Dartmouth-Hitchcock Clinic

CENTER FOR RURAL HEALTH CARE DELIVERY SCIENCE - PROJECT SUMMARY/ABSTRACT THIS CENTERS OF BIOMEDICAL RESEARCH EXCELLENCE (COBRE) PROPOSAL ESTABLISHES A CENTER FOR RURAL HEALTH CARE DELIVERY SCIENCE AT DARTMOUTH-HITCHCOCK HEALTH (D-HH), ONE OF THE MOST RURAL ACADEMIC MEDICAL CENTERS IN THE UNITED STATES. NEARLY 20% OF AMERICANS LIVE IN NON-METROPOLITAN AREAS AND EXPERIENCE POORER HEALTH OUTCOMES, BUT RESEARCH ON RURAL HEALTH CARE HAS BEEN LIMITED BY CHALLENGES ASSOCIATED WITH RELATIVELY SMALL AND GEOGRAPHICALLY DISPERSED POPULATIONS. ACCORDINGLY, OUR CENTER WILL CONCENTRATE ON UNDERSTANDING AND SOLVING CHALLENGES ASSOCIATED WITH THE PROVISION OF HEALTH CARE IN RURAL AREAS, FOCUSING ON A COMMUNITY- ENGAGED APPROACH TO RESEARCH. THE OVERARCHING GOAL OF THIS COBRE IS TO ESTABLISH A MULTIDISCIPLINARY RESEARCH PROGRAM IN RURAL HEALTH CARE DELIVERY SCIENCE AND TO PROVIDE EXPERT MENTORSHIP AND INFRASTRUCTURE TO TRAIN AND SUPPORT A CRITICAL MASS OF EARLY-CAREER CLINICIAN-SCIENTISTS AS THEY TRANSITION INTO INDEPENDENT RESEARCHERS DEDICATED TO DECREASING HEALTH CARE DISPARITIES IN RURAL COMMUNITIES. TO ACHIEVE THIS GOAL, THE CENTER WILL PURSUE THE FOLLOWING FOUR SPECIFIC AIMS: (1) INTEGRATE RESEARCH EXPERTISE, MENTORSHIP, AND COMMUNITY ENGAGEMENT TO ESTABLISH A CENTER FOR RURAL HEALTH CARE DELIVERY SCIENCE; (2) ENHANCE THE TRANSITION OF EARLY- CAREER CLINICIAN-SCIENTISTS INTO INDEPENDENT RESEARCHERS THROUGH STRONG RESEARCH SUPPORT AND DEDICATED MENTORING; (3) ASSURE ACCOUNTABILITY AND ACHIEVEMENT OF MILESTONES THROUGH THE IMPLEMENTATION OF A RIGOROUS PROGRAM EVALUATION PLAN; AND (4) LEVERAGE SHARED RESOURCES TO SUPPORT THE CENTER FOR RURAL HEALTH CARE DELIVERY SCIENCE AS A SELF-SUSTAINING SCIENTIFIC COMMUNITY. THE PROPOSED CENTER WILL BRING AN INNOVATIVE AND IMPACTFUL APPROACH TO RURAL HEALTH CARE DELIVERY RESEARCH BY FOCUSING ON THE FUNDAMENTAL CAUSES OF RURAL HEALTH DISPARITIES ACROSS SYSTEMS AND PROCESSES, AS WELL AS ADDRESSING BARRIERS THAT IMPEDE DISEASE DETECTION, ACCESS TO CARE, AND MANAGEMENT OF HEALTH CONDITIONS THAT ARE PARTICULARLY PREVALENT IN RURAL POPULATIONS. THE INITIAL FOUR RESEARCH PROJECT LEADERS WILL ADDRESS DISEASE PREVENTION AND SCREENING (PROJECT 1), DIGITAL HEALTH TECHNOLOGIES FOR DISEASE MANAGEMENT (PROJECT 2), AS WELL AS SOCIO-ECONOMIC FACTORS AND HEALTH POLICY THAT IMPACT THE MANAGEMENT OF COMPLEX CONDITIONS (PROJECT 3) AND THE PROVISION OF END-OF-LIFE CARE (PROJECT 4). THE CENTER'S SCIENTIFIC CORES WILL SUPPORT THE CENTER BY: (1) STRENGTHENING METHODOLOGY FOR MECHANISTIC STUDIES IN RURAL POPULATIONS; AND (2) PROVIDING NEEDED RESOURCES FOR EXPANDING AND STRENGTHENING CRITICAL RELATIONSHIPS BETWEEN RESEARCHERS AND KEY STAKEHOLDERS VIA COMMUNITY-BASED PARTICIPATORY RESEARCH. COBRE FUNDING, COUPLED WITH SUBSTANTIAL INSTITUTIONAL FUNDING AND A COMMITMENT TO HIRE ADDITIONAL FACULTY MEMBERS DURING PHASE I, WILL PROVIDE AN OUTSTANDING FOUNDATION FOR THE DEVELOPMENT OF A VIBRANT CENTER. IN SUMMARY, THE PROPOSED CENTER WILL SUPPORT THE ESTABLISHMENT OF A SELF-SUSTAINING, MULTIDISCIPLINARY RESEARCH PROGRAM IN RURAL HEALTH CARE DELIVERY SCIENCE AT D-HH.

DARTMOUTH CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE - THE COVID-19 PANDEMIC BROUGHT INTO STARK RELIEF THE MANY HEALTHCARE CHALLENGES FACING INDIVIDUALS LIVING IN RURAL AREAS—THE COMPOUNDED NEEDS OF AN AGING POPULATION, GEOGRAPHIC DISPERSION, INADEQUATE PUBLIC TRANSPORTATION, SPOTTY INTERNET SERVICE, SPIKES IN SUBSTANCE USE, VACCINE HESITANCY. THESE DISPARITIES—LIKE MOST PUBLIC HEALTH PROBLEMS—REFLECT A COMPLEX INTERPLAY OF BIOLOGICAL, ENVIRONMENTAL, PSYCHOLOGICAL, SOCIAL, AND SYSTEMS-LEVEL FACTORS. AT THE SAME TIME, THE PANDEMIC HIGHLIGHTED POTENTIAL SOLUTIONS AND SPURRED A WEALTH OF RESEARCH IN HEALTHCARE DELIVERY SCIENCE IN RURAL AREAS. MUCH OF THIS WORK WAS CONDUCTED BY SCIENTISTS AFFILIATED WITH SYNERGY, DARTMOUTH’S CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE, FOUNDED IN 2013. SYNERGY FACULTY REPORTED THE EXPANDED USE OF TELEHEALTH, DIGITAL HEALTH, MACHINE LEARNING; STRENGTHENED PARTNERSHIPS BETWEEN HEALTHCARE SYSTEMS AND COMMUNITY HEALTH CENTERS; AND DEVELOPED A “COVID COMPASS” TO GUIDE POLICYMAKING. OUR WORK IN THIS AREA, CENTERED IN SYNERGY’S EARLIEST YEARS, HAS DEEPENED OUR COMMITMENT TO TRANSLATIONAL SCIENCE THAT CENTERS RURAL HEALTHCARE DELIVERY AND HEALTH EQUITY, WHILE EXPLORING THE FULL SPECTRUM OF TRANSLATIONAL SCIENCE AND WORKFORCE DEVELOPMENT. HENCE, WE PROPOSE TO RETURN SYNERGY TO THE NATIONAL CTSA CONSORTIUM. THE OVERARCHING GOAL OF THIS APPLICATION IS TO CONTINUE TO SPUR INNOVATION IN CLINICAL AND TRANSLATIONAL SCIENCE WITH A FOCUS ON RURAL HEALTHCARE, IN COLLABORATION WITH OTHER CTSA HUBS, AND TO STUDY A NEW MODEL TO CATALYZE T3 TRANSLATIONAL SCIENCE IN HEALTHCARE SETTINGS. SYNERGY REFLECTS A CLOSE PARTNERSHIP BETWEEN DARTMOUTH HEALTH (DH) AND DARTMOUTH COLLEGE (DC). DH IS THE LARGEST HEALTHCARE SYSTEM IN NEW HAMPSHIRE, WITH ITS FLAGSHIP HOSPITAL IN A RURALLY DESIGNATED AREA. DC BRINGS THE RESOURCES OF A RESEARCH- INTENSIVE COLLEGE, INCLUDING SCHOOLS OF MEDICINE, ENGINEERING, BUSINESS, AND GRADUATE STUDIES. SYNERGY INCLUDES OUR NEW CENTER FOR RURAL HEALTHCARE DELIVERY SCIENCE AND KEY REGIONAL COLLABORATORS, INCLUDING THE NORTHERN NEW ENGLAND CLINICAL TRANSLATIONAL RESEARCH NETWORK (A PARTNERSHIP BETWEEN MAINEHEALTH AND THE UNIVERSITY OF VERMONT), A VETERANS AFFAIRS HOSPITAL, COMMUNITY GROUPS, AND A “PIPELINE” PROGRAM TO GROW THE SCIENTIFIC WORKFORCE. SYNERGY’S GOALS ARE TO (1) ACCELERATE THE DELIVERY OF EVIDENCE-BASED DIAGNOSTICS, THERAPEUTICS, AND PROCESSES TO ADDRESS THE HEALTHCARE NEEDS OF RURAL COMMUNITIES; (2) ASSURE THE AVAILABILITY OF TIMELY, ACTIONABLE PATIENT- AND POPULATION-LEVEL DATA TO MITIGATE THE TRANSLATIONAL BLOCK OF “SILOING” BETWEEN TRANSLATIONAL SCIENTISTS AND HEALTHCARE SYSTEM LEADERSHIP BY DEPLOYING A NOVEL COPRODUCTION LEARNING HEALTH SYSTEM (LHS); (3) TRAIN THE NEXT GENERATION OF TRANSLATIONAL SCIENTISTS, WITH A PARTICULAR FOCUS ON IDENTIFYING FUTURE LEADERS IN HEALTHCARE DELIVERY SCIENCE AND RURAL HEALTH; (4) DISSEMINATE THESE PRACTICES AND LESSONS LEARNED WITHIN THE CTSA COMMUNITY THROUGH ENGAGEMENT WITH SUBNETWORKS ADDRESSING RURAL HEALTH, IMPLEMENTATION SCIENCE, AND LEARNING HEALTH SYSTEMS SCIENCE; AND (5) INVOLVE LOCAL COMMUNITIES IN THE DESIGN, CONDUCT, ANALYSIS, AND DISSEMINATION OF OUR WORK, WHILE ENGAGING IN STUDIES OF STAKEHOLDER ENGAGEMENT.

WOMEN'S HEALTH AFTER ASSISTED REPRODUCTIVE TECHNOLOGY: A POPULATION-BASED STUDY

GERIATRICS WORKFORCE ENHANCEMENT PROGRAM

THERAPEUTIC TARGETING OF THE TUMOR MICROENVIRONMENT IN TRIPLE-NEGATIVE BREAST CANCER PATIENTS AT HIGH RISK OF RELAPSE AND PRECLINICAL MODELS OF LUNG METASTASES

NUCLEAR RECEPTOR CONTROL OF T CELL FUNCTION IN DISCRETE INTESTINAL MICROENVIRONMENTS - PROJECT SUMMARY THE GUT IS A CENTRAL IMMUNOLOGICAL ORGAN, WHERE HOST-MICROBE INTERACTIONS SHAPE IMMUNE TOLERANCE AND INFLAMMATION, BOTH LOCALLY AND SYSTEMICALLY. YET PREVAILING IMMUNOLOGICAL VIEWS CONFLATE THE TWO DISTINCT ORGANS THAT COMPRISE THE GUT—SMALL AND LARGE INTESTINE (OR SI AND LI)—WHICH IMPEDES MORE ROBUST UNDERSTANDING OF MUCOSAL IMMUNE REGULATION, AND MISSES OPPORTUNITIES TO DEVELOP SAFER, MORE TARGETED THERAPIES FOR HUMAN INFLAMMATORY BOWEL DISEASES (IBDS). THE PREMISE OF THIS APPLICATION, FOUNDED ON RECENT DISCOVERIES FROM, AND SYNERGY BETWEEN, THE TWO PIS (SUNDRUD, WEAVER), IS THAT MUCOSAL CD4+ T CELLS USE DISTINCT SETS OF NUCLEAR RECEPTORS (NRS) IN THE SI AND LI TO INTERFACE WITH DIVERGENT CLASSES OF HOST- AND MICROBE-DERIVED METABOLITES, RESPECTIVELY. RECENT WORK FROM THE SUNDRUD LAB ESTABLISHES THAT FOXP3- T EFFECTOR (TEFF) SUBSETS—TH1, TH17 CELLS—USE A NR WITH NO PREVIOUSLY KNOWN IMMUNOLOGICAL FUNCTION, THE CONSTITUTIVE ANDROSTANE RECEPTOR (CAR/NR1I3), TO DIRECT A ‘HEPATOCYTE-LIKE’ TRANSCRIPTIONAL RESPONSE TO CONTEND WITH POTENTIALLY CYTOTOXIC BILE ACID (BA) CONCENTRATIONS IN THE SI. A LARGE GRADIENT OF BAS EXISTS BETWEEN THE SI (MILLIMOLAR) AND LI (MICROMOLAR) DUE TO ‘ENTEROHEPATIC’ CIRCULATION—PRIMARY BAS SYNTHESIZED IN THE LIVER, STORED IN THE GALLBLADDER, AND SECRETED POST- PRANDIALLY INTO THE DUODENUM ARE ACTIVELY REABSORBED BY SPECIALIZED ENTEROCYTES IN THE ILEUM FOR PORTAL RECIRCULATION TO THE LIVER. BECAUSE BAS ARE LIPOPHILIC, THEY CAN BE TOXIC AND PRO-INFLAMMATORY IN ENTEROHEPATIC TISSUES; A HOST OF NUCLEAR RECEPTORS—INCLUDING CAR—HAVE EVOLVED TO SUPPRESS BA TOXICITY IN HEPATOCYTES AND ENTEROCYTES. OUR DATA SUGGEST THAT ENTEROHEPATIC CIRCULATION CREATES A UNIQUELY HARSH SI MICROENVIRONMENT TO WHICH INFILTRATING T CELLS MUST ADAPT TO MAINTAIN TOLERANCE AND TISSUE HOMEOSTASIS. THE LI, BY CONTRAST, HARBORS 103-107 TIMES MORE BACTERIA THAN THE SI, AND ~1000-FOLD LESS BAS. ACCORDINGLY, MICROBES AND THEIR METABOLITES— SHORT CHAIN FATTY ACIDS (SCFAS; E.G., BUTYRATE), SECONDARY BAS (PRODUCED VIA MICROBIAL METABOLISM OF RESIDUAL PRIMARY BAS)—BECOME CENTRAL TO IMMUNE REGULATION IN THE LI. SCFAS INHIBIT HISTONE DEACETYLASE ENZYMES (HDACS) AND STABILIZE FOXP3 GENE EXPRESSION IN PERIPHERALLY-INDUCED T REGULATORY CELLS (ITREGS), WHEREAS SECONDARY BAS PROMOTE LI TREG MAINTENANCE THROUGH ANOTHER NR, VITAMIN D RECEPTOR (VDR). THUS, WHILE ANTIGENS FROM THE ENTERIC FLORA ARE REQUIRED FOR PRIMING BOTH PRO- AND ANTI-INFLAMMATORY T CELL RESPONSES THROUGHOUT THE INTESTINAL TRACT, WE HYPOTHESIZE THAT MARKED DIFFERENCES IN THE ABUNDANCE OF BUGS AND BILE IN THE SI VS. LI ESTABLISH CONSEQUENTIAL METABOLITE GRADIENTS THAT ARE SENSED BY DIFFERENT NRS TO INSTRUCT COMPARTMENTALIZED T CELL REGULATORY FUNCTIONS. WE TEST THIS HYPOTHESIS THROUGH COMPLEMENTARY, BUT NOT INTER- DEPENDENT, AIMS, LEVERAGING NEW MOUSE MODELS, AS WELL AS A LIBRARY OF RECOMBINANT PROTEIN-BASED NR ACTIVITY ASSAYS, TO DEFINE THE MECHANISMS GOVERNING THE TRANSCRIPTIONAL REGULATION, BIOCHEMICAL ACTIVATION, AND DOWNSTREAM CELLULAR FUNCTIONS OF CAR (IN SI TEFF CELLS) AND VDR (IN LI ITREG CELLS). SUCCESSFUL COMPLETION OF THESE AIMS WILL ESTABLISH NEW BIOLOGICAL PARADIGMS AND INFORM MORE PRECISE APPROACHES TO TREAT HUMAN IBDS.

DARTMOUTH REGIONAL PEDIATRIC CLINICAL TRIALS UNIT

CANNABIS, SCHIZOPHRENIA AND REWARD: SELF-MEDICATION AND AGONIST TREATMENT

TRAINING GERIATRIC MENTAL HEALTH SERVICES RESEARCHERS

COREGISTERED FLUORESCENCE-ENHANCED RESECTION OF MALIGNANT GLIOMA

NRSA FOR PRIMARY MEDICAL CARE

(PQ2) PD-L1/PD-1 SIGNALS IN AGED HOSTS UNDERGOING CANCER IMMUNOTHERAPY

GERIATRICS WORKFORCE ENHANCEMENT PROGRAM

URBAN-RURAL DISPARITIES IN HEALTHCARE QUALITY FOR CHILDREN WITH COMPLEX OR DISABLING HEALTH CONDITIONS

OPTIMIZING COLORECTAL CANCER PREVENTION: A MULTI-DISCIPLINARY, POPULATION-BASED INVESTIGATION OF SERRATED POLYPS USING RISK PREDICTION AND MODELING

FIRST-IN-HUMAN CLINICAL TRANSLATION OF A NEAR-INFRARED, NERVE-SPECIFIC FLUOROPHORE TO FACILITATE TISSUE-SPECIFIC FLUORESCENCE-GUIDED SURGERY

AUTOMATED TELEHEALTH TO IMPROVE PSYCHIATRIC SELF-MANAGEMENT AND COMMUNITY TENURE

DARTMOUTH/PENN RESEARCH ETHICS TRAINING AND PROGRAM DEVELOPMENT FOR TANZANIA

INCISIONAL NEGATIVE PRESSURE WOUND THERAPY TO REDUCE INFECTION AND COMPLICATIONS IN HIGH RISK FRACTURES A MULTICENTER RANDOMIZED CONTROLLED TRIAL

CENTER FOR AGING WITH SERIOUS ILLNESS (CASI) - THIS PHASE I CENTERS OF BIOMEDICAL RESEARCH EXCELLENCE (COBRE) PROPOSAL ESTABLISHES THE CENTER FOR AGING WITH SERIOUS ILLNESS (CASI) AT DARTMOUTH HEALTH (DH). THE GROWING NUMBER OF OLDER ADULTS LIVING WITH CHRONIC, SERIOUS ILLNESS REPRESENTS ONE OF THE MOST PRESSING PUBLIC HEALTH CHALLENGES IN THE UNITED STATES. HOWEVER, RESEARCH ADDRESSING THE UNIQUE NEEDS OF THIS POPULATION HAS NOT KEPT PACE WITH ITS RAPID EXPANSION. BUILDING A ROBUST EVIDENCE BASE TO IMPROVE THE QUALITY OF LIFE FOR THIS GROUP IS CRITICAL TO ADVANCING HEALTHCARE. TO ADDRESS THIS GAP, IT IS ESSENTIAL THAT RESEARCH BE DESIGNED TO NAVIGATE THE COMPLEXITIES OF PROVIDING CARE FOR OLDER ADULTS FACING SERIOUS ILLNESS. THE PRIMARY GOAL OF THIS COBRE IS TO CREATE THE FOUNDATIONAL INFRASTRUCTURE REQUIRED TO DEVELOP A MULTIDISCIPLINARY RESEARCH PROGRAM FOCUSED ON AGING WITH SERIOUS ILLNESS AL DH, ONE OF THE MOST RURAL ACADEMIC MEDICAL CENTERS IN THE COUNTRY. THIS PROGRAM WILL PROVIDE EXPERT MENTORSHIP, PROTECTED RESEARCH TIME, AND INSTITUTIONAL SUPPORT TO RECRUIT AND NURTURE A CRITICAL MASS OF EARLY-CAREER CLINICIAN-SCIENTISTS, FACILITATING THEIR TRANSITION INTO INDEPENDENT RESEARCHERS DEDICATED TO IMPROVING CARE FOR OLDER ADULTS WITH SERIOUS ILLNESS. TO ACHIEVE THIS OVERARCHING GOAL, CASI WILL PURSUE THREE SPECIFIC AIMS: (1) ESTABLISH A ROBUST FRAMEWORK THAT INTEGRATES RESEARCH EXPERTISE AND MENTORSHIP TO FORMALIZE CASI AND STRENGTHEN DH'S RESEARCH INFRASTRUCTURE, IN COLLABORATION WITH AFFILIATE INSTITUTIONS; (2) DEVELOP A STRUCTURED PATHWAY TO SUPPORT EARLY-CAREER CLINICIANSCIENTISTS AS RESEARCH PROJECT LEADERS (RPLS) AND ENHANCE THEIR TRANSITION TO INDEPENDENT INVESTIGATORS THROUGH TAILORED, MILESTONE-DRIVEN RESEARCH PLANS; AND, (3) ENSURE THE SUCCESS OF RPLS AND PILOT PROJECT LEADERS BY PROVIDING COMPREHENSIVE TECHNICAL ASSISTANCE THROUGH THE BIOSTATISTICS, ETHICS, DATA MANAGEMENT, RESEARCH DESIGN, AND COMMUNITY ENGAGEMENT (BEDROC) CORE, WHICH WILL SERVE THE BROADER DH RESEARCH COMMUNITY FOCUSED ON IMPROVING CARE FOR OLDER ADULTS WITH SERIOUS ILLNESS. CASI WILL CONCENTRATE ON BUILDING A NETWORK OF EXPERTS WHO WILL CONDUCT CLINICAL, BEHAVIORAL, AND HEALTH SERVICES RESEARCH TO ADDRESS THE CHALLENGES FACED BY OLDER ADULTS WITH SERIOUS ILLNESS. OUR INVESTIGATORS WILL FOCUS ON SOLVING KEY ISSUES IN AGING WITH SERIOUS ILLNESS AND USE THEIR FINDINGS TO INFORM HEALTHCARE POLICY AND STAKEHOLDER DECISION-MAKING. THE INITIAL THREE RPLS WILL FOCUS ON SHARED DECISION-MAKING FOR SURGERY IN OLDER ADULTS, PALLIATIVE CARE FOR OLDER PATIENTS WITH CANCER, AND MANAGEMENT OF OSTEOARTHRITIS IN OLDER ADULTS WITH MULTIMORBIDITY. THE BEDROC CORE WILL SUPPORT CASI BY: (1) PROVIDING THE THREE RPLS SPECIALIZED EXPERTISE IN STATISTICAL ANALYSIS, RESEARCH ETHICS, AND COMMUNITY ENGAGEMENT TO AID IN THE PLANNING AND EXECUTION OF THEIR PROJECTS, AND (2) CREATING AN INNOVATIVE LEARNING COLLABORATIVE THAT PROVIDES WORKSHOPS, TUTORIALS, RESOURCES, AND SERVICES TO PROMOTE CONTINUOUS RESEARCHER DEVELOPMENT. COBRE FUNDING, COMBINED WITH SUBSTANTIAL INSTITUTIONAL INVESTMENT AND PLANS TO HIRE ADDITIONAL FACULTY, WILL LAY A STRONG FOUNDATION FOR CREATING A SELF-SUSTAINING, VIBRANT CENTER. THIS CENTER WILL FOSTER INDEPENDENT INVESTIGATORS WHOSE WORK WILL ULTIMATELY IMPROVE THE CARE AND QUALITY OF LIFE FOR OLDER ADULTS.

REAL-TIME FLUORESCENCE-BASED MEASUREMENT OF BONE PERFUSION IN POST-TRAUMATIC INFECTION

BILE ACID-DEPENDENT T CELL REGULATION IN THE INTESTINE

NUCLEAR RECEPTOR NETWORKS IN MUCOSAL IMMUNE REGULATION - PROJECT SUMMARY THE GUT IS A MAJOR IMMUNOLOGICAL ORGAN WHERE HOST-MICROBE INTERACTIONS SHAPE BOTH LOCAL AND SYSTEMIC IMMUNE TOLERANCE. HOWEVER, CURRENT VIEWS OF INTESTINAL IMMUNE REGULATION IGNORE FUNDAMENTAL DIFFERENCES IN THE FUNCTION AND METABOLITE COMPOSITION OF THE TWO DISTINCT ORGANS THAT COMPRISE THE GUT—THE SMALL AND LARGE INTESTINE (OR SI AND LI). THIS IMPEDES A MORE DETAILED UNDERSTANDING OF IMMUNE REGULATORY MECHANISMS ALONG THE INTESTINAL TRACT, AND LIMITS EFFORTS TO DEVELOP SAFER, MORE TARGETED TREATMENTS FOR THE TWO MAJOR FORMS OF HUMAN INFLAMMATORY BOWEL DISEASES (IBDS), ULCERATIVE COLITIS AND SMALL BOWEL CROHN’S DISEASE. WE HYPOTHESIZE THAT MUCOSAL CD4 T CELLS USE DIFFERENT SETS OF LIGAND-REGULATED NUCLEAR RECEPTORS (NRS) IN THE SI AND LI TO CONTROL KEY REGULATORY FUNCTIONS, INCLUDING IL-10 EXPRESSION, TO LOCAL CONCENTRATION GRADIENTS OF BILE- AND MICROBE-DERIVED METABOLITES. ON ONE HAND, WE HAVE DISCOVERED THAT FOXP3– EFFECTOR (TEFF) SUBSETS IN THE SI—INCLUDING TH1 AND TH17 CELLS— UTILIZE THE NUCLEAR XENOBIOTIC RECEPTOR, CONSTITUTIVE ANDROSTANE RECEPTOR (CAR/NR1I3), TO DIRECT A ‘HEPATOCYTE-LIKE’ TRANSCRIPTIONAL RESPONSE TO CONTEND WITH HIGH LOCAL BILE ACID (BA) CONCENTRATIONS, WHICH ARE FAR GREATER IN SI THAN IN LI (MILLIMOLAR VS MICROMOLAR) DUE TO ‘ENTEROHEPATIC’ CIRCULATION—WHERE PRIMARY BAS SYNTHESIZED IN THE LIVER, STORED IN THE GALLBLADDER, AND SECRETED INTO THE DUODENUM ARE ACTIVELY REABSORBED BY SPECIALIZED ENTEROCYTES IN THE ILEUM FOR PORTAL RECIRCULATION TO THE LIVER. BECAUSE BAS ARE LIPOPHILIC, THEY CAN BE TOXIC AND PRO-INFLAMMATORY, AND SEVERAL NUCLEAR RECEPTORS—INCLUDING CAR—HAVE EVOLVED TO SUPPRESS BA TOXICITY. THESE STUDIES SUGGEST THAT ENTEROHEPATIC CIRCULATION ESTABLISHES A UNIQUE SI MICROENVIRONMENT THAT IS DISTINCT FROM THAT IN THE LI AND REQUIRES UNIQUE TRANSCRIPTIONAL MACHINERY TO PROTECT T CELLS IN THE SI. CONVERSELY, THE LI HARBORS 103-107 TIMES MORE BACTERIA THAN SI, AND ~1000-FOLD LOWER BA CONCENTRATIONS. ACCORDINGLY, MICROBES AND THEIR METABOLITES— SHORT CHAIN FATTY ACIDS (SCFAS; E.G., BUTYRATE), SECONDARY BAS (PRODUCED VIA MICROBIAL METABOLISM OF RESIDUAL PRIMARY BAS)—ARE CENTRAL TO IMMUNE REGULATION IN THE LI. SCFAS INHIBIT HISTONE DEACETYLASE ENZYMES (HDACS) AND STABILIZE FOXP3 GENE EXPRESSION IN PERIPHERALLY-INDUCED T REGULATORY CELLS (ITREGS), WHEREAS SECONDARY BAS APPEAR TO PROMOTE REGULATORY FUNCTIONS OF RORGT+ TREGS IN THE LI THROUGH ANOTHER NR, VITAMIN D RECEPTOR (VDR). THUS, WHILE ANTIGENS FROM THE ENTERIC FLORA PRIME BOTH PRO- AND ANTI-INFLAMMATORY T CELL RESPONSES THROUGHOUT THE GUT, MARKED CONCENTRATION GRADIENTS OF BILE- AND BACTERIA-DERIVED METABOLITES IN THE SI VS. LI ARE SENSED BY DIFFERENT NRS TO EXECUTE COMPARTMENTALIZED T CELL REGULATORY FUNCTIONS. IN TESTING THIS HYPOTHESIS, WE WILL APPLY CUTTING-EDGE GENOMICS AND COMPUTATIONAL APPROACHES TO COMPREHENSIVELY MAP THE CONTRIBUTIONS OF EACH OF THE 49 MOUSE NRS TO SPECIALIZED REGULATORY FUNCTIONS IN THE SI AND LI IN VIVO, USING IL-10 EXPRESSION AS THE PRIMARY SCREENING TARGET. WE WILL ALSO INTERROGATE THE REGULATION AND MOLECULAR FUNCTIONS OF TWO KEY NRS, CAR/NR1I3 AND VDR/NR1I1, IN SI TYPE 1 REGULATORY (TR1) AND LI ITREG CELLS, RESPECTIVELY. THESE STUDIES WILL ADVANCE UNDERSTANDING OF LYMPHOCYTE SPECIALIZATION IN THE GUT, AND INFORM NEW APPROACHES TO TREAT IBDS.

NCI NATIONAL CLINICAL TRIALS NETWORK - NETWORK LEAD ACADEMIC PARTICIPATING SITES (UG1)

HARM REDUCTION FOR SMOKERS WITH MENTAL ILLNESS: RCT OF E-CIGARETTE PROVISION WITH OR WITHOUT BEHAVIORAL SUPPORT TO BOOST SWITCHING - PROJECT SUMMARY/ABSTRACT AMONG THE 51.5 MILLION US ADULTS WITH MENTAL ILLNESS (MI), OVER 18 MILLION SMOKE CIGARETTES, 7-9,50-52 LEADING TO HIGH MORBIDITY60-62 AND DRAMATIC EARLY MORTALITY.12-14 SMOKERS WITH MI ARE LESS LIKELY TO QUIT AND/OR SUSTAIN ABSTINENCE THAN SMOKERS WITHOUT MI,17-21 DUE IN PART TO LOWER SELF-EFFICACY65 AND MORE USE OF SMOKING TO COPE WITH STRESS.67-69 LOWER LEVELS OF READINESS TO PURSUE SMOKING CESSATION TREATMENTS,64,66 MOST OF WHICH REQUIRE A DESIRE FOR COMPLETE ABSTINENCE, LEAVES MOST SMOKERS WITH MI CONTINUING TO SMOKE, CREATING AN URGENT NEED TO DEVELOP NEW WAYS TO DECREASE THE HARMS FROM CIGARETTES. TOBACCO HARM REDUCTION IS NOT CLEARLY DEFINED, BUT IT INVOLVES A VALUE-NEUTRAL VIEW OF SMOKING, FOCUSED ON DECREASING THE HARMS FROM TOBACCO USE, NEITHER OBJECTING TO NOR INSISTING ON ABSTINENCE AS THE ONLY GOAL.71 E-CIGARETTES (E-CIGS) DELIVER MUCH LOWER LEVELS OF CARCINOGENS THAN CIGARETTES;72,73 THUS, SUPPORT FOR REPLACEMENT OF MOST OR ALL CIGARETTES WITH E-CIGS (“SWITCHING”) MAY BE AN EFFECTIVE HARM REDUCTION STRATEGY FOR SMOKERS WITH MI. THREE PILOT STUDIES FOUND THAT PROVIDING E-CIGS TO SMOKERS WITH MI SIGNIFICANTLY REDUCED USE OF CIGARETTES (UP TO 65%),34-36 AND 10-14.3% OF SMOKERS REPLACED THEIR CIGARETTES WITH E-CIGS.34,35 IN THE ONLY RCT COMPARING E-CIG PROVISION TO SMOKING-AS-USUAL IN SMOKERS WITH MI (R01DA041416), WE FOUND THAT 18.6% OF THE E-CIG GROUP SWITCHED TO E-CIGS, 46% REDUCED TO ≤5 CIGS/DAY, AND NNAL, A POTENT CARCINOGEN, WAS SIGNIFICANTLY REDUCED.3 BUT, MANY SMOKERS DID NOT ACHIEVE HARM REDUCTION WITH E-CIG PROVISION ALONE. FEEDBACK FROM PARTICIPANTS INDICATED THAT A KEY BARRIER TO GIVING UP CIGARETTES WAS THE HABITUAL USE OF CIGARETTES WHEN UNDER STRESS. THIS STUDY RESPONDS TO PAR-22-182’S CALL FOR “RESEARCH ON TOBACCO HARM REDUCTION STRATEGIES SUCH AS SWITCHING FROM COMBUSTIBLES TO E-CIGARETTES.” WE DEVELOPED AND PILOTED “SWITCH IT,” CONSISTING OF BEHAVIORAL SUPPORT TO BOOST E-CIG USE AND MANAGE STRESS, FOR SMOKERS WITH MI WHO ARE NOT READY TO QUIT. SWITCH IT WAS DELIVERED TO 50 SMOKERS WITH MI VIA 10 VIDEO CALLS. ATTENDANCE WAS 90.3%, INDICATING HIGH APPEAL OF BEHAVIORAL SUPPORT. TWICE AS MANY SMOKERS (38% VS. 19%) SWITCHED TO E-CIGS (CONFIRMED BY BREATH CO<10 PPM) COMPARED TO THE E-CIG GROUP IN OUR RCT. WE NOW PROPOSE TO TEST THE EFFECT OF SWITCH IT ON “SWITCHING” USING SEVERAL MEASURES OF HARM REDUCTION (≤5 CIGS/DAY AND CO<10; 0 CIGS/DAY AND CO<6, AND NNAL). WE WILL ALSO EXPLORE POTENTIAL BARRIERS TO SWITCHING (CRAVINGS, POSITIVE AND NEGATIVE AFFECT, E-CIG SATISFACTION) AND POSSIBLE MECHANISMS OF BEHAVIORAL CHANGE FROM SWITCH IT (COPING WITH STRESS WITHOUT SMOKING, AND SELF-EFFICACY). FINALLY, WE WILL EXPLORE THE ROLE OF E-CIGS IN SWITCHING BY COMPARING TRAJECTORIES OF CHANGE IN CIGARETTE AND E-CIG USE OVER TIME. WE WILL ASSIGN 250 SMOKERS WITH MI IN 2 US STATES TO RECEIVE SWITCH IT AND AN 8-WEEK SUPPLY OF E-CIGS OR E-CIGS ONLY. PARTICIPANTS WILL BE ASSESSED AT BL, 2, 4, 6, 8, 12, AND 26 WEEKS. THIS PROJECT WOULD BREAK NEW GROUND AND ADVANCE THE FIELD OF TOBACCO HARM REDUCTION BY EMPIRICALLY EXPLORING DEFINITIONS OF HARM REDUCTION AND “SWITCHING,” AND TESTING THE EFFICACY OF USING BEHAVIORAL SUPPORT FOR E-CIG USE TO AUGMENT HARM REDUCTION IN SMOKERS WITH MI.

