Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes.

The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10-10, OR = 2.3[95% CI = 1.75-3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability

Recognising the Symptoms:How Common Are Eating Disorders in Pregnancy?

This study aimed to investigate eating disorder diagnostic status and related symptoms in early pregnancy

Assessment of readiness for interprofessional education among various healthcare professions in Europe and North America

Objectives This is a survey-based research project to determine students’ from a given healthcare institution: 1. readiness for IPE 2. attitudes toward IPE 3. readiness to teach other providers. 4. readiness to learn from other providers. 5. specialty-specific attitudes toward IPE. 6. relationship between the degree of development of professional identity and attitude toward IPE. 7. optimal number of specialties to participate in an IPE training. 8. intercultural differences regarding IPE. 9. confounding factors that affect readiness for IPE. Method An international group of INHWE members from the United States, Spain, Portugal, Bulgaria, Romania, Albania, Sweden, and Poland has developed a 29 item survey to assess readiness healthcare students for IPE. The survey is a modification of the original survey developed by the University of South Dakota Sanford School of Medicine that was designed for assessing medical students. This project’s survey has been modified to be applicable to the other healthcare specialties including nursing, nursing assistant programs, pharmacy, paramedicine, social work, laboratory medicine, respiratory therapy, and physical and occupational therapies. To cover a broad spectrum of international participants, the survey has been translated into eight languages including Albanian, Bulgarian, English, French, Polish, Romanian and Spanish. The survey has been deployed via PsychData in March 2018. Results Collected data identified distinctive trends in the attitudes toward IPE among healthcare professions and variouscultures. Preliminary data analysis demonstrates positive attitudes toward IPE in general, younger students are more open toward IPE that their elder classmates, best time to institute IPE education is the early stage of clinical rotation, students with interest in primary care are more interested in IPE than students with interest in surgical specialties, etc. The research team is currently conducting an in-depth data analysis of the obtained results. Conclusions IPE is an important component of modern healthcare education. It is a common trend in curricula development in many European and North American countries. The data obtained in this project help to overcome challenges and successfully implement IPE in various countries in Europe and North America

A De Novo Mutation in the Sodium-Activated Potassium Channel KCNT2 Alters Ion Selectivity and Causes Epileptic Encephalopathy

Summary: Early infantile epileptic encephalopathies (EOEE) are a debilitating spectrum of disorders associated with cognitive impairments. We present a clinical report of a KCNT2 mutation in an EOEE patient. The de novo heterozygous variant Phe240Leu SLICK was identified by exome sequencing and confirmed by Sanger sequencing. Phe240Leu rSlick and hSLICK channels were electrophysiologically, heterologously characterized to reveal three significant alterations to channel function. First, [Cl−]i sensitivity was reversed in Phe240Leu channels. Second, predominantly K+-selective WT channels were made to favor Na+ over K+ by Phe240Leu. Third, and consequent to altered ion selectivity, Phe240Leu channels had larger inward conductance. Further, rSlick channels induced membrane hyperexcitability when expressed in primary neurons, resembling the cellular seizure phenotype. Taken together, our results confirm that Phe240Leu is a “change-of-function” KCNT2 mutation, demonstrating unusual altered selectivity in KNa channels. These findings establish pathogenicity of the Phe240Leu KCNT2 mutation in the reported EOEE patient. : Gururaj et al. report a KCNT2 mutation in a patient with epileptic encephalopathy and employ electrophysiological analyses to establish channel properties that could underlie epileptogenesis: namely, inhibition by high [Cl−]i and loss of exclusive selectivity to K+. Furthermore, primary neurons expressing Ph240Leu display a hyperexcitable phenotype. Keywords: seizures, epileptic encephalopathy, ion channels, potassium channels, Slick, KCNT2, selectivity, Xenopus oocytes, Slack, KCNT

Formative Usability Testing for Rapidly Manufactured Ventilator Systems by Chartered Ergonomist and Human Factors Specialists (C.ErgHF)

This document is intended to be used by C.ErgHF when providing advice and support for rapidly manufactured ventilator systems (RMVS)

Human factors/ergonomics to support the design and testing of rapidly manufactured ventilators in the UK during the COVID-19 pandemic.

BACKGROUND This paper describes a rapid response project from the Chartered Institute of Ergonomics & Human Factors (CIEHF) to support the design, development, usability testing and operation of new ventilators as part of the UK response during the COVID-19 pandemic. METHOD A five-step approach was taken to (1) assess the COVID-19 situation and decide to formulate a response; (2) mobilise and coordinate Human Factors/Ergonomics (HFE) specialists; (3) ideate, with HFE specialists collaborating to identify, analyse the issues and opportunities, and develop strategies, plans and processes; (4) generate outputs and solutions; and (5) respond to the COVID-19 situation via targeted support and guidance. RESULTS The response for the rapidly manufactured ventilator systems (RMVS) has been used to influence both strategy and practice to address concerns about changing safety standards and the detailed design procedure with RMVS manufacturers. CONCLUSION The documents are part of a wider collection of HFE advice which is available on the CIEHF COVID-19 website (https://covid19.ergonomics.org.uk/)

Minor allele frequencies WTCCC vs pooled NGS (24 pools combined).

<p>MAFs for 153 SNPs were compared between allele frequency estimates based on pooled NGS and genotyping data from the WTCCC [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004955#pgen.1004955.ref047" target="_blank">47</a>] for 634 individuals. MAFs are strongly correlated between both datasets (Spearman rank correlation coefficient R = 0.976), with only two SNPs showing substantial differences.</p