL INTERPRETATION OF THESE BIOMARKERS; AND 3) HOW THEIR INTERPRETATION MAY DIFFER BETWEEN MEN AND WOMEN. TOGETHER, THESE LARGE KNOWLEDGE GAPS HIGHLIGHT A CRUCIAL NEED TO DEVELOP THE FIRST SEX-SPECIFIC RISK SCORE FOR ADRD THAT INCORPORATES BLOOD AT(N) BIOMARKERS AND ADRD RISK FACTORS. OUR OVERARCHING HYPOTHESIS IS THAT AT(N) PLASMA BIOMARKERS WILL BE PREDICTIVE OF ADRD IN INITIALLY HEALTHY COMMUNITY-DWELLING OLDER INDIVIDUALS, BEYOND KNOWN RISK FACTORS (INCLUDING AGE, EDUCATION, LIVING ALONE, DIABETES, HYPERTENSION, SMOKING, ALCOHOL CONSUMPTION, PHYSICAL ACTIVITY), AND THAT THESE ASSOCIATIONS WILL VARY BY SEX. THIS PROJECT PROVIDES AN UNPRECEDENTED OPPORTUNITY TO ADDRESS THIS IMPORTANT QUESTION WITHIN THE CONTEXT OF A RIGOROUS, LARGE-SCALE STUDY OF INITIALLY HEALTHY INDIVIDUALS AGED 65-98 YEARS FROM THE US AND AUSTRALIA (12,716 WHITES, 412 BLACKS, 339 OTHER MINORITIES) WITH COMPREHENSIVE ANNUAL IN-PERSON COGNITIVE ASSESSMENTS, ADJUDICATED CLINICAL OUTCOMES, DETAILED DATA ON SOCIO-ECONOMIC STATUS, LIFESTYLE AND HEALTH FACTORS COLLECTED OVER A MEDIAN 9+ YEARS, AND EXISTING GENETIC DATA (APOE4, DEMENTIA POLYGENIC RISK SCORES). LEVERAGING UNIQUE BLOOD SAMPLES AVAILABLE AT TWO TIME-POINTS (N=13,435 AT BASELINE, AND ~8000 AT 7 TO 10 YEARS), AT(N) BIOMARKERS WILL BE MEASURED LONGITUDINALLY. THIS PROPOSAL IS A UNIQUE, HIGHLY COST-EFFICIENT OPPORTUNITY TO ADDRESS GAPS IN OUR ABILITY TO ACCURATELY DETERMINE WHO IS AT THE GREATEST RISK OF ADRD, INDIVIDUALLY FOR WOMEN AND MEN. WE WILL ADDRESS CRITICAL GAPS IN IDENTIFYING WHICH FACTORS INFLUENCE BLOOD BIOMARKER LEVELS AND MUST BE CONSIDERED WHEN ESTABLISHING THEIR CLINICAL REFERENCE RANGES. THE SEX-SPECIFIC RISK SCORE RESULTING FROM THIS PROJECT WILL PROVIDE A POWERFUL NEW TOOL FOR PRACTITIONERS TO PREDICT RISK OF COGNITIVE DECLINE AND ADRD THAT CONSIDERS COMMON COMORBIDITIES, SOCIAL, LIFESTYLE, AND GENOMIC RISK FACTORS, TOGETHER WITH THE UNIQUE PREDICTIVE STRENGTH OF THE PLASMA AT(N) BIOMARKERS.