OPTIMIZING SURGICAL DEBRIDEMENT FOLLOWING HIGH-ENERGY, OPEN TRAUMA WITH DYNAMIC, CONTRAST-ENHANCED FLUORESCENCE IMAGING

REGIONAL HYPOXIA IMPACTS THE HETEROGENEITY OF INFLAMMATORY LUNG DISEASE

IMPACT OF TISSUE RESIDENT MEMORY T CELLS ON THE NEURO-IMMUNEPATHOPHYSIOLOGY OF ANTERIOR EYE DISEASE - ABSTRACT T CELLS ARE MAJOR CLINICAL TARGETS FOR ANTI-INFLAMMATORY TREATMENT OF PERSISTENT OCULAR PAIN INDUCED BY ANTERIOR EYE DISEASES SUCH AS DRY EYE, YET IDENTIFICATION OF WHICH T CELL SUBSETS DRIVE THE PATHOPHYSIOLOGY OF ANTERIOR EYE DISEASE REMAINS A TOPIC OF INTENSIVE PRECLINICAL INVESTIGATION. EMERGING DATA SHOWS THAT A RELATIVELY RECENTLY DISCOVERED PRO-INFLAMMATORY SUBSET OF T CELLS THAT RARELY RE-ENTER CIRCULATION DOMINATE THE T CELL NICHE ON THE OCULAR SURFACE OF HUMANS, BUT ARE ALMOST NONEXISTENT IN PRECLINICAL MODELS OF DRY EYE DISEASE. ESTABLISHMENT OF THESE TISSUE RESIDENT MEMORY T CELLS (TRM) IN THE EYE REQUIRES PATHOGEN EXPOSURE OR VACCINATION, AND BECAUSE WE HOUSE LABORATORY RODENTS IN UNNATURALLY CLEAN ENVIRONMENTS, THEY HAVE EXTREMELY LIMITED EXPOSURE TO PATHOGENS. THIS LACK OF IMMUNOLOGIC EXPERIENCE HAS PRECLUDED THE USE OF EXTANT RODENT MODELS TO INVESTIGATE THE IMPACT OF TRM IN NEURO-IMMUNE MECHANISMS OF ANTERIOR EYE DISEASE, AND THE POTENTIAL INTERACTION BETWEEN TRM AND NOCICEPTORS IN OCULAR INFLAMMATION AND PAIN REMAINS A PRESSING GAP IN KNOWLEDGE. WE PROPOSE TO ADDRESS THIS GAP BY INFECTING MICE WITH A CLINICALLY RELEVANT OCULAR PATHOGEN TO ESTABLISH A POPULATION OF “HUMAN- LIKE” TRM IN THE EYE THAT CAN BE SPECIFICALLY TARGETED FOR ACTIVATION OR DEPLETION. USING THIS RODENT MODEL, WE WILL MODULATE THE ACTIVITY/PRESENCE OF TRM AND/OR NOCICEPTORS IN THE ANTERIOR EYE TO TEST THE CENTRAL HYPOTHESIS THAT TRM AND NOCICEPTORS ENGAGE IN BIDIRECTIONAL NEURO-IMMUNE INTERACTIONS THAT CAUSE OCULAR PAIN AND INFLAMMATION. THESE STUDIES WILL GAIN CRITICAL INSIGHTS INTO NEURO-IMMUNE MECHANISMS THAT DRIVE THE PATHOPHYSIOLOGY OF ANTERIOR EYE DISEASE, AND SHOW HOW PRIOR VIRAL INFECTION SHAPES THE MANIFESTATION OF SUBSEQUENT NEURO-INFLAMMATION. THIS WORK WILL INFORM INNOVATIVE AVENUES FOR THE TREATMENT OF OCULAR PAIN AND INFLAMMATION, AND BEAR BROAD IMPACT IN THE FIELD OF NEURO-IMMUNOLOGY THROUGH A FIRST-EVER INVESTIGATION OF TRM INTERACTIONS WITH THE SENSORY NERVOUS SYSTEM.

MELANOCYTE PDL1 CONTROL OF UVB-INDUCED IFN-I - THIS NEW R01 PROPOSAL ASSEMBLES A TEAM WITH EXPERTISE IN TUMOR IMMUNOLOGY AND IMMUNOTHERAPY, MOUSE CANCER MODELS, MELANOMA, IFN-I SIGNALS, TUMOR SIGNALING, SINGLE CELL SPATIAL OMICS AND NOVEL STATISTICAL APPROACHES. WE DEVELOPED AN AUTOCHTHONOUS MELANOMA MODEL TO GENERATE TUMORS FROM MELANOMA CELLS OF ORIGIN (MELANOCYTES) THAT ARE PDL1KO OR CTRL AND BEAR THE NRASQ61R MUTATION. OUR OVERARCHING HYPOTHESIS IS THAT UVB ELICITS LOCAL AND SYSTEMIC MELPDL1-DEPENDENT IFN-I PRODUCTION THAT PROMOTES MELANOMA PROGRESSION AND TREATMENT RESISTANCE THROUGH TUMOR INFLAMMATORY MEMORY. GENERAL APPROACHES. WE COMPARE OUTCOMES OF MELANOCYTE PDL1 (MELPDL1) EXPRESSION ON TUMOR IMMUNE SURVEILLANCE AND TME COMPOSITION AND TUMOR PROGRESSION IN AUTOCHTHONOUS MELANOMAS INDUCED ± UVB. TRANSPLANTABLE TUMOR LINES FROM AUTOCHTHONOUS TUMORS WILL BE GENETICALLY ENGINEERED AND USED IN DISTINCT HOSTS TO TEST TUMOR SIGNAL EFFECTS MEDIATING RELEVANT OUTCOMES TO CONFIRM MECHANISMS. THESE OUTCOMES WILL BE COMPARED TO DATA FROM HUMAN MATERIALS TO VALIDATE HUMAN RELEVANCE. AIM 1 TEST THE HYPOTHESIS THAT UVB-INDUCED IFN-I ELICITS MELPDL1-DEPENDENT INFLAMMATORY MEMORY. CTRL VERSUS MELPDL1KO MT/MG TNQ61R MICE (WITH A MELANOCYTE EGFP REPORTER) WILL BE INDUCED ± UVB. TME EFFECTS WILL BE ASSESSED BY SPECTRAL FLOW CYTOMETRY, RPPA, BULK RNA-SEQ, SCRNA-SEQ AND SPATIAL IMAGING APPROACHES. CELL-CELL INTERACTIONS ARE TESTED BY COMMOT AND CONFOCAL IMAGING. IFN-I EFFECTS ARE TESTED BY ΑIFNAR AND IFN-I QUANTIFICATION. EFFECTS ON TUMOR-SPECIFIC IMMUNITY USE PMEL CELLS WITH GENE REPORTERS OR IFNARKO FOR CELL EFFECTOR FUNCTION AND TRAFFICKING ASSAYS. OUTCOMES INCLUDE TUMOR INFLAMMATORY MEMORY, LATENCY AND GROWTH CONTROL. DETAILED MECHANISMS ARE INTERROGATED WITH TRANSPLANTABLE LINES FROM AUTOCHTHONOUS TUMORS ENGINEERED TO TEST SPECIFIC MOLECULES AND PATHWAYS. HUMAN RELEVANCE IS CONFIRMED IN HUMAN TISSUES. AIM 2 TEST THE HYPOTHESIS THAT ACUTE UVB AFFECTS LATER MELANOMA TREATMENT RESPONSES. EFFECTS OF UVB AND IFN-I ON TREATMENT RESISTANCE (E.G., THROUGH TUMOR INFLAMMATORY MEMORY VERSUS ALTERNATIVES) ARE ASSESSED WITH IMMUNE CHECKPOINT BLOCKADE AND SELECTED SMALL MOLECULE INHIBITORS. MECHANISMS ARE DEFINED USING ABOVE APPROACHES. CUTANEOUS UVB AND IFN-I EFFECTS ON METASTATIC SITES (TUMOR DRAINING LYMPH NODES, LUNGS) WILL BE ELUCIDATED AND PRELIMINARY STUDIES DONE, BUT LOGISTICS PREVENT FULL DETAILED MECHANISTIC STUDIES. METASTASES ARE TRACKED BY IMAGING AND IDENTIFIED IN RNA-SEQ DATA SETS USING MT/MG MICE. NOVEL STATISTICAL ANALYTIC APPROACHES ARE USED FOR ALL OUTCOMES, ESPECIALLY SCRNASEQ AND SPATIAL IMAGING.

BLADDER CANCER PD-L1 CONTROL OF HOMOLOGOUS RECOMBINATION: BASIC MECHANISMS APPLIED TO NOVEL TREATMENTS - THIS REVISED MPI PROPOSAL ASSEMBLES EXPERTS IN BLADDER CANCER, TUMOR BIOLOGY, DNA DAMAGE RESPONSE (DDR) AND PRE-CLINICAL MODELS WITH A LONG-STANDING HISTORY OF PRODUCTIVE COLLABORATIONS TO STUDY EFFECTS OF INTRACELLULAR BLADDER CANCER PD-L1 SIGNALS ON BRCA1-MEDIATED DDR, AND HOW SUCH SIGNALS ALTER SENSITIVITY TO PARP INHIBITORS AND IMMUNE CHECKPOINT BLOCKADE IMMUNOTHERAPY IN ORTHOTOPIC/METASTATIC MOUSE AND HUMAN MODELS. WE TEST TRANSPLANTABLE MOUSE BLADDER CANCER LINES MB49 AND MBT-2, AND THE HUMAN BLADDER CANCER LINES RT4, UM-UC3 AND UM-UC14, REPRESENTING BASAL AND LUMINAL HISTOLOGIES PLUS NEW PDX, XENOGRAFT AND ORGANOID MODELS AND OUR NOVEL GEMM ALL PER REVIEWER REQUEST . INTRACELLULAR PD-L1 SIGNALS ARE INTERROGATED USING CONTROL VERSUS GENETICALLY MANIPULATED TUMORS AND OTHER APPROACHES INCLUDING NEW NON-BIOCHEMICAL APPROACHES PER REVIEWER REQUEST . WE WILL USE THESE CLINICALLY RELEVANT MODELS TOGETHER TO TEST OUR OVERARCHING HYPOTHESIS THAT BLADDER CANCER PD-L1 SIGNALS PROMOTE THE HOMOLOGOUS RECOMBINATION DDR PATHWAY THAT SUPPRESSES PARP INHIBITOR AND IMMUNE CHECKPOINT BLOCKADE IMMUNOTHERAPY EFFICACY. AIM 1: DEFINE MECHANISMS FOR PD-L1-MEDIATED CONTROL OF HR. WE WILL USE WELL-VALIDATED GENETIC, BIOCHEMICAL AND PHARMACOLOGIC APPROACHES PLUS DEFINITIVE CELL REPORTER ASSAYS FOR HOMOLOGOUS RECOMBINATION, RNA-SEQ, PROTEOMICS, RPPA, IMMUNOBLOTS, CRISPR LIBRARY SCREENS, ORGANOIDS AND DIGITAL IMAGING WITH IMAGE ANALYSIS SOFTWARE TO UNDERSTAND HOW PD-L1 REGULATES BRCA1 FUNCTIONALITY AND TO TEST MECHANISMS, INCLUDING FOR TUMOR IMMUNOGENICITY. WE IDENTIFIED FDA-APPROVED PHARMACOLOGIC AGENTS THAT WE REPURPOSED TO DEPLETE TUMOR PD-L1 AND INHIBIT HR, FOR WHICH WE DEFINE MECHANISMS. AIM 2: DEFINE TREATMENT CONSEQUENCES OF PD-L1 CONTROLLED HOMOLOGOUS RECOMBINATION/BRCA1 EFFECTS. CONTROL VERSUS GENETICALLY PD-L1 DEPLETED CELLS WITH GENETIC PERTURBATIONS OF BRCA1 AND RELATED MOLECULES WILL BE TESTED FOR IN VIVO EFFECTS BY CHALLENGING ENGINEERED CELLS INTO MICE AND TREATING WITH SINGLE AGENTS OR COMBINATIONS, BASED ON FINDINGS FROM AIM 1 TO ASSESS TREATMENT EFFICACY AND SPECIFIC MECHANISMS. WE USE TRANSPLANTABLE, SYNGENEIC MOUSE MODELS, AND HUMAN XENOGRAFT AND HUMANIZED MOUSE MODELS IN WHICH WE HAVE EXTENSIVE EXPERIENCE. NOTABLY, WE WILL ASSESS TUMOR MICROENVIRONMENTAL AND IMMUNE CONTRIBUTIONS TO TREATMENTS USING GENETICALLY IMMUNE ALTERED MICE, ADOPTIVE CELL TRANSFERS AND IMMUNE BLOCKING/NEUTRALIZING MOLECULES. IN VIVO DATA ARE MECHANISTICALLY REFINED IN IN VITRO ASSAYS IN WHICH WE ARE EXPERT. PDX, ORGANOIDS

PEER SUPPORT AND MOBILE TECHNOLOGY TARGETING CARDIOMETABOLIC RISK REDUCTION IN YOUNG ADULTS WITH SMI

ADVANCED RESEARCH INSTITUTE IN GERIATRIC MENTAL HEALTH

DARTMOUTH LEAD PARTICIPATION IN NCI NATIONAL CLINICAL TRIALS NETWORK

THE APPEAL AND IMPACT OF E-CIGARETTES IN SMOKERS WITH SERIOUS MENTAL ILLNESS

MECHANISMS OF IMPAIRED INFLAMMATION RESOLUTION IN CYSTIC FIBROSIS LUNG DISEASE - PATIENTS WITH CYSTIC FIBROSIS (CF) SUFFER FROM CHRONIC INFECTIONS AND LUNG INFLAMMATION LEADING TO BRONCHIECTASIS AND, ULTIMATELY, RESPIRATORY FAILURE. ALTHOUGH RECENT ADVANCES, INCLUDING THE APPROVAL OF HIGHLY EFFECTIVE CFTR MODULATOR THERAPY (HEMT), HAVE IMPROVED THE OVERALL QUALITY OF LIFE OF PEOPLE WITH CF (PWCF), CHRONIC INFECTION AND INFLAMMATION ARE THE PRIMARY CAUSE OF MORBIDITY. ALTHOUGH THE MAGNITUDE OF THE INFLAMMATORY RESPONSE IS KNOWN TO BE INCREASED IN THE CF LUNG, THE MECHANISMS UNDERLYING PERSISTENT INFLAMMATION ARE UNKNOWN. WE HAVE SHOWN THAT LUNG MACROPHAGES ARE CRITICAL TO THE LOCAL INFLAMMATORY RESPONSE IN CF. LUNG MACROPHAGES INCLUDE FUNCTIONALLY DISTINCT SUBPOPULATIONS INCLUDING CD169+ AND CD169- LUNG MACROPHAGES. OUR PRELIMINARY DATA DEMONSTRATE THAT CF CD169- LUNG MACROPHAGES HAVE DECREASED EXPRESSION OF NRF2, A TRANSCRIPTION FACTOR KNOWN TO REGULATE CELLULAR METABOLISM, COMPARED TO NON-CF BRONCHIECTASIS AND CONTROL SUBJECTS, AND THIS DID NOT IMPROVE WITH HEMT. WE ALSO FOUND THAT CF CD169- LUNG MACROPHAGES ARE PERSISTENTLY GLYCOLYTIC AND INFLAMMATORY, EVEN IN THE SETTING OF HEMT, WHILE NON-CF BRONCHIECTASIS AND HEALTHY CD169- LUNG MACROPHAGES CAN TRANSITION TO AN INFLAMMATION RESOLVING PHENOTYPE. AS IMMUNE CELL CROSSTALK CAN BE MEDIATED BY EXTRACELLULAR VESICLES (EVS), WE INVESTIGATED THE IMPACT OF CD169+ LUNG MACROPHAGE EVS ON THE INFLAMMATORY RESPONSE OF CD169- LUNG MACROPHAGES AND FOUND THAT CF CD169+ LUNG MACROPHAGE EVS INDUCE PERSISTENT INFLAMMATION IN CD169- LUNG MACROPHAGES. LASTLY, WE HAVE PRELIMINARY DATA SHOWING ALTERED EXPRESSION OF MIRNAS PREDICTED TO INHIBIT NRF2 AND REDUCED LEVELS OF INFLAMMATION RESOLVING LIPIDS IN EVS FROM CF CD169+ LUNG MACROPHAGES. THUS, WE HYPOTHESIZE THAT SPECIFIC MIRNAS AND LIPIDS WITHIN CF CD169+ LM EVS REDUCE NRF2 LEVELS IN CD169- LMS, CAUSING PERSISTENT GLYCOLYSIS AND FAILURE TO TRANSITION TO AN INFLAMMATION RESOLVING PHENOTYPE. IN AIM 1, WE WILL TEST THE HYPOTHESIS THAT THERE ARE FUNCTIONALLY IMPORTANT IMMUNOMETABOLIC DIFFERENCES IN CF LUNG MACROPHAGES THAT ARE SPECIFIC TO CF AND PERSIST AFTER HEMT. IN THIS AIM, WE WILL FULLY CHARACTERIZE SUBPOPULATIONS OF LUNG MACROPHAGES IN THE CF LUNG AND WILL QUANTIFY DIFFERENCES IN CELLULAR METABOLISM AND INFLAMMATION RESOLUTION BETWEEN CD169+ AND CD169- LUNG MACROPHAGES IN PWCF, NON-CF BRONCHIECTASIS SUBJECTS, AND HEALTHY SUBJECTS. IN AIM 2, WE WILL TEST THE HYPOTHESIS THAT SPECIFIC MIRNAS WITHIN EVS RELEASED BY CF CD169+ LUNG MACROPHAGES IMPACT THE INFLAMMATORY RESPONSE OF CD169- LUNG MACROPHAGES. IN AIM 3, WE WILL TEST THE HYPOTHESIS THAT THE LIPID CONTENT OF EVS RELEASED BY CF CD169+ LUNG MACROPHAGES PREVENTS THE SHIFT TO AN INFLAMMATION RESOLUTION PHENOTYPE IN R CD169- LUNG MACROPHAGES. THE PROPOSED STUDIES ARE UNIQUE BECAUSE THEY INVOLVE HUMAN SUBJECTS BEFORE AND AFTER HEMT AND THUS, OUR DATA WILL BE DIRECTLY RELEVANT TO PWCF. IN ADDITION, OUR STUDIES WILL PROVIDE NEW AND ESSENTIAL INFORMATION ON THE MECHANISMS OF PERSISTENT LUNG INFLAMMATION IN CF AND WILL ALLOW US TO IDENTIFY TARGETS FOR NOVEL THERAPIES TO REDUCE HARMFUL CF LUNG INFLAMMATION AND IMPROVE THE LIVES AND LONGEVITY OF PEOPLE LIVING WITH CF.

ORTHOPAEDIC RESIDENT CLINICIAN/RESEARCHER PROGRAM

EVALUATING THE POTENTIAL OF NEURAL OSCILLATION BIOMARKERS IN A RODENT MODEL OF INTERVENTION OUTCOME VARIATION: TOWARD PERSONALIZED MENTAL HEALTH CARE - PROJECT SUMMARY/ABSTRACT A MAJOR CHALLENGE IN MENTAL HEALTH CARE INCLUDES INCONSISTENT OUTCOMES OF CURRENT PSYCHOTHERAPEUTIC, PHARMACOLOGIC, AND BRAIN STIMULATION INTERVENTIONS. WE THEORIZE THAT ACROSS INDIVIDUALS, HETEROGENEOUS NEURAL UNDERPINNINGS MANIFEST AT A SYSTEMS LEVEL, LEADING TO IMPAIRED DOMAINS OF FUNCTION AND SPECIFIC DIAGNOSES. THIS HETEROGENEITY CAUSES THE SAME INTERVENTION TO PRODUCE DIFFERENT OUTCOMES ACROSS INDIVIDUALS. TO OVERCOME THIS CHALLENGE, WE HYPOTHESIZE THAT SYSTEMS-LEVEL BRAIN ACTIVITY (NEURAL OSCILLATIONS) CONTAINS THE INFORMATION NECESSARY TO PREDICT BOTH INDIVIDUAL VARIATION IN A DOMAIN OF BRAIN FUNCTION AND IDENTIFY BIOMARKERS TO GUIDE THE INDIVIDUALIZED IMPLEMENTATION OF AN INTERVENTION. TO TEST THESE HYPOTHESES, A MODEL BRAIN SYSTEM IS NEEDED WITH SUFFICIENT VARIATION AND COMPLEXITY TO PRODUCE HETEROGENEITY IN BEHAVIOR AND INTERVENTION OUTCOMES. PRIOR WORK, INCLUDING OUR OWN PRELIMINARY DATA, DEMONSTRATES SUCH BEHAVIORAL VARIATION EXISTS ACROSS INDIVIDUALS AND SEXES IN AN OUTBRED RAT STRAIN (SPRAGUE DAWLEY) PERFORMING THE DELAY DISCOUNTING TASK (DDT) AND RISK DISCOUNTING TASK (RDT). WHEN BRAIN STIMULATION (AIM 1), PHARMACOLOGIC (AIM 2) OR CHEMOGENETIC (AIM 3) INTERVENTIONS HAVE BEEN IMPLEMENTED IN THESE RATS, THEY PRODUCE HETEROGENEOUS EFFECTS ON TASK PERFORMANCE ACROSS INDIVIDUALS MAKING THIS AN EXCELLENT MODEL SYSTEM TO EVALUATE OUR HYPOTHESES. OUR PROPOSED PROOF-OF-CONCEPT STUDY WILL DETERMINE THE POTENTIAL UTILITY OF NEURAL OSCILLATIONS AS BIOMARKERS REFLECTING INDIVIDUAL VARIATION IN THE NEURAL UNDERPINNINGS OF DELAY AND RISK DISCOUNTING AND THE PREDISPOSITION OF THOSE INDIVIDUALS TO RESPOND TO INTERVENTIONS. WE WILL USE MACHINE LEARNING TO DETERMINE IF: 1) OSCILLATIONS CAN PREDICT VARIATION IN TASK PERFORMANCE ACROSS INDIVIDUALS AND TIME; 2) OSCILLATIONS CAN PREDICT INDIVIDUAL INTERVENTION OUTCOMES; AND 3) CHANGES IN OSCILLATIONS INDUCED BY INTERVENTIONS ARE PREDICTIVE OF CORRESPONDING CHANGES IN DDT OR RDT PERFORMANCE. FURTHER ENHANCING THE TRANSLATIONAL RELEVANCE OF THIS PROPOSAL, THE NEURAL SYSTEMS THAT MODULATE THE VALUE OF REWARDS ASSOCIATED WITH DELAY AND RISK DISCOUNTING SHARE HOMOLOGY BETWEEN RODENTS AND HUMANS AND HAVE BEEN LINKED TO IMPORTANT CLINICAL OUTCOMES. FOR INSTANCE, THE EXCESSIVE REDUCTION OF REWARD VALUE BY DELAY RELATES TO A SIGNIFICANT RISK FOR POOR OUTCOMES IN MULTIPLE PSYCHIATRIC CONDITIONS (E.G., ADHD, SCHIZOPHRENIA AND BORDERLINE PERSONALITY DISORDER). ABNORMAL DELAY AND RISK DISCOUNTING HAVE ALSO BEEN LINKED TO SPECIFIC BEHAVIORS, INCLUDING SUICIDE, VIOLENCE AND RISKY SUBSTANCE USE, ENHANCING THE IMPACT OF THE PROPOSED STUDIES. AS AN EARLY-CAREER INVESTIGATOR, FUNDING FOR THIS PROPOSAL WOULD ALLOW ME TO LAUNCH AN INNOVATIVE TRANSLATIONAL RESEARCH PROGRAM ALIGNED WITH NIMH STRATEGIC GOALS FOCUSED ON DEVELOPING SYSTEMS- LEVEL BRAIN ACTIVITY BIOMARKERS TO GUIDE THE INDIVIDUALIZED IMPLEMENTATION OF INTERVENTIONS FOR PATIENTS WITH MENTAL ILLNESS.

A TELEHEALTH INTERVENTION TO ENHANCE QUALITY OF LIFE FOR PEOPLE WITH MULTIPLE SCLEROSIS AND THEIR CARE PARTNERS

INVESTIGATING TOXIC ELEMENTS AND NANOPARTICLES IN ALS ETIOLOGY: A GEOSPATIAL AND TOXICOLOGICAL EVALUATION OF MASSACHUSETTS ALS REGISTRY PATIENTS - PROJECT SUMMARY/ABSTRACT AMYOTROPHIC LATERAL SCLEROSIS (ALS) IS A FATAL AND PRIMARILY SPORADIC NEURODEGENERATIVE DISEASE INVOLVING THE DEATH OF UPPER AND LOWER MOTOR NEURONS. THERE ARE A MYRIAD OF PATHOLOGICAL MECHANISMS UNDERLYING THIS DISEASE, WHICH MAKES IDENTIFYING A SINGLE TARGET FOR TREATMENT A GREAT CHALLENGE. IT IS LARGELY ACCEPTED THAT ALS IS CAUSED BY A COMBINATION OF GENETIC SUSCEPTIBILITY AND ENVIRONMENTAL FACTORS. THE IMPORTANCE OF ENVIRONMENTAL FACTORS IS SUPPORTED BY INTER ALIA DISCORDANCE IN MONOZYGOTIC TWINS, CONJUGAL ALS AND INCREASED RISK OF ALS WITH SPECIFIC OCCUPATIONS AND TOXIC EXPOSURES. WHILE THERE REMAINS AN URGENT NEED TO DEFINE THE PATHOLOGICAL ETIOLOGY OF ALS, EXPOSURE ASSESSMENTS WITHIN ETIOLOGICALLY-RELEVANT, PRE-SYMPTOM TIME INTERVALS HAS PROVEN DIFFICULT DUE TO DIFFERENCES IN METHODOLOGY AND POOR ASSESSMENT METHODS. IN REGARDS PHYSIOLOGICAL ASSESSMENTS, CERTAIN CHEMICAL ELEMENTS HAVE BEEN LINKED TO NEUROTOXICITY (E.G. LEAD). TO DATE, LEAD REPRESENTS ONE OF THE STRONGEST ENVIRONMENTAL RISK FACTORS CONNECTED TO ALS. THE IDENTIFICATION OF ADDITIONAL ALS-ASSOCIATED ELEMENTS HOWEVER HAS BEEN STYMIED BY (1) DISCREPANCIES IN REPORTED MEASUREMENTS AND (2) THE FACT THAT PERIPHERAL MEASUREMENTS RARELY REFLECT THE PHYSIOLOGICAL LOAD WITHIN THE CENTRAL NERVOUS SYSTEM. IN LIGHT OF THESE CHALLENGES, OUR PRELIMINARY WORK INDICATES AN ASSOCIATION BETWEEN TOXIC ELEMENT EXPOSURES AND ALS IN EPOCHS PRIOR TO DIAGNOSIS FOR LEAD, MERCURY AND MANGANESE. WE HAVE FURTHER DETECTED THE PRESENCE OF THESE SAME ELEMENTS IN ALS PATIENT BRAIN TISSUE. WE NOW PROPOSE TO VALIDATE THESE AND OTHER ELEMENTS AS ENVIRONMENTAL RISK FACTORS IN MASSACHUSETTS (MA), THE ONLY STATE IN THE COUNTRY WITH A REPORTABLE (MANDATORY) ALS REGISTRY. UTILIZING THE NATIONAL RESIDENTIAL HISTORY OF MA ALS REGISTRY PARTICIPANTS, WE WILL ESTIMATE SUBJECT EXPOSURE TO POTENTIALLY TOXIC AND PERSISTENT ELEMENTS PRIOR TO DIAGNOSIS TO IDENTIFY ELEMENTS ASSOCIATED WITH INCREASED ALS RISK IN A CASE-CONTROL ANALYSIS USING SPATIOTEMPORAL GEOGRAPHICAL INFORMATION SYSTEMS (GIS) TECHNIQUES. IN PARALLEL, WE WILL EVALUATE THE CONCENTRATIONS, COMBINATIONS AND SPATIAL DISTRIBUTION OF A SUITE OF ELEMENTS IN DISEASE-RELEVANT BRAIN TISSUE FROM MA ALS REGISTRY PATIENTS AND NON-NEURODEGENERATIVE MA AUTOPSY CONTROLS AND CORRELATE THESE FINDINGS TO OUR GIS STUDIES. WE WILL ALSO CHARACTERIZE THE SUBCELLULAR DISTRIBUTION AND COMPOSITION OF NANOPARTICLES IN ALS CASES RELATIVE TO CONTROLS. TOGETHER, THIS UNIQUE AND NOVEL RESEARCH WILL IDENTIFY WELL-FOUNDED, RISK-RELATED EXPOSURES FOR ALS AS WELL AS PROVIDE NOVEL INSIGHT INTO THE ETIOLOGY OF THIS DISEASE.

IDENTIFY, ANALYZE, AND EVALUATE POTENTIAL RISK FACTORS FOR AMYOTROPHIC LATERAL SCLEROSIS (ALS) - 2018

DISPARITIES IN EARLY CHILDHOOD HEALTH OUTCOMES FOLLOWING PRENATAL OPIOID EXPOSURE AND PROTECTIVE HEALTH SYSTEM FACTORS: A POPULATION PERSPECTIVE - PROJECT SUMMARY/ABSTRACT OPIOID MISUSE IS A PUBLIC HEALTH CRISIS IN THE UNITED STATES, AFFECTING ALMOST 700,000 WOMEN OF REPRODUCTIVE AGE IN 2022. OPIOID USE DISORDER (OUD) HAS INTERGENERATIONAL IMPACTS; INFANTS BORN WITH PRENATAL OPIOID EXPOSURE HAVE INCREASED RISKS OF NEONATAL OPIOID WITHDRAWAL SYNDROME (NOWS), PRETERM DELIVERY, CONGENITAL ABNORMALITIES, AND POOR INTRAUTERINE GROWTH. HOWEVER, AT A POPULATION LEVEL, OUR KNOWLEDGE OF THE HEALTH AND DEVELOPMENTAL TRAJECTORIES OF OPIOID-EXPOSED CHILDREN FOLLOWING DISCHARGE FROM THEIR BIRTH HOSPITALIZATION IS EXTRAORDINARILY SCANT. FURTHER, THE VAST MAJORITY OF RESEARCH CONDUCTED TO DATE HAS BEEN PERFORMED IN PREDOMINANTLY NON-HISPANIC WHITE POPULATIONS, LEAVING A MAJOR KNOWLEDGE GAP IN HOW HEALTH OUTCOMES MAY DIFFER ON THE BASIS OF RACE AND ETHNICITY AS WELL AS RURALITY AND MATERNAL DISABILITY. THE OVERALL GOALS OF THIS PROJECT ARE TO CHARACTERIZE HEALTH OUTCOMES DURING THE CRITICAL PERIOD OF BIRTH TO FIVE YEARS OF AGE IN CHILDREN BORN TO PEOPLE WITH OUD, IDENTIFY DISPARITIES AMONG POPULATIONS HISTORICALLY AND CURRENTLY UNDER-REPRESENTED IN RESEARCH, AND ASCERTAIN PROTECTIVE HEALTH SYSTEM FACTORS USING DATA FROM THE TEXAS NEONATAL CARE RESEARCH COLLABORATIVE. GIVEN PAST RESEARCH SHOWING THAT A NOWS DIAGNOSIS MAY BE PROTECTIVE AGAINST INFANT MORTALITY IN OPIOID-EXPOSED INFANTS, THIS WORK WILL FIRST EXAMINE VARIATION IN THE DIAGNOSIS OF NOWS ACROSS 150 HOSPITALS, CHARACTERIZE DISPARITIES IN NOWS DIAGNOSIS RATES, AND DETERMINE THE EXTENT TO WHICH VARIATION IN NOWS DIAGNOSIS RATES MAY BE EXPLAINED BY CLINICAL, SOCIAL, AND BIRTH HOSPITAL FACTORS. SECOND, THIS WORK WILL DETERMINE THE CUMULATIVE INCIDENCE OF NEURODEVELOPMENTAL AND COMPLEX CHRONIC MEDICAL CONDITIONS AT FIVE YEARS OF AGE IN CHILDREN WITH PRENATAL OPIOID EXPOSURE RELATIVE TO CHILDREN WITHOUT THIS EXPOSURE, EXAMINING HOW THESE OUTCOMES DIFFER BETWEEN CHILDREN WITH AND WITHOUT A HISTORY OF NOWS, AND CHARACTERIZING DISPARITIES ON THE BASIS OF MATERNAL RACE, ETHNICITY, RURALITY AND DISABILITY. THIRD, THIS WORK WILL IDENTIFY HEALTH SYSTEM FACTORS THAT ARE PROTECTIVE AGAINST INFANT MORTALITY AND NEURODEVELOPMENTAL AND COMPLEX CHRONIC MEDICAL CONDITIONS AT 5 YEARS OF AGE. A RESEARCH TEAM COMPRISED OF MULTIDISCIPLINARY CLINICIANS, STATISTICIANS, DATA SCIENTISTS, AND KEY POLICY AND PROGRAM STAKEHOLDERS WILL CONDUCT A POPULATION-LEVEL ANALYSIS OF 1.7 MILLION RACIALLY AND ETHNICALLY DIVERSE MATERNAL-INFANT DYADS INSURED BY MEDICAID USING DATA FROM 2010-2023. THE POPULATION WILL INCLUDE >1.3 MILLION WOMEN WHO IDENTIFY AS HISPANIC AND/OR BLACK, >250,000 WHO ARE RURAL-RESIDING, >26,000 WITH DISABILITIES, AND >12,000 WITH OUD. INVESTIGATORS WILL DEVELOP MULTI-LEVEL MODELS TO ACCOUNT FOR THE HIERARCHICAL DATA STRUCTURES, ADJUSTING FOR CONFOUNDING VARIABLES AND IDENTIFYING HEALTH SYSTEM FACTORS ASSOCIATED WITH POSITIVE CHILD HEALTH OUTCOMES. COMPLETION OF THIS WORK WILL RAPIDLY ADDRESS A KEY KNOWLEDGE GAP REGARDING THE DEVELOPMENTAL AND HEALTH TRAJECTORIES OF CHILDREN BORN TO PEOPLE WITH OUD, CHARACTERIZING MODIFIABLE HEALTH SYSTEM FACTORS THAT MAY BE LEVERAGED TO IMPROVE BOTH MATERNAL HEALTHCARE AND CHILD HEALTH.

