Ann & Robert H Lurie Childrens Hospital Of Chicago

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

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)

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

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

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

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

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.

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

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.

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

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.

MOLECULAR GENETICS OF BBS

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

GENETIC AND FUNCTIONAL STUDIES OF HUMAN CILIARY SYNDROMES

CATEGORY A - COMMUNITIES PUTTING PREVENTION TO WORK

CLINICAL CENTER--BILIARY ATRESIA CLINICAL RESEARCH CONS*

UNITS FOR HIV/AIDS CLINICAL TRIALS NETWORKS

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.

FUNCTIONAL DISSECTION OF CNVS IN NEURODEVELOPMENTAL TRAITS

BIOLOGICAL CHARACTERIZATION OF CARDIAC STEM CELLS

REDOX REGULATION OF VASCULAR CGMP SIGNALING IN NEONATAL LUNGS

LONG-TERM ENDOTYPES OF PREMATURITY ASSOCIATED RESPIRATORY DISEASE (LEOPARD) - PROJECT SUMMARY INFANTS BORN BEFORE 28 WEEKS OF GESTATION ARE AT HIGH RISK FOR MORBIDITY THAT OFTEN PERSISTS THROUGH CHILDHOOD IN THE FORM OF ASTHMA, ALVEOLAR DISEASE, OR PULMONARY VASCULAR DISEASE. BRONCHOPULMONARY DYSPLASIA (BPD) IS THE CLINICAL DESCRIPTION OF CHRONIC RESPIRATORY DISEASE THAT IS TYPICALLY DEFINED BY THE NEED FOR RESPIRATORY SUPPORT AT 36 WEEKS POST-MENSTRUAL AGE (PMA, TERMED “TYPICAL BPD”). THIS DESCRIPTION, THOUGH, MAY BE DISCORDANT WITH LATER OUTCOMES, THAT IS, APPROXIMATELY 60% OF BABIES WITH BPD HAVE LONG-TERM CARDIORESPIRATORY MORBIDITY, BUT CONVERSELY, APPROXIMATELY 40% OF INFANTS WITHOUT BPD HAVE SOME LONG-TERM CARDIORESPIRATORY MORBIDITY. THUS, THERE IS AN UNMET NEED TO ANTICIPATE THESE OUTCOMES EARLY IN THE NEWBORN PERIOD TO DEVELOP PRECISE, MECHANISM- BASED INTERVENTIONS FOR PREVENTION OR TREATMENT. WE HYPOTHESIZE THAT THESE LATER CARDIORESPIRATORY OUTCOMES REPRESENT ENDOTYPES OF BPD THAT CAN BE DEFINED BY KEY MECHANISTICALLY LINKED GENE PATHWAYS (“BPD ENDOTYPES”). WE HAVE A UNIQUE OPPORTUNITY TO ADDRESS THE LIMITATIONS OF PRECEDING GENETIC STUDIES BY LEVERAGING SEVERAL COHORTS OF APPROXIMATELY 2000 FORMER PREMATURE CHILDREN WHO WERE ENROLLED IN PROSPECTIVE STUDIES IN THE NEWBORN INTENSIVE CARE UNIT (NICU), WHO HAVE EXISTING GENOME-WIDE DATA OR DNA SAMPLES, AND WHO ARE BEING FOLLOWED AT SCHOOL-AGE AND ABOVE. THROUGH LEVERAGING EXTANT DATA OBTAINED THROUGH THE ENVIRONMENTAL INFLUENCES ON CHILD HEALTH OUTCOMES (ECHO) PROGRAM (N=~1500) AND DEEPER PHENOTYPING OF A PROSPECTIVE COHORT OF CHILDREN WITH ECHOCARDIOGRAPHY AND SPIROMETRY (N=~500), WE WILL PERFORM WHAT WE BELIEVE WILL BE THE LARGEST CROSS-COHORT GENETIC META-ANALYSIS THAT WILL INTEGRATE GENETIC NETWORKS AND LONGITUDINAL DATA AND WILL HAVE THE STATISTICAL POWER TO CHARACTERIZE THESE LONGER-TERM BPD ENDOTYPES. OUR OVERALL GOALS ARE TO INCLUDE GENETIC VARIATION AND LONGITUDINAL CLINICAL DATA IN DIRECTED AND AGNOSTIC FASHIONS TO ADDRESS A CRITICAL GAP BY PROVIDING PHYSIOLOGIC AND GENETIC CRITERIA FOR EARLY DIAGNOSIS OF SUBTYPES OF RESPIRATORY DISEASE. WE WILL USE A COMBINATION OF TRADITIONAL GENETIC ASSOCIATION APPROACHES THAT FOCUS ON GENE PATHWAYS RATHER THAN INDIVIDUAL VARIANTS OR GENES, AS WELL AS NOVEL GENE-FORWARD APPROACHES THAT INCORPORATE GENETIC PATHWAYS TO INFORM MECHANISM-BASED BPD ENDOTYPES. AS WE TRY TO MOVE AWAY FROM THE CONCEPT OF “TYPICAL BPD,” UNDERSTANDING THE PHYSIOLOGIC PROCESSES RESULTING IN THESE “BPD ENDOTYPES” WILL PERMIT DEVELOPING PERSONALIZED, MECHANISM-SPECIFIC INTERVENTIONS TO PREVENT OR TREAT THESE RESPIRATORY CONSEQUENCES OF PREMATURITY.

1/2 ALLOGENEIC HUMAN MESENCHYMAL STEM CELL (MSC) INJECTION IN PATIENTS WITH HYPOPLASTIC LEFT HEART SYNDROME: A PHASE IIB CLINICAL TRIAL - THIS APPLICATION FOR THE "ALLOGENEIC HUMAN MESENCHYMAL STEM CELL (MSC) INJECTION IN PATIENTS WITH HYPOPLASTIC LEFT HEART SYNDROME: A PHASE IIB CLINICAL TRIAL (ELPIS)" CLINICAL COORDINATING CENTER (CCC) IS COLLABORATIVE WITH THE ELPIS DATA COORDINATING CENTER (DCC) APPLICATION. THE CCC WILL HAVE ULTIMATE RESPONSIBILITY FOR MANAGING THE ELPIS CLINICAL CONSORTIUM OF SIX CLINICAL SITES, MEETING, PLANNING ENROLLMENT MILESTONES, DISTRIBUTING CCC RESOURCES, AND OVERSEEING ALL ASPECTS OF CLINICAL DESIGN OF THE STUDIES. HYPOPLASTIC LEFT HEART SYNDROME (HLHS) IS ONE OF THE MOST COMPLEX FORMS OF CONGENITAL HEART DISEASE (CHD), WITH A REPORTED INCIDENCE OF 0.2 PER 1000 LIVE BIRTHS OR 3% OF CHILDREN BORN WITH CHD. ONCE A UNIVERSALLY FATAL DIAGNOSIS, DRAMATIC IMPROVEMENTS IN THREE STAGED PALLIATIVE OPERATIONS NOW ALLOW THE SINGLE RIGHT VENTRICLE (RV) TO FUNCTIONALLY SUPPORT THE CIRCULATION. DESPITE THESE STRIDES IN MEDICAL CARE, THE MORTALITY RATE OF THESE INFANTS REMAINS AS HIGH AS 25 TO 35 PERCENT DURING THE FIRST YEAR OF LIFE AND CONTINUES WITH A HIGH MORTALITY RATE FOR THE REST OF THEIR LIFE. THOSE SURVIVING CHILDHOOD ARE LIKELY TO PROGRESS TOWARDS CARDIAC TRANSPLANTATION, USUALLY DUE TO FAILURE OF THE SYSTEMIC RV. TO ADDRESS THIS RV DYSFUNCTION, OUR STEM CELL TRIAL IS BASED ON A DECADE OF BASIC RESEARCH AND THE ELPIS PHASE I STUDY USING ALLOGENEIC MSCS IN HLHS PATIENTS AT THE STAGE II OPERATION. OUR COMPLETED ENROLLED ELPIS PHASE I STUDY SUPPORTS BOTH THE FEASIBILITY FOR THIS INVESTIGATIVE STRATEGY AND THE SAFETY PROFILE OF THE ALLOGENEIC MSCS. SECONDARY ENDPOINTS DEMONSTRATED THAT THE INITIAL MSC TREATED PATIENTS SHOWED BY CARDIAC MRI (CMR) NO DIFFERENCE IN RV EJECTION FRACTION, OR END DIASTOLIC VOLUMES, HOWEVER A SIGNIFICANT DECREASE IN RV MASS WAS PRESENT, A SURROGATE FOR DECREASED HYPERTROPHY. OUR HYPOTHESIS FOR THIS TRIAL IS THAT INTRAMYOCARDIAL DELIVERY OF ALLOGENEIC MSCS WILL IMPROVE THE PERFORMANCE OF THE SINGLE SYSTEMIC RV IN HLHS PATIENTS AT THE STAGE II OPERATION. A TOTAL OF 36 HLHS PATIENTS WHO ARE UNDERGOING THE STAGE II OPERATION WILL BE SINGLE BLINDED AND RANDOMIZED TO EITHER RECEIVE MSC TREATMENT OR STANDARD OF CARE. PATIENTS WILL BE FOLLOWED FOR ONE YEAR. THE PRIMARY OUTCOME MEASUREMENT WILL BE DECREASE IN RV MASS AS DETERMINED BY CMR STUDIES AT BASELINE, 6 AND 12 MONTHS FOLLOWING MSC INJECTION. SECONDARY OUTCOMES WILL INCLUDE IMPROVEMENTS IN CLINICAL AND PHYSIOLOGIC ENDPOINTS, IMPROVEMENTS SEEN BY OTHER GLOBAL RV CARDIAC FUNCTION PARAMETERS MEASURED BY SERIAL CMR STUDIES, EXOSOME BIOMARKER ANALYSIS AND SAFETY ENDPOINTS. THIS SINGLE BLINDED RANDOMIZED CLINICAL TRIAL IS DESIGNED TO ADDRESS THE FOLLOWING SPECIFIC AIMS: (1) TO ANALYZE MSC DELIVERY FOR RV FUNCTION IMPROVEMENT AT THE STAGE II OPERATION; (2) TO DETERMINE DYNAMIC CHANGES OF THE AMOUNT AND COMPOSITION OF PLASMA BIOMARKERS DERIVED FROM THE TRANSPLANTED MSCS; AND (3) TO ANALYZE SAFETY OF MSC TREATMENT. ALTHOUGH NOT PLANNED AS A SURVIVAL STUDY, WE ANTICIPATE THAT THE PROPOSED STUDY WILL PROVIDE VALUABLE DATA ON THE SAFETY AND BENEFIT OF MSC TREATMENT IN HLHS PATIENTS. THE SUFFICIENTLY DEFINITIVE INFORMATION WILL INFORM THE DECISION ON WHETHER TO PROCEED WITH A PHASE III CLINICAL TRIAL OF THERAPEUTIC MSC DELIVERY TO REDUCE MORTALITY IN HLHS PATIENTS AND TO DIRECT ITS STUDY DESIGN.

HIV PREVENTION INTERVENTION FOR YOUNG TRANSGENDER WOMEN

ADAPTIVE MECHANISMS RESPONSIBLE FOR WEIGHT REGAIN IN YOUTH WITH OBESITY AND THE INFLUENCE OF SEX - PROJECT SUMMARY / ABSTRACT PEDIATRIC OBESITY IS A PERVASIVE PROBLEM IN THE UNITED STATES. WHILE SHORT-TERM WEIGHT LOSS CAN BE ACHIEVED IN A HIGH PROPORTION OF ADOLESCENTS WITH OBESITY THE ABILITY TO PREVENT SUBSEQUENT WEIGHT AND FAT MASS REGAIN LONG-TERM IS EXTREMELY CHALLENGING. THE MECHANISMS UNDERLYING WEIGHT AND FAT MASS REGAIN IN ADOLESCENTS WITH OBESITY ARE POORLY DEFINED AND WILL BE DETERMINED BY THIS STUDY. NEUROENDOCRINE CHANGES IN THE GUT-BRAIN AXIS (INFLUENCING APPETITE AND SATIETY) AND METABOLIC ADAPTATION (CHANGES IN ENERGY EXPENDITURE AND REGULATION) HAVE BEEN IDENTIFIED AS KEY MECHANISMS CONTRIBUTING TO WEIGHT AND FAT MASS REGAIN AFTER WEIGHT LOSS IN ADULTS. WHETHER THESE ADAPTIVE RESPONSES ARE APPLICABLE TO PUBERTAL ADOLESCENTS REMAINS UNKNOWN. PRESUMING THAT ADULT MECHANISMS ARE APPLICABLE TO PEDIATRICS IS PREMATURE, ADOLESCENTS UNDERGO UNIQUE AND DYNAMIC CHANGES, SUCH AS SEX-SPECIFIC DEVELOPMENTAL GROWTH AND PUBERTY-DRIVEN HORMONAL ALTERATIONS, WHICH COULD INFLUENCE THE BIOLOGY REGULATING ENERGY BALANCE IN A FUNDAMENTAL WAY CONTRIBUTING TO FAT MASS ACCUMULATION. GAINING A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS DRIVING FAT MASS REGAIN FOLLOWING WEIGHT LOSS DURING ADOLESCENCE WILL ADVANCE THE CURRENT PARADIGM FOR TREATING PEDIATRIC OBESITY TOWARDS, 1) OPTIMIZING THE TIMING AND INTENSITY OF TREATMENT, 2) TAILORING THERAPIES BASED ON SEX-SPECIFIC DEVELOPMENTAL CHARACTERISTICS, AND 3) LEAD TO NEW INTERVENTION STRATEGIES. WE PROPOSE A STUDY TO IDENTIFY THE BIOLOGICAL MECHANISMS AND HEALTH BEHAVIORS DRIVING WEIGHT AND FAT MASS REGAIN AMONG ADOLESCENTS (11 TO 15 YEARS OLD) WITH OBESITY BY CAREFULLY CONSIDERING THE IMPACT OF SEX-DIFFERENCES. WE WILL USE AN ESTABLISHED APPROACH OF SHORT-TERM (8 WEEKS) MEAL REPLACEMENT THERAPY TO ELICIT WEIGHT LOSS (=5% BMI REDUCTION). FOLLOWING SUCCESSFUL WEIGHT LOSS, WE WILL FOLLOW INDIVIDUALS (N=100) ON LIFESTYLE MODIFICATION THERAPY FOR 26 WEEKS WHERE WE EXPECT A WIDE-RANGE OF RESPONSES RANGING FROM CONTINUED WEIGHT AND FAT MASS LOSS, MAINTENANCE OF WEIGHT AND FAT LOSS, AND WEIGHT AND FAT MASS REGAIN. TO EXAMINE THE IMPACT OF SEX, WE WILL HAVE AN EVEN DISTRIBUTION OF MALES AND FEMALES AT BASELINE, AND WE WILL CAREFULLY EXAMINE THE BIOLOGICAL INFLUENCE OF SEX-SPECIFIC DIFFERENCES. OUR PRIMARY OUTCOME WILL BE CHANGE IN TOTAL FAT MASS (KG) MEASURED BY DUAL ENERGY X-RAY ABSORPTIOMETRY. OUR OVERALL HYPOTHESIS IS THAT CHANGES IN ENERGY EXPENDITURE AND APPETITE AND SATIETY REGULATING HORMONES WILL INDEPENDENTLY EXPLAIN THE VARIABILITY IN FAT MASS TRAJECTORIES, WITH SEX-SPECIFIC DIFFERENCES PLAYING AN IMPORTANT ROLE IN MEDIATING THESE RELATIONSHIPS. THIS STUDY WILL IDENTIFY NEW TREATMENT TARGETS TO ENHANCE WEIGHT LOSS MAINTENANCE IN ADOLESCENTS WITH OBESITY BY: 1) UNCOVERING THE KEY ASPECTS OF ENERGY REGULATION AND APPETITE/SATIETY HORMONES PROMOTING FAT MASS REGAIN AND; 2) DETERMINING SEX-SPECIFIC FACTORS TO INFORM TAILORED THERAPIES TO PREVENT FAT MASS REGAIN.

SYNDEMIC DEVELOPMENT AND HIV RISK AMONG VULNERABLE YOUNG MEN

THE CONSORTIUM FOR TECHNOLOGY & INNOVATION IN PEDIATRICS: CTIP 3.0 - PROJECT SUMMARY THE CONSORTIUM FOR TECHNOLOGY & INNOVATION IN PEDIATRICS (CTIP 3.0) IS A PEDIATRIC MEDICAL DEVICE CONSORTIUM BASED AT LURIE CHILDREN’S HOSPITAL (LCH) AND CHILDREN’S HOSPITAL LOS ANGELES (CHLA) ESTABLISHED IN 2011 AND FUNDED BY THE FDA IN 2013 AND 2018. CTIP FACILITATES THE DEVELOPMENT AND COMMERCIALIZATION OF PEDIATRIC MEDICAL DEVICES BY SIMULTANEOUSLY ENGAGING AND COORDINATING CLINICIANS, ENGINEERS, REGULATORS, HOSPITAL ADMINISTRATORS, INDUSTRY, PATIENTS, AND THE BUSINESS COMMUNITY TO GUIDE AND SUPPORT MEDICAL DEVICE DEVELOPMENT FOR CHILDREN. FOR PORTFOLIO COMPANIES, CTIP FOSTERS NETWORKING OPPORTUNITIES, CLINICAL PARTNERSHIPS, RESEARCH AND EVIDENCE GENERATION, AND DIRECT AND INDIRECT FINANCIAL SUPPORT AND EXPERT GUIDANCE ON ISSUES RELATED, BUT NOT LIMITED TO, INTELLECTUAL PROPERTY, PROTOTYPING, ENGINEERING, TESTING, GRANT WRITING, BUSINESS DEVELOPMENT, REGULATORY STRATEGY, AND CLINICAL TRIAL DESIGN. CTIP HAS ESTABLISHED A NETWORK OF CHILDREN’S HOSPITALS, ACADEMIC INSTITUTIONS, ACCELERATORS, INCUBATORS, AND ECOSYSTEM PARTNERS TO SUPPORT THE COMMERCIALIZATION OF PEDIATRIC MEDICAL DEVICES. OVER THE PAST TEN YEARS, CTIP HAS EXPANDED FROM SOUTHERN CALIFORNIA, TO THE ENTIRE WEST COAST, AND NOW TO A NATIONAL CONSORTIUM WITH ACADEMIC AND INDUSTRY PARTNERS IN CALIFORNIA, OREGON, WASHINGTON, ILLINOIS, COLORADO, MICHIGAN, MISSOURI, AND WISCONSIN. CTIP’S OVERARCHING GOALS ARE: 1) ACCELERATE PEDIATRIC MEDTECH FORWARD, NO MATTER HOW SMALL OR LARGE THE STEP, THROUGH NON-DILUTIVE FUNDING AND COMPREHENSIVE WRAP-AROUND SERVICES AT EVERY STAGE OF THE TOTAL PRODUCT LIFE CYCLE; 2) CONNECT PEDIATRIC MEDICAL DEVICE INNOVATORS TO OUR NATIONAL NETWORK OF EXPERTS AND MULTIDISCIPLINARY STAKEHOLDERS TO FOSTER RESEARCH, CLINICAL, AND BUSINESS PARTNERSHIPS; AND 3) ADVOCATE FOR PEDIATRIC HEALTH EQUITY AND CHAMPION PEDIATRIC-SPECIFIC INNOVATION THROUGH RESEARCH, PUBLICATIONS, PUBLIC EVENTS, EDUCATION, AND COLLABORATIONS. THE SYSTEMATIC BARRIERS TO PEDIATRIC DEVICE INNOVATION ARE TOO COMPLEX FOR ANY ONE ENTITY TO ADDRESS, SO WE HAVE WORKED TIRELESSLY TO BE EFFECTIVE PARTNERS TO THE OTHER PDCS, THE FDA, HEALTHCARE ORGANIZATIONS, INVESTORS, AND OTHER ECOSYSTEM PARTNERS. BY COORDINATING WITH LARGER ORGANIZATIONS, WE MULTIPLY OUR EFFORTS AND REACH IN THE FIELD OF PEDIATRIC MEDICAL DEVICES. FOR THE NEXT FUNDING CYCLE, CTIP PLANS TO CONTINUE TO DELIVER EXCELLENT SUPPORT TO ALL OF OUR PORTFOLIO MEMBERS, AND EXPAND OUR ACTIVITIES IN FOUR KEY AREAS: 1) BUSINESS DEVELOPMENT AND FOLLOW-ON FUNDING OPPORTUNITIES TO ENSURE OUR COMPANIES HAVE THE FINANCIAL RUNWAY THEY NEED TO BRING THEIR DEVICES TO MARKET; 2) GROWING OUR ROBUST PEDIATRIC MEDICAL DEVICE CLINICAL TRIALS INFRASTRUCTURE AND SERVICES; 3) ENGAGING PATIENTS AND FAMILIES INTENTIONALLY AS PARTNERS IN DEVICE DEVELOPMENT AND ADVOCACY; AND 4) ADDRESSING FOUNDERS’ CRITICAL KNOWLEDGE GAPS IN HEALTHCARE INFORMATICS, INCLUDING DATA INTEGRATION, INTEROPERABILITY, CYBERSECURITY, AND EHR WORKFLOWS. THESE NEW ACTIVITIES WILL HELP CTIP CONTINUE TO BUILD A SUSTAINABLE, NEEDS-DRIVEN PIPELINE OF NEW PEDIATRIC MEDICAL DEVICES, WITH THE ULTIMATE GOAL OF HAVING MORE AND BETTER DEVICES AVAILABLE ON THE MARKET THAT ARE DESIGNED TO SPECIFICALLY MEET THE HEALTH NEEDS OF CHILDREN.

A PROSPECTIVE STUDY OF CFS FOLLOWING INFECTIOUS MONONUCLEOSIS IN COLLEGE STUDENTS

THE ASPIRES STUDY: ACTIVATING CANCER SURVIVORS AND THEIR PRIMARY CARE PROVIDERS TO INCREASE COLORECTAL CANCER SCREENING - PROJECT SUMMARY CHILDHOOD CANCER SURVIVORS TREATED WITH ABDOMINAL OR PELVIC RADIOTHERAPY (RT) ARE ALMOST FOUR TIMES MORE LIKELY TO DEVELOP COLORECTAL CANCER (CRC) COMPARED TO THE GENERAL POPULATION WITH THEIR ELEVATED RISK EVIDENT BY THE AGE OF 30 YEARS WITH NO PLATEAU. SINCE EARLIER DETECTION OF PRECANCEROUS LESIONS (I.E. ADENOMAS) OR CRC IS STRONGLY ASSOCIATED WITH IMPROVED SURVIVAL, SCREENING WITH COLONOSCOPY OR MULTITARGET STOOL DNA TESTING (MT- SDNA) WITH A COLONOSCOPY AFTER A POSITIVE TEST IS RECOMMENDED STARTING AT AGE 30. UNFORTUNATELY, THE VAST MAJORITY OF SURVIVORS AT HIGH-RISK FOR CRC ARE NOT ADHERENT TO RECOMMENDED SCREENING. MAGNIFYING THIS PROBLEM, MOST CHILDHOOD CANCER SURVIVORS ARE NO LONGER FOLLOWED AT A CANCER CENTER, ARE UNAWARE OF THEIR RISKS AND ARE BEING FOLLOWED BY PRIMARY CARE PROVIDERS (PCPS) WHO ARE NOT INFORMED ABOUT THE RECOMMENDED FOLLOW-UP CARE. IN ORDER TO IMPROVE ADHERENCE TO CRC SCREENING GUIDELINES IN HIGH-RISK CHILDHOOD CANCER SURVIVORS, WE PROPOSE THE ASPIRES (ACTIVATING CANCER SURVIVORS AND THEIR PRIMARY CARE PROVIDERS TO INCREASE COLORECTAL CANCER SCREENING) STUDY, WHICH IS THE FIRST KNOWN INTERVENTION TO ATTEMPT TO INCREASE CRC SCREENING RATES IN THIS POPULATION USING A REMOTE DIGITAL MHEALTH INTERVENTION. THIS IS A 3-ARM RANDOMIZED CONTROLLED TRIAL TO EVALUATE THE UTILITY OF PATIENT ACTIVATION WITH AND WITHOUT ADDED PCP ACTIVATION TO INCREASE CRC SCREENING. WE PROPOSE TO RANDOMIZE 315 SURVIVORS, WHO ARE AT LEAST 30 YEARS OF AGE, WITH A HISTORY OF ABDOMINAL OR PELVIC RADIATION FOR A CHILDHOOD CANCER AND WITHOUT A HISTORY OF CRC. THE PRIMARY OUTCOME IS OBTAINING CRC SCREENING WITH COLONOSCOPY OR MT-SDNA DURING THE 12-MONTH STUDY PERIOD. WE WILL DETERMINE THE COMPARATIVE EFFECTIVENESS OF (1) A MHEALTH PATIENT ACTIVATION INTERVENTION AND (2) PATIENT ACTIVATION PLUS PCP ACTIVATION, COMPARED TO CONTROL. SECONDARY AIMS INCLUDE (1) CONDUCTING A MULTI-STAKEHOLDER MIXED-METHODS CONSOLIDATED FRAMEWORK FOR IMPLEMENTATION RESEARCH (CFIR)-INFORMED EVALUATION TO UNDERSTAND PATIENT, PROVIDER AND SYSTEM FACTORS ASSOCIATED WITH UPTAKE OF THE INTERVENTION, TO EXPLORE ENABLERS AND BARRIERS TO UPTAKE OF CRC SCREENING, AND TO GENERATE RECOMMENDATIONS FOR FUTURE ADAPTATION, SCALABILITY AND SUSTAINABILITY; (2) IDENTIFY POTENTIAL MODERATORS AND MEDIATORS OF UPTAKE OF CRC SCREENING; AND (2) ESTIMATE THE COST-EFFECTIVENESS OF THE INTERVENTION. THE PROPOSED ASPIRES STUDY BRINGS TOGETHER A RESEARCH TEAM WITH NECESSARY EXPERTISE AND EXPERIENCE IN SURVIVORSHIP, CRC SCREENING, DISSEMINATION AND IMPLEMENTATION, AND MHEALTH INTERVENTION RESEARCH WITH THE UNIQUE RESOURCE OF THE 31-INSTITUTION CHILDHOOD CANCER SURVIVOR STUDY (CCSS). NOTABLY, THE CCSS REPRESENTS THE SINGLE LARGEST COHORT OF SURVIVORS IN THE TARGET POPULATION AND THE INFRASTRUCTURE TO CONDUCT THE PROPOSED STUDY. RESULTS FROM THIS INTERVENTION WILL HAVE IMPORTANT IMPLICATIONS FOR PATIENTS AT HIGH-RISK FOR CRC AND WE EXPECT THAT FINDINGS FROM THIS STUDY WILL PROVIDE THE EVIDENCE FOR IMPLEMENTATION AND DISSEMINATION OF OUR CRC SCREENING INTERVENTIONS TARGETING THESE POPULATIONS.

UNDERSTANDING INFLAMMATORY AND METABOLIC PATHWAYS OF MYOCARDIAL AND VASCULAR DYSFUNCTION IN SOUTH AFRICAN YOUTH LIVING WITH PERINATAL HIV

RESILIENCE PROMOTION IN TEENS WITH TYPE 1 DIABETES: PREVENTING NEGATIVE OUTCOMES

EMPLOYING ESBI IN A COMMUNITY-BASED HIV TESTING ENVIRONMENT FOR AT-RISK YOUTH

ABERRANT DNA METHYLATION UNDERLYING PRENATAL EXPOSURES AND INCREASED NEWBORN AND CHILDHOOD ADIPOSITY

SPINAL MUSCULAR ATROPHY: INDUCING SMN EXPRESSION

THE TSHILO DIKOTLA STUDY: METABOLIC OUTCOMES OF CHILDREN HIV/ARV-EXPOSED UNINFECTED IN BOTSWANA

UNITS FOR HIV/AIDS CLINICAL TRIALS NETWORKS

THE PRO-INFLAMMATORY EFFECTS OF ACUTE EXERCISE IN CHILDREN WITH SICKLE CELL ANEMIA

CLINICAL DECISION RULES TO DISCRIMINATE BRUISING CAUSED BY PHYSICAL CHILD ABUSE

TINY CARGO, BIG DEAL! AN ADAPTIVE ED-BASED EHEALTH INTERVENTION TO PROMOTE CORRECT AND CONSISTENT SIZE-APPROPRIATE CHILD PASSENGER SAFETY BEHAVIORS AND REDUCE DISPARITIES

MATCHING PANELS OF IN VIVO AND IN VITRO MODEL SYSTEM OF PEDIATRIC BRAIN TUMORS

CHARACTERIZATION OF THE CARDIAC PROGENITOR CELL EXOSOMES FOR OPTIMAL THERAPEUTICS

SOY ISOFLAVONES FOR INNER CITY INFANTS AT RISK FOR ASTHMA (SIRA) - ABSTRACT: A FREQUENT GAIN OF FUNCTION PROMOTER POLYMORPHISM FOR THE PAI-1 GENE (~60% OF THE POPULATION ARE HOMOZYGOUS OR HETEROZYGOUS) IS ASSOCIATED WITH ELEVATED CIRCULATING PAI-1 LEVELS. CHILDREN HOMO OR HETEROZYGOUS FOR THIS ALLELE WHO HAD A MEDICALLY ATTENDED RESPIRATORY VIRAL ILLNESS BEFORE AGE 2, HAD A 12 (ANY VIRUS) TO 18-FOLD (RSV) INCREASED RISK OF ASTHMA. THE MECHANISMS FOR THIS ASSOCIATION ARE NOT ESTABLISHED. PAI- 1 IS ASSOCIATED WITH AIRWAY THYMIC STROMAL LYMPHOPOIETIN (TSLP) PRODUCTION, WHICH PROMOTES TH2 TYPE AIRWAY RESPONSES. FURTHERMORE, THE PAI-1 OVERPRODUCING GENOTYPE IS ASSOCIATED WITH INCREASED SERUM LEVELS OF IGE. IGE ELEVATION INCREASES FCERI LEVELS ON PDCS WHICH ATTENUATES TYPE I INTERFERON ANTIVIRAL RESPONSES. OF NOTE, SOY ISOFLAVONES REDUCE TGF-1-INDUCED PAI-1 GENE EXPRESSION AND PROTEIN PRODUCTION FROM AIRWAY EPITHELIAL CELLS, AND HAVE BEEN SHOWN TO DECREASE THE RISK OF ASTHMA EXACERBATIONS BY 70% IN INDIVIDUALS WITH THE GENOTYPE. IT IS NOT KNOWN WHETHER SUPPLEMENTATION WITH SOY ISOFLAVONES WILL DECREASE THE RISK OF DEVELOPING TH2 AIRWAY INFLAMMATION OR THE LIKELIHOOD OF ALLERGIC SENSITIZATION IF IT IS GIVEN TO CHILDREN AT RISK OF ASTHMA IN THE FIRST YEAR OF LIFE. SOY ISOFLAVONES FOR INNER CITY INFANTS AT RISK FOR ASTHMA (SIRA) IS A SINGLE CENTER, PROSPECTIVE RANDOMIZED, QUADRUPLE MASKED TRIAL OF HIGH-RISK INFANTS WITH THE PAI-1 GENOTYPE TO COMPARE SUPPLEMENTATION WITH SOY GENISTEIN AT DOSES SIMILAR TO SOY FORMULA INGESTION OR PLACEBO DURING PEAK VIRAL SEASON OF THE FIRST YEAR OF LIFE. CHILDREN AGED 2-6 MONTHS AT ENROLLMENT WILL BE RANDOMIZED TO SOY ISOFLAVONE OR PLACEBO IN AUGUST, RECEIVING ACTIVE TREATMENT FROM AUGUST TO MARCH 1ST, FOLLOWED BY OBSERVATION OVER THE NEXT YEAR FOR EACH YEARLY COHORT. THE OBJECTIVE OF THIS PROPOSAL IS TO DETERMINE 1) WHETHER SOY ISOFLAVONES CAN MODULATE DEVELOPMENT OF TH2 AIRWAY ENDOTYPES, DECREASE EOSINOPHILIC AIRWAY INFLAMMATION, AND REDUCE SENSITIZATION IN HIGH RISK INFANTS WITH THE PAI-1 RISK GENOTYPE, AND 2) DECREASE IGE PRODUCTION VIA EFFECTS ON PAI-1, AND THEREBY IMPROVE RHINOVIRUS-INDUCED IFN-A RESPONSE. AS SUCH, THE PRIMARY OUTCOME OF THE TRIAL WILL BE THE DEVELOPMENT OF T2 AIRWAY ENDOTYPES BY INTERRUPTING THE PAI-1/TSLP AXIS. SECONDARY OUTCOMES WILL INCLUDE NASAL PAI-1, NASAL ECP, NASAL TH2 CYTOKINE LEVELS, SERUM PERIOSTIN, TOTAL AND SPECIFIC IGE, AND RESPIRATORY MORBIDITY. THE SECONDARY AIM WILL DETERMINE IF ANTIVIRAL IFN-A RESPONSES BY PBMC STIMULATED BY HRV AND IGE CROSSLINKING ARE AUGMENTED BY SOY GENISTEIN IN A SIMILAR FASHION AS HAS BEEN DESCRIBED FOR OMALIZUMAB. SECONDARY OUTCOMES FOR THIS AIM WILL EVALUATE IF SOY GENISTEIN WILL AUGMENT IFN-A RESPONSES BY PDC IN SIMILAR EXPERIMENTS. THE CURRENT PROJECT USES A SAFE AND INEXPENSIVE INTERVENTION, SOY GENISTEIN, DIRECTED TO A COMMON GENOTYPE AS A PRECISION MEDICINE APPROACH TO PROVIDE A BETTER UNDERSTANDING OF KEY PATHWAYS RELEVANT TO DEVELOPMENT OF ALLERGIC AIRWAY INFLAMMATION IN EARLY LIFE. IF CONFIRMATORY, THESE RESULTS WOULD LEAD INTO INTERVENTION TRIALS FOCUSED ON CLINICAL OUTCOMES. THIS LINE OF INQUIRY HAS THE POTENTIAL TO BENEFIT A LARGE NUMBER OF CHILDREN AT RISK OF DEVELOPING ASTHMA.

AN INJURY PLAUSIBILITY ASSESSMENT MODEL FOR DIFFERENTIATING ABUSIVE FROM ACCIDENTAL FRACTURES IN YOUNG CHILDREN

ROLE OF THE INTESTINAL MICROVASCULATURE IN NECROTIZING ENTEROCOLITIS

NEGATIVE REGULATORS OF ENDOTHELIAL REGENERATION IN AGING LUNGS AND ARDS - NEGATIVE REGULATORS OF ENDOTHELIAL REGENERATION IN AGING LUNGS AND ARDS ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) IS A COMPLEX, MULTI-FACTORIAL SYNDROME WITH A MORTALITY RATE AS GREAT AS 30-40%. A FUNDAMENTAL PATHOLOGICAL CHANGE FOUND IN ARDS THAT RESULTS FROM SEPSIS, AND PNEUMONIA IS INJURY TO THE ENDOTHELIAL BARRIER, AND, AS A RESULT, INCREASED LUNG VASCULAR PERMEABILITY AND INTRACTABLE PROTEIN- RICH EDEMA. COMPARED TO YOUNG ADULT PATIENTS, THE INCIDENCE OF ARDS RESULTING FROM SEPSIS AND PNEUMONIA IN ELDERLY PATIENTS IS MUCH HIGHER AND THE MORTALITY RATE IS 10-FOLD HIGHER. HOWEVER, THE UNDERLYING CAUSES OF AGING-RELATED HIGH INCIDENCE AND MORTALITY OF ARDS ARE POORLY UNDERSTOOD. THERE IS NO EFFECTIVE TREATMENT OF ARDS. EMPLOYING GENETIC LINEAGE TRACING, OUR SUPPORTING DATA SHOW THAT THE ENDOGENOUS ENDOTHELIAL REGENERATION PROGRAM WAS SEVERELY IMPAIRED IN AGED LUNGS FOLLOWING SEPSIS CHALLENGE, AND RESTORATION OF FOXM1 EXPRESSION COULD NORMALIZE THIS REGENERATIVE AND REPARATIVE PROGRAM. FURTHERMORE, OUR SUPPORTING DATA SHOW THAT FOXO1 IS A SUPPRESSOR OF FOXM1 EXPRESSION IN AGED LUNGS. SIRTUIN 1 (SIRT1) FUNCTIONS AS AN AGING-REGULATED EPIGENETIC REGULATOR OF FOXO1. THUS, WE HYPOTHESIZE THAT EPIGENETIC DYSREGULATION OF ENDOTHELIAL FOXO1FOXM1 EXPRESSION BY SIRT1 IN AGED LUNGS IS RESPONSIBLE FOR THE IMPAIRED ENDOTHELIAL REGENERATION AND VASCULAR REPAIR AND THEREBY REACTIVATION OF THE FOXM1-DEPENDENT REGENERATIVE AND REPARATIVE PATHWAY THROUGH EC-TARGETED NANOPARTICLE DELIVERY OF FOXM1 TRANSGENE MAY REPRESENT A NOVEL THERAPEUTIC APPROACH FOR RESTORING LUNG MICROVESSEL INTEGRITY AND RESOLVING INFLAMMATORY EDEMA AND THUS IMPROVING SURVIVAL OF ELDERLY ARDS PATIENTS. THE PROPOSED STUDIES WILL ADDRESS THE FOLLOWING THREE SPECIFIC AIMS. STUDIES IN AIM1 WILL DETERMINE THE ROLE OF ENDOTHELIAL FOXO1 IN REGULATING ENDOTHELIAL REGENERATION AND VASCULAR REPAIR IN AGED LUNGS FOLLOWING SEPSIS CHALLENGE AND DEFINE FOXO1 AS A TRANSCRIPTIONAL REPRESSOR OF FOXM1 IN ENDOTHELIAL CELLS. IN AIM 2, WE WILL DEFINE THE EPIGENETIC MECHANISM OF AGING ACTIVATION OF FOXO1 VIA SIRT1. WE WILL CHARACTERIZE THE UNEXPECTED ROLE OF ENDOTHELIAL SIRT1 IN INHIBITING ENDOTHELIAL REGENERATION AND RESOLUTION OF INFLAMMATORY INJURY IN AGED LUNGS THROUGH FOXO1-MEDIATED SUPPRESSION OF FOXM1 EXPRESSION. STUDIES IN AIM 3 WILL DEVELOP NOVEL BIODEGRADABLE NANOPARTICLES FOR ENDOTHELIAL DELIVERY OF FOXM1 TRANSGENE IN AGED LUNGS. THIS TRANSLATIONAL AIM WILL EXPLORE THE POTENTIAL OF NOVEL NANOPARTICLE DELIVERY OF FOXM1 AS AN EC-TARGETED GENE THERAPY APPROACH FOR TREATMENT OF ARDS IN ELDERLY PATIENTS. SUCCESSFUL COMPLETION OF THE PROPOSED STUDIES WILL PROVIDE NOVEL UNDERSTANDING OF THE MOLECULAR MECHANISMS OF IMPAIRED ENDOTHELIAL REGENERATION AND VASCULAR REPAIR AND THUS HIGH INCIDENCE AND MORTALITY OF ARDS IN ELDERLY PATIENTS AND PROVIDE FUNDAMENTALLY IMPORTANT PRECLINICAL DATA NEEDED FOR FUTURE CLINICAL AND COMMERCIAL TRANSLATION OF OUR DISCOVERY INTO ARDS THERAPY IN ELDERLY PATIENTS. THUS, THE TRANSLATION POTENTIAL OF THE PROPOSED STUDIES IS EXTREMELY HIGH.