ENHANCING T AND B CELL RESPONSES TO PLASMODIUM INFECTION AND VACCINATION VIA IL-15 - PROJECT SUMMARY/ABSTRACT MALARIA, WHICH RESULTS FROM INFECTION WITH PLASMODIUM PARASITES, IS A SIGNIFICANT GLOBAL HEALTH PROBLEM WITH NEARLY 250 MILLION CLINICAL CASES AND OVER 600,000 DEATHS ANNUALLY WORLDWIDE. WITH GROWING ANTI-MALARIAL DRUG AND INSECTICIDE RESISTANCE, NEW THERAPEUTIC STRATEGIES AND HIGHLY EFFECTIVE VACCINES ARE URGENTLY NEEDED. PROTECTION AGAINST SYMPTOMATIC DISEASE DEVELOPS AFTER YEARS OF REPEATED EXPOSURES TO PLASMODIUM PARASITES. HOWEVER, THERE IS NO DEFINITIVE EVIDENCE OF LONG-LIVED, STERILIZING IMMUNITY IN HUMANS FOLLOWING REPEATED EXPOSURE TO PLASMODIUM PARASITES, AND CLINICAL IMMUNITY TO MALARIA RAPIDLY WANES IN THE ABSENCE OF RE- INFECTION. SIMILARLY, THE LIMITED PROTECTION OFFERED BY THE MOST ADVANCED MALARIA VACCINES LOSE EFFICACY QUICKLY IN MALARIA ENDEMIC AREAS. DYSREGULATED INFLAMMATION IS THOUGHT TO CONTRIBUTE TO THE SHORT-LIVED RESPONSE TO PLASMODIUM. THE CELLULAR PROCESSES IMPAIRING THE ACQUISITION AND MAINTENANCE OF CELLULAR AND HUMORAL IMMUNITY TO PLASMODIUM ARE NOT KNOWN. THERAPIES THAT BOOST THE ROBUSTNESS AND DURABILITY OF THE IMMUNE RESPONSE COULD BE TRANSFORMATIVE IN VACCINE DEVELOPMENT. THIS PROJECT CENTERS ON INVESTIGATING AN IL-15 CYTOKINE-BASED THERAPY THAT ENHANCES THE IMMUNE RESPONSE TO PLASMODIUM INFECTION AND VACCINATION. THE PROPOSED STUDIES WILL UTILIZE NOVEL PEPTIDE:MHC CLASS II AND B CELL TETRAMERS IN EXPERIMENTAL PLASMODIUM INFECTION AND VACCINATION MOUSE MODELS. WE FOUND THAT IN THE CONTEXT OF PLASMODIUM INFECTION IN MICE, IL-15 THERAPY PROMOTES THE DIFFERENTIATION OF T FOLLICULAR HELPER (TFH) CELLS, WHICH ARE CRITICAL FOR PROMOTING LONG-LIVED AND HIGH-QUALITY ANTIBODY RESPONSES. IN THE CONTEXT OF WHOLE SPOROZOITE PLASMODIUM VACCINATION, IL- 15 THERAPY INCREASES THE NUMBER OF LIVER-RESIDENT CD8 T MEMORY (TRM) CELLS AND ANTIBODY LEVELS, SUGGESTING THAT IL-15 COULD BE HARNESSED AS AN ADJUVANT TO ENHANCE PLASMODIUM VACCINE IMMUNOGENICITY. IN THIS PROPOSAL, WE WILL DEFINE THE MECHANISM BY WHICH IL-15 THERAPY PROMOTES TFH DIFFERENTIATION AS WELL AS GERMINAL CENTER FORMATION AND ANTIBODY GENERATION IN THE CONTEXT OF PLASMODIUM INFECTION USING NOVEL CONDITIONAL KNOCKOUT MOUSE MODELS AND OUR NOVEL TETRAMER REAGENTS (AIM 1). WE WILL ALSO DEFINE THE IMPACT OF IL-15 THERAPY AS A VACCINE ADJUVANT TO ENHANCE CD8 T CELL RESPONSES AS WELL AS CD4 T CELL AND B CELL/ANTIBODY RESPONSES TO A WHOLE SPOROZOITE PLASMODIUM VACCINE (AIM 2). THESE STUDIES WILL DEFINE THE MECHANISTIC PATHWAYS INDUCED BY IL-15 TREATMENT THAT ENHANCE PLASMODIUM CONTROL TO BOTH UNDERSTAND THE DISEASE MORE COMPLETELY AND DEVELOP THERAPIES THAT EXPLOIT THESE PATHWAYS. OVERALL, THESE STUDIES WILL DELIVER FOUNDATIONAL KNOWLEDGE OF THE NATURALLY-ACQUIRED AND VACCINE-ELICITED IMMUNE RESPONSE TO PLASMODIUM. THIS INFORMATION WILL BE LEVERAGED FOR THE RATIONAL DESIGN OF VACCINATION STRATEGIES TO IMPROVE ANTI-PLASMODIUM IMMUNITY.

