Preventing and lessening exacerbations of asthma in school-age children associated with a new term (PLEASANT) : Study protocol for a cluster randomised control trial

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedBackground: Within the UK, during September, there is a pronounced increase in the number of unscheduled medical contacts by school-aged children (4-16 years) with asthma. It is thought that that this might be caused by the return back to school after the summer holidays, suddenly mixing with other children again and picking up viruses which could affect their asthma. There is also a drop in the number of prescriptions administered in August. It is possible therefore that children might not be taking their medication as they should during the summer contributing to them becoming ill when they return to school. It is hoped that a simple intervention from the GP to parents of children with asthma at the start of the summer holiday period, highlighting the importance of maintaining asthma medication can help prevent increased asthma exacerbation, and unscheduled NHS appointments, following return to school in September.Methods/design: PLEASANT is a cluster randomised trial. A total of 140 General Practices (GPs) will be recruited into the trial; 70 GPs randomised to the intervention and 70 control practices of "usual care" An average practice is expected to have approximately 100 children (aged 4-16 with a diagnosis of asthma) hence observational data will be collected on around 14000 children over a 24-month period. The Clinical Practice Research Datalink will collect all data required for the study which includes diagnostic, prescription and referral data.Discussion: The trial will assess whether the intervention can reduce exacerbation of asthma and unscheduled medical contacts in school-aged children associated with the return to school after the summer holidays. It has the potential to benefit the health and quality of life of children with asthma while also improving the effectiveness of NHS services by reducing NHS use in one of the busiest months of the year. An exploratory health economic analysis will gauge any cost saving associated with the intervention and subsequent impacts on quality of life. If results for the intervention are positive it is hoped that this could be adopted as part of routine care management of childhood asthma in general practice. Trial registration: Current controlled trials: ISRCTN03000938 (assigned 19/10/12) http://www.controlled-trials.com/ISRCTN03000938/.UKCRN ID: 13572.Peer reviewe

Clinical and cost-effectiveness of teen online problem-solving for adolescents who have survived an acquired brain injury in the UK: protocol for a randomised, controlled feasibility study (TOPS-UK).

INTRODUCTION: Paediatric acquired brain injury is a leading cause of mortality in children in the UK. Improved treatment during the acute phase has led to increased survival rates, although with life-long morbidity in terms of social and emotional functioning. This is the protocol for a feasibility randomised controlled trial with an embedded qualitative study and feasibility economic evaluation. If feasible, a later definitive trial will test the effectiveness and cost-effectiveness of an online intervention to enhance problem solving ability versus treatment as usual. METHODS AND ANALYSIS: Twenty-five adolescents and their families identified by primary or secondary care clinicians at participating UK National Health Service Trusts will be recruited and individually randomised in a 1:1 ratio to receive the online intervention or treatment as usual. Participants will be followed up by online questionnaires 17 weeks after randomisation to capture acceptability of the study and intervention and resource use data. Qualitative interviews will capture participants' and clinicians' experiences of the study. ETHICS AND DISSEMINATION: This study has been granted ethical approval by the South West-Exeter Research Ethics Committee (ref 17/SW/0083). Results will be disseminated via peer-reviewed publications and will inform the design of a larger trial. TRIAL REGISTRATION NUMBER: ISRCTN10906069

Disruption of TWIST1 translation by 5' UTR variants in Saethre-Chotzen syndrome

Saethre-Chotzen syndrome (SCS), one of the most common forms of syndromic craniosynostosis (premature fusion of the cranial sutures), results from haploinsufficiency of TWIST1, caused by deletions of the entire gene or loss-of-function variants within the coding region. To determine whether non-coding variants also contribute to SCS, we screened 14 genetically undiagnosed SCS patients using targeted capture sequencing, and identified novel single nucleotide variants (SNVs) in the 5' untranslated region (UTR) of TWIST1 in two unrelated SCS cases. We show experimentally that these variants, which create translation start sites in the TWIST1 leader sequence, reduce translation from the main open reading frame (mORF). This is the first demonstration that non-coding SNVs of TWIST1 can cause SCS, and highlights the importance of screening the 5' UTR in clinically diagnosed SCS patients without a coding mutation. Similar 5' UTR variants, particularly of haploinsufficient genes, may represent an under-ascertained cause of monogenic disease. This article is protected by copyright. All rights reserved

Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans

This is the final version. It first appeared at http://www.nature.com/ncomms/2015/150901/ncomms9086/full/ncomms9086.html.Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting.L.E.D. and F.I.R. were supported by the Medical Research Council (MR/J000329/1). J.B., K.B., B.H., L.S. M.B. and T.E. were supported by Bundesministerium fu?r Bildung und Forschung (grant number 01GM1513A and 01GM1513C) and C.T. was supported by an Ipsen Fellowship Grant. The cohort ?Imprinting Disorders-Finding out Why? was accrued through the support of the Newlife Foundation for Disabled Children and through support from the Wessex NIHR clinical research network and NIHR Wellcome Southampton clinical research facility. Funding for DNA collection and methylation analysis of normal control samples was provided in part by the National Institutes of Health R01 AI091905-01, R01 AI061471 and R01 HL082925. ERM thanks Action Medical Research for support

PURA syndrome : clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

Background De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. Objectives T o delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. Methods Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotypephenotype correlations by analysis of both recurrent mutations as well as mutation classes. Results We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. Conclusion We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.Peer reviewe

Schimke immunoosseous dysplasia: defining skeletal features

Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by prominent spondyloepiphyseal dysplasia, T cell deficiency, and focal segmental glomerulosclerosis. Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. We hypothesized that skeletal features distinguish between those with or without SMARCAL1 mutations. Therefore, we analyzed the skeletal radiographs of 22 patients with and 11 without detectable SMARCAL1 mutations. We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal. Additionally, we found that several of the adolescent and young adult patients developed osteoporosis and coxarthrosis. Of the 11 patients without detectable SMARCAL1 mutations, seven had a SED indistinguishable from patients with SMARCAL1 mutations. We conclude therefore that SED is a feature of patients with SMARCAL1 mutations and that skeletal features do not distinguish who of those with SED have SMARCAL1 mutations

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)