The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme

Ink Magazine: Issue 2

INK magazine – a showcase for the work of students and staff at the University of Lincoln. Our first issue focuses on the College of Arts, with contributions from courses across the School of Design

Elective surgical referral guidelines : background educational material or essential shared decision making tool? : a survey of GPs' in England

Background: To investigate general practitioners’ (GPs’) attitudes to guidelines for elective surgical referral in England. To understand their use of guidelines, and attitudes to shared decision making in the referral decision. Methods: A questionnaire was developed which investigated attitudes to and use of guidelines. It was given to a stratified random sample 30% (n = 310) drawn from GP lists of 10 English health districts (primary care trusts (PCTs)). GPs were invited to respond online, by telephone, fax or post. Data were analysed using descriptive statistics and backwards stepwise logistic regression. Results: Responses were representative of GPs in England, but (despite up to 6 contacts per non-responder) the overall response rate was 41.6% (n = 129; with the range across PCTs of 25-61%). Most responding GPs indicated support for referral guidelines but 18% reported that they had never used them. Less than three per cent reported use for most or all referral decisions. The odds of using guidelines decreased with increasing age, with a ten year increase in age associated with halving odds of use (OR = 0.53, 95%CI = 0.29-0.90). Over 50% of GPs wanted good access to electronic guidelines with expert information and advice on guideline availability. Almost all (>89%) GPs agreed with sharing referral decisions with patients. Female doctors (OR = 5.2, 95%CI: 1.02-26.3) were more likely to agree with this than male GPs as were those working in larger compared to small or single handed practices (OR = 5.3, 95%CI: 1.4-19.9). Conclusions: This group of responding GPs was supportive of guidelines but used them in different ways. Referral guidelines should have an educational component for background reading; include key messages for internalisation and application; and incorporate mechanisms to facilitate accessibility and appropriate shared decision making with patients