Predicting mortality after acute coronary syndromes in people with chronic obstructive pulmonary disease

Objective To assess the accuracy of Global Registry of Acute Coronary Events (GRACE) scores in predicting mortality at 6 months for people with chronic obstructive pulmonary disease (COPD) and to investigate how it might be improved. Methods Data were obtained on 481 849 patients with acute coronary syndrome admitted to UK hospitals between January 2003 and June 2013 from the Myocardial Ischaemia National Audit Project (MINAP) database. We compared risk of death between patients with COPD and those without COPD at 6 months, adjusting for predicted risk of death. We then assessed whether several modifications improved the accuracy of the GRACE score for people with COPD. Results The risk of death after adjusting for GRACE score predicted that risk of death was higher for patients with COPD than that for other patients (RR 1.29, 95% CI 1.28 to 1.33). Adding smoking into the GRACE score model did not improve accuracy for patients with COPD. Either adding COPD into the model (relative risk (RR) 1.00, 0.94 to 1.02) or multiplying the GRACE score by 1.3 resulted in better performance (RR 0.99, 0.96 to 1.01). Conclusions GRACE scores underestimate risk of death for people with COPD. A more accurate prediction of risk of death can be obtained by adding COPD into the GRACE score equation, or by multiplying the GRACE score predicted risk of death by 1.3 for people with COPD. This means that one third of patients with COPD currently classified as low risk should be classified as moderate risk, and could be considered for more aggressive early treatment after non-ST-segment elevation myocardial infarction or unstable angina

Systematic review of the effectiveness of preventing and treating Staphylococcus aureus carriage in reducing peritoneal catheter-related infections

Objectives: To determine the clinical effectiveness and cost-effectiveness of (1) alternative strategies for the prevention of Staphylococcus aureus carriage in patients on peritoneal dialysis (PD) and (2) alternative strategies for the eradication of S. aureus carriage in patients on PD. Data sources: Major electronic databases were searched up to December 2005 (MEDLINE Extra up to 6 January 2006). Review methods: Electronic searches were undertaken to identify published and unpublished reports of randomised controlled trials and systematic reviews evaluating the effectiveness of preventing and treating S. aureus carriage on peritoneal catheterrelated infections. The quality of the included studies was assessed and data synthesised. Where data were not sufficient for formal meta-analysis, a qualitative narrative review looking for consistency between studies was performed. Results: Twenty-two relevant trials were found. These fell into several groups: the first split is between prophylactic trials, aiming to prevent carriage, and trials which aimed to eradicate carriage in those who already had it; the second split is between antiseptics and antibiotics; and the third split is between those that included patients having the catheter inserted before dialysis started and people already on dialysis. Many of the trials were small or short-term. The quality was often not good by today’s standards. The body of evidence suggested a reduction in exit-site infections, but this did not seem to lead to a significant reduction in peritonitis, although to some extent this reflected insufficient power in the studies and a low incidence of peritonitis in them. The costs of interventions to prevent or treat S. aureus carriage are relatively modest. For example, the annual cost of antibiotic treatment of S. aureus carriage per identified carrier of S. aureus was estimated at £179 (£73 screening and £106 cost of antibiotic). However, without better data on the effectiveness of the interventions, it is not clear whether such costs are offset by the cost of treating infections and averting changes from peritoneal dialysis to haemodialysis. Although treatment is not expensive, the lack of convincing evidence of clinical effectiveness made cost-effectiveness analysis unrewarding at present. However, consideration was given to the factors needed in a hypothetical model describing patient pathways from methods to prevent S. aureus carriage, its detection and treatment and the detection and treatment of the consequences of S. aureus (e.g. catheter infections and peritonitis). Had data been available, the model would have compared the costeffectiveness of alternative interventions from the perspective of the UK NHS, but as such it helped identify what future research would be needed to fill the gaps. Conclusions: The importance of peritonitis isnot in doubt. It is the main cause of people having to switch from peritoneal dialysis to haemodialysis, which then leads to reduced quality of life for patients and increased costs to the NHS. Unfortunately, the present evidence base for the prevention of peritonitis is disappointing; it suggests that the interventions reduce exit-site infections, but not peritonitis, although this may be due to trials being in too small numbers for too short periods. Trials are needed with larger numbers of patients for longer durations.No peer reviewPublisher PD

CHC22 and CHC17 clathrins have distinct biochemical properties and display differential regulation and function

