IMPH Research in Child and Adolescent Health

Addressing Health Literacy and Numeracy to Prevent Childhood Obesity 
Determinants of Early Childhood Asthma and Atopy Following Infant RSV Infection 
Growing Right Onto Wellness (GROW): Changing Early Childhood BMI Trajectories 
Host and Viral Determinants of Childhood Allergy and Asthma 
Midcareer Investigator Patient-Oriented Research Award in Bronchiolitis & Asthma 
Optimizing Integrated PMTCT Services in Rural North-Central Nigeria 
Parent-Child Communication About Cancer 
Prescribed
Opiod Safety in Children 
Pregnancy Folate Status & Early Childhood Respiratory & Atopic Disease Outcomes 
Prematurity and Respiratory Outcomes Program (PROP) 
Primary Prevention of Strokes in Nigerian Children with Sickle Cell Disease 
Rates of Rhinovirus Species in Adults and Children with Acute Respiratory Illness 
Rational Design of a Respiratory Syncytial Virus Vaccine to Prevent Asthma 
Returning Research Results of Pediatric Genomic Research to Participants 
Studies on Emergent Diarrheagenic E. Coli Pathogens 
Telephone Counseling - Caregivers for Children with Cancer 
Tools to Reduce Infant RSV Morbidity and Asthma: Use,
Adherence and Effectiveness 
Using Social Learning to Improve Adolescent Diabetes Adherence Problem Solving

Addressing Health Literacy and Numeracy to Prevent Childhood Obesity

In 2003, Surgeon General Richard Carmona stated that low health literacy was "one of the largest contributors to our nation's epidemic of overweight and obesity." This assertion is supported by recent studies which have found that low health literacy or numeracy is associated with poorer caregiver breastfeeding knowledge, incorrect mixing of infant formula, difficulty understanding food labels and portion sizes, and higher Body Mass Index (BMI) in adults and children. Of particular concern is the impact of the obesity epidemic on our youngest children. Over 26% of preschool children are now overweight (BMIe85%) or obese (BMIe95%) (based on 2007 HHS/CDC Expert Panel definitions). Rates of obesity in preschool children have doubled over the past decade, with the highest increases among low income and minority children-- the same communities most affected by low health literacy. To date, clinical efforts to prevent or treat childhood obesity have had limited efficacy. Efforts need to start early, because children who are overweight by age two are five times as likely to become overweight adolescents, and subsequently at higher risk for obesity-related complications including early-onset Type-2 Diabetes and cardiovascular disease. No published clinical studies have rigorously addressed obesity prevention prior to age 2 with a specific low-literacy and numeracy focus. Addressing caregiver health literacy in early childhood is an innovative strategy to promote healthy nutrition and activity among these families and prevent unhealthy weight gain across the child's life, which would have great public health significance by preventing both child and adult chronic illness. The proposed study is a multi-site randomized, controlled trial to assess the efficacy of a low- literacy/numeracy-oriented intervention designed to promote healthy family lifestyles and to prevent early childhood obesity. The intervention will be delivered through pediatric resident physicians in primary care settings in under-resourced communities. Four academic medical centers will be randomized: Vanderbilt University, the University of Miami, the University of North Carolina at Chapel Hill, and New York University. Two centers will receive the intervention, while the other two centers will receive an active control. At each site, a cohort of 250 English- or Spanish-speaking caregiver-child dyads will be enrolled and followed from the child's 4-6 month well-child visit through the 24-month well-child visit. The intervention will include a low- literacy-oriented toolkit for pediatric residents to use with families and clear health communication training for the pediatric residents. At control sites, pediatric residents will provide "usual care" with respect to lifestyle counseling, but they will also receive an injury-prevention education program to act as an attention control. The primary hypotheses are that the intervention will improve family dietary and physical activity behaviors and that it will reduce the rate of childhood overweight (BMIe85%) at age 24 months. Project Narrative In 2003, Surgeon General Richard Carmona suggested that low health literacy is "one of the largest contributors to our nation's epidemic of overweight and obesity." Over 26% of preschool children are now overweight or obese, and children who are overweight by age 24 months are five times as likely as non- overweight children to become overweight adolescents. The aim of the study is to assess the efficacy of a low- literacy/numeracy-oriented intervention aimed at teaching pediatric resident physicians to promote healthy family lifestyles and prevent overweight among young children (age 0-2) and their families in under-resourced communities. Read more.

Funding Source: NIH/NICHD
PI: Russell Rothman

Determinants of Early Childhood Asthma and Atopy Following Infant RSV Infection

RSV bronchiolitis and early childhood asthma are the most common, serious, acute, and chronic conditions of infancy and childhood, respectively, and diseases that disproportionately burden vulnerable populations. Opportunity and Impact. This project draws together three important elements in understanding the role of RSV on recurrent wheezing and asthma inception - RSV infection severity, host response and susceptibility. In studying the association of RSV with asthma inception, studies have overwhelmingly focused on the 3-5% of RSV-infected infants requiring hospitalization, while the vast majority of RSV infections are mild. Whether mild infection confers intermediate risk or has a protective effect is an important question. The answer will influence proposals for primary asthma prevention strategies. The proposed series of investigations will aid in our understanding of the role and mechanisms through which RSV may both lead to chronic lung disease, and may protect from chronic lung disease. Approach. Utilizing the ReSPIRA cohort, established for this investigation and described in Core B, we will investigate the relationship between infant RSV infection, host response to infection, and genetic determinants of recurrent wheezing, asthma and allergic disease development following RSV infection. Our specific aims are to: (1) Establish the association between RSV LRTI, RSV URI/exposure, and no RSV infection in the first 6 months of life on the risk of recurrent wheezing and asthma, (2) Define whether host immune response and/or airway injury biomarkers assessed during infant RSV infection are associated with recurrent wheezing, atopic disease or early childhood asthma, and (3) Identify the genetic determinants of the phenotype of recurrent wheezing, early childhood asthma and atopy following infant RSV infection. Utilizing the ReSPIRA cohort which includes 2000 infants followed from early infancy through early childhood, and established through this U19 grant, this project will answer the following questions: (1) how does RSV cause asthma, (2) does mild RSV infection during infancy increase or decrease the risk of asthma, and (3) what host factors are important in the progression from infant RSV infection to early childhood asthma. Answering these questions will allow us to develop preventive interventions for chronic lung disease in children, and ultimately improve the health of infants and children with bronchiolitis and asthma in the U.S. and worldwide. Read more.

Funding Source: NIH/NIAID
PI: Tina Hartert

Growing Right Onto Wellness (GROW): Changing Early Childhood BMI Trajectories

Food preferences and activity habits set in early childhood can profoundly influence lifelong trajectories for Body l\/lass Index (BMI) and health. Specifically, rapid BMI gain in early childhood has been established to affect adulthood mortality and morbidity. Unfortunately, the longer such unhealthy patterns are in place, the more difficult it can be to reverse them. Therefore, healthy lifestyle interventions targeted at children as early as preschool 'have enormous potential to affect lifelong health. Furthermore, nutrition and activity patterns are determined not only at the child level, but within the family and the community. Building on the success of an existing partnership between Vanderbilt Pediatrics and Metro Parks and Recreation in Nashville, TN, we will conduct and evaluate an intervention intended to prevent obesity in preschoolers in an approach that affects multiple levels of risk and is both family-based and community centered. Prior to launching a large randomized controlled trial (RCT), formative research (focus groups and pilot studies) will be conducted to refine the intervention components. In the RCT, 600 parent-preschool children dyads from low income neighborhoods will be randomly assigned to one of two conditions. In the intervention condition, groups of parent-child dyads will participate in an empirically tested, literacy-sensitive, skills building curriculum to improve: 1) caloric intake with appropriate macronutrients, and 2) routine physical activity for both parent and child. The intervention condition will occur in community centers and utilize tools including goal setting, self-monitoring, and problem solving. In the control condition parent-child dyad groups will receive a literacy promotion/school success curriculum. Both conditions will have 90-minute sessions in: 1) an initiation phase (weekly for 3 months); 2) a maintenance phase (biweekly for 6 months); and 3) a sustainability phase (monthly for 27 months). The primary outcome of interest will be early childhood BMI trajectories measured at multiple time points over the three year RCT. Additional measures collected throughout the study from children and parents will include: bioelectrical impedance; waist circumference; actigraphy; 3-day diet recalls; questionnaires; social network data; and saliva to assess a genetic risk score associated with obesity. RELEVANCE: Pediatric obesity prevention must occur in preschool given that 60% of oven/weight preschoolers will go on to become overweight adolescents. By conducting and testing trials in public community centers, exportable interventions could result allowing for a macro-level system change to address this expanding public health crisis. Read more.

Funding Source: NIH/NHLBI 
PI: Shari Barkin

Host and Viral Determinants of Infant and Childhood Allergy and Asthma

This application will examine the effects of both host genetic and immune response determinants, as well as the influence of specific RSV strains on severity of RSV bronchiolitis and childhood asthma, and define the role of a novel therapeutic target, PGI2, in RSV pathogenesis.  The long-term objective is to define the relationship between infant respiratory syncytial virus (RSV) infection and the host response that enables asthma inception. Read more.