EFFECTIVENESS OF NICOTINE REPLACEMENT THERAPY SAMPLING IN DENTAL PRACTICES

MOLECULAR AND CELLULAR ANALYSIS OF ALLOGRAFT LOSS IN KIDNEY TRANSPLANT BIOPSIES - AFRICAN AMERICANS (AAS) HAVE HIGHER RISK FOR KIDNEY ALLOGRAFT LOSS AFTER KIDNEY TRANSPLANTATION COMPARED WITH OTHER RACES. OUR DETERIORATION OF KIDNEY ALLOGRAFT FUNCTION GENOMICS STUDY (DEKAF: U19 AI070119) SHOWED A SIGNIFICANT DISPARITY IN ALLOGRAFT LOSS AFTER THE FIRST BIOPSY FOR CHRONIC ALLOGRAFT DYSFUNCTION (CGD) BETWEEN AAS AND NON-AAS. THE DEKAF STUDY ENROLLED NEARLY 3,000 TRANSPLANT RECIPIENTS, FROM 2005 TO 2011, AND CONDUCTED GENOME WIDE ASSOCIATION STUDIES (GWAS). DEKAF PARTICIPANTS ARE LINKED TO THE UNITED STATES RENAL DATA SYSTEM (USRDS) FOR LONG-TERM CLINICAL DATA. WE DEFINED AA BY SELF-REPORT AND VERIFIED BY GWAS PRINCIPAL COMPONENTS. CGD WAS DEFINED AS >25% INCREASE IN CREATININE RELATIVE TO A 3-MONTH BASELINE AND IS ASSOCIATED WITH ALLOGRAFT LOSS. ALTHOUGH 91% OF CGD BIOPSIES HAVE INFLAMMATION, NOT ALL PROGRESS TO ALLOGRAFT LOSS. THE MOLECULAR AND CELLULAR DIFFERENCES BETWEEN AA AND NON-AA CGD BIOPSIES ARE UNKNOWN; BIOPSIES FROM THE DEKAF COHORT CAN BE LEVERAGED TO DETERMINE THESE DIFFERENCES. TO ADDRESS KIDNEY ALLOGRAFT LOSS DISPARITIES AFTER CGD, WE AIM TO DETERMINE THE MOLECULAR AND CELLULAR DIFFERENCES BETWEEN AA AND NON-AA CGD BIOPSIES AND ASSOCIATIONS WITH ALLOGRAFT LOSS. DUE TO ESTABLISHED ROLES FOR MACROPHAGES AND NATURAL KILLER (NK) CELLS IN ALLOGRAFT REJECTION, THE CENTRAL HYPOTHESIS IS THAT THESE CELL TYPES HAVE HIGHER ABUNDANCE IN AA CGD BIOPSIES AND THESE CELL TYPES WILL BE ASSOCIATED WITH INCREASED RISK FOR KIDNEY ALLOGRAFT LOSS. WE WILL DETERMINE DIFFERENCES IN MACROPHAGE (AIM 1) AND NK CELL (AIM 2) ABUNDANCE IN CGD KIDNEY ALLOGRAFT BIOPSIES BETWEEN AAS AND ON-AAS AND ASSOCIATION WITH ALLOGRAFT LOSS. WE WILL USE DIGITAL SPATIAL PROFILING (DSP) TO DETERMINE DIFFERENCES BETWEEN AA AND NON-AA CGD BIOPSIES. DSP COMBINES FLUORESCENT IMAGING OF TISSUE STRUCTURES AND WHOLE TRANSCRIPTOME PROFILING. DSP IS INNOVATIVE BECAUSE IT DIFFERENTIATES RNA AND PROTEIN EXPRESSION IN SEPARATE TISSUE COMPARTMENTS SUCH AS TUBULES, INTERSTITIUM OR GLOMERULUS. THE REASON FOR THE DSP APPROACH: HISTOLOGY SHOWED MORE FIBROSIS IN THE INTERSTITIAL AREAS OF THE KIDNEY ALLOGRAFTS AND INCREASED TUBULAR ATROPHY IN AA CGD BIOPSIES FROM DEKAF, BUT NOT WHAT CELL TYPES ARE ASSOCIATED WITH KIDNEY DAMAGE. WE WILL EVALUATE CGD BIOPSIES IN EACH OF 4 GROUPS: 1) AAS WITH ALLOGRAFT LOSS 2) AAS WITHOUT ALLOGRAFT LOSS 3) NON-AAS WITH ALLOGRAFT LOSS AND 4) NON-AAS WITHOUT ALLOGRAFT LOSS. WE EXPECT TO FIND HIGHER ABUNDANCE OF MACROPHAGES AND NK CELLS ASSOCIATED WITH AAS AND ALLOGRAFT LOSS. THIS PROPOSAL WILL DEVELOP THE INNOVATIVE DSP TECHNOLOGY TO ASSESS CGD BIOPSIES LEADING TO A DEFINITION OF THE MOLECULAR, CELLULAR AND SPATIAL DIFFERENCES IN AAS AND NON-AAS KIDNEY ALLOGRAFTS AND STUDY ASSOCIATIONS WITH ALLOGRAFT LOSS. THIS STUDY WILL LEAD TO CREATION OF A SPATIAL ATLAS OF VARIOUS CELL TYPES AND TRANSCRIPTS IN AA AND NON-AA BIOPSIES THAT ASSOCIATE WITH ALLOGRAFT LOSS. THIS STUDY SHOULD DEVELOP A WEALTH OF DATA, AS THE FOUNDATION FOR A MECHANISTIC AND INTERVENTIONAL R01 PROPOSAL TO FOLLOW. WE ENVISION DSP SUPPLEMENTING PATHOLOGY TO GUIDE PERSONALIZED THERAPY FOR CGD AND HELP CLOSE THE GAP IN AA TRANSPLANT OUTCOME DISPARITIES.

