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In England, the development of teachers' curriculum design capabilities has been identified as a 'challenge remaining' (Department for Education [DfE]. (2022). "Opportunity for all: Strong schools with great teachers for your child." https://www.gov.uk/government/publications/opportunity-for-all-strong-schools-with-great-teachers-for-your-child). A recent White Paper (Department for Education [DfE]. (2022). "Opportunity for all: Strong schools with great teachers for your child." https://www.gov.uk/government/publications/opportunity-for-all-strong-schools-with-great-teachers-for-your-child) offered access to a publicly funded online platform as a solution. Drawing on Stenhouse's concepts of teachers as researchers and curriculum as an inquiry process, this article argues that such a policy initiative restricts both curriculum and professional development. An alternative approach to curriculum design, one based on Stenhouse's conception of the iterative development of teachers' professional and curriculum knowledge is profiled. In this article, we, as four teacher-researchers, analyse a project which featured the Curriculum Design Coherence (CDC) model. We share insights gained from our involvement, both in relation to our professional learning and the impact of our curriculum design work on our pupils. We argue that the 'othering' of teachers in research contributes towards the under valuing of practice-informed evidence in policy making. We draw on the work of Lawrence Stenhouse to inform a different means of generating educational research evidence, one that sustains teacher-researchers through engagement with principles and concepts so as to inform policy and curriculum development.

Abstract Background Housing insecurity can be understood as experiencing or being at risk of multiple house moves that are not through choice and related to poverty. Many aspects of housing have all been shown to impact children/young people’s health and wellbeing. However, the pathways linking housing and childhood health and wellbeing are complex and poorly understood. Methods We undertook a systematic review synthesising qualitative data on the perspectives of children/young people and those close to them, from the United Kingdom (UK). We searched databases, reference lists, and UK grey literature. We extracted and tabulated key data from the included papers, and appraised study quality. We used best fit framework synthesis combined with thematic synthesis, and generated diagrams to illustrate hypothesised causal pathways. Results We included 59 studies and identified four populations: those experiencing housing insecurity in general (40 papers); associated with domestic violence (nine papers); associated with migration status (13 papers); and due to demolition-related forced relocation (two papers). Housing insecurity took many forms and resulted from several interrelated situations, including eviction or a forced move, temporary accommodation, exposure to problematic behaviour, overcrowded/poor-condition/unsuitable property, and making multiple moves. Impacts included school-related, psychological, financial and family wellbeing impacts, daily long-distance travel, and poor living conditions, all of which could further exacerbate housing insecurity. People perceived that these experiences led to mental and physical health problems, tiredness and delayed development. The impact of housing insecurity was lessened by friendship and support, staying at the same school, having hope for the future, and parenting practices. The negative impacts of housing insecurity on child/adolescent health and wellbeing may be compounded by specific life circumstances, such as escaping domestic violence, migration status, or demolition-related relocation. Conclusion Housing insecurity has a profound impact on children and young people. Policies should focus on reducing housing insecurity among families, particularly in relation to reducing eviction; improving, and reducing the need for, temporary accommodation; minimum requirements for property condition; and support to reduce multiple and long-distance moves. Those working with children/young people and families experiencing housing insecurity should prioritise giving them optimal choice and control over situations that affect them.

Abstract We conducted a rapid review examining the effectiveness of organisational interventions intended to improve job-related wellbeing of adult employees working from home. A systematic search was conducted on MEDLINE, PsycINFO, and Social Sciences Citation Index in June 2021. Studies were included of adult employees working from home, with wellbeing interventions implemented by organisations for all (or groups of) employees and study designs with any (or no) comparator group. Outcomes were quantitative/qualitative data related to employee psychological and subjective well-being. A total of 1906 unique records were retrieved, of which five studies with a total of 332 participants were included. All five studies included an online intervention, and each had a different type of intervention: well-being and performance coaching; positive psychology coaching; employee empowering sessions; corporate wellbeing programme; and yoga. Interventions showed a pattern of reducing stress levels and enhancing wellbeing. Review results should be interpreted with caution due to study small sample sizes, occurring during the pandemic and having inactive control or no control group, which may mean fluctuating levels of stress unrelated to interventions. The nature of the rapid review meant grey literature may have yielded more studies. This review was registered on Prospero (CRD42021262655).

Objectives The COVID-19 pandemic has led to increased use of digital clinical consultations (phone or video calls) within UK maternity services. This project aimed to review the evidence on digital clinical consultations in maternity systems to illuminate how, for whom and in what contexts, they can be used to support safe, personalised and equitable care.Design A realist synthesis, drawing on diverse sources of evidence (2010–present) from OECD countries, alongside insights from knowledge user groups (representing healthcare providers and service users).Methods The review used three analytical processes (induction, abduction and retroduction) within three iterative stages (development of initial programme theories; evidence retrieval and synthesis; validation and refinement of the programme theories).Results Ninety-three evidence sources were included in the final synthesis. Fifteen programme theories were developed showing that digital clinical consultations involve different mechanisms operating across five key contexts: the organisation, healthcare providers, the clinical relationship, the reason for consultation and women. The review suggests that digital clinical consultations can be effective and acceptable to stakeholders if there is access to appropriate infrastructure/digital resources and if implementation is able to ensure personalisation, informed choice, professional autonomy and relationship-focused connections. The review found relatively less evidence in relation to safety and equity.Conclusions Due to the complexity of maternity systems, there can be ‘no one-size fits all’ approach to digital clinical consultations. Nonetheless, the review distills four ‘CORE’ implementation principles: C—creating the right environment, infrastructure and support for staff; O—optimising consultations to be responsive, flexible and personalised to different needs and preferences; R—recognising the importance of access and inclusion; and E—enabling quality and safety through relationship-focused connections. Service innovation and research are needed to operationalise, explore and evaluate these principles, particularly in relation to safety and equity.PROSPERO registration number CRD42021288702.

Introduction One approach to reducing alcohol consumption and related harm is to limit physical availability. However, a recent review found alcohol licensing decisions are not consistently associated with improved local health outcomes in the UK, despite public health teams (PHTs) having a statutory role in licensing. This may be explained by limitations in regulatory powers, or because PHTs have been unable to sufficiently influence the use of regulation. This review aims to synthesise qualitative evidence to understand the nature, barriers and enablers, and value of PHT involvement in alcohol licensing decisions in the UK.Methods A systematic review of qualitative evidence was conducted. Five electronic databases were searched, supplemented by web searches for grey literature and author, reference and citation searches for included studies. Data was extracted and quality assessed using the Critical Appraisal Skills Programme (CASP) checklist. Data was synthesised using thematic synthesis, and confidence in the findings was judged using the Confidence in Evidence from Reviews of Qualitative research (CERQual) approach.Results 10 reports, relating to four separate studies, met the eligibility criteria. Thematic synthesis generated seven analytical themes. We found variation in how PHTs’ role in licensing is understood and enacted, with shared barriers and enablers. PHTs are often not regarded as a key consultee, though some teams found success in pursuing a more strategic approach. While the public health licensing objective in Scotland is considered an asset, it does not guarantee influence. Regardless of its presence, there is variation in the perceived value of PHTs’ involvement in licensing.Conclusions A more strategic focus may be of value to PHTs and help strengthen their impact on licensing. However, given the limited potential for public health benefits through influencing regulatory decision-making, PHTs may want to consider if it is the most effective use of limited resource in tackling alcohol-related harms.PROSPERO registration number CRD42023452508.