TARGETING KNOWLEDGE AND COGNITION TO IMPROVE QUALITY OF LIFE: AN INNOVATIVE TELEHEALTH APPROACH FOR BRAIN TUMOR SURVIVORS AND THEIR CARE PARTNERS I

REAL-TIME DIAGNOSIS OF LIFE-THREATENING NECROTIZING SOFT-TISSUE INFECTIONS USING INDOCYANINE GREEN KINETIC MODELING - PROJECT SUMMARY NECROTIZING SOFT-TISSUE INFECTIONS (NSTIS, A.K.A. “NECROTIZING FASCIITIS” OR “FLESH-EATING BACTERIA”) ARE AGGRESSIVE INFECTIONS THAT CAN PROGRESS RAPIDLY FROM MILD SYMPTOMS TO SEPSIS, MULTI-ORGAN FAILURE, AND DEATH. NSTI CASES PRESENT WITH NON-SPECIFIC CLINICAL, IMAGING, AND LABORATORY FINDINGS, AND STANDARD-OF-CARE TECHNIQUES FOR NSTI DIAGNOSIS LACK SENSITIVITY AND SPECIFICITY, RESULTING IN FREQUENT MISDIAGNOSIS AND DELAYED CARE, WHICH IS THE SINGLE MOST IMPORTANT PREDICTOR OF SURVIVAL. CONSEQUENTLY, THE CUMULATIVE MORTALITY RATE FOR PATIENTS WITH NSTIS IS 20- 30%; A DIRE NEED EXISTS FOR MORE ACCURATE AND RAPID DETECTION OF NSTIS. FLUORESCENCE-GUIDED SURGERY IS A NASCENT TECHNOLOGY SEEKING TO IMPROVE THE RECOGNITION OF ANATOMICAL STRUCTURES AND DISEASE PROCESSES USING FLUORESCENT PROBES (FLUOROPHORES). INDOCYANINE GREEN (ICG) IS AN FDA-APPROVED, NEAR-INFRARED FLUOROPHORE WITH A >60-YEAR SAFETY RECORD FOR VASCULAR PERFUSION ASSESSMENT. A DISTINGUISHING HISTOLOGICAL FEATURE OF NSTIS IS PROMINENT BLOOD VESSEL THROMBOSIS IN AFFECTED TISSUES. LEVERAGING THESE PRO-THROMBOTIC EFFECTS, OUR STUDY GROUP HAS DEMONSTRATED IN A FIRST-IN-HUMAN STUDY (NCT04839302) THAT INTRAVENOUS ADMINISTRATION OF ICG AND IMMEDIATE FLUORESCENCE IMAGING REVEALS PROMINENT SIGNAL DEFICITS IN NSTI-POSITIVE TISSUES THAT DIFFERENTIATE SIGNIFICANTLY WITH INCREASED SIGNAL SEEN WITH MORE COMMON—AND LESS VIRULENT—INFECTIONS SUCH AS CELLULITIS. WE SEEK NOW TO EVALUATE THIS IMAGING TECHNIQUE ON A BROADER SCALE AND DETERMINE IF OUR FINDINGS ARE CONSISTENT FOR PATIENTS AFFECTED BY NSTI-CAUSING PATHOGENS THAT ARE NOT ENDEMIC TO OUR REGION. IN THIS PROPOSAL, A PROSPECTIVE, OBSERVATIONAL, MULTICENTER CLINICAL STUDY WILL INVOLVE VIDEO-RATE ICG FLUORESCENCE IMAGING OF PATIENTS SUSPECTED OF HAVING NSTIS WHO PRESENT TO SEVEN TERTIARY, LEVEL 1 MEDICAL CENTERS ACROSS THE UNITED STATES (AIM 1). USING DYNAMIC CONTRAST-ENHANCED FLUORESCENCE IMAGING (DCE-FI), TIME PROFILES OF ICG FLUORESCENCE INTENSITY FROM DIFFERENT TISSUE PIXELS/REGIONS WILL BE EXTRACTED AND PARAMETERIZED TO EXTRACT FIRST-PASS KINETIC FEATURES. THESE DCE-FI FEATURES, WHICH CHARACTERIZE TISSUE PERFUSION, WILL BE EVALUATED ALONE AND IN COMBINATION WITH ANONYMIZED ELECTRONIC MEDICAL RECORD DATA TO CREATE A DCE-FI-BASED CLINICAL DECISION TOOL AND A MACHINE- LEARNING-BASED FUSION (DCE FI+LAB/IMAGING DATA) TOOL; THESE WILL BE COMPARED TO IDENTIFY THE MOST ACCURATE MEANS OF DIAGNOSING NSTIS (AIM 2). THE BEST-PERFORMING TOOL WILL THEN BE EVALUATED—COMPARED TO CURRENT DIAGNOSTIC TESTS—IN A PROSPECTIVE OBSERVATIONAL CLINICAL STUDY OF PATIENTS PRESENTING TO TERTIARY EMERGENCY DEPARTMENTS WITH FINDINGS CONCERNING FOR NSTIS (AIM 3). BASED ON OUR HUMAN STUDY, FLUORESCENCE IMAGING WILL NOT DELAY CURRENT STANDARD OF CARE. TO ENSURE DATA FIDELITY, ALL SITES WILL USE SIMILAR: 1) COMMERCIAL FLUORESCENCE IMAGING SYSTEMS AND ACCESSORIES; AND 2) VALIDATED COMMERCIAL FLUORESCENCE REFERENCE PHANTOMS. BASED ON OUR EARLY RESULTS, WE HAVE STRONG CONFIDENCE THAT FOLLOWING RIGOROUS TESTING, ICG DCE-FI WILL LEAD TO AN ENTIRELY NEW METHODOLOGY FOR RAPID IDENTIFICATION OF PATIENTS WITH NSTIS, WHICH WILL ULTIMATELY REDUCE PATIENT MORBIDITY AND IMPROVE SURVIVAL.

ADJUVANT PHOTODYNAMIC THERAPY TO REDUCE BACTERIAL BIOBURDEN IN HIGH-ENERGY CONTAMINATED OPEN FRACTURES - PROJECT SUMMARY THIS PROPOSAL AIMS TO EVALUATE AND OPTIMIZE PHOTODYNAMIC THERAPY (PDT) AS AN ADJUVANT TREATMENT FOR CONTAMINATED HIGH-ENERGY OPEN FRACTURES TO REDUCE BACTERIAL BIOBURDEN AND, THUS, REDUCE RATE OF INFECTION. INFECTION FOLLOWING FRACTURE TREATMENT IS ONE OF THE MOST CHALLENGING COMPLICATIONS FACING MUSCULOSKELETAL TRAUMA PATIENTS. INFECTION CAN BE CATASTROPHIC, LEADING TO PROLONGED MORBIDITY, LOSS OF FUNCTION, AND POTENTIAL LOSS OF LIMB. SEVERAL FACTORS MAKE HIGH-ENERGY OPEN TRAUMA PARTICULARLY SUSCEPTIBLE TO INFECTION: THE PRESENCE OF TRAUMATIZED TISSUES, CONTAMINATION OF THE FRACTURE, POOR SOFT TISSUE COVERAGE, POOR NUTRITIONAL STATE DUE TO POLYTRAUMA, PROLONGED HOSPITALIZATION WITH EXPOSURE TO NOSOCOMIAL BACTERIA, AND PRESENCE OF METALLIC IMPLANTS. INFECTION PREVENTION STRATEGIES CURRENTLY EMPLOYED INCLUDE SYSTEMIC ANTIBIOTICS, THOROUGH SURGICAL DEBRIDEMENT OF OPEN FRACTURE, LOCAL ANTIBIOTICS, MECHANICAL STABILITY OF THE EXTREMITY WITH METALLIC IMPLANTS AS WELL AS SOFT TISSUE COVERAGE. HOWEVER, DESPITE THESE PREVENTION STRATEGIES, INFECTION OCCURS IN 10-60% OF OPEN FRACTURES. THIS IS DUE, AT LEAST IN PART, TO INADEQUATE ERADICATION OF CONTAMINATING BACTERIA, PARTICULARLY IN THE CONTEXT OF HARDWARE AT THE FRACTURE SITE. THUS, THE OVERALL GOAL OF THIS PROPOSAL IS TO EVALUATE THE EFFICACY OF PDT AT REDUCING WOUND BIOBURDEN IN CONTAMINATED HIGH-ENERGY OPEN FRACTURE, THUS REDUCING THE RISK OF FRACTURE RELATED INFECTION IN PREPARATION FOR TRANSLATION INTO HUMAN PATIENTS. THE SCIENTIFIC PREMISE OF THIS PROPOSAL IS UNDERPINNED BY DATA FROM OUR PRIOR IN VITRO STUDIES DEMONSTRATING ENORMOUS EFFICACY, KILLING >90% OF BACTERIA IN MATURE ESTABLISHED BIOFILM, WHICH IS FAR SUPERIOR TO CURRENTLY UTILIZED ADJUVANT TREATMENT, AND OUR IN VIVO STUDIES SHOWING ERADICATION OF MRSA FROM CONTAMINATED OPEN FRACTURE. TO ATTAIN OUR OVERALL OBJECTIVE, THREE AIMS WILL BE PURSUED. IN AIM 1 WE WILL OPTIMIZE THE FORMULATION, LIGHT DOSE, AND TIMING OF PDT; IN AIM 2 WE WILL DETERMINE THE EFFICACY OF ADJUVANT TOPICAL PDT ON TWO DIFFERENT FIXATION STRATEGIES, WHICH HAVE DIFFERENT CONSEQUENCES IN TERMS OF BIOFILM FORMATION (INTRAMEDULLARY FIXATION AND PLATE FIXATION); IN AIM 3 WE WILL DEVELOP AND PRELIMINARILY ASSESS THE EFFICACY OF REPEAT PDT ADMINISTRATION THROUGH A SURGICALLY PLACED EXTRAOSSEOUS CATHETER. INTEGRATION OF PDT INTO TREATMENT OF HIGH-RISK CONTAMINATED HIGH-ENERGY OPEN FRACTURES HAS THE POTENTIAL TO REVOLUTIONIZE TREATMENT OF THESE INJURIES, RESULTING IN A REDUCTION IN WOUND BIOBURDEN AND, THUS, A REDUCTION IN RISK OF INFECTION. THIS PROJECT LEVERAGES AN EXTENSIVE INFRASTRUCTURE AND EXPERIENCE IN FLUORESCENCE-GUIDED SURGERY AS WELL AS LONGSTANDING COLLABORATIONS BETWEEN ORTHOPAEDIC SURGERY AND BIOMEDICAL ENGINEERS.

DYNAMIC SUSTAINMENT OF EVIDENCE-BASED HEALTH PROMOTION INTERVENTIONS IN MENTAL HEALTH - PROJECT ABSTRACT ADULTS WITH SERIOUS AND DISABLING MENTAL ILLNESS (SMI) EXPERIENCE A 15-30 YEAR REDUCED LIFE EXPECTANCY PRIMARILY DUE TO MODIFIABLE CARDIOVASCULAR RISK FACTORS THAT CAN BE EFFECTIVELY ADDRESSED WITH BEHAVIORAL LIFESTYLE INTERVENTIONS. LIFESTYLE INTERVENTIONS HAVE REDUCED OBESITY-RELATED CARDIOVASCULAR RISK IN UPWARDS OF 50% OF ADULTS WITH SMI IN COMMUNITY-BASED TRIALS, EVEN AMONG THOSE TAKING ANTIPSYCHOTIC MEDICATIONS; HOWEVER, THESE INTERVENTIONS ARE RARELY SUSTAINED ONCE RESEARCH PROJECTS ARE COMPLETED. THIS LATER STAGE TRANSLATIONAL STUDY FOCUSES ON LONG-TERM SUSTAINMENT OF AN EVIDENCE-BASED LIFESTYLE INTERVENTION (INSHAPE) IMPLEMENTED IN U.S. MENTAL HEALTH ORGANIZATIONS WHERE INTEGRATED HEALTH PROMOTION IS NOT NECESSARILY PART OF THE CORE MISSION, BUT IS CRITICAL TO STEM THE TIDE OF EARLY MORTALITY IN ADULTS WITH SMI. INSHAPE IS THE ONLY LIFESTYLE INTERVENTION FOR ADULTS WITH SMI THAT HAS BEEN TESTED MULTIPLE TIMES WITH HEALTH BENEFITS REPLICATED IN TWO RCTS AND A STATEWIDE AND NATIONAL IMPLEMENTATION STUDY. THERE HAS YET TO BE AN INVESTIGATION OF LONG-TERM SUSTAINMENT OF INSHAPE OR ANY OTHER EVIDENCE-BASED HEALTH PROMOTION INTERVENTIONS FOR ADULTS WITH SMI IN MENTAL HEALTH ORGANIZATIONS. FROM 2014-2019, OUR TEAM LED AN NIMH-FUNDED TYPE 3 HYBRID EFFECTIVENESS-IMPLEMENTATION STUDY OF INSHAPE IN MENTAL HEALTH ORGANIZATIONS ACROSS THE U.S. IN 2023, 14 (36%) OF 39 ORGANIZATIONS THAT COMPLETED OUR PRIOR IMPLEMENTATION STUDY CONTINUED TO DELIVER INSHAPE. IN THE PROPOSED STUDY, WE WILL EVALUATE LONG-TERM SUSTAINMENT OF INSHAPE (6-8 YEARS POST-IMPLEMENTATION) ON TWO DIMENSIONS: 1) SUSTAINED DELIVERY OF THE INSHAPE PROGRAM, AND 2) SUSTAINED INSHAPE PROGRAM HEALTH BENEFITS. WE WILL LEVERAGE DATA COLLECTED IN OUR PRIOR TRIAL TO EXAMINE MULTI-LEVEL FACTORS THAT PREDICT LONG-TERM SUSTAINMENT OF INSHAPE AT 39 IMPLEMENTATION SITES; COLLECT NEW DATA ON CONTEXTUAL FACTORS, ADAPTATIONS AND FIDELITY TO INSHAPE; AND COLLABORATE WITH AN EXISTING NATIONAL NETWORK OF INSHAPE TEAMS TO DEVELOP A SUSTAINMENT PRACTICE GUIDE TAILORED FOR INSHAPE. WHILE THE PRACTICE GUIDE WILL BE BASED ON INSHAPE, IT WILL BE GUIDED BY THE PROGRAM SUSTAINABILITY FRAMEWORK AND THUS WILL INCLUDE KEY CONSIDERATIONS FOR SUSTAINING EVIDENCE-BASED HEALTH PROMOTION PROGRAMS MORE BROADLY IN MENTAL HEALTH ORGANIZATIONS. THE PROPOSED STUDY HAS HIGH PUBLIC HEALTH AND IMPLEMENTATION SCIENCE IMPACT AS ONE OF THE FIRST STUDIES TO IDENTIFY ADAPTATIONS ASSOCIATED WITH SUSTAINED HEALTH PROMOTION INTERVENTIONS WHILE ALSO ADDRESSING LONGSTANDING ASSUMPTIONS ABOUT THE ‘VOLTAGE DROP’ IN INDIVIDUAL BENEFITS OF EVIDENCE-BASED INTERVENTIONS AS THEY MOVE FROM IMPLEMENTATION TO SUSTAINMENT. IT IS HIGHLY INNOVATIVE AND IMPACTFUL AS ONE OF THE FIRST STUDIES TO USE PARTICIPATORY GROUP MODEL BUILDING AND TO LEVERAGE A LARGE NETWORK OF IMPLEMENTATION SITES TO IDENTIFY FACTORS, INCLUDING FIDELITY AND ADAPTATION, THAT INFLUENCE LONG-TERM SUSTAINMENT OF AN EVIDENCE-BASED HEALTH PROMOTION INTERVENTION IN MENTAL HEALTH ORGANIZATIONS AND TO BUILD ON THESE FINDINGS TO DEVELOP, EVALUATE, AND REFINE A SUSTAINMENT PRACTICE GUIDE FOR FUTURE RESEARCH AND PRACTICE.

INCREASING EPILEPSY SELF-MANAGEMENT ACCESS BY EMBRACING A HUB AND SPOKE MODEL - THE PURPOSE OF THE PROPOSED PROJECT IS TO INCREASE HEALTH SYSTEMS CAPACITY TO MAKE THE HOBSCOTCH (HOME BASED SELF-MANAGEMENT AND COGNITIVE TRAINING CHANGES LIVES) PROGRAM ACCESSIBLE TO PEOPLE WITH EPILEPSY (PWE) AND COGNITIVE DYSFUNCTION AND THE CLINICIANS WHO CARE FOR THEM. WE WILL UTILIZE A SCALABLE HUB AND SPOKE ORGANIZATIONAL DESIGN WHICH SUPPORTS DIVERSE CLINICAL SITE ADOPTION AND STANDARDIZED REFERRAL PATHWAYS. FOR EVIDENCE BASED EPILEPSY SELF-MANAGEMENT (ESM) PROGRAMS TO BE TRANSLATED FROM SCIENCE TO SERVICE DELIVERY A PROCESS OF LOCAL ADAPTATION THAT SERVES TO INCREASE THE RELEVANCE AND MEANING TO PATIENTS, PROVIDERS AND PRACTICES WILL BE REQUIRED. HOBSCOTCH IS AN EVIDENCE-BASED ESM WHICH TARGETS COGNITIVE DYSFUNCTION IN ADULTS WITH EPILEPSY. THE PROGRAM IS DELIVERED BY A TRAINED COGNITIVE COACH (PSYCHOLOGIST, APRN), ONE-TO ONE, BY TELEHEALTH INCORPORATING ONLINE AND TELEPHONE COMPONENTS. IT IS DESIGNED TO ASSIST PWE MANAGE AND COPE WITH THEIR COGNITIVE PROBLEMS IN ORDER TO LEAD HAPPIER MORE PRODUCTIVE LIVES. THE HOBSCOTCH INTERVENTION, AT BASELINE, REPRESENTS AN INNOVATIVE WAY OF ADDRESSING NEUROCOGNITIVE DIFFICULTIES AND IMPROVING QUALITY OF LIFE IN PEOPLE WITH EPILEPSY. THE PROPOSED PROJECT BUILDS ON THE FOUNDATIONAL WORK OF THE HOBSCOTCH INSTITUTE, BY BRINGING TOGETHER A NETWORK OF PARTNERS COMMITTED TO IMPROVING THE LIVES PWE. THE PROJECT WILL TARGET BUILDING STREAMLINED MECHANISMS FOR PROVIDER ENGAGEMENT, ADOPTION SUPPORT AND PATIENT REFERRAL TO HOBSCOTCH IN TWO CLINICAL SETTINGS. THE FIRST SETTING, DIVERSE US EPILEPSY CENTERS WITH CLINICIANS AND RESEARCHERS WITH EXPERTISE IN EPILEPSY CARE IN 14 STATES (NC, MA, CA, GA, ME, FL, AZ, MN, CT, OH, PA, NH, TX, MO) AND THE SECOND SETTING, A NORTHERN NEW ENGLAND COOPERATIVE OF COMMUNITY AND FAMILY MEDICINE NETWORK OF PRACTICES CARING FOR PEOPLE WITH EPILEPSY IN RURAL AND UNDERSERVED AREAS. THE FRAMEWORK FOR THE PROJECT SUPPORTS THE GOALS AND INTENT OF THE CDC’S BUILDING CAPACITY FOR IMPLEMENTING EVIDENCE-BASED EPILEPSY SELF-MANAGEMENT SUPPORTS IN HEALTH CARE SETTINGS (COMPONENT 1) BY UTILIZING THE COMBINED RESOURCES AND DEPTH OF EXPERTISE AT THE HOBSCOTCH INSTITUTE, DARTMOUTH HEALTH, THE DARTMOUTH INSTITUTE AND DARTMOUTH COLLEGE TO DEVELOP PARTNERSHIPS WITH HEALTHCARE ORGANIZATIONS AND OTHER INTERESTED AND AFFECTED GROUPS FOR INTERVENTION IMPLEMENTATION, AND TO COORDINATE AND IMPLEMENT EVIDENCE-BASED EPILEPSY SELF-MANAGEMENT SUPPORTS USING BEST PRACTICE STRATEGIES FOR HEALTH SYSTEM CHANGE. OUR APPROACH WILL BE COLLABORATIVE WITH A ROBUST CENTRAL HUB OF SUPPORT BEING THE HOBSCOTCH INSTITUTE, AND THE SPOKES INCREASING OUR POTENTIAL TO ADDRESS DISPARITIES THROUGH ESM SUPPORT THAT REACHES RURAL, URBAN, DISADVANTAGED AND UNDERSERVED COMMUNITIES, AND PEOPLE WITH EPILEPSY ACROSS THE LIFESPAN AND THOSE WITH COMORBID DISABILITIES. PROJECT OUTCOMES WILL INCLUDE IMPROVED AWARENESS OF TELEHEALTH DELIVERABLE SELF-MANAGEMENT SUPPORTS FOR HEALTH PROFESSIONALS AND PWE, INCREASED PROVIDER REFERRALS FOR EVIDENCE-BASED ESM HOBSCOTCH, INCREASED IMPLEMENTATION OF HOBSCOTCH IN CLINICAL SETTINGS, INCREASED USE OF QUALITY IMPROVEMENT STRATEGIES OR TOOLS TO ENSURE EFFECTIVE PROGRAM ACCESS AND IMPLEMENTATION, IMPROVED COMPLETION OF EVIDENCE-BASED ESM SUPPORTS AMONG PWE AND COGNITIVE DYSFUNCTION, IMPROVED QUALITY OF LIFE AND HEALTH OUTCOMES FOR PWE AND COGNITIVE DYSFUNCTION, DECREASED HEALTH CARE UTILIZATION COSTS AND INCREASED USE OF APPROPRIATE COMMUNITY SUPPORTS. THIS PROJECT HAS POTENTIAL FOR REPLICABLE MODELS IN PRIMARY CARE AND AT EPILEPSY CENTERS TO EMERGE, AND SHARES AN INNOVATIVE MODEL THAT ENGAGES PSYCHOLOGY TRAINING PROGRAMS TO GROW SUSTAINABILITY.

DEEP LEARNING TO IMPROVE INTERPRETATION OF INTRAPARTUM FETAL MONITORING - PROJECT SUMMARY ELECTRONIC FETAL MONITORING (EFM) IS USED IN GREATER THAN 85% OF BIRTHS IN THE UNITED STATES, WITH THE GOAL OF ALLOWING CLINICIANS TO DETECT CHANGES IN THE FETAL HEART RATE THAT MAY INDICATE FETAL ACADEMIA, ENABLING THEM TO INTERVENE PRIOR TO IRREVERSIBLE FETAL INJURY. EFM WAS DISSEMINATED INTO PRACTICE PRIOR TO ROBUST ASSESSMENT OF ITS EFFICACY, AND DECADES OF WORK SINCE HAVE SHOWN THAT EFM IS LIMITED IN ACHIEVING ITS INTENDED GOAL OF PREVENTING INTRAPARTUM HYPOXIC-ISCHEMIC INJURY, AND IS ASSOCIATED WITH A SIGNIFICANT INCREASE IN OBSTETRIC INTERVENTION, ESPECIALLY CESAREAN DELIVERY. MUCH WORK HAS BEEN DONE TO DEVELOP GUIDELINES AND STANDARDIZED FRAMEWORKS FOR EFM INTERPRETATION IN THE HOPES OF IMPROVING BOTH NEONATAL OUTCOMES AND THE PRECISION OF OBSTETRIC INTERVENTIONS, BUT NEARLY 175,000 CESAREAN DELIVERIES CONTINUE TO BE PERFORMED UNNECESSARILY IN THE US ANNUALLY DUE TO FALSE-POSITIVE INTERPRETATIONS OF EFM. IN RESPONSE TO MANY OF THESE CHALLENGES, COMPUTERIZED INTERPRETATION OF EFM HAS BEEN EXPLORED SINCE THE 1980S. UNFORTUNATELY, THE EXISTING SOFTWARE PROGRAMS, WHICH ARE LARGELY DESIGNED TO DETECT THE SAME EFM FEATURES THAT CLINICIANS DO, HAVE NOT DEMONSTRATED CLINICAL BENEFIT IN RANDOMIZED CONTROLLED TRIALS. IN ANSWER, OUR GROUP HYPOTHESIZED THAT A NOVEL, DATA-DRIVEN DEEP LEARNING APPROACH COULD POTENTIALLY DETECT MEANINGFUL DATA PATTERNS IN EFM, BEYOND THOSE FEATURES THAT CLINICIANS OR OTHER SOFTWARE PROGRAMS RECOGNIZE, THAT COULD HELP IMPROVE THE PREDICTIVE ACCURACY OF EFM. ACCORDINGLY, WE DEVELOPED A DEEP-LEARNING MODEL THAT USES EFM DATA TO PREDICT FETAL ACIDEMIA. THE BEST PERFORMING MODEL ACHIEVED AN AUROC OF 0.85 AT AN UMBILICAL CORD GAS PH THRESHOLD OF <7.05. THESE INITIAL RESULTS PROVIDE PROOF-OF-CONCEPT THAT A PURELY DATA-DRIVEN MODEL CAN ACHIEVE PROMISING PREDICTIVE PERFORMANCE. GIVEN THIS EXCITING START, WE ARE NOW SEEKING TO FURTHER VALIDATE AND REFINE THIS MODEL, AND ASSESS ITS POTENTIAL ROLE IN CLINICAL CARE. ACCORDINGLY, WE PROPOSE TO 1) IMPROVE AND REFINE OUR PRELIMINARY AI-EFM MODEL BY LEVERAGING LARGE, DIVERSE DATASETS 2) COMPARE THE PERFORMANCE OF THE MODEL TO CLINICAL INTERPRETATION (GOLD STANDARD) AND 3) ASSESS THE ACCEPTABILITY AND PERCEIVED BARRIERS TO USE OF SUCH A MODEL IN INTRAPARTUM PATIENT CARE BY CONDUCTING QUALITATIVE INTERVIEWS WITH CLINICIANS. THE COMPLETION OF THIS PROPOSAL AND EACH OF THESE AIMS ARE ESSENTIAL NEXT STEPS IN MOVING THIS INNOVATIVE TECHNOLOGY TOWARDS IMPACTFUL CLINICAL APPLICATION AND FUTURE EVALUATION IN A RANDOMIZED CONTROLLED TRIAL. THIS WORK HAS THE POTENTIAL TO ENHANCE THE ACCURATE DETECTION OF TRUE FETAL DISTRESS WARRANTING OBSTETRIC INTERVENTION, WHILE ALSO REDUCING THE SUBJECTIVITY AND COGNITIVE BIASES IN INTERPRETATION OF EFM. IF RIGOROUSLY TESTED AND PRUDENTLY DEPLOYED, THIS TECHNOLOGY HAS THE POTENTIAL TO IMPROVE OUTCOMES FOR MILLIONS OF BIRTHING PATIENTS AND NEONATES.

VIDEO INSPIRED DISCUSSIONS ABOUT ETHICAL OUTCOMES IN PEDIATRICS (VIDEO-PEDS) - PARENTS OF CHILDREN WITH CANCER OFTEN FACE COMPLICATED DECISION MAKING THROUGHOUT THEIR CHILD’S ILLNESS. GOALS-OF-CARE (GOC) INTERVENTIONS HELP PATIENTS, THEIR FAMILIES, AND CLINICIANS COMMUNICATE AND DISCUSS PREFERENCES FOR TREATMENTS TOGETHER TO ENSURE MEDICAL CARE IS CONSISTENT WITH THE FAMILY’S VALUES, GOALS, AND INFORMED PREFERENCES. TO DATE, MOST GOC INTERVENTIONS HAVE FOCUSED ON ADULTS AND ADOLESCENTS RESULTING IN A CRITICAL DISPARITY OF AVAILABLE TOOLS FOR CHILDREN DYING OF CANCER. GOC CONVERSATIONS BETWEEN PARENTS, WHO SERVE AS PRIMARY DECISION MAKERS FOR CHILDREN, AND CLINICIANS OFTEN RELY ON VERBAL OR WRITTEN INFORMATION ABOUT POSSIBLE MEDICAL INTERVENTIONS, SUCH AS CARDIOPULMONARY RESUSCITATION OR PLACEMENT ON A RESPIRATOR, DURING CRISES OF CLINICAL DECLINE. HOWEVER, THIS GOC PROCESS IS OFTEN INADEQUATE AS IT IS PRESENTLY CONDUCTED, LEAVING FAMILIES ILL-PREPARED IN TIMES OF DISTRESS. THE MAJORITY OF CHILDREN WITH CANCER AND THEIR FAMILIES PREFER TO DIE AT HOME, YET THE MAJORITY OF CHILDREN WITH CANCER DIE IN THE HOSPITAL, AND THIS DISPROPORTIONATELY AFFECTS AFRICAN AMERICAN, HISPANIC, AND RURAL PATIENTS. NOVEL INTERVENTIONS ARE NEEDED TO ENSURE GOC CONVERSATIONS HAPPEN EARLIER TO ENSURE GOAL-CONCORDANT CARE. TO ADDRESS THESE SHORTCOMINGS, WE HAVE DEVELOPED THEORY-BASED GOC VIDEO DECISION AIDS IN ENGLISH AND SPANISH FOR PARENTS OF CHILDREN WITH CANCER. WE HAVE SHOWN THE EFFICACY OF SIMILAR DECISION AIDS IN ADULTS USING NATURAL LANGUAGE PROCESSING (NLP), A FORM OF COMPUTER-ASSISTED ABSTRACTION, IN PRAGMATIC TRIALS; BUT HAVE NOT EXAMINED THE IMPACT OF THESE VIDEOS IN CHILDREN WITH CANCER AND THEIR PARENTS. THE OVERALL OBJECTIVE OF THIS UG3/UH3 PROPOSAL ENTITLED VIDEO INSPIRED DISCUSSIONS FOR ETHICAL OUTCOMES IN PEDIATRICS (VIDEO-PEDS) IS TO BUILD THE INFRASTRUCTURE FOR AND CONDUCT A LARGE RANDOMIZED PRAGMATIC TRIAL OF A GOC VIDEO DECISION AID IN THREE DIVERSE HEALTH CARE SYSTEMS (DANA-FARBER CANCER INSTITUTE, CHILDREN’S HEALTHCARE OF ATLANTA, AND THE UNIVERSITY OF ALABAMA). DURING THE UG3 PHASE (FIRST TWO YEARS), WE WILL REFINE THE GOC VIDEO, FINALIZE CLINICS AND WORKFLOWS, VALIDATE OUR NLP PROCESS, AND PILOT-TEST THE INTERVENTION. DURING THE UH3 PHASE (SUBSEQUENT FOUR YEARS), WE WILL CONDUCT A LARGE, PRAGMATIC, RANDOMIZED, WAITLIST-CONTROLLED TRIAL INCLUDING 504 CHILDREN WITH CANCER AGED 0-12 YEARS. THIS TRIAL WILL INCLUDE 76 AFRICAN AMERICAN, 76 HISPANIC, AND 76 RURAL CHILDREN WITH CANCER BY DESIGN. CHILDREN WILL BE RANDOMIZED TO WAITLIST- CONTROL OR THE GOC VIDEO INTERVENTION IN WHICH THE VIDEO WILL BE SHARED WITH PARENTS ALONG WITH IN-PERSON AND TELEHEALTH SESSIONS CONDUCTED BY NAVIGATORS TO ELUCIDATE GOC PREFERENCES. AFTER THE INTERVENTION PERIOD, THE WAITLIST WILL OPEN AND ALL PARENTS (I.E., WAITLIST-CONTROLS) WILL RECEIVE THE INTERVENTION. USING NLP TO DETECT OUTCOMES (E.G., GOC DOCUMENTATION), WE HYPOTHESIZE THAT INTERVENTION CHILDREN, AS COMPARED TO CONTROLS, WILL HAVE MORE GOC DOCUMENTATION (PRIMARY OUTCOME). THIS PROPOSAL IS SIGNIFICANT, INNOVATIVE, AND FEASIBLE. THE INTERVENTION IS A PRACTICAL AND INNOVATIVE APPROACH TO HELP CHILDREN WITH CANCER AND THEIR PARENTS.

