Evaluating Patient Preferences of Maintenance Therapy for the Treatment of Chronic Obstructive Pulmonary Disease: A Discrete Choice Experiment in the UK, USA and Germany.

Introduction: With increasing availability of different treatments for chronic obstructive pulmonary disease (COPD), we sought to understand patient preferences for COPD treatment in the UK, USA, and Germany using a discrete choice experiment (DCE). Methods: Qualitative research identified six attributes associated with COPD maintenance treatments: ease of inhaler use, exacerbation frequency, frequency of inhaler use, number of different inhalers used, side effect frequency, and out-of-pocket costs. A DCE using these attributes, with three levels each, was designed and tested through cognitive interviews and piloting. It comprised 18 choice sets, selected using a D-efficient experimental design. Demographics and disease history were collected and the final DCE survey was completed online by participants recruited from panels in the UK, USA and Germany. Responses were analyzed using mixed logit models, with results expressed as odds ratios (ORs). Results: Overall, 450 participants (150 per country) completed the DCE; most (UK and Germany, 97.3%; USA, 98.0%) were included in the final analysis. Based on relative attribute importance, avoidance of side effects was found to be most important (UK: OR 11.65; USA: OR 7.17; Germany: OR 11.45; all p<0.0001), followed by the likelihood of fewer exacerbations (UK: OR 2.22; USA: OR 1.63; Germany: OR 2.54; all p<0.0001) and increased ease of use (UK: OR 1.84; USA: OR 1.84; Germany: OR 1.60; all p<0.0001). Number of inhalers, out-of-pocket costs, and frequency of inhaler use were found to be less important. Preferences were relatively consistent across the three countries. All participants required a reduction in exacerbations to accept more frequent inhaler use or use of more inhalers. Conclusion: When selecting COPD treatment, individuals assigned the highest value to the avoidance of side effects, experiencing fewer exacerbations, and ease of inhaler use. Ensuring that patients' preferences are considered may encourage treatment compliance

Management of type 2 diabetes mellitus in people with severe mental illness: an online cross-sectional survey of healthcare professionals

Objectives To establish healthcare professionals’ (HCPs) views about clinical roles, and the barriers and enablers to delivery of diabetes care for people with severe mental illness (SMI). Design Cross-sectional, postal and online survey. Setting Trusts within the National Health Service (NHS), mental health and diabetes charities and professional bodies. Participants HCPs who care for people with type 2 diabetes mellitus (T2DM) and/or SMI in the UK. Primary and secondary outcome measures The barriers, enablers and experiences of delivering T2DM care for people with SMI, informed by the Theoretical Domains Framework (TDF). Results Responders were 273 HCPs, primarily mental health nurses (33.7%) and psychiatrists (32.2%). Only 25% of respondents had received training in managing T2DM in people with SMI. Mental health professionals felt responsible for significantly fewer recommended diabetes care standards than physical health professionals (p<0.001). For those seeing diabetes care as part of their role, the significant barriers to its delivery in the regression analyses were a lack of knowledge (p=0.003); a need for training in communication and negotiation skills (p=0.04); a lack of optimism about the health of their clients (p=0.04) and their ability to manage T2DM in people with SMI (p=0.003); the threat of being disciplined (p=0.02); fear of working with people with a mental health condition (p=0.01); a lack of service user engagement(p=0.006) and a need for incentives (p=0.04). The significant enablers were an understanding of the need to tailor treatments (p=0.04) and goals (p=0.02) for people with SMI. Conclusions This survey indicates that despite current guidelines, diabetes care in mental health settings remains peripheral. Even when diabetes care is perceived as part of a HCP’s role, various individual and organisational barriers to delivering recommended T2DM care standards to people with SMI are experienced

Inference of random walk models to describe leukocyte migration

While the majority of cells in an organism are static and remain relatively immobile in their tissue, migrating cells occur commonly during developmental processes and are crucial for a functioning immune response. The mode of migration has been described in terms of various types of random walks. To understand the details of the migratory behaviour we rely on mathematical models and their calibration to experimental data. Here we propose an approximate Bayesian inference scheme to calibrate a class of random walk models characterized by a specific, parametric particle re-orientation mechanism to observed trajectory data. We elaborate the concept of transition matrices (TMs) to detect random walk patterns and determine a statistic to quantify these TM to make them applicable for inference schemes. We apply the developed pipeline to in vivo trajectory data of macrophages and neutrophils, extracted from zebrafish that had undergone tail transection. We find that macrophage and neutrophils exhibit very distinct biased persistent random walk patterns, where the strengths of the persistence and bias are spatio-temporally regulated. Furthermore, the movement of macrophages is far less persistent than that of neutrophils in response to wounding

The Effect of Resistance Training in Healthy Adults on Body Fat Percentage, Fat Mass and Visceral Fat: A Systematic Review and Meta-Analysis

Background: Resistance training is the gold standard exercise mode for accrual of lean muscle mass, but the isolated effect of resistance training on body fat is unknown. Objectives: This systematic review and meta-analysis evaluated resistance training for body composition outcomes in healthy adults. Our primary outcome was body fat percentage; secondary outcomes were body fat mass and visceral fat. Design: Systematic review with meta-analysis. Data Sources: We searched five electronic databases up to January 2021. Eligibility Criteria: We included randomised trials that compared full-body resistance training for at least 4 weeks to no-exercise control in healthy adults. Analysis: We assessed study quality with the TESTEX tool and conducted a random-effects meta-analysis, with a subgroup analysis based on measurement type (scan or non-scan) and sex (male or female), and a meta-regression for volume of resistance training and training components. Results: From 11,981 records, we included 58 studies in the review, with 54 providing data for a meta-analysis. Mean study quality was 9/15 (range 6–15). Compared to the control, resistance training reduced body fat percentage by − 1.46% (95% confidence interval − 1.78 to − 1.14, p < 0.0001), body fat mass by − 0.55 kg (95% confidence interval − 0.75 to − 0.34, p < 0.0001) and visceral fat by a standardised mean difference of − 0.49 (95% confidence interval − 0.87 to − 0.11, p = 0.0114). Measurement type was a significant moderator in body fat percentage and body fat mass, but sex was not. Training volume and training components were not associated with effect size. Summary/Conclusions: Resistance training reduces body fat percentage, body fat mass and visceral fat in healthy adults. Study Registration: osf.io/hsk32

Acute liver effects, disposition and metabolic fate of [14C]-fenclozic acid following oral administration to normal and bile-cannulated male C57BL/6J Mice

The distribution, metabolism, excretion and hepatic effects of the human hepatotoxin fenclozic acid were investigated following single oral doses of 10 mg/kg to normal and bile-duct cannulated male C57BL/6J mice. Whole body autoradiography showed distribution into all tissues except the brain, with radioactivity still detectable in blood, kidney and liver at 72 h post dose. Mice dosed with [14C]-fenclozic acid showed acute centrilobular hepatocellular necrosis but no other regions of the liver were affected. The majority of the [14C]-fenclozic acid-related material recovered was found in the urine/aqueous cage wash, (49%) whilst a smaller portion (13%) was eliminated via the faeces. Metabolic profiles for urine, bile and faecal extracts, obtained using liquid chromatography and a combination of mass spectrometric and radioactivity detection, revealed extensive metabolism of fenclozic acid in mice that involved biotransformations via both oxidation and conjugation. These profiling studies also revealed the presence of glutathione-derived metabolites providing evidence for the production of reactive species by mice administered fenclozic acid. Covalent binding to proteins from liver, kidney and plasma was also demonstrated, although this binding was relatively low (less than 50 pmol eq./mg protein)

Genome-wide signatures of convergent evolution in echolocating mammals

Evolution is typically thought to proceed through divergence of genes, proteins, and ultimately phenotypes(1-3). However, similar traits might also evolve convergently in unrelated taxa due to similar selection pressures(4,5). Adaptive phenotypic convergence is widespread in nature, and recent results from a handful of genes have suggested that this phenomenon is powerful enough to also drive recurrent evolution at the sequence level(6-9). Where homoplasious substitutions do occur these have long been considered the result of neutral processes. However, recent studies have demonstrated that adaptive convergent sequence evolution can be detected in vertebrates using statistical methods that model parallel evolution(9,10) although the extent to which sequence convergence between genera occurs across genomes is unknown. Here we analyse genomic sequence data in mammals that have independently evolved echolocation and show for the first time that convergence is not a rare process restricted to a handful of loci but is instead widespread, continuously distributed and commonly driven by natural selection acting on a small number of sites per locus. Systematic analyses of convergent sequence evolution in 805,053 amino acids within 2,326 orthologous coding gene sequences compared across 22 mammals (including four new bat genomes) revealed signatures consistent with convergence in nearly 200 loci. Strong and significant support for convergence among bats and the dolphin was seen in numerous genes linked to hearing or deafness, consistent with an involvement in echolocation. Surprisingly we also found convergence in many genes linked to vision: the convergent signal of many sensory genes was robustly correlated with the strength of natural selection. This first attempt to detect genome-wide convergent sequence evolution across divergent taxa reveals the phenomenon to be much more pervasive than previously recognised

Efficacy, acceptability, and safety of muscle relaxants for adults with non-specific low back pain: Systematic review and meta-analysis

AbstractObjective To investigate the efficacy, acceptability, and safety of muscle relaxants for low back pain. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Medline, Embase, CINAHL, CENTRAL, ClinicalTrials.gov, clinicialtrialsregister.eu, and WHO ICTRP from inception to 23 February 2021. Eligibility criteria for study selection Randomised controlled trials of muscle relaxants compared with placebo, usual care, waiting list, or no treatment in adults (≥18 years) reporting non-specific low back pain. Data extraction and synthesis Two reviewers independently identified studies, extracted data, and assessed the risk of bias and certainty of the evidence using the Cochrane risk-of-bias tool and Grading of Recommendations, Assessment, Development and Evaluations, respectively. Random effects meta-analytical models through restricted maximum likelihood estimation were used to estimate pooled effects and corresponding 95% confidence intervals. Outcomes included pain intensity (measured on a 0-100 point scale), disability (0-100 point scale), acceptability (discontinuation of the drug for any reason during treatment), and safety (adverse events, serious adverse events, and number of participants who withdrew from the trial because of an adverse event). Results 49 trials were included in the review, of which 31, sampling 6505 participants, were quantitatively analysed. For acute low back pain, very low certainty evidence showed that at two weeks or less non-benzodiazepine antispasmodics were associated with a reduction in pain intensity compared with control (mean difference -7.7, 95% confidence interval-12.1 to-3.3) but not a reduction in disability (-3.3, -7.3 to 0.7). Low and very low certainty evidence showed that non-benzodiazepine antispasmodics might increase the risk of an adverse event (relative risk 1.6, 1.2 to 2.0) and might have little to no effect on acceptability (0.8, 0.6 to 1.1) compared with control for acute low back pain, respectively. The number of trials investigating other muscle relaxants and different durations of low back pain were small and the certainty of evidence was reduced because most trials were at high risk of bias. Conclusions Considerable uncertainty exists about the clinical efficacy and safety of muscle relaxants. Very low and low certainty evidence shows that non-benzodiazepine antispasmodics might provide small but not clinically important reductions in pain intensity at or before two weeks and might increase the risk of an adverse event in acute low back pain, respectively. Large, high quality, placebo controlled trials are urgently needed to resolve uncertainty. Systematic review registration PROSPERO CRD42019126820 and Open Science Framework https://osf.io/mu2f5/