Mass General Brigham Incorporated

DISCOVERY: DETERMINANTS OF INCIDENT STROKE COGNITIVE OUTCOMES AND VASCULAR EFFECTS ON RECOVERY

CCC FOR NHLBI PREVENTION AND EARLY TREATMENT OF ACUTE LUNG INJURY PETAL NETWORK

REPRIEVE - CCC - LEAD APPLICATION

POINT OF CARE TECHNOLOGY RESEARCH CENTER IN PRIMARY CARE

MECHANISMS OF IMMUNE FAILURE IN CHRONIC INFECTION: HEPATITIS C AS A KEY PARADIGM

IMPACT OF AMYLOID ON THE AGING BRAIN

CLINICAL COORDINATING CENTER NETWORK OF EXCELLENCE IN NEUROSCIENCE CLINICAL TRIAL

CENTER FOR INNOVATIVE NEUROTECH ADVANCEMENT - CINTA - PROJECT ABSTRACT - OVERALL WE PROPOSE TO CREATE THE CENTER FOR INNOVATIVE NEUROTECH ADVANCEMENT (CINTA), A NEW CENTER FOR RAPID TRANSFORMATION OF EMERGING TECHNOLOGIES INTO COMMERCIALLY VIABLE, CLINICALLY FOCUSED SOLUTIONS FOR DISORDERS OF THE NERVOUS SYSTEM. THE PD/PIS, DRS. STEVEN SCHACHTER AND PAOLO BONATO, TOGETHER HAVE MANY DECADES OF EXPERIENCE CREATING AND MANAGING COMPLEX MULTI-INSTITUTIONS, MULTI-DISCIPLINARY, NATIONAL TRANSLATIONAL RESEARCH ORGANIZATIONS, AND EXPERTISE IN NEUROTECHNOLOGY-RELATED RESEARCH, AND WILL LEVERAGE THEIR EXPERIENCE TO FURTHER INNOVATE, ADAPT, AND DEPLOY THE WELL-DEVELOPED, PROVEN APPROACH TO NEEDS-DRIVEN HEALTHCARE TECHNOLOGY INNOVATION PIONEERED, DEVELOPED, AND VALIDATED FOR 23 YEARS BY THE CONSORTIA FOR IMPROVING MEDICINE WITH INNOVATION & TECHNOLOGY (CIMIT). LED FOR THE PAST 23 YEARS BY DR. SCHACHTER AND COLLEAGUES, CIMIT HAS A PROVEN TRACK RECORD OF SUCCESS AS A NATIONAL CENTER FOR HEALTHCARE INNOVATION AND A UNIQUE MODEL TO IDENTIFY UNMET MEDICAL NEEDS; FIND, FUND, AND FACILITATE TECHNOLOGY-BASED PROJECTS TO SOLVE THOSE NEEDS; AND RAPIDLY MOVE THESE INNOVATIONS FROM CONCEPT TO MANUFACTURING TO COMMERCIALIZATION TO THE END-USER. COMBINING THEIR DECADES-LONG EXPERTISE AND INTEREST IN NEUROLOGICAL DISORDERS AND REHABILITATION, THE PD/PIS WILL OVERSEE THE ADVANCEMENT OF PROJECTS UNDER CINTA’S FIVE CORES: ADMINISTRATIVE CORE, OUTREACH CORE, EVALUATION CORE, INNOVATOR SUBPROJECTS CORE, AND RESOURCE SUBAWARDS CORE. PAUL TESSIER, PROGRAM DIRECTOR FOR THE ADMINISTRATIVE CORE, WILL HAVE OVERALL RESPONSIBILITY FOR INTEGRATING THE ACTIVITIES OF THE DIFFERENT CORES TO ACCOMPLISH THE OVERALL GOALS OF THE PROPOSED CENTER UNDER THE GUIDANCE OF THE CENTER PD/PIS. THE ADMINISTRATIVE CORE WILL ENSURE ONGOING INPUT FROM NIH PROGRAM DIRECTORS AND SCIENCE OFFICERS, AS WELL AS INPUT FROM THE STEERING COMMITTEE MEMBERS WHO ARE INTEGRAL IN PROVIDING GUIDANCE TO THE PROGRAM TO HELP DIVERSIFY THE TYPES OF PROJECTS AS WELL AS INCREASE REPRESENTATION OF PROPOSERS OF VARYING BACKGROUNDS. KEY CENTER ACTIVITIES TO ACCOMPLISH THE OVERALL GOALS INCLUDE ESTABLISHED NEEDS ASSESSMENT AND PROJECT SOLICITATION PROCESSES, AND CIMIT’S VIRTUAL COLLABORATION PLATFORM, COLAB, TO HELP CINTA INVESTIGATORS AND FACILITATORS TRACK IMPORTANT DELIVERABLES IN FOUR AREAS CRITICAL TO COMMERCIAL SUCCESS. COLAB WILL ALSO BE USED AS A PLATFORM FOR SHARED CINTA RESOURCES, SUCH AS A CINTA WEBSITE WITH ACCESS TO RESOURCES AVAILABLE TO KEY STAKEHOLDERS. FINALLY, CINTA WILL DRAW UPON THE WELL-ESTABLISHED NATIONAL AND INTERNATIONAL COLLABORATION NETWORKS OF CIMIT AND SPAULDING TO ACHIEVE CINTA’S GOALS AND ENHANCE EXTERNALLY FUNDED COLLABORATIONS.