Funding Source: NIH/NIAID
Project and Core PI: Tina Hartert

Midcareer Investigator Patient-Oriented Research Award in Bronchiolitis & Asthma

Asthma is the result of host and environment interactions. Lower respiratory tract infections (LRTI), caused by viruses such as respiratory syncytial virus (RSV) and rhinovirus (RV), are a leading cause of bronchiolitis in infants. Infants hospitalized with bronchiolitis not only experience significant morbidity, but are also at significantly increased risk for both recurrent wheezing and childhood asthma. We have established that respiratory syncytial viral infections appear to directly contribute to asthma causation, not just simply identify persons at risk for subsequent wheezing. Viral infections outside the infant period are also important, as they are modifiable environmental factors that have been established to be the most common cause of asthma exacerbations in both children and adults. This proposal uses a combined, parallel clinical and experimental approach to evaluate the contribution of, causality, and mechanisms through which respiratory syncytial virus, and human rhinovirus, contribute to asthma development and disease natural history. These studies all relate to the central hypothesis that viruses, as one significant environmental factor, alter the risk for developing asthma, as well as the natural history of prevalent disease. Specific testable questions related to this hypothesis include: 1) to determine the host factors among those with RSV and HRV infection that contribute to asthma development, 2) to determine the timing of infection during infancy and how that impacts the risk of developing childhood asthma; 3) to determine the mechanisms through which RSV and HRV contribute to asthma development, specifically focusing on lung injury and differential immune response to infection; 4) to determine if there are allelic variations in host genes involved with severity of respiratory viral infection that correlate with a predisposition or resistance to both infant bronchiolitis and childhood asthma; 5) to determine if there are allelic variation in RSV genes that are associated with both infant LRTI severity, and subsequent risk of asthma development. PROJECT NARRATIVE The aims of this mid-career investigator award will be met by allowing the candidate to translate her experimental expertise to both mentor trainees and to direct patient-oriented studies of the progression and functional outcome of childhood viral illness in asthma development, moving from risk factor determination to intervention studies, and ultimately to disease prevention. Read more.

Funding Source: NIH/NIAID
PI: Tina Hartert

Optimizing Integrated PMTCT Services in Rural North-Central Nigeria

In resource-limited settings progress in scaling up services for prevention of mother-to-child transmission of HIV (PMTCT) continues to lag behind the rest of the world. Nigeria has one of the highest burdens of mother-to-child transmission of HIV in the world. The elimination of mother-to-child transmission of HIV in Nigeria will require innovative methods of PMTCT service delivery at the lowest level of the health care system, consistent with appropriate, feasible and effective care. The goal of this study is to implement and evaluate the impact of a family- focused integrated PMTCT package comprising task shifting, point-of-care CD4 testing, and a prominent role for influential family members (particularly male partners) in rural primary health centers in Nigeria. The specific aims of this study are: (1) To evaluate whether implementation of the integrated PMTCT package in primary level antenatal clinics increases the proportion of eligible pregnant women who initiate antiretroviral medications for the purposes of PMTCT; (2) To determine whether implementation of the PMTCT package improves postpartum retention of mother-infant pairs at 6 weeks; and (3) Conduct a cost-effectiveness analysis of the impact of this novel PMTCT intervention compared to the existing standard-of-care referral model. We have assembled a strong team of Nigerian and American scientists with expertise in PMTCT cluster randomized trials, adherence and retention in care, HIV risk behavior, cART outcomes, and cost-effectiveness analysis of HIV programs. We include a rigorous study design and triangulation of data collection methods (quantitative outcomes, cost effectiveness analysis, qualitative surveys) that will yield valuable complimentary data. We will build on existing in- country PEPFAR infrastructure, established partnerships, and strong local presence, thereby increasing the likelihood of successful study implementation. Read more.