Clathrins are cytoplasmic proteins that play essential roles in endocytosis and other membrane traffic pathways. Upon recruitment to intracellular membranes, the canonical clathrin triskelion assembles into a polyhedral protein coat that facilitates vesicle formation and captures cargo molecules for transport. The triskelion is formed by trimerization of three clathrin heavy-chain subunits. Most vertebrates have two isoforms of clathrin heavy chains, CHC17 and CHC22, generating two clathrins with distinct cellular functions. CHC17 forms vesicles at the plasma membrane for receptor-mediated endocytosis and at the trans-Golgi network for organelle biogenesis. CHC22 plays a key role in intracellular targeting of the insulin-regulated glucose transporter 4 (GLUT4), accumulates at the site of GLUT4 sequestration during insulin resistance, and has also been implicated in neuronal development. Here, we demonstrate that CHC22 and CHC17 share morphological features, in that CHC22 forms a triskelion and latticed vesicle coats. However, cellular CHC22-coated vesicles were distinct from those formed by CHC17. The CHC22 coat was more stable to pH change and was not removed by the enzyme complex that disassembles the CHC17 coat. Moreover, the two clathrins were differentially recruited to membranes by adaptors, and CHC22 did not support vesicle formation or transferrin endocytosis at the plasma membrane in the presence or absence of CHC17. Our findings provide biochemical evidence for separate regulation and distinct functional niches for CHC17 and CHC22 in human cells. Furthermore, the greater stability of the CHC22 coat relative to the CHC17 coat may be relevant to its excessive accumulation with GLUT4 during insulin resistance. [Abstract copyright: Copyright © 2017, The American Society for Biochemistry and Molecular Biology.

Assessing the healthcare resource use associated with inappropriate prescribing of inhaled corticosteroids for people with chronic obstructive pulmonary disease (COPD) in GOLD groups A or B:an observational study using the Clinical Practice Research Datalink (CPRD)

Abstract Background Recent recommendations from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) position inhaled corticosteroids (ICS) for use in chronic obstructive pulmonary disease (COPD) patients experiencing exacerbations (≥ 2 or ≥ 1 requiring hospitalisation); i.e. GOLD groups C and D. However, it is known that ICS is frequently prescribed for patients with less severe COPD. Potential drivers of inappropriate ICS use may be historical clinical guidance or a belief among physicians that intervening early with ICS would improve outcomes and reduce resource use. The objective of this study was to compare healthcare resource use in the UK for COPD patients in GOLD groups A and B (0 or 1 exacerbation not resulting in hospitalisation) who have either been prescribed an ICS-containing regimen or a non-ICS-containing regimen. Methods Linked data from the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) database were used. For the study period (1 July 2005 to 30 June 2015) a total 4009 patients met the inclusion criteria; 1745 receiving ICS-containing therapy and 2264 receiving non-ICS therapy. Treatment groups were propensity score-matched to account for potential confounders in the decision to prescribe ICS, leaving 1739 patients in both treatment arms. Resource use was assessed in terms of frequency of healthcare practitioner (HCP) interactions and rescue therapy prescribing. Treatment acquisition costs were not assessed. Results Results showed no benefit associated with the addition of ICS, with numerically higher all-cause HCP interactions (72,802 versus 69,136; adjusted relative rate: 1.07 [p = 0.061]) and rescue therapy prescriptions (24,063 versus 21,163; adjusted relative rate: 1.05 [p = 0.212]) for the ICS-containing group compared to the non-ICS group. Rate ratios favoured the non-ICS group for eight of nine outcomes assessed. Outcomes were similar for subgroup analyses surrounding potential influential parameters, including patients with poorer lung function (FEV1 <  50% predicted), one prior exacerbation or elevated blood eosinophils. Conclusions These data suggest that ICS use in GOLD A and B COPD patients is not associated with a benefit in terms of healthcare resource use compared to non-ICS bronchodilator-based therapy; using ICS according to GOLD recommendations may offer an opportunity for improving patient care and reducing resource use

Comparative adherence and persistence of single- and multiple-inhaler triple therapies among patients with chronic obstructive pulmonary disease in an English real-world primary care setting.