INFECTION PREVENTION IN TOTAL KNEE REPLACEMENT

INVESTIGATING PLASMODIUM VACCINATION IN 'DIRTY' MICE - PROJECT SUMMARY/ABSTRACT MALARIA, WHICH RESULTS FROM INFECTION WITH PLASMODIUM PARASITES, IS A SIGNIFICANT GLOBAL HEALTH PROBLEM WITH NEARLY 250 MILLION CLINICAL CASES AND OVER 600,000 DEATHS ANNUALLY WORLDWIDE. WITH GROWING ANTI-MALARIAL DRUG AND INSECTICIDE RESISTANCE, NEW THERAPEUTIC STRATEGIES AND HIGHLY EFFECTIVE VACCINES ARE URGENTLY NEEDED. WHOLE SPOROZOITE VACCINES ARE THE ONLY STRATEGY TO ELICIT HIGH LEVELS OF STERILIZING IMMUNITY IN HUMANS, INCLUDING >90% IN CONTROLLED HUMAN MALARIA INFECTION (CHMI) STUDIES. WHOLE SPOROZOITE VACCINE STRATEGIES INCLUDE GENETICALLY ATTENUATED PARASITES (GAPS), IN WHICH PARASITE ARREST IS MEDIATED BY THE TARGETED DELETION OF GENES CRITICAL FOR LIVER STAGE DEVELOPMENT. HOWEVER, PLASMODIUM VACCINES HAVE LARGELY FAILED TO INDUCE DURABLE PROTECTION IN ENDEMIC COUNTRIES. ADDITIONALLY, THERE IS CONSIDERABLE EVIDENCE THAT ONGOING EXPOSURE TO PATHOGENS WITHIN MALARIA ENDEMIC AREAS, BOTH CO-INFECTIONS AND HISTORIC MALARIA EXPOSURE, AS WELL AS MICROBIOTA CAN MODULATE VACCINE IMMUNITY. TO ADDRESS THIS GAP IN KNOWLEDGE, THIS PROPOSAL WILL UTILIZE AN IMPROVED SMALL ANIMAL MODEL THAT MIMICS HUMAN IMMUNE RESPONSES MORE CLOSELY TO DEFINE THE IMMUNE RESPONSE PLASMODIUM VACCINATION AND TEST AN ADJUVANT TO BOOST IMMUNITY AGAINST PLASMODIUM. OUR GROUP HAS SHOWN THAT SPECIFIC PATHOGEN-FREE (SPF) MICE COHOUSED WITH PET STORE MICE ACQUIRE DIVERSE MICROBIAL EXPOSURE (DME) AND UNDERGO IMMUNE SYSTEM CHANGES THAT BETTER RECAPITULATE THE HUMAN IMMUNE SYSTEM. COMPARING SPF AND DME MICE WILL ALLOW US TO TEST WHETHER AND HOW MICROBIAL EXPOSURE AND RESULTING INFLAMMATION IMPACT PLASMODIUM VACCINE IMMUNOGENICITY AND EFFICACY. THERE IS ALSO A NEED TO OPTIMIZE SPOROZOITE VACCINE IMMUNOGENICITY SUCH AS VIA AN ADJUVANT. IN MICE, LIVER-RESIDENT CD8+ T (TRM) CELLS ARE CRITICAL FOR STERILIZING IMMUNITY FOLLOWING SPOROZOITE VACCINATION, AND LIVER TRM FORMATION IS HIGHLY DEPENDENT ON IL-15. THUS, IL-15 COULD BE HARNESSED AS A VACCINE ADJUVANT TO ENHANCE TRM FORMATION. INDEED, WE SHOW THAT, IN SPF MICE, COMPLEXING IL-15 WITH THE IL-15R (IL-15C) BOOSTS LIVER TRM FORMATION FOLLOWING GAP VACCINATION AND RESULTS IN REDUCED LIVER PARASITE LOAD AFTER CHALLENGE. INTERESTINGLY, EXPRESSION OF THE IL-15RΒ/Γ CHAINS IS SIGNIFICANTLY INCREASED IN LIVER LEUKOCYTES FROM DME MICE, SUGGESTING THAT LIVER TRM CELLS IN DME MICE MAY BE ESPECIALLY SUSCEPTIBLE TO AUGMENTATION BY IL-15C. IN AIM 1, WE WILL DEFINE THE T CELL AND ANTIBODY RESPONSE TO PLASMODIUM VACCINATION IN DME MICE AND TEST IL-15C AS A VACCINE ADJUVANT TO BOOST TRM FORMATION. IN AIM 2, WE WILL DETERMINE GAP VACCINE EFFICACY IN DME AND SPF MICE WITH OR WITHOUT IL-15C AND COMPARE VACCINE EFFICACY TO A CSP PROTEIN-SUBUNIT VACCINE IN SPF AND DME MICE. IN SUM, OUR DATA SUPPORT THE HYPOTHESIS THAT DME MICE REPRESENT A MORE PHYSIOLOGICALLY RELEVANT MODEL TO DEFINE PLASMODIUM VACCINE IMMUNOGENICITY AND EFFICACY AND THAT IL-15C REPRESENTS A NOVEL PLASMODIUM VACCINE ADJUVANT. THIS WILL FACILITATE IMPROVED CONTROL OF PLASMODIUM INFECTION AND PROTECTION FROM DISEASE BY INFORMING VACCINE DESIGN.

MODELING BEHAVIORAL TREATMENTS FOR STIMULANT ABUSE

PLASMA-BASED NEURONAL INSULIN SIGNALING EXOSOMES AS A BIOMARKER FOR COGNITIVE IMPAIRMENT IN DIABETES - PROJECT SUMMARY APPROXIMATELY 30% OF OLDER ADULTS IN THE UNITED STATES HAVE DIABETES MELLITUS (DM). ALZHEIMER’S DISEASE AND ALZHEIMER'S DISEASE-RELATED DEMENTIAS (AD/ADRD) ARE HIGHLY PREVALENT IN THIS POPULATION AND COGNITIVE IMPAIRMENT IS A MAJOR PREDICTOR FOR FUNCTIONAL DECLINE AND DISABILITY IN DM. CURRENT GUIDELINES RECOMMEND SCREENING FOR COGNITIVE IMPAIRMENT IN OLDER ADULTS WITH DM AND PROVIDING GUIDANCE FOR DM MANAGEMENT. NONETHELESS, NO DISEASE-MODIFYING TREATMENT IS AVAILABLE AND MORE IMPORTANTLY THE EXACT MECHANISM UNDERLYING THE LINK BETWEEN DM AND AD/ADRD IS UNCLEAR. LONG TERM HYPERGLYCEMIA IS KNOWN TO CAUSE BRAIN INSULIN RESISTANCE AND IMPAIRED NEURONAL INSULIN SIGNALING (NIS). IMPAIRED NIS RESULTS IN NEURONAL CELL DEATH, NEUROINFLAMMATION, AMYLOID Β DEPOSITION AND TAU PHOSPHORYLATION; CENTRAL COMPONENTS OF AD/ADRD PATHOPHYSIOLOGY. GIVEN THE CRUCIAL ROLES OF NIS IN BRAIN STRUCTURAL INTEGRITY AND COGNITIVE FUNCTION, ABNORMAL NIS IS A HIGHLY PLAUSIBLE, YET UNDERSTUDIED, MECHANISM UNDERLYING THE HIGH RISK OF COGNITIVE IMPAIRMENT IN DM. THE OVERARCHING HYPOTHESIS OF THIS PROJECT IS THAT ABNORMAL NIS PRECEDES ACCELERATED BRAIN STRUCTURAL AND COGNITIVE CHANGES IN PATIENTS WITH DM AND MODIFICATION OF NIS CAN POTENTIALLY SERVE AS A KEY STRATEGY TO PREVENT COGNITIVE DECLINE IN THIS POPULATION. NIS MEDIATORS ARE HIGHLY EXPRESSED IN PLASMA ENRICHED EXTRACELLULAR VESICLES (EXOSOMES) AND IN THIS STUDY WE WILL USE THIS PHENOMENON TO ASSESS THE STATE OF NIS IN EACH INDIVIDUAL. WE PLAN TO LEVERAGE THE EXISTING DATA FROM THE ACCORD-MIND STUDY (A LANDMARK MULTI-ETHNIC STUDY THAT INVESTIGATED THE EFFECT OF GLYCEMIC CONTROL ON BRAIN STRUCTURES AND COGNITIVE FUNCTION IN DM). WE WILL SAMPLE 200 MALE AND FEMALE PATIENTS WITH DM WITH VARIOUS LEVELS OF GLYCEMIC CONTROL FROM THE ACCORD-MIND STUDY WITH EXTENSIVE LONGITUDINAL COGNITIVE, CLINICAL, AND NEURO-IMAGING DATA (7 YEARS OF FOLLOW UP). THE NIS EXOSOMES WILL BE ISOLATED AND QUANTIFIED FROM AVAILABLE FASTING BLOOD SAMPLES TO INVESTIGATE WHETHER IMPAIRED NIS PRECEDES BRAIN VOLUME LOSS AND COGNITIVE DECLINE. WE WILL TAKE A STEPWISE ANALYTICAL APPROACH TO INVESTIGATE THE ASSOCIATION OF NIS WITH THE TRAJECTORIES OF CHANGES IN BRAIN STRUCTURE AND COGNITIVE FUNCTION IN OUR STUDY POPULATION. WE WILL ADDRESS THE DOSE-RESPONSE IMPACT OF GLYCEMIC CONTROL, MEASURED BY CHANGES IN HEMOGLOBIN A1C (A1C), ON NIS AND EXPLORE THE ROLE OF NIS ON THE ASSOCIATION OF GLYCEMIC CONTROL MEASURES WITH COGNITIVE DECLINE AND BRAIN VOLUME LOSS. IDENTIFICATION AND CHARACTERIZATION OF NIS BIOMARKERS RELATED TO PRECLINICAL AD/ADRD PHENOTYPES, SUCH AS BRAIN VOLUME LOSS OR COGNITIVE DECLINE, WILL OFFER OPPORTUNITIES FOR EARLY INTERVENTIONS TO SLOW DOWN THE PACE OF COGNITIVE DECLINE IN DM. FINDINGS OF THIS STUDY CAN INFORM FUTURE STUDIES ON TARGETED SYSTEMIC GLYCEMIC CONTROL DEPENDENT ON THE STATE OF NIS IN ORDER TO PROMOTE BRAIN HEALTH IN PATIENTS WITH DM.