Funding Source: NIH/NICHD
PI: Muktar Aliyu

Parent-Child Communication About Cancer

This is a competing renewal application to conduct theoretically-driven research to determine the course and predictors of mental health, social, and physical health outcomes in a cohort of children with cancer and their parents. We have been following a sample of 258 children (ages 5 to 17-years at entry into the study) from near the time of their cancer diagnosis over the first year after their diagnosis with a very high retention rate. By the end of this grant period we will have collected 3 waves of data including observations, interviews and questionnaires and we now propose to collect 2 additional waves of data, including direct observations of parent-child interactions, up to 5 years after diagnosis. Child and their parents completed measures about sources of cancer-related stress, how they cope with cancer, standardized indicators of distress and mental health problems, and they participated in video recorded observations. We propose to extend this work to examine the transition off treatment and into survivorship. Our aims are: 1) To examine continuity and change in parent-child communication about cancer; 2) To identify early predictors of later mental and physical health outcomes for children with cancer and their parents; and 3) To examine reciprocal relationships between parent and child coping, mental and physical health. To meet these aims, we propose to collect 2 additional waves of interview, observational and multi-agent questionnaire data spaced 12 months apart. The project is designed to identify risk and protective factors and processes that can be used to establish a theory-driven model of coping and adaptation to childhood cancer and to identify targets for the future early preventive psychosocial interventions with children with cancer and their parents. Read more.

Funding Source: NIH/NCI 
PI: Bruce Compas

Prescribed Opiod Safety in Children

The epidemic of toxicity related to prescription opioid use among U.S. adults is thought to be related to drug abuse. Thus, the public health response has focused on programs to reduce non-medical uses. However, little attention has been given to the possibility of a parallel epidemic among children, particularly vulnerable to opioid toxicit. Preliminary Tennessee Medicaid data suggest this epidemic now possibly affects children: the proportion of children 2-17 years old prescribed opioid analgesics increased from 5% in 1996 to 11% in 2007, with a comparable trend in medical care possibly consistent with opioid toxicity. What is the appropriate public health response to this potential threat to the safety of children? Because children's prescriptions must be filled by a parent or guardian, non-medical use is less plausible, particularly for young children. For this reason, pediatric opioid toxicity is most likey to be an unintended consequence of therapeutic use, which would need to be considered as part of prescription risk-benefit evaluation. Thus, there is an urgent need to quantify the incidence of opioid toxicity in children to inform pediatric practitioners' decision-making. Furthermore, opioid prescribing practices associated with elevated risk need to be identified so these can be avoided when possible. Potentially hazardous practices include higher doses, high-potency opioids such as oxycodone, and concurrent central nervous system depressants. To address this unmet public health need, we will conduct a large retrospective cohort study in an estimated 500,000 Tennessee Medicaid children 2-17 years of age with 1,000,000 filled opioid prescriptions and 1400 confirmed cases of opioid toxicity. There are two specific aims: Aim 1. Quantify the incidence of toxicity related to prescription opioid use according to a) the child's age, b) toxicity severity, and c) whether or not the toxicity was related to therapeutic use. Aim 2 Test the hypothesis that opioid toxicity risk increases with: a) increased opioid dose, b) high-potency opioids, and c) concurrent use of other CNS-depressant drugs. These data on the risks of opioid medications increasingly used by children will provide a sound basis for altering pediatric practice to address a novel threat to the safety of this vulnerable population. Read more.

Funding Source: NIH/NICHD
Pi: Wayne Ray

Pregnancy Folate Status & Early Childhood Respiratory & Atopic Disease Outcomes

The long-term goal of this project is to determine whether maternal folic acid supplementation during pregnancy increases the risk of early childhood asthma and atopy. Supplementation with folic acid, synthetic folate, is recommended during the periconceptional period to prevent neural tube defects (NTD). Studies in different populations have suggested an association between reported folic acid supplementation during pregnancy and increased risk of infant lower respiratory tract infection and early childhood asthma, but data are limited. While adequate intake of folate is essential for prevention of NTDs, it is important to delineate the impact of supplementation on the risk of common respiratory and atopic diseases. Folate plays an important role in DNA methylation, a regulator of gene expression. A causal relationship between folic acid supplementation and respiratory outcomes in children has not been established. However, this relationship does have some biologic plausibility. In a pregnant mouse model, a diet high in methyl donors, including folate, resulted in an augmented allergic phenotype in the offspring, as seen in asthma. Opportunity and Impact. There is no primary prevention strategy for atopic diseases such as asthma. Our objective is to determine whether higher maternal folate intake or the timing of this intake increases the risk of wheezing, asthma, and other atopic diseases in children. This collective work will characterize maternal folate status using objective measures and will assess childhood wheezing, asthma, allergic rhinitis, and atopic dermatitis using validated tools and objective measures. This will be the first investigation in a country with a national fortification program, where individuals may have high intake of folic acid from the diet. Approach. This work will use complementary retrospective and prospective cohorts of mother-child pairs. Specific aim #1 will investigate the population-based incidence of wheezing and asthma during the first 6 years of life, by the timing of folic acid containing prescriptions filled during pregnancy in a retrospective cohort of 80,000 mother-child dyads from the Tennessee Medicaid population. Specific Aim #2 will determine if a) measured maternal plasma folate levels or b) reported folate intake is associated with prospective development of wheezing, asthma, and/or atopy in the first 5 years of life in mother-child dyads enrolled in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) cohort. Innovation and Sustainability. This innovative, cost-efficient project will have the advantages of 1) a well-characterized retrospective cohort with a large number of mother-child dyads and determination of folic acid prescriptions filled by month of pregnancy and 2) a prospective cohort that includes the rich, existing infrastructure of the CANDLE cohort with maternal and infant biospecimens, nutritional data, and prospective follow-up using validated tools and objective measures to assess respiratory and atopic outcomes. This study has potential to inform prenatal recommendations and identify modifiable risk factors for asthma and atopy. Read more.

