A safely tolerated dose of daily subcutaneous IL-6 is 10 micrograms/kg, with hepatotoxicity and cardiac arrhythmia being the dose-limiting toxicities at 30 micrograms/kg. Phase II trials of IL-6 administered subcutaneously daily for at least 7 days for two cycles with an intervening week of rest are recommended for phase II trials. However, patients with extensive replacement of liver by tumor and abnormal liver functions should receive IL-6 therapy with caution.
BackgroundThe prognosis of children with juvenile dermatomyositis (JDM) has improved remarkably since the 1960’s with the use of corticosteroid and immunosuppressive therapy. Yet there remain a minority of children who have refractory disease. Since 2003 the sporadic use of biologics (genetically-engineered proteins that usually are derived from human genes) for inflammatory myositis has been reported. In 2011–2016 we investigated our collective experience of biologics in JDM through the Childhood Arthritis and Rheumatology Research Alliance (CARRA).MethodsThe JDM biologic study group developed a survey on the CARRA member experience using biologics for Juvenile DM utilizing Delphi consensus methods in 2011–2012. The survey was completed online by the CARRA members interested in JDM in 2012. A second survey was similarly developed that provided more opportunity to describe their experiences with biologics in JDM in detail and was completed by CARRA members in Feb 2013. During three CARRA meetings in 2013–2015, nominal group techniques were used for achieving consensus on the current choices of biologic drugs. A final survey was performed at the 2016 CARRA meeting.ResultsOne hundred and five of a potential 231 pediatric rheumatologists (42%) responded to the first survey in 2012. Thirty-five of 90 had never used a biologic for Juvenile DM at that time. Fifty-five of 91 (denominators vary) had used biologics for JDM in their practice with 32%, 5%, and 4% using rituximab, etanercept, and infliximab, respectively, and 17% having used more than one of the three drugs. Ten percent used a biologic as monotherapy, 19% a biologic in combination with methotrexate (mtx), 52% a biologic in combination with mtx and corticosteroids, 42% a combination of a biologic, mtx, corticosteroids (steroids), and an immunosuppressive drug, and 43% a combination of a biologic, IVIG and mtx. The results of the second survey supported these findings in considerably more detail with multiple combinations of drugs used with biologics and supported the use of rituximab, abatacept, anti-TNFα drugs, and tocilizumab in that order. One hundred percent recommended that CARRA continue studying biologics for JDM. The CARRA meeting survey in 2016 again supported the study and use of these four biologic drug groups.ConclusionsOur CARRA JDM biologic work group developed and performed three surveys demonstrating that pediatric rheumatologists in North America have been using multiple biologics for refractory JDM in numerous scenarios from 2011 to 2016. These survey results and our consensus meetings determined our choice of four biologic therapies (rituximab, abatacept, tocilizumab and anti-TNFα drugs) to consider for refractory JDM treatment when indicated and to evaluate for comparative effectiveness and safety in the future.Significance and InnovationsThis is the first report that provides a substantial clinical experience of a large group of pediatric rheumatologists with biologics for refractory JDM over five years.This experience with biologic thera...
Underlying molecular genetic mechanisms of diseases can be deciphered with unbiased strategies using recently developed technologies enabling genome-wide scale investigations. These technologies have been applied in scanning for genetic variations, gene expression profiles, and epigenetic changes for oral and craniofacial diseases. However, these approaches as applied to oral and craniofacial conditions are in the initial stages, and challenges remain to be overcome, including analysis of high throughput data and their interpretation. Here, we review methodology and studies using genome-wide approaches in oral and craniofacial diseases and suggest future directions.
item information functions. Results: Thirteen relevant papers from the 200 set retrieved and 19 in-depth interviews yielded seven themes -6 mental health and one physical health. Out of 1600 potential items 100 items were tested for content validity with 76 service users -59 adults and 17 aged 16-18. Over 3600 service users completed a pool of 40 items. Factor analyses and Classical psychometric analyses have informed the selection of items for a six-dimension classification for ReQoL each item containing five levels. ConClusions: ReQoL provides an important basis for a new QALY measure that better reflects the way different mental health problems impact on the lives of people who use services. The next stage is to obtain preference weights so that the measure can be used in the economic evaluation of interventions in mental health. PMH49Preferences for Pediatric attention-deficit/HyPeractivity disorder ManageMent and Medication cHanges and caregiver-rePorted iMProveMent over a 6-MontH follow-UP
Introduction Insomnia affects 10–20% of the US population and is associated with negative health and psychosocial sequelae. Despite the public health impact of insomnia little is known about its underlying molecular mechanisms. The purpose of this study is to examine differentially expressed genes in 15 patients with chronic insomnia and age- and sex-matched good sleepers (n=15). Methods We performed total RNA-seq on 30 whole blood samples collected at 09:00 at 150 bp paired-ends on the Illumina NovaSeq-6000 platform. Alignment was performed using the STAR version 2.7.2a software on the human reference genome (GRCh38). Differential gene expression analysis was performed using DESeq2 version 1.24.0. Pathway analysis was performed using IPA, release 2019-08-30. Results An average of 86.7 million paired end reads per sample were sequenced. We found that 289 genes were differentially expressed in insomnia patients with a log fold change (LFC) ±0.50 and had a FDR p-value < 0.05. Top dysregulated genes include CSMD1 (L2FC=-2.78; p=1.35E-06), DUX4L9 (L2FC=3.40; p=2.81E-06) and GRM4 (L2FC=2.45; p=4.50E-05). Among the functionally relevant genes, CSMD encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing central nervous system. UTS2 (L2FC=1.778; p=8.94E-06) is involved in regulation of orexin A and B activity and rapid eye movement during sleep. Ingenuity Pathway Analysis revealed 3 associated networks: Hematological, Hereditary Disorder, Organismal Injury and Abnormalities (score: 46), Developmental, Hereditary Disorder, Metabolic Disease (score: 43), and Cell Cycle, Cell mediated Immune Response, Cellular Development (score: 43). Conclusion Overall, our study revealed dysregulated genes in individuals who suffer from insomnia. Notably, dysregulation of these functionally relevant genes could impair functional brain connectivity and synaptic function. Further investigation of these biological pathways will be useful to elucidate the pathogenesis of insomnia and identify novel biomarkers or drug targets for developing improved diagnostics and therapeutics. Support National Institutes of Nursing Research, Graduate Partnership Program
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