Over the past year, I became a Tenure Track Investigator and Chief of the Neuromuscular Symptoms Unit in the Tissue Injury Branch of the NINR. Prior to that, I was an Assistant Clinical Investigator in the same branch, a position I started in September of 2012. Over the past year, I have enrolled participants in three active protocols. The first one is a study to develop the first proxy motor outcome assessment in young children with neuromuscular disease, entitled Development of a Proxy Motor Outcome Measure in Young Children with Neuromuscular Disease. Over the past 2 years, we completed all necessary qualitative phone interviews for Aim 1 of the protocol. We transcribed and analyzed these interviews to uncover their main themes. This analysis was followed by an in-person focus group of expert clinicians to further analyze the interview transcriptions and to develop common themes relevant for the questionnaire, related to motor function. All parents who participated in the interviews were also informed about these themes and our projected domains for the questionnaire and their feedback was welcomed. The themes were used to create the items for the new scale. After the items were developed, the same focus group of experts was queried an initial rounds of emailing, using the Delphi method, to finalize the items on the new scale. This past year, and additional round of the Delphi was completed and the final 43 items were selected by the focus group through the Delphi process. We are presently setting up cognitive interviews for all parents who were initially interviewed to assess whether the items developed have captured their intended meaning. The goal is to use the new scale in future clinical trials to decrease parent stress related to travel to research centers for clinical trials and to improve ecological validity of motor function by utilizing parent insight in the home setting. My team also continues to enrolled participants to date in the second active protocol, The Calibration and Validation of the PROMIS and Neuro-QOL Questionnaires in Cerebral Palsy and Congenital Muscular Dystrophy. We now have 41 pediatric participants, and 63 proxy participants, 38 dyads (pediatric and proxy from same family), 19 retested proxies and 10 retested meds. Preliminary item response theory analyses will soon resume with Columbia University, the collaborating institution, to validate these two questionnaires for use in neuromuscular disease patients. A third study, which received the Bench to Bedside Award in 2014, is also progressed over the past year. This is a clinical trial of antioxidant therapy in patients with RYR1 congenital myopathy, and 40 participants with this rare disease have been enrolled since March 2015 (18 additional patients since last year). We have identified preliminary findings regarding decreased oxidative stress in humans with RYR1, which are consistent with findings in three preclinical models (mice, zebrafish, human myotubes) and need to be substantiated with a larger sample size. This finding is encouraging because the treatment is a known antioxidant in this trial, N-acetylcyesteine. We are also analyzing data describing the natural history of the disease from the first part of the study (prior to study drug/placebo administration). We continue to analyze significant correlations between cardiopulmonary exercise testing, arterial occlusion with near infrared spectroscophy, forced vital capacity, and the six minute walk test. We also identified changes in muscle ultrasound and muscle MRI in specific muscle groups in these patients. The research fellow on my team, Dr. Witherspoon, and and I recently had a review of the literature on RYR1 and its associated pathomechanisms accepted with revisions for publication in Acta Neuropathological Communications. We have also drafted 3 manuscripts about the baseline findings of this research and will be publishing them this coming year. I continue to be an Associate Investigator on an NINDS protocol entitled Clinical and Molecular Manifestations of Neuromuscular and Neurogenetic Disorders of Childhood. As part of this protocol, I took a 5-year project with me from NINDS when left NINDS and started with NINR. The project was a 5-year study of clinical outcome measures in two subtypes of congenital muscular dystrophy, Collagen VI-Related Myopathy and Laminin 2 Related Muscular Dystrophy. The 5 year data is now in final stages of analysis and a manuscript is being prepared describing sensitivvity to change of the main outcome measures over the entire 5 years. Several manuscripts arose from this data. A first author manuscript of mine focusing on forced vital capacity in these 2 disease subtypes has been accepted in Pediatric Pulmonology. Another senior author manuscript of mine has been submitted describing the validation of several upper extremity measures in this population to Neuromuscular Disorders. A manuscript on the validation of the ActiGraph accelerometer in this population is being revised and resubmitted by my team. Another manuscript describing the validation of the PedsQoL is also in final stages of preparation. Manuscripts in press: 1. Meilleur, K.G., Linton, M.M., Fontana, J., Rutkowksi, A., Elliott, J., Barton, A., McGraw, P., Kokkinis, A., Donkervoort, S, Leach, M., Jain, M., Dastgir, J., Collins, J., Szczesniak, R., Yang, K., Sawnani, H., Bonnemann, C.G. (2016). Comparison of sitting and supine forced vital capacity in Collagen VI-Related Dystrophy and Laminin 2-Related Dystrophy. Ped. Pulm. (In press). 2. Witherspoon, J.W. & Meilleur, K.G. (2016) Review of RyR1 Pathway and Associated Pathomechanisms. Acta Neuropath Comm (Accepted with Revisions).
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