Childrens Hospital Medical Center

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

ADMINISTRATIVE COORDINATING CENTER: CARDIOVASCULAR DEVELOPMENT AND PEDIATRIC CARDIAC GENOMICS CONSORTIA

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

EPITHELIAL GENES IN ALLERGIC INFLAMMATION

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

CONSORTIUM OF EOSINOPHILIC GASTROINTESTINAL DISEASE RESEARCHERS

DEVELOPMENTAL MECHANISMS OF TRACHEA-ESOPHAGEAL BIRTH DEFECTS

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

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

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.

ENHANCED SURVEILLANCE FOR NEW VACCINE PREVENTABLE DISEASES

CLINICAL CENTER FOR BILIARY ATRESIA: ETIOPATHOGENESIS A*

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.

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

BUILDING MODULAR PEDIATRIC CHRONIC DISEASE REGISTRIES FOR QI AND CE RESEARCH

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

PERSONALIZED CYSTIC FIBROSIS THERAPY AND RESEARCH CENTER

NATIONAL BIOLOGICAL SAMPLE AND DATA REPOSITORY FOR PAH

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.

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

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

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

PEDIATRIC GASTROENTEROLOGY AND NUTRITION TRAINING GRANT

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CRITICAL TRANSLATIONAL STUDIES IN PEDIATRIC NEPHROLOGY

EDITING ALVEOLAR PROGENITOR CELLS FOR CORRECTION OF MONOGENIC DISEASE

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

GENE EXPRESSION IN PEDIATRIC ARTHRITIS

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

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.

POLYGENIC RISK SCORES FOR HEALTHIER AFRICAN AMERICAN FAMILIES

PEDIATRIC CENTER FOR GENE EXPRESSION AND DEVELOPMENT

GENE REGULATION AS A FOUNDATION FOR AUTOIMMUNE DISEASE PREVENTION

OPEN SOURCE SCIENCE: TRANSFORMING CHRONIC ILLNESS CARE

CINCINNATI RHEUMATIC DISEASES RESOURCE CENTER

THE ROLE OF HUMAN MILK IN INFANT NUTRITION AND HEALTH

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

CINCINNATI CENTER OF NEUROFIBROMATOSIS RESEARCH

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

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.

SICKLE CELL TREATMENT DEMONSTRATION PROGRAM

ADOLESCENT BARIATRICS: ASSESSING HEALTH BENEFITS & RISKS

COGNITIVE OUTCOME MEASURES IN SCHOOL AGE CHILDREN WITH DOWN SYNDROME

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

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

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

COMPREHENSIVE SICKLE CELL CENTER

EMERGENCY MEDICAL SERVICES FOR CHILDREN: NETWORK DEVELOPMENT DEMONSTRATION PROJECT

EPIDEMIOLOGIC IMPACT OF HPV VACCINATION

SUPRASPINAL PROCESSING OF SENSORY ASPECTS OF PAIN

IMMUNOPATHOGENESIS OF NON-ALCOHOLIC FATTY LIVER DISEASE

IMMUNOLOGICAL IDENTITY REDEFINED BY GENETICALLY FOREIGN MICROCHIMERIC CELLS

IMMUNOLOGIC DYSFUNCTION IN BILIARY ATRESIA

MODELING DIABETES USING AN INTEGRATED PLATE SYSTEM

MECHANISMS OF GRANULOCYTE HOMEOSTASIS

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

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.

CONTINUED STUDIES OF ENVIRONMENT IMPACT ON PUBERTY

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

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.

PULMONARY AND CARDIOVASCULAR DEVELOPMENT TRAINING GRANT

PROGESTERONE INDUCED IMMUNE MODULATION DURING PREGNANCY

CINCINNATI COOPERATIVE CENTER OF EXCELLENCE IN HEMATOLOGY - SUMMARY/ABSTRACT: THE LONG-TERM GOAL OF THE CINCINNATI COOPERATIVE CENTER OF EXCELLENCE IN HEMATOLOGY (CCCEH) IS TO UNDERSTAND AND CORRECT, AT THE MOLECULAR LEVEL, HEMATOLOGICAL DISEASES OF VARIOUS LINEAGES. TO ATTAIN THIS GOAL, WE MUST UNDERSTAND BASIC BIOLOGICAL PROCESSES THAT AFFECT BEHAVIORS OF HEMATOPOIETIC STEM CELLS AND THEIR VARIOUS DIFFERENTIATED PROGENIES IN VITRO AND IN VIVO. WE ENVISION THIS LONG-TERM GOAL WILL BE BEST ACCOMPLISHED BY INTERDISCIPLINARY AND COLLABORATIVE APPROACHES USING STATE-OF-THE-ART METHODS, ALONG WITH TIMELY AND RATIONAL USE OF TRANSLATIONAL STUDIES INTO THE PRECLINICAL AND CLINICAL SETTINGS. CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER (CCHMC) HAS DEVELOPED A RICH AND STIMULATING INTELLECTUAL ENVIRONMENT THAT BRINGS TOGETHER OUTSTANDING EXPERTISE AND BASIC RESEARCH IN STEM CELL BIOLOGY, VIRUS VECTOR TECHNOLOGY, IMMUNOHEMATOLOGIC CELL BIOLOGY, GENOMICS AND GENETICS, AND HEMATOPOIESIS; IN ADDITION, THE CCCEH HAS WORLD-CLASS EXPERTISE IN TRANSLATIONAL AND CLINICAL RESEARCH IN HEMATOLOGY, IMMUNOLOGY AND HEMATOPOIETIC STEM CELL TRANSPLANTATION. THIS FOCUS HAS BEEN GREATLY STRENGTHENED BY THE RECRUITMENT OF OVER 30 FACULTY MEMBERS IN THESE AREAS OF HEMATOLOGY RESEARCH OVER THE LAST 15 YEARS AT CCHMC, AND THE INCLUSION OF OVER 15 EXTERNAL HEMATOLOGY RESEARCHERS AROUND US. BASIC RESEARCH IS LINKED WITH CINCINNATI NIH-FUNDED CLINICAL AND TRANSLATIONAL SCIENCE AWARD (CTSA), WHICH HAS FACILITATED INTERDISCIPLINARY INTERACTIONS AND DEVELOPED AN INFRASTRUCTURE THAT SUPPORTS STATE-OF-THE-ART CLINICAL TRIALS IN CELL AND GENE THERAPY. HERE WE SEEK TO SOLIDIFY THE EXCITING AND SYSTEMIC GROWTH OF RESEARCH IN HEMATOLOGY AT CCHMC TO SUPPORT A NATIONAL CENTER OF EXCELLENCE, USING THE SHARED SERVICES AND ADMINISTRATIVE STRUCTURE OF THE CENTER GRANT MECHANISM. THE CCCEH ADMINISTRATIVE CORE SUPPORTS AN EXCEPTIONAL ARRAY OF RESEARCH CORES, WHICH FUNCTION TOGETHER TO SUPPORT INNOVATIVE BASIC AND TRANSLATIONAL RESEARCH BOTH LOCALLY AND NATIONALLY, IN NON-MALIGNANT HEMATOLOGY. OUR THREE PROPOSED RESEARCH CORES INCLUDE (1) XENOTRANSPLANT AND GENOME EDITING CORE, WHICH MAINTAINS SPECIALIZED MOUSE STRAINS AND PROVIDES MOUSE TRANSPLANT AND TRANSGENIC SERVICES; (2) SINGLE CELL CHARACTERIZATION AND PROCUREMENT CORE THAT INCLUDES STATE- OF-THE-ART IMAGING AS WELL AS SINGLE CELL CAPTURE AND GENE EXPRESSION CAPABILITIES; AND (3) GENE DELIVERY CORE THAT COVERS SERVICES SUCH AS EX VIVO MANIPULATION OF BLOOD CELLS BY LENTIVIRUS AND RETROVIRUS TRANSDUCTION AND SHRNA/SGRNA SCREENING. FINALLY, THIS CENTER SEEKS SUPPORT FOR AN INNOVATIVE ENRICHMENT PROGRAM THAT FOSTERS A COLLABORATIVE AND EDUCATIONAL ENVIRONMENT IN THE CENTER AND FOR OUTREACH TO THE BROAD HEMATOLOGY RESEARCH COMMUNITY AROUND US.

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

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

"IMPROVING ADHD TEEN DRIVING"

MOLECULAR MECHANISMS CONTROLLING FORMATION OF BASAL GANGLIA CIRCUITRY

NOVEL VACCINE AGAINST NOROVIRUS

MOLECULAR CONTROL OF NEUROGENESIS IN THE ADULT SUBVENTRICULAR ZONE

TRANSCRIPTIONAL PROGRAMMING OF ASTHMA RELATED PATHOLOGY IN RESPIRATORY EPITHELIA

MRI PHENOTYPING OF EARLY BPD AND PREDICTION OF OUTCOMES

LONGITUDINAL ASSESSMENT OF MANIC SYMPTOMS

DECODING INNATE IMMUNE SIGNALING IN NORMAL AND MYELODYSPLASTIC HEMATOPOIESIS

PBPK PREDICTION OF ONTOGENY MEDIATED ALTERATION IN HEPATIC DRUG ELIMINATION

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

LUNGMAP PHASE II - BUILDING A MULTIDIMENSIONAL MAP OF DEVELOPING HUMAN LUNG

MACROPHAGE BASED GENE THERAPY FOR HEREDITARY PULMONARY ALVEOLAR PROTEINOSIS

THE ROLE OF REGULATORY T CELLS IN BILIARY ATRESIA

INNATE MECHANISMS OF REGULATION OF MEMORY TH17 CELL RESPONSES

ROLES OF GSH1 & GSH2 IN TELENCEPHALIC NEUROGENESIS

GENETIC LINKAGE IN LUPUS

SELF-MANAGEMENT OF TYPE 1 DIABETES DURING ADOLESCENCE

DECODING INNATE IMMUNE SIGNALING IN NORMAL AND MYELODYSPLASTIC HEMATOPOIESIS - ABSTRACT MYELODYSPLASTIC SYNDROMES (MDS) ARE HETEROGENOUS AND POORLY UNDERSTOOD HEMATOPOIETIC STEM CELL (HSC) FAILURE SYNDROMES COMMON IN INDIVIDUALS >60 YEARS OF AGE. WITH INCREASED LIFE EXPECTANCIES, THE INCIDENCE OF MDS CONTINUES TO RISE, AND WILL SOON BE THE MOST PREVALENT HEMATOLOGIC DISORDER IN ELDERLY. THERE ARE NO EFFECTIVE TREATMENTS FOR MDS PATIENTS, DUE TO AN INSUFFICIENT UNDERSTANDING OF THE UNDERLYING PATHOBIOLOGY AND A LACK OF FAITHFUL MOUSE MODELS. OUR RESEARCH PROGRAM IS FOCUSED ON FILLING THESE GAPS, AND THEN LEVERAGING THE RESULTING KNOWLEDGE AND TOOLS TO DEVELOP EFFECTIVE DRUG THERAPIES. ALREADY, WE HAVE DISCOVERED GENETICALLY-DRIVEN ABERRANT ACTIVATION OF INNATE IMMUNE PATHWAYS IN MDS HSCS. WE HAVE ALSO IDENTIFIED A CRITICAL FUNCTION OF INNATE IMMUNE PATHWAYS IN NORMAL HSCS, WHICH HAS IMPLICATIONS FOR CHRONIC IMMUNE-RELATED DISORDERS, CARDIOVASCULAR DISEASES, AND HEMATOPOIESIS. WE HYPOTHESIZE THAT DYSREGULATED INNATE IMMUNE SIGNALING IS A MAJOR CONTRIBUTOR TO THE INITIATION AND DEVELOPMENT OF MDS, AND IS A FEASIBLE THERAPEUTIC TARGET. HEREIN, WE PROPOSE TO TEST THIS HYPOTHESIS BY CARRYING OUT THE FOLLOWING COMPLIMENTARY 3-PART RESEARCH PROGRAM: (1) DISSECT THE GENETIC AND CELLULAR UNDERPINNINGS OF MDS HSCS, WITH AN EMPHASIS ON CELL-INTRINSIC AND CELL-EXTRINSIC IMMUNE-INFLAMMATORY FACTORS. (2) IDENTIFY AND CHARACTERIZE NOVEL SIGNALING PATHWAYS DRIVING MDS PHENOTYPE IN HSCS. (3) DEVELOP NOVEL THERAPEUTIC STRATEGIES FOR THE TREATMENT OF MDS. THE RESULTS OF OUR RESEARCH PROGRAM WILL ADVANCE OUR PARADIGM-SHIFTING MODEL OF THE INITIATION, PROGRESSION, AND TREATMENT OF MDS.

PURSUING PERFECTION IN PEDIATRIC THERAPUTICS

BINDING OF EPSTEIN BARR VIRUS EBNA2 UNIFIES MULTIPLE SCLEROSIS GENETIC MECHANISMS

BETTER OUTCOMES FOR CHILDREN: PROMOTING EXCELLENCE IN HEALTHCARE GENOMICS TO INFORM POLICY

EVALUATING ASSESSMENT AND MEDICATION TREATMENT OF ADHD IN CHILDREN WITH DOWN SYNDROME - PROJECT SUMMARY CHILDREN WITH DOWN SYNDROME (DS) HAVE A 3-5 TIMES GREATER PREVALENCE OF ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD) THAN TYPICALLY DEVELOPING CHILDREN. DESPITE THIS HIGHER RISK OF ADHD, RATES OF STIMULANT MEDICATION TREATMENT ARE DISPROPORTIONATELY LOW IN CHILDREN WITH DS+ADHD EVEN THOUGH STIMULANTS ARE THE MOST EFFICACIOUS ADHD TREATMENT AND ARE RECOMMENDED BY CONSENSUS GUIDELINES FOR USE IN CHILDREN WITH INTELLECTUAL DISABILITY (ID) AND COMORBID ADHD. POSSIBLE REASONS FOR UNDER-UTILIZATION OF STIMULANT TREATMENT IN DS+ADHD INCLUDE: 1) DIAGNOSTIC UNCERTAINTY REGARDING HOW TO ACCURATELY DIAGNOSE ADHD IN CHILDREN WITH DS, MAKING PROVIDERS PRONE TO “DIAGNOSTIC OVERSHADOWING” (I.E., ATTRIBUTING ADHD TO THE ID); 2) THERE IS NOT A SINGLE CLINICAL TRIAL EXAMINING THE SAFETY AND EFFICACY OF STIMULANT MEDICATION IN CHILDREN WITH DS+ADHD; AND 3) CONCERNS ABOUT CARDIAC SAFETY, GIVEN THE HIGH INCIDENCE OF CONGENITAL HEART DISEASE OR DEFECTS (CHD) IN THE DS POPULATION. WE PROPOSE A PILOT STUDY TO DEFINE THE CLINICAL FEATURES OF DS+ADHD THEREBY ENABLING MORE ACCURATE DIAGNOSIS AND A PILOT CLINICAL TRIAL TO INFORM SAMPLE SIZE ESTIMATES FOR A LARGER CLINICAL TRIAL. WE PROPOSE TO PERFORM THE FIRST RANDOMIZED CLINICAL TRIAL OF STIMULANT MEDICATION IN CHILDREN WITH DS+ADHD TO PROVIDE EVIDENCE REGARDING THE SHORT AND LONG-TERM SAFETY AND EFFICACY OF STIMULANT USE IN CHILDREN WITH DS+ADHD, BOTH WITH AND WITHOUT CHD. ONE HUNDRED (100) CHILDREN WITH DS+ADHD AND 70 CHILDREN WITH DS AND NO ADHD (DS-ADHD), ALL AGED 6-12 AND MATCHED ON AGE, GENDER, AND IQ, WILL PARTICIPATE. ALL 170 CHILDREN ENROLLED IN THE STUDY WILL COMPLETE A COMPREHENSIVE ASSESSMENT BATTERY EVALUATING ADHD DIAGNOSTIC CRITERIA AS WELL AS BEHAVIORAL, COGNITIVE, ACADEMIC, AND FUNCTIONAL IMPAIRMENTS. THE 100 CHILDREN IN THE DS+ADHD GROUP WILL ALSO COMPLETE A MULTI-PHASED RANDOMIZED, DOUBLE-BLIND CLINICAL TRIAL WITH CROSSOVER TO PLACEBO AND LONG-TERM FOLLOW- UP TO ASSESS THE SHORT- AND LONG-TERM EFFICACY AND SAFETY OF STIMULANT MEDICATIONS FOR TREATING ADHD SYMPTOMS AND IMPAIRMENT IN CHILDREN WITH DS. STUDY AIMS WILL FOCUS ON 1) IDENTIFYING BEHAVIORAL, COGNITIVE, ACADEMIC, AND FUNCTIONAL IMPAIRMENTS THAT DIFFERENTIATE CHILDREN WITH DS+ADHD FROM CHILDREN WITH DS-ADHD; 2) INFORMING SAMPLE SIZE OF LARGER CLINICAL TRIAL; 3) ASSESSING THE SHORT- AND LONG-TERM SAFETY OF STIMULANT TREATMENT IN CHILDREN WITH DS+ADHD WITH A SPECIFIC FOCUS ON CARDIAC SAFETY; 4) DETERMINING THE SHORT- AND LONG-TERM EFFICACY OF STIMULANT TREATMENT AT REMEDIATING COGNITIVE, BEHAVIORAL, AND FUNCTIONAL IMPAIRMENTS IN CHILDREN WITH DS+ADHD; AND 5) EXPLORING MODERATORS (E.G., IQ, ADHD SUBTYPE, EXECUTIVE FUNCTIONING, COMORBID INTERNALIZING DISORDERS, CHD) OF STIMULANT RESPONSE AND SIDE EFFECTS. RESULTS FROM THIS STUDY WILL PROVIDE MUCH NEEDED DIAGNOSTIC AND TREATMENT DATA THAT WILL DIRECTLY IMPACT THE OUTCOMES OF THE APPROXIMATELY 45,000 CHILDREN WITH DS+ADHD NATIONWIDE.

DECIPHERING MECHANISMS OF MYOBLAST FUSION

FOX TRANSCRIPTION FACTORS IN DEVELOPMENT OF PULMONARY CAPILLARIES

HOST INTEGRATION OF COMMENSAL AND PATHOGENIC BACTERIAL-DERIVED SIGNALS

BIOCHEMICAL AND GENETIC ANALYSIS OF NOTCH SIGNALING

BIOPSYCHOSOCIAL DETERMINANTS OF PEDIATRIC-ONSET CHRONIC MUSCULOSKELETAL PAIN - ABSTRACT PEDIATRIC-ONSET CHRONIC MUSCULOSKELETAL PAIN DISORDERS ARE COMMON, BUT THE MECHANISMS UNDERLYING THEIR PATHOPHYSIOLOGY ARE POORLY UNDERSTOOD. CURRENT BEST PRACTICES IN PEDIATRIC PAIN MANAGEMENT FOCUS ON SYMPTOM MANAGEMENT AND RESTORATION OF FUNCTION. ABSENT A MORE MECHANISTIC UNDERSTANDING OF THE DRIVERS OF PEDIATRIC CHRONIC PAIN AND POTENTIAL SUB-TYPES OF CHRONIC PAIN BASED ON UNDERLYING PATHOPHYSIOLOGY (AS OPPOSED TO PHENOTYPIC CLASSIFICATIONS), PAIN PROVIDERS ARE UNABLE TO TARGET TREATMENTS TO THE ROOT CAUSES OF PATIENTS’ SYMPTOMS. THERE IS NO CURE FOR PEDIATRIC-ONSET CHRONIC PAIN, AND MANY CHILDREN AND ADOLESCENTS CONTINUE TO HAVE PAIN IN ADULTHOOD, HIGHLIGHTING THE NEED FOR GREATER RESEARCH INTO THE DEVELOPMENT OF NOVEL TREATMENT STRATEGIES. AT CINCINNATI CHILDREN’S HOSPITAL MEDICAL CENTER, WE HAVE A LARGE AND WELL-ESTABLISHED MULTIDISCIPLINARY TEAM OF INVESTIGATORS WHO ARE ALREADY WORKING TO UNRAVEL THE COMPLEX BIOPSYCHOSOCIAL CONTRIBUTORS TO CHRONIC MUSCULOSKELETAL (MSK) PAIN IN CHILDREN. OUR MULTIPLE ONGOING REGISTRIES AND COHORTS HAVE MORE THAN 2400 PATIENTS WITH PEDIATRIC-ONSET PRIMARY MSK PAIN DISORDERS, PEDIATRIC RHEUMATIC DISEASES, AND SURGICAL INTERVENTIONS FOR WHOM WE HAVE RICH MEDICAL HISTORY, PAIN-RELATED AND PSYCHOSOCIAL DATA. THE PROPOSED RESEARCH WOULD LEVERAGE THESE EXISTING REGISTRIES AND COHORTS TO ENROLL A HETEROGENEOUS SAMPLE OF N=600 ADOLESCENTS AND YOUNG ADULTS (AGES 16-26); N= 400 WITH PRIMARY CHRONIC MSK PAIN, OR CHRONIC MSK PAIN SECONDARY TO RHEUMATIC DISEASE OR MAJOR MSK SURGERY, AND N=200 WITH A RHEUMATIC DISEASE OR HISTORY OF MAJOR MSK SURGERY, BUT NO CHRONIC PAIN. USING A MIXED RETROSPECTIVE-PROSPECTIVE COHORT STUDY DESIGN, WE FIRST PROPOSE TO COMBINE AND HARMONIZE RETROSPECTIVE DATA FROM PATIENTS’ PAST CLINICAL REGISTRY AND RESEARCH RECORDS. WE THEN WILL ACQUIRE PROSPECTIVE DATA REGARDING PAIN CHARACTERISTICS, QUANTITATIVE SENSORY TESTING AND CYTOKINE PROFILING AND APPLY A MODEL-BASED UNSUPERVISED CLUSTERING ANALYTIC APPROACH TO DEFINE MECHANISTICALLY DISTINCT CHRONIC MSK PAIN SUBGROUPS. FURTHER, WE WILL USE SERUM SAMPLES FROM PATIENTS TO CONDUCT IN VITRO EXPERIMENTS TO IDENTIFY NEURO-IMMUNE SIGNALING PATHWAYS IMPACTING SENSORY TRANSDUCTION USING AN INNOVATIVE INDUCED PLURIPOTENT STEM CELL (IPSC) MODEL. THIS MECHANISTIC EXAMINATION WILL BE FURTHER AUGMENTED BY ANALYSIS OF HOW PSYCHOSOCIAL, BEHAVIORAL AND LIFESTYLE FACTORS MEDIATE PAIN-RELATED OUTCOMES AMONG PARTICIPANTS. IN PURSUING AN ANALYSIS OF PATIENTS THAT EXTENDS FROM THE LEVEL OF COMMUNITY CHARACTERISTICS TO SINGLE-CELL ASSAYS, THIS RESEARCH WILL RESULT IN THE CONSTRUCTION OF A ROBUST BIOPSYCHOSOCIAL MODEL IN WHICH PATIENTS ACROSS MULTIPLE PAIN SUB-GROUPS MAY BE CLASSIFIED ACCORDING TO GENETIC AND CELLULAR MECHANISMS AS WELL AS PSYCHOLOGICAL, BEHAVIORAL, AND SOCIAL FEATURES PROMOTING RISK AND RESILIENCE. THROUGH COLLABORATION ACROSS DISCIPLINES ALONG WITH PATIENT ADVISORY PARTNERS, THIS STUDY WILL REVEAL MECHANISTICALLY DRIVEN TREATMENT TARGETS FOR FUTURE THERAPEUTIC TRIALS AS WELL AS NOVEL INSIGHTS INTO THE RELATIONSHIP BETWEEN PAINFUL MSK CONDITIONS OF CHILDHOOD AND THE BIOPSYCHOSOCIAL FACTORS THAT CONTRIBUTE TO PATIENT OUTCOMES.

BETTER OUTCOMES FOR CHILDREN: GWAS & PHEWAS IN EMERGEII.

INVESTIGATION OF REGIONAL IDENTITY IN HUMAN INTESTINAL STEM CELLS

NATIONAL RESEARCH SERVICE AWARD

CINCINNATI CENTER FOR EXCELLENCE IN MOLECULAR HEMATOLOGY

ROLE OF FA PROTEIN COMPLEXES IN HEMATOPOIESIS

IMAGING AND MOLECULAR PHENOTYPING OF CYSTIC FIBROSIS LUNG DISEASE - CYSTIC FIBROSIS (CF) IS AMONG THE MOST COMMON FATAL GENETIC DISEASES IN THE U.S. AND INVOLVES PROGRESSIVE LUNG FUNCTION LOSS AND STRUCTURAL REMODELING, LEADING TO LUNG TRANSPLANT OR DEATH. THOUGH LIFE EXPECTANCY IN CF PATIENTS HAS INCREASED DUE TO IMPROVED TREATMENTS, PATHOLOGICAL CHANGES STILL OCCUR WITHIN THE FIRST YEAR OF LIFE. IT HAS BEEN DIFFICULT TO DETECT THESE EARLY CHANGES, BECAUSE CONVENTIONAL MEASURES OF LUNG FUNCTION SUCH AS SPIROMETRY (E.G., FORCED EXPIRATORY VOLUME IN 1 SECOND, FEV1) ARE LAGGING INDICATORS AND INSENSITIVE TO EARLY DISEASE. IN CONTRAST, ULTRA-SHORT ECHO-TIME (UTE) AND HYPERPOLARIZED (HP) 129XE MRI CAN DETECT PATHOLOGY YEARS BEFORE FEV1. ADDI- TIONALLY, PROTEOMIC BIOMARKERS FROM HIGH-PRECISIONS MASS SPECTROMETRY (MS), WHEN COUPLED WITH MODELING BASED ON FUNCTIONAL DATA (FD) ANALYSIS, ACCURATELY FORECAST CF LUNG DISEASE PROGRESSION. HOWEVER, THESE BIOMARKERS HAVE ONLY BEEN VALIDATED IN PATIENTS WITH ESTABLISHED DISEASE. THE LONG-TERM GOAL OF THIS RESEARCH IS TO VALIDATE PROTEOMIC MARKERS THAT DETECT AND PREDICT LUNG FUNCTION DECLINE AND STRUCTURAL REMODELING IN EARLY LUNG DISEASE. THE OBJECTIVE OF THIS APPLICATION IS TO USE STATE-OF-THE-ART HP 129XE AND UTE MRI TO VALIDATE PROTEOMIC MARKERS IN EARLY CF. THIS WILL BE ACCOMPLISHED USING BLOOD SERUM AND CLINICALLY OBTAINED BRONCHOALVEOLAR LAVAGE (BAL) FLUID FROM CF PATIENTS WITH KNOWN LUNG PATHOLOGY. OUR CENTRAL HYPOTHESIS IS THAT IMAGE-GUIDED PROTEOMICS CAN FORECAST PATHOPHYSIOLOGY BEFORE SPIROMETRIC CHANGES ARE OBSERVED. OUR RATIONALE IS THAT, WHILE 129XE AND UTE MRI ARE CURRENTLY LIMITED TO SPECIALIZED CENTERS, MS PROTEOMICS CAN BE PERFORMED ON READILY OBTAINED CLINICAL SPECIMENS, AND TRANSLATED WITH FD ANALYSIS INTO AN EASILY DISSEMINATED TOOL TO PREDICT IMPENDING LUNG DISEASE PROGRESSION, AND THUS ENABLE INTERVENTIONS BEFORE PERMANENT LUNG DAMAGE OCCURS. GUIDED BY COMBINED MRI AND PROTEOMIC DATA AND THE UTILITY OF FD ANALYSIS TO PREDICT LUNG FUNCTION DECLINE, OUR CENTRAL HYPOTHESIS WILL BE TESTED BY COMPLETING THE FOLLOWING SPECIFIC AIMS: 1) VALIDATE OUR PREDICTIVE BIOMARKERS IN CF PATIENTS WITH NORMAL SPIROMETRY BUT ABNORMAL VENTILATION; 2) DETERMINE THE SENSITIVITY AND SPECIFICITY OF SYSTEMIC BIOMARKERS IN PRE- DICTING EARLY STRUCTURAL RE-MODELING IN CF LUNG DISEASE; AND 3) PERFORM CLINICAL BRONCHOSCOPY TO IDENTIFY MOLECULAR SIGNATURES OF IRREVERSIBLE LUNG REMODELING. WE HAVE DEVELOPED THE MRI SEQUENCES AND RECONSTRUCTION PIPELINE NEEDED TO COMPLETE THE WORK. FOR AIMS 1 & 2, WE HAVE USED MRI AND MS PROTEOMICS TO IDENTIFY KEY BIOMARKERS TO PREDICT STRUCTURAL AND FUNCTIONAL ABNORMALITIES IN CF. FOR AIM 3, WE HAVE USED BAL PROTEOMICS TO IDENTIFY MOLECULAR CHANGES AT THE PATHWAY LEVEL IN CF PATIENTS. THE PROPOSED RESEARCH IS INNOVATIVE, BECAUSE IT WILL USE CUTTING-EDGE IMAGING TO VALIDATE MOLECULAR TOOLS TO ASSESS EARLY LUNG DISEASE. THESE RESULTS WILL BE SIGNIFICANT, BECAUSE THEY WILL PRODUCE AN EASILY DISSEMINATED TOOL TO PREDICT PERMANENT STRUCTURAL REMODELLING AND IRREVERSI- BLE FUNCTIONAL LOSSES. THIS WORK WILL HAVE AN IMMEDIATE POSITIVE IMPACT BY DEVELOPING AND TRANSLATING NON-INVA- SIVE TESTS TO IDENTIFY CF PATIENTS AT HIGH RISK OF LUNG DAMAGE AND INTERVENE BEFORE IRREVERSIBLE CHANGES OCCUR. IT WILL ALSO PROVIDE A UNIQUE PLATFORM TO ASSESS PATHOLOGICAL PROGRESSION IN A WIDE RANGE OF LUNG DISEASES.

MOLECULAR MECHANISMS OF ATRIAL DEVELOPMENT AND REGENERATION

"LUNG MAP" ATLAS RESEARCH CENTER

GENOMICS OF INFLAMMATORY BOWEL DISEASE

A REVOLUTIONARY VACCINE APPROACH TO PREVENT HIV INFECTION IN SUBSTANCE ABUSE

SIROLIMUS TSC EPILEPSY PREVENTION STUDY (STEPS) IND#145820 11/8/2019 - SUMMARY/ABSTRACT EPILEPSY IS VERY PREVALENT AND HIGHLY REFRACTORY TO CURRENTLY AVAILABLE MEDICAL TREATMENTS IN TUBEROUS SCLEROSIS COMPLEX (TSC), A GENETIC DISORDER AFFECTING 1:6000 LIVE BIRTHS. MEDICALLY-REFRACTORY EPILEPSY IN TSC IS ASSOCIATED WITH LIFELONG INTELLECTUAL DISABILITY AND NEURODEVELOPMENTAL DEFICITS. EVEROLIMUS AND SIROLIMUS, PHARMACOLOGICAL INHIBITORS OF THE MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1 (MTORC1), HAVE BEEN SUCCESSFULLY REPURPOSED TO TREAT MAY CLINICAL MANIFESTATIONS OF TSC, INCLUDING FOCAL-ONSET EPILEPSY. HOWEVER, FEW PATIENTS BECOME SEIZURE- FREE FOLLOWING TREATMENT WITH MTORC1 INHIBITORS AND 60% OF PATIENTS WITH TSC ARE STILL IN NEED OF EFFECTIVE TREATMENT. MOUSE MODELS OF TSC AND HUMAN CLINICAL TRIALS INDICATE EARLY TREATMENT WITH MTORC1 INHIBITORS, BEFORE THE ONSET OF SEIZURES, MAY BE A MORE EFFECTIVE TREATMENT STRATEGY AGAINST EPILEPSY AND EPILEPSY- ASSOCIATED DEFICITS IN NEURODEVELOPMENT IN PATIENTS DIAGNOSED WITH TSC. THE CURRENT STUDY PROPOSES A PHASE IIB MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL WITH SIROLIMUS TO TEST THIS HYPOTHESIS. THE PRIMARY AIMS OF THE CLINICAL TRIAL ARE (1) TO DEMONSTRATE THAT SIROLIMUS PREVENTS OR DELAYS SEIZURES IN INFANTS WITH TSC THAT ARE 0-12 MONTHS OF AGE; AND (2) TO DEMONSTRATE THAT SIROLIMUS IS SAFE AND WELL-TOLERATED IN INFANTS WITH TSC THAT ARE 0-12 MONTHS OF AGE. ADDITIONAL (SECONDARY) AIMS OF THE TRIAL ARE: (1) TO DEMONSTRATE THAT EARLY SIROLIMUS TREATMENT IMPROVES DEVELOPMENTAL DELAY, LANGUAGE IMPAIRMENT, ADAPTIVE SKILLS, AND AUTISM RISK; (2) TO ASSESS THE UTILITY OF EEG AND MRI BIOMARKERS FOR MEASURING MTORC1 INHIBITION IN THE BRAIN; AND (3) TO VALIDATE PRECISION DOSING OF SIROLIMUS IN INFANTS WITH TSC.

MECHANISTIC AND TRANSLATIONAL MEDICINE STUDIES OF BRAIN NEUROPHYSIOLOGY AND PHENOTYPIC HETEROGENEITY IN FRAGILE X SYNDROME - THE DEVELOPMENT OF NEXT-GENERATION THERAPEUTICS (GENOMIC, CELLULAR, AND SMALL MOLECULE) IN FRAGILE X SYNDROME (FXS) IS HINDERED BY THREE KNOWLEDGE GAPS: 1) POOR UNDERSTANDING OF THE DEVELOPMENTAL TRAJECTORY OF BRAIN DYSFUNCTION, 2) LIMITED ABILITY TO ACCOUNT FOR PHENOTYPIC HETEROGENEITY, AND 3) INADEQUATE VALIDATION OF HOW TRANSLATIONAL MODELS REPRESENT THE HUMAN CONDITION. OUR TEAM, ESTABLISHED OVER A DECADE AGO, HAS DEVELOPED A STAKEHOLDER-INFORMED TRANSLATIONAL RESEARCH PROGRAM DEDICATED TO UNDERSTANDING FXS BRAIN PHYSIOLOGY ACROSS CELLULAR, CIRCUIT, AND SYSTEMS LEVELS. OUR PREVIOUS CENTERS HAVE LED THE FIELD IN ESTABLISHING AN EMPIRICAL FRAMEWORK FOR CHARACTERIZING SHARED ELECTROPHYSIOLOGICAL BIOMARKERS IN ADULTS WITH FXS AND THE FMR1-/- KNOCKOUT (KO) MOUSE. TO ADDRESS THE PRESENT GAPS, OUR TEAM PROPOSES TO SYNCHRONIZE HUMAN PEDIATRIC AND MOUSE DEVELOPMENTAL STUDIES, LEVERAGING RECENT DISCOVERIES AND OUR WELL-ESTABLISHED METHODS TO ESTABLISH TRANSLATIONAL PARALLELS. THE PROPOSED WORK ADDRESSES KEY LIMITATIONS OUR OF PREVIOUS WORK WHILE DIRECTLY ADDRESSING ALL THREE RFA-HD-25-002 SPECIFIC POINTS OF INTEREST: 1) DEVELOPMENT OF TRANSLATABLE BIOMARKERS, 2) RESOLVING PHENOTYPIC HETEROGENEITY, AND 3) IDENTIFICATION OF NOVEL MECHANISMS. THE NIH CENTER MECHANISM PROVIDES AN IDEAL PLATFORM FOR OUR “CELLS TO CIRCUITS TO SYSTEMS TO COMMUNITY” APPROACH, MARKED BY CLOSE COLLABORATION WITH SCIENTISTS AND COMMUNITY STAKEHOLDERS, AND FACILITATING THREE LINKED PROJECTS THAT SPAN PATIENT-CENTERED RESEARCH TO IN VIVO ANIMAL EXPERIMENTS TO LAYER-SPECIFIC MICRO-CIRCUIT PHYSIOLOGY: PROJECT 1 (ERICKSON/SCHMITT, CINCINNATI CHILDREN’S) WILL STUDY FXS YOUTH AGED 2-17 YEARS TO DETERMINE AGE-RELATED CHANGES AND DEVELOPMENTAL TRAJECTORY OF TRANSLATABLE BIOMARKERS IN FXS USING RESTING, EVOKED AUDITORY, AND COGNITIVE PARADIGMS AND EVALUATE HETEROGENEITY BY CONSIDERING THE IMPACT OF SEX, AGE, FMRP EXPRESSION, AND EEG SIGNATURES ON COGNITIVE DEFICITS AND DRUG RESPONSE. PROJECT 2 (BINDER/RAZAK, UC RIVERSIDE) WILL STUDY BRAIN ACTIVITY USING SURFACE MULTI-ELECTRODE ARRAY (MEA) AND DEPTH ARRAY IN VIVO ELECTROPHYSIOLOGY IN THE FMR1 KO MOUSE ACROSS DEVELOPMENTAL STAGES USING RESTING AND EVOKED AUDITORY PARADIGMS IN PARALLEL WITH HUMAN STUDIES AND EXAMINE NOVEL MECHANISTIC APPROACHES TO ADDRESS CIRCUIT HYPEREXCITABILITY USING GENETIC MODELS AND PHARMACOLOGIC PROBES IMPACTING GLUTAMATE NMDA RECEPTORS GLUN2C/D AND T-TYPE CA+ CHANNELS. PROJECT 3 (HUBER/GIBSON, UT SOUTHWESTERN) WILL DETERMINE SYNAPTIC, CELLULAR AND MICROCIRCUIT MECHANISMS BY WHICH GLUN2C/D DRIVES EXCITABILITY OF CIRCUITS AND ALTERATIONS IN THALAMIC-DRIVEN LAMINAR ACTIVITY AND SYNCHRONY AS WELL AS STUDY THE MATURATION OF MULTI-SITE, NETWORK-LEVEL FUNCTION IN FMR1 KO MICE USING TETRODE-BASED IN VIVO RECORDINGS DURING COGNITIVE PARADIGMS USED IN HUMAN STUDIES. ACROSS PROJECTS, PHENOTYPIC VARIABILITY WILL BE EXAMINED ACROSS A LARGE SAMPLE OF HUMAN PARTICIPANTS, MOUSE BACKGROUND STRAIN, SEX, AGE AND FMRP EXPRESSION. THIS COMPREHENSIVE APPROACH AIMS TO ACCELERATE TREATMENT DISCOVERY IN FXS BY PROVIDING A FOUNDATION INFORMED BY DEVELOPMENT, VARIABILITY, AND MECHANISTIC INSIGHTS TO ADVANCE TRANSLATIONAL MEDICINE GOALS IN FXS.

A PHASE 3 CLINICAL TRIAL OF AN E-HEALTH BEHAVIORAL INTERVENTION TO IMPROVE EXECUTIVE FUNCTIONING IN ADOLESCENTS WITH EPILEPSY - EPILEPSY IS A COMMON PEDIATRIC NEUROLOGICAL CONDITION AFFECTING ~470,000 YOUTH IN THE UNITED STATES. ADOLESCENTS WITH EPILEPSY ARE AT SIGNIFICANT RISK FOR NEUROBEHAVIORAL COMORBIDITIES (I.E., DEPRESSIVE/BEHAVIORAL SYMPTOMS) AND SUBOPTIMAL SOCIAL, ACADEMIC, AND QUALITY OF LIFE OUTCOMES. RESEARCH SUGGESTS THAT DEFICITS IN EXECUTIVE FUNCTIONING (EF), DEFINED AS THE SKILLS NECESSARY FOR GOAL-DIRECTED AND COMPLEX ACTIVITIES, INCLUDING PROBLEM-SOLVING, INITIATION, MONITORING, ORGANIZATION, PLANNING, SELF-REGULATION AND WORKING MEMORY, CONTRIBUTE TO SUBOPTIMAL FUNCTIONING. EF DEFICITS HAVE BEEN DOCUMENTED IN UP TO 50% OF YOUTH WITH EPILEPSY, WHICH IS 3 TIMES THE PREVALENCE IN HEALTHY YOUTH. EVIDENCE-BASED INTERVENTIONS TO IMPROVE EF COULD PLAY A CRITICAL ROLE IN PREVENTING ADVERSE OUTCOMES AND PROMOTING OPTIMAL FUNCTIONING IN ADOLESCENTS WITH EPILEPSY; HOWEVER NONE EXISTS FOR THIS VULNERABLE POPULATION. TO FILL THIS GAP, WE SUCCESSFULLY DEVELOPED AND TESTED EPILEPSY JOURNEY (EJ), A COMPREHENSIVE E-HEALTH BEHAVIORAL MULTI-COMPONENT PROBLEM-SOLVING INTERVENTION THAT COMBINES 10 SELF-GUIDED LEARNING MODULES WITH 10 TELEHEALTH SESSIONS. THE PROMISING PROOF-OF-CONCEPT TRIAL (N=39) SHOWED HIGH FEASIBILITY, ACCEPTABILITY, PATIENT SATISFACTION, AND SIGNIFICANT IMPROVEMENTS IN PARENT-REPORTED EF BEHAVIORS, NEUROBEHAVIORAL FUNCTIONING, AND QUALITY OF LIFE. THE NEXT LOGICAL PHASE OF THIS RESEARCH IS TO CONDUCT A DEFINITIVE RANDOMIZED CLINICAL TRIAL TO EXAMINE: 1) WHETHER THE TWO COMPONENTS OF TREATMENT (EJ MODULES AND TELEHEALTH) ARE BOTH ESSENTIAL, 2) IF THE INTERVENTION GENERALIZES TO A RACIALLY DIVERSE SAMPLE, AND 3) HAS A DURABLE IMPACT ON IMPROVING PARENT-REPORTED AND PERFORMANCE-BASED EF BEHAVIORS. THUS, THE AIM OF THE CURRENT PROPOSAL IS TO CONDUCT A MULTI-SITE PHASE 3 RANDOMIZED CONTROLLED CLINICAL TRIAL (RCT) USING A 2X2 FACTORIAL DESIGN TO EXAMINE THE EFFICACY OF SEPARATE (EJ MODULES AND EJ TELEHEALTH) AND COMBINED COMPONENTS OF EJ ON EF. PARTICIPANTS POSITIVE FOR EF DEFICITS (N=232) WILL BE RANDOMIZED TO ONE OF FOUR ARMS: 1) EJ MODULES WITH TELEHEALTH SESSIONS, 2) EJ MODULES ALONE, 3) EJ TELEHEALTH SESSIONS ALONE, OR 4) USUAL CARE (NO EJ MODULES OR TELEHEALTH SESSIONS). TREATMENT PARTICIPANTS WILL EITHER INDEPENDENTLY REVIEW EJ MODULES FOCUSED ON EF SKILLS (~15-30 MIN.) AND/OR HAVE WEEKLY TELEHEALTH SESSIONS (~30-45 MIN.) WITH A THERAPIST FOR THREE MONTHS. THE GROUPS WILL LEARN AND APPLY PROBLEM-SOLVING STRATEGIES TO THEIR INDIVIDUAL EF DIFFICULTIES. PARTICIPANTS WILL COMPLETE MEASURES AT BASELINE, POST-TREATMENT, 3- AND 12-MONTHS POST-TREATMENT TO EXAMINE MAINTENANCE OF EFFECTS. THERE IS A CRITICAL NEED FOR EVIDENCE-BASED INTERVENTIONS TO IMPROVE EXECUTIVE FUNCTIONING BEHAVIORS IN YOUTH WITH EPILEPSY. IF THE AIMS OF THIS UG3/UH3 ARE ACHIEVED, WE WILL HAVE DEFINITIVE EVIDENCE FOR ADDRESSING EF DEFICITS. WE EXPECT THAT EJ MODULES AND EJ TELEHEALTH WILL DEMONSTRATE EFFICACY ALONE AND IN COMBINATION, WHICH WILL ALLOW PATIENTS TO SELECT THE APPROACH BEST SUITED TO THEIR SPECIFIC SITUATION. CONSEQUENTLY, WE CAN IMPROVE LONG-TERM OUTCOMES (E.G., NEUROBEHAVIORAL COMORBIDITIES, ACADEMIC SUCCESS, SOCIAL RELATIONSHIPS, AND QOL) IN ADOLESCENTS WITH EPILEPSY, A HIGH-RISK POPULATION.

ROLE AND REGULATION OF TSLP IN CHILDHOOD ALLERGIC DISEASE

MIR-155 AND RUNX FUNCTION IN NEUROFIBROMA TUMORIGENESIS AND THERAPY

MOLECULAR GENETIC ANALYSIS OF CRANIOFACIAL DEVELOPMENT

EARLIEST PREDICTORS OF LANGUAGE OUTCOMES IN HIGH-RISK INFANTS

NATIONAL RESEARCH SERVICE AWARD

LONGITUDINAL EXAMINATION OF SLUGGISH COGNITIVE TEMPO AND INTERNALIZING PSYCHOPATHOLOGY IN ADOLESCENCE - PROJECT SUMMARY/ABSTRACT SLUGGISH COGNITIVE TEMPO (SCT) IS A SET OF BEHAVIORAL SYMPTOMS CHARACTERIZED BY EXCESSIVE DAYDREAMING, SLOWED THINKING, AND MENTAL CONFUSION AND FOGGINESS. IT IS NOW ESTABLISHED THAT SCT CAN BE RELIABLY MEASURED ACROSS PARENT, TEACHER, AND SELF-REPORT RATINGS AND IS DISTINCT FROM OTHER PSYCHOPATHOLOGY DIMENSIONS INCLUDING ADHD AND INTERNALIZING SYMPTOMS. A RAPIDLY GROWING BODY OF RESEARCH ALSO DEMONSTRATES SCT TO BE STRONGLY ASSOCIATED WITH FUNCTIONAL IMPAIRMENT, ABOVE AND BEYOND OTHER PSYCHOPATHOLOGIES. HOWEVER, SCT REMAINS ABSENT FROM CURRENT MODELS OF PSYCHOPATHOLOGY, IN LARGE PART BECAUSE THE FIELD LACKS RIGOROUS LONGITUDINAL RESEARCH EXAMINING SCT IN RELATION TO OTHER PSYCHOPATHOLOGIES. IN CROSS-SECTIONAL STUDIES, SCT SYMPTOMS ARE CONSISTENTLY AND STRONGLY ASSOCIATED WITH INTERNALIZING SYMPTOMS. PRELIMINARY FINDINGS ALSO DOCUMENT ASSOCIATIONS BETWEEN SCT AND INCREASED SUICIDE RISK. IMPORTANTLY, OUR PILOT DATA SHOW SCT PREDICTS INCREASED INTERNALIZING SYMPTOMS RATHER THAN THE REVERSE. FURTHER, SCT SYMPTOMS UNIQUELY PREDICT INTERNALIZING PROBLEMS AND NOT EXTERNALIZING BEHAVIORS, SUGGESTING THAT SCT MAY BE A UNIQUE FACTOR IN UNDERSTANDING THE DEVELOPMENT OF INTERNALIZING PROBLEMS SPECIFICALLY. YET STUDIES LINKING SCT TO INTERNALIZING SYMPTOMS IN YOUTH ARE LIMITED IN SEVERAL WAYS, INCLUDING: (A) USE OF CROSS-SECTIONAL DESIGNS THAT PRECLUDE ESTABLISHMENT OF TEMPORAL ASSOCIATIONS, (B) USING CONVENIENCE SAMPLES (E.G., ADHD) RATHER THAN A SAMPLE ENRICHED FOR SCT SPECIFICALLY, (C) FAILING TO EXAMINE POSSIBLE MECHANISMS OR VULNERABILITIES LINKING SCT TO INTERNALIZING SYMPTOMS, AND (D) FOCUSING ON SCHOOL-AGED CHILDREN EVEN THOUGH SCT SYMPTOMS AND INTERNALIZING PROBLEMS SHARPLY INCREASE IN ADOLESCENCE. THIS STUDY WILL ADDRESS THESE LIMITATIONS BY USING A PROSPECTIVE LONGITUDINAL, MULTI-INFORMANT, MULTI-METHOD DESIGN ACROSS THE DEVELOPMENTALLY SENSITIVE PERIOD OF EARLY ADOLESCENCE TO EXAMINE SCT SYMPTOMS AS A PREDICTOR OF DIVERSE INTERNALIZING OUTCOMES AND TO TEST MECHANISMS AND VULNERABILITIES LINKING SCT TO INTERNALIZING SYMPTOMS IN A COMMUNITY SAMPLE ENRICHED FOR SCT SYMPTOMATOLOGY. SPECIFICALLY, A COMMUNITY-BASED SAMPLE OF 330 YOUNG ADOLESCENTS (AGES 10-12 YEARS) ENRICHED FOR SCT SYMPTOMATOLOGY WILL BE RECRUITED AND ASSESSED AT THREE TIMEPOINTS ONE YEAR APART. CONSISTENT WITH THE NIMH RESEARCH DOMAIN CRITERIA (RDOC) INITIATIVE AND A DEVELOPMENTAL PSYCHOPATHOLOGY FRAMEWORK, A MULTI-INFORMANT, MULTI-METHOD BATTERY THAT CUTS ACROSS PHYSIOLOGICAL, BEHAVIORAL, AND SELF-REPORT UNITS OF ANALYSIS WILL BE USED. WE WILL EXAMINE DIMENSIONAL SCT SYMPTOMS AS A PREDICTOR OF INTERNALIZING PSYCHOPATHOLOGY CHANGE OVER TIME, TEST MECHANISMS OF THE LONGITUDINAL RELATION BETWEEN SCT AND INTERNALIZING PSYCHOPATHOLOGIES, AND EXPLORE VULNERABILITIES (PHYSIOLOGICAL REACTIVITY, PUNISHMENT SENSITIVITY) THAT EXACERBATE THESE LONGITUDINAL RELATIONS. FINDINGS ESTABLISHING LONGITUDINAL EFFECTS AND IDENTIFYING MECHANISMS AND VULNERABILITIES THAT CUT ACROSS UNITS OF ANALYSIS WILL ADVANCE THE DEVELOPMENT OF THEORETICAL MODELS OF SCT. FINDINGS FROM THIS STUDY WILL ALSO PROVIDE AVENUES FOR TARGETED CLINICAL ASSESSMENT AND TREATMENT.

DISSECTING NEURAL MECHANISMS SUPPORTING MIND AND BODY APPROACHES TO PAIN REDUCTION IN YOUTH WITH MIGRAINE

VALIDATING QUANTITATIVE MAGNETIC RESONANCE IMAGING BIOMARKERS OF IDIOPATHIC PULMONARY FIBROSIS

DYNAMIC COMPUTATIONAL MODELING OF OBSTRUCTIVE SLEEP APNEA IN DOWN SYNDROME

EFFECT OF REPRODUCTIVE HISTORY ON LONGITUDINAL CHANGE IN CARDIAC, VASCULAR AND LIPID PARAMETERS - ABSTRACT PREGNANCY IS OFTEN DESCRIBED AS A PHYSIOLOGIC “STRESS TEST” THAT MAY UNCOVER LATENT RISK FOR HYPERTENSION, DIABETES AND CVD. EVEN IN UNCOMPLICATED PREGNANCIES, WOMEN EXPERIENCE RAPID CARDIOMETABOLIC CHANGES TO SUPPORT FETAL DEVELOPMENT. WHILE MANY OF THESE ADAPTATIONS NORMALIZE SOON AFTER DELIVERY, SOME CHANGES PERSIST, INCLUDING ECHOCARDIOGRAPHIC CHANGES IN CARDIAC STRUCTURE AND LOWER HIGH-DENSITY LIPOPROTEIN CHOLESTEROL (HDL-C). WHETHER THESE PREGNANCY-RELATED CHANGES, OR ALTERATIONS IN HDL PARTICLE STRUCTURE OR FUNCTION, CONTRIBUTE TO LONG-TERM CARDIOVASCULAR RISK IS UNKNOWN. PARITY, OR THE TOTAL NUMBER OF LIVE BIRTHS, AMONG POST- MENOPAUSAL WOMEN IS ALSO ASSOCIATED WITH GREATER RISK OF CARDIOVASCULAR DISEASE AND ALTERATIONS IN HDL-C LEVELS, HDL STRUCTURE AND FUNCTION, AND CARDIAC AND VASCULAR FUNCTION. HOWEVER, A SIGNIFICANT RESEARCH GAP EXISTS IN LINKING OBSERVED CARDIOVASCULAR CHANGES ACROSS PREGNANCY TO THE OBSERVED ASSOCIATIONS OF PARITY WITH CARDIOVASCULAR HEALTH POST-MENOPAUSE. WE WILL ADDRESS THIS GAP BY LEVERAGING EXISTING DATA AND SAMPLES FROM THE NHLBI GROWTH AND HEALTH STUDY (NGHS) AND CONDUCT A NEW IN-PERSON VISIT IN 350 PARTICIPANTS AT MEDIAN AGE 46, WHEN THE WOMEN WILL BE PRE- OR PERI-MENOPAUSAL. NGHS ENROLLED 871 GIRLS (50% AFRICAN- AMERICAN AND 50% WHITE) IN 1987 AT AGE 9 OR 10 AND EXAMINED THEM UP TO 17 TIMES, TO AGE 27, INCLUDING 7 ECHOCARDIOGRAMS BETWEEN AGES 20-27, MULTIPLE SAVED SAMPLES AND REPRODUCTIVE HISTORY QUESTIONNAIRES. THIS STUDY WILL CONDUCT DETAILED LIPOPROTEIN SIZING AND FUNCTIONALITY ASSESSMENTS FROM STORED AND NEW SAMPLES AND CONDUCT CARDIOVASCULAR IMAGING AND REPEAT ECHOCARDIOGRAMS AT MEDIAN AGE 46 TO: 1) DETERMINE THE SPECIFIC LIPOPROTEIN PARTICLE SIZE DISTRIBUTION AND FUNCTION CHANGES WHICH OCCUR FROM BEFORE TO SHORT- AND LONG-TERM POST PREGNANCY; 2) DETERMINE WHETHER PREGNANCY-RELATED CARDIAC ADAPTATIONS RESULT IN LONG-TERM ALTERATIONS IN CARDIAC STRUCTURE AND FUNCTION, THEREBY INCREASING CVD RISK FOR WOMEN IN THEIR FORTIES; AND 3) TEST WHETHER PARITY INCREASES CV RISK INDEPENDENTLY OF SOCIOECONOMIC STATUS (SES) IN AFRICAN-AMERICAN AND WHITE WOMEN. WITH THE COMPLETION OF OUR AIMS, WE WILL HAVE DETERMINED THE PROSPECTIVE PATHWAYS BETWEEN PREGNANCY-RELATED LIPOPROTEIN AND CARDIOVASCULAR CHANGES AND PRE-MENOPAUSAL CARDIOVASCULAR HEALTH FOR WOMEN IN THEIR FORTIES. RESULTS FROM OUR PROPOSED STUDIES WILL FILL A CRITICAL GAP IN OUR UNDERSTANDING OF HOW SUCH RISKS MAY ACCUMULATE DURING A WOMAN'S REPRODUCTIVE LIFE, AS WELL AS HOW SOCIOECONOMIC STATUS CONTRIBUTES TO PARITY- RELATED RISK LONG-TERM. WOMEN IN THIS STUDY HAVE ALSO BEEN EXPOSED TO THE OBESITY EPIDEMIC, LENDING GREATER UNDERSTANDING TO CONTEMPORARY REPRODUCTIVE DEVELOPMENT.

NICHD COOPERATIVE MULTICENTER NEONATAL RESEARCH NETWORK

RLDC: MOLECULAR PATHWAY-DRIVEN DIAGNOSTICS & THERAPEUTICS FOR RARE LUNG DISEASES

REGULATION OF GASTROINTESTINAL EOSINOPHILS

ENGAGING ADOLESCENTS IN DECISIONS ABOUT RETURN OF GENOMIC RESEARCH RESULTS

CONTRIBUTIONS OF ABERRANT GRANULE CELL INTEGRATION TO THE DEVELOPMENT OF EPILEPSY