Development of oedema is associated with an improved glycaemic response in patients initiating thiazolidinediones: a MASTERMIND study

Abstracts of the 51st EASD Annual Meeting, Stockholm, Sweden, 14–18 September 2015This is the author accepted manuscript. The final version is available from Springer VerlagBackground and aims: Oedema is a common and serious side effect of thiazolidinedione therapy. A stratified medicines approach would aim to give thiazolidinediones to patients likely to have a good glycaemic response but to not develop oedema. We investigated whether oedema was associated with glycaemic response to thiazolidinedione therapy. Materials and methods: We retrospectively studied 11,459 patients initiating a thiazolidinedione from UK primary care data (Clinical Practice Research Datalink), and identified medical records of new oedema in the subsequent twelve months. Response was defined as change in HbA1c at twelve months and was adjusted for baseline HbA1c, baseline BMI, gender and compliance (medication possession ratio). In secondary analyses we restricted oedema classification to patients with concomitant weight gain. As a comparison the same analysis was performed in 13,089 patients initiating a sulfonylurea. Results: The 5% of patients with recorded oedema on thiazolidinediones had a mean (CI) 2.2 (1.1-3.2)mmol/mol greater fall in HbA1c (p3 kg (p< 0.001) and a 3.6 (1.8-5.4)mmol/mol greater fall when weight gain >5 kg (p3 kg (p=0.19). Conclusion: Patients with Type 2 diabetes who develop oedema on initiating thiazolidinediones have an improved glycaemic response, and more severe oedema may be associated with greater reductions in HbA1c. An association between oedema and glycaemic response was not observed in patients initiating sulfonylureas. This supports glycaemic lowering and fluid retention being mediated by a common pathway of thiazolidinedione drug action.Supported by: MRC grant MR-K005707-

Patients who develop oedema on initiating thiazolidinedione therapy have an improved glycaemic response: a MASTERMIND study

Special Issue: Abstracts of the Diabetes UK Professional Conference 2015, ExCeL London, 11–13 March 2015This is the author accepted manuscript. The final version is available from WileyBackground/aim: Oedema is a common and serious side effect ofthiazolidinedione therapy. A stratified medicine approach wouldaim to give thiazolidinediones to patients likely to have a goodglycaemic response but not to develop oedema. We investigatedwhether oedema was associated with glycaemic response tothiazolidinedione therapy.Methods: We studied 10,486 patients initiating a thiazolidinedionefrom Clinical Practice Research Datalink (CPRD), and identifiedmedical records of oedema in the subsequent 12 months. Responsewas defined as change in HbA1c at 12 months and was adjusted forbaseline HbA1c, baseline body mass index, gender and adherence(medication possession ratio). In secondary analyses we restrictedoedema classification to patients with concomitant weight gain. As acomparison the same analysis was performed in 13,089 patientsinitiating a sulfonylurea.Results: The 3% of patients with recorded oedema onthiazolidinediones had a mean (confidence interval) 3 (1.7–4.3)mmol/mol greater fall in HbA1c (p 3kg (p 8kg (p 3kg (p=0.19).Conclusion: Patients with Type 2 diabetes who develop oedemaon initiating thiazolidinediones have an improved glycaemicresponse, and more severe oedema is associated with greaterHbA1c reduction. This supports glycaemic lowering andfluid retention being mediated by a common pathway ofthiazolidinedione drug action

Comparisons of the factor structure and measurement invariance of the Spence children’s anxiety scale - parent version in children with autism spectrum disorder and typically developing anxious children

The Spence Children’s Anxiety Scale - Parent version (SCAS-P) is often used to assess anxiety in children with autism spectrum disorder (ASD), however, little is known about the validity of the tool in this population. The aim of this study was to determine whether the SCAS-P has the same factorial validity in a sample of young people with ASD (n=285), compared to a sample of typically developing young people with anxiety disorders (n=224). Poor model fit with all of the six hypothesised models precluded invariance testing. Exploratory factor analysis indicated that different anxiety phenomenology characterises the two samples. The findings suggest that cross-group comparisons between ASD and anxious samples based on the SCAS-P scores may not always be appropriat

Prior event rate ratio adjustment produced estimates consistent with randomized trial: a diabetes case study

Objectives: Electronic health records (EHR) provide a valuable resource for assessing drug side-effects, but treatments are not randomly allocated in routine care creating the potential for bias. We conduct a case study using the Prior Event Rate Ratio (PERR) Pairwise method to reduce unmeasured confounding bias in side-effect estimates for two second-line therapies for type 2 diabetes, thiazolidinediones, and sulfonylureas. Study design and settings: Primary care data were extracted from the Clinical Practice Research Datalink (n = 41,871). We utilized outcomes from the period when patients took first-line metformin to adjust for unmeasured confounding. Estimates for known side-effects and a negative control outcome were compared with the A Diabetes Outcome Progression Trial (ADOPT) trial (n = 2,545). Results: When on metformin, patients later prescribed thiazolidinediones had greater risks of edema, HR 95% CI 1.38 (1.13, 1.68) and gastrointestinal side-effects (GI) 1.47 (1.28, 1.68), suggesting the presence of unmeasured confounding. Conventional Cox regression overestimated the risk of edema on thiazolidinediones and identified a false association with GI. The PERR Pairwise estimates were consistent with ADOPT: 1.43 (1.10, 1.83) vs. 1.39 (1.04, 1.86), respectively, for edema, and 0.91 (0.79, 1.05) vs. 0.94 (0.80, 1.10) for GI. Conclusion: The PERR Pairwise approach offers potential for enhancing postmarketing surveillance of side-effects from EHRs but requires careful consideration of assumptions.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.The MASTERMIND (MRC APBI Stratification and Extreme Response Mechanism IN Diabetes) consortium is funded by the U.K Medical Research Council funded study grant number MR/N00633X/1. The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. IQVIA provided some funding for this project.published version, accepted version (12 month embargo), submitted versio

