Plastic circuits: regulatory flexibility in fine tuning pathogen success

Bacterial pathogens employ diverse fitness and virulence mechanisms to gain an advantage in competitive niches. These lifestyle-specific traits require integration into the regulatory network of the cell and are often controlled by pre-existing transcription factors. In this review, we highlight recent advances that have been made in characterizing this regulatory flexibility in prominent members of the Enterobacteriaceae. We focus on the direct global interactions between transcription factors and their target genes in pathogenic Escherichia coli and Salmonella revealed using chromatin immunoprecipitation coupled with next-generation sequencing. Furthermore, the implications and advantages of such regulatory adaptations in benefiting distinct pathogenic lifestyles are discussed

Making the links between domestic violence and child safeguarding:an evidence-based pilot training for general practice

We describe the development of an evidence-based training intervention on domestic violence and child safeguarding for general practice teams. We aimed – in the context of a pilot study – to improve knowledge, skills, attitudes and self-efficacy of general practice clinicians caring for families affected by domestic violence. Our evidence sources included: a systematic review of training interventions aiming to improve professional responses to children affected by domestic violence; content mapping of relevant current training in England; qualitative assessment of general practice professionals' responses to domestic violence in families; and a two-stage consensus process with a multi-professional stakeholder group. Data were collected between January and December 2013. This paper reports key research findings and their implications for practice and policy; describes how the research findings informed the training development and outlines the principal features of the training intervention. We found lack of cohesion and co-ordination in the approach to domestic violence and child safeguarding. General practice clinicians have insufficient understanding of multi-agency work, a limited competence in gauging thresholds for child protection referral to children's services and little understanding of outcomes for children. While prioritising children's safety, they are more inclined to engage directly with abusive parents than with affected children. Our research reveals uncertainty and confusion surrounding the recording of domestic violence cases in families' medical records. These findings informed the design of the RESPONDS training, which was developed in 2014 to encourage general practice clinicians to overcome barriers and engage more extensively with adults experiencing abuse, as well as responding directly to the needs of children. We conclude that general practice clinicians need more support in managing the complexity of this area of practice. We need to integrate and further evaluate responses to the needs of children exposed to domestic violence into general practice-based domestic violence training

Causes and Consequences of Diachronous V-Shaped Ridges in the North Atlantic Ocean

In the North Atlantic Ocean, the geometry of diachronous V‐shaped features that straddle the Reykjanes Ridge is often attributed to thermal pulses which advect away from the center of the Iceland plume. Recently, two alternative hypotheses have been proposed: rift propagation and buoyant mantle upwelling. Here we evaluate these different proposals using basin‐wide geophysical and geochemical observations. The centerpiece of our analysis is a pair of seismic reflection profiles oriented parallel to flow lines that span the North Atlantic Ocean. V‐shaped ridges and troughs are mapped on both Neogene and Paleogene oceanic crust, enabling a detailed chronology of activity to be established for the last 50 million years. Estimates of the cumulative horizontal displacement across normal faults help to discriminate between brittle and magmatic modes of plate separation, suggesting that crustal architecture is sensitive to the changing planform of the plume. Water‐loaded residual depth measurements are used to estimate crustal thickness and to infer mantle potential temperature which varies by ±25°C on timescales of 3–8 Ma. This variation is consistent with the range of temperatures inferred from geochemical modeling of dredged basaltic rocks along the ridge axis itself, from changes in Neogene deep‐water circulation, and from the regional record of episodic Cenozoic magmatism. We conclude that radial propagation of transient thermal anomalies within an asthenospheric channel that is 150 ± 50 km thick best accounts for the available geophysical and geochemical observations

Application of normalisation process theory in understanding implementation processes in primary care settings in the UK: a systematic review

Abstract: Background: Normalisation Process Theory (NPT) provides a framework to understand how interventions are implemented, embedded, and integrated in healthcare settings. Previous reviews of published literature have examined the application of NPT across international healthcare and reports its benefits. However, given the distinctive clinical function, organisational arrangements and the increasing management of people with a wide variety of conditions in primary care settings in the United Kingdom, it is important to understand how and why authors utilise and reflect on NPT in such settings to inform and evaluate implementation processes. Methods: A systematic review of peer-reviewed literature using NPT in primary care settings in the United Kingdom (UK) was conducted. Eight electronic databases were searched using replicable methods to identify articles published between January 2012 and April 2018. Data were analysed using a framework approach. Results: Thirty-one articles met the inclusion criteria. Researchers utilised NPT to explore the implementation of interventions, targeting a wide range of health services and conditions, within primary care settings in the UK. NPT was mostly applied qualitatively; however, a small number of researchers have moved towards mixed and quantitative methods. Some variation was observed in the use of NPT constructs and sub-constructs, and whether and how researchers undertook modification to make them more relevant to the implementation process and multiple stakeholder perspectives. Conclusion: NPT provides a flexible framework for the development and evaluation of complex healthcare interventions in UK primary care settings. This review updates the literature on NPT use and indicates that its application is well suited to these environments, particularly in supporting patients with long-term conditions and co-morbidities. We recommend future research explores the receipt of interventions by multiple stakeholders and suggest that authors reflect on justifications for using NPT in their reporting

A multi-stakeholder approach to the co-production of the research agenda for medicines optimisation

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence (http://creativecommons.org/licenses/by/4.0/), and indicate if changes were made.BACKGROUND: Up to 50% of medicines are not used as intended, resulting in poor health and economic outcomes. Medicines optimisation is 'a person-centred approach to safe and effective medicines use, to ensure people obtain the best possible outcomes from their medicines'. The purpose of this exercise was to co-produce a prioritised research agenda for medicines optimisation using a multi-stakeholder (patient, researcher, public and health professionals) approach. METHODS: A three-stage, multiple method process was used including: generation of preliminary research questions (Stage 1) using a modified Nominal Group Technique; electronic consultation and ranking with a wider multi-stakeholder group (Stage 2); a face-to-face, one-day consensus meeting involving representatives from all stakeholder groups (Stage 3). RESULTS: In total, 92 research questions were identified during Stages 1 and 2 and ranked in order of priority during stage 3. Questions were categorised into four areas: 'Patient Concerns' [e.g. is there a shared decision (with patients) about using each medicine?], 'Polypharmacy' [e.g. how to design health services to cope with the challenge of multiple medicines use?], 'Non-Medical Prescribing' [e.g. how can the contribution of non-medical prescribers be optimised in primary care?], and 'Deprescribing' [e.g. what support is needed by prescribers to deprescribe?]. A significant number of the 92 questions were generated by Patient and Public Involvement representatives, which demonstrates the importance of including this stakeholder group when identifying research priorities. CONCLUSIONS: A wide range of research questions was generated reflecting concerns which affect patients, practitioners, the health service, as well the ethical and philosophical aspects of the prescribing and deprescribing of medicines. These questions should be used to set future research agendas and funding commissions.Peer reviewedFinal Published versio

Incidence of Chlamydia trachomatis infection in women in England:two methods of estimation

Information on the incidence of Chlamydia trachomatis (CT) is essential for models of the effectiveness and cost-effectiveness of screening programmes. We developed two independent estimates of CT incidence in women in England: one based on an incidence study, with estimates ‘recalibrated’ to the general population using data on setting-specific relative risks, and allowing for clearance and re-infection during follow-up; the second based on UK prevalence data, and information on the duration of CT infection. The consistency of independent sources of data on incidence, prevalence and duration, validates estimates of these parameters. Pooled estimates of the annual incidence rate in women aged 16–24 and 16–44 years for 2001–2005 using all these data were 0·05 [95% credible interval (CrI) 0·035–0·071] and 0·021 (95% CrI 0·015–0·028), respectively. Although, the estimates apply to England, similar methods could be used in other countries. The methods could be extended to dynamic models to synthesize, and assess the consistency of data on contact and transmission rates

Adjusting trial results for biases in meta-analysis:combining data-based evidence on bias with detailed trial assessment

Flaws in the conduct of randomised trials can lead to biased estimation of the intervention effect. Methods for adjustment of within-trial biases in meta-analysis include use of empirical evidence from an external collection of meta-analyses, and use of expert opinion informed by assessment of detailed trial information. Our aim is to present methods to combine these two approaches in order to gain the advantages of both. We make use of the risk of bias information routinely available in Cochrane reviews, by obtaining empirical distributions for the bias associated with particular bias profiles (combinations of risk of bias judgements). We propose three methods: (i) formal combination of empirical evidence and opinion in a Bayesian analysis; (ii) asking experts to give an opinion on bias informed by both summary trial information and a bias distribution from the empirical evidence, either numerically or by (iii) selecting areas of the empirical distribution. The methods are demonstrated through application to two example binary outcome meta-analyses. Bias distributions based on opinion informed by trial information alone were most dispersed on average, and those based on opinions obtained by selecting areas of the empirical distribution were narrowest. Although the three different methods for combining empirical evidence with opinion vary in ease and speed of implementation, they yielded similar results in the two examples

Impact of opioid substitution therapy on antiretroviral therapy outcomes:a systematic review and meta-analysis

BACKGROUND: Human immunodeficiency virus (HIV)-infected people who inject drugs (PWID) frequently encounter barriers accessing and remaining on antiretroviral therapy (ART). Some studies have suggested that opioid substitution therapy (OST) could facilitate PWID's engagement with HIV services. We conducted a systematic review and meta-analysis to evaluate the impact of concurrent OST use on ART-related outcomes among HIV-infected PWID. METHODS: We searched Medline, PsycInfo, Embase, Global Health, Cochrane, Web of Science, and Social Policy and Practice databases for studies between 1996 to November 2014 documenting the impact of OST, compared to no OST, on ART outcomes. Outcomes considered were coverage and recruitment onto ART, adherence, viral suppression, attrition from ART, and mortality. Meta-analyses were conducted using random-effects modeling, and heterogeneity assessed using Cochran Q test and I2 statistic. RESULTS: We identified 4685 articles, and 32 studies conducted in North America, Europe, Indonesia, and China were included. OST was associated with a 69% increase in recruitment onto ART (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.32-2.15), a 54% increase in ART coverage (odds ratio [OR], 1.54; 95% CI, 1.17-2.03), a 2-fold increase in adherence (OR, 2.14; 95% CI, 1.41-3.26), and a 23% decrease in the odds of attrition (OR, 0.77; 95% CI, .63-.95). OST was associated with a 45% increase in odds of viral suppression (OR, 1.45; 95% CI, 1.21-1.73), but there was limited evidence from 6 studies for OST decreasing mortality for PWID on ART (HR, 0.91; 95% CI, .65-1.25). CONCLUSIONS: These findings support the use of OST, and its integration with HIV services, to improve the HIV treatment and care continuum among HIV-infected PWID