INVESTIGATING IL-10-PRODUCING SUPPRESSIVE NK CELLS

STRESS BIOMARKERS AMONG PATIENTS UNDERGOING TREATMENT FOR EXCITED DELIRIUM AND SEVERE PAIN IN THE EMERGENCY DEPARTMENT

EARLY ANTIGEN-SPECIFIC B CELL RESPONSES AS MARKERS OF OXYCODONE VACCINE EFFICACY

THE EFFECTS OF AGE AND TREATED HIV INFECTION ON MYOCARDIAL DISEASE IN SOUTH AFRICA

STROKE AND ITS IMPLICATIONS ACROSS THE SPECTRUM OF CHRONIC KIDNEY DISEASE

DETERMINING PREVALENCE OF ACUTE BILIRUBIN ENCEPHALOPATHY IN DEVELOPING COUNTRIES

ANIMAL MODELS FOR EVALUATING THE RELATIVE ABUSE LIABILITY OF ELECTRONIC CIGARETTES

EXPANDING THE DIABETES HOMELESSNESS MEDICATION SUPPORT (D-HOMES) PROGRAM TO SPANISH SPEAKING HISPANICS - PROJECT SUMMARY/ABSTRACT HOMELESS PEOPLE IN THE US FACE DISPROPORTIONATE RISK FOR EARLY DEATH IN PART DUE TO POORLY CONTROLLED CHRONIC DISEASES INCLUDING DIABETES. 1.5 MILLION UNIQUE US ADULTS ACCESS HOMELESS SHELTERS ANNUALLY. PEOPLE EXPERIENCING DIABETES AND HOMELESSNESS DEVELOP COMPLICATIONS 10 YEARS EARLIER AND DIE PREMATURELY COMPARED TO THEIR HOUSED COUNTERPARTS. THIS PROJECT WORKS TO ACHIEVE HEALTH EQUITY FOR THESE PEOPLE. SUBSTANTIAL EVIDENCE LINKS MEDICATION ADHERENCE AS A LEADING MODIFIABLE HEALTH BEHAVIOR DRIVING POOR DIABETES OUTCOMES IN LOW-INCOME AND HOMELESS POPULATIONS. BEHAVIORAL SUPPORT FOR IMPROVED MEDICATION ADHERENCE AMONG PEOPLE EXPERIENCING DIABETES AND HOMELESSNESS IS THE FOCUS OF OUR TEAM’S ONGOING WORK (K23DK118117). WE’VE USED QUALITATIVE DATA AND COMMUNITY ENGAGED APPROACHES TO DEVELOP A TAILORED BEHAVIORAL INTERVENTION (THE DIABETES HOMELESS MEDICATION SUPPORT PROGRAM [D-HOMES]); PILOT TESTING OF THIS NEW INTERVENTION IS ONGOING. D-HOMES OFFERS 10 COACHING SESSIONS OVER 12 WEEKS TARGETING GLYCEMIC CONTROL VIA IMPROVED MEDICATION ADHERENCE. COACHING INCLUDES DIABETES EDUCATION AND STRUCTURED GOAL SETTING TARGETING MEDICATION ADHERENCE AND PSYCHOLOGICAL WELLNESS. TO DATE ENGLISH FLUENCY HAS BEEN AN ENROLLMENT CRITERION DUE TO LIMITED RESOURCES IN THE EXISTING K23 AWARD. YET THE HISPANIC COMMUNITY HAS DISPROPORTIONATELY HIGHER RATES OF BOTH HOMELESSNESS AND DIABETES. THIS R-03 AWARD WILL EXPAND THE D-HOMES INTERVENTION TO INCLUDE SPANISH SPEAKERS IN TWO AIMS: (1) ADAPT D-HOMES PROTOCOLS AND TRANSLATED TREATMENT MATERIALS BASED ON FEEDBACK FROM PEOPLE WITH DIABETES AND HOMELESSNESS WHO SPEAK SPANISH AND ARE HISPANIC (DH-SH). WE WILL CONDUCT 8-10 INTERVIEWS TO REVIEW MATERIALS, PLANNED RECRUITMENT AND RETENTION STRATEGIES, AND STUDY LOGISTICS. (2) ASSESS FEASIBILITY AND ACCEPTABILITY OF THE ADAPTED D-HOMES FOR DH-SH. WE WILL RECRUIT 12 DH-SH INTO A SINGLE-ARM TRIAL TO ASSESS ACCEPTABILITY AND FEASIBILITY OF (I) RECRUITMENT AND RETENTION; (II) COACHING CONTENT AND TREATMENT MATERIALS; (III) OUTCOME ASSESSMENTS. DATA WILL INCLUDE SYSTEMATIC TRACKING OF RECRUITMENT AND RETENTION EFFORTS, STAFF FEEDBACK, PROGRAM SATISFACTION AND POST-TREATMENT QUALITATIVE INTERVIEWS. WE HYPOTHESIZE UNIQUE RECRUITMENT/RETENTION NEEDS AND UNIQUE FACILITATORS/BARRIERS TO MEDICATION ADHERENCE AMONG DH-SH COMPARED TO ENGLISH-SPEAKING PARTICIPANTS. DATA WILL DEFINE SOLUTIONS FOR USE IN FUTURE WORK. THIS STUDY IS SIGNIFICANT BECAUSE FINDINGS WILL ENABLE A FUTURE, FULLY POWERED CLINICAL TRIAL OF D-HOMES THAT WILL ENROLL BOTH ENGLISH AND SPANISH SPEAKERS. OUR TEAM’S EXPERIENCE PROVIDES A ROBUST FOUNDATION FOR THIS WORK: (1) OUR BILINGUAL/BICULTURAL RESEARCH STAFF SUPPORTS OUR ONGOING NIDDK-FUNDED TRIAL WITH HISPANIC PARTICIPANTS WITH TYPE 2 DIABETES (R01 DK113999); (2) THE PI’S MEXICAN HERITAGE, SPANISH LANGUAGE SKILLS, AND LEADERSHIP ROLE AT THE LOCAL HEALTH CARE FOR THE HOMELESS PROGRAM; (3) OUR TEAM’S SUCCESSFUL RECRUITMENT AND RETENTION OF DIVERSE PARTICIPANTS IN SEVERAL BEHAVIORAL TRIALS WITH DIFFICULT-TO-REACH POPULATIONS. THIS STUDY IS INNOVATIVE AS IT WILL DEFINE NECESSARY TAILORING BASED ON LANGUAGE AND A KEY SOCIAL RISK FACTOR TO DIABETES CARE, HOMELESSNESS.