This is the final version. Available from Dove Press via the DOI in this record. Data Sharing Statement: The data analyzed in this publication are derived from the Clinical Practice Research Datalink (www.cprd.com) and Hospital Episode Statistics database (https://digital.nhs.uk/data-and-information/data-tools-and-services/data-services/hospital-episodestatistics). Authors had access to the study data for the purposes of this work only. Data were accessed through an existing GSK license to address the prespecified research questions only. Therefore, the data cannot be broadly disclosed or made publicly available at this time. Access to each database can be requested via the respective websites.PURPOSE: Triple therapy comprising a long-acting muscarinic antagonist, long-acting β2-agonist and inhaled corticosteroid is recommended for patients with chronic obstructive pulmonary disease (COPD) who continue to experience frequent exacerbations or symptoms whilst receiving dual therapy. Adherence and persistence to multiple-inhaler triple therapy (MITT) is known to be poor. This study assessed comparative adherence to single-inhaler triple therapy (SITT) versus MITT in a real-world setting in England. PATIENTS AND METHODS: This was a retrospective cohort study using linked primary care (Clinical Practice Research Datalink Aurum) and secondary care (Hospital Episode Statistics [HES] Admitted Patient Care) data to identify patients with COPD who were newly initiated on SITT or MITT between November 2017 and June 2019. Eligible patients were aged ≥35 years and had a forced expiratory volume in 1 second/forced vital capacity 30 days between the end of a prescription and the following refill used to determine non-persistence. RESULTS: Overall, 4080 SITT and 6579 MITT users comprised the study cohort. After weighting, the baseline characteristics between the cohorts were comparable (absolute standardized mean difference <10%). SITT users had significantly higher adherence than MITT users at 6, 12, and 18 months post-initiation (p<0.001 for all comparisons). Median persistence was higher among SITT users than MITT users (5.09 months vs 0.99 months). CONCLUSION: Patients with COPD in England initiating SITT had significantly better adherence and persistence compared with MITT initiators. These improvements continued at least 18 months following treatment initiation.GlaxoSmithKlei

Single molecule fluorescence for membrane proteins

The cell membrane is a complex milieu of lipids and proteins. In order to understand the behaviour of individual molecules is it often desirable to examine them as purified components in in vitro systems. Here, we detail the creation and use of droplet interface bilayers (DIBs) which, when coupled to TIRF microscopy, can reveal spatiotemporal and kinetic information for individual membrane proteins. A number of steps are required including modification of the protein sequence to enable the incorporation of appropriate fluorescent labels, expression and purification of the membrane protein and subsequent labelling. Following creation of DIBs, proteins are spontaneously incorporated into the membrane where they can be imaged via conventional single molecule TIRF approaches. Using this strategy, in conjunction with step-wise photobleaching, FRET and / or single particle tracking, a host of parameters can be determined such as oligomerisation state and dynamic information. We discuss advantages and limitations of this system and offer guidance for successful implementation of these approaches

APP controls the formation of PI(3,5)P2 vesicles through its binding of the PIKfyve complex

Phosphoinositides are signalling lipids that are crucial for major signalling events as well as established regulators of membrane trafficking. Control of endosomal sorting and endosomal homeostasis requires phosphatidylinositol-3-phosphate (PI(3)P) and phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2), the latter a lipid of low abundance but significant physiological relevance. PI(3,5)P2 is formed by phosphorylation of PI(3)P by the PIKfyve complex which is crucial for maintaining endosomal homeostasis. Interestingly, loss of PIKfyve function results in dramatic neurodegeneration. Despite the significance of PIKfyve, its regulation is still poorly understood. Here we show that the Amyloid Precursor Protein (APP), a central molecule in Alzheimer’s disease, associates with the PIKfyve complex (consisting of Vac14, PIKfyve and Fig4) and that the APP intracellular domain directly binds purified Vac14. We also show that the closely related APP paralogues, APLP1 and 2 associate with the PIKfyve complex. Whether APP family proteins can additionally form direct protein–protein interaction with PIKfyve or Fig4 remains to be explored. We show that APP binding to the PIKfyve complex drives formation of PI(3,5)P2 positive vesicles and that APP gene family members are required for supporting PIKfyve function. Interestingly, the PIKfyve complex is required for APP trafficking, suggesting a feedback loop in which APP, by binding to and stimulating PI(3,5)P2 vesicle formation may control its own trafficking. These data suggest that altered APP processing, as observed in Alzheimer’s disease, may disrupt PI(3,5)P2 metabolism, endosomal sorting and homeostasis with important implications for our understanding of the mechanism of neurodegeneration in Alzheimer’s disease

Expression and purification of recombinant G protein-coupled receptors: A review

Given their extensive role in cell signalling, GPCRs are significant drug targets; despite this, many of these receptors have limited or no available prophylaxis. Novel drug design and discovery significantly rely on structure determination, of which GPCRs are typically elusive. Progress has been made thus far to produce sufficient quantity and quality of protein for downstream analysis. As such, this review highlights the systems available for recombinant GPCR expression, with consideration of their advantages and disadvantages, as well as examples of receptors successfully expressed in these systems. Additionally, an overview is given on the use of detergents and the styrene maleic acid (SMA) co-polymer for membrane solubilisation, as well as purification techniques

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability