Quinolone-resistant gyrase mutants demonstrate decreased susceptibility to triclosan

Objectives: Cross-resistance between antibiotics and biocides is a potentially important driver of MDR. A relationship between susceptibility of Salmonella to quinolones and triclosan has been observed. This study aimed to: (i) investigate the mechanism underpinning this; (ii) determine whether the phenotype is conserved in Escherichia coli; and (iii) evaluate the potential for triclosan to select for quinolone resistance. Methods: WT E. coli, Salmonella enterica serovar Typhimurium and gyrA mutants were used. These were characterized by determining antimicrobial susceptibility, DNA gyrase activity and sensitivity to inhibition. Expression of stress response pathways (SOS, RpoS, RpoN and RpoH) was measured, as was the fitness of mutants. The potential for triclosan to select for quinolone resistance was determined. Results: All gyrase mutants showed increased triclosan MICs and altered supercoiling activity. There was no evidence for direct interaction between triclosan and gyrase. Identical substitutions in GyrA had different impacts on supercoiling in the two species. For both, there was a correlation between altered supercoiling and expression of stress responses. This was more marked in E. coli, where an Asp87Gly GyrA mutant demonstrated greatly increased fitness in the presence of triclosan. Exposure of parental strains to low concentrations of triclosan did not select for quinolone resistance. Conclusions: Our data suggest gyrA mutants are less susceptible to triclosan due to up-regulation of stress responses. The impact of gyrA mutation differs between E. coli and Salmonella. The impacts of gyrA mutation beyond quinolone resistance have implications for the fitness and selection of gyrA mutants in the presence of non-quinolone antimicrobials

Preliminary, real-world, multicenter experience with omadacycline for Mycobacterium abscessus infections

Twelve patients were treated with omadacycline (OMC) as part of a multidrug regimen fo

What stops children with a chronic illness accessing health care: A mixed methods study in children with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)

Background: Paediatric Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is relatively common and disabling with a mean time out of school of more than one academic year. NICE guidelines recommend referral to specialist services immediately if severely affected, within 3 months if moderately affected and within 6 months if mildly affected. However, the median time-to-assessment by a specialist service in the UK is 18 months. This study used a mixed-methods approach to examine factors associated with time taken to access specialist services. Methods. Time-to-assessment was analysed as a continuous "survival-time" variable in Cox regression models using data from self-completed assessment forms for children attending a regional specialist CFS/ME service between January 2006 and December 2009. Semi-structured interviews about barriers experienced in accessing healthcare for their child were conducted with nine parents of children aged < 17 years (8 individual and one parent couple). Interviews were digitally recorded and analysed using "thematic analysis". Results: 405 children were assessed between 2006 and 2009 and information on school attendance was available on 388. Only 1/125 with severe CFS/ME and 49/263 (19%) with mild to moderate CFS/ME were seen within NICE recommended timeframe. Increased fatigue was associated with shorter time to assessment (HR = 1.15; 95% CI 1.03, 1.29 per unit increase in Chalder fatigue score; P = 0.01). Time-to-assessment was not associated with disability, mood, age or gender. Parents described difficulties accessing specialist services because of their own as well as their GP's and Paediatrician's lack of knowledge. They experienced negative attitudes and beliefs towards the child's condition when they consulted GPs, Paediatricians and Child Psychiatrists. Parents struggled to communicate an invisible illness that their child and not themselves were experiencing. Conclusions: GPs, Child Psychiatrists and Paediatricians need more knowledge about CFS/ME and the appropriate referral pathways to ensure timeliness in referral to specialist services. © 2011 Webb et al; licensee BioMed Central Ltd

Risk sharing arrangements for pharmaceuticals: potential considerations and recommendations for European payers