DEVELOPING A STRATEGY BUNDLE TO PREPARE, IMPLEMENT, AND SCALE INTEGRATED PERINATAL OPIOID USE DISORDER CARE IN HEALTHCARE SYSTEMS - ABSTRACT THE OVERARCHING GOAL OF THIS MENTORED CAREER DEVELOPMENT AWARD (K01), RESPONSIVE TO PAS-22-206, IS TO SUPPORT ME IN MY DEVELOPMENT AS AN INDEPENDENT INVESTIGATOR FOCUSED ON IMPROVING BEHAVIORAL HEALTHCARE FOR MOTHERS, THEIR CHILDREN AND FAMILIES. THE PROPOSED STUDY FOCUSES ON THE HUNDREDS OF THOUSANDS OF U.S. WOMEN WITH OPIOID USE DISORDER (OUD) WHO ARE PREGNANT OR PARENTING CHILDREN UP TO AGE 5 (“MOTHERS WITH OUD”), A CRITICAL PERIOD OF DEVELOPMENT FOR CHILDREN AND ELEVATED MOTIVATION FOR OUD RECOVERY IN MOTHERS. OUD SEVERELY IMPAIRS A PERSON’S ABILITY TO FUNCTION AS A HEALTHY PARENT AND THUS CONTINUES GENERATIONAL TRAUMA AND CHALLENGES THAT COULD BE MITIGATED WITH TREATMENT. YET, MOTHERS WITH OUD FACE SIGNIFICANT PUNISHMENT (CHILD CUSTODY LOSS, INVOLUNTARY COMMITMENT) AND THEREFORE AVOID HEALTHCARE ENGAGEMENT AND OUD TREATMENT. HOWEVER, THESE CONSEQUENCES HAVE BEEN LESSENING AS MORE PROFESSIONALS RECOGNIZE THE BENEFITS OF HARM REDUCTION AND TRAUMA-INFORMED APPROACHES; IT IS TIME TO BETTER ENGAGE MOTHERS WITH OUD IN APPROPRIATE CARE. INTEGRATED CARE, A MULTIDISCIPLINARY TEAM THAT PROVIDES SUBSTANCE USE, MENTAL, AND MEDICAL HEALTHCARE; SOCIAL WORK; PEER RECOVERY AND DOULA SERVICES, HAS BEEN SHOWN TO BE THE MOST EFFECTIVE APPROACH FOR MOTHERS WITH OUD, BUT IT IS DIFFICULT TO IMPLEMENT DUE TO HISTORICAL INERTIA KEEPING THESE SERVICES SEPARATE AND OTHER BARRIERS. RESEARCH SUPPORTING EFFECTIVE IMPLEMENTATION IS NEEDED. THIS INNOVATIVE PROPOSAL WILL BUILD ON MY STRONG CLINICAL BACKGROUND TREATING SUBSTANCE USE IN FAMILIES AND MY RESEARCH EXPERIENCE WITH IMPLEMENTATION SCIENCE AND INTEGRATING BEHAVIORAL HEALTH INTO MEDICAL SETTINGS. IT WILL SUPPORT ME IN ACHIEVING THREE TRAINING GOALS: 1) ESTABLISH EXPERTISE IN APPLIED IMPLEMENTATION RESEARCH IN HEALTH SYSTEMS INCLUDING EHR DATA MANAGEMENT AND USAGE, 2) ESTABLISH EXPERTISE IN COMPREHENSIVE PERINATAL ADDICTION SERVICES AND 3) DEVELOP COMPETENCY IN MULTISITE CLINICAL AND IMPLEMENTATION TRIALS METHODOLOGY. THESE SKILLS WILL ALLOW ME TO ACHIEVE THE FOLLOWING STUDY AIMS: 1) DEVELOP A FEASIBLE MULTI-LEVEL IMPLEMENTATION STRATEGY BUNDLE FOR INTEGRATED CARE FOR MOTHERS WITH OUD BY PILOTING AND ADAPTING IMPLEMENTATION STRATEGIES AT HENNEPIN HEALTHCARE, 2) DEVELOP A MICRO-THEORY OF IMPLEMENTING INTEGRATED CARE FOR MOTHERS WITH OUD BY INTERVIEWING KEY INFORMANTS AT SUCCESSFUL PROGRAMS, AND 3) FINALIZE THE IMPLEMENTATION PROTOCOL FOR A FUTURE MULTISITE IMPLEMENTATION TRIAL WITH PROSPECTIVE SITES. MY EXPERT MENTORING TEAM INCLUDES TWO ADDICTION MEDICINE PHYSICIANS, ONE SPECIALIZED IN SUBSTANCE USE IN PREGNANCY (JONES) AND THE OTHER AN EXPERIENCED CLINICAL TRIALIST AND PI OF A NIDA CTN NODE (BART); A PSYCHOLOGIST WITH EXPERTISE IN CLINICAL AND IMPLEMENTATION TRIALS RELATED TO SUBSTANCE TREATMENT WITHIN HEALTHCARE SYSTEMS (JAPUNTICH), AND AN IMPLEMENTATION SCIENTIST WITH EXPERIENCE IMPLEMENTING SUBSTANCE USE TREATMENT ACROSS THE VA HEALTHCARE SYSTEM (HAGEDORN). ADDITIONAL ADVISORS IN PERINATAL PSYCHIATRY (KIM) AND BIOSTATISTICS (LANGWORTHY), AND INSTITUTIONAL RESOURCES, MEAN I WILL HAVE THE FULL SUPPORT AND KNOWLEDGE NEEDED TO SUCCESSFULLY COMPLETE MY TRAINING AND STUDY AIMS AND ACHIEVE R01-LEVEL FUNDING TO CONDUCT A MULTISITE TRIAL.

