Mercy Hospital

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHRONIC KIDNEY DISEASE IN CHILDREN (CKID)

IP21-002, US ENHANCED SURVEILLANCE NETWORK TO ASSESS BURDEN, NATURAL HISTORY, AND EFFECTIVENESS OF VACCINES TO PREVENT ENTERIC AND RESPIRATORY VIRUSES IN CHILDREN

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - A PROPOSED FREESTANDING CANCER CENTER IN ADA, OKLAHOMA, IS THE RESULT OF AN UNPRECEDENTED AND EXCITING COLLABORATION BETWEEN MERCY AND THE CHICKASAW NATION. MERCY AND THE CHICKASAW NATION HAVE A SHARED PASSION TO HELP MORE PATIENTS WIN THEIR CANCER BATTLES WHILE THEY REMAIN CLOSE TO HOME – SURROUNDED BY LOVED ONES DURING ONE OF THE MOST CHALLENGING TIMES OF THEIR LIVES. THAT’S WHY WE ARE JOINING FORCES TO IMPROVE THE QUALITY OF CANCER CARE IN OKLAHOMA. RURAL AMERICANS FACE UNIQUE CHALLENGES WHEN IT COMES TO CANCER CARE. ACCORDING TO THE MOST RECENT COMMUNITY HEALTH NEEDS ASSESSMENT, THE POVERTY LEVEL AND THE UNINSURED IN OUR SERVICE AREA IS HIGHER THAN BOTH STATE AND NATIONAL AVERAGES. ALSO, RURAL RESIDENTS ARE OLDER WITH LESS EDUCATION AND INCOME THAN THEIR URBAN COUNTERPARTS. WHEN CANCER OCCURS WITHIN THIS POPULATION, THE OUTCOMES ARE GENERALLY WORSE DUE TO LATE DIAGNOSIS AND LIMITED ACCESS TO CARE WHICH UNFORTUNATELY CAUSES HIGHER MORTALITY RATES. FURTHERMORE, PATIENTS MUST OFTEN DRIVE SEVERAL MILES OUT OF TOWN TO RECEIVE CARE WHICH CAN FURTHER IMPACT THEIR TREATMENT OUTCOMES. THE CURRENT DEMAND FOR CANCER CARE OUTPACES AVAILABLE RESOURCES AT MERCY HOSPITAL ADA. FURTHERMORE, A CANCER CENTER 60 MILES EAST OF THE HOSPITAL RECENTLY CLOSED, AND MERCY IS NOW CARING FOR THOSE PATIENTS. THE NEW CENTER WILL EXPAND ACCESS TO SERVE MORE PEOPLE WHILE ENHANCING THE QUALITY OF CARE. EVERYONE, REGARDLESS OF THEIR ABILITY TO PAY, ARE WELCOME TO RECEIVE CARE AT MERCY. TO ADDRESS THIS GAP, THE CONCEPT OF THE ADA COMMUNITY CANCER CENTER WAS CREATED. THE PROJECT WILL BE A PARTNERSHIP BETWEEN MERCY AND THE CHICKASAW NATION. THE VALLEY VIEW FOUNDATION HAS GRACIOUSLY DONATED UP TO 20 ACRES OF LAND ADJACENT TO THE MAIN HOSPITAL TO CONSTRUCT THE CENTER. THE CENTER WILL INCREASE ACCESS TO MORE ADVANCED TREATMENT OPTIONS AND PROVIDE ADDITIONAL CAPACITY TO SERVE MORE PATIENTS. THE PROPOSED $40.5M 40,000 SQUARE-FOOT, COMMUNITY CANCER CENTER WILL INCLUDE: • AD VANCED DIAGNOSTIC AND TREATMENT TECHNOLOGIES, INCLUDING RADIATION THERAPY AND CT, PET AND 3D IMAGING. • EXPANDED SPACE FOR INFUSION THERAPY ROOMS, A COMFORTABLE WAITING AREA, CONFERENCE ROOM AND SPECIALTY PHARMACY. • CLINIC SPACE FOR MORE CANCER SPECIALTIES, INCLUDING BREAST, LUNG, COLON, SKIN AND OTHERS. • SUPPORT FOR PATIENTS’ PHYSICAL, SPIRITUAL AND EMOTIONAL HEALTH. • PROFESSIONAL NURSE NAVIGATORS TO GUIDE PATIENTS AND COORDINATE CARE DURING AND AFTER TREATMENT. THE PROJECT WILL SERVE A FIVE-COUNTY REGION (GARVIN, HUGHES, JOHNSTON, PONTOTOC, AND SEMINOLE) WITH A POPULATION OF 122,778 IN ADDITION TO OTHER COMMUNITIES AND RURAL AREAS AS WELL AS NEIGHBORING CHICKASAW NATION WITH A POPULATION OF MORE THAN 49,000.

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

KANSAS CITY - NEW VACCINE SURVEILLANCE NETWORK (KC-NVSN)

CHARACTERIZATION OF SEDENTARY PATTERNS AND CARDIOVASCULAR DISEASE RISK MARKERS IN HISPANICS/LATINOS

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

MILITARY MEDICAL RESEARCH AND DEVELOPMENT

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

NATURAL KILLER CELL REGULATION OF THE GERMINAL CENTER HIV NEUTRALIZING ANTIBODY RESPONSE

UNDERSTANDING MECHANISMS UNDERLYING CHRONIC STRESS-INDUCED ASTHMA IN CHILDREN BY POPULATION AND SINGLE-CELL EPIGENOMICS APPROACHES

ENHANCED SURVEILLANCE FOR NEW VACCINE PREVENTABLE DISEASES

CHILDRENS MERCY HOSPITAL FELLOWSHIP PROGRAM IN PEDIATRIC PHARMACOLOGY

SYSTEMATIC IDENTIFICATION AND PHENOTYPIC CHARACTERIZATION OF CAUSAL GENETIC VARIANTS IN RARE DISEASE-ASSOCIATED BIRTH DEFECTS - PROJECT SUMMARY ALTHOUGH THE IMPLEMENTATION OF WHOLE EXOME SEQUENCING (WES) AND WHOLE GENOME SEQUENCING (WGS) IN A CLINICAL SETTING HAS GREATLY FACILITATED THE IDENTIFICATION OF BIRTH DEFECT-ASSOCIATED GENETIC VARIANTS, DISTINGUISHING THE SPECIFIC VARIANTS THAT CAUSE CONGENITAL DEFECTS REMAINS A MAJOR CHALLENGE. MORE SPECIFICALLY, MOST VARIANTS DETECTED IN CLINICAL SEQUENCING OCCUR IN GENES NOT PREVIOUSLY ASSOCIATED WITH DISEASE OR IN NONCODING REGIONS OF THE GENOME THAT LACK PREDICTABLE FUNCTIONAL CONSEQUENCES. ENHANCING THE ABILITY TO ILLUMINATE CAUSAL VARIANTS HOLDS THE PROMISE OF IMPROVING THE QUALITY OF LIFE FOR PATIENTS AND IN SOME CASES MAY PROVIDE A WINDOW FOR THERAPEUTIC INTERVENTION THAT WOULD OTHERWISE BE MISSED. IN THIS PROPOSAL WE LEVERAGE OUR INSTITUTE’S UNPARALLELED PEDIATRIC GENETIC DATA REPOSITORY TO GUIDE THE DEVELOPMENT OF SCALABLE CELL-BASED SYSTEMS THAT, WHEN COUPLED WITH PHENOTYPIC VALIDATION IN BOTH ANIMAL AND PATIENT-DERIVED ORGANOID MODELS, WILL SYSTEMATICALLY IDENTIFY GENETIC VARIANTS THAT ARE RESPONSIBLE FOR CONGENITAL DEFECTS IN OUR UNDIAGNOSED RARE DISEASE PATIENT POPULATION. WE WILL (AIM 1) CATALOG LOSS-OF-FUNCTION VARIANTS ASSOCIATED WITH THE MOST PREVALENT CONGENITAL DEFECTS IN OUR PATIENT POPULATION, PERFORM GENOME-SCALE CRISPR SCREENS IN RELEVANT ORGANOID MODELS TO DISTINGUISH VARIANT-HARBORING GENES THAT PLAY A ROLE IN DEVELOPMENT, AND VALIDATE THE PHENOTYPIC CONSEQUENCES OF GENE LOSS IN A ZEBRAFISH MODEL. IN PARALLEL, WE WILL (AIM 2) CATALOG NONCODING VARIANTS (I.E. INTRONIC, PUTATIVE CIS-REGULATORY) ASSOCIATED WITH PREVALENT CONGENITAL DEFECTS, DEVELOP A SUITE OF MASSIVELY PARALLEL GENOMIC ASSAYS CAPABLE OF PROFILING THE REGULATORY IMPACT OF NONCODING GENETIC VARIANTS AT SCALE, AND PERTURB THE EXPRESSION OF CANDIDATE VARIANT- ASSOCIATED GENES IN A ZEBRAFISH MODEL TO DETERMINE THE PHENOTYPIC CONSEQUENCES. FINALLY, WE WILL (AIM 3) GENERATE PATIENT-DERIVED ORGANOID MODELS, UTILIZE PRECISION GENOME ENGINEERING IN COMBINATION WITH SINGLE-CELL TRANSCRIPTOMICS IN PATIENT-DERIVED ORGANOIDS TO VALIDATE THE CAUSAL ROLE OF SPECIFIC VARIANTS IN CONGENITAL DEFECTS, AND CHARACTERIZE THE IMPACT OF VARIANTS ON DEVELOPMENT USING SPATIAL TRANSCRIPTOMICS IN PATIENT-DERIVED ORGANOIDS AS A PROXY. WE ANTICIPATE THAT THE WORK OUTLINED IN THIS PROPOSAL WILL ESTABLISH AN EXPERIMENTAL FRAMEWORK THAT CAN BE DEPLOYED TO IDENTIFY GENETIC VARIANTS THAT ARE RESPONSIBLE FOR A WIDE VARIETY OF CONGENITAL DEFECTS.

GENOMIC- AND ONTOGENY-LINKED DOSE INDIVIDUALIZATION AND CLINICAL OPTIMIZATION FOR KIDS

EXOGENOUS AND ENDOGENOUS BIOMARKERS OF CYP2D6 VARIABILITY IN PEDIATRICS

ADAPTING THE DIABETES PREVENTION PROGRAM FOR A DEVELOPING WORLD CONTEXT

SINGLE IMMUNOGLOBULIN INTERLEUKIN-1 RELATED RECEPTOR AND NECROTIZING ENTEROCOLITIS IN PREMATURE INFANTS

A HISTAMINE PHARMACODYNAMIC BIOMARKER TO GUIDE TREATMENT IN PEDIATRIC ASTHMA

DLL4 IN THE DEVELOPING LUNG AND BRONCHOPULMONARY DYSPLASIA (BPD) - BRONCHOPULMONARY DYSPLASIA IS A DEBILITATING LUNG DISEASE IN PREMATURE INFANTS CHARACTERIZED BY DISRUPTED LUNG VASCULARIZATION AND ALVEOLARIZATION. THE ENDOTHELIAL CELL (EC) MOLECULAR PLAYERS THAT REGULATE NORMAL AND ABNORMAL (BPD) ALVEOLARIZATION REMAIN UNCLEAR. OUR DATA IN DLL4+/- MICE INDICATE THAT DELTA-LIKE PROTEIN 4 (DLL4), AN EC NOTCH LIGAND, IS REQUIRED FOR LUNG VASCULARIZATION AND ALVEOLARIZATION. SPECIFICALLY, DLL4 APPEARS TO REGULATE THE DEVELOPMENT OF CAR4+EC, A LUNG-SPECIFIC EC SUBSET THAT INTERACTS WITH ALVEOLAR EPITHELIAL TYPE I CELLS (AT1). INTERESTINGLY, WE ALSO FOUND THAT THE AT1 POPULATION IS DEPLETED IN DLL4+/- MICE, AS WELL AS MICE WITH EC- SPECIFIC DLL4 DELETION [DLL4EC+/-] IN RELATION WITH IMPAIRED EC HEPATOCYTE GROWTH FACTOR - AT1 MET [HGF RECEPTOR] SIGNALING. EXAMINING DLL4’S ROLE IN BPD, WE NOTED THAT BOTH IN EXPERIMENTAL BPD AND IN HUMAN BPD, THERE WAS DECREASED DLL4 EXPRESSION AND DEVIANT LUNG VASCULARIZATION. TESTING A NEW THERAPY FOR BPD, WE NOTED THAT CICLESONIDE (CIC), A SYNTHETIC GLUCOCORTICOID PRO-DRUG WITH BRAIN-SPARING EFFECTS, RESCUED HYPEROXIA (HOX)- INDUCED DLL4 REPRESSION IN THE MOUSE LUNG AND IN HUMAN PULMONARY MICROVASCULAR ENDOTHELIAL CELLS (HPMEC). THESE DATA INFORM OUR HYPOTHESIS THAT EC-DLL4 REGULATES CAR4+ EC AND AT1 DEVELOPMENT DURING DISTAL LUNG MORPHOGENESIS, AND DISRUPTION OF EC-DLL4 SIGNALING IN HYPEROXIA PROGRAMS VASCULAR AND ALVEOLAR DEFECTS IN BPD. WE WILL INVESTIGATE THIS HYPOTHESIS BY: 1) TESTING WHETHER EC-DLL4 REGULATION OF CAR4+ EC IS CRITICAL FOR LUNG VASCULARIZATION, 2) DEFINING THE MOLECULAR PATHWAYS BY WHICH EC-DLL4 REGULATES AT1 DEVELOPMENT DURING LUNG ONTOGENY, AND 3) DETERMINING WHETHER REPRESSION OF EC DLL4 SIGNALING PROGRAMS EXPERIMENTAL AND HUMAN BPD. IN AIM 1, WE WILL STUDY HOW EC-DLL4 DELETION IN SEQUENTIAL LUNG STAGES REPROGRAMS LUNG EC FATE, HETEROGENEITY AND THE CAR4+ EC POPULATION. CELL AUTONOMOUS REGULATION OF CAR4+ FATE AND ANGIOGENESIS BY DLL4 WILL BE PROBED IN PRIMARY AND DLL4-DEFICIENT HPMEC LINES WE CREATED. IN AIM 2, WE WILL STUDY REGULATION OF AT1 DEVELOPMENT/FUNCTION AND ALVEOLARIZATION BY EC DLL4. WE WILL USE SINGLE CELL RNA SEQUENCING TO IDENTIFY THE EC LIGAND - AT1 RECEPTOR INTERACTIONS AND AT1 MOLECULAR PATHWAYS DISRUPTED WITH EC DLL4 DELETION. WE WILL ALSO STUDY WHETHER DLL4 LOSS DISRUPTS EC ANGIOCRINE SIGNALING THROUGH HEPATOCYTE GROWTH FACTOR. IN AIM 3, WE WILL COMBINE MOLECULAR PHENOTYPING OF HUMAN BPD SAMPLES WITH STUDIES IN DLL4EC -/- VS. +/- VS. +/+ MICE TO DETERMINE EC- DLL4’S ROLE IN DISRUPTING EC FATE, AT1 ONTOGENY AND LUNG MORPHOGENESIS IN HOX. THE THERAPEUTIC MECHANISMS BY WHICH CICLESONIDE RESCUES DLL4 SIGNALING AND LUNG INJURY IN HOX WILL ALSO BE TESTED. OUR PROPOSAL IMPACTS THE FIELD BY DISCOVERING DLL4’S ROLE IN LUNG EC FATE SPECIFICATION AND AT1 ONTOGENY USING INNOVATIVE STRATEGIES. THE SIGNIFICANCE LIES IN ADDRESSING CRITICAL BARRIERS UNDERPINNING THE VASCULAR ORIGINS OF BPD AND TRANSLATIONAL POTENTIAL. IN SA1 AND SA2, WE EXAMINE DLL4-REGULATION OF CAR4 EC AND AT1 ONTOGENY AS CRITICAL MECHANISMS UNDERPINNING DLL4-REGULATION OF LUNG DEVELOPMENT. IN SA3, WE STUDY DLL4’S ROLE IN BPD, AND TEST THE EFFICACY OF CICLESONIDE TO RESCUE DLL4 SIGNALING AND MITIGATE BPD IN A PRE-CLINICAL MODEL.

SPATIAL AND BAYESIAN MODELING METHODS FOR ASSESSMENT OF THE TUMOR IMMUNE MICROENVIRONMENT AND SURVIVAL OF WOMEN WITH OVARIAN CANCER - PROJECT SUMMARY/ABSTRACT MULTIPLEX IMMUNOFLUORESCENCE (MIF) MICROSCOPY AND ACCOMPANYING AUTOMATED IMAGE ANALYSIS IS A WIDELY USED TECHNIQUE WHICH ALLOWS FOR THE ASSESSMENT AND VISUALIZATION OF THE TUMOR IMMUNE MICROENVIRONMENT (TIME). GENERALLY, MIF DATA HAS BEEN USED TO SIMPLY EXAMINE THE PRESENCE AND ABUNDANCE OF IMMUNE CELLS IN CANCER PATIENTS; HOWEVER, THIS AGGREGATE MEASURE ASSUMES UNIFORM PATTERNS OF IMMUNE CELLS AND OVERLOOKS SPATIAL HETEROGENEITY. THE SPATIAL CONTEXTURE OF THE TIME HAS NOT BEEN ADEQUATELY EXPLORED, IN PART DUE TO THE LACK OF AVAILABLE ANALYTICAL APPROACHES AND TOOLS. THEREFORE, THE GOAL OF THIS RESEARCH IS TO DEVELOP NOVEL STATISTICAL METHODS AND SOFTWARE FOR THE DOWNSTREAM ANALYSIS OF MIF DATA. WE WILL APPLY THESE METHODS TO THE STUDY OF EPITHELIAL OVARIAN CANCER (EOC), THE DEADLIEST GYNECOLOGIC MALIGNANCY IN THE US, TO DEVELOP AN IMMUNOSCORE PREDICTIVE OF SURVIVAL AMONG EOC PATIENTS. AIM 1 IS FOCUSED ON DEVELOPING SPATIAL STATISTICAL APPROACHES FOR THE ANALYSIS OF MIF DATA WHICH LEVERAGES THE SPATIAL ARCHITECTURE OF THE TIME. AIM 2 WILL DEVELOP BAYESIAN MODELS FOR THE ANALYSIS OF MIF DATA WHICH ACCOUNTS FOR THE ZERO-INFLATED AND OVER-DISPERSED NATURE OF THE IMMUNE COUNT DATA FOR DETERMINATION OF IMMUNE SUBTYPES. LASTLY, AIM 3 WILL CHARACTERIZE THE IMMUNE LANDSCAPE OF OVARIAN TUMORS AND DEVELOP AN IMMUNOSCORE (OIMMUNO) PREDICTIVE OF SURVIVAL USING EXISTING MIF DATA FROM ~2,500 DIVERSE EOC PATIENTS ENROLLED IN ESTABLISHED EPIDEMIOLOGICAL STUDIES. WE WILL VALIDATE THE OIMMUNO BY GENERATING TARGETED MIF DATA IN TWO INDEPENDENT COHORTS, EACH WITH MORE THAN 1,200 EOC PATIENTS. IN SUMMARY, THIS PROPOSAL WILL DEVELOP AND TEST NOVEL STATISTICAL METHODS FOR THE ANALYSIS OF MIF DATA THAT INCORPORATES THE SPATIAL HETEROGENEITY OF THE TIME, IN ADDITION TO ABUNDANCE MEASURES OF IMMUNE CELLS, PRODUCING FREELY AVAILABLE SOFTWARE THAT CAN BE USED IN THE STUDY OF EOC OR ADAPTED FOR USE IN OTHER CANCER TYPES. THE DERIVATION OF METHODS TO QUANTIFY THE SPATIAL CONTEXTURE OF IMMUNE CELLS HAS IMPORTANT APPLICATIONS AS SUCH BIOMARKER DISCOVERY FOR PREDICTORS OF OUTCOMES AND THERAPEUTIC EFFICACY IN CANCER PATIENTS, ULTIMATELY REDUCING CANCER MORTALITY.

5-BASE HIFI SEQUENCING TO ADVANCE THE UNDERSTANDING OF GENETIC DETERMINANTS OF PREGNANCY LOSS - SUMMARY OUR PROGRAM WILL DEVELOP A COMPREHENSIVE GENOMIC RESOURCE TO CHARACTERIZE NOVEL CAUSES OF UNEXPLAINED RECURRENT PREGNANCY LOSS (RPL). WE ACCESS LARGE CLINICAL SERVICE FOR RPL TO PROSPECTIVELY PROCURE CAREFULLY PHENOTYPED TRIOS WITH FETAL CELLS AVAILABLE FROM SPONTANEOUS PREGNANCY LOSSES ALONG WITH BOTH PARENTS’ DNA AND PATERNAL GERM CELLS. IN ADDITION, WE LEVERAGE OUR LARGE HEALTH-SYSTEM WIDE GENOMIC ANSWERS FOR KIDS (GA4K) PROGRAM DEVELOPED FOR UNDERSTANDING PEDIATRIC RARE DISEASE CURRENTLY WITH OVER 5500 TRIOS ENROLLED ENRICHED FOR PRIOR PREGNANCY LOSSES. USING THESE RICH DATA AND CLINICAL RESOURCES, WE AIM TO EXTEND GENETIC TESTING WORKFLOW BY INTEGRATING OUR CLINICALLY DEPLOYED LONG-READ GENOME SEQUENCING (HIFI-GS) PIPELINE USING PACBIO REVIO ALLOWING SIMULTANEOUS DNA (CYTOSINE) METHYLATION IN LONG, CONTIGUOUS READ (‘5-BASE HIFI-GS’) FOR THE IDENTIFICATION OF UNDEREXPLORED GENOMIC VARIANTS AND HIDDEN FUNCTIONAL FEATURES. WE COUPLE THESE THIRD- GENERATION GENOMIC ANALYSES IN TRIOS WITH CONTEMPORARY ELECTRONIC MEDICAL RECORDS (EHR) AND CLINICAL AND POPULATION-BASED BIOBANK RESOURCES (UK BIOBANK). THE DATA INTEGRATION WILL LEVERAGE AND EXTEND OUR PRELIMINARY FINDINGS TO TEST A CENTRAL HYPOTHESIS THAT UNEXPLAINED RPL IS DUE TO INHERITED OR DE NOVO CHANGES IN FULL GENOME SEQUENCES. SPECIFICALLY, WE PROPOSE IN AIM 1 TO LEVERAGE GA4K’S AND OUR HOSPITAL’S DETAILED CLINICAL AND MOLECULAR DIAGNOSTIC DATA TOGETHER WITH DYNAMIC ACCESS TO EHR AND EXTRACT PREGNANCY HISTORY TO CLASSIFY MOLECULAR VARIATION LINKED TO RPL. WE VALIDATE THESE LINKS IN THOUSANDS OF RPL CASES OBSERVED IN UK BIOBANK BY IDENTIFYING DELETERIOUS VARIANTS IN THE AVAILABLE EXOME SEQUENCING DATA. IN AIM 2 WE UTILIZE OUR HIGH- THROUGHPUT 5-BASE HIFI-GS PLATFORM TO CONSOLIDATE ALL KNOWN MOLECULAR TESTS FOR GENETIC DISEASE INTO A SINGLE SEQUENCING RUN FOR THE IDENTIFICATION OF PUTATIVE VARIANTS AND COMPLEX DNA CHANGES MISSED BY CLINICAL MICROARRAY AND UNMEASURED BY STANDARD GS. WE WILL ASSESS 100 UNSOLVED RARE DISEASE FAMILIES FROM GA4K WITH HISTORY OF PREGNANCY LOSS AND 100 RPL TRIOS. THIS 5-HIFI-GS RESOURCE WILL ALSO ALLOW UNBIASED INFORMATION ON SKEWED X- INACTIVATION AND IMPRINTING DEFECTS IN FETAL DNA, WITH POORLY UNDERSTOOD IMPACTS ON FETAL VIABILITY. FINALLY, IN AIM 3 WE APPLY CPG METHYLATION DETECTION BY 5-HIFI-GS IN PATERNAL GERM CELLS (SPERM) CONTRASTING SAMPLES DERIVED FROM MALE PARTNER WITH RPL WITH THOSE WHO HAVE PROVEN PATERNITY TO COMPARE LEVELS OF GONADAL MOSAICISM FOR GENETIC VARIANTS AS WELL AS EPIGENOMIC TRANSMISSION OBSERVABLE IN 5-HIFI-GS FROM PATERNAL BLOOD AND SPERM TOGETHER WITH FETAL DNA. EXPECTED RESULTS ENTAIL COMPENDIUM OF HIGH-QUALITY FULL RPL GENOMES TO SPARK COMMUNITY-WIDE RESEARCH WITH NOVEL INSIGHT TO DOZENS OF RPL GENES LINKED TO GENETIC DISEASE AND IMPACTING FETAL VIABILITY.

AWARENESS AND ACCESS TO CARE FOR CHILDREN AND YOUTH WITH EPILEPSY

TARGETING PGE2 RECEPTORS TO ATTENUATE SHEAR STRESS-INDUCED GLOMERULAR INJURY

WEBSMART: EFFICACY OF WEB-BASED PAIN SELF-MANAGEMENT FOR ADOLESCENTS WITH JIA

PHARMACOGENE VARIATION CONSORTIUM

ST LOUIS-CAPE GIRARDEAU CCOP

ABANDONED INFANTS ASSISTANCE

INFLAMMATORY ANGIOGENESIS IN THE LUNG

DNA REPAIR DEFICIENCIES IN INFERTILE MEN AND CANCER RISK - THERE IS A NEED TO IDENTIFY THE CAUSES OF THE MOST SEVERE FORM OF MALE INFERTILITY, NON-OBSTRUCTIVE AZOOSPERMIA (NOA), WHERE THERE IS SPERMATOGENIC FAILURE RESULTING IN AN EJACULATE WITH NO SPERM. YET, THERE IS A POOR UNDERSTANDING OF THE MECHANISMS REGULATING SPERM PRODUCTION AND THE GENETIC, GENOMIC OR EPIGENETIC DEFECTS THAT UNDERLIE NOA BEYOND STRUCTURAL AND NUMERICAL CHROMOSOMAL DEFECTS, A FEW ENDOCRINOPATHIES AND GENE DEFECTS. NOA MEN HAVE AN INCREASED RISK OF SERIOUS DISEASES, SUCH AS CANCER, WHEN COMPARED WITH FERTILE MEN OR MEN WITH SPERM IN THEIR EJACULATES. HOWEVER, THE LINK BETWEEN THEIR INFERTILITY AND THEIR INCREASED DISEASE RISK HAS REMAINED ELUSIVE. THIS PROJECT WILL BUILD ON THE INTRIGUING DATA OBTAINED TO DATE SHOWING THE PRESENCE OF DEFICIENCIES OF MISMATCH REPAIR (MMR) AND/OR MSH5 EXPRESSION FROM GENE MUTATION OR EPIGENETIC VARIANT IS PRESENT IN NOA MEN RESULTING IN AN ABNORMAL CELLULAR RESPONSE TO ALKYLATING AGENT DNA DAMAGE, GENOMIC INSTABILITY AND A DEFICIENCY OF DOUBLE-STRAND BREAK REPAIR SUGGESTING THE PRESENCE OF DNA REPAIR DEFECTS. MMR OR MSH5 DEFICIENCY CAN CAUSE THESE CELLULAR RESPONSES AND IS ASSOCIATED WITH MALIGNANCIES (TESTIS, HEMATOLOGIC, COLON, PROSTATE, BREAST, THYROID) AND INFERTILITY DUE TO OVARIAN AND SPERMATOGENIC FAILURE. WE WILL TEST THE HYPOTHESIS THAT THE DECREASED MISMATCH REPAIR AND/OR MSH5 EXPRESSION IN A SUBSET OF INFERTILE MEN LEADS NOT ONLY TO DECREASED GENETIC STABILITY, IMPAIRED DNA BREAK, AND DEFECTIVE HOMOLOGOUS RECOMBINATION BUT ALSO LEADS MALIGNANCIES AND NOA. WE HYPOTHESIZE THAT MISMATCH REPAIR AND/OR MSH5 DEFICIENCY IS A COMMON LINK BETWEEN INFERTILITY AND THE INCREASED RISK OF MALIGNANCIES. THESE STUDIES WILL PROVIDE INSIGHTS INTO AN UNRECOGNIZED ETIOLOGY OF NOA AND THE NON-REPRODUCTIVE RELATED HEALTH RISKS, SPECIFICALLY CANCERS ASSOCIATED WITH NOA.

CONTROL OF MUTANT P53 STABILITY VIA THE MEVALONATE PATHWAY-DNAJA1 AXIS

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - NON-CONSTRUCTION

MAPPING CAUSAL GENETIC PROCESSES IN NON-MENDELIAN PEDIATRIC RARE DISEASE - SUMMARY GENOME SEQUENCING HAS LED TO RAPID ADVANCES IN THE DIAGNOSIS OF PEDIATRIC RARE DISEASES, BUT CURRENT APPROACHES FAIL TO DIAGNOSE 60-70% OF ALL CASES. EFFORTS TOWARD THE INTERPRETATION OF DISEASE VARIANTS HAS TENDED TO FOCUS ON A RELATIVELY SMALL SET OF RARE OR DE NOVO CODING VARIANTS IMPLICATED IN MENDELIAN RARE DISEASE; IN THIS PROPOSAL, WE OUTLINE APPROACHES TO SUBSTANTIALLY EXPAND VARIANT INTERPRETATION METHODS BEYOND THE EXOME AND ENCOMPASSING COMPLEX, NON-MENDELIAN DISEASE PROCESSES. WE HAVE PREVIOUSLY PROVIDED INTEGRATED FUNCTIONAL GENOMIC RESOURCES AND COMPUTATIONAL TOOLS TO CONNECT VARIANTS TO RARE DISEASE PHENOTYPES. OUR LARGE-SCALE I2QTL INDUCED PLURIPOTENT STEM CELL (IPSC) RESOURCE PROVIDES A MAP OF DEVELOPMENTAL GENE REGULATION ACROSS 1,490 CELL LINES, UNCOVERING DIFFERENTIAL ISOFORM EXPRESSION, NOVEL SPLICING AND REGULATORY EFFECTS IN KNOWN RARE DISEASE GENES, INCLUDING IN THOSE NOT EXPRESSED IN SOMATIC TISSUES. FURTHERMORE, WE RECENTLY RELEASED THE IOGC MODEL FOR CONNECTING RARE VARIANTS TO FUNCTION THROUGH GENOMEWIDE ASSAYS OF MULTIPLE MOLECULAR PHENOTYPES, PROVIDING A SYSTEMATIC METHOD TO UNCOVER LARGE-EFFECT RARE VARIANTS IN BOTH CODING AND NON-CODING REGIONS. INTEGRATED WITH POPULATION-SCALE DISEASE BIOBANKS, WE HAVE SHOWN HOW THESE VARIANTS PROVIDE A POWERFUL SYSTEM TO MAP THE COMBINED DOWNSTREAM CONSEQUENCES ON BOTH CIS- AND TRANS-REGULATORY NETWORKS, IDENTIFYING DYSREGULATED CORE DISEASE GENE MODULES ASSOCIATED WITH EXTREME EFFECTS ON DISEASE RISK. IN THIS PROPOSAL, WE WILL CONDUCT A COMPREHENSIVE GENOMIC AND FUNCTIONAL ASSESSMENT OF PEDIATRIC PATIENTS FROM ACROSS THE MIDWEST ENROLLED IN THE GENOMIC ANSWERS FOR KIDS (GA4K) INITIATIVE AT CHILDREN’S MERCY HOSPITAL WHO HAVE A SUSPECTED RARE DISEASE NOT EXPLAINED BY EXOME SEQUENCING (N=1,860). WE HAVE ALREADY EMBARKED ON GENERATING FUNCTIONAL PROFILES ACROSS DISEASE TISSUES AND PATIENT- DERIVED IPSCS USING MULTIPLE MOLECULAR ASSAYS, CURRENTLY CONSISTING OF WGS (N=1,860), PACBIO LONG-READ HIFI WGS (N=384), SINGLE-CELL ATAC-SEQ (N=433) AND SINGLE-CELL RNA-SEQ (N=528). THESE ASSAYS WILL ALLOW US TO SYSTEMATICALLY EVALUATE THEIR USE IN IDENTIFYING RARE VARIANTS ASSOCIATED WITH DOWNSTREAM MOLECULAR DYSREGULATION IN RARE DISEASE. WE WILL THEN DEVELOP NEW STATISTICAL APPROACHES INTEGRATING OUR PEDIATRIC RARE DISEASE VARIANT-TO-FUNCTION MAPS TO UNCOVER CAUSAL DIAGNOSTIC VARIATION EXPLAINING COMPLEX RARE DISEASE PHENOTYPES. THIS PROPOSAL BUILDS ON THE PI’S PREVIOUS CONTRIBUTIONS IN INTEGRATED FUNCTIONAL GENOMICS RESEARCH WITHIN THE NIH UNDIAGNOSED DISEASES NETWORK AND GTEX CONSORTIUMS. NOW, WITHIN THE DIVERSE, LARGE-SCALE GA4K INITIATIVE, THE PI IS LEADING EFFORTS TO CATALYZE NEXT-GENERATION DIAGNOSTICS IN PEDIATRIC RARE DISEASE GENOMICS IN COLLABORATION WITH RESEARCH AND CLINICAL TEAMS. OVERALL, WE EXPECT OUR RESEARCH PROGRAM WILL LEAD TO THE IMPROVED DIAGNOSIS OF PEDIATRIC RARE DISEASES THROUGH THE PRECISE IDENTIFICATION OF UNDERLYING CAUSAL GENETIC DISEASE PROCESSES.

SH3BP2-MEDIATED IMMUNE ACTIVATION PLAYS A KEY ROLE IN IMMUNOPATHOGENESIS OF NEPHROTIC SYNDROME

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - ADDRESS: 607 SOUTH NEW BALLAS ROAD, ST. LOUIS, MO 63141 PROJECT DIRECTOR NAME: JOSEPH PECORARO PHONE: 314-251-7952 EMAIL: JOSEPH.PECORARO@MERCY.NET WEBSITE: WWW.MERCY.NET REQUEST AMOUNT: $1,500,000 MERCY IS BUILDING A NEW, 17,230 SQUARE FOOT PROTON THERAPY CENTER WHICH WILL BE AN ADDITION TO THE EXISTING DAVID C. PRATT CANCER CENTER LOCATED ON MERCY’S MAIN CAMPUS IN ST. LOUIS, MISSOURI. THIS PROJECT WILL BRING PREVIOUSLY UNAVAILABLE SERVICES AND NEW CANCER TREATMENT MODALITIES TO OUR COMMUNITY, MAKING EASILY ACCESSIBLE PROTON THERAPY A REALITY FOR ST. LOUIS AND THE SURROUNDING AREAS. PROTON THERAPY IS THE MOST ADVANCED FORM OF RADIOTHERAPY CURRENTLY AVAILABLE AND IS NO LONGER LIMITED TO ACADEMIC CENTERS WITH A RESEARCH FOCUS. COMMUNITY CANCER CENTERS THAT PROVIDE CLINICAL CARE ARE ADDING PROTON THERAPY TO THE MIX OF SERVICES OFFERED ACROSS THE UNITED STATES. THE PRIMARY ADVANTAGE OF THIS TREATMENT METHOD IS ITS PINPOINT ACCURACY. THE PROTONS CAN BE FOCUSED DIRECTLY ON THE CANCER TUMOR, WITH UNNECESSARY RADIATION AND VERY MINIMAL SIDE-EFFECTS ON SURROUNDING HEALTHY TISSUE. TRADITIONAL RADIATION THERAPY CANNOT TARGET SUCH TUMORS BECAUSE IT CAN DAMAGE THE SURROUNDING NERVES. PROTON THERAPY IS PAINLESS AND NON-INVASIVE. IT IS VERY PRECISE, AND THERE IS NO ADDITIONAL RADIATION. PROTON BEAM THERAPY HAS BEEN AVAILABLE SINCE 1990 IN THE UNITED STATES, BUT ITS USE HAS NOT SPREAD WIDELY DUE TO HIGH COSTS. THIS PROJECT WILL ADDRESS THE SHORTAGE OF PROTON THERAPY SERVICES IN THE STATE OF MISSOURI. IN FACT, THERE ARE ONLY TWO PROTON CENTERS IN MISSOURI. THE NEAREST CENTERS OUTSIDE THE ST. LOUIS AREA ARE IN CHICAGO AND TENNESSEE, AND SOON KANSAS CITY. THE LIMITED ACCESS IN OUR SERVICE REGION RESULTS IN PROTON THERAPY NOT BEING AVAILABLE TO MANY CANCER PATIENTS. SOME PATIENTS ARE FORCED TO TRAVEL LONG DISTANCES TO RECEIVE CARE. THIS ADDS ADDITIONAL STRESS FOR FAMILIES, ESPECIALLY FOR THOSE WHO ARE ECONOMICALLY CHALLENGED AND STRUGGLE WITH TRANSPORTATION AND GAS COSTS. ACCESS CAN ALSO BE INFLUENCED BY A PATIENT'S HEALTH INSURANCE COVERAGE. IN SOME INSTANCES, PATIENTS REFERRED BY MERCY PHYSICIANS CANNOT BE TREATED AT THE OTHER PROTON THERAPY CENTERS DUE TO MANAGED CARE AGREEMENTS OR OTHER INSURANCE ISSUES THAT PREVENT THEM FROM RECEIVING CARE. ANOTHER ADVANTAGE SPECIFIC TO MERCY IS OUR REACH THAT GOES DEEP INTO RURAL AND UNDERSERVED COMMUNITIES. PATIENTS CAN BE EVALUATED FOR TREATMENT AT THEIR NEAREST MERCY ONCOLOGY FACILITY, ELIMINATING UNNECESSARY TRAVEL. MERCY OFFERS CHARITY CARE, WHICH IS A FINANCIAL ASSISTANCE PROGRAM FOR LOW-INCOME AND UNINSURED PATIENTS. THE PROTON THERAPY CENTER IS PART OF A LARGER CAMPAIGN AT MERCY HOSPITAL ST. LOUIS TO IMPROVE ACCESS TO HIGH-QUALITY CANCER CARE. AS PART OF OUR COMMITMENT TO THE REGION, MERCY OPENED THE DAVID C. PRATT CANCER CENTER, CREATED A PERSONALIZED MODEL OF CARE, AND BECAME A TOP ROBOTIC SURGERY PROGRAM. WE'VE SEEN CONSISTENT GROWTH IN THE NUMBER OF PATIENTS SEEKING CANCER CARE AT MERCY. SINCE OPENING THE DAVID C. PRATT CANCER, WE ARE SERVING TWICE AS MANY CANCER PATIENTS. FROM 2007 TO 2019, 36,759 PATIENTS HAVE CHOSEN THE DAVID C. PRATT CANCER CENTER FOR THEIR CANCER CARE. THE ESTIMATED 2020 POPULATION OF THE PRIMARY SERVICE AREA IS 2,506,549 AND SPANS A FOURTEEN-COUNTY AREA IN AND AROUND ST. LOUIS. MERCY HAS AN EXTENSIVE NETWORK OF CLINICS AND HOSPITALS ALONG THE I-44 CORRIDOR AND IN SOUTHWEST MISSOURI. ALTHOUGH THIS APPLICATION SPEAKS TO THE NEED FOR MERCY PATIENTS IN THE ST. LOUIS AREA, MERCY PATIENTS FROM ROLLA, LEBANON, SPRINGFIELD, JOPLIN AND OTHER COMMUNITIES ALONG THE I-44 CORRIDOR WILL ALSO ACCESS PROTON THERAPY AT MERCY' S CENTER IN ST. LOUIS. IN 2020, MERCY CANCER PROGRAMS DIAGNOSED 6,905 NEW CANCER PATIENTS IN THIS AREA AND A SIMILAR NUMBER OF PATIENTS WERE DIAGNOSED THE TWO PRIOR YEARS. WHILE THIS TECHNOLOGY WILL BE LOCATED AT THE DAVID C. PRATT CANCER CENTER IN ST. LOUIS, IT WILL BE AVAILABLE TO P

GREAT PLAINS REGIONAL HEMOPHILIA DIAGNOSTIC TREATMENT CENTERS PROGRAM

TYPE 1 DIABETES TRIALNET CLINICAL CENTERS - KANSAS CITY

THE CHILDREN'S MERCY-TRUMAN-UMKC CENTER: A NEW ADDITION FOR THE NEXT 5 YEARS

TIES (TEAM FOR INFANTS ENDANGERED BY SUBSTANCE ABUSE) PROGRAM

TRIMETHOPRIM: AN OVERLOOKED CONTRIBUTOR OF TRIMETHOPRIM-SULFAMETHOXAZOLE IDIOSYNCRATIC ADVERSE DRUG REACTIONS

COMPLETE HUMAN PARENT-OF-ORIGIN GENOME: FUNCTIONAL SIGNATURES AND DEVELOPMENTAL DETERMINANTS OF DISEASE. - SUMMARY THERE ARE OVER 10 MILLION CHILDREN IN THE US SUFFERING FROM RARE DISEASE, MOST OF THESE DISEASES ARE GENETIC AND REQUIRE DNA SEQUENCING FOR DIAGNOSIS, HOWEVER EVEN WITH CONTEMPORARY CLINICAL SEQUENCING AND KNOWLEDGE OF THOUSANDS OF DISEASES MOST PATIENTS REMAIN UNDIAGNOSED. ONE AREA OF UNDERSTUDIED RARE DISEASE IS IMPRINTING DISEASES WITH ONLY DOZEN DISEASES KNOWN TO DATE, WHERE DEVELOPMENTALLY THE PARENTAL COPIES (MATERNAL AND PATERNAL) OF GENES ARE REGULATED DIFFERENTIALLY AND THE DNA VARIANTS CAN BE HARMFUL ONLY IF INHERITED FROM EITHER MOTHER OR FATHER. THIS REGULATORY DIFFERENCE CAN BE READ BY SEQUENCING DNA CPG-METHYLATION. THE GENOMIC MEDICINE CENTER (GMC) AT CHILDREN’S MERCY KANSAS CITY (CMKC) HAS SPEARHEADED SYSTEMATIC GENERATION OF FULL GENOMES BY LONG-READ 5-BASE SEQUENCING (5MC-HIFI-GS) THAT COLLECTS CPG-METHYLATION DATA IN PARALLEL WITH ALL GENETIC VARIATION AND APPLIED IT TO THOUSANDS OF RARE DISEASE FAMILIES, INCLUDING FAMILIES SUFFERING FROM UNUSUAL PREGNANCY LOSSES BUILDING A COMPREHENSIVE RESOURCE OF LONG-READ, PARENTALLY RESOLVED GENOMES ACROSS DIFFERENT HUMAN CELL TYPES AND DEVELOPMENTAL STAGES. USING THIS 5MC-HIFI-GS RESOURCE WE HAVE FOUND HUNDREDS OF GENES AND THOUSANDS CPG DINUCLEOTIDES NOT PREVIOUSLY KNOWN TO BE IMPRINTED TO SHOW UNEQUIVOCAL EVIDENCE OF PARENT-OF-ORIGIN (POFO). THESE OBSERVATIONS ARE HARNESSED HERE TO CHARACTERIZE NEW DISEASES AND DEVELOPMENTAL PROCESSES GOVERNED BY PARENTAL DIFFERENCES IN GENE REGULATION. SPECIFICALLY, WE WILL DEVELOP A COMPREHENSIVE AND ENHANCED MAP OF HUMAN IMPRINTED GENES OR “IMPRINTOME” IN THE 5MC-HIFI-GS RESOURCES, WHICH INCLUDES OPTIMIZED TECHNOLOGY, SCALE AND SAMPLE PROCUREMENT FOR SENSITIVELY AND SPECIFICALLY DETECTING POFO DEPENDENT DNA IN HUMAN GENOME. THE POFO REGIONS IN GENOME ARE THEN CHARACTERIZED BY SINGLE NUCLEI EPIGENOME ANALYSES AND LONG-READ RNA SEQUENCING TO LINK EACH NOVEL IMPRINTED SEQUENCE TO ITS TARGET GENE. FINALLY, IN THREE RARE DISEASE COHORTS WE WILL LOOK FOR NEW VARIANTS AND DISEASES CAUSED BY PERTURBATION IN POFO REGULATED GENES AND DNA. IN PARALLEL, WE WILL STUDY THE OVERALL DEVELOPMENTAL INFLUENCES OF THESE GENE REGIONS BEYOND SPECIFIC RARE DISEASES USING COMMON VARIATION IN GROWTH (E.G. HEIGHT) USING OUR PATIENT COHORTS AND THEN VALIDATE IN POPULATION SAMPLES (UK BIOBANK). THROUGH THE EXTENSIVE NEW INFORMATION ON HUMAN GENOME REGULATION DIFFERENTIALLY BETWEEN MATERNAL AND PATERNAL COPIES COMBINED WITH DETAILED FAMILY-BASED COHORTS WE WILL UNCOVER NEW DETERMINANTS OF DEVELOPMENT AND DISEASE IN THIS UNDERSTUDIED LAYER OF HUMAN GENOME VARIATION.

UNRAVELING THE GENOMIC CAUSES FOR UNSOLVED LEUKODYSTROPHY PATIENTS BY HIFI-GS - SUMMARY LEUKODYSTROPHIES (LD) ARE A GROUP OF RARE GENETIC DISORDERS PREFERENTIALLY AFFECTING CEREBRAL WHITE MATTER (MYELIN) IN PREVIOUSLY HEALTHY CHILDREN AND IS ASSOCIATED WITH EXTREMELY POOR PROGNOSIS. SOME SUBTYPES OF LD INCLUDING HYPOMYELINATING (HLD) HAVE HIGH DNA DIAGNOSTIC RATE (70%) WHEREAS MORE COMPLEX FORMS MOSTLY REMAIN UNSOLVED EVEN AFTER STANDARD SHORT-READ GENOME SEQUENCING (SRGS). WE HYPOTHESIZE THAT COMPLEX GENETIC VARIANTS SUCH AS REPEAT EXPANSIONS AND OTHER STRUCTURAL VARIANTS (SVS) MAPPING TO BLIND SPOTS OF SRGS ACCOUNT FOR MISSED MOLECULAR DIAGNOSES IN LD. WE HAVE SHOWN THAT HUMAN GENOMES ACCESSED BY LONG-READ GS USING PACBIO SEQUEL IIE (HIFI-GS) CAN REVEAL SMALL NUCLEOTIDE VARIANTS (SNVS) IN DIFFICULT-TO-MAP REGIONS, EXPANSIONS, AND SVS THROUGHOUT THE GENOME. MORE SPECIFICALLY, USING OUR LARGE HIFI-GS DATASET (N=1191 INDIVIDUALS) DEVELOPED FOR UNDERSTANDING PEDIATRIC RARE DISEASE IN THE CONTEXT OF THE GENOMIC ANSWERS FOR KIDS (GA4K) PROGRAM, WE SHOWED THAT HIFI-GS YIELDED INCREASED DISCOVERY RATE WITH >4-FOLD MORE RARE CODING SVS THAN SRGS. OUR GOAL HERE IS TO FIRST UTILIZE AI/ML ASSISTED SRGS ANALYSES ON LD CASES TO DEFINE 125 CASES OF UNSOLVED LD. THEN, USING THE GA4K HIFI-GS RESOURCE AS REFERENCE WE WILL EXPLORE THE UTILITY OF EXPANDED LONG-READ CAPABILITIES (SV DETECTION, METHYLATION, PERSONAL HAPLOID ASSEMBLIES) TO ALLOW FINE DEFINITION OF UNDEREXPLORED GENOMIC FEATURES IN UNSOLVED PEDIATRIC LD. BY STUDYING CONTIGUOUS HAPLOID ASSEMBLIES, WE AIM TO PROVIDE FULL ASSESSMENT OF MATERNAL AND PATERNAL DNA EVEN IN COMPLEX REPETITIVE REGIONS OF THE GENOME. IN PARALLEL, WE WILL STUDY DNA METHYLATION SIGNATURES OBTAINED BY 5MC-HIFI-GS RUNS AND ESTABLISH FUNCTION OF VARIATION IN NON-CODING SPACES AND INDIRECT EFFECTS OF REPEAT EXPANSIONS. FINALLY, WE WILL VALIDATE THE FINDINGS IN FUNCTIONAL DATA (PATIENT DERIVED INDUCED PLURIPOTENT STEM CELLS ,IPSCS) TO SYSTEMATICALLY STUDY IMPACT IN RNA AND FOR A SUBSET IN MYELINATION (OLIGODENDROCYTES DERIVED FROM IPSCS). WE WILL ALSO EXPLOIT ZEBRAFISH MODEL ORGANISM TO FUNCTIONALLY STUDY NEW LD DISEASE GENES AND VARIANTS IN VIVO. WE ANTICIPATE THAT HIFI-GS PLATFORM COMBINED WITH DISTINCT CLINICAL ENDOPHENOTYPE AMONG RARE NEUROLOGICAL DISEASE WILL MAXIMIZE POTENTIAL FOR DISCOVERING NEW MECHANISMS FOR “VANISHING WHITE MATTER” AND MORE GENERALLY ACCELERATE THE DEVELOPMENT OF 3RD GENERATION TOOLS FOR UNSOLVED GENETIC DISEASE.

SIGIRR IN THE NEONATAL INTESTINE - ABSTRACT DEVELOPMENTALLY REGULATED PROGRAMS THAT INHIBIT PATHOLOGICAL ACTIVATION OF INTESTINAL TOLL LIKE RECEPTORS (TLR) BY GUT MICROBIOTA ARE DEFICIENT IN PRETERM INFANTS. A LIFE-THREATENING CONSEQUENCE OF INTESTINAL DYSMATURITY IN PRETERM INFANTS IS A LOSS IN BARRIER FUNCTION TO GUT MICROBIOTA RESULTING IN NECROTIZING ENTEROCOLITIS (NEC), CHARACTERIZED BY INFLAMMATION, BACTERIAL INVASION, AND NECROSIS. A LACK OF INSIGHT INTO THE IMMUNOGENETIC MECHANISMS REGULATING INTESTINAL BARRIER FUNCTION AND TLR SENSITIVITY DURING POSTNATAL GUT ADAPTATION HAS LIMITED OUR KNOWLEDGE OF NEC. OUR LABORATORY HAS A LONG-STANDING INTEREST IN STUDYING HOW GENETIC MUTATIONS PROGRAM DEVIANT HOST-PATHOGEN INTERACTIONS UNDERLYING NEC. WE HAVE REPORTED THAT SINGLE IMMUNOGLOBULIN INTERLEUKIN-1 RELATED RECEPTOR (SIGIRR) INHIBITS TLR-MEDIATED INTESTINAL INFLAMMATION BY INHIBITING NFΚB AND INDUCING STAT3 SIGNALING IN NEONATAL MICE. SIGIRR VARIANTS IDENTIFIED IN HUMAN NEC EXAGGERATE INFLAMMATION IN INTESTINAL EPITHELIAL CELLS (IEC) EXPOSED TO BACTERIAL LIGANDS, WHILE SIGIRRMUT MICE ENCODING A SIGIRR MUTATION (P.Y168X) IDENTIFIED IN NEC EXHIBIT TLR HYPERSENSITIVITY AND IMPAIRED INTESTINAL ADAPTATION. ONGOING STUDIES REVEAL THAT SIGIRR DEFICIENCY LEADS TO A MARKED LOSS IN THE IEC ADHERENS JUNCTION (AJ) AND TIGHT JUNCTION (TJ) PROTEINS, E-CADHERIN AND ZONA OCCLUDENS 1, WHICH PROGRAMS INCREASED GUT PERMEABILITY TO PATHOGENIC GRAM-NEGATIVE BACTERIA (GNB). SEEKING MECHANISTIC INSIGHT INTO THE LOSS OF E CADHERIN IN SIGIRRMUT MICE, WE INVESTIGATED TWIST1, A BHLH FAMILY TRANSCRIPTION FACTOR THAT TRANSCRIPTIONALLY REPRESSES E-CADHERIN ENABLING CELLULAR METASTASIS IN CANCER. IEC TWIST1 EXPRESSION AND NUCLEAR TRANSLOCATION WERE INDUCED IN SIGIRRMUT MICE AND IN INTESTINAL AUTOPSY SAMPLES OBTAINED FROM PRETERM INFANTS WITH NEC. THESE PILOT DATA INFORM OUR CENTRAL HYPOTHESIS THAT SIGIRR PROMOTES AJ ASSEMBLY AND IEC BARRIER FUNCTION IN THE NEONATAL INTESTINE BY INHIBITING TWIST1-MEDIATED REPRESSION OF E-CADHERIN. IN SEQUENTIAL AIMS, WE WILL THE TEST THIS HYPOTHESIS BY STUDYING WHETHER IEC-SIGIRR: 1) REGULATES AJ ASSEMBLY AND FUNCTION IN THE NEONATAL GUT, 2) INHIBITS TWIST1-MEDIATED REPRESSION OF IEC AJ AND TJ FUNCTION, AND 3) PREVENTS EXPERIMENTAL NEC IN MICE BY INHIBITING TLR4 AND TWIST1 SIGNALING. SIGIRR REGULATION OF IEC AJ AND TJ COMPONENT MEMBERS, TWIST1 INHIBITION, AND GUT PERMEABILITY TO GNB WILL BE EVALUATED IN TRANSGENIC MICE WITH GLOBAL OR IEC-SPECIFIC LOSS/GAIN OF SIGIRR FUNCTION. SURGICAL PATHOLOGY NEC SAMPLES AND PRETERM INFANT ENTEROIDS TRANSDUCED WITH SIGIRR VARIANTS IDENTIFIED IN NEC WILL PROVIDE HUMAN CORROBORATION TO SIGIRR’S ROLE IN PRESERVING AJ FUNCTION THROUGH TWIST1 INHIBITION. WE WILL ALSO EXAMINE THE OPPOSING EFFECTS OF SIGIRR AND TWIST1 IN REGULATING NEC VULNERABILITY IN SIGIRR TRANSGENIC MICE AND PRETERM INTESTINAL ENTEROIDS. WE STUDY SIGIRR AS A PARADIGM TO REVEAL HOW HOST GENETICS REGULATES INTESTINAL BARRIER FUNCTION DURING POSTNATAL ADAPTATION. THIS PROPOSAL IMPACTS THE FIELD BY DISCOVERING SIGIRR-TWIST1’S ROLE IN REGULATING IEC-AJ ASSEMBLY AND FUNCTION USING INNOVATIVE STRATEGIES. THE SIGNIFICANCE LIES IN REVEALING NOVEL MECHANISMS BY WHICH GENETIC VARIANTS PROGRAM THE DEFECTIVE MUCOSAL BARRIER IN NEC WITH THE POTENTIAL FOR CLINICAL TRANSLATION.

INVESTIGATING THE RELATIONSHIP BETWEEN SYMPATHETIC NERVOUS SYSTEM DEVELOPMENT AND NEUROBLASTOMA - PROJECT SUMMARY A COMMON FEATURE OF EMBRYONIC DEVELOPMENT IS THAT CELLS ARE BORN IN ONE PLACE AND HAVE TO MOVE AS A CLUSTER AND REGULATE THEIR DIFFERENTIATION BEFORE CONNECTING WITH A VITAL TARGET IN A DIFFERENT LOCATION. ONE RESULT OF THIS DYNAMIC MORPHOGENETIC EVENT IS ASSEMBLY OF THE SYMPATHETIC NERVOUS SYSTEM THAT IS ESSENTIAL FOR MAINTAINING BLOOD PRESSURE, HEART RATE, AND TEMPERATURE CONTROL WITH IMPROPER DEVELOPMENT LEADING TO BIRTH DEFECTS AND NEUROBLASTOMA CANCER IN INFANTS. WE ARE INTERESTED IN UNDERSTANDING HOW THE SIGNALS THAT REGULATE THE COLLECTIVE CELL MOVEMENT AND DIFFERENTIATION OF THE EMBRYONIC NEURAL CREST CELLS ARE ORCHESTRATED, SPATIALLY AND TEMPORALLY, TO DRIVE THE EMERGENCE OF THE PATTERNED SYMPATHETIC NERVOUS SYSTEM. TO ADDRESS THIS, WE WILL IMPLEMENT AN INNOVATIVE COMBINATION OF TECHNIQUES FROM BIOLOGICAL, IN VIVO IMAGING AND SINGLE CELL SPATIAL TRANSCRIPTOMIC SCIENCES APPLIED TO THE AVIAN MODEL SYSTEM, MOST OF WHICH ARE NOT CURRENTLY POSSIBLE BUT MAY BE TRANSLATED TO DEVELOPING MAMMALIAN SYSTEMS. THIS STUDY WILL BE SIGNIFICANT BECAUSE IT WILL IDENTIFY THE SIGNALS INVOLVED IN SYMPATHETIC NERVOUS SYSTEM DEVELOPMENT, LINKING THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS -- WITH SPECIAL FOCUS ON THE ROLE OF TRKB AND ON DETERMINING THE SIGNALS THAT MEDIATE THE MIGRATION, DIFFERENTIATION, SURVIVAL, AND MOLECULAR CROSSTALK BETWEEN NEURAL CREST CELLS THAT ENSURE SYMPATHETIC NERVOUS SYSTEM CIRCUIT FORMATION. THE RESULTS OF THIS STUDY WILL PROVIDE CRITICAL INFORMATION FOR SURGICAL METHODS TO CORRECT BY NEURAL REPAIR AND MITIGATE THE EFFECTS OF SYMPATHETIC NERVOUS SYSTEM BIRTH DEFECTS AND TRANSLATE INTO AND INFORM IMPROVED DRUG DESIGN EFFORTS TARGETING RECEPTOR TYROSINE KINASE SIGNALING AS A TREATMENT FOR NEUROBLASTOMA AND POSSIBLE INCREASE IN INFANT SURVIVAL.

NOVEL ROLE OF PRE-B-CELL COLONY ENHANCING FACTOR IN ALI

REGION VII HEMOPHILIA PROGRAM

CHILDREN'S CENTER FOR CLINICAL PHARMACOLOGY STUDIES

SIMULTANEOUS ROS PRODUCTION AND DDR INHIBITION TO TRIGGER P53 SYNTHETIC LETHALITY - PROJECT SUMMARY/ABSTRACT ANTI-CANCER DRUGS THAT TARGET CANCER-SPECIFIC EVENTS ARE EXPECTED TO CAUSE MINIMAL DAMAGE IN NORMAL TISSUES, RESULTING IN SIGNIFICANTLY REDUCED SIDE EFFECTS. DEFICIENCY IN THE TUMOR SUPPRESSOR P53 GENE BY GENE MUTATIONS OR DELETIONS ARE DETECTED IN ~50% OF HUMAN CANCERS, ONE OF THE MOST FREQUENT CANCER-SPECIFIC EVENTS. THE GOAL OF THIS PROPOSAL IS TO IDENTIFY A STRATEGY AND NOVEL COMPOUNDS THAT EFFICIENTLY INDUCE CELL DEATH SPECIFICALLY IN CANCER CELLS DEFICIENT IN P53, KNOWN AS “P53 SYNTHETIC LETHALITY”. SIMILAR COMPOUNDS OR DRUGS HAVE BEEN UNDER DEVELOPMENT; HOWEVER, THEIR EFFICACY IS NOT ROBUST AND HAS NOT YET BEEN CLINICALLY PROVEN. THIS IS MAINLY DUE TO POOR UNDERSTANDING OF MECHANISMS THAT INDUCE P53 SYNTHETIC LETHALITY, CONTEXT-DEPENDENT SPECIFICITY, AND LOW EFFICACY OF IDENTIFIED COMPOUNDS. OUR RECENT HIGH-THROUGHPUT SCREEN HAS IDENTIFIED A COMPOUND, CALLED “KU”, THAT SPECIFICALLY INDUCES DNA DAMAGE, MITOTIC ARREST, AND CELL DEATH IN VARIOUS P53-DELETED OR -MUTATED OSTEOSARCOMA (OS) CELLS WITH MINIMAL EFFECTS ON NON-TUMOR CELLS CARRYING INTACT P53. “KU” INDUCES REACTIVE OXYGEN SPECIES (ROS) PRODUCTION AND INHIBITS ATM PHOSPHORYLATION. WE HAVE ALSO IDENTIFIED THAT DEUTERATED AND/OR FLUORINATED KU ANALOGS, CALLED KU-D2 AND KU-D2F, RESPECTIVELY, HAVE MUCH HIGHER CYTOTOXIC ACTIVITIES WITH INCREASED SPECIFICITY TO P53 DEFICIENCY, AS COMPARED TO KU. OUR HYPOTHESIS IS THAT KU ANALOGS (KU-D2, KU-D2F) INDUCE MITOTIC ARREST AND CELL DEATH SPECIFICALLY IN P53-DEFICIENT CELLS AS A SINGLE AGENT THROUGH THE DUAL EFFECTS OF CAUSING ROS-MEDIATED DNA DOUBLE-STRAND BREAKS (DSBS) AND INHIBITING ATM-MEDIATED DNA DAMAGE RESPONSE (DDR), OFFERING AN EFFICIENT AND UNIQUE STRATEGY TO INDUCE P53 SYNTHETIC LETHALITY. AIM 1 IS TO DETERMINE REQUIREMENT OF ROS (NOT BY OTHER CHEMOTHERAPY DRUGS)-MEDIATED DSBS AND DDR INHIBITION FOR EFFICIENT INDUCTION OF P53 SYNTHETIC LETHALITY, PHENOCOPYING THE EFFECTS OF KU ANALOGS. WE WILL SHOW THAT SIMULTANEOUS INDUCTION OF ROS- MEDIATED DSBS AND INHIBITION OF DDR PHENOCOPY THE MECHANISM OF ACTION OF KU ANALOGS, LEADING TO EFFICIENT INDUCTION OF P53 SYNTHETIC LETHALITY. WE WILL ALSO IDENTIFY AND VALIDATE PROTEINS BINDING TO KU ANALOGS INVOLVED IN THE OBSERVED BIOLOGICAL PHENOTYPES. AIM 2 WILL DETERMINE IN VIVO TOXICITY/SAFETY AND PHARMACOLOGICAL PROPERTIES OF KU-D2 AND KU-D2F, AS WELL AS THE IN VIVO EFFECTS OF THESE COMPOUNDS ON TUMOR SUPPRESSION IN ORTHOTOPIC (ALLO- AND XENO-GRAFTS) AND PATIENT-DERIVED XENOGRAFTS (PDXS) OS MOUSE MODELS. WE WILL ALSO SHOW THAT SIMULTANEOUS TREATMENT OF BOTH A ROS INDUCER AND AN ATM INHIBITOR CAN SELECTIVELY INHIBIT GROWTH OF P53-DEFICIENT TUMORS AND WHETHER OVEREXPRESSION OF POTENTIAL KU ANALOG-TARGET PROTEINS, INCLUDING NBS1 AND PRDX3, RESCUES THE IN VIVO TUMOR SUPPRESSIVE EFFECTS OF KU-D2F. THUS, THIS STUDY REVEALS THAT P53-DEFICIET CELLS ARE VULNERABLE TO SIMULTANEOUS TREATMENT OF ROS-MEDIATED DSB INDUCTION AND DDR INHIBITION, WHICH IS AN EFFICIENT STRATEGY TO INDUCE P53 SYNTHETIC LETHALITY. WE WILL ALSO IDENTIFY NOVEL COMPOUNDS THAT EFFICIENTLY INDUCE P53 SYNTHETIC LETHALITY AS A SINGLE AGENT BY TARGETING VULNERABILITIES IMPOSED BY P53 DEFICIENCY, WHICH COULD BE EMPLOYED TO DEVELOP NOVEL ANTI-CANCER THERAPIES TO TREAT P53-DEFICIENT CANCERS.

PORTLAND AREA RESIDENTIAL SERVICES CONSORTIUM

ARP ECONOMIC DEVELOPMENT GRANT FOR RURAL HEALTH CARE FACILITIES

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - ADDRESS: 4300 W MEMORIAL RD, OKLAHOMA CITY, OK 73120 PROJECT DIRECTOR NAME: KATE BLAKE PHONE: 405-936-5574 EMAIL: KATHERINE.BLAKE@MERCY.NET WEBSITE: WWW.MERCY.NET REQUEST AMOUNT: $1,000,000 IMPROVING ACCESS TO COMPREHENSIVE AND INNOVATIVE HEALTH CARE FOR ALL WOMEN IS CRITICAL. IN OKLAHOMA CITY AND SURROUNDING COMMUNITIES, THE NEED FOR HIGH-QUALITY WOMEN’S AND CHILDREN’S SERVICES OUTWEIGHS THE AVAILABLE OPTIONS FOR CARE. AFTER MANY YEARS OF CONTINUOUS GROWTH, MERCY HOSPITAL OKLAHOMA CITY’S CAPACITY TO SERVE OBSTETRIC PATIENTS HAS PLATEAUED DUE TO THE HARD-LIMIT OF PHYSICAL SPACE IN WHICH CARE CAN BE PROVIDED. IN FACT, COMMUNITY FEEDBACK SHOWS THAT AN ADDITIONAL 2,000 – 3,000 WOMEN DESIRE TO HAVE THEIR BABIES AT MERCY ANNUALLY BUT CANNOT DUE TO THE LACK OF PHYSICAL SPACE AVAILABLE. THE LIMITS OF PHYSICAL SPACE HAVE ALSO IMPACTED PROGRAMS, HOLDING BACK INNOVATION. FOR EXAMPLE, THE HOSPITAL HAS BEEN UNABLE TO RESPOND TO THE COMMUNITY’S DEMAND FOR LOW-RISK PREGNANCY CARE OPTIONS. HOWEVER, THE MOST DIFFICULT REALITY MERCY FACES IS TURNING AWAY THOUSANDS OF MOTHERS WHO NEED CARE, INCLUDING MANY WHO RELY ON MEDICAID. THUS, LIMITED CAPACITY HINDERS OUR ABILITY TO CARE FOR ECONOMICALLY DISADVANTAGED WOMEN IN OUR COMMUNITIES. A MAJOR LEAP FORWARD IS NEEDED BOTH IN PHYSICAL SPACE AND IN THE QUALITY OF THE HEALING ENVIRONMENT DEMANDED BY A POPULATION THAT HAS ENJOYED DECADES OF STEADY GROWTH. MERCY HOSPITAL OKLAHOMA CITY WAS DESIGNED TO FACILITATE 3,000 DELIVERIES ANNUALLY, HOWEVER, SAW NEARLY 4,000 BIRTHS IN 2020 WITH AS MANY AS 6,000 ANTICIPATED ANNUAL DELIVERIES TO MEET CURRENT DEMAND MERCY IS BUILDING THE LOVE’S FAMILY WOMEN’S CENTER ON ITS OKLAHOMA CITY MAIN CAMPUS TO ADDRESS THE LACK OF ACCESS TO WOMEN’S SERVICES ACROSS THE REGION. THE WOMEN’S CENTER IS A FOUR STORY,174,000 SQUARE FOOT ADDITION CONNECTING TO THE MAIN HOSPITAL IN THE NORTHWEST CORNER OF THE CAMPUS. THE BUILDING IS FOCUSED ON WOMEN’S HEALTH AND WILL INCLUDE A CAFE, CHAPEL, IMAGING, CL INIC, BIRTHING, PRE/POST & SURGERY SERVICES FOR WOMEN. IT WILL BE THE ENTRY POINT FOR THOUSANDS OF COMPREHENSIVE WOMEN’S HEALTH SERVICE VISITS. IN TOTAL, INCLUDING LABOR AND DELIVERY PLUS OTHER SERVICES, THE NEW WOMEN’S CENTER WILL SERVE OVER 10,000 WOMEN ANNUALLY. THE FULL SPECTRUM OF SERVICES AND FEATURES INCLUDE: - FOUR-STORY, 174,000-SQUARE-FOOT FACILITY NEW CONSTRUCTION - OBSTETRICAL EMERGENCY ROOM - DIRECT CONNECTION TO NEONATAL INTENSIVE CARE UNIT - HIGH RISK PRENATAL CARE - LABOR, DELIVERY AND POSTPARTUM CARE - LOW INTERVENTION BIRTHING OPTIONS - LACTATION SUPPORT - POSTPARTUM DEPRESSION CARE - INFANT LOSS AND BEREAVEMENT SUPPORT - COMPREHENSIVE WOMEN'S SERVICES, INCLUDING SPECIALIZED WOMEN’S SURGERY, MENTAL HEALTH SERVICES AND MANY OTHER SERVICES ON-SITE - CONFERENCE CENTER, CHAPEL, CAFE AND BOUTIQUE - SUPPORT FOR LOW-INCOME WOMEN THE ESTIMATED 2020 POPULATION OF THE PRIMARY SERVICE AREA IS 1,342,647 WITH PROJECTED GROWTH EACH YEAR. GEOGRAPHICALLY, THE PROJECT WILL SERVE WOMEN AND BABIES IN THE OKLAHOMA CITY REGION, BUT ALSO EXTEND TO THE NEIGHBORING RURAL COMMUNITIES WHERE THERE IS LIMITED ACCESS TO WOMEN’S SERVICES. THIS PROJECT WILL IMPROVE HEALTH EQUITY AMONG BOTH MEDICAID AND RURAL PATIENTS. ROUGHLY 30% OF WOMEN’S ADMISSIONS AND 50% OF NEONATAL INTENSIVE CARE UNIT ADMISSIONS CONSIST OF MEDICAID OR UNINSURED PATIENTS. MERCY OFFERS FINANCIAL AID FOR ECONOMICALLY DISADVANTAGED FAMILIES SO THEY CAN RECEIVE THE SAME HIGH-QUALITY CARE AS THOSE WHO HAVE INSURANCE. THIS PROJECT WILL ENSURE QUALITY WOMEN’S SERVICES ARE EQUALLY AVAILABLE TO ALL COMMUNITY MEMBERS.

SEE NOTICE OF AWARD, ATTACHMENT 1 - TERMS AND CONDITIONS, ATTACHMENT D, STATEMENT OF WORK, ABSTRACT

LEAD HEALTHY HOME

HEALTH CARE AND OTHER FACILITIES

TRANSITION FOR YOUTH WITH AUTISM AND/OR EPILEPSY DEMONSTRATION PROJECTS - TRANSITION OF CARE (TOC) IS THE PROCESS BY WHICH YOUTH ARE TRANSITIONED FROM PEDIATRIC TO ADULT MEDICINE. THIS PROCESS CAN BE DIFFICULT FOR MANY YOUTHS AND THEIR FAMILIES. THIS IS ESPECIALLY TRUE OF THOSE WITH COMPLEX MEDICAL NEEDS, SUCH AS EPILEPSY AND OTHER SPECIAL NEEDS. EPILEPSY IS ONE OF THE MOST COMMON NEUROLOGICAL DISORDERS. IN THE USA ALONE, ABOUT 450,000 CHILDREN LIVE WITH EPILEPSY (<17 YEARS OLD). MANY OF THESE CHILDREN HAVE SPECIAL NEEDS, INCLUDING LEARNING DISABILITIES AND OTHER HEALTH ISSUES. IT IS ESTIMATED THAT 9% OF CHILDREN WITH EPILEPSY HAVE INTELLECTUAL DISABILITY. AMONG SPECIAL POPULATIONS, SUCH AS CHILDREN WITH AUTISM OR CEREBRAL PALSY, THE PROPORTION OF THOSE WITH EPILEPSY IS ESPECIALLY HIGH (20% AND 30%, RESPECTIVELY). FOR THESE POPULATIONS, TOC CAN BE ESPECIALLY COMPLEX AND TRAUMATIZING. WHILE THERE ARE MANY ORGANIZATIONS THAT ASSIST WITH TOC, THE PROCESS IS FRAGMENTED, MAKING IT DIFFICULT FOR FAMILIES TO ACCESS CARE IN A SEAMLESS AND FLUID WAY. IN THIS PROPOSAL, WE AIM TO DEVELOP A FRAMEWORK TO SUPPORT YOUTH WITH EPILEPSY AND SPECIAL NEEDS DURING TOC. OUR GOAL IS TO CREATE A FRAMEWORK THAT FACILITATES A SMOOTH TOC PROCESS WHILE ADDRESSING THE DIVERSE NEEDS OF BOTH THE YOUTH AND THEIR FAMILIES, ENCOMPASSING MEDICAL, LEGAL, SOCIETAL, AND EMOTIONAL ASPECTS. ACKNOWLEDGING THAT MANY ESSENTIAL COMPONENTS ARE ALREADY IN PLACE BUT DISPERSED ACROSS VARIOUS ORGANIZATIONS AT LOCAL, REGIONAL, AND NATIONAL LEVELS, OUR PROPOSED FRAMEWORK OFFERS AN INTEGRATED SOLUTION. IT BRINGS TOGETHER KEY ELEMENTS AND STAKEHOLDERS IN A COHESIVE AND EFFICIENT MANNER, ENSURING A UNIFIED APPROACH TO TOC IMPLEMENTATION. OUR FRAMEWORK IS STRUCTURED AROUND A CLEAR DISTRIBUTION OF TASKS AND ROLES, BOTH TIME AND SPACE. IT BEGINS AT THE AGE OF 13, MARKING THE INITIATION OF THE TRANSITION PROCESS WITH A FOCUS ON EDUCATION. THIS PHASE AIMS TO EQUIP YOUTH AND THEIR FAMILIES WITH THE NECESSARY KNOWLEDGE AND SKILLS TO NAVIGATE TOC EFFECTIVELY. THROUGH TAILOR ED EDUCATIONAL INTERVENTIONS, THEY WILL ENHANCE THEIR ABILITY TO ARTICULATE ALL NEEDS, INCLUDING DIAGNOSES, MEDICATIONS, AND SOCIAL NEEDS, THEREBY BOLSTERING THEIR SELF-EFFICACY. THE LEGAL LEARNING SKILLS WILL INCLUDE APPLYING FOR THE LEAST RESTRICTIVE OPTIONS FOR GUARDIANSHIP. FINANCIAL SKILLS WILL ADDRESS ISSUES WITH MEDICAL INSURANCE, EMPLOYMENT, AND OTHER AVAILABLE GOVERNMENTAL ASSISTANCE. SOCIETAL SKILLS TARGET THE ABILITY TO LIVE INDEPENDENTLY. AFFECTIVE SKILLS ARE GEARED TO PREPARE THE FAMILY TO ENTER THE ADULT WORLD, OFTEN REQUIRING LETTING GO OF STRONG EMOTIONAL BONDS. THE SECOND PHASE OF THE PROJECT INVOLVES IMPLEMENTATION, TAKING PLACE BETWEEN THE AGES OF 17 AND 21, MARKING THE ACTUAL PHYSICAL TRANSITION TO ADULT CARE. THIS CRUCIAL STEP HINGES ON A “WARM HAND-OFF,” ENSURING A SEAMLESS TRANSFER BY FACILITATING AT LEAST ONE JOINT VISIT WITH BOTH PEDIATRIC AND ADULT PROVIDERS PRESENT. THE FINAL STAGE OF THE PROPOSAL FOCUSES ON ENSURING SUSTAINABILITY. THE OVERARCHING AIM OF ESTABLISHING THIS FRAMEWORK IS TO CREATE A MODEL EASILY ADAPTABLE TO OTHER DISEASES AND HEALTHCARE INSTITUTIONS. FOR WIDESPREAD ADOPTION, IT IS IMPERATIVE TO DEMONSTRATE ITS BENEFITS FOR ALL STAKEHOLDERS, INCLUDING YOUTH AND THEIR FAMILIES, HEALTHCARE PROVIDERS, AND THE MEDICAL SYSTEM AS A WHOLE. ADDITIONALLY, IT MUST BE PROVEN TO BE FINANCIALLY VIABLE. THIS PROJECT HAS BEEN METICULOUSLY DESIGNED WITH MEASURES IN PLACE TO OBJECTIVELY DEMONSTRATE THE BENEFITS ACROSS ALL AFFECTED LEVELS. WE AIM TO ILLUSTRATE THAT IMPLEMENTING THIS TOC FRAMEWORK WILL NOT ONLY BENEFIT YOUTH AND THEIR FAMILIES BUT ALSO ENHANCE MEDICAL CARE IN A FISCALLY RESPONSIBLE MANNER, ULTIMATELY CONTRIBUTING TO THE BETTERMENT OF SOCIETY AS A WHOLE.

ARP ECONOMIC DEVELOPMENT GRANT FOR RURAL HEALTH CARE FACILITIES

MULTI-LEVEL EMERGENCY DEPARTMENT INTERVENTION TO REDUCE PREGNANCY RISK AMONG ADOLESCENTS

AN INTEGRATIVE APPROACH TO IDENTIFY BIOMARKERS AND INVESTIGATE MECHANISMS OF ADVERSE DRUG REACTIONS - PROJECT SUMMARY/ABSTRACT IDIOSYNCRATIC ADVERSE DRUG REACTIONS (IADRS) OCCUR IN A SMALL BUT SIGNIFICANT PERCENTAGE OF THE POPULATION, ARE UNPREDICTABLE, AND FREQUENTLY CAUSE LIFE-THREATENING EVENTS REQUIRING INTENSIVE MEDICAL CARE. IADRS ARE TYPICALLY ONLY DISCOVERED LATE IN DRUG DEVELOPMENT, OR AFTER A DRUG IS APPROVED AND WIDELY AVAILABLE. MOST IADRS ARE PRESUMED TO BE IMMUNE MEDIATED. GENETIC PREDISPOSITION HAS BEEN IDENTIFIED AS A RISK FACTOR IN SOME IADRS WITH SPECIFIC HUMAN LEUKOCYTE ANTIGEN (HLA) ALLELES ASSOCIATED WITH SPECIFIC IADRS. A SINGLE DRUG CAN CAUSE STRIKINGLY DIFFERENT IADR PHENOTYPES AND BE LINKED WITH DIFFERENT HLA MARKERS BASED ON PHENOTYPE. DRUG METABOLISM HAS ALSO BEEN AN IMPORTANT FOCUS OF IADR ETIOLOGY. REACTIVITY OF DRUG METABOLITES AS MEASURED BY THE FORMATION OF PROTEIN ADDUCTS CORRELATES WITH THE TENDENCY OF A DRUG TO CAUSE AN IADR. REACTIVE METABOLITES HAVE BEEN IMPLICATED IN FORMING HAPTENS AND ACTIVATING ANTIGEN-PRESENTING CELLS, YET FEW STUDIES INVESTIGATE THE INTERFACE BETWEEN DRUG METABOLITES AND IMMUNE-MEDIATED REACTIONS. WE PLAN TO LEVERAGE OUR PRIOR WORK TO BUILD AN INTEGRATIVE RESEARCH PLATFORM THAT ADDRESSES MULTIPLE FACTORS INVOLVED IN THE DEVELOPMENT OF IADRS. WE WILL FOCUS OUR RESEARCH ON TRIMETHOPRIM-SULFAMETHOXAZOLE (TMP-SMX) IADRS GIVEN OUR GROUP’S EXTENSIVE EXPERIENCE WITH THIS DRUG. TMP-SMX IS A COMMONLY USED ANTIBIOTIC AND IS ASSOCIATED WITH UNPREDICTABLE, LIFE- THREATENING IADRS INCLUDING SEVERE SKIN, LIVER, AND LUNG INJURY. OUR GOAL IS TO COMBINE METABOLISM, GENETICS AND IMMUNE SIGNALING STUDIES TO IDENTIFY PUTATIVE BIOMARKERS FOR TMP-SMX IADRS. OUR APPROACH INCLUDES IDENTIFYING TISSUE SPECIFIC METABOLITES TO EVALUATE HOW THESE MOLECULES INTERACT WITH IMMUNE PATHWAYS AND ANTIGEN PRESENTATION. WE PLAN TO 1) IDENTIFY HIGH RISK METABOLITES BASED UPON ABUNDANCE, REACTIVITY AND TISSUE SPECIFICITY, 2) USE THE IDENTIFIED METABOLITES TO PROBE IMMUNE PATHWAY RESPONSES, 3) DETERMINE THE INFLUENCE OF SELECTED METABOLITES ON HLA PEPTIDE PRESENTATION. THROUGH THE INTEGRATION OF DRUG METABOLISM, IMMUNE SIGNALING, AND HLA ANTIGEN PRESENTATION, WE WILL GAIN A GREATER UNDERSTANDING OF IADR BIOMARKERS AND MECHANISTIC INSIGHT. OUR OVERALL VISION OF THIS RESEARCH PROGRAM IS THAT OUR MULTI-PRONGED APPROACH WILL ENHANCE IADR RESEARCH RESULTING IN THE SAFER USE OF DRUGS.

GENE-ENVIRONMENT INTERACTIONS IN NECROTIZING ENTEROCOLITIS: IMPACT OF SIGIRR MUTATION AND GUT MICROBIOTA ON INTESTINAL TLR HYPERACTIVITY

METABOLISM, APPETITE, AND PHYSICAL ACTIVITY IN ADOLESCENTS

ADDRESSING SOCIAL DETERMINANTS OF HEALTH IN CHILD OBESITY TREATMENT USING COMMUNITY HEALTH WORKERS: THE ROLE OF PARENTAL BANDWIDTH IN TREATMENT EFFECTIVENESS - FEASIBILITY STUDY FOR FULL - SCALE RCT - PROJECT ABSTRACT CHILDHOOD OBESITY REMAINS A SIGNIFICANT PROBLEM WHICH IMPACTS CHILDREN’S HEALTH. FAMILY-FOCUSED CHILD OBESITY TREATMENT IS EFFICACIOUS BUT UNFORTUNATELY NOT ALL CHILDREN RECEIVE THE SAME BENEFIT, ESPECIALLY RACIAL AND ETHNIC MINORITY GROUPS, THOSE ON MEDICAID AND THOSE WITH INSECURE HOUSING. ADVERSE SOCIAL DETERMINANTS OF HEALTH, SOCIAL RISK FACTORS (SRF), ARE KEY FACTORS INFLUENCING CHILD OBESITY TREATMENT OUTCOMES. SOME CHALLENGES ARE LOGISTICAL (E.G., LACK OF TRANSPORTATION). YET, JUGGLING SCARCE RESOURCES (E.G., MONEY, FOOD) ALSO TAKES PHYSICAL, EMOTIONAL, AND MENTAL ENERGY. BANDWIDTH IS OUR CAPACITY TO ALLOCATE AND USE OUR LIMITED COGNITIVE RESOURCES EFFECTIVELY AND IS IMPACTED BY SCARCITY OF TIME OR RESOURCES. LACK OF BANDWIDTH CAN LEAD TO POOR FOOD CHOICES, WEIGHT GAIN AND DIFFICULTY LEARNING. INTERVENING ON SRF MAY HAVE A SIGNIFICANT IMPACT ON PARENT BANDWIDTH, ALLOWING PARENTS AND CHILDREN TO BENEFIT MORE FULLY FROM CHILD OBESITY INTERVENTIONS. A COMMUNITY HEALTH WORKER (CHW) CAN BE USED TO CONNECT FAMILIES TO RESOURCES TO ADDRESS SRF AND SUPPORT THEIR ABILITY TO ENGAGE IN CHILD OBESITY TREATMENT. THE LONG-TERM GOALS OF THIS WORK ARE TO TEST WHETHER CHILD OBESITY TREATMENT OUTCOMES CAN BE IMPROVED BY SYSTEMATICALLY ADDRESSING SRF AND WHETHER BANDWIDTH IS AN IMPORTANT MEDIATOR. THIS PROPOSAL WILL COMPLETE A PILOT IN PREPARATION FOR A LARGER TRIAL. THE SPECIFIC AIMS OF THIS PROJECT ARE 1. TO TEST THE FEASIBILITY AND ACCEPTABILITY OF A TRIAL COMPARING FAMILIES WITH SRF RECEIVING CHW SUPPORT PLUS A CHILD OBESITY TREATMENT INTERVENTION (CHW+PHIT KIDS) AND THOSE RECEIVING ONE-TIME RESOURCE REFERRALS AND THE OBESITY INTERVENTION (PHIT KIDS). WE WILL LOOK AT RECRUITMENT, RETENTION, SATISFACTION WITH CHW INTERVENTION AND PHIT KIDS, AND OTHER IMPLEMENTATION OUTCOMES. 2. TO COMPARE OUTCOMES BETWEEN CHW+PHIT KIDS AND PHIT KIDS AND GATHER EFFECT SIZES ON OUTCOME MEASURES TO GUIDE A FUTURE FULL-SCALE TRIAL. OUTCOMES TO BE EXAMINED OVER 6 MONTHS INCLUDE1) BMI Z-SCORE (PRIMARY), 2) CHILD DIETARY INTAKE (24-HOUR DIET RECALLS: SERVINGS OF FRUITS AND VEGETABLES, SUGAR-SWEETENED BEVERAGES, AND HIGH-SUGAR/HIGH FAT FOODS), 3) CHILD MODERATE-TO-VIGOROUS PHYSICAL ACTIVITY (ACCELEROMETER, MINUTES PER DAY) AND 4) PARENT WEIGHT. 3. TO EXPLORE THE ROLE OF PARENTS’ BANDWIDTH AS A POTENTIAL MEDIATOR FOR THE IMPLEMENTATION AND TREATMENT OUTCOMES. THE PROJECT WILL RECRUIT 60 FAMILIES WITH AN 8- TO 12-YEAR-OLD CHILD WITH OBESITY OR OVERWEIGHT AND A POSITIVE SRF SCREEN. FAMILIES WILL BE RANDOMIZED TO 1) ASSISTANCE OBTAINING NEEDED RESOURCES USING AN EXISTING SCALABLE CHW INTERVENTION OR 2) A ONE-TIME STANDARD OF CARE REFERRAL TO RESOURCES. AT THREE MONTHS ALL FAMILIES WILL RECEIVE A VIRTUALLY DELIVERED 3-MONTH CHILD OBESITY TREATMENT INTERVENTION. DATA WILL BE COLLECTED AT BASELINE, 3, 6, AND 12 MONTHS. THIS RESEARCH IS SIGNIFICANT AS IT WILL GIVE INSIGHT INTO HOW TO IMPROVE THE EFFICACY OF CHILD OBESITY TREATMENT INTERVENTIONS FOR OUR MOST VULNERABLE CHILDREN BY SYSTEMATICALLY ATTENDING TO SRF AND INNOVATIVE IN EXPLORING BANDWIDTH AS A MEDIATOR OF THIS RELATIONSHIP. THIS RESEARCH WILL PROVIDE THE NECESSARY DATA TO SUPPORT A FULL-SCALE CLINICAL TRIAL. THIS WORK COULD SIGNIFICANTLY ALTER THE WAY PROVIDERS DELIVER OBESITY TREATMENT AND IMPROVE HEALTH EQUITY.

PROMOTING HEALTHY RELATIONSHIPS AMONG AT-RISK ADOLESCENTS: A FEASIBILITY TRIAL IN THE EMERGENCY DEPARTMENT

FEASIBILITY TRIAL OF HOME-BASED IMMERSIVE NEUROFEEDBACK SELF-REGULATION TRAINING (INSERT) FOR THE PREVENTIVE TREATMENT OF PEDIATRIC MIGRAINE - SUMMARY. MIGRAINE IS A HIGHLY PREVALENT NEUROLOGICAL DISEASE IN CHILDREN FOR WHICH THERE REMAINS A CRITICAL NEED FOR WELL-ACCEPTED, SAFE AND EFFECTIVE PREVENTIVE TREATMENTS TO MITIGATE THE PROGRESSION TOWARD A MORE CHRONIC AND COSTLY CONDITION. CORTICAL EXCITABILITY IS HYPOTHESIZED TO PLAY A KEY ROLE IN MAINTAINING THE VULNERABILITY TO FUTURE MIGRAINE ATTACKS. NEUROFEEDBACK IS A MIND-BODY APPROACH THAT MAY FACILITATE ONE'S ABILITY TO SELF-REGULATE CORTICAL REACTIVITY. HOWEVER, NEUROFEEDBACK IN USUAL CARE SETTINGS IS OFTEN DIFFICULT FOR FAMILIES TO ACCESS RELIABLY, AND THERE IS A LACK OF OUTCOME DATA SPECIFICALLY FOR PEDIATRIC MIGRAINE. IN PRELIMINARY WORK, WE FOUND THAT CHILDREN WITH MIGRAINE RESPONDED POSITIVELY TO A NEUROFEEDBACK-ASSISTED SELF-REGULATION TREATMENT THAT INTEGRATES DATA FROM A WEARABLE ELECTROENCEPHALOGRAM (EEG) HEADBAND INTO CONTENT VIEWED ON AN IMMERSIVE VIRTUAL REALITY HEADSET ( IMMERSIVE NEUROFEEDBACK SELF-REGULATION TRAINING - INSERT). WE HYPOTHESIZE THAT USING THIS INTERVENTION PROSPECTIVELY FROM HOME MAY BE A PRACTICAL AND APPEALING APPROACH FOR CHILDREN TO LEARN TO SELF-MODULATE CORTICAL EXCITABILITY, THEREBY REDUCING THEIR VULNERABILITY TO FUTURE MIGRAINE ATTACKS. THE CURRENT PROPOSAL SEEKS TO FURTHER EVALUATE THIS IDEA BY MEANS OF A PRE-EFFICACY FEASIBILITY TRIAL. SPECIFIC AIMS ARE: (1) TO EVALUATE AND HONE THE ENROLLMENT, RETENTION, RANDOMIZATION, AND OUTCOME ASSESSMENT PROCEDURES PLANNED FOR A FUTURE EFFICACY TRIAL OF THE INSERT INTERVENTION, AND (2) TO DETERMINE THE FEASIBILITY IN CHILDREN WITH MIGRAINE OF COMPLETING THE INSERT TREATMENT PROTOCOL. DURING A BASELINE PHASE, 38 PARTICIPANTS (AGES 10-16 YEARS) DIAGNOSED WITH MIGRAINE WILL COMPLETE PATIENT-REPORTED OUTCOME MEASURES, 4 WEEKS OF MIGRAINE LOGS, AND A LAB-BASED EEG PROTOCOL DESIGNED TO COMPREHENSIVELY EVALUATE BASELINE CORTICAL REACTIVITY. AFTER COMPLETION OF THE BASELINE PHASE, PARTICIPANTS WILL BE RANDOMIZED INTO ONE OF TWO GROUPS: (A) IMMERSIVE NEUROFEEDBACK SELF-REGULATION TRAINING, OR (B) A COMPARATOR GROUP THAT WILL ONLY VIEW IMMERSIVE IMAGERY (WITHOUT GUIDED RELAXATION TRAINING OR NEUROFEEDBACK). BOTH GROUPS WILL RECEIVE TRAINING ON HOW TO COMPLETE THE PROCEDURES FROM HOME, FOLLOWING A SCHEDULE OF THREE SESSIONS PER WEEK (APPROXIMATELY 8 MINUTES PER SESSION) FOR A DURATION OF FOUR WEEKS. PARTICIPANTS WILL COMPLETE OUTCOME MEASURES REMOTELY AT POST-TREATMENT AND AGAIN AT A 3-MONTH FOLLOW-UP TIMEPOINT; THE LAB-BASED EEG PROTOCOL FOR ASSESSING CORTICAL REACTIVITY WILL BE REPEATED AT THE POST-TREATMENT TIMEPOINT. THE PRIMARY TRIAL ENDPOINTS COMPRISE METRICS RELATED TO INTERVENTION FEASIBILITY (I.E., TREATMENT ADHERENCE, ACCEPTABILITY AND TOLERABILITY) AND TRIAL FEASIBILITY (I.E., RATES OF ENROLLMENT AND RANDOMIZATION, RETENTION, AND OUTCOME MEASURE COMPLETION). THESE DATA WILL INFORM WHETHER FURTHER TESTING OF THIS INTERVENTION APPROACH IS WARRANTED, AND IF SO, HOW TO OPTIMIZE PARAMETERS OF THE INTERVENTION AND STUDY PROCEDURES FOR A FUTURE SUCCESSFUL EFFICACY TRIAL. THE PLANNED WORK IS SIGNIFICANT AS IT WILL ENHANCE OUR UNDERSTANDING OF PREVENTING MIGRAINE ATTACKS THROUGH MECHANISM-INFORMED MIND-BODY TREATMENTS, POTENTIALLY EXPANDING PEDIATRIC OPTIONS FOR REDUCING DISEASE PROGRESSION.

HEALTHY HOMES TECH STUDIES

REGULATION OF INVASIVE TROPHOBLAST CELL LINEAGE DEVELOPMENT

REMOTELY DELIVERED CARDIAC REHABILITATION FOR ADOLESCENTS WITH CONGENITAL HEART DISEASE - PROJECT SUMMARY/ABSTRACT ADOLESCENTS WITH CONGENITAL HEART DISEASE [CHD], INCLUDING REPAIR OF TETRALOGY OF FALLOT [TOF], DEXTRO-TRANSPOSI- TION OF THE GREAT VESSELS [D-TGA], OR FUNCTIONALLY UNIVENTRICULAR HEART PHYSIOLOGY [FONTAN], HAVE LOWER CARDIORESPIR- ATORY FITNESS [FIT] COMPARED WITH HEALTHY PEERS. FIT IS A WELL-ESTABLISHED PREDICTOR OF MORBIDITY, QUALITY OF LIFE [QOL], AND HEART TRANSPLANTATION AND IS AMONG THE STRONGEST PREDICTORS OF MORTALITY IN THIS POPULATION. HOWEVER, ADOLESCENTS WITH CHD HAVE SIGNIFICANTLY LOWER FIT WHEN COMPARED TO CARDIO-TYPICAL PEERS, DUE TO ABNORMAL HEMODYNAMICS AS WELL AS LOW DURATIONS AND INTENSITIES OF PHYSICAL ACTIVITY [PA] AND EXERCISE. PEDIATRIC CARDIAC REHABILITATION [CR] PROGRAMS WHICH PRESCRIBE AEROBIC AND RESISTANCE EXERCISE OVER 12-WKS. HAVE DEMONSTRATED IMPROVEMENTS IN FIT FOR PATIENTS WITH CHD WHICH PERSIST MONTHS AFTER COMPLETION OF THE PROGRAM. UNFORTUNATELY, FEW HOSPITALS/CLINICS OFFER CR PROGRAMMING FOR CHILDREN AND ADOLESCENTS DUE TO THE FINANCIAL COSTS OF BUILDING AND MAINTAINING A CR FACILITY, AS WELL AS THE TRAVEL COST, TIME REQUIREMENT, AND BURDEN FOR PARENTS/CAREGIVERS TO TRANSPORT THEIR CHILD TO/FROM A HOSPITAL FOR CR EXERCISE SESSIONS MULTIPLE TIMES PER WEEK. IN-HOME CR REDUCES BARRIERS RELATED TO PATIENT ACCESS AND THE FINANCIAL BURDEN FOR HOSPITALS, THOUGH DATA SUPPORTING THE EFFECTIVENESS OF IN-HOME CR FOR YOUTH IS LIMITED. THE USE OF GROUP VIDEO CONFERENCING TECHNOLOGY VIA TABLET COMPUTER REPRE- SENTS A NOVEL AND POTENTIALLY TRANSFORMATIONAL STRATEGY FOR DELIVERING REAL-TIME, LIVE, SUPERVISED CR TO GROUPS OF ADOLESCENTS WITH CHD IN THEIR HOMES. THE GOAL OF THIS K23 RESEARCH PLAN IS TO EVALUATE THE EFFECTIVENESS OF VIDEO CONFERENCING FOR THE DELIVERY OF REAL-TIME CR TO GROUPS OF ADOLESCENTS WITH CHD IN THEIR HOMES. WE PROPOSE A 12-WK. RANDOMIZED-CONTROLLED CLINICAL TRIAL ASSIGNING 74 ADOLESCENTS [12-19 YEARS OLD] WITH 1 OF 3 CHD DIAGNOSES [FONTAN, TOF, OR D-TGA] TO REMOTE CR [RCR] [IN-HOME, LIVE, REMOTE GROUP EXERCISE, 3-45-MIN SESSIONS/WEEK.] OR ACTIVE CONTROL [IN-HOME, SELF-DIRECTED EXERCISE]. OUR AIMS WILL ASSESS THE EFFECTIVENESS OF THE RCR APPROACH BY COMPARING BETWEEN-GROUP CHANGES [0-12 WEEKS] IN: FIT, CARDIAC FUNCTION, LEAN BODY MASS, AND FRAILTY. EX- PLORATORY AIMS WILL ASSESS BETWEEN GROUP DIFFERENCES [0-12 WEEKS] IN PHYSICAL FUNCTION, QOL, PA SELF-EFFICACY, AND WILL EVALUATE THE IMPACT OF DEMOGRAPHIC CHARACTERISTICS ON PROGRAM PARTICIPATION AND SATISFACTION, AND DAILY PA. WE HYPOTHESIZE THE RCR INTERVENTION WILL ELICIT GREATER IMPROVEMENTS IN EACH OUTCOME COMPARED TO THE CONTROL GROUP. THE PI’S SHORT TERM CAREER DEVELOPMENT GOAL OF ENHANCING KNOWLEDGE, SKILLS, AND EXPERIENCES IN CLINICAL TRIALS RESEARCH, CHD PHYSIOLOGY, AND IMPLEMENTATION AND DISSEMINATION [I&D] OUTCOMES RESEARCH IN YOUTH WITH CHD WILL BE ACCOMPLISHED THROUGH A MULTIDISCIPLINARY TEAM OF MENTORS, FORMAL PROGRAMMING/COURSEWORK, INDEPENDENT STUDY, AND SCIENTIFIC MEETINGS. CAREER DEVELOPMENT TRAINING AND EXPERIENCES AND DATA FROM THE RESEARCH PLAN WILL PREPARE THE PI TO ACCOMPLISH HIS LONG-TERM CAREER GOALS TO 1] ESTABLISH AN INDEPENDENTLY FUNDED RESEARCH PROGRAM CONDUCTING CLINICAL TRIALS TO EVALUATE THE IMPACT OF EXERCISE, FIT ON PHYSICAL AND PSY- CHOSOCIAL FUNCTION IN YOUTH WITH CHD; AND 2] I&D OF CR PROGRAMS ACROSS MULTIPLE SITES.

SEQUENTIAL AND COMPONENT ANALYSES OF MI MECHANISMS WITH COLLEGE DRINKERS

EXPLAINING STATE VARIABILITY IN PEDIATRIC HOSPITALIZATIONS AND REPORTED CHILD MALTREATMENT - CHILDREN FROM FAMILIES WITH LOW SOCIOECONOMIC STATUS (SES) HAVE DIMINISHED HEALTH AND WELL-BEING COMPARED TO CHILDREN FROM FAMILIES WITH HIGHER SES, INCLUDING HIGHER RATES OF HOSPITALIZATIONS AND CHILD MALTREATMENT. SES IS MULTIDIMENSIONAL AND, FOR CHILDREN, INCLUDES FAMILY INCOME. THE INVESTIGATORS RECENTLY DISCOVERED SUBSTANTIAL VARIABILITY ACROSS STATES IN THE RELATIONSHIP OF FAMILY INCOME WITH RATES OF BOTH PEDIATRIC HOSPITALIZATIONS AND CHILD MALTREATMENT. STATE SAFETY NET POLICIES, BY SUPPORTING FAMILIES WITH LOW INCOME, MAY EXPLAIN THIS VARIABILITY. HOWEVER, THERE HAS BEEN NO PREVIOUS RESEARCH ON WHETHER STATE SAFETY NET POLICIES ARE ASSOCIATED WITH HOSPITALIZATIONS FOR EITHER CHILDREN OR ADULTS. ALONG WITH OTHERS, THE INVESTIGATORS DEMONSTRATED AT THE STATE LEVEL THAT SAFETY NET POLICIES ARE ASSOCIATED WITH REDUCED RATES OF CHILD MALTREATMENT, BUT THE PRECISION OF THAT WORK WAS LIMITED BY STATE LEVEL ECOLOGICAL APPROACHES. THEIR PRELIMINARY DATA SUGGESTS THAT THE FORM OF THESE POLICIES — AS EITHER “BOLUS” OR “CONTINUOUS” SUPPORTS — MAY BE A CRITICAL AND MODIFIABLE ASPECT OF THEIR IMPACT. THREE STATE POLICIES ACT AS AN INCOME “BOLUS” FOR FAMILIES VIA ANNUAL ONE-TIME INCOME SUPPORT. IN CONTRAST, STATE MINIMUM WAGE POLICIES ACT AS A “CONTINUOUS” INCOME SUPPORT ACROSS THE YEAR. THE INVESTIGATORS WILL EXPLOIT THE VARIABILITY IN THESE STATE POLICIES TO DETERMINE THEIR ASSOCIATIONS WITH TWO DIMENSIONS OF CHILD WELL-BEING: PHYSICAL AND MENTAL HEALTH (HOSPITALIZATIONS) AND ADVERSE CHILDHOOD EXPERIENCES (CHILD MALTREATMENT). THEIR APPROACH OVERCOMES THE LIMITATIONS OF PRIOR STATE LEVEL ECOLOGICAL ANALYSES, ALLOWING THEM TO EXAMINE THE IMPACT OF THE POLICIES AT THE LEVEL OF CENSUS PUBLIC-USE MICRODATA AREAS (PUMAS) AND COUNTIES. THEY HAVE THREE SPECIFIC AIMS: (1) CREATE A PUBLICLY AVAILABLE DATASET OF FOUR STATE SAFETY NET POLICIES THAT ADHERES TO THE HIGHEST STANDARDS OF LEGAL RESEARCH IN ALL 50 STATES FROM 2000- 2020. THEN, TO DETERMINE IF STATE VARIABILITY IN THREE “BOLUS” POLICIES AND ONE “CONTINUOUS” POLICY ARE ASSOCIATED WITH (2) ALL PEDIATRIC HOSPITALIZATIONS BY MERGING 225 AHRQ HCUP STATE INPATIENT DATABASES FROM ALL STATES THAT HAVE THE PATIENT’S HOME ZIP CODE (N=15) EVERY YEAR DURING A 15-YEAR PERIOD (2005-2019) AND (3) ALL REPORTS OF CHILD MALTREATMENT INVESTIGATED BY CHILD PROTECTIVE SERVICES FROM ALL 50 STATES IN THE NATIONAL CHILD ABUSE AND NEGLECT DATA SYSTEM (NCANDS) EVERY YEAR DURING A 15-YEAR PERIOD (2005-2019). THE STUDY WILL ALSO EXPLORE THE RELATIONSHIP OF THESE POLICIES WITH PEDIATRIC ED VISITS AND SPECIFIC DIAGNOSES WHICH MAY BE MORE SENSITIVE TO THE POLICIES’ EFFECTS. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE IT WILL FILL A CRITICAL KNOWLEDGE GAP ON THE RELATIONSHIPS OF SPECIFIC SAFETY NET POLICIES WITH PEDIATRIC HOSPITALIZATIONS AND MALTREATMENT. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE IT IS THE FIRST STUDY TO EXAMINE THE IMPACTS OF SAFETY NET POLICIES ON HOSPITALIZATIONS, THE FIRST TO EXAMINE THE FORM OF SUCH POLICIES (I.E., BOLUS VS. CONTINUOUS), AND IT OVERCOMES IMPRECISE STATE-LEVEL METHODOLOGICAL LIMITATIONS THROUGH THE EXAMINATION OF OUTCOMES AT THE PUMA AND COUNTY LEVELS.

