STIM1 and ORAI1 mutations leading to tubular aggregate myopathies are sensitive to the Store-operated Ca2+-entry modulators CIC-37 and CIC-39.

Gain-of-function mutations on STIM1 and ORAI1 genes are responsible for an increased store-operated calcium entry, and underlie the characteristic symptoms of three overlapping ultra-rare genetic disorders (i.e tubular aggregate myopathy, Stormorken syndrome, York platelet syndrome) that can be grouped as tubular aggregate myopathies. These mutations lead to a wide spectrum of defects, which usually include muscle weakness and cramps. Negative modulators of store-operated Ca2+-entry targeting wild-type STIM1 and ORAI1 have entered clinical trials for a different array of disorders, including pancreatitis, COVID-19, cancer, and autoimmune disorders and, while efficacy data is awaited, safety data indicates tolerability of this STIM1/ORAI1 mutations are amenable to pharmacological intervention. If this were so, given that there are no approved treatments or clinical trials ongoing for these rare disorders, it could be envisaged that these agents could also rehabilitate tubular aggregate myopathy patients. In the present contribution we characterized the Ca2+-entry patterns induced by eleven STIM1 and three ORAI1 mutations in heterologous systems or in patient-derived cells, i.e. fibroblasts and myotubes, and evaluated the effect of CIC-37 and CIC-39, two novel store-operated calcium entry modulators. Our data show that all STIM1 and ORAI1 gain-of-function mutations tested, with the possible exception of the R304Q STIM1 mutation, are amenable to inhibition, albeit with slightly different sensitivities, paving the way to the development of SOCE modulators in tubular aggregate myopathies.

Examining the Associations Between Parent Concerns and School-Age Children's Language and Reading Abilities: A Comparison of Samples Recruited for In-School Versus Online Participation.

PURPOSE: The purpose of this study was to examine the relationship between parent concerns about children's oral language, reading, and related skills and their children's performance on standardized assessments of language and reading, with a particular focus on whether those relationships differed between children recruited for in-school versus online participation. METHOD: This study used data from a larger, longitudinal project focused on children with and without developmental language disorder (DLD) and/or dyslexia. The "in-school" sample (n = 133) completed assessments in-person before school closures, and the "online" sample (n = 84) recruited via advertisements completed assessments online. Parents completed a checklist of concerns. All children completed norm-referenced assessments of language and reading. RESULTS: The two recruitment strategies yielded samples that differed in racial diversity (higher in the in-school sample), caregiver education levels (higher in the online sample), and word reading test scores (higher in the online sample). Parents in both samples reported higher levels of concerns about literacy skills than oral language skills, and the correlation between parent concerns about literacy and children's word reading test scores was stronger than the correlation between parent concerns about oral language and children's language test scores. CONCLUSIONS: Researchers and clinicians should be aware of how recruitment strategies and assessment modalities (e.g., in-person vs. tele-assessment) may impact participation in studies and clinical service. A reliance on parent concerns about oral language to prompt a language evaluation may contribute to low rates of identification of children who meet criteria for DLD. Future research can consider parent concerns about literacy, attention, and executive functions as indicators of a need for language evaluation, especially considering the high comorbidity between language and other developmental disorders.

The learning experiences of dyslexic medical students during the COVID-19 pandemic: a phenomenological study.

Dyslexia is a Specific Learning Difficulty that impacts on reading and writing abilities. During the COVID-19 pandemic, medical schools have been forced to undertake distance learning and assessment. The wider literature suggested that e-learning might pose additional challenges for dyslexic students. Here we explore their overall experiences of learning/studying during this time in a phenomenological study. Five medical students were interviewed in depth and the audio-recordings were transcribed verbatim. Transcripts then underwent an interpretive phenomenological analysis. Our results highlighted a largely positive experience, with an improved culture of togetherness, freedom and sense of control. They also revealed issues with a lack of clinical exposure, potential negative impacts on ranking positions for those with dyslexia, and possible cheating in exams. There are some surprising results-in particular the positive responses to how remote learning was delivered. These seemed to put our participants more on a par with their non-dyslexic colleagues-except in some examinations. It is our hope that medical educators may resist a return to 'the way things have always been done' when the pandemic has resolved, and by doing so, continue to foster this new, positive culture and paradigm shift.