NOVEL ROLES OF RNA MODIFICATIONS IN THE PATHOGENESIS OF PULMONARY VASCULAR REMODELING AND PAH - PULMONARY ARTERIAL HYPERTENSION (PAH) IS CHARACTERIZED BY PROGRESSIVE INCREASE OF PULMONARY VASCULAR RESISTANCE AND OBLITERATIVE VASCULAR REMODELING THAT CAUSES RIGHT HEART FAILURE AND PREMATURE DEATH. GIVEN THE UNDERLYING MOLECULAR MECHANISMS OF OBLITERATIVE VASCULAR REMODELING REMAIN ENIGMATIC, CURRENT THERAPIES HAVE NOT TARGETED THE FUNDAMENTAL DISEASE MODIFYING MECHANISMS AND HENCE ONLY RESULTED IN A MODEST IMPROVEMENT IN THE MORBIDITY AND MORTALITY. WHILE SEVERAL TRANSCRIPTION FACTORS AND TRANSCRIPTIONAL CO- ACTIVATORS HAVE BEEN STUDIED IN THE CONTEXT OF PAH, POST-TRANSCRIPTIONAL REGULATIONS OF MRNAS THAT CAN AFFECT EXPRESSION OF KEY PROTEINS REMAIN LARGELY UNEXPLORED. RNA MODIFICATIONS INCLUDING N6-METHYLADENOSINE (M6A) HAVE RECENTLY BEEN DISCOVERED AS ESSENTIAL REGULATORS OF GENE EXPRESSION. THE M6A MODIFICATION CONTROLS RNA STABILITY, TRANSPORT, AND TRANSLATION AND HAS BEEN LINKED TO HUMAN DISEASES SUCH AS OBESITY AND CANCERS. DESPITE ITS FUNCTIONAL IMPORTANCE IN VARIOUS FUNDAMENTAL BIOPROCESSES, STUDIES OF M6A MODIFICATION OF MRNAS IN PAH ARE LACKING. OUR SUPPORTING DATA SHOW THAT EXPRESSION OF FAT MASS AND OBESITY-ASSOCIATED PROTEIN (FTO), A WELL-CHARACTERIZED RNA DEMETHYLASE, IS MARKEDLY ELEVATED IN PULMONARY VASCULAR ENDOTHELIAL CELLS (ECS) OF IDIOPATHIC PAH PATIENTS. TIE2CRE-MEDIATED DELETION OF FTO IN ECS (FTOTIE2CRE) INHIBITED PH INDUCED BY CHRONIC HYPOXIA. OUR MECHANISTIC STUDIES PROVIDE EVIDENCE THAT SEVERAL PAH-CAUSING GENES ARE POTENTIAL FTO TARGETS IN HUMAN LUNG ECS. FURTHERMORE, PHARMACOLOGICAL INHIBITION OF FTO IN MONOCROTALINE- CHALLENGED RATS INHIBITED PULMONARY VASCULAR REMODELING AND PH. THUS, WE HYPOTHESIZE THAT ENDOTHELIAL FTO, AS A MAJOR M6A ERASER, ACTS AS A KEY REGULATOR OF MRNA STABILITY AND ACCUMULATION OF KEY PAH-CAUSING GENES IN ECS TO REGULATE PULMONARY VASOCONSTRICTION AND VASCULAR REMODELING AND THUS IS A NOVEL THERAPEUTIC TARGET FOR PAH. WE PROPOSE THE FOLLOWING 3 SPECIFIC AIMS. IN AIM 1, WE WILL DEFINE THE FUNDAMENTAL ROLE OF ENDOTHELIAL FTO IN THE PATHOGENESIS OF PAH. IN AIM 2, WE WILL DELINEATE THE MOLECULAR MECHANISMS UNDERLYING FTO REGULATION OF ENDOTHELIAL DYSFUNCTION LEADING TO PULMONARY VASOCONSTRICTION AND VASCULAR REMODELING. WE WILL IDENTIFY THE KEY FTO TARGETS IN ECS AND ADDRESS THE POSSIBILITY OF RESCUING THE PHENOTYPE OF FTOTIECRE BY NOVEL NANOPARTICLE-MEDIATED IN VIVO EC-SPECIFIC GENE TRANSFER. IN AIM 3, WE WILL EXPLORE THE THERAPEUTIC POTENTIAL OF FTO INHIBITORS INCLUDING A REPURPOSED FDA-APPROVED DRUG IN THE TREATMENT OF PAH EMPLOYING 3 COMPLIMENTARY ANIMAL MODELS OF PAH. BASED ON THE CLEAR CLINICAL RELEVANCE OF OUR NOVEL FINDINGS, WE EXPECT THAT THE PROPOSED STUDIES HAVE SIGNIFICANT TRANSLATIONAL POTENTIAL BY DELINEATING THE MOLECULAR AND CELLULAR MECHANISMS OF ENDOTHELIAL DYSFUNCTION LEADING TO PULMONARY VASOCONSTRICTION AND VASCULAR REMODELING, IDENTIFYING DRUGGABLE TARGETS, AND EXPLORING PHARMACOLOGICAL AGENTS THAT CAN PHARMACOLOGICALLY INHIBIT/REVERSE VASCULAR REMODELING AND ALSO INHIBIT VASOCONSTRICTION FOR THE PREVENTION AND TREATMENT OF PAH IN PATIENTS. THUS, WE BELIEVE THE PROPOSED STUDIES HAVE GREAT TRANSLATIONAL POTENTIAL.

INTEGRATED ANALYSIS OF AUTONOMIC BIOMARKERS IN PREMATURITY-RELATED VENTILATORY CONTROL: DETERMINATION OF NEURORESPIRATORY MATURATION AND PREDICTORS O

ELUCIDATING THE ROLE OF TYPE I INTERFERON SIGNALING AND MACROPHAGE-DERIVED INFLAMMATION IN THE JUVENILE HOST WITH VIRAL PNEUMONIA - PROJECT SUMMARY: VIRAL RESPIRATORY INFECTIONS ARE A LEADING CAUSE OF HOSPITALIZATION IN CHILDREN. IN THE ABSENCE OF CO-MORBIDITIES, CHILDREN ARE MUCH MORE LIKELY THAN ADULTS TO REQUIRE HOSPITALIZATION FOR MOST RESPIRATORY VIRUSES, INCLUDING INFLUENZA A VIRUS (IAV). AGE-RELATED CHANGES IN INNATE IMMUNE SIGNALING OVER THE FIRST FEW YEARS OF LIFE LIKELY IMPACT THE COURSE OF VIRAL RESPIRATORY INFECTIONS, BUT THE MECHANISMS DRIVING VIRAL-INDUCED RESPIRATORY FAILURE IN CHILDREN ARE UNKNOWN. VIRAL LOAD HAS NOT BEEN ASSOCIATED WITH SEVERITY OF ILLNESS IN CHILDREN WITH IAV PNEUMONIA, SO FAILURE TO CONTROL VIRAL REPLICATION IS NOT LIKELY THE PRIMARY DRIVER OF SEVERE ILLNESS IN CHILDREN. WE HAVE FOUND THAT JUVENILE MICE RECRUIT MORE MONOCYTE-DERIVED ALVEOLAR MACROPHAGES AND HAVE INCREASED ACTIVATION OF THE NLRP3 INFLAMMASOME COMPARED TO ADULT MICE LATE IN IAV INFECTION. THIS WAS ASSOCIATED WITH INCREASED PRODUCTION OF TYPE I INTERFERON (IFN) IN JUVENILE MICE, DESPITE EQUAL VIRAL BURDEN. IMPORTANTLY, INHIBITION OF MACROPHAGE RECRUITMENT DECREASED TYPE I IFN LEVELS AND IMPROVED SURVIVAL IN JUVENILE IAV INFECTION. THESE DATA SUGGEST THAT AGE-RELATED DIFFERENCES IN TYPE I IFN PRODUCTION IN RESPONSE TO IAV INFECTION PROMOTE THE RECRUITMENT OF INFLAMMATORY MACROPHAGES AND CONTRIBUTE TO MORTALITY IN JUVENILE MICE. IN PRELIMINARY DATA, WE NOW SHOW THAT GENETIC DELETION OR PHARMACOLOGIC INHIBITION OF THE TYPE I IFN RECEPTOR, IFNAR1, ON RECRUITED MACROPHAGES IMPROVES SURVIVAL IN IAV-INFECTED JUVENILE MICE. THEREFORE, WE HYPOTHESIZE THAT CHILDREN FAIL TO RECOVER FROM IAV INFECTION DUE TO INCREASED TYPE I IFN SIGNALING AND MACROPHAGE RECRUITMENT TO THE LUNGS. WE FURTHER HYPOTHESIZE THAT RECRUITED MACROPHAGES MAINTAIN AN INJURIOUS INFLAMMATORY PHENOTYPE IN THE JUVENILE LUNG DUE TO AGE-RELATED DIFFERENCES IN THE LUNG MICROENVIRONMENT. WE WILL TEST THESE HYPOTHESES IN THE FOLLOWING SPECIFIC AIMS: AIM 1: DETERMINE WHETHER AGE-RELATED DIFFERENCES IN THE MICROENVIRONMENT OF THE JUVENILE LUNG PROMOTE AN INFLAMMATORY PHENOTYPE IN RECRUITED MACROPHAGES. AIM 2: DETERMINE WHETHER INHIBITION OF TYPE I IFN SIGNALING IN RECRUITED MACROPHAGES DECREASES LUNG INJURY AND IMPROVES OUTCOMES IN JUVENILE VIRAL PNEUMONIA. AIM 3: DETERMINE WHETHER INCREASED TYPE I IFN SIGNALING IN EPITHELIAL CELLS CONTRIBUTES TO SEVERITY OF ILLNESS IN JUVENILE VIRAL PNEUMONIA. COMPLETION OF THESE AIMS WILL IDENTIFY MECHANISMS DRIVING VIRAL-INDUCED RESPIRATORY FAILURE IN THE JUVENILE HOST AND EXPLORE THE POTENTIAL BENEFIT OF TARGETING IFNAR1 SIGNALING IN MACROPHAGES TO MINIMIZE LUNG INJURY CAUSED BY VIRAL RESPIRATORY INFECTIONS IN CHILDREN. USING AGE-APPROPRIATE MOUSE MODELS OF IAV PNEUMONIA AND MULTIDIMENSIONAL PHENOTYPING OF CHILDREN WITH VIRAL-INDUCED RESPIRATORY FAILURE, WE ARE POSITIONED TO DEFINE KEY DETERMINANTS OF DISEASE SEVERITY IN CHILDREN WITH IAV PNEUMONIA THAT WILL SUPPORT THE RATIONALE DESIGN OF NEW TREATMENT STRATEGIES TO MINIMIZE LUNG INJURY AND OPTIMIZE RECOVERY.

NEURAL PREDICTION TO ENHANCE LANGUAGE OUTCOMES IN CHILDREN WITH COCHLEAR IMPLANT - PROJECT SUMMARY/ABSTRACT ALTHOUGH COCHLEAR IMPLANTATION (CI) IS THE MOST EFFECTIVE METHOD FOR MANAGING SEVERE TO PROFOUND SENSORINEURAL HEARING LOSS, CHILDREN WITH CI AS A GROUP PERFORM AT ABOUT 15TH PERCENTILE OF THEIR NORMAL-HEARING PEERS ON LANGUAGE MEASURES. MOST INTRIGUINGLY, THEIR LANGUAGE OUTCOMES ARE HIGHLY VARIABLE AT THE INDIVIDUAL LEVEL, DESPITE IMPLANTATION AT A YOUNG AGE. USING PRE-SURGICAL BRAIN MAGNETIC RESONANCE IMAGING (MRI) SCANS, DONE AS PART OF THE ROUTINE CLINICAL EVALUATION, AS WELL AS AI-ENABLED ANALYTICAL METHODS, OUR RESEARCH WILL CONSTRUCT NEURAL PREDICTIVE MODELS TO FORECAST INDIVIDUAL-LEVEL LANGUAGE OUTCOMES IN ENGLISH- AND SPANISH-LEARNING CHILDREN UP TO 4 YEARS AFTER SURGERY. THE CLINICAL UTILITY OF THESE MODELS WILL ALSO BE EVALUATED BY INVESTIGATING THE EXTENT TO WHICH THE MODELS' PREDICTION IS ASSOCIATED WITH THE DEGREE TO WHICH A CHILD RESPONDS TO A PROGRAM OF INTENSIVE COMMUNICATION TREATMENT. WE HYPOTHESIZE THAT DURING THE 4 YEARS IMMEDIATELY AFTER SURGERY, YOUNG CHILDREN WITH CI FOLLOW THREE STAGES OF LANGUAGE DEVELOPMENT: 1) GLOBAL ATTENTION TO SPOKEN LANGUAGE AS THE CHILD ACCLIMATIZES TO ELECTRIC AUDITORY INPUT ABOUT LANGUAGE, 2) ENCODING OF PHONOLOGICAL PATTERNS WITH SUFFICIENT INFORMATION TO DEVELOP AUDITORY-BASED LEXICAL REPRESENTATIONS, AND 3) DEVELOPMENT OF SPOKEN LANGUAGE SYNTAX TO COMMUNICATE ORALLY IN LONGER UTTERANCES. WE ALSO HYPOTHESIZE THAT THE INTEGRITY OF BRAIN NETWORKS ASSOCIATED WITH HIGHER-ORDER COGNITIVE, AUDITORY AND SYNTACTIC PROCESSING DIFFERENTIALLY CONTRIBUTES TO LANGUAGE OUTCOMES ACROSS THESE THREE STAGES IN MONOLINGUAL ENGLISH-LEARNING CHILDREN WITH CI (AIM 1). WE FURTHER HYPOTHESIZE THAT THESE NETWORKS ARE LARGELY INVARIANT FOR TYPOLOGICALLY SIMILAR LANGUAGES DURING THE FIRST STAGE, BUT THAT THE CONTRIBUTION OF THE AUDITORY NETWORK WOULD BE PROLONGED AND REQUIRE HIGHER-ORDER COGNITIVE NETWORKS TO AN EVEN GREATER EXTENT TO LANGUAGE OUTCOMES FOR SPANISH-ENGLISH BILINGUAL CHILDREN WITH CI (AIM 2). AS PART OF OUR CURRENT R21 PROJECT, WE HAVE DEVELOPED A STANDARDIZED CLINICAL EVALUATION AND FOLLOW-UP PROTOCOL ACROSS DIFFERENT CI CENTERS THAT WILL FACILITATE THE INVESTIGATIONS REQUIRED TO ACHIEVE AIMS 1 AND 2. AIM 3 CONCERNS THE INTERACTION BETWEEN NEURAL PREDICTION OF OUTCOMES AND BEHAVIORAL TREATMENT. THE MAIN CI CENTER OF THIS PROJECT WILL ENROLL MONOLINGUAL ENGLISH-LEARNING CHILDREN FOR AN INTENSIVE, PARENT-IMPLEMENTED COMMUNICATION TREATMENT (PICT) PROGRAM, WHICH IS THE ONLY TREATMENT PROGRAM TO DATE WHOSE EFFECTIVENESS HAS BEEN SUPPORTED BY A RANDOMIZED CONTROLLED TRIAL. WE WILL EVALUATE WHETHER NEURAL PREDICTION OF LANGUAGE OUTCOMES IS INVERSELY RELATED TO THE DEGREE OF LANGUAGE GAINS FROM PICT. SPECIFICALLY, WE HYPOTHESIZE THAT THE MORE SEVERE THE PREDICTED LANGUAGE IMPAIRMENT BASED ON OUR NEURAL PREDICTIVE ALGORITHMS, THE MORE THE CHILD COULD BENEFIT FROM PICT. OUR TRANSLATIONAL RESEARCH PROGRAM WILL ADVANCE THE FIELD OF COMMUNICATION DISORDERS IN TECHNOLOGICAL, THEORETICAL AND CLINICAL INNOVATIONS. IT WILL BE AMONG THE FIRST TO DEMONSTRATE THAT A PREDICT-TO- PRESCRIBE APPROACH TO HOLISTICALLY TREAT HEARING LOSS IS FEASIBLE, COST-EFFECTIVE AND CAN LEAD TO OPTIMIZATION OF LANGUAGE OUTCOMES OF ALL CHILDREN WITH CI.

OUR VOICES MATTER: RACIAL JUSTICE ACTIVISM INTERVENTION TO ADDRESS STRUCTURAL RACISM AND PREVENT DEPRESSION IN BLACK AND LATINX YOUTH - PROJECT SUMMARY/ABSTRACT OVER 15 MILLION PEOPLE PARTICIPATED IN RACIAL JUSTICE PROTESTS NATIONWIDE, FOLLOWING THE MURDERS OF GEORGE FLOYD AND BREONNA TAYLOR, SPOTLIGHTING ACTIVISM AS A COLLECTIVE TOOL AGAINST STRUCTURAL RACISM AND DISCRIMINATION (SRD). SRD MANIFESTS AS POLICIES AND PRACTICES (E.G., REDLINING, VOTER SUPPRESSION, MASS INCARCERATION) THAT PRODUCE HOSTILE ENVIRONMENTS WHICH CONTRIBUTE TO PSYCHOLOGICAL DISTRESS, ELEVATED ALLOSTATIC LOAD, AND AN ELEVATED RISK FOR CHRONIC DISEASES AND PREMATURE DEATH, CONCENTRATED WITHIN BLACK AND LATINX POPULATIONS. WHILE THE CONNECTION BETWEEN SRD AND HEALTH IS WELL DOCUMENTED, FEW STUDIES PROVIDE EVIDENCE ON STRATEGIES TO REDUCE SRD AND MITIGATE CONSEQUENCES ON PSYCHOLOGICAL AND PHYSIOLOGICAL OUTCOMES. THUS, THERE IS A CRITICAL NEED TO RIGOROUSLY TEST INTERVENTIONS THAT ADDRESS THE ROOT CAUSES OF SRD AND REDUCE SRD’S INFLUENCE ON THE MENTAL AND PHYSICAL HEALTH OF BLACK AND LATINX POPULATIONS, BEGINNING IN ADOLESCENCE. THE SPECIFIC AIMS OF THE STUDY ARE TO 1) DETERMINE WHETHER A RACIAL JUSTICE ACTIVISM BEHAVIORAL INTERVENTION PREVENTS AND REDUCES DEPRESSIVE SYMPTOMS IN BLACK AND LATINX ADOLESCENTS AND YOUNG ADULTS AND 2) DETERMINE WHETHER A RACIAL JUSTICE ACTIVISM BEHAVIORAL INTERVENTION LOWERS ALLOSTATIC LOAD SCORES IN BLACK AND LATINX ADOLESCENTS AND YOUNG ADULTS. TO ACCOMPLISH THESE AIMS, THE TEAM WILL CONDUCT A STAGE II GROUP-BASED, MULTI-COMPONENT, AND MULTILEVEL RANDOMIZED BEHAVIORAL CLINICAL TRIAL. WE WILL COLLECT PSYCHOLOGICAL AND PHYSIOLOGICAL MEASURES AT BASELINE, THEN AT 6-MONTH INTERVALS FOR 2 YEARS POST RACIAL JUSTICE ACTIVISM INTERVENTION.

IMPROVING THE QUALITY OF PEDIATRIC EMERGENCY CARE USING AN ELECTRONIC MEDICAL REC

REGULATION OF MITOCHONDRIAL DNA HOMEOSTASIS AND NEUROINFLAMMATION BY FASCIN IN ALZHEIMER?S DISEASE - PROJECT SUMMARY/ABSTRACT ALZHEIMER’S DISEASE (AD), THE MOST COMMON NEURODEGENERATIVE DISORDER, AFFECTS ONE IN TEN PEOPLE AGE 65 AND OLDER. DUE TO LIMITED UNDERSTANDING OF MECHANISMS UNDERLYING AD PATHOGENESIS, THERE IS NO EFFECTIVE TREATMENT FOR THIS DEVASTATING DISEASE. THE GOAL OF THIS APPLICATION IS TO INVESTIGATE AN UNEXPECTED ROLE FOR ACTIN BUNDLING PROTEIN FASCIN IN REGULATING MITOCHONDRIAL NUCLEOID DNA (MTDNA) HOMEOSTASIS, OXIDATIVE PHOSPHORYLATION (OXPHOS), MITOCHONDRIAL OXIDATIVE STRESS, NEUROINFLAMMATION, AND NEURODEGENERATION, AS WELL AS HOW DYSREGULATION OF THESE PROCESSES CONTRIBUTES TO AD PATHOGENESIS. FASCIN IS AN ACTIN BUNDLING PROTEIN ESSENTIAL FOR THE CROSS-LINKING OF ACTIN FILAMENTS INTO COMPACT AND RIGID BUNDLES. THE CURRENT PARADIGM POSITS THAT FASCIN PROMOTES CELL MIGRATION AND TUMOR INVASION BY GENERATING PROTRUSIVE MEMBRANE STRUCTURES SUCH AS FILOPODIA. WE RECENTLY MADE THE SURPRISING FINDING THAT DEPLETION OF FASCIN DISRUPTS MITOCHONDRIAL F-ACTIN BUNDLING, WHICH IN TURN CAUSES ABNORMAL MITOCHONDRIAL RESPIRATORY COMPLEX BIOGENESIS AND IMPAIRED MITOCHONDRIAL OXPHOS, SUGGESTING A NOVEL ROLE OF FASCIN IN THE REGULATION OF MITOCHONDRIAL FUNCTION. MECHANISTICALLY THE MITOCHONDRIAL DYSFUNCTION IN FASCIN DEPLETED CELLS WAS DUE TO INCREASED MTDNA AGGREGATION AND LEAKAGE. GIVEN THAT MTDNA CAN ROBUSTLY INDUCE INFLAMMASOME ACTIVATION AND INFLAMMATORY CYTOKINE EXPRESSION, FASCIN DEFICIENCY MAY PLAY AN UNEXPECTED ROLE IN CAUSING NEUROINFLAMMATION. IMPORTANTLY, WE FOUND THAT FASCIN IS CLEAVED INTO A 37KDA FUNCTIONALLY DOMINANT-NEGATIVE FORM IN THE BRAINS OF AD PATIENTS AND AD MOUSE MODELS. VIRUS-MEDIATED EXPRESSION OF FASCIN IN AD MOUSE HIPPOCAMPUS MITIGATED DISEASE SYMPTOMS. IN ADDITION, FASCIN KNOCKOUT MICE WE GENERATED SHOWED PROFOUND MITOCHONDRIAL DEFECTS AND SIGNIFICANT LOSS OF NEURONS IN THE BRAIN. BASED ON THESE PRELIMINARY DATA, WE HYPOTHESIZE THAT FASCIN CONTROLS MITOCHONDRIAL FUNCTION AND MTDNA HOMEOSTASIS IN THE BRAIN. FASCIN FUNCTIONAL DEFICIENCY IN AD LEADS TO SIGNIFICANT MITOCHONDRIAL DEFECTS, NEUROINFLAMMATION AND NEURODEGENERATION. TO TEST THE HYPOTHESIS, IN AIM 1 WE WILL DEFINE THE ROLE OF FASCIN IN REGULATING MITOCHONDRIAL FUNCTION, MTDNA HOMEOSTASIS, NEUROINFLAMMATION AND NEURONAL CELL DEATH IN THE MOUSE BRAIN IN VIVO. IN AIM 2 WE WILL INVESTIGATE THE FUNCTIONAL DEFICIENCY OF FASCIN CAUSED BY PROTEOLYTIC CLEAVAGE DURING THE COURSE OF AD PATHOGENESIS USING BRAIN TISSUES FROM AD PATIENTS AND MOUSE MODELS, AND TO ELUCIDATE MECHANISMS UNDERLYING HOW FASCIN FUNCTIONAL DEFICIENCY CAUSES MTDNA LEAKAGE, OXIDATIVE STRESS, NEUROINFLAMMATION, AND DEGENERATION. IN AIM 3 WE WILL STUDY THE EFFECTS OF TRANSGENIC EXPRESSION OF FASCIN ON ALLEVIATING AD PATHOLOGICAL PHENOTYPES AND DISEASE SYMPTOMS IN MICE. SUCCESSFUL COMPLETION OF THE PROPOSED STUDIES WILL REVEAL FASCIN’S NOVEL ROLE IN REGULATING MITOCHONDRIAL FUNCTION, MTDNA HOMEOSTASIS, NEUROINFLAMMATION AND NEURODEGENERATION. INVESTIGATING FASCIN FUNCTIONAL DEFICIENCY IN AD WILL HELP UNDERSTAND DISEASE PATHOGENIC MECHANISMS AND FACILITATE THERAPEUTIC DEVELOPMENT.

NOVEL MECHANISMS OF ENDOTHELIAL INJURY IN THE PATHOGENESIS OF ARDS

DEVELOPMENTAL ORIGINS OF POLYCYSTIC OVARY SYNDROME: VERY EARLY PHENOTYPES DURING THE MINI PUBERTY OF INFANCY AND BEYOND - PROJECT SUMMARY POLYCYSTIC OVARY SYNDROME (PCOS) IS AMONG THE MOST COMMON ENDOCRINE DISORDERS IN WOMEN OF REPRODUCTIVE AGE AND IS ASSOCIATED WITH SIGNIFICANT NEGATIVE REPRODUCTIVE AND METABOLIC OUTCOMES. AS PCOS IS HIGHLY HERITABLE, DAUGHTERS OF AFFECTED WOMEN HAVE INCREASED RISK, WITH REPORTED PREVALENCE RATES AS HIGH AS ~70%. SEVERAL STUDIES HAVE ESTABLISHED THAT DISTINCT REPRODUCTIVE AND METABOLIC PHENOTYPES CAN BE OBSERVED IN PCOS DAUGHTERS PRIOR TO PUBERTY, SUGGESTING THE PATHOGENESIS OF PCOS BEGINS AT AN EARLY DEVELOPMENTAL STAGE IN THESE AT-RISK GIRLS. FURTHER, STUDIES IN ANIMAL MODELS OF PCOS HAVE DEMONSTRATED THAT EXPOSURE TO ANDROGENS OR ANTI-MULLERIAN HORMONE (AMH) DURING CRITICAL DEVELOPMENTAL PERIODS SUCH AS FETAL LIFE, THE NEONATAL PERIOD, OR PUBERTY CAN PROGRAM THE OFFSPRING TO DEVELOP THE REPRODUCTIVE AND/OR METABOLIC PHENOTYPES OF PCOS DURING REPRODUCTIVE MATURITY. PRIOR TO PUBERTY, THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AXIS IS QUIESCENT, EXCEPT DURING THE “MINI PUBERTY OF INFANCY”, A TRANSIENT DEVELOPMENTAL STAGE DURING THE FIRST SEVERAL MONTHS OF LIFE. THE HPG AXIS IS ACTIVE DURING THIS TIME AND GONADOTROPIN AND SEX STEROIDS REACH PUBERTAL LEVELS. OUR OVERARCHING HYPOTHESIS IS THAT MINI PUBERTY WILL UNMASK AN EARLY REPRODUCTIVE PHENOTYPE IN DAUGHTERS OF WOMEN WITH PCOS, CHARACTERIZED BY ALTERATIONS IN GONADOTROPIN AND AMH SECRETION. STUDIES DURING THIS VERY EARLY AGE HAVE BEEN LIMITED DUE TO THE CHALLENGES OF PURSUING INVASIVE TESTING IN THIS AGE GROUP. WE WILL EMPLOY MINIMALLY INVASIVE METHODS WHICH WILL ALLOW US TO EXAMINE EARLY METABOLIC AND REPRODUCTIVE PHENOTYPES IN PCOS DAUGHTERS WITHOUT RISK OF HARM TO THESE YOUNG GIRLS. THREE AIMS WILL TEST THE HYPOTHESES THAT: 1) PCOS DAUGHTERS HAVE A DISTINCT REPRODUCTIVE PHENOTYPE DURING THE MINI PUBERTY OF INFANCY CHARACTERIZED BY INCREASED GONADOTROPIN AND AMH LEVELS AND DECREASED SEX HORMONE BINDING GLOBULIN (SHBG); 2) PCOS DAUGHTERS WILL DEVELOP A METABOLIC PHENOTYPE CHARACTERIZED BY INCREASED BODY FAT ACCRUAL AND DECREASED INSULIN SENSITIVITY IN THE FIRST TWO YEARS OF LIFE; 3) LH AND AMH LEVELS IN PCOS DAUGHTERS DURING THE MINI PUBERTY OF INFANCY WILL BE POSITIVELY ASSOCIATED WITH MATERNAL TESTOSTERONE AND AMH LEVELS AND NEGATIVELY ASSOCIATED WITH MATERNAL INSULIN SENSITIVITY AND ADIPONECTIN LEVELS DURING THE SECOND TRIMESTER OF GESTATION. WE WILL ENROLL 120 WOMEN WITH PCOS AND 120 CONTROL WOMEN EARLY IN THEIR SECOND TRIMESTER OF PREGNANCY. WE WILL MEASURE REPRODUCTIVE HORMONES AND MARKERS OF INSULIN SENSITIVITY AND SECRETION IN THESE WOMEN BETWEEN 24 AND 28 WEEKS GESTATION. WE WILL COLLECT TIMED URINE SAMPLES FOR ASSESSMENT OF C-PEPTIDE, GONADOTROPIN SECRETION, AND STEROID HORMONE METABOLISM IN THEIR INFANT DAUGHTERS AT 1, 2, AND 3 MONTHS OF AGE. WE WILL OBTAIN MEASURES OF ADIPOSITY AND CAPILLARY BLOOD SAMPLES FOR MEASUREMENT OF SHBG, AMH, AND ADIPONECTIN AT 3, 6, 12, 18, AND 24 MONTHS OF AGE IN THE INFANT DAUGHTERS. IF THE AIMS ARE ACHIEVED, THE IMPACT OF THIS RESEARCH WILL RESULT IN A PARADIGM SHIFT IN OUR UNDERSTANDING OF THE EARLY MECHANISMS OF PCOS. THROUGH THE PROPOSED STUDY, WE WILL ALSO ESTABLISH A COHORT FOR CONTINUED LONGITUDINAL STUDIES IN GIRLS AT INCREASED RISK FOR PCOS.

NOVEL INTRINSIC ENDOTHELIAL STEM CELLS RESPONSIBLE FOR LUNG ENDOTHELIAL REGENERATION AND VASCULAR REPAIR IN ARDS - ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) IS A COMPLEX, MULTI-FACTORIAL SYNDROME WITH AN UNACCEPTABLE HIGH MORTALITY RATE. ENDOTHELIAL INJURY CHARACTERIZED BY PERSISTENTLY INCREASED LUNG MICROVASCULAR PERMEABILITY RESULTING IN PROTEIN-RICH LUNG EDEMA IS A HALLMARK OF ARDS. IN BOTH ANIMAL MODELS OF ACUTE LUNG INJURY INDUCED BY SEPSIS AND ARDS PATIENTS, THERE ARE MOUNTING EVIDENCE DEMONSTRATE LOSS OF ENDOTHELIAL CELLS (ECS). RECENT STUDIES PROVIDE SOME INFORMATION THAT ECS PLAY PREDOMINANT ROLE IN LUNG ENDOTHELIAL REGENERATION. HOWEVER, THE PULMONARY VASCULAR ECS ARE QUITE HETEROGENOUS. IT IS UNKNOWN WHETHER ALL RESIDENT ECS CONTRIBUTE TO ENDOTHELIAL REGENERATION FOLLOWING SEPSIS-INDUCED VASCULAR INJURY. THE MOST IMPORTANT QUESTION IN THE FIELD IS WHETHER THERE IS A SPECIAL ENDOTHELIAL STEM CELLS RESPONSIBLE FOR ENDOTHELIAL REGENERATION AND VASCULAR REPAIR FOLLOWING SEPSIS-INDUCED LUNG INJURY. OUR SUPPORTING DATA SHOW THAT THERE IS A NOVEL RARE SUBPOPULATION OF ECS RESPONSIBLE FOR LUNG ENDOTHELIAL REGENERATION AND VASCULAR REPAIR FOLLOWING SEPSIS-INDUCED LUNG INJURY. THESE CELLS EXPRESS MANY OF THE GENES ESSENTIAL FOR CELL CYCLE PROGRESSION AND PROLIFERATION AND ALSO SOME OF THE STEM CELL GENES, HOWEVER, NOT THE MARKERS OF RECENTLY IDENTIFIED VASCULAR ENDOTHELIAL STEM CELLS/PROGENITOR CELLS SUCH AS APELIN, CD157 AND EPCR. BASED ON THEIR UNIQUE EXPRESSION OF 2 GENES, WE NAMED THIS RARE SUBPOPULATION OF ECS AS UC+ ENDOTHELIAL STEM CELLS (UC+ESCS). GENETIC DEPLETION OF UC+ESCS IN MOUSE LUNGS LED TO INHIBITED ENDOTHELIAL REGENERATION AND IMPAIRED VASCULAR REPAIR RESULTING IN PERSISTENT INFLAMMATORY LUNG INJURY. THUS, WE HYPOTHESIZE THAT UC+ESCS ARE THE LONG-SOUGHT ENDOTHELIAL STEM CELLS RESPONSIBLE FOR ENDOTHELIAL REGENERATION AND VASCULAR REPAIR FOLLOWING INFLAMMATORY LUNG INJURY INDUCED BY SEPSIS CHALLENGE. THE PROPOSED STUDIES WILL ADDRESS THE FOLLOWING SPECIFIC AIMS. STUDIES IN AIM 1 WILL DETERMINE THE FUNDAMENTAL ROLE OF UC+ESCS IN VASCULAR REPAIR AND RESOLUTION OF INFLAMMATORY LUNG INJURY INDUCED BY SEPSIS CHALLENGE VIA GENETIC DEPLETION OF UC+ESCS. TWO COMPLEMENTARY SEPSIS MODELS INCLUDING I.P. LPS AND CECAL LIGATION AND PUNCTURE (CLP) WHICH INDUCES POLYMICROBIAL SEPSIS WILL BE USED. AIM 2 WILL DEFINE THE ROLE OF UC+ESCS IN REGENERATING ENDOTHELIAL SUBPOPULATION(S) AND THE MOLECULAR MECHANISMS OF UC+ESC PROLIFERATION AND EXPANSION FOLLOWING SEPSIS CHALLENGE. THESE STUDIES WILL DEFINE A NOVEL RARE ENDOTHELIAL STEM CELL SUBPOPULATION RESPONSIBLE FOR ENDOTHELIAL REGENERATION FOLLOWING SEPSIS- INDUCED INFLAMMATORY LUNG INJURY AND PROVIDE A PARADIGM SHIFT IN OUR UNDERSTANDING OF THE CELLULAR MECHANISMS OF ENDOTHELIAL REGENERATION AND VASCULAR REPAIR. WE BELIEVE SUCCESSFUL COMPLETION OF THE STUDIES WILL LEAD TO NOVEL THERAPEUTIC STRATEGY TO HARNESS THIS SPECIFIC INTRINSIC ENDOTHELIAL STEM CELL SUBPOPULATION FOR THE PREVENTION AND EFFECTIVE TREATMENT OF ARDS INDUCED BY SEPSIS.

IDENTIFYING SPECIFIC ANTIGENIC TARGETS OF KAWASAKI DISEASE

UNDERSTANDING THE MULTILEVEL IMPACT OF RACISM ON SUICIDAL THOUGHTS AND BEHAVIORS AMONG BLACK CHILDREN WITH ADHD: INTERSECTIONALITY, RISK, AND PROTECTIVE FACTORS - OVER THE PAST TWO DECADES, SUICIDE RATES HAVE BEEN RISING AMONG SCHOOL-AGE BLACK CHILDREN (5-11 YEARS OLD), DESPITE DECREASING RATES AMONG WHITE CHILDREN OF THE SAME AGE. BLACK SCHOOL-AGE CHILDREN REPORT SUICIDAL THOUGHTS AND BEHAVIOR (STB) MORE FREQUENTLY THAN THEIR WHITE PEERS AND ARE TWICE AS LIKELY TO DIE FROM SUICIDE. THE STRONGEST PSYCHIATRIC RISK FACTOR FOR STB AND SUICIDE AMONG BLACK SCHOOL-AGE CHILDREN IS ATTENTION- DEFICIT/HYPERACTIVITY DISORDER (ADHD). CHILDREN WITH ADHD ARE PREDISPOSED TO STB DUE TO IMPULSIVITY, EMOTION DYSREGULATION, SCHOOL FAILURE, PEER PROBLEMS, FAMILY CONFLICT, AND DEMORALIZATION. BLACK CHILDREN MAY FACE A DISPROPORTIONATE IMPACT FROM ADHD-RELATED RISK FOR STB DUE TO RACISM. BOTH STRUCTURAL RACISM (UNEQUAL SYSTEMS OF OPPORTUNITY) AND INTERPERSONAL RACISM (BIASED INTERACTIONS WITH OTHERS) PROFOUNDLY AND NEGATIVELY INFLUENCE CHILD HEALTH AND MAY COMPOUND THE RISK FOR STB AMONG CHILDREN WITH ADHD. FOR EXAMPLE, STRUCTURAL RACISM LEADS TO LESS EDUCATIONAL AND TREATMENT RESOURCES, AND INTERPERSONAL RACISM LEADS TO BIASED DISCIPLINARY AND TREATMENT DECISIONS. HOWEVER, LITTLE EVIDENCE EXISTS ON IF AND HOW RACISM INCREASES RISK FOR STB AND WHICH FACTORS COULD MITIGATE RISK AMONG SCHOOL-AGE BLACK CHILDREN WITH ADHD. THUS, OUR OBJECTIVE IS TO UNDERSTAND HOW STRUCTURAL, INTERPERSONAL, AND CLINICAL RISK AND PROTECTIVE FACTORS INTERSECT TO DETERMINE RISK FOR FUTURE STB IN THIS POPULATION TO INFORM SUICIDE PREVENTION STRATEGIES. TO ACHIEVE OUR OBJECTIVE, WE PROPOSE A MIXED-METHODS PROSPECTIVE COHORT STUDY OF 320 BLACK CHILDREN AGED 6-11 YEARS WITH ADHD ASSESSED EVERY 6 MONTHS FOR 2 YEARS, WITH A PRIMARY OUTCOME OF STB REPORTED BY CHILD OR PARENT. WE HAVE 3 AIMS: (1) QUANTITATIVELY EXAMINE THE IMPACT OF STRUCTURAL AND INTERPERSONAL RACISM ON THE DEVELOPMENT OF SUICIDAL THOUGHTS AND BEHAVIOR (STB) AMONG SCHOOL-AGE BLACK CHILDREN WITH ADHD, STATISTICALLY CONTROLLING FOR PSYCHIATRIC COMORBIDITY, USING A RANDOM-INTERCEPT CROSS-LAGGED PANEL ANALYSIS (RI-CLPM). WE WILL USE THE CHILD OPPORTUNITY INDEX (COI) BASED ON CENSUS TRACT DATA AS A PROXY FOR ACCESS TO RESOURCES AND OPPORTUNITIES SHAPED BY STRUCTURAL RACISM, AND THE EVERYDAY DISCRIMINATION SCALE (EDS) AS A PARENT REPORT OF YOUTH DISCRIMINATION EXPERIENCES. (2) WE WILL QUANTITATIVELY EXAMINE THE IMPACT OF CLINICAL AND CONTEXTUAL PROTECTIVE FACTORS (ADHD MEDICATION TREATMENT, SCHOOL CLIMATE, AND FAMILY RELATIONSHIPS) ON FUTURE STB USING RI-CLPM. (3) WE WILL QUALITATIVELY IDENTIFY PARENT AND CHILD-REPORTED PERSPECTIVES ON AND EXPERIENCES WITH RACISM AND STB VIA THEMATIC ANALYSIS OF SEMI- STRUCTURED INTERVIEW DATA (COLUMBIA-SUICIDE SEVERITY RATING SCALE SEMI-STRUCTURED INTERVIEWS AND SEPARATE IN- DEPTH INTERVIEWS WITH PARENTS AND CHILDREN). OUR OVERARCHING HYPOTHESIS IS THAT BOTH STRUCTURAL AND INTERPERSONAL RACISM INCREASE RISK FOR DEVELOPMENT OF STB AMONG CHILDREN WITH ADHD BEYOND THE RISK CONFERRED BY CLINICAL SEVERITY, AND THAT PROTECTIVE FACTORS RELATED TO MEDICATION TREATMENT AND SOCIAL CONTEXT MAY REDUCE RISK FOR STB IN THIS POPULATION. THIS WORK WILL LEAD TO THE DEVELOPMENT OF SUICIDE PREVENTION STRATEGIES FOR A HIGH-RISK GROUP OF CHILDREN.

INTERPREGNANCY AS A CRITICAL PERIOD FOR MATERNAL-CHILD CARDIOVASCULAR HEALTH IN PEDIATRIC CLINICS: ANCILLARY TO YOUNG HEARTS - PROJECT SUMMARY / ABSTRACT POOR MATERNAL CARDIOVASCULAR HEALTH (CVH: BEHAVIORS + FACTORS) IN THE PERI-PREGNANCY PERIOD CONTRIBUTES TO POOR OFFSPRING CVH OVER THE LIFE COURSE, ESPECIALLY IN SOCIALLY DISADVANTAGED GROUPS. MANY INTERVENTIONS HAVE TARGETED MATERNAL CVH BEHAVIORS DURING PREGNANCY, BUT TO IMPROVE OFFSPRING OUTCOMES, TARGETING MATERNAL CVH DURING PRECONCEPTION MAY BE MORE EFFECTIVE DUE TO CRITICAL EARLY GESTATIONAL EVENTS. HOWEVER, PRECONCEPTION MATERNAL CVH IS UNDERSTUDIED BECAUSE HALF OF PREGNANCIES ARE UNPLANNED, AND CLINICAL CARE AMONG INDIVIDUALS OF CHILDBEARING AGE IS INCONSISTENT. PEDIATRIC CLINICAL SETTINGS OFFER A NOVEL ACCESS POINT FOR MATERNAL PRECONCEPTION CVH, SINCE >60% OF BIRTHS ANNUALLY ARE TO MOTHERS WHO ALREADY HAVE CHILDREN. LEVERAGING THIS ACCESS TO INVES- TIGATE KEY TIMING AND DRIVERS OF MATERNAL-CHILD CVH ACROSS THE ENTIRE PERI-PREGNANCY PERIOD (PRECONCEPTION, PREGNANCY, AND POSTPARTUM) COULD REVEAL OPPORTUNITIES TO BREAK INTERGENERATIONAL CYCLES OF CARDIOVASCULAR DIS- EASE AND RELATED DISPARITIES. OUR LONG-TERM GOAL IS TO DEVELOP STRATEGIES THAT OPTIMIZE CVH FROM THE BEGINNING OF LIFE. OUR OBJECTIVE HERE IS TO CHARACTERIZE KEY TIMING AND DRIVERS OF MATERNAL-CHILD CVH ACROSS PERI-PREGNANCY TO INFORM FUTURE PERSON-CENTERED INTERVENTIONS. WE WILL LEVERAGE OUR YOUNG HEARTS STUDY OF DIVERSE CHILDREN FROM CLINICS ACROSS CHICAGO TO ENROLL AND FOLLOW MOTHERS WHO ARE LIKELY TO HAVE ANOTHER PREGNANCY, AS WELL AS FA- THERS/CO-PARENTS AND SUBSEQUENT OFFSPRING, AND STUDY THEM FROM PRECONCEPTION THROUGH POSTPARTUM. BASED ON OUR PRELIMINARY DATA, WE HYPOTHESIZE THAT 1) PRECONCEPTION IS A SENSITIVE PERIOD FOR THE IMPACT OF MATERNAL CVH ON OFFSPRING CVH, 2) SPECIFIC SOCIAL AND PSYCHOLOGICAL FACTORS SHAPE MATERNAL CAPACITY, OPPORTUNITY, AND MOTIVA- TION FOR HEALTHY LIFESTYLE AND CVH, AND 3) PARENTS AND CLINICIANS DESIRE SPECIFIC INTERVENTION STRATEGIES TO OPTIMIZE MATERNAL AND CHILD CVH. WE WILL TEST OUR HYPOTHESIS VIA THREE SPECIFIC AIMS: 1) COMPARE THE CONTRIBUTIONS OF PRECONCEPTION, PREGNANCY, AND POSTPARTUM MATERNAL CVH TO CHILD OUTCOMES; 2) MAP THE CONTRIBUTIONS OF SOCIAL AND PSYCHOLOGICAL FACTORS TO MATERNAL CVH; AND 3) DETERMINE PARENTS’ AND CLINICIANS’ PREFERENCES FOR INTERVENTION CHARACTERISTICS TO OPTIMIZE MATERNAL-CHILD CVH. WE WILL ANALYZE DATA FROM ONLINE SURVEYS AND ELECTRONIC MEDICAL RECORDS AMONG ~650 FAMILIES TO ADDRESS AIMS 1 AND 2, AND WE WILL INTERVIEW ~40 MOTHERS (TWICE), 20 FATHERS/CO- PARENTS, AND 30 CLINICIANS TO ADDRESS AIMS 2 AND 3. WE WILL THEN INTEGRATE QUANTITATIVE AND QUALITATIVE FINDINGS INTO A THEORY-BASED LOGIC MODEL FOR CHANGE AND GUIDING PRINCIPLES FOR INTERVENTION. KEY INNOVATIONS ARE A NOVEL APPROACH TO ACCESS PRECONCEPTION, PRAGMATIC TECHNOLOGY-ENABLED COHORT DESIGN, AND INTEGRATION OF HEALTH PSY- CHOLOGY THEORY AND PERSON-CENTEREDNESS IN A REFINED MIXED-METHODS APPROACH. THE OUTCOMES OF THIS RESEARCH ON WHEN TO INTERVENE, WHAT TO INTERVENE ON, AND HOW TO INTERVENE WILL HELP DIRECT PUBLIC HEALTH RESOURCES AND WILL PROVIDE A STRONG EVIDENCE BASE TO DEVELOP NOVEL INTERVENTIONS THAT PROMOTE OPTIMAL MATERNAL-CHILD CVH IN DI- VERSE PSYCHOSOCIAL CONTEXTS. THE PROPOSED PROJECT WILL THUS ENABLE SIGNIFICANT PROGRESS TOWARD ELIMINATING MA- TERNAL-CHILD HEALTH DISPARITIES AND LAUNCHING FUTURE GENERATIONS OF CHILDREN WITH OPTIMAL CVH.

MECHANISMS REGULATING EVF2 LONG NON-CODING RNA TRANSCRIPTIONAL CONTROL

AWARENESS AND ACCESS TO CARE FOR CHILDREN AND YOUTH WITH EPILEPSY

INVESTIGATING STRUCTURAL AND GENETIC SUBSTRATES OF EARLY-ONSET ATRIAL FIBRILLATION - PROJECT SUMMARY/ABSTRACT EARLY-ONSET ATRIAL FIBRILLATION (A FIRST EVENT OF ATRIAL FIBRILLATION BEFORE 35 YEARS OF AGE) IS ASSOCIATED WITH FREQUENT RECURRENCES, OFTEN REQUIRING ELECTRICAL SHOCKS TO STOP THE ARRHYTHMIA, MEDICATION TO PREVENT ARRHYTHMIA OR SURGICAL/INTERVENTIONAL MANAGEMENT. RECENT WORK HAS DEMONSTRATED THAT ADULT INTERVENTIONS FOR ATRIAL FIBRILLATION (AF) ARE NOT EFFECTIVE IN CHANGING THE FREQUENCY OF RECURRENCE IN CHILDREN AND YOUNG ADULTS. IN CLINICAL PRACTICE, PEDIATRIC CARDIOLOGISTS DO NOT FOLLOW THE AF RECOMMENDATIONS DESIGNED FOR ADULTS. RECOMMENDATIONS FOR THERAPY HAVE NOT BEEN ESTABLISHED IN EARLY-ONSET AF, IN PART BECAUSE WE MAY BE CURRENTLY ASSESSING THE WRONG MARKERS FOR RISK. OUR CENTRAL HYPOTHESIS IS THAT IDENTIFIABLE GENETIC FACTORS ARE ASSOCIATED WITH CLINICAL RECURRENCE IN CHILDREN AND YOUNG ADULTS WITH AF AT = 35 YEARS OF AGE. WE WILL USE THREE GENOMIC APPROACHES TO ADDRESSING OUR CENTRAL HYPOTHESIS: A VALIDATED GENE PANEL (AIM 1), COMMON-VARIANT ANALYSIS (AIM 2A), AND RARE VARIANT ANALYSIS WITH WHOLE GENOME SEQUENCING (AIM 2B). WE WILL RECRUIT PATIENTS WITH EARLY-ONSET AF IN A MULTICENTER NETWORK. IN A PROSPECTIVE, OBSERVATIONAL STUDY, WE WILL RECORD PHENOTYPE INFORMATION AND OBTAIN GENETIC MATERIAL. IN OUR FIRST AIM, WE WILL DETERMINE IF PATIENTS WITH PATHOGENIC AND LIKELY PATHOGENIC (P/LP) VARIANTS IN 311 ESTABLISHED CARDIAC GENES HAVE A SHORTER TIME TO FIRST AF RECURRENCE THAN PATIENTS WITHOUT A P/LP VARIANT. BY TESTING CLINICALLY RELEVANT GENES IN COMMERCIALLY AVAILABLE PANELS, WE WILL BE ABLE TO RAPIDLY TRANSLATE THE RESULTS OF OUR FIRST AIM TO CLINICAL PRACTICE. IN THE SECOND AIM, WE WILL FOCUS ON NEW GENOMIC RELATIONSHIPS. DATA FROM GENOME-WIDE ASSOCIATION STUDIES OF AF IN OLDER ADULTS HAVE GENERATED POLYGENIC RISK SCORES (PRS). HIGH SCORES ON PRS HAVE BEEN ASSOCIATED WITH INCREASED MORBIDITY AND MORTALITY IN OLDER ADULTS. HOWEVER, IT IS NOT KNOWN WHETHER AF PRS HAVE ANY RELEVANCE IN CHILDREN AND YOUNG ADULTS, NOR WHETHER THEY ARE MARKERS OF LIFELONG GENOMIC AND MYOPATHIC RISK. THEREFORE, WE WILL VALIDATE WHETHER EXISTING AF PRS ARE HIGHER IN EARLY-ONSET AF THAN IN A CONTROL POPULATION WITHOUT CARDIAC PHENOTYPE. FINALLY, IN A SECOND GENOMIC ANALYSIS, WE IDENTIFY PROBANDS WHO HAVE NO P/LP VARIANTS IN AIM 1 OF THE STUDY. FROM THOSE P/LP-NEGATIVE PROBANDS, WE WILL IDENTIFY TRIOS WHERE THE PROBAND HAS EARLY-ONSET AF AND BOTH PARENTS ARE NEGATIVE FOR CARDIAC DISEASE WITH A NEGATIVE FAMILY HISTORY OF EARLY-ONSET AF. WE WILL PERFORM TRIO WHOLE GENOME SEQUENCING TO IDENTIFY NOVEL GENETIC MARKERS OF RISK IN EARLY-ONSET AF. IF OUR CENTRAL HYPOTHESIS IS CORRECT, THESE THREE APPROACHES WILL IDENTIFY A NOVEL SET OF RISK FACTORS IN EARLY-ONSET AF. THE IMMEDIATE IMPACT WILL BE THE ABILITY TO TEST FOR COMMERCIALLY AVAILABLE GENETIC ABNORMALITIES THAT IDENTIFY RISK OF EARLY AF RECURRENCE AND THAT MAY IDENTIFY LIFELONG RISK FOR PROGRESSION OF MYOPATHY, WITH IMPLICATIONS FOR THERAPY AND PREVENTION. AS A SECONDARY BENEFIT, THE IDENTIFICATION OF P/LP VARIANTS IN A PROBAND HAS IMPLICATIONS FOR CASCADE SCREENING IN FAMILIES. FINALLY, WORK ON THE GENOMIC UNDERPINNINGS OF EARLY-ONSET AF HAS IMPLICATIONS NOT ONLY IN THE YOUNG, BUT AS A HYPOTHESIS THAT THE LIFELONG RISKS OF ATRIAL MYOPATHY AFFECT THE LATER INCIDENCE OF ATRIAL FIBRILLATION IN OLDER ADULTS.

TARGETING SMOOTH MUSCLE PROGENITOR CELLS FOR TREATMENT OF PULMONARY ARTERIAL HYPERTENSION

NOVEL SIGNALINGS AND MOLECULAR TARGETS OF ENDOTHELIAL REGENERATION IN AGING LUNG

MECHANISMS OF SGLT2 INHIBITION IN PEDIATRIC NAFLD - PROJECT SUMMARY / ABSTRACT NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), CHARACTERIZED BY EXCESSIVE DEPOSITION OF FAT IN THE LIVER, IS THE MOST COMMON PEDIATRIC LIVER DISEASE (~13% PREVALENCE AMONG 2-19 YEARS OLD) AND IS EXACERBATED BY OBESITY AND INSULIN RESISTANCE. PRESENTLY, THERE ARE NO TREATMENT OPTIONS FOR PEDIATRIC NAFLD THAT PRODUCE MEANINGFUL AND DURABLE HEPATIC FAT REDUCTIONS. PHARMACOTHERAPY MAY BE ABLE TO CLOSE THE TREMENDOUS GAP IN CLINICAL CARE. SODIUM GLUCOSE CO-TRANSPORTER-2 INHIBITORS (SGLT2I) REPRESENT AN ATTRACTIVE AND POTENTIALLY EFFECTIVE TREATMENT OPTION FOR NAFLD WITH SUPPORTIVE DATA IN ADULTS AND ANIMAL MODELS BUT HAS YET TO BE EXAMINED IN PEDIATRICS. IN ADULTS WITH TYPE 2 DIABETES AND OBESITY, SGLT2I MEDICATIONS REDUCE BODY WEIGHT, IMPROVE INSULIN SENSITIVITY, AND DECREASE HEPATIC FAT. UNLIKE ADULTS, THE VAST MAJORITY OF ADOLESCENTS WITH OBESITY AND NAFLD ARE INSULIN RESISTANT BUT HAVE YET TO DEVELOP TYPE 2 DIABETES. THUS, THE PEDIATRIC POPULATION IS IDEAL TO TEST THE FIRST CENTRAL HYPOTHESIS THAT SGLT2I THERAPY DRIVES REDUCTIONS OF HEPATIC FAT IN THE ABSENCE OF DIABETES. SGLT2I PARADOXICALLY INCREASES FASTING ENDOGENOUS GLUCOSE PRODUCTION (EGP), WHICH IS NOT COMMONLY ENCOUNTERED WITH OTHER INSULIN SENSITIZATION MEDICATIONS. THEREFORE, THE SECOND CENTRAL HYPOTHESIS IS THAT SGLT2I AUGMENTS HEPATIC MITOCHONDRIAL FATTY ACID BETA-OXIDATION, PRODUCING THE ACETYL-COA THAT STIMULATES GLUCONEOGENESIS-DERIVED EGP IN A PEDIATRIC, NON- DIABETIC POPULATION. THE COLLABORATIVE TRANSDISCIPLINARY TEAM IS UNIQUELY POSITIONED TO LEVERAGE A RANDOMIZED, CONTROLLED TRIAL TO TEST WHETHER THE SGLT2I EMPAGLIFLOZIN MAY BE A SUCCESSFUL TREATMENT FOR PEDIATRIC NAFLD. A FOCUSED, MECHANISTIC CLINICAL TRIAL WILL BE PERFORMED STUDYING OLDER ADOLESCENTS (AGES 16-≤20 YEARS; N=40) WITH MRI-DETERMINED NAFLD (HEPATIC FAT ≥5.5%) AND OBESITY (BMI ≥30KG/M2) WITHOUT T2D, TO EXAMINE THE RESPONSE TO 10MG, ONCE-DAILY ORAL DOSE OF EMPAGLIFLOZIN FOR 26-WEEKS TO IDENTIFY MECHANISMS OF ACTION AND INITIAL EFFICACY OF THE SGLT2I AGENT EMPAGLIFLOZIN AS A TREATMENT FOR PEDIATRIC NAFLD, THROUGH THE FOLLOWING SPECIFIC AIMS: (1) USE SGLT2I TREATMENT TO QUANTIFY THE DYNAMIC RELATIONSHIP BETWEEN HEPATIC FAT CONTENT AND INSULIN SENSITIVITY IN AN ADOLESCENT POPULATION. GOLD-STANDARD 2-STAGE HYPERINSULINEMIC-EUGLYCEMIC CLAMPS AND MRI-DETERMINED NAFLD WILL BE USED TO DETERMINE WHETHER SGLT2I DRIVEN REDUCTIONS IN HEPATIC FAT ARE ASSOCIATED WITH THE DEGREE OF IMPROVEMENT IN BOTH HEPATIC AND PERIPHERAL INSULIN SENSITIVITY. (2) TO DETERMINE THE MECHANISMS THROUGH WHICH SGLT2 INHIBITION DECREASES HEPATIC FAT CONTENT. NON-INVASIVELY DELIVERED DUAL STABLE ISOTOPE TRACERS AND MAGNETIC RESONANCE SPECTROSCOPY-BASED METHODS WILL BE USED TO QUANTIFY ADIPOSE TISSUE LIPOLYSIS, HEPATIC FAT OXIDATION (BOTH TERMINAL OXIDATION AND KETOGENESIS), AND THE GLUCONEOGENIC AND GLYCOGENOLYTIC COMPONENTS OF EGP, TO DETERMINE WHETHER THE DEGREE OF HEPATIC FAT REDUCTION CORRELATES WITH THE DEGREE TO WHICH SGLT2I DRIVES HEPATIC FAT OXIDATION. THIS STUDY REPRESENTS A NOVEL AND INNOVATIVE INVESTIGATION INTO A PROMISING MEDICAL THERAPY FOR A HIGHLY PREVALENT DISEASE IN THE PEDIATRIC POPULATION, WHICH CURRENTLY HAS LIMITED TREATMENT OPTIONS.

SURGICAL STUDIES OF GUT EPITHELIAL APOPTOSIS-INITIATED CRITICAL ILLNESS

DEVELOPING NOVEL BIOMARKERS OF PLEXIFORM NEUROFIBROMA TUMOR BURDEN - PROJECT SUMMARY/ABSTRACT NEUROFIBROMATOSIS TYPE 1 (NF1) IS A COMMON INHERITED HUMAN DISORDER, WITH A FREQUENCY OF APPROXIMATELY 1:2500 WORLDWIDE. A HALLMARK OF NF1 IS DEVELOPMENT OF PLEXIFORM NEUROFIBROMAS (PNFS) IN 30 TO 50% OF NF1 PATIENTS. CURRENTLY, THERE ARE NO BIOMARKERS OF TUMOR BURDEN AND WHOLE BODY MAGNETIC RESONANCE IMAGING (MRI) IS EXPENSIVE AND LIMITED TO FEW CENTERS. WE ESTABLISHED AN UNBIASED PIPELINE TO IDENTIFY CANDIDATE BIOMARKER SIGNALS OF TUMOR BURDEN USING PLASMA FROM NEUROFIBROMA-BEARING DHHCRE;NF1FL/FL MICE USING UNTARGETED METABOLOMICS. OUR PRELIMINARY DATA SHOW THAT GLUCOSYLCERAMIDE (GC) IS THE MOST SIGNIFICANTLY DEREGULATED COMPOUND IN PLASMA FROM NEUROFIBROMA-BEARING DHHCRE;NF1FL/FL MICE. WE DEVELOPED A NOVEL TARGETED MASS SPECTROMETRY METHOD TO ACCURATELY QUANTIFY MULTIPLE ELEVATED GC AND LACTOSYLCERAMIDE (LC) SPECIES. FURTHER ANALYSIS OF THESE CANDIDATE TUMOR BURDEN BIOMARKER SIGNATURES IN PLASMA FROM NF1 INDIVIDUALS WITH PNFS AND DHHCRE;NF1FL/FL MICE STRATIFIED BY TUMOR VOLUME SHOWED A PRELIMINARY STRONG CORRELATION. IN THIS PROPOSAL, WE WILL COMBINE THE CLINICAL AND RESEARCH INFRASTRUCTURE OF THE NF1 COMPREHENSIVE PROGRAM WITH THE ADVANCE IMAGING AND MASS SPECTROMETRY CAPABILITIES OF CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER. TAKING ADVANTAGE OF OUR LARGE, WELL-CHARACTERIZED, CINCINNATI CHILDREN’S NF1 POPULATION AND THE RASOPATHIES BIOREPOSITORY, WE PROPOSE TO PERFORM ANALYTICAL VALIDATION STUDIES OF CANDIDATE GC/LC BIOMARKER SIGNATURE OF TUMOR BURDEN IN PLASMA FROM NF1 PATIENTS AND NEUROFIBROMA-BEARING MICE WITH DEFINED NUMBERS OF PNF (TUMOR BURDEN) BY WHOLE BODY MRI. THE POTENTIAL OUTCOMES OF OUR STUDY ARE IDENTIFICATION OF CANDIDATE BIOMARKER OF TUMOR BURDEN THAT CONTRIBUTE TO PATIENT RISK STRATIFICATION, AND ANALYTICAL VALIDATION OF GC/LC BIOMARKER SIGNATURE (CONTEXT OF USE). COLLECTIVELY, THIS WORK REPRESENTS A SYNERGISTIC APPROACH FOR DISCOVERY AND VALIDATION OF BIOMARKERS OF TUMOR BURDEN IN NF1.

PRESERVATION OF MUCOSAL BARRIER IN SURGICAL DISEASES

SUPPORTING PURPOSEFUL INTERVENTIONS & RESILIENCE IN TRAUMA (SPIRIT) PROGRAM: IMPLEMENTING TRAUMA-SPECIFIC SCREENING AND STRATIFIED INTERVENTIONS FOR YOUTH WITH A CHRONIC MEDICAL CONDITION - THE SUPPORTING PURPOSEFUL INTERVENTIONS & RESILIENCE IN TRAUMA (SPIRIT) PROGRAM WILL IMPLEMENT TRAUMA-SPECIFIC SCREENING AND STRATIFIED INTERVENTION BY TRIAGING YOUTH WITH CHRONIC MEDICAL CONDITIONS. SPIRIT WILL USE THE PEDIATRIC TRAUMATIC STRESS CARE PROCESS MODEL (CPM) TO ASSESS YOUTH AND FAMILIES FOR TRAUMA-RELATED PSYCHOLOGICAL DISTRESS AND MATCH THEM WITH AN APPROPRIATE INTERVENTION. CARE COORDINATION WILL BE EMBEDDED WITHIN EACH SERVICE. YOUTH ENROLLED WILL BE AGED 8-18 YEARS. IT IS ANTICIPATED THAT YOUTH MOST YOUTH WILL HAVE MEDICAID AS THEIR INSURANCE PAYOR, THE MAJORITY WILL BE FROM RACIALLY MINORITIZED POPULATIONS, AND PRESENTING WITH AN ARRAY OF TRAUMA EXPOSURES BASED ON HISTORICAL DEMOGRAPHICS OF YOUTH SERVED BY SPIRIT PROVIDERS. SPIRIT STAFF WILL WORK DIRECTLY WITH MEDICAL PROVIDERS TO PROVIDE EDUCATION AND TRAINING ON TRAUMA-SPECIFIC SCREENING WITHIN THE CPM FRAMEWORK. EACH INTERVENTION PATHWAY PROVIDES STRATIFIED CARE BASED ON THE NEEDS OF THE YOUTH AND INCLUDE ONLINE MODULES, GROUP PSYCHOTHERAPY, AND INDIVIDUAL/FAMILY THERAPY. SPIRIT PATIENT NAVIGATOR WILL ASSIST ALL FAMILIES WITH CASE COORDINATION AND PATIENT ADVOCACY. SPIRIT WILL SERVE 150 YOUTH AND FAMILIES IN YEAR 1 AND 1,250 YOUTH AND FAMILIES THROUGHOUT THE LIFE OF THE PROJECT. GOAL 1: INCREASE PEDIATRIC HEALTHCARE PROVIDER ABILITY TO IDENTIFY TRAUMA EXPOSURE AND DISTRESS AND LINK WITH APPROPRIATE MATCHED INTERVENTIONS. SPIRIT WILL RECRUIT CLINICS TO PROVIDE TRAUMA SCREENING AND REFERRALS, WILL TAILOR WORKFLOWS SPECIFIC TO CLINIC NEEDS AND POLICIES, AND USE THE CPM TO MATCH TO APPROPRIATE TREATMENT. GOAL 2: DECREASE TRAUMA SYMPTOMS AND IMPAIRMENT VIA EVIDENCE-BASED, TRAUMA-FOCUSED TREATMENT SERVICES. SPIRIT WILL USE PATIENT CARE NAVIGATION TO PROBLEM-SOLVE BARRIERS TO TREATMENT ENGAGEMENT WITH GOAL OF ≥ 75% SESSION ATTENDANCE. 70% OF PARTICIPANTS WILL DEMONSTRATE A CLINICALLY RELIABLE IMPROVEMENT IN FUNCTIONAL IMPAIRMENT AND POSTTRAUMATIC STRESS SYMPTOM SEVERITY AT PROGRAM DISCHARGE. GOAL 3: ELICIT STAKEHOLDER FEEDBACK ON STRATIFIED INTERVENTION PROCESSES AND INCORPORATE FEEDBACK. SPIRIT STAFF WILL COMPLETE INDEPENDENT FOCUS GROUPS TO ADAPT INTERVENTIONS. AN ADVISORY BOARD WITH PATIENT, PARENT, AND MEDICAL PROVIDERS WILL MEET QUARTERLY AND CONSULT ON PROJECT IMPLEMENTATION. ALL INTERVENTION MATERIALS WILL BE TAILORED FOR YOUTH LIVING WITH A CHRONIC MEDICAL CONDITION. GOAL 4: DELIVER TRAINING RELATED TO THE INTERSECTION OF TRAUMA EXPOSURE AND CHRONIC MEDICAL CONDITIONS ON YOUTH DEVELOPMENT AND FUNCTIONING. SPIRIT STAFF WILL IMPLEMENT PROFESSIONAL EDUCATION ON TRAUMA EXPOSURE AND CHRONIC MEDICAL CONDITIONS. SPIRIT WILL DEVELOP A BRIEF WEB-BASED CURRICULUM FOR MEDICAL PROVIDERS, ON-DEMAND TRAINING FOR SCHOOL NURSES, AND PROVIDE LIVE TRAININGS WITHIN THE HOSPITAL AND WITHIN THE COMMUNITY AS REQUESTED. GOAL 5: USE PROGRAMMATIC OUTCOME EVALUATION TO JUSTIFY INSTITUTIONAL AND STATE SUPPORT FOR EXPANDING THE DEVELOPED SCREENING AND STRATIFIED INTERVENTION MODEL. SPIRIT STAFF WILL ANALYZE OUTCOME DATA, PROVIDE STATISTICS ON PROGRAM IMPACT ON TRAUMA SYMPTOMS AND IMPAIRMENT, MEASURE PROGRAM ACCEPTABILITY AND SATISFACTION, AND PRESENT RESULTS AT STATE AND NATIONAL FORUMS AND CONFERENCES.

DISEASE CHRONICITY IN JUVENILE DERMATOMYOSITIS (JDM): EPIGENETIC CLUES

EPIGENETIC EFFECT OF THE MICROENVIRONMENT ON STEM CELL PLASTICITY AND FUNCTION

REVERSE ENGINEERING THE EXTRACELLULAR NEIGHBORHOOD TO SUPPORT THE FUNCTIONAL TISSUE UNIT: A USE CASE TO RESTORE OVARIAN FUNCTION - PROJECT SUMMARY/ABSTRACT STATIC HUMAN BIOMOLECULAR ATLASES MISS DIMENSIONALITY THAT IS CRITICAL FOR ESTABLISHING THE HEALTHY CONDITION. WE ARE UNIQUELY POSITIONED WITH RARE RESOURCES AND EXPERTISE TO FILL IN THESE DIMENSIONS AND ENHANCE THE HEALTHY HUMAN OVARY HUBMAP DATA. HERE, WE WILL CONTRIBUTE THE DEVELOPMENTAL DIMENSION BY DEFINING THE CHANGE IN INTERSTITIAL CELLS ACROSS THE PUBERTAL TRANSITION; WE WILL CREATE THE SPATIAL DIMENSION BY PROBING THE BIOCHEMICAL AND PHYSICAL CUES OF THE EXTRACELLULAR MATRIX (ECM) ACROSS ANATOMICAL COMPARTMENTS AND FUNCTIONAL CELL UNIT NEIGHBORHOODS, AND WE WILL CREATE THE TEMPORAL DIMENSION BY INVESTIGATING THE CHANGES IN FUNCTIONAL CELL UNITS DURING OOPLASM MATURATION AND HORMONE PRODUCTION. WITHOUT THESE ADDED DIMENSIONS, THE HUBMAP DATASETS ARE LESS EFFECTIVE IN IDENTIFYING AND UNDERSTANDING DISEASE MODALITIES. OUR LONG-TERM GOAL IS TO INCREASE THE UTILITY OF THE OVARY ATLAS USING EXISTING AND NEW DATASETS TO INFORM REGENERATIVE MEDICINE TECHNOLOGIES THAT IMPROVE THE SAFETY, EFFICACY AND LONGEVITY OF FERTILITY AND HORMONE RESTORATION OPTIONS FOR PATIENTS WITH PREMATURE OVARIAN INSUFFICIENCY (POI), A DISEASE THAT OCCURS IN APPROXIMATELY 1% OF WOMEN IN THE USA. INDIVIDUALS WITH POI HAVE A REDUCED QUALITY OF LIFE AND LIFE EXPECTANCY OF ~ 2 YEARS SHORTER FROM COMORBIDITIES THAT INCLUDE COGNITIVE AND CARDIOVASCULAR DISEASES. WE WILL INCORPORATE DATA FROM THE UNIVERSITY OF PENNSYLVANIA (UPENN) HUBMAP TISSUE MAPPING CENTER (TMC) AND THE UNIVERSITY OF MICHIGAN (UM) CHAN ZUCKERBERG INITIATIVE HUMAN CELL ATLAS (HCA) MULTIOME MAPS OF HEALTHY ADULT OVARIES. THE VANDERBILT UNIVERSITY BIOMOLECULAR MULTIMODAL IMAGING CENTER (BIOMIC) DEVELOPED IMAGING AND BIOCOMPUTATIONAL ANALYSIS PIPELINES THAT ENABLE 3D MULTIMODEL RECONSTRUCTION AND MOLECULAR PROFILING. ADDITIONALLY, WE HAVE GENERATED ECM AND ASSOCIATED PROTEIN MAPS ON MODEL AND HUMAN OVARIES, IN COLLABORATION WITH THE NORTHWESTERN UNIVERSITY (NU) HUBMAP RAPID TECHNOLOGY IMPLEMENTATION (RTI) CENTER. FINALLY, WE HAVE DEVELOPED ENGINEERING TOOLS, SUCH AS SCAFFOLDS THAT SUPPORT OVARIAN FOLLICLES AND PROTOCOLS TO MAKE OVARIAN HORMONE-PRODUCING CELLS FROM HUMAN INDUCED PLURIPOTENT STEM CELLS (IPSCS). THESE RESOURCES AND COLLABORATIONS WILL PROVIDE VALUABLE TISSUE AND FUNCTIONAL UNIT INSIGHTS AND, COMBINED WITH OUR EXPERTISE IN TISSUE ENGINEERING, WILL ENABLE US TO REVERSE ENGINEER THE EXTRACELLULAR NEIGHBORHOOD THAT SUPPORTS OVARIAN FOLLICLE GROWTH TO IMPROVE FERTILITY AND HORMONE RESTORATION OPTIONS. WE WILL (1) ADD DEVELOPMENTAL AND SPATIAL DIMENSIONS TO THE HUMAN OVARY ATLAS TO IDENTIFY CHANGES IN THE NEIGHBORHOOD THAT IMPACT FOLLICULOGENESIS, (2) DEMONSTRATE THE UTILITY OF THE HUBMAP DATA AND TOOLS TO ADDRESS IMPORTANT BIOLOGICAL QUESTIONS WITHIN THE OVARY AND REVERSE ENGINEER A NEIGHBORHOOD THAT SUPPORTS FOLLICLE GROWTH, AND (3) REVERSE ENGINEER A PERSONALIZED OVARIAN HORMONE-REPLACEMENT THERAPY FROM HUMAN IPSCS BY DEFINING AND VALIDATING THE RESPONSE OF CELLS TO ECM ENVIRONMENTS. BY ACHIEVING THESE MILESTONES, WE WILL ADD TO THE FUNCTIONALITY OF THE HUBMAP OVARY ATLAS, DEMONSTRATE THE UTILITY OF THESE DATASETS, AND DEVELOP PIPELINES AND TECHNOLOGIES FOR FUTURE REGENERATIVE TECHNOLOGIES THAT MAY BE DEVELOPED FROM OTHER HUBMAP TISSUE ATLASES.

MICRORNAS AND PERINATAL HYPOXIA-ISCHEMIA

THE ROLE OF BASAL BODIES IN WNT SIGNALING

REGULATION OF MITOCHONDRIAL FUNCTION AND MOTOR NEURON DEGENERATION IN SMA

ENDOTHELIAL TRANSDIFFERENTIATION OF INVASIVE TUMOR CELLS

ANTIFIBROTIC ACTIONS OF SARA

DEFINING THE MICROENVIRONMENT THAT WILL ENABLE A LONG-TERM BIOPROSTHETIC OVARY TRANSPLANT - PROJECT SUMMARY/ABSTRACT THE OVARIES CONTAIN A FINITE RESOURCE OF POTENTIAL EGGS AND SEX HORMONE-PRODUCING CELLS, AND THEREFORE, LIFE- SAVING CANCER TREATMENTS THAT IRRADIATE OR CHEMICALLY INDUCE CELL DEATH WITHIN THE OVARIES WILL LIKELY RESULT IN PREMATURE OVARIAN INSUFFICIENCY (POI) WITH REDUCED OVARIAN HORMONES AND INFERTILITY. THE OPTION TO HAVE BIOLOGICAL CHILDREN, IS A KEY QUALITY OF LIFE MEASURE FOR CANCER SURVIVORS. WOMEN WITH POI WILL EXPERIENCE CO-MORBIDITIES ASSOCIATED WITH LOSS OF OVARIAN HORMONES AND A SHORTER LIFE EXPECTANCY. THE ONLY METHOD FOR FERTILITY PRESERVATION FOR PEDIATRIC PATIENTS, WHO DO NOT YET MAKE EGGS, IS OVARIAN TISSUE CRYOPRESERVATION (OTC). THIS TISSUE CAN THEN BE TRANSPLANTED BACK TO RESTORE FERTILITY AND HORMONE FUNCTION. HOWEVER, ONLY 20 – 30% OF TRANSPLANTS RESULT IN LIVEBIRTH AND IT PRODUCES AN AVERAGE OF 2 – 5 YEARS OF HORMONE RESTORATION, LEAVING MANY WITHOUT BIOLOGICAL CHILDREN AND DECADES OF POST-CANCER SURVIVAL WITHOUT ESSENTIAL HORMONE PRODUCTION. ONE MAJOR CONTRIBUTOR TO THE SHORTENED FUNCTION OF TRANSPLANTED OVARIAN TISSUE IS THE SIGNIFICANT SPIKE IN ACTIVATION OF THE OVARIAN RESERVE (PRIMORDIAL FOLLICLES) AND SUBSEQUENT DEPLETION, AT LEAST IN PART, DUE TO THE DISRUPTION IN THE MICROENVIRONMENT. ADDITIONALLY, SOME PATIENTS HAVE METASTATIC DISEASE WITHIN THE OVARY AND THEREFORE CANNOT USE THAT TISSUE IN ITS CURRENT FORM. THEREFORE, A SAFE, LONG-TERM SOLUTION FOR FERTILITY AND HORMONE RESTORATION WOULD INVOLVE ISOLATING THE OVARIAN CELLS THAT ARE ESSENTIAL FOR FUNCTION FROM POTENTIAL CANCER CELLS AND HOUSING THEM IN A MICROENVIRONMENT THAT MAINTAINS THE BANK OF POTENTIAL EGGS AND PROLONGS HORMONE PRODUCTION. WE HAVE PREVIOUSLY DEVELOPED AN ENGINEERED 3D PRINTED SCAFFOLD THAT RESTORED FERTILITY AND HORMONE FUNCTION IN MICE. WE WILL TEST THE HYPOTHESIS THAT THE MATRISOME IMPOSES BIOCHEMICAL AND PHYSICAL CUES THAT CONTROLS PRIMORDIAL FOLLICLE ACTIVATION. ADDITIONALLY, WE PREDICT THAT THE CONTRIBUTION OF STROMAL CELLS IS NECESSARY FOR FULL FOLLICULOGENESIS. WE WILL USE COW OVARIES AS MONO-OVULATORY MODELS OF HUMAN OVARIES. IN AIM 1, WE WILL INVESTIGATE THE BIOCHEMICAL CUES OF THE MATRISOME AND HOW THEY REGULATE PRIMORDIAL FOLLICLE ACTIVATION, BY DEFINING THE MATRISOME PROTEINS THAT EXIST IN THE OVARY AND MODULATING CANDIDATE PROTEINS THAT MAY BE KEY TO CONTROLLING PRIMORDIAL FOLLICLE ACTIVATION THROUGH EXTRACELLULAR INHIBITION OR INDUCTION OF INTRACELLULAR PATHWAYS. IN AIM 2, WE WILL INVESTIGATE THE PHYSICAL PROPERTIES OF THE OVARY AND HOW THEY CONTROL PRIMORDIAL FOLLICLE QUIESCENCE, BY DEFINING THE NATIVE STIFFNESS OF THE OVARIAN MICROENVIRONMENT AND MONITORING HOW PRIMORDIAL FOLLICLES RESPONSE TO DIFFERENT PHYSICAL PROPERTIES IN CULTURE. IN AIM 3, WE WILL INVESTIGATE THE ROLE OF STROMAL CELLS IN FOLLICULOGENESIS SUPPORTED BY A TRANSPLANTABLE SCAFFOLD. WE WILL DEFINE THE MATRISOME PROTEINS AND PARACRINE FACTORS THAT ARE SECRETED BY STROMAL CELLS AND INVESTIGATE HOW THEY CONTRIBUTE TO FOLLICULOGENESIS WITHIN A 3D PRINTED BIOPROSTHETIC SCAFFOLD IN A TRANSPLANT MODEL. THE AIMS IN THIS APPLICATION WILL BUILD ON OUR PREVIOUS SUCCESSES AND A BIOPROSTHETIC OVARY, DEFINED BY THE RESULTS HERE, WOULD IMPROVE CURRENT OPTIONS FOR FERTILITY AND HORMONE RESTORATION FOR WOMEN.

REFINEMENT AND VALIDATION OF A SYMPTOM REPORT-BASED FOOD ALLERGY PREVALENCE QUESTIONNAIRE FOR POPULATION-BASED STUDIES - PROJECT SUMMARY/ABSTRACT: WHILE THERE IS GENERAL AGREEMENT THAT IGE-MEDIATED FOOD ALLERGY PREVALENCE HAS INCREASED IN RECENT DECADES, THE ESTIMATION OF ITS POPULATION-LEVEL BURDEN IS COMPLICATED BY INCREASED AWARENESS OF A VARIETY OF FOOD-INDUCED CONDITIONS (E.G., INTOLERANCES, POLLEN-FOOD ALLERGY SYNDROME, CELIAC DISEASE). UNLIKE OTHER SURVEY INSTRUMENTS THAT EVALUATE CHRONIC DISEASES LIKE ASTHMA, SYMPTOM-REPORT- ALGORITHM BASED SURVEY INSTRUMENTS OFTEN UTILIZED FOR FOOD ALLERGY PREVALENCE ESTIMATION REMAIN UNVALIDATED AMONG THE GENERAL US PEDIATRIC AND ADULT POPULATIONS. BY VALIDATING THESE ALGORITHMS VIA GOLD-STANDARD CLINICAL DIAGNOSTIC METHODS, THE ABILITY TO CONDUCT ROUTINE DISEASE SURVEILLANCE, ADVANCE TREATMENTS, UNDERSTAND CLINICAL MANAGEMENT, AND EVALUATE EMERGING ALLERGY PREVENTION INTERVENTIONS, WILL EACH BE GREATLY ENHANCED. FIRST (AIM 1), WE WILL ASSEMBLE AN EXPERT DELPHI PANEL TO DEVELOP A BANK OF FA SURVEY QUESTIONS THAT ASSESS KEY FEATURES BELIEVED TO MOST ACCURATELY, RELIABLY PREDICT TRUE, IGE-MEDIATED FOOD ALLERGY AND CAPTURE KEY DIFFERENTIAL DIAGNOSES FOR SPECIFIC ALLERGIES (E.G. LACTOSE INTOLERANCE FOR MILK ALLERGY). THIS BANK WILL BUILD UPON OUR ESTABLISHED, PREVIOUSLY ADMINISTERED NATIONAL FOOD ALLERGY PREVALENCE QUESTIONNAIRE. NEXT (AIM 2), A COMPREHENSIVE CLINICAL VALIDATION STUDY OF THIS SURVEY INSTRUMENT WILL BE CONDUCTED BY SAMPLING PARTICIPANTS FROM THE GENERAL US POPULATION RESIDING WITHIN THE US CENSUS DESIGNATED COMBINED STATISTICAL AREAS CONTAINING HOUSTON, NEW YORK CITY, AND CHICAGO. SURVEYS WILL BE COMPLETED BY 6000 HOUSEHOLDS (OBTAINING SURVEY RESPONSES FOR ROUGHLY 10,000 INDIVIDUALS). 720 INDIVIDUALS REPORTING ≥1 CURRENT FOOD ALLERGY AND 40 WITH NO REPORTED FA WILL BE EVALUATED FOR REPORTED “TOP 9” FOOD ALLERGIES INCLUDING ALLERGENS THAT MEET AND DO NOT MEET THE REFINED ALGORITHMIC “CONVINCING” CRITERIA. A STANDARDIZED DIAGNOSTIC APPROACH ADAPTED FROM THE NIAID-SUPPORTED CONSORTIUM FOR FOOD ALLERGY RESEARCH WILL BE USED. FINALLY (AIM 3) WE WILL ANALYZE THE SURVEY AND CLINICAL DATA COLLECTED IN AIM 2 TO PROVIDE CLINICALLY- CONFIRMED ESTIMATES OF PEANUT, MILK, EGG, TREE NUT, SHELLFISH, FIN FISH, WHEAT, SOY, & SESAME ALLERGY PREVALENCE. WE WILL ALSO FINALIZE OUR FOOD ALLERGY PREVALENCE QUESTIONNAIRE, ALONG WITH A NEWLY DEVELOPED “SHORT-FORM” OF THE PREVALENCE QUESTIONNAIRE USING ONLY THE MOST STRONGLY PREDICTIVE QUESTIONS. BY CARRYING OUT THE PROPOSED RESEARCH, WE WILL: 1) ENHANCE UNDERSTANDING OF WIDELY-CITED FOOD ALLERGY PREVALENCE ESTIMATES PREVIOUSLY PUBLISHED BY OUR GROUP AND CURRENTLY USED TO GUIDE POLICY AND PUBLIC HEALTH DECISION-MAKING; 2) VALIDATE AND OPTIMIZE FULL AND SHORT-FORM FOOD ALLERGY PREVALENCE QUESTIONNAIRES, ESTABLISHING THEIR DIAGNOSTIC PROPERTIES IN DIVERSE POPULATION-BASED SAMPLES; AND 3) ESTIMATE THE CURRENT BURDEN OF FOOD ALLERGY AND RELATED CONDITIONS AMONG THE GENERAL US PEDIATRIC AND ADULT POPULATIONS IN THREE MAJOR US REGIONS (WITH ≈40 MILLION INHABITANTS FROM 8 STATES), WHICH WILL BE APPLIED TO BETTER UNDERSTAND LONG- TERM TRENDS IN US ALLERGIC DISEASE BURDEN AND FORM THE FOUNDATION OF FUTURE FOOD ALLERGY SURVEILLANCE EFFORTS.

CELL-SPECIFIC ROLE OF NF-KB IN NECROTIZING ENTEROCOLITIS

THE MICROBIOTA OF THE PEDIATRIC CF AIRWAY: WHAT ROLE DOES IT PLAY?

OPTICAL GENOME MAPPING AS A NOVEL DIAGNOSTIC APPROACH IN PEDIATRIC BRAIN TUMORS - ABSTRACT ONE OF THE GREATEST ADVANCES IN PEDIATRIC BRAIN TUMOR MANAGEMENT HAS BEEN THE INCORPORATION OF TUMOR MOLECULAR FINDINGS IN THE DIAGNOSIS, PROGNOSTIC STRATIFICATION, AND TREATMENT OF PATIENTS. BECAUSE OF THIS, TREATMENT OPTIONS AND OUTCOMES FOR PATIENTS WITH SPECIFIC ALTERATIONS, INCLUDING STRUCTURAL VARIANTS (SVS) RESULTING IN FUSIONS, HAVE GREATLY IMPROVED. HOWEVER, DESPITE MULTIPLE RESEARCH STUDIES THAT SHOW SVS ARE IMPORTANT FOR TUMOR DEVELOPMENT, MAINTENANCE, AND PROGRESSION, CLINICAL ANALYSES ARE GENERALLY LIMITED TO TARGETED GENE SEQUENCING PANELS (DNA +/- RNA) AND TARGETED FLUORESCENT IN SITU HYBRIDIZATION (FISH). THIS TYPE OF TESTING IS SUFFICIENT FOR BRAIN TUMORS THAT HARBOR CLASSIC GENOMIC ALTERATIONS, BUT INADEQUATE FOR TUMORS THAT HAVE ATYPICAL HISTOLOGICAL OR MOLECULAR ABERRATIONS, OFTENTIMES RESULTING IN “NEGATIVE” GENOMIC TESTING. IN ADDITION, SOME OF THESE TESTS HAVE A LONG TURNAROUND TIME, LEADING TO DELAYS IN DIAGNOSIS AND TREATMENT. WE ARE IN GREAT NEED FOR A CLINICAL TEST THAT WILL ALLOW FOR MORE ACCURATE AND RAPID DISCOVERY OF CLINICALLY SIGNIFICANT SVS THAT CAN BE USED ALONG WITH SEQUENCING TO CREATE TREATMENT PLANS WITH MAXIMUM BENEFIT. OPTICAL GENOME MAPPING (OGM) IS A PROMISING GENOMIC TECHNOLOGY THAT CAN HELP FILL THIS MOLECULAR DIAGNOSTIC GAP. OUR PRELIMINARY DATA UTILIZING ABOUT 60 PEDIATRIC BRAIN TUMOR SAMPLES DEMONSTRATES THE UTILITY OF OGM TO IDENTIFY PREVIOUSLY KNOWN DIAGNOSTIC SVS (I.E., BRAF-FUSION), CRYPTIC SVS THAT WERE NOT IDENTIFIED BY CLINICAL TESTS, AND NOVEL SVS THAT HAVE NEVER BEEN DESCRIBED IN PEDIATRIC BRAIN TUMORS. ALTHOUGH NOVEL IN THE FIELD OF PEDIATRIC BRAIN TUMORS, OGM IS BEING USED CLINICALLY AS A CLIA/CAP CERTIFIED DIAGNOSTIC TEST FOR FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY (FSHD), A DISORDER THAT PREVIOUSLY REQUIRED SOUTHERN BLOTTING FOR DIAGNOSIS. MORE RECENTLY, THE AUGUSTA UNIVERSITY PATHOLOGY DEPARTMENT SUBMITTED A SUCCESSFUL LABORATORY DEVELOPED TEST APPLICATION FOR OGM AS A DIAGNOSTIC TEST FOR HEMATOLOGIC MALIGNANCIES TO THE AMERICAN MEDICAL ASSOCIATION. WE PROPOSE TO IMPLEMENT OPTICAL GENOME MAPPING (OGM) AS A FIRST LINE DIAGNOSTIC APPROACH FOR PEDIATRIC BRAIN TUMORS IN A CLINICAL SETTING AND UTILIZE OGM TO DISCOVER GENOMIC SVS WITH POTENTIAL CLINICAL RELEVANCE. THIS STUDY WILL BE THE FIRST TO GENERATE PRE-CLINICAL EVIDENCE THAT BRAIN TUMOR-DRIVING GENETIC ALTERATIONS CAN BE RAPIDLY IDENTIFIED USING OGM, WITH THE POTENTIAL TO GUIDE CLINICAL TREATMENT PLANS FOR CHILDREN WITH THESE TUMORS. BY THE END OF THE STUDY PERIOD, OGM WILL BE VALIDATED IN CLIA/CAP CERTIFIED LABORATORIES (CHILDREN’S NATIONAL HOSPITAL PATHOLOGY, BIONANO LABORATORIES, AUGUSTA UNIVERSITY), AND A LABORATORY DEVELOPED TEST APPLICATION SUBMITTED PENDING PROMISING RESULTS. THIS STUDY WILL ALSO UTILIZE OGM FOR THE DISCOVERY OF NOVEL PATHOGENIC SVS IN A LARGE COHORT OF PEDIATRIC BRAIN TUMORS SAMPLES, WHICH MAY BE USED TO IMPROVE DIAGNOSIS, ALLOW FOR BETTER OUTCOME PREDICTION, AND ULTIMATELY ADVANCE THERAPIES FOR AFFECTED CHILDREN WITH BRAIN TUMORS. THE RESULTS OF THIS STUDY WILL HAVE A DIRECT IMPACT ON CLINICAL CARE WITHOUT REQUIRING A CLINICAL TRIAL. ALTHOUGH THIS STUDY WILL PRIMARILY FOCUS ON PEDIATRIC BRAIN TUMORS, OGM CAN ALSO BE APPLIED TO OTHER TUMOR TYPES, EXPANDING THE THERAPEUTIC POSSIBILITIES FOR CHILDREN AND ADULTS DIAGNOSED WITH THESE CANCERS.

DEVELOPING NOVEL BIOMARKERS OF PLEXIFORM NEUROFIBROMA TUMOR BURDEN - PROJECT SUMMARY/ABSTRACT NEUROFIBROMATOSIS TYPE 1 (NF1) IS A COMMON INHERITED HUMAN DISORDER, WITH A FREQUENCY OF APPROXIMATELY 1:2500 WORLDWIDE. A HALLMARK OF NF1 IS DEVELOPMENT OF PLEXIFORM NEUROFIBROMAS (PNFS) IN 30 TO 50% OF NF1 PATIENTS. CURRENTLY, THERE ARE NO BIOMARKERS OF TUMOR BURDEN AND WHOLE BODY MAGNETIC RESONANCE IMAGING (MRI) IS EXPENSIVE AND LIMITED TO FEW CENTERS. WE ESTABLISHED AN UNBIASED PIPELINE TO IDENTIFY CANDIDATE BIOMARKER SIGNALS OF TUMOR BURDEN USING PLASMA FROM NEUROFIBROMA-BEARING DHHCRE;NF1FL/FL MICE USING UNTARGETED METABOLOMICS. OUR PRELIMINARY DATA SHOW THAT GLUCOSYLCERAMIDE (GC) IS THE MOST SIGNIFICANTLY DEREGULATED COMPOUND IN PLASMA FROM NEUROFIBROMA-BEARING DHHCRE;NF1FL/FL MICE. WE DEVELOPED A NOVEL TARGETED MASS SPECTROMETRY METHOD TO ACCURATELY QUANTIFY MULTIPLE ELEVATED GC AND LACTOSYLCERAMIDE (LC) SPECIES. FURTHER ANALYSIS OF THESE CANDIDATE TUMOR BURDEN BIOMARKER SIGNATURES IN PLASMA FROM NF1 INDIVIDUALS WITH PNFS AND DHHCRE;NF1FL/FL MICE STRATIFIED BY TUMOR VOLUME SHOWED A PRELIMINARY STRONG CORRELATION. IN THIS PROPOSAL, WE WILL COMBINE THE CLINICAL AND RESEARCH INFRASTRUCTURE OF THE NF1 COMPREHENSIVE PROGRAM WITH THE ADVANCE IMAGING AND MASS SPECTROMETRY CAPABILITIES OF CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER. TAKING ADVANTAGE OF OUR LARGE, WELL-CHARACTERIZED, CINCINNATI CHILDREN’S NF1 POPULATION AND THE RASOPATHIES BIOREPOSITORY, WE PROPOSE TO PERFORM ANALYTICAL VALIDATION STUDIES OF CANDIDATE GC/LC BIOMARKER SIGNATURE OF TUMOR BURDEN IN PLASMA FROM NF1 PATIENTS AND NEUROFIBROMA-BEARING MICE WITH DEFINED NUMBERS OF PNF (TUMOR BURDEN) BY WHOLE BODY MRI. THE POTENTIAL OUTCOMES OF OUR STUDY ARE IDENTIFICATION OF CANDIDATE BIOMARKER OF TUMOR BURDEN THAT CONTRIBUTE TO PATIENT RISK STRATIFICATION, AND ANALYTICAL VALIDATION OF GC/LC BIOMARKER SIGNATURE (CONTEXT OF USE). COLLECTIVELY, THIS WORK REPRESENTS A SYNERGISTIC APPROACH FOR DISCOVERY AND VALIDATION OF BIOMARKERS OF TUMOR BURDEN IN NF1.

REGULATION OF MITOCHONDRIAL DNA HOMEOSTASIS AND NEUROINFLAMMATION BY FASCIN IN ALZHEIMER’S DISEASE - PROJECT SUMMARY/ABSTRACT ALZHEIMER’S DISEASE (AD), THE MOST COMMON NEURODEGENERATIVE DISORDER, AFFECTS ONE IN TEN PEOPLE AGE 65 AND OLDER. DUE TO LIMITED UNDERSTANDING OF MECHANISMS UNDERLYING AD PATHOGENESIS, THERE IS NO EFFECTIVE TREATMENT FOR THIS DEVASTATING DISEASE. THE GOAL OF THIS APPLICATION IS TO INVESTIGATE AN UNEXPECTED ROLE FOR ACTIN BUNDLING PROTEIN FASCIN IN REGULATING MITOCHONDRIAL NUCLEOID DNA (MTDNA) HOMEOSTASIS, OXIDATIVE PHOSPHORYLATION (OXPHOS), MITOCHONDRIAL OXIDATIVE STRESS, NEUROINFLAMMATION, AND NEURODEGENERATION, AS WELL AS HOW DYSREGULATION OF THESE PROCESSES CONTRIBUTES TO AD PATHOGENESIS. FASCIN IS AN ACTIN BUNDLING PROTEIN ESSENTIAL FOR THE CROSS-LINKING OF ACTIN FILAMENTS INTO COMPACT AND RIGID BUNDLES. THE CURRENT PARADIGM POSITS THAT FASCIN PROMOTES CELL MIGRATION AND TUMOR INVASION BY GENERATING PROTRUSIVE MEMBRANE STRUCTURES SUCH AS FILOPODIA. WE RECENTLY MADE THE SURPRISING FINDING THAT DEPLETION OF FASCIN DISRUPTS MITOCHONDRIAL F-ACTIN BUNDLING, WHICH IN TURN CAUSES ABNORMAL MITOCHONDRIAL RESPIRATORY COMPLEX BIOGENESIS AND IMPAIRED MITOCHONDRIAL OXPHOS, SUGGESTING A NOVEL ROLE OF FASCIN IN THE REGULATION OF MITOCHONDRIAL FUNCTION. MECHANISTICALLY THE MITOCHONDRIAL DYSFUNCTION IN FASCIN DEPLETED CELLS WAS DUE TO INCREASED MTDNA AGGREGATION AND LEAKAGE. GIVEN THAT MTDNA CAN ROBUSTLY INDUCE INFLAMMASOME ACTIVATION AND INFLAMMATORY CYTOKINE EXPRESSION, FASCIN DEFICIENCY MAY PLAY AN UNEXPECTED ROLE IN CAUSING NEUROINFLAMMATION. IMPORTANTLY, WE FOUND THAT FASCIN IS CLEAVED INTO A 37KDA FUNCTIONALLY DOMINANT-NEGATIVE FORM IN THE BRAINS OF AD PATIENTS AND AD MOUSE MODELS. VIRUS-MEDIATED EXPRESSION OF FASCIN IN AD MOUSE HIPPOCAMPUS MITIGATED DISEASE SYMPTOMS. IN ADDITION, FASCIN KNOCKOUT MICE WE GENERATED SHOWED PROFOUND MITOCHONDRIAL DEFECTS AND SIGNIFICANT LOSS OF NEURONS IN THE BRAIN. BASED ON THESE PRELIMINARY DATA, WE HYPOTHESIZE THAT FASCIN CONTROLS MITOCHONDRIAL FUNCTION AND MTDNA HOMEOSTASIS IN THE BRAIN. FASCIN FUNCTIONAL DEFICIENCY IN AD LEADS TO SIGNIFICANT MITOCHONDRIAL DEFECTS, NEUROINFLAMMATION AND NEURODEGENERATION. TO TEST THE HYPOTHESIS, IN AIM 1 WE WILL DEFINE THE ROLE OF FASCIN IN REGULATING MITOCHONDRIAL FUNCTION, MTDNA HOMEOSTASIS, NEUROINFLAMMATION AND NEURONAL CELL DEATH IN THE MOUSE BRAIN IN VIVO. IN AIM 2 WE WILL INVESTIGATE THE FUNCTIONAL DEFICIENCY OF FASCIN CAUSED BY PROTEOLYTIC CLEAVAGE DURING THE COURSE OF AD PATHOGENESIS USING BRAIN TISSUES FROM AD PATIENTS AND MOUSE MODELS, AND TO ELUCIDATE MECHANISMS UNDERLYING HOW FASCIN FUNCTIONAL DEFICIENCY CAUSES MTDNA LEAKAGE, OXIDATIVE STRESS, NEUROINFLAMMATION, AND DEGENERATION. IN AIM 3 WE WILL STUDY THE EFFECTS OF TRANSGENIC EXPRESSION OF FASCIN ON ALLEVIATING AD PATHOLOGICAL PHENOTYPES AND DISEASE SYMPTOMS IN MICE. SUCCESSFUL COMPLETION OF THE PROPOSED STUDIES WILL REVEAL FASCIN’S NOVEL ROLE IN REGULATING MITOCHONDRIAL FUNCTION, MTDNA HOMEOSTASIS, NEUROINFLAMMATION AND NEURODEGENERATION. INVESTIGATING FASCIN FUNCTIONAL DEFICIENCY IN AD WILL HELP UNDERSTAND DISEASE PATHOGENIC MECHANISMS AND FACILITATE THERAPEUTIC DEVELOPMENT.

A BIOMECHANOCOMPATIBLE SMALL MOLECULE RELEASING SCAFFOLD FOR BLADDER AUGMENTATION - PROJECT SUMMARY/ABSTRACT PATIENTS WITH A PATHOLOGIC BLADDER HAVE CHRONIC MEDICAL PROBLEMS WITH URINARY INCONTINENCE, INFECTIONS, AND POTENTIAL RENAL FAILURE. CONVENTIONAL SURGICAL MANAGEMENT OF THE END-STAGE PATHOLOGIC BLADDER USES DETUBULARIZED BOWEL AS A PATCH (ENTEROCYSTOPLASTY) TO ENLARGE THE BLADDER TO LIMIT INCREASES IN INTRAVESICAL PRESSURE. ALTHOUGH ENTEROCYSTOPLASTY PROVIDES FUNCTIONAL IMPROVEMENT, IT IS ASSOCIATED WITH SIGNIFICANT SHORT- AND LONG-TERM COMPLICATIONS. THUS, ALTERNATIVE METHODS TO ENTEROCYSTOPLASTY HAVE BEEN EXPLORED THROUGH TISSUE ENGINEERING APPROACHES. ONE APPROACH UTILIZED SEEDING AUTOLOGOUS, PATIENT-CULTURED BLADDER CELLS ON SYNTHETIC SCAFFOLDS AS AN AUGMENTATION PATCH. WITH THESE TECHNIQUES, POOR TO MARGINAL RESULTS WERE DESCRIBED BUT REGENERATION OF FULLY FUNCTIONAL NORMAL BLADDER TISSUE WAS NOT ACHIEVED. SEVERAL OBSTACLES CURRENTLY LIMIT THE ADVANCEMENT IN THIS RESEARCH FIELD INCLUDING: 1) A CELL-FREE APPROACH TO DRIVE NATIVE BLADDER TISSUE REGENERATION WITHOUT THE USE OF SUSPECT, EXOGENOUS CELLS; 2) THE LACK OF A TRULY TRANSLATIONAL BLADDER TISSUE REGENERATION ANIMAL MODEL; 3) POOR GRAFT PERIPHERAL NERVE REGENERATION AND VASCULARIZATION; AND 4) PRIMITIVE BIOSCAFFOLD DESIGN. THUS, AN ALTERNATIVE TO THESE BARRIERS ARE DESPERATELY NEEDED TO ADDRESS UNMET CLINICAL NEEDS. BONE MARROW STEM/PROGENITOR CELLS (BMSPCS) REPRESENT A HIGHLY-DEFINED POPULATION OF CELLS AND OUR GROUP HAS SHOWN ITS EFFECTIVENESS IN REGENERATING BLADDER TISSUE. HOWEVER, THERE ARE NUMEROUS OBSTACLES THAT EFFECT THE UTILITY OF THESE CELLS. THESE INCLUDE THE QUALITY, LOW FREQUENCY AND HETEROGENEITY OF STEM CELLS FOUND IN THE BONE MARROW ESPECIALLY IN PATIENTS WITH INCREASING AGE AND THOSE LIKELY TO BE SUFFERING FROM BLADDER DISEASE. AS AN ALTERNATIVE, WE PROPOSE THE USE OF A SMALL MOLECULE THAT CAN DRIVE BLADDER TISSUE REGENERATION IN VIVO AND CAN EITHER PERFORM SIMILARLY TO OR OUT-PERFORM ANALOGOUS BMSPC CELL-SEEDED GRAFTS. THIS WOULD ELIMINATE THE NEED OF EXOGENOUS CELL SOURCES FOR BLADDER TISSUE REGENERATION OR BOWEL FOR BLADDER AUGMENTATION ENTEROCYSTOPLASTY, WHERE APPLICABLE. WE HAVE DEMONSTRATED THAT OUR TEAM CAN REPRODUCIBLY SYNTHESIZE ELASTOMERIC SCAFFOLDS THAT POSSESS ANTI-INFLAMMATORY PROPERTIES AND CAN MIMIC THE MECHANICAL PROPERTIES OF THE BLADDER. LASTLY, WE HAVE ESTABLISHED A UNIQUE NONHUMAN PRIMATE ANIMAL MODEL THAT IS PHYLOGENETICALLY SIMILAR TO HUMANS WITH REGARDS TO BLADDER ANATOMY AND PHYSIOLOGY. THIS PROPOSAL WILL DEMONSTRATE THAT OUR SMALL MOLECULE DIRECTED PLATFORM WILL PROMOTE BLADDER TISSUE REGENERATION THAT IS ANATOMICALLY CORRECT AND PHYSIOLOGICALLY FUNCTIONAL.

GENOME-WIDE ASSOCIATION STUDY OF FOOD ALLERGY

NEONATAL RESEARCH NETWORK: THE LURIE CHILDREN'S - NORTHWESTERN UNIVERSITY STUDY CENTER - PROJECT SUMMARY IMPROVING NEONATAL OUTCOMES AND ADDRESSING OUTCOME DISPARITIES FOR MOTHERS AND THEIR INFANTS REQUIRE NATIONAL CENTERS WITH EXCELLENCE IN CLINICAL CARE AND RESEARCH THAT PARTNER WITH COMMUNITIES TO ADDRESS THESE CHALLENGES EQUITABLY. THE EXISTENCE OF THESE DISPARITIES BASED ON RACE AND ETHNICITY, SPECIFICALLY IN MATERNAL AND INFANT MORTALITY AND PRETERM BIRTH, HIGHLIGHT THE COMPLEX PRENATAL AND POSTNATAL SOCIAL AND BIOLOGICAL FACTORS THAT INFLUENCE PREGNANCY OUTCOMES. THE NICHD NEONATAL RESEARCH NETWORK (NRN), BY CREATING A GEOGRAPHICALLY DIVERSE MULTI-INSTITUTIONAL RESEARCH INFRASTRUCTURE, HAS AN ONGOING COMMITMENT TO IMPROVING HEALTH OUTCOMES AND REDUCING KNOWN DISPARITIES IN INFANTS BORN PRETERM AND IN OTHER HIGH-RISK SITUATIONS. THE LURIE CHILDREN’S - NORTHWESTERN UNIVERSITY STUDY CENTER, COMPRISED OF THE DIVISION OF NEONATOLOGY AT THE ANN & ROBERT H. LURIE CHILDREN’S HOSPITAL OF CHICAGO AND THE DEPARTMENT OF PEDIATRICS AT NORTHWESTERN UNIVERSITY FEINBERG SCHOOL OF MEDICINE, IS ANCHORED BY 12,000 DELIVERIES PER YEAR AND 1700 ADMISSIONS PER YEAR TO OUR 148 NICU BEDS AT LURIE CHILDREN’S HOSPITAL AND PRENTICE WOMEN’S HOSPITAL AND OUR COLLABORATION WITH OUR PARTNERS AT THE NORTHWESTERN MATERNAL-FETAL MEDICINE UNITS (MFMU) STUDY CENTER. WE HAVE A LONG-STANDING TRADITION OF CLINICAL EXCELLENCE, INVESTIGATOR-INITIATED AND MULTI-CENTER INVESTIGATION, A COMMITMENT TO TRAIN THE NEXT GENERATION OF PHYSICIAN SCIENTISTS, AND ADVOCACY TO PROMOTE HEALTH EQUITY. THUS, WE ARE WELL-POSITIONED TO BE A STRONG ADDITION AS A CLINICAL CENTER TO THE NRN. TO ACHIEVE THE GOALS OF THE NRN, THE LURIE CHILDREN’S-NORTHWESTERN STUDY CENTER WILL: 1) CAPITALIZE ON THE EXISTING SYNERGISTIC RELATIONSHIPS WITHIN THE LURIE CHILDREN’S / NORTHWESTERN MEDICAL CENTER AND UNDERSERVED NEIGHBORHOODS OF CHICAGO TO “FACILITATE GREATER INVOLVEMENT OF DIVERSE POPULATIONS” AND PROMOTE RECRUITMENT OF PREGNANT WOMEN AND THEIR NEWBORNS FOR STUDY PROTOCOLS AND FACILITATE THEIR RETENTION THROUGH THE FOLLOW-UP PERIOD; 2) PROPOSE AND PARTICIPATE IN NOVEL CLINICAL STUDIES AND ANALYSES THAT CAPITALIZE ON UNIQUE RESOURCES AT THE LURIE CHILDREN’S-NORTHWESTERN SITE; 3) UTILIZE OUR SITE’S EFFECTIVE ORGANIZATIONAL STRUCTURE AND MANAGEMENT APPROACH TO SUPPORT THE OBJECTIVES OF THE NRN; 4) ESTABLISH AND IMPLEMENT HIGH-QUALITY DATA AND BIOSPECIMEN COLLECTION PROCESSES THAT MEET THE REQUIREMENTS AND STANDARDS OF THE NRN BASED ON OUR CURRENT SUCCESS WITH THESE PROCESSES; AND 5) CONTRIBUTE TO THE SCIENTIFIC COLLABORATION AMONG THE NICHD, THE NRN AND MFMU CLINICAL CENTERS, AND THE DATA COORDINATING CENTER TO SUPPORT THE RESEARCH NETWORKS’ OBJECTIVES.

ADAPTATION OF AN INHALED SUBSTANCE USE INTERVENTION FOR ADOLESCENT AND YOUNG ADULT CANCER SURVIVORS

THE ROLE OF LMP4 IN THE REGULATION OF THE CARDIAC TRANSCRIPTION FACTOR TBX5

ASSESSING THE BURDEN OF DIABETES BY TYPE IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS (DICAYA) - 2020

ASSESSING THE BURDEN OF DIABETES BY TYPE IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS (DICAYA) - 2020

MEASURING AND MAPPING NATIONAL PEDIATRIC ACUTE CARE OUTCOMES - PROJECT SUMMARY/ABSTRACT ACROSS 25 MILLION EMERGENCY DEPARTMENT (ED) VISITS ANNUALLY, CHILDREN EXPERIENCE WIDELY VARIABLE CARE DUE TO MAJOR DIFFERENCES IN READINESS AND CAPABILITIES BETWEEN EDS. THESE DIFFERENCES BEAR ON THE LIKELIHOOD THAT A PATIENT WILL RECEIVE AN ACCURATE DIAGNOSIS AND TIMELY, HIGH-QUALITY TREATMENT. MEASURING OUTCOMES ACROSS THE ENTIRE NATIONAL PEDIATRIC ACUTE CARE SYSTEM HAS PROVED DIFFICULT BECAUSE GRANULAR, NATIONAL, GEOCODED HEALTHCARE DATA HAVE BEEN UNAVAILABLE; INVESTIGATORS HAVE FOCUSED ON INDIVIDUAL DISEASES; REGIONAL HEALTHCARE MAPS ARE OUTDATED; CHALLENGES ABOUND WITH RISK ADJUSTMENT FOR INDIVIDUALS’ PERSONAL RISK; AND BECAUSE EACH DISEASE REQUIRES A DIFFERENT APPROACH TO MEASURE ITS OUTCOMES. FURTHER COMPLICATING EFFORTS IS THE COMPLEX NETWORK OF RELATIONSHIPS BETWEEN HOSPITALS IN WHICH MULTIPLE FACILITIES SHARE RESPONSIBILITY FOR OUTCOMES. THESE RELATIONSHIPS ARE SUBSTANTIALLY DIFFERENT BETWEEN ADULT AND CHILD PATIENTS, AND THERE IS NO WORKING UNDERSTANDING OF THE STRUCTURE OF THE NATIONAL PEDIATRIC NETWORK. THIS PROPOSAL WILL OVERCOME THOSE CHALLENGES TO CREATE THE ATLAS OF PEDIATRIC ACUTE CARE, A COMPREHENSIVE EXAMINATION OF THE ACUTE CARE OUTCOMES OF 37.7 MILLION CHILDREN ACROSS THE NATION, WHICH REPRESENTS HALF OF THE US CHILD POPULATION. THE ATLAS WILL MAP REGIONAL HOSPITAL SYSTEMS USING SOPHISTICATED NETWORK ANALYSIS ALGORITHMS KNOWN AS COMMUNITY DETECTION. THE MAP THAT RESULTS WILL DEFINE REGIONS OF PEDIATRIC CARE IN WHICH THERE IS A SHARED RESPONSIBILITY FOR CARE. IT WILL BE USED TO DETERMINE REGIONAL OUTCOMES ACROSS THREE SERIOUS CONDITIONS IN CHILDREN: APPENDICITIS (THE MOST COMMON SURGICAL CONDITION IN CHILDREN), NEUROTRAUMA (THE MOST COMMON CAUSE OF SERIOUS INJURY), AND SEPSIS (A NOTORIOUSLY DIFFICULT-TO-DIAGNOSE CONDITION THAT IS ONE OF THE COSTLIEST). THIS KNOWLEDGE WILL THEN PROVIDE THE BASIS TO COMPARE REGIONAL SYSTEMS TO ELUCIDATE THE FACTORS ASSOCIATED WITH HIGH PERFORMANCE. WE WILL ALSO USE THE HIGHEST-QUALITY METHODS TO UNDERSTAND COSTS, USING ACTUAL PATIENT AND PAYER EXPENDITURES, ACROSS US PEDIATRIC REGIONS. THIS PROPOSAL REFLECTS THE PRIORITIES OF THE EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT: TO USE “LARGE-SCALE DATASETS TO OPTIMIZE OUTCOMES FOR TRAUMATIZED, INJURED, AND CRITICALLY ILL CHILDREN” AND TO “EXAMINE THE EPIDEMIOLOGY AND TREATMENT OF ALL FORMS OF CRITICAL ILLNESS.” FOCUSING EFFORTS TO IMPROVE OUTCOMES NATIONALLY HAS THE POTENTIAL TO IMPROVE THE POPULATION HEALTH, BUT DEPENDS ON AN ACCURATE, MULTI-DISEASE UNDERSTANDING OF OUTCOMES. THE ATLAS WILL PROVIDE SUCH AN UNDERSTANDING AND WILL EMERGE AS AN ENDURING RESOURCE TO SUPPORT EFFORTS TO IMPROVE PEDIATRIC ACUTE CARE, WHICH WILL TRANSLATE TO BETTER SURVIVAL AND HIGHER QUALITY OF LIFE FOR THE NATION’S CHILDREN.

THE CONTRIBUTION OF HSV-2 ICP34.5 VARIATION TO NEUROVIRULENCE DURING NEONATAL INFECTION - PROJECT SUMMARY / ABSTRACT HERPES SIMPLEX VIRUS (HSV)-2 INFECTION OF THE NEONATAL BRAIN CAUSES SEVERE MENINGOENCEPHALITIS AND PERMANENT NEUROLOGIC DEFICITS. HOWEVER, INFANTS INFECTED WITH HSV-2 AT THE TIME OF BIRTH FOLLOW DIFFERENT CLINICAL COURSES. SOME INFANTS DEVELOP ONLY EXTERNAL INFECTION OF THE SKIN, EYES, OR MOUTH (SEM DISEASE), WHILE OTHERS DEVELOP INVASIVE INFECTION OF THE CENTRAL NERVOUS SYSTEM RESULTING IN ENCEPHALITIS (CNS DISEASE). THE FACTORS THAT PROMOTE HSV-2 INFECTION OF THE NEONATAL BRAIN ARE NOT WELL UNDERSTOOD. WHILE ADULTS CAN BE PREDISPOSED TO HSV ENCEPHALITIS BY AN INNATE IMMUNE DEFECT, NO SUCH HOST SUSCEPTIBILITY HAS BEEN IDENTIFIED IN NEONATES. RECENT WORK HAS SHOWN THAT VARIATION IN NEUROVIRULENCE POTENTIAL EXISTS BETWEEN CLINICAL HSV-2 STRAINS ISOLATED FROM NEONATES. THESE DATA SUGGEST AN OPPORTUNITY TO USE NATURALLY-OCCURRING VIRAL VARIATION TO ELUCIDATE KEY VIRAL VIRULENCE FACTORS, AND CRITICAL FEATURES OF A SUCCESSFUL HOST IMMUNE DEFENSE, IN THE NEONATAL BRAIN. HOWEVER, THE SPECIFIC VARIATIONS DRIVING CLINICALLY MEANINGFUL DIFFERENCES IN NEUROVIRULENCE AND THE MOLECULAR MECHANISMS RESPONSIBLE REMAIN UNKNOWN. THIS KNOWLEDGE GAP PREVENTS THE DEVELOPMENT OF NEUROPROTECTIVE ANTI-VIRAL THERAPIES. AN UNBIASED ANALYSIS OF HSV-2 WHOLE GENOME SEQUENCES REVEALED VARIATIONS IN THE NEUROVIRULENCE GENE G34.5, WHICH WERE UNIQUE TO ISOLATES PRODUCING THE MOST SEVERE NEUROLOGIC DISEASE IN BOTH HUMAN NEONATES AND MOUSE MODELS OF ENCEPHALITIS. THIS PROPOSAL WILL DETERMINE THE IMPACT OF G34.5 EXPRESSION ON HSV-2 INFECTION OF THE NEONATAL BRAIN. THE CENTRAL HYPOTHESIS IS THAT VIRAL GENOMIC VARIATION IN HSV-2 G34.5 CONTRIBUTES TO NEUROVIRULENCE BY PROMOTING EVASION OF EFFECTIVE INNATE AND ADAPTIVE IMMUNITY. AIM 1 WILL DETERMINE THE EFFECT OF NATURALLY-OCCURRING G34.5 GENOMIC VARIATIONS ON KEY PROTEIN CHARACTERISTICS. THIS AIM WILL UTILIZE INFECTION WITH CLINICAL ISOLATES, AND TRANSFECTION OF ISOLATE-SPECIFIC EXPRESSION PLASMIDS, TO DETERMINE HOW VARIATIONS IN G34.5 ALTER RNA SPLICING AND STABILITY, PROTEIN LOCALIZATION, AND ULTIMATELY HOST PROTEIN BINDING PARTNERS. AIM 2 WILL DETERMINE THE IMPACT OF G34.5 GENOMIC VARIATIONS ON HSV DISEASE WITHIN THE BRAIN. SINGLE-NUCLEUS RNA-SEQUENCING OF MURINE BRAIN AT EARLY TIMEPOINTS FOLLOWING INFECTION WITH CLINICAL OR MUTANT VIRUSES WILL BE USED TO DETERMINE THE RESPONSE OF CNS-RESIDENT CELLS TO NEUROVIRULENT G34.5 VARIATIONS. ADDITIONALLY, WE WILL EVALUATE HOW NEUROVIRULENT G34.5 VARIATIONS ALTER THE INFLUX OF ADAPTIVE IMMUNE CELLS INTO THE BRAIN AT LATE TIMEPOINTS FOLLOWING MURINE INFECTION. SUCCESSFUL COMPLETION OF THESE AIMS WILL HARNESS NATURALLY- OCCURRING VIRAL VARIATION TO DETERMINE THE IMPACT OF HSV-2 G34.5 ON NEUROVIRULENCE, AND IDENTIFY CRITICAL ASPECTS OF THE INNATE AND ADAPTIVE NEUROIMMUNE RESPONSE WHICH DETERMINE THE OUTCOME OF NEUROLOGIC INFECTION, TO INFORM DEVELOPMENT OF NEW NEUROPROTECTIVE THERAPIES THAT DRIVE CLEARANCE OF VIRUS FROM THE BRAIN IN ALL CHILDREN.

PHENOTYPE PREDICTION AND THERAPEUTIC TARGETS IN HIGH-RISK PEDIATRIC SEPSIS-ASSOCIATED MODS - ABSTRACT SEPSIS-ASSOCIATED MULTIPLE ORGAN DYSFUNCTION SYNDROME (MODS) AFFECTS APPROXIMATELY 1 IN EVERY 6 CHILDREN ADMITTED TO A PEDIATRIC INTENSIVE CARE UNIT (PICU) IN THE U.S. AND IS ASSOCIATED WITH ABOUT 1 IN EVERY 3 PICU DEATHS. DESPITE THIS, THE CURRENT MANAGEMENT APPROACH FOR PEDIATRIC SEPSIS AND SEPSIS-ASSOCIATED MODS AND THE USE OF ADJUVANT THERAPIES REMAINS HIGHLY VARIABLE IN THE PICU. THIS IS IN PART DUE TO THE HETEROGENEITY OF SEPSIS AND THE HIGH VARIABILITY IN WHICH IT PRESENTS AND EVOLVES IN CHILDREN. THIS HETEROGENEITY CAN DELAY THE RECOGNITION OF SEPSIS AND THE EARLY IDENTIFICATION OF PATIENTS AT HIGH RISK OF POOR OUTCOMES, AND HAS LIMITED THE DEVELOPMENT OF TARGETED INTERVENTIONS. UNRAVELING THIS HETEROGENEITY AND IDENTIFYING HIGH-RISK SEPSIS PHENOTYPES WITH PROGNOSTIC AND THERAPEUTIC RELEVANCE IS CONSIDERED A MAJOR RESEARCH PRIORITY IN THE PATH TOWARDS PRECISION MEDICINE IN SEPSIS. HOWEVER, FOR PRECISION MEDICINE STRATEGIES TO BE MOST CLINICALLY IMPACTFUL FOR CHILDREN WITH SEPSIS, IT IS CRITICAL THAT THEY ARE IMPLEMENTABLE IN REAL-TIME, GENERALIZABLE TO MORE SETTINGS, AND COST-EFFECTIVE. THIS WOULD ENABLE TIMELY ENROLLMENT IN ENRICHED RANDOMIZED CONTROLLED TRIALS AND INITIATION OF TARGETED INTERVENTIONS WITH POTENTIAL FOR HIGHER PUBLIC HEALTH IMPACT. WE PREVIOUSLY IDENTIFIED AND CHARACTERIZED THE PERSISTENT HYPOXEMIA AND SHOCK PHENOTYPE IN CRITICALLY ILL CHILDREN WITH SEPSIS-ASSOCIATED MODS USING A DATA-DRIVEN APPROACH. THIS PHENOTYPE WAS PRESENT IN ALMOST A THIRD OF CHILDREN WITH SEPSIS-ASSOCIATED MODS, HAD FEATURES OF SYSTEMIC INFLAMMATION AND ENDOTHELIAL ACTIVATION, WAS HIGHLY REPRODUCIBLE, AND WAS INDEPENDENTLY ASSOCIATED WITH MORTALITY, ACCOUNTING FOR MORE THAN TWO-THIRDS OF ALL DEATHS IN THIS POPULATION. FURTHERMORE, IN A CAUSAL INFERENCE ANALYSES, PATIENTS WITH PERSISTENT HYPOXEMIA AND SHOCK WERE ASSOCIATED WITH A HIGHER LIKELIHOOD TO BENEFIT FROM INTRAVENOUS HYDROCORTISONE AND ALBUMIN WHEN COMPARED TO OTHER PATIENTS. IMPORTANTLY, PHENOTYPES WITH SIMILAR CHARACTERISTICS IN TERMS OF HYPOXEMIA, SHOCK, INFLAMMATION, AND ENDOTHELIAL ACTIVATION HAS BEEN IDENTIFIED IN PRIOR STUDIES OF SEPSIS AND ACUTE RESPIRATORY DISTRESS SYNDROME IN CHILDREN AND ADULTS. HOWEVER, THE PERSISTENT HYPOXEMIA AND SHOCK PHENOTYPE CURRENTLY REQUIRES LONGITUDINAL DATA FOR UP TO 72 HOURS TO BE CLASSIFIED, SO THERE IS A NEED TO DETERMINE WHETHER IT CAN BE PREDICTED EARLY IN THE COURSE USING ROUTINELY COLLECTED CLINICAL DATA. FURTHERMORE, AMONGST PATIENTS WHO ACHIEVE A HIGH PROBABILITY OF HAVING THE PHENOTYPE, THERE IS A NEED TO DETERMINE WHICH COMMON ADJUVANT THERAPIES ARE ASSOCIATED WITH HETEROGENEITY OF TREATMENT EFFECT (HTE) IN ORDER TO INFORM FUTURE CLINICAL TRIALS. IN THIS STUDY WE AIM TO: (1) DERIVE AND EXTERNALLY VALIDATE A PREDICTION MODEL OF PERSISTENT HYPOXEMIA AND SHOCK IN CHILDREN ADMITTED TO THE PICU WITH CONFIRMED OR SUSPECTED INFECTION; (2) DETERMINE WHICH COMMON ADJUVANT THERAPIES AND THERAPEUTIC GOALS ARE ASSOCIATED WITH HTE AMONGST CHILDREN WITH HIGH PROBABILITY OF HAVING PERSISTENT HYPOXEMIA AND SHOCK; AND (3) IMPLEMENT AND PROSPECTIVELY EVALUATE THE PERFORMANCE OF THE PREDICTION MODEL OF PERSISTENT HYPOXEMIA AND SHOCK IN THE EHRS OF THREE INSTITUTIONS.

WNT SIGNALING IN CRANIOFACIAL CARTILAGE MORPHOGENESIS

NEWBORN CIRCUMCISION CARE REDESIGN - PROJECT SUMMARY/ABSTRACT CIRCUMCISION IS ONE OF THE MOST COMMON SURGICAL PROCEDURES PERFORMED IN THE UNITED STATES. PERIPROCEDURAL RISK IS LOWEST, COSTS ARE LOWEST, AND HEALTH BENEFITS (E.G., DECREASED RISK OF URINARY TRACT AND SEXUALLY TRANSMITTED INFECTIONS) ARE GREATEST WHEN CIRCUMCISION IS PERFORMED AS A NEONATAL CIRCUMCISION (NC) UNDER LOCAL ANESTHESIA, RATHER THAN AS AN OPERATIVE CIRCUMCISION (OC) UNDER GENERAL ANESTHESIA LATER IN LIFE. HOWEVER, YOUNG BOYS FOR WHOM AN INFANT CIRCUMCISION WAS DESIRED COMMONLY PRESENT FOR ELECTIVE OC AFTER THE NEONATAL PERIOD. PREVIOUS RESEARCH INDICATES THAT BOYS OF LOWER SOCIOECONOMIC STATUS HAVE MORE DIFFICULTY ACCESSING NC SUCH THAT THE INCREASED RISKS AND DECREASED HEALTH BENEFITS OF OC DISPROPORTIONALLY AFFECT BOYS OF LOWER SOCIOECONOMIC STATUS. RECENT DATA SHOW THAT CHANGES IN MEDICAID COVERAGE OF NC DISPROPORTIONATELY AFFECT BLACK/AFRICAN AMERICAN BOYS COMPARED WITH BOYS OF OTHER RACIAL/ETHNIC BACKGROUNDS. AVAILABLE DATA INDICATE THAT BOTH HEALTHCARE OPERATIONAL AND INSURANCE COVERAGE FACTORS CONTRIBUTE TO THE DISPARITY IN ACCESS TO NC. CHICAGO-AREA CLINICIAN INTERVIEWS HAVE IDENTIFIED MULTIPLE OPERATIONAL BARRIERS TO NC, INCLUDING CLINICAL LOGISTICAL CHALLENGES AND LACK OF STANDARDIZED PROCESSES THAT COMPOUND SUBSTANTIAL VARIATION IN NC REIMBURSEMENT THAT DIS-INCENTIVIZES SOME BIRTH HOSPITALS FROM UNIFORMLY OFFERING NC. THE PROPOSED STUDY AIMS TO ADDRESS THE OPERATIONAL BARRIERS TO PROVIDING NC TO DESIROUS FAMILIES. THE WORLD HEALTH ORGANIZATION’S EVIDENCE-BASED STANDARDS AND PROCEDURES FOR HIGH-QUALITY, HIGH-VOLUME NC PROGRAMS WILL BE USED AS A FRAMEWORK (DEVELOPED FOR LOW- AND MIDDLE-INCOME COUNTRIES) AND ADAPTED FOR UTILIZATION IN MULTIPLE CLINICAL SETTINGS IN THE UNITED STATES (US). THE GOALS OF THIS PROPOSAL ARE TO (1) LEVERAGE THE WHO STANDARDS AND PROCEDURES TO DEVELOP AND IMPLEMENT SAFE, EFFICIENT, AND CONTEXTUALLY-ADAPTED NC PROGRAMS AT 3 HOSPITALS THAT PROMOTE EQUITY OF NC; (2) EVALUATE EACH NC PROGRAM’S IMPACT ON PATIENT OUTCOMES; AND (3) PROVIDE A COST ANALYSIS OF THE NC PROGRAM TO SUPPORT DISSEMINATION. A MULTIDISCIPLINARY TEAM (PEDIATRICS, OBSTETRICS, PEDIATRIC UROLOGY, HEALTH SERVICES RESEARCH, HEALTH ECONOMICS, AND GLOBAL HEALTH) HAS BEEN ASSEMBLED TO EXECUTE THE STUDY. FINDINGS FROM THIS STUDY WILL PROVIDE US BIRTHING HOSPITALS WITH EXAMPLES OF SAFE, EFFICIENT, AND CONTEXTUALLY ADAPTABLE NC PROGRAMS, BASED ON THE EVIDENCE-BASED WHO STANDARDS AND PROCEDURES. THESE EXAMPLES WILL INCLUDE COST ANALYSES FROM BOTH HOSPITAL AND PATIENT PERSPECTIVES TO FACILITATE DISSEMINATION. ULTIMATELY, BY IMPLEMENTING NC PROGRAMS THAT OVERCOME BOTH STRUCTURAL AND HEALTH SYSTEM BARRIERS, EQUITY IN NC SHOULD IMPROVE.

GENOMICS, BIOMETRICS AND IDENTITY

MIDWEST TXTXT: SCALE UP OF AN EVIDENCE-BASED INTERVENTION TO PROMOTE HIV MEDICATION ADHERENCE

ILLINOIS VIOLENT DEATH REPORTING SYSTEM (IVDRS)

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION

SLEEP AND ADIPOSITY: A PROSPECTIVE TWIN STUDY

CONNECT FOR YOUTH (C4Y)

STRENGTHENING CHICAGOS YOUTH (SCY), A VIOLENCE PREVENTION COLLABORATIVE CONVENED BY ANN & ROBERT H. LURIE CHILDRENS HOSPITAL OF CHICAGO WILL DEVELOP THE SCY-HOSPITAL BASED VIOLENCE INTERVENTION PROGRAM (SCY-HVIP) TO PROVIDE TRAUMA-INFORMED CARE COORDINATION FOR CHILDREN WHO ARE EXPOSED TO VIOLENCE. THE SCY-HVIP WILL ALLOW THE EMERGENCY DEPARTMENT (ED) TO IMPROVE THE IDENTIFICATION AND REFERRAL OF PATIENTS WHO HAVE EXPERIENCED TRAUMA AND VIOLENT INJURY AND ENSURE SERVICES SUPPORT CHILDREN AND FAMILIES LIVING IN UNDERSERVED AREAS OF CHICAGO AND AT HIGHEST RISK OF INJURY RECIDIVISM AND SYSTEM INVOLVEMENT.OVER THREE YEARS, THE SCY-HVIP WILL SCREEN AND ASSESS 375 CHILDREN AGES 0-19 WHO PRESENT TO THE ED WITH A VIOLENT INJURY AND PROVIDE SIX MONTHS OF CARE COORDINATION AND CONNECTION TO EVIDENCE-BASED PROGRAMMING TO 200 SURVIVORS IN NEED OF ADDITIONAL CARE AND SUPPORT AFTER DISCHARGE FROM THE HOSPITAL. THE GOALS OF THE PROJECT ARE THREE-FOLD. FIRST, THE SCY-HVIP AIMS TO PROVIDE HOLISTIC AND TRAUMA-INFORMED CARE FOR VICTIMS OF VIOLENCE PRESENTING TO THE ED, INCLUDING SCREENING AND ASSESSING YOUTH AND FAMILIES TO ADDRESS IMMEDIATE NEEDS AND DEVELOPING A FAMILY CARE PLAN FOR PATIENTS NEEDING ADDITIONAL SUPPORT.SECOND, THE PROGRAM WILL IMPROVE THE PHYSICAL AND MENTAL WELL-BEING OF CHILDREN EXPOSED TO VIOLENCE AND MINIMIZE FUTURE EXPOSURE TO VIOLENCE AND TRAUMA BY ESTABLISHING A MULTIDISCIPLINARY PLANNING TEAM TO DESIGN AND IMPLEMENT A COMMUNITY-CLINIC COLLABORATION BETWEEN THE ED AND VICTIM SERVICE PROVIDERS IN HIGH NEED AREAS OF CHICAGO WEST SIDE. BUILDING FROM MORE THAN A DECADE OF CONVENING VIOLENCE PREVENTION STAKEHOLDERS IN CHICAGO, SCY WILL WORK WITH EXISTING AND NEW PARTNERS TO DEVELOP A REGIONAL STRATEGY TO SUPPORT VICTIMS IN UNDERSERVED AREAS AND IDENTIFY ONGOING TRAINING AND PROFESSIONAL DEVELOPMENT OPPORTUNITIES TO ENSURE THE DELIVERY OF HOLISTIC, TRAUMA-INFORMED SERVICES. FURTHERMORE, THE PLANNING TEAM MEMBERSHIP WILL ALLOW FOR INPUT INCLUSIVE OF YOUTH AND PARENTS WHO HAVE BEEN EXPOSED TO VIOLENCE, AND PARTNERS WITH EXPERTISE IN MENTAL HEALTH, TRAUMA, YOUTH DEVELOPMENT, VICTIM SERVICES, COMMUNITY VIOLENCE INTERVENTION, RACIAL JUSTICE, AND DISABILITY EQUITY.THIRD, THE SCY-HVIP AIMS TO REDUCE THE RATE OF INJURY RECIDIVISM, REPEAT HOSPITALIZATIONS AND OTHER SYSTEMS INVOLVEMENT THROUGH CARE COORDINATION AND CONNECTION TO EVIDENCE-BASED SERVICES IN THE COMMUNITY FOR VICTIMS OF VIOLENCE AND THEIR FAMILIES. THESE SERVICES WILL BUILD PROTECTIVE FACTORS AND ADDRESS THEIR LONG-TERM HEALING AND RECOVERY AFTER BEING DISCHARGED FROM THE ED.

THE SAFECARE@HOME4KIDS LEARNING LAB: DESIGNING SAFER HEALTHCARE AT HOME FOR CHILDREN - PROJECT SUMMARY/ABSTRACT CHILDREN WITH MEDICAL COMPLEXITY ARE A GROWING POPULATION OF MEDICALLY FRAGILE PATIENTS WITH DISABILITY. CHILDREN WITH MEDICAL COMPLEXITY EXPERIENCE ~70% OF UNPLANNED HOSPITAL READMISSIONS AND HAVE A 10X HIGHER ODDS OF MORTALITY COMPARED TO OTHER CHILDREN. THESE CHILDREN’S DAILY SURVIVAL REQUIRES PARENTS AND HOME NURSES TO SAFELY ADMINISTER INTRICATE MEDICATION REGIMENS THROUGH IMPLANTED DEVICES, SUCH AS A TUBE INSERTED INTO THE STOMACH. WHILE WE KNOW THAT MEDICATION ERRORS OR DEVICE-RELATED ADVERSE EVENTS ARE HAPPENING AT HOME, NO HOME HEALTHCARE REPORTING OR RESPONSE STANDARDS EXIST TO ADDRESS AND PREVENT THEM. VOLUNTARY REPORTING DOES NOT EQUITABLY CAPTURE EVENTS IN CHILDREN OF MINORITY BACKGROUNDS OR NECESSARILY ADDRESS PREVENTION. PARENTS EXPRESS FEAR OF LOSING THEIR CHILD’S NURSING CARE OR THEIR CHILD’S CUSTODY IF THEY RAISE SAFETY CONCERNS, ESPECIALLY THOSE OF RACIAL MINORITY BACKGROUNDS. WHILE HOME IS AN ESSENTIAL HEALTHCARE SITE FOR CMC, NO SCIENTIFIC APPROACHES EXIST TO MAKE SURE HEALTHCARE SAFETY EVENTS DO NOT HAPPEN AT HOME. THERE IS A CRITICAL NEED TO IDENTIFY, COMMUNICATE, AND PREVENT SAFETY ERRORS AND ADVERSE EVENTS THAT OCCUR IN THE HOME BY DIVERSE PARENTS AND HOME HEALTHCARE PROVIDERS IN A MANNER THAT WILL MAKE SURE THE CHILDREN ARE OKAY, NOTIFIES THE CHILDREN’S CARE PROVIDERS, PREVENTS RECURRENCE, AND IS EQUITABLE TO ALL PATIENTS AND FAMILIES. OUR SPECIFIC AIMS ARE TO 1) CONSTRUCT THE SAFECARE@HOME4KIDS MULTIDISCIPLINARY LAB OF EXPERTS, INCLUDING IN PATIENT SAFETY, HUMAN FACTORS ENGINEERING, NURSING, PEDIATRICS, HHC, INFORMATICS, AND LIVED FAMILY EXPERIENCE TO WORK TOGETHER TO DESIGN INNOVATIVE, EFFECTIVE, AND EQUITABLE APPROACHES TO PREVENT HEALTHCARE SAFETY ERRORS AND ADVERSE EVENTS EXPERIENCED BY DIVERSE CMC AT HOME; 2) DETERMINE HOW FAMILY CAREGIVERS AND HOME NURSES CURRENTLY IDENTIFY, COMMUNICATE, AND PREVENT MEDICATION AND DEVICE-RELATED ERRORS AND ADVERSE EVENTS IN THE CONTEXT OF THE HOME WORK SYSTEM; AND 3) CO-DESIGN, IMPLEMENT, AND EVALUATE A SAFETY TOOLKIT THAT ADDRESSES THESE ELEMENTS OF MEDICATION AND DEVICE SAFETY USING INPUT FROM FAMILIES, HOME NURSES, PRESCRIBING PROVIDERS, AND OUR LAB EXPERTS, TO IMPROVE PATIENT SAFETY AT HOME. OUR PEDIATRIC PSLL WILL BE AN INNOVATIVE PARADIGM SHIFT IN SAFETY RESEARCH BY FOCUSING ON THE HOME AS A FUNDAMENTAL HEALTHCARE PRACTICE SETTING FOR CMC. THIS WORK IS SIGNIFICANT BECAUSE SAFECARE@HOME4KIDS SERVES INTERSECTING AHRQ PRIORITY POPULATIONS WHO MAY NOT OTHERWISE BE EMPOWERED OR SUPPORTED TO ADDRESS THE SAFETY OF THEIR HEALTHCARE AND ADDRESSES COMMON REASONS CHILDREN WITH MEDICAL COMPLEXITY USE THE EMERGENCY DEPARTMENT OR ARE HOSPITALIZED. BY USING A HUMAN FACTORS ENGINEERING APPROACH WITH NATIONAL INTERDISCIPLINARY EXPERTS, PARTNERING WITH PATIENT FAMILY LEADERS, AND RECRUITING A LINGUISTICALLY AND RACIALLY DIVERSE PARTICIPANT POPULATION, WE WILL ADVANCE WHOLE-PERSON 360-DEGREE BY EQUITABLY IMPACTING THE SAFETY OF CARE NO MATTER WHERE A CHILD CALLS HOME.

INFANT PEANUT ALLERGY PREVENTION: UNDERSTANDING AND SUPPORTING CAREGIVERS TO ACHIEVE ADHERENCE - PROJECT SUMMARY PEANUT ALLERGY (PA) IS THE MOST COMMON FOOD ALLERGY IN THE US; IT IS ALSO ONE OF THE LEAST FREQUENTLY OUTGROWN AND THE LEADING CAUSE OF FATAL FOOD-ALLERGIC REACTIONS. THE LANDMARK LEARNING EARLY ABOUT PEANUT STUDY FOUND THAT THE INGESTION OF PEANUT PRODUCTS IN INFANCY CAN DECREASE PA DEVELOPMENT BY OVER 81%. THUS, IN 2017 THE NIAID PUBLISHED THE PREVENTION OF PEANUT ALLERGY (PPA) GUIDELINES. HOWEVER, IMPLEMENTATION OF THESE GUIDELINES IS UNIQUE IN THAT THEY ARE A REVERSAL OF PREVIOUS GUIDELINES, POSING ADDITIONAL CHALLENGES FOR ALL STAKEHOLDERS. FOR CAREGIVERS OF YOUNG INFANTS SPECIFICALLY, COMPLIANCE WITH THE PPA GUIDELINES REQUIRES THEM TO UNDERSTAND THE CHANGING SCIENCE AROUND FOOD ALLERGY DEVELOPMENT, PARTICIPATE IN EARLY PEANUT FEEDING DURING SHORT TIME WINDOW (4-6 MONTHS OF AGE), AND ACCEPT THE RISKS INVOLVED WITH FEEDING THEIR INFANT A POTENTIALLY ALLERGENIC FOOD. WHILE STUDIES INVOLVING PEDIATRICIANS AND ALLERGISTS HAVE BEEN CONDUCTED, OUR CURRENT UNDERSTANDING OF CAREGIVER OPINIONS PPA GUIDELINES AND OUR INTERVENTIONS TO SUPPORT CAREGIVERS TO ADHERE TO EARLY PEANUT INTRODUCTION ARE LIMITED. UTILIZING AN ESTABLISHED CLINICAL NETWORK OF OVER 30 PEDIATRIC CLINICS IN ILLINOIS (PRIMARY MENTOR’S PARENT GRANT IREACH), THIS PROPOSAL WILL EVALUATE CAREGIVER BARRIERS AND FACILITATORS TO THE PPA GUIDELINES AND INVESTIGATE THE KEY DRIVING FACTORS FOR ADHERENCE AND NONADHERENCE BY CONDUCTING QUALITATIVE INTERVIEWS WITH CAREGIVERS OF YOUNG CHILDREN. THIS DATA WILL BE INCORPORATED INTO BUILDING A DISTINCT INTERACTIVE INTERVENTION: ICARE (INTERVENTION TO IMPROVE CAREGIVER ADHERENCE REGARDING EARLY PEANUT INTRODUCTION). USING WEB-, MOBILE-, AND/OR VIDEO-BASED APPLICATIONS, THE GOAL OF ICARE WILL BE TO ADDRESS CAREGIVER BARRIERS AND UNMET NEEDS TO FACILITATE EARLY PEANUT INTRODUCTION. AFTER FOLLOWING AN ITERATIVE PROTOTYPING PROCESS TO DEVELOP ICARE WITH STAKEHOLDERS AND EXPERTS, IT WILL BE TESTED AMONG CAREGIVERS TO UNDERSTAND ITS EFFICACY, ACCEPTABILITY, AND FEASIBILITY. THIS WILL PROVIDE PRELIMINARY DATA FOR AN R01 PROPOSAL STUDYING THE EFFECTIVENESS OF ICARE IN A RANDOMIZED CLINICAL TRIAL. AS CAREGIVERS ARE THE ULTIMATE DRIVERS OF PPA GUIDELINE IMPLEMENTATION, THIS PROJECT ADDRESSES A GAP IN OUR CURRENT APPROACH TO PA PREVENTION. THIS K23 PROPOSAL ADDRESSES MULTIPLE GAPS IN DR. SAMADY’S RESEARCH SKILLSET, PROVIDING ADDITIONAL TRAINING IN: 1) QUALITATIVE DATA ANALYSIS, 2) BEHAVIORAL SCIENCE TRAINING, 3) DEVELOPMENT AND EVALUATION OF NOVEL BEHAVIORAL INTERVENTIONS. HER PRIMARY MENTOR, DR. GUPTA IS A NATIONAL LEADER IN FOOD ALLERGY PREVENTION STUDIES, HER CO- MENTOR DR. MCGEE IS A LEADING EXPERT IN QUALITATIVE RESEARCH AND PROFESSIONAL DEVELOPMENT, AND HER CO- MENTORS DRS. VAN HORN, AND PONGRACIC HAVE ADDITIONAL EXPERTISE IN DEVELOPING AND EVALUATING BEHAVIORAL INTERVENTIONS. COMPLETION OF THESE AIMS AND TRAINING GOALS WILL SUPPORT DR. SAMADY’S LONG-TERM GOAL OF BECOME AN INDEPENDENT INVESTIGATOR AND NATIONAL LEADER STUDYING INFANTS WITH ATOPIC DISEASE, FOCUSED ON IMPROVING THE IMPLEMENTATION OF CURRENT FOOD ALLERGY PREVENTION EFFORTS AND IDENTIFYING NEW PREVENTION STRATEGIES.

IMPROVING KIDNEY HEALTH ASSESSMENT IN YOUNG PATIENTS WITH SPINA BIFIDA

MOLECULAR SIGNATURES OF EARLY-ONSET NEONATAL SEPSIS IN UMBILICAL CORD BLOOD

RESPONSE OF THE GUT MICROBIOME AND CIRCULATING METABOLOME TO DIET INTERVENTION IN YOUNG CHILDREN: ANCILLARY STUDY TO THE KEEPING IDEAL CARDIOVASCULAR HEALTH FAMILY INTERVENTION TRIAL (KIDFIT)

EVALUATION OF FIRST-DEGREE RELATIVES AFTER SUDDEN UNEXPLAINED DEATH

INVESTIGATING A NOVEL CO-REGULATION OF MULTI-DRUG EFFLUX PUMPS AND POLYSACCHARIDE CAPSULE IN E. COLI

HEALTH CARE AND OTHER FACILITIES

CHILDREN’S SURGERY METHODOLOGY AND RESEARCH TRAINING (C-SMART) - SUMMARY SURGICAL TRAINEES SEEKING FORMAL RESEARCH TRAINING FACE SUBSTANTIAL CHALLENGES. SURGEON-SCIENTISTS ARE AN UNDERREPRESENTED POPULATION IN ACADEMIC MEDICINE, AND FEDERALLY FUNDED PHYSICIAN-SCIENTIST–LED RESEARCH HAS BEEN IN DECLINE OVER THE PAST DECADE. AT THE INTERSECTION OF PEDIATRIC SURGICAL CARE AND SCIENTIFIC RESEARCH, THERE ARE VERY FEW RESEARCH TRAINING OPPORTUNITIES FOR EITHER SURGICAL RESIDENTS OR PHD POSTDOCTORAL FELLOWS. SURGICAL RESIDENT TRAINING PROGRAMS THAT INCORPORATE PROTECTED TIME FOR DEDICATED EXPERIENTIAL RESEARCH TRAINING HAVE EFFECTIVELY CONTRIBUTED TO THE “PIPELINE” OF SUCCESSFUL, INDEPENDENTLY FUNDED SURGEON-SCIENTISTS. THE PROPOSED CHILDREN’S SURGERY METHODOLOGY AND RESEARCH TRAINING (C-SMART) PROGRAM WILL BRING TOGETHER THE EXTENSIVE EXPERTISE AT NORTHWESTERN UNIVERSITY’S FEINBERG SCHOOL OF MEDICINE (NUFSM) AND THE ANN & ROBERT H. LURIE CHILDREN’S HOSPITAL OF CHICAGO (LCH) TO CREATE A MULTIDISCIPLINARY, 2-YEAR RESEARCH TRAINING PROGRAM CONSISTING OF (1) A HEALTH SERVICES AND OUTCOMES RESEARCH (HSOR) TRACK AND (2) A BASIC SCIENCE AND TRANSLATIONAL (BTS) RESEARCH TRACK. THE C-SMART PROGRAM WILL SYNERGIZE NUFSM RESOURCES WITH TRAINING COLLABORATION WITH OPPORTUNITIES WITHIN THE GROWING LCH STANLEY MANNE CHILDREN'S RESEARCH INSTITUTE. OVER THE PAST 10 YEARS, WE HAVE LEVERAGED THIS COLLABORATION AND CURATED A PIPELINE FOR NEARLY A DOZEN SURGICAL RESEARCH TRAINEES AND PHD POSTDOCTORAL FELLOWS TO PURSUE SUCCESSFUL ACADEMIC CAREERS AT THE INTERSECTION OF CHILD HEALTH AND SURGERY. DURING THE PROPOSED 2-YEAR, INTENSIVE TRAINING PERIOD, TRAINEES IN THE C-SMART PROGRAM WILL BE IMMERSED IN MULTIDISCIPLINARY, EXPERIENTIAL RESEARCH TRAINING, USING A TEAM SCIENCE APPROACH, WITH TAILORED MENTORSHIP AND FOCUSED DIDACTIC TEACHING (E.G., SYMPOSIA, LECTURE SERIES, MASTER’S DEGREE COURSES). EACH TRAINEE WILL HAVE AN EXPERIENCED AND DIVERSE MENTOR TEAM OF CONTENT, METHODOLOGICAL, AND CLINICAL EXPERTS, TAILORED TO THEIR TRAINING NEEDS. THE C-SMART PROGRAM CORE CURRICULUM WILL INCLUDE COURSES IN STUDY DESIGN AND ANALYTIC APPROACHES, BEST PRACTICES AND ETHICS IN RESEARCH, AND CAREER DEVELOPMENT. TRAINEES WILL PARTICIPATE IN WORKSHOPS, SEMINARS, AND RESEARCH TRAINING OPPORTUNITIES AT NUFSM, LCH, AND AT RELEVANT SURGICAL AND PEDIATRIC PROFESSIONAL SOCIETIES. TRAINEES WILL DESIGN AND EXECUTE RESEARCH PROJECTS THAT CULMINATE IN PRESENTATIONS AT MAJOR NATIONAL CONFERENCES AND PUBLICATIONS IN HIGH-IMPACT JOURNALS. THE PROGRAM WILL LEVERAGE BOTH DIVERSITY & INCLUSION AND PIPELINE COMMITTEES TO ATTRACT COMPETITIVE APPLICANTS AND FOSTER THE RETENTION AND SUCCESS OF TRAINEES WHO ARE HISTORICALLY UNDERREPRESENTED IN SURGERY. CONTINUOUS MONITORING AND ITERATIVE PROGRAM IMPROVEMENT WILL BE ACHIEVED BY ENGAGING A HIGHLY ACCOMPLISHED EXTERNAL ADVISORY COMMITTEE AND THROUGH ROBUST EVALUATION BY NORTHWESTERN’S PROGRAM EVALUATION CORE. THE GOAL OF THE C-SMART PROGRAM IS TO INCREASE THE NUMBER OF INVESTIGATORS WHO SUCCESSFULLY ACHIEVE ACADEMIC CAREERS AS INDEPENDENTLY FUNDED PEDIATRIC SURGICAL SCIENTISTS. NUFSM AND LCH ARE UNIQUELY POSITIONED TO ENSURE THE SUCCESS OF THE C-SMART PROGRAM AND THE CONTINUED DEVELOPMENT OF FUTURE CHILDREN’S SURGICAL SCIENTIFIC LEADERS.

TECHNOLOGY-ENHANCED ASTHMA CARE IN CHILDREN AT CLINIC AND HOME (TEACCCH) STUDY - PROJECT SUMMARY/ABSTRACT CANDIDATE: KRISTIN KAN, MD MPH MSC IS A PEDIATRIC PHYSICIAN AND CLINICAL INVESTIGATOR FOCUSED ON DESIGNING AND IMPLEMENTING EVIDENCE-BASED, HEALTH-SYSTEM INTERVENTIONS TO SUPPORT CHILDREN WITH ASTHMA. DR. KAN’S LONG-TERM GOAL IS TO BE AN INDEPENDENT PHYSICIAN-INVESTIGATOR AND LEADING EXPERT IN IMPLEMENTATION SCIENCE AND HEALTH SYSTEM INTERVENTIONS THAT IMPROVE THE OUTCOMES AND QUALITY OF CARE FOR CHILDREN WITH ASTHMA. RESEARCH CONTEXT: OF THE 5.5 MILLION US CHILDREN WITH PEDIATRIC ASTHMA, OVER HALF HAVE UNCONTROLLED SYMPTOMS DUE IN PART TO POOR ASTHMA SELF-MANAGEMENT, LEADING TO HIGH RATES OF ACUTE UNSCHEDULED CARE AND ACTIVITY LIMITATIONS. SUPPORTING GUIDELINE-BASED PREVENTIVE ASTHMA CARE, ESPECIALLY ADHERENCE TO MEDICATIONS, IS A CRITICAL STEP IN REDUCING UNCONTROLLED SYMPTOMS AMONG HIGH-RISK ASTHMA POPULATIONS. THERE IS EVIDENCE SUGGESTING THAT MOBILE HEALTH (MHEALTH) TECHNOLOGIES CAN BE PART OF AN EFFECTIVE INTERVENTION TO IMPROVE ADHERENCE AND SYMPTOM CONTROL. HOWEVER, DATA FROM OUR PREVIOUS MHEALTH ASTHMA TRIAL AND OTHER STUDIES SUGGEST THAT LIMITATIONS IN MHEALTH USE IN REAL-WORLD HEALTH CARE ARE PARTLY ATTRIBUTABLE TO THE LACK OF OPTIMIZING HEALTH SYSTEM INTEGRATION OF THE MHEALTH TOOL AND THE IMPLEMENTATION STRATEGY. SPECIFIC AIMS: (1) OPTIMIZE A MHEALTH PEDIATRIC ASTHMA INTERVENTION AND IMPLEMENTATION PLAN WITH CAREGIVERS AND HEALTH SYSTEM STAKEHOLDERS THROUGH USER-CENTERED DESIGN WORKSHOPS AND INTERVIEWS. (2) CONDUCT A FEASIBILITY STUDY OF AN ADAPTIVE, MHEALTH ASTHMA INTERVENTION AND MULTI-STAKEHOLDER IMPLEMENTATION PLAN TO IMPROVE ASTHMA SYMPTOM CONTROL AND MEDICATION ADHERENCE. RESEARCH PLAN: TO ACCOMPLISH THESE AIMS, DR. KAN WILL ENGAGE CAREGIVERS OF CHILDREN WITH ASTHMA, CLINICAL STAFF, AND HEALTH SYSTEM ADMINISTRATORS TO REFINE THE DESIGN OF AN EXISTING MHEALTH ASTHMA INTERVENTION, IDENTIFY HEALTH CARE SERVICES TO INTEGRATE THE INTERVENTION IN HEALTH CARE DELIVERY, AND DESIGN AN IMPLEMENTATION STRATEGY. DR. KAN WILL THEN CONDUCT A FEASIBILITY TRIAL WITH CAREGIVER-CHILD DYADS, WHOM WILL BE RANDOMIZED TO AN ADAPTIVE MHEALTH ASTHMA INTERVENTION. FINDINGS WILL HELP PREPARE FOR A FUTURE, FULL-SCALE HYBRID IMPLEMENTATION- EFFECTIVENESS TRIAL. CAREER DEVELOPMENT PLAN: DR. KAN’S TRAINING GOALS INCLUDE: (1) ACQUIRE EXPERIENCE IN USER-CENTERED DESIGN (UCD) METHODS, (2) DEVELOP EXPERTISE IN CLINICAL TRIAL DESIGN & EVALUATION IN HEALTH CARE SETTINGS, (3) INCREASE COMPETENCIES IN IMPLEMENTATION SCIENCE RESEARCH METHODS, AND (4) LEARN STATISTICAL TECHNIQUES FOR ANALYZING LONGITUDINAL DATA. DR. KAN’S CAREER DEVELOPMENT GOALS WILL BE WELL-SUPPORTED BY AN INTERDISCIPLINARY MENTORSHIP TEAM, A PLANNED SERIES OF DIDACTIC LEARNING, AND IMPLEMENTATION OF HER RESEARCH PLAN. ENVIRONMENT: DR. KAN HAS A NIH-FUNDED CORE MENTORSHIP AND ADVISORY TEAM, WHO ARE DEDICATED TO MENTORING HER TO INDEPENDENCE, AND IS ALSO SUPPORTED BY NORTHWESTERN UNIVERSITY AND LURIE CHILDREN’S HOSPITAL, BOTH WITH OUTSTANDING RESEARCH INFRASTRUCTURES AND COMMITMENTS TO SUPPORTING JUNIOR INVESTIGATORS.

THE PATH YOUTH PROGRAM: HIV/AIDS INTERVENTIONS IN ADOLE*

ALPHA-SYNUCLEIN RNA INTERFERENCE

ACHIP-ACES AND CARDIOMETABOLIC HEALTH IN PEDIATRICS: USING A COPING AND STRESS REDUCTION INTERVENTION TO REDUCE CARDIOMETABOLIC RISK IN ADOLESCENTS WITH ADVERSITY

THE MECHANISM AND SIGNIFICANCE OF EVF NCRNA REGULATION OF THE DIX GENES

THALASSEMIA

FACULTY DEVELOPMENT PROGRAM FOR PEDIATRIC CLINICIAN-SCIENTISTS

NEUROVIRULENCE DETERMINANTS OF NEONATAL HSV DISEASE

OPTIMIZING THE DIAGNOSIS OF PEDIATRIC CLOSTRIDIUM DIFFICILE INFECTION

REACHING EVERY ADOLESCENT IN CHICAGO THROUGH HARM REDUCTION (REACH) - ANN & ROBERT H. LURIE CHILDREN’S HOSPITAL OF CHICAGO’S POTOCSNAK FAMILY DIVISION OF ADOLESCENT & YOUNG ADULT MEDICINE (LCH) SEEKS A THREE-YEAR GRANT OF $375,000/YEAR FOR REACHING EVERY ADOLESCENT IN CHICAGO THROUGH HARM REDUCTION (REACH), A TRAUMA-INFORMED, EVIDENCE-BASED OUTREACH INTERVENTION THAT DELIVERS HARM REDUCTION EDUCATION AND SUPPLIES, SUD/COD SCREENINGS, AND REFERRALS TO TREATMENT AND RECOVERY SUPPORTS TO CHICAGOANS AGES 16–25 IN COMMUNITY SETTINGS. WHILE ALL CHICAGO YOUTH AGES 16–25 WILL BE ELIGIBLE, REACH FOCUSES ON LOW-INCOME, BLACK, INDIGENOUS, AND PEOPLE OF COLOR (BIPOC), AND/OR SEXUAL MINORITY (LGBTQ+) POPULATIONS IN UNDER-RESOURCED COMMUNITY AREAS EXPERIENCING A HIGH PREVALENCE OF SUBSTANCE USE/MISUSE DISORDERS, MENTAL HEALTH DISORDERS, AND TRAUMA. REACH LEVERAGES LCH’S MOBILE HEALTH UNIT (MHU) TO REDUCE BARRIERS SPECIFIC TO YOUTH ENGAGEMENT (E.G., LACK OF FAMILIARITY WITH AVAILABLE BEHAVIORAL HEALTH RESOURCES, LACK OF KNOWLEDGE AROUND ACCESSING SUD/COD DIAGNOSIS AND TREATMENT, AND/OR LACK OF TRANSPORTATION TO CLINIC LOCATIONS). IN PARTNERSHIP WITH FOUR COMMUNITY-BASED PROVIDERS OF YOUTH SERVICES—LAWRENCE HALL (SOUTH SIDE), YOUTH OUTREACH SERVICES (SOUTH AND/OR WEST SIDES), IGNITE (SOUTH SIDE), AND PHALANX FAMILY SERVICES (FAR SOUTH SIDE)—LCH WILL DEPLOY THE MHU TO PARTNER AGENCY SITES TO ENGAGE YOUTH POPULATIONS ALREADY ACCESSING OTHER SERVICES VIA THESE PROVIDERS. THROUGHOUT THE PROJECT, REACH STAFF WILL USE MOTIVATIONAL INTERVIEWING, CONTINGENCY MANAGEMENT, AND TEXT-MESSAGING INTERVENTIONS TO ENCOURAGE UPTAKE OF REACH SERVICES AND ADOPTION OF HEALTHIER BEHAVIORS. GOALS/OBJECTIVES: 1) DECREASE INCIDENCE OF OPIOID-RELATED OVERDOSES AND FATALITIES AMONG CHICAGOANS AGES 16–25 BY DISTRIBUTING OPIOID HARM-REDUCTION SUPPLIES TO YOUTH AND PROVIDING RELATED OVERDOSE PREVENTION EDUCATION TO YOUTH AND YOUTH-SERVICE PROVIDERS. OBJECTIVE 1A: REACH WILL PROVIDE OVERDOSE AND DISEASE PREVENTION KITS (INCLUDING NARCAN [NALOXONE] AND FENTANYL TEST STRIPS) AND RELATED TRAINING TO AT LEAST 45 UNDUPLICATED YOUTH IN YEAR 1 (Y1) AND AT LEAST 60 UNDUPLICATED YOUTH ANNUALLY IN YEAR 2 (Y2) AND YEAR 3 (Y3), SERVING AT LEAST 165 UNDUPLICATED YOUTH IN Y1–Y3. OBJECTIVE 1B: REACH WILL TRAIN STAFF AT PARTNER AGENCIES TO IDENTIFY OPIOID SUBSTANCES, RECOGNIZE AN OPIOID OVERDOSE, AND ADMINISTER NARCAN. LCH WILL TRAIN A MINIMUM 30 UNDUPLICATED PROVIDER STAFF IN Y1 AND A MINIMUM 10 UNDUPLICATED PROVIDER STAFF ANNUALLY IN Y2 AND Y3, TRAINING AT LEAST 50 UNDUPLICATED PROVIDER STAFF IN Y1–Y3. 2) INCREASE LOCAL CAPACITY TO IDENTIFY CHICAGOANS AGES 16–25 IN NEED OF SUD AND/OR COD TREATMENT AND RECOVERY SUPPORTS. REACH WILL OFFER SUD, COD, AND RECOVERY SUPPORT SCREENINGS TO PARTICIPATING YOUTH. OBJECTIVE 2A) REACH WILL PROVIDE SCREENINGS FOR SUD, COD, AND RECOVERY SUPPORTS TO AT LEAST 19 PARTICIPATING YOUTH IN Y1 AND AT LEAST 25 PARTICIPATING YOUTH ANNUALLY IN Y2 AND Y3, SCREENING A MINIMUM 69 PARTICIPANTS IN Y1–Y3. OBJECTIVE 2B) BY THE CONCLUSION OF Y3, 62 REACH YOUTH (90%) WILL SCREEN POSITIVE FOR SUD/COD AND NEEDED RECOVERY SUPPORTS.3) STRENGTHEN ACCESS TO SUD/COD TREATMENT AND RECOVERY SUPPORTS FOR CHICAGOANS AGES 16–25. LCH WILL REFER REACH YOUTH SCREENING POSITIVE FOR SUD/COD TO APPLICABLE CLINICAL SERVICES AT LCH OR ANOTHER PREFERRED PROVIDER, AS WELL AS TO ANY NEEDED RECOVERY SUPPORTS (E.G. TRANSPORTATION ASSISTANCE, HOUSING SERVICES) TO PROMOTE ENGAGEMENT/RETENTION IN CARE. OBJECTIVE 3A: LCH WILL REFER AT LEAST 17 REACH YOUTH TO TREATMENT AND RECOVERY SUPPORTS IN Y1 AND AT LEAST 22 REACH YOUTH ANNUALLY IN Y2 AND Y3, REFERRING A MINIMUM 61 PARTICIPATING YOUTH TO INDIVIDUALIZED CLINICAL CARE AND WRAPAROUND SUPPORTS IN Y1–Y3. APPROXIMATELY 50% OF YOUTH SCREENING POSITIVE WILL INITIATE TREATMENT/RECOVERY SUPPORTS. OBJECTIVE 3B: NINE (9) PARTICIPATING YOUTH IN Y1, AND 10 PARTICIPATING YOUTH ANNUALLY IN Y2 AND Y3, WILL INITIATE CARE, FOR A TOTAL 29 REACH YOUTH INITIATING SUD/C

AN MHEALTH STRATEGY TO IMPROVE MEDICATION ADHERENCE IN ADOLESCENTS WITH SICKLE CELL DISEASE

CROSS-SPECIES MODELING OF EPILEPTOGENESIS IN KCNT1-ASSOCIATED EPILEPSY

EPIDEMIOLOGY OF THE METABOLIC SYNDROME IN CHILDREN

MECHANISMS OF HYDROCORTISONE REGULATION OF THE PERINATAL PULMONARY VASCULATURE

MIR-17~92 HAPLOINSUFFICIENCY INFLUENCES ALVEOLAR AND VASCULAR ENDOTHELIAL DEVELOPMENT

FUNCTIONAL ANALYSIS OF THE ROLE OF TRANSCRIPTION FACTOR 21 (TCF21) IN NEPHRON PROGENITOR CELLS IN CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT

PROGRESSING TOWARD CLINICAL TRIAL READINESS IN CCHS: NATURAL HISTORY STUDY TO INCORPORATE PATIENT VOICE, HARMONIZE CLINICAL AND REGISTRY DATA, AND STANDARDIZE ASSESSMENTS - ABSTRACT CONGENITAL CENTRAL HYPOVENTILATION SYNDROME (CCHS) IS A RARE AND SEVERE NEUROCRISTOPATHY CAUSED BY PHOX2B GENE MUTATIONS. CCHS IS CHARACTERIZED BY PROFOUND HYPOVENTILATION AND AUTONOMIC NERVOUS SYSTEM DYSREGULATION, NECESSITATING LIFE-LONG ARTIFICIAL VENTILATION. PATIENTS MAY SUFFER REPETITIVE HYPOXEMIC AND HYPERCARBIC EXPOSURE RESULTING IN POTENTIAL NEUROCOGNITIVE COMPROMISE. AUTONOMIC CARDIOVASCULAR DYSFUNCTION LEADS TO RISK OF HYPERTENSION, BLOOD PRESSURE LABILITY, IMPAIRED RESPONSES TO ORTHOSTATIC STRESS, AND SINUS PAUSES OFTEN REQUIRING A CARDIAC PACEMAKER. ADDITIONALLY, CCHS IS ASSOCIATED WITH HIGH RISK OF HIRSCHSPRUNG’S DISEASE AND TUMORS OF NEURAL CREST ORIGIN. THERE IS SUBSTANTIAL VARIABILITY IN PRESENTATION AND DISEASE SEVERITY AND THERE IS A LACK OF CONSENSUS AMONG EXPERT CLINICIANS ON OPTIMAL MANAGEMENT. CURRENTLY, THERE ARE NO PHARMACOLOGIC INTERVENTIONS APPROVED TO DECREASE DISEASE BURDEN IN CCHS, AND THE LIMITED TREATMENT OPTIONS AVAILABLE ARE HIGHLY INVASIVE, BURDENSOME AND OFFER ONLY PALLIATIVE SUPPORT. DESPITE PROMISING PRE-CLINICAL MODELS, ANECDOTAL REPORTS OF OFF-LABEL DRUG SUCCESSES, AND APPROVED DRUGS AND DEVICES IN OTHER POPULATIONS WITH CONSIDERABLE POTENTIAL IN CCHS, THERAPEUTIC DEVELOPMENT IS HAMPERED BY A LACK OF ESTABLISHED MEASURES OF DISEASE STATE AND COMPREHENSIVE NATURAL HISTORY (NH) DATA. FACTORS LEADING TO THE WIDE PHENOTYPIC VARIABILITY IN CCHS ARE NOT WELL UNDERSTOOD, AND SEVERITY STRATIFICATION CRITERIA ARE LACKING. IMPORTANTLY, THE IMPACT OF DISEASE AND DIFFERENT TREATMENT APPROACHES (E.G., TRACHEOSTOMY VS. MASK VENTILATION) ON PATIENT AND CAREGIVER QUALITY OF LIFE (QOL) REMAINS UNQUANTIFIED. ADDRESSING THESE KNOWLEDGE GAPS IS CRITICAL TO ADVANCE CCHS TREATMENT AND INFORM EFFECTIVE THERAPEUTIC STRATEGIES. ACCURATE CLINICAL, FUNCTIONAL, AND QUALITY OF LIFE ASSESSMENTS ARE PARAMOUNT TO UNDERSTANDING DISEASE PROGRESSION, STRATIFYING DISEASE SEVERITY, FORMULATING EFFECTIVE TREATMENT STRATEGIES, AND ASSESSING THERAPEUTIC INTERVENTIONS. THIS PROPOSAL ASSEMBLES PREEMINENT CCHS EXPERTS, LEADING INTERNATIONAL CCHS CENTERS OF EXCELLENCE, CCHS PATIENT ADVOCACY GROUPS, AND INDUSTRY PARTNERS CURRENTLY DEVELOPING INTERVENTIONS FOR CCHS TO ADDRESS THIS GAP IN THE SCIENCE. TOGETHER, THIS TEAM HAS IDENTIFIED CANDIDATE MEASURES THAT REFLECT THE CORE CCHS PHENOTYPE BUT ARE LACKING VALIDATION DATA. THIS PROJECT WILL CAPTURE EXTENSIVE, LONGITUDINAL NH DATA USING RIGOROUSLY DEFINED PROTOCOLS, COMMON DATA ELEMENTS (CDES), AND ESTABLISHED MEASURES REFLECTING PATIENT AND CAREGIVER VOICES. ULTIMATELY, WE WILL DEVELOP A FLEXIBLE, ADAPTABLE DATA HUB OF CORE MEASURES OF CCHS NH WHICH WILL INFORM FUTURE THERAPEUTIC DEVELOPMENT, INTERVENTION TRIALS, RESEARCH AND CLINICAL CARE. BY MERGING TRADITIONALLY SILOED CCHS DATA, EXPERTISE, RESOURCES AND COHORTS, THIS STUDY WILL ENRICH KNOWLEDGE OF CCHS NH, ESTABLISH MEASURES THAT BEST CORRELATE WITH DISEASE SEVERITY, INFORM THERAPEUTIC DEVELOPMENT, AND ACCELERATE PROGRESS TOWARD CLINICAL TRIALS. RECENT ADVANCES IN PRECLINICAL MODELS AND ONGOING THERAPEUTIC DEVELOPMENT MAKES THIS STUDY TIME-SENSITIVE, AND SUCCESS PARAMOUNT TO ADVANCING TOWARD APPROVED THERAPEUTICS IN THIS UNDERSERVED POPULATION.

ACHIEVING EQUITY FOR DISEASE PREVENTION IN CYSTIC FIBROSIS (ACED-CF) - CYSTIC FIBROSIS (CF) IS AN INHERITED, LIFELONG DISORDER THAT REQUIRES MEDICAL CARE THROUGHOUT THE LIFESPAN. ONE OF THE MOST COMMON LIFE-SHORTENING MONOGENIC DISORDERS, IT IS CHARACTERIZED BY CHRONIC PROGRESSIVE LUNG DISEASE AND PANCREATIC EXOCRINE AND ENDOCRINE INSUFFICIENCY. ADVANCES IN CYSTIC FIBROSIS (CF) DIAGNOSIS AND TREATMENT, INCLUDING NEWBORN SCREENING (NBS) AND CFTR MODULATOR THERAPIES, HAVE TRANSFORMED PROGNOSIS FROM SEVERELY REDUCED LIFESPAN TO A CHRONIC DISEASE OF ADULTS WITH RAPIDLY INCREASING LIFE EXPECTANCY. NEWBORN SCREENING FOR CF IMPROVES GROWTH, WHICH PREDICTS IMPROVED PULMONARY FUNCTION AND SURVIVAL. WHILE CF IS AN AUTOSOMAL RECESSIVE GENETIC DISEASE WITH PRENATAL DISEASE MANIFESTATIONS, ADVANCES IN NBS AND EXTENSION OF HIGHLY EFFECTIVE CFTR MODULATOR THERAPIES TO CHILDREN WITH CF, THE DISEASE MANIFESTATIONS OF CYSTIC FIBROSIS ARE LARGELY PREVENTABLE. WE HAVE DISCOVERED THAT IMPLEMENTATION OF UNIVERSAL SCREENING IN THE US HAS NOT MET THE GOAL OF INITIATING TREATMENT FOR CF WITHIN 30 DAYS OF AGE. IN A STUDY FUNDED BY A CYSTIC FIBROSIS FOUNDATION (CFF) GRANT AND USING CFF PATIENT REGISTRY DATA , 23% OF 6354 INFANTS WITH CF BORN 2010-2018 HAD INITIAL CF CENTER EVALUATION (AGE AT FIRST EVENT, AFE) > 30 DAYS OF AGE, AND 10% HAD AFE > 60DAYS. FURTHERMORE, THE MEDIAN AFE FOR INFANTS WHO ARE BLACK, INDIGENOUS AND PEOPLE OF COLOR (BIPOC) IS LATER THAN THAT OF WHITE, NOT HISPANIC INFANTS (31 DAYS V 22 DAYS, P<.001). LATER AFE LATER AFE IS ASSOCIATED WITH LOWER WEIGHT FOR AGE Z-SCORE AT 1 YEAR OF AGE. STRUCTURED INTERVIEWS, STATE NBS PROGRAM PERSONNEL AND CF CENTER DIRECTORS IDENTIFIED EDUCATION OF PRIMARY CARE PHYSICIAN AND PARENTS AS THE MOST IMPORTANT TARGET TO PREVENT DELAYS IN REFERRAL AFTER A POSITIVE NBS FOR CF. THIS PROPOSAL AIMS TO OVERCOME CURRENT DELAYS IN INITIATING TREATMENT FOR CF THROUGH DISSEMINATION OF STUDY FINDINGS AND DISTRIBUTION OF STATE SPECIFIC CFF PATIENT REGISTRY DATA ON CARE PROCESSES AND PATIENT OUTCOMES TO STATE NBS PROGRAM PERSONNEL AND CF CENTER DIRECTORS. SURVEYS WILL BE DEPLOYED TO PARENTS OF CHILDREN WITH CF AND TO GENERAL POPULATION PARENTS TO FILL KEY KNOWLEDGE GAPS IN EXPERIENCES AND KNOWLEDGE OF NEWBORN SCREENING. PARTNERING WITH NONPROFIT INSTITUTIONS AND ACADEMIC COLLABORATORS, WE WILL DEVELOP A PUBLIC AWARENESS CAMPAIGN FOCUSED ON NEWBORN SCREENING AND THE NEED FOR TIMELY EVALUATION AFTER AN OUT-OF RANGE TEST RESULT. WE WILL DEVELOP AND IMPLEMENT CONTINUING MEDICAL EDUCATION AND QUALITY IMPROVEMENT ACTIVITIES, ELIGIBLE FOR MAINTENANCE OF CERTIFICATION BY THE AMERICAN BOARD OF PEDIATRICS, FOR PRIMARY CARE PEDIATRICIANS, PROVIDING IT AT NO COST TO PARTICIPATING PHYSICIANS.

ROLE OF FLT-1 IN NECROTIZING ENTEROCOLITIS DEVELOPMENT - ABSTRACT: NECROTIZING ENTEROCOLITIS (NEC) IS A MAJOR CAUSE OF MORBIDITY AND MORTALITY AMONG PREMATURE INFANTS THAT COMMONLY LEADS TO OVERWHELMING SEPSIS AND EXTENSIVE INTESTINAL TISSUE NECROSIS REQUIRING SURGERY. NEC PATHOGENESIS IS NOT COMPLETELY UNDERSTOOD, AND NO SPECIFIC THERAPIES CURRENTLY EXIST TO PREVENT OR TREAT NEC. WE FOUND NOVEL EVIDENCE THAT DEFECTIVE INTESTINAL MICROVASCULAR DEVELOPMENT PLAYS A CRUCIAL ROLE IN NEC AND THAT INHIBITING MONOCYTE RECRUITMENT PRESERVES GUT MICROVASCULAR NETWORK AND DECREASES THE INCIDENCE OF NEC. OUR PRELIMINARY DATA SUGGEST THAT: (1) IN THE NEONATAL INTESTINE, MONOCYTES AND MONOCYTE-DERIVED MACROPHAGES (MMF) ARE THE MAJOR CELLS EXPRESSING FMS-LIKE TYROSINE KINASE-1 (FLT-1) WHICH IS KNOWN TO INHIBIT VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2 (VEGFR2) SIGNALING AND ANGIOGENESIS BY TRAPPING ITS LIGAND VEGF; (2) TNF-ACTIVATED MYELOID CELLS PRODUCE SOLUBLE FLT-1 (SFLT-1); (3) PUPS SUBJECTED TO EXPERIMENTAL NEC HAVE INCREASED CIRCULATING SFLT-1 AND INCREASED INTESTINAL FLT-1+ MONOCYTES; (4) THE NUMBER OF FLT-1+ MΦ IS INCREASED IN HUMAN NEC GUT AND (5) BLOCKING FLT-1 DECREASES NEC IN MOUSE PUPS. TOGETHER, THIS SUGGESTS THAT, IN THE GUT, RECRUITED MONOCYTES AND MMF MAY DOWNREGULATE ENDOTHELIAL CELL (ENC) VEGFR2 SIGNALING VIA AN FLT-1-DEPENDENT MECHANISM. FURTHERMORE, OUR DATA SUGGEST THAT ENC PGD (6-PHOSPHOGLUCONATE DEHYDROGENASE), AN ENZYME REQUIRED FOR DNA SYNTHESIS, IS DEPENDENT ON VEGFR2/FOXM1 SIGNALING. PGD IS SIGNIFICANTLY HIGHER IN NEONATAL ENC AND IS DECREASED DURING EXPERIMENTAL NEC. THESE DATA SUPPORT OUR OVERARCHING PREMISE THAT, IN THE INTESTINE OF INFANTS SUSCEPTIBLE TO NEC, MONOCYTES RECRUITED UPON STRESS AND MMΦ EXPRESS OR RELEASE FLT-1, THUS IMPAIRING ENC VEGFR2-DEPENDENT PROLIFERATION AND ANGIOGENESIS. THUS, THE GUT MICROVASCULATURE REMAINS UNDERDEVELOPED AND INADEQUATE TO COPE WITH POSTNATAL METABOLIC DEMANDS, SUCH AS ENTERAL FEEDING AND IMMUNE CHALLENGE, RESULTING IN ISCHEMIA, NECROSIS AND NEC. IN THIS PROPOSAL, USING NOVEL APPROACHES, WE WILL TEST THE HYPOTHESIS THAT, DURING NEC DEVELOPMENT IN THE INTESTINE, RECRUITED MONOCYTES AND MMΦ PRODUCE FLT-1 WHICH TRAPS VEGF, DECREASES ENC VEGFR2 SIGNALING AND SUBSEQUENTLY DECREASES FOXM1- MEDIATED PGD EXPRESSION. THE RESULTING DECREASE IN ENC PROLIFERATION CAUSES ABNORMAL GUT MICROVASCULAR DEVELOPMENT AND PREDISPOSES PREMATURE NEONATES TO NEC. WE WILL TEST OUR HYPOTHESIS WITH THE FOLLOWING 3 AIMS: (1) DEFINE THE MECHANISM BY WHICH RECRUITED MONOCYTES AND MMF INHIBIT MICROVASCULAR DEVELOPMENT TO PROMOTE INTESTINAL INJURY DURING NEC INDUCTION; (2) DETERMINE THE CLINICAL RELEVANCE OF MONOCYTE/MMΦ-DERIVED FLT-1-MEDIATED INHIBITION OF ENC PROLIFERATION IN HUMAN NEC; (3) DEFINE THE MECHANISM MEDIATING FLT-1-INDUCED MICROVASCULAR IMPAIRMENT IN THE NEONATAL INTESTINE DURING NEC DEVELOPMENT. THE GOAL OF THIS PROPOSAL IS TO CHARACTERIZE THE MYELOID CELL-ENC CROSSTALK AND KEY ANTI-ANGIOGENIC SIGNALING MECHANISM(S) THAT IMPAIR INTESTINAL MICROVASCULAR DEVELOPMENT, THUS PROMOTING NEC. THESE STUDIES WILL PROVIDE A SOLID FOUNDATION FOR TESTING NOVEL THERAPEUTIC STRATEGIES THAT CAN PRESERVE LOCAL VEGFR2 SIGNALING TO PREVENT NEC DEVELOPMENT.

HOMEVENT4KIDS: HOME-BASED OPTIMIZATION OF MECHANICAL VENTILATION FOR CHILDREN

DELAYED DIAGNOSIS OF SERIOUS PEDIATRIC EMERGENCY CONDITIONS

FUNCTIONAL OUTCOMES IN PEDIATRIC LIVER TRANSPLANTATION

BIOMARKERS AND RISK STRATIFICATION IN PEDIATRIC COMMUNITY-ACQUIRED PNEUMONIA

EPIGENETIC REGULATION IN SELF-RENEWING AND DIFFERENTIATING MALE GERM CELLS

DEVELOPING A NOVEL ADOLESCENT CARDIOVASCULAR HEALTH PROMOTION PROGRAM (CPP) - PROJECT SUMMARY / ABSTRACT CARDIOVASCULAR DISEASE (CVD) RISK FACTORS IN ADOLESCENCE ARE COMMON AND ROBUSTLY ASSOCIATED WITH ADULT CVD EVENTS. CLINICAL CAPACITY FOR INTENSIVE BEHAVIORAL INTERVENTION IS INSUFFICIENT TO MEET DEMAND, AND MOREOVER, STANDARD BEHAVIORAL INTERVENTIONS HAVE HAD LIMITED EFFICACY IN ADOLESCENTS. PEDIATRIC GUIDELINES IDENTIFY CRITICAL GAPS: WE NEED MORE EFFECTIVE ADOLESCENT INTERVENTIONS, WITH A GREATER FOCUS ON CVD RISK FACTORS BEYOND BMI, AND WE NEED TO BUILD LEAN, EFFECTIVE AND SCALABLE TREATMENT PACKAGES USING THE MULTIPHASE OPTIMIZATION STRATEGY (MOST). IN RESPONSE, WE PROPOSE TO DEVELOP AND PILOT-TEST A NOVEL CARDIOVASCULAR HEALTH (CVH) PROMOTION PROGRAM (CPP) PRECISELY TAILORED FOR ADOLESCENTS WITH CVD RISK FACTORS. OUR PREPARATORY WORK SYSTEMATICALLY IDENTIFIED INTERVENTION COMPONENTS EXPECTED TO BE EFFECTIVE BASED ON THEORY, EVIDENCE, AND USER PREFERENCES. WE PROPOSE TO OVERCOME EFFICACY LIMITATIONS OF STANDARD INTERVENTIONS BY ADDING NOVEL COMPONENTS TO ENGAGE EMOTION AND IDENTITY MECHANISMS OF ADOLESCENT BEHAVIOR. THESE CORE MOTIVATIONAL MECHANISMS ARE HIGHLY SALI- ENT IN ADOLESCENCE, WHICH IS MARKED BY SELF-IDENTITY FORMATION, HEIGHTENED EMOTIONALITY, AND EMOTION REGULATION DIFFICULTIES. CONCURRENTLY, WE PROPOSE TO OVERCOME SCALABILITY ISSUES THROUGH PROTOCOLIZED, REMOTE, AND LARGELY SELF-GUIDED DELIVERY METHODS, BASED ON OUR SUCCESSFUL ADULT INTERVENTIONS. WE WILL EMPLOY THE MOST FRAMEWORK TO SYSTEMATICALLY OPTIMIZE CPP FOR EFFICACY WHILE BALANCING THE NEED FOR SCALABILITY. THE CURRENT R34 WILL BE THE PREPARATION PHASE OF MOST, YIELDING REFINED INTERVENTION COMPONENTS AND OPERATIONAL GUIDELINES FOR THE OPTI- MIZATION-PHASE RCT. IN AIM 1, WE WILL ADAPT AND ITERATIVELY REFINE EXISTING INTERVENTION CONTENT, INCLUDING THE DIABETES PREVENTION PROGRAM FOR STANDARD BEHAVIORAL CONTENT, THE UNIFIED PROTOCOL FOR TRANSDIAGNOSTIC TREAT- MENT OF EMOTIONAL DISORDERS IN ADOLESCENTS FOR EMOTION REGULATION CONTENT, AND ACADEMIC INTERVENTIONS FOR IDEN- TITY CONTENT. WE WILL TAILOR CONTENT FOR THE TARGET POPULATION AND ADAPT IT FOR REMOTE DELIVERY VIA SELF-GUIDED VIDEOS AND WORKSHEETS, BRIEF 1:1 COACHING, AND GROUP SESSIONS. OUR PERSON-CENTERED ITERATIVE DESIGN PROCESS WILL EN- GAGE ADOLESCENTS TO REFINE INTERVENTION PROTOTYPES AND PROTOCOLS VIA THINK-ALOUD/INTERVIEW SESSIONS, WITH FURTHER INPUT FROM OUR TEEN AND ADULT COMMUNITY ADVISORY BOARDS. IN AIM 2, WE WILL RANDOMIZE 42 ADOLESCENTS WITH CVD RISK FACTORS TO 1 OF 3 ARMS IN AN 8-WEEK PRE-POST PILOT TRIAL. ARMS WILL VARY 4 COMPONENTS ADDED TO STANDARD BEHAVIORAL CONTENT: EMOTION CONTENT (YES/NO), IDENTITY CONTENT (YES/NO), GROUP SESSIONS (YES/NO), AND COACHING DOSE (HIGH/LOW). THE 3 ARMS WILL TEST CONDITIONS WITH THE HIGHEST BURDEN (ALL YES/HIGH), LOWEST NOVELTY (ALL NO/LOW), AND GREATEST CONTAMINATION RISK (MIXED). MIXED QUANTITATIVE/QUALITATIVE DATA WILL ESTABLISH FEASIBILITY, ACCEPTABILITY, AND FIDELITY AGAINST PREDEFINED BENCHMARKS. THIS R34 WILL FULLY PREPARE US TO CONDUCT THE OPTIMIZATION-PHASE FACTORIAL RCT AND ASSEMBLE ‘ACTIVE’ COMPONENTS INTO A LEAN CPP PACKAGE FOR EVALUATION-PHASE EFFECTIVENESS TESTING. THIS WORK DIRECTLY RESPONDS TO NHLBI’S CALLS (NOT-HL-21-020) AND IS EXPECTED TO ULTIMATELY PRODUCE A SCALABLE, ACCESSIBLE INTERVENTION THAT EMPOWERS DIVERSE ADOLESCENTS TO ENTER ADULTHOOD WITH FAVORABLE CVH.

PEDIATRIC ACUTE LIVER FAILURE (PALF) TREATMENT FOR IMMUNE MEDIATED PATHOPHYSIOLOGY (TRIUMPH)

PEDIATRIC HEART TRANPLANTATION: TRANSITIONING TO ADULT CARE

ADAPT TO ENGAGE: ASSESSING FOR DISPARITIES AND POTENTIAL TARGETS FOR INTERVENTION TO ENGAGE ACUTELY ILL CHILDREN IN RESEARCH

COLLECTING VIOLENT DEATH INFORMATION USING NATIONAL VIOLENT DEATH REPORTING SYSTEM (NVDRS): ILLINOIS

PROCALCITONIN TO REDUCE ANTIBIOTIC USE IN PEDIATRIC PNEUMONIA (P-RAPP)

DEVELOPING A PEDIATRICS-BASED SOCIAL NEEDS INTERVENTION TO REDUCE DISPARITIES IN ADHD OUTCOMES FOR LOW-INCOME CHILDREN

DEUBIQUITINATING ENZYMES AS TARGETS FOR MALE CONTRACEPTION

NEW INVESTIGATION INITIATIVES FOR THE PREVENTION OF COMPLICATIONS OF THALASSEMIA

RSV I-PREP: IMPROVING EVIDENCE-BASED IMPLEMENTATION OF RSV IMMUNO-PROPHYLAXIS WITHIN ETHICAL AND POLICY CONTEXTS - 1 PROJECT SUMMARY/ABSTRACT 2 CANDIDATE: JENNIFER KUSMA, MD, MS IS A PEDIATRICIAN AND JUNIOR CLINICAL INVESTIGATOR FOCUSED ON IMPROVING THE 3 EVIDENCE-BASE FOR THE HEALTH CARE POLICY AND ACCESS FOR CHILDREN WITH SPECIAL HEALTH CARE NEEDS (CSHCN). DR. 4 KUSMA’S LONG-TERM CAREER GOAL IS TO BECOME AN INDEPENDENT PHYSICIAN-INVESTIGATOR WHO WORKS IN CROSS- 5 DISCIPLINARY TEAMS TO EVALUATE EVIDENCE-BASED HEALTH CARE POLICY AND DELIVERY, WITH A FOCUS ON DELIVERY OF 6 IMMUNOPROPHYLAXIS AGAINST RESPIRATORY SYNCYTIAL VIRUS (RSV) FOR INFANTS AT HIGH-RISK FOR MORBIDITY AND MORTALITY, 7 WITH A FOCUS ON INFANTS WITH CONGENITAL HEART DISEASE (CHD). 8 RESEARCH CONTEXT/OBJECTIVE: RSV INFECTION IS INCREDIBLY PREVALENT, ALMOST ALL CHILDREN WILL CONTRACT RSV WITHIN 9 THE FIRST TWO YEARS OF LIFE. RSV CONTRIBUTES TO SIGNIFICANT MORBIDITY AND MORTALITY FOR SPECIFIC POPULATIONS OF 10 CSHCN INCLUDING CHD, CHRONIC LUNG DISEASE OF PREMATURITY, AND PREMATURE INFANTS, WHICH IS COSTLY, SO AN 11 IMMUNOPROPHYLACTIC (IP) TREATMENT IS AVAILABLE. HOWEVER, ONLY 33% OF ELIGIBLE INFANTS RECEIVE THEIR COMPLETE 12 RSV IP. THEREFORE, THE OBJECTIVE OF THIS AWARD IS FOR DR. KUSMA TO LEARN HOW TO ASSESS THE FACTORS ASSOCIATED 13 WITH RECEIPT OF COMPLETE RSV IP, ETHICALLY EVALUATE TRADEOFFS IN RSV IP POLICY, AND PRIORITIZE BARRIERS AND 14 FACILITATORS TO IMPLEMENTATION OF RSV IP POLICY. 15 SPECIFIC AIMS: 1) TO IDENTIFY PATIENT, PROVIDER, AND INSTITUTIONAL LEVEL FACTORS ASSOCIATED WITH RECEIPT OF 16 COMPLETE RSV IP (5 DOSES WITHIN THE 6-MONTH RSV SEASON) GUIDED BY THE CFIR MODEL. 2) TO DETERMINE ETHICAL 17 TRADEOFFS OF POTENTIAL RSV IP PRACTICES AND POLICIES, APPLYING AN ETHICAL FRAMEWORK FOR INFANTS WITH CHD AS 18 COMPARED WITH OTHER IP-ELIGIBLE INFANTS. 3) TO EVALUATE DETERMINANTS OF SUBOPTIMAL IMPLEMENTATION OF RSV IP 19 PRACTICES AND POLICIES INFORMED BY THE CFIR MODEL. 20 RESEARCH PLAN: DR. KUSMA WILL RETROSPECTIVELY ANALYZE EXISTING PATIENT, PROVIDER, INSTITUTION, AND INSURANCE 21 LEVEL FACTORS ASSOCIATED WITH COMPLETE RECEIPT OF RSV IP USING DATA FROM PEDSNET, A LEARNING HEALTH SYSTEM, 22 GUIDED BY THE CFIR MODEL (AIM 1); EVALUATE ETHICAL TRADEOFFS OF KEY STAKE HOLDERS REGARDING RSV IP POLICY 23 (AIM 2); AND APPLY MIXED METHODS TO PRIORITIZE BARRIERS AND FACILITATORS OF IMPLEMENTATION OF RSV IP (AIM 3). 24 CAREER DEVELOPMENT PLAN/ENVIRONMENT: THROUGH LOCAL AND NATIONAL COURSES, EXPERIENTIAL LEARNING, 25 WORKSHOPS, SEMINARS, AND PROFESSIONAL ACTIVITIES, DR. KUSMA WILL ACQUIRE EXPERTISE IN EVALUATING HIERARCHICAL 26 MODELING, LEARNING HEALTH SYSTEMS, ETHICAL EVALUATION, MIXED METHODS ANALYSIS, AND IMPLEMENTATION SCIENCE. 27 DR. KUSMA WILL STRENGTHEN HER PROFESSIONAL SKILLS NEEDED FOR AN INDEPENDENT PHYSICIAN-INVESTIGATOR CAREER 28 THROUGH CLOSE MENTORSHIP BY AN EXPERIENCED, COMPLEMENTARY TEAM OF NIH-FUNDED TEAM MENTORS AND ADVISORS. 29 NORTHWESTERN UNIVERSITY AND LURIE CHILDREN’S HOSPITAL WILL PROVIDE OUTSTANDING RESEARCH INFRASTRUCTURES TO 30 ENABLE A SUCCESSFUL AWARD AND ARE STRONGLY COMMITTED TO DR. KUSMA’S TRANSITION TO RESEARCH INDEPENDENCE.

ROLE OF PRENATAL FACTORS AND GENE-ENVIRONMENT INTERACTIONS IN RECURRENT WHEEZING

FUNCTIONAL DISSECTION OF THE K27M HISTONE MUTATION IN VIVO

THE PHYSIOLOGIC ASSESSMENT OF EXERCISE CAPACITY IN PEDIATRIC SICKLE CELL ANEMIA

THALASSEMIA

THE AYA ONCOLOGY SELF-CARE MOVEMENT (#AYAOSM): AN INFLUENCER-DRIVEN SOCIAL MEDIA INTERVENTION FOR ORAL CHEMOTHERAPY ADHERENCE - PROJECT SUMMARY/ABSTRACT FOR ADOLESCENTS AND YOUNG ADULTS (AYAS) WITH ACUTE LYMPHOBLASTIC LEUKEMIA, ORAL CHEMOTHERAPY ADHERENCE IS CRITICAL FOR MAINTAINING CANCER REMISSION, BUT DIFFICULT TO ACHIEVE. PRIOR RESEARCH HAS SHOWN THAT NEARLY 50% OF AYAS HAD SUBOPTIMAL ORAL CHEMOTHERAPY ADHERENCE (DEFINED AS <95% ADHERENT), INCREASING THEIR RELAPSE RISK 2.5-FOLD. DESPITE POTENTIALLY LIFE-THREATENING NONADHERENCE AMONG AYAS, FEW ORAL CHEMOTHERAPY ADHERENCE INTERVENTIONS HAVE BEEN TESTED IN THIS POPULATION, WITH LIMITED EVIDENCE OF INTERVENTION EFFECTIVENESS. THIS GAP MAY BE BECAUSE RESEARCHERS HAVE LARGELY TESTED GENERIC INTERVENTIONS THAT WERE NOT TAILORED TO OR CO-DESIGNED WITH AYAS AND REQUIRED THE ADOPTION OF A NEW DIGITAL ADHERENCE TOOL THAT WAS NOT ALREADY PART OF AYAS’ DAILY TECHNOLOGY USE. IN CONTRAST, SOCIAL MEDIA IS UBIQUITOUS, A PLACE WHERE AYAS ALREADY SEEK CANCER-RELATED SUPPORT, AND WHERE “SOCIAL MEDIA INFLUENCERS” POST APPEALING, FIRST-HAND CONTENT ABOUT CANCER EXPERIENCES, REACHING THOUSANDS OF FOLLOWERS. OUR LONG-TERM GOAL IS TO IMPROVE ADHERENCE AND REDUCE DISPARITIES IN AYA CANCER OUTCOMES THROUGH SCALABLE DIGITAL HEALTH STRATEGIES. THE OBJECTIVE OF THIS PROJECT, THE AYA ONCOLOGY SELF-CARE MOVEMENT (#AYAOSM) IS TO EVALUATE A TAILORED SOCIAL MEDIA INTERVENTION FOR ORAL CHEMOTHERAPY ADHERENCE IN AYAS WITH ACUTE LYMPHOBLASTIC LEUKEMIA. ALIGNED WITH PAR-22-164, THIS WILL INVOLVE THE “TESTING OF RAPID CANCER COMMUNICATION INTERVENTION USING INNOVATIVE METHODS AND DESIGNS” WITHIN AN EXISTING “INFORMATION ECOSYSTEM” THAT HAS NEVER BEEN USED FOR ORAL CHEMOTHERAPY ADHERENCE—SOCIAL MEDIA AND THE INFLUENCERS THEREIN. WE BUILD FROM OUR PILOT DATA THAT HAS SHOWN AYAS PREFER A SOCIAL MEDIA-ENABLED ADHERENCE INTERVENTION OVER OTHER DIGITAL ALTERNATIVES, AND THAT INFLUENCER-BASED ADHERENCE MESSAGES ARE FEASIBLE TO DELIVER AND ACCEPTABLE TO AYAS. IN AIM 1, USING OUR BANK OF TAILORED AND THEORY-INFORMED SOCIAL MEDIA MESSAGES FOR ADHERENCE, WE WILL CONDUCT A BEST-WORST SCALING EXERCISE TO IDENTIFY PRIORITY MESSAGE ATTRIBUTES. THE RESULTS WILL BE INTERPRETED WITH RESEARCHER AND INFLUENCER INPUT TO FINALIZE THE INTERVENTION. IN AIM 2, VIA A PROSPECTIVE RANDOMIZED CONTROLLED TRIAL WITH 200 AYAS WITH LEUKEMIA, WE WILL TEST THE HYPOTHESIS THAT RECEIVING THE AYA-TAILORED SOCIAL MEDIA MESSAGES WILL RESULT IN A GREATER PROPORTION OF AYAS REACHING THE ADHERENCE THRESHOLD FOR RELAPSE PREVENTION COMPARED TO A NO MESSAGE CONTROL GROUP (ELECTRONIC ADHERENCE MONITORING AND REFERRAL TO A MEDICATION EDUCATION WEBSITE ONLY). TO SUPPORT A FUTURE, NATIONAL SOCIAL MEDIA CAMPAIGN, IN AIM 3, WE WILL STUDY POTENTIAL BARRIERS AND FACILITATORS TO IMPLEMENTING THE SOCIAL MEDIA ADHERENCE INTERVENTION WITH FUTURE ADOPTERS AND IMPLEMENTERS, INCLUDING ONCOLOGY CLINICIANS AND LEADERS FROM CANCER AGENCIES. TOGETHER, THIS PROJECT WILL EXPAND THE KNOWLEDGE BASE ON HOW TO TAILOR ADHERENCE MESSAGES TO A DIVERSE AND GROWING POPULATION OF AYAS, DETERMINE THE EFFICACY OF A SOCIAL MEDIA-ENABLED INTERVENTION FOR ADHERENCE, BUILD SUSTAINABLE PARTNERSHIPS WITH SOCIAL MEDIA INFLUENCERS, AND UNDERSTAND BARRIERS AND FACILITATORS TO SCALING THIS APPROACH FOR A FUTURE SOCIAL MEDIA CAMPAIGN.

PATHOPHYSIOLOGY OF INFLUENZA A VIRUS-INDUCED LUNG INJURY IN JUVENILES

TEXT MESSAGING INTERVENTION TO IMPROVE ART ADHERENCE AMONG HIV-POSITIVE YOUTH

ILLINOIS VIOLENT DEATH REPORTING SYSTEM (IVDRS)

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - THIS PROJECT WILL EXPAND LURIE CHILDREN’S MOBILE HEALTHCARE PLUS PROGRAM, WHICH STARTED IN OCT 2019 USING A MODIFIED AMBULANCE, WITH THE PURCHASE OF A NEW MOBILE HEALTH UNIT TO INCREASE ACCESS TO CARE AND COMMUNITY-RESPONSIVE HEALTH PROMOTION. MOBILE HEALTH UNITS BRING EQUIPMENT, SUPPLIES, AND SKILLED PROFESSIONALS TO MEDICALLY UNDERSERVED COMMUNITIES, THEREBY DECREASING DISPARITIES RELATED TO TRANSPORTATION OR GEOGRAPHIC BARRIERS, INSURANCE STATUS AND LINGUISTIC OR CULTURAL BARRIERS. HISTORICALLY, THEY HAVE BRIDGED THE GAP IN ACCESSING CARE INCLUDING SCHOOL PHYSICALS, PRENATAL CARE AND, MOST RECENTLY, COVID-19 TESTING AND IMMUNIZATIONS. OUR CURRENT MOBILE UNIT ALLOWED US TO TEST OVER 1200 STUDENTS FOR COVID-19 AND DISTRIBUTE MORE THAN 1400 COVID-19 VACCINATIONS TO EDUCATORS AND YOUTH LIVING IN COMMUNITIES MOST IMPACTED BY THE PANDEMIC. WE HAVE ALSO HAD EARLY SUCCESS WITH INCREASING SCHOOL PHYSICAL AND IMMUNIZATION COMPLIANCE, THROUGH SERVING CHILDREN AND ADOLESCENTS WHO HAD NOT COMPLETED THEIR REQUIRED PHYSICAL EXAMS AND VACCINATIONS FOR SCHOOL ENTRY. HOWEVER, OUR CURRENT MOBILE HEALTH UNIT IS INSUFFICIENT IN MEETING COMMUNITY NEEDS. IT DOES NOT HAVE THE NECESSARY AMENITIES TO ADDRESS HEALTH CHALLENGES, SUCH AS RUNNING WATER, POINT-OF-CARE TESTING FOR ANEMIA AND LEAD, AND SEPARATE SPACES TO ENSURE PRIVACY AND CONFIDENTIALITY. FURTHERMORE, THE COVID-19 PANDEMIC HIGHLIGHTED RACIAL/ETHNIC AND SOCIOECONOMIC INEQUITIES IN HEALTHCARE ACCESS AND THE IMPORTANCE OF ALTERNATIVE MODALITIES TO SECURE CRITICAL HEALTHCARE SERVICES. WITH COMMUNITY PARTNERS, WE RECOGNIZED THE UNTAPPED POTENTIAL FOR THE MOBILE UNIT TO PROVIDE SERVICES AND RESOURCES BEYOND SCREENINGS AND VACCINES, INCLUDING HEALTH PROMOTION, EDUCATION AND PROGRAMMING FOCUSED ON GUN VIOLENCE PREVENTION, MENTAL HEALTH SCREENINGS AND TREATMENT, SUICIDE AWARENESS AND PREVENTION, OBESITY PREVENTION, SEXUAL AND REPRODUCTIVE HEALTH, HIV/STI SCREENING AND TREATMENT, UNINTENTIONAL INJURY PREVENTION, SU BSTANCE USE PREVENTION, MATERNAL AND CHILD HEALTH AND LGBTQ+ HEALTH. A MORE BROADLY FUNCTIONAL MOBILE UNIT WILL ENABLE US TO PROVIDE MORE SPECIALTY CARE FOR CHRONIC DISEASES SUCH AS ASTHMA, BEHAVIORAL HEALTH DISORDERS AND SUBSTANCE USE, CARDIAC CONDITIONS AND HIV/STIS, WHICH OFTEN REQUIRES SPECIAL EQUIPMENT FOR OPTIMAL MANAGEMENT. A MORE COMPREHENSIVE MOBILE UNIT WILL ALLOW US TO REACH MORE YOUTH AND FAMILIES THE EXPANDED SERVICES DESCRIBED ABOVE. AN ECOLOGICAL APPROACH THAT ALLOWS US TO PARTNER WITH COMMUNITY-BASED ORGANIZATIONS, FEDERALLY QUALIFIED HEALTH CENTERS, PARKS, LIBRARIES, SCHOOLS, AND SOCIAL SERVICE AGENCIES POSITIONS US TO HAVE THE GREATEST IMPACT TO PROMOTE HEALTH AND WELL-BEING. EXPANDING THE LINKS BETWEEN HIGH-QUALITY PEDIATRIC MEDICAL CARE, HEALTH EDUCATION AND COMMUNITY-BASED RESOURCES WILL INCREASE AVAILABILITY OF CARE FOR THOSE IN UNDER-RESOURCED COMMUNITIES – ESSENTIALLY MEETING YOUTH AND FAMILIES WHERE THEY LIVE, LEARN, AND PLAY. IN COLLABORATION WITH COMMUNITY PARTNERS AND HEALTHCARE PROVIDERS, THIS FULL-SERVICE MOBILE HEALTH UNIT ALIGNS WITH THE 19 FOCUS COMMUNITIES WITH THE HIGHEST RATES OF CHILD POVERTY, VIOLENCE, AND INEQUALITY, AS IDENTIFIED BY THE CHICAGO HOSPITAL ENGAGEMENT, ACTION, AND LEADERSHIP (HEAL) INITIATIVE STARTED BY SENATOR RICHARD J. DURBIN.

PROGNOSTIC BIOMARKERS TO PREDICT PROGRESSION OF PEDIATRIC CHRONIC KIDNEY DISEASE

MECHANISMS UNDERLYING DISRUPTION OF INTESTINAL EPITHELIAL BARRIER IN CRITICAL ILLNESS

CIRCADIAN RHYTHMS OF SKIN BARRIER, PRURITUS AND INFLAMMATION IN ATOPIC DERMATITIS

SEROLOGIC TEST FOR NEONATAL HEMOCHROMATOSIS IN INFANTS WITH ACUTE LIVER FAILURE

ADVANCING THE APPROACH TO SUBCLINICAL DIASTOLIC DYSFUNCTION IN YOUTH WITH CHRONIC KIDNEY DISEASE - PROJECT SUMMARY: DR. ALEX KULA, MD, MHS, IS AN ASSISTANT PROFESSOR IN THE DEPARTMENT OF PEDIATRICS AT NORTHWESTERN UNIVERSITY FEINBERG SCHOOL OF MEDICINE (NU) AND ATTENDING PHYSICIAN IN THE DIVISION OF PEDIATRIC NEPHROLOGY AT THE ANN AND ROBERT H. LURIE CHILDREN’S HOSPITAL OF CHICAGO (LCH). THE K23 AWARD WILL HELP DR. KULA BECOME AN INDEPENDENT PHYSICIAN-SCIENTIST WHO APPLIES PATIENT-ORIENTED RESEARCH (POR) METHODS TO ADVANCE OUR UNDERSTANDING AND TREATMENT OF SUBCLINICAL CARDIOVASCULAR DISEASE (CVD) IN YOUTH WITH CHRONIC KIDNEY DISEASE (CKD). EVIDENCE OF SUBCLINICAL CVD IS PRESENT IN YOUTH WITH CKD, AND RISK FOR CVD IS CARRIED AND COMPOUNDED INTO ADULTHOOD. ADULTS WITH CKD ARE AT NOTABLY HIGH RISK FOR HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF). TRANSITION FROM SUBCLINICAL DIASTOLIC DYSFUNCTION TO SYMPTOMATIC HFPEF MAY BE PREVENTED WITH MEDICATIONS, INCLUDING SODIUM GLUCOSE CO-TRANSPORTER 2 INHIBITORS (SGLT2I). YET, ADVANCED ECHOCARDIOGRAPHIC PARAMETERS USED TO IDENTIFY DIASTOLIC DYSFUNCTION IN ADULTS HAVE NOT BEEN STUDIED IN PEDIATRIC CKD. THE OBJECTIVE OF THIS PROPOSAL IS TO LEVERAGE INSIGHTS DEVELOPED IN ADULTS WITH CKD TO DEFINE A PHENOTYPE OF SUBCLINICAL DIASTOLIC DYSFUNCTION IN PEDIATRIC CKD AND TO BEGIN TO TEST THE REVERSIBILITY OF THIS PHENOTYPE IN AN INTERVENTIONAL STUDY. DR. KULA WILL PURSUE THIS OBJECTIVE THROUGH 2 COMPLEMENTARY POR AIMS: 1) AN IN-DEPTH PHYSIOLOGIC STUDY OF DIASTOLIC FUNCTION AT REST AND WITH EXERCISE USING ECHOCARDIOGRAPHY IN YOUTH WITH STAGE 3-4 CKD (N=50) AND AGE- AND SEX- MATCHED HEALTHY CONTROLS (N= 25); 2) A FEASIBILITY STUDY OF SGLT2I IN YOUTH WITH STAGES 3-4 CKD (N=40) THAT WILL ASSESS PRIMARY END-POINTS OF FEASIBILITY AND SECONDARY END-POINTS OF SGLT2I EFFECT ON INTERMEDIATE MEASURES ASSOCIATED WITH RISK OF HFPEF. THE RESULTS WILL IMPACT OUR UNDERSTANDING OF SUBCLINICAL CVD IN YOUTH WITH CKD AND SERVE AS PRELIMINARY DATA FOR FUTURE R01 PROPOSALS. TO ENSURE HIS TRANSITION TO SCIENTIFIC INDEPENDENCE, DR. KULA HAS DESIGNED A ROBUST CAREER DEVELOPMENT PLAN, WITH THE FOLLOWING GOALS: 1) GAIN EXPERTISE IN CONDUCTING POR STUDIES; 2) LEARN ABOUT CARDIOVASCULAR PHENOTYPING USING ECHOCARDIOGRAPHY; 3) DEVELOP PROFICIENCY IN CLINICAL TRIALS; 4) STRENGTHEN CROSS-DISCIPLINARY COLLABORATIONS, ENRICH RESEARCH PORTFOLIO AND MASTER SCIENTIFIC MANAGEMENT SKILLS. DR. KULA’S SCIENTIFIC AND TRAINING GOALS WILL BE OVERSEEN BY A MULTI-DISCIPLINARY AND EXPERIENCED MENTORSHIP TEAM. HIS PRIMARY MENTOR, DR. TAMARA ISAKOVA, IS A LEADER IN POR METHODS AND CLINICAL TRIALS IN NEPHROLOGY. HIS CO-MENTOR, DR. SANJIV SHAH, HAS EXPERTISE IN CLINICAL PHENOTYPING OF DIASTOLIC DYSFUNCTION AND HFPEF. EXTERNAL ADVISORY COMMITTEE MEMBERS WILL PROVIDE EXPERTISE IN PEDIATRIC POR, CARDIAC PHENOTYPING IN YOUTH (DR. LUC MERTENS), AND STUDIES OF CVD IN PEDIATRIC CKD (DR. RULAN PAREKH). DR. KULA WILL BENEFIT FROM THE EXCEPTIONAL INSTITUTIONAL ENVIRONMENT OF LCH AND NU, INCLUDING: 1) HIGH-VOLUME OF YOUTH WITH CKD SEEN IN LCH NEPHROLOGY CLINIC; 2) RESEARCH INFRASTRUCTURE OF THE STANLEY MANNE CHILDREN’S RESEARCH INSTITUTE AT LCH; 3)ROBUST AND COLLABORATIVE ACADEMIC ENVIRONMENT WITHIN LCH AND NU. UPON COMPLETING THE K23, DR. KULA WILL BE UNIQUELY POSITIONED TO STUDY INTERVENTIONS FOR CVD RISK REDUCTION IN A HIGH-RISK, BUT UNDERSTUDIED, POPULATION.

OXIDANT STRESS AND GENE POLYMORPHISMS IN BRONCHOPULMONARY DYSPLASIA

NATIONAL SPINA BIFIDA PATIENT REGISTRY-LURIE CHILDREN?S SPINA BIFIDA CENTER

MULTI-SYSTEM EVALUATION OF MASSAGE THERAPY ON HIV+ ADOLESCENTS

THALASSEMIA

RED KARD: REDUCING DISPARITIES IN KNEE ARTHROSCOPY FOR ADOLESCENTS - PROJECT SUMMARY THE PURPOSE OF THIS K23 PROPOSAL IS TO FACILITATE DR. NEERAJ PATEL’S DEVELOPMENT INTO AN INDEPENDENT SURGEON SCIENTIST WHO WILL PARTNER WITH COMMUNITIES, GENERATE COMMUNITY-CENTERED INPUT, AND DESIGN AND IMPLEMENT INTERVENTIONS TO REDUCE INEQUITIES IN PEDIATRIC SPORTS MEDICINE. HUNDREDS OF THOUSANDS OF YOUTH ATHLETES REQUIRE SURGERY FOR KNEE INJURIES ANNUALLY. THE INCIDENCE OF OPERATIVE KNEE INJURIES HAS SKYROCKETED, BUT SURGERY CAN BE DELAYED DUE TO LATE RECOGNITION AND BARRIERS, SUCH AS INSURANCE, LANGUAGE, AND DIFFICULTY NAVIGATING THE HEALTHCARE SYSTEM. DELAYS MAY HAVE LIFELONG EFFECTS, INCLUDING ARTHRITIS, PERSISTENT INSTABILITY, POOR PATIENT REPORTED OUTCOMES, AND REOPERATION. THERE IS LITTLE PATIENT-CENTERED RESEARCH ON BARRIERS TO ORTHOPAEDIC CARE, AND NONE ON INTERVENTIONS TO REDUCE DISPARITIES IN PEDIATRIC SPORTS MEDICINE. TO ACCOMPLISH HIS LONG-TERM GOALS, DR. PATEL REQUIRES TRAINING IN COMMUNITY ENGAGED RESEARCH (CENR), QUALITATIVE METHODS, AND IMPLEMENTATION SCIENCE. HE WILL ACHIEVE THESE TRAINING GOALS THROUGH A COMPREHENSIVE CAREER DEVELOPMENT PLAN THAT INCLUDES STRONG MENTORING, FOCUSED DIDACTICS, GROWING COLLABORATIONS, AND EXPERIENTIAL TRAINING. THIS WILL GUIDE HIM TOWARDS NATIONAL EXPERTISE IN DISCIPLINES WHERE FEW ORTHOPAEDIC SURGEONS HAVE ANY BACKGROUND. HIS PRIMARY MENTOR IS DR. RINAD BEIDAS, AN INTERNATIONAL LEADER IN IMPLEMENTATION SCIENCE WITH EXTENSIVE RECORD OF FEDERALLY FUNDED COMMUNITY RESEARCH AND MENTORSHIP. THE MENTORING TEAM ALSO INCLUDES A DIVERSE, MULTIDISCIPLINARY GROUP OF RESEARCHERS WITH COMPLEMENTARY EXPERTISE: DRS. NAMRATHA KANDULA (CENR AND INTERVENTION DESIGN), MATTHEW DAVIS (PEDIATRIC CER AND POPULATION HEALTH RESEARCH), AND JULIE JOHNSON (QUALITATIVE METHODS). DR. PATEL’S DEVELOPMENT WILL BE BOLSTERED BY THE ROBUST RESOURCES OF LURIE CHILDREN’S HOSPITAL AND NORTHWESTERN UNIVERSITY. THE PROPOSED STUDY WILL FOCUS ON HISPANIC CHILDREN, A GROWING POPULATION NATIONALLY AND 38% OF THE CHICAGO’S CHILDREN, WHO ARE AT INCREASED RISK OF DELAYED KNEE SURGERY AND ITS SEQUELAE COMPARED TO WHITE, NON-HISPANIC PATIENTS. THE OVERALL OBJECTIVES ARE TO IDENTIFY BARRIERS TO TIMELY KNEE SURGERY IN HISPANIC ATHLETES AND DEVELOP AN INTERVENTION TO IMPLEMENT EVIDENCE ON EXPEDIENT TREATMENT. UNDER THE LENS OF THE HEALTH EQUITY IMPLEMENTATION FRAMEWORK, THE SPECIFIC AIMS ARE TO: (1) IDENTIFY BARRIERS AND FACILITATORS TO TIMELY CARE OF KNEE INJURIES FOR HISPANIC HIGH SCHOOL ATHLETES; (2) DESIGN AN EVIDENCE- BASED, CULTURALLY-TAILORED INTERVENTION FOR HISPANIC ATHLETES, FAMILIES, AND COACHES TO REDUCE DELAYS IN EVALUATION OF ACUTE KNEE INJURIES VIA USER-CENTERED PRINCIPLES; AND (3) EVALUATE FEASIBILITY, ACCEPTABILITY, AND APPROPRIATENESS OF THE CULTURALLY-TAILORED INTERVENTION IN A PILOT STUDY OF HISPANIC YOUTH SOCCER LEAGUES. THE PROPOSED AIMS WILL DRIVE CREATION OF A FUTURE COMMUNITY TRIAL OF A CULTURALLY-TAILORED INTERVENTION, WHICH WILL BE THE BASIS FOR R03 AND R01 FUNDING APPLICATIONS. IN THE PROCESS, DR. PATEL WILL BECOME AN EXPERT IN CENR, QUALITATIVE METHODS, AND IMPLEMENTATION SCIENCE, ESTABLISHING HIM AS ONE OF THE ONLY ORTHOPAEDIC SURGEONS CONDUCTING HEALTH EQUITY CER AND A RESOURCE FOR OTHERS SEEKING TO ADDRESS ORTHOPAEDIC DISPARITIES.

PRECISION MEDICINE APPROACHES IN THE DIAGNOSIS OF COMMUNITY-ACQUIRED PNEUMONIA IN CHILDREN - PROJECT SUMMARY/ABSTRACT CANDIDATE: SRIRAM RAMGOPAL, MD IS A PEDIATRIC EMERGENCY MEDICINE PHYSICIAN AND EARLY CAREER CLINICAL INVESTIGATOR FOCUSED ON IMPROVING THE DIAGNOSIS OF COMMUNITY-ACQUIRED PNEUMONIA (CAP) AMONG CHILDREN IN THE ACUTE CARE SETTING. DR. RAMGOPAL’S LONG-TERM CAREER GOAL IS TO BECOME AN INDEPENDENT PHYSICIAN- INVESTIGATOR FOCUSED ON IMPROVING THE HEALTH OUTCOMES OF CHILDREN WITH COMMON INFECTIOUS EMERGENCIES USING PREDICTIVE ANALYTICS, INFORMATICS, AND IMPLEMENTATION SCIENCE APPROACHES. RESEARCH CONTEXT/OBJECTIVE: CAP IS THE SECOND MOST COMMON REASON FOR HOSPITALIZATION AND THE SECOND MOST COSTLY PEDIATRIC CONDITION TO TREAT AMONG CHILDREN IN THE UNITED STATES. THE DIAGNOSIS OF CAP IS COMPLICATED BY A LACK OF DATA DRIVEN TOOLS AND OVERLAPPING PRESENTING FEATURES WITH OTHER COMMON RESPIRATORY CONDITIONS, RESULTING IN OVERUSE, AND OCCASIONALLY UNDERUSE, OF CHEST RADIOGRAPHS (CXR) AND ANTIBIOTICS. THERE ARE A PAUCITY OF VALIDATED TOOLS TO GUIDE THE DIAGNOSIS OF CHILDREN WITH SUSPECTED CAP. TO ADDRESS THIS KNOWLEDGE AND PRACTICE GAP, THE OBJECTIVES OF THIS PROPOSAL ARE TO DEVELOP A CLINICAL PREDICTION MODEL FOR CAP USING ELECTRONIC HEALTH RECORD (EHR) DATA, VALIDATE A PREDICTION MODEL FOR CAP, AND DEVELOP A PROTOTYPE CLINICAL DECISION SUPPORT (CDS) SYSTEM FOR CAP. SPECIFIC AIMS: 1) DERIVE AND INTERNALLY VALIDATE A PREDICTION MODEL FOR THE DIAGNOSIS OF CAP USING AN EHR REGISTRY; 2) DETERMINE HOW A PREDICTION MODEL FOR PEDIATRIC CAP WILL BE IMPLEMENTED AS A CDS SYSTEM IN ROUTINE CLINICAL PRACTICE USING IMPLEMENTATION SCIENCE AND HUMAN-CENTERED DESIGN METHODS; AND 3) PROSPECTIVELY EVALUATE THE PERFORMANCE OF CLINICAL AND EHR-BASED PREDICTION MODELS FOR CAP. RESEARCH PLAN: DR. RAMGOPAL WILL PERFORM A RETROSPECTIVE COHORT STUDY USING DATA FROM A HARMONIZED, HIGH-RESOLUTION PEDIATRIC EMERGENCY DEPARTMENT REGISTRY TO DEVELOP A PREDICTION MODEL TO IDENTIFY THE RISK OF CAP IN CHILDREN. HE WILL LEAD CO-DESIGN SESSIONS TO DEVELOP A CDS SYSTEM PROTOTYPE USING IMPLEMENTATION SCIENCE APPROACHES, AND EXTERNALLY VALIDATE THREE CLINICAL PREDICTION RULES FOR CAP WITHIN A PEDIATRIC EMERGENCY DEPARTMENT. CAREER DEVELOPMENT PLAN/ENVIRONMENT: THROUGH A COMBINATION OF LOCAL AND NATIONAL DIDACTIC ACTIVITIES, EXPERIENTIAL LEARNING, WORKSHOPS, SEMINARS, PROFESSIONAL ACTIVITIES, AND COURSEWORK, DR. RAMGOPAL WILL ACQUIRE EXPERTISE IN CLINICAL INFORMATICS, PREDICTIVE ANALYTICS, AND IMPLEMENTATION SCIENCE METHODOLOGY. DR. RAMGOPAL IS SUPPORTED BY AN EXPERIENCED, MULTIDISCIPLINARY TEAM OF NIH-FUNDED MENTORS, ADVISORS, AND COLLABORATORS WITH EXPERTISE IN LOWER RESPIRATORY TRACT INFECTIONS, PREDICTION MODELING, MACHINE LEARNING, AND IMPLEMENTATION SCIENCE. DR. RAMGOPAL WILL MEET REGULARLY WITH HIS MENTORS INDIVIDUALLY, AND QUARTERLY AS A FULL COMMITTEE, TO ENSURE COMPLETION OF ALL RESEARCH AND TRAINING BENCHMARKS. THE INSTITUTIONAL COMMITMENT TO RESEARCHERS AT NORTHWESTERN UNIVERSITY AND LURIE CHILDREN’S HOSPITAL PROVIDE AN OUTSTANDING INFRASTRUCTURE TO ENABLE A SUCCESSFUL AWARD AND ENSURE DR. RAMGOPAL’S DEVELOPMENT INTO AN INDEPENDENT CLINICIAN-SCIENTIST.

CHICAGO AREA SURVEILLANCE, STATISTICS, AND ANALYSIS NETWORK FOR DIABETES, WITH REPRESENTATIVE ASCERTAINMENT

DEVELOPING A PEDIATRIC ADVANCE CARE PLANNING WORKSHEET

HEALTH CARE AND OTHER FACILITIES

HEALTH CARE AND OTHER FACILITIES

METABOLOMIC SIGNATURES OF INSULIN RESISTANCE AND VISCERAL ADIPOSITY CHANGES IN HIV-INFECTED ADULTS ON NEWER LINE ANTIRETROVIRAL THERAPY

A DATA-DRIVEN ANALYSIS OF PEDIATRIC ORGAN DYSFUNCTION PATTERNS TO DISCOVER SEPSIS PHENOTYPES

THE UNFOLDED PROTEIN RESPONSE IN MURINE AND PEDIATRIC CHOLESTATIC LIVER DISEASES - CHOLESTATIC LIVER DISEASES, INCLUDING BILIARY ATRESIA (BA), ARE THE LEADING INDICATION FOR PEDIATRIC LIVER TRANSPLANT AND THERE ARE NO EFFECTIVE MEDICAL THERAPIES FOR PATIENTS THAT DECREASE THE NEED FOR TRANSPLANTATION. THIS IS DUE, IN PART, TO THE LACK OF UNDERSTANDING OF HOW THE LIVER REACTS TO BILE ACID INDUCED INJURY IN CHILDREN, INCLUDING THE HEPATOCYTE ACTIVATION OF THE UNFOLDED PROTEIN RESPONSE (UPR). THE UPR IS A PROTECTIVE MOLECULAR RESPONSE THAT DECREASES ENDOPLASMIC RETICULUM (ER) STRESS WHICH CAN OCCUR IN THE SETTING OF CHOLESTASIS, IN PART THROUGH INDUCTION OF ER-ASSOCIATED DEGRADATION (ERAD) PATHWAYS. OUR LABORATORY’S PREVIOUSLY PUBLISHED AND PRESENT PRELIMINARY DATA USING SEVERAL MODELS OF ER STRESS DEMONSTRATE THAT YOUNG MICE HAVE INADEQUATE UPR ACTIVATION (SPECIFICALLY WITHIN THE XBP1 PATHWAY) COMPARED TO ADULT MICE, AND THIS IS ASSOCIATED WITH INCREASED LIVER INJURY. THE SAME PATTERN OF IMPAIRED XBP1 PATHWAY ACTIVATION OCCURS IN EXPLANTED LIVERS FROM PEDIATRIC PATIENTS WITH CHOLESTATIC LIVER DISEASES COMPARED TO BOTH NORMAL AND DISEASE CONTROLS. THE GOAL OF MY CURRENT INVESTIGATIONS IS TO INCREASE THE UNDERSTANDING OF THE PATHOPHYSIOLOGIC HEPATIC RESPONSES OF THE XBP1 PATHWAY TO CHOLESTATIC LIVER INJURY AND IDENTIFY CHANGES DURING POSTNATAL DEVELOPMENT THAT INFLUENCE UPR ACTIVATION. THIS WILL ALLOW US TO TARGET SPECIFIC UPR PATHWAYS FOR THE DEVELOPMENT OF NOVEL TREATMENTS FOR PEDIATRIC CHOLESTATIC LIVER DISEASES. THEREFORE, I HAVE FORMULATED THE FOLLOWING SPECIFIC AIMS: 1) TO DEFINE AGE-DEPENDENT CHANGES IN XBP1 TRANSCRIPTION FACTOR FUNCTION USING MURINE MODELS OF ER STRESS 2) TO DEFINE THE PROTECTIVE MECHANISM OF XBP1 REGULATION OF ERAD IN CHRONIC CHOLESTASIS AND 3) TO DETERMINE THE CHANGES IN MECHANISM OF XBP1 SIGNALING WHICH OCCUR IN MURINE AND HUMAN BILIARY ATRESIA (BA). USING MURINE MODELS OF ER STRESS AND CHOLESTASIS AND HUMAN LIVER TISSUE FROM BA PATIENTS WE WILL IDENTIFY THE MECHANISM OF XBP1 SPECIFIC PATHWAY CHANGES THAT OCCUR DURING POST-NATAL DEVELOPMENT, AND HOW THESE CHANGES INFLUENCE DISEASE PROGRESSION IN RESPONSE TO CHOLESTASIS-INDUCED ER STRESS. CANDIDATE AND CAREER DEVELOPMENT: I AM A PEDIATRIC HEPATOLOGIST AT NORTHWESTERN UNIVERSITY WHO HAS A DEMONSTRATED COMMITMENT TO BASIC/TRANSLATIONAL RESEARCH THROUGHOUT MY EARLY CAREER. MY LONG-TERM CAREER GOAL IS TO BECOME AN INDEPENDENT, EXTRAMURALLY FUNDED PHYSICIAN-SCIENTIST WITH A FOCUS ON THE HEPATOCELLULAR UPR RESPONSE IN PEDIATRIC CHOLESTATIC LIVER DISEASES. THIS K08 PROPOSAL WILL HELP ACHIEVE THIS GOAL BY ADVANCING MY SCIENTIFIC SKILLS AND KNOWLEDGE IN GENE REGULATION, CELLULAR SIGNALING PATHWAY ANALYSIS AND HIGH-THROUGHPUT DATA ANALYSIS, AS WELL AS DEFINING THE ROLE OF THE UNFOLDED PROTEIN RESPONSE IN MURINE CHOLESTATIC LIVER DISEASE MODELS AND CORRELATIVE HUMAN DISEASES. ALONG WITH MY CO-MENTORS, DRS. GREEN AND BARISH, I HAVE DEVELOPED A CAREER DEVELOPMENT PLAN TO ACHIEVE THESE GOALS THROUGH DIDACTIC LECTURES, MENTORING, AND HANDS-ON LABORATORY TRAINING. THIS PROPOSAL WILL PROVIDE THE PROTECTED TIME AND RESEARCH TRAINING FOR FUTURE R01-LEVEL PROPOSALS EXTENDING MECHANISTIC XBP1 PATHWAY STUDIES WITHIN PEDIATRIC CHOLESTATIC LIVER DISEASES AND INVESTIGATING UPR-RELATED THERAPEUTICS.

A PROSPECTIVE STUDY OF BIOCHEMICAL AND GENETIC PREDICTORS OF PCOS IN HIGH RISK EARLY POSTMENARCHAL GIRLS

IMPACCT ? INFRASTRUCTURE FOR MUSCULOSKELETAL PEDIATRIC ACUTE CARE CLINICAL TRIALS

ITERATIVELY DEVELOPING AND TESTING A BRIEF, ENGAGEMENT FOCUSED INTERVENTION FOR PARENTS AND EDUCATORS: PARENT EDUCATION ACTION RESPONSE (PEAR) - PROJECT SUMMARY SYMPTOMS OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD) EMERGE AS EARLY AS PRESCHOOL AND ARE HIGHLY PERSISTENT THROUGHOUT CHILDHOOD. EARLY AND EFFECTIVE TREATMENT CAN BLUNT THE TYPICAL DEVELOPMENTAL PROGRESSION SEEN WITH ADHD. DESPITE THE IMPORTANCE OF EARLY INTERVENTION, HISTORICALLY MINORITIZED CHILDREN ARE LESS LIKELY TO BE IDENTIFIED AS NEEDING SUPPORTS, AND LESS LIKELY TO RECEIVE APPROPRIATE TREATMENT COMPARED TO WHITE CHILDREN. THIS DISPROPORTIONATELY IN SERVICE DELIVERY MAY PLACE SOME CHILDREN ON NEGATIVE LONG-TERM BEHAVIORAL HEALTH TRAJECTORIES. TO REDUCE THIS DRAMATIC DISPARITY IN ADHD THAT IS STRONGLY ASSOCIATED WITH THE TRAJECTORY OF A CHILD’S FUTURE, IT IS CRITICAL THAT WE IDENTIFY MALLEABLE FACTORS ASSOCIATED WITH ELIMINATING ADHD DISPARITIES IN PRESCHOOL. FOR PRESCHOOLERS WHO DISPLAY ELEVATED ADHD SYMPTOMS, BEHAVIORAL INTERVENTIONS ARE RECOMMENDED AS THE FIRST LINE OF TREATMENT AND ARE MOST EFFECTIVE WHEN THEY TARGET BOTH PARENTS AND TEACHERS. HOWEVER, PARENTS AND TEACHERS EXPERIENCE BARRIERS TO IMPLEMENTING BEHAVIORAL INTERVENTIONS WITH THE RECOMMENDED FREQUENCY AND FIDELITY WITH TEACHERS FREQUENTLY CITING PARENTS AS BARRIERS TO ADHERENCE OF BEHAVIORAL INTERVENTIONS. IN THE CURRENT STUDY, WE PROPOSE THAT THE RELATIONSHIP BETWEEN PARENTS AND TEACHERS IS A DETERMINANT OF ADHD OUTCOMES BY IMPACTING THE POTENCY (AND USE) OF BEHAVIORAL INTERVENTIONS. OUR OVERARCHING GOAL IS TO DISCOVER, DESIGN, AND TEST A BRIEF INTERVENTION TO IMPROVE PARENT AND TEACHER ENGAGEMENT IN BEHAVIORAL INTERVENTIONS FOR PRESCHOOLERS DEMONSTRATING ELEVATED ADHD SYMPTOMS (PARENT-EDUCATOR ACTION RESPONSE; PEAR). THE PROJECT WILL BE CONDUCTED IN 3 PHASES: 1) DISCOVER BARRIERS TO ENGAGING IN BEHAVIORAL INTERVENTIONS AMONG PARENTS AND PRESCHOOL EDUCATORS AS WELL AS STAKEHOLDER-INFORMED STRATEGIES TO ADDRESS THESE BARRIERS THROUGH AN INNOVATION TOURNAMENT (AIM 1), (2) ITERATIVELY DESIGN AND BUILD PEAR TO ADDRESS IDENTIFIED BARRIERS FROM AIM 1 THROUGH A PROGRAM DEVELOPMENT TEAM AND RAPID PROTOTYPING (AIM 2), AND (3) TEST THE ACCEPTABILITY AND FEASIBILITY OF PEAR IN SMALL-SCALE RANDOMIZED CONTROLLED TRIAL OF THE PEAR + BEHAVIORAL INTERVENTION COMPARED TO BEHAVIORAL INTERVENTION ONLY WITH 14 CLASSROOMS (42 PARENTS AND 14 EDUCATORS OF CHILDREN AGED 3-6 YEARS OLD WITH ELEVATED ADHD SYMPTOMS; AIM 3). THIS K23 REFLECTS THE NOTICES OF SPECIAL INTEREST IN DIVERSITY (NOT-OD- 20-31), NIMH STRATEGIC PLAN GOAL 3 (STRIVE FOR PREVENTION AND CURES), AND THE NIMH CALL TO PREVENT OR FORESTALL THE EMERGENCE OF ADHD IN PRESCHOOL (RFA-MH-21-230) BY FOCUSING ON PROMOTING PARENT AND TEACHER ENGAGEMENT IN BEHAVIORAL INTERVENTIONS TO IMPROVE IMPLEMENTATION, ULTIMATELY IMPROVING OUTCOMES FOR PRESCHOOLERS FROM HISTORICALLY MINORITIZED BACKGROUNDS WITH ELEVATED ADHD SYMPTOMS. THE RESEARCH AIMS WILL ALSO SERVE AS VEHICLES FOR PRAGMATIC LEARNING OF THE FOLLOWING TRAINING GOALS: 1) CULTURALLY HUMILITY, 2) EXPERTISE IN INTERVENTION DEVELOPMENT TO REDUCE DISPARITIES, 3) ADVANCED STATISTICAL MODELING AND MEASUREMENT MODELS FOR SOCIAL DETERMINANTS RESEARCH. THIS MENTORED K23 AWARD WILL FACILITATE DR. ZULAUF-MCCURDY’S LONG-TERM GOAL OF BECOMING AN INDEPENDENT INVESTIGATOR WITH EXPERTISE IN REDUCING MENTAL HEALTH DISPARITIES IN PRESCHOOL.

INTERVENTION DEVELOPMENT: REDUCING HIV RISK IN VULNERABLE YOUTH

MITOCHONDRIAL METABOLIC REGULATION OF GABAERGIC INTERNEURONS - PROJECT SUMMARY/ABSTRACT PRIMARY MITOCHONDRIAL DISEASES (PMDS) RESULT FROM INTRINSIC DYSFUNCTION OF MITOCHONDRIA AND HAVE A PREVALENCE OF 1 IN 5,000. ALTHOUGH OVER HALF EXPERIENCE NEUROLOGIC SYMPTOMS, PMDS ARE HETEROGENEOUS BOTH GENETICALLY AND PHENOTYPICALLY. GIVEN THE DISEASE HETEROGENEITY, METABOLIC PATHWAYS COMMON TO MULTIPLE FORMS OF PMD ARE APPEALING THERAPEUTIC TARGETS. HOWEVER, THE FULL EXTENT OF MITOCHONDRIAL METABOLISM IN NEURONS IS INCOMPLETELY UNDERSTOOD AS IN ADDITION TO GENERATING ENERGY IN THE FORM OF ATP THROUGH THE ELECTRON TRANSPORT CHAIN (ETC), MITOCHONDRIA ALSO GENERATE METABOLITES THROUGH THE TCA CYCLE AND REACTIVE OXIDATION SPECIES, ANY OF WHICH MAY CONTRIBUTE TO NEURONAL FUNCTION. THE FOUNDATION OF THIS PROPOSAL IS BASED ON PRELIMINARY STUDIES INDICATING THAT THE MITOCHONDRIAL TCA CYCLE PLAYS A CRITICAL ROLE IN GABAERGIC INHIBITORY INTERNEURONS WHICH ARE ESSENTIAL FOR REGULATING EXCITATORY NEURONAL CIRCUITS. THE FOCUS OF THE PROPOSAL IS TO TEST WHETHER THE ETC IS REQUIRED FOR INHIBITORY INTERNEURON SURVIVAL OR GABA METABOLISM. THE TWO AIMS WILL: (1) USE AN IN VITRO IPSC-DERIVED INHIBITORY INTERNEURON SYSTEM TO EVALUATE ACUTE MANIPULATION OF MITOCHONDRIA; AND (2) USE MICE LACKING MITOCHONDRIAL FUNCTION IN HIPPOCAMPAL GABAERGIC INTERNEURONS TO ESTABLISH THE EFFECTS OF CHRONIC MITOCHONDRIAL IMPAIRMENT. THE SCIENTIFIC PURPOSE OF THIS PROPOSAL IS TO BEGIN DEFINING THE EFFECTS OF MITOCHONDRIAL METABOLISM IN GABAERGIC HIPPOCAMPAL NEURONS, WITH THE VISION OF EXPANDING THE TOOLS AND MEASUREMENTS IN GABAERGIC NEURONS INCLUDING THOSE OUTSIDE THE HIPPOCAMPUS, AND EVENTUALLY TRANSLATE FINDINGS BY THERAPEUTICALLY TARGETING METABOLISM TO PROMOTE NEURONAL HEALTH IN MITOCHONDRIAL DISEASE. THE PROPOSAL IS A FIVE-YEAR PHYSICIAN-SCIENTIST DEVELOPMENT PROGRAM FOR THE CANDIDATE WHO IS AN ASSISTANT PROFESSOR OF PEDIATRICS AT NORTHWESTERN UNIVERSITY, WITH 75% PROTECTED TIME FOR RESEARCH, INDEPENDENT LABORATORY SPACE AND START-UP FUNDING. IN ADDITION, HIS CLINICAL TIME AT LURIE CHILDREN’S IS DEDICATED TO MANAGING CHILDREN WITH MITOCHONDRIAL DISEASE IN BOTH THE OUTPATIENT AND INPATIENT CRITICAL CARE SETTING. HE IS COMMITTED TO A CAREER IN TRANSLATIONAL MITOCHONDRIAL METABOLISM RESEARCH FOCUSED ON NEUROLOGIC SYMPTOMS AND IS STRONGLY SUPPORTED BY HIS DEPARTMENT OF PEDIATRICS, SECTION OF CHILD NEUROLOGY AND HIS MENTORSHIP TEAM. THE CANDIDATE WILL BUILD ON HIS PRIOR EXPERIENCE IN NEUROSCIENCE BY LEARNING ADVANCED TECHNIQUES IN MITOCHONDRIAL METABOLISM RESEARCH UNDER THE GUIDANCE OF HIS PRIMARY MENTOR, DR. NAVDEEP CHANDEL. ADDITIONALLY, HIS CO- MENTOR, DR. MUSTAFA SAHIN AT BOSTON CHILDREN’S AND HARVARD, WILL PROVIDE PROJECT- AND CAREER-LEVEL GUIDANCE AS AN EXPERIENCED TRANSLATIONAL RESEARCHER AND CHILD NEUROLOGIST. TOGETHER, THE PROPOSED EXPERIMENTS, COLLABORATIONS WITH EXPERTS, ADVICE FROM CONSULTANTS AND FORMAL DIDACTICS WILL PROVIDE THE SKILLS AND EXPERIENCE FOR HIS TRANSITION TO INDEPENDENCE AS A PHYSICIAN-SCIENTIST WITH UNIQUE EXPERTISE STUDYING MITOCHONDRIAL METABOLISM IN NEURONS, WITH THE LONG TERM GOAL OF TRANSLATING THE FINDINGS INTO TREATMENTS FOR PMD.

ESTABLISHING PRECURSORS OF FOOD ALLERGY IN NEWBORNS

INVESTIGATING THE IMPACT OF ESBL E. COLI COLONIZATION ON INFANT MICROBIOME - ABSTRACT THE RAPID RISE OF EXTENDED SPECTRUM BETA-LACTAMASE-PRODUCING (ESBL) ENTEROBACTERIACEAE IS SEVERELY THREATENING THE WAY WE TREAT COMMON INFECTIOUS DISEASES. ENTEROBACTERIACEAE SUCH AS ESCHERICHIA COLI (E. COLI) ARE A MAJOR CAUSE OF INFECTIONS SUCH AS BACTEREMIA, MENINGITIS, AND URINARY TRACT INFECTIONS IN NEONATES. GUT COLONIZATION WITH ESBL E. COLI IS A RISK FACTOR FOR THESE INVASIVE INFECTIONS. ADDITIONALLY, INFANTS WHO ARE ASYMPTOMATICALLY COLONIZED WITH ESBL E. COLI ALSO CONTRIBUTE TO THE COMMUNITY RESERVOIR OF THESE STRAINS. SEVERAL RECENT STUDIES HAVE SHOWN THAT ACQUISITION AND PERSISTENCE OF GUT COLONIZATION WITH ESBL E. COLI CAN OCCUR EVEN IN THE ABSENCE OF ANTIBIOTIC EXPOSURE, TRADITIONALLY CONSIDERED A KEY RISK FACTOR. AT BIRTH THE NEONATAL GUT IS ONLY SPARSELY POPULATED WITH MICROBES, AND THEREFORE PROVIDES A UNIQUE ENVIRONMENT FOR ACQUISITION OF ESBL E. COLI DUE TO THE LIMITED COMPETITION FROM OTHER MICROBES. A SIGNIFICANT PROPORTION OF INFANTS WHO ACQUIRE ESBL E. COLI EARLY IN LIFE REMAIN PERSISTENTLY COLONIZED WITH THEM. HOWEVER, THE IMPACT OF EARLY LIFE ACQUISITION ON THE RAPIDLY DEVELOPING INFANT GUT MICROBIOME IS NOT WELL STUDIED, ESPECIALLY IN THE SETTING OF VARYING AGE OF ACQUISITION AND NUTRITIONAL INTAKE. PREVIOUS WORK IN THE ARSHAD LABORATORY USING A MURINE MODEL OF EARLY LIFE E. COLI ACQUISITION HAS SHOWN THAT SEVERAL ESBL E. COLI PERSISTENTLY COLONIZE THE MOUSE GUT THROUGH ADULTHOOD WITH A SIGNIFICANTLY HIGHER BURDEN OF COLONIZATION COMPARED TO COMMENSAL NON-ESBL E. COLI. IN VITRO STUDIES SHOW THAT SOME OF THE STRAINS ADEPT IN GUT COLONIZATION ARE ALSO ABLE TO OUT COMPETE NON-ESBL E. COLI IN A LIMITED NUTRIENT GROWTH MEDIA AS WELL AS IN VIVO IN THE ANIMAL MODEL. PERINATAL TRANSMISSION OF AT LEAST ONE ESBL E. COLI IN OUR MURINE MODEL RESULTS IN AN OVERABUNDANCE OF E. COLI IN THE INFANT GUT MICROBIOME AND A DISPLACEMENT OF USUAL COMMENSAL MICROBES. THIS PROPOSAL AIMS TO UTILIZE CLINICALLY RELEVANT ESBL E. COLI, GENOMIC SEQUENCING, AND ANIMAL MODELS TO 1) DETERMINE THE GUT MICROBIOME CHARACTERISTICS ASSOCIATED WITH ESBL E. COLI COLONIZATION DURING THE EARLY LIFE PERIOD, AND 2) ASSESS GUT COLONIZATION WITH ESBL E. COLI AND IMPACT ON MICROBIOME ACCORDING TO AGE AND NUTRITIONAL STATUS. THESE OBJECTIVES WILL BE ACHIEVED BY BUILDING ON EXISTING COLLABORATIONS BETWEEN THE ARSHAD LAB (EXPERTISE IN BACTERIAL PATHOGENESIS AND ANIMAL MODELS) AND DEPLAEN LAB (EXPERTISE IN MOUSE GUT NUTRITION) AT LURIE CHILDREN’S HOSPITAL, AND HARTMANN LAB AT NORTHWESTERN UNIVERSITY (EXPERTISE IN BACTERIAL GENOMICS, NEXT-GENERATION SEQUENCING), AND GROBE LAB AT UNIVERSITY OF WISCONSIN (EXPERTISE IN CALORIC ASSESSMENT OF STOOL). WE ANTICIPATE THAT THE RESULTS FROM THE PROPOSED EXPERIMENTS WILL PROVIDE IN VIVO EVIDENCE OF THE LONG-TERM IMPACT OF GUT COLONIZATION WITH ESBL E. COLI ON THE INFANT GUT MICROBIOME. FURTHER, THE RESULTS OF THE PROPOSED STUDY WILL AID IN DEVELOPING NUTRITIONAL INTERVENTIONS AND/OR IDENTIFICATION OF COMMENSAL MICROBES THAT MAY BE USED AS PROBIOTICS, TO PREVENT LONG-TERM COLONIZATION WITH ESBL E. COLI.

DETERMINING THE BIOMECHANICAL AND BIOLOGICAL RESPONSE OF STRETCHED SKIN

CLOSTRIDIUM INNOCUUM AS AN EMERGING MULTIDRUG-RESISTANT ANTIBIOTIC-ASSOCIATED DIARRHEAL PATHOGEN

RATIONAL IDENTIFICATION OF CORYNEBACTERIUM STRAINS FOR USE AS PROBIOTICS - PROJECT SUMMARY PNEUMONIA IS THE LEADING INFECTIOUS KILLER OF CHILDREN. BACTERIAL PATHOGENS, PARTICULARLY STREPTOCOCCUS PNEUMONIAE, CAUSE THE MOST SERIOUS DISEASE AND MORTALITY. VACCINATION REDUCES INVASIVE DISEASES SUCH AS BACTEREMIA AND MENINGITIS CAUSED BY VACCINE SEROTYPES. HOWEVER, VACCINATION DOES NOT EQUALLY LOWER THE BURDEN OF PNEUMONIA, AND NON-VACCINE S. PNEUMONIAE SEROTYPES CONTINUE TO EMERGE TO CAUSE RESPIRATORY AND INVASIVE INFECTIONS. THUS, AN OPPORTUNITY EXISTS FOR NEW WAYS TO PREVENT THESE INFECTIONS. NASOPHARYNGEAL COLONIZATION PRECEDES BACTERIAL PNEUMONIA AND OTHER RESPIRATORY INFECTIONS, AND THE MICROBIOTA SERVES AS A BARRIER TO PATHOGEN COLONIZATION AND SUBSEQUENT INVASION OF THE LOWER RESPIRATORY TRACT. OUR STUDIES AND OTHERS DEMONSTRATE THAT COMMENSAL, NON-PATHOGENIC CORYNEBACTERIUM SPECIES ARE ASSOCIATED WITH A LOWER PREVALENCE OF COLONIZATION BY BACTERIAL RESPIRATORY PATHOGENS, INCLUDING S. PNEUMONIAE. THE DATA SHOW AN INVERSE CORRELATION BETWEEN THE RELATIVE ABUNDANCE OF CORYNEBACTERIUM IN THE NASOPHARYNGEAL MICROBIOTA AND THE RISK OF COLONIZATION BY S. PNEUMONIAE. THESE CORYNEBACTERIUM SPECIES MAY BE PROMISING BIOTHERAPEUTIC CANDIDATES FOR DEVELOPMENT IF THEY EXERT SPECIFIC MECHANISTIC CONTROL OF BACTERIAL RESPIRATORY PATHOGENS. THE OVERALL OBJECTIVE HEREIN IS TO IDENTIFY THE MECHANISMS BY WHICH CORYNEBACTERIUM SPP. COLONIZE THE HUMAN NASOPHARYNX AND EXCLUDE S. PNEUMONIAE COLONIZATION. THE RATIONALE IS THAT DEFINING THE MECHANISMS OF THESE INTERSPECIES INTERACTIONS WILL LEAD TO IDENTIFYING CORYNEBACTERIUM SPP. THAT EXERT MULTIPLE MECHANISMS OF PATHOGEN EXCLUSION AND ARE CANDIDATES FOR FUTURE BIOTHERAPEUTICS TO PREVENT RESPIRATORY INFECTIONS. THE SPECIFIC AIMS ARE: 1) IDENTIFY MECHANISMS BY WHICH CORYNEBACTERIUM SPP. ADHERE TO THE RESPIRATORY EPITHELIUM AND INHIBIT SP COLONIZATION THROUGH COMPETITIVE ADHERENCE, AND 2) ELUCIDATE NON-ADHERENCE MECHANISMS BY WHICH CORYNEBACTERIUM SPP. INHIBIT SP COLONIZATION. THIS PROPOSAL WILL COMBINE MODELS OF BACTERIA-HOST AND BACTERIA-BACTERIA INTERACTIONS TO DEFINE MECHANISMS THROUGH WHICH CORYNEBACTERIUM INHIBIT S. PNEUMONIAE COLONIZATION. WE WILL LEVERAGE COMPARATIVE GENOMICS OF A LARGE CORYNEBACTERIUM STRAIN REPOSITORY TO IDENTIFY ACCESSORY GENE CANDIDATES THAT MEDIATE RESPIRATORY EPITHELIUM ATTACHMENT, COMPETITIVE ADHERENCE WITH S. PNEUMONIAE, AND PNEUMOCOCCAL GROWTH INHIBITION THROUGH SECRETED FACTORS. THE IMPACT OF THIS WORK IS EXPECTED FROM THE MECHANISTIC INSIGHTS AND CORYNEBACTERIUM STRAIN IDENTIFICATION THAT MAY LEAD TO THE FIRST RATIONALLY-DESIGNED BIOTHERAPEUTICS TO PREVENT PNEUMONIA AND OTHER RESPIRATORY INFECTIONS.

IMMUNE MODULATION OF MACROPHAGES IN OBSTRUCTIVE CHOLESTASIS

PRETERM HUMAN MILK COMPOSITION IN CONDITIONS OF MATERNAL OVERWEIGHT AND OBESITY AND EFFECTS OF MILK CONSTITUENTS ON PRETERM INFANT BODY COMPOSITION - CONSIDERING THE INCREASING RATES OF MATERNAL OVERWEIGHT AND OBESITY (OW/OB) IN PREGNANCY AND LACTATION, A KNOWLEDGE GAP EXISTS REGARDING INFLUENCES OF THE MATERNAL METABOLISM ON PRETERM INFANT HEALTH THROUGH ALTERATIONS IN PRETERM HUMAN MILK COMPOSITION. THERE IS A CRITICAL NEED TO DEFINE LONGITUDINAL CHANGES IN PRETERM MILK COMPOSITION RESULTING FROM MATERNAL OW/OB ESPECIALLY IN CONJUNCTION WITH PRETERM INFANT HEALTH OUTCOMES. OUR LONG-TERM GOAL IS TO OPTIMIZE KNOWLEDGE OF HUMAN MILK NUTRIENT QUALITY IN CONDITIONS OF PRETERM BIRTH WHILE AC- COUNTING FOR THE CHANGING EPIDEMIOLOGY OF MATERNAL HEALTH IN PREGNANCY AND LACTATION. THE OVERALL OBJECTIVE IS TO DOCUMENT LONGITUDINAL CHANGES IN PRETERM HUMAN MILK COMPOSITION, SPECIFICALLY MILK FATTY ACIDS (FA) AND HORMONES, ASSOCIATED WITH MATERNAL OW/OB AND MEASURE REGULATORY EFFECTS OF MILK COMPONENTS ON INFANT BODY COMPOSITION. OUR CENTRAL HYPOTHESIS IS THAT WOMEN WITH OW/OB PRODUCE PRETERM MILK THAT IS COMPOSITIONALLY DIFFERENT FROM WOMEN WITH NORMAL WEIGHT AND THAT PRETERM INFANT ADIPOSITY IS SUSCEPTIBLE TO MATERNAL METABOLIC STATUS AND DIET VIA ALTERED MILK COMPOSITION. THE RATIONALE FOR THIS PROPOSED RESEARCH IS TO ADVANCE AND TAILOR RECOMMENDATIONS FOR PRETERM INFANT NUTRITION, ASSURING GUIDELINES ACCOUNT FOR INFANT AND MATERNAL METABOLISM. TO FULFILL THESE OBJECTIVES AND TEST THE HYPOTHESES, AIM 1 WILL DOCUMENT LONGITUDINAL CHANGES IN PRETERM MILK FA AND HORMONES ASSOCIATED WITH REGULATION OF INFANT BODY COMPOSITION, MEASURING VARIABILITY RESULTING FROM MATERNAL OW/OB. THIS WILL BE ACCOMPLISHED IN A PROSPECTIVE COHORT STUDY OF MOTHER-PRETERM INFANT DYADS WITH TWO GROUPS ENROLLED (N=144 TOTAL PARTICIPANTS): 1. PRIMARY: WOMEN WHO DELIVER AT 280/7-316/7 WEEKS OF GESTATION AND THEIR INFANTS (N=42 WOMEN, N=42 INFANTS) AND 2. REFERENCE: COMPARISON WOMEN WHO DELIVER AT 340/7-366/7 WEEKS OF GESTATION AND THEIR INFANTS (N=30 WOMEN, N=30 INFANTS). SCREENING AND ENROLLMENT WILL AC- COUNT FOR PRE-PREGNANCY BODY MASS INDEX (BMI) TO ACCRUE AN EVEN DISTRIBUTION ACROSS NORMAL, OVERWEIGHT AND OBESE BMIS (ONE-THIRD IN EACH) FOR BOTH GROUPS. SERIAL PRETERM MILK SAMPLES WILL BE OBTAINED THROUGH WEEK 5 OF LACTATION. RIGOROUS CLINICAL PHENOTYPING OF WOMEN AND INFANTS WILL OCCUR AS WELL AS OBTAINING WOMEN’S DIETARY INTAKE DURING LACTATION. AIM 2 WILL ASSESS THE ASSOCIATION OF MILK FA AND HORMONE INTAKE WITH PRETERM INFANT BODY COMPOSITION. AIR DISPLACEMENT PLETHYSMOGRAPHY AS WELL AS SKIN FOLDS THICKNESS WILL MEASURE INFANT BODY COMPOSITION. INFANT INTAKE OF MILK FA AND HORMONES WILL BE ESTIMATED BY DOCUMENTING DAILY NUTRITIONAL INTAKE AND THEN EVALUATED IN RELATION TO INFANT BODY COMPOSITION. THE PROPOSED CONTRIBUTIONS ARE SIGNIFICANT BECAUSE THEY WILL IDENTIFY ASPECTS OF BOTH MATERNAL AND PRETERM INFANT NUTRITION THAT ARE AMENABLE TO INTERVENTION AND WHICH HOLD GREATEST POTENTIAL TO ADDRESS HUMAN MILK VARIABILITY AND THE METABOLIC SUSCEPTIBILITIES OF THE PRETERM INFANT NOT AS YET INCORPORATED WITHIN INFANT FEEDING STANDARDS. THE PLANNED RESEARCH IS INNOVATIVE IN PROPOSING TO ADVANCE THE SCIENCE TOWARDS DEFINING PRETERM INFANT NUTRITIONAL STATUS AND REQUIREMENTS USING ENHANCED RISK STRATIFICATION, BASED IN PART ON INDICATORS OF MATERNAL METABOLISM AND HEALTH DURING PREGNANCY AND LACTATION.

SUBVENTRICULAR ZONE RESPONSES TO NEONATAL HYPOXIA-ISCHEMIA

RELEASING, ACTIVATING, AND MATURING FOLLICLES FROM CORTICAL TISSUE UTILIZING DYNAMIC SYNTHETIC MICROENVIRONMENT - PROJECT SUMMARY/ABSTRACT OVARIAN TISSUE CRYOPRESERVATION (OTC), A FERTILITY PRESERVATION OPTION FOR CANCER PATIENTS AND OTHERS AT INCREASED RISK OF DEVELOPING INFERTILITY THAT IS IDEALLY PERFORMED PRIOR TO THE GONADOTOXIC TREATMENT, HAS ENABLED >140 LIVE BIRTHS. HOWEVER, FERTILITY RESTORATION IS CURRENTLY LIMITED TO TRANSPLANTATION OF OTC TISSUE, AND SOME PATIENTS MAY NOT BE ABLE TO USE THIS OPTION DUE TO THE RISK OF REINTRODUCING THEIR DISEASE. AN ALTERNATIVE THAT IS NOT YET DEVELOPED FOR THE CLINIC, WOULD BE TO USE THE PRIMORDIAL FOLLICLES, THE OOCYTE AND SUPPORT CELL UNITS THAT ARE CRYOPRESERVED IN OTC, AND PERFORM IN VITRO GROWTH AND MATURATION (IVGM) TO PRODUCE EGGS. CURRENT ASSISTED REPRODUCTIVE TECHNOLOGIES REQUIRE 20 – 30 EGGS TO OFFER A GOOD CHANCE OF PRODUCING A CHILD. HOWEVER, CURRENT IVGM PROTOCOLS PERFORMED IN THE RESEARCH LAB ARE NOT EFFICIENT AND YIELD ONLY A FEW EGGS FOR EVERY 10 OR MORE PATIENTS. IMPORTANTLY, THE SUCCESS OF CURRENT METHODS FOR ISOLATING PRIMORDIAL FOLLICLES FROM OVARIAN TISSUE DRASTICALLY DIFFERS BETWEEN PATIENTS AND, AT BEST, ONLY A SMALL PERCENTAGE ARE OBTAINED INTACT. SECONDARY FOLLICLES MORE EASILY REMAIN INTACT, BUT FEW ARE CRYOPRESERVED DURING OTC. THEREFORE, PRIMORDIAL FOLLICLES MUST BE ACTIVATED TO GROW TO SECONDARY FOLLICLES IF OTC TISSUE IS USED TO MAKE EGGS. THE RATE LIMITING STEPS FOR ADVANCING IVGM ARE: (1) EFFICIENTLY AND RELIABLY ISOLATING HEALTHY PRIMORDIAL FOLLICLES THAT ARE ACTIVATED TO GROW, AND (2) EFFICIENTLY AND RELIABLY GROWING AND MATURING SECONDARY FOLLICLES INTO GOOD QUALITY EGGS. 3D-PRINTED BIOSCAFFOLDS OF SPECIFIC ARCHITECTURES CAN SUPPORT THE VIABILITY AND GROWTH OF SECONDARY FOLLICLES THROUGH EGG MATURATION IN VITRO, AS WELL AS PRIMORDIAL FOLLICLE GROWTH AND MATURATION THROUGH EGG MATURATION, OVULATION, AND LIVE BIRTH IN MICE. THESE PROMISING RESULTS LAY THE FOUNDATION TO FURTHER EXPLORE THE USE OF SPECIFICALLY DESIGNED BIOSCAFFOLDS TO ADDRESS CURRENT LIMITATIONS OF IVGM. THIS APPLICATION TESTS THE HYPOTHESIS THAT A DYNAMIC SYNTHETIC MICROENVIRONMENT WILL PROVIDE THE NECESSARY MECHANICAL AND ARCHITECTURAL CUES TO INDUCE STROMAL CELL MIGRATION OUT OF OVARIAN TISSUE, RELEASE OF THE EMBEDDED FOLLICLES, AND SUPPORT FOLLICLE GROWTH AND OOCYTE MATURATION INTO AN EGG. 3D-PRINTED BIOSCAFFOLDS OF VARYING MECHANICAL AND REMODELING PROPERTIES USING TUNABLE HIGHLY POROUS BIOMATERIALS WILL BE UTILIZED TO INDUCE FOLLICLE MIGRATION FROM CORTICAL TISSUE AND PROVIDE A DYNAMIC ENVIRONMENT THAT REMODELS OVER TIME AS THE FOLLICLES GROW. BOVINE OVARIES AS USED TO MIMIC HUMAN OVARIES IN SIZE, CORTICAL DENSITY, FOLLICLE GROWTH AND MATURATION FOR THE FOLLOWING AIMS: (1) TO DEFINE THE BIOSCAFFOLDS THAT SUPPORT STROMAL CELL MIGRATION AND SUBSEQUENT RELEASE, ACTIVATION, AND GROWTH OF PRIMORDIAL FOLLICLES; AND (2) TO DEFINE THE BIOSCAFFOLDS THAT INDUCE GROWTH AND MATURATION OF ISOLATED SECONDARY FOLLICLES IN VITRO. THESE STUDIES WILL IDENTIFY SPECIFIC PROPERTIES OF SYNTHETIC MICROENVIRONMENTS THAT CAN ENHANCE FOLLICLE ISOLATION FROM OVARIAN TISSUE, AS WELL AS THOSE THAT SUPPORT THE GROWTH AND MATURATION OF FOLLICLES INTO EGGS. IF SUCCESSFUL, THIS WORK WOULD ENABLE RESEARCHERS TO STUDY FOLLICULOGENESIS FROM PRIMORDIAL FOLLICLE ACTIVATION TO AN EGG IN A CONTROLLED ENVIRONMENT, WOULD UNCOVER A COMPLETELY NOVEL APPROACH TO IVGM AND SUPPORT THE DEVELOPMENT OF FUTURE TECHNOLOGIES FOR IVGM IN HUMANS.

FERTILITY DECISION-MAKING IN YOUTH AND YOUNG ADULTS

US PREVALENCE, DISTRIBUTION AND DETERMINANTS OF ADULT AND CHILDHOOD FOOD ALLERGY

ROLE OF THE KYNURENINE PATHWAY IN NEONATAL INTESTINAL MICROVASCULAR MALDEVELOPMENT AND NECROTIZING ENTEROCOLITIS - NECROTIZING ENTEROCOLITIS (NEC), CHARACTERIZED BY ACUTE ONSET INTESTINAL TISSUE DAMAGE AND ISCHEMIC NECROSIS, IS A MAJOR CAUSE OF MORBIDITY AND MORTALITY AMONG PREMATURE INFANTS. INTESTINAL VEGF/VEGFR2 PROTEINS AND INTESTINAL ENDOTHELIAL CELL (IENC) PROLIFERATION ARE SIGNIFICANTLY DECREASED IN OUR EXPERIMENTAL NEC MODEL PRIOR TO INTESTINAL TISSUE INJURY AND IN RESECTED HUMAN NEC TISSUE SAMPLES. WE PREVIOUSLY SHOWED THAT NEONATAL IENC ARE HIGHLY PROLIFERATIVE COMPARED TO ADULTS. GROWING EVIDENCE INDICATES THAT CELL METABOLISM PLAYS AN IMPORTANT ROLE IN ENDOTHELIAL CELL (ENC) PROLIFERATION AND ANGIOGENESIS BY PROVIDING ENERGY FOR CELL FUNCTIONS AND GENERATING BIOMASS, SUCH AS NUCLEOTIDES, FOR RNA/DNA SYNTHESIS. CURRENTLY, NOT MUCH IS KNOWN ABOUT THE DEVELOPMENTAL REGULATION OF IENC METABOLISM AND HOW IT IMPACTS IENC PROLIFERATION. FURTHERMORE, IT IS NOT KNOWN HOW NEONATAL IENC METABOLISM IS AFFECTED DURING STRESS AND ITS IMPACT ON INTESTINAL MICROVASCULAR NETWORK DEVELOPMENT AND NEC. MECHANISTIC STUDIES THAT INVESTIGATE THE UNDERLYING MOLECULAR PATHWAYS MAY REVEAL NEW PUTATIVE THERAPEUTIC TARGETS FOR TREATING NEC AND ARE STRONGLY NEEDED. KYNURENINE (KYN) IS A TRYPTOPHAN (TRP) METABOLITE AND A KEY INTERMEDIATE OF THE DE NOVO NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD) SYNTHESIS PATHWAY, LEADING TO FORMATION OF ADENOSINE, A PURINE NUCLEOSIDE. ABNORMALLY HIGH KYN AND NUCLEOSIDE LEVELS SUCH AS ADENOSINE HAVE BEEN PREVIOUSLY REPORTED TO INHIBIT CELL PROLIFERATION. OUR PRELIMINARY STUDIES INDICATED THAT THE LEVELS OF SEVERAL METABOLITES OF THE KYN PATHWAY AND PURINE RELATED PRODUCTS (KYN, ADENOSINE AND THE PURINE WASTE PRODUCT URIC ACID) WERE SIGNIFICANTLY LOWER IN NEONATAL IENCS COMPARED TO ADULT IENCS. WHILE THE KYN/TRP RATIO AND URIC ACID LEVELS WERE LOW IN NORMAL NEONATAL SERUM, THEY WERE SIGNIFICANTLY INCREASED IN THE SERUM OF NEONATAL PUPS SUBJECTED TO EXPERIMENTAL NEC AND AT HIGHER LEVELS IN ADULT ANIMALS, SUGGESTING HIGHER INDOLEAMINE 2,3-DIOXYGENASE 1(IDO1) ENZYMATIC ACTIVITY AND ACTIVATION OF THE KYN PATHWAY. THEREFORE, WE HYPOTHESIZE THAT THE ACTIVITY OF THE KYN PATHWAY NEEDS TO BE LOW TO SUPPORT THE HIGH PROLIFERATION RATE OF NEONATAL IENC NEEDED FOR POSTNATAL GUT ANGIOGENESIS AT BASELINE, WHILE HIGH ACTIVITY OF THE KYN PATHWAY CONTRIBUTES TO IMPAIRED IENC PROLIFERATION DURING NEC DEVELOPMENT. TO TEST OUR HYPOTHESIS, WE WILL CONDUCT TWO SPECIFIC AIMS: 1) TO INVESTIGATE WHETHER AND HOW IENC METABOLISM IS DEVELOPMENTALLY REGULATED AND TEST THE HYPOTHESIS THAT LOW ACTIVITY OF THE KYN PATHWAY IS REQUIRED FOR THE HIGHER PROLIFERATION RATE OF NEONATAL IENC. 2) TO EXAMINE THE ROLE OF THE KYN PATHWAY DURING NEC DEVELOPMENT USING OUR EXPERIMENTAL MOUSE NEC MODEL. THIS PROPOSAL WILL HELP CHARACTERIZE THE ROLE OF THE KYN PATHWAY IN IENC PROLIFERATION AND DURING NEC DEVELOPMENT, SO PREVENTATIVE AND/OR THERAPEUTIC INTERVENTIONS TO PRESERVE IENC PROLIFERATION COULD BE DEVELOPED TO MITIGATE NEONATAL MORBIDITY AND MORTALITY DUE TO NEC.

STRUCTURED PUBERTAL SUPPRESSION READINESS ASSESSMENT FOR GENDER DYSPHORIC YOUTH

NOVEL NON-INVASIVE APPROACH FOR PREDICTING RETINOPATHY OF PREMATURITY IN PREMATURE NEONATES - ABSTRACT: MALDEVELOPMENT OF THE MICROVASCULATURE IN PREMATURE NEONATES PLAYS A MAJOR ROLE IN COMPLICATIONS OF PREMATURITY WITH LIFE-LONG CONSEQUENCES SUCH AS RETINOPATHY OF PREMATURITY (ROP), NECROTIZING ENTEROCOLITIS (NEC) AND PULMONARY HYPERTENSION (PHTN) COMPLICATING BRONCHOPULMONARY DYSPLASIA (BPD), WHICH ARE MAJOR CAUSES OF MORBIDITY AND MORTALITY IN PREMATURE INFANTS. UNFORTUNATELY, THERE IS NO NON-INVASIVE METHOD ESTABLISHED TO ASSESS AND MONITOR SYSTEMIC MICROVASCULAR DEVELOPMENT IN PREMATURE BABIES TO PREDICT WHICH INFANT WILL DEVELOP THESE COMPLICATIONS. NAILFOLD CAPILLAROSCOPY IS A NON-INVASIVE TECHNIQUE USEFUL IN ADULTS AND CHILDREN WITH CONNECTIVE TISSUE DISEASES TO PREDICT RELAPSES, BUT NOT CURRENTLY USED IN PREMATURE NEONATES TO ASSESS CAPILLARY DEVELOPMENT. OUR PRELIMINARY DATA SUGGEST THAT, IN VERY-LOW-BIRTHWEIGHT (VLBW) INFANTS, NAILBED CAPILLARY NETWORK DENSITY PARAMETERS (E.G. CAPILLARY SKELETAL LENGTH PER AREA AND BRANCH POINTS PER AREA) SIGNIFICANTLY DECREASE DURING THE FIRST MONTH OF LIFE. OUR DATA ALSO SUGGEST THAT BABIES WHO ULTIMATELY DEVELOPED ROP HAD A HIGHER CAPILLARY DENSITY IN THE FIRST FEW WEEKS AFTER BIRTH COMPARED TO THOSE WHO DO NOT. IN THIS PROPOSAL, WE WILL TEST THE HYPOTHESIS THAT NAILFOLD CAPILLAROSCOPY CAN NON-INVASIVELY DETECT CAPILLARY DEVELOPMENT IMPAIRMENT IN PREMATURE INFANTS AND PREDICT DEVELOPMENT OF ROP REQUIRING MEDICAL INTERVENTION. THEREFORE, WE WILL ADDRESS THE FOLLOWING SPECIFIC AIMS: 1) IDENTIFY THE LONGITUDINAL DEVELOPMENTAL CHANGES OF NAILFOLD CAPILLARIES IN PREMATURE INFANTS; 2) DEFINE CAPILLARY NAILFOLD PARAMETERS THAT MOST RELIABLY PREDICT MODERATE TO SEVERE ROP DEVELOPMENT IN VLBW INFANTS. WE HAVE ESTABLISHED A MULTI-DISCIPLINARY RESEARCH TEAM WHICH INCLUDES THE NORTHWESTERN UNIVERSITY (NU) IMAGING CORE, THE NU SCHOOL OF ENGINEERING AND THE DEPARTMENTS OF OPHTHALMOLOGY AND NEONATOLOGY AT ANN & ROBERT H. LURIE CHILDREN’S HOSPITAL OF CHICAGO. IF SUCCESSFUL, THE SCIENTIFIC PREMISE OF THIS PROJECT WOULD INCLUDE: 1) TO NON-INVASIVELY IDENTIFY INFANTS WITH VASCULAR GROWTH IMPAIRMENT WHICH COULD BENEFIT FROM NOVEL THERAPEUTIC INTERVENTIONS AIMED AT PREVENTING MICROVASCULAR COMPLICATIONS OF PREMATURITY, INCLUDING ROP, THUS IMPROVING PATIENT OUTCOMES; 2) TO MONITOR THE SYSTEMIC EFFECT OF THERAPIES TARGETING THE MICROVASCULATURE E.G. ANTI-VEGF ANTIBODIES. FOR THIS PROOF-OF-PRINCIPLE STUDY, WE WILL FOCUS ON PREDICTION OF MODERATE TO SEVERE ROP AS ITS DIAGNOSIS IS DIRECTLY BASED ON THE EXTENT OF RETINAL CAPILLARY MALDEVELOPMENT. HOWEVER, WE PLAN IN THE FUTURE TO EXPAND OUR STUDY TO OTHER MICROVASCULAR BEDS THAT ARE LESS ACCESSIBLE TO EXAM AND TO DETERMINE WHETHER ABNORMAL NAILFOLD CAPILLARY DEVELOPMENT IS ABLE TO PREDICT OTHER COMPLICATIONS OF PREMATURITY E.G. NEC, BPD-RELATED PHTN.