HARVARD-WIDE PROGRAM ON ANTIBIOTIC RESISTANCE

INTERMEDIATE-SIZE EXPANDED ACCESS TRIAL OF AUTOLOGOUS HYBRID TREG/TH2 CELL THERAPY (RAPA-501) OF AMYOTROPHIC LATERAL SCLEROSIS - ALS IS A LETHAL NEURODEGENERATIVE DISEASE ACCELERATED BY NEUROINFLAMMATION. CURRENT FDA-APPROVED THERAPIES HAVE MODEST BENEFITS AND DO NOT ADDRESS INFLAMMATION. TO ADDRESS THIS, RAPA THERAPEUTICS, LLC (RAPA) HAS DEVELOPED AN AUTOLOGOUS T CELL THERAPY (RAPA-501) THAT REDUCES INFLAMMATION, WITH THE GOAL OF REDUCING ALS MORBIDITY AND MORTALITY. RAPA-501 ARE MANUFACTURED EX VIVO TO ATTAIN DUAL TREG/TH2 ANTI- INFLAMMATORY ACTIVITY AND A T-STEM PHENOTYPE THAT PERMITS T CELL THERAPY WITHOUT CONDITIONING CHEMOTHERAPY. IN AN ONGOING CLINICAL TRIAL OF RAPA-501 IN PEOPLE WITH ALS (PWALS) (NCT04220190), RAPA-501 CELLS WERE FOUND TO BE SAFE (NO PRODUCT-RELATED ADVERSE EVENTS), BIOLOGICALLY ACTIVE (DIVERSE ANTI-INFLAMMATORY EFFECTS IN PWALS), AND SHOWED EARLY TRENDS TOWARD STABILIZING PULMONARY FUNCTION DECLINE. A PHASE 2/3 EXPANSION COHORT WAS ADDED TO THE TRIAL TO ASSESS WHETHER RAPA-501 IS EFFICACIOUS IN STANDARD-RISK PWALS. WE WILL EXTEND RAPA-501 THERAPY TO PWALS NOT ELIGIBLE FOR THIS ONGOING PHASE 2/3 TRIAL OR OTHER ALS TRIALS, WHICH NEARLY UNIVERSALLY REQUIRE THAT PARTICIPANTS HAVE A SLOW VITAL CAPACITY (SVC) VALUE OF =50% OF PREDICTED NORMAL. THE PROPOSED EAP WILL ENROLL PWALS WHO HAVE SVC VALUES <50%. THIS POPULATION OF PWALS IS CONSIDERED “HIGH RISK” (~50% CHANCE OF RESPIRATORY FAILURE OR DEATH WITHIN 180 DAYS) AND THUS PARTICULARLY SUITABLE FOR EXPERIMENTAL IMMUNE THERAPIES SUCH AS RAPA-501. IN ADDITION, THE RAPA-501-EAP WILL NOT EXCLUDE PWALS WHO HAVE A PROLONGED TIME FROM ALS-RELATED SYMPTOMS OR LOW ALSFRS-R SCORES. PARTICIPANTS WILL RECEIVE FOUR RAPA-501 IV INFUSIONS (EVERY 42-DAYS AT ESTABLISHED SAFE DOSE, 80 X 106 CELLS/INFUSION). THIS RAPA-501-EAP WILL FURTHER EVALUATE THE SAFETY OF THIS THERAPY, EXPAND AN UNDERSTANDING OF THE RAPA-501 THERAPEUTIC MECHANISM OF ACTION, AND EVALUATE SIGNALS OF EFFICACY IN THIS REAL-WORLD POPULATION OF PWALS USING STANDARD METHODS AND ORIGENT DATA SCIENCES MACHINE LEARNING ALS PREDICTION ALGORITHMS. THE RAPA-501 EAP WILL BE LED BY INVESTIGATORS AT MASS GENERAL HOSPITAL (MGH; DRS. BERRY, BABU, AND PAGANONI) AND SPONSORED BY RAPA, WHICH IS RESPONSIBLE FOR RAPA-501 MANUFACTURING AND FDA REGULATORY FILINGS UNDER EXISTING IND 019480 (DR. FOWLER, SPONSOR). CLINICAL TRIAL SITE INVESTIGATORS HAVE EXPERIENCE WITH RAPA-501 THERAPY (MGH; HACKENSACK UNIVERSITY MEDICAL CENTER; AND MAYO CLINIC ARIZONA) OR OTHER CELLS THERAPIES. SITES ARE GEOGRAPHICALLY DIVERSE AND LIKELY TO ACCRUE A SIGNIFICANT NUMBER OF UNDERSERVED PWALS (U OF IOWA; U OF IDAHO; PROVIDENCE HOSPITAL, PORTLAND, OREGON; UC-IRVINE; COLUMBIA, NYC). IN ADDITION, SEVERAL RESEARCH COLLABORATIONS WILL EMANATE FROM THE INTENSIVE STUDY OF THE CLINICALLY-ANNOTATED, VALUABLE RESEARCH SAMPLES OBTAINED FROM THE RAPA-501 EAP.

MASSACHUSETTS ALZHEIMER'S DISEASE RESEARCH CENTER

HORMONAL CONTROL OF CALCIUM METABOLISM

AN INTERMEDIATE-SIZE EXPANDED ACCESS PROTOCOL FOR AMYOTROPHIC LATERAL SCLEROSIS WITH PRIDOPIDINE - THE SIGMA 1 RECEPTOR (S1R) HAS EMERGED AS AN ATTRACTIVE THERAPEUTIC TARGET IN ALS. MUTATIONS IN THE S1R ARE CAUSATIVE OF ALS AND THE DEGREE OF LOSS OF FUNCTION IN S1R PROTEIN DETERMINES AGE OF ONSET. S1R KNOCK-DOWN EXACERBATES PHENOTYPES IN ALS MOUSE MODELS, AND S1R ACTIVATION IMPACTS PATHWAYS THAT ARE KNOWN TO BE IMPLICATED IN ALS, I.E., NUCLEOCYTOPLASMIC TRANSPORT, PROTEIN QUALITY CONTROL, ENDOPLASMIC RETICULUM (ER) STRESS, MITOCHONDRIAL FUNCTION, AND AUTOPHAGY. RILUZOLE, EDARAVONE, AND PB-TURSO, THE CURRENT STANDARD-OF-CARE MEDICATIONS FOR ALS IN THE US, OFFER ONLY MODEST CLINICAL BENEFIT AND ARE NOT KNOWN TO ACT THROUGH THE S1R. NUEDEXTA, A NON-SELECTIVE S1R AGONIST, IS APPROVED FOR THE TREATMENT OF PSEUDOBULBAR AFFECT AND HAS BEEN SHOWN TO IMPROVE BULBAR FUNCTION IN A SUBSET OF PEOPLE LIVING WITH ALS. PRIDOPIDINE (PRILENIA THERAPEUTICS) IS A POTENT AND HIGHLY SELECTIVE SMALL MOLECULE S1R AGONIST. THE S1R SHOWS HIGH EXPRESSION THROUGHOUT THE BRAIN, PARTICULARLY IN BRAINSTEM MOTOR NUCLEI. IN THE G93A SOD1 ALS MOUSE MODEL, PRIDOPIDINE MODIFIED DISEASE PROGRESSION. THE SAFETY AND EFFICACY OF PRIDOPIDINE ARE CURRENTLY BEING TESTED INTHE HEALEY ALS PLATFORM TRIAL. THE TRIAL DESIGN INCLUDES AN EFFICACY RANDOMIZED CONTROLLED TRIAL (RCT) FOLLOWED BY AN OPEN LABEL EXTENSION (OLE). THE RCT PORTION OF THE PRIDOPIDINE REGIMEN ENROLLED 162 ALS PARTICIPANTS. WHILE IT DID NOT REACH THE PRIMARY ENDPOINT, IT SHOWED TRENDS TOWARD BENEFICIAL EFFECTS OF PRIDOPIDINE ON SEVERAL OUTCOME MEASURES, WITH THE GREATEST IDENTIFIABLE EFFECT ON FUNCTIONAL SCORES, QUANTITATIVE MOTOR SPEECH, AND NEUROFILAMENT LIGHT LEVELS IN EARLY AND FASTER PROGRESSING PARTICIPANTS. THE OLE IS ONGOING. A SECOND EFFICACY TRIAL TARGETING A SELECTED POPULATION OF PEOPLE WITH ALS IS BEING PLANNED. UNFORTUNATELY, A LARGE SEGMENT OF THE REAL-WORLD ALS POPULATION WON’T BE ELIGIBLE TO ENROLL IN THIS SECOND EFFICACY STUDY DUE TO THE RESTRICTIVE ELIGIBILITY CRITERIA. THE CURRENT PROPOSAL IS AN EXPANDED ACCESS PROTOCOL (EAP) OF PRIDOPIDINE IN 200 INDIVIDUALS WITH ALS WHO ARE INELIGIBLE FOR CLINICAL TRIALS. PARTICIPANTS WOULD RECEIVE PRIDOPIDINE FOR UP TO 24 MONTHS, WHILE THE OLE AND THE PLANNED SECOND EFFICACY TRIAL ARE ONGOING. THIS STUDY WILL PROVIDE REAL- WORLD DATA BY EVALUATING THE EFFECTS OF THE DRUG IN A POPULATION THAT IS BROADER THAN THE ONE INCLUDED IN THE EFFICACY TRIALS AND BY COLLECTING SAFETY, CLINICAL, AND BIOLOGICAL OUTCOMES OVER LONGER TERM EXPOSURE.

