The Adapt Study: adaptation of evidence-informed complex population health interventions for implementation and/or re-evaluation in new contexts: protocol for a Delphi consensus exercise to develop guidance.

Introduction: Complex population health interventions that are effective in one context may not be effective elsewhere, and may even be harmful. As such, an intervention may require adaptation to ensure it fits with a new context. To date, there is no overarching guidance to help researchers to adapt and evaluate interventions in new contexts, and no criteria to support research funders or journals assess proposed or reported adaptations or evaluation. There is limited assistance for policy-makers and practitioners to decide if evidence-informed interventions are appropriate to their context, or if adaptation and further evaluation is needed. This Delphi exercise will contribute to the development of guidance for these communities to support the adaptation, implementation and/or re-evaluation of complex population health interventions in new contexts. Methods: We will conduct a Delphi consensus exercise to gather expert opinion from researchers, research funders, journal editors and policy-makers. Expert opinion will be sought on: appropriate definitions and concepts, identifying key methodological considerations and establishing adaptations and processes to be undertaken during adaptation of complex population health interventions in new contexts. Ethics and dissemination: Ethics approval for the Delphi exercise has been obtained from the University of Glasgow and and the RAND institutional research board. Dissemination of the results of this study will be through peer-reviewed publications, workshops at national and international conferences, and a summary of the guidance developed for key organisations and stakeholders

Realist complex intervention science: applying realist principles across all phases of the Medical Research Council framework for developing and evaluating complex interventions

The integration of realist evaluation principles within randomised controlled trials (‘realist RCTs’) enables evaluations of complex interventions to answer questions about what works, for whom and under what circumstances. This allows evaluators to better develop and refine mid-level programme theories. However, this is only one phase in the process of developing and evaluating complex interventions. We describe and exemplify how social scientists can integrate realist principles across all phases of the Medical Research Council framework. Intervention development, modelling, and feasibility and pilot studies need to theorise the contextual conditions necessary for intervention mechanisms to be activated. Where interventions are scaled up and translated into routine practice, realist principles also have much to offer in facilitating knowledge about longer-term sustainability, benefits and harms. Integrating a realist approach across all phases of complex intervention science is vital for considering the feasibility and likely effects of interventions for different localities and population subgroups

ADAPT study: adaptation of evidence-informed complex population health interventions for implementation and/or re-evaluation in new contexts: protocol for a Delphi consensus exercise to develop guidance

Introduction Complex population health interventions that are effective in one context may not be effective elsewhere, and may even be harmful. As such, an intervention may require adaptation to ensure it fits with a new context. To date, there is no overarching guidance to help researchers to adapt and evaluate interventions in new contexts, and no criteria to support research funders or journals assess proposed or reported adaptations or evaluation. There is limited assistance for policy-makers and practitioners to decide if evidence-informed interventions are appropriate to their context, or if adaptation and further evaluation is needed. This Delphi exercise will contribute to the development of guidance for these communities to support the adaptation, implementation and/or re-evaluation of complex population health interventions in new contexts. Methods We will conduct a Delphi consensus exercise to gather expert opinion from researchers, research funders, journal editors and policy-makers. Expert opinion will be sought on: appropriate definitions and concepts, identifying key methodological considerations and establishing adaptations and processes to be undertaken during adaptation of complex population health interventions in new contexts. Ethics and dissemination Ethics approval for the Delphi exercise has been obtained from the University of Glasgow and and the RAND institutional research board. Dissemination of the results of this study will be through peer-reviewed publications, workshops at national and international conferences, and a summary of the guidance developed for key organisations and stakeholders

Flight Crew Alertness and Sleep Relative to Timing of In-Flight Rest Periods in Long-Haul Flights

BACKGROUND: In-flight breaks are used during augmented long-haul flight operations, allowing pilots a sleep opportunity. The U.S. Federal Aviation Administration duty and rest regulations restrict the pilot flying the landing to using the third rest break. It is unclear how effective these restrictions are on pilots’ ability to obtain sleep. We hypothesized there would be no difference in self-reported sleep, alertness, and fatigue between pilots taking the second vs. third rest breaks. METHODS: Pilots flying augmented operations in two U.S.-based commercial airlines were eligible for the study. Volunteers completed a survey at top-of-descent (TOD), including self-reported in-flight sleep duration, and Samn-Perelli fatigue and Karolinska Sleepiness Scale ratings. We compared the second to third rest break using noninferiority analysis. The influence of time of day (home-base time; HBT) was evaluated in 4-h blocks using repeated measures ANOVA. RESULTS: From 787 flights 500 pilots provided complete data. The second rest break was noninferior to the third break for self-reported sleep duration (1.5 6 0.7 h vs. 1.4 6 0.7 h), fatigue (2.0 6 1.0 vs. 2.9 6 1.3), and sleepiness (2.6 6 1.4 vs. 3.8 6 1.8) at TOD for landing pilots. Measures of sleep duration, fatigue, and sleepiness were influenced by HBT circadian time of day. DISCUSSION: We conclude that self-reported in-flight sleep, fatigue, and sleepiness from landing pilots taking the second in-flight rest break are equivalent to or better than pilots taking the third break. Our findings support providing pilots with choice in taking the second or third in-flight rest break during augmented operations

Importance of the Active Site "Canopy" Residues in an O_2-Tolerant [NiFe]-Hydrogenase

The active site of Hyd-1, an oxygen-tolerant membrane-bound [NiFe]-hydrogenase from Escherichia coli, contains four highly conserved residues that form a “canopy” above the bimetallic center, closest to the site at which exogenous agents CO and O_2 interact, substrate H_2 binds, and a hydrido intermediate is stabilized. Genetic modification of the Hyd-1 canopy has allowed the first systematic and detailed kinetic and structural investigation of the influence of the immediate outer coordination shell on H_2 activation. The central canopy residue, arginine 509, suspends a guanidine/guanidinium side chain at close range above the open coordination site lying between the Ni and Fe atoms (N–metal distance of 4.4 Å): its replacement with lysine lowers the H_2 oxidation rate by nearly 2 orders of magnitude and markedly decreases the H_2/D_2 kinetic isotope effect. Importantly, this collapse in rate constant can now be ascribed to a very unfavorable activation entropy (easily overriding the more favorable activation enthalpy of the R509K variant). The second most important canopy residue for H_2 oxidation is aspartate 118, which forms a salt bridge to the arginine 509 headgroup: its mutation to alanine greatly decreases the H_2 oxidation efficiency, observed as a 10-fold increase in the potential-dependent Michaelis constant. Mutations of aspartate 574 (also salt-bridged to R509) to asparagine and proline 508 to alanine have much smaller effects on kinetic properties. None of the mutations significantly increase sensitivity to CO, but neutralizing the expected negative charges from D118 and D574 decreases O_2 tolerance by stabilizing the oxidized resting Ni^(III)–OH state (“Ni-B”). An extensive model of the catalytic importance of residues close to the active site now emerges, whereby a conserved gas channel culminates in the arginine headgroup suspended above the Ni and Fe

Comparison of substance use, subjective well-being and interpersonal relationships among young people in foster care and private households: a cross sectional analysis of the School Health Research Network survey in Wales

Objective: To investigate the association of living in foster care (FC) with substance use and subjective well-being in a sample of secondary school students (11–16 years) in Wales in 2015/16, and to examine whether these associations are attenuated by the perceived quality of interpersonal relationships. Design: Cross-sectional, population-based health behaviour and lifestyle questionnaire. Setting and participants: Wales, UK; young people who took part in the 2015/16 School Health Research Network (SHRN) questionnaire (n=32 479). Primary outcome: Health behaviours among young people in FC were compared with those from private households. Results: The prevalence of all adverse outcomes was higher among young people in FC. Those in FC were significantly more likely to report mephedrone use (OR=9.24, 95% CI 5.60 to 15.34), multiple substance misuse behaviours (OR=3.72, 95% CI 2.30 to 6.00), poorer relationships with peers (RR=1.88, 95% CI 1.23 to 2.88) and teachers (RR=1.83, 95% CI 1.31 to 2.56), having experienced bullying (OR=1.80, 95% CI 1.38 to 2.35), dating violence (OR=1.66, 95% CI 1.13 to 2.43) and poor well-being (RR=1.72, 95% CI 1.20 to 2.46). The association between FC and substance use remained significant, though was attenuated after accounting for relationship variables. The association between FC and subjective well-being became nonsignificant after adjustment for relationship variables. Conclusions: Young people living in FC experience significantly worse outcomes than young people not in care, likely due to a range of care and precare factors, which impact adversely on subsequent social relationships. The analyses are consistent with the hypothesis that the associations of FC with substance use and life satisfaction are partially explained by poorer quality social relationships. Large scale, longitudinal studies are required to investigate the relationship between being in care and health, educational and social outcomes. Mental health interventions and interventions to reduce substance use and improve well-being in FC should include a focus on supporting healthy social relationships