GENOMIC- AND ONTOGENY-LINKED DOSE INDIVIDUALIZATION AND CLINICAL OPTIMIZATION FOR KIDS

THE IMPACT OF PUBLIC REPORTING ON PROCEDURAL OUTCOMES FOLLOWING CONGENITAL HEART SURGERY - PROJECT SUMMARY/ABSTRACT NATALIE JAYARAM, MD MSB IS AN ASSISTANT PROFESSOR OF PEDIATRICS AT THE UNIVERSITY OF MISSOURI-KANSAS CITY AND A FACULTY MEMBER IN THE DEPARTMENT OF PEDIATRICS AND DIVISION OF CARDIOLOGY AT CHILDREN’S MERCY HOSPITAL IN KANSAS CITY, MISSOURI. AS A PEDIATRIC CARDIOLOGIST AND HEALTH SERVICES RESEARCHER, HER LONG-TERM CAREER GOALS ARE TO IMPROVE THE CARE OF PEDIATRIC PATIENTS WITH CONGENITAL HEART DISEASE (CHD) BY CONTRIBUTING TO THE SCIENCE OF QUALITY ASSESSMENT, BY EXAMINING THE EFFECTIVENESS OF POLICY-BASED INITIATIVES ON CARE, AND BY PARTNERING DIRECTLY WITH PATIENTS TO FACILITATE CHANGES IN CARE. THE GOAL OF THE CURRENT PROJECT IS TO STUDY PUBLIC REPORTING FOR CONGENITAL HEART SURGERY (CHS). PUBLIC REPORTING IS DESIGNED TO PROVIDE HEALTHCARE CONSUMERS WITH OUTCOME DATA FOR A GIVEN PROVIDER OR INSTITUTION. PROPONENTS OF PUBLIC REPORTING ADVOCATE FOR TRANSPARENT DISCLOSURE OF HEALTH OUTCOMES DATA AND CONTEND THAT PUBLIC REPORTING RESULTS IN IMPROVED OUTCOMES.1-4 CRITICS OF PUBLIC REPORTING CITE EVIDENCE THAT PUBLIC REPORTING MAY NOT SUBSTANTIALLY IMPROVE OUTCOMES AND COULD RESULT IN UNINTENDED CONSEQUENCES, INCLUDING RISK AVOIDANCE PRACTICES.5-14 FORMAL STUDY REGARDING THE IMPACT OF PUBLIC REPORTING ON OUTCOMES FOR CHS HAS NEVER BEEN PERFORMED. THE HIGHLY SPECIALIZED NATURE OF CHD CARE, WITH RELATIVELY LESS LOCAL OR REGIONAL COMPETITION COMPARED TO MORE PREVALENT CONDITIONS (E.G. ADULT CARDIOVASCULAR DISEASE) BUT WITH PATIENTS WILLING TO TRAVEL TO SEEK THE ‘BEST’ CARE,15 SUGGEST THAT PUBLIC REPORTING FOR CHS WARRANTS INDEPENDENT INVESTIGATION. THE PRIMARY AIMS OF THE PROPOSED PROJECT ARE: 1) TO EVALUATE WHETHER, AS AN UNINTENDED CONSEQUENCE OF PUBLIC REPORTING, THERE IS A SHIFT IN PATIENT CASE MIX, SUGGESTING THAT CENTERS COULD BE AVOIDING SURGICAL INTERVENTION IN PATIENTS AT HIGHEST RISK FOR POOR OUTCOME 2) TO EVALUATE THE ASSOCIATION BETWEEN IMPLEMENTATION OF PUBLIC REPORTING FOR CHS AND SURGICAL OUTCOMES, AND 3) TO BETTER UNDERSTAND THE TYPE AND FORMAT OF DATA THAT CHD PATIENTS AND FAMILIES WOULD FIND MOST MEANINGFUL TO HELP THEM MAKE INFORMED DECISIONS REGARDING CARE. STUDY AIMS 1 AND 2 OF THE PROJECT PROPOSE OBTAINING DATA FROM THE STATE INPATIENT DATABASE IN ORDER TO STUDY THE ASSOCIATION BETWEEN PUBLIC REPORTING, INSTITUTIONAL CASE MIX, AND SURGICAL OUTCOMES AT CENTERS THROUGHOUT THE US PERFORMING CHS. STUDY AIM 3 PROPOSES FOCUS GROUPS INVOLVING CHD PATIENTS AND CAREGIVERS TO GAIN AN IMPROVED UNDERSTANDING OF THEIR PREFERENCES WITH REGARDS TO PUBLIC REPORTING. TOGETHER WITH HER MENTORSHIP TEAM, DR. JAYARAM HAS WORKED TO CREATE A CAREER DEVELOPMENT PLAN THAT WILL PROVIDE HER WITH ADDITIONAL TRAINING, EDUCATION, AND EXPERIENCE IN THE AREAS OF ADVANCED STATISTICAL METHODOLOGY, EXPERIENCE IN WORKING WITH ADMINISTRATIVE DATA, AND FORMAL TRAINING IN QUALITATIVE RESEARCH AND PATIENT ENGAGEMENT. OVERALL, THE SKILLS LEARNED FROM THIS PROJECT AND EDUCATIONAL PLAN COUPLED WITH AN OUTSTANDING MENTORSHIP TEAM WILL ALLOW DR. JAYARAM TO ACHIEVE HER ULTIMATE GOAL OF BECOMING AN INDEPENDENT INVESTIGATOR AND LEADER IN THE FIELD OF PEDIATRIC CARDIOVASCULAR OUTCOMES RESEARCH.

REDUCING REPRODUCTIVE HEALTH DISPARITIES AMONG LATINX YOUTH LIVING IN RURAL COMMUNITIES - PROJECT SUMMARY/ABSTRACT TEENAGE PREGNANCY (TP) IS LARGELY UNINTENDED AND CAN LEAD TO ADVERSE HEALTH, EDUCATIONAL, AND ECONOMIC OUTCOMES FOR BOTH THE MOTHER AND THE CHILD. ALTHOUGH TP RATES HAVE DECLINED IN THE U.S. OVER SEVERAL DECADES, DISPARITIES PERSIST. BIRTH RATES AMONG LATINX TEENS IN THE U.S. ARE 1.5 TIMES HIGHER THAN THE NATIONAL AVERAGE AND MORE THAN 2 TIMES HIGHER IN RURAL AREAS COMPARED TO RURAL WHITE TEENS. LATINX IMMIGRANTS SETTLING IN RURAL AREAS REPRESENT THE LARGEST AND FASTEST GROWING MINORITY GROUP IN RURAL AMERICA. BEST PRACTICES FOR IMPLEMENTING EVIDENCE-BASED TP PREVENTION PROGRAMS IN THESE UNIQUE COMMUNITIES REMAIN LARGELY UNKNOWN. THUS, A CRITICAL NEED EXISTS TO DEVELOP AND EVALUATE A SET OF RESPONSIVE INTERVENTIONS TAILORED SPECIFICALLY TO THESE VULNERABLE TEENS. THE TRANSCREATION IMPLEMENTATION SCIENCE FRAMEWORK HAS BEEN USED TO ADDRESS OTHER HEALTH DISPARITIES AMONG LATINX RURAL COMMUNITIES. BASED ON OUR PREVIOUS WORK DEMONSTRATING THE NEED FOR TP PREVENTION INTERVENTIONS TAILORED TO MEET NEEDS IN THIS UNIQUE POPULATION, WE WILL USE THIS FRAMEWORK TO BUILD UPON CUIDATE (TAKE CARE), AN EVIDENCE-BASED, CULTURALLY RESPONSIVE INTERVENTION THAT HAS BEEN SHOWN TO DECREASE SEXUAL RISK BEHAVIORS AMONG URBAN LATINX YOUTH. DR. BARRAL, AN ADOLESCENT MEDICINE PHYSICIAN AND CANDIDATE FOR THIS CAREER DEVELOPMENT AWARD, IS COMMITTED TO A PATIENT-ORIENTED CLINICAL RESEARCH CAREER TARGETING INTERVENTIONS TO REDUCE REPRODUCTIVE HEALTH DISPARITIES. HER FIVE-YEAR CAREER DEVELOPMENT PLAN INCLUDES STRUCTURED MENTORING AND FORMAL DIDACTICS TO ADDRESS CRITICAL GAPS IN HER TRAINING THROUGH ACQUISITION OF EXPERTISE IN THEORIES OF BEHAVIOR CHANGE, CLINICAL TRIALS FOR ADOLESCENT BEHAVIORAL RESEARCH, AND COMMUNITY ENGAGED RESEARCH. THE PROPOSED STUDY COMPLEMENTS OTHER TRAINING ACTIVITIES BY ENABLING HANDS-ON EXPERIENCE IN INTERVENTION CO-DEVELOPMENT AND FEASIBILITY TRIAL. FOLLOWING IDENTIFICATION OF KEY FACTORS NEEDED FOR THE DEVELOPMENT OF AN ACCEPTABLE TP PREVENTION INTERVENTION FOR RURAL LATINX TEENS, DR BARRAL WILL USE THE TRANSCREATION FRAMEWORK TO CO-DEVELOP AN INTERVENTION THAT BEST FITS THE COMMUNITY’S UNIQUE NEEDS AND CONTEXT. DR. BARRAL WILL CONDUCT A ONE ARM FEASIBILITY TRAIL TO EVALUATE ACCEPTABILITY AND PRACTICALITY OF THE CO-CREATED INTERVENTION. THE PROPOSED INVESTIGATION WILL IMPROVE SCIENTIFIC KNOWLEDGE IN DISPARITIES IN TP PREVENTION BY ADDRESSING THE INTERSECTIONALITY AND CONTEXT OF TP OCCURRING AMONG EMERGING IMMIGRANT LATINX POPULATIONS EMBEDDED IN RURAL COMMUNITIES. SHE WILL COMPREHENSIVELY INCORPORATE COMMUNITY AND STAKEHOLDER GUIDANCE INTO A CO-CREATED AND NOVEL INTERVENTION THAT OPTIMALLY FITS LOCAL NEEDS OF THESE UNIQUE NEW IMMIGRANT POPULATIONS. STUDY FINDINGS WILL INFORM THE DEVELOPMENT OF A LARGER HYBRID EFFICACY IMPLEMENTATION STUDY, SUPPORTED BY AN R01 SUBMISSION DURING THE K23 AWARD PERIOD. THIS TRAINING AND RESEARCH PLAN ARE CONSISTENT WITH THE MISSION OF THE NATIONAL INSTITUTES OF HEALTH AND THE NATIONAL INSTITUTE ON MINORITY HEALTH AND HEALTH DISPARITIES.

CHARACTERIZATION OF THE ROLE OF HISTAMINE IN CHILDREN WITH ASTHMA

EFFECT OF OBESITY ON PANTOPRAZOLE PHARMACOKINETICS AND PHARMACODYNAMICS IN CHILDREN

ENHANCING COMMUNICATION ON RELATIONSHIP PRESERVATION, SAFER CONCEPTION AND PREP TO PROMOTE HIV TESTING - PROJECT SUMMARY OPTIMIZING UPTAKE OF HIV TESTING IS CRITICAL TO MEETING 95-95-95 GOALS IN SUB-SAHARAN AFRICA. AS 30% OF NEW INFECTIONS IN OCCUR WITHIN MARRIED OR COHABITATING COUPLES, MAXIMIZING TESTING AMONG INDIVIDUALS WHO ARE OR MAY SOMEDAY BE IN SERIOUS HETEROSEXUAL RELATIONSHIPS HAS BEEN IDENTIFIED AS ONE OF THE MOST COST-EFFECTIVE STRATEGIES TO CURB THE EPIDEMIC. CHILDBEARING IS HIGHLY VALUED THROUGHOUT SUB-SAHARAN AFRICA, AND FEARS OF RELATIONSHIP DISSOLUTION AND LOSS OF THE ABILITY TO HAVE CHILDREN REMAIN SIGNIFICANT BARRIERS TO HIV TESTING. THE EXPANDING AVAILABILITY OF PRE-EXPOSURE PROPHYLAXIS (PREP) PRESENTS AN OPPORTUNITY TO COUNTER THESE FEARS WITH STRATEGIC COMMUNICATION (NOT-MH-21-105) THAT REASSURE COUPLES OF THEIR ABILITY TO HAVE A HEALTHY FAMILY EVEN IF ONE OR BOTH MEMBERS ARE HIV POSITIVE. OUR LONG-TERM OBJECTIVE IS TO LEVERAGE THE GROWING AVAILABILITY OF PREP TO DETERMINE IF AND HOW A COMMUNICATION STRATEGY FOCUSED ON RELATIONSHIP PRESERVATION AND SAFER CONCEPTION CAN INCREASE TESTING AND ENTRY INTO TREATMENT (ANTIRETROVIRAL THERAPY) OR PREVENTION (PREP) AMONG PARTNERED INDIVIDUALS IN UGANDA. WE RECENTLY SUCCESSFULLY PILOTED THIS COMMUNICATION STRATEGY WITHIN UGANDA’S ASSISTED PARTNER NOTIFICATION PROGRAM (APN). IN THIS R34, WE WILL: (1) CONDUCT FORMATIVE RESEARCH TO EXPAND THE COMMUNICATION STRATEGY INTO A MULTI-COMPONENT INTERVENTION WITH BROADER REACH; AND (2) CONDUCT A PILOT TRIAL OF THE INTERVENTION, PREPING HEALTHY FAMILIES. TO ACHIEVE AIM 1, WE WILL WORK WITH A COMMUNITY ADVISORY BOARD (CAB) OF PROVIDERS TO A) CREATE COMMUNICATION MATERIALS (BROCHURES, SCRIPTS) AND COUNSELING PROTOCOLS TAILORED TO CLIENTS AND PARTNERS ACROSS THE ARRAY OF COUPLES’ TESTING PATHWAYS IN APN AND ANTENATAL CARE (ANC). AS CAB PROVIDERS PILOT MATERIALS AND TRACKING SYSTEMS WITH CLIENTS AND PARTNERS DURING THIS DEVELOPMENT PHASE, STUDY STAFF WILL CONDUCT FIELD OBSERVATIONS AND QUALITATIVE INTERVIEWS FOCUSED ON FEASIBILITY AND ACCEPTABILITY, INFORMING REVISED INTERVENTION MATERIALS. TO ACHIEVE AIM 2, WE WILL COLLECT BASELINE DATA AT APN AND ANC CLINICS WITHIN TWO LARGE PUBLIC HEALTHCARE FACILITIES OVER NINE MONTHS. SITES WILL THEN BE RANDOMIZED TO IMPLEMENT PREPING HEALTHY FAMILIES OR THEIR EXISTING COMMUNICATION APPROACH (USUAL CARE) OVER THE NEXT NINE MONTHS. WE WILL COLLECT MIXED-METHODS DATA ON FEASIBILITY AND ACCEPTABILITY THROUGH INTERVENTION TRACKING IN APN/ANC REGISTERS, CLIENT EXIT SURVEYS, AND QUALITATIVE INTERVIEWS WITH CLIENTS, PARTNERS AND PROVIDERS. THROUGH REGISTER EXTRACTION, WE WILL EXAMINE LIMITED EFFICACY ON OUTCOMES THAT WOULD BE RELEVANT TO A LARGER TRIAL (PARTNER HIV TESTING, CLIENT SERVICE UPTAKE INITIATION OF PREP/ART), AND EXPLORE POTENTIAL MODERATORS. OVERALL, RESULTS WILL YIELD IMPORTANT INSIGHTS IN A PROMISING NEW COMMUNICATION STRATEGY (NOT-MH-21-105) THAT MAY CONNECT MORE INDIVIDUALS TO THE HIV CASCADES OF CARE FOR TREATMENT OR PREVENTION AND PREPARE US FOR A LARGE-SCALE, CLUSTER RANDOMIZED CONTROLLED TRIAL TO DETERMINE IMPACT ON TESTING AND INITIATION OF PREP/ART.

STANDARDIZING ANTIBIOTIC PRESCRIBING FOR CHILDREN HOSPITALIZED WITH INFECTIONS USING NOVEL METRICS AND ELECTRONIC CLINICAL DECISION SUPPORT TOOLS - PROJECT SUMMARY/ABSTRACT ANTIBIOTICS ARE ONE OF THE MOST PRESCRIBED CLASSES OF MEDICATIONS FOR CHILDREN, YET 30-50% OF ALL ANTIBIOTICS ARE INAPPROPRIATELY PRESCRIBED OR COMPLETELY UNNECESSARY. DESPITE THE AVAILABILITY OF NATIONALLY ENDORSED TREATMENT GUIDELINES AND THE EXPANSION OF ANTIMICROBIAL STEWARDSHIP PROGRAMS, DEVIATION FROM EVIDENCE-BASED PRACTICES OCCURS ADDING TO PRESCRIBING VARIABILITY. INDIVIDUAL PROVIDER CHARACTERISTICS INCLUDING KNOWLEDGE DEFICITS ARE KNOWN TO CONTRIBUTE TO VARIABILITY IN ANTIBIOTIC SELECTION. HOWEVER, OTHER FACTORS, INCLUDING USABILITY OF AVAILABLE PRESCRIBING RESOURCES, LOCAL CULTURE, SOCIAL PRESSURES, AND THE WORK ENVIRONMENT LIKELY ALSO CONTRIBUTE TO THIS VARIATION, BUT HAVE RECEIVED LESS ATTENTION. DEVELOPING A RICH UNDERSTANDING OF SOURCES OF ANTIBIOTIC PRESCRIBING VARIABILITY AMONG FRONT-LINE PROVIDERS CAN INFORM USABILITY AND WORKFLOW INTEGRATION TO MAXIMIZE UPTAKE OF PRESCRIBING INTERVENTIONS. AS MOBILE ELECTRONIC CLINICAL DECISION SUPPORT (ECDS) TOOLS HAVE THE POTENTIAL TO REACH BROAD AUDIENCES AND TO INTEGRATE THE END-USERS (I.E., FRONT-LINE PRESCRIBERS) AND USER ENVIRONMENT (I.E., BUSY INPATIENT WARD) THEY MAY SERVE AS POWERFUL TOOLS IN THE DISSEMINATION OF EVIDENCE-BASED ANTIBIOTIC PRACTICES. DR. MARKHAM, A PEDIATRIC HOSPITALIST PHYSICIAN AND THE CANDIDATE FOR THIS CAREER DEVELOPMENT AWARD, TOGETHER WITH A STRONG INTERDISCIPLINARY MENTORSHIP TEAM HAS CREATED A 5-YEAR CAREER DEVELOPMENT PLAN WHICH INCLUDES STRUCTURED MENTORING, COMPLETION OF TRAINING IN HUMAN FACTORS SCIENCE AND THE APPLICATION OF QUALITATIVE METHODS WITHIN SYSTEMS ANALYSES, IMPLEMENTATION SCIENCE, AND CLINICAL INFORMATICS. THIS UNIQUE COMBINATION OF TRAINING ACTIVITIES IN COMBINATION WITH DR. MARKHAM’S CLINICAL EXPERTISE WILL PLACE DR. MARKHAM AT THE FOREFRONT OF ECDS TOOL IMPLEMENTATION IN PEDIATRICS. ACQUISITION OF THESE SKILLS WILL ESTABLISH A PATHWAY FOR DR. MARKHAM TO BECOME A LEADER IN ADDRESSING THE QUALITY AND SAFETY OF PEDIATRIC HOSPITALIZATIONS THROUGH THE DEVELOPMENT AND IMPLEMENTATION OF NOVEL ECDS TOOLS AND INTERVENTIONS TARGETING OTHER HIGH-PRIORITY DIAGNOSES AFFECTING CHILDREN. DR. MARKHAM'S TRAINING ACTIVITIES WILL BE COMPLEMENTED BY AN INNOVATIVE PROJECT THAT WILL FACILITATE PRACTICAL APPLICATION OF THESE NEW SKILLS. THE GOALS OF THE PROJECT ARE TO: (1) MEASURE AND UNDERSTAND INTER- AND INTRA- HOSPITAL ANTIBIOTIC PRESCRIBING VARIABILITY FOR CHILDREN HOSPITALIZED WITH COMMON INFECTIONS; (2) UTILIZE USABILITY TESTING AND PSYCHOMETRIC ANALYSIS TO EVALUATE THE IMPACT OF AN ECDS TOOL TO DELIVER EVIDENCE-BASED ANTIBIOTIC RECOMMENDATIONS WITHIN SIMULATED SCENARIOS; AND (3) PERFORM A PILOT IMPLEMENTATION STUDY TO EXPLORE BARRIERS AND FACILITATORS TO WIDESCALE DEPLOYMENT OF A USABILITY INFORMED ANTIBIOTIC ECDS TOOL. FINDINGS FROM THIS STUDY WILL BE USED TO PRIORITIZE INFECTIONS IN NEED OF STANDARDIZATION OF TREATMENT, TO TRACK ANTIBIOTIC STANDARDIZATION IMPROVEMENT OVER TIME, AND TO INFORM FUTURE IMPLEMENTATION STUDIES EXAMINING THE IMPACT OF ECDS TOOLS ON STANDARDIZATION OF ANTIBIOTIC USE AND PATIENT OUTCOMES. THE ULTIMATE GOAL OF THIS PROPOSAL IS TO PROVIDE DR. MARKHAM WITH THE SKILLS TO EFFECTIVELY ENHANCE HEALTHCARE SYSTEMS BY IMPROVING THE ACCURACY AND EFFICIENCY WITH WHICH HEALTHCARE PROFESSIONALS CAN PROVIDE HIGH-QUALITY, EVIDENCE-BASED CARE TO CHILDREN.

ENHANCED INTERVENTION TO IMPROVE ADOLESCENT OUTCOMES: A CLINICAL TRIAL

DEVELOPMENT OF A PHARMACODYNAMIC BIOMARKER OF OPIOID ANTAGONISM IN ADOLESCENTS WITH EATING DISORDERS - PROJECT SUMMARY THE OVERALL GOAL OF THIS 4-YEAR K23 PROPOSAL IS TO SUPPORT DR. STEPHANI STANCIL TO BECOME AN INDEPENDENT INVESTIGATOR IN THE FIELD OF PHARMACODYNAMIC BIOMARKER DEVELOPMENT TO SUPPORT QUANTITATIVE EARLY-STAGE DRUG DEVELOPMENT IN PEDIATRIC NEUROPSYCHOPHARMACOLOGY, SPECIFICALLY EATING DISORDER THERAPEUTICS. THIS PROPOSAL ALIGNS WITH NIMH’S PRIORITIZATION OF AND THE NATIONAL ADVISORY MENTAL HEALTH COUNCIL WORKGROUP RECOMMENDATIONS FOR QUANTITATIVE PHARMACOLOGIC EARLY-STAGE TRIALS, PARTICULARLY IN VULNERABLE POPULATIONS. EATING DISORDERS (ED), INCLUDING BULIMIA NERVOSA, ANOREXIA NERVOSA-BINGE/PURGE AND BINGE EATING DISORDER, ARE CHARACTERIZED BY BINGE EATING AND PURGE BEHAVIORS (E.G., VOMITING), TYPICALLY BEGIN IN ADOLESCENCE, AND AFFECT UP TO 5% OF TEENS. EDS ARE ASSOCIATED WITH SIGNIFICANT MORBIDITY (E.G., MALNUTRITION, CARDIAC COMPROMISE, DEVELOPMENT OF SUBSTANCE USE DISORDER), HAVE THE HIGHEST MORTALITY RATE OF ANY PSYCHIATRIC ILLNESS AND ARE NOT RESPONSIVE TO CURRENT PHARMACOTHERAPY. THIS CAREER DEVELOPMENT PROPOSAL WILL LEVERAGE DR. STANCIL’S CLINICAL PHARMACOLOGY EXPERTISE IN DRUG EXPOSURE INQUIRY AND EXPAND HER CAREER FOCUS TO CLINICAL NEUROPSYCHOPHARMACOLOGY TO ENABLE HER TO DEFINE CENTRAL NERVOUS SYSTEM DRUG ACTION IN CHILDREN AND ADOLESCENTS. THE COMPREHENSIVE CAREER DEVELOPMENT PLAN (CDP) CONTAINS THREE TRAINING OBJECTIVES: 1) NEUROIMAGING, 2) PEDIATRIC RANDOMIZED CLINICAL TRIALS, AND 3) EXPOSURE-RESPONSE MODELING, TO TRANSITION DR. STANCIL INTO A SUCCESSFUL, INDEPENDENT INVESTIGATOR. THE CDP’S STRUCTURED MENTORING, DIDACTIC TRAINING AND EXPERIENTIAL LEARNING WILL BE APPLIED TO A RANDOMIZED, PLACEBO-CONTROLLED CROSSOVER TRIAL IN ADOLESCENTS WITH BINGE/PURGE ED TO ACCOMPLISH THE FOLLOWING AIMS: AIM 1) DETERMINE THE SENSITIVITY OF A NEUROIMAGING BIOMARKER TO REWARD SYSTEM MODULATION BY OPIOID ANTAGONISM, AIM 2) DEVELOP AN EXPOSURE-RESPONSE MODEL FOR NALTREXONE. DR. STANCIL’S CAREER DEVELOPMENT AND RESEARCH WILL TAKE PLACE IN A HIGHLY FAVORABLE AND WELL- SUITED ENVIRONMENT THAT INCLUDES A TERTIARY ACADEMIC CHILDREN’S MEDICAL CENTER, CHILDREN’S RESEARCH INSTITUTE, JOINT DEPARTMENT OF PEDIATRICS SHARED BY TWO REGIONAL MEDICAL SCHOOLS, AN OUTSTANDING IMAGING CENTER AND THE FRONTIERS CTSA. AFTER COMPLETING THIS PROJECT, DR, STANCIL WILL HAVE ADVANCED THE FIELD OF PHARMACODYNAMIC BIOMARKER DEVELOPMENT IN PEDIATRIC MENTAL HEALTH AND GENERATED DATA TO SUPPORT AN R01 APPLICATION TO ESTABLISH THE VALIDITY OF THE PROPOSED PHARMACODYNAMIC BIOMARKER. SHE WILL BE WELL-POSITIONED TO BECOME A LEADER IN THE FIELD OF PHARMACODYNAMIC BIOMARKER DEVELOPMENT AND EXPOSURE-RESPONSE LINKAGE TO DE-RISK EARLY-STAGE DRUG DEVELOPMENT AND FACILITATE A PRECISION THERAPEUTICS APPROACH TO PEDIATRIC NEUROPSYCHOPHARMACOLOGY.

USE OF A MEDICAL DATA WAREHOUSE IN A LABORATORY QUALITY IMPROVEMENT INITIATIVE THAT LINKS TO PATIENT AND SYSTEM OUTCOMES - 2016

RURAL ACCESS TO EMERGENCY DEVICES

RURAL HEALTH NETWORK DEVELOPMENT PROGRAM

AN IMMERSIVE EXPERIENCE IN MEDICAL GENOMICS

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - ADDRESS OF PROJECT: 44 OHIO STREET, BANGOR, ME 04401 APPLICANT ADDRESS: 175 FORE RIVER PARKWAY, PORTLAND, ME 04102 PROJECT DIRECTOR NAME: MELISSA SKAHAN CONTACT PHONE NUMBERS (OFFICE,): 1 207 879 3000 EMAIL ADDRESS: SKAHANM@NORTHERNLIGHT.ORG PROJECT WEBSITE ADDRESS: HTTPS://NORTHERNLIGHTHEALTH.ORG/MCAULEY-RESIDENCE APPLICANT WEBSITE ADDRESS: HTTPS://NORTHERNLIGHTHEALTH.ORG/MERCY-HOSPITAL LIST ALL GRANT PROGRAM FUNDS REQUESTED IN THE APPLICATION, IF APPLICABLE: CONGRESSIONALLY DIRECTED SPENDING (CDS): CONSTRUCTION PROJECTS (HRSA-22-134) - $510,000 THE MCAULEY RESIDENCE, IS A LEASED SPACE THAT HOUSES WOMEN WITH SUBSTANCE USE DISORDER (SUD), AND THEIR YOUNG CHILDREN, IN A THERAPEUTIC ENVIRONMENT. THE BUILDING AND GROUNDS ARE LOCATED AT 44 OHIO STREET IN BANGOR, MAINE. THIS PROJECT WILL INVOLVE THE IMPROVEMENT AND RECONFIGURATION OF THE INTERIOR SPACES OF THE MCAULEY RESIDENCE AS WELL AS MODIFICATIONS AND BUILDING REPAIR TO THE EXTERIOR OF THE RESIDENCE AND GROUNDS. CONSTRUCTION WILL OCCUR IN THE MAIN RESIDENCE, PORCH AREA, AND EXTERIOR GROUNDS. EXTERIOR ACTIVITIES WILL INCLUDE THE ADAPTATION OF EXISTING OUTDOOR SPACE TO ENHANCE OUTDOOR THERAPEUTIC ACTIVITIES FOR CHILDREN, THE INSTALLATION OF AN AMERICANS WITH DISABILITIES ACT (ADA) ACCESSIBLE RAMP FOR STROLLERS AND WHEELCHAIRS, A FENCED AND FALL-SAFE PLAYGROUND WITH A CLIMBER, A MUSIC STATION, AND A SWING-SET INCLUDING ADA AND AGE-APPROPRIATE SWINGS. ADDITIONAL EXTERNAL REPAIRS WILL INCLUDE THERMAL AND MOISTURE PROTECTION TO TWO SECTIONS OF BUILDING ROOF (LIVING ROOM AND PORCH. INTERIOR IMPROVEMENTS AND RENOVATIONS WILL INCLUDE ADAPTATIONS TO PROVIDE SAFE SPACES FOR THERAPEUTIC INTERVENTIONS, INCLUDING PLAY THERAPY AND ART THERAPY, FOR CHILDREN LIVING AT THE MCAULEY RESIDENCE. ADDITIONAL INTERIOR SPACE WILL BE RENOVATED AND EQUIPPED WITH WORKSTATIONS TO PROVIDE AN ACCESSIBLE FAMILY LEARNING LAB FOR WOMEN ENGAGED IN HIGHER EDUCATION AND FOR CHILDREN TO ACCESS REMOTE LEARNING ACTIVITIES. I NTERIOR FINISHES INCLUDING WINDOW TREATMENTS, DOORS, PAINTING, AND ACCESS CONTROLS WILL SUPPORT THE ACCESSIBILITY, UTILITY, COMFORT, AND SAFETY OF RESIDENTS AND STAFF. ALL RENOVATIONS WILL BE MADE TO COMPLY WITH ACCESSIBILITY REQUIREMENTS UNDER THE ADA AND LOCAL BUILDING CODES. THE PROJECT WILL ADDRESS HEATING, VENTILATION, AND AIR-CONDITIONING (HVAC) MODIFICATIONS VIA THE INSTALLATION OF HEAT-PUMPS (AND ASSOCIATED WIRING). ALL CDS FUNDING WILL BE UTILIZED SOLELY TO MAKE INTERIOR AND EXTERIOR RENOVATIONS AND SPACE DEVELOPMENT IN ORDER TO DELIVER FAMILY LEARNING OPPORTUNITIES FOR WOMEN WITH SUD AND THERAPEUTIC INTERVENTIONS FOR CHILDREN. THE POTENTIAL FOR MCAULEY’S TWO GENERATIONAL PROGRAM TO EXPAND ONSITE LEARNING LAB OPPORTUNITIES AS WELL AS PROVIDE ART AND PLAY THERAPY WITH NEW INDOOR AND OUTDOOR SPACES WILL ADD SIGNIFICANT VALUE TO FAMILIES AS THEY PURSUE REUNIFICATION, TRAUMA-INFORMED CARE, AND RECOVERY.

BRIEF MENTAL HEALTH TREATMENT FOR PARENTS OF CHILDREN WITH PEDIATRIC FEEDING DISORDER - PROJECT SUMMARY PARENT MENTAL HEALTH (MH) PROBLEMS ARE AN UNADDRESSED BARRIER TO EFFECTIVE TREATMENT OF PEDIATRIC FEEDING DISORDER (PFD). PFD AFFECTS UP TO ONE-THIRD OF YOUNG CHILDREN AND IS CHARACTERIZED BY SEVERELY RESTRICTED VOLUME OR VARIETY OF FOOD INTAKE. MANY CHILDREN DO NOT RESPOND TO OUR MOST EFFECTIVE TREATMENTS, AND ADDRESSING BARRIERS TO EFFECTIVE TREATMENT IS CRITICAL TO IMPROVING OUR ABILITY TO TREAT PFD. WITHOUT EFFECTIVE TREATMENT, PFD CAN LEAD TO MALNUTRITION AND HIGH HEALTHCARE UTILIZATION. UP TO 40% OF PARENTS OF CHILDREN WITH PFD EXPERIENCE MENTAL HEALTH (MH) PROBLEMS SUCH AS DEPRESSION, ANXIETY, AND PARENTING STRESS, WHICH IS FAR GREATER THAN RATES IN PARENTS OF HEALTHY CHILDREN. PARENT MH PROBLEMS ARE ASSOCIATED WITH SUBOPTIMAL CHILD FEEDING PRACTICES AND POOR ADHERENCE TO TREATMENT RECOMMENDATIONS. POSITIVE, NON-COERCIVE, PARENT-CHILD MEALTIME INTERACTIONS ARE PARAMOUNT TO EFFECTIVE TREATMENT OF PFD. HOWEVER, PARENT MH PROBLEMS CONTRIBUTE TO INCREASED STRESS AT MEALS AND PARENTS OFTEN REPORT HAVING “BATTLES” WITH THEIR CHILDREN OVER EATING, RATHER THAN ENGAGING IN RECOMMENDED STRATEGIES. DESPITE THE WELL-KNOWN IMPACT OF PARENT MH PROBLEMS ON EFFECTIVE PFD TREATMENT, IT IS EXTREMELY RARE THAT PARENT MH IS ADDRESSED IN PFD CARE. NO MH TREATMENTS HAVE BEEN TESTED WITH PARENTS OF CHILDREN WITH PFD, AND THERE ARE NO UNIVERSAL PFD STANDARDS OF CARE TO ENCOURAGE OR GUIDE PARENT MH TREATMENT IMPLEMENTATION. WITHOUT IDENTIFYING AN EFFECTIVE AND EFFICIENT (I.E., BRIEF) MH TREATMENT FOR PARENTS OF CHILDREN WITH PFD, OUR MOST EFFECTIVE PFD TREATMENTS WILL CONTINUE TO FAIL MANY CHILDREN. FOCUSED ACCEPTANCE AND COMMITMENT THERAPY (FACT) IS IDEAL TO ADDRESS THIS GAP, AS IT CAN BE EFFECTIVE IN JUST 1-2 SESSIONS. IN A RECENT STUDY OF FACT WITH PARENTS OF CHILDREN WITH NEURODEVELOPMENTAL DISORDERS, PARENT DEPRESSION AND ANXIETY IMPROVED IN 2-SESSIONS, AND DEMONSTRATED DOWNSTREAM IMPROVEMENTS IN CHILD BEHAVIOR. THE DEVELOPERS OF FACT PROPOSE THIS TREATMENT EFFECT LIKELY OCCURS THROUGH PSYCHOLOGICAL FLEXIBILITY, WHICH IS ASSOCIATED WITH ADAPTIVE PARENTING BEHAVIORS (E.G., POSITIVE REINFORCEMENT, LIMIT SETTING). HOWEVER, THE ASSOCIATION BETWEEN PARENT PSYCHOLOGICAL FLEXIBILITY AND PARENT-CHILD MEALTIME INTERACTIONS REMAINS UNTESTED. THE OBJECTIVE OF THIS K23 STUDY IS TO ASSESS THE EFFICACY OF A 2-SESSION FACT INTERVENTION FOR PARENTS OF CHILDREN WITH PFD. WE HYPOTHESIZE THAT FACT-PFD WILL BE EFFECTIVE IN REDUCING PARENT MH PROBLEMS, IMPROVING PARENT PSYCHOLOGICAL FLEXIBILITY, AND IMPROVING PARENT-CHILD MEALTIME INTERACTIONS. THE PROPOSED TRAINING WILL FOCUS ON CLINICAL TRIAL CONDUCT AND ANALYSIS, OBSERVATIONAL BEHAVIORAL CODING, AND IMPLEMENTATION SCIENCE. RESULTS OF THIS PROJECT HAVE THE POTENTIAL TO IDENTIFY AN EFFECTIVE PARENT MH TREATMENT AND TO LAUNCH THE INDEPENDENT CAREER OF A HIGHLY PROMISING JUNIOR SCIENTIST.

ONTOGENY AND GENETICS OF NSAID DOSE-EXPOSURE RELATIONSHIP IN PRETERM INFANTS

CHILDHOOD HOUSING ASSISTANCE AND ADULT HEALTH: LIFE COURSE CRITICAL PERIODS AND CUMULATIVE IMPACT - POVERTY-RELATED HOUSING NEEDS DURING CHILDHOOD INCREASE THE RISK OF CHRONIC HEALTH CONDITIONS AS AN ADULT. IN PARTICULAR, CUMULATIVE EXPOSURE TO POVERTY-RELATED HOUSING NEEDS ACROSS CHILDHOOD AND EXPOSURE DURING SPECIFIC CRITICAL PERIODS OF CHILDHOOD ELEVATE THE RISK OF ADULT CHRONIC HEALTH CONDITIONS. GOVERNMENT HOUSING ASSISTANCE ASSISTS ~5 MILLION LOW INCOME FAMILIES WITH THOSE POVERTY-RELATED HOUSING NEEDS ON A POPULATION- WIDE SCALE. HOWEVER, PRIOR RESEARCH HAS NOT INVESTIGATED WHETHER HOUSING ASSISTANCE DURING CHILDHOOD MITIGATES THE IMPACT OF CHILDHOOD POVERTY-RELATED HOUSING NEEDS ON THE DEVELOPMENT OF ADULT CHRONIC HEALTH CONDITIONS. MORE SPECIFICALLY, PRIOR RESEARCH HAS NOT EXAMINED THE IMPACT OF HOUSING ASSISTANCE DURING CHILDHOOD ON THE DEVELOPMENT OF ADULT OBESITY AND TWO OF ITS COMPLICATIONS, DIABETES AND HYPERTENSION. SINCE THESE THREE CHRONIC CONDITIONS ARE INCREASING AT EPIDEMIC PROPORTIONS, THERE IS A CRITICAL NEED TO IDENTIFY WHETHER GOVERNMENT HOUSING ASSISTANCE IN CHILDHOOD IMPACTS THE DEVELOPMENT OF ADULT OBESITY, DIABETES, AND HYPERTENSION. IF SO, EXPANSION OF GOVERNMENT HOUSING ASSISTANCE COULD AMELIORATE THE IMPACT OF CHILDHOOD POVERTY-RELATED HOUSING NEEDS ON THESE ADULT CONDITIONS ON A POPULATION-WIDE SCALE. THIS RESEARCH HAS TWO SPECIFIC AIMS: (1) EXAMINE IF THE TIMING (“CRITICAL PERIODS”) OF GOVERNMENT HOUSING ASSISTANCE (IF ANY) DURING CHILDHOOD IS ASSOCIATED WITH ADULT OBESITY, AND (2) EXAMINE WHETHER DURATION (“CUMULATIVE EXPOSURE”) OF GOVERNMENT HOUSING ASSISTANCE RECEIVED DURING CHILDHOOD (IF ANY) IS ASSOCIATED WITH ADULT OBESITY. TO ACCOMPLISH THESE AIMS, THE INVESTIGATORS WILL UTILIZE THE PANEL STUDY OF INCOME DYNAMICS’S (PSID) 51-YEAR LONGITUDINAL DESIGN (1968 - 2019) TO FOLLOW OVER 7,000 LOW INCOME INDIVIDUALS FROM BEFORE THEIR BIRTH INTO ADULTHOOD. THEY WILL ALSO TAKE ADVANTAGE OF PSID’S FAMILY STRUCTURE TO COMPARE OUTCOMES AMONG SIBLINGS USING FAMILY FIXED EFFECTS. IN ADDITION, THEY WILL LEVERAGE PSID’S RESTRICTED LINKAGES TO HUD DATA AND THE EXOGENOUS VARIABILITY OF WHEN COUNTIES ADOPTED HOUSING ASSISTANCE. THEIR APPROACH REFLECTS THE TEAM’S PUBLIC HEALTH AND ECONOMETRIC PERSPECTIVES: EXPOSURE TO HOUSING ASSISTANCE WILL BE EXAMINED IN TWO WAYS--AVAILABILITY OF HOUSING ASSISTANCE IN A COUNTY (INTENT-TO-TREAT) AND ACTUAL RECEIPT OF HOUSING ASSISTANCE (TREATMENT-ON-TREATED.) ENDOGENEITY IS ADDRESSED THROUGH THE INTENT-TO-TREAT APPROACH AS WELL AS THROUGH PROPENSITY SCORE MATCHING. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE IT WILL FILL A CRITICAL GAP IN WHETHER HOUSING ASSISTANCE CAN AMELIORATE THE IMPACT OF CHILDHOOD POVERTY-RELATED HOUSING NEEDS ON ADULT OBESITY, HYPERTENSION, AND DIABETES ON A POPULATION-WIDE SCALE. FURTHERMORE, IT IS SIGNIFICANT BY IDENTIFYING THE CRITICAL PERIODS AND CUMULATIVE EXPOSURES THAT ARE NEEDED TO OPTIMIZE THE ADMINISTRATION OF HOUSING ASSISTANCE TO MOST IMPROVE HEALTH ON A POPULATION-WIDE SCALE. THIS RESEARCH IS INNOVATIVE THROUGH ITS UNIQUE RESTRICTED LINKAGE TO HUD DATA AND ITS 51- YEAR LONGITUDINAL DESIGN. IT IS ALSO INNOVATIVE BY UTILIZING BOTH INTENT-TO-TREAT AND TREATMENT-ON-TREATED APPROACHES AND LEVERAGING THE EXOGENOUS VARIABILITY OF WHEN COUNTIES ADOPTED HOUSING ASSISTANCE.

DEVELOPMENT OF A NOVEL DIAGNOSTIC MODALITY FOR UPPER AIRWAY OBSTRUCTION VIA INTEGRATING DYNAMIC COMPUTED TOMOGRAPHY WITH COMPUTATIONAL FLUID DYNAMICS - PROJECT SUMMARY/ABSTRACT IN THE CURRENT STATE, CLINICAL AIRWAY MANAGEMENT DECISIONS FOR PATIENTS WITH UPPER AIRWAY OBSTRUCTION (UAO) ARE MADE BASED ON A COMBINATION OF QUALITATIVE IMAGING MODALITIES, CLINICIAN EXPERIENCE, AND A LIMITED NUMBER OF PHYSIOLOGIC MEASURES. AVAILABLE DIAGNOSTICS ARE INADEQUATE AND DO NOT TAKE INTO ACCOUNT THE CRITICAL, DYNAMIC NATURE OF THE RESPIRATORY CYCLE. OUR GOAL IS TO CREATE PATIENT SPECIFIC, QUANTITATIVE, DATA DRIVEN METRICS FOR STRATIFYING THE SEVERITY OF UAO FOR USE IN CLINICAL DECISION MAKING. THE UPPER AIRWAY (NARES TO LARYNX) CONSISTS OF DYNAMIC STRUCTURES THAT CHANGE THROUGHOUT THE RESPIRATORY CYCLE. ROBIN SEQUENCE (RS) IS A POTENTIALLY FATAL CONGENITAL CRANIOFACIAL CONDITION CHARACTERIZED BY UNDERSIZED JAW, POSTERIORLY DISPLACED TONGUE, AND RESULTANT UAO. WE CHOSE TO FOCUS OUR INITIAL EFFORTS ON RS PATIENTS DUE TO THE CONSISTENT CLINICAL PHENOTYPE. TREATMENT OPTIONS FOR PATIENTS WITH RS RANGE FROM CONSERVATIVE MEASURES SUCH AS PRONE POSITIONING TO INVASIVE AND MORBID SURGICAL PROCEDURES. CLINICAL DECISIONS FOR RS PATIENTS WITH UAO ARE MADE BASED ON STATIC IMAGING STUDIES OBTAINED AT A RANDOM PHASE IN THE RESPIRATORY CYCLE, SUBJECTIVE INTERPRETATION OF AWAKE FLEXIBLE AIRWAY ENDOSCOPY, BLOOD CO2 LEVELS, POLYSOMNOGRAMS, THE TREATMENT TEAM’S CLINICAL IMPRESSION OF THE PATIENT’S CONDITION AND THE FAMILY’S GOALS OF CARE. THE FACTORS CONTRIBUTING TO CLINICAL DECISIONS ARE NUMEROUS BUT HEAVILY INFLUENCED BY MULTIPLE SOURCES OF BIAS BASED ON THE RESOURCES AVAILABLE AT THE TREATMENT FACILITY AND THE CLINICAL TRAINING BACKGROUND/COMPOSITION OF THE CARE TEAM. THERE IS A CLEAR, UNMET CLINICAL NEED FOR A DIAGNOSTIC MODALITY THAT CAN BOTH CHARACTERIZE THE ANATOMIC NARROWING AND QUANTIFY UAO. WE PLAN TO ADDRESS THIS NEED BY INTEGRATING COMPUTATIONAL FLUID DYNAMIC (CFD) MODELING WITH A NOVEL COMPUTED TOMOGRAPHY PROTOCOL THAT CAPTURES DYNAMIC AIRWAY CHANGES THROUGHOUT THE RESPIRATORY CYCLE (4D-CT). IN THE FUTURE STATE, WE ANTICIPATE THE 4D-CT/CFD-BASED DIAGNOSTIC MODALITY WILL BE USED TO DEFINE THE ANATOMIC LOCATION(S) OF DYNAMIC UAO AND QUANTIFY THE SEVERITY OF THE UAO AT EACH LEVEL. THIS INFORMATION WILL BE USED, IN PART, TO DETERMINE WHICH TREATMENT IS OPTIMAL FOR INDIVIDUAL PATIENTS. AS PART OF THIS WORK, WE WILL DEFINE SPECIFIC CFD AND CLINICAL OUTCOME MEASURES THAT ARE MOST CRITICAL TO UAO TREATMENT DECISIONS. PRELIMINARY DATA SHOWS THAT THE CFD ANALYSIS OUTPUT (BREATHING RESISTANCE, ENERGY LOSS, PEAK VELOCITY) CAN IDENTIFY THE LEVEL(S) AND SEVERITY OF AIRWAY COMPROMISE. THE AIMS OF THIS PROPOSAL ARE TO FURTHER DEVELOP, REFINE AND VALIDATE THE TECHNIQUE FOR INTEGRATING 4D-CT ACQUISITION WITH CFD ANALYSIS TO ULTIMATELY INFORM TREATMENT DECISIONS IN INFANTS WITH UAO. BY COMBINING 4D-CT IMAGING WITH CFD TECHNIQUES, WE AIM TO CREATE A SIMPLE, ACCURATE, QUANTITATIVE, PATIENT SPECIFIC DIAGNOSTIC MODALITY THAT WILL ADDRESS THE CURRENT GAP. ONCE VALIDATED IN RS PATIENTS THIS DIAGNOSTIC APPROACH COULD BE APPLIED TO NUMEROUS OTHER CONDITIONS IMPACTED BY UAO INCLUDING OBSTRUCTIVE SLEEP APNEA AND LARYNGOMALACIA.

LESS LUMPING, SMARTER SPLITTING: GENOMICS AND METABOLOMICS OF SYSTEMIC STEROID RESPONSE IN BRONCHOPULMONARY DYSPLASIA

PPHF ? 2013 - COOPERATIVE AGREEMENT TO SUPPORT NAVIGATORS IN FEDERALLY-FACILITATED AND STATE PARTNERSHIP EXCHANGES

ASSESSMENT OF EVEROLIMUS AS A THERAPY FOR VICI SYNDROME IN A PRECLINICAL MODEL - PROJECT SUMMARY/ABSTRACT VICI SYNDROME (VS) IS A RARE PEDIATRIC GENETIC DISORDER CHARACTERIZED BY PROFOUND DEVELOPMENTAL DELAY, SEIZURES, IMMUNODEFICIENCY, CARDIOMYOPATHY, AND PROGRESSIVE MOTOR DECLINE, WITH A MEDIAN SURVIVAL OF JUST 42 MONTHS, THIS DEVASTATING DISORDER IS CAUSED BY PATHOGENIC VARIANTS IN THE EPG5 GENE, WHICH ENCODES A CRITICAL REGULATOR IN AUTOPHAGY. LOSS OF EPG5 FUNCTION RESULTS IN THE ACCUMULATION OF TOXIC INTRACELLULAR MATERIAL AND PROGRESSIVE CELLULAR DYSFUNCTION. VS IS A MEMBER OF A BROADER CLASS OF DISEASES KNOWN AS 'CONGENITAL DISORDERS OF AUTOPHAGY' (CDAS), IN WHICH CORE COMPONENTS OF AUTOPHAGY ARE DEFECTIVE. THERE ARE ESSENTIALLY NO TREATMENT OPTIONS FOR CHILDREN WITH VS OR OTHER CDAS. WE HYPOTHESIZE THAT AGENTS THAT INDUCE PHARMACOLOGICAL ENHANCEMENT OF AUTOPHAGY IN VS AND OTHER CDAS REPRESENT A VIABLE THERAPEUTIC STRATEGY. IN COLLABORATION WITH VS FAMILIES, WE HAVE DEVELOPED AND CHARACTERIZED CRITICAL PRECLINICAL MODELS FOR VS FOR THERAPEUTIC DISCOVERY AND VALIDATION, INCLUDING PATIENT-DERIVED INDUCED PLURIPOTENT STEM (IPS) CELLS AND NOVEL GENETICALLY ENGINEERED MOUSE MODELS. THESE EPG5 MUTANT MICE RECAPITULATE A RANGE OF NEUROLOGICAL PHENOTYPES SEEN IN VS INCLUDING BIOCHEMICAL DEFICITS IN AUTOPHAGY, PROGRESSIVE MOTOR DYSFUNCTION, AND A STRONG MOLECULAR AND CELLULAR SIGNATURE INDICATIVE OF NEUROINFLAMMATION. IN PARALLEL, WE HAVE ESTABLISHED A NOVEL ENGINEERED IPS CELL-BASED PLATFORM FOR HIGH THROUGHPUT CELL-BASED SCREENS, WHICH HAS IDENTIFIED RAPAMYCIN-RELATED CLASS OF COMPOUNDS (RAPALOGS) AS ENHANCERS OF AUTOPHAGY IN THE VS CELLS. THIS PROJECT WILL EVALUATE THE THERAPEUTIC POTENTIAL OF THE RAPALOG EVEROLIMUS, AN FDA-APPROVED DRUG WITH OVER 14 YEARS OF SAFETY DATA, INCLUDING WELL-DESCRIBED USE IN PEDIATRIC POPULATIONS, LEVERAGING THE VS MOUSE MODELS FOR IN VIVO PRECLINICAL PROOF-OF-PRINCIPLE STUDIES. IN AIM 1, WE WILL DEFINE THE PHARMACOKINETICS (PK) AND PHARMACODYNAMICS (PD) OF EVEROLIMUS IN THE VS MOUSE MODEL, OPTIMIZING DOSING REGIMENS TO SUSTAIN AUTOPHAGY INDUCTION IN VIVO AFTER EXTENDED USE. IN AIM 2, WE WILL ASSESS THE ABILITY OF EVEROLIMUS TO SLOW OR HALT DISEASE PROGRESSION IN VIVO USING THE VS MOUSE MODEL. NEUROLOGICAL FUNCTION AND INFLAMMATORY RESPONSE IN THE VS ANIMAL MODEL WILL BE MONITORED DURING LONGITUDINAL TREATMENT WITH EVEROLIMUS. PHENOTYPIC MONITORING WILL INCLUDE WHOLE ANIMAL BEHAVIORAL ASSAYS OF MOTOR FUNCTION AND MOLECULAR AND HISTOLOGICAL BIOMARKERS OF NEUROINFLAMMATION IN VARIOUS CNS TISSUES. SUCCESSFUL COMPLETION OF THIS PROJECT WILL PROVIDE CRITICAL PRECLINICAL DATA SUPPORTING THE REPURPOSING OF EVEROLIMUS FOR CLINICAL PROOF OF CONCEPT IN VS PATIENTS. OUR MULTIDISCIPLINARY TEAM, COMBINING EXPERTISE IN DRUG DISCOVERY, PRECLINICAL DISEASE MODELING AND ANALYSIS IN MICE, CLINICAL TREATMENT OF VS PATIENTS, AND RARE DISEASE RESEARCH, IS WELL-POSITIONED TO ADVANCE THIS THERAPEUTIC STRATEGY TOWARD CLINICAL TRANSLATION IN PARTNERSHIP WITH HIGHLY ENGAGED VS FAMILIES.

PHARMACOGENETICS OF PEDIATRIC SICKLE CELL DISEASE

INHALED CICLESONIDE - A PHASE I STUDY IN PRETERM INFANTS - PRETERM INFANTS BORN BEFORE 30 WEEKS GESTATION ARE AT RISK OF DEVELOPING BRONCHOPULMONARY DYSPLASIA (BPD), A LEADING CAUSE OF DEATH AND LONG-TERM PULMONARY INSUFFICIENCY. BOTH HYDROCORTISONE AND SYNTHETIC GLUCOCORTICOID (SGC) ARE COMMONLY USED TO PREVENT BPD IN PREMATURE INFANTS. CLINICAL TRIALS HAVE SHOWN THAT HYDROCORTISONE TARGETED TO INFANTS WITH EMERGING LUNG DISEASE DOES NOT PREVENT BPD, WHILE INHALED SGC THERAPY HAS SHOWN MIXED EFFICACY WITH POTENTIALLY INCREASED MORTALITY. DEXAMETHASONE (DEX) HAS BEEN SHOWN IN CLINICAL TRIALS TO REDUCE BPD RATES IN PREMATURE INFANTS BUT IS ASSOCIATED WITH SHORT TERM AND LONG-TERM ADVERSE EFFECTS INCLUDING CEREBRAL PALSY. THERE IS AN UNMET NEED FOR EFFICACIOUS GC THERAPY IN PREMATURE INFANTS TO PREVENT BPD WITHOUT ENCUMBERING SERIOUS ADVERSE EVENTS. TO ADDRESS THIS CHALLENGE, OUR GROUP HAS BEEN INVESTIGATING CICLESONIDE (CIC), A SGC PRO-DRUG THAT IN THE INHALED FORM IS FDA APPROVED FOR USE IN ASTHMA AND ALLERGIC RHINITIS IN OLDER CHILDREN. WE RECENTLY SHOWED THAT DEX AND CIC REGULATE GR TRANSCRIPTIONAL TARGETS AND SEVERAL GENES IMPLICATED IN LUNG PROTECTIVE EFFECTS IN NEONATAL RATS. REMARKABLY, CIC DOES NOT SUPPRESS SOMATIC GROWTH, IGF- 1 LEVELS, INDUCE HYPERGLYCEMIA OR CAUSE NEUROANATOMICAL CHANGES IN THE CEREBRAL CORTEX OF NEONATAL RATS, WHICH ARE KNOWN PATHOLOGIES CAUSED BY DEX IN PREMATURE INFANTS. FURTHERMORE, ONGOING STUDIES REVEAL THAT CIC IS AS EFFICACIOUS AS DEX IN PREVENTING LUNG INJURY IN A HYPEROXIA-MODEL OF EXPERIMENTAL BPD. WE HYPOTHESIZE THAT CIC WILL HAVE MINIMAL SYSTEMIC ABSORPTION AND A FAVORABLE SAFETY PROFILE IN PREMATURE INFANTS AT RISK OF DEVELOPING BPD. IN AIM 1, WE WILL DETERMINE THE MAXIMUM TOLERABLE DOSE (MTD) OF INHALED CIC IN PRETERM INFANTS THAT DOES NOT TRIGGER ADVERSE SYSTEMIC SIDE EFFECTS CHARACTERISTIC OF GCS. AN OPEN LABEL DOSE ESCALATION STUDY WILL BE DONE IN PRETERM INFANTS BORN AT <31 WEEKS GESTATION USING A 3+3+3 STUDY DESIGN. INFANTS REQUIRING INVASIVE MECHANICAL VENTILATION BETWEEN DAYS OF LIFE 14 TO 35 WILL BE TREATED WITH INHALED CIC FOR 2 WEEKS. DATA PERTAINING TO GROWTH, HYPERGLYCEMIA, BLOOD PRESSURE, AND ADRENOCORTICAL SUPPRESSION WILL BE COMPARED BETWEEN INFANTS TREATED WITH CIC AND CONTROLS. IN AIM 2, WE WILL QUANTIFY SERUM LEVELS OF CIC METABOLITES AND CHANGES IN THE GR TRANSCRIPTOME AFTER CIC THERAPY. BLOOD SAMPLES COLLECTED AT DAYS 3, 7 AND 15 POST-INITIATION OF INHALED CIC WILL BE USED TO MEASURE CIC AND DES-CIC BY LIQUID CHROMATOGRAPHY-HIGH RESOLUTION MASS SPECTROMETRY. WHOLE BLOOD RNA WILL BE SUBJECTED TO QRT PCR ANALYSIS OF GC RESPONSIVE GENES TO ASSESS ACTIVATION OF GR. THE FEAR OF LONG-TERM NEUROLOGICAL ADVERSE EFFECTS HAS LIMITED OPTIMAL USE OF SGC THERAPY TO PREVENT BPD. THIS APPLICATION IS SIGNIFICANT AS IT PROPOSES TO REPURPOSE CIC, AN EXISTING SGC, FOR NOVEL THERAPEUTIC USE IN PRETERM INFANTS TO PREVENT BPD (PAR-23-131). WE BELIEVE OUR STUDY IS IMPACTFUL AND TRANSLATIONALLY RELEVANT AS IT ADDRESSES AN UNMET NEED FOR EFFICACIOUS GC THERAPY TO PREVENT BPD IN PREMATURE INFANTS WITHOUT ENCUMBERING THE NEUROLOGICAL AND SOMATIC ADVERSE EFFECTS. SUCCESSFUL TESTING OF OUR HYPOTHESIS WILL PAVE THE WAY FOR A LARGE, MULTICENTER RANDOMIZED CONTROL TRIAL OF CIC THERAPY IN PREMATURE INFANTS TO PREVENT BPD.

DEVELOPMENT OF MOSAIC ENTEROVIRUS MRNA VACCINE TO PREVENT HAND, FOOT AND MOUTH DISEASE - PROJECT SUMMARY/ABSTRACT HAND FOOT MOUTH DISEASE (HFMD) IS PRIMARILY CAUSED BY HUMAN ENTEROVIRUS SEROTYPE A VIRUSES (HEV-A), AND PREDOMINANTLY AFFECTS YOUNG CHILDREN. MOST CASES RESULT IN MILD FLU-LIKE SYMPTOMS AND PAINFUL SORES AND RASH, BUT SEVERE COMPLICATIONS CAN OCCUR THAT INVOLVE THE CENTRAL NERVOUS SYSTEM (CNS), SUCH AS VIRAL MENINGITIS AND ENCEPHALITIS, THAT CAN LEAD TO SERIOUS ILLNESS AND DEATH. MOREOVER, EMERGENT VIRAL STRAINS COULD EVOLVE TO HAVE ENHANCED INFECTIVITY AND SEVERE DISEASE IN FUTURE VIRAL OUTBREAKS. CURRENTLY, THERE ARE NO ANTIVIRALS OR VACCINES THAT TARGET THE BROAD DIVERSITY OF VIRAL STRAINS THAT CAUSE HFMD. THUS, THERE IS AN URGENT NEED TO DEVELOP BROADLY PROTECTIVE VACCINES AND EFFECTIVE ANTIVIRALS TO THE BROAD RANGE OF VIRAL STRAINS THAT CAUSE HFMD. IN THIS PROJECT, WE PROPOSE TO DEVELOP BROAD MOSAIC MULTIVALENT HFMD MRNA VACCINES FOR OPTIMAL VACCINE EFFICACY AND LONGEVITY, AND TO ISOLATE BROADLY NEUTRALIZING ENTEROVIRUS ANTIBODIES FOR THERAPEUTIC DEVELOPMENT. AN EFFECTIVE AND BROAD VACCINE AGAINST HFMD WILL NEED TO ACCOMMODATE THE DIVERSE VIRAL SEQUENCE DIVERSITY WITHIN HEV-A. WE HAVE COMPUTATIONALLY DESIGNED A HEXAVALENT MOSAIC HEV-A VACCINE BY TAKING CONSERVED B AND T CELL EPITOPES FROM MULTIPLE HEV-A VIRUSES AND CREATING MOSAIC VACCINE ANTIGENS FOR BROAD VIRAL SEQUENCE COVERAGE OF HEV-A VIRUSES. WE SHOWED THAT MICE IMMUNIZED WITH OUR HEXAVALENT HEV-A VACCINE HAD INCREASED ANTIBODY TITERS AGAINST MULTIPLE HEV-A VIRAL PROTEINS COMPARED TO A SINGLE-STRAIN VACCINE. OUR OVERALL HYPOTHESIS IS THAT COMPUTATIONALLY-DESIGNED MOSAIC HEV-A VACCINES WILL ELICIT BROADER AND MORE CROSS-REACTIVE B AND T CELL IMMUNE RESPONSES TO THE VIRUSES THAT CAUSE HFMD COMPARED TO SINGLE EV-A71 STRAIN-SPECIFIC VACCINES. OUR OVERALL OBJECTIVE OF THIS PROPOSAL IS TO DEVELOP AND TEST AN MRNA-ENCODED VIRUS- LIKE PARTICLE (VLP) VACCINE THAT CONSISTS OF MULTIVALENT HEV-A CAPSID ANTIGENS THAT WERE DESIGNED FOR OPTIMIZED SEQUENCE COVERAGE OF HEV-A SEROTYPE VIRUSES. MOREOVER, WE WILL ISOLATE HEV-A BROADLY NEUTRALIZING ANTIBODIES TO IDENTIFY CROSS-REACTIVE B CELL EPITOPES THAT COULD BE FURTHER DEVELOPED AS THERAPEUTIC MONOCLONAL ANTIBODIES. THIS WORK IS SIGNIFICANT BECAUSE IT WILL LEAD TO THE DEVELOPMENT OF A BROAD HEV-A VACCINE THAT COULD BE UTILIZED AS AN EFFECTIVE VACCINE FOR HFMD AND UTILIZES AN INNOVATIVE VACCINE DEVELOPMENT PLATFORM INTEGRATING COMPUTATIONAL ANTIGEN DESIGN AND MRNA-ENCODED VLP TECHNOLOGY THAT COULD ALSO BE APPLIED TO OTHER PATHOGENS. IN AIM 1, WE WILL ENGINEER A MULTIVALENT MOSAIC HEV-A MRNA-ENCODED VLP VACCINE AND DETERMINE B AND T CELL IMMUNE RESPONSES COMPARED TO A STRAIN SPECIFIC VACCINES. IN AIM 2, WE WILL ISOLATE AND CHARACTERIZE CROSS-REACTIVE BROADLY NEUTRALIZING HEV-A ANTIBODIES. THIS PROJECT WILL DEVELOP A NOVEL MRNA HEV-A VACCINE THAT GENERATES CROSS-REACTIVE IMMUNITY AGAINST THE DIVERSE VIRUSES THAT CAUSE HFMD AND UTILIZED TO PREVENT INFECTION AND DISEASE. MOREOVER, WE WILL ISOLATE BROADLY NEUTRALIZING ANTIBODIES THAT WILL IDENTIFY CONSERVED NEUTRALIZING EPITOPES WITHIN HEV-A VIRUSES, FOR FURTHER DEVELOPMENT AS IMMUNOTHERAPIES FOR HFMD AND RELATED HEV-A INFECTIONS.

NOVEL COMPUTATIONAL APPROACHES TO CHARACTERIZE THE EFFECTS OF RARE FUNCTIONAL OUTLIER VARIANTS ON CIS- AND TRANS-REGULATORY DISEASE PROCESSES - SUMMARY THE RECENT AVAILABILITY OF LARGE-SCALE WHOLE GENOME DATASETS HAS REVEALED THE STARTLING SCALE OF RARE GENETIC VARIATION PRESENT IN HUMAN POPULATIONS. THERE IS INCREASING EVIDENCE THAT RARE GENETIC VARIANTS CAN HAVE PROFOUND EFFECTS ON MULTIPLE COMPLEX DISEASE PHENOTYPES; HOWEVER, THE SYSTEMATIC CHARACTERIZATION OF THESE VARIANTS IS LIMITED BY CURRENT COHORT SIZES AND APPROACHES TO INTERPRETATION. ONE POWERFUL EMERGING APPROACH FOR RARE VARIANT INTERPRETATION IS IN THE INTEGRATION OF FUNCTIONAL DATA TO ENABLE IN VIVO ASSAY OF RARE VARIANT-DRIVEN MOLECULAR DYSREGULATION, ENABLED BY LARGE-SCALE DATA INTEGRATION OF GENOMIC, FUNCTIONAL, AND PHENOTYPIC RESOURCES. IN THIS PROPOSAL, WE OUTLINE COMPUTATIONAL AND STATISTICAL APPROACHES TO SYSTEMATICALLY ANNOTATE AND ISOLATE – ON A GENOME-WIDE SCALE – RARE VARIANTS LINKED WITH EXTREME EFFECTS ON MULTIPLE MOLECULAR PHENOTYPES (RARE MOLECULAR OUTLIER VARIANTS) AND, THROUGH INTEGRATING BIOBANK-SCALE PHENOTYPIC DATA, THEIR DOWNSTREAM EFFECTS ON DIVERSE COMPLEX DISEASE RISK. WE RECENTLY APPLIED THIS APPROACH IN GTEX AND TOPMED TO SHOW THAT UTILIZING OUTLIER GENE EXPRESSION PROVIDES A POWERFUL FRAMEWORK FOR IDENTIFYING LARGE PHENOTYPIC-EFFECT RARE VARIANTS IN GENES WITH KNOWN IMPACT ON COMPLEX DISEASES. SPECIFICALLY, IN THIS PROPOSAL WE WILL COMBINE LARGE-SCALE GENOMIC AND DIVERSE MULTI-OMICS DATA TO DEVELOP AND EXTEND NOVEL COMPUTATIONAL AND STATISTICAL METHODS TO PROVIDE THE FIRST SYSTEMATIC CHARACTERIZATION OF PERSONALIZED COMPLEX DISEASE RISK CONTRIBUTED BY RARE GENETIC VARIANTS. OUR METHODS ARE READILY APPLICABLE TO RESEARCH IN ANY COMPLEX DISEASE AREA, INCLUDING ANTHROPOMETRIC, NEUROLOGICAL AND CANCER RESEARCH. OUR EFFORTS WILL INCREASE OUR UNDERSTANDING OF HOW RARE VARIANTS INTERACT WITH POLYGENIC DISEASE RISK PREDICTIONS DERIVED FROM POLYGENIC RISK SCORES, CURRENTLY LIMITED TO RELATIVELY SMALL-EFFECT COMMON VARIANT GWAS HITS, AND SHOW HOW RARE MOLECULAR OUTLIER VARIANTS PROVIDE A FRAMEWORK FOR SYSTEMATICALLY CHARACTERIZING BOTH CIS- AND TRANS-REGULATORY DISEASE NETWORKS IMPACTING CORE DISEASE GENES AS THEORIZED IN THE OMNIGENIC MODEL. FURTHERMORE, WE OUTLINE PRELIMINARY RESULTS SUGGESTING THAT RARE MOLECULAR OUTLIER VARIANTS SUBSTANTIALLY INCREASE POWER FOR UNCOVERING LARGE-EFFECT RARE VARIANTS OVER GENOME ANNOTATION METHODS (NAMELY, PROTEIN TRUNCATING VARIANTS – LIMITED TO CODING REGIONS ONLY), AND OUTLINE AN APPROACH FOR QUANTIFYING THESE EFFECTS IN DISEASE PREDICTION AND DRUG TARGETING APPLICATIONS. OVERALL, THESE ACTIVITIES WILL INCREASE OUR UNDERSTANDING OF COMPLEX DISEASE GENETICS. THE USE OF GENETIC-ONLY METHODS SUCH AS GWAS WOULD REQUIRE COHORT SIZES WITHIN THE MILLIONS, ILLUSTRATING THE IMPORTANCE OF FUNCTIONAL GENOMIC DATA TO OUR APPROACH. WE HAVE A STRONG TRACK RECORD OF RELEASING SOFTWARE AND PIPELINES TO IMPLEMENT PRIOR METHODS, AND WILL MAKE ANY NEW WORK RAPIDLY AVAILABLE ON PUBLIC REPOSITORIES. OUR EFFORTS WILL PROVIDE IMPORTANT CONTRIBUTIONS TO UNDERSTANDING THE RAPIDLY GROWING DISCOVERY OF RARE VARIANTS FROM WHOLE GENOME DATA AND THE URGENT NEED FOR METHODS TO INTERPRET THESE VARIANTS.

LOCAL CONDITIONS AND CHILD HEALTH

HEALTH CARE AND OTHER FACILITIES

A NOVEL PLATFORM TO ENHANCE SINGLE CELL INTERROGATION OF NERVOUS SYSTEM DEVELOPMENT - PROJECT SUMMARY DURING DEVELOPMENT, THE VAST MAJORITY OF THE PERIPHERAL NERVOUS SYSTEM (PNS) IS GENERATED FROM NEURAL CREST CELLS THAT MIGRATE EXTENSIVELY INTO THE EMBRYO AND GIVE RISE TO THE SYMPATHETIC, PARASYMPATHETIC, SENSORY AND ENTERIC NERVOUS SYSTEMS. SYMPATHETIC NERVOUS SYSTEM (SNS) FUNCTION IS TIGHTLY LINKED TO HEART RATE, BLOOD PRESSURE AND TEMPERATURE CONTROL. DURING DEVELOPMENT THE SYMPATHETIC GANGLIA (SG) MUST MOVE AND INTERACT WITH AXONS THAT PROJECT FROM PREGANGLIONIC NEURONS (PGNS) IN THE VENTRAL SPINAL CORD TO WIRE THE CIRCUIT BETWEEN THE CENTRAL NERVOUS SYSTEM (CNS) AND PNS. TISSUE REPAIR OR REGENERATION THERAPIES FOR BIRTH DEFECTIVE OR DAMAGED NEURAL CONNECTIONS BETWEEN THE CNS AND SNS OFFER A POTENTIAL THERAPEUTIC STRATEGY, HOWEVER, WILL REQUIRE THE MOLECULAR SIGNATURE OF PGN AND SG CELL POPULATIONS PRIOR TO CLINICAL TRANSLATION. FURTHERMORE, ONE CLINICALLY SIGNIFICANT EXAMPLE OF MISTAKES IN SNS DEVELOPMENT IS NEUROBLASTOMA CANCER IN INFANTS. HERE, WE EXPLORE AN INNOVATIVE STRATEGY OF NOVEL SPATIAL TRANSCRIPTOMICS APPROACHES, INTEGRATED MULTIPLEXED RNA/PROTEIN DETECTION AND VISUALIZATION, AND COMPUTATIONAL ALGORITHMS TO UNIQUELY IDENTIFY AND MAP MOLECULAR MARKERS OF THE PGN AND SG PROGENITOR CELL POPULATIONS TO THE TISSUE ARCHITECTURE OF THE CHICK TRUNK ANATOMY. IF SUCCESSFUL, THIS NOVEL PLATFORM WILL PROVIDE A TRANSFORMATIVE FOUNDATION FOR BASIC RESEARCH OF PERIPHERAL NERVOUS SYSTEM BIRTH DEFECTS AND REPAIR USING STEM CELL-BASED THERAPIES, AND FUTURE STUDIES OF NEUROBLASTOMA INITIATION.

SYSTEMIC CORTICOSTEROID PHARMACOKINETICS AND PHARMACODYNAMIC BIOMARKER IDENTIFICATION IN CHILDREN WITH ASTHMA AND OBESITY - PROJECT SUMMARY THE OVERALL GOAL OF THIS 5-YEAR K23 PROPOSAL IS TO SUPPORT DR. KATHRYN KYLER TO BECOME AN INDEPENDENT INVESTIGATOR IN THE FIELD OF PHARMACOKINETIC (PK) MODELING AND PHARMACODYNAMIC (PD) BIOMARKER DEVELOPMENT FOR CHILDREN WITH ASTHMA AND OBESITY. THIS PROPOSAL ALIGNS WITH THE NHLBI’S PRECISION MEDICINE INITIATIVE, AS WELL AS PRIORITIZATION OF OBESITY RELATED RESEARCH IN RELEVANT DISEASES LIKE ASTHMA. THE PROPOSAL ALSO ALIGNS WITH THE NIH BETTER PHARMACEUTICALS FOR CHILDREN ACT WHICH HAS NAMED PK/PD STUDIES FOCUSED ON CHILDREN WITH OBESITY AS A PRIORITY. CHILDREN WITH ASTHMA AND OBESITY HAVE A DISTINCT ASTHMA PHENOTYPE AND ENDOTYPE, CHARACTERIZED BY MORE SEVERE ASTHMA THAN THOSE WITHOUT OBESITY (E.G., MORE EXACERBATIONS, HOSPITALIZATIONS), AND DIFFERENT BASELINE INFLAMMATORY PATTERNS (I.E., ELEVATED IL-6 AND TNF-) THAN ASTHMATIC CHILDREN WITHOUT OBESITY (I.E., ALLERGIC-TYPE INFLAMMATION). IT IS CURRENTLY UNKNOWN HOW THESE DIFFERENCES MODULATE DRUG EXPOSURE AND RESPONSE FOR MEDICATIONS LIKE SYSTEMIC CORTICOSTEROIDS (SCS) USED TO TREAT ASTHMA EXACERBATIONS. THIS CAREER DEVELOPMENT PROPOSAL WILL LEVERAGE DR. KYLER’S EXPERTISE AS A PEDIATRIC HOSPITALIST AND CLINICAL PHARMACOLOGIST-IN-TRAINING TO EXPAND HER SKILLS IN CLINICAL AND TRANSLATIONAL PK/PD STUDY METHODS, ENABLING HER TO DEFINE OBESITY’S EFFECT ON SCS DOSE-EXPOSURE-RESPONSE RELATIONSHIPS. THE COMPREHENSIVE CAREER DEVELOPMENT PLAN CONTAINS THREE TRAINING OBJECTIVES TO IMPROVE DR. KYLER’S SKILLS IN: 1) ADVANCED PK MODELING, 2) PD BIOMARKER DEVELOPMENT, AND 3) PEDIATRIC CLINICAL TRIAL BEST PRACTICES. THIS PLAN INCLUDES STRUCTURED MENTORING, DIDACTIC TRAINING, AND EXPERIENTIAL LEARNING WHICH WILL BE APPLIED TO THE FOLLOWING SCIENTIFIC AIMS: 1) DETERMINE DIFFERENCES IN SCS-MEDIATED IMMUNE CELL RESPONSE IN VITRO ACROSS WEIGHT GROUPS, 2) DETERMINE DIFFERENCES IN SCS EXPOSURE AMONG ASTHMATIC CHILDREN WITH AND WITHOUT OBESITY, 3) EVALUATE THE RELATIONSHIP BETWEEN SCS EXPOSURE AND PD BIOMARKERS. DR. KYLER’S CAREER DEVELOPMENT AND RESEARCH PLANS WILL TAKE PLACE IN AN EXCELLENT ENVIRONMENT WHICH INCLUDES A TERTIARY ACADEMIC CHILDREN’S MEDICAL CENTER, A PEDIATRIC RESEARCH INSTITUTE, A MULTI-INSTITUTIONAL CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE (CTSI), AS WELL AS ACCESS TO EXPERTS IN FIELDS DIRECTLY RELATED TO BOTH HER TRAINING AND SCIENTIFIC AIMS. AFTER COMPLETING THIS PROJECT, DR. KYLER WILL HAVE ADVANCED THE FIELD OF DRUG PHARMACOKINETICS AND DYNAMICS IN CHILDREN WITH ASTHMA AND OBESITY AND GENERATED DATA TO SUPPORT AN R01 APPLICATION TO VALIDATE AND TEST PK AND PD MODEL-INFORMED SCS DOSING STRATEGIES IN CHILDREN WITH ASTHMA AND OBESITY. THIS WORK WILL POSITION HER TO BECOME A LEADER IN THE FIELD OF PRECISION THERAPEUTICS FOR CHILDREN WITH ASTHMA AND OBESITY, ABLE TO LINK PHARMACOLOGIC TRANSLATIONAL SCIENCE TO THE BEDSIDE FOR PERFORMANCE OF PEDIATRIC CLINICAL TRIALS.

AUTOMATED ECOLOGICAL VIDEO IDENTIFICATION OF PHYSICAL ACTIVITY (E-VIP) SOFTWARE

PHARMACOGENOMIC CONTRIBUTION TO THE BIOTRANSFORMATION OF TRIHEXYPHENIDYL AND DEVELOPMENT OF A PRECISION DOSING MODEL FOR CHILDREN WITH DYSTONIA AND CEREBRAL PALSY - PROJECT SUMMARY THE GOAL OF THIS 5-YEAR K23 PROPOSAL IS TO SUPPORT DR. GELINEAU-MOREL AS SHE BECOMES AN INDEPENDENT INVESTIGATOR IN MODEL-INFORMED PRECISION DOSING TO FACILITATE CLINICAL TRIALS FOR CHILDREN WITH CEREBRAL PALSY (CP), AND ESPECIALLY DYSTONIA (DCP). DCP IS A MOVEMENT DISORDER WITH A SIMILAR INCIDENCE TO PARKINSON’S DISEASE (1 IN 1000) AND IS THE GREATEST DETERMINANT OF FUNCTIONAL IMPAIRMENT IN CHILDREN WITH CP. YET, THERE ARE NO FDA- APPROVED TREATMENTS, AND EVEN OFF-LABEL TREATMENTS ARE MINIMALLY EFFECTIVE. TRIHEXYPHENIDYL (THP), A RACEMIC MIXTURE OF R AND S ENANTIOMERS, WAS EFFECTIVE FOR DCP IN A CLINICAL TRIAL, BUT SOME PARTICIPANTS HAD TREATMENT- LIMITING SIDE EFFECTS LIKELY DUE TO SUPRATHERAPEUTIC EXPOSURE TO THP OR ITS ENANTIOMERS, SUPPORTING THE NEED FOR PRECISION DOSING TO STANDARDIZE EXPOSURES. IN FACT, THE CP COMMUNITY RECENTLY NAMED IDENTIFYING NEW AND EFFECTIVE TREATMENTS TO BE THEIR TOP RESEARCH PRIORITY IN DCP. THIS ALIGNS WITH THE NICHD/NINDS STRATEGIC PLAN FOR CP RESEARCH WHICH RECOMMENDS IMPROVED PRECISION TREATMENTS. DR. GELINEAU-MOREL IS IDEALLY POSITIONED TO ADDRESS THIS NEED AS A CHILD NEUROLOGIST AND MOVEMENT DISORDER SPECIALIST WITH FELLOWSHIP TRAINING IN CLINICAL PHARMACOLOGY. THIS CAREER DEVELOPMENT PROPOSAL (CDP) WILL EXPAND DR. GELINEAU-MOREL'S SKILLSET WITH ADDITIONAL TRAINING TO SYSTEMATICALLY INVESTIGATE PHARMACOGENETIC SOURCES OF VARIABILITY IN DRUG EXPOSURE AND DEVELOP MODEL-INFORMED PRECISION DOSING RECOMMENDATIONS FOR EXPOSURE-CONTROLLED CLINICAL TRIALS. THE CDP HAS THE FOLLOWING OBJECTIVES: 1) DEVELOP EXPERTISE IN QUANTIFYING PHARMACOGENOMIC CONTRIBUTION TO DRUG EXPOSURE, 2) BECOME SKILLED IN PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING, 3) GAIN KNOWLEDGE OF CLINICAL TRIAL DESIGN. THE CDP WILL BE FACILITATED THROUGH STRUCTURED MENTORING, DIDACTICS, AND EXPERIENTIAL TRAINING, AND APPLIED TO A RESEARCH PLAN QUANTIFYING THE CONTRIBUTION OF CYP2D6 AND CYP2C19 TO THE BIOTRANSFORMATION OF TRIHEXYPHENIDYL AND DEVELOPING A PBPK MODEL. THE RESEARCH STUDY HAS THESE AIMS: 1) DETERMINE THE IMPACT OF CYP2D6 AND CYP2C19 GENOTYPE ON EXPOSURE TO R-THP AND S-THP 2) DEVELOP A PEDIATRIC PBPK MODEL TO SIMULATE EXPOSURES TO THP, R-THP, AND S-THP BASED ON INDIVIDUAL’S PHARMACOGENOTYPE, AGE, WEIGHT, AND SEX AND 3) ESTABLISH THE FEASIBILITY OF A FUTURE EXPOSURE-CONTROLLED CLINICAL TRIAL OF THP IN DCP. STUDY RESULTS COULD ALSO JUSTIFY AN INVESTIGATIONAL NEW DRUG APPLICATION FOR R-THP, TO MAXIMIZE THERAPEUTIC BENEFIT WHILE MINIMIZING SIDE EFFECTS. DR. GELINEAU-MOREL'S CAREER DEVELOPMENT AND RESEARCH PLAN WILL TAKE PLACE IN THE IDEAL ENVIRONMENT WITH A LARGE, TERTIARY CARE, ACADEMIC CHILDREN’S HOSPITAL, A PEDIATRIC RESEARCH INSTITUTE, AND THE FRONTIERS CTSI. SHE WILL BE MENTORED BY INTERNATIONAL EXPERTS IN PHARMACOGENOMICS AND DRUG BIOTRANSFORMATION, PBPK MODELING, AND CLINICAL TRIALS. UPON COMPLETION OF THIS K23, DR. GELINEAU-MOREL WILL HAVE THE NECESSARY SKILLS AND EXPERTISE TO BECOME A LEADER IN PRECISION NEUROTHERAPEUTICS AND COMPLETE AN R01 APPLICATION FOR AN EXPOSURE-CONTROLLED CLINICAL TRIAL IN DCP.

LOW COST MONITORING STRATEGY TO OPTIMIZE TUBERCULOSIS TREATMENT IN CHILDREN

PRECISION MEDICINE IN PEDIATRIC REHABILITATION - VARIABILITY IN GABAPENTIN EXPOSURE - PROJECT SUMMARY ALTHOUGH GABAPENTIN IS THE MOST COMMONLY PRESCRIBED MEDICATION FOR PATIENTS WITH NEUROPATHIC PAIN, THE HIGH LEVEL OF VARIABILITY IN REDUCTION IN PAIN LIMITS EFFECTIVE TREATMENT OF PAIN. WORK PRODUCTS FROM THIS GRANT WOULD ALLOW THE FORMATION OF A MODEL-INFORMED DOSING STRATEGY FOR THIS DISORDER. THIS RESEARCH WILL HAVE A LASTING IMPACT ON THE WAY IN WHICH DRUGS ARE PRESCRIBED TO PEDIATRIC PATIENTS WITH DISABILITIES. MEDICATIONS WHICH REQUIRE TRANSPORT ACROSS THE BLOOD-BRAIN BARRIER (BBB) FREQUENTLY REQUIRE TRANSPORT TO REACH THE CEREBROSPINAL FLUID (CSF). THE GENE SLC7A5 ENCODES FOR A LIGHT-CHAIN PROTEIN (LAT1) THAT FORMS A HETERODIMER WITH THE A HEAVY CHAIN PROTEIN CD98HC (ENCODED BY SLC3A2) TO CREATE A MEMBRANE TRANSPORT PROTEIN REFERRED TO AS THE L-TYPE AMINO ACID TRANSPORTER-1 (LAT1). 21 PREVIOUS IN VITRO STUDIES HAVE SHOWN THAT THIS TRANSPORTER IS ONE OF THE PRIMARY MECHANISMS OF GABAPENTIN TRANSPORT ACROSS THE BBB. THIS TRANSPORTER IS ALSO THE CONFIRMED OR THEORIZED TRANSPORTER OF SEVERAL OTHER COMMONLY PRESCRIBED MEDICATIONS FREQUENTLY PRESCRIBED BY REHABILITATION PROVIDERS. DETERMINING THE VARIABILITY IN THE AMOUNT OF GABAPENTIN A PATIENT HAS IN THEIR PLASMA (SYSTEMIC EXPOSURE) AND THE AMOUNT THAT CROSSES THE BLOOD-BRAIN-BARRIER (BBB) (CENTRAL EXPOSURE) IS SIGNIFICANT TO OPTIMALLY DETERMINE THE MOST APPROPRIATE DOSE FOR EACH INDIVIDUAL CHILD (AIM1). THE OVERALL GOAL OF MY RESEARCH STRATEGY IS TO IDENTIFY FACTORS INFLUENCING VARIABILITY IN CENTRAL EXPOSURE (CEREBROSPINAL FLUID) IN PEDIATRIC PATIENTS WITH CP. AIM 1 INVESTIGATES THE AMOUNT OF CENTRAL EXPOSURE BY DETERMINING THE AMOUNT OF GABAPENTIN THAT CROSSES THE BBB. A SECONDARY PORTION OF AIM 1 ADDRESSES THE IMPACT OF THE SCL7A5 GENE (LAT1 TRANSPORTER) BY PERFORMING WHOLE- EXOME SEQUENCING TO EVALUATE THE SLC7A5 GENE AND GENOTYPING OF SELECTED SINGLE-NUCLEOTIDE POLYMORPHISMS IN THE INTRONIC REGION OF THE LAT1 TRANSPORTER. AIM 2 IS DIVIDED INTO TWO SUB-AIMS USING SIMILAR METHODOLOGY. THE FIRST SUB-AIM EVALUATES THE IMPACT OF CONCURRENTLY ADMINISTERED MEDICATIONS THAT ALSO UTILIZE THE LAT1 TRANSPORTER USING A CELL LINE MODEL THAT IS TRANSFECTED WITH THE SLC7A5 GENE TO EVALUATE POTENTIAL DRUG-DRUG INTERACTIONS WITH COMMONLY PRESCRIBED MEDICATIONS IN REHABILITATION MEDICINE, SPECIFICALLY LEVODOPA, BACLOFEN, AND PREGABALIN. THE SECOND SUB-AIM OF AIM 2 INVOLVED TRANSFECTION OF GENETIC VARIANTS OF THE LAT1 TRANSPORTER TO DETERMINE THE IMPACT OF CODING REGION CHANGES TO THE FUNCTION OF THIS TRANSPORTER. THESE VARIANTS MAY BE INFORMED BY THE WHOLE-EXOME SEQUENCING VARIANTS FOUND IN AIM 1. BOTH OF THESE INDEPENDENT BUT COMPLEMENTARY AIMS ALLOWS FOR DATA THAT WILL BE INCORPORATED WITHIN FUTURE DECISION SUPPORT TOOLS TO MORE APPROPRIATE ANTICIPATE WHAT DOSE OF GABAPENTIN IS NEEDED TO REACH A DESIRED LEVEL OF EXPOSURE AND, SUBSEQUENTLY, A DESIRED LEVEL OF CLINICAL RESPONSE (NEUROPATHIC PAIN REDUCTION).

RURAL COMMUNITIES OPIOID RESPONSE PROGRAM-OVERDOSE RESPONSE - MERCY HOSPITAL LEBANON WILL LEAD THE PROPOSED HRSA RCORP-OVERDOSE RESPONSE PROJECT ALONG WITH FOUR RURAL, CRITICAL ACCESS HOSPITALS (MERCY HOSPITAL AURORA, MERCY HOSPITAL CASSVILLE, MERCY ST. FRANCIS HOSPITAL, AND MERCY HOSPITAL CARTHAGE) IN 16 COUNTIES IN RURAL MISSOURI (BARRY, DALLAS, DOUGLAS, HOWELL, JASPER, LACLEDE, LAWRENCE, PHELPS, POLK, PULASKI, SHANNON, STONE, TANEY, TEXAS, WEBSTER, AND WRIGHT). ALL COUNTIES ARE FULLY RURAL EXCEPT JASPER, WHERE SERVICES SUPPORTED BY THIS AWARD WILL ONLY BE DELIVERED IN HRSA-DESIGNATED RURAL CENSUS TRACTS. THE PROJECT WILL PROVIDE IMMEDIATE ACCESS TO EVIDENCE-BASED CARE FOR RURAL PATIENTS PRESENTING IN THE EMERGENCY DEPARTMENTS AT THESE FIVE HOSPITALS FOR OPIOID USE DISORDER (OUD) AND CREATE BRIDGE CLINICS THAT CAN BE ACCESSED BY PATIENTS TO MEET SHORT-TERM NEEDS TO REDUCE AND PREVENT THE RISK OF OVERDOSES IN RURAL AREAS. THE OBJECTIVES INCLUDE ESTABLISHING AND/OR EXPANDING OUD PREVENTION, HARM REDUCTION, TREATMENT, AND RECOVERY SERVICES IN THE TARGET RURAL SERVICE AREA BY INITIATING MEDICATION-ASSISTED TREATMENT (MAT) WHERE APPROPRIATE THROUGH AN INITIAL DOSE PRIOR TO PATIENT DISCHARGE WHEN PRESENTING AT THE EMERGENCY DEPARTMENT; ESTABLISHING THE FIVE HOSPITALS AS BRIDGE CLINICS THAT WILL PROVIDE A THREE-DAY BRIDGE PRESCRIPTION OF MAT, TERTIARY PREVENTION SUPPLIES, AND CONNECTIONS WITH RELEVANT COMMUNITY SUPPORTS SUCH AS PEER-RECOVERY MEETINGS; PROVIDING DIRECT REFERRALS TO MERCY’S VIRTUAL SUBSTANCE USE RECOVERY PROGRAM (VSURP) WHO WILL REACH OUT TO PATIENTS WITHIN 24-72 HOURS AND BEGIN CARE IMMEDIATELY TO ASSURE THERE IS NO GAP IN TREATMENT FROM THE BRIDGE CLINIC; AND PROVIDING CLINICAL TRAINING AND SUPPORT TO OVERCOME STIGMA, INCREASE BUY-IN, AND EDUCATE PROVIDERS ON THE USE OF THE NEW OUD SERVICES AND RESOURCES TO BE IMPLEMENTED. VSURP WILL PROVIDE A VIRTUAL FOLLOW-UP VISIT VIA A TELEHEALTH CONSULT WITH AN ADDICTION MEDICINE PROFESSIONAL TO BEGIN A LONGER-TERM TREATMENT REGIMEN WITH A COMBINATION OF COUNSELING, MAT, AND CONNECTION WITH A SOCIAL WORKER TO ADDRESS ANY SOCIAL DETERMINANTS OF HEALTH. VSURP IS CURRENTLY SUCCESSFULLY BRINGING THESE SERVICES TO OTHER LOCATIONS WITHIN MERCY AND SEEKS TO EXPAND INTO THE RURAL PARTS OF MISSOURI TARGETED IN THIS APPLICATION. OUD RESOURCES IN THE TARGETED REGION ARE EXTREMELY LIMITED, SO THE PROPOSED PROJECT WILL FILL THIS GAP BY ESTABLISHING FIVE NEW BRIDGE CLINICS AND PROVIDING TREATMENT ACCESS VIA TELEHEALTH. THE NEEDS TO BE ADDRESSED BY THE PROPOSED PROJECT ARE THE LACK OF OUD AND BRIDGE SERVICES AVAILABLE IN THE TARGET RURAL AREAS (TO BE ADDRESSED BY ESTABLISHING BRIDGE CLINICS IN THE FIVE RURAL HOSPITALS AND PROVIDING ACCESS TO CARE VIA VSURP); OVERCOMING STIGMA FROM CLINICAL STAFF AND FRUSTRATION FROM A LACK OF AVAILABLE REFERRAL SERVICES (ADDRESSED BY CLINICAL TRAINING AND SUPPORT, BRIDGE CLINICS, AND VSURP); THE LACK OF PROVIDER EDUCATION ON MAT INDUCTION IN THE EMERGENCY DEPARTMENT (ADDRESSED BY CLINICAL TRAINING AND SUPPORT AND VSURP); THE LACK OF AFFORDABLE ACCESS TO NALOXONE (ADDRESSED BY PROVIDING THIS TERTIARY PREVENTION ITEM IN “TAKE-HOME PACKS” FOR BRIDGE CLINIC PATIENTS); AND THE LACK OF ACCESS TO ADDICTION MEDICINE PROFESSIONALS IN THE RURAL AREAS (ADDRESSED BY SCREENING AND ACCESS TO TREATMENT AS WELL AS THROUGH SERVICES FROM VSURP VIA TELEHEALTH). THE PROPOSED SERVICES INCLUDE TIER 1, PREVENTION #1—TERTIARY PREVENTION (1.1); TIER 1, TREATMENT #3—SCREENING AND CONNECTION TO TREATMENT (1.3); TIER 1, TREATMENT #4—BRIDGE CLINICS (1.4); AND TIER 2, CAPACITY BUILDING—CLINICAL TRAINING AND SUPPORT (2.CB). THE POPULATION GROUP TO BE SERVED IS ADULTS AGES 18 AND OLDER IN 16 COUNTIES IN RURAL MISSOURI THAT EXPERIENCE ECONOMIC DISTRESS AND LOWER MEDIAN HOUSEHOLD INCOMES AND HAVE HIGH RATES OF POOR PHYSICAL AND MENTAL HEALTH DAYS, UNINSURED AND MEDICAID RATES, SUBSTANCE USE DISORDER PREVALENCE, OVERDOSE MORTALITY, AND DEATHS OF DESPAIR, WHICH CAN BE INDICATIVE OF POOR MENTAL HEALTH AND CAN RESULT IN OR LEAD TO SUBSTANCE USE.

IDENTIFYING MECHANISMS OF MOTIVATIONAL INTERVIEWING

REGISTRY-ASSISTED DISSEMINATION OF MOBILE PAIN MANAGEMENT FOR YOUTH WITH ARTHRITIS

A MULTI-OMICS APPROACH TO OVERCOME RESISTANCE IN INFANT LEUKEMIA BY IDENTIFYING IMMUNE THERAPY FAILURE MECHANISMS

THIS PROJECT WILL PROVIDE ENVIRONMENTAL EDUCATION THAT FOCUSES ON PEDIATRIC ENVIRONMENTAL HEALTH AND HEALTHY HOMES WITH EMPHASIS ON INDOOR/OUTDOOR AI

HEALTH CARE AND OTHER FACILITIES

HEALTH CARE AND OTHER FACILITIES

HEALTH CARE AND OTHER FACILITIES

COMMUNITY FACILITY GRANTS

HEALTH CARE AND OTHER FACILITIES

IMPLEMENTATION STRATEGIES AND EFFECTIVENESS FOR WALKING SCHOOL BUS PROGRAMS

DRUG RELEASING MICRODISCS FOR ESOPHAGEAL DRUG DELIVERY

UNDERSTANDING OBESITY-RELATED BEHAVIORS AND THE ROLE OF SCHOOL AND NON-SCHOOL ENVIRONMENTS USING LOCATION-BASED MEASURES

AUTISM AND OBESITY: CO-OCCURRING CONDITIONS OR DRUG SIDE EFFECTS

NATURAL KILLER CELL REGULATION OF THE GERMINAL CENTER HIV NEUTRALIZING ANTIBODY RESPONSE

RECELLULARIZATION MECHANISMS IN MONONUCLEAR CELL SEEDED TISSUE ENGINEERED VALVES

HEALTH CARE AND OTHER FACILITIES

RURAL HEALTH CLINIC VACCINE CONFIDENCE PROGRAM

HEALTH CARE AND OTHER FACILITIES

RBPI-21 IN CHILDREN UNDERGOING CARDIOPULMONARY BYPASS

ARP ECONOMIC DEVELOPMENT GRANT FOR RURAL HEALTH CARE FACILITIES

HEALTH CARE AND OTHER FACILITIES

COMMUNITY FACILITIES LOANS AND GRANTS - ARRA

PURPOSE: TO SUPPORT A RANDOMIZED-CONTROLLED FEASIBILITY STUDY TO EVALUATE BEHAVIORAL LANGUAGE-RELATED AND PHYSIOLOGICAL OUTCOMES OF A MUSIC-BASED INTERVENTION INVOLVING PARENT-CHILD PAIRINGS FROM LOW SOCIOECONOMIC BACKGROUNDS IN THE UNITED STATES.

THE PRESUMPTIVE CASE AGAINST RETURNING INDIVIDUAL RESULTS IN BIOBANKING RESEARCH

ARP ECONOMIC DEVELOPMENT GRANT FOR RURAL HEALTH CARE FACILITIES

THE PURPOSE OF THIS PROJECT IS TO ENHANCE INDOOR AIR QUALITY OF SCHOOLS THROUGH THE USE OF EPA'S TOOLS FOR SCHOOLS PROGRAM. IN COLLABORATION WITH T

ENSURING MEDICATION SAFETY IN PEDIATRIC EMERGENCIES

COMMUNITY FACILITY GRANTS

COMMUNITY FACILITY GRANTS

PEDIATRIC PHARMACOGENOMICS AND PERSONALIZED MEDICINE

COMMUNITY FACILITY GRANTS

DESCRIPTION:THIS PROJECT SUPPORTS THE OPERATION OF PROTECTING CHILDREN FROM ENVIRONMENTAL HEALTH RISKS AND PROVIDES FLEXIBILITY TO ADDRESS ENVIRONMENTAL PRIORITIES. THIS AGREEMENT PROVIDES FUNDING TO THE CHILDREN'S MERCY HOSPITAL, THROUGH ITS REGION 7 PEDIATRIC ENVIRONMENTAL HEALTH SPECIALTY UNIT (PEHSU). ACTIVITIES:THE PEHSU WILL DEVELOP AND DISSEMINATE EDUCATION MATERIALS AND SUPPLIES TO BUILD KNOWLEDGE RELATED TO CHILDREN'S LEAD, PESTICIDE SAFETY, AND EXPOSURE RISKS REDUCTION TO IN-HOME DAY CARE PROVIDERS LOCATED IN VULNERABLE COMMUNITIES. THIS AGREEMENT FUNDS OUTREACH AND EDUCATION EFFORTS IN ST. LOUIS, MISSOURI TO PROTECT CHILDREN FROM ENVIRONMENTAL HEALTH RISKS IN VULNERABLE COMMUNITIES. THE PEHSU'S EDUCATION ACTIVITIES WILL ASSURE THAT CHILDREN UNDER THE AGE OF SIX EXPOSURES TO LEAD AND PESTICIDES WILL BE REDUCED THROUGH OUTREACH TO IN-HOME DAYCARE CENTERS.SUBRECIPIENT:NO SUBAWARDS ARE INCLUDED IN THIS ASSISTANCE AGREEMENT.OUTCOMES: THE PEHSU WILL DELIVER OUTREACH AND EDUCATION, ESTABLISH A SERIES OF DIGITAL PESTICIDE SAFETY MESSAGES, AND INCREASE THE AWARENESS AND AVAILABILITY OF TESTING FOR ELEVATED BLOOD LEVELS IN CHILDREN. THIS FUNDING WILL DIRECTLY BENEFIT THE CITIZENS OF MISSOURI.

COMMUNITY FACILITIES - ECONOMIC IMPACT INITIATIVE GRANTS

TO SUPPORT A STUDY THAT EXAMINES WHETHER VISUAL ARTISTS--WORKING WITH BIOMEDICAL RESEARCHERS--CAN DEPICT COMPLEX RESEARCH CONCEPTS COMMONLY USED IN B

THE 10TH INTERNATIONAL MDM2 WORKSHOP - PROJECT SUMMARY/ABSTRACT THE P53 PROTEIN IS THE MOST FREQUENTLY MUTATED GENE IN HUMAN CANCERS AND FUNCTIONS AS A TUMOR SUPPRESSOR BY TRANSCRIPTIONALLY REGULATING NUMEROUS DOWNSTREAM TARGET GENES INVOLVED IN CELL CYCLE PROGRESSION AND APOPTOSIS. MDM2 AND ITS HOMOLOG MDM4 (ALSO KNOWN AS MDMX) ARE TWO OF THE MOST IMPORTANT NEGATIVE REGULATORS OF P53 BY ACTING AS AN E3 UBIQUITIN LIGASE COMPLEX TO PROMOTE P53 DEGRADATION AND BY PHYSICAL BINDING TO INHIBIT THE P53’S TRANSCRIPTIONAL FUNCTION. THESE PROTEINS ARE ALSO OVEREXPRESSED IN APPROXIMATELY 30% OF HUMAN CANCERS. OVEREXPRESSION OF MDM2/MDM4 NOT ONLY INHIBITS P53 FUNCTION, BUT ALSO SHOWS P53-INDEPENDENT ONCOGENIC ACTIVITIES. INTRIGUINGLY, GENE AMPLIFICATION OF MDM2 AND MDM4 IS ASSOCIATED WITH ADVERSE HYPERPROGRESSIVE RESPONSE TO ANTI-PDL1 CANCER IMMUNOTHERAPY IN A SUBSET OF PATIENTS. THUS, INHIBITORS FOR MDM2 AND MDM4 HAVE BEEN DEVELOPED TO INHIBIT THEIR ONCOGENIC ACTIVITIES AND TO REACTIVATE WILD-TYPE P53 IN TUMORS. IMPORTANTLY, SOME MDM2/MDM4 INHIBITORS ARE IN CLINICAL TRIALS. THE FIRST INTERNATIONAL MDM2 WORKSHOP, HELD IN 2001 IN THE UNITED KINGDOM, WAS PRIMARILY IN RESPONSE TO A SIGNIFICANT INCREASE IN THE RESEARCH RELATED TO P53 AND ITS NEGATIVE REGULATORS MDM2/MDM4, AS WELL AS STRONG DEMAND FOR DRUG DISCOVERY TARGETING MDM2/MDM4/P53. THE EXPANSION OF THE SCIENTIFIC COMMUNITY STUDYING MDM2/MDM4 AND THE NEED TO PURSUE THIS AREA OF RESEARCH WITH A COLLABORATIVE MULTIDISCIPLINARY APPROACH HAVE FURTHER MADE THE MDM2 WORKSHOP NECESSARY. THE MDM2 WORKSHOP IS HELD EVERY TWO OR THREE YEARS, AT LOCATIONS ALTERNATING BETWEEN THE UNITED STATES AND EUROPE, TO BRING TOGETHER THE P53/MDM2 FIELD, PRESENT THE LATEST RESEARCH, AND FACILITATE COLLABORATION AND EXCHANGE OF REAGENTS. INDEED, BOTH THE P53 AND MDM2 WORKSHOPS HAVE BECOME IMPORTANT PLATFORMS FOR LONG-TERM SCIENTIFIC EXCHANGE AND NEW INVESTIGATORS OF THE MDM2-P53 PATHWAY. THE 10TH INTERNATIONAL MDM2 WORKSHOP WILL BE HELD AT AN AUDITORIUM OF THE NEWLY BUILT NATIONAL CANCER CENTER RESEARCH INSTITUTE (NCCRI) IN TOKYO, JAPAN, ON OCTOBER 15-18, 2023. THIS WILL BE THE FIRST INTERNATIONAL P53/MDM2 WORKSHOP ORGANIZED AND HELD IN JAPAN. THE MEETING WILL BE CO-ORGANIZED BY DR. RIEKO OHKI (NCCRI, TOKYO, JAPAN), DR. KOJI ITAHANA (DUKE-NUS MEDICAL SCHOOL, SINGAPORE), AND DR. TOMOO IWAKUMA (CHILDREN’S MERCY RESEARCH INSTITUTE, MO, USA). NOTABLY, DUE TO COVID-19, WE HAVE NOT HAD THE MDM2 WORKSHOP FOR OVER 4 YEARS, SINCE THE 9TH MDM2 WORKSHOP ON NOVEMBER 4-7, 2018 IN FLORIDA. WE EXPECT MORE PARTICIPANTS WITH HIGHER ENTHUSIASM FOR THIS 10TH MDM2 WORKSHOP, AS COMPARED WITH THE PREVIOUS MDM2 WORKSHOPS. SIGNIFICANT NUMBERS OF US RESEARCHERS, INCLUDING THE INTERNATIONAL ORGANIZING COMMITTEE (11 OUT OF 16, 38% WOMEN), ARE EXPECTED TO PARTICIPATE IN AND BENEFIT FROM THE MEETING. HENCE, WE ARE APPLYING FOR R13 FUNDING TO SUPPORT THIS IMPORTANT AND EXCITING INTERNATIONAL MEETING THAT WILL ENERGIZE RESEARCH IN US AND PROMOTE SCIENTIFIC PROGRESS AND INTERACTIONS IN THE P53/MDM2 FIELD. FUNDS ARE REQUESTED TO SUPPORT THREE IMPORTANT SPECIFIC AIMS DESIGNED TO PROMOTE PARTICIPATION OF THE US INVESTIGATORS AND TRAINEES.

COMMUNITY FACILITIES - ECONOMIC IMPACT INITIATIVE GRANTS

ONE CENTER, TWO STATES

COMMUNITY FACILITY GRANTS

RURAL HEALTH NETWORK DEVELOPMENT PROGRAM