We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Wholetranscriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.

SummaryHeterozygous loss-of-function mutations in GRIN2B, a subunit of the NMDA receptor, cause intellectual disability and language impairment. We developed clonal models of GRIN2B deletion and loss-of-function mutations in a region coding for the glutamate binding domain in human cells and generated neurons from a patient harboring a missense mutation in the same domain. Transcriptome analysis revealed extensive increases in genes associated with cell proliferation and decreases in genes associated with neuron differentiation, a result supported by extensive protein analyses. Using electrophysiology and calcium imaging, we demonstrate that NMDA receptors are present on neural progenitor cells and that human mutations in GRIN2B can impair calcium influx and membrane depolarization even in a presumed undifferentiated cell state, highlighting an important role for non-synaptic NMDA receptors. It may be this function, in part, which underlies the neurological disease observed in patients with GRIN2B mutations.

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Back pain is significantly more common among adults compared with children; however, it still represents an important issue in the pediatric population, and back pain in childhood is a predictor for back pain in adulthood. One potential predictor of back pain in childhood is adolescent idiopathic scoliosis. The authors of this article conducted a retrospective chart review involving 310 patients with adolescent idiopathic scoliosis. The prevalence of back pain and management of the pain/scoliosis were assessed, as well as the relationship between the severity of scoliosis and intensity of the pain.

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BackgroundAdolescent idiopathic scoliosis is the most common spinal deformity occurring in adolescents and its established prevalence varies from 2 to 3%. Adolescent idiopathic scoliosis has been identified as a potential risk factor for the development of low back pain in adolescents. The purpose of this study was to systematically review studies of the prevalence of low back pain in adolescents with idiopathic scoliosis in order to establish the quality of the evidence and determine whether the prevalence estimates could be statistically pooled.MethodsSystematic electronic searches were undertaken in PubMed, CINAHL, and CENTRAL without any restrictions. Studies were eligible for inclusion if they reported the prevalence of low back pain in adolescents with idiopathic scoliosis. Studies were excluded if they detailed the prevalence of pain in post-surgical subjects or were published in languages other than English or French. Data were reported qualitatively, since there was insufficient evidence for statistical pooling.ResultsThe electronic search strategies yielded 1811 unique studies. Only two studies fulfilled the eligibility criteria. The prevalence of low back pain in adolescents with idiopathic scoliosis ranged from 34.7 to 42.0%. However, these prevalence estimates should be viewed cautiously as the included studies were at high risk of bias.ConclusionThe results of this systematic review indicate that adolescents with idiopathic scoliosis frequently experience low back pain. However, there was insufficient evidence to confidently estimate low back pain prevalence in adolescents with idiopathic scoliosis and further studies are needed in this area.Electronic supplementary materialThe online version of this article (doi:10.1186/s12998-017-0143-1) contains supplementary material, which is available to authorized users.

IntroductionNeedle-related procedures are considered as the most important source of pain and distress in children in hospital settings. Considering the physiological and psychological consequences that could result from these procedures, management of pain and distress through pharmacological and non-pharmacological methods is essential. Therefore, it is important to have interventions that are rapid, easy-to-use and likely to be translated into clinical practice for routine use. The aim of this study will be to determine whether a device combining cold and vibration (Buzzy) is non-inferior to a topical anaesthetic (liposomal lidocaine 4% cream) for pain management of children undergoing needle-related procedures in the emergency department.Methods and analysisThis study will be a randomised controlled non-inferiority trial comparing the Buzzy device to liposomal lidocaine 4% cream for needle-related pain management. A total of 346 participants will be randomly assigned in a 1:1 ratio to one of the two study groups. The primary outcome will be the mean difference in pain intensity between groups during needle-related procedures. A non-inferiority margin of 0.70 on the Color Analogue Scale will be considered. A Non-inferiority margin of 0.70 on the Color Analogue Scale will be considered. The secondary outcomes will be the level of distress during the procedure, the success of the procedure at first attempt, the occurrence of adverse events, the satisfaction of both interventions and the memory of pain 24 hours after the procedure. The primary outcome will be assessed for non-inferiority and the secondary outcomes for superiority.Ethics and disseminationThis study protocol was reviewed and approved by the institutional review board of the study setting. Findings of this trial will be disseminated via peer-reviewed publications and conference presentations.Trial registration number NCT02616419.