NMR Metabolomics of Cerebrospinal Fluid and Urine for Accelerated Diagnosis of Pediatric Encephalomyelitis
This project addresses the challenge that standard medical practice for encephalomyelitis is limited while outcomes are often poor, including death or permanent disability. Our project is very high impact given (a) the critical importance of neurological function to quality of life, (b) the change-making paradigm shift of diagnosing and treating encephalomyelitis by profiling brain metabolism, and (c) the practicality of immediate translation of our research into clinical practice. The research is highly collaborative, nucleating strategically focused CTSA teams at the Medical College of Wisconsin, New York University, University of Alabama (Birmingham), University of Cincinnati, and University of Massachusetts. This translational project is well matched to the missions of the respective Departments of Pediatrics, their CTSAs and the NIH, including NIAID, NINDS, NIAMS and NCI.
Our research delivers improved diagnostic speed, broader diagnostic range, and a theoretical framework that potentially identifies novel therapies. In our hands, nuclear magnetic resonance (NMR) metabolomics differentiates rabies, West Nile and Lyme encephalitis, cerebral malaria, multiple sclerosis and controls, and can likely do so for other brain diseases. The assay is rapid, cheap, ubiquitous, commercially adaptable and consumes less volume of CSF than current practices.
POD 1 proposes to prospectively enroll at least 15 children at each institution (75 total) with possible meningoencephalitis. Cerebrospinal fluids and concomitant urine samples will be analyzed by NMR. Metabolites will be identified and quantified by Chenomx software. Metabolic profiles will be clustered, distances between clusters compared, and correlations with clinical diagnoses reported. Study protocols will include sample collection and archiving for next generation sequencing, lateral flow assays, and proxy measures of treatment effects by CHAMP members.
Building Capacity to Deliver Effective Obesity Management Interventions within Primary Care Settings
The translation of research discovery to clinical and community practice is both a complex challenge and an absolute necessity if health providers are to effectively disseminate evidence-based health behavior change interventions. Building provider capacity to deliver effective obesity management interventions for youth in pragmatic healthcare settings is especially needed given the widespread prevalence and negative health outcomes associated. However, most health care providers are not adequately trained to address youth obesity management, and a major contributing factor is the inaccessibility of training resources, a particularly acute problem in rural areas. Mindful Eating (ME) programs represents one novel training approach as they specifically target two significant predictors of youth obesity including psychological distress and disordered eating behaviors. Recent research findings point to the efficacy of mindfulness-based approaches for weight loss in adults and an untapped opportunity to utilize ME interventions for youth populations. Researchers at the University of New Mexico Health Sciences Center have recently developed a healthcare provider training for a brief youth-based ME intervention for use within a clinic setting that could be conducted via telehealth.
Thus, the overall goal of this pilot project is to initiate a collaborative research effort between five diverse CTSA hubs to examine how teleconferencing technology can expand access to, coordinate, and improve the quality of youth obesity health care services, especially those which may also serve the broader community and rural areas. Specifically, we will examine the degree to which a promising treatment model for obesity (mindful eating) can be effectively standardized and taught via video teleconferencing to health providers, increasing access to training resources and establishing a foundation for future studies examining patient outcomes.
Design considerations are based on optimal positioning for future larger multisite studies examining the feasibility of tailoring ME programs for clinical healthcare settings.
The Feasibility of Common Screening for Adverse Childhood Experiences in the Primary Care Setting
With the high prevalence of adverse childhood experiences (ACEs) and the strong association between ACEs and significant lifelong increases in morbidity and mortality, health care providers and systems need to understand how to prevent, prioritize, promote resilience and mitigate these toxic effects. However, despite its importance, child health providers such as pediatricians do not routinely screen for ACEs. This workgroup from the University of Florida and the University of Minnesota brings complementary knowledge and strengths to successfully plan for a large-scale implementation of ACEs screening.
POD 3 will begin by planning an ACEs Summit to develop plans to work towards large-scale projects that will link pre-existing data from our respective institutions with existing EHR data. The goal will be three-fold: 1) identify common language used to describe early identifiable risk factors for ACEs observed in primary care settings, 2) develop and pilot test a set of screeners for various age groups of children to be implemented at each of the four institutions and 3) calculate the sensitivity and specificity of the of the screeners being used to identify subsequent ACEs by collecting follow-up data on a random sample of children and their families.
Working off the central hypothesis that health care systems that implement a common system, specifically linked to electronic health records, will best address children’s needs to avoid or mitigate the toxic effects of ACEs, we believe this grant will make a significant impact on improving the health of children across their lifespan.
Kawasaki Disease Project
We propose here the “re-purposing” of atorvastatin to reduce pro-inflammatory host responses and improve cardiovascular outcome in children with acute Kawasaki disease (KD), a self-limited vasculitis that is the most common cause of acquired heart disease in children. Although high-dose intravenous immunoglobulin (IVIG) plus aspirin reduces the risk of coronary artery damage, 5-10% of children with KD will go on to develop coronary artery aneurysms that may result in myocardial ischemia, infarction, or death. Once aneurysms have formed, the damage to the arterial wall is irreversible and although myointimal proliferation can restore the lumen to a more normal caliber, these arteries are never normal and over time stenoses and calcification lead to ischemic complications.
Thus, the goal of treatment should be prevention or attenuation of coronary artery damage. Based on preliminary data from our laboratory, arterial damage in KD results from immune activation and vessel wall infiltration by myofibroblasts, neutrophils, and T-cells with secretion of pro-inflammatory cytokines, elastases, and matrix metalloproteinases (MMPs). The proposed, multicenter, blinded, placebo-controlled Phase III study will assess the efficacy on the attenuation of coronary artery abnormalities (Specific Aim 1) and anti-inflammatory and anti-oxidant effects (Specific Aim 2) of atorvastatin in acute KD.
This study will determine if atorvastatin could reduce the morbidity and mortality of acute KD. This University of California Biomedical Research Acceleration, Integration, & Development (UC BRAID) grant will fund the coordination of the necessary infrastructure to bring together the 5 UC campuses in order to apply to the NIH for an R01 to support a Phase III clinical trial.
The University of California (UC) Center for Pediatric Microbiome Research
Our mission is to understand microbial development in childhood and leverage this knowledge to promote pediatric health. We started a system-wide initiative across the University of California, coalescing an inter-disciplinary group of clinical and basic science investigators with expertise in pediatric gastroenterology, neurology, microbial metagenomics, metabolomics, immunology, ecology, genomics, bioinformatics and biostatistics. We have secured pilot funding from the University of California Biomedical Research Acceleration, Integration, & Development (UC BRAID) consortium, providing resources to support initial sample collection, microbiome analyses, shared databases and training.
Our ultimate aim is to develop a large, multi-center study that leverages the expertise, technology and infrastructure developed in this UC BRAID funded pilot initiative to explore microbial dynamics during pregnancy and over the first 1,000 days of life, when the microbiome changes most rapidly, as it relates to health outcomes in childhood. The ultimate goal of these studies is to understand the factors that influence microbiome dynamics and health outcomes in early life in a population that reflects the diversity of California and the US, to leverage this knowledge to develop preventative therapies, and to influence policy to promote healthy microbiome development across pediatric populations.
A focus on early life during microbiome assembly is ideal, when change is most rapid and the potential to elicit effective interventions to reduce disease risk is greatest.