The structural effects of mutations can aid in differential phenotype prediction of beta-myosin heavy chain (Myosin-7) missense variants

MOTIVATION: High-throughput sequencing platforms are increasingly used to screen patients with genetic disease for pathogenic mutations, but prediction of the effects of mutations remains challenging. Previously we developed SAAPdap (Single Amino Acid Polymorphism Data Analysis Pipeline) and SAAPpred (Single Amino Acid Polymorphism Predictor) that use a combination of rule-based structural measures to predict whether a missense genetic variant is pathogenic. Here we investigate whether the same methodology can be used to develop a differential phenotype predictor, which, once a mutation has been predicted as pathogenic, is able to distinguish between phenotypes-in this case the two major clinical phenotypes (hypertrophic cardiomyopathy, HCM, and dilated cardiomyopathy, DCM) associated with mutations in the beta-myosin heavy chain (MYH7) gene product (Myosin-7). RESULTS: A random forest predictor trained on rule-based structural analyses together with structural clustering data gave a Matthews' correlation coefficient (MCC) of 0.53 (accuracy, 75%). A post hoc removal of machine learning models that performed particularly badly, increased the performance (MCC = 0.61, Acc = 79%). This proof of concept suggests that methods used for pathogenicity prediction can be extended for use in differential phenotype prediction

Computer simulation of syringomyelia in dogs

Syringomyelia is a pathological condition in which fluid-filled cavities (syringes) form and expand in the spinal cord. Syringomyelia is often linked with obstruction of the craniocervical junction and a Chiari malformation, which is similar in both humans and animals. Some brachycephalic toy breed dogs such as Cavalier King Charles Spaniels (CKCS) are particularly predisposed. The exact mechanism of the formation of syringomyelia is undetermined and consequently with the lack of clinical explanation, engineers and mathematicians have resorted to computer models to identify possible physical mechanisms that can lead to syringes. We developed a computer model of the spinal cavity of a CKCS suffering from a large syrinx. The model was excited at the cranial end to simulate the movement of the cerebrospinal fluid (CSF) and the spinal cord due to the shift of blood volume in the cranium related to the cardiac cycle. To simulate the normal condition, the movement was prescribed to the CSF. To simulate the pathological condition, the movement of CSF was blocked

Dietary assessment of British police force employees: A description of diet record coding procedures and cross-sectional evaluation of dietary energy intake reporting (The Airwave Health Monitoring Study)

Objectives: Dietary intake is a key aspect of occupational health. To capture the characteristics of dietary behaviour that is affected by occupational environment that may affect disease risk, a collection of prospective multiday dietary records is required. The aims of this paper are to: (1) collect multiday dietary data in the Airwave Health Monitoring Study, (2) describe the di etary coding procedures applied and (3) investigate the plausibility of dietary reporting in this occupational cohort. Design: A dietary coding protocol for this large-scale study was developed to minimise coding error rate. Participants (n 4412) who completed 7-day food records were included for cross-sectional analyses. Energy intake (EI) misreporting was estimated using the Goldberg method. Multivariate logistic regression models were applied to determine participant characteristics associated with EI misreporting. Setting: British police force employees enrolled (2007-2012) into the Airwave Health Monitoring Study. Results: The mean code error rate per food diary was 3.7% (SD 3.2%). The strongest predictors of EI under-reporting were body mass index (BMI) and physical activity. Compared with participants with BMI 30 kg/m2 had increased odds of being classified as under-reporting EI (men OR 5.20 95% CI 3.92 to 6.89; women OR 2.66 95% CI 1.85 to 3.83). Men and women in the highest physical activity category compared with the lowest were also more likely to be classified as underreporting (men OR 3.33 95% CI 2.46 to 4.50; women OR 4.34 95% CI 2.91 to 6.55). Conclusions: A reproducible dietary record coding procedure has been developed to minimise coding error in complex 7-day diet diaries. The prevalence of EI under-reporting is comparable with existing national UK cohorts and, in agreement with previous studies, classification of under-reporting was biased towards specific subgroups of participants

Characterisation of feline renal cortical fibroblast cultures and their transcriptional response to transforming growth factor beta 1

Chronic kidney disease (CKD) is common in geriatric cats, and the most prevalent pathology is chronic tubulointerstitial inflammation and fibrosis. The cell type predominantly responsible for the production of extra-cellular matrix in renal fibrosis is the myofibroblast, and fibroblast to myofibroblast differentiation is probably a crucial event. The cytokine TGF-β1 is reportedly the most important regulator of myofibroblastic differentiation in other species. The aim of this study was to isolate and characterise renal fibroblasts from cadaverous kidney tissue of cats with and without CKD, and to investigate the transcriptional response to TGF-β1

Developing a digital intervention for cancer survivors: an evidence-, theory- and person-based approach

This paper illustrates a rigorous approach to developing digital interventions using an evidence-, theory- and person-based approach. Intervention planning included a rapid scoping review which identified cancer survivors’ needs, including barriers and facilitators to intervention success. Review evidence (N=49 papers) informed the intervention’s Guiding Principles, theory-based behavioural analysis and logic model. The intervention was optimised based on feedback on a prototype intervention through interviews (N=96) with cancer survivors and focus groups with NHS staff and cancer charity workers (N=31). Interviews with cancer survivors highlighted barriers to engagement, such as concerns about physical activity worsening fatigue. Focus groups highlighted concerns about support appointment length and how to support distressed participants. Feedback informed intervention modifications, to maximise acceptability, feasibility and likelihood of behaviour change. Our systematic method for understanding user views enabled us to anticipate and address important barriers to engagement. This methodology may be useful to others developing digital interventions

Human helminth therapy to treat inflammatory disorders - where do we stand?

Parasitic helminths have evolved together with the mammalian immune system over many millennia and as such they have become remarkably efficient modulators in order to promote their own survival. Their ability to alter and/or suppress immune responses could be beneficial to the host by helping control excessive inflammatory responses and animal models and pre-clinical trials have all suggested a beneficial effect of helminth infections on inflammatory bowel conditions, MS, asthma and atopy. Thus, helminth therapy has been suggested as a possible treatment method for autoimmune and other inflammatory disorders in humans

The optical/NIR afterglow of GRB 111209A: Complex yet not unprecedented

Context. Afterglows of gamma-ray bursts (GRBs) are simple in the most basic model, but can show many complex features. The ultra-long duration GRB 111209A, one of the longest GRBs ever detected, also has the best-monitored afterglow in this rare class of GRBs. Aims. We want to address the question whether GRB 111209A was a special event beyond its extreme duration alone, and whether it is a classical GRB or another kind of high-energy transient. The afterglow may yield significant clues. Methods. We present afterglow photometry obtained in seven bands with the GROND imager as well as in further seven bands with the Ultraviolet/Optical Telescope (UVOT) on-board the Neil Gehrels Swift Observatory. The light curve is analysed by multi-band modelling and joint fitting with power-laws and broken power-laws, and we use the contemporaneous GROND data to study the evolution of the spectral energy distribution. We compare the optical afterglow to a large ensemble we have analysed in earlier works, and especially to that of another ultra-long event, GRB 130925A. We furthermore undertake a photometric study of the host galaxy. Results. We find a strong, chromatic rebrightening event at ≈0.8 days after the GRB, during which the spectral slope becomes redder. After this, the light curve decays achromatically, with evidence for a break at about 9 days after the trigger. The afterglow luminosity is found to not be exceptional. We find that a double-jet model is able to explain the chromatic rebrightening. The afterglow features have been detected in other events and are not unique. Conclusions. The duration aside, the GRB prompt emission and afterglow parameters of GRB 111209A are in agreement with the known distributions for these parameters. While the central engine of this event may differ from that of classical GRBs, there are multiple lines of evidence pointing to GRB 111209A resulting from the core-collapse of a massive star with a stripped envelope

Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task

Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR) function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT2CR on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT2CR antagonist SB242084 (0.5 mg/kg) in a between-groups serial design and Experiment 2 used 5-HT2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS−), in a T- or Y-maze configuration. This was followed by three conditions; (1) Full reversal, where contingencies reversed; (2) Perseverance, where the previous CS+ became CS− and the previous CS− was replaced by a novel CS+; (3) Learned non-reward, where the previous CS− became CS+ and the previous CS+ was replaced by a novel CS-. SB242084 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT2CR KO mice showed increased perseverance. 5-HT2CR KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT2CR function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT2CR antagonism and constitutive loss of the 5-HT2CR have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT2CR loss on the development and maintenance of cognitive function

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Quality target negotiation in health care : evidence from the English NHS

We examine how public sector third-party purchasers and hospitals negotiate quality targets when a fixed proportion of hospital revenue is required to be linked to quality. We develop a bargaining model linking the number of quality targets to purchaser and hospital characteristics. Using data extracted from 153 contracts for acute hospital services in England in 2010/11, we find that the number of quality targets is associated with the purchaser’s population health and its budget, the hospital type, whether the purchaser delegated negotiation to an agency, and the quality targets imposed by the supervising regional health authority