Abstract Biologic treatments can alleviate severe asthma symptoms and reduce health service use. However, service capacity limits and low referral rates from primary care indicate unmet patient need. We report a mixed-methods evaluation of an enhanced severe asthma pathway implemented in Staffordshire and Stoke-on-Trent, UK which aimed to optimise primary care referrals through training/education, and increased capacity in specialist clinics. Quantitative analysis assessed patient wait times between pathway stages, prescribing changes, exacerbations, hospital admissions and asthma control. Interviews with 12 stakeholders evaluated perceptions of the enhanced pathway across settings. In 12 months, 564 patients from 28 general practices were reviewed for biologics eligibility, of whom 125 (22.2%) were referred for specialist assessment. Wait times were significantly lower under the enhanced pathway when compared against historic patients following the standard pathway, and reduced overall from a mean of 76.4 to 26.7 weeks between referral and biologics initiation (p

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a shift of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Objectives To systematically review and synthesise evidence on the effectiveness and implementation barriers/facilitators of pharmacist-led interventions to promote medicines optimisation and reduce overprescribing in UK primary care.Design Systematic review.Setting UK primary care.Methods We searched MEDLINE, Embase, CINAHL PsycINFO and The Cochrane Library for UK-based studies published between January 2013 and February 2023. Targeted searches for grey literature were conducted in May 2023. Quantitative and qualitative studies (including conference abstracts and grey literature) that addressed a relevant intervention and reported a primary outcome related to changes in prescribing were eligible for inclusion. Quality of included studies was assessed using the Multiple Methods Appraisal Tool. We performed a narrative synthesis, grouping studies by publication status, setting and type of data reported (effectiveness or implementation).Results We included 14 peer-reviewed journal articles and 11 conference abstracts, together with 4 case study reports. The journal articles reported 10 different interventions, 5 delivered in general practice, 4 in care homes and 1 in community pharmacy. The quality of evidence was higher in general practice than in care home settings. It was consistently reported that the intervention improved outcomes related to prescribing, although the limited number of studies and wide range of outcomes reported made it difficult to estimate the size of any effect. Implementation was strongly influenced by relationships between pharmacists and other health and care professionals, especially general practitioners. Implementation in care homes appeared to be more complex than in general practice because of differences in systems and ‘culture’ between health and social care.Conclusions Pharmacist-led interventions have been reported to reduce overprescribing in primary care settings in the UK but a shortage of high-quality evidence means that more rigorous studies using high-quality designs are needed. More research is also needed in community pharmacy settings; to assess intervention effects on patient outcomes other than prescribing and to investigate how reducing overprescribing can impact health inequalities.PROSPERO registration number CRD42023396366.

Objective: To provide an overview review of international evidence of vocational outcomes in Individual Placement and Support (IPS) interventions for populations other than severe mental health. Methods: An overview of reviews published in English since 2000 reporting vocational outcomes (job entry, work sustainment, earnings, work hours, time to job entry) against counterfactuals of IPS interventions for population groups other than severe mental health. The overview review maximises data from individual studies and includes additional recent primary studies. DerSimonian-Laird random effects meta-analysis was performed. Results: Thirteen eligible studies were identified from five reviews and five more recent individual studies were also identified. IPS studies covered a range of groups with a concentration towards mental health. For the primary vocational outcome of job entry all IPS studies showed superior job entry rates compared to control groups with an overall weighted odds ratio of 1.78 [1.42,2.22]. Substantial heterogeneity was identified by study size and the overall weighted odds ratio of 1.32 [1.2,1.46] estimated from the large and medium sized studies seems a more plausible estimate of the likely effects of scaled-up IPS interventions in groups beyond severe mental health. Secondary vocational outcomes including job sustainment, total earnings, average weekly hours worked and time to job entry were typically superior in IPS services than control groups. Conclusions: IPS services are consistently more effective in supporting diverse population groups into sustained employment compared to business-as-usual employment services. The evidence is limited by unclear terminology, small sample sizes, incomplete intervention fidelity, intervention contamination and inconsistent measurement.

Background International evidence reviews suggest that reducing the availability of alcohol positively impacts both levels of alcohol consumption and associated harms. To understand the impact of recent changes to alcohol licensing and public health in the UK, this review aimed to identify and synthesise quantitative research evidence on the impact of local alcohol licensing decisions on the health and well-being of the community.Methods We searched peer-reviewed articles and grey literature for UK studies. We extracted and tabulated key data from the included papers and appraised study quality. We included topic expert and public consultation to confirm the scope of the evidence synthesis and suggest evidence for inclusion. We synthesised narratively and made recommendations based on our findings.Results We identified a small volume (seven papers) of evidence regarding the health (and related) impacts of local alcohol licensing decision undertaken in the UK local authorities. The evidence we identified did not demonstrate a consistent or sustained association between local interventions and health or crime outcomes downstream. This was despite relatively sophisticated study designs using a range of available data sources and some longer-term analysis.Conclusion Given that the impacts of local licensing decisions are currently limited, greater regulatory powers are needed if local licensing interventions are to be an effective public health interventions to reduce alcohol-related harms.

