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.

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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.

BackgroundIn Australia, about 1 in 3 chiropractors choose not to belong to either of the two professional associations and this is considerably lower compared to other health professional organisations in this country. The reasons for this remain unknown. We sought to explore possible reasons by asking chiropractic students their perceptions of barriers and facilitators to joining a professional association. However, we were unable to identify validated survey instruments that could be used to obtain information about reasons for joining health professional associations.AimTherefore, the objectives of this study were to: 1) develop a survey instrument that captures information about what influences chiropractic students in joining professional association; and 2) identify factors that promote association membership among chiropractic students.MethodsA literature review was undertaken to identify known determinants of professional association membership and were used to construct a preliminary survey instrument, which comprised 47 items. Six fourth-year chiropractic students assessed the preliminary survey instrument’s content validity. Principal components analysis was used to establish the structure of the scales. Cronbach’s alpha was derived to determine whether all items in each scale tapped a discrete construct. Logistic regression was used to examine the association between the scale scores and having joined a chiropractic professional association.ResultsIn March 2019, 348 chiropractic students from Murdoch University (71.0%) responded to a voluntary, anonymous questionnaire. Principal components analysis resulted in the retention of 21 items that strongly loaded onto 6 factors. Internal consistency was found to be adequate. The results of the logistic regression analysis demonstrated that only “development of the profession” was significantly associated with have joined a professional chiropractic association (p = 0.049, OR = 2.22; 95% CI = 1.26–3.40).ConclusionChiropractic organisations can probably most effectively increase membership numbers through raising awareness of their contribution to the development of the profession.