Childrens Hospital Inc

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

ADMINISTRATIVE COORDINATING CENTER: CARDIOVASCULAR DEVELOPMENT AND PEDIATRIC CARDIAC GENOMICS CONSORTIA

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

THE IMPACT OF COVID-19 ON PEOPLE LIVING WITH RARE DISEASES AND THEIR FAMILIES

IMPACT OF THE INITIAL INFLUENZA EXPOSURE ON THE QUALITY, MAGNITUDE, BREADTH, POTENCY AND DURABILITY OF INFLUENZA IMMUNITY

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

ABCD-USA CONSORTIUM: RESEARCH PROJECT

SOUTHERN CALIFORNIA CENTER FOR CHRONIC HEALTH DISPARITIES IN LATINO CHILDREN AND FAMILIES. - OBESITY AND RELATED CHRONIC DISEASES, TYPE 2 DIABETES, NON-ALCOHOLIC FATTY LIVER DISEASE, AND DYSLIPIDEMIA CONTINUE TO INCREASE IN THE U.S., AND LATINOS ARE DISPROPORTIONALLY AFFECTED. THESE DISPARITIES BEGIN IN EARLY LIFE, OCCUR WITHIN FAMILIES, AND ARE DRIVEN BY MULTI-LEVEL FACTORS, INCLUDING INDIVIDUAL (DIET, EATING BEHAVIORS), SOCIAL (CULTURAL VALUES, ECONOMIC FACTORS), AND ENVIRONMENTAL (ACCESS TO HEALTHY FOODS, CHEMICAL EXPOSURES SUCH AS AIR POLLUTION). THESE FACTORS INTERACT TO AFFECT LATINO HEALTH BUT ARE RARELY STUDIED IN A HOLISTIC MANNER. OUR OVERARCHING GOAL IS TO UNDERSTAND HOW THESE MULTI-LEVEL FACTORS CONTRIBUTE TO MULTIPLE CHRONIC DISEASE DISPARITIES IN LATINOS ACROSS THE LIFE COURSE, AND TO DEVELOP AND EVALUATE FAMILY-BASED, CULTURALLY SENSITIVE SOLUTIONS. WE PROPOSE TO ACCOMPLISH THIS AMBITIOUS GOAL BY ESTABLISHING THE SOUTHERN CALIFORNIA CENTER FOR CHRONIC HEALTH DISPARITIES IN LATINO FAMILIES AND CHILDREN (SCC-CHDLFC), A COALITION OF ACADEMIC, CLINICAL, GOVERNMENT, AND COMMUNITY STAKEHOLDERS ACROSS THE REGION THAT IS HOME TO 10.8 MILLION LATINOS REPRESENTING 45.2% OF THE POPULATION. THE CENTER IS LED BY DRS. GORAN (CHILDREN’S HOSPITAL LOS ANGELES; CHLA) AND BAEZCONDE-GARBANATI (UNIV. OF SOUTHERN CALIFORNIA; USC), WHO PROVIDE COMPLEMENTARY EXPERTISE IN LATINO HEALTH DISPARITIES RESEARCH. THE ADMINISTRATIVE CORE PROVIDES LEADERSHIP, OVERSIGHT, COMMUNICATION, AND EVALUATION TO STRENGTHEN AND BUILD COLLABORATION, ACCELERATE RESEARCH, AND DRIVE INNOVATION TO ENSURE CENTER SUCCESS AND IMPACT. PROJECT 1 (LED BY DR. GORAN, CHLA) UTILIZES AN ONGOING BIRTH-COHORT TO EXAMINE HOW EARLY-LIFE NUTRITION, ENVIRONMENT, AND SOCIAL FACTORS AFFECT CHRONIC DISEASE RISK BY AGE 5Y, AND HOW THESE FACTORS AFFECT RESPONSE TO FAMILY-BASED INTERVENTIONS IN PROJECTS 2 AND 3. PROJECT 2 (LED BY DR. BOUTELLE, UC SAN DIEGO) TESTS A PARENT-ONLY INTERVENTION FOR TREATMENT OF OBESITY AND CHRONIC DISEASE RISK IN LATINO CHILDREN. THE INTERVENTION, DESIGNED TO ADDRESS CULTURAL ISSUES RELEVANT TO LATINO FAMILIES, IS DELIVERED BY TELEHEALTH TO PARENTS ONLY, INCREASING DISSEMINATION POTENTIAL. PROJECT 3 (LED BY DR. COHEN, KAISER PERMANENTE) EXAMINES THE EFFICACY OF AN AFFORDABLE GROCERY DELIVERY PROGRAM (AT A COST NOT EXCEEDING SNAP DOLLARS), IN CONJUNCTION WITH CULTURALLY APPROPRIATE MEAL PLANNING, ON CHRONIC DISEASE RISK REDUCTION IN LATINO MULTI-GENERATION HOUSEHOLDS. WE WILL SUPPORT SYNERGY AND COLLABORATION ACROSS THESE PROJECTS AND BUILD THE RESEARCH ENTERPRISE THROUGH CENTER CORES. THE METHODS & DATA SUB-CORE LED BY DR. ESPINOZA (CHLA) WILL PROVIDE EXPERTISE IN ASSESSMENT OF DIET, SOCIAL, ENVIRONMENTAL, AND GEOSPATIAL FACTORS, AND DATA ANALYSIS AND MANAGEMENT, TO SUPPORT DATA HARMONIZATION AND SHARING. THE INVESTIGATOR DEVELOPMENT CORE LED BY DRS. SPRUIJT-METZ AND DE LA HAYE (USC) AND ELDER (SAN DIEGO STATE UNIV.) WILL ESTABLISH A MENTORING NETWORK AND PILOT STUDY PROGRAM TO SUPPORT EARLY-STAGE OR UNDERREPRESENTED RESEARCHERS, WHILE ALSO PROMOTING TEAM SCIENCE. THE COMMUNITY ENGAGEMENT CORE LED BY DRS. KIPKE (CHLA) AND BAEZCONDE-GARBANATI (USC) ENGAGES THE COMMUNITY IN THE RESEARCH PROCESS VIA BI-DIRECTIONAL INTERACTION WITH THE OVERALL GOAL TO ACCELERATE THE IMPACT OF CENTER FINDINGS ON THE LATINO COMMUNITY TO MITIGATE CHRONIC DISEASE RISK ACROSS THE REGION.

EPITHELIAL GENES IN ALLERGIC INFLAMMATION

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

YOUNG MEN OF COLOR WHO HAVE SEX WITH MEN COHORT STUDY

XENBASE: A XENOPUS MODEL ORGANISM DATABASE

DIGESTIVE HEALTH CENTER: BENCH TO BEDSIDE RESEARCH IN PEDIATRIC DIGESTIVE DISEASE

CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER VACCINE AND TREATMENT EVALUATION UNITS (UM1 CLINICAL TRIAL REQUIRED)

TCD WITH TRANSFUSIONS CHANGING TO HYDROXYUREA

SIGNALING PROCESSES UNDERLYING CARDIOVASCULAR FUNCTION

CHILDHOOD ABSENCE EPILEPSY RX, PK-PD-PHARMACOGENETICS

PEDIATRIC ACUTE LIVER FAILURE IMMUNE RESPONSE NETWORK (PALF IRN): TREATMENT FOR IMMUNE MEDIATED PATHOPHYSIOLOGY (TRIUMPH) - PROJECT SUMMARY PEDIATRIC ACUTE LIVER FAILURE (PALF) IS A RARE, DEVASTATING CONDITION THAT AFFECTS AN ESTIMATED 250 CHILDREN PER YEAR IN NORTH AMERICA, CAUSING DEATH IN APPROXIMATELY 15% AND THE NEED FOR LIVER TRANSPLANTATION (LT) IN AN ADDITIONAL 20-30%. IN THE MAJORITY OF CASES, A SPECIFIC CAUSE OF THE LIVER INJURY IS NEVER DETERMINED. RECENT RESEARCH CONDUCTED IN THESE PATIENTS SUPPORTS THE THEORY THAT MANY OF THESE PATIENTS HAVE LIVER INJURY RELATED TO A HYPERINFLAMMATORY IMMUNE RESPONSE TO EVERYDAY INFECTIONS OR ENVIRONMENTAL EXPOSURES. STUDIES HAVE RECENTLY IMPLICATED T LYMPHOCYTES AS THE CENTRAL DRIVERS OF THE INFLAMMATORY PROCESS. PHYSICIANS CARING FOR PALF PATIENTS ARE SEARCHING FOR THERAPIES THAT QUIET THIS T CELL RESPONSE, DAMPEN THE INFLAMMATORY CASCADE AND ALLOW THE PATIENT’S REMAINING LIVER CELLS TO HEAL AND REGENERATE. CLINICAL EXPERIENCE IN CHILDREN WITH ABNORMAL HYPERINFLAMMATORY IMMUNE RESPONSES ASSOCIATED WITH OTHER DISEASE STATES SUCH AS SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS AND ACQUIRED APLASTIC ANEMIA HAS DEMONSTRATED THAT BOTH HIGH DOSE CORTICOSTEROIDS AND EQUINE ANTI- THYMOCYTE GLOBULIN CAN SUPPRESS IMMUNE RESPONSES AND REVERSE PROGRESSIVE TISSUE DAMAGE. THE GOAL OF THE PEDIATRIC ACUTE LIVER FAILURE IMMUNE RESPONSE NETWORK (PALF IRN) IS TO SUPPORT A TREATMENT TRIAL OF IMMUNOSUPPRESSIVE THERAPY USING HIGH DOSE CORTICOSTEROIDS OR EQUINE ANTI-THYMOCYTE GLOBULIN TO REVERSE HARMFUL INFLAMMATORY IMMUNE RESPONSES IN CHILDREN WITH PALF TO PREVENT FURTHER DISEASE PROGRESSION AND REDUCE MORTALITY AND LT IN THIS POPULATION. WE PROPOSE THE TREATMENT FOR IMMUNE MEDIATED PATHOPHYSIOLOGY (TRIUMPH) TRIAL, A DOUBLE-BLIND, THREE ARM, RANDOMIZED, PLACEBO CONTROLLED TRIAL OF HIGH DOSE METHYLPREDNISOLONE OR EQUINE ANTI-THYMOCYTE GLOBULIN. WE WILL TEST THE HYPOTHESIS THAT SURVIVAL WITH NATIVE LIVER AT 21 DAYS POST RANDOMIZATION WILL BE SIGNIFICANTLY HIGHER IN PATIENTS RECEIVING IMMUNOSUPPRESSIVE THERAPY AS COMPARED TO PATIENTS THAT RECEIVE SUPPORTIVE CARE ALONE. WE WILL ALSO DETERMINE THE SAFETY OF IMMUNOSUPPRESSIVE THERAPY IN PALF PATIENTS AND DEFINE THE BALANCE BETWEEN RISK OF SIDE-EFFECTS AND TREATMENT BENEFIT. OUR OUTCOMES WILL INCLUDE NOT ONLY CLINICAL END-POINTS SUCH AS PATIENT SURVIVAL, TIME TO RESOLUTION OF DISEASE AND ADVERSE HEALTH EVENTS, BUT ALSO MEASURES OF PATIENT REPORTED OUTCOMES DURING REHABILITATION FROM THE ILLNESS. TRIAL PARTICIPANTS WILL PROVIDE BLOOD AND LIVER SAMPLES THAT WILL BE EXAMINED TO BETTER UNDERSTAND THEIR IMMUNE RESPONSES, ESPECIALLY THAT OF T LYMPHOCYTES, IN BOTH THE CIRCULATION AND IN THE LIVER. SAMPLES WILL BE STORED IN A REPOSITORY TO SUPPORT FUTURE STUDIES EXPLORING NEW ASPECTS OF THIS RARE DISEASE.

NEIGHBORHOOD INTEGRATED CARE FOR KIDS (NINCK)