Background Pharmacological prophylaxis to prevent venous thromboembolism is currently recommended for women assessed as being at high risk of venous thromboembolism during pregnancy or in the 6 weeks after delivery (the puerperium). The decision to provide thromboprophylaxis involves weighing the benefits, harms and costs, which vary according to the individual’s venous thromboembolism risk. It is unclear whether the United Kingdom’s current risk stratification approach could be improved by further research. Objectives To quantify the current decision uncertainty associated with selecting women who are pregnant or in the puerperium for thromboprophylaxis and to estimate the value of one or more potential future studies that would reduce that uncertainty, while being feasible and acceptable to patients and clinicians. Methods A decision-analytic model was developed which was informed by a systematic review of risk assessment models to predict venous thromboembolism in women who are pregnant or in the puerperium. Expected value of perfect information analysis was used to determine which factors are associated with high decision uncertainty and should be the target of future research. To find out whether future studies would be acceptable and feasible, we held workshops with women who have experienced a blood clot or have been offered blood-thinning drugs and surveyed healthcare professionals. Expected value of sample information analysis was used to estimate the value of potential future research studies. Results The systematic review included 17 studies, comprising 19 unique externally validated risk assessment models and 1 internally validated model. Estimates of sensitivity and specificity were highly variable ranging from 0% to 100% and 5% to 100%, respectively. Most studies had unclear or high risk of bias and applicability concerns. The decision analysis found that there is substantial decision uncertainty regarding the use of risk assessment models to select high-risk women for antepartum prophylaxis and obese postpartum women for postpartum prophylaxis. The main source of decision uncertainty was uncertainty around the effectiveness of thromboprophylaxis for preventing venous thromboembolism in women who are pregnant or in the puerperium. We found that a randomised controlled trial of thromboprophylaxis in obese postpartum women is likely to have substantial value and is more likely to be acceptable and feasible than a trial recruiting women who have had a previous venous thromboembolism. In unselected postpartum women and women following caesarean section, the poor performance of risk assessment models meant that offering prophylaxis based on these models had less favourable cost effectiveness with lower decision uncertainty. Limitations The performance of the risk assessment model for obese postpartum women has not been externally validated. Conclusions Future research should focus on estimating the efficacy of pharmacological thromboprophylaxis in pregnancy and the puerperium, and clinical trials would be more acceptable in women who have not had a previous venous thromboembolism. Study registration This study is registered as PROSPERO CRD42020221094. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR131021) and is published in full in Health Technology Assessment; Vol. 28, No. 9. See the NIHR Funding and Awards website for further award information. Plain language summary Women who are pregnant or who have given birth in the previous 6 weeks are at increased risk of developing blood clots that can cause serious illness or death. Small doses of blood thinners given by injection are safe in pregnancy and can reduce the risk of blood clots, but they can slightly increase the risk of bleeding. Healthcare professionals use risk assessment tools to decide if a woman is at high risk of blood clots and should be offered blood thinners. We wanted to find out what research would be useful to help them make better decisions. We reviewed previous research to establish which risk assessment tools are best at predicting who will have a blood clot. We then created a mathematical model to predict what would happen when using different risk assessment tools to decide who should be offered blood thinners, both during pregnancy and after giving birth. We found that there was a lot of uncertainty about which women should be offered blood thinners. This was mainly because there have only been a few small studies comparing blood thinners to no treatment in pregnant women or women who have recently given birth. We estimated the value of future studies comparing blood thinners to no treatment, in groups of women with different risk factors, by predicting what information we would gain and how this would be used to improve decisions about using blood thinners. To find out whether these studies would be acceptable and feasible, we held workshops with women who have experienced a blood clot or have been offered blood thinners and surveyed healthcare professionals. We found that a study in obese women who have recently given birth would have substantial value and may be more acceptable than a study in pregnant women with a previous blood clot. Scientific summary Background Pharmacological prophylaxis to prevent venous thromboembolism (VTE) is currently recommended for women who are deemed to be at high risk of VTE during pregnancy or in the 6 weeks after delivery (the puerperium). The decision to provide prophylaxis involves weighing the benefits, harms and costs, which will vary according to the individual’s VTE risk. It is unclear whether the current risk stratification approach could be improved by further research. Aims and objectives The aim of this research was to determine whether further primary research is worthwhile to inform NHS practice on the use of risk assessment models (RAMs) for the prediction of VTE and appropriate provision of thromboprophylaxis for women in pregnancy and in the puerperium. The specific objectives were: to estimate the expected costs and health benefits of providing thromboprophylaxis using current and alternative RAMs and quantify decision uncertainty to determine which factors are the most important drivers of uncertainty when trying to determine the optimal risk-based thromboprophylaxis strategy to identify one or more potential future studies that would reduce the current decision uncertainty, while being feasible and acceptable to patients and clinicians to evaluate the value of future research studies in terms of the net health benefits to patients and the cost of the research. Methods To identify all relevant RAMs and their predictive performance, we undertook a systematic review in accordance with the preferred reporting items for systematic review and meta-analysis (PRISMA) statement. Systematic searches were performed across five electronic databases, including MEDLINE, EMBASE and the Cochrane Library, from inception to February 2021. We included all primary validation studies that examined the comparative accuracy of a multivariable RAM (or scoring system) for predicting the risk of developing VTE in women who are pregnant or in the puerperium. Two or more reviewers independently undertook study selection, data extraction and risk of bias assessments using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). We used narrative synthesis to summarise the findings. A decision-analytic model was used to estimate lifetime expected costs and quality-adjusted life-years (QALYs) under alternative thromboprophylaxis strategies. The decision-analytic modelling focused on the following subgroups for which data were available on the performance of RAMs: high-risk antepartum women (e.g. prior VTE or known thrombophilia) unselected postpartum women obese postpartum women postpartum women following caesarean section. In the analysis for high-risk antepartum women, the strategies compared were: antepartum and postpartum prophylaxis for all (from booking to 6 weeks postpartum) antepartum prophylaxis according to a RAM followed by 6 weeks postpartum prophylaxis for all six weeks postpartum prophylaxis for all no prophylaxis. In the analyses for postpartum women, the strategies compared were: postpartum prophylaxis for all (10 days) postpartum prophylaxis according to a RAM (10 days) no prophylaxis. In all cases, the thromboprophylaxis agent was assumed to be low-molecular-weight heparin (LMWH). In high-risk antepartum women, the RAMs compared were the Lyon RAM and the Efficacy of Thromboprophylaxis as an Intervention during Gravidity (EThIG) RAM. For the unselected postpartum population, the RAMs compared were Royal College of Obstetricians and Gynaecologists (RCOG), Swedish Society of Obstetrics and Gynecology (SFOG), Caprini and the novel Sultan RAM. In the subgroup of obese postpartum women, the only RAM included was the novel Ellis-Kahana RAM. In the subgroup of postpartum women following caesarean section, the RAMs compared were RCOG and the novel Binstock RAM. We also conducted an analysis assuming that a RAM was available for the post-caesarean section population with performance similar to the Sultan RAM in the unselected postpartum population. The model takes a United Kingdom (UK) NHS and Personal Social Services perspective with future costs and QALYs discounted at 3.5% per annum. Costs are reported in Great British pounds based on 2020 prices. Short-term outcomes are captured in a decision-tree phase and long-term outcomes in a lifetime state-transition model. The decision tree is used to estimate for each strategy: the number of women receiving thromboprophylaxis; the impact of thromboprophylaxis on VTE outcomes (fatal and non-fatal pulmonary embolisms and deep-vein thromboses); and the incidence of major bleeds during either thromboprophylaxis or VTE treatment with anticoagulants and wound haematoma. Major bleeds are separated into fatal bleeds, non-fatal intracerebral haemorrhages (ICH) and other major bleeds. Symptomatic VTEs are assumed to result in 3 months of anticoagulant treatment which should be continued until at least 6 weeks post delivery. Outcomes captured in the long-term model include post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension. These are in addition to the long-term model capturing the QALY losses from fatalities and ongoing morbidity from ICH. For women