DEVELOPMENT OF AN INTEGRATED DEPRESSION AND BEHAVIORAL RISK FACTOR REDUCTION INTERVENTION FOR SECONDARY PREVENTION FOLLOWING ACUTE CORONARY SYNDROME

STRATEGIES TO ADDRESS INFECTION PREVENTION AND TREATMENT IN THE REDUCED INFLAMMATORY MILIEU OF IRRIGATED OPEN WOUND.

WITHDRAWAL FROM DIALYSIS: ROLE OF DISEASE BURDEN, HEALTHCARE USE, AND FRAILTY

RYAN WHITE TITLE III HIV CAPACITY DEVELOPMENT AND PLANNING GRANTS

RESEARCH CONFERENCE TO DEVELOP A NATIONAL HEALTHCARE WORKFORCE WELLNESS RESEARCH AGENDA FOR AHRQ IN THE LEARNING HEALTH SYSTEM (LHS) PROGRAM - PROJECT SUMMARY/ABSTRACT THE AHRQ-SPONSORED CONFERENCE SERIES ON “DEVELOPING A RESEARCH AGENDA FOR WELLNESS WITHIN THE LHS FRAMEWORK” HAS AN OVERARCHING GOAL OF CREATING A FOUNDATION FOR DEVELOPMENT OF THE NEXT GENERATION OF HEALTHCARE WORKER (HCW) WELLNESS SCHOLARS AND EQUIPPING THEM WITH TOOLS TO CARRY OUT A STRUCTURED RESEARCH AGENDA ON HCW REACTIONS TO CHALLENGING WORK ENVIRONMENTS. THESE CONFERENCES WILL CONVENE A MULTIDISCIPLINARY GROUP OF STAKEHOLDERS STUDYING HCW WELLNESS AND WORK CULTURE. OUR OBJECTIVES ARE TO IDENTIFY PROMISING STRATEGIES TO STUDY HCW WELLNESS AND DEVELOP COMPETENCIES REQUIRED FOR THIS RIGOROUS AREA OF SCHOLARSHIP. THE YEAR 1 CONFERENCE WILL DEVELOP THE WORKFORCE PROTECTION RESEARCH AGENDA, WHILE THE YEAR 2 CONFERENCE WILL ASSEMBLE STAKEHOLDERS AND SCHOLARS TO DISSEMINATE FINDINGS AND BUILD CAREER DEVELOPMENT IN WELLNESS INTO LHS PROGRAMS. A “LEARNING COMMUNITY” ESTABLISHED BEFORE CONFERENCE 1 WILL SUSTAIN PROGRESS BETWEEN MEETINGS AND AFTER MEETING #2. THE CONFERENCES WILL FOCUS ON RESEARCH DEVELOPMENT, INTEGRATING THEMES RELATED TO AHRQ PRIORITY AREAS OF RESEARCH DESIGN, DISSEMINATION, IMPLEMENTATION, RESEARCH TRAINING AND CAREER DEVELOPMENT. A CORE GROUP OF WELLNESS SCHOLARS CALLED “EISENBERG SCHOLARS”, AFTER AHRQ’S FORMER LEADER JOHN EISENBERG, WILL BE SELECTED AND INVITED TO CONFERENCE 2 TO POPULATE AND CATALYZE A NEW RESEARCH COMMUNITY DEVOTED TO THIS WORK. APPLICABILITY TO PRIORITY POPULATIONS AND EQUITY IN RESEARCH WILL BE CORE ASPECTS OF EACH ACTIVITY.

PILOT STUDY OF ROLE OF CONTINUOUS TISSUE PH MEASUREMENT IN THE DIAGNOSIS OF ACUTE COMPARTMENT SYNDROME

DENTAL REIMBURSEMENT PROGRAM

BEHAVIORAL ECONOMIC MODELING OF TOBACCO AND ALCOHOL CO-ABUSE LIABILITY

SPECIAL PROJECTS OF NATIONAL SIGNIFICANCE

EARLY INTERVENTION SERVICES

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