The depression in visual impairment trial (DEPVIT): trial design and protocol

<b>Background</b> The prevalence of depression in people with a visual disability is high but screening for depression and referral for treatment is not yet an integral part of visual rehabilitation service provision. One reason for this may be that there is no good evidence about the effectiveness of treatments in this patient group. This study is the first to evaluate the effect of depression treatments on people with a visual impairment and co morbid depression.<p></p> <b>Methods/design</b> The study is an exploratory, multicentre, individually randomised waiting list controlled trial. Participants will be randomised to receive Problem Solving Therapy (PST), a ‘referral to the GP’ requesting treatment according to the NICE’s ‘stepped care’ recommendations or the waiting list arm of the trial. The primary outcome measure is change (from randomisation) in depressive symptoms as measured by the Beck’s Depression Inventory (BDI-II) at 6 months. Secondary outcomes include change in depressive symptoms at 3 months, change in visual function as measured with the near vision subscale of the VFQ-48 and 7 item NEI-VFQ at 3 and 6 months, change in generic health related quality of life (EQ5D), the costs associated with PST, estimates of incremental cost effectiveness, and recruitment rate estimation.<p></p> <b>Discussion</b> Depression is prevalent in people with disabling visual impairment. This exploratory study will establish depression screening and referral for treatment in visual rehabilitation clinics in the UK. It will be the first to explore the efficacy of PST and the effectiveness of NICE’s ‘stepped care’ approach to the treatment of depression in people with a visual impairment.<p></p&gt

Mental health and wellbeing interventions for care-experienced children and young people: Systematic review and synthesis of process evaluations

Background The mental health and well-being of care-experienced children and young people remains a concern. Despite a range of interventions, the existing evidence base is limited in scope, with a reliance on standalone outcome evaluations which limits understanding of how contextual factors influence implementation and acceptability. The Care-experienced cHildren and young people’s Interventions to improve Mental health and wEll-being outcomes Systematic review (CHIMES) aimed to synthesise evidence of intervention theory, outcome, process and economic effectiveness. This paper reports the process evaluation synthesis, exploring how system factors facilitate and inhibit implementation and acceptability of mental health and wellbeing interventions for care-experienced children and young people. Methods Sixteen databases and 22 websites were searched between 2020 and 2022 for studies published from 1990 and May 2022. This was supplemented with contacting experts in the field, citation tracking, screening of relevant systematic reviews and stakeholder consultations. We drew on framework synthesis of qualitative data and incorporated a systems lens, taking account of contextual influences across socio-ecological domains. Quality appraisal assessed reliability and usefulness. Confidence in synthesised findings was assessed with the GRADE-CERQual tool. We report the review in accordance with relevant elements of both the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), and the Enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) checklist. Results Searches retrieved 15,068 unique study reports, and 23 of these were eligible for process evaluation synthesis, reporting on sixteen interventions. Studies were published between 2003 and 2021. Nine interventions were from the UK and Ireland, six interventions were from the USA, and one was from Australia. They were largely classified as interpersonal, where the aim was to modify carer-child relationships. Five key context factors were identified that supported and prohibited intervention delivery: (1) lack of system resources; (2) intervention burden, which encompasses the time, cognitive, and emotional burden associated with implementation and participation; (3) interprofessional relationships between health and social care professionals; (4) care-experienced young people’s identity; and (5) carer identity. Conclusion We identified several supportive and restrictive factors across social and health care systems that may impact intervention implementation and acceptability. Key implications include: the importance of involving diverse stakeholders in intervention development and delivery; the need to better resource and support those involved in interventions, particularly training and support for carers; and ensuring future evaluations integrate process evaluations in order to optimise interventions

The Structure of Hydrogenase-2 from <i>Escherichia coli</i>:Implications for H₂ -Driven Proton Pumping

Under anaerobic conditions Escherichia coli is able to metabolize molecular hydrogen via the action of several [NiFe]-hydrogenase enzymes. Hydrogenase-2, which is typically present in cells at low levels during anaerobic respiration, is a periplasmic-facing membrane-bound complex that functions as a proton pump to convert energy from H2 oxidation into a proton gradient; consequently, its structure is of great interest. Empirically, the complex consists of a tightly-bound core catalytic module, comprising large (HybC) and small (HybO) subunits, which is attached to an Fe-S protein (HybA) and an integral membrane protein, HybB. To date, efforts to gain a more detailed picture have been thwarted by low native expression levels of hydrogenase-2 and the labile interaction between HybOC and HybA/HybB subunits. In this paper we describe a new over-expression system that has facilitated determination of high-resolution crystal structures of HybOC and, hence, a prediction of the quaternary structure of the HybOCAB complex