being assessed for postpartum prophylaxis, a single decision tree captures the short-term outcomes. For women being assessed for antepartum prophylaxis, the decision-tree phase of the model is repeated to capture the antepartum and postpartum periods separately. Those patients who have experienced a symptomatic VTE or a non-fatal ICH in the antepartum model are assumed to remain in the same health state in the postpartum phase; all other patients remain at risk of VTE and progress to the postpartum decision tree. All model parameters were based on published literature or clinical opinion where published evidence was lacking. Sources specific to the target population were identified for the following parameters: data related to population characteristics [age, body mass index (BMI) and life expectancy]; absolute risks of VTE, bleeding and PTS; costs of prophylaxis and VTE treatment. There is a paucity of data on the efficacy of thromboprophylaxis during pregnancy and in the puerperium. Based on the clinical expert’s understanding of the mechanism of action of prophylaxis, their personal experience and the prothrombotic physiologic changes during pregnancy, it was decided that the relative risk (RR) for VTE should be based on a single small pilot trial in antepartum women with prior VTE, while the RR for bleeding should be extrapolated from studies in medical inpatients. Other data were generally based on sources used in a published cost-effectiveness analysis of thromboprophylaxis in hospitalised patients (who are not pregnant or in the puerperium), with costs updated to reflect changes in prices. Parameter uncertainty was incorporated using probabilistic sensitivity analysis and structural uncertainty was explored using deterministic scenario analysis. Expected value of perfect information (EVPI) analysis was used to identify the key drivers of decision uncertainty that could be reduced by future studies. We held workshops with women with a prior VTE or who had been offered thromboprophylaxis during pregnancy, and undertook a survey of healthcare professionals, to understand whether potential future trials would be acceptable to the individuals who would be invited to take part. Expected value of sample information (EVSI) analysis was then used to estimate the value of these potential future research studies. Results Our systematic review of RAMs included 17 studies, comprising 19 unique externally validated RAMs and 1 internally validated model (Ellis-Kahana). Estimates of sensitivity were highly variable ranging from 0% to 100% for RAMs that were applied to antepartum women and 0% to 100% for RAMs applied to postpartum women. Specificity estimates were similarly diverse ranging from 28% to 98% and 5% to 100%, respectively. Most studies had unclear or high risk of bias and applicability concerns, mainly due to limitations in participant selection and statistical analysis. In the decision analysis for high-risk antepartum women, using the EThIG RAM to select patients for antepartum prophylaxis had a 42% probability of having an incremental cost-effectiveness ratio (ICER) under £30,000 per QALY compared to a strategy of offering only postpartum prophylaxis. This led to considerable decision uncertainty, with an overall EVPI of £1454 per patient for high-risk antepartum women, equivalent to £21.8 million over 5 years of births. A high proportion of this (94%) was related to uncertainty in the effectiveness of LWMH to reduce VTE risk compared to no prophylaxis. The EVSI analysis found that a randomised controlled trial (RCT) of 30 patients per arm comparing LMWH with no prophylaxis would have a value of £13.1 million over 5 years of births, rising to £19.7 million for a RCT of 500 patients per arm. Small trials such as these would have substantial value compared to the typical cost of trials in these populations (£1.1–2.0 million), assuming decision-makers are willing to use the estimates of efficacy obtained, to make better informed decisions about prophylaxis in this population, without requiring them to meet a formal hypothesis test. In the decision analysis for unselected postpartum women, the poor performance of the available RAMs (including RCOG, SFOG and Sultan), combined with the relatively low absolute risk of VTE, meant that a strategy of offering no prophylaxis had an 89% probability of being optimal, when valuing a QALY at £30,000. This was reflected in an EVPI of £0.68 per person; £2.0 million over 5 years of births. No EVSI was conducted for this population due to the low EVPI estimates. In the decision analysis for obese postpartum women, there was substantial decision uncertainty, with the Ellis-Kahana RAM having a 64% probability of being the optimal strategy when valuing a QALY at £30,000, despite the fact that on average it had lower QALYs and higher costs than a strategy of offering no prophylaxis. The overall EVPI was £22.35 per patient, or £13.4 million across 5 years of births, with a high proportion (99%) being related to the RR of VTE. The EVSI analysis found that a RCT of LMWH versus no prophylaxis in obese postpartum women would have a value of £2.8 million, over 5 years of births, if it enrolled 300 patients per arm, rising to £11.6 million if enrolling 10,000 patients per arm. In the decision analysis for postpartum women following caesarean section, neither of the RAMs that had been specifically validated in women following caesarean section (RCOG and Binstock) performed sufficiently well to have an ICER under £30,000 per QALY compared to a strategy of offering no prophylaxis. Offering no prophylaxis had the highest probability of being the optimal strategy (when valuing a QALY at £30,000) even when assuming that a RAM could be identified for the post-caesarean section group which performed similarly to the Sultan RAM in the unselected cohort. In this scenario, the EVPI was £7.74 per patient, equivalent to £5.6 million over 5 years of births and 68% of the overall EVPI was related to the RR of VTE. In the post-caesarean section group, a RCT of 5000 patients per arm would be needed to generate an EVSI of £2.2 million over 5 years of births, when assuming that a RAM is available which performs similarly to the Sultan RAM. The only RAM validated in an unselected antepartum population had poor performance; therefore, analysis in this group was limited to an exploratory analysis which suggested that for a RAM to be cost-effective for use in an unselected antepartum population, it would need to have high specificity (90–95% for a sensitivity of 100–53%). Exploratory analyses were also conducted for women with three antepartum risk factors. This found that offering antepartum prophylaxis from 28 weeks to women with three antepartum risk factors (excluding prior VTE) as per current RCOG guidance is unlikely to have an ICER under £30,000 per QALY. However, a formal analysis of EVPI could not be conducted as the absolute risk in this group is not well quantified. The workshops indicated that a study randomising women to LMWH or placebo would be less acceptable to women who have had a prior VTE or thrombophilia than for other groups of women. Surveyed healthcare professionals reported lower clinical equipoise for women with prior VTE, thrombophilia or BMI > 40 kg/m2. The survey also suggests that healthcare professionals have greater clinical equipoise for a study determining the effectiveness of thromboprophylaxis in antepartum women with three clinical risk factors (other than prior VTE or thrombophilia) who are currently eligible for prophylaxis from 28 weeks. The survey results also suggest that in postpartum women there is greater clinical equipoise in women whose risk factors are an elective caesarean section combined with either age over 35 years or obesity, and women whose only clinical risk factors are age and a BMI between 30 and 40 kg/m2. Workshop participants reported receiving limited information about VTE or risks and benefits of thromboprophylaxis during pregnancy and the puerperium and those without prior VTE often did not understand why they had received treatment. However, women with experience of a prior VTE felt that it would not be ethical to randomise women to placebo given the perceived risk of VTE and the perceived effectiveness of LMWH in this group. Although the workshop participants generally favoured cluster randomisation over individual randomisation, clinicians felt individual randomisation was more acceptable. Conclusions The benefits of thromboprophylaxis clearly outweigh the risks in those with the highest risk of VTE, such as women with a prior VTE, but the balance of benefits and harms is less clear in lower-risk groups. There is substantial decision uncertainty regarding the use of RAMs to select high-risk women for antepartum prophylaxis and obese postpartum women for postpartum prophylaxis. The main source of decision uncertainty was related to the RR reduction of thromboprophylaxis for preventing VTE due to a lack of RCTs in pregnancy and the puerperium. This uncertainty is reflected in the widely variant strategies and guidelines for use of thromboprophylaxis in obstetric populations in different countries, notably the USA and UK. The expected benefits of conducting further trials to reduce this uncertainty are highly relative to typical research costs, but in the UK, clinical trials are more likely to be acceptable and feasible in the group of women who have not had a previous VTE. In unselected postpartum women and women following caesarean section, the poor performance of available RAMs (including RCOG) meant that RAM-based prophylaxis strategies had less favourable cost-effectiveness with lower decision uncertainty. Recommendations for future research Future research should focus on estimating the efficacy of thromboprophylaxis in preventing VTE in pregnancy and the puerperium. Clinical trials comparing LMWH with no prophylaxis would be more acceptable to both healthcare professionals and the public, in women who have not had a previous VTE, but who have other risk factors, such as obesity. Study registration This study is registered as PROSPERO CRD42020221094. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR131021) and is published in full in Health Technology Assessment; Vol. 28, No. 9. See the NIHR Funding and Awards website for further award information.