INCREASING EPILEPSY SELF-MANAGEMENT ACCESS FOR VETERANS BY EMBRACING A PARTNERED HUB AND SPOKE MODEL

I-CARE: THE EFFECTIVENESS OF A MODULAR DIGITAL INTERVENTION TO REDUCE SUICIDAL IDEATION AND EMOTIONAL DISTRESS DURING PEDIATRIC PSYCHIATRIC BOARDING - PROJECT SUMMARY THE COVID-19 PANDEMIC HAS CONTRIBUTED TO A SUBSTANTIAL INCREASE IN SUICIDAL IDEATION, SUICIDE ATTEMPTS, AND SUICIDE DEATHS AMONG US ADOLESCENTS. EMERGENCY DEPARTMENTS (EDS) AT ACUTE CARE HOSPITALS INCREASINGLY SERVE AS GATEWAYS TO CARE FOR YOUTH WITH SUICIDALITY; THIS TREND HAS BEEN FURTHER EXACERBATED DURING COVID-19. WHEN YOUTH WITH SUICIDAL IDEATION OR ATTEMPT ARE DEEMED TO REQUIRE INPATIENT PSYCHIATRIC CARE, THE DEMAND FOR BEDS OFTEN EXCEEDS SUPPLY, LEADING TO PSYCHIATRIC BOARDING. DURING THIS TIME, YOUTH MAY WAIT DAYS TO WEEKS IN AN ED OR INPATIENT MEDICAL UNIT UNTIL PSYCHIATRIC ADMISSION; BOARDING FREQUENCIES AND DURATIONS HAVE BOTH INCREASED DURING COVID-19. YOUTH EXPERIENCING BOARDING RARELY RECEIVE EVIDENCE-BASED PSYCHOTHERAPIES GIVEN A NATIONAL SHORTAGE AND UNEVEN DISTRIBUTION OF MENTAL HEALTH PROFESSIONALS. TO ADDRESS THIS GAP, A MULTIDISCIPLINARY TEAM OF PEDIATRICIANS, PSYCHOLOGISTS, CLINICAL SOCIAL WORKERS AND PATIENT PARTNERS DEVELOPED A MODULAR DIGITAL INTERVENTION TO DELIVER EVIDENCE-BASED PSYCHOSOCIAL SKILLS TO YOUTH WITH SUICIDALITY DURING BOARDING. THIS PROGRAM, CALLED I-CARE (IMPROVING CARE, ACCELERATING RECOVERY & EDUCATION), CONSISTS OF A SERIES OF WEB-BASED ANIMATED VIDEOS AND ACTIVITIES GROUNDED IN COGNITIVE BEHAVIORAL THERAPY, PRIORITIZED THROUGH A RIGOROUS DELPHI PROCESS. I-CARE IS DESIGNED TO BE FACILITATED BY SAFETY ATTENDANTS WHO CURRENTLY PROVIDE 1-ON-1 SAFETY SUPERVISION FOR YOUTH DURING BOARDING. ACCORDINGLY, I-CARE REQUIRES MINIMAL ADDITIONAL RESOURCES BEYOND THOSE ALREADY AVAILABLE AT ACUTE CARE HOSPITALS. IN A PILOT PROGRAM EVALUATION, I-CARE HAS BEEN SHOWN TO BE FEASIBLE TO IMPLEMENT AND ACCEPTABLE TO YOUTH, CLINICIANS, AND THEIR CAREGIVERS, WITH LEVELS OF EMOTIONAL DISTRESS SIGNIFICANTLY DECREASED FOLLOWING PARTICIPATION. BUILDING ON THIS PRELIMINARY DATA, THIS HYBRID TYPE 1 EFFECTIVENESS TRIAL WILL USE A CLUSTER RANDOMIZED STEPPED WEDGE DESIGN AT 6 HOSPITALS (960 YOUTH 12-17 YEARS WITH SUICIDAL IDEATION OR ATTEMPT) TO: (I) APPLY THE DYNAMIC ADAPTATION PROCESS TO OPTIMIZE I-CARE TRAINING AND IMPLEMENTATION WHILE MAINTAINING INTERVENTION FIDELITY AND TAKING INTO ACCOUNT COVID-19 AND VARIATION ACROSS HOSPITALS; (II) DETERMINE THE EFFECTIVENESS OF I-CARE TO REDUCE EMOTIONAL DISTRESS, SUICIDAL IDEATION AND SUICIDE ATTEMPTS USING VALIDATED MEASURES COMPARED TO USUAL CARE, ASSESS THE EFFECTS OF I-CARE ON MOTIVATION FOR CHANGE (TARGET MECHANISM), AND DETERMINE WHETHER GREATER MOTIVATION FOR CHANGE MEDIATES I-CARE EFFECTS ON EMOTIONAL DISTRESS, SUICIDAL IDEATION AND ATTEMPTS, AND (III) APPLY THE RE-AIM FRAMEWORK TO IDENTIFY BARRIERS TO AND FACILITATORS OF I-CARE REACH, EFFECTIVENESS, ADOPTION, IMPLEMENTATION AND MAINTENANCE FROM THE PERSPECTIVES OF YOUTH, CAREGIVERS, AND CLINICIANS. THE RESULTS OF THIS STUDY HAVE THE POTENTIAL TO TRANSFORM HEALTHCARE DELIVERY FOR A POPULATION CURRENTLY UNDERSERVED BY THE HEALTH SYSTEM, INCREASING ACCESS TO MENTAL HEALTH SERVICES DURING A PERIOD OF TREMENDOUS VULNERABILITY WHILE APPLYING A NOVEL DIGITAL INTERVENTION WITH SUBSTANTIAL POTENTIAL FOR SCALABILITY.

RFA-TS-24-010: PERSISTENT ENVIRONMENTAL TOXICANTS IN VETERAN CNS TISSUE: IDENTIFYING EXPOSURES DETERMINING HIGHER ALS RISK

DECISION MAKING IN METOIDIOPLASTY AND PHALLOPLASTY GENDER AFFIRMING SURGERY (MAPGAS) - PROJECT SUMMARY/ABSTRACT METOIDIOPLASTY AND PHALLOPLASTY GENDER AFFIRMING SURGERIES (MAPGAS) ARE INCREASINGLY PERFORMED BUT REMAIN HIGH RISK PROCEDURES THAT REQUIRE PATIENTS TO MAKE COMPLEX DECISIONS AFFECTING FUTURE GENDER CONGRUENCE, FERTILITY, URINARY, AND SEXUAL FUNCTION. PRIOR STUDIES DEMONSTRATE THERE IS DECISIONAL UNCERTAINTY AMONG TRANSGENDER AND NON-BINARY INDIVIDUALS ASSIGNED FEMALE AT BIRTH CONSIDERING MAPGAS WHICH MAY LEAD TO POOR DECISION QUALITY AND OUTCOMES. IN THESE HIGH RISK SURGICAL DECISIONS WITH MULTIPLE OPTIONS WITH CLINICAL EQUIPOISE, IT IS PARAMOUNT TO EMPOWER PATIENTS WITH DECISION SUPPORT THAT FACILITATES QUALITY DECISIONS THAT ARE WELL INFORMED, DELIBERATED, AND ALIGN WITH PERSONAL GOALS AND VALUES. HOWEVER, THERE IS A LACK OF VALIDATED MAPGAS DECISION SUPPORT DUE TO A HISTORICAL LACK OF UNDERSTANDING OF PATIENTS’ DECISIONAL NEEDS AND DEARTH OF HIGH QUALITY PUBLISHED OUTCOMES OR GUIDELINES. TAKEN TOGETHER, THIS LIMITS THE EXTENT OF MAPGAS COUNSELING AND SHARED DECISION MAKING, POTENTIALLY LEADING TO POOR QUALITY DECISIONS AND UNEXPECTED OUTCOMES. IN OUR PRIOR R21 WE USED A MIXED METHODS DESIGN GROUNDED IN THE OTTAWA DECISION SUPPORT FRAMEWORK WITH COMMUNITY AND PROVIDER STAKEHOLDERS, TO IDENTIFY KEY THEMES SURROUNDING PATIENT SURGICAL GOALS, VALUES, AND DECISION MODERATORS FROM GEOGRAPHICALLY DIVERSE LOCATIONS IN THE US. THIS WAS COMBINED WITH A SYSTEMATIC REVIEW OF THE LITERATURE AND MODIFIED DELPHI CONSENSUS OF HIGH VOLUME MAPGAS SURGEONS ON PATIENT FOCUSED SURGICAL OUTCOMES TO CREATE, ITERATIVELY REVISE, AND SANDPIT TEST A COMMUNITY DEVELOPED, WEB-BASED MAPGAS PICTURE DECISION AID (DA) PROTOTYPE. THE DA PROVIDES INFORMATION ON THE MOST COMMON MAPGAS OPTIONS AND A DECISION SUPPORT TOOL APPLICABLE TO PATIENTS OF VARIOUS HEALTH LITERACY LEVELS. THE PURPOSE OF THIS STUDY IS TO 1) EVALUATE THE USABILITY AND ACCEPTABILITY OF THE MAPGAS DA USING A MIXED METHODS APPROACH INCLUDING THE VALIDATED SYSTEM USABILITY SCALE TRIANGULATED WITH KEY STAKEHOLDER FOCUS GROUPS FEEDBACK. FURTHER, TO 2) EVALUATE PRELIMINARY MAPGAS DA EFFICACY THROUGH A PROSPECTIVE RANDOMIZED CONTROLLED TRIAL AT TWO GEOGRAPHICALLY DIVERSE INSTITUTIONS. THE PRIMARY OUTCOME INCLUDES CHANGE IN PRE AND POST DA DECISIONAL CONFLICT (DECISIONAL CONFLICT SCALE) AND DECISION READINESS (PREPARATION FOR DECISION MAKING SCALE) AS COMPARED TO USUAL CARE. THE SECONDARY OUTCOME WILL INCLUDE POST-SURGICAL CONSULTATION EVALUATION WITH THE COLLABORATE MEASURE COUPLED WITH SEMI STRUCTURED PATIENT AND PROVIDER INTERVIEWS ON OPTIMAL DA ADMINISTRATION TIMING, IMPLEMENTATION, AND IMPACT ON SHARED DECISION MAKING. SUCCESSFUL COMPLETION OF THIS STUDY WILL REFINE THE MAPGAS DA, TEST PRELIMINARY EFFICACY, AND INFORM A LARGER PROSPECTIVE STUDY DESIGNED TO TEST BROADER ACCEPTABILITY, EFFICACY, AND ULTIMATELY IMPROVE MAPGAS SHARED DECISION MAKING.

SEMI-AUTOMATED BLADDER CANCER SCREENING USING MACHINE LEARNING: CLINICAL VALIDATION AND IMPLEMENTATION. - PROJECT SUMMARY / ABSTRACT: BLADDER CANCER IS THE 7TH MOST COMMON MALIGNANCY WORLDWIDE AND HAS THE HIGHEST RECURRENCE RATE OF ANY CANCER (70%).1–3 PATIENTS WITH RISK FACTORS (SMOKING, ARSENIC / CHEMICAL DYE EXPOSURE) AND / OR HEMATURIA ARE ROUTINELY SCREENED FOR BLADDER CANCER VIA ANALYSIS OF VOIDED URINE. THE CELLULAR ELEMENTS OF THE URINE ARE DEPOSITED TO GLASS SLIDES, STAINED, AND EXAMINED BY A CYTOPATHOLOGIST FOR FEATURES OF BLADDER CANCER USING THE GOLD STANDARD PARIS SYSTEM FOR URINE CYTOPATHOLOGY.4 HOWEVER, THE PARIS SYSTEM IS SUBJECTIVE AND THE MORPHOLOGY OF UROTHELIAL CELLS IS HIGHLY VARIED, MAKING THE PROCESS DIFFICULT AND PRONE TO HIGH INTEROBSERVER VARIABILITY AND HUMAN ERRORS BORNE OF FATIGUE AND OVERWORK.5,6 A MORE QUANTITATIVE, AUTOMATED METHOD OF ASSESSING URINE CYTOPATHOLOGY FOR BLADDER CANCER IS NEEDED. MACHINE LEARNING (ML) TECHNOLOGIES HAVE PROVEN TO BE HIGHLY EFFECTIVE IN IMAGE BASED CLASSIFICATION IN PATHOLOGY, IN THAT ML MODELS OPERATE REPRODUCIBLY AND WITHOUT BIAS (UNLESS THE TRAINING DATA IS BIASED) OR FATIGUE. PAP SMEARS ARE ALREADY ROUTINELY PROCESSED BY A SEMI-AUTOMATED ML SYSTEM (BD FOCALPOINT), AND SHARE MANY COMMON FEATURES WITH URINE CYTOLOGY SPECIMENS IN THAT BOTH ARE CANCER SCREENING TESTS RELYING ON CELLULAR AND NUCLEAR MORPHOLOGY AND PREPARED BY LIQUID BASED PREPARATION (LBP, E.G. THINPREP) METHODS. YET TO DATE NO SYSTEM HAS BEEN DEVELOPED TO HARNESS ML FOR BLADDER CANCER IN THIS WAY, A FACT I INTEND TO CHANGE. WHILE IT IS MY STRONG BELIEF THAT PATHOLOGY AS A DISCIPLINE IS POISED TO MAKE THE TRANSITION TO A 100% DIGITAL SERVICE, THERE IS SIGNIFICANT INERTIA TO OVERCOME TO REPLACE THE CURRENT ANALOG MICROSCOPE TECHNOLOGY. WE MUST GO BEYOND SIMPLY PROVIDING A DIGITAL ALTERNATIVE BY AUGMENTING THE SKILLS OF THE PATHOLOGIST WITH ML ALGORITHMS THAT EMPOWER THEM TO WORK MORE EFFICIENTLY, QUICKLY AND SAFELY. URINE CYTOLOGY SCREENING FOR BLADDER CANCER IS AN IDEAL USE CASE. THUS WE SOUGHT TO CREATE A PROTOTYPE ML BASED ALGORITHM, DUBBED AUTOPARIS, THAT WOULD AUTOMATE THE TABULATION OF THE PARIS SYSTEM. THE INITIAL PROTOTYPE OF AUTOPARIS PROVED TO BE HIGHLY EFFECTIVE AT RISK STRATIFYING URINE CYTOLOGY SPECIMENS BY TABULATING STATISTICS RELATED TO NUCLEAR TO CYTOPLASMIC RATIO (NC RATIO, A VERY IMPORTANT INDICATOR OF NEOPLASIA) AND CELLULAR / NUCLEAR MORPHOLOGICAL ATYPIA.7 DEPLOYING AUTOPARIS AS A DIAGNOSTIC AID TO THE CYTOPATHOLOGIST WILL REQUIRE SEVERAL ADDITIONAL STEPS. ALTHOUGH I WAS SKILLED ENOUGH TO CODE THE FIRST ITERATION OF THE MODEL, I AM REACHING THE LIMITS OF WHAT I CAN ACCOMPLISH AS A SELF-TAUGHT PROGRAMMER AND DATA SCIENTIST. IN ORDER TO COMPLETE MY WORK ON AUTOPARIS AND CONTINUE TO INNOVATE IN THE FIELD OF DIGITAL PATHOLOGY AND ML, I NEED A MORE FORMALIZED EDUCATION IN SPECIALIZED MATHEMATICS, STATISTICS, ML THEORY AND PROGRAMMING. THROUGH THIS AWARD I WILL PURSUE A CURRICULUM OF COURSES AT DARTMOUTH COLLEGE GUIDED BY A TEAM OF EXPERT MENTORS. MY MENTORS AND COLLABORATORS WERE ALSO SELECTED FOR THEIR ABILITY TO HELP WITH THE TESTING AND VALIDATION OF DIGITAL DECISION AIDS, GRANT AND MANUSCRIPT PREP AND LAB MANAGEMENT. I WILL EMERGE FROM THIS EXPERIENCE WITH THE SKILLS I NEED TO BE A LEADER IN THE FUTURE OF ML DEVELOPMENT AND ITS ADOPTION IN CLINICAL MEDICINE.

THERAPEUTIC TARGETING OF THE TUMOR MICROENVIRONMENT IN TRIPLE NEGATIVE BREAST CANCER PATIENTS AT HIGH RISK OF RELAPSE AND PRECLINICAL MODELS OF LUNG METASTASES - OUR LONG-TERM GOAL IS TO SIGNIFICANTLY IMPROVE OUTCOME FOR PATIENTS (PTS) WITH TRIPLE NEGATIVE BREAST CANCER (TNBC). TUMOR GENERATED MICROENVIRONMENTS IN DISTAL TARGET ORGANS PROVIDE HOSPITABLE SITES (“PRE-METASTATIC NICHES”) THAT SUPPORT METASTATIC COLONIZATION AND OUTGROWTH. BONE MARROW-DERIVED PROGENITOR CELLS INCLUDING VEGFR2+ EPCS AND VEGFR1+ HPCS, COPPER (CU) DEPENDENT LYSYL OXIDASE (LOX) AND COLLAGEN RE-MODELLING CONSTITUTE UNDERLYING METASTASIS-SUPPORTING FEATURES OF THE PRE-METASTATIC NICHE. OUR CENTRAL HYPOTHESIS IS THAT CU DEPLETION USING TETRATHIOMOLYBDATE (TM) PREVENTS RELAPSE BY DISRUPTING THREE KEY ASPECTS OF METASTASIS: (1) CANCER CELL INTRINSIC MITOCHONDRIAL BIOENERGETICS THAT MEDIATES INVASION/METASTASIS/CHEMORESISTANCE, 2) THE “PRE-METASTATIC NICHE” THAT SUPPORTS COLONIZATION, AND OUTGROWTH OF DISSEMINATED METASTATIC TUMOR CELLS, AND (3) STROMAL REMODELING THAT PROMOTES IMMUNE EVASION AND IMMUNOTHERAPY RESISTANCE. STRIKINGLY, RESULTS FROM OUR PHASE II TRIAL OF TM IN 75 BREAST CANCER (BC) PATIENTS AT HIGH RISK FOR RELAPSE SHOWED TM DECREASED VEGFR2+EPCS, REDUCED CIRCULATING LOX LEVELS BY > 50% AND NORMALIZED THE COLLAGEN MICROENVIRONMENT. IMPORTANTLY, TM WAS WELL TOLERATED, AND RELAPSES WERE RARE PAST FOUR YEARS ON STUDY. THE OBJECTIVE OF THIS PROPOSAL IS TO TEST THIS HYPOTHESIS BY CONDUCTING A SMALL PHASE IB TRIAL OF ADDING 3 YEARS OF ADJUVANT TM TO STANDARD 6 MONTHS TREATMENT OF ADJUVANT CAPECITABINE AND PEMBROLIZUMAB IN HIGH RISK FOR RELAPSE TNBC (RCB 2, 3, RISK FOR RELAPSE >60% AT 5 YEARS) AFTER COMPLETION OF NEOADJUVANT THERAPY AND SURGERY TO ESTABLISH THE SAFETY OF THE COMBINATION FOLLOWED BY A RANDOMIZED PHASE II CLINICAL TRIAL OF ADJUVANT TM AND CAPECITABINE VS CAPECITABINE ALONE. IF PEMBROLIZUMAB WAS ADMINISTERED IN THE NEOADJUVANT SETTING, IT MAY BE CONTINUED IN THE ADJUVANT SETTING PER INVESTIGATOR DISCRETION. THE PRIMARY ENDPOINT IS THE EFFECT OF THE ADDITION OF TM ON DISTANT RELAPSE-FREE SURVIVAL (DRFS). SECONDARY ENDPOINTS INCLUDE: (A) OVERALL SURVIVAL (OS) AND INVASIVE DISEASE-FREE SURVIVAL (IDFS) BETWEEN THE TWO ARMS, (B) SAFETY AND TOLERABILITY OF TM, (C) OS AND IDFS IN PATIENTS THAT COMPLETE AT LEAST 6 MONTHS OF TM (D) VEGFR2+ EPCS, LOXL2, CTDNA, (E) PATIENT-REPORTED QUALITY OF LIFE (PROS) AND (F) PHARMACOKINETICS IN A SUB-STUDY COHORT OF PATIENTS (AIM 1). AIM 2 EXPLORATORY TRANSLATIONAL ENDPOINTS INCLUDE THE EFFECT OF TM ON SINGLE NUCLEOTIDE POLYMORPHISMS OF CERULOPLASMIN, AND CTR1 ON THE ABILITY TO CU-DEPLETE PTS, THE INFLUENCE OF ATOX1 AND COLLAGEN BIOMARKERS (C1M, PROC3 AND C6M) ON DRFS AND OS AND THE EFFECT OF COPPER DEPLETION ON IMMUNE BIOMARKERS AND THE METABOLIC PROFILE OF A SELECTED COHORT OF PATIENTS ENROLLED IN THE TRIAL.

GEOSPATIAL DRIVERS OF CANCER CARE DISPARITIES AND THEIR SUSCEPTIBILITY TO HEALTH POLICY CHANGES - PROJECT SUMMARY LACK OF INSURANCE COVERAGE AND INDIVIDUAL INCOME HAVE BEEN ASSOCIATED WITH CONSIDERABLE DISPARITIES IN CANCER CARE FOR PATIENTS WITH SOLID ORGAN MALIGNANCIES, INCLUDING LATER STAGE DISEASE AT TIME OF PRESENTATION, DECREASED PROBABILITY OF UNDERGOING CANCER-DIRECTED SURGERY, AND DECREASED SURVIVAL. HOWEVER, MUCH LESS IS UNDERSTOOD ABOUT UPSTREAM GEOSPATIAL DETERMINANTS OF HEALTH THAT INFLUENCE ACCESS TO AND RECEIPT OF CARE FOR THE 20% OF AMERICANS THAT LIVE IN RURAL COMMUNITIES. FURTHERMORE, THE DEGREE TO WHICH RECENT HEALTH POLICY CHANGES HAVE IMPACTED CANCER CARE DELIVERY FOR PATIENTS LIVING IN RURAL AND SOCIOECONOMICALLY VULNERABLE COMMUNITIES REMAINS UNCLEAR. TO ADDRESS THESE GAPS, DR. LOEHRER PLANS TO CONDUCT A POPULATION-BASED OBSERVATIONAL AND QUASI-EXPERIMENTAL COHORT STUDY TO EVALUATE THE INFLUENCE OF RURAL RESIDENCE, COMMUNITY- LEVEL SOCIOECONOMIC DEPRIVATION, AND THEIR INTERACTION WITH INSURANCE COVERAGE ON PRESENTATION WITH AND MANAGEMENT OF SOLID ORGAN MALIGNANCIES. ADDITIONALLY, WE WILL EVALUATE THE DEGREE TO WHICH AFFORDABLE CARE ACT ASSOCIATED INSURANCE EXPANSION INFLUENCED CANCER CARE DELIVERY ACROSS RURAL AND SOCIOECONOMICALLY DIVERSE COMMUNITIES. THE STUDY CAPITALIZES ON THE NOVEL USE OF SELECT STATE CANCER REGISTRIES WITH GEOGRAPHICALLY LINKED MEASURES OF COMMUNITY-LEVEL SOCIOECONOMIC DEPRIVATION. MULTILEVEL QUANTITATIVE METHODS, GEOVISUALIZATION, GEOCOMPUTATIONAL APPROACHES, SPATIOTEMPORAL ANALYSES, AND ECONOMETRIC MODELLING WILL ALL BE USED TO DESCRIBE AND VISUALIZE COMPLEX RELATIONSHIPS BETWEEN INSURANCE COVERAGE, RURAL RESIDENCE, LOCAL COMMUNITY-LEVEL SOCIOECONOMIC FACTORS IN ADDITION TO DETERMINING THE INFLUENCE OF STATE-LEVEL INSURANCE EXPANSION ON DISPARITIES IN CANCER CARE DELIVERY. THE STUDY WILL PROVIDE IMPORTANT INFORMATION ON UPSTREAM GEOSPATIAL DRIVERS OF CANCER CARE DISPARITIES WHILE ALSO EVALUATING THE HETEROGENEOUS INFLUENCE OF HEALTH POLICY ON RURAL CANCER DISPARITIES. DR. LOEHRER IS A SURGICAL ONCOLOGIST AND HEALTH SERVICES RESEARCHER AT DARTMOUTH-HITCHCOCK MEDICAL CENTER AND THE DARTMOUTH INSTITUTE FOR HEALTH POLICY AND CLINICAL PRACTICE. HIS CLINICAL PRACTICE INCLUDES CARE FOR PATIENTS WITH SKIN, SOFT-TISSUE, AND LIVER MALIGNANCIES WHILE HIS ACADEMIC FOCUS IS AT THE INTERSECTION HEALTH POLICY, SOCIAL DETERMINANTS OF HEALTH, AND EQUITY OF CANCER CARE DELIVERY. HIS LONG-TERM CAREER GOAL IS TO BECOME AN INNOVATIVE AND INDEPENDENTLY FUNDED HEALTH POLICY RESEARCHER WITH A FOCUS ON VULNERABLE POPULATIONS. THE RESEARCH PLAN PRESENTED COMPLEMENTS BOTH CAREER DEVELOPMENT AND TRAINING PLANS THAT ARE FOCUSED ON GEOSPATIAL METHODOLOGIES AND APPLICATION. THE AWARD WILL LAY THE METHODOLOGICAL AND POLICY FOUNDATION FOR FOLLOW-UP STUDIES ON STATE-SPECIFIC WAIVERS IN MEDICAID DELIVERY THAT ARE TOO EARLY TO BE EVALUATED AT PRESENT.

INCREASING PHYSICAL ACTIVITY AMONG BREAST CANCER SURVIVORS: USE OF THE ORBIT MODEL TO REFINE AND TEST A NOVEL APPROACH TO EXERCISE PROMOTION BASED ON AFFECT-REGULATION - PROJECT SUMMARY/ABSTRACT THE GOAL OF THIS K08 MENTORED CLINICAL SCIENTIST RESEARCH CAREER DEVELOPMENT AWARD IS TO PREPARE THE CANDIDATE FOR AN INDEPENDENT RESEARCH CAREER BREAST CANCER SURVIVORS WHO EXERCISE REGULARLY IN BEHAVIORAL ONCOLOGY AND HEALTH BEHAVIOR INTERVENTION SCIENCE. POST-CANCER DIAGNOSIS ARE LESS LIKELY TO DIE FROM CANCER AND EVEN MODEST INCREASES IN PHYSICAL ACTIVITY (= RELATED MORTALITY. HOWEVER, LONGITUDINAL STUDIES SHOW SIGNIFICANT DECLINES IN EXERCISE ENGAGEMENT DURING THE 12- 15 MINUTES/WEEK) YIELD CLINICALLY MEANINGFUL REDUCTIONS IN BREAST CANCER- MONTHS POST-DIAGNOSIS, WITH MOST BREAST CANCER SURVIVORS NEVER FULLY RETURNING TO PRE-DIAGNOSIS ACTIVITY LEVELS. THE CANDIDATE PROPOSES AN INNOVATIVE APPROACH, BASED ON AFFECT-REGULATION, TO ADDRESSING PHYSICAL INACTIVITY AS A PUBLIC HEALTH RISK FACTOR NEGATIVELY IMPACTING BREAST CANCER SURVIVORSHIP. THE TRAINING AND MENTORING PLAN IS DESIGNED TO PROVIDE KNOWLEDGE AND SKILLS IN (1) EARLY-PHASE INTERVENTION DEVELOPMENT, (2) INTENSIVE LONGITUDINAL DATA COLLECTION AND ANALYSIS METHODS, (3) RANDOMIZED CLINICAL TRIAL DESIGN, AND (4) PROFESSIONAL DEVELOPMENT. THE PROPOSED RESEARCH WILL REFINE AN AFFECT-REGULATED EXERCISE PRESCRIPTION STRATEGY (AFFECT-RX) FOR USE WITH PHYSICALLY INACTIVE BREAST CANCER SURVIVORS (AIM 1), TEST FOR PROOF-OF-CONCEPT THE EFFECT OF AFFECT-RX ON CLINICALLY MEANINGFUL MODERATE-VIGOROUS PHYSICAL ACTIVITY PARTICIPATION POST-INTERVENTION, OPERATIONALIZED AS = 90 MINS/WEEK (AIM 2), AND QUANTIFY THE STRENGTH OF WITHIN-PERSON ASSOCIATIONS BETWEEN AFFECTIVE FACTORS AND TOTAL PHYSICAL ACTIVITY (AIM 3). THE CANDIDATE WILL USE THE MILESTONES FOR EARLY-PHASE INTERVENTION DEVELOPMENT ESTABLISHED BY THE OBESITY- RELATED BEHAVIORAL INTERVENTION TRIALS (ORBIT) TWO STUDIES. IN BOTH STUDIES, PARTICIPANTS’ DAILY MODEL TO GUIDE THE METHODS AND OUTCOMES TO BE TESTED ACROSS AFFECTIVE FEELING STATES AND PHYSICAL ACTIVITY WILL BE MEASURED USING ECOLOGICAL MOMENTARY ASSESSMENT (EMA) AND ACCELEROMETRY AT BASELINE AND 2-, 6- AND 12-WEEKS FOLLOW- UP. THE AFFECT-RX STRATEGY WILL BE REFINED FOR ACCEPTABILITY IN STUDY 1 (N = 20) AND TESTED (WITH REFINEMENTS) IN STUDY 2 (N = 60). IN CONSULTATION WITH HER TEAM OF MENTORS AND SCIENTIFIC ADVISORS, THE CANDIDATE WILL USE THE TRAINING, THE RESULTS OF THE RESEARCH, AND THE ORBIT INTERVENTION DEVELOPMENT FRAMEWORK TO SYSTEMATICALLY GUIDE THE NEXT STEPS IN THIS AFFECT-BASED PHYSICAL ACTIVITY PROMOTION LINE OF WORK AND SUBMIT HER FIRST R01 PROPOSAL.

INDOOR AIR POLLUTION, MUCOCILIARY CLEARANCE, AND MUCUS PROPERTIES IN COPD

BILE ACID-DEPENDENT INTESTINAL IMMUNE REGULATION - PROJECT SUMMARY BILE ACIDS (BAS) HAVE EMERGED AS A RICH AND IMPORTANT SOURCE OF IMMUNOREGULATORY METABOLITES IN THE INTESTINES. YET CURRENT VIEWS OF BAS ARE INCOMPLETE. REDUCTIONIST STUDIES ADMINISTERING SINGLE BAS TO CELLS OR MICE, WHILE USEFUL FOR INFORMING BASIC BA PHYSICOCHEMICAL PROPERTIES, ENGENDER ‘1 BA = 1 FUNCTION’ MODELS THAT HAVE LIMITED RELEVANCE TO THE VASTLY MORE COMPLEX PHYSIOLOGY THAT UNDERPINS BA METABOLISM AND SIGNALING IN VIVO. OUR GOALS ARE TO QUANTIFY INTESTINAL BA POOLS IN MICE, UNDERSTAND HOW AND WHY THEY CHANGE DURING INTESTINAL INFLAMMATION, AND MAP THEIR INTERACTIONS WITH HOST INTESTINAL CELLS AND RECEPTORS. RECOGNIZING THAT INTESTINAL BA POOLS ARE FORMED AND DYNAMICALLY REGULATED BY ENDOCRINE-LIKE SIGNALING CONNECTIONS BETWEEN THE LIVER (WHERE BAS ARE MADE), ILEUM (WHERE MOST BAS ARE ABSORBED) AND COLONIC MICROBIOTA (WHERE MOST BAS ARE METABOLIZED), WE DEVELOPED AN INTEGRATED METHODS SET TO INTERROGATE THE SIZE, COMPLEXITY, REGULATION AND FUNCTION OF INTESTINAL BA POOLS IN MICE. WE VALIDATED THESE APPROACHES IN MICE THAT LACK THE ILEAL BA REUPTAKE TRANSPORTER, ASBT/SLC10A2, AND THAT HARBOR ROBUST AND PREDICTABLE DIFFERENCES IN BA METABOLISM. WE ALSO ESTABLISHED NEW COMPUTATIONAL MODELS, CALIBRATED TO IN VIVO DATASETS, THAT OFFER QUANTITATIVE INSIGHTS INTO THE INDEPENDENT INPUTS THAT HEPATIC SYNTHESIS, ILEAL ABSORPTION AND MICROBIAL METABOLISM EACH CONTRIBUTE TO THE ESTABLISHMENT AND MAINTENANCE OF ENTEROHEPATIC BA POOLS. NEW PRELIMINARY DATA SUGGEST THAT CROHN’S DISEASE-LIKE ILEITIS, WHICH ARISES SPONTANEOUSLY IN HUMAN CROHN’S DISEASE PATIENTS AND TNFARE/+ MICE, ALTERS BA CIRCULATION AND METABOLISM IN WAYS THAT ULTIMATELY PRODUCE A SMALLER AND MORE PRO-INFLAMMATORY BA POOL. WE HYPOTHESIZE THAT ABERRANT ILEAL BA ABSORPTION IS TRIGGERED BY CYTOKINE-DRIVEN ASBT DOWNREGULATION IN ENTEROCYTES PRIOR TO OVERT HISTOPATHOLOGY AND IS A DISTINCTIVE FEATURE OF ILEITIS IN MICE AND HUMANS ONCE PRODUCED, WE POSIT THE ILEITIS-ASSOCIATED BA POOL PROPAGATES IMMUNE DYSFUNCTION AND ILEITIS BY DISTURBING THE BALANCE OF PRO- VS. ANTI-INFLAMMATORY NR LIGANDS AVAILABLE TO T CELLS. WE TEST THESE HYPOTHESES THROUGH TWO INTER-RELATED, BUT NOT INTER-DEPENDENT, AIMS. WE EXPECT THESE STUDIES WILL HAVE BROAD AND LASTING IMPACTS IN THE FIELD, BOTH BY GENERATING FUNDAMENTAL NEW INSIGHTS INTO THE REGULATION OF BA HOMEOSTASIS, AND BY YIELDING ACTIONABLE NEW PARADIGMS IN THE UNDERSTANDING AND TREATMENT OF HUMAN CROHN’S DISEASE.