<p>Abstract</p> <p>Background</p> <p>There has been an increase in 'risk sharing' schemes for pharmaceuticals between healthcare institutions and pharmaceutical companies in Europe in recent years as an additional approach to provide continued comprehensive and equitable healthcare. There is though confusion surrounding the terminology as well as concerns with existing schemes.</p> <p>Methods</p> <p>Aliterature review was undertaken to identify existing schemes supplemented with additional internal documents or web-based references known to the authors. This was combined with the extensive knowledge of health authority personnel from 14 different countries and locations involved with these schemes.</p> <p>Results and discussion</p> <p>A large number of 'risk sharing' schemes with pharmaceuticals are in existence incorporating both financial-based models and performance-based/outcomes-based models. In view of this, a new logical definition is proposed. This is "<it>risk sharing' schemes should be considered as agreements concluded by payers and pharmaceutical companies to diminish the impact on payers' budgets for new and existing schemes brought about by uncertainty and/or the need to work within finite budgets</it>". There are a number of concerns with existing schemes. These include potentially high administration costs, lack of transparency, conflicts of interest, and whether health authorities will end up funding an appreciable proportion of a new drug's development costs. In addition, there is a paucity of published evaluations of existing schemes with pharmaceuticals.</p> <p>Conclusion</p> <p>We believe there are only a limited number of situations where 'risk sharing' schemes should be considered as well as factors that should be considered by payers in advance of implementation. This includes their objective, appropriateness, the availability of competent staff to fully evaluate proposed schemes as well as access to IT support. This also includes whether systematic evaluations have been built into proposed schemes.</p

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Correction: What stops children with a chronic illness accessing health care: a mixed methods study in children with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)

Correction to: BMC Health Services Research (2011) 11:308. https://doi.org/10.1186/1472-6963-11-308.Following a report of a publications review jointly commissioned by the Health Research Authority and the University of Bristol, the authors would like to correct the following element of the ethics statement provided in the original article [1]:Ethical permission for the qualitative part of the study was granted by the North Somerset and South Bristol Research Ethics Committee (REC Reference number 09/H0106/81). The study was also approved by the Research and Development department of the RNHRD. The North Somerset & South Bristol Research Ethics Committee decided that the collection and analysis of these data for service evaluation did not require ethical review by an NHS research ethics committee or approval from the NHS R&D Office (REC reference number 07/Q2006/48).The original article [1] has been corrected.ReferencesWebb et al. What stops children with a chronic illness accessing health care: a mixed methods study in children with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). BMC Health Serv Res. 2011;11:308. https://doi.org/10.1186/1472-6963-11-308

Simplifying the selection of evidence synthesis methods to inform environmental decisions: a guide for decision makers and scientists

Achieving evidence-based environmental management requires that decision-makers have access to evidence that can help identify the most effective interventions for their management context. Evidence synthesis supports evidence-based decision-making because it collates, filters and makes sense of a sometimes large and often conflicting evidence-base, potentially yielding new insights. There are many approaches to evidence synthesis. They each have different strengths and weaknesses, making them suited to different purposes, questions and contexts, given particular constraints. To make sense of the wide array of approaches, we outline the important considerations when selecting the most appropriate method for a particular decision context. These include the purpose for the synthesis, the required outcomes, and the multiple constraints within which decision-makers must operate. We then critically assess a spectrum of approaches to evidence synthesis commonly used within environmental management, detailing the characteristics of each that can be used to determine when it is a suitable method. To guide this selection process we provide a decision tree for those commissioning (e.g., decision-makers or stakeholders) or conducting (e.g., scientists) evidence synthesis, which can be used to identify an appropriate method. The decision tree classifies evidence synthesis methods according to whether their purpose is to test or generate hypotheses, the level of resources they require, the level of certainty in the outputs, and the type and scope of the question being addressed. This tool is a major advance because it helps select an appropriate synthesis method based on the multiple constraints that impact the decision. We conclude that there is an approach to evidence synthesis that will suit all management contexts, but that selecting the right approach requires careful consideration of what is fit for purpose