Funding Source: NIH/NHLBI 
PI: Kecia Carroll

Prematurity and Respiratory Outcomes Program (PROP)

This proposal will explore developmental, genetic and environmental interactions and identify biochemical markers to predict BPD development and severity, with the ultimate goal of designing new treatments to prevent BPD and improve long-term lung function in premature infants. Read more.

Funding Source: NIH/NHLBI
PI: Judy Aschner, Tina Hartert, Paul Moore

Primary Prevention of Strokes in Nigerian Children with Sickle Cell Disease

Sickle cell disease (SCD) is the most common genetic disease in the world. Approximately 150,000 Nigerian children are born each year with SCD, making it the country with the largest burden of sickle cell disease in the world. SCD is the most common cause of stroke in children and results in considerable morbidity in affected children. The current primary prevention approach of regular monthly blood transfusion therapy of children at high risk of stroke (identified by elevated transcranial Doppler measurements) is not feasible in a low income country such as Nigeria due to scarcity of supply, cost, and high rate of blood borne infections. In the United States, hydroxyurea (HU) is standard therapy for adults with SCD and may be a reasonable prevention alternative to regular blood transfusion for treatment of primary stroke in high-risk children. Given large absolute numbers of individuals with SCD in Nigeria, HU therapy for all individuals with SCD may not be initially feasible; however, a targeted strategy of HU use for primary prevention of strokes is an alternative to the standard therapy (observation) for high-risk individuals. We therefore propose a feasibility study to determine the acceptability of randomization to HU vs. placebo for primary prevention of strokes in Nigerian children with sickle cell anemia (SCA) in preparation for a NIH sponsored multicenter, phase III Trial. We will establish a safety protocol for using HU in a clinical trial setting and complete the necessary preparations for a definitive phase III trial. To accomplish these aims we have assembled a strong multidisciplinary team representing Vanderbilt University and two premier in-country institutions: Aminu Kano Teaching Hospital, Nigeria, and Friends in Global Health-Nigeria. Completion of a definitive trial will not only benefit children wth SCA in sub-Saharan Africa, where the majority of children with SCA live in the world, but could provide reasonable evidence for an alternative to blood transfusion therapy for the primary prevention of strokes in the US. To our knowledge this would be the first stroke prevention trial in Nigeria and could establish a precedent to expand to secondary stroke prevention for children and adults with SCA, as regrettably, no therapy is available to prevent recurrent stroke in these high-risk patients in resource-poor nations. Read more.

Funding Source: NIH/NINDS
PI: Michael Debaun et al.

Rates of Rhinovirus Species in Adults and Children with Acute Respiratory Illness

Human rhinoviruses (HRV) are the leading cause of the common cold and more recently have been implicated in lower respiratory illness, in infants and children. While many respiratory viruses have been associated with asthma exacerbations, HRV are the most common trigger of asthma exacerbations and chronic obstructive pulmonary disease (COPD) in children and adults. The rates of HRV-associated acute respiratory illness medical visits in US adults are not known. Recently, a new group of HRV designated HRVC was identified that may associate with asthma and COPD exacerbations. The impact of the novel HRVC on US adults has not been established, and the association of HRVC with obstructive wheezing diseases such as asthma and COPD is unclear. We propose to define the role of HRV and the novel HRVC group in adults and children seen as outpatients or hospitalized with ARI/fever, including those with asthma or COPD exacerbation. The central hypotheses of our proposal are that HRV are commonly associated with ARI/fever in adults and children and that HRVC associate with wheezing and more severe respiratory disease. The results of the proposed research will help guide vaccine development and elucidate mechanisms of virus-induced asthma. The findings of this work may lead to new approaches to treat and prevent asthma. We propose three Specific Aims: 1) to determine the rates of HRV in adults and children who seek medical care for acute respiratory illness (ARI) or fever, 2) to determine the rates of HRV species A, B, and C that are associated with ARI/fever in adults and children seen in different clinical settings, and 3) to determine rates of HRV and HRV species associated with obstructive wheezing illness such as asthma and chronic obstructive pulmonary disease (COPD) among adults and children. This research allows us to understand the burden of HRV and HRVC in US adults and children, as well as which HRV genotypes affect certain age groups, and elucidates the relationship between severity and type of respiratory disease and viral species. This may ultimately allow for a more targeted vaccine to be developed against HRV and may shed light on certain groups, such as those with asthma or COPD, at risk for more severe HRV-associated disease. Read more.

Funding Source: NIH/NIAID
PI: Eva Kathryn Miller

Rational Design of a Respiratory Syncytial Virus Vaccine to Prevent Asthma

Respiratory syncytial virus (RSV) severe lower respiratory tract infections (LRTIs) in infants and young children associate with 25-80% greater subsequent rates of recurrent wheezing, airways hyperreactivity (AHR) and asthma compared to same age children not experiencing severe RSV LRTIs. Some of these severe RSV LRTIs may identify those infants genetically predisposed to develop asthma at older age, but epidemiological studies and animal models suggest that severe RSV LRTIs may also specifically contribute to asthma inception. In fact, enough evidence exists today to consider a potential role for protective RSV vaccines in decreasing pediatric asthma rates by preventing severe RSV LRTI. Interestingly, and in line with the overwhelming evidence supporting the Hygiene Hypothesis, upper respiratory tract infections (URTIs) during infancy have been shown to decrease the rates of pediatric asthma and AHR. Moreover, epidemiological data, studies in animal models, and preliminary data from our laboratory support the hypothesis that a rationally designed live attenuated intranasal (IN) RSV vaccine (mimicking an RSV URTI) may contribute to modulate the development of immunity in the host and prevent asthma inception. Data from others and our laboratory show that RSV and its main protective antigen, the fusion (F) protein, can elicit a long-lived natural T regulatory (nTreg) lymphocyte response, presumably through Myd88-dependent activation, negatively modulating asthma inception. In addition, animal and human data from our laboratory demonstrate that RSV can downregulate TLR4 expression in the respiratory tract. TLR4 expression in the respiratory epithelium is critical for the inception f asthma in the classic house dust mite (HDM) model of disease. Therefore, if all these observations - which we propose to study- are confirmed, rationale design of an RSV vaccine considering the aforementioned effects, may change the landscape of pediatric asthma by: I) protecting against the pro-asthmatic effects of RSV LRTI, and 2) "maturing" host immunity. Understanding the protective effects of RSV vaccines and the virus glycoproteins against the inception of asthma, and their mechanisms of risk modulation, can lead to the rationale design of a pediatric vaccine working simultaneously against two critical pediatric diseases. Our Specific Aims are: Aim 1. Determine whether intranasal immunization using RSV surface glycoproteins F and G modulates the inception of asthma. Aim 2. Determine whether RSV F vaccines decrease inception of asthma by expanding nTregs through Tlr2 activation and downregulation of Tlr4 expression in respiratory epithelium. Aim 3. Determine whether IN immunization with cptsRSV248-404 prevents the inception of asthma. Read more.

Funding Source: NIH/NIAID
PI: Fernando Polack

Returning Research Results of Pediatric Genomic Research to Participants

The specific aim of this project is to determine what criteria should govern return of individual results of pediatric genomic research, using analysis of US law and international guidelines regarding decision making for and by minors as the foundation. This issue, which has received remarkably little attention, must be resolved if this research, which is vital to understanding the contributions of genetic variation to the health of children, is to proceed. In order to develop these criteria, it will be necessary to draw upon a host of ethical, legal, and sociocultural factors, using standard legal analytic tools. ¿ There is a long tradition within genetics, embodied in policy statements, such as those by the American Society of Human Genetics, the American College of Medical Genetics, and the American Academy of Pediatrics, of performing genetic tests on minors only when the results would alter the minor's immediate medical care. These limits are justified in part by the claim that, in the absence of need for immediate intervention, the minor should be allowed to decide about genetic testing upon reaching adulthood. ¿ More generally, decisions regarding the health care of children are treated differently from those of adults because children, as a matter of law, typically cannot make their own health care decisions. Procedurally, ethical and legal decision making authority, instead, is allocated among: 1) Parents who have broad authority to make choices among available options that affect their children. The scope of parental permission for their children's care, however, is not as broad as their discretion with regard to their own health care; 2) Clinicians who have an independent obligation to the welfare of the minor, which is bounded by the standards of clinical practice as well as legal requirements; 3) Minors who many hold have an increasingly important ethical and legal voice as they mature; and 4) In cases of abuse, neglect, or need to protect public health, the state. Substantively, defining the minor's best interest is often contested. One issue that is particularly challenging is deciding what weight should be given to various potential benefits from returning results, ranging from immediate benefit to the minor's health or reproductive information for the minor's later use to benefits that redound primarily to the family unit as a whole or exclusively to the parents or even to other minors of the same age or with the same condition. ¿ Research involving minors is subject to more legal and ethical requirements and limitations than apply to adults. This project brings together three internationally known lawyers, each of whom has written extensively about legal and policy issues in genomics research and in pediatrics, as well as an internationally known pediatrician- philosopher as a consultant, to define the applicable legal rules and to develop guidelines for returning results of genomic research involving minors. Read more.

Funding Source: NIH/NHGRI
PI: Ellen Clayton

Studies on Emergent Diarrheagenic E. Coli Pathogens

Childhood diarrhea leads to 2 million deaths every year among children less than 5 years of age mainly in underserved countries. E. coli pathogens are believed to be the second most common cause of death after Rotavirus. Six categories of diarrheagenic E. coli have been known to cause diarrhea, yet, recent studies by our group have identified a new diarrheagenic category designated localized adherent E. coli (LAEC) that is significantly associated with childhood diarrhea in Colombia, South America. The long term goal of this study is to understand the epidemiology and the molecular mechanisms of pathogenesis of this new LAEC emergent pathogen. The first specific aim proposes to evaluate the frequency and association of LAEC with childhood diarrhea by conducting two international multicenter case-control studies. We hypothesize that LAEC is associated with childhood diarrhea in children less than 5 years of age living in developing countries. The second specific aim will explain how LAEC virulence factors are essential to cause disease in a piglet model of human infection. We hypothesize that the type IV bundle-forming pilus and a novel type III secretion system directing bacterial-cell invasion are directly associated with the pathogenesis of LAEC diarrhea. The last specific aim will conduct genome DNA sequencing analysis of LAEC strains to identify the genetic elements that resulted in the emergence of LAEC as a pathogen. We hypothesize that LAEC shares in common well defined virulence genes that were acquired by horizontal gene transfer. This project if significant because it will bring fundamental knowledge on the epidemiology, genetics, and pathogenesis of LAEC and will generate molecular biology tools to facilitate future studies on LAEC diarrhea epidemiology, prevention measures and vaccine. Read more.

Funding Source: NIH/NIAID
PI: Oscar Gomez

Telephone Counseling - Caregivers for Children with Cancer

The rate of survival for childhood cancer continues to improve and now approaches 80%. Coincident with this survival are adverse long-term health-related outcomes for survivors and their family members. Throughout the cancer care continuum, from time of diagnosis through long-term survivorship, children and their families are confronted with multiple and pervasive stressors, including uncertainty about the chance of survival, treatment- related adverse health effects, disruption in daily activities and disruption of the parental role function. This may result in clinically significant global distress, depression, posttraumatic stress (PTS) and reduced self-efficacy. Therefore, providing psychosocial services to parents of children with cancer is necessary. Yet, feasible and theory-based psychosocial intervention studies are extremely limited, particularly at the completion of the child's cancer treatment, a time known to be anxiety-provoking and often characterized by feelings of abandonment and uncertainty about the future. Barriers to participation in face-to-face interventions at the treating institution include the considerable distance that many families live from the institution, difficulty leaving children, households or jobs and potential for sensory and interpersonal experiences at the treating institution to trigger symptoms of anxiety and PTS. In response to these concerns, we are proposing to extend the reach of essential psychosocial counseling services to primary caregivers of children with cancer by designing and implementing a small-scale feasibility pilot of an innovative and highly translatable telephone-based psychosocial intervention. This intervention will be implemented during the transition from primary active oncology treatment to follow-up care, reflecting a neglected area of research. Specifically, we propose to design and then test the feasibility of a two-group randomized trial of a psychosocial telephone counseling program for primary caregivers of children who have completed cancer therapy in the previous year, consisting of an attention control condition (educational materials and outcalls with no counseling) and an experimental condition (telephone counseling plus the educational materials). We will evaluate the proposed telephone counseling intervention for feasibility, satisfaction and perceived helpfulness. The primary endpoints will include psychosocial distress and benefit finding. Furthermore, we will assess and explore the plausible intervention mechanisms and pathways that may explain and elucidate intervention efficacy (mediator variables). The main theory-based mediator variables that will be tested include secondary appraisal (coping self-efficacy) and coping effort. Lastly, based on the preliminary data obtained from this study, we will seek funding to design and implement a larger randomized clinical efficacy trial, whose ultimate goal will be to develop a highly effective and exportable telephone counseling intervention for primary caregivers of children with cancer that could be become an integral component of care given to pediatric oncology patients. Read more.

Funding Source: NIH/NCI 
PI: Debra Friedman

Tools to Reduce Infant RSV Morbidity and Asthma: Use, Adherence and Effectiveness

One ubiquitous and modifiable environmental factor associated with both significant infant morbidity, as well as asthma development, is infant respiratory syncytial virus (RSV) infection. While most children who experience RSV infection have mild symptoms, a significant minority experience more severe disease, often requiring hospitalization and sometimes intensive care. We, and others, have shown that, among children with RSV infection severe enough to require medical attention, the severity of the infection has a strong association with subsequent development and severity of asthma. In addition, we have shown a causal relationship between RSV-attributable infant illness and childhood asthma inception. Because an RSV vaccine is not currently available, RSV immunoprophylaxis is the only currently available alternative approach, licensed for use in preventing RSV-attributable morbidity in high-risk infant groups. RSV immunoprophylaxis been evaluated in children who experience excessive RSV morbidity. While there have been a number of randomized clinical trials that have enrolled selective populations investing significant resources to ensure adherence that have established "efficacy" (can it work?), the "effectiveness" (does it work?) data are limited and conflicting. No investigations have assessed patterns of use, adherence, and effectiveness in US Medicaid and insured "real world" populations. Neither are there any investigations of the impact of reducing RSV infant morbidity on long-term outcomes such as asthma. These are critically important questions to answer in informing policy for the most costly preventive therapy in pediatrics, and in assessing effectiveness of our only currently available "tool" for decreasing infant RSV morbidity. Lastly, neither are there investigations of the more long-term impact of reducing RSV infant morbidity on the development of asthma, a lifelong chronic disease known to be more common among most groups of children considered high-risk for RSV. In three specific aims utilizing two denominator-based study populations of children enrolled in Tennessee Medicaid and six Kaiser Permanente-Northern California integrated medical care practices, we will study infants born between 1995 and 2008 and followed longitudinally to: (1) Determine RSV immunoprophylaxis utilization patterns and adherence; (2) Determine the effectiveness of RSV immunoprophylaxis on RSV hospitalizations and outpatient visits as well as comparative effectiveness with birth timing; and (3) assess the impact of RSV immunoprophylaxis on asthma inception, estimate the effect size, and compare the impact of RSV immunoprophylaxis on asthma inception with the effect we have shown of timing of birth on reducing childhood asthma. Read more.

Funding Source: AHRQ
PI: Tina Hartert

Using Social Learning to Improve Adolescent Diabetes Adherence Problem Solving

Adolescents with type 1 diabetes (T1D) are at high risk for poor adherence and glycemic control. Some of the most prevalent barriers to adherence in adolescents are psychosocial in nature, such as stress, stigma, time pressures, social situations, and communication with peers and parents. Diabetes research and professional organizations support the development of problem solving skills to resolve barriers to adolescent adherence. In order to address the needs of adolescents with T1D, parents, and clinics, we created an Internet adherence problem solving intervention, named YourWay. Initial results indicated moderate impact on adherence but variable engagement with the intervention. Based on our preliminary studies, we propose substantially advancing our intervention through three new design features: 1) a mobile data collection system using ecological momentary assessment (EMA) to populate the intervention with behavioral adherence data and multimedia content and improve awareness of adherence barriers, 2) a new homepage that integrates EMA data, BG values, and adolescent-generated multimedia content into personal adherence stories, and 3) social learning activities with peers focused on adherence problem solving. These enhanced features will provide more objective and more engaging data to guide and motivate adherence problem solving and provide intrinsically motivated social interactions with peers about adherence. Our aims include 1) establishing current behaviors and beliefs regarding adolescent use of health information technology for diabetes, and specifically those related to sharing personal health information with peers, 2) focused iterative design cycles for each of these features to identify the most engaging and acceptable interface and adherence data sharing activities, and 3) a pilot randomized trial to assess the impact of the intervention on glycemic control (A1C). There are currently no resources for this population that integrate social interactions with peers with skill building activities to improve adherence. The proposed Internet intervention will innovatively combine these features into a personal story format. The intervention has a high potential for engaging adolescents in adherence problem solving, improving adherence, and reducing the serious medical consequences related to poor glycemic control. Read more.

Funding Source: NIH/NIDDK
PI: Shelagh Mulvaney