Summary: Background: Treatment-simplification strategies are important tools for patient-centred management. We evaluated long-term outcomes from a PI monotherapy switch strategy. Methods: Eligible participants attending 43 UK treatment centres had a viral load (VL) below 50 copies/ml for at least 24 weeks on combination ART. Participants were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected PI monotherapy (PI-mono) with prompt return to combination therapy if VL rebounded. The primary outcome, previously reported, was loss of future drug options after 3 years, defined as new intermediate/high level resistance to at least one drug to which the participant's virus was considered sensitive at trial entry. Here we report resistance and disease outcomes after further extended follow-up in routine care. The study was registered as ISRCTN04857074. Findings: We randomised 587 participants to OT (291) or PI-mono (296) between Nov 4, 2008, and July 28, 2010 and followed them for a median of more than 8 years (100 months) until 2018. At the end of this follow-up time, one or more future drug options had been lost in 7 participants in the OT group and 6 in the PI-mono group; estimated cumulative risk by 8 years of 2.7% and 2.1% respectively (difference −0.6%, 95% CI −3.2% to 2.0%). Only one PI-mono participant developed resistance to the protease inhibitor they were taking (atazanavir). Serious clinical events (death, serious AIDS, and serious non-AIDS) were infrequent; reported in a total of 12 (4.1%) participants in the OT group and 23 (7.8%) in the PI-mono group (P = 0.08) over the entire follow-up period. Interpretation: A strategy of PI monotherapy, with regular VL monitoring and prompt reintroduction of combination treatment following rebound, preserved future treatment options. Findings confirm the high genetic barrier to resistance of the PI drug class that makes them well suited for creative, patient-centred, treatment-simplification approaches. The possibility of a small excess risk of serious clinical events with the PI monotherapy strategy cannot be excluded. Funding: The National Institute for Health Research Health Technology Assessment programme.