THE ROLE OF INFLAMMATION IN KNEE OSTEOARTHRITIS - PROJECT SUMMARY: SYMPTOMATIC KNEE OSTEOARTHRITIS (OA) AFFECTS 14 MILLION ADULTS IN THE U.S. AND IS A LEADING CAUSE OF DISABILITY. THERE IS GROWING RECOGNITION OF DISTINCT PHENOTYPES WITHIN OA AND THE NEED TO TAILOR THERAPIES TO SPECIFIC PHENOTYPES. INTRA-ARTICULAR INFLAMMATION MANIFESTING AS SYNOVITIS HAS EMERGED AS AN IMPORTANT PHENOTYPIC FEATURE ASSOCIATED WITH PAIN AND STRUCTURAL PROGRESSION. THIS PROPOSAL CENTERS ON UNDERSTANDING THE ROLE OF SYNOVITIS AND ITS TOPOGRAPHIC AND TEMPORAL EFFECTS ON PAIN AS WELL AS ITS POTENTIAL AS A TREATMENT TARGET. THE FIRST AIM INVESTIGATES WHETHER DISCORDANCE IN EFFUSION-SYNOVITIS BETWEEN AN INDIVIDUAL’S KNEES PORTENDS DIFFERENTIAL PAIN REPORTING BETWEEN THE KNEES. LONGITUDINALLY WE WILL INVESTIGATE WHETHER CHANGES IN SYNOVITIS OVER 24 MONTHS ARE ASSOCIATED WITH CHANGES IN PAIN. THESE ANALYSES WILL INCLUDE ADJUSTMENT FOR BOTH KNEE AND INDIVIDUAL LEVEL CONTRIBUTORS TO PAIN TO BETTER ASCERTAIN THE INDEPENDENT EFFECT OF SYNOVITIS ON PAIN. THE SECOND AIM USES ULTRASOUND, A READILY AVAILABLE AND INEXPENSIVE IMAGING TECHNIQUE, TO EXAMINE WHETHER THE PRESENCE OF EFFUSION-SYNOVITIS IN THE KNEE IDENTIFIES A SUBGROUP THAT WILL HAVE A GREATER REDUCTION IN PAIN AFTER INTRA-ARTICULAR STEROID INJECTION. LASTLY, AIM 3 WILL UTILIZE SINGLE-CELL RNA SEQUENCING OF THE SYNOVIUM IN PATIENTS WITH MILD, MODERATE AND SEVERE OA TO BETTER DEFINE CELL TYPES AND TRANSCRIPTIONAL PROFILES ACTIVE AT VARIOUS OA STAGES. IF, AS WE SUSPECT, INFLAMMATION IS MORE PREDOMINANT EARLY IN THE DISEASE PROCESS, ANTI- INFLAMMATORY THERAPIES MAY BE MOST EFFECTIVE IN EARLY OA. THIS FUNDING OPPORTUNITY AND PROJECT ARE SPECIFICALLY GEARED TOWARD MY TRANSITIONING TO AN INDEPENDENT INVESTIGATOR AND R01 FUNDING. I WILL HAVE PROTECTED TIME FOR THIS PROJECT AND A UNIQUELY SUPPORTIVE AND RICH ACADEMIC ENVIRONMENT WITH ACCESS TO WORLD-LEADING MENTORS, COURSEWORK, AND CAREER DEVELOPMENT SERIES THROUGH THE HARVARD MEDICAL SCHOOL, HARVARD T.H. CHAN SCHOOL OF PUBLIC HEALTH AND BRIGHAM AND WOMEN’S HOSPITAL. SPECIFICALLY, THE AIMS IN THIS PROPOSAL WILL PROVIDE EXPERIENCE WITH ADVANCED HIERARCHICAL, CLUSTERED AND LONGITUDINAL STATISTICAL MODELING, USE OF ULTRASOUND AND MAGNETIC RESONANCE IMAGING VARIABLES IN ANALYSIS, AND RNA SEQUENCING OF THE SYNOVIUM. THESE AIMS AND EDUCATIONAL OPPORTUNITIES WILL GIVE ME AN IN-DEPTH UNDERSTANDING OF METHODS TO INVESTIGATE KEY FACETS OF INFLAMMATION IN OA, POSITIONING ME TO LEAD FUTURE WORK ON THE TIMING AND TARGETING OF NOVEL OA THERAPIES.

GREEN SCHOLARS IN TRANSLATIONAL SCIENCE PROGRAM AT DARTMOUTH - THE OVERALL GOAL OF THE GREEN SCHOLARS IN CLINICAL AND TRANSLATIONAL SCIENCE K12 PROGRAM IS TO IDENTIFY, RECRUIT, TRAIN, AND SUPPORT HIGH-POTENTIAL EARLY-CAREER FACULTY, PROMOTING THE DEVELOPMENT AND SUCCESSFUL FUTURE OF THESE SCHOLARS AS INDEPENDENT INVESTIGATORS LEADING HIGH-IMPACT CLINICAL AND TRANSLATIONAL SCIENCE. IN ORDER TO ACHIEVE THIS GOAL, WE WILL PROVIDE STRUCTURED TRAINING, MENTORING, AND PROTECTED RESEARCH TIME FOR EARLY CAREER FACULTY TO SUPPORT THEIR DEVELOPMENT INTO RIGOROUS, INDEPENDENT CLINICAL AND TRANSLATIONAL SCIENTISTS. UPON COMPLETION OF THE PROGRAM, THESE SCHOLARS WILL HAVE DEMONSTRATED THE CHARACTERISTICS NECESSARY TO SUCCESSFULLY TRANSITION INTO RESEARCH INDEPENDENCE INCLUDING: DOMAIN EXPERTISE, CROSSING BOUNDARIES TO COLLABORATE ACROSS RESEARCH AREAS, PRACTICING TEAM SCIENCE, BEING A PROCESS INNOVATOR AND A SKILLED COMMUNICATOR, BEING A SYSTEMS THINKER, AND CONDUCTING RESEARCH AT THE HIGHEST LEVELS OF RIGOR AND REPRODUCIBILITY TOWARDS ADDRESSING UNMET HEALTHCARE NEEDS. WE WILL ALSO LEVERAGE OUR UNIQUE INSTITUTIONAL STRENGTHS TO EQUIP THESE CLINICAL AND TRANSLATIONAL SCIENTISTS WITH THE SPECIFIC KNOWLEDGE, SKILLS, AND ABILITIES NECESSARY TO IDENTIFY, STUDY, AND MITIGATE CHALLENGES TO HEALTHCARE, INCLUDING THOSE FACED BY RURAL POPULATIONS. WE WILL LEVERAGE OUR EXPERTISE IN HEALTHCARE RESEARCH THROUGH THE DARTMOUTH INSTITUTE, OUR DEEP EXPERIENCE IN PROVIDING HEALTHCARE TO AGING, RURAL POPULATIONS AS NEW HAMPSHIRE’S LARGEST HEALTHCARE SYSTEM AND FLAGSHIP ACADEMIC MEDICAL CENTER IN A DESIGNATED RURAL AREA, AND OUR INTERACTIONS WITH THE UM1 COMMUNITY ENGAGEMENT MODULE TO SUPPORT SCHOLARS’ CONSIDERATION OF CHALLENGES FACED BY THE POPULATIONS TO BE IMPACTED BY THEIR RESEARCH ACROSS THE TRANSLATIONAL SPECTRUM. ADDITIONALLY, WE WILL BUILD MENTORING CAPACITY BY PROVIDING MENTORS WITH THE INFRASTRUCTURE, TRAINING, SUPPORT, GUIDANCE, AND OTHER TOOLS. PARTICIPATING FACULTY AND PRECEPTORS WILL BE TRAINED TO USE EVIDENCE-INFORMED MENTORING PRACTICES THAT LAUNCH SCHOLARS FROM ALL BACKGROUNDS INTO INDEPENDENT, RESEARCH-FOCUSED CAREERS. THE GREEN SCHOLARS PROGRAM WILL PROVIDE THE FLEXIBILITY NEEDED TO DEVELOP SUCCESSFUL INDEPENDENT RESEARCH CAREERS FOR SCIENTISTS CONDUCTING RIGOROUS STUDIES ACROSS THE TRANSLATIONAL SPECTRUM, WHILE PROVIDING A FOUNDATION IN KEY APPROACHES AND STRATEGIES AIMED AT PROMOTING QUALITY HEALTHCARE. MOREOVER, THE MENTOR DEVELOPMENT INITIATIVES WILL MAXIMIZE THE GREEN SCHOLARS PROGRAM’S CAPACITY TO MEET EACH SCHOLAR’S UNIQUE NEEDS, AND THE EXPERT MENTORING TEAMS, INCLUDING NEAR-PEER MENTORS, WILL STRENGTHEN THEIR LIKELIHOOD OF SUCCESS. SUCCESSFUL DEVELOPMENT OF INVESTIGATORS LEADING INNOVATIVE AND RIGOROUS CLINICAL AND TRANSLATIONAL SCIENCE IS ESSENTIAL TO THE NIH’S MISSION TO ENHANCE HEALTH, LENGTHEN LIFE, AND REDUCE ILLNESS AND DISABILITY. THE PROGRAM IS DESIGNED TO MEET THESE GOALS BY IDENTIFYING AND SUPPORTING THE DEVELOPMENT OF HIGH-POTENTIAL EARLY-CAREER FACULTY INTO THE NEXT GENERATION OF LEADERS IN HIGH-IMPACT TRANSLATIONAL SCIENCE ACROSS THE TRANSLATIONAL SPECTRUM, WITH A PARTICULAR FOCUS ON IDENTIFYING AND ADDRESSING CRITICAL HEALTH ISSUES, INCLUDING THOSE FACED BY RURAL POPULATIONS.

A FULLY REMOTE PILOT RANDOMIZED CONTROLLED TRIAL TO INVESTIGATE THE IMPACT OF INSOMNIA TREATMENT ON CROHN?S DISEASE - PROJECT SUMMARY POOR SLEEP IS COMMON IN PEOPLE WITH CROHN’S DISEASE (CD) AND PREDICTS GREATER LIKELIHOOD OF SYMPTOM FLARES, SURGERY, HOSPITALIZATION, AND REDUCED QUALITY OF LIFE. INSOMNIA DISORDER – CHRONIC DIFFICULTY WITH INITIATING OR MAINTAINING SLEEP – IS THE MOST COMMON SLEEP DISORDER IN THIS POPULATION. IT IS ALSO ASSOCIATED WITH INCREASES IN BOTH CHRONIC PAIN AND INFLAMMATION. WHILE INSOMNIA IN THIS POPULATION MAY INITIALLY DEVELOP DUE TO CD FLARES, OUR PRELIMINARY DATA INDICATE THAT PEOPLE WITH CD AND INSOMNIA REPORT INSOMNIA-RELATED BEHAVIORS AND ARE INTERESTED IN TREATMENT FOR THEIR SLEEP PROBLEMS. COGNITIVE BEHAVIORAL THERAPY FOR INSOMNIA (CBT-I) IS THE RECOMMENDED FIRST-LINE TREATMENT FOR INSOMNIA DISORDER. IT IS HIGHLY EFFECTIVE NOT ONLY FOR TREATING INSOMNIA, BUT ALSO FOR IMPROVING PAIN AND INFLAMMATION. HOWEVER, WHILE EFFECTIVENESS OF CBT-I HAS BEEN DEMONSTRATED IN OTHER POPULATIONS, NIGHTTIME BOWEL MOVEMENTS AND THE HYPERVIGILANCE THAT RESULTS FROM FEAR OF FECAL INCONTINENCE ARE UNIQUE TO CROHN’S, HIGHLIGHTING THE IMPORTANCE OF INVESTIGATION IN THIS POPULATION. IN THIS K23 PROJECT, THE APPLICANT WILL CONDUCT A PILOT RANDOMIZED CONTROLLED TRIAL OF CBT-I ADAPTED FOR CD VS CONTROL IN 60 ADULTS WITH CD AND INSOMNIA. USING A MIXED-METHODS APPROACH, SHE WILL INVESTIGATE: 1) THE FEASIBILITY AND ACCEPTABILITY OF CBT-I IN CD; 2) THE IMPACT OF CBT-I ON INSOMNIA, SLEEP PATTERNS, CD SYMPTOMS, AND INFLAMMATION; AND 3) TREATMENT RESPONSE SUBGROUPS AND BARRIERS AND FACILITATORS TO INTERVENTION ENGAGEMENT. THIS RESEARCH IS EXPECTED TO ADVANCE OUR UNDERSTANDING OF THE SLEEP/CD RELATIONSHIP AND POSSIBLE TREATMENT OPTIONS FOR A SIGNIFICANT PROBLEM AFFECTING THIS POPULATION. TO SUPPORT THE APPLICANT’S CAREER DEVELOPMENT, TRAINING GOALS, AND PROPOSED RESEARCH PROJECT, SHE HAS ASSEMBLED AN EXCEPTIONAL MENTORSHIP TEAM THAT BRINGS EXPERTISE IN CD PATHOPHYSIOLOGY, ASSESSMENT, AND MANAGEMENT (DR. COREY SIEGEL), OBJECTIVE SLEEP ASSESSMENT AND CBT-I (DR. MICHAEL SMITH), MIXED-METHODS RESEARCH (DR. KELLY ASCHBRENNER), BEHAVIORAL CLINICAL TRIALS IN IBD (DR. LAURIE KEEFER), AND LONGITUDINAL METHODS AND DATA ANALYSIS (DR. TOR TOSTESON). THE APPLICANT’S TRAINING WILL INVOLVE A COMBINATION OF DIDACTIC AND PRACTICAL EXPERIENCES, CONFERENCES, AND USE OF THE EXCELLENT RESEARCH INFRASTRUCTURE SUPPORTED BY DARTMOUTH- HITCHCOCK HEALTH AND THE GEISEL SCHOOL OF MEDICINE AT DARTMOUTH. THIS COMPREHENSIVE PROGRAM OF TRAINING AND RESEARCH WILL PREPARE HER TO COMPETE FOR NIH R01 FUNDING TO EVALUATE THE EFFECTIVENESS OF CBT-I COMPARED TO CONTROL IN A LARGER, FULLY POWERED RANDOMIZED CONTROLLED TRIAL.

THE IMPACT OF QUALITY METRICS ON OUTCOMES AMONG ELDERLY HEART FAILURE PATIENTS

MOLECULAR GUIDED SURGERY FOR ENHANCED RESECTION OF SOLID TUMORS

TARGETING KNOWLEDGE AND COGNITION TO IMPROVE QUALITY OF LIFE: AN INNOVATIVE TELEHEALTH APPROACH FOR PEOPLE WITH POST-TRAUMATIC EPILEPSY AND THEIR CAREGIVERS.

PREVENTION OF IMPLANT SKIN BONE INTERFACE INFECTION IN OSSEOINTEGRATED PROSTHESES WITH PHOTODYNAMIC THERAPY

A PILOT RANDOMIZED TRIAL OF VIDEO-BASED FAMILY THERAPY FOR HOME-VISITED MOTHERS WITH PERINATAL DEPRESSIVE SYMPTOMS - PROJECT SUMMARY THE MATERNAL, INFANT, AND EARLY CHILDHOOD HOME VISITING PROGRAM IS A NATIONAL CHILD ABUSE PREVENTION STRATEGY THAT SERVES VULNERABLE FAMILIES THROUGHOUT THE UNITED STATES. DEPRESSED MOTHERS (PREGNANT AND POST- DELIVERY) MAKE UP A SIGNIFICANT PORTION OF HOME VISITED CLIENTS. THESE MOTHERS EXPERIENCE FAMILY CONFLICT THAT PRECIPITATES OR WORSENS THEIR DEPRESSIVE SYMPTOMS. FURTHERMORE, THEY INFREQUENTLY GET TREATMENT DUE TO MULTIPLE BARRIERS. THESE BARRIERS ARE COMPOUNDED FOR THOSE WHO LIVE IN RURAL AREAS. THE PROPOSED STUDY WILL TEST THE PRELIMINARY EFFECTIVENESS OF AN INNOVATIVE FAMILY THERAPY INTERVENTION, RESILIENCE ENHANCEMENT SKILLS TRAINING (REST), THAT AIMS TO REDUCE MATERNAL DEPRESSIVE SYMPTOMS AND FAMILY CONFLICT, AND INCREASE FAMILY COHESION AND FAMILY COGNITIVE REAPPRAISAL IN THIS VULNERABLE POPULATION. IT BUILDS ON OUR SUCCESSFUL PRELIMINARY STUDY OF REST THAT SHOWED IT SIGNIFICANTLY REDUCED PERINATAL DEPRESSIVE SYMPTOMS IN HOME VISITED MOTHERS AND SIGNIFICANTLY REDUCED FAMILY CONFLICT, AND SIGNIFICANTLY IMPROVED FAMILY COHESION AND FAMILY COGNITIVE REAPPRAISAL. THE PROPOSED STUDY ADDRESSES A CRITICAL SERVICE NEED FOR HOME VISITED MOTHERS WITH MODERATE TO SEVERE DEPRESSIVE SYMPTOMS, LIVING IN RURAL AREAS, WITH LOW ACCESS TO TREATMENT. THE PROPOSED STUDY ALIGNS WITH THE NIMH DIVISION OF SERVICES AND INTERVENTION RESEARCH HIGH PRIORITY AREA IN THE DEVELOPMENT OF INNOVATIVE SERVICE DELIVERY APPROACHES FOR DIVERSE AND UNDERSERVED POPULATIONS. THE LONG-TERM GOAL OF THE PROPOSED STUDY IS TO INTEGRATE THE REST INTO RURAL HOME VISITING AGENCIES THROUGHOUT THE UNITED STATES. TO ACCOMPLISH THIS GOAL, WE MUST FIRST ACCOMPLISH THE AIMS OF THE CURRENT APPLICATION. THE PROPOSED STUDY USES AN EFFECTIVENESS-IMPLEMENTATION HYBRID TYPE 1 DESIGN WITH A PILOT RANDOMIZED TRIAL AND INCLUDES THREE AIMS: 1) TEST THE FEASIBILITY, ACCEPTABILITY, TOLERABILITY, AND SAFETY OF REST CONDUCTED BY COMMUNITY THERAPISTS; 2) TEST THE PRELIMINARY EFFECTIVENESS OF THE REST COMPARED TO STANDARD OF CARE IN REDUCING MATERNAL DEPRESSIVE SYMPTOMS AND FAMILY CONFLICT, INCREASING MATERNAL SCHOOL ENROLLMENT/JOB ATTAINMENT, AND IMPROVING FAMILY COHESION AND FAMILY COGNITIVE REAPPRAISAL; AND 3) COLLECT PRELIMINARY DATA ON BARRIERS AND FACILITATORS TO IMPLEMENTATION OF REST. THE RESULTS WILL BE USED TO INFORM A LARGER RANDOMIZED TRIAL THAT RIGOROUSLY TESTS THE EFFECTIVENESS OF REST.

COMPUTATIONALLY GUIDED MODULATION OF CORTICAL-STRIATAL ACTIVITY: TOWARD BRAIN STIMULATION-BASED TREATMENTS FOR IMPULSIVE AND RISKY DECISION MAKING

EFFECTIVENESS AND IMPLEMENTATION OF BRIEF COGNITIVE-BEHAVIORAL THERAPY FOR HEALTH ANXIETY IN PRIMARY CARE

MULTIMODAL FLUORESCENCE- AND IMAGING-GUIDED SURGICAL NAVIGATION: DEVELOPING METHODS FOR SUBSURFACE, INDIRECT VISUALIZATION OF CANCERS REQUIRING WIDE LOCAL EXCISION

THE ROLE OF MACROPHAGE METABOLIC CROSSTALK IN CF CHRONIC LUNG INFLAMMATION - PROJECT SUMMARY PATIENTS WITH CYSTIC FIBROSIS (CF) SUFFER FROM CHRONIC INFECTIONS AND LUNG INFLAMMATION LEADING TO BRONCHIECTASIS AND, ULTIMATELY, RESPIRATORY FAILURE. ALTHOUGH RECENT ADVANCES, INCLUDING THE APPROVAL OF HIGHLY EFFECTIVE CFTR MODULATOR THERAPY (HEMT), HAVE IMPROVED THE OVERALL QUALITY OF LIFE OF PEOPLE WITH CF (PWCF), CHRONIC INFECTION AND INFLAMMATION ARE THE PRIMARY CAUSE OF MORBIDITY. ALTHOUGH THE MAGNITUDE OF THE INFLAMMATORY RESPONSE IS KNOWN TO BE INCREASED IN THE CF LUNG, THE MECHANISMS UNDERLYING PERSISTENT INFLAMMATION ARE UNKNOWN. WE HAVE SHOWN THAT LUNG MACROPHAGES ARE CRITICAL TO THE LOCAL INFLAMMATORY RESPONSE IN CF. LUNG MACROPHAGES INCLUDE RESIDENT LUNG MACROPHAGES, AS WELL AS LUNG MACROPHAGES THAT ARE RECRUITED TO THE LUNG IN RESPONSE TO INFLAMMATORY STIMULI. OUR PRELIMINARY DATA DEMONSTRATE THAT CF RECRUITED LUNG MACROPHAGES HAVE DECREASED EXPRESSION OF NRF2, A TRANSCRIPTION FACTOR KNOWN TO REGULATE CELLULAR METABOLISM, COMPARED TO NON-CF BRONCHIECTASIS AND CONTROL SUBJECTS, AND THIS DID NOT IMPROVE WITH HEMT. WE ALSO FOUND THAT CF RECRUITED LUNG MACROPHAGES ARE PERSISTENTLY GLYCOLYTIC AND INFLAMMATORY, EVEN IN THE SETTING OF HEMT, WHILE NON-CF BRONCHIECTASIS AND HEALTHY RECRUITED LUNG MACROPHAGES CAN TRANSITION TO AN INFLAMMATION RESOLVING PHENOTYPE. AS IMMUNE CELL CROSSTALK CAN BE MEDIATED BY EXTRACELLULAR VESICLES (EVS), WE INVESTIGATED THE IMPACT OF RESIDENT LUNG MACROPHAGE EVS ON THE INFLAMMATORY RESPONSE OF RECRUITED LUNG MACROPHAGES AND FOUND THAT CF RESIDENT LUNG MACROPHAGE EVS INDUCE PERSISTENT INFLAMMATION IN RECRUITED LUNG MACROPHAGES. LASTLY, WE HAVE PRELIMINARY DATA SHOWING INCREASED MIRNAS PREDICTED TO INHIBIT NRF2 AND REDUCED LEVELS OF INFLAMMATION RESOLVING LIPIDS IN EVS FROM CF RESIDENT LUNG MACROPHAGES. THUS, WE HYPOTHESIZE THAT SPECIFIC MIRNAS AND LIPIDS WITHIN CF RESIDENT LM EVS REDUCE NRF2 LEVELS IN RECRUITED LMS, CAUSING PERSISTENT GLYCOLYSIS AND FAILURE TO TRANSITION TO AN INFLAMMATION RESOLVING PHENOTYPE. IN AIM 1, WE WILL TEST THE HYPOTHESIS THAT THERE ARE FUNCTIONALLY IMPORTANT IMMUNOMETABOLIC DIFFERENCES IN CF LUNG MACROPHAGES THAT ARE SPECIFIC TO CF AND PERSIST AFTER HEMT. IN THIS AIM, WE WILL FULLY CHARACTERIZE SUBPOPULATIONS OF LUNG MACROPHAGES IN THE CF LUNG AND WILL QUANTIFY DIFFERENCES IN CELLULAR METABOLISM AND INFLAMMATION RESOLUTION BETWEEN RESIDENT AND RECRUITED LUNG MACROPHAGES IN PWCF, NON-CF BRONCHIECTASIS SUBJECTS, AND HEALTHY SUBJECTS. IN AIM 2, WE WILL TEST THE HYPOTHESIS THAT SPECIFIC MIRNAS WITHIN EVS RELEASED BY CF RESIDENT LUNG MACROPHAGES IMPACT THE INFLAMMATORY RESPONSE OF RECRUITED LUNG MACROPHAGES. IN AIM 3, WE WILL TEST THE HYPOTHESIS THAT THE LIPID CONTENT OF EVS RELEASED BY CF RESIDENT LUNG MACROPHAGES PREVENTS THE SHIFT TO AN INFLAMMATION RESOLUTION PHENOTYPE IN RECRUITED LUNG MACROPHAGES. THE PROPOSED STUDIES ARE UNIQUE BECAUSE THEY INVOLVE HUMAN SUBJECTS BEFORE AND AFTER HEMT AND THUS, OUR DATA WILL BE DIRECTLY RELEVANT TO PWCF. IN ADDITION, OUR STUDIES WILL PROVIDE NEW AND ESSENTIAL INFORMATION ON THE MECHANISMS OF PERSISTENT LUNG INFLAMMATION IN CF AND WILL ALLOW US TO IDENTIFY TARGETS FOR NOVEL THERAPIES TO REDUCE HARMFUL CF LUNG INFLAMMATION AND IMPROVE THE LIVES AND LONGEVITY OF PEOPLE LIVING WITH CF.

PEER-DELIVERED AND TECHNOLOGY-ASSISTED INTEGRATED ILLNESS MANAGEMENT AND RECOVERY

MATERNAL AND CHILD HEALTH RESEARCH CONSORTIUM - RURAL POPULATIONS IN THE UNITED STATES EXPERIENCE SIGNIFICANTLY WORSE BIRTH OUTCOMES THAN URBAN PEERS. THIS DIFFERENCE IS SET AGAINST THE HIGHEST MATERNAL MORTALITY RATE OF ANY HIGH-INCOME COUNTRY GLOBALLY AND THE PERSISTENT CLOSING OF RURAL OBSTETRIC UNITS, ESPECIALLY IN IMPOVERISHED COMMUNITIES. HALF OF RURAL COUNTIES IN THE US NO LONGER HAVE A HOSPITAL WITH A BIRTHING UNIT, LEAVING NEARLY 7 MILLION PEOPLE WITHOUT TIMELY ACCESS TO CHILDBIRTH SERVICES AND AT RISK FOR POOR BIRTH OUTCOMES DUE TO GEOGRAPHIC RISK. DESPITE THIS LARGE AND GROWING PROBLEM, THE LIST OF SOLUTIONS FOR RURAL WOMEN AND THEIR REMAINING OBSTETRIC UNITS IS SMALL. RESEARCH DESCRIBING INNOVATIVE AND EFFECTIVE SOLUTIONS TO IMPROVE RURAL MATERNITY CARE ACCESS IS THEREFORE URGENTLY NEEDED. ELECTIVE INDUCTION OF LABOR (EIOL39), OR ARTIFICIALLY STARTING LABOR WITH MEDICATIONS OR CLINAL PROCEDURES, IS A POTENTIAL AVENUE FOR HELPING TO NARROW THE GAP BETWEEN RURAL AND URBAN BIRTH OUTCOMES BY GETTING PREGNANT WOMEN TO THEIR FACILITY OF CHOICE BEFORE LABOR BEGINS. RECENT EVIDENCE, INCLUDING A LARGE TRIAL IN 2018, SHOWS THAT EIOL39 IS AS SAFE AS WAITING FOR LABOR AND MAY REDUCE THE RATES OF CESAREAN SECTION AND HYPERTENSIVE DISORDERS OF PREGNANCY. THE AMERICAN COLLEGE OF OBSTETRICIANS AND GYNECOLOGISTS NOW SAYS THAT EIOL39 SHOULD BE OFFERED AS AN OPTION TO ELIGIBLE WOMEN AND MAY BE PARTICULARLY USEFUL FOR THOSE LIVING FAR AWAY FROM THEIR BIRTH FACILITY. THEY ALSO RECOMMEND GOOD COUNSELING ON THE RISKS AND BENEFITS OF EIOL39. THE NEW EVIDENCE AND RECOMMENDATIONS HAVE LED TO A SIGNIFICANT RISE IN EIOL39 IN THE COUNTRY FROM 12.6% OF BIRTHS BEFORE THE 2018 TRIAL TO 17% POST-TRIAL. EIOL39 RATES IN RURAL POPULATIONS ARE NOT WELL DOCUMENTED IN THE LITERATURE. DESPITE THE RISE IN INDUCTION, PATIENTS, PROVIDERS, AND MANAGERS DESCRIBE CONCERNS ABOUT EIOL39. PATIENTS TALK ABOUT THE “CASCADE OF INTERVENTION” TRIGGERED BY INDUCTION AND WORRY ABOUT LOSS OF CONTROL DURING CHILDBIRTH. MANY PROVIDERS, ESPECIALLY MIDWIVES, ALSO WORRY ABOUT OVERMEDICALIZATION OF BIRTH. SECOND, THE RESEARCH BEHIND EIOL39 WAS CONDUCTED IN HIGH-VOLUME FACILITIES, POTENTIALLY LIMITING ITS GENERALIZABILITY TO RURAL HOSPITAL SETTINGS. THIRD, PROVIDERS AND MANAGERS CITE THE LOGISTICAL COMPLICATIONS OF IMPLEMENTING EIOL39 IN SMALL RURAL FACILITIES. FINALLY, THE TOOLS AND DECISION-AIDS TO HELP RURAL PATIENTS AND PROVIDERS COME TO A SHARED DECISION ARE NOT YET AVAILABLE. WE ARE A GROUP OF RURAL MATERNITY CARE PROVIDERS AND RESEARCHERS ACROSS SEVEN STATES (NEBRASKA, COLORADO, WEST VIRGINIA, GEORGIA, MAINE, NEW HAMPSHIRE, AND VERMONT) WHO WILL WORK COLLABORATIVELY TO ADDRESS THESE GAPS THROUGH FOUR KEY OBJECTIVES: 1) DEVELOP A RESEARCH NETWORK FOCUSED ON RURAL MATERNITY CARE; 2) CONDUCT THREE STUDIES RELATED TO EIOL39 TO MITIGATE GEOGRAPHIC RISK; 3) DISSEMINATE AND TRANSLATE FINDINGS ACROSS ACADEMIC AND SERVICE DELIVERY PLATFORMS; 4) MENTOR EARLY CAREER INVESTIGATORS INTERESTED IN RURAL MATERNITY CARE. FOR OUR FIRST STUDY WE WILL USE MEDICAID INSURANCE CLAIMS DATA TO DESCRIBE THE RATES AND PATTERNS OF ELECTIVE INDUCTION AND RELATED BIRTH OUTCOMES IN RURAL VERSUS URBAN POPULATIONS NATIONALLY. IN THE SECOND STUDY WE WILL ANALYZE THE CHALLENGES THAT RURAL FACILITIES IN OUR STATES FACE IN OFFERING EIOL39 AND WHAT STRATEGIES THEY ARE USING TO OVERCOME THESE CHALLENGES. IN THE THIRD STUDY WE WILL ADAPT A SHARED DECISION-MAKING TOOL FOR RURAL SETTINGS AND TEST THE IMPACT OF ITS USE IN OUR STATES ON PATIENT UNDERSTANDING OF THE OPTIONS AND OUTCOMES OF THEIR DECISIONS, THEIR INVOLVEMENT IN DECISION-MAKING, AND THE EXTENT TO WHICH THEY RECEIVE TREATMENT THAT ALIGNS WITH THEIR VALUES AND GOALS. OUR WORK AND METHODS ARE ROOTED IN PARTICIPATORY IMPLEMENTATION SCIENCE AND ARE INTENDED TO PRODUCE PRACTICAL AND ACTIONABLE INFORMATION FOR RURAL POPULATIONS AND THEIR MATERNITY CARE PROVIDERS.

COMPARATIVE-EFFECTIVENESS OF PROCEDURES FOR CAROTID REVASCULARIZATION - PROJECT SUMMARY 1 CAROTID ARTERY STENOSIS IS A MAJOR RISK FACTOR FOR ISCHEMIC STROKE, A LEADING CAUSE OF MORBIDITY AND MORTALITY IN THE 2 UNITED STATES. PATIENTS WITH CAROTID STENOSIS ARE TYPICALLY MANAGED WITH A COMBINATION OF ANTIPLATELET AND 3 CHOLESTEROL-LOWERING MEDICATIONS AND ARE CONSIDERED FOR PROCEDURAL REVASCULARIZATION TO DECREASE THEIR RISK OF 4 STROKE. THERE ARE THREE DIFFERENT PROCEDURES FOR CAROTID REVASCULARIZATION: SURGICAL CAROTID ENDARTERECTOMY (CEA), 5 PERCUTANEOUS TRANSFEMORAL CAROTID ARTERY STENTING (TF-CAS), AND A PROCEDURE THAT WAS RECENTLY APPROVED IN 6 2015, TRANSCAROTID ARTERY REVASCULARIZATION (TCAR). THE EFFICACY AND SAFETY OF CEA AND TF-CAS HAVE BEEN 7 RIGOROUSLY STUDIED IN MORE THAN A DOZEN RANDOMIZED CLINICAL TRIALS. HOWEVER, TCAR HAS NOT, AND EVIDENCE 8 SUPPORTING ITS USE IS CURRENTLY LIMITED TO SMALL SINGLE-ARM PROSPECTIVE STUDIES AND PROPENSITY-MATCHED ANALYSES 9 WITH LIMITED FOLLOW UP. FURTHERMORE, THE MAJOR NATIONAL INSTITUTES OF HEALTH-SPONSORED RANDOMIZED TRIAL OF CAROTID 10 REVASCULARIZATION, THE CAROTID REVASCULARIZATION AND MEDICAL MANAGEMENT FOR ASYMPTOMATIC CAROTID STENOSIS 11 TRIAL (CREST-2), WHICH BEGAN IN DECEMBER 2014 AND IS STILL IN PROGRESS, DOES NOT INCLUDE TCAR AND THEREFORE 12 CANNOT RESOLVE THE QUESTION OF TCARS EFFECTIVENESS. DESPITE THIS, TCAR HAS RISEN TO RAPID POPULARITY AND IS NOW 13 IN USE AT 570 CENTERS IN THE UNITED STATES WITH 30,951 IMPLANTS AS OF APRIL 2022. THE OBJECTIVE OF THIS PROJECT IS 14 TWO-FOLD. FIRST, WITH NO ONGOING COMPARATIVE TRIAL OF TCAR, DETERMINING HOW THIS NEW PROCEDURE SHOULD BE USED 15 IN CONTEMPORARY PRACTICE RELIES ON OBSERVATIONAL RESEARCH. IN THIS PROPOSAL, WE WILL DEFINE THE 5-YEAR RISK OF STROKE 16 AFTER TCAR VERSUS CEA VERSUS TF-CAS. WE WILL RESOLVE IMPORTANT LIMITATIONS OF PRIOR PUBLISHED STUDIES OF TCAR, 17 INCLUDING LACK OF LONG-TERM RESULTS, ACCOUNTING FOR THE COMPETING RISK OF DEATH, AND IN ESTABLISHING WHICH PATIENTS 18 ARE MOST LIKELY TO BENEFIT FROM THIS NEW PROCEDURE. IN DOING SO, WE WILL INFORM BOTH PATIENTS AND CLINICIANS WHAT 19 ROLE TCAR SHOULD PLAY IN THEIR TREATMENT PLANS. SECOND, TCAR REPRESENTS AN OPPORTUNITY TO BOTH ADVANCE OUR 20 KNOWLEDGE OF THIS NEW PROCEDURE, AND SIMULTANEOUSLY FILL KEY CONCEPTUAL KNOWLEDGE GAPS IN DR. COLUMBO’S 21 TRAINING AS A COMPARATIVE-EFFECTIVENESS RESEARCHER. IN VASCULAR CARE, IT IS NOT UNCOMMON FOR PROCEDURES TO BE 22 IMPLEMENTED IN PATIENTS WITHOUT A RANDOMIZED TRIAL. THIS MAKES COMPARATIVE-EFFECTIVENESS RESEARCH USING 23 OBSERVATIONAL DATA VITAL TO ENSURE THAT PATIENTS ARE RECEIVING SAFE AND EFFECTIVE CARE. TCAR IS AN EXCELLENT 24 EXAMPLE OF WHY THIS TYPE OF RESEARCH IS IMPORTANT. THIS MENTORED AWARD WILL ALLOW DR. COLUMBO TO WORK UNDER 25 THE GUIDANCE OF THE MENTORSHIP TEAM TO FURTHER HIS DEVELOPMENT IN COMPARATIVE-EFFECTIVENESS RESEARCH USING 26 OBSERVATIONAL DATA, TRAINING IN THE RESPONSIBLE CONDUCT OF RESEARCH, INTERPRETATION AND CLINICAL APPLICABILITY OF THE 27 FINDINGS, AND GRANT WRITING. THE EDUCATIONAL OBJECTIVES OUTLINED IN THIS PROPOSAL WILL COMPLEMENT DR. COLUMBO’S 28 EXISTING SKILLS AND PROVIDE HIM WITH A WELL-ROUNDED SKILLSET FOR COMPARATIVE-EFFECTIVENESS WORK. WHILE THESE SKILLS 29 WILL BE USED TO EVALUATE TCAR IN THIS PROPOSAL, THEY ARE BROADLY APPLICABLE TO EVALUATING NEW PROCEDURES THAT 30 ARE INTRODUCED IN THE FUTURE, LAUNCHING DR. COLUMBO’S CAREER AS AN INDEPENDENT INVESTIGATOR.

IDH1-TARGETED FLUORESCENCE GUIDED SURGERY OF LOW GRADE GLIOMA - ABSTRACT: LOW GRADE GLIOMAS (LGG) ARE DIFFUSELY INFILTRATIVE BRAIN TUMORS THAT DISPROPORTIONATELY AFFECT YOUNG ADULTS. LEFT UNTREATED THESE TUMORS HAVE A DEVASTATING COURSE DEFINED BY TUMOR PROGRESSION, DISABLING NEUROLOGIC SYMPTOMS, AND ULTIMATELY DEATH. SURGERY HAS AN ESSENTIAL ROLE IN THEIR MANAGEMENT. GROSS TOTAL RESECTION (GTR) OF LGG HAS A PROFOUND IMPACT ON SURVIVAL GIVING YOUNG PATIENTS DECADES OF ADDITIONAL QUALITY LIFE. THE VALUE OF A TOTAL RESECTION IS WELL RECOGNIZED, BUT UNFORTUNATELY OCCURS IN ONLY 15% OF SURGERIES FOR LOW GRADE GLIOMA. THESE TUMORS LACK DISTINCTIVE FEATURES SUCH AS TUMOR NECROSIS OR INCREASED VASCULARITY TYPICALLY USED TO IDENTIFY TUMOR TO BE REMOVED, AND THE BOUNDARY BETWEEN TUMOR AND NORMAL TISSUE IS FREQUENTLY BLURRED DUE TO THEIR DIFFUSE INFILTRATION. EFFORTS TO IMPROVE RATES OF GROSS TOTAL RESECTION IN LGG HAVE BEEN SPARSE AND LARGELY FOCUSED ON HIGH GRADE TUMORS. ADVANCED METHODS OF INTRAOPERATIVE IMAGE GUIDANCE USING MRI ARE RESOURCE INTENSIVE AND FREQUENTLY PROHIBITIVE, WHILE OTHER STANDARD TECHNOLOGIES SUCH AS ULTRASOUND ARE OFTEN INADEQUATE FOR LGG. FLUORESCENCE GUIDED SURGERY (FGS) USING 5-AMINOLEVULINIC ACID (ALA) HAS DEMONSTRATED ENORMOUS PROMISE AND IS IN WIDESPREAD USE. ALA IS ADMINISTERED PRIOR TO SURGERY AND PREFERENTIALLY CONVERTED TO THE FLUORESCENT COMPOUND PROTOPORPHYRIN IX IN TUMOR CELLS PROVIDING VISIBLE CONTRAST BETWEEN NORMAL TISSUE AND TUMOR. ALTHOUGH FGS HAS CLEARLY BENEFITED PATIENTS WITH HGG, IT REMAINS INEFFECTIVE IN THE SETTING OF LOW GRADE GLIOMA. LESS THAN ONE-THIRD OF LGG EXHIBIT ANY VISIBLE FLUORESCENCE WITH 5-ALA, AND THE DIAGNOSTIC ACCURACY REMAINS POOR EVEN WHEN USING ADVANCED QUANTITATIVE METHODS OF FLUORESCENCE IMAGING. ALTERNATIVE FLUORESCENT AGENTS UNDER INVESTIGATION RELY ON THE PRESENCE OF A DISRUPTED BLOOD BRAIN BARRIER OR RECEPTORS THAT ARE NOT RELEVANT IN LGG. WE OUTLINE AN INNOVATIVE STRATEGY FOR FLUORESCENCE GUIDED SURGERY IN LOW GRADE GLIOMA THAT UTILIZES THE UNIQUE MOLECULAR BIOLOGY OF THESE TUMORS TO DEVELOP A NOVEL TARGETED AGENT. A CONSERVED MUTATION (R132H) IN THE PROTEIN ISOCITRATE DEHYDROGENASE (IDH) IS FOUND IN MORE THAN 80% OF LOW GRADE GLIOMAS REGARDLESS OF SUBTYPE. MUTATION OF IDH DRIVES TUMOR FORMATION, AND THE MUTATED PROTEIN IS FOUND THROUGHOUT THE TUMOR IN HIGH LEVELS. FOR THESE REASONS THE IDH (R132H) MUTATION IS AN IDEAL THERAPEUTIC TARGET, AND A NUMBER OF SMALL MOLECULE INHIBITORS HAVE RECENTLY ENTERED CLINICAL TRIALS. WE PROPOSE TO CONSTRUCT A FLUORESCENT IDH IMAGING AGENT USING EXISTING SMALL MOLECULE INHIBITORS AND NOVEL SYNTHETIC CHEMISTRY. IT IS OUR HYPOTHESIS THAT THIS FLUORESCENT AGENT WILL BE HIGHLY TARGETED TO IDH MUTANT LOW GRADE TUMORS PROVIDING VISIBLE CONTRAST DURING SURGERY, AND ULTIMATELY HAVE A PROFOUND IMPACT ON SURVIVAL IN THESE PATIENTS.

MACROPHAGE PATHOGEN INTERACTIONS IN REGIONAL CYSTIC FIBROSIS LUNG INFLAMMATION

DECISION MAKING IN TRANSMASCULINE GENITAL RECONSTRUCTION SURGERY (TMGRS)

DEVELOPING AND TESTING AN INTERACTIVE VISUAL AID FOR APPROACHING DECISION MAKING TO STOP CANCER TREATMENT IN ADVANCED CANCER - PROJECT SUMMARY/ABSTRACT THE LONG-TERM OBJECTIVE OF THIS K08 MENTORED CLINICAL SCIENTIST RESEARCH CAREER DEVELOPMENT AWARD IS TO PREPARE THE CANDIDATE FOR AN INDEPENDENT RESEARCH CAREER IN HEALTH SERVICES AND COMMUNICATION RESEARCH IMPROVING CARE OUTCOMES FOR PATIENTS WITH ADVANCED CANCER. DESPITE ONCOLOGY PRACTICE GUIDELINES EMPHASIZING ALIGNMENT IN PATIENT-CLINICIAN UNDERSTANDING OF PROGNOSIS, TREATMENT INTENT, AND PATIENT VALUES FOR TREATMENT DECISIONS IN ADVANCED CANCER, DISCORDANCE IS COMMON. CONSEQUENTLY, ONE THIRD OF PATIENTS WITH ADVANCED CANCER RECEIVE END-OF-LIFE CARE INCONSISTENT WITH THEIR PREFERENCES. EXISTING APPROACHES TO ALLEVIATE THESE GAPS IN UNDERSTANDING TO PROMOTE GOAL-CONCORDANT CARE HAVE HAD DISAPPOINTING RESULTS. INADEQUATE ATTENTION TO EMOTIONAL SUPPORT AND MANAGING UNCERTAINTY LIKELY CONTRIBUTE TO THE SHORTCOMINGS OF EXISTING APPROACHES. WE HYPOTHESIZE THAT AN INTERACTIVE VISUAL AID (VIS) USED BY PATIENTS, THEIR CAREGIVERS, AND CLINICIANS DURING AN OUTPATIENT VISIT CAN EFFICIENTLY AND EFFECTIVELY PROMPT THE NECESSARY COMMUNICATION BEHAVIORS THAT TARGET EMOTIONAL SUPPORT AND UNCERTAINTY MANAGEMENT. THE CANDIDATE PROPOSES AN INNOVATIVE APPROACH TO DESIGN AND EVALUATE A VIS TO FACILITATE PATIENT-CLINICIAN EMOTIONAL SUPPORT AND MANAGEMENT OF UNCERTAINTY IN THE CONTEXT OF DECISION-MAKING AROUND STOPPING CANCER TREATMENT (E.G., CHEMOTHERAPY, RADIATION THERAPY). THE TRAINING AND MENTORING PLAN IS DESIGNED TO PROVIDE KNOWLEDGE AND SKILLS IN (1) DESIGNING AND LEADING CLINICAL TRIALS, (2) BEHAVIORAL INTERVENTION DEVELOPMENT (3) IMPLEMENTATION SCIENCE, AND (4) PROFESSIONAL DEVELOPMENT. THE PROPOSED RESEARCH WILL ASSESS PATIENT-CAREGIVER-CLINICIAN SHARED UNDERSTANDING FOLLOWING A SERIOUS ILLNESS CONVERSATION IN THE OUTPATIENT SETTING (AIM 1), DEVELOP AND REFINE A HIGHLY ACCEPTABLE AND USABLE, INTERACTIVE VIS FOR APPROACHING DECISIONS TO STOP CANCER TREATMENT OVER TIME (AIM 2), AND EVALUATE THE USABILITY OF THE DEVELOPED VIS FOR PATIENTS WITH ADVANCED CANCER, THEIR CAREGIVERS AND CLINICIANS DURING OUTPATIENT ONCOLOGY VISITS (AIM 3). THE CANDIDATE WILL USE THE PROCESS OF USER-CENTERED DESIGN AND THE BEHAVIOR CHANGE WHEEL INTERVENTION DEVELOPMENT FRAMEWORK TO GUIDE THE METHODS AND ANALYSIS. AIM 1 IS ANTICIPATED TO GENERATE NOVEL INSIGHTS INTO THE PROCESSES PROMOTING SHARED UNDERSTANDING, AND THE PATIENT PERSPECTIVE ON THE PERCEIVED ACCURACY OF CLINICIAN-GENERATED DOCUMENTATION FOR SERIOUS ILLNESS CONVERSATIONS. FINDINGS FROM AIM 1 WILL BE USED TO IDENTIFY THE EXISTING COMMUNICATION GAPS FOR STRUCTURED SERIOUS ILLNESS CONVERSATIONS IN ONCOLOGY THAT A VIS COULD ADDRESS (I.E., NEEDS ASSESSMENT). AIMS 2 AND 3 WILL GENERATE AND EVALUATE A NOVEL COMMUNICATION TOOL – VIS – FOR APPROACHING DECISIONS TO STOP CANCER TREATMENT. IN CONSULTATION WITH HIS TEAM OF MENTORS AND SCIENTIFIC COLLABORATORS/ADVISORS, THE CANDIDATE WILL USE THE TRAINING, THE RESULTS OF THE RESEARCH, AND THE BEHAVIOR CHANGE WHEEL INTERVENTION DEVELOPMENT FRAMEWORK TO SYSTEMATICALLY GUIDE THE NEXT STEPS IN THIS LINE OF WORK PROMOTING GOAL-CONCORDANT CARE AND SUBMIT HIS FIRST R01 PROPOSAL.

OTOENDOSCOPE PAIRED AGENT IMAGING OF OPIOID RECEPTOR KINETICS DURING DEPENDENCY AND WITHDRAWAL

TRANSCRIPT-SELECTIVE TRANSLATIONAL CONTROL OF TH17 CELL DEVELOPMENT AND FUNCTION - PROJECT SUMMARY DIFFERENTIATION OF NAÏVE CD4+ T HELPER (TH) CELLS INTO EFFECTOR OR REGULATORY SUBSETS DETERMINES WHETHER AN IMMUNE RESPONSE IS PROTECTIVE, INEFFECTIVE OR PATHOGENIC. THROUGH A STANDING COLLABORATION WITH DR. MALCOLM WHITMAN, WE HAVE SHOWN THAT THE FEBRIFUGINE FAMILY OF PLANT NATURAL PRODUCTS—INCLUDING THE SYNTHETIC DERIVATIVE HALOFUGINONE (HF)—POTENTLY AND SELECTIVELY BLOCKS HUMAN AND MOUSE TH17 CELL DIFFERENTIATION BY ACTIVATING A CONSERVED STRESS RESPONSE PATHWAY, CALLED THE AMINO ACID RESPONSE (AAR). WE FURTHER SHOWED THAT HF ACTIVATES THE AAR BY BINDING TO THE CATALYTIC DOMAIN OF THE MAMMALIAN PROLYL-TRNA SYNTHETASE, EPRS, AND INHIBITING PROLYL-TRNA AMINOACYLATION (I.E., CHARGING). UNCHARGED TRNAS ACCUMULATE IN CELLS DURING PERIODS OF AMINO ACID RESTRICTION, AND SIGNAL SEQUENTIAL TRANSLATIONAL AND TRANSCRIPTIONAL RESPONSES VIA THE RIBOSOME- ASSOCIATED PROTEIN KINASE, GCN2, TO REDUCE AMINO ACID DEMAND, INCREASE AMINO ACID SUPPLY AND FACILITATE A RETURN TO HOMEOSTASIS. ALTHOUGH HF-MEDIATED EPRS INHIBITION INDUCES RAPID ACCUMULATION OF UNCHARGED PROLYL- TRNAS AND GCN2 ACTIVATION, WE HAVE SHOWN THAT HF-MEDIATED EPRS INHIBITION ACTS INDEPENDENT OF KNOWN AMINO ACID SENSING PATHWAYS, INCLUDING GCN2, TO REPRESS BOTH IL-6-DRIVEN TH17 CELL DIFFERENTIATION AND IL-23- INDUCED ‘PATHOGENIC’ TH17 CELL FUNCTION BY SELECTIVELY REPRESSING STAT3 PROTEIN SYNTHESIS (I.E., TRANSLATION). THIS PROPOSAL INTERROGATES TWO PATHWAYS THAT WE HYPOTHESIZE UNDERLIE HF/EPRS-MEDIATED STAT3 TRANSLATIONAL SILENCING. FIRST, EPRS (THE CELLULAR RECEPTOR FOR HF) HAS AN AUXILIARY, OR ‘MOONLIGHTING’, FUNCTION AS THE RNA- BINDING SUB-UNIT OF A TRANSCRIPT-SELECTIVE TRANSLATIONAL REGULATORY COMPLEX, CALLED GAIT (GAMMA INTERFERON- ACTIVATED INHIBITOR OF TRANSLATION). ASSEMBLED GAIT COMPLEXES BIND AND REPRESS TRANSLATION OF SELECT SETS OF INFLAMMATION-ASSOCIATED TRANSCRIPTS CONTAINING STRUCTURALLY CONSERVED STEM-LOOP MOTIFS IN THEIR 3’ UNTRANSLATED REGIONS (UTRS), BUT HAS YET TO BE FORMALLY EVALUATED IN TH CELLS. SECOND, WE HAVE SHOWN THAT BOTH HF- MEDIATED AAR ACTIVATION (GCN2-DEPENDENT) AND HF-DEPENDENT ANTI-INFLAMMATORY REPROGRAMMING (GCN2- INDEPENDENT) IN STROMAL CELLS REQUIRES ANOTHER RIBOSOME-ASSOCIATED PROTEIN, GCN1. ALTHOUGH GCN1 IS KNOWN ONLY FOR ENHANCING GCN2-BINDING TO UNCHARGED TRNAS, OUR DATA SUGGEST THAT GCN1 CAN BE FUNCTIONALLY UNCOUPLED FROM GCN2, AND MAY SERVE AS A BRANCH POINT FROM THE CANONICAL AAR PATHWAY IN CELLS RESPONDING TO AMINO ACID STRESS. TO ELUCIDATE THE CONTRIBUTION OF THESE PATHWAYS TO CELLULAR RESPONSES TO AMINO ACID DEPRIVATION, AND WITH AN EYE TOWARDS ENGINEERING NEW DRUG-LIKE SMALL MOLECULES THAT RETAIN STAT3 TRANSLATIONAL SILENCING ACTIVITY WITHOUT INHIBITING AN ESSENTIAL ENZYME (EPRS), WE WILL: (I) EMPLOY EPRS IMMUNOPRECIPITATION EXPERIMENTS TO ASSESS HF-DRIVEN GAIT COMPLEX ASSEMBLY AND STAT3 MRNA-BINDING IN DEVELOPING TH17 CELLS; AND (II) USE INDUCIBLE RNAI COUPLED WITH RIBO-TAG MICE TO DETERMINE IF HF/EPRS-MEDIATED STAT3 TRANSLATIONAL REPRESSION REQUIRES GCN1.TOGETHER, THESE STUDIES WILL REVEAL NOVEL INSIGHTS INTO THE TRANSLATIONAL REGULATION OF TH CELL DIFFERENTIATION, AND INFORM NEW, MORE SELECTIVE APPROACHES TO TREAT TH17-DRIVEN IMMUNE PATHOLOGIES.

RURALITY, TOBACCO USE, AND COPD: AN ANALYSIS OF TWO NATIONAL DATASETS - PROJECT ABSTRACT INDIVIDUALS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) WHO LIVE IN RURAL AREAS OF THE UNITED STATES HAVE WORSE HEALTH OUTCOMES COMPARED WITH THEIR NON-RURAL COUNTERPARTS. ALTHOUGH IT IS KNOWN THAT RURAL AREAS HAVE HIGHER RATES OF CIGARETTE SMOKING, AND THAT CIGARETTE SMOKING IS ASSOCIATED WITH WORSE OUTCOMES IN COPD, LESS IS KNOWN ABOUT GEOGRAPHIC VARIATIONS IN THE MOTIVATIONS AND BELIEFS THAT INFLUENCE TOBACCO PRODUCT APPEAL AND USE, ESPECIALLY AMONG NEWER TOBACCO PRODUCTS INCLUDING E-CIGARETTES. FURTHER, IT IS LARGELY UNKNOWN HOW MUCH VARIABILITY IN TOBACCO USE ACCOUNTS FOR THE GEOGRAPHIC DIFFERENCES SEEN IN COPD OUTCOMES. OUR LONG-TERM GOAL IS TO IDENTIFY POTENTIALLY MODIFIABLE DETERMINANTS OF TOBACCO PRODUCT USE THAT CONTRIBUTE TO WORSE COPD IN RURAL US, LEADING TO FUTURE GEOGRAPHICALLY TAILORED INTERVENTIONS DESIGNED TO IMPROVE OUTCOMES. OUR OVERALL OBJECTIVE FOR THIS APPLICATION, WHICH IS THE NEXT STEP TOWARD ATTAINMENT OF OUR LONG-TERM GOAL, IS TO QUANTIFY THE PERCEPTIONS OF RISK AND BENEFIT ON THE PATTERN OF TOBACCO USE IN RURAL AND URBAN POPULATIONS IN THE UNITED STATES, AND TO DETERMINE THE IMPACT OF SUCH PATTERNS ON COPD OUTCOMES. OUR CENTRAL HYPOTHESIS IS THAT PERCEPTIONS OF RISK AND BENEFIT OF TOBACCO PRODUCTS DIFFER BY GEOGRAPHIC LOCATION IN THE US, AND THAT TOBACCO EXPOSURE CONTRIBUTES SIGNIFICANTLY TO THE INCREASED COPD RISKS ASSOCIATED WITH RURAL LOCATION. THE RATIONALE FOR THIS PROJECT IS THAT IDENTIFYING FACTORS THAT INFLUENCE TOBACCO PRODUCT APPEAL AND USE WILL PROVIDE DETAILED INSIGHT INTO POTENTIALLY MODIFIABLE CONTRIBUTORS TO GEOGRAPHIC DISPARITIES IN HEALTH OUTCOMES AND INFORM REGULATORY STRATEGY. USING EXISTING DATASETS, WE WILL TEST OUR HYPOTHESIS IN TWO SPECIFIC AIMS: 1) TO QUANTIFY AND COMPARE PATTERNS OF TOBACCO PRODUCT USE BY GEOGRAPHIC LOCATION, AND TO DETERMINE HOW PERCEPTIONS OF RISK AND BENEFIT OF TOBACCO PRODUCTS DIFFER BY GEOGRAPHIC LOCATION; 2) TO DETERMINE THE RELATIONSHIP BETWEEN GEOGRAPHIC LOCATION AND COPD PREVALENCE, INCIDENCE, AND RESPIRATORY SYMPTOMS, AND TO QUANTIFY THE CONTRIBUTION OF TOBACCO PRODUCT EXPOSURE TO THESE RELATIONSHIPS. TO ADDRESS OUR AIMS, WILL USE DATA FROM THE POPULATION ASSESSMENT OF TOBACCO AND HEALTH (PATH) STUDY AND THE NATIONAL HEALTH INTERVIEW SURVEY (NHIS).THE PATH STUDY IS A LONGITUDINAL, NATIONALLY REPRESENTATIVE STUDY THAT INCLUDES DETAILED QUESTIONS ON THE MOTIVATIONS, BELIEFS, AND PERCEPTIONS INFLUENCING TOBACCO PRODUCT USE, ALLOWING US TO ANALYZE THE LONGITUDINAL ASSOCIATION OF THESE TRENDS WITH COPD RISK AND RESPIRATORY SYMPTOMS WITHIN A BROAD DEFINITION OF URBANICITY. IN A SEPARATE, FOCUSED ANALYSIS, WE WILL DETERMINE THE CROSS-SECTIONAL ASSOCIATION BETWEEN TOBACCO PRODUCTS AND COPD PREVALENCE ACROSS URBAN/RURAL CONTINUUM USING NATIONALLY REPRESENTATIVE DATA FROM THE NHIS STUDY. OUR RESEARCH TEAM HAS EXTENSIVE EXPERIENCE WORKING WITH THESE DATASETS, EACH PROVIDING COMPLIMENTARY LONGITUDINAL AND CROSS SECTIONAL PERSPECTIVES TO ALLOW FOR COMPREHENSIVE ASSESSMENT OF THE CONTRIBUTION OF TOBACCO USE TO OBSERVED DISPARITIES IN COPD OUTCOMES IN RURAL POPULATIONS.

REWARD CIRCUIT DYSFUNCTION, SUBSTANCE USE DISORDER AND SCHIZOPHRENIA: A PRECLINICAL FMRI-BASED CONNECTIVITY STUDY

WHOLE-ANIMAL, HIGH-RESOLUTION IMAGING OF AAV TROPISM FOR THE NERVOUS SYSTEM - PROJECT SUMMARY/ABSTRACT ADENO-ASSOCIATED VIRUSES (AAVS) ARE THE MOST COMMONLY USED GENE THERAPY VECTOR AND AAV TECHNOLOGY IS POSED TO DELIVER NEW TREATMENTS FOR A WIDE RANGE OF PREVIOUSLY INCURABLE CONDITIONS. AAVS ARE NON-PATHOGENIC TO HUMANS AND INFECT NON-DIVIDING CELLS, MAKING THEM IDEAL VECTORS FOR TARGETED REGULATION OF GENE EXPRESSION IN THE HUMAN CENTRAL AND PERIPHERAL NERVOUS SYSTEM (CNS/PNS). THESE HIGHLY ATTRACTIVE FACTORS HAVE BROADLY INCREASED INTEREST IN THERAPEUTIC AAVS; HOWEVER, EXISTING AAV VECTORS REQUIRE VERY HIGH DOSES TO EXPRESS TRANSGENES IN CNS/PNS TARGETS AT LEVELS THAT MITIGATE PATHOLOGY. THE RESULTING DOSE-DEPENDENT TOXICITIES IN OTHER ORGANS HAVE LED TO CLINICAL FAILURES AND UNPREDICTABLE OFF-TARGET DELIVERY, WHICH IS A MAJOR LIMITATION OF MODERN GENE THERAPY. THERE IS A CRITICAL NEED FOR HIGH-THROUGHPUT, COMPREHENSIVE PROFILING OF VIRAL TROPISM AND TRANSDUCTION EFFICIENCY THAT COULD SPEED DEVELOPMENT OF SAFE AND EFFECTIVE AAVS. AAV TROPISM IS TYPICALLY DETERMINED USING IMMUNOHISTOCHEMICAL TECHNIQUES, WHICH ARE THE GOLD STANDARD FOR DETECTION OF TRANSGENE EXPRESSION. HOWEVER, THESE METHODS ARE LABOR-INTENSIVE AND PERMIT TESTING OF ONLY A SMALL NUMBER OF PRE-DETERMINED TISSUES. EFFICIENT AND COMPREHENSIVE AAV TROPISM PROFILING TECHNOLOGIES WOULD FACILITATE DISCOVERY OF AAV VARIANTS WITH GREATER CNS/PNS TROPISM BY ENABLING FAST ITERATIVE TESTING AND DIRECT COMPARISON OF AAV MUTANT VECTORS. MY LONG-TERM GOAL IS TO DEVELOP NOVEL GENE THERAPY TREATMENTS FOR PERIPHERAL NERVE INJURIES. THE OBJECTIVE OF THIS PROPOSAL IS TO TEST FEASIBILITY OF USING A CUSTOM HYPERSPECTRAL WHOLE-BODY IMAGING CRYOMACROTOME (BIOSLICE) FOR RAPID, AUTOMATED EVALUATION OF AAV TROPISM FOR THE NERVOUS SYSTEM. OUR PROPOSED EXPERIMENTS COMBINE TWO POWERFUL TECHNOLOGIES—TRANSGENIC FLUORESCENT REPORTER MICE AND WHOLE-BODY, HIGH-RESOLUTION HYPERSPECTRAL WIDE-FIELD IMAGING—TO DETECT AAV TRANSDUCTION AND PROVIDE A NEW APPROACH TO AAV TROPISM PROFILING. IN AIM 1, WE WILL USE THE BIOSLICE TO SEARCH FOR OFF-TARGET DELIVERY IN AI14 MICE THAT HAVE BEEN INJECTED WITH THREE AAV VARIANTS THAT HAVE KNOWN TROPISM FOR THE CNS/PNS. IN AIM 2, WE WILL TEST WHETHER THE BIOSLICE CAN DETECT MULTIPLEXED AAVS USING DISTINCT FLUORESCENT REPORTERS IN THE SAME ANIMAL, AND EXAMINE EFFECTS ON AAV TROPISM RELATED TO INJECTION SITE. COMPLETION OF THESE AIMS WILL DELIVER AN INNOVATIVE APPLICATION OF AN ADVANCED IMAGING TECHNOLOGY TO ADDRESS A FUNDAMENTAL BOTTLENECK IN AAV DEVELOPMENT. IF SUCCESSFUL, OUR WORK WILL PROVIDE ROBUST PROOF-OF-CONCEPT THAT THE BIOSLICE CAN BE USED TO RIGOROUSLY EVALUATE PRE-CLINICAL AAVS FOR THERAPEUTIC USE. THIS TRANSDISCIPLINARY APPROACH HAS THE POTENTIAL TO ENABLE TROPISM DISCOVERY THROUGH UNBIASED INVESTIGATION OF ALL TISSUES IN THE MOUSE, THEREBY ACCURATELY MODELING POTENTIAL OFF-TARGET DELIVERY AND NEGATIVE SIDE-EFFECTS ACROSS AAV SEROTYPES, EXPRESSION CASSETTES AND INJECTION SITES.

NOVEL TECHOLOGY FOR EARLY INDENTIFICATION OF SURGICAL INFECTIONS

AUDITORY INSIGHTS INTO POST-ACUTE SEQUELAE OF SARS-COV-2 INFECTION: UNVEILING ABNORMAL AUDITORY PERCEPTION AND DIAGNOSTIC MARKERS THROUGH COMPLEX AUDITORY PERFORMANCE TESTS. - SUMMARY: POST-ACUTE SEQUELAE OF SARS-COV-2 INFECTION (PASC) INCLUDE AUDITORY SYMPTOMS SUCH AS IMPAIRED SPEECH UNDERSTANDING IN BACKGROUND NOISE, INCREASED RINGING IN THE EARS (TINNITUS), AND HEIGHTENED SOUND SENSITIVITY (HYPERACUSIS). THESE SYMPTOMS LIKELY ORIGINATE IN THE CENTRAL NERVOUS SYSTEM (CNS), NOT THE EAR, AND SO REFLECT CNS INVOLVEMENT IN PACS. THIS MEANS THAT TESTS OF THE BRAIN’S ABILITY TO PROCESS SOUND (COMPLEX AUDITORY PERFORMANCE TESTS - CAPTS) MIGHT PROVIDE A WINDOW INTO CNS DYSFUNCTION IN PASC AND MAY BE RELATED TO OTHER PREVALENT SUBJECTIVE PASC SYMPTOMS SUCH AS COGNITIVE FATIGUE. IF SO, CAPTS WOULD OFFER AN INNOVATIVE AND OBJECTIVE WAY TO DIAGNOSE AND TRACK PATIENTS WITH PASC. WE COMPARED PERFORMANCE ON A CENTRAL-AUDITORY- FOCUSED TEST BATTERY BETWEEN 40 INDIVIDUALS WITH PASC TO 36 CONTROLS. THIS WORK SHOWED PASC PATIENTS HAD: 1) INCREASED PREVALENCE OF SELF-REPORTED ABNORMAL PERCEPTIONS/REACTIONS TO SOUND SUCH AS RINGING IN THE EARS AND INABILITY TO TOLERATE LOUD SOUNDS, 2.) WORSE PERFORMANCE ON A CHALLENGING BEHAVIORAL CAPTS, AND 3.) INCREASED AUDITORY BRAINSTEM RESPONSE V/I AMPLITUDES THAT RESEMBLE THE NEUROPHYSIOLOGICAL PROFILE OF ABERRANT SOUND PERCEPTION AND SUGGESTS DYSREGULATED CENTRAL GAIN. THE OBJECTIVE OF THIS PROJECT SEEKS TO EXPAND ON THIS WORK AND EVALUATE CAPTS AS TOOLS TO ASSESS CNS FUNCTION IN PASC. BUILDING ON THE TEAM'S PRELIMINARY WORK AND LEVERAGING EXPERTISE IN AUDITORY PROCESSING, NEUROPSYCHOLOGY, AND STATISTICS, THE RESEARCH GOAL IS TO LINK CNS FUNCTION AND SUBJECTIVE COGNITIVE CONCERNS IN PERSONS WITH PASC, PROVIDING AN APPROACH TO IDENTIFYING THE RELATIONSHIP BETWEEN THE CNS, NEUROCOGNITIVE SYMPTOMOLOGY (COGNITIVE FATIGUE), AND AUDITORY PROCESSING IN INDIVIDUALS WITH PASC. THREE SPECIFIC AIMS WILL FOCUS ON: 1.) QUANTIFYING SUBJECTIVE AUDITORY SYMPTOMOLOGY, 2.) DETERMINING AUDITORY DEFICITS USING AN IMPROVED SUITE OF BEHAVIORAL CAPTS, AND 3.) ASSESSING ALTERATIONS IN NEURAL GAIN IN INDIVIDUALS WITH PASC USING AN EXPANDED SET OF NEUROPHYSIOLOGICAL TESTS FOCUSED CENTRAL AUDITORY PROCESSING. THE EXPECTED OUTCOME IS A COMPREHENSIVE UNDERSTANDING OF AUDITORY SYMPTOMOLOGY AND THE IDENTIFICATION OF DEFICITS IN BEHAVIORAL AND NEUROPHYSIOLOGICAL CAPTS, OFFERING POTENTIAL DIAGNOSTIC MARKERS FOR PASC AND PAVING THE WAY FOR THEIR USE IN TRACKING TREATMENT EFFECTS. THE PROJECT CAPITALIZES ON A UNIQUE CLINIC AT DARTMOUTH-HITCHCOCK MEDICAL CENTER DEDICATED TO THE DIAGNOSIS AND TREATMENT OF PASC AND UNITES A MULTIDISCIPLINARY TEAM. THE PI AND STUDY TEAM HAVE EXTENSIVE EXPERIENCE IN USING CAPTS TO ASSESS THE NEUROCOGNITIVE EFFECTS OF VIRAL INFECTIONS FROM THEIR WORK WITH INDIVIDUALS LIVING WITH HIV. THE RESULTS ARE ANTICIPATED TO PROVIDE EVIDENCE-BASED PROOF OF PRINCIPAL FOR CAPTS' DEVELOPMENT AS CRUCIAL DIAGNOSTIC TOOLS FOR PASC AND POTENTIALLY OTHER CONDITIONS WITH DIFFUSE CNS DYSFUNCTION.

MOBILE SMARTPHONE AUDIOMETRY TO IMPROVE HEARING OUTCOMES IN NICARAGUAN CHILDREN

NEUROMODULATION OF AFFECTIVE VALENCE IN HUMANS BY AMYGDALA STIMULATION - PROJECT SUMMARY: NEUROMODULATION OF AFFECTIVE VALENCE IN HUMANS BY AMYGDALA STIMULATION STUDIES INVESTIGATING GLOBAL BURDEN OF DISEASE HAVE SHOWN THAT A SIGNIFICANT PROPORTION OF ALL DISABILITY- ADJUSTED LIFE YEARS ARE LOST DUE TO UNCONTROLLED MENTAL HEALTH DISORDERS. FOR PATIENTS WITH MENTAL ILLNESS WHO HAVE NOT BENEFITED FROM CONVENTIONAL PSYCHIATRIC INTERVENTIONS, NEUROMODULATION VIA DEEP BRAIN STIMULATION (DBS) IS AN EMERGING TREATMENT OPTION. MULTIPLE LINES OF EVIDENCE SHOW THAT DYSFUNCTION OF THE HUMAN AMYGDALA PLAYS A PIVOTAL ROLE IN THE PATHOPHYSIOLOGY OF MANY PSYCHIATRIC DISORDERS THE LONG- TERM GOAL IS TO DETERMINE IF THE HUMAN AMYGDALA CAN BE A SUITABLE DBS TARGET TO TREAT PSYCHIATRIC DISORDERS. THE MAIN OBJECTIVE FOR THIS APPLICATION IS TO TAKE ADVANTAGE OF OPPORTUNITY IN PATIENTS WHO HAVE INTRACRANIAL ELECTRODES FOR EPILEPSY TO INVESTIGATE HOW THE AMYGDALA PROCESSES AFFECTIVE VALENCE AND TO DETERMINE IF ELECTRICAL STIMULATION TARGETED TO THE BASOLATERAL NUCLEUS OF THE AMYGDALA CAN BE SAFELY USED TO INDUCE A CHANGE IN NEURAL NETWORK FOR VALENCE PERCEPTION AND ON JUDGMENT OF AFFECTIVE VALENCE. OUR CENTRAL HYPOTHESIS IS THAT ELECTRICAL STIMULATION OF THE BASOLATERAL NUCLEUS OF THE AMYGDALA DURING PERFORMANCE OF AN AFFECTIVE VALENCE PERCEPTION TASK WILL CHANGE THE OSCILLATORY PROPERTIES OF THE VALENCE NETWORK AND IN TURN CHANGE HOW PATIENTS PERCEIVE AFFECTIVE VALENCE IN PICTURES WITHOUT CAUSING THE UNDESIRABLE SIDE EFFECTS OF STIMULATION. WE PROPOSE THAT THE INDUCTION OF THIS EFFECT ON COGNITION WILL HAVE FUTURE IMPLICATIONS FOR THE TREATMENT OF SPECIFIC PSYCHIATRIC DISORDERS THAT ARE KNOWN TO INVOLVE THE AMYGDALA. THE CENTRAL HYPOTHESIS WILL BE TESTED BY PURSUING TWO SPECIFIC AIMS: (1) CHARACTERIZE OSCILLATIONS OF THE VALENCE NETWORK DURING JUDGMENT OF VALENCE; (2A) MEASURE THE EFFECT OF STIMULATION OF THE BASOLATERAL NUCLEUS OF THE AMYGDALA ON THE OSCILLATORY PROPERTIES OF THE VALENCE NETWORK; AND (2B) MEASURE THE EFFECT OF BASOLATERAL NUCLEUS OF THE AMYGDALA STIMULATION ON PERCEPTION OF AFFECTIVE VALENCE. FOR AIM 1, WE RECORD AND ANALYZE INTRACRANIAL EEG DURING PERCEPTION OF THE JUDGMENT OF VALENCE AND AROUSAL TASK TO GAIN BETTER UNDERSTANDING OF THE OSCILLATORY MARKERS OF AFFECTIVE VALENCE. FOR THE AIM 2A, WE WILL USE INHIBITORY STIMULATION PARAMETERS AND INTRACRANIAL EEG TO UNDERSTAND HOW STIMULATION OF THE BASOLATERAL NUCLEUS OF THE AMYGDALA AFFECTS THE OSCILLATORY PROPERTIES OF NEURAL NETWORKS FOR REPRESENTATION OF VALENCE. FOR AIM 2B, WE WILL DETERMINE HOW STIMULATION AFFECTS PERCEPTION AND JUDGMENT OF VALENCE. THE RESEARCH IS INNOVATIVE BECAUSE IT USES INTRACRANIAL EEG TO GAIN UNDERSTANDING OF NEURAL REPRESENTATION OF VALENCE AND HOW STIMULATION EFFECTS NEURAL NETWORKS AND BEHAVIOR. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE IT WILL IMPROVE OUR UNDERSTANDING OF NEURAL REPRESENTATION OF VALENCE AND EFFECT OF STIMULATION PARAMETERS ON NEURAL NETWORK. THE RESEARCH WILL PROVIDE A STRONG FOUNDATION FOR FUTURE DEVELOPMENT OF AMYGDALA DBS FOR THE TREATMENT OF SPECIFIC PSYCHIATRIC DISORDERS.

TRANSLAMINAR INTERNEURONS IN THE SPINAL CORD DORSAL HORN - ABSTRACT THE CIRCUIT DYNAMICS THAT UNDERLIE THE TRANSITION FROM ACUTE TO CHRONIC PAIN REMAINS POORLY UNDERSTOOD. CHRONIC PAIN IS CHARACTERIZED BY ENHANCED PERCEPTION OF SOMATOSENSORY STIMULI AND THESE CHANGES ARE DRIVEN BY ALTERED FUNCTIONING OF NEURAL CIRCUITS IN THE SPINAL CORD DORSAL HORN (SCDH) THAT REGULATE THE INTEGRATION OF DISTINCT SOMATOSENSORY MODALITIES. WITHIN THE SCDH, TRANSLAMINAR EXCITATORY INTERNEURONS HAVE BEEN PROPOSED TO FUNCTION AS HUBS OF SOMATOSENSORY INTEGRATION, HOWEVER, THE IMPACT OF PERIPHERAL NERVE DAMAGE ON THE INHIBITORY TONE AND EXCITATORY/INHIBITORY BALANCE OF THESE NEURONS REMAINS UNDEREXPLORED. WE HAVE DISCOVERED A NOVEL GENETIC MARKER THAT ALLOWS FOR TARGETED ANALYSIS OF EXCITATORY TRANSLAMINAR SCDH INTERNEURONS IN MICE. OUR PRELIMINARY DATA SHOW THAT THESE PUTATIVE HUB NEURONS, CLASSIFIED MORPHOLOGICALLY AS VERTICAL AND ANTENNA CELLS, CAN BE TARGETED FOR PHYSIOLOGICAL STUDY BASED ON THEIR CONTINUED EXPRESSION OF A DEVELOPMENTAL TRANSCRIPTION FACTOR. WE WILL COMBINE THIS DISCOVERY WITH CUTTING-EDGE VOLTAGE IMAGING, ELECTROPHYSIOLOGICAL, AND HISTOLOGICAL STRATEGIES TO QUANTIFY THEIR INVOLVEMENT IN SPINAL CIRCUITS THAT MEDIATE ALLODYNIA, AND NERVE INJURY INDUCED ALTERATIONS IN THEIR INHIBITORY TONE AND SYNAPTIC BALANCE. VOLTAGE IMAGING IN THE SCDH, AND A FOCUS ON EXCITATORY TRANSLAMINAR INTERNEURONS WILL GREATLY INCREASE OUR UNDERSTANDING OF THE NEURAL CIRCUITS THAT UNDERLY THE TRANSITION FROM ACUTE TO CHRONIC PAIN. INSIGHTS GAINED WILL PROGRESS THE SEARCH FOR NOVEL NON-OPIOID ANALGESICS THAT PREVENT THE TRANSITION FROM ACUTE TO CHRONIC PAIN FOLLOWING PERIPHERAL NERVE DAMAGE.

LONGITUDINAL MEASUREMENT OF NEURODEGENERATION IN TWO MURINE MODELS OF MULTIPLE SCLEROSIS: A CLINICAL AND HISTOPATHOLOGIC VALIDATION STUDY - PROJECT SUMMARY MULTIPLE SCLEROSIS (MS) IS AN INFLAMMATORY AND NEURODEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM WHEREBY RELENTLESS DEMYELINATION AND NEUROAXONAL LOSS ARE THE PRIMARY CAUSE OF IRREVERSIBLE DISABILITY. TESTING STRATEGIES TO ADDRESS THE NEURODEGENERATIVE COMPONENT OF THE DISEASE, IN AN ATTEMPT TO HALT THE PROGRESSION AND PROMOTE FUNCTIONAL RECOVERY, IS A SIGNIFICANT FOCUS OF TRANSLATIONAL RESEARCH IN MS. HOWEVER, A LACK OF SUITABLE BIOMARKERS TO MONITOR DISEASE PROGRESSION IS A SIGNIFICANT IMPEDIMENT TO THIS EFFORT. RECENT ADVANCES IN NEUROIMAGING OFFER NOVEL OPPORTUNITIES TO DEVELOP AND VALIDATE BIOMARKERS OF NEURODEGENERATION AS VALUABLE ADJUNCTS TO DIAGNOSTIC AND MONITORING TOOLS. TO THIS END, RECENT WORK PERFORMED AT VANDERBILT UNIVERSITY MEDICAL CENTER LED TO THE TECHNICAL DEVELOPMENT OF TWO INNOVATIVE QUANTITATIVE MAGNETIC RESONANCE IMAGING (MRI) TECHNIQUES, I.E., THE SELECTIVE INVERSION RECOVERY QUANTITATIVE MAGNETIZATION TRANSFER IMAGING (SIR-QMT) AND THE DIFFUSION IMAGING USING THE SPHERICAL MEAN TECHNIQUE (SMT). SIRQMT AND SMT PROVIDE A NOVEL FRAMEWORK FOR NON-INVASIVE QUANTIFICATION OF MYELIN AND AXONAL INJURY, RESPECTIVELY. SEVERAL ANIMAL MODELS OF MS ARE CURRENTLY AVAILABLE TO STUDY DIFFERENT CLINICAL AND BIOLOGICAL FEATURES OF THE DISEASE. FOR EXAMPLE, THE MYELIN PROTEOLIPID PROTEIN (PLP)-INDUCED EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS (EAE) RESEMBLES THE RELAPSING-REMITTING MS PHENOTYPE (R-EAE) AND SERVES AS A VALUABLE MODEL TO STUDY THE DEVELOPMENT OF RELAPSES, ACUTE INFLAMMATION AND DEMYELINATION/REMYELINATION. CONVERSELY, THE THEILER’S MURINE ENCEPHALOMYELITIS VIRUS-INDUCED DEMYELINATING DISEASE (TMEV-IDD) MOUSE MODEL UNIQUELY REPRODUCES CLINICAL AND PATHOLOGICAL FEATURES OF PROGRESSIVE MS, SUCH AS DEMYELINATION, CHRONIC NEUROINFLAMMATION, AND AXONAL DAMAGE, LEADING TO SLOWLY PROGRESSING DISABILITY. THE TWO MODELS PROVIDE COMPLEMENTARY INFORMATION REGARDING MS DEVELOPMENT AND EVOLUTION AND TOGETHER FORM AN IDEAL MODEL SYSTEM TO TEST THE POTENTIALS OF NOVEL THERAPIES. ACCORDINGLY, WE HYPOTHESIZE THAT THE POOL SATURATION RATIO (PSR) DERIVED FROM SIR-QMT AND THE (APPARENT) AXONAL VOLUME FRACTION (VAX) DERIVED FROM SMT WILL PROVIDE EARLY AND SENSITIVE BIOMARKERS OF MYELIN AND AXONAL INJURY, RESPECTIVELY, IN THE BRAIN AND SPINAL CORD OF THE TWO MURINE MODELS. BRAIN AND SPINAL CORD MRIS WILL BE LONGITUDINALLY PERFORMED IN R-EAE, TMEV-IDD AND AGE-MATCHED SHAM- TREATED MICE, USING HISTOLOGY AND BEHAVIORAL ANALYSIS TO VALIDATE IMAGING DERIVED BIOMETRICS. THE SHORT-TERM GOAL AND OBJECTIVE OF THIS STUDY ARE TO APPLY SIR-QMT AND SMT IN TWO CLINICALLY DISTINCT MOUSE MODELS OF MS TO VALIDATE PSR AND VAX AGAINST HISTOPATHOLOGIC AND CLINICAL COUNTERPARTS. THE LONG-TERM GOAL OF OUR RESEARCH IS TO DEVELOP MORE EFFECTIVE AND NON-INVASIVE BIOMARKERS OF NEURODEGENERATION AND REPAIR THAT CAN BE USED TO INVESTIGATE CHANGES OF MS, BOTH IN ANIMAL MODELS AND HUMANS, DURING NATURAL HISTORY STUDIES AND EXPERIMENTAL CLINICAL TRIALS.

HEATING MAGNETIC NANOPARTICLES USING LOW FREQUENCY FERROMAGNETIC RESONANCE - PROJECT SUMMARY: SEVERAL CANCER THERAPIES INVOLVE INDUCING HEAT IN THE DISEASE: ABLATION AND HEAT RELEASED DRUGS ARE BUT A FEW OF THEM. MANY OF THESE THERAPIES USE MAGNETIC FIELDS TO HEAT MAGNETIC NANOPARTICLES. THE MOST SIGNIFICANT LIMITATION IS THE TRADE-OFF BETWEEN ENERGY DEPOSITION IN THE NANOPARTICLES AND PENETRATION INTO NORMAL TISSUE. HIGHER FREQUENCY MAGNETIC FIELDS DEPOSIT MORE ENERGY IN THE NANOPARTICLES BUT HAVE MUCH HIGHER ABSORPTION IN NORMAL TISSUE SO THE NORMAL TISSUE IS HEATED RATHER THAN THE NANOPARTICLES IN THE CANCER. WE PROPOSE A NANOPARTICLE HEATING SYSTEM THAT ADDS A VERY LOW FREQUENCY ALTERNATING MAGNETIC FIELD PRODUCING LOWER FREQUENCY PULSED RF FIELDS TO DEPOSIT MORE ENERGY INTO THE NANOPARTICLES. THE PULSED RF WILL BE DELIVERED AT THE FERROMAGNETIC RESONANT FREQUENCY OF THE NANOPARTICLES TO DEPOSIT ENERGY INTO THE NANOPARTICLES VERY EFFICIENTLY. THE VERY LOW FREQUENCY MAGNETIC FIELD WILL REDUCE THE LARMOR FREQUENCY OF THE FERROMAGNETIC RESONANCE TO A FREQUENCY SELECTED TO MITIGATE HEATING OF SURROUNDING NORMAL TISSUE.

ADVANCING ANTIMICROBIAL PHOTODYNAMIC THERAPY TO PREVENT INFECTION IN OSSEOINTEGRATED PROSTHESIS PATIENTS - PROJECT SUMMARY OVER 2.2 MILLION US PATIENTS ARE ESTIMATED TO HAVE LIMB LOSS, WITH THE NUMBER PROJECTED TO RISE TO 3.6 MILLION BY 2050. THE CURRENT STANDARD FOR REHABILITATION AND MOBILITY FOLLOWING AMPUTATION IS A SOCKET-MOUNTED PROSTHESIS WHICH BEARS FORCE THROUGH THE SKIN OF THE RESIDUAL LIMB. HOWEVER, THIS TRADITIONAL ATTACHMENT METHOD IS FREQUENTLY ASSOCIATED WITH FUNCTIONALLY- LIMITING PROBLEMS INCLUDING CHRONIC PAIN, DISCOMFORT, AND MEDICAL COMPLICATIONS AT THE RESIDUUM- PROSTHESIS INTERFACE. OSSEOINTEGRATION (OI) FOR RECONSTRUCTION IN AMPUTEES IS A PROCEDURE IN WHICH A METAL IMPLANT IS DIRECTLY ANCHORED TO THE RESIDUAL BONE. A PROSTHETIC LIMB IS THEN ATTACHED TO THE DISTAL END OF THE IMPLANT (ABUTMENT) WHICH PROTRUDES THROUGH A SMALL OPENING IN THE SKIN. DIRECTLY ANCHORING A PROSTHETIC DEVICE TO THE BONE MUCH MORE CLOSELY MATCHES THE PHYSIOLOGY AND MECHANICS OF A NON-AMPUTATED LIMB, RESULTING IN SUPERIOR OUTCOMES WITH REGARDS TO PHYSICAL FUNCTION, SKIN-RELATED COMPLICATIONS, CHRONIC PAIN AND OSSEOPERCEPTION. HOWEVER, TO DATE, RISK OF INFECTION REPRESENTS THE BIGGEST BARRIER TO WIDESPREAD ADOPTION OF OI PROSTHESES DUE TO THE TRANSCUTANEOUS NATURE OF THE IMPLANT. ANTIMICROBIAL PHOTODYNAMIC THERAPY (APDT) IS A TREATMENT MODALITY IN WHICH A TOPICAL PHOTOSENSITIZING (PS) AGENT (FDA- APPROVED 5-AMINOLEVULINIC ACID, 5-ALA) IS APPLIED, IS PREFERENTIALLY TAKEN UP BY MICROBIAL CELLS, AND IS SUBSEQUENTLY ACTIVATED BY APPLICATION OF LIGHT, PRODUCING CYTOTOXIC SINGLET OXYGEN AND FREE RADICALS THAT ERADICATE MICROORGANISMS. OUR PREVIOUS WORK HAS DEMONSTRATED THAT TOPICAL APDT ELIMINATES >95% OF BOTH BIOFILM-BASED AND PLANKTONIC BACTERIA BOTH IN VITRO AND IN AN IN VIVO RODENT MODEL—SUBSTANTIALLY MORE EFFECTIVE AS A MICROBIOCIDE THAN ANY OTHER CURRENTLY UTILIZED ADJUVANT TREATMENT STRATEGY. THUS, OUR OVERALL OBJECTIVES IN THIS PROPOSAL ARE TO BUILD AN OPTIMIZED LIGHT ADMINISTRATION DEVICE AND EVALUATE FEASIBILITY, ACCEPTABILITY, USABILITY, PRELIMINARY EFFICACY AND SAFETY IN HUMAN PATIENTS WITH OI PROSTHESES. THIS REPRESENTS THE NEXT STEP TOWARD ATTAINMENT OF OUR LONG-TERM GOAL, WHICH IS TO FACILITATE WIDESPREAD IMPLEMENTATION OF OI BY INTEGRATING APDT INTO THE REGULAR WOUND-CARE REGIMEN THUS PREVENING INFECTION. TO ATTAIN OUR OBJECTIVES TWO AIMS WILL BE PURSUED: (1) DESIGN AND BUILD A LIGHT TUNNEL OPTIMIZED FOR DELIVERY OF APDT AT THE IMPLANT-SKIN INTERFACE AND (2) EVALUATE FEASIBILITY, ACCEPTABILITY, USABILITY, PRELIMINARY EFFICACY AND SAFETY FOR INFECTION PREVENTION IN OI PATIENTS. THE COMPLETION OF THIS STUDY IS A CRITICAL STEP TO THE DEVELOPMENT AND IMPLEMENTATION OF A MULTICENTER DEFINITIVE RCT POWERED TO DETECT A REDUCTION IN RATE OF INFECTION IN OI PATIENTS. SUCCESSFUL REDUCTION IN INFECTION WOULD BE PARADIGM-SHIFTING.

CENTRAL AUDITORY PROCESSING ABNORMALITIES AS AN INDICATOR OF PEDIATRIC HEAVY METAL NEUROTOXICITY

VISTA REGULATES TYPE I INTERFERON RESPONSE TO ULTRAVIOLET LIGHT - PROJECT SUMMARY SENSITIVITY TO UV LIGHT AFFECTS ~80% OF LUPUS PATIENTS AND CAN EXACERBATE LOCAL SKIN DISEASE AND LEAD TO SYSTEMIC DISEASE FLARES. THE MOLECULAR PATHWAYS PREDISPOSING LUPUS PATIENTS TO PHOTOSENSITIVITY AND THE MECHANISMS DRIVING THE INFLAMMATORY RESPONSES TO UV LIGHT ARE POORLY UNDERSTOOD. WE SHOWED THAT A SINGLE EXPOSURE TO UV LIGHT LEADS TO A RAPID TYPE I INTERFERON (IFN- I) RESPONSE IN HUMAN AND MURINE SKIN IN VIVO. THAT UV LIGHT IS A POTENT STIMULUS OF THE IFN-I RESPONSE IS PARTICULARLY RELEVANT AS LUPUS PATIENTS (~75%) HAVE A HIGH IFN-I SIGNATURE IN BOTH THE SKIN TISSUE AND THE PERIPHERAL BLOOD CELLS, INDICATIVE OF WORSE DISEASE. THEREFORE, THERE IS A CRITICAL NEED TO DISCOVER WHAT REGULATES THE IFN-I PRODUCTION IN RESPONSE TO UV LIGHT AND IN LUPUS SKIN. RECENT STUDIES SHOWED THAT DEFICIENCY IN VISTA RESULT IN LUPUS-LIKE SKIN DISEASE AND ACCELERATE SYSTEMIC DISEASE IN LUPUS MOUSE MODELS. THE OBSERVED PATHOLOGIES WERE ACCOMPANIED BY AN INCREASE IN THE IFN-I SIGNATURE, SUGGESTING VISTA CAN MODULATE THE IFN-I RESPONSE. INDEED, WE DEMONSTRATED THAT AN AGONISTIC ANTI-VISTA ANTIBODY INHIBITS THE IFN-I RESPONSE IN HUMAN MONOCYTES. WHILE FINDINGS THAT THE TRANSCRIPTIONAL PROFILE OF CELLS FROM LUPUS PATIENTS RESEMBLES THAT OF MURINE VISTA-/- CELLS SUGGEST AN IMPORTANT ROLE FOR VISTA IN LUPUS PATHOGENESIS, HOW VISTA MODULATES THE IFN-I RESPONSE IN LUPUS SKIN AND IN RESPONSE TO UV LIGHT IS UNKNOWN. HERE, WE HYPOTHESIZE THAT VISTA NEGATIVELY REGULATES THE IFN-I RESPONSE TO UV LIGHT AND THAT VISTA ACTIVITY IN KERATINOCYTES MODULATES THE BASELINE AND UV-TRIGGERED IFN-I PRODUCTION. TO TEST THESE HYPOTHESES, WE WILL PURSUE THE FOLLOWING SPECIFIC AIMS: IN AIM 1, WE WILL DEFINE HOW VISTA REGULATES LOCAL AND SYSTEMIC IFN-I RESPONSE TO UV LIGHT IN VIVO. WE PREDICT THAT THE IFN-I RESPONSE TO UV LIGHT IN THE SKIN AND BLOOD OF VISTA-/- MICE WILL BE OF GREATER MAGNITUDE AND/OR DURATION, COMPARED TO VISTA-SUFFICIENT CONTROLS. WE WILL EXAMINE THE THERAPEUTIC POTENTIAL OF TARGETING VISTA TO MODULATE THE IFN-I RESPONSE TO UV LIGHT USING AN AGONISTIC ANTI-HUMAN VISTA MONOCLONAL ANTIBODY IN HUMANIZED VISTA KNOCK-IN MICE. IN AIM 2, WE WILL CHARACTERIZE UV-LIGHT TRIGGERED IFN-I PRODUCTION BY KERATINOCYTES AND DEFINE KERATINOCYTE VISTA FUNCTION. THE CELLULAR SOURCE AND CLASS OF IFN-I IN UV LIGHT EXPOSED SKIN IS UNKNOWN AS IS THE FUNCTION OF VISTA EXPRESSED BY KERATINOCYTES. GIVEN THE RAPID IFN-B PRODUCTION IN THE SKIN AFTER UV EXPOSURE, WE WILL INVESTIGATE THE CONTRIBUTION OF KERATINOCYTES AS THE LIKELY SOURCE OF IFN-IS IN UV LIGHT-EXPOSED SKIN OF NORMAL AND LUPUS MOUSE STRAINS. WE WILL ALSO DEFINE THE KERATINOCYTE-SPECIFIC VISTA FUNCTION IN VIVO IN VISTA CONDITIONAL KNOCKOUT MICE AND IN PRIMARY LUPUS KERATINOCYTES.

LINKING ENVIRONMENTAL CONTAMINATION TO RESIDENTIAL HISTORY FOR RISK IDENTIFICATION

FUNGAL VIRULENCE FACTORS DURING CORNEAL INFECTIONS

REDUCING INAPPROPRIATE USE OF SURVEILLANCE COLONOSCOPY IN OLDER ADULTS

IMPROVING SCREENING AND ACCESS TO TREATMENT FOR DEPRESSION IN CARE PARTNERS OF PEOPLE LIVING WITH DEMENTIA - DEPRESSION AFFECTS UP TO 34% OF CARE PARTNERS (CP) OF PEOPLE LIVING WITH ALZHEIMER’S DISEASE/ALZHEIMER’S DISEASE-RELATED DEMENTIA (PLWD) EACH YEAR AND DESPITE THE EXPANSION OF TREATMENTS, MOST INDIVIDUALS DO NOT RECEIVE TREATMENT. THREE KEY BARRIERS TO TREATMENT EXIST: LOW DETECTION, LOW MENTAL HEALTH LITERACY (MHL) AND LIMITED TREATMENT ACCESSIBILITY, EXACERBATED IN RURAL SETTINGS. INNOVATIVE INFORMATICS SOLUTIONS TO BARRIERS EXIST INCLUDING AUTOMATING SCREENING, ENHANCING MHL THROUGH DECISION AIDS (DA) AND INCREASING ACCESSIBILITY VIA LOCATION-INDEPENDENT, ONLINE TREATMENTS. YET THERE IS A GAP IN IDENTIFYING STRATEGIES TO SCREEN AND CONNECT CP OF PLWD WITH UNMET MENTAL HEALTH NEEDS TO TREATMENTS. THE OBJECTIVE FOR THIS GEMSSTAR IS TO MODIFY AN INNOVATIVE APPLICATION, IPATH*D, DEVELOPED PREVIOUSLY BY THE RESEARCH TEAM, FOR CP OF PLWD. IPATH*D IS AN ONLINE PLATFORM THAT CONNECTS PATIENTS SCREENING POSITIVE FOR CLINICALLY SIGNIFICANT DEPRESSION IN RURAL CANCER SETTINGS TO A RANGE OF ONLINE AND IN-PERSON EVIDENCE-BASED TREATMENTS. INVESTIGATORS PLAN TO ADAPT BOTH THE CONTENT AND IMPLEMENTATION OF IPATH*D, THEN ESTABLISH ITS ACCEPTABILITY, USABILITY, AND FEASIBILITY, OVERCOMING THE UNIQUE CHALLENGES TO HELP-SEEKING CP OF PLWD. THE SPECIFIC AIMS ARE: AIM 1. OPTIMIZE AND ASSESS FEASIBILITY AND ACCEPTABILITY OF A PATHWAY TO IDENTIFY CARE PARTNERS OF PERSONS LIVING WITH ALZHEIMER’S DISEASE AND ALZHEIMER’S DISEASE-RELATED DEMENTIA AT RISK FOR DEPRESSION; AND AIM 2. DETERMINE FEASIBILITY, ACCEPTABILITY, AND USABILITY OF IMPLEMENTING IPATH*D WITH CARE PARTNERS OF PERSONS LIVING WITH ALZHEIMER’S DISEASE/ALZHEIMER’S DISEASE-RELATED DEMENTIA AND ITS PRELIMINARY IMPACT ON MHL, SCREENING AND TREATMENT RATES. THE STUDY TESTS THE HYPOTHESES THAT: (1) IPATH*D WILL BE ACCEPTABLE AND HIGHLY USABLE AND WILL DEMONSTRATE PRELIMINARY IMPACT OF INCREASED MHL, SCREENING RATES AND TREATMENT ACCESS. THE DEVELOPMENT OF IPATH*D FOLLOWS A USER CENTERED DESIGN MODEL. IN AIM 1, USING PARTICIPATORY DESIGN ACTIVITIES TO INFORM NEEDED ADAPTATIONS OF IPATH*D, 15 CARE PARTNERS WILL CO-DESIGN IPATH*D AND INFORM THE DEVELOPMENT OF LOW AND HIGH-FIDELITY IPATH*D PROTOTYPES. THESE PROTOTYPES WILL GO THROUGH ROUNDS OF ITERATIVE DEVELOPMENT, WITH EXTENSIVE USABILITY EVALUATIONS, ENSURING IPATH*D SURPASSES USABILITY METRICS. IN AIM 2, AN OPEN LABEL, SINGLE ARM PILOT, 15 CARE PARTNERS SCREENING POSITIVE FOR DEPRESSION WILL RECEIVE IPATH*D. WE WILL ASSESS REAL WORLD USABILITY, ACCEPTABILITY AND FEASIBILITY, COLLECT PRELIMINARY DATA ON MHL, AND GATHER RATES OF SCREENING AND TREATMENT ACCESS, TREATMENT INITIATION, ADHERENCE, CHANGE IN CAREGIVER BURDEN, AND DEPRESSION SYMPTOM IMPROVEMENT. THIS RESEARCH IS INNOVATIVE IN DEVELOPING AND TESTING A NOVEL SERVICES DELIVERY MODEL (IPATH*D) THAT ADDRESSES EXISTING BARRIERS TO CARE. THE RESULTS ARE EXPECTED TO HAVE A MAJOR POSITIVE IMPACT BY PROVIDING PROOF-OF-PRINCIPLE FOR THE USE OF AN ONLINE PATHWAY TO TREATMENT WITH THE POTENTIAL FOR REACHING AN UNPRECEDENTED NUMBER OF INDIVIDUALS IN RURAL SETTINGS WITH UNMET MENTAL HEALTH NEEDS BY UNDERSTANDING AND IMPLEMENTING THE OPTIMAL DESIGN OF AN INNOVATIVE MODEL OF SERVICES DELIVERY FOR CP OF PLWD WHO EXPERIENCE DEPRESSION.

DOWN SYNDROME AND PSORIASIS: AN INVESTIGATION OF CARDIOMETABOLIC RISK - PROJECT SUMMARY/ABSTRACT THIS PROJECT IS A NOVEL STUDY OF PSORIASIS IN INDIVIDUALS WITH DOWN SYNDROME (DS). ALTHOUGH CLINICAL OBSERVATIONS AND EXISTING LITERATURE CONTEND THAT PSORIASIS IS A COMMON SKIN CONDITION IN DS, THERE IS NO SUPPORTIVE POPULATION-BASED RESEARCH. STUDIES EXPLORING DISEASE SEVERITY AND TREATMENTS ARE LIMITED TO CASE REPORTS OR SMALL CASE SERIES. THERE IS LIKELY AN IMMUNOLOGIC BASIS FOR THIS ASSOCIATION: INTERFERON (IFN) GAMMA IS BELIEVED TO BE A SIGNIFICANT CAUSE OF PSORIASIS AND INDIVIDUALS WITH DS OFTEN HAVE A HYPERACTIVE IFN PATHWAY DUE TO THE TRIPLICATION OF CHROMOSOME 21. IMPROVING OUR UNDERSTANDING OF PSORIASIS IN PEOPLE WITH DS IS PARAMOUNT. WE NEED TO BETTER UNDERSTAND THE BURDEN OF DISEASE ACROSS THE AGE RANGE, CAPTURE DISEASE SEVERITY, AND EVALUATE MEDICAL MANAGEMENT. PSORIASIS IS NOT A CONDITION LIMITED TO THE SKIN, BUT RATHER A DISEASE OF SYSTEMIC INFLAMMATION ASSOCIATED WITH MULTIPLE COMORBIDITIES, SPECIFICALLY CARDIOVASCULAR DISEASE AND CARDIOMETABOLIC RISK FACTORS INCLUDING OBESITY, HYPERTENSION, DYSLIPIDEMIA, TYPE II DIABETES, AND METABOLIC SYNDROME. RECENT GUIDELINES BY THE AMERICAN HEART ASSOCIATION AND AMERICAN COLLEGE OF CARDIOLOGY HAVE IDENTIFIED PSORIASIS AS AN ENHANCED RISK-INDUCING FACTOR FOR ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. ALTHOUGH THESE CARDIOVASCULAR ASSOCIATIONS HAVE BEEN WELL ESTABLISHED IN THE GENERAL POPULATION, THE LINK BETWEEN CARDIOMETABOLIC RISK AND CARDIOVASCULAR DISEASE IN INDIVIDUALS WITH DS AND PSORIASIS IS UNKNOWN. THIS POTENTIAL ASSOCIATION BETWEEN PSORIASIS AND CARDIOMETABOLIC HEALTH IS OF PARTICULAR INTEREST SINCE INDIVIDUALS WITH DS ARE CONSIDERED PROTECTED AGAINST CARDIOVASCULAR DISEASE. COULD PSORIASIS BE AN EXCEPTION TO THE PRESUMED RESILIENCY IN PEOPLE WITH DS OR REVEAL AN EXCEPTION TO THE ESTABLISHED ELEVATED RISK IN THE GENERAL POPULATION? EITHER ASSOCIATION WOULD PROMOTE FURTHER INVESTIGATION INTO THE IMMUNOLOGY AND PATHOPHYSIOLOGY BEHIND THE ASSOCIATION AND PROMPT REEVALUATION OF CARDIOVASCULAR MONITORING AND MEDICAL MANAGEMENT IN PATIENTS WITH DS AND PSORIASIS. TO INVESTIGATE THIS HYPOTHESIS, WE PROPOSE UTILIZING EPIC COSMOS, THE LARGEST INTEGRATED DATA PLATFORM OF CLINICAL HEALTH INFORMATION IN THE UNITED STATES WITH RECORDS FROM OVER 96,000 INDIVIDUALS WITH DS AND APPROXIMATELY 2,000 PATIENTS WITH DS AND PSORIASIS. WE WILL USE EPIC COSMOS TO 1) EVALUATE THE DEMOGRAPHICS, OCCURRENCE, TREATMENT, AND SEVERITY OF PSORIASIS IN DS PATIENTS AND 2) DETERMINE THE ASSOCIATION OF CARDIOMETABOLIC RISK FACTORS AND CARDIOVASCULAR EVENTS IN DS PATIENTS WITH PSORIASIS AND WITHOUT. SKIN CONDITIONS IN DS SHOULD BE CONSIDERED A WINDOW INTO SYSTEMIC HEALTH. WE WILL ESTABLISH THE IMPORTANCE OF THINKING BEYOND “THE VISIBLE” BY EXAMINING CUTANEOUS DISORDERS, SUCH AS PSORIASIS, FOR THEIR GREATER SYSTEMIC IMPACT. THE INNOVATIVE USE OF COSMOS WILL ADVANCE A NOVEL AND IMPORTANT TRANSLATIONAL METHODOLOGY THAT CAN BE LEVERAGED FOR FUTURE PROJECTS WITHIN THE DS RESEARCH COMMUNITY.

SETTING THE AGENDA: EMPOWERING PEOPLE WITH CKD IN RURAL AMERICA THROUGH PARTICIPATORY RESEARCH TO DEVELOP, IMPLEMENT AND TRIAL A CLINICAL VISIT AGENDA-SETTING INTERVENTION - PROJECT SUMMARY/ABSTRACT PEOPLE LIVING IN RURAL AREAS WITH CHRONIC KIDNEY DISEASE (CKD) EXPERIENCE UNDERSTUDIED AND UNDER-ADDRESSED CHALLENGES. U.S. CKD PREVALENCE IS HIGHER IN RURAL AREAS THAN URBAN AREAS, RESULTING IN A CRITICAL NEED TO STUDY AND IMPROVE CKD EXPERIENCES. RURAL-RESIDING PEOPLE WITH CKD OFTEN HAVE COMPLEX, MULTI-MORBID CONDITIONS REQUIRING INTENSIVE TECHNOLOGICAL TREATMENT AND EXTENSIVE TRAVEL TO REACH CARE AND SERVICES. LOCATION ASIDE, ALL PATIENTS WITH CKD HAVE DIFFICULT-TO-MANAGE SYMPTOMS AND REQUIRE TREATMENTS ASSOCIATED WITH HEFTY SELF-MANAGEMENT. AS A RESULT, PATIENTS WITH CKD OFTEN STRUGGLE WITH DISEMPOWERMENT. THEY ASK FEW QUESTIONS AND STRUGGLE TO SELF-ADVOCATE. IN ONE STUDY, ≈90% OF PEOPLE WITH CKD REPORTED WISHING THEY HAD MORE INFORMATION ABOUT THEIR DISEASE; ≈50% EXPRESSED THEY COULD NOT ASK INFORMED QUESTIONS. IN ADVANCED CKD (STAGES 4-5), PATIENTS OFTEN LACK UNDERSTANDING ABOUT THEIR DISEASE, MAKING SELF-MANAGEMENT CHALLENGING. RURAL-RESIDING INDIVIDUALS WITH CKD MUST MANAGE ADDITIONAL LOGISTICAL CHALLENGES WITH FEWER TREATMENT OPTIONS, SERVICES AND SUPPORTS. THERE ARE CURRENTLY FEW FLEXIBILITY-DESIGNED (IN-PERSON AND TELEHEALTH) INTERVENTIONS TO IMPROVE THE SELF-ADVOCACY OF RURAL-RESIDING PATIENTS WITH CKD. IN OTHER CONTEXTS, HOWEVER, PATIENT-CENTERED COMMUNICATIONS INTERVENTIONS SUCH AS COLLABORATIVE AGENDA-SETTING HAVE SHOWN PROMISE. AGENDA-SETTING ENABLES CLINICIANS TO COLLABORATIVELY GENERATE AND PRIORITIZE DISCUSSION TOPICS IN CLINICAL VISITS WITH PATIENTS AND CARE PARTNERS. AGENDA-SETTING PRACTICE IS ASSOCIATED WITH IMPROVED CLINICIAN UNDERSTANDING OF PATIENTS’ CONCERNS, INCREASED PATIENT SATISFACTION AND – NOTABLY – BETTER ADHERENCE TO MEDICATION REGIMENS. AIM 1 OF THIS TRAINING AND RESEARCH PROGRAM IS TO CO-ADAPT AN EXISTING GENERALIZED VISIT AGENDA-SETTING INTERVENTION AND CO-DESIGN AN INTERVENTION DELIVERY STRATEGY FOR RURAL RESIDENTS WITH CKD, THEIR CARE PARTNERS AND THEIR CLINICIANS. USING PARTICIPATORY RESEARCH METHODS, WE WILL CONDUCT ITERATIVE SEMI-STRUCTURED COGNITIVE INTERVIEWS (N=30) WITH PEOPLE EXPERIENCING CKD, THEIR FAMILIES AND THEIR CLINICIANS, REVISING THE AGENDA-SETTING INTERVENTION BASED ON THEIR FEEDBACK. AIM 2 IS TO DETERMINE THE FEASIBILITY AND PRELIMINARY EFFICACY OF USING THE AGENDA-SETTING INTERVENTION FOR PATIENTS, CARE PARTNERS AND CLINICIANS. OUTCOMES INCLUDE SELF-ADVOCACY (PRIMARY) AND UTILIZATION (SECONDARY). THIS WILL CONSIST OF AN OPEN PILOT (N=30), FOLLOWED BY A PILOT STEPPED WEDGE RANDOMIZED CONTROLLED TRIAL (RCT) (N=108). THE GOAL OF THE TRAINING OUTLINED IN THIS PROPOSAL IS TO PRODUCE AN INDEPENDENT INVESTIGATOR EQUIPPED TO DESIGN, TRIAL, AND IMPLEMENT INTERVENTIONS, TO IMPROVE EQUITY FOR RURAL-RESIDING AMERICANS WITH CKD. TRAINING WILL COVER FOUR DOMAINS: 1) RURAL HEALTH EQUITY, 2) CKD SERIOUS ILLNESS COMMUNICATION, 3) IMPLEMENTATION SCIENCE, AND 4) RCTS. THE TRAINING AND EXPERIENTIAL LEARNING DESCRIBED WILL PRODUCE AN INDEPENDENT INVESTIGATOR COMMITTED TO IMPROVING EXPERIENCES FOR RURAL-RESIDING PEOPLE WITH CKD.

LONG COVID HEALTH LITERACY PROJECT: BRINGING HEALTH INFORMATION TO PATIENTS AND PROVIDERS WITH HEALTH DISPARITIES IN RURAL NORTHERN NEW ENGLAND - THE PURPOSE OF THIS PROJECT IS TO ADDRESS HEALTH DISPARITIES IN THE CARE OF PATIENTS WITH POST-ACUTE COVID SYNDROME (PACS) DUE TO THE RURAL NATURE OF NORTHERN NEW ENGLAND AND ITS SHORTAGE OF MEDICAL SERVICES. WE WILL DEVELOP USEFUL, UNDERSTANDABLE AND RELATABLE INFORMATION FOR PATIENTS AND PROVIDERS, IN PARTNERSHIP WITH RURAL AND BIOMEDICAL LIBRARIES. THE FOUNDATION FOR OUR PROJECT IS THE DARTMOUTH-HITCHCOCK PACS CLINIC, AN ESTABLISHED, COMPREHENSIVE CLINIC SERVING PATIENTS IN VERMONT AND NEW HAMPSHIRE. THE RURAL NATURE OF NORTHERN NEW ENGLAND POSES A CHALLENGE TO DELIVERY OF COMPREHENSIVE CARE TO PACS PATIENTS. MOST PARTS OF VT AND NH ARE CHARACTERIZED AS BEING “SMALL TOWN/ISOLATED RURAL” OR “LARGE RURAL TOWN.” THE DEBILITATING NATURE OF PACS THREATENS JOB SECURITY, FINANCIAL STABILITY, AND THE ABILITY TO FUNCTION NORMALLY, AND THERE IS LIMITED ACCESS TO PRIMARY CARE, PHYSICAL THERAPY, OCCUPATIONAL THERAPY, AND MENTAL HEALTH SERVICES THAT CAN ACCEPT AND ARE FAMILIAR WITH THE COMPLEX NATURE OF PACS. FURTHERMORE, THE AREA DEPRIVATION INDEX (ADI), BASED ON A MEASURE CREATED BY HRSA, SHOWS THAT AT LEAST HALF OF THE TWO STATES HAVE ADI SCORES OF >50, INDICATING THAT THEY ARE “DISADVANTAGED” IN RELATION TO NATIONAL STANDARDS. A LARGE PERCENTAGE OF THE 1300 PATIENTS REFERRED TO OUR PACS CLINIC REPORT DIFFICULTIES IN ACCESSING RELIABLE INFORMATION ABOUT MANAGING THEIR CONDITION AND FINDING LOCALLY BASED SERVICES. AFFORDABLE, HIGH-SPEED INTERNET SERVICE IS OFTEN LIMITED IN RURAL SETTINGS, AND MANY RELY ON LOCAL LIBRARIES TO MEET THOSE NEEDS. ABOVE ALL, PATIENTS EXPRESS A SENSE OF ISOLATION, BOTH PHYSICAL AND EMOTIONAL. OUR EXPERIENCE HAS TAUGHT US THAT BRIDGING THAT SENSE OF ISOLATION IS OFTEN THE GREATEST SERVICE WE CAN PROVIDE. OUR GOAL IS TO “REACH MORE PEOPLE IN MORE WAYS THROUGH ENHANCED ENGAGEMENT PATHWAYS.” OUR AIMS ARE:  TO IMPROVE THE CARE OF PATIENTS WITH PACS IN RURAL VT AND NH BY DISSEMINATING USEFUL, USABLE, AND UNDERSTANDABLE INFORMATION TO THIS HEALTH-DISPARITY POPULATION.  TO PROMOTE A BETTER UNDERSTANDING OF PACS FOR PATIENTS AND PROVIDERS BY MEANS OF NEW, APPROPRIATELY TARGETED RESOURCES. WE WILL CREATE AN ONLINE ARCHIVE OF “DIGITAL STORIES” THAT HIGHLIGHT LIVED EXPERIENCES OF PATIENTS WITH PACS AND CREATE AN INDEPENDENT WEBSITE AND MONTHLY NEWSLETTER WITH CONTENT ABOUT PACS THAT IS RESPONSIVE TO THE EMERGING SCIENCE AND MEETS THE NEEDS OF OUR PATIENTS AND PROVIDERS.  TO RAISE AWARENESS ABOUT PACS IN RURAL COMMUNITIES AND PROMOTE COMMUNITY ACCESS TO INFORMATION ABOUT PACS AND POST-COVID CARE. WE WILL PARTNER WITH RURAL LIBRARIES, WHICH ARE OFTEN A PRIMARY HUB OF INFORMATION-SHARING IN RURAL COMMUNITIES, TO ASSIST IN DEPLOYING COMPUTER AND INFORMATION TECHNOLOGY THAT IS OTHERWISE UNAVAILABLE OR DIFFICULT TO USE FOR MANY OF OUR PATIENTS. WE WILL TAILOR INFORMATION TO MEET THE NEEDS OF OUR POPULATION. OUR EFFORTS SHOULD BE GENERALIZABLE TO OTHER RURAL COMMUNITIES IN THE US.

REGULATION OF THE TYPE I INTERFERON RESPONSE TO ULTRAVIOLET LIGHT

UNDERSTANDING THE MOLECULAR MECHANISMS OF AKKERMANSIA GLYCAN-BINDING ADHESINS IN SHAPING MICROBIAL COMMUNITIES AND BALANCING INTESTINAL INFLAMMATION IN RESPONSE TO HOST SIGNALS - PROJECT SUMMARY/ABSTRACT AKKERMANSIA MUCINIPHILA IS A BACTERIAL RESIDENT OF THE HUMAN INTESTINE THAT IS ASSOCIATED WITH PROTECTION FROM CHRONIC INFLAMMATORY DISEASES SUCH AS INFLAMMATORY BOWEL DISEASES, COLORECTAL CANCERS, AND TYPE-2 DIABETES. THE MOLECULAR MECHANISMS THAT DETERMINE HOW A. MUCINIPHILA INHABITS THE INTESTINE AND HOW IT PROMOTES HOST HEALTH ARE NOT KNOWN. A. MUCINIPHILA GROWS IN DENSE AGGREGATES IN TIGHT ASSOCIATION WITH THE GLYCAN-RICH MUCIN LINING OF THE INTESTINE. WHEN CULTURED IN MUCIN MEDIUM, A. MUCINIPHILA PRODUCES ANTI-INFLAMMATORY COMPOUNDS AND STIMULATES OTHER GLYCAN-COATED GUT MICROBES LIKE RUMINOCOCCUS GNAVUS TO PRODUCE BUTYRATE, A FERMENTATION BYPRODUCT WITH THERAPEUTIC PROPERTIES. THE BOARD AND LONG-TERM OBJECTIVE OF THIS PROJECT IS TO LEARN HOW THE GLYCAN ENVIRONMENT OF THE INTESTINE SHAPES A. MUCINIPHILA’S ANTI-INFLAMMATORY ACTIVITIES AND DECODE SPECIES- LEVEL MECHANISMS THAT DRIVE VARIABILITY AMONG CLINICAL ISOLATES. THIS WORK HAS WIDE-REACHING IMPLICATIONS IN FIELDS SUCH AS PROBIOTIC AND THERAPEUTIC DEVELOPMENT AIMED AT TREATING INFLAMMATORY DISEASES. THE FOCUS OF THIS PROPOSAL IS TO DEVELOP A MOLECULAR UNDERSTANDING OF HOW A. MUCINIPHILA STRAINS REGULATE A DIVERSE GROUP OF GLYCAN-BINDING CELL SURFACE ADHESINS REFERRED TO AS PBH1-CONTAINING ADHESINS (PBHAS) TO ENGAGE WITH THE MUCIN ENVIRONMENT OF THE INTESTINE, TO INTERACT WITH AND MANIPULATE BUTYRATE FERMENTATION IN OTHER SYMBIONTS, AND TO MODULATE INNATE IMMUNE PATHWAYS IN THE HOST. IN SPECIFIC AIM 1 I WILL ENGINEER A ZEBRAFISH BACTERIAL SYMBIONT TO EXPRESS EACH OF THE SEVEN DIVERSE PBHAS ENCODED BY TWO A. MUCINIPHILA SPECIES OF INTEREST (MUCT AND AKK2750) AND TEST HOW EXPRESSION SHAPES THEIR AGGREGATION PROPERTIES IN CULTURE AND INFLUENCES THEIR SPATIAL ORGANIZATION IN THE LARVAL ZEBRAFISH GUT. FURTHER, I WILL USE EXPERIMENTAL EVOLUTION TO UNCOVER THE GENETIC PATHWAYS THAT DRIVE MUCT AND AKK2750 AGGREGATION IN MUCIN MEDIUM. SPECIFIC AIM 2 WILL INVESTIGATE THE ROLE OF PBHAS IN CO-AGGREGATION WITH R. GNAVUS AND DETERMINE HOW MUCT AND AKK2750 MUCIN-SENSING AND CO-AGGREGATION WITH R. GNAVUS INFLUENCE BUTYRATE FERMENTATION. LASTLY, SPECIFIC AIM 3 WILL USE A ZEBRAFISH MODEL OF MICROBE- INDUCED INTESTINAL INFLAMMATION TO IDENTIFY PBHAS AND OTHER SPECIES-SPECIFIC FACTORS THAT REDUCE INFLAMMATION AND PROMOTE INTESTINAL HEALTH. I WILL USE A PATHOGEN-TARGETING PBHA TO DESIGN THERAPEUTIC BEADS THAT BIND AND DEPLETE AN INTESTINAL PATHOGEN AND RESTORES GUT HEALTH. THE MOLECULAR INSIGHTS I WILL DISCOVER, RESEARCH REAGENTS I WILL GENERATE, AND SKILLS I WILL ACQUIRE THROUGH THESE STUDIES WILL POSITION ME TO ESTABLISH MY OWN INDEPENDENT RESEARCH LABORATORY INVESTIGATING THE MOLECULAR MECHANISMS OF MICROBIOME-MEDIATED HUMAN HEALTH.

MULTIPLEXED REPORTER PLATFORMS FOR PROBING THE BILE ACID- NUCLEAR RECEPTOR INTERACTOME - PROJECT SUMMARY BILE ACIDS (BAS) ARE CORE GASTROINTESTINAL (GI) METABOLITES WITH DUAL FUNCTIONS IN LIPID ABSORPTION AND CELL SIGNALING. THE PAST DECADE HAS SEEN A RESURGENCE IN BA RESEARCH THANKS TO SEMINAL STUDIES – INCLUDING FROM OUR LAB – THAT ESTABLISHED BAS AS DIRECT REGULATORS OF INTESTINAL IMMUNE CELLS. NUCLEAR RECEPTORS (NRS) – A LARGE FAMILY OF LIGAND- REGULATED TRANSCRIPTION FACTORS – ARE A PRIMARY SOURCE OF HOST BA RECEPTORS IN THE GI TRACT, INCLUDING IN IMMUNE CELLS. STILL, ONLY A FRACTION OF THE PUTATIVE BA-NR ‘INTERACTOME’ HAS BEEN EXPLORED, IN PART BECAUSE GOLD-STANDARD REPORTER ASSAYS NEEDED TO IDENTIFY NR LIGANDS ARE TEDIOUS AND SINGLEPLEX. OUR GOAL IS TO BUILD AND USE MULTIPLEX NR REPORTER SYSTEMS CAPABLE OF MAPPING GLOBAL INTERACTIONS BETWEEN PHYSIOLOGICALLY DEFINED BA POOLS AND ALL 48 NRS. TO THIS END, WE HAVE DEVELOPED A NOVEL ‘MULTI-GI-OMICS’ PLATFORM THAT FEATURES PARALLEL SAMPLING OF NEARLY 100 ENDOGENOUS BA SPECIES AND METABOLITES FROM ACROSS THREE GI SITES OF INDIVIDUAL MICE, AND THAT YIELDS HIGH-RESOLUTION INSIGHTS INTO DYNAMICS OF SMALL INTESTINAL BA REABSORPTION – A KEY AND RATE-LIMITING STEP IN ENTEROHEPATIC CIRCULATION THAT DETERMINES WHICH BAS IN THE SMALL INTESTINAL LUMEN ULTIMATELY GAIN ACCESS TO MUCOSAL IMMUNE AND EPITHELIAL CELLS IN VIVO. USING THIS APPROACH, WE DESCRIBED THAT THE POOL OF ENDOGENOUS BAS WHICH CIRCULATES THROUGH THE DISTAL SMALL INTESTINE (I.E., ILEUM) OF FASTING C57BL/6 MICE TOTALS AT LEAST 0.3 MOLES/G AND CONTAINS AT LEAST 42 DISCRETE SPECIES. 80% OF THIS POOL IS COMPRISED OF A SMALL HANDFUL OF ‘PRIMARY’ BA SPECIES SYNTHESIZED IN THE LIVER [E.G., TAURINE-CONJUGATED CHOLIC ACID (TCA)], AND IS MAINTAINED BY AN ACTIVE TRANSPORT MECHANISM (ASBT/SLC10A2) UNIQUE TO ILEAL ENTEROCYTES. THE REMAINING 20% INCLUDES MOSTLY ‘SECONDARY’ BAS – PRODUCED VIA MICROBIAL METABOLISM OF PRIMARY BAS IN THE LARGE INTESTINE [E.G., DEOXYCHOLIC ACID (DCA), LITHOCHOLIC ACID (LCA)] – AND ENTER THE ILEUM VIA PASSIVE DIFFUSION. MOST RECENTLY, WE HAVE DISCOVERED THAT SPONTANEOUS ILEAL INFLAMMATION (I.E., ILEITIS) – A HALLMARK OF HUMAN CROHN’S DISEASE MODELLED EXPERIMENTALLY IN TNFARE MICE – ALTERS ILEAL BA ABSORPTION IN WAYS THAT PRODUCE A SMALLER AND MORE PRO-INFLAMMATORY BA POOL. IN SEEKING TO SCREEN FOR PUTATIVE NR-DEPENDENT MECHANISMS THROUGH WHICH HEALTHY OR ILEITIS-ASSOCIATED MOUSE BA POOLS MAY ELICIT TOLEROGENIC OR INFLAMMATORY IMMUNE RESPONSES, RESPECTIVELY, WE HAVE PERFORMED PILOT STUDIES USING A MULTIPLEX NR REPORTER SYSTEM, CALLED TRANS-FACTORIALTM AVAILABLE AT ATTAGENE, INC. APPRECIATING BOTH THE TRANSFORMATIVE POTENTIAL OF MULTIPLEX NR REPORTER SYSTEMS GENERALLY, AS WELL AS THE LIMITATIONS OF THE TRANS- FACTORIALTM SYSTEM SPECIFICALLY, WE HAVE BEGUN BUILDING A MORE UNIVERSAL NR REPORTER FORMAT THAT FEATURES DNA-BARCODED FLUORESCENT REPORTER GENES READABLE BY FLOW CYTOMETRY OR RNA-SEQ. OUR HYPOTHESIS IS THAT USING AND REFINING MULTIPLEX NR REPORTER SYSTEMS WILL LAY THE FOUNDATION FOR MORE BROADLY DECIPHERING THE BA:NR ‘INTERACTOME’, WHILE ALSO ENHANCING NR LIGAND AND DRUG DISCOVERY RESEARCH BY US AND OTHERS.

A SELF-ADMINISTERED, MOTOR-FREE, COGNITIVE SCREENING BATTERY FOR MS: DEVELOPMENT AND INITIAL VALIDATION. NEW AWARD.

DEVELOPMENT OF NEAR-INFRARED MOLECULAR SURGICAL IMAGING FOR SARCOMA MARGIN DEFINITION

GERIATRICS WORKFORCE ENHANCEMENT PROGRAM COVID

TOWARD DYSFUNCTIONAL BRAIN CIRCUITRY IN SCHIZOPHRENIA AND ALCOHOL USE DISORDER: A PRECLINICAL NEUROIMAGING STUDY

ANALYZE AND EVALUATE POTENTIAL RISK FACTORS FOR AMYOTROPHIC LATERAL SCLEROSIS (ALS)

TO SUPPORT A STUDY EXAMINING WHETHER CREATIVE ARTS INTERVENTIONS CAN REDUCE DISTRESS AND IMPROVE MOOD FOR EPILEPSY PATIENTS.

PATHOGENIC MECHANISM OF INTRATHECALLY SYNTHESIZED IMMUNOGLOBULINS IN A MOUSE MODEL OF PROGRESSIVE MULTIPLE SCLEROSIS - PROJECT SUMMARY/ABSTRACT RELAPSING AND PROGRESSIVE MULTIPLE SCLEROSIS (MS) ARE CHARACTERIZED BY AN INTRATHECAL SYNTHESIS OF IMMUNOGLOBULINS (IIGS). THIS OCCURS THROUGHOUT THE DISEASE AND IS THE ONLY WIDELY AGREED UPON MOLECULAR DIAGNOSTIC CRITERIA FOR MS. A GROWING BODY OF EVIDENCE ALSO SUGGESTS THAT IIGS CORRELATES WITH MS DISEASE PROGRESSION, ALTHOUGH THE PATHOLOGICAL ROLE OF THESE ANTIBODIES REMAINS TO BE DETERMINED. CYTOTOXIC ACTIVITIES IN THE CENTRAL NERVOUS SYSTEM (CNS) ARE CRITICAL DETERMINANTS OF MS DISEASE PROGRESSION. INTERESTINGLY, ANTIBODIES CAN ACTIVATE TWO DISTINCT CYTOTOXIC MECHANISMS: ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY (ADCC) AND COMPLEMENT-DEPENDENT CYTOTOXICITY (CDC). THEREFORE, I INITIALLY HYPOTHESIZED THAT, IN MS, IIGS TRIGGERS ADCC AND CDC WITHIN THE CNS, THEREBY ACCRUING CNS DAMAGE AND WORSENING DISEASE PROGRESSION. THUS, OVER THE PAST FEW YEARS, THE PRIMARY GOAL OF MY WORK HAS BEEN TO DEFINE THE CYTOTOXIC ACTIVITY OF THESE IGS BY USING THEILER’S MURINE ENCEPHALOMYELITIS VIRUS-INDUCED DEMYELINATING DISEASE (TMEV-IDD) AS A MODEL OF PROGRESSIVE MS. PARTICULARLY, I HAVE BEEN FOCUSING ON CDC AND THE CLASSICAL COMPLEMENT PATHWAY. THE FIRST COMPONENT OF THE CLASSICAL COMPLEMENT PATHWAY (C1Q) RECOGNIZES AND BINDS TO IGS COMPLEXED TO ANTIGEN AND INITIATES THE COMPLEMENT CASCADE, ULTIMATELY TRIGGERING CDC. SINCE THE RESULTS OF MY STUDIES SUGGEST HIGHER LEVELS OF C1Q IN THE CNS INDICATE MORE SEVERE CLINICAL AND PATHOLOGICAL DISEASE, I DEVELOPED A REFINED WORKING HYPOTHESIS. THUS, I NOW HYPOTHESIZE THAT THERAPEUTIC INHIBITION OF C1Q IN THE CNS OF TMEV-IDD MICE WILL PREVENT DISEASE PROGRESSION BY REDUCING NEUROAXONAL DAMAGE AND NEUROINFLAMMATION. I WILL TEST THIS HYPOTHESIS BY ACCOMPLISHING THE FOLLOWING THREE AIMS: AIM 1 WILL DEMONSTRATE THAT ANTI-C1Q TREATMENT IMPROVES CLINICAL OUTCOMES. TO ACCOMPLISH THIS AIM, TMEV- IDD MICE WILL BE TREATED WITH EITHER AN INTRAVENTRICULARLY INJECTED MURINE ANTI-C1Q ANTIBODY (M1) OR A SYSTEMICALLY ADMINISTERED ANTI-C1Q CAMELID VHH ANTIBODY (AKA NANOBODY). MOTOR AND COGNITIVE OUTCOMES WILL BE EVALUATED. AIM 2 WILL DEMONSTRATE THAT ANTI-C1Q TREATMENT REDUCES NEUROAXONAL DAMAGE. TO ACCOMPLISH THIS AIM, NEUROAXONAL DAMAGE IN TREATED VS. UNTREATED MICE WILL BE ASSESSED THROUGHOUT THE DISEASE BY 1) MEASUREMENT OF CEREBROSPINAL FLUID (CSF) BIOMARKERS OF NEUROAXONAL DAMAGE, 2) HISTOLOGY, AND 3) QUANTITATIVE MAGNETIC RESONANCE IMAGING (MRI) TECHNIQUES. AIM 3 WILL DEMONSTRATE THAT ANTI-C1Q TREATMENT REDUCES NEUROINFLAMMATION. TO ACCOMPLISH THIS AIM, NEUROINFLAMMATION WILL BE ASSESSED IN TREATED AND UNTREATED MICE BY 1) FLOW CYTOMETRY, 2) IMMUNOFLUORESCENCE, AND 3) MEASUREMENT OF INTRATHECALLY PRODUCED INFLAMMATORY BIOMARKERS. OVERALL, THIS WORK WILL PROVIDE COMPELLING EVIDENCE FOR THE SIGNIFICANT ROLE PLAYED BY IIGS IN PMS, THEREBY DEFINING A NEW PARADIGM FOR ITS TREATMENT.

A RANDOMIZED TRIAL OF A VIDEO-BASED FAMILY INTERVENTION FOR HOME VISITED MOTHERS WITH PERINATAL DEPRESSIVE SYMPTOMS - PROJECT SUMMARY THE MATERNAL, INFANT, AND EARLY CHILDHOOD HOME VISITING PROGRAM IS A NATIONAL CHILD ABUSE PREVENTION STRATEGY THAT FACILITATES EVIDENCE-BASED HOME VISITING FOR VULNERABLE FAMILIES THROUGHOUT THE U.S. MOTHERS (PREGNANT AND POSTPARTUM) WITH CLINICALLY SIGNIFICANT DEPRESSIVE SYMPTOMS MAKE UP A SIGNIFICANT PORTION OF HOME VISITED CLIENTS. THESE MOTHERS EXPERIENCE FAMILY CONFLICT THAT PRECIPITATES AND EXACERBATES THEIR DEPRESSIVE SYMPTOMS. THEY INFREQUENTLY GET TREATMENT DUE TO MULTIPLE BARRIERS THAT ARE COMPOUNDED FOR THOSE WHO LIVE IN RURAL AREAS. THE PROPOSED STUDY ADDRESSES A CRITICAL SERVICE NEED FOR HOME VISITED MOTHERS WITH MODERATE TO SEVERE DEPRESSIVE SYMPTOMS, INCLUDING THOSE WITH CO-OCCURRING MODERATE TO SEVERE ANXIETY SYMPTOMS, IN RURAL AREAS WITH LOW ACCESS TO TREATMENT. THE PROPOSED STUDY BUILDS ON THE SUCCESS OF OUR NIMH- FUNDED R34 THAT ASSESSED THE FEASIBILITY, ACCEPTABILITY, SAFETY, TOLERABILITY AND PRELIMINARY EFFECTIVENESS OF AN INNOVATIVE VIDEO-BASED FAMILY THERAPY INTERVENTION (RESILIENCE ENHANCEMENT SKILLS TRAINING, REST) FOR HOME VISITED MOTHERS WITH MODERATE TO SEVERE DEPRESSIVE SYMPTOMS AND MODERATE TO HIGH FAMILY CONFLICT. OUR R01 APPLICATION ALIGNS WITH NIMH’S HIGH PRIORITY AREA (NOT-MH-21-270) TO TEST THE EFFECTIVENESS OF REST COMPARED TO STANDARD OF CARE (VIDEO-BASED PROBLEM SOLVING INDIVIDUAL THERAPY, V-PST) FOR TREATMENT OF HOME VISITED MOTHERS WITH MODERATE TO SEVERE DEPRESSIVE SYMPTOMS, INCLUDING THOSE WITH CO-OCCURRING MODERATE TO SEVERE ANXIETY SYMPTOMS, AND MODERATE TO HIGH FAMILY CONFLICT. THE PROPOSED STUDY USES AN EFFECTIVENESS- IMPLEMENTATION HYBRID TYPE 1 DESIGN WITH A RANDOMIZED TRIAL AND INCLUDES THREE SPECIFIC AIMS: 1) DETERMINE REST’S SUSTAINED IMPACTS ON OUTCOMES (FAMILY CONFLICT, FAMILY COHESION, MATERNAL DEPRESSIVE SYMPTOM SEVERITY, CO-OCCURRING MATERNAL ANXIETY SYMPTOM SEVERITY, AND MATERNAL JOB ATTAINMENT/SCHOOL ENROLLMENT) AT POST-INTERVENTION, 3-MONTH, 6-MONTH, 12-MONTH, AND 18-MONTH FOLLOW-UPS; 2) IDENTIFY FAMILY-LEVEL MECHANISMS OF CHANGE ON TREATMENT RESPONSE AT 12-MONTH AND 18-MONTH FOLLOW-UPS; AND 3) INVESTIGATE IMPLEMENTATION STRATEGIES PREFERRED BY HOME VISITING AGENCY AFFILIATED THERAPISTS TO SUSTAIN HIGH FIDELITY TO REST. SUCCESSFUL COMPLETION OF THE AIMS IS THE INITIAL STEP TO ACCOMPLISH OUR LONG-TERM GOAL TO DISSEMINATE REST TO HOME VISITING AGENCY AFFILIATED THERAPISTS WHO SERVE HOME VISITED FAMILIES IN RURAL REGIONS OF THE U.S.