2022 MILITARY MEDICAL PHOTONICS PROGRAM AT WELLMAN CENTER FOR PHOTOMEDICINE

GENETICALLY-ENGINEERED PIG ORGAN TRANSPLANTATION INTO NONHUMAN PRIMATES

COCHLEAR SYNAPTOPATHY: PREVALENCE, DIAGNOSIS AND FUNCTIONAL CONSEQUENCES

CENTER FOR THE STUDY OF INFLAMMATORY BOWEL DISEASE

HARVARD CLINICAL NUTRITION RESEARCH CENTER

TOLERANCE-AN APPROACH TO CARDIAC ALLO & XENOTRANSPLANTS

CLINICAL RESEARCH CENTER FOR THE IMPROVED PREVENTION, DIAGNOSIS, AND TREATMENT OF VOCAL HYPERFUNCTION

OVERCOMING RESISTANCE TO BRAF(V600E) TARGETED THERAPIES IN MELANOMA

FUNCTIONAL CONSEQUENCES OF STEM AND PROGENITOR CELL HETEROGENEITY

GENERAL ANESTHETIC SITES ON LIGAND-GATED ION CHANNELS

R&D, SCIENCE AND ENGINEERING, IN THE AREA OF MEDICAL SCIENCES

CENTER FOR BIOMEDICAL OCT RESEARCH AND TRANSLATION

IDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVAL

BOSTON AREA DIABETES ENDOCRINOLOGY RESEARCH CENTER

VCID BIOMARKER'S COORDINATING CENTER

MOLECULAR RESPONSE AND IMAGING-BASED COMBINATION STRATEGIES FOR OPTIMAL PDT

AN EXPANDED ACCESS PROTOCOL OF INTRAVENOUS TREHALOSE INJECTION 90 MG/ML TREATMENT OF PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS - AMYOTROPHIC LATERAL SCLEROSIS (ALS) IS A RAPIDLY PROGRESSIVE NEURODEGENERATIVE. THERE ARE TWO FDA-APPROVED MEDICATIONS TO SLOW ALS PROGRESSION, RILUZOLE AND EDARAVONE; THEIR EFFECT IS MODEST, BUT ADDITIVE GIVEN THAT THEY TARGET DIFFERENT BIOLOGICAL PATHWAYS. ADDITIONAL PATHOPHYSIOLOGIC PATHWAYS CAN BE TARGETED TO PROVIDE EVEN MORE ADDITIVE EFFECT. AUTOPHAGY IS DYSREGULATED IN ALS AND IS A PROMISING TARGET FOR NOVEL THERAPEUTIC DEVELOPMENT. TREHALOSE (SLS-005, SEELOS THERAPEUTICS) IS A DISACCHARIDE THAT IS WELL KNOWN FOR ITS ABILITY TO ACTIVATE AUTOPHAGY. THREE IN VIVO STUDIES DEMONSTRATED A PROTECTIVE EFFECT IN SOD1 MOUSE MODELS (G93T AND G86R). IN HUMANS, TREHALASE BREAKS DOWN TREHALOSE IN THE GUT, SO IT MUST BE DELIVERED INTRAVENOUSLY (IV) TO PRESERVE ITS EFFECT. THE SAFETY AND EFFICACY OF TREHALOSE ARE CURRENTLY BEING TESTED IN THE HEALEY ALS PLATFORM TRIAL. THE TRIAL DESIGN INCLUDES AN EFFICACY RANDOMIZED CONTROLLED TRIAL (RCT) FOLLOWED BY AN OPEN LABEL EXTENSION (OLE). IN THE TRIAL, PARTICIPANTS UNDERGO WEEKLY IV INFUSIONS OF TREHALOSE, WHICH ARE DONE EITHER AT THE CENTER OR AT HOME BY A TRAINED INFUSION NURSE. UNFORTUNATELY, THE TREHALOSE OLE WILL END FOR MOST PARTICIPANTS BEFORE THE RESULTS OF THE RCT ARE KNOWN DUE TO FINANCIAL CONSTRAINTS AS SEELOS IS A SMALL BUSINESS. FOR THE SAME REASON, EXPANDED ACCESS IS NOT CURRENTLY AVAILABLE TO PEOPLE WHO ARE NOT ELIGIBLE FOR THE RCT. THE CURRENT PROPOSAL IS AN EXPANDED ACCESS PROTOCOL (EAP) OF TREHALOSE THAT WILL INCLUDE BOTH PEOPLE WHO ARE NOT ELIGIBLE FOR CLINICAL TRIALS (COHORT 1) AS WELL AS PEOPLE WHO COMPLETED THEIR PARTICIPATION IN THE TREHALOSE OLE OF THE HEALEY ALS PLATFORM TRIAL AND ARE NO LONGER ELIGIBLE FOR PARTICIPATION IN OTHER TRIALS (COHORT 2). THE LATTER GROUP WILL BE EXPOSED FOR AN ADDITIONAL SIX MONTHS. OUTCOME MEASURES FOR THIS EAP WILL INCLUDE SAFETY, THE BIOFLUID BIOMARKER NEUROFILAMENT LIGHT (NFL), CLINICAL MEASURES OF DISEASE PROGRESSION, AND SURVIVAL. THIS STUDY WILL PROVIDE REAL- WORLD DATA TO SUPPLEMENT THE TREHALOSE CLINICAL DEVELOPMENT PROGRAM BY EVALUATING THE EFFECTS OF THE DRUG IN A POPULATION THAT IS BROADER THAN THE ONE INCLUDED IN THE RCT AND BY COLLECTING OUTCOMES OVER LONGER TERM EXPOSURE. DATA WILL BE COLLECTED IN FORMAT THAT CAN BE SUBMITTED TO FDA AND COULD THEREFORE BE INCLUDED IN A POTENTIAL NDA SUBMISSION.

GENE THERAPY FOR BRAIN TUMORS

BRAIN CONNECTS: THE CENTER FOR LARGE-SCALE IMAGING OF NEURAL CIRCUITS (LINC) - PROJECT SUMMARY: THIS PROJECT WILL DEVELOP AND VALIDATE A COMPREHENSIVE TOOLSET OF NOVEL TECHNOLOGIES FOR IMAGING AXONAL PROJECTIONS ACROSS SCALES, AND WILL DEPLOY THIS TOOLSET TO MAP A COMPLEX SYSTEM OF CORTICO- SUBCORTICAL PROJECTIONS IN THE MACAQUE AND HUMAN BRAIN. WE WILL COMBINE THE COMPLEMENTARY STRENGTHS OF THREE INNOVATIVE MICROSCOPY TECHNIQUES. FIRST, POLARIZATION-SENSITIVE OPTICAL COHERENCE TOMOGRAPHY (PS-OCT) WILL PROVIDE LABEL-FREE, UNDISTORTED IMAGING OF AXONAL ORIENTATIONS AT THE SCALE OF MICROSCOPIC FASCICLES, ALLOWING US TO FOLLOW FASCICLES ACROSS THE BRAIN WITHOUT THE NEED FOR AXON SEGMENTATION. SECOND, WHOLE-MOUNT LIGHT- SHEET MICROSCOPY (LSM) OF CLEARED AND IMMUNOLABELED SECTIONS WILL ALLOW US TO IMAGE FASCICLES AT THE SUB- MICRON SCALE, RESOLVING INDIVIDUAL AXONS. THIRD, HIERARCHICAL PHASE-CONTRAST TOMOGRAPHY (HIP-CT) WILL ALLOW US TO IMAGE BOTH THE AXONS AND THEIR MICRO-ENVIRONMENT, AT A RANGE OF SCALES FROM A FEW MICRONS DOWN TO SUB- MICRON. WE WILL SCALE THESE THREE MICROSCOPY TECHNIQUES UP TO IMAGE A LARGE SUB-VOLUME OF THE BRAIN (UP TO TWO THIRDS OF A HEMISPHERE) THAT CONTAINS SUBCORTICAL PROJECTIONS OF THE MOTOR, PREMOTOR, AND PREFRONTAL CORTEX. IN THE MACAQUE BRAINS, FLUORESCENT TRACER INJECTIONS WILL ALLOW DIRECT VALIDATION OF OUR NOVEL MICROSCOPY TECHNIQUES. IN COMBINATION WITH AN EXTENSIVE COLLECTION OF PRIOR TRACER INJECTIONS, THE MACAQUE DATA WILL ALSO PROVIDE THE TOPOGRAPHIC ORGANIZATIONAL RULES OF FIBERS IN CORTICO-SUBCORTICAL BUNDLES, WHICH WE WILL THEN USE TO VALIDATE OUR NOVEL MICROSCOPY TECHNIQUES IN HUMAN BRAINS. IN BOTH MACAQUE AND HUMAN SPECIMENS, WE WILL ALSO COLLECT EXTENSIVE, CUTTING-EDGE, WHOLE-BRAIN DIFFUSION MRI DATA, WHICH WILL PROVIDE THE LINK TO NON-INVASIVE NEUROIMAGING. THE UNPRECEDENTED DATASETS GENERATED BY OUR PROJECT WILL ENABLE RESEARCH DISCOVERY IN TWO USE CASES. IN THE FIRST USE CASE, WE WILL ANNOTATE PROJECTIONS OF THE MOTOR, PREMOTOR, AND PREFRONTAL CORTEX TO THE SUBTHALAMIC NUCLEUS (STN). WE WILL USE THEM TO ADVANCE OUR UNDERSTANDING OF CIRCUITS ASSOCIATED WITH CLINICAL IMPROVEMENTS IN FOUR DISEASES THAT ARE TREATED WITH DEEP-BRAIN STIMULATION IN NEIGHBORING SUBZONES OF THE STN: DYSTONIA, TOURETTE’S SYNDROME, PARKINSON’S DISEASE, AND OBSESSIVE-COMPULSIVE DISORDER. IN THE SECOND USE CASE, WE WILL INVESTIGATE THE MAPPING FROM THE AXONAL ORIENTATIONS AND MICROSTRUCTURAL FEATURES OBTAINED FROM THE MICROSCOPY DATA TO DMRI SIGNALS ACQUIRED IN THE SAME BRAINS. IN ADDITION TO THE UNPRECEDENTED DATASETS AND THE TWO USE CASES DESCRIBED ABOVE, THIS PROJECT WILL GENERATE STATE-OF-THE-ART PIPELINES FOR PRE- PROCESSING, CO-REGISTRATION, AXON SEGMENTATION, TRACTOGRAPHY, AND QUANTIFICATION, ACROSS THE SCALES SPANNED BY THE ACQUIRED DATA. WE WILL DEVELOP A NOVEL PLATFORM FOR SHARING THE MICROSCOPY, TRACER, AND MRI DATA WITH THE RESEARCH COMMUNITY. THIS WILL GO WELL BEYOND A STATIC DATA REPOSITORY, ALLOWING THE USER TO INTERACT WITH THE DATA REMOTELY AND PROVIDING A “VALIDATION ENGINE” FOR TESTING NEUROIMAGING SOFTWARE TOOLS AGAINST THE GOLD STANDARD POST MORTEM DATA COLLECTED BY THIS PROJECT. IF SUCCESSFUL, THIS PROJECT WILL GENERATE A SCALABLE AND VALIDATED TOOLSET FOR IMAGING CONNECTIONAL ANATOMY, WITH A DIRECT LINK IT TO ITS APPLICATIONS IN THE STUDY OF HUMAN DISEASE.

HEMATOPOIESIS IN CARDIOVASCULAR DISEASE

PROGRAM PROJECT: GENE MUTATION AND RESCUE IN HUMAN DIAPHRAGMATIC HERNIA

PHASE 3 TRIAL OF INOSINE FOR PARKINSON'S DISEASE CCC

NOVEL TREATMENT TARGETS FOR AFFECTIVE DISORDERS THROUGH CROSS-SPECIES INVESTIGATION OF APPROACH/AVOIDANCE DECISION MAKING

TARGETING INFLAMMATION AND ALLOIMMUNITY IN LUNG TRANSPLANT RECIPIENTS WITH CLAZAKIZUMAB - PROJECT SUMMARY/ABSTRACT THE 5-YEAR SURVIVAL AFTER LUNG TRANSPLANTATION IS A DISMAL 53% AND CHRONIC LUNG ALLOGRAFT DYSFUNCTION (CLAD) HAS EMERGED AS THE PRIMARY OBSTACLE TO BETTER LONG-TERM OUTCOMES. CLEARLY, CURRENT STANDARD-OF-CARE IMMUNOSUPPRESSIVE REGIMENS ARE FAILING LUNG TRANSPLANT RECIPIENTS, AND THERE IS A CRITICAL UNMET NEED TO IMPROVE SURVIVAL. PRIMARY GRAFT DYSFUNCTION (PGD), EPISODES OF ACUTE CELLULAR REJECTION (ACR), ANTIBODY-MEDIATED REJECTION (AMR), AND THE DEVELOPMENT OF DONOR-SPECIFIC ANTIBODIES (DSA) ARE WIDELY RECOGNIZED RISK FACTORS FOR THE DEVELOPMENT OF CLAD. FURTHERMORE, MECHANISTIC STUDIES LINK THESE INFLAMMATORY AND ALLOIMMUNE INJURIES TO THE FIBROTIC LESIONS THAT CHARACTERIZE CLAD. IL-6 IS A PLEIOTROPIC CYTOKINE THAT DRIVES THESE DELETERIOUS INFLAMMATORY, IMMUNE, AND FIBROGENIC RESPONSES THUS, AN ESPECIALLY ATTRACTIVE CYTOKINE TO TARGET. INDEED, IN EXPERIMENTAL MODELS, IL-6 SIGNALING BLOCKADE HAS BEEN SHOWN TO SKEW THE TH17/TREG BALANCE IN FAVOR OF REGULATORY CELL COMMITMENT THEREBY EXPANDING TREG NUMBERS, REDUCING ALLOGRAFT REJECTION, AND DIMINISHING MEMORY B CELL NUMBERS AND ANTIBODY FORMATION (PRIMARY AND RECALL). IN HUMAN TRIALS, IL-6R INHIBITION REDUCED ALLOANTIBODY LEVELS IN HIGHLY SENSITIZED KIDNEY ALLOGRAFT RECIPIENTS AND IMPROVED GRAFT AND PATIENT SURVIVAL IN KIDNEY RECIPIENTS WITH THE MOST SEVERE FORM OF CHRONIC ANTIBODY-MEDIATED REJECTION. THESE DATA FORM THE BASIS OF OUR HYPOTHESIS THAT EARLY IL-6 INHIBITION AFTER LUNG TRANSPLANTATION WILL INDUCE A PROTECTIVE/ANTI-INFLAMMATORY MILIEU THAT WILL HAVE LONG- LASTING EFFECTS ON THE HOST'S IMMUNE SYSTEM AND ALLOGRAFT RESULTING IN IMPROVED LONG-TERM GRAFT AND PATIENT SURVIVAL. TO TEST THIS HYPOTHESIS, WE PROPOSE TO CONDUCT A PHASE 2, MULTICENTER, DOUBLE BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL EXAMINING THE IMPACT OF EARLY IL-6 INHIBITION WITH CLAZAKIZUMAB ON CLAD-FREE ALLOGRAFT SURVIVAL AFTER LUNG TRANSPLANTATION. CLAZAKIZUMAB (CSL BEHRING) IS A GENETICALLY ENGINEERED, HIGH AFFINITY, HUMANIZED MONOCLONAL ANTIBODY (IGG1) WHICH BINDS TO IL-6 AND IS A FULL AND COMPETITIVE ANTAGONIST OF IL-6- INDUCED CELL FUNCTION. THE PRIMARY ENDPOINT OF THE CLINICAL TRIAL IS A COMPOSITE OF 1) CLAD, 2) RE-TRANSPLANTATION, OR 3) DEATH. KEY SECONDARY ENDPOINTS INCLUDE PGD, ACR, AMR, DSA. FURTHERMORE, WE PLAN TO LEVERAGE THE RICH CLINICAL DATA AND HUMAN BIOSPECIMENS THAT THIS CLINICAL TRIAL WILL GENERATE TO DEFINE THE UTILITY OF SEVERAL NONINVASIVE BIOMARKERS AS RISK ASSESSMENT, DIAGNOSTIC, AND PREDICTIVE TESTING STRATEGIES. FINALLY, WE WILL CONDUCT MECHANISTIC STUDIES TO EXPLAIN THE EFFECTS OF CLAZAKIZUMAB OBSERVED IN THE CLINICAL TRIAL. THIS TRIAL REPRESENTS THE FIRST APPLICATION OF IL-6 BLOCKADE IN LUNG TRANSPLANTATION AND HAS THE POTENTIAL CHANGE CLINICAL PRACTICE AND IMPROVE OUTCOMES FOR LUNG TRANSPLANT RECIPIENTS. IF CZK THERAPY IS SUCCESSFUL, OUR COMPREHENSIVE AND INTEGRATED MECHANISTIC STUDIES WILL ALLOW US TO ELUCIDATE MECHANISMS OF IMPROVED GRAFT OUTCOMES. IF THERAPY FAILS, WE WILL BE ABLE TO UNDERSTAND WHY. EITHER WAY, INSIGHTS INTO THE MECHANISMS OF ALLOIMUNE INJURY AND CHRONIC LUNG ALLOGRAFT DYSFUNCTION COULD LEAD TO NEW PREVENTATIVE OR TREATMENT REGIMENS.

NOVEL APPROACHES TO INDUCING LUNG ALLOGRAFT TOLERANCE IN NHPS - PROJECT SUMMARY/ABSTRACT OVER 40% OF LUNG ALLOGRAFT RECIPIENTS SUCCUMB WITHIN FIVE YEARS OF BEING TRANSPLANTED, MAKING IT CLEAR THAT THERE IS AN URGENT UNMET NEED TO ADDRESS THE INADEQUACIES OF CHRONIC IMMUNOSUPPRESSION (IS) IN THESE PATIENTS. ACHIEVING A ROBUST STATE OF TOLERANCE IN LUNG RECIPIENTS WOULD REDUCE OR ELIMINATE THE MAJOR LUNG-SPECIFIC AND DRUG-RELATED FACTORS THAT CONTRIBUTE TO THIS DISMAL STATISTIC. TOLERANCE OF KIDNEY ALLOGRAFTS HAS BEEN ACHIEVED IN NONHUMAN PRIMATES (NHPS) AND HUMANS BY USING A COMBINATION OF NONMYELOABLATIVE CONDITIONING AND DONOR BONE MARROW TRANSPLANTATION THAT RESULTS IN TRANSIENT MIXED HEMATOPOIETIC CHIMERISM. HOWEVER, IDENTICAL PROTOCOLS HAVE FAILED TO INDUCE TOLERANCE IN RECIPIENTS OF LUNG ALLOGRAFTS. DESPITE THE RESISTANCE OF LUNG ALLOGRAFTS TO TOLERANCE INDUCTION, WE HAVE NOW SHOWN FOR THE FIRST TIME, THAT ACHIEVING A STATE OF DURABLE (FOR THE LIFE OF THE ORGAN) MIXED CHIMERISM IN NHP RECIPIENTS RESULTS IN LONG-TERM, IS-FREE SURVIVAL OF LUNG ALLOGRAFTS. THIS REMARKABLE RESULT WAS ACHIEVED BY MODIFYING THE MIXED CHIMERISM CONDITIONING TO AUGMENT HOST REGULATORY MECHANISMS. WHILE A SIGNIFICANT ADVANCE, THIS MODIFIED MIXED CHIMERISM PROTOCOL WAS ONLY SUCCESSFUL IN RECIPIENTS OF MHC HAPLO-MATCHED LUNG ALLOGRAFTS AND WAS ASSOCIATED WITH SIGNIFICANT TOXICITY IN THE FORM OF POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE (PTLD), CYTOMEGALOVIRUS (CMV) INFECTION, AND RADIATION-INDUCED MYELOSUPPRESSION. OUR GOAL NOW IS TO RENDER THIS BREAKTHROUGH CLINICALLY APPLICABLE BY GENERATING A SAFER AND MORE EFFECTIVE PROTOCOL THAT IS CAPABLE OF INDUCING LONG-TERM TOLERANCE OF UNRELATED, FULLY MHC MISMATCHED LUNG ALLOGRAFTS USING FDA-APPROVED OR SOON-TO-BE-APPROVED DRUGS. THIS PROGRAM’S UNIFYING HYPOTHESIS IS THAT INDUCING DURABLE CHIMERISM AND LONG-TERM TOLERANCE IN RECIPIENTS OF STRINGENT LUNG ALLOGRAFTS WILL REQUIRE NEXT-GENERATION MIXED CHIMERISM PROTOCOLS THAT AUGMENT SYSTEMIC AND INTRA-GRAFT ADAPTIVE AND INNATE REGULATORY MECHANISMS. IN PROJECT 1, WE WILL TEST THIS HYPOTHESIS USING INTRA-ORGAN DELIVERY OF AIL-6R-SPECIFIC AND MTORI-SPECIFIC NANOTHERAPIES TO REDUCE IS-RELATED COMPLICATIONS, BLOCK TRAINED IMMUNITY, AND PROMOTE INTRA-GRAFT REGULATION. BCL-2 INHIBITION WILL BE USED TO PROMOTE DURABLE MIXED CHIMERISM WHILE DIMINISHING THE TOXICITIES RELATED TO TOTAL BODY IRRADIATION (TBI)-DRIVEN MYELOSUPPRESSION. THESE STUDIES WILL BE COMPLEMENTED BY PROJECT 2, WHICH WILL TEST OUR UNIFYING HYPOTHESIS USING NOVEL STRATEGIES FOR ANTIBODY-BASED CONDITIONING, REGULATORY T CELLS (TREG)-SUPPORTIVE IMMUNOMODULATION, AND GENE- MODIFIED TREGS, ALL POISED FOR IMMEDIATE CLINICAL TRANSLATION. STATE-OF-THE-ART MECHANISTIC ASSAYS COORDINATED BY CORE A (THE MOLECULAR IMMUNOLOGY CORE, ‘MIC’) WILL ENABLE RAPID CROSS-FERTILIZATION OF INSIGHTS GAINED IN EACH PROJECT. WE ANTICIPATE THAT TOGETHER, THESE HIGHLY INTERACTIVE PROJECTS WILL GENERATE ONE OR MORE SAFE AND EFFECTIVE DURABLE MIXED CHIMERISM TOLERANCE PROTOCOLS READY FOR CLINICAL TRIALS BY THE END OF THE FUNDING PERIOD. IF SUCCESSFUL, THESE STUDIES COULD IMPACT THE ENTIRE FIELD OF TRANSPLANTATION AND PROVIDE INSIGHTS THAT COULD ALSO BE FIELD-CHANGING FOR BONE MARROW TRANSPLANTATION AND AUTOIMMUNE DISEASE.

LABORATORY FOR EARLY PSYCHOSIS RESEARCH (LEAP)

MA/REGION 1 PARTNERSHIP FOR REGIONAL HEALTH DISASTER RESPONSE

CLINICAL RESEARCH CAREER DEVELOPMENT PROGRAM

1/2 REPRIEVE EXTENSION FOR TRIAL COMPLETION - PROJECT SUMMARY-ABSTRACT GLOBALLY, CARDIOVASCULAR DISEASE (CVD) BURDEN IS INCREASING AND A MAJOR CAUSE OF MORTALITY AMONG PEOPLE WITH HIV (PWH). HOWEVER, DATA ARE NOT YET AVAILABLE FROM LARGE TRIALS ON AN EFFECTIVE PRIMARY CVD PREVENTION STRATEGY FOR PWH. THE ONGOING REPRIEVE TRIAL WILL ADDRESS THIS CRITICAL KNOWLEDGE GAP, HYPOTHESIZING THAT STATIN THERAPY, WITH PLEIOTROPIC EFFECTS ON LDL, IMMUNE ACTIVATION AND INFLAMMATORY PATHWAYS, WILL MODIFY TRADITIONAL AND NONTRADITIONAL RISKS AND PREVENT MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) IN PWH. REPRIEVE IS WELL-POSITIONED TO PROVIDE HIGH QUALITY, CLINICALLY ACTIONABLE AND GENERALIZABLE INFORMATION TO SHIFT THE CURRENT PARADIGM OF HIV CARE, IN ALIGNMENT WITH THE GOALS OF NHLBI AND OAR TO REDUCE CVD AND IMPROVE THE OVERALL HEALTH OF PWH. REPRIEVE HAS MET MAJOR CHALLENGES, ANTICIPATED FOR A LARGE TRIAL. 7,770 PARTICIPANTS (31% FEMALE, 43% BLACK, 25% LATINO) WERE ENROLLED FROM OVER 100 SITES IN 12 COUNTRIES, A DIVERSE, GENERALIZABLE POPULATION. RETENTION IS HIGH, >90%. ENDPOINT (MACE) ARE ACCUMULATING STEADILY DESPITE A LOW MEDIAN ASCVD RISK SCORE OF 4.5%, CONSISTENT WITH THE HYPOTHESIS THAT NONTRADITIONAL RISKS CONTRIBUTE TO CVD IN HIV. THE MECHANISTIC SUBSTUDY HAS MET ITS GOAL, ENROLLING OVER 800 PARTICIPANTS FOR SERIAL CORONARY CT ANGIOGRAPHY (CTA) AND IMMUNE FUNCTION. PRELIMINARY BASELINE DATA FROM THE SUBSTUDY SUPPORT OUR HYPOTHESIS, LINKING PLAQUE TO CVD RISK BUT ALSO INDEPENDENTLY TO IL-6 AND LP-PLA2, KEY INDICES OF IMMUNE FUNCTION AND ARTERIAL INFLAMMATION THAT ARE BEING TARGETED IN REPRIEVE. MOREOVER, REPRIEVE IS BEING LEVERAGED TO ASSESS STATIN EFFECTS ON COVID SEVERITY, AND LONG-TERM EFFECTS IN PWH, CRITICAL UNANSWERED QUESTIONS FOR THE FIELD. REPRIEVE HAS EXECUTED WELL OVER 6 YEARS AND IS FUNDAMENTALLY STRONG. HOWEVER, WITH A LONG DURATION OF RECRUITMENT AND PROTOCOL REVISIONS TO IDENTIFY THE OPTIMAL AT-RISK GROUP GIVEN NEW GUIDELINES, MEDIAN DURATION OF FOLLOW UP IS STILL SHORT AT 3.5 YEARS. REPRIEVE NEEDS ADDITIONAL TIME, PROJECTED AT 2 YEARS, PLUS A CLOSE OUT YEAR, TO COLLECT NECESSARY MACE TO ENSURE ADEQUATE POWER, ANALYZE, AND DISSEMINATE THIS DATA. THE PRESSING NEED FOR DATA FROM A LARGE GLOBAL PRIMARY PREVENTION TRIAL HAS ONLY GROWN SINCE REPRIEVE WAS INITIATED. COMPLETION OF THE TRIAL WILL PROTECT THE VALUE OF THE INITIAL NIH INVESTMENT AND HONOR THE COMMITMENT TO OUR PARTICIPANTS AND SCIENTIFIC COMMUNITY TO MEET THE AIMS OF THE TRIAL. THIS APPLICATION FOR THE CLINICAL COORDINATING CENTER (CCC) OF THE REPRIEVE EXTENSION FOR TRIAL COMPLETION FOCUSES ON THE CLINICAL RATIONALE AND COORDINATION OF THE TRIAL. THE DATA COORDINATING CENTER (DCC) APPLICATION FOCUSES ON DATA MANAGEMENT, INCLUDING THE CORONARY CTA DATA OF THE MECHANISTIC SUBSTUDY, AND THE STATISTICAL RATIONALE FOR THE TRIAL DESIGN.

CONNECTOME 2.0: DEVELOPING THE NEXT GENERATION HUMAN MRI SCANNER FOR BRIDGING STUDIES OF THE MICRO-, MESO- AND MACRO-CONNECTOME

TRAINING PROGRAM IN ENDOCRINOLOGY AND DIABETES

OPTIMIZING HIV CARE IN LESS DEVELOPED COUNTRIES

INTEGRATING PATIENT-SPECIFIC CLINICAL AND BIOLOGICAL FACTORS TOWARDS INDIVIDUALIZING UTILIZATION OF PROTON AND PHOTON RADIATION THERAPY. - OVERALL - SUMMARY THIS IS A JOINT APPLICATION FOR A PROGRAM PROJECT GRANT BY MASSACHUSETTS GENERAL HOSPITAL AND MD ANDERSON CANCER CENTER. THE PROGRESS WE MADE IN OUR MOST RECENT PROGRAM PROJECTS (A P01 AND A U19) HAS BEEN CRITI- CAL TO THE CLINICAL, PHYSICAL, AND BIOLOGICAL ASPECTS OF PROTON THERAPY AND ITS SIGNIFICANCE AS AN IMPORTANT CANCER TREATMENT MODALITY. THE MAIN ACHIEVEMENTS OF THE RECENTLY COMPLETED U19 (END DATE 8/31/20) WERE (1) THE DE- VELOPMENT AND ACTIVATION OF DEFINITIVE ESOPHAGUS, LIVER AND GLIOMA RANDOMIZED PROTON VS. PHOTON THERAPY TRIALS IN COOPERATION WITH NRG, NCI AND NCTN; (2) UNDERSTANDING AND MODELING THE DIFFERENCES IN RESPONSE OF NOR- MAL TISSUES TO HIGHLY DISPARATE PROTON AND PHOTON DOSE DISTRIBUTION PATTERNS; (3) UNDERSTANDING THE COMPLEXITIES OF THE BIOLOGICAL EFFECTS OF PROTONS RELATIVE TO PHOTONS; AND (4) THE DEVELOPMENT OF ADVANCED INTENSITY MODU- LATED PROTON THERAPY INCORPORATING PHYSICAL UNCERTAINTIES AND THE VARIABLE BIOLOGICAL EFFECTIVENESS OF PROTONS. OUR RESEARCH ALSO REVEALED MAJOR GAPS IN THE KNOWLEDGE OF THE BIOLOGICAL EFFECTS OF PROTONS, SIGNIFICANT LIMITA- TIONS OF THE CURRENT POPULATION-BASED MODELS OF NORMAL TISSUE AND TUMOR RESPONSE TO PROTONS VS. PHOTONS, AND UNCERTAINTY IN THE APPROPRIATENESS OF PROTON THERAPY IN THE FACE OF HETEROGENEITIES IN PATIENT CHARACTERISTICS AND TREATMENT TECHNIQUES IN UNSELECTED GROUPS OF PATIENTS. ON THE BRIGHT SIDE, OUR RESEARCH ALSO DISCOVERED THE STRONG POTENTIAL OF PROTON THERAPY TO REDUCE SUPPRESSION OF THE IMMUNE SYSTEM, WHICH IS COMMONLY ASSOCIATED WITH PHOTON THERAPY AND HAS BEEN SHOWN TO LEAD TO ADVERSE OUTCOMES. THE OVERALL GOALS OF THE PROPOSED P01 ARE (A) UNDERSTANDING RELATIVE CLINICAL, BIOLOGICAL AND IMMUNOSUPPRESSIVE EFFECTS OF PROTON THERAPY VS. PHOTON THERAPY; (B) ENHANCING OUTCOMES BASED ON THE PHYSICAL, BIOLOGICAL AND IMMUNOLOGICAL PROPERTIES OF PROTONS AND PHOTONS; AND (C) APPLYING INDIVIDUALIZED (AS OPPOSED TO POPULATION-BASED) APPROACHES FOR THE SE- LECTION OF THE OPTIMUM RADIATION MODALITY FOR EACH PATIENT AND TO ENHANCE THE POTENTIAL FOR OUTCOMES WITH THE USE OF RADIATION DOSE DISTRIBUTIONS TAILORED TO THE INDIVIDUAL PATIENT’S BASELINE AND TUMOR CHARACTERISTICS. THE ACHIEVEMENT OF THESE GOALS WILL BE CARRIED OUT IN THREE PROJECTS. PROJECT 1: UNDERSTANDING NORMAL TISSUE TOX- ICITY TO IDENTIFY PATIENTS MOST LIKELY TO BENEFIT FROM PROTON VS. PHOTON THERAPY; PROJECT 2: RADIATION-INDUCED LYMPHOPENIA (RIL): UNDERSTANDING, PREDICTIVE MODELING AND DEVELOPING PHOTON AND PROTON-BASED MITIGATION STRATEGIES; AND PROJECT 3: INVESTIGATING ENHANCED SENSITIVITY OF TUMORS TO PROTON BEAM THERAPY: MECHANISMS AND BIOMARKERS. THE PROJECTS ARE HIGHLY INTEGRATED IN THAT DECISIONS REGARDING TREATMENT MODALITY SELECTION, TREATMENT TECHNIQUE AND OPTIMIZATION TO MAXIMALLY ENHANCE THE THERAPEUTIC RATIO CANNOT BE ACCOMPLISHED BY ANY ONE PROJECT ALONE. SUCH DECISIONS MUST CONSIDER AND BALANCE NORMAL TISSUE COMPLICATIONS, TUMOR RE- SPONSE BASED ON GENOTYPIC FACTORS, AND RADIATION-INDUCED IMMUNOSUPPRESSION. THE THREE PROJECTS WILL BE SUP- PORTED BY AN ADMINISTRATIVE CORE AND THREE RESOURCE CORES: CORE 1: DATA MANAGEMENT AND COMPUTATIONAL SUPPORT; CORE 2: TRANSLATIONAL BIOSPECIMENS AND IMAGING BIOMARKERS; AND CORE 3: BIOSTATISTICS.

BIO-MICROELECTROMECHANICAL SYSTEMS RESOURCE CENTER

SILVIO O. CONTE CENTER FOR STRESS PEPTIDE ADVANCED RESEARCH, EDUCATION, & DISSEMINATION (SPARED) AT MCLEAN HOSPITAL

CENTER FOR SUICIDE RESEARCH AND PREVENTION - SUICIDE IS ONE OF THE LEADING CAUSES OF DEATH WORLDWIDE AND THE 10TH LEADING CAUSE OF DEATH IN THE US. A MAJOR BARRIER TO SUICIDE PREVENTION HAS BEEN THAT THE CUTTING-EDGE SCIENTIFIC ADVANCES THAT HAVE OCCURRED IN THE PAST FEW DECADES HAVE NOT YET BEEN TRANSLATED AND IMPLEMENTED INTO CLINICAL PRACTICE SETTINGS. WE PROPOSE THE DEVELOPMENT OF A PRACTICE-BASED CENTER FOR SUICIDE RESEARCH AND PREVENTION (CSRP) THAT WILL SUPPORT THE DEVELOPMENT, DEPLOYMENT, AND EVALUATION OF PRACTICE-READY AND DEPLOYMENT-FOCUSED INTERVENTIONS AIMED AT IMPROVING THE IDENTIFICATION AND EFFECTIVE TREATMENT OF THOSE AT RISK OF SUICIDE. THIS CENTER WILL BE A COLLABORATIVE EFFORT BETWEEN RESEARCHERS, CLINICIANS, AND STAKEHOLDERS AT MASS GENERAL BRIGHAM (MGB) AND HARVARD UNIVERSITY. OUR FOCUS IS ON IMPROVING THE IDENTIFICATION AND PREVENTION OF SUICIDE-RELATED BEHAVIORS (SRBS) AMONG PATIENTS PRESENTING FOR TREATMENT AT EMERGENCY DEPARTMENTS (EDS) AND PSYCHIATRIC INPATIENT UNITS. DECADES OF RESEARCH HAVE SHOWN THAT 50% OF PEOPLE WHO DIE BY SUICIDE ARE SEEN IN A HEALTHCARE SETTING WITHIN ONE MONTH BEFORE THEIR DEATH, 40% VISIT AN ED THE YEAR BEFORE THEIR DEATH, AND THE SUICIDE RATE IS HIGHEST IN THE WEEKS IMMEDIATELY FOLLOWING DISCHARGE FROM A PSYCHIATRIC INPATIENT HOSPITALIZATION. OUR FIRST AIM IS TO BUILD AND MAINTAIN A COHESIVE AND INNOVATIVE TRANSDISCIPLINARY CENTER DEDICATED TO ADVANCING SUICIDE PREVENTION. THIS WILL BE ACCOMPLISHED VIA THE WORK OF OUR PROPOSED ADMINISTRATIVE CORE AND METHODS CORE. OUR SECOND AIM IS TO CONDUCT FOUR PRACTICE-FOCUSED RESEARCH PROJECTS THAT TARGET PREDICTION AND PREVENTION OF SUICIDAL BEHAVIORS IN ED AND INPATIENT SETTINGS. OUR SIGNATURE PROJECT (SIG) WILL IMPLEMENT A PREVIOUSLY-DEVELOP MACHINE LEARNING PREDICTION ALGORITHM BASED ON ELECTRONIC HEALTH RECORD (EHR) AND SELF-REPORT DATA COLLECTED IN THE ED AND RANDOMLY ASSIGN THE CLINICIANS OF 4,000 PATIENTS TO RECEIVE (EXPERIMENTAL CONDITION) OR NOT RECEIVE (CONTROL CONDITION) THE PREDICTED PROBABILITY THAT THEIR PATIENT WILL MAKE A SUICIDE ATTEMPT AFTER ED DISCHARGE. WE WILL TEST THE IMPACT OF THIS INTERVENTION ON THE SUICIDE ATTEMPT RATE AND CLINICIAN DECISION-MAKING. THE SIG ALSO WILL EXAMINE CLINICIAN ACCEPTABILITY AND ADHERENCE, PREDICTION MODEL IMPROVEMENT, AND THE DEVELOPMENT OF TREATMENT OPTIMIZATION RULES REGARDING PATIENTS' LIKELIHOOD OF BENEFITING FROM HOSPITALIZATION VERSUS ALTERNATIVE TREATMENTS. OUR THREE EXPLORATORY PROJECTS (EXP): (EXP1) WILL USE THE SIG PREDICTION MODEL TO IDENTIFY ED PATIENTS AT RISK OF SUICIDAL BEHAVIOR AND EXPERIMENTALLY TEST THE EFFECTIVENESS OF AN ENHANCED OUTREACH INTERVENTION ADMINISTERED IN COLLABORATION WITH A COMMUNITY PARTNER – SAMARITANS OF BOSTON; (EXP2) WILL IMPLEMENT AND TEST EHR-BASED RISK ALGORITHMS IN TWO INPATIENT UNITS WITH A SPECIAL FOCUS ON THE USE OF SOCIAL DETERMINANTS OF HEALTH TO IMPROVE PREDICTION AMONG UNDER-REPRESENTED ADOLESCENTS; AND (EXP3) WILL TEST A JUST-IN-TIME ADAPTIVE INTERVENTION USING AN INNOVATIVE MICRO-RANDOMIZED TRIAL DESIGN TO CONNECT AT-RISK PATIENTS WITH CARE WHEN NEEDED MOST. THE THIRD AIM OF THE CENTER IS TO SUPPORT EDUCATION, DISSEMINATION, AND IMPLEMENTATION EFFORTS THAT WILL HAVE A SIGNIFICANT AND SUSTAINED EFFECT ON SUICIDE PREVENTION.

AIRWAY MICROBIOME AND AGE 6Y ASTHMA PHENOTYPES IN 2 DIVERSE MULTICENTER COHORTS