Lost in the system : responsibilisation and burden for women with multiple long-term health conditions during pregnancy

We would like to thank our patient and public involvement representatives for their input into the design, conduct and analysis of this work. Thanks also to our participants who took part in the study. This work was funded by the Strategic Priority Fund “Tackling multimorbidity at scale” programme (grant number MR/W014432/1) delivered by the Medical Research Council and the National Institute for Health Research in partnership with the Economic and Social Research Council and in collaboration with the Engineering and Physical Sciences Research Council.Peer reviewe

The Diabetes Remission Clinical Trial (DiRECT): protocol for a cluster randomised trial

Background: Despite improving evidence-based practice following clinical guidelines to optimise drug therapy, Type 2 diabetes (T2DM) still exerts a devastating toll from vascular complications and premature death. Biochemical remission of T2DM has been demonstrated with weight loss around 15kg following bariatric surgery and in several small studies of non-surgical energy-restriction treatments. The non-surgical Counterweight-Plus programme, running in Primary Care where obesity and T2DM are routinely managed, produces >15 kg weight loss in 33 % of all enrolled patients. The Diabetes UK-funded Counterpoint study suggested that this should be sufficient to reverse T2DM by removing ectopic fat in liver and pancreas, restoring first-phase insulin secretion. The Diabetes Remission Clinical Trial (DiRECT) was designed to determine whether a structured, intensive, weight management programme, delivered in a routine Primary Care setting, is a viable treatment for achieving durable normoglycaemia. Other aims are to understand the mechanistic basis of remission and to identify psychological predictors of response. Methods/Design: Cluster-randomised design with GP practice as the unit of randomisation: 280 participants from around 30 practices in Scotland and England will be allocated either to continue usual guideline-based care or to add the Counterweight-Plus weight management programme, which includes primary care nurse or dietitian delivery of 12-20weeks low calorie diet replacement, food reintroduction, and long-term weight loss maintenance. Main inclusion criteria: men and women aged 20-65years, all ethnicities, T2DM 0-6years duration, BMI 27-45 kg/m2. Tyneside participants will undergo Magnetic Resonance (MR) studies of pancreatic and hepatic fat, and metabolic studies to determine mechanisms underlying T2DM remission. Co-primary endpoints: weight reduction ≥ 15 kg and HbA1c <48 mmol/mol at one year. Further follow-up at 2 years. Discussion: This study will establish whether a structured weight management programme, delivered in Primary Care by practice nurses or dietitians, is a viable treatment to achieve T2DM remission. Results, available from 2018 onwards, will inform future service strategy

Dependence on Mincle and Dectin-2 Varies With Multiple Candida Species During Systemic Infection

FUNDING SO was supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant No. 099953/Z/12/Z) and by a Wellcome Trust Cross-Disciplinary Award. NG acknowledges Wellcome Trust support of a Senior Investigator (101873/Z/13/Z), Collaborative (200208/A/15/Z) and Strategic Awards (097377/Z11/Z) and the MRC Centre for Medical Mycology (MR/N006364/2). PT was funded by a Wellcome Trust Investigator Award (107964/Z/15/Z) and the UK Dementia Research Institute. ACKNOWLEDGMENTS We wish to acknowledge the NIH-sponsored Mutant Mouse Regional Resource Center (MMRRC) National System as the source of genetically altered mice (C57BL/6-Clec4et m1. 1C fg /Mmucd 031936-UCD) for use in this study. The mice were produced and deposited to the MMRRC by the Consortium for Functional Glycomics supported by the National Institute of General Medical Sciences (GM62116). We also thank the Microscopy and Histology Core Facility at the University of Aberdeen for expert assistance with TEM.Peer reviewedPublisher PD

Within-trial cost and 1-year cost-effectiveness of the DiRECT/Counterweight-Plus weight-management programme to achieve remission of type 2 diabetes

No abstract available

A comparison of a structured home-based rehabilitation programme with conventional supervised pulmonary rehabilitation:A randomised non-inferiority trial

Background: Standardised home-based pulmonary rehabilitation (PR) programmes offer an alternative model to centre-based supervised PR for which uptake is currently poor. We determined if a structured home-based unsupervised PR programme was non-inferior to supervised centre-based PR for participants with COPD. Methods: A total of 287 participants with COPD who were referred to PR (187 male, mean (SD) age 68 (8.86) years, FEV1% predicted 48.34 (17.92)) were recruited. They were randomised to either centre-based PR or a structured unsupervised home-based PR programme including a hospital visit with a healthcare professional trained in motivational interviewing, a self-management manual and two telephone calls. Fifty-eight (20%) withdrew from the centre-based group and 51 (18%) from the home group. The primary outcome was dyspnoea domain in the chronic respiratory disease questionnaire (Chronic Respiratory Questionnaire Self-Report; CRQ-SR) at 7 weeks. Measures were taken blinded. We undertook a modified intention-to-treat (mITT) complete case analysis, comparing groups according to original random allocation and with complete data at follow-up. The non-inferiority margin was 0.5 units. Results: There was evidence of significant gains in CRQ-dyspnoea at 7 weeks in both home and centre-based groups. There was inconclusive evidence that home-based PR was non-inferior to PR in dyspnoea (mean group difference, mITT: −0.24, 95% CI −0.61 to 0.12, p=0.18), favouring the centre group at 7 weeks. Conclusions: The standardised home-based programme provides benefits in dyspnoea. Further evidence is needed to definitively determine if the health benefits of the standardised home-based programme are non-inferior or equivalent to supervised centre-based rehabilitation

Haemoptysis in pregnancy caused by a well-differentiated fetal adenocarcinoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Haemoptysis in pregnancy is frequently assumed to be caused by a pulmonary embolism. However, it can also be an indicator of serious pathology.</p> <p>Case presentation</p> <p>We report the case of a 27-year-old Caucasian woman who presented with haemoptysis in pregnancy that was discovered to be caused by a well-differentiated fetal adenocarcinoma of the lung.</p> <p>Conclusion</p> <p>This case demonstrates the importance of establishing an accurate diagnosis when a pregnant woman presents with haemoptysis and that more serious pathology should be considered if the clinical symptoms persist and/or the presumed diagnosis of pulmonary embolism is not confirmed.</p

Evolutionary resurrection of flagellar motility via rewiring of the nitrogen regulation system

A central process in evolution is the recruitment of genes to regulatory networks. We engineered immotile strains of the bacterium Pseudomonas fluorescens that lack flagella due to deletion of the regulatory gene fleQ. Under strong selection for motility, these bacteria consistently regained flagella within 96 hours via a two-step evolutionary pathway. Step 1 mutations increase intracellular levels of phosphorylated NtrC, a distant homologue of FleQ, which begins to commandeer control of the fleQ regulon at the cost of disrupting nitrogen uptake and assimilation. Step 2 is a switch-of-function mutation that redirects NtrC away from nitrogen uptake and towards its novel function as a flagellar regulator. Our results demonstrate that natural selection can rapidly rewire regulatory networks in very few, repeatable mutational steps

Quantifying single nucleotide variant detection sensitivity in exome sequencing

BACKGROUND: The targeted capture and sequencing of genomic regions has rapidly demonstrated its utility in genetic studies. Inherent in this technology is considerable heterogeneity of target coverage and this is expected to systematically impact our sensitivity to detect genuine polymorphisms. To fully interpret the polymorphisms identified in a genetic study it is often essential to both detect polymorphisms and to understand where and with what probability real polymorphisms may have been missed. RESULTS: Using down-sampling of 30 deeply sequenced exomes and a set of gold-standard single nucleotide variant (SNV) genotype calls for each sample, we developed an empirical model relating the read depth at a polymorphic site to the probability of calling the correct genotype at that site. We find that measured sensitivity in SNV detection is substantially worse than that predicted from the naive expectation of sampling from a binomial. This calibrated model allows us to produce single nucleotide resolution SNV sensitivity estimates which can be merged to give summary sensitivity measures for any arbitrary partition of the target sequences (nucleotide, exon, gene, pathway, exome). These metrics are directly comparable between platforms and can be combined between samples to give “power estimates” for an entire study. We estimate a local read depth of 13X is required to detect the alleles and genotype of a heterozygous SNV 95% of the time, but only 3X for a homozygous SNV. At a mean on-target read depth of 20X, commonly used for rare disease exome sequencing studies, we predict 5–15% of heterozygous and 1–4% of homozygous SNVs in the targeted regions will be missed. CONCLUSIONS: Non-reference alleles in the heterozygote state have a high chance of being missed when commonly applied read coverage thresholds are used despite the widely held assumption that there is good polymorphism detection at these coverage levels. Such alleles are likely to be of functional importance in population based studies of rare diseases, somatic mutations in cancer and explaining the “missing heritability” of quantitative traits