CONSORTIUM OF EOSINOPHILIC GASTROINTESTINAL DISEASE RESEARCHERS

DEVELOPMENTAL MECHANISMS OF TRACHEA-ESOPHAGEAL BIRTH DEFECTS

BIOLOGY AND THERAPY OF HIGH RISK NEUROBLASTOMA

CHILDHOOD CV RISK AND ADULT CVD OUTCOMES: AN INTERNATIONAL LONG-TERM FOLLOW-UP

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

ENHANCED SURVEILLANCE FOR NEW VACCINE PREVENTABLE DISEASES

CLINICAL CENTER FOR BILIARY ATRESIA: ETIOPATHOGENESIS A*

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

BUILDING MODULAR PEDIATRIC CHRONIC DISEASE REGISTRIES FOR QI AND CE RESEARCH

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

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

THE LUNGMAP DATA COORDINATION CENTER FOR NEXT GEN SYSTEMS BIOLOGY OF RESPIRATION

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

TEEN LONGITUDINAL ASSESSMENT OF BARIATRIC SURGERY (TEEN-LABS) RENEWAL

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

NATIONAL BIOLOGICAL SAMPLE AND DATA REPOSITORY FOR PAH

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

THE IMPACT OF EARLY MEDICAL TREATMENT IN TRANSGENDER YOUTH

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

MULTIMODAL BIOPHYSICAL MARKERS OF VASCULAR DISEASE IN HEMOGLOBINOPATHIES

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

4/6 HBCD PRENATAL EXPERIENCES AND LONGITUDINAL DEVELOPMENT (PRELUDE) CONSORTIUM - PROJECT SUMMARY/ABSTRACT BRAIN DEVELOPMENT OCCURS AT A RAPID PACE PRENATALLY AND THROUGHOUT CHILDHOOD, IMPACTED BY DYNAMIC GENETIC AND ENVIRONMENTAL INFLUENCES. STUDIES USING ADVANCED NEUROIMAGING HAVE PROVIDED SIGNIFICANT INSIGHTS INTO BRAIN DEVELOPMENT BUT HAVE BEEN LIMITED BY SMALL SAMPLE SIZE, ESPECIALLY FOR HIGH-RISK POPULATIONS. SUBSTANCE- EXPOSED INFANTS ARE AT PARTICULARLY HIGH RISK FOR ADVERSE OUTCOMES; HOWEVER, FINDINGS ARE INCONSISTENT, MAKING IT DIFFICULT TO DISENTANGLE PRENATAL EXPOSURE EFFECTS FROM OTHER ADVERSE INFLUENCES. THE OBJECTIVES OF OUR HEALTHY BRAIN AND CHILD DEVELOPMENT (HBCD) PRENATAL EXPERIENCES AND LONGITUDINAL DEVELOPMENT (PRELUDE) CONSORTIUM ARE TO CHARACTERIZE TYPICAL TRAJECTORIES OF BRAIN DEVELOPMENT FROM BIRTH THROUGH CHILDHOOD, MEASURING THE INFLUENCE OF KEY BIOLOGIC AND ENVIRONMENTAL FACTORS AND THEIR INTERACTIONS ON CHILD SOCIAL, COGNITIVE, AND EMOTIONAL DEVELOPMENT. WE WILL ASSESS HOW CHILDREN PRENATALLY EXPOSED TO OPIOIDS AND OTHER SUBSTANCES, AS WELL AS ENVIRONMENTAL ADVERSITY, DIFFER IN THOSE BRAIN TRAJECTORIES AND OUTCOMES. OUR CONSORTIUM CONSISTS OF SIX CENTERS (ARKANSAS CHILDREN’S RESEARCH INSTITUTE, CASE WESTERN RESERVE UNIVERSITY, CINCINNATI CHILDREN’S HOSPITAL, CHILDREN’S NATIONAL MEDICAL CENTER, UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL, AND VANDERBILT UNIVERSITY) WHICH HAVE COLLABORATED PREVIOUSLY AND HAVE COMPLEMENTARY EXPERTISE IN NEUROIMAGING, NEUROPHYSIOLOGY, LONGITUDINAL CLINICAL RESEARCH, CHILD DEVELOPMENT, SUBSTANCE EXPOSURE AND ADDICTION, ETHICAL/LEGAL ISSUES, AND CLINICAL CARE OF HIGH-RISK INFANTS/CHILDREN. THE PRELUDE CONSORTIUM WILL RECRUIT 680 PREGNANT WOMEN WITH SUBSTANCE USE, 680 AT-RISK PREGNANT WOMEN WITHOUT SUBSTANCE USE, AND 1360 COMPARISON PREGNANT WOMEN REPRESENTATIVE OF THE GENERAL POPULATION TO CONTRIBUTE TO THE OVERALL HBCD STUDY. WE WILL WORK CLOSELY WITH THE OTHER SITES, THE HBCD CONSORTIUM ADMINISTRATIVE CORE, AND THE HBCD DATA COORDINATING CENTER TO DEVELOP A COMPREHENSIVE STUDY PROTOCOL AND ENSURE COMPLIANCE OF STUDY WORKFLOW AND DATA TRANSFER. OUR CONSORTIUM HAS AN OPTIMIZED RESEARCH PROTOCOL AND 4 SPECIFIC AIMS: 1) EMPLOY ETHICAL AND EVIDENCE-BASED BEST PRACTICES TO ENROLL AND RETAIN A DIVERSE COHORT OF PREGNANT WOMEN INTO A LONGITUDINAL STUDY OF INFANT/CHILD BRAIN DEVELOPMENT, OVERSAMPLING MOTHERS FROM HIGH-RISK BACKGROUNDS AND THOSE USING SUBSTANCES DURING PREGNANCY; 2) ENGAGE A COMPREHENSIVE ARRAY OF MATERNAL- AND CHILD-ORIENTED COMMUNITY STAKEHOLDERS TO IDENTIFY COMMUNITY CONCERNS AND PRIORITIES REGARDING THIS RESEARCH, MINIMIZE RISKS, AND PROMOTE LONG-TERM ENGAGEMENT OF THE RECRUITED CHILD-MOTHER DYADS; 3) COLLECT RICH DATA TO EXAMINE HOW MATERNAL HEALTH CONTEXT AND BROADER ENVIRONMENTAL FACTORS MAY AFFECT THE MATERNAL-FETAL DYAD AND NEURODEVELOPMENT OF CHILDREN; 4) CAPTURE KEY DEVELOPMENTAL WINDOWS DURING WHICH MATERNAL AND ENVIRONMENTAL FACTORS MAY INTERACT WITH BRAIN AND BEHAVIORAL DEVELOPMENT OF CHILDREN. THE INSIGHTS FROM THESE DATA WILL PROVIDE GREATER UNDERSTANDING OF FACTORS AFFECTING EARLY CHILDHOOD BRAIN DEVELOPMENT, ALLOWING TARGETED INTERVENTIONS AND IMPROVED OUTCOMES FOR MOTHER-CHILD DYADS.

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

REALIZING EFFECTIVENESS ACROSS CONTINENTS WITH HYDROXYUREA(REACH): A PHASE I/II PILOT STUDY OF HYROXYUREA FOR CHILDREN WITH SICKLE CELL ANEMIA

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

USC/UAP LEND PROJECT

FUNCTION AND STRUCTURE ADAPTATIONS IN FOREBRAIN DEVELOPMENT

PERSONALIZED CYSTIC FIBROSIS THERAPY AND RESEARCH CENTER

GENETICS, MECHANISMS AND CLINICAL PHENOTYPES OF ARRHYTHMOGENIC CARDIOMYOPATHY

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CINCINNATI CENTER OF EXCELLENCE IN HEMOGLOBINOPATHIES RESEARCH

AMITRIPTYLINE AND TOPIRAMATE IN THE PREVENTION OF CHILDHOOD MIGRAINE

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

MULTI-SITE RANDOMIZED CLINICAL TRIAL OF FIT TEENS FOR JUVENILE FIBROMYALGIA

PEDIATRIC GASTROENTEROLOGY AND NUTRITION TRAINING GRANT

RANDOMIZED CONTROL TRIAL OF OXYGEN THERAPY IN CHILDREN AND ADOLESCENTS WITH DOWN SYNDROME AND OBSTRUCTIVE SLEEP APNEA - ABSTRACT: A LARGE PERCENTAGE OF CHILDREN WITH DOWN SYNDROME (DS) HAVE OBSTRUCTIVE SLEEP APNEA (OSA) THAT IS SUBOPTIMALLY TREATED BY FIRST-LINE SURGICAL INTERVENTIONS. THE PERSISTENCE OF OSA-RELATED NIGHTLY INTERMITTENT HYPOXEMIA AND FRAGMENTED SLEEP MAY CONTRIBUTE TO A COGNITIVE IMPAIRMENT, AS WELL AS PULMONARY VASCULAR DISEASE, MYOCARDIAL DYSFUNCTION, REDUCED QUALITY OF LIFE AND DAILY FUNCTIONAL IMPAIRMENT. WHILE OXYGEN IS SOMETIMES USED WHEN OTHER OSA THERAPIES FAIL, ITS EFFICACY AND SAFETY HAVE NOT BEEN SYSTEMATICALLY STUDIED. THIS R61/R33 IS THEREFORE DESIGNED TO TEST THE HYPOTHESIS THAT INDIVIDUALS WITH DS AND MODERATE TO SEVERE OSA WILL HAVE A SAFE AND FAVORABLE RESPONSE TO LOW-FLOW OXYGEN TREATMENT DUE TO ITS EFFECTS ON DIRECTLY ATTENUATING HYPOXIC EPISODES, WITH SUBSEQUENT INCREASED VENTILATORY STABILITY AND IMPROVEMENT IN OSA. WE FURTHER HYPOTHESIZE THAT OXYGEN SUPPLEMENTATION WILL LEAD TO IMPROVEMENT IN NEUROCOGNITION, CARDIAC FUNCTION, SLEEP, AND QUALITY OF LIFE. THE R61 PHASE WILL ACTIVELY ENGAGE FAMILIES OF PATIENTS WITH DS AND OUR MULTI-STAKEHOLDER TEAM TO REFINE AND PILOT THE PROTOCOL AND RECRUITMENT STRATEGIES TO ENSURE THAT WE MEET OUR RECRUITMENT/RETENTION MILESTONES IN THE R33 PHASE AND WE GENERATE DATA MOST RELEVANT TO OUR PATIENT POPULATION. IN TOTO, WE WILL SCREEN APPROXIMATELY 328 CHILDREN WITH DS AND MODERATE TO SEVERE OSA, 5-17 YRS OF AGE, WHO FAILED ADENOTONSILLECTOMY, TO IDENTIFY OXYGEN RESPONDERS, AND THEN RANDOMIZE 230 CHILDREN TO OXYGEN PLUS CONSERVATIVE THERAPY (OXT; ADMINISTERED USING A PATIENT-SPECIFIC DOSE) OR CONSERVATIVE THERAPY (CT) ALONE (WEIGHT MANAGEMENT, SLEEP HYGIENE, NASAL DILATORS) FOR 6 MONTHS. THE PRIMARY OUTCOME OF THE TRIAL IS WORKING MEMORY MEASURED BY CO-PRIMARY ENDPOINTS THAT RESPECTIVELY ASSESS CAREGIVER-REPORTED AND OBJECTIVELY MEASURED FUNCTIONS. SECONDARY OUTCOMES INCLUDE CARDIAC FUNCTION AND STRUCTURE, RIGHT VENTRICULAR PRESSURE, QUALITY OF LIFE AND SLEEP MEASURES THAT WILL BE COLLECTED UNDER THE SUPERVISION OF EXPERIENCED, CENTRAL CORE LABORATORIES. SIX CLINICAL SITES EXPERIENCED WITH PEDIATRIC CLINICAL TRIALS AND ESTABLISHED DS CENTERS WILL PARTICIPATE IN THE TRIAL. A DATA COORDINATING CENTER EXPERIENCED WITH PEDIATRIC SLEEP TRIALS WITH A STRONG HISTORY OF WORKING WITH THESE CLINICAL SITES WILL IMPLEMENT AND MONITOR DATA QUALITY CONTROL PROCESSES THAT ADDRESSES ALL STAGES OF DATA HANDLING. THIS STUDY WILL FILL A KEY KNOWLEDGE GAP IN A POTENTIALLY EFFICACIOUS THERAPY FOR OSA, AND PROVIDE EVIDENCE TO SUPPORT (OR REFUTE) THE USE OF SUPPLEMENTAL OXYGEN, AS WELL AS IDENTIFY PHYSIOLOGICAL MARKERS TO POTENTIALLY IDENTIFY PATIENT SUBGROUPS MOST LIKELY TO EXPERIENCE BENEFIT FROM THIS THERAPY.

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CRITICAL TRANSLATIONAL STUDIES IN PEDIATRIC NEPHROLOGY

EDITING ALVEOLAR PROGENITOR CELLS FOR CORRECTION OF MONOGENIC DISEASE

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

TRANSLATIONAL MEDICINE AND MECHANISTIC STUDIES OF BRAIN NEUROPHYSIOLOGY IN FRAGILE X SYNDROME

INTERVENTION TO REDUCE EARLY (PEANUT) ALLERGY IN CHILDREN (IREACH)

GENE EXPRESSION IN PEDIATRIC ARTHRITIS

RANDOMIZED STUDY OF LOW VERSUS MODERATE DOSE BUSULFAN IN TRANSPLANT FOR SEVERE COMBINED IMMUNODEFICIENCY

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

2/24 HEALTHY BRAIN AND CHILD DEVELOPMENT NATIONAL CONSORTIUM - PROJECT SUMMARY/ABSTRACT NEURODEVELOPMENTAL PROCESSES ARE SHAPED BY DYNAMIC INTERACTIONS BETWEEN GENES AND ENVIRONMENTS. MALADAPTIVE EXPERIENCES EARLY IN LIFE CAN ALTER DEVELOPMENTAL TRAJECTORIES, LEADING TO HARMFUL AND ENDURING DEVELOPMENTAL SEQUELAE. PRE- AND POSTNATAL HAZARDS INCLUDE MATERNAL SUBSTANCE EXPOSURE, TOXICANT EXPOSURES IN PREGNANCY AND EARLY LIFE, MATERNAL HEALTH CONDITIONS, PARENTAL PSYCHOPATHOLOGY, MALTREATMENT, STRUCTURAL RACISM, AND EXCESSIVE STRESS. TO ELUCIDATE HOW VARIOUS ENVIRONMENTAL HAZARDS IMPACT CHILD DEVELOPMENT, IT IS IMPERATIVE THAT A NORMATIVE TEMPLATE OF DEVELOPMENTAL TRAJECTORIES OVER THE FIRST 10 YEARS OF LIFE BE ESTABLISHED BASED ON A SUFFICIENTLY LARGE AND DEMOGRAPHICALLY DIVERSE SAMPLE OF THE US POPULATION. TO ACCOMPLISH THIS, THE HEALTHY BRAIN AND CHILD DEVELOPMENT NATIONAL CONSORTIUM (HBCD-NC) HAS BEEN FORMED TO DEPLOY A HARMONIZED, OPTIMIZED, AND INNOVATIVE SET OF NEUROIMAGING (MRI, EEG) MEASURES COMPLEMENTED BY AN EXTENSIVE BATTERY OF BEHAVIORAL, PHYSIOLOGICAL, AND PSYCHOLOGICAL TOOLS, AND BIOSPECIMENS TO UNDERSTAND NEURODEVELOPMENTAL TRAJECTORIES IN A SAMPLE OF 7,500 MOTHERS AND INFANTS ENROLLED AT 24 SITES ACROSS THE UNITED STATES (US). THE HBCD-NC WILL CARRY OUT A COMMON RESEARCH PROTOCOL UNDER DIRECTION OF THE HBCD-NC ADMINISTRATIVE CORE (HCAC) AND WILL ASSEMBLE AND DISTRIBUTE A COMPREHENSIVE AND WELL-CURATED RESEARCH DATASET TO THE SCIENTIFIC COMMUNITY AT LARGE UNDER THE DIRECTION OF THE HBCD-NC DATA COORDINATING CENTER (HDCC). THE OVERARCHING GOAL OF THE HBCD-NC IS TO CREATE A COMPREHENSIVE, HARMONIZED, AND HIGH- DIMENSIONAL DATASET THAT WILL CHARACTERIZE TYPICAL NEURODEVELOPMENTAL TRAJECTORIES IN US CHILDREN AND THAT WILL ASSESS HOW BIOLOGICAL AND ENVIRONMENTAL EXPOSURES AFFECT THOSE TRAJECTORIES. A SPECIAL EMPHASIS WILL BE PLACED ON UNDERSTANDING THE IMPACT OF PRE- AND POSTNATAL EXPOSURE TO OPIOIDS, MARIJUANA, ALCOHOL, TOBACCO AND/OR OTHER SUBSTANCES. TO ADDRESS THESE BROAD OBJECTIVES, THE SAMPLE OF WOMEN ENROLLED WILL INCLUDE: 1) A RACIALLY, ETHNICALLY, AND SOCIOECONOMICALLY DIVERSE COHORT THAT IS REPRESENTATIVE OF THE US POPULATION; 2) PREGNANT WOMEN WITH USE OF TARGETED SUBSTANCES (OPIOIDS, MARIJUANA, ALCOHOL, TOBACCO); AND 3) DEMOGRAPHICALLY AND BEHAVIORALLY SIMILAR WOMEN WITHOUT SUBSTANCE USE IN PREGNANCY TO ENABLE VALID CAUSAL INFERENCES. IN ADDITION, THE HBCD-NC WILL IDENTIFY KEY DEVELOPMENTAL WINDOWS DURING WHICH BOTH HARMFUL AND PROTECTIVE ENVIRONMENTS HAVE THE MOST INFLUENCE ON LATER NEURODEVELOPMENTAL OUTCOMES. THE LARGE, MULTI-MODAL, LONGITUDINAL, AND GENERALIZABLE DATASET THAT WILL BE PRODUCED FOR THE FIRST TIME BY THIS STUDY WILL PROVIDE NOVEL INSIGHTS INTO CHILD DEVELOPMENT USING STATE- OF-THE-ART METHODS. THE HBCD-NC STUDY WILL INFORM PUBLIC POLICY TO IMPROVE THE HEALTH AND DEVELOPMENT OF CHILDREN ACROSS THE NATION.

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

ADOLESCENT BARIATRICS: CONTROLLED LONGITUDINAL STUDY OF PSYCHOSOCIAL DEVELOPMENT

MITOGENIC ACTIVITIES IN NEUROFIBROMATOSIS

HARNESSING THE THERAPEUTIC POTENTIAL OF NEURAL CREST CELLS BY MANIPULATING THE PRIMARY CILIUM

MOLECULAR, CELLULAR AND PHYSIOLOGICAL MECHANISMS OF THE MAMMALIAN CIRCADIAN CLOCK

THE GROWTH STUDY, GLYCEMIA RANGE AND OFFSPRING WEIGHT AND ADIPOSITY IN RESPONSE TO HUMAN MILK - ABSTRACT MATERNAL METABOLISM DURING PREGNANCY IS A KEY CONTRIBUTOR TO DEVELOPMENTAL ORIGINS OF METABOLIC DISEASE. OFFSPRING EXPOSED TO MATERNAL HYPERGLYCEMIA AND OBESITY HAVE INCREASED RATES OF OBESITY AND DISORDERED GLUCOSE METABOLISM. THE LACTATION PERIOD IS ALSO A CRITICAL WINDOW FOR PROGRAMMING. LACTOGENESIS INITIATES IN THE SECOND HALF OF GESTATION, THUS HUMAN MILK (HM) BIOSYNTHESIS IS SUSCEPTIBLE MATERNAL METABOLISM. INTERINDIVIDUAL VARIATION IN HM NUTRIENTS REVEALS THE INFLUENCE OF MATERNAL METABOLISM ON MILK BIOSYNTHESIS. A KNOWLEDGE GAP EXISTS AS TO WHETHER HM COMPOSITION ALTERS DEVELOPMENTAL PATHWAYS OF OFFSPRING PROGRAMMED IN UTERO. MATERNAL METABOLIC STATES INCLUDING GESTATIONAL DIABIETES (GDM) AND OBESITY ALTER HM NUTRIENT PROFILES, INCLUDING MILK FATTY ACIDS (FA). OUR STUDIES IDENTIFIED ALTERED HM LINOLEIC ACID AND DIHOMO-GAMMA-LINOLENIC ACID (DGLA) IN CONDITIONS OF MATERNAL DIABETES, HYPERGLYCEMIA, AND OBESITY, AS WELL AS HM PALMITIC ACID AND DGLA ASSOCIATIONS WITH INFANT GROWTH. HOWEVER, ANY IMPACT OF MATERNAL METABOLISM ACROSS THE ENTIRE RANGE OF GLYCEMIA ON BOTH HM COMPOSITION AND OFFSPRING PROGRAMMING HAS NOT BEEN EVALUATED IN CONTEXT OF DETAILED PROFILING OF IN UTERO EXPOSURES. OUR GOAL IS TO UNDERSTAND HOW HM SUSCEPTIBILITY TO MATERNAL METABOLISM IMPACTS OFFSPRING METABOLISM, IDENTIFYING INTERVENTIONS TO MITIGATE ADVERSE DEVELOPMENTAL PROGRAMMING. THIS PROPOSAL’S OBJECTIVE IS TO DETERMINE THE IMPACT OF MATERNAL GLYCEMIA IN PREGNANCY ON HM COMPOSITION AND EFFECTS OF HM NUTRIENTS ON OFFSPRING ADIPOSITY. TRANSLATIONAL SCIENCE APPROACHES WILL DETERMINE HOW MATERNAL GLYCEMIA ALTERS MAMMARY GLAND EPITHELIAL CELL GENE EXPRESSION AND HOW HM LIPIDS ACROSS THE RANGE OF MATERNAL GLYCEMIA REGULATE INFANT ADIPOCTYES. OUR OVERARCHING HYPOTHESIS IS THAT MATERNAL GLYCEMIA IN NORMAL AND PATHOLOGIC RANGES IMPACTS HM COMPOSITION, WHICH IN TURN INFLUENCES OFFSPRING METABOLIC PROGRAMMING AS REFLECTED BY EARLY CHILDHOOD ADIPOSITY. CAPITALIZING ON THE DETAILED METABOLIC PHENOTYPING OF THE GO MOMS COHORT, WE WILL CONDUCT PROSPECTIVE HM PROFILING AT 1, 2 AND 6 MONTHS POST-PARTUM IN A COHORT OF 450 WOMEN TO ASSOCIATE MATERNAL GLYCEMIA DURING AND AFTER PREGNANCY, FOCUSING ON HM LIPIDS KNOWN TO REGULATE OFFSPRING ADIPOSITY (AIM 1). MAMMARY EPITHELIAL CELLS SHED IN EXPRESSED HM WILL BE EVALUATED USING TRANSCRIPTOMICS (SUBAIM 1). FOR REPRODUCIBILITY, HM LIPIDS WILL BE COMPARED TO A SEPARATE VALIDATION COHORT ENROLLING WOMEN WITH GDM. WE WILL MEASURE OFFSPRING BODY COMPOSITION TO DISCERN ADIPOSITY AT MONTHS 1, 2, AND 6 AND 2 YEARS, ACCOUNTING FOR CHILDHOOD DIET (AIM 2). A HUMAN INFANT PREADIPOCYTE STRAIN WILL BE EXPOSED TO HM LIPIDS COLLECTED AND GROUPED BY QUARTILES OF MATERNAL GLYCEMIA TO DETERMINE MECHANISMS ALTERING INFANT ADIPOCYTE DEVELOPMENT (AIM 3). COMPLETING THE AIMS WILL DEFINE HM COMPOSITION IN A PREGNANCY COHORT WITH COMPREHENSIVE METABOLIC PROFILING THROUGHOUT PREGNANCY AND LACTATION ACROSS THE RANGE OF GLYCEMIA AND BMI. OFFSPRING GROWTH AND TRANSLATIONAL STUDIES WILL ADVANCE UNDERSTANDING OF HOW LACTATION EXPOSURES MODIFY IN UTERO PROGRAMMING. THIS WILL FURTHER THE FIELD BY REVEALING INTERVENTIONS TO REDUCE RISK OF ADVERSE OFFSPRING METABOLIC HEALTH.

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

HYPERGLYCEMIA AND ADVERSE PREGNANCY OUTCOME STUDY-CARDIOVASCULAR HEALTH OF HAPO OFFSPRING (HAPO CVH) - PROJECT SUMMARY HALTING THE INTERGENERATIONAL TRANSFER OF CARDIOVASCULAR DISEASE (CVD) RISK IS A PRIORITY FOR NHLBI AND THE AMERICAN HEART ASSOCIATION (AHA). YET, LIMITED UNDERSTANDING AROUND THE TIMING, PATHWAYS, AND MECHANISMS UNDERLYING THE OBSERVED ASSOCIATIONS BETWEEN MATERNAL GESTATIONAL HEALTH AND OFFSPRING CARDIOVASCULAR HEALTH (CVH) REMAINS A SIGNIFICANT BARRIER TO DEVELOPING TARGETED, TIMELY INTERVENTIONS. WE PROPOSE TO LEVERAGE THE HYPERGLYCEMIA AND ADVERSE PREGNANCY OUTCOME (HAPO) STUDY COHORT TO SUBSTANTIALLY ADVANCE UNDERSTANDING OF THE IN UTERO ORIGINS OF OFFSPRING CVH AND CVD, AS MEASURED DURING THE CRITICAL PERIOD OF YOUNG ADULTHOOD. THE ORIGINAL HAPO STUDY RECRUITED ~25,500 WOMEN IN 2000-2006 TO PROSPECTIVELY AND UNIFORMLY EXAMINE THE ASSOCIATION OF GESTATIONAL GLYCEMIA, UNCOMPLICATED BY TREATMENT, WITH MATERNAL AND NEONATAL OUTCOMES. ELEVEN YEARS LATER, 4,832 OFFSPRING RETURNED TO STUDY EFFECTS OF GDM ON OFFSPRING ADIPOSITY AND GLYCEMIA. WE HYPOTHESIZE THAT THERE ARE SIGNIFICANT INDEPENDENT ASSOCIATIONS OF MATERNAL ADIPOSITY, GLYCEMIA, BP, AND LIPIDS AT ~28 WEEKS GESTATION WITH CVH AND ARTERIAL INJURY AMONG OFFSPRING AT AGE 18-25 YEARS, AND THAT DNA METHYLATION (DNAM) WILL BE ASSOCIATED WITH UPSTREAM INTRAUTERINE EXPOSURES AND DOWNSTREAM CVH AND ARTERIAL INJURY. HAPO CVH WILL INCLUDE A COMPREHENSIVE CVH ASSESSMENT OF 1,000 HAPO FUS OFFSPRING FROM 4 HAPO CENTERS. WE WILL MEASURE BP, ADIPOSITY, LIPIDS, GLYCEMIA, AND LIFESTYLE BEHAVIORS, CHARACTERIZE TOTAL CVH WITH AHA’S ‘LIFE’S SIMPLE 7’ FRAMEWORK, AND OBTAIN CAROTID ULTRASONOGRAPHY TO IDENTIFY THE EARLIEST CHANGES OF SUBCLINICAL CVD. WE WILL ALSO ANALYZE EXISTING CORD BLOOD DNAM DATA AND WILL ACQUIRE NEW EPIGENOME-WIDE ASSOCIATION DATA FROM YOUNG ADULT DNA USING THE ILLUMINA 850K CHIP. WE WILL ACHIEVE OUR OBJECTIVES THROUGH THE FOLLOWING SPECIFIC AIMS: SPECIFIC AIM 1: DEFINE ASSOCIATIONS OF THE IN UTERO CARDIOMETABOLIC MILIEU AT ~28 WEEKS’ GESTATION WITH OFFSPRING CVH AND SUBCLINICAL CVD IN YOUNG ADULTHOOD. HYPOTHESIS 1A: POORER MATERNAL GESTATIONAL METABOLIC HEALTH IS ASSOCIATED WITH POORER OFFSPRING CVH (CO-PRIMARY OUTCOME) IN YOUNG ADULTHOOD. HYPOTHESIS 1B: POORER MATERNAL GESTATIONAL METABOLIC HEALTH IS ASSOCIATED WITH HIGHER CAROTID IMT (CO-PRIMARY OUTCOME), LOWER CAROTID DISTENSIBILITY, AND UNFAVORABLE CAROTID ARTERY GRAYSCALE FEATURES IN YOUNG ADULTHOOD. HYPOTHESIS 1C: POORER MATERNAL GESTATIONAL METABOLIC HEALTH IS ASSOCIATED WITH WORSENING OF CARDIOVASCULAR HEALTH FROM CHILDHOOD TO YOUNG ADULTHOOD. SPECIFIC AIM 2: EXAMINE THE ROLE OF EPIGENETIC MECHANISMS IN THE ASSOCIATION OF UPSTREAM INTRAUTERINE CARDIOMETABOLIC EXPOSURES AND DOWNSTREAM CVH AND SUBCLINICAL CVD. HYPOTHESIS 2A: POORER MATERNAL GESTATIONAL METABOLIC HEALTH IS ASSOCIATED WITH DIFFERENTIAL DNAM IN AGING-RELATED PATHWAYS (MEASURED AS ACCELERATED EPIGENETIC AGING) IN CORD BLOOD AND YOUNG-ADULT OFFSPRING. HYPOTHESIS 2B : POORER MATERNAL GESTATIONAL METABOLIC HEALTH IS ASSOCIATED WITH DIFFERENTIAL DNAM IN SPECIFIC CARDIOMETABOLIC PATHWAYS IN YOUNG- ADULT OFFSPRING BLOOD CELLS, AND THIS DIFFERENTIAL DNAM PARTLY STATISTICALLY MEDIATES THE ASSOCIATION OF ADVERSE INTRAUTERINE EXPOSURES WITH LATER CVH STATUS AND CAROTID ARTERIAL INJURY IN YOUNG ADULTHOOD

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

THROMBOSPONDIN 4 REGULATES ADAPTIVE ER STRESS RESPONSE

RANDOMIZED CONTROL TRIAL OF OXYGEN THERAPY IN CHILDREN AND ADOLESCENTS WITH DOWN SYNDROME AND OBSTRUCTIVE SLEEP APNEA - ABSTRACT: A LARGE PERCENTAGE OF CHILDREN WITH DOWN SYNDROME (DS) HAVE OBSTRUCTIVE SLEEP APNEA (OSA) THAT IS SUBOPTIMALLY TREATED BY FIRST-LINE SURGICAL INTERVENTIONS. THE PERSISTENCE OF OSA-RELATED NIGHTLY INTERMITTENT HYPOXEMIA AND FRAGMENTED SLEEP MAY CONTRIBUTE TO A COGNITIVE IMPAIRMENT, AS WELL AS PULMONARY VASCULAR DISEASE, MYOCARDIAL DYSFUNCTION, REDUCED QUALITY OF LIFE AND DAILY FUNCTIONAL IMPAIRMENT. WHILE OXYGEN IS SOMETIMES USED WHEN OTHER OSA THERAPIES FAIL, ITS EFFICACY AND SAFETY HAVE NOT BEEN SYSTEMATICALLY STUDIED. THIS R61/R33 IS THEREFORE DESIGNED TO TEST THE HYPOTHESIS THAT INDIVIDUALS WITH DS AND MODERATE TO SEVERE OSA WILL HAVE A SAFE AND FAVORABLE RESPONSE TO LOW-FLOW OXYGEN TREATMENT DUE TO ITS EFFECTS ON DIRECTLY ATTENUATING HYPOXIC EPISODES, WITH SUBSEQUENT INCREASED VENTILATORY STABILITY AND IMPROVEMENT IN OSA. WE FURTHER HYPOTHESIZE THAT OXYGEN SUPPLEMENTATION WILL LEAD TO IMPROVEMENT IN NEUROCOGNITION, CARDIAC FUNCTION, SLEEP, AND QUALITY OF LIFE. THE R61 PHASE WILL ACTIVELY ENGAGE FAMILIES OF PATIENTS WITH DS AND OUR MULTI-STAKEHOLDER TEAM TO REFINE AND PILOT THE PROTOCOL AND RECRUITMENT STRATEGIES TO ENSURE THAT WE MEET OUR RECRUITMENT/RETENTION MILESTONES IN THE R33 PHASE AND WE GENERATE DATA MOST RELEVANT TO OUR PATIENT POPULATION. IN TOTO, WE WILL SCREEN APPROXIMATELY 328 CHILDREN WITH DS AND MODERATE TO SEVERE OSA, 5-17 YRS OF AGE, WHO FAILED ADENOTONSILLECTOMY, TO IDENTIFY OXYGEN RESPONDERS, AND THEN RANDOMIZE 230 CHILDREN TO OXYGEN PLUS CONSERVATIVE THERAPY (OXT; ADMINISTERED USING A PATIENT-SPECIFIC DOSE) OR CONSERVATIVE THERAPY (CT) ALONE (WEIGHT MANAGEMENT, SLEEP HYGIENE, NASAL DILATORS) FOR 6 MONTHS. THE PRIMARY OUTCOME OF THE TRIAL IS WORKING MEMORY MEASURED BY CO-PRIMARY ENDPOINTS THAT RESPECTIVELY ASSESS CAREGIVER-REPORTED AND OBJECTIVELY MEASURED FUNCTIONS. SECONDARY OUTCOMES INCLUDE CARDIAC FUNCTION AND STRUCTURE, RIGHT VENTRICULAR PRESSURE, QUALITY OF LIFE AND SLEEP MEASURES THAT WILL BE COLLECTED UNDER THE SUPERVISION OF EXPERIENCED, CENTRAL CORE LABORATORIES. SIX CLINICAL SITES EXPERIENCED WITH PEDIATRIC CLINICAL TRIALS AND ESTABLISHED DS CENTERS WILL PARTICIPATE IN THE TRIAL. A DATA COORDINATING CENTER EXPERIENCED WITH PEDIATRIC SLEEP TRIALS WITH A STRONG HISTORY OF WORKING WITH THESE CLINICAL SITES WILL IMPLEMENT AND MONITOR DATA QUALITY CONTROL PROCESSES THAT ADDRESSES ALL STAGES OF DATA HANDLING. THIS STUDY WILL FILL A KEY KNOWLEDGE GAP IN A POTENTIALLY EFFICACIOUS THERAPY FOR OSA, AND PROVIDE EVIDENCE TO SUPPORT (OR REFUTE) THE USE OF SUPPLEMENTAL OXYGEN, AS WELL AS IDENTIFY PHYSIOLOGICAL MARKERS TO POTENTIALLY IDENTIFY PATIENT SUBGROUPS MOST LIKELY TO EXPERIENCE BENEFIT FROM THIS THERAPY.

TRANSPIRE: A PROSPECTIVE COHORT STUDY OF LUNG INJURY AFTER HEMATOPOIETIC STEM CELL TRANSPLANT IN CHILDREN. - PROJECT SUMMARY HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) IS INCREASINGLY USED FOR NON-MALIGNANT HEMATOLOGIC DISORDERS SUCH AS SICKLE CELL ANEMIA AND MARROW FAILURE, AND COMPLICATIONS OF HSCT ARE MORE PREVALENT AND IMPORTANT AS CAUSES OF LONG TERM MORBIDITY. IMPROVED DIAGNOSIS AND TREATMENT AND TREATMENT ARE URGENT ISSUES. LUNG INJURY IS FREQUENT AFTER HSCT, WITH AS MANY AS 15% OF CHILDREN TRANSPLANTED HAVING REDUCED FEV1, LATER LEADING TO OVERT BRONCHIOLITIS OBLITERANS (BO) WHICH IS ASSOCIATED WITH HIGH MORBIDITY AND MORTALITY. DIAGNOSIS OF BO IN ADULTS DEPENDS ON SPIROMETRY, AND EVIDENCE SUGGESTS THAT EARLY DIAGNOSIS MAY IMPROVE CHANCES OF RECOVERY OF LUNG FUNCTION AND SURVIVAL. SMALL CHILDREN, AND EVEN OLDER CHILDREN AND TEENAGERS WHO FEEL UNWELL AND ARE UNCOOPERATIVE, ARE UNABLE TO PERFORM SPIROMETRY, MEANING THAT LUNG IMPAIRMENT IS “INVISIBLE” UNTIL SEVERE AND CLINICALLY MANIFEST. PROGRESS IN IMPROVING LUNG OUTCOMES OF HSCT IN CHILDREN HAS BEEN HINDERED BY LACK OF DIAGNOSTIC STRATEGIES, AND BY THE NEED FOR A LARGE GROUP OF CASES TO ALLOW TESTING OF BIOLOGICAL, PATHOLOGICAL AND DIAGNOSTIC HYPOTHESES TO ADVANCE THE FIELD. WE PROPOSE ASSEMBLING A PROSPECTIVE COHORT STUDY OF ALL CHILDREN RECEIVING HSCT AT 6 MAJOR US TRANSPLANT CENTERS. WE WILL PERFORM STANDARDIZED PROSPECTIVE TESTING OF LUNG FUNCTION AND CLINICAL DATA COLLECTION IN ALL CHILDREN IN THE COHORT, TO DETERMINE THE FREQUENCY, CLINICAL PHENOTYPES AND RISK FACTORS FOR BO (SPECIFIC AIM 1). BO IS A RARE DISEASE SO PROGRESS WILL NOT BE MADE ABSENT A MULTI-CENTER COHORT STUDY THAT UNIFORMLY DEFINES CLINICAL PHENOTYPE AND PROSPECTIVELY COLLECTS SAMPLES, ALLOWING RETROSPECTIVE STUDY OF EARLY MOLECULAR EVENTS THAT PREDICT LATER DISEASE. IN SPECIFIC AIM 2 WE WILL COLLECT CALENDAR AND EVENT-DRIVEN BIOLOGICAL SAMPLES, INCLUDING SERUM, PLASMA, PERIPHERAL BLOOD MONONUCLEAR CELLS AND BRONCHIOLAR LAVAGE FLUID, WHICH WILL BE STORED AND USED TO IDENTIFY BIOMARKERS OF ONSET OF BO AND OF RESPONSE TO THERAPY. MOREOVER, WE WILL COLLECT PATHOLOGICAL SAMPLES THAT WILL BE ANALYZED USING A PRE- EXISTING RARE LUNG DISEASE PATHOLOGY PLATFORM TO IDENTIFY GENETIC AND ANATOMIC CHANGES THAT DEFINE BO. LASTLY, IN SPECIFIC AIM 3 WE WILL TEST AND DISSEMINATE NOVEL LUNG TESTING STRATEGIES, INCLUDING INNOVATIVE IMAGING, TO ADDRESS THE CRITICAL CLINICAL CHALLENGE OF LATE DIAGNOSIS OF LUNG IMPAIRMENT IN CHILDREN. WE PROVIDE EXAMPLES OF ESSENTIAL BIOLOGICAL STUDIES THAT CAN ONLY BE PERFORMED USING THE RESOURCES OF THE COHORT, FOR WHICH WE WILL SEEK ADDITIONAL R01 FUNDING. TAKEN TOGETHER, THIS COHORT STUDY CAN FUNDAMENTALLY CHANGE THE PARADIGM OF LUNG INJURY AFTER TRANSPLANT AND PROVIDE A PLATFORM FOR TESTING PREVENTIVE AND THERAPEUTIC TREATMENTS.

POLYGENIC RISK SCORES FOR HEALTHIER AFRICAN AMERICAN FAMILIES

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

PEDIATRIC CENTER FOR GENE EXPRESSION AND DEVELOPMENT

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

GENE REGULATION AS A FOUNDATION FOR AUTOIMMUNE DISEASE PREVENTION

OPEN SOURCE SCIENCE: TRANSFORMING CHRONIC ILLNESS CARE

WEST COAST CONSORTIUM FOR TECHNOLOGY AND INNOVATION IN PEDIATRICS

RYAN WHITE TITLE IV PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

THE ROLE OF HUMAN MILK IN INFANT NUTRITION AND HEALTH

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

UTE MRI TO MONITOR CF LUNG DISEASE AND RESPONSE TO CFTR MODULATION IN YOUNG CHILDREN

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CINCINNATI CENTER OF NEUROFIBROMATOSIS RESEARCH

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

A NEW MODEL TO IDENTIFY PRETERM NEONATES AT HIGH-RISK FOR COGNITIVE DEFICITS

IMPACCT: INFRASTRUCTURE FOR MUSCULOSKELETAL PEDIATRIC ACUTE CARE CLINICAL TRIALS - ABSTRACT THE MANAGEMENT OF TWO COMMON UPPER EXTREMITY INJURIES, PEDIATRIC MEDIAL EPICONDYLE FRACTURES (MEF) AND DISPLACED DISTAL RADIUS FRACTURES (DRF), IS CONTROVERSIAL WITH HIGH PRACTICE VARIATION. THE DEBATE LARGELY FOCUSSES ON WHETHER TO REDUCE THESE INJURIES TO RESTORE THEIR USUAL POSITION OR TO ALLOW THE FRACTURES TO HEAL IN THEIR INJURED POSITION WITH SIMPLE IMMOBILIZATION. OBSERVATIONAL STUDIES SUPPORT BOTH REDUCTION AND SIMPLE IMMOBILIZATION FOR MEF AND DRF. IN BOTH INJURIES, THERE HAVE BEEN FEW PROSPECTIVE AND NO RANDOMIZED STUDIES EVALUATING THEIR TREATMENT. GIVEN THE WIDESPREAD VARIATION IN PRACTICE, CHILDREN ARE EITHER UNDERGOING UNNECESSARY PROCEDURES AND ANESTHETIC EVENTS WHEN SURGEONS OPT FOR REDUCTION UNDER ANESTHESIA/ CONSCIOUS SEDATION OR ARE BEING UNDERTREATED BY SIMPLE IMMOBILIZATION. BOTH SCENARIOS ARE UNACCEPTABLE IN THAT CHILDREN FACE EITHER ANESTHETIC RISKS AND EXTRA COSTS OR POOR ALIGNMENT WITH POTENTIAL LONG TERM FUNCTIONAL DISABILITY TO ADDRESS SUCH CLINICAL DILEMMAS, THE INFRASTRUCTURE FOR MUSCULOSKELETAL PEDIATRIC ACUTE CARE CLINICAL TRIALS (IMPACCT) CONSORTIUM WAS ORGANIZED TO DEVELOP THE INFRASTRUCTURE AND EXPERIENCE NECESSARY FOR MULTICENTER RANDOMIZED CLINICAL TRIALS. IMPACCT’S LEADERSHIP HAS EXPERTISE IN LEADING MULTICENTER CLINICAL TRIALS AND ITS MEMBERS REPRESENT 32 DIVERSE CENTERS FROM THE PEDIATRIC ORTHOPAEDIC SOCIETY OF NORTH AMERICA (POSNA). DURING THE IMPACCT CONSENSUS CONFERENCE, PARTICIPANTS AGREED THAT THAT MEF AND DRF HAVE THE EQUIPOISE NECESSARY AND ARE THE MOST PRESSING CLINICAL CONTROVERSIES. A SIMILAR PRIORITY-SETTING STUDY FROM THE UNITED KINGDOM IDENTIFIED THESE QUESTIONS AS IMPORTANT CONTROVERSIES IN CHILDREN’S ORTHOPAEDIC SURGERY. POSNA-WIDE SURVEYS CONFIRMED MEF AND DRF TREATMENT VARIATION AND SURGEONS’ WILLINGNESS TO RANDOMIZE. A MULTICENTER RANDOMIZED SUPERIORITY TRIAL OF CHILDREN WITH MEF AND DRF IS REQUIRED TO EVALUATE THE CLINICAL EFFECTIVENESS OF REDUCTION UNDER ANESTHESIA/SEDATION VS. SIMPLE IMMOBILIZATION. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT CHILDREN TREATED WITH REDUCTION UNDER GENERAL ANESTHESIA (MEF) OR CONSCIOUS SEDATION (DRF) WILL HAVE HIGHER PATIENT REPORTED OUTCOME SCORES COMPARED TO THOSE TREATED WITH SIMPLE IMMOBILIZATION ALONE. TRIALS ON BOTH FRACTURES WILL BE CONDUCTED SIMULTANEOUSLY TO TAKE ADVANTAGE OF THE ECONOMY OF SCALE AND ARE SIMILAR IN TERMS OF ANATOMIC LOCATION, OUTCOME MEASURES, AND WHETHER AN INTERVENTION IS NECESSARY. THIRTY- ONE SITES HAVE AGREED TO RECRUIT, RANDOMIZE AND TREAT A TOTAL OF 688 PATIENTS ACCORDING TO THE PRAGMATIC PROTOCOLS. INVESTIGATORS HAVE PARTNERED WITH THE TRIAL INNOVATION NETWORK TO INCREASE THE EFFICIENCY OF TRIAL DEVELOPMENT AND EXECUTION. NIAMS HAS AWARDED THIS INITIATIVE AN R34 CLINICAL TRIALS PLANNING GRANT. THIS PROPOSAL WILL SUPPORT THE ACTIVE STUDY PHASE WHEN PATIENTS ARE RECRUITED, TREATED, AND FOLLOWED AND WHEN RESULTS ARE ANALYZED AND DISSEMINATED. THE COMPLETION OF THESE TRIALS WILL PROVIDE A FRAMEWORK, INFRASTRUCTURE AND EXPERIENCE FOR FUTURE PROSPECTIVE MULTICENTER CLINICAL TRIALS IN PEDIATRIC ORTHOPAEDICS AS ITS RESULTS GUIDE CLINICAL DECISION-MAKING.

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

IN VIVO DRUG TESTING OF PEDIATRIC CNS TUMORS USING PATIENT DERIVED ORTHOTOPIC XENOGRAFT MODELS

DATA COORDINATING CENTER: B2B CHANGE COHORT - PROJECT ABSTRACT CONGENITAL HEART DISEASE (CHD) OCCURS IN APPROXIMATELY 40,000 INFANTS IN THE UNITED STATES EACH YEAR. THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NLHBI) LAUNCHED ITS BENCH TO BASSINET PROGRAM (B2B) IN 2009 TO OVERCOME THE MAJOR BARRIERS IN TRANSLATIONAL RESEARCH, IDENTIFY THE CAUSES OF HUMAN CHD, AND IMPROVE OUTCOMES FOR INDIVIDUALS WITH CHD. THROUGH THE CONGENITAL HEART DISEASE GENETIC NETWORK STUDY (CHD GENES), THE B2B PROGRAM HAS ENROLLED OVER 14,000 PARTICIPANTS WITH CHD AND 18,000 FAMILY MEMBERS, CONDUCTING GENOMIC SEQUENCING TO IDENTIFY AN ESTIMATED 25% OF PREVIOUSLY UNEXPLAINED CHD CASES. DESPITE THESE ADVANCES, CRITICAL GAPS PERSIST IN OUR UNDERSTANDING OF HOW GENETIC VARIANTS INFLUENCE GENOTYPE- PHENOTYPE CORRELATIONS AND LONG-TERM OUTCOMES IN CHD. ALTHOUGH NOT INITIALLY DESIGNED AS A LONGITUDINAL COHORT, THE NHLBI RECOGNIZED THE UNIQUE POTENTIAL OF THE CHD GENES AND DIRECTED THE COORDINATING CENTER (CC) TO ORGANIZE DEEP PHENOTYPING AND RE-ENROLLMENT OF A SUBSET OF PARTICIPANTS FOR AN IN-PERSON CLINICAL ASSESSMENT AND TO MAKE THE DATA AVAILABLE TO THE SCIENTIFIC COMMUNITY AS THE B2B CONGENITAL HEART DISEASE ADVANCING NEW UNDERSTANDING IN GENOMICS (CHANGE) COHORT. THE NEW ITERATION OF THE CC IS A UNIQUE, INTEGRATED COMBINATION OF WORLD-LEADING CARDIOVASCULAR AND CLINICAL/TRANSLATIONAL RESEARCH EXPERTISE, ADVANCED INFRASTRUCTURE, OUTSTANDING OPERATIONAL SUPPORT, AND STATE-OF-THE-ART TECHNOLOGY. THE SPECIFIC AIMS ARE TO: 1) ESTABLISH AND MAINTAIN THE B2B CHANGE COHORT, 2) CREATE A UNIQUE RESOURCE FOR CHD RESEARCH BY INTEGRATING NEW DATA SOURCES WITH THE EXISTING CLINICAL AND GENOMIC INFORMATION MAINTAINED IN THE B2B DATAHUB (HEARTSMART) AND SHARED WITH NHLBI’S BIODATA CATALYST SYSTEM, AND 3) ENSURE THE CHD COMMUNITY HAS THE NECESSARY ACCESS, TOOLS, AND SUPPORT TO TRANSLATE B2B DATA INTO IMPROVED HEALTH AND QUALITY OF LIFE FOR THOSE AFFECTED BY CHD. B2B CHANGE WILL BE ESTABLISHED USING A MULTIFACETED AND PATIENT-INFORMED COHORT OUTREACH AND ENGAGEMENT APPROACH INCORPORATING NATIONALLY RECOGNIZED EXPERT LEADERSHIP AND CONSULTATION AND ADAPTATION TO LOCAL CONTEXTS AS APPROPRIATE. INNOVATIVE CLINICAL ASSESSMENTS AND TECHNICAL ADVANCEMENTS TO HEARTSMART WILL EXPAND AND ENRICH EXISTING PHENOTYPING APPROACHES, EXTEND THE DURATION OF FOLLOW-UP, AND ALLOW FOR NEW BIOLOGICAL SAMPLE ACQUISITION FOR FUTURE MECHANISTIC AND TRANSLATIONAL STUDIES. THROUGH RESOURCES INCLUDING HEARTSMART AND BIODATA CATALYST, AND EXTENSIVE OUTREACH, EDUCATION, AND ENGAGEMENT, THE CC WILL ENSURE THE CHD COMMUNITY HAS ACCESS TO THIS VITAL RESOURCE TO SUPPORT RIGOROUS, INDEPENDENTLY FUNDED, INVESTIGATOR-INITIATED ANCILLARY STUDIES. THE B2B CC HAS PROVIDED EXCELLENCE IN ADMINISTRATIVE SUPPORT AND COORDINATION FOR THE B2B PROGRAM FOR THE PREVIOUS TWO FUNDING CYCLES AND WILL CONTINUE TO BE A SUCCESSFUL PARTNER WITH SITE INVESTIGATORS, THE NHLBI, AND THE CHD COMMUNITY, LEADING THE COORDINATION OF KNOWLEDGE AND DATA FOR THIS IMPORTANT CARDIOVASCULAR RESEARCH EFFORT.

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

SICKLE CELL TREATMENT DEMONSTRATION PROGRAM

ADOLESCENT BARIATRICS: ASSESSING HEALTH BENEFITS & RISKS

CINCINNATI RHEUMATIC DISEASES RESOURCE CENTER

COGNITIVE OUTCOME MEASURES IN SCHOOL AGE CHILDREN WITH DOWN SYNDROME

ROLE OF ANTI-GM-CSF ANTIBODIES IN MYELOID CELL FUNCTION & INNATE IMMUNITY

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

POST-VENT, THE SEQUELAE: PERSONALIZED PROGNOSTIC MODELING FOR CONSEQUENCES OF NEONATAL INTERMITTENT HYPOXEMIA IN PRETERM INFANTS AT PRE-SCHOOL AGE - PROJECT SUMMARY / ABSTRACT THIS IS THE APPLICATION FROM COLLABORATORS OF THE PREMATURITY-RELATED VENTILATORY CONTROL (PRE-VENT): ROLE IN RESPIRATORY OUTCOMES NHLBI COLLABORATIVE PROGRAM. CENTRAL TO THIS PROPOSAL IS A PROSPECTIVE STUDY ENTITLED “POST-VENT, THE SEQUELAE: PERSONALIZED PROGNOSTIC MODELING FOR CONSEQUENCES OF NEONATAL INTERMITTENT HYPOXEMIA IN PRETERM INFANTS AT PRE-SCHOOL AGE”. THIS MULTICENTER PROPOSAL INNOVATIVELY COMBINES DETAILED CLINICAL PHENOTYPING WITH ADVANCED ANALYTICS OF LONGITUDINAL RECORDINGS OF INTERMITTENT HYPOXEMIA (IH) EVENTS TO DEVELOP PERSONALIZED PROGNOSTIC MODELS OF LONG-TERM OUTCOMES THAT COULD TRANSFORM CLINICAL CARE BY ALLOWING FOR TIMELY IDENTIFICATION OF AT-RISK INFANTS AND SPECIFIC PATHOLOGIC IH PATTERNS FOR FUTURE TRIALS OF TARGETED INTERVENTION. EXTREMELY PREMATURE BIRTH AND VARIOUS POSTNATAL FACTORS CAN NEGATIVELY AFFECT OUTCOME. IN A SIGNIFICANT PROPORTION OF EXTREMELY PREMATURE INFANTS THE SEQUELAE PERSIST BEYOND INFANCY WITH RELATIVELY HIGH RATES OF ASTHMA AND SLEEP DISORDERED BREATHING (SDB) IN CHILDHOOD AND WORRISOME PREVALENCE OF NEURODEVELOPMENTAL IMPAIRMENT (NDI). THIS MULTICENTER PROPOSAL WILL SYSTEMATICALLY AND INNOVATIVELY EXAMINE THE INTERACTION BETWEEN IH DURING NEONATAL INTENSIVE CARE AND THESE SEQUELAE BY MEANS OF DETAILED CLINICAL PHENOTYPING AND ADVANCED ANALYTICS. THE PROPOSED INVESTIGATION WILL PROVIDE PERSONALIZED PROGNOSIS AND IDENTIFICATION OF INFANTS AT RISK OF POOR LONG-TERM OUTCOME THAT COULD TRANSFORM CLINICAL CARE AND UNCOVER TARGETS FOR PREVENTIVE OR THERAPEUTIC STRATEGIES. THE MAIN GOAL OF THIS PROPOSAL IS TO BUILD PROGNOSTIC MODELS OF ASTHMA, SDB, AND NDI AT PRE-SCHOOL AGE IN FORMER EXTREMELY PREMATURE INFANTS BASED ON PHYSIOLOGIC WAVEFORMS AND CLINICAL CHARACTERISTICS IN THE NEONATAL INTENSIVE CARE UNIT. TO ACHIEVE THIS GOAL THIS TIME-SENSITIVE PROPOSAL LEVERAGES THE POPULATION, RESEARCH STRUCTURE AND EXPERTISE, AND ANALYTIC RESOURCES DEVELOPED FOR THE NHLBI-FUNDED PRE-VENT COLLABORATION.