ObjectiveThe objective of this study is to map the international evidence for extreme heat related adaptation strategies by health systems, with a particular focus on how heat-vulnerable populations and local situational awareness are considered in these strategies.IntroductionSince the Paris Climate Accords in 2015, awareness has increased of the health risks posed by extreme heat along with interest in adaptations which aim to reduce heat-health-risks for vulnerable populations. However, the extant literature on these adaptations suggest they are insufficient, and call for research to examine whether, how, and what adaptations for extreme heat are effective as public health interventions.Inclusion criteriaWe will include English-language review articles describing and/or evaluating health system adaptations for extreme heat. Health systems will be defined broadly using the WHO Building Blocks model [1] and adaptations will range from the individual level to institutional, regional and national levels, with particular attention to localisation and the protection of vulnerable individuals.MethodsA comprehensive literature search of the published literature will be conducted using MEDLINE, Embase, CINAHL, the Cochrane Library and Web of Science. Searches will be limited to reviews published since 2015 in the English language. Results will be exported to EndNote for screening (with a sample checked by two reviewers to ensure consistency). A complementary search for related reports by major international agencies (e.g. WHO; International Association of Emergency Managers), as well as local searches for current guidance and case studies, will be conducted in parallel. Data from included papers will be presented in tables with a narrative commentary.

ObjectivesTo evaluate the diagnostic accuracy of the aortic dissection detection risk score (ADD-RS) used alone or in combination with D-dimer for detecting acute aortic syndrome (AAS) in patients presenting with symptoms suggestive of AAS.MethodsWe searched MEDLINE, EMBASE, and the Cochrane Library from inception to February 2024. Additionally, the reference lists of included studies and other systematic reviews were thoroughly searched. All diagnostic accuracy studies that assessed the use of ADD-RS alone or with D-Dimer for diagnosing AAS compared with a reference standard test (e.g. computer tomographic angiography (CTA), ECG-gated CTA, echocardiography, magnetic resonance angiography, operation, or autopsy) were included. Two reviewers independently selected and extracted data. Risk of bias was appraised using QUADAS-2 tool. Data were synthesised using hierarchical meta-analysis models.ResultsWe selected 13 studies from the 2017 citations identified, including six studies evaluating combinations of ADD-RS alongside D-dimer>500ng/L. Summary sensitivities and specificities (95% credible interval) were: ADD-RS>0 94.6% (90%, 97.5%) and 34.7% (20.7%, 51.2%), ADD-RS>1 43.4% (31.2%, 57.1%) and 89.3% (80.4%, 94.8%); ADD RS>0 or D-Dimer>500ng/L 99.8% (98.7%, 100%) and 21.8% (12.1%, 32.6%); ADD RS>1 or D-Dimer>500ng/L 98.3% (94.9%, 99.5%) and 51.4% (38.7%, 64.1%); ADD RS>1 or ADD RS = 1 with D-dimer>500ng/L 93.1% (87.1%, 96.3%) and 67.1% (54.4%, 77.7%).ConclusionsCombinations of ADD-RS and D-dimer can be used to select patients with suspected AAS for imaging with a range of trade-offs between sensitivity (93.1% to 99.8%) and specificity (21.8% to 67.1%).