Are the new drugs better? Changing UK prescribing of Type 2 diabetes medications and effects on HbA1c and weight, 2010 to 2016

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Aim: The availability of new glucose‐lowering drugs has changed UK National Institute of Clinical Excellence Type 2 diabetes guidelines, but there has been little evaluation of real‐world use of these drugs, or of the population‐level impact of their use. We examined changes in UK prescribing for patients starting second‐ and third‐line medications, and population‐level trends in glycaemic response and weight change. Methods: We extracted incident second‐ and third‐line oral prescription records for patients with Type 2 diabetes in the UK‐representative Clinical Practice Research Datalink, 2010 to 2016 (n = 68,902). Each year we calculated the proportion of each drug prescribed as the percentage of the total prescribed. We estimated annual mean six‐month HbA1c response and weight change using linear regression, standardised for clinical characteristics. Results: Use of Dipeptidyl peptidase‐4 (DPP4) inhibitors has increased markedly to overtake sulfonylureas as the most commonly prescribed second‐line drug in 2016 (43% vs 34% of total prescriptions compared with 18% v 59% in 2010). Use of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors has increased rapidly to 14% of second‐line and 27% of third‐line prescriptions in 2016. Mean HbA1c response at six months was stable over time (2016: 13.5 (95% confidence interval 12.8, 14.1) mmol/mol vs 2010: 13.9 (13.6;14.2) mmol/mol, p = 0.21). We found mean weight loss at six months in 2016, in contrast to 2010 where there was mean weight gain (2016: −1.2 (−0.9; −1.5) kg vs 2010: +0.4 (+0.3; +0.5) kg, p < 0.001). Conclusion: The pattern of drug prescribing to manage patients with Type 2 diabetes has changed rapidly in the United Kingdom. Increasing use of DPP4 inhibitors and SGLT2 inhibitors has not resulted in improved glycaemic control but has improved the body weight of patients starting second‐ and third‐line therapy. Acknowledgement: This abstract is submitted on behalf of the MASTERMIND consortium

Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes

Drug resistant infections represent one of the most challenging medical problems of our time. D-cycloserine is an antibiotic used for six decades without significant appearance and dissemination of antibiotic resistant strains, making it an ideal model compound to understand what drives resistance evasion. We therefore investigated why Mycobacterium tuberculosis fails to become resistant to D-cycloserine. To address this question, we employed a combination of bacterial genetics, genomics, biochemistry and fitness analysis in vitro, in macrophages and in mice. Altogether, our results suggest that the ultra-low rate of emergence of D-cycloserine resistance mutations is the dominant biological factor delaying the appearance of clinical resistance to this antibiotic. Furthermore, we also identified potential compensatory mechanisms able to minimize the severe fitness costs of primary D-cycloserine resistance conferring mutations

Plasticity of the Muscle Stem Cell Microenvironment

Satellite cells (SCs) are adult muscle stem cells capable of repairing damaged and creating new muscle tissue throughout life. Their functionality is tightly controlled by a microenvironment composed of a wide variety of factors, such as numerous secreted molecules and different cell types, including blood vessels, oxygen, hormones, motor neurons, immune cells, cytokines, fibroblasts, growth factors, myofibers, myofiber metabolism, the extracellular matrix and tissue stiffness. This complex niche controls SC biology-quiescence, activation, proliferation, differentiation or renewal and return to quiescence. In this review, we attempt to give a brief overview of the most important players in the niche and their mutual interaction with SCs. We address the importance of the niche to SC behavior under physiological and pathological conditions, and finally survey the significance of an artificial niche both for basic and translational research purposes

The sperm factor: paternal impact beyond genes

The fact that sperm carry more than the paternal DNA has only been discovered just over a decade ago. With this discovery, the idea that the paternal condition may have direct implications for the fitness of the offspring had to be revisited. While this idea is still highly debated, empirical evidence for paternal effects is accumulating. Male condition not only affects male fertility but also offspring early development and performance later in life. Several factors have been identified as possible carriers of non-genetic information, but we still know little about their origin and function and even less about their causation. I consider four possible non-mutually exclusive adaptive and non-adaptive explanations for the existence of paternal effects in an evolutionary context. In addition, I provide a brief overview of the main non-genetic components found in sperm including DNA methylation, chromatin modifications, RNAs and proteins. I discuss their putative functions and present currently available examples for their role in transferring non-genetic information from the father to the offspring. Finally, I identify some of the most important open questions and present possible future research avenues

Low Spigelian hernia in a 6-year-old boy presenting as an incarcerated inguinal hernia: a case report

<p>Abstract</p> <p>Introduction</p> <p>Lower Spigelian hernia is a very rare entity. The clinical findings are similar to those of inguinal hernias and in many cases may be misdiagnosed. In the literature, only a few references to this entity have been reported in children. To the best of our knowledge, this is the first case report of a lower Spigelian hernia in a child who presented with an acute painful scrotum.</p> <p>Case presentation</p> <p>We discuss the case of a 6-year-old Greek boy who presented to our emergency department complaining of severe pain in the left inguinal area and scrotum. The acute painful swelling started suddenly, without any obvious cause. The initial diagnosis was incarcerated inguinal hernia which was reduced with difficulty. Five days later, the patient still experienced mild pain during palpation and he was operated on. During the operation, a large lower Spigelian hernia was revealed and reconstructed.</p> <p>Conclusion</p> <p>Although Spigelian hernias are rare in children and difficult to diagnose, physicians should be aware of them and include them in the differential diagnosis.</p