SELECTIVE DISRUPTION OF HIPPOCAMPAL DENTATE GRANULE CELLS IN AUTISM: IMPACT OF PT

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

MOLECULAR GENETICS OF BBS

RFA-PS-23-001 - PROJECT PROVIDE: PREP OPTIMIZATION VIA IMPLEMENTATION, DISSEMINATION, AND EVALUATION

IMPACT OF SUGARS AND HUMAN MILK OLIGOSACCHARIDES ON INFANT MICROBIOME AND OBESITY

GENETIC AND FUNCTIONAL STUDIES OF HUMAN CILIARY SYNDROMES

CARDIAC FIBROBLASTS IN POSTNATAL DEVELOPMENT AND ADULT INJURY RESPONSE

HEALTHY START INITIATIVE-ELIMINATING RACIAL/ETHNIC DISPARITIES

CINCINNATI MULTIDISCIPLINARY CLINICAL RESEARCH CENTER

MOLECULAR EXAMINATION OF MITOCHONDRIAL CALCIUM CONTROL

GENETIC AND IMMUNOLOGICAL DISSECTION OF EOSINOPHILIC ESOPHAGITIS

CATEGORY A - COMMUNITIES PUTTING PREVENTION TO WORK

COMPREHENSIVE SICKLE CELL CENTER

USC/UAP LEND PROJECT

CLINICAL CENTER--BILIARY ATRESIA CLINICAL RESEARCH CONS*

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

PEDIATRIC SOLID TUMOR MICROENVIRONMENT ATLAS - OVERALL SUMMARY/ABSTRACT THE MAJORITY OF SOLID TUMORS IN CHILDREN HAVE A UNIQUE ORIGIN COMPARED TO THOSE IN ADULTS, STEMMING FROM THEIR RISE FROM EMBRYONIC CELLS. DESPITE THIS DISTINCTION, THERE IS STILL LIMITED UNDERSTANDING OF THE DIFFERENCES IN THE MICROENVIRONMENTS OF THESE PEDIATRIC TUMORS COMPARED TO ADULT CANCERS, AND HOW THESE DIFFERENCES MIGHT CONTRIBUTE TO LINEAGE PLASTICITY AND TREATMENT RESISTANCE. TO ADDRESS THIS KNOWLEDGE GAP, WE PROPOSE A COMPREHENSIVE INVESTIGATION INTO THE SPATIAL BIOLOGY OF THESE TUMORS. OUR GOAL IS TO SHED LIGHT ON THE SPECIFIC CELLS AND MECHANISMS WITHIN THE TUMOR MICROENVIRONMENT THAT PLAY A ROLE IN INDUCING THERAPY RESISTANCE IN PEDIATRIC SOLID TUMORS. THIS RESEARCH WILL FOCUS ON PROMINENT PEDIATRIC CANCERS SUCH AS RHABDOMYOSARCOMA, NEUROBLASTOMA, AND WILMS TUMORS. THE PRIMARY GOAL OF THIS MULTI-DISCIPLINARY PROGRAM IS TO ESTABLISH A COMPREHENSIVE PEDIATRIC SOLID TUMOR MICROENVIRONMENT (PSTME) ATLAS THAT WOULD LEAD TO DISCOVERING BASIC MECHANISMS OF DE NOVO AND ACQUIRED RESISTANCE TO MODERN THERAPIES, AND UNCOVERING TUMOR MICROENVIRONMENT (TME) TARGETABLE VULNERABILITIES DRIVEN BY RESISTANCE. THE MOTIVATION FOR CREATING THE PSTME ATLAS IS THE URGENT NEED TO IMPROVE SURVIVAL OF PATIENTS WITH HIGH-RISK SUBTYPES OF THE PROPOSED CANCERS, AND TO DECREASE TREATMENT- RELATED MORBIDITIES. BY DELVING INTO THE INTRICACIES OF THE TUMOR MICROENVIRONMENT AND ITS IMPACT ON TREATMENT RESPONSE, WE AIM TO ADVANCE OUR UNDERSTANDING OF PEDIATRIC SOLID TUMORS AND PAVE THE WAY FOR MORE EFFECTIVE THERAPEUTIC STRATEGIES. THE PROJECT WILL BE SUPPORTED BY COLLABORATION AMONG TWO INSTITUTIONS WITH DISTINCT AND UNIQUE RESOURCES AND TECHNOLOGIES, AND COMPLEMENTARY EXPERTISE: A) CHILDREN’S HOSPITAL LOS ANGELES (CHLA) GROUP WILL PROVIDE WELL ANNOTATED TUMOR SPECIMENS WITH CLINICAL INFORMATION IN AN ETHNICALLY DIVERSE PATIENT POPULATION, AND LEAD IN GENERATING SPATIAL PROTEOMICS DATA USING PEDIATRIC AND TME SPECIFIC ANTIBODY PANELS. B) CALIFORNIA INSTITUTE OF TECHNOLOGY (CALTECH) GROUP WILL PROVIDE INNOVATIVE SPATIAL OMICS TECHNOLOGIES INCLUDING SPATIAL TRANSCRIPTOMICS AND COPY NUMBER, AND NOVEL DATA SCIENCE APPROACHES FOR INTEGRATIVE ANALYSIS OF THE GENERATED DATA. THE SAMPLES WILL BE SELECTED TO REPRESENT SOLID TUMOR DIVERSITY BASED ON ESTABLISHED CLINICAL RISK STRATIFICATIONS, AND CRITICAL POINTS OF TRANSITION (POST CHEMOTHERAPY RESPONSE, RELAPSE) TO ENSURE CAPTURE OF THE DIVERSITY OF PSTME. THE PSTME ATLAS WILL IMPACT THE COMMUNITY THROUGH GENERATION OF EASILY ACCESSIBLE TME ATLAS PROVIDING A USER FRIENDLY, SEARCHABLE DATABASE OF MULTIOMICS SPATIAL ANALYSES OF COMMON EXTRACRANIAL SOLID TUMORS WITH CLINICAL AND OUTCOME DATA. IT WILL ALSO PROVIDE NOVEL COMPUTATIONAL PIPELINES FOR INTEGRATION AND ANALYSIS OF SPATIAL DATA. THESE OPENSOURCE TOOLS WILL BE MADE AVAILABLE TO THE COMMUNITY. IN SUMMARY, THE SIGNIFICANCE OF THE PROPOSED PROJECT IS THE ESTABLISHMENT OF AN ATLAS THAT WILL ALLOW DISCOVERY OF FUNDAMENTAL MECHANISMS OF EXTRINSIC CANCER THERAPY RESISTANCE WITH THE GOAL OF LEADING TO SUBSTANTIVELY IMPROVED PROBABILITY OF CURE COUPLED WITH REDUCED THERAPY-RELATED MORBIDITY FOR CHILDREN AFFLICTED WITH SOLID TUMORS.

EPIDEMIOLOGIC IMPACT OF HPV VACCINATION

IMMUNOPATHOGENESIS OF NON-ALCOHOLIC FATTY LIVER DISEASE

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

IMMUNOLOGICAL IDENTITY REDEFINED BY GENETICALLY FOREIGN MICROCHIMERIC CELLS

IMMUNOLOGIC DYSFUNCTION IN BILIARY ATRESIA

MODELING DIABETES USING AN INTEGRATED PLATE SYSTEM

MAPPING THE BRAIN, THE FACE AND NEUROCOGNITIVE FUNCTION IN FASD (U01)

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

LONGITUDINAL IMPACT OF AIR POLLUTION ON MENTAL HEALTH AND NEUROIMAGING OUTCOMES DURING ADOLESCENCE IN THE CINCINNATI COMBINED CHILDHOOD COHORTS (C4) - PROJECT SUMMARY / ABSTRACT MORE THAN ONE IN FIVE ADOLESCENTS WILL EXPERIENCE A MENTAL HEALTH DISORDER, INCLUDING DEPRESSION AND ANXIETY, AND THE PREVALENCE OF THESE CONDITIONS IS INCREASING. AMONG ADOLESCENTS, DEPRESSION AND ANXIETY ARE LINKED TO INCREASED RISK OF SUICIDE, A LEADING CAUSE OF DEATH IN THIS AGE GROUP. IDENTIFYING UNDERLYING AND MODIFIABLE CONTRIBUTORS TO THESE CONDITIONS IS CRUCIAL AS CURRENT RESEARCH AND INTERVENTIONS FOCUS ON SCREENING AND TREATMENT RATHER THAN PREVENTION. HERE, WE POSIT THAT AIR POLLUTION, IN ADDITION TO GENETIC SUSCEPTIBILITY, SOCIAL DETERMINANTS, FAMILIAL AND SCHOOL ISSUES, AND OTHER FACTORS, IS A CONTRIBUTOR TO MENTAL HEALTH DISORDERS. TOXICOLOGICAL STUDIES DEMONSTRATE THAT FINE PARTICULATE MATTER (PM2.5) AND TRAFFIC-RELATED AIR POLLUTION (TRAP) ARE NEUROTOXIC, AND EPIDEMIOLOGIC STUDIES CONSISTENTLY LINK THESE POLLUTANTS TO REDUCED COGNITIVE ABILITIES AND INCREASED EXTERNALIZING BEHAVIORS. HOWEVER, FEW STUDIES HAVE PROSPECTIVELY EVALUATED THE ROLE OF AIR POLLUTION EXPOSURE ON MENTAL HEALTH DISORDERS IN CHILDHOOD. RECENTLY, WE FOUND THAT CHILDHOOD AIR POLLUTION EXPOSURE IS ASSOCIATED WITH INCREASED RISK FOR DEPRESSION AND ANXIETY AT AGE 12 YEARS. HOWEVER, THE ROLE OF AIR POLLUTION IN THE ONSET AND PERSISTENCE OF MENTAL HEALTH DISORDERS DURING ADOLESCENCE, AND CHANGES IN BRAIN STRUCTURE, ORGANIZATION, AND FUNCTION LINKED TO THESE OUTCOMES, REMAIN POORLY UNDERSTOOD. THEREFORE, WE HYPOTHESIZE THAT EXPOSURE TO AIR POLLUTION DURING CRITICAL PERIODS OF BRAIN DEVELOPMENT, INCLUDING ADOLESCENCE, IS ASSOCIATED WITH ADVERSE MENTAL HEALTH OUTCOMES. WE WILL LEVERAGE EXISTING LONGITUDINAL DATA FROM THE CINCINNATI CHILDHOOD ALLERGY AND AIR POLLUTION STUDY (CCAAPS) AND THE HEALTH OUTCOMES AND MEASURES OF THE ENVIRONMENT (HOME) STUDY, TWO PROSPECTIVE COHORTS LOCATED IN CINCINNATI, OHIO, TO ADDRESS THIS HYPOTHESIS. BOTH COHORTS HAVE BEEN FOLLOWED FROM BIRTH AND EVALUATED WITH CONCORDANT MEASURES OF MENTAL HEALTH AND NEUROIMAGING AT AGE 12 YEARS. WE WILL CONDUCT NEW FOLLOW-UP AT AGE 18 YEARS TO ASSESS THE ONSET AND PERSISTENCE OF MENTAL HEALTH OUTCOMES THROUGH ADOLESCENCE AND APPLY VALIDATED MODELS FOR PM2.5 AND TRAP TO CHARACTERIZE AIR POLLUTION EXPOSURE FROM CONCEPTION THROUGH AGE 18 YEARS. WE WILL ALSO ACQUIRE NOVEL NEUROIMAGING OUTCOMES, INCLUDING BRAIN -AMINOBUTYRIC ACID AND GLUTATHIONE CONCENTRATIONS ACCOMPANIED BY ANATOMICAL AND FUNCTIONAL MAGNETIC RESONANCE IMAGING. OUR AIMS ARE TO: 1) DETERMINE THE ASSOCIATION BETWEEN EXPOSURE TO PM2.5 AND TRAP DURING DISTINCT DEVELOPMENTAL PERIODS AND THE ONSET AND PERSISTENCE OF MENTAL HEALTH OUTCOMES IN ADOLESCENCE; 2) DETERMINE THE ASSOCIATION BETWEEN EXPOSURE TO PM2.5 AND TRAP DURING DISTINCT DEVELOPMENTAL PERIODS AND NEUROIMAGING OUTCOMES IN LATE ADOLESCENCE; AND 3) DETERMINE WHETHER CHANGES IN BRAIN VOLUME, ORGANIZATION, METABOLISM, AND FUNCTION MEDIATE ASSOCIATIONS BETWEEN PM2.5 AND TRAP EXPOSURE AND MENTAL HEALTH OUTCOMES. EXAMINING AIR POLLUTION AS A NOVEL AND MODIFIABLE RISK FACTOR WILL PROVIDE CRITICAL DATA TO GUIDE PRIMARY PREVENTION AIMED AT REDUCING THE BURDEN OF MENTAL HEALTH DISORDERS IN ADOLESCENCE.

MOLECULAR SIGNALING IN UTERINE RECEPTIVITY TO IMPLANTATION

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

UNITS FOR HIV/AIDS CLINICAL TRIALS NETWORKS

CONTINUED STUDIES OF ENVIRONMENT IMPACT ON PUBERTY

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

INTRAMUSCULAR VS. ENTERAL PENICILLIN PROPHYLAXIS TO PREVENT PROGRESSION OF LATENT RHEUMATIC HEART DISEASE: A NON-INFERIORITY RANDOMIZED TRIAL. (GOALIE) - PROJECT SUMMARY ABSTRACT RHEUMATIC HEART DISEASE (RHD) REMAINS A HIGH PREVALENCE CONDITION IN LOW-AND-MIDDLE-INCOME COUNTRIES, CURRENTLY AFFECTING AT LEAST 40 MILLION PEOPLE, MANY OF WHOM SUFFER PREMATURE DEATH. MOST PATIENTS WITH RHD PRESENT LATE, MISSING THE OPPORTUNITY TO BENEFIT FROM SECONDARY ANTIBIOTIC PROPHYLAXIS. SCREENING ECHOCARDIOGRAPHY IN RHD ENDEMIC SETTINGS IDENTIFIES MANY CHILDREN WITH EARLY, LATENT RHD, BUT UNTIL RECENTLY THE EFFECTIVENESS OF PROPHYLAXIS TO PROTECT CHILDREN WITH LATENT RHD WAS NOT KNOWN. THE GOAL TRIAL (CONDUCTED IN UGANDA BY THIS INVESTIGATIVE TEAM) FOUND THAT CHILDREN WITH LATENT RHD WHO RECEIVE PROPHYLAXIS WITH INTRAMUSCULAR PENICILLIN ARE LESS LIKELY TO PROGRESS AT TWO-YEARS (0.8% PENICILLIN VS. 8.3% NO PENICILLIN, P<0.001). HOWEVER, DESPITE THESE RESULTS, SCALE-UP OF ECHOCARDIOGRAPHIC SCREENING AND EARLY INITIATION OF PROPHYLAXIS WITH INTRAMUSCULAR (IM) PENICILLIN FOR RHD HAS A MYRIAD OF CHALLENGES. AMONG THE MOST CRITICAL ARE SUBSTANTIAL PATIENT (INCLUDING PAIN AND MISSED WORK/SCHOOL) AND HEALTH SYSTEM-LEVEL BARRIERS (INCLUDING COST, TIME, AND TRAINING) TO DELIVERING PROLONGED COURSES OF IM INJECTIONS IN LOW-RESOURCE SETTINGS. INTRAMUSCULAR VS. ENTERAL PENICILLIN PROPHYLAXIS TO PREVENT PROGRESSION OF LATENT RHEUMATIC HEART DISEASE (GOALIE) WILL DETERMINE IF A LESS BURDENSOME FORM OF PROPHYLAXIS, ORAL PENICILLIN, IS NON- INFERIOR TO IM PENICILLIN IN PREVENTING LATENT RHD PROGRESSION. GOALIE IS A RANDOMIZED NON-INFERIORITY TRIAL COMPARING THE EFFICACY OF INTRAMUSCULAR TO ENTERAL (ORAL) PENICILLIN PROPHYLAXIS TO PREVENT PROGRESSION OF LATENT RHD AT TWO YEARS. BASED ON OUR STRONG HISTORY OF RECRUITMENT AND RETENTION, WE WILL CONDUCT SCHOOL- BASED ECHOCARDIOGRAPHIC SCREENING OF ~100,000 CHILDREN AND ENROLL 1004 CHILDREN INTO GOALIE, WHICH WILL PROVIDE 90% POWER TO DETERMINE IF ORAL PENICILLIN PROPHYLAXIS IS NON-INFERIOR TO IM PENICILLIN PROPHYLAXIS. GOALIE WILL ALSO EXAMINE ECONOMIC EQUIVALENCE AND COST-EFFECTIVENESS OF THESE TWO PROPHYLAXIS STRATEGIES (AIM 2) AND THE PATIENT REPORTED OUTCOMES BETWEEN THESE TWO STRATEGIES (AIM 3), PROVIDING CRITICAL DATA TO INFORM THE INTEGRATION OF PROPHYLAXIS FOR LATENT RHD INTO CLINICAL PRACTICE. GOALIE BUILDS OFF OUR DECADE LONG COLLABORATION, INCLUDING STRONG MINISTRY OF HEALTH AND COMMUNITY SUPPORT. GOALIE WILL LEVERAGE THE STRUCTURE OF THE GOAL TRIAL WHICH DEVELOPED STREAMLINED PROTOCOLS FOR ECHOCARDIOGRAPHIC SCREENING (>102,000 SCREENED) AND HIGHLY SUCCESSFUL RECRUITMENT (>99% ELIGIBLE CHILDREN), RETENTION (97% COMPLETION), AND ADHERENCE SUPPORT (99% ADHERENCE) STRATEGIES. THE RESULTS OF OUR STUDY WILL HAVE HIGH CLINICAL AND PUBLIC HEALTH IMPACT, IMMEDIATELY INFORMING INTERNATIONAL POLICY ON THE STANDARD OF CARE FOR CHILDREN DIAGNOSED WITH LATENT RHD.

A GENERALIZABLE FRAMEWORK FOR LINKING SINGLE-CELL GENOMIC STATES WITH CELL FATE OUTCOMES IN HEMATOPOIESIS

BRAIN AND COGNITIVE DEVELOPMENT IN THE PASS COHORT: THE IMPACT OF PRENATAL ALCOHOL EXPOSURE

PERSONAL RESPONSIBILITY EDUCATION PROGRAM (PREP) INNOVATIVE STRATEGIES

BONE MINERAL ACCRETION IN YOUNG CHILDREN

EMERGENCY MEDICAL SERVICES FOR CHILDREN: NETWORK DEVELOPMENT DEMONSTRATION PROJECT

CINCINNATI RHEUMATIC DISEASES CENTER

RESEARCH TRAINING IN CHILD BEHAVIOR AND NUTRITION

HUMAN GENE TRANSFER & MACROPHAGE CELL TRANSPLANTATION THERAPY OF HEREDITARY PAP (HPAP) - ABSTRACT GENE COMPLEMENTATION AND PULMONARY MACROPHAGE TRANSPLANTATION (PMT THERAPY) IS A PROMISING POTENTIAL THERAPY OF HEREDITARY PULMONARY ALVEOLAR PROTEINOSIS (HPAP) – A DISORDER OF PROGRESSIVE OF ALVEOLAR SURFACTANT ACCUMULATION AND RESPIRATORY FAILURE – FOR WHICH NO PHARMACOTHERAPY THERAPY EXISTS. WE DEFINED THE PATHO- GENESIS, PRESENTATION, DIAGNOSIS, AND MANAGEMENT OF HPAP, SHOWED IT IS CAUSED BY THE LOSS OF GM-CSF RE- CEPTOR SIGNALING AND DISRUPTION OF ALVEOLAR MACROPHAGE (AM) FUNCTIONS INCLUDING THE REMOVAL OF SURFACTANT FROM ALVEOLI. WE DEMONSTRATED LENTIVIRAL VECTOR-MEDIATED COMPLEMENTATION OF FUNCTION-DISRUPTING CSF2RA MUTATIONS RESTORED GM-CSF RECEPTOR SIGNALING IN HUMAN AMS INCLUDING RESCUE OF SURFACTANT CLEARANCE. DESPITE OUTSTAND- ING PROGRESS, INCLUDING DEMONSTRATION OF THE SAFETY, TOLERABILITY, EFFICACY, AND DURABILITY OF PMT THERAPY IN TWO VALIDATED HPAP ANIMAL MODELS, LACK OF CLINICAL STUDIES OF PMT THERAPY IN HUMANS IS A CRITICAL BARRIER TO ITS FUR- THER THERAPEUTIC DEVELOPMENT. OUR LONG-TERM GOAL IS TO DEVELOP PMT THERAPY AS THE AN EFFECTIVE, DISEASE- SPECIFIC THERAPY OF HPAP (AND POSSIBLY OTHER DISEASES). THE OBJECTIVE HERE IS TO COMPLETE PREPARATIONS FOR, AND THEN TO CONDUCT, A PHASE I TRIAL TO ESTABLISH THE SAFETY OF PMT IN HUMAN PATIENTS WITH HPAP AND ALSO IDENTIFY USEFUL CLINICAL AND BIOLOGICAL OUTCOME MEASURES INFORMING THE DESIGN OF A FUTURE PHASE II EFFICACY TRIAL. THE CENTRAL HYPOTHESIS IS THAT AFTER PMT OF AUTOLOGOUS CD34+ CELL-DERIVED CSF2RA GENE-CORRECTED MACRO- PHAGES WITHOUT MYELOABLATION, THE TRANSPLANTED CELLS WILL SURVIVE, ENGRAFT, ADOPT THE PHENOTYPE AND FUNCTION OF NORMAL AMS, REPLACE ENDOGENOUS AMS, REESTABLISH A NORMAL-SIZED AM POPULATION THAT REMAINS IN THE LUNGS AND RESULTS IN A SAFE, WELL-TOLERATED, EFFECTIVE, AND DURABLE TREATMENT BENEFIT. THE RATIONALE FOR THE PROPOSED RESEARCH IS THAT A ‘FIRST-IN-HUMAN’ STUDY ESTABLISHING THE SAFETY OF PMT THERAPY IN HUMANS WILL UNBLOCK FURTHER CLINICAL DEVELOPMENT OF PMT THERAPY INCLUDING PREPARATION FOR CONDUCT OF A FUTURE PHASE 2 CLINICAL EFFICACY TRIAL. WE PLAN TO ADDRESS OUR HYPOTHESIS BY PURSUING FOUR SPECIFIC AIMS IN THE R61 PHASE AND THREE AIMS IN THE R33 PHASE: 1) FINALIZE STABILITY TESTING OF CSF2RA GENE-CORRECTED MACROPHAGES; COMPLETE 2) TRIAL-RELATED AND 3) IND-RELATED DOCUMENTS; 4) OBTAIN REGULATORY APPROVALS (INSTITUTIONAL REVIEW BOARD AND BIOSAFETY COMMITTEE, DATA, SAFETY, AND MONITORING BOARD, FDA); 5) ASSESS THE SAFETY, 6) MEASURE THE PHARMACOKINETICS AND PHAR- MACODYNAMICS, AND 7) IDENTIFY USEFUL MEASURES OF THE CLINICAL OUTCOMES AND BIOLOGICAL SIGNATURE OF PMT THER- APY IN HPAP PATIENTS. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE IT REPRESENTS A MARKED DEPARTURE FROM THE CURRENT TREATMENT APPROACH, WHOLE LUNG LAVAGE (AN INVASIVE, INEFFICIENT, PROCEDURE TO PHYSICALLY REMOVE SURFAC- TANT) BY ESTABLISHING, IN HPAP PATIENTS, THE FEASIBILITY OF A NEW APPROACH TO RESTORE A GM-CSF-RESPONSIVE, FUNCTIONAL AM POPULATION. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE ESTABLISHING THE SAFETY, PHARMACOKI- NETICS AND PHARMACODYNAMICS, AND IDENTIFYING USEFUL CLINICAL OUTCOME MEASURES OF PMT THERAPY IN HUMANS IS THE NEXT STEP IN OUR CLINICAL RESEARCH PROGRAM TO DEVELOP PMT AS THE FIRST SPECIFIC THERAPY OF HPAP.

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

PROGESTERONE INDUCED IMMUNE MODULATION DURING PREGNANCY

DOSING AND PILOT EFFICACY OF 2'-FUCOSYLLACTOSE IN INFLAMMATORY BOWEL DISEASE

SUPRASPINAL PROCESSING OF SENSORY ASPECTS OF PAIN

EMERGENCY MEDICAL SERVICES FOR CHILDREN: NETWORK DEVELOPMENT DEMONSTRATION PROJECT

ADOLESCENT MEDICINE TRIALS NETWORK FOR HIV/AIDS INTERVE*

VENOUS MALFORMATIONS (VM): A MURINE MDOEL TO IDENTIFY THERAPIES TO TARGER ABERRANT VENOUS DEVELOPMENT

NOVEL MECHANISMS OF OBLITERATIVE PULMONARY VASCULAR REMODELING AND SEVERE PULMONARY ARTERIAL HYPERTENSION

DERIVATION AND VALIDATION OF THE PEDIATRIC COMMUNITY-ACQUIRED PNEUMONIA SEVERITY (PEDCAPS) SCORE - PROJECT SUMMARY ALTHOUGH COMMUNITY-ACQUIRED PNEUMONIA (CAP) IS ONE OF THE MOST COMMON SERIOUS INFECTIONS IN CHILDREN AND A LEADING REASON THAT CHILDREN SEEK EMERGENCY CARE, NO VALIDATED TOOLS EXIST TO PREDICT CAP SEVERITY IN CHILDREN. WITHOUT OBJECTIVE TOOLS, MANAGEMENT DECISIONS ARE INEFFICIENT AND POTENTIALLY INACCURATE, RESULTING IN UNNECESSARY TESTING, TREATMENT, AND HOSPITALIZATION IN LOW-RISK CHILDREN OR DELAYS IN CRITICALLY IMPORTANT THERAPIES IN THOSE AT HIGH RISK OF SEVERE CAP. THE LONG-TERM GOAL OF THIS RESEARCH IS TO IMPROVE RISK STRATIFICATION OF CHILDREN WITH CAP. IN ADULTS WITH CAP, THE USE OF RISK PREDICTION RULES DECREASES MORTALITY AND GUIDES ANTIBIOTIC DECISIONS, WHILE MINIMIZING HOSPITALIZATIONS FOR THOSE AT LOW RISK. NO VALIDATED RISK PREDICTION RULES EXIST FOR CHILDREN PRESENTING TO THE EMERGENCY DEPARTMENT (ED) WITH CAP. WE PREVIOUSLY DERIVED A 7-VARIABLE RISK PREDICTION RULE IN 1128 CHILDREN 3 MONTHS TO 18 YEARS OLD WHO PRESENTED TO A SINGLE PEDIATRIC ED WITH SUSPECTED CAP. TO OVERCOME LIMITATIONS INHERENT IN A RULE DERIVED IN A SINGLE CENTER, MULTICENTER DERIVATION AND EXTERNAL VALIDATION OF A PEDIATRIC CAP RISK PREDICTION RULE IS NECESSARY TO ENSURE GENERALIZABILITY AND INFORM SUBSEQUENT WIDESPREAD IMPLEMENTATION. WE ALSO FOUND THAT BIOMARKERS, INCLUDING C-REACTIVE PROTEIN, PROCALCITONIN, PROADRENOMEDULLIN, AND VIRAL DETECTION, ARE ASSOCIATED WITH SEVERE OUTCOMES IN CHILDREN WITH CAP. IT IS UNKNOWN IF THE ADDITION OF THESE BIOMARKERS TO A CLINICAL RISK PREDICTION RULE WILL IMPROVE RULE PERFORMANCE. LED BY A MULTIDISCIPLINARY TEAM OF EXPERTS IN CAP, PEDIATRIC EMERGENCY AND HOSPITAL MEDICINE, INFECTIOUS DISEASES, BIOMARKERS, EPIDEMIOLOGY AND BIOSTATISTICS, PREDICTION MODELING, AND MACHINE LEARNING, THE PROPOSED RESEARCH WILL ADDRESS THESE IMPORTANT KNOWLEDGE AND RESEARCH GAPS THROUGH THE FOLLOWING SPECIFIC AIMS: (1) TO DERIVE A SEVERITY RISK PREDICTION RULE IN A MULTICENTER COHORT OF CHILDREN PRESENTING TO THE ED WITH CAP; (2) TO EXTERNALLY VALIDATE THE DERIVED PREDICTION RULE IN CHILDREN WITH CAP; AND (3) TO EVALUATE THE ABILITY OF BIOMARKERS TO IMPROVE PREDICTIVE ACCURACY OF A PURELY CLINICAL RISK PREDICTION RULE. THIS STUDY WILL LEVERAGE THE ROBUST INFRASTRUCTURE, EXPERIENCE, AND EXPERTISE OF THE PEDIATRIC EMERGENCY CARE APPLIED RESEARCH NETWORK (PECARN). WE WILL ACCOMPLISH THE STUDY AIMS BY CONDUCTING A PROSPECTIVE MULTICENTER OBSERVATIONAL STUDY IN TWO PHASES. FIRST, WE WILL ENROLL 2000 CHILDREN WITH CAP PRESENTING TO ONE OF 7 PECARN EDS TO DERIVE THE RULE OVER 2 YEARS. WE WILL THEN ENROLL 2000 CHILDREN WITH CAP IN 7 DIFFERENT PECARN EDS OVER THE FOLLOWING 2 YEARS TO EXTERNALLY VALIDATE THE RULE. A RISK PREDICTION RULE IN CHILDREN WITH CAP WILL BE SIGNIFICANT IN (A) ADVANCING OUR UNDERSTANDING OF RISK FACTORS OF CAP SEVERITY, (B) IMPROVING EVIDENCE-BASED MANAGEMENT AND CLINICAL OUTCOMES BY GUIDING AND STANDARDIZING CLINICAL DECISION MAKING, AND (C) FACILITATING FUTURE RESEARCH. THIS PROPOSAL IS INNOVATIVE AS IT WILL SHIFT THE PARADIGM OF ED MANAGEMENT OF CAP, MOVING FROM SUBJECTIVE DECISIONS TOWARD A NOVEL, OBJECTIVE APPROACH WHERE INDIVIDUALIZED, EVIDENCE-BASED RISK ESTIMATES CAN AUGMENT AND IMPROVE ACCURACY OF CLINICAL DECISION MAKING.

CHLA ADOLESCENT HEALTH AND EQUITY INNOVATION HUB - THE DIVISION OF ADOLESCENT AND YOUNG ADULT MEDICINE AT CHILDREN’S HOSPITAL LOS ANGELES (CHLA), ALONG WITH THE TEAM AT OUR INNOVATION STUDIO, ARE APPLYING TO ESTABLISH THE CHLA ADOLESCENT HEALTH AND EQUITY INNOVATION HUB, AN INCUBATOR HUB FOR TEEN PREGNANCY PREVENTION. THE CHLA ADOLESCENT HEALTH AND EQUITY INNOVATION HUB REPRESENTS A UNIQUE APPROACH TO INNOVATION IN THIS FIELD IN THAT IT BRINGS TOGETHER A VAST RESOURCE OF KNOWLEDGE AND SKILL IN TEEN PREGNANCY PREVENTION AND INNOVATION. THE DIVISION OF ADOLESCENT AND YOUNG ADULT MEDICINE CONTAINS THE FULL CONTINUUM OF EXPERTISE IN ADOLESCENT HEALTH AND THE TEEN PREGNANCY PREVENTION ECOSPHERE. THIS INCLUDES DIRECT SERVICE PROVIDERS; INTERNAL SUBJECT MATTER EXPERTS ON REACHING VULNERABLE POPULATIONS; SOCIAL SCIENTISTS AND RESEARCHERS; AND SKILLED TRAINERS AND CAPACITY BUILDING PROFESSIONALS. THIS EXPERTISE WILL BE COMBINED WITH THE CHLA INNOVATION STUDIO’S EXPERIENCE IN GENERATING, CURATING, AND ADVANCING INNOVATIVE SOLUTIONS TO COMPLEX PROBLEMS FACING YOUTH ALONGSIDE ITS ACCESS TO A NATIONAL COMMUNITY OF INDIVIDUALS DEDICATED TO IMPROVING THE LIVES OF YOUNG PEOPLE. TOGETHER, THIS TEAM WILL BE CATALYST FOR RESEARCH-BASED, EQUITABLE, AND YOUTH-INFORMED SOLUTIONS THAT TRANSFORM THE LANDSCAPE OF ADOLESCENT HEALTH BY FOSTERING COLLABORATION, DRIVING INNOVATION, AND IMPROVING OUTCOMES FOR YOUNG PEOPLE. EXTERNAL PARTNERS, INCLUDING CURRENT AND PRIOR TPP GRANTEES AND TITLE X PROVIDERS AND OTHER CBOS, WILL SUPPLEMENT THE CORE TEAM WITH EXPERTISE IN A BROAD RANGE OF VULNERABLE POPULATIONS, AND ENVIRONMENTS. THROUGH OUR INCUBATOR, CHLA STRIVES TO SUPPORT GROUNDBREAKING SOLUTIONS, EMPOWER DIVERSE AND NON-TRADITIONAL STAKEHOLDERS, AND INSPIRE COLLECTIVE ACTION TO ENSURE THAT ALL ADOLESCENTS REACH THEIR FULL POTENTIAL. OUR VISION IS A WORLD WHERE ADOLESCENTS HAVE THE SUPPORT, CONFIDENCE, AND RESOURCES TO THRIVE, BE HEALTHY, AND BUILD THEIR MOST BRILLIANT FUTURES.

MOLECULAR MECHANISMS CONTROLLING FORMATION OF BASAL GANGLIA CIRCUITRY

ESTABLICHMENT OF CHLA'S CHILDREN CLINICAL CENTER

THE PEDIATRIC LUPUS NEPHRITIS MYCOPHENOLATE MOFETIL (PLUMM) STUDY - TITLE EFFICACY & SAFETY OF PHARMACOKINETICALLY-DRIVEN DOSING OF MYCOPHENOLATE MOFETIL FOR THE TREATMENT OF PEDIATRIC PROLIFERATIVE LUPUS NEPHRITIS - A DOUBLE-BLIND CONTROLLED CLINICAL TRIAL THE PEDIATRIC LUPUS NEPHRITIS MYCOPHENOLATE MOFETIL (PLUMM) STUDY PROJECT SUMMARY: META-ANALYSES IN ADULTS SUGGEST EQUIVALENCE OF CLINICAL EFFICACY OF INTRAVENOUS CYCLOPHOSPHAMIDE AND MYCOPHENOLATE MOFETIL WHEN DOSED BASED ON PATIENT WEIGHT OR BODY-SURFACE-AREA (MMFBSA) AS IS THE CURRENT STANDARD FOR THE TREATMENT OF PROLIFERATIVE LUPUS NEPHRITIS (LN) TREATMENTS IN THE U.S. PHARMACOKINETICALLY- GUIDED PRECISION DOSING OF MMF (MMKPK) MAY OFFER A BENEFICIAL MODIFICATION OF THE CURRENT STANDARD TREATMENT IN THAT MMKPK PROMISES OVER 30% HIGHER LN RESPONSE RATES THAN MMFBSA. THE OBJECTIVE OF THE PROPOSED, ADEQUATELY POWERED, RANDOMIZED, DOUBLE-BLIND CONTROLLED CLINICAL TRIAL IS TO COMPARE THE EFFICACY AND SAFETY OF PHARMACOKINETICALLY-GUIDED PRECISION DOSING OF MMF (MMFPK) WITH CONVENTIONAL DOSING REGIMENS OF MMF (MMFBSA) AMONG CHILDREN WITH PROLIFERATIVE LN. THE PRINCIPAL HYPOTHESIS TO BE TESTED IN THIS 2-ARM 104-WEEK STUDY IS THAT, COMPARED TO MMFBSA, MMFPK RESULTS IN SIGNIFICANTLY HIGHER RATES OF RENAL REMISSION IN CHILDREN WITH PROLIFERATIVE LN. THE PRIMARY ENDPOINT IS THE PROPORTION OF SUBJECTS ACHIEVING AT LEAST PARTIAL RENAL REMISSION (PRR) AT WEEK 26 OF THE STUDY IN THE INTENTION TO TREAT POPULATION. THE KEY SECONDARY ENDPOINT IS ACHIEVEMENT OF COMPLETE RENAL REMISSION (CRR) AT WEEK 26 OF THE STUDY. OUR APPROACH WILL BE TO ENROLL 105 PEDIATRIC SUBJECTS, AGES 8 YEARS OR OLDER, WHO HAVE BEEN NEWLY DIAGNOSED WITH PROLIFERATIVE LN PLUS HAVE CHOSEN MMF FOR INDUCTION THERAPY PLUS TOLERATE ORAL MMF. RANDOMIZATION WILL OCCUR AT BASELINE (1:1) TO THE MMKPK ARM OR THE MMFBSA ARM, RESPECTIVELY. AFTER WEEK 26, NON-RESPONDERS WILL BE DISCONTINUED FROM THE ACTIVE STUDY INTERVENTION, AND SUBJECTS RANDOMIZED AT BASELINE TO THE MMFBSA ARM WHO ACHIEVED PRR BUT NOT CRR WILL CROSS OVER TO THE MMFPK ARM. VOLUMETRIC ABSORPTIVE MICROSAMPLING (VAMS) DEVICES WILL BE USED TO FACILITATE ESTIMATION OF THE EXPOSURE TO MYCOPHENOLIC ACID (MPA) IN WHOLE BLOOD AS IS NEEDED TO PERSONALIZE MMF DOSING IN THE MMFPK ARM. USE OF CORTICOSTEROID WILL BE STANDARDIZED AND CLOSELY REGULATED DURING THE STUDY, AND ADHERENCE TO MMF WILL BE MONITORED. PATENTED BIOMARKERS WILL BE ASSAYED IN THE URINE IN SUPPORT OF THE SUPERIORITY OF MMFPK OVER MMFBSA IN CONTROLLING LN ACTIVITY. UPON COMPLETION OF THIS TRIAL, WE EXPECT TO HAVE UNEQUIVOCAL EVIDENCE OF THE SUPERIORITY MMFPK THERAPY COMPARED TO MMFBSA USE, AND TO SHOW THAT MMFPK DOSAGE IS WELL TOLERATED AND HAS AN ACCEPTABLE SAFETY PROFILE IN CHILDREN. RELEVANCE: THE PROPOSED TRIAL IS RELEVANT TO PUBLIC HEALTH BECAUSE THERAPIES FOR LN ARE INVESTIGATED, I.E. DISEASE COMPLICATIONS THAT CONCERN THE MAJORITY OF CHILDREN WITH CSLE. IN THIS SETTING, OPTIMIZING DRUG USE PROMISES TO IMPROVE LONG-TERM DISEASE OUTCOMES THROUGH RAPID CONTROL OF KIDNEY INFLAMMATION, WHILE MINIMZING UNNECESSARY EXPOSURES TO AN IMMUNOSUPPRESSIVE AND TERATOGENIC MEDICATION. THIS IS RELEVANT TO THE PART OF NIH’S MISSION THAT PERTAINS TO FOSTERING RESEARCH IN TREATMENT; AND THE DISSEMINATION OF INFORMATION ON RESEARCH PROGRESS IN LUPUS. LN IS CENTRAL TO NIAMS STRATEGIC PLAN AND ITS LUPUS RESEARCH AGENDA IN PURSUANCE OF IMPROVED PUBLIC HEALTH AND PATIENT-CENTERED PERSONALIZED CARE.

NOVEL VACCINE AGAINST NOROVIRUS

MOLECULAR CONTROL OF NEUROGENESIS IN THE ADULT SUBVENTRICULAR ZONE

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

TRANSCRIPTIONAL PROGRAMMING OF ASTHMA RELATED PATHOLOGY IN RESPIRATORY EPITHELIA

FUNCTIONAL DISSECTION OF CNVS IN NEURODEVELOPMENTAL TRAITS

LONGITUDINAL ASSESSMENT OF MANIC SYMPTOMS

MECHANISMS OF GRANULOCYTE HOMEOSTASIS

DECODING INNATE IMMUNE SIGNALING IN NORMAL AND MYELODYSPLASTIC HEMATOPOIESIS

PULMONARY AND CARDIOVASCULAR DEVELOPMENT TRAINING GRANT

PBPK PREDICTION OF ONTOGENY MEDIATED ALTERATION IN HEPATIC DRUG ELIMINATION

CELLULAR PREDISPOSITION TO RETINOBLASTOMA TUMORIGENESIS

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

IMPLEMENTATION OF SCREENING, BRIEF INTERVENTION, AND REFERRAL TO TREATMENT SERVICES TO REDUCE ALCOHOL AND OTHER DRUG CONSUMPTION AMONG FOSTER YOUTH - THERE ARE MORE THAN 420,000 CHILDREN IN FOSTER CARE IN THE UNITED STATES; 38% ARE AGED 10 YEARS OR OLDER. THIS HIGH-RISK GROUP HAS BEEN IDENTIFIED TO HAVE INCREASED HEALTH PROBLEMS COMPARED WITH PEERS IN THE GENERAL POPULATION AND, DUE TO A LACK OF COORDINATED PREVENTION SERVICES, INCREASED EXPOSURE TO POVERTY AND MALTREATMENT, AND OTHER SYSTEMIC CHALLENGES, ARE UP TO 5 TIMES MORE LIKELY TO RECEIVE A SUBSTANCE USE DISORDER (SUD) DIAGNOSIS BY AGE 18 COMPARED TO THE GENERAL POPULATION. HOWEVER, SBIRT HAS HAD LIMITED IMPACT ON YOUTH IN FOSTER CARE. THIS IS RELATED TO A FAILURE TO SPREAD SBIRT IN SPECIALIZED FOSTER CARE HEALTH CENTERS IN PEDIATRIC SETTINGS, FEW EFFECTIVE IMPLEMENTATION EFFORTS WITH CHILDREN’S SERVICES, AND FREQUENT DISRUPTIONS IN BEHAVIORAL HEALTHCARE AND SCHOOL EXPERIENCED BY FOSTER YOUTH. THIS STUDY SEEKS TO INCREASE ABSTINENCE OF ALCOHOL AND OTHER DRUG (AOD) USE AMONG ADOLESCENTS IN FOSTER CARE, REDUCE FREQUENCY OF AOD USE AMONG FOSTER YOUTH WHO HAVE INITIATED USE, AND INCREASE REFERRAL TO TREATMENT FOR ADOLESCENTS AT HIGHEST RISK FOR SUD THROUGH STANDARDIZED IMPLEMENTATION OF SBIRT INTO SPECIALIZED FOSTER CARE HEALTH CENTERS IN OUR REGION. IN PARTNERSHIP WITH CHILDREN’S SERVICES AND COMMUNITY BEHAVIORAL HEALTH, INCLUDING ORGANIZATIONS PROVIDING SUBSTANCE USE DISORDER TREATMENT TO YOUTH IN FOSTER CARE, WE WILL SCREEN ALL YOUTH IN FOSTER CARE IN OUR REGION (N = 2240) AND PROVIDE BRIEF INTERVENTION DURING MANDATED VISITS FOR PHYSICAL HEALTH CONCERNS THAT OCCUR WHEN CHILDREN 10 AND OLDER ENTER FOSTER CARE OR EXPERIENCE A CHANGE IN PLACEMENT SETTING. WHEN CLINICALLY INDICATED, YOUTH WILL ALSO BE REFERRED TO TREATMENT. AN EVALUATION OF SBIRT FOR FOSTER YOUTH WITH N = 832 YOUTH WILL INCLUDE A COMPARISON SAMPLE COLLECTED IN YEARS 1-3 AT A SITE DELAYING IMPLEMENTATION OF SBIRT. RESULTS WILL DEMONSTRATE THAT 1) SBIRT CAN BE EFFECTIVELY IMPLEMENTED AND SUSTAINED IN SETTINGS TAILORED TO MEET THE UNIQUE NEEDS OF FOSTER YOUTH; 2) EXISTING COMMUNITY BEHAVIORAL HEALTH SERVICES FOR FOSTER YOUTH CAN BE ENHANCED TO ADDRESS TREATMENT NEEDS WITH THIS POPULATION, IN PARTNERSHIP WITH FOSTER YOUTH HEALTHCARE CENTERS; AND 3) WHEN STANDARDIZED SUBSTANCE USE SCREENING AND RESPONSE (SBIRT) IS IMPLEMENTED, IT IS ASSOCIATED WITH AN INCREASE IN ABSTINENCE, A REDUCTION IN THE FREQUENCY OF AOD USE, AND AN INCREASE IN YOUTH WHO ARE SUCCESSFULLY REFERRED AND RECEIVE TREATMENT FOR SUD. ADDITIONAL EFFORTS FOCUSED ON TRAINING PROVIDERS AND STAKEHOLDERS WHO WORK WITH FOSTER YOUTH IN SBIRT (E.G., CLINICIANS, THERAPISTS, CASEWORKERS) AND IN DEMONSTRATING SUSTAINABILITY THROUGH STANDARDIZED AUTOMATION OF SCREENING AND REFERRAL PRACTICES AND MODIFICATIONS TO BILLING AND REIMBURSEMENT WILL PROMOTE GENERALIZABILITY OF THE FINDINGS FROM THIS PROJECT TO THE MORE THAN 50 SPECIALIZED FOSTER CARE CLINICS ACROSS THE US, ENSURING FURTHER BENEFIT OF THIS PROPOSED WORK.

HOX REGULATION OF SENSORY ORGAN DEVELOPMENT IN DROSOPHILA