Background Housing insecurity can be understood as experiencing or being at risk of multiple house moves that are (1) not through choice and (2) related to poverty. For example, due to short-term private rental tenancies, temporary or emergency housing, and homelessness. Housing insecurity has grown due to recent trends in the cost and availability of housing. The quality, affordability and stability of housing have all been shown to impact children’s health and well-being. However, the pathways linking housing and child health and well-being are complex and poorly understood. Objectives To identify, appraise and synthesise research evidence that explores the relationship between housing insecurity and the health and well-being of children and young people. Data sources MEDLINE via Ovid (searched 8 April 2022), EMBASE via Ovid (searched 8 April 2022), PsycINFO via Ovid (searched 8 April 2022). Review methods We undertook a systematic review synthesising qualitative data. We searched databases, reference lists and United Kingdom grey literature. We extracted and tabulated key data from the included papers, and appraised study quality. We synthesised the data qualitatively into an a priori conceptual framework using best-fit framework synthesis combined with thematic synthesis, and generated logic models to highlight links between specific exposures, impacts and outcomes. Results We included 59 studies and identified four populations: those experiencing housing insecurity in general (40 papers); associated with domestic violence (nine papers); associated with migration status (13 papers) and those forced to relocate due to demolition (two papers). Most published studies had an overall assessment of moderate-high quality, and most grey literature originated from known and valued sources. Housing insecurity took many forms and resulted from several, often inter-related, situations, including being evicted or having a forced move, living in temporary accommodation, exposure to problematic behaviour, overcrowded/poor-condition/unsuitable property, and making multiple moves. The resultant housing insecurity had multiple impacts, including school-related, psychological, financial and family well-being impacts, long-distance travel to attend school and see friends, living in a poor-condition or unsuitable property, all of which could further exacerbate housing insecurity. These experiences impacted health and well-being, in terms of mental health problems (often manifesting physically/behaviourally) and physical health problems related to poor housing conditions. Some factors lessened the impact of housing insecurity, including friendship and support, staying at the same school, having hope for the future and protective parenting. The negative impacts of housing insecurity on health and well-being may be compounded by specific situations and life circumstances, such as escaping domestic violence, migration status, or a forced relocation due to housing demolition. Limitations Many accounts were from parents or other informants, and more data directly from children and young people may give a more nuanced picture. Likewise, there was little information relating to outcomes, and it is difficult to know whether the current evidence has captured all relevant outcomes, and the links from impacts to health and well-being outcomes are less well understood. The complexity and diversity of the data added additional challenges to the synthesis process. Conclusions Our findings suggest that policies should focus on reducing housing insecurity among families, particularly in relation to reducing eviction, improving and reducing the need for temporary accommodation, minimum requirements for property condition, and support to reduce multiple moves and moves far from families’ desired location. Those working with children and families experiencing housing insecurity should give them optimal choice and control over situations that affect them. Future work Future qualitative research should focus explicitly on the health and well-being of children and young people experiencing housing insecurity, and how it links with the impacts identified in the current review, foregrounding the accounts of children and young people themselves, including specific groups of young people who are likely to be marginalised. Qualitative research focusing on the impact of interventions to address housing insecurity among families in the United Kingdom is also needed. Study registration This study is registered as PROSPERO CRD42022327506. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (Award ref: NIHR135455) and is published in full in Public Health Research; Vol. 11, No. 13. See the NIHR Funding and Awards website for further award information. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Plain language summary Introduction Housing insecurity is being at risk of moving house many times, due to poverty and having no choice, for example, due to a short-term rental house/flat, emergency housing and homelessness. Children’s health and well-being are known to be affected by how suitable, affordable and stable their housing is. However, the reasons for this are poorly understood. Methods We looked for studies exploring how housing insecurity can affect the health and well-being of children and young people (aged 0–16) in the United Kingdom. We included the views of children, parents/close family members and professionals (e.g. teachers). We searched for studies published in academic journals, searched relevant websites and received suggestions from experts. Results We included 59 studies on the impact of housing insecurity on young people. We found that children are affected in many ways including their social life (e.g. being far from friends), schooling (e.g. joining a new school), health, financial and family well-being. This led to anxiety/stress, trouble eating and sleeping, wetting the bed and health problems, such as asthma, due to poor living conditions. Some things can help to protect children experiencing housing insecurity, including friendship and support, staying at the same school, and support from parents. The problems of housing insecurity may be made worse by life circumstances, including domestic violence, being a migrant/refugee/asylum seeker and a forced relocation. Most studies included parents/professionals, with few seeking the views of the children and young people themselves. Conclusions Our review suggests that it is important to reduce housing insecurity among families. All those working with children and families experiencing housing insecurity should give them as much choice and control over situations that affect them as possible. Future studies should gather the views of children and young people themselves. Scientific summary Introduction Housing insecurity can be understood as experiencing or being at risk of multiple house moves that are (1) not through choice and (2) related to poverty. This may include a range of precarious housing situations (e.g. private rental accommodation with short-term or insecure tenancy agreements; temporary or emergency housing and homelessness). Housing insecurity has grown as a result of a number of trends in the cost and availability of housing, reflecting in particular the rapid increase in the number of low-income families with children in the private rental sector. The evidence from cohort studies that show a relationship between housing insecurity, homelessness or frequent moves in childhood and health-related outcomes can usefully quantify the proportion of children and families at risk of poorer health associated with housing instability. Such evidence, however, cannot determine causal associations, and the complex pathways linking housing and child health and well-being have not been synthesised. Objectives The current review aimed to identify, appraise and synthesise research evidence that explores the relationship between housing insecurity and the health and well-being of children and young people (CYP). We aimed to highlight the relevant factors and causal mechanisms. Methods We undertook a systematic review synthesising qualitative data, employing elements of rapid review methodology. Database searches [of MEDLINE, EMBASE, PsycINFO, Applied Social Sciences Index and Abstracts (ASSIA), International Bibliography of the Social Sciences (IBSS) and the Social Sciences Citation Index] were accompanied by scrutiny of reference lists of included papers and relevant systematic reviews, and grey literature searching of key websites, including those identified by stakeholders. We extracted and tabulated key data from the included papers. Data extraction was performed by one reviewer, with a 10% sample checked by a second reviewer. We appraised study quality of the published literature using the Critical Appraisal Skills Programme (CASP) qualitative checklist, and the quality of grey literature sources using the authority, accuracy, coverage, objectivity, date, significance (AACODS) checklist. Before commencing the review, we developed an initial a priori conceptual framework in consultation with stakeholders and topic experts, to inform and guide the review and synthesis. The framework consisted of: the policy context, population, exposures, impacts (i.e. interim outcomes) and outcomes (health and well-being outcomes in childhood/youth). We synthesised the data qualitatively into the conceptual framework using best-fit framework synthesis combined with thematic synthesis, and generated logic models to highlight the links between specific exposures, impacts and outcomes by population. Inclusion criteria Population The population included families with children aged 0–16 experiencing or at risk of housing insecurity, living in a family unit, in the UK. This could include, but not be limited to, those on low incomes, lone parents and ethnic minority groups including migrants, refugees and asylum seekers. Informants could include the children themselves, parents/close family members (e.g. grandparents, if the children live with them), or other informants with insight into the child’s/children’s experiences (e.g. teachers, clinicians). Children outside a family unit (i.e. who had left home or who were being looked after by the local authority) and traveller families were excluded. Exposure We defined ‘housing insecurity’ according to the Children’s Society (3) definition: those experiencing and at risk of multiple moves that are (1) not through choice and (2) related to poverty. This included actual or perceived insecurity related to housing situations, which may include the following: private rental accommodation with short-term or insecure tenancy agreements; temporary emergency housing; homelessness (including ‘hidden’ homelessness). We also aimed to include research related to interventions that have the specific aim of reducing housing insecurity and/or mitigating the impact of housing insecurity on the health and well-being of children, where identified. Context The current UK policy context shows exacerbation of factors that can lead to housing insecurity. These include the following: trends in poverty and inequality exacerbated by the COVID pandemic; changes in the housing market (an increase in investment properties, loss of social housing); increased numbers of low-income families living in the private rental sector; insecure or short-term tenancies; increasing housing costs (and fuel/food costs) and lack of affordable properties (see Background). Outcomes Any reported immediate and short-term outcomes related to childhood mental and physical health and well-being (up to the age of 16) were included. Studies reporting on the long-term outcomes and impacts in adulthood of housing insecurity experienced in childhood were excluded, as were short-term outcomes reported by adults. Studies We included studies reporting qualitative data on the views of young people and/or parents with young children on how housing insecurity has impacted on their (or their children’s) well-being. Books (with the exception of searchable e-books) and dissertations were excluded. Conference abstracts were only included if they contained relevant data unavailable elsewhere. Results In total, 59 studies were included in the review, which included 16 from database searches, 37 from grey literature searches, and 6 from reference lists of included studies and relevant reviews. Most published studies had an overall assessment of moderate-high quality, although few reported reflexivity. Most of the grey literature included originated from known and valued sources, and although methodologies and methods were often poorly described, primary data in the form of quotations were usually available. We identified four distinct populations for which research evidence was available during the process of study selection and data extraction: general population (housing insecurity in general) (reported in 40 papers) domestic violence population (housing insecurity associated with domestic violence) (reported in nine papers) migrant, refugee and asylum seeker population (housing insecurity associated with migration status) (reported in 13 papers) relocation population (families forced to relocate due to planned demolition) (reported in two papers). We detected all elements of the conceptual framework in the data from the included studies and identified an additional element through thematic synthesis: protective factors. We included this new element in our logic models and constructed a separate logic model for each population. Although we anticipated potentially different experiences of housing insecurity and its impacts and outcomes across the four populations, the evidence reviewed suggests many similarities across all the populations in terms of impacts, exposures, outcomes and protective factors. Common exposures included being evicted or having a forced move, living in temporary accommodation, experiencing overcrowding, exposure to problematic behaviour, poor-condition/unsuitable property and making multiple moves. Common impacts included social, school-related, psychological, financial and family well-being impacts, having to travel long distances to attend school and see friends, having to live in a property that was unsuitable or in a poor state of repair, overcrowded and often noisy, all of which could then further exacerbate housing insecurity. Common outcomes reported were mental health problems (which could manifest in physical ways, e.g. trouble eating and sleeping, or wetting the bed) and physical health problems, such as skin complaints and asthma related to poor housing conditions. Protective factors common to several populations included friendship and support, staying at the same school, having hope for the future, and protective parenting. Pervasive throughout all populations and accounts was an overall lack of choice or control over the housing situation. In addition, some considerations specific to certain populations were identified. In the domestic violence population, there was an additional consideration of the family choosing to remain in the property or leave the property, but both options came with insecurity attached, as those who stayed were not sure if they would be evicted due to the perpetrator defaulting on the mortgage. Some positive results were reported in relation to an intervention that helped families to feel safe if they chose to stay in their property (the Sanctuary Scheme), which reduced fear related to the perpetrator returning. Housing insecurity negatively impacted on friendships in all populations, with CYP reporting greater difficulty in forming close bonds and a peer network in each new location. However, this could be potentially more challenging for those escaping domestic violence, due to the need to keep information about themselves confidential to keep the family safe. In the migrant, refugee and asylum seeker population, parents and children spoke of having very little notice before having to move out of a property, in some cases only 48 hours. This could lead to a housing emergency for the family, and in this population there were several accounts of families becoming homeless and having to sleep in unsuitable places, such as the accident and emergency (A&E) waiting room and on a night bus. In some families, parents had no recourse to public funds, so even in cases where a child or children were born in the UK, the family still ended up destitute and homeless. This situation caused significant worry for the parents, which in turn was perceived and experienced by the children. A key commonality across everyone in the relocation population was that they were forced to move by a particular date, as their property (a flat in a high-rise block) was scheduled for demolition. Many families desired a move, due to a lack of space, overcrowding and unsafe outdoor spaces; however, many did not want to leave behind social networks and schools in the community, and even some who wanted to move had difficulty finding a property that was suitable (e.g. for their family size). In synthesising the evidence, a key challenge was the complexity of the data, in particular of the relationships between exposures and impacts. Factors that were exposures in the first instance could then become impacts, and particular impacts could then drive housing insecurity. Another key challenge in synthesising the qualitative evidence was that many elements of the experience of housing insecurity have been separated out in the logic models, but are likely to have been experienced simultaneously by the CYP, such that the experience of these elements may have been conflated and difficult to separate out. It has been particularly challenging to highlight this complexity in our synthesis. Policy-makers and practitioners should consider that the logic models presented here may be somewhat simplified, and that conflation of the factors represented as well as complexity in relationships is likely to occur among families experiencing housing insecurity. Conclusions Housing insecurity among CYP in families in the UK can take many forms and result from several, often inter-related, situations including being evicted or having a forced move, living in temporary accommodation, experiencing overcrowding, exposure to problematic behaviour, poor-condition/unsuitable property, and making multiple moves. The resultant housing insecurity can have multiple (often simultaneous) impacts, including school-related, psychological, financial and family well-being impacts, having to travel long distances to attend school and see friends, having to live in a property that was unsuitable or in a poor state of repair, overcrowded and often noisy, all of which could then further exacerbate housing insecurity. These experiences can impact on health and well-being, in terms of mental health problems (which could manifest in physical ways) and physical health problems related to poor housing conditions. Some experiences and situations can lessen the impact of housing insecurity, including friendship and support, staying at the same school, having hope for the future and protective parenting; and in some groups, as the relocation population, influencing the decision was also a protective factor. The negative impacts of housing insecurity on health and well-being may be compounded by specific situations and life circumstances, such as escaping domestic violence, being a migrant, refugee or asylum seeker (or having a parent with that status), or a forced relocation due to housing demolition. Our review findings suggest that policies should focus on reducing housing insecurity among families, particularly in relation to reducing eviction, improving and reducing the need for temporary accommodation, minimum requirements for property condition, and support to reduce multiple moves and moves far from families’ desired location. All those working with children and families experiencing housing insecurity should give them optimal choice and control over situations that affect them, as far as possible. Study registration This study is registered as PROSPERO CRD42022327506. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: NIHR135455) and is published in full in Public Health Research; Vol. 11, No. 13. See the NIHR Funding and Awards website for further award information. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Background Smoking cessation interventions are being introduced into routine secondary care in the United Kingdom (UK), but there are person and setting-related factors that could moderate their success in quitting smoking. This review was conducted as part of an evaluation of the QUIT hospital-based tobacco dependence treatment service (https://sybics-quit.co.uk). The aim of the review was to identify a comprehensive set of variables associated with quitting success among tobacco smokers contacting secondary healthcare services in the UK who are offered support to quit smoking and subsequently set a quit date. The results would then be used to inform the development of a statistical analysis plan to investigate quitting outcomes. Methods Systematic literature review of five electronic databases. Studies eligible for inclusion investigated quitting success in one of three contexts: (a) the general population in the UK; (b) people with a mental health condition; (c) quit attempts initiated within a secondary care setting. The outcome measures were parameters from statistical analysis showing the effects of covariates on quitting success with a statistically significant (i.e., p-value

Increased funding: one of the biggest problems facing psychologists in Ukraine is the lack of resources and funding. Increased funding for mental health services and training could help improve the quality of care that psychologists can provide to their patients. The necessary recognition of mental health and the role of psychologists in providing care can help reduce stigma and increase collaboration between psychologists and other health professionals. More resources and educational materials in Ukrainian are needed to improve access to information and resources for Ukrainian psychologists, and to support the development of a strong, locally focused research base. Creating more jobs for psychologists, especially in underserved areas, can help increase access to mental health services for those who need them. Continuous education: psychologists. Education and public awareness can help encourage more people to seek help from psychologists and other mental health professionals. Of course, these steps are only a starting point and a solution to the complex problems faced by psychologists in Ukraine

Background Severe acute respiratory syndrome coronavirus 2 is the virus that causes coronavirus disease 2019. Over six million deaths worldwide have been associated with coronavirus disease 2019. Objective To assess the cost-effectiveness of treatments used for the treatment of coronavirus disease 2019 in hospital or used in the community in patients with coronavirus disease 2019 at high risk of hospitalisation. Setting Treatments provided in United Kingdom hospital and community settings. Methods Clinical effectiveness estimates were taken from the coronavirus disease-network meta-analyses initiative and the metaEvidence initiative. A mathematical model was constructed to explore how the interventions impacted on patient health, measured in quality-adjusted life-years gained. The costs associated with treatment, including those of hospital care, were also estimated and used to form a cost per quality-adjusted life-year gained value which was compared with thresholds published by the National Institute for Health and Care Excellence. Estimates of cost-effectiveness compared against current standard of care were produced in both the hospital and community settings at three different levels of efficacy: mean, low and high. Public list prices were used for interventions with neither confidential patient access schemes nor confidential list prices considered. Results incorporating confidential pricing data were provided to the National Institute for Health and Care Excellence appraisal committee. Results The treatments were estimated to be clinically effective although not all reached statistical significance. All treatments in the hospital setting, or community, were estimated to plausibly have a cost per quality-adjusted life-year gained value below National Institute for Health and Care Excellence’s thresholds when compared with standard of care. However, almost all drugs could plausibly have cost per quality-adjusted life-years above National Institute for Health and Care Excellence’s thresholds. However, there is considerable uncertainty in the results as the prevalent severe acute respiratory syndrome coronavirus 2 variant, vaccination status, history of being infected with severe acute respiratory syndrome coronavirus 2 and standard of care have all evolved since the pivotal studies were conducted which could have significant impact on the efficacy of each drug. For drugs used in high-risk patients in the community setting, the proportion of people at high risk who need hospital admission was a large driver of the cost per quality-adjusted life-year. Limitations No studies were identified that were conducted in current conditions. This may be a large limitation as the severe acute respiratory syndrome coronavirus 2 variant changes. No head-to-head studies of interventions were identified. Conclusions The results produced could be informative to decision-makers, although conclusions regarding the most clinical – and cost-effectiveness of each intervention should be tentative due to the evolving nature of the decision problem and, in this report, the use of list prices only. Comparisons between interventions should also be treated with caution due to potentially large heterogeneity between studies. Future work Research assessing the relative clinical effectiveness of interventions within head-to-head studies in current conditions would be beneficial. Contemporary information related to the probability of hospital admission and death for patients at high risk in the community would improve the precision of the estimates generated. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR135564) and will be published in full in Health Technology Assessment; Vol. 27, No. 14. See the NIHR Journals Library website for further project information. Plain language summary Coronavirus disease 2019 is an infectious disease that can cause death and long-term ill-health. Treatments exist that can be provided in hospital to reduce the number of deaths from coronavirus disease 2019. Treatments also exist which can be provided in the community for people at high risk of needing to be admitted to hospital to reduce the number of admissions and to reduce the number of deaths from coronavirus disease 2019. However, the value for money of these treatments has not been estimated. We took the clinical effectiveness of nine treatments from published literature sources and built a model that estimated the value for money of six treatments compared with care without these treatments. Three treatments were excluded due to confidential prices. The results of the model showed that many treatments in a hospital setting had estimates of cost-effectiveness that would normally be seen to be good value for money using the thresholds published by the National Institute of Health and Care Excellence. The same was true for some treatments in a community setting. However, it is also possible that these treatments are not good value for money. The benefit of the drugs and value for money is highly uncertain as studies trying to estimate the gain have been done with (1) previous variants of the virus causing coronavirus disease 2019 being widespread, (2) where the proportion of people who have had vaccinations or who had previously had coronavirus disease 2019 is low and (3) where standard treatment was that when coronavirus disease 2019 was first identified, and not the drugs used now. Because of these differences, and the unknown price of some interventions, we cannot confidently say which (if any) treatments help patients the most, or which treatment represents the best value for money. Further research, in current conditions, would improve the accuracy of our answers. Scientific summary Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19). At the time of writing (January 2023) there had been over 620 million confirmed cases and over six-and-a-half million deaths worldwide associated with COVID-19. For the UK, these values are more than 24 million cases and nearly 200,000 deaths. In addition to the widespread vaccination programme, treatments exist that can help people who have been hospitalised due to COVID-19 (casirivimab and imdevimab (henceforth casirivimab/imdevimab), tocilizumab, remdesivir, baricitinib, and baricitinib with remdesivir) or be used in patients who have COVID-19 and are at high risk of needing hospitalisation [casirivimab/imdevimab, molnupiravir, nirmatrelvir and ritonavir (henceforth nirmatrelvir/ritonavir), remdesivir, sotrovimab, and tixagevimab and cilgavimab (henceforth tixagevimab/cilgavimab)]. For reasons related to urgency, these treatments, unlike interventions in other disease areas, have not received positive guidance from the National Institute of Health and Care Excellence (NICE) before being routinely used. As the pandemic subsides there is more need for a formal evaluation of the clinical and cost-effectiveness of these treatments. Objectives The objective of this study is to summarise the current knowledge related to the clinical efficacy of the interventions and to conduct an economic evaluation that estimates the cost-effectiveness of each intervention against standard of care (SoC), as of January 2023. A full incremental analysis is performed while noting the caveats in the comparison of all interventions simultaneously. Methods Given the timescale of the project, where there were ˂ 3 months between the publication of the final scope and the deadline of a report for NICE and the consultation process, a literature review following best practice was not possible. Instead, a pragmatic, alternative approach was undertaken where evidence was taken from two living systematic reviews (supported by the COVID-network meta-analyses (NMA) initiative and the metaEvidence initiative) in line with current best practice guidelines. For interventions related to use in hospitals, data were extracted on time to death, clinical improvement and time to discharge. For interventions that are used in the community for patients at high risk of hospitalisation, data were extracted on the risks of hospitalisation or death, and the risks of death. These measures of efficacy were assumed generalisable to January 2023 despite changes in background conditions which include the SoC, the percentage of people who have been vaccinated and a change in the dominant SARS-CoV-2 variant. This is noted as a very large limitation as drugs that have looked effective in previous variants have not worked as well in later variants and sensitivity analysis on the efficacy of the interventions has been conducted. A mathematical model was constructed that used the data from the living systematic reviews to simulate the experiences of patients in hospital, and requirement for supplemental oxygen, until discharge or death in hospital. Due to the (conditional) marketing authorisations of the interventions, the model was developed such that results could be produced for the supplemental oxygen group and the non-supplemental oxygen group separately. The model structure used an eight-point ordinal scale that was used in clinical trials to categorise patients during their admissions. Outputs from this model included the costs associated with interventions and care, and the quality-adjusted life-years (QALYs) gained by the patient both within the hospital episode and after discharge, incorporating decrements in health-related quality of life associated with the lasting impact of COVID-19. For interventions used in the hospital, these values allowed a cost per QALY gained to be calculated for each treatment compared with SoC, and for completeness, a full incremental analysis to be conducted although the External Assessment Group (EAG) cautions against comparisons between treatments due to the heterogenous conditions when pivotal studies were undertaken. The costs of each intervention were taken from public sources where available. However, baricitinib, sotrovimab and tocilizumab have confidential patient access schemes agreed, which discount the price of the intervention, and are not considered in this document, but were provided to the NICE Appraisal Committee in a separate confidential appendix. The price of three treatments (casirivimab/imdevimab, molnupiravir and tixagevimab/cilgavimab) were not publicly available at the time of writing and the cost-effectiveness results for these three drugs are contained in a confidential appendix. For patients at high risk of hospitalisation treated in the community, a decision tree was put before the hospital model, which simulated the reduced need for hospitalisation associated with early treatment. The total costs and QALYs associated with treatment options were estimated to allow an evaluation of the cost per QALY of each treatment against SoC and for completeness, a full incremental analysis to be undertaken, noting the same caveat as for interventions used in hospital when comparing treatments. The modelling did not assess the logistical aspects of treatment in the community, but the EAG notes that this could be a large factor in deciding which treatments could be preferred, as oral treatments could be more acceptable to patients and healthcare systems than treatments that are given intravenously or subcutaneously. The costs of providing treatment within the community were provided by National Health Service (NHS) England. Three scenarios were run changing the efficacy of interventions. The ‘mean efficacy’ estimate used the mean of each distribution extracted from the living systematic reviews, the ‘high efficacy’ estimate used the most favourable limits of the 95% confidence intervals (CIs) and the ‘low efficacy’ estimate used the least favourable limits of the 95% CIs. The EAG has acknowledged a limitation that the CI is influenced by the number of observed events and the sample size, such that two identical treatments could have markedly different confident intervals purely due to the size of the pivotal study. Seven scenario analyses were performed, explored the impact of changing: (1) the duration of long COVID (ranging from half to double that of the base case); (2) changing the rate of hospital admission in the community with people being at ‘high risk’ of hospitalisation from a value of 2.79% to 1.00%, 5.00% and 10.00%; (3) changing the average age of patients at high risk of hospitalisation in the community from 55 years to 50 and 60 years; (4) using a hazard ratio (HR) of unity for all interventions in relation to time to hospital discharge and time to clinical improvement; (5) changing the baseline distribution of supplemental oxygen requirements from that associated with SoC (19% no supplemental oxygen, 55% high-flow oxygen, 16% non-invasive ventilation and 10% invasive ventilation) to an arbitrarily less severe baseline distribution (25% no supplemental oxygen, 60% high-flow oxygen, 10% non-invasive ventilation and 5% invasive ventilation) for patients who have received an intervention in the community; (6) assuming a utility decrement of 0.02 per day for patients receiving intravenous (i.v.) treatment in the community; and (7) changing the standardised mortality ratio for people during the period of long COVID from 7.7 to 5.0 and 10.0. Two scenario analyses were conducted that explored the use of different efficacy measures based on the Solidarity study for remdesivir and the ‘Efficacy and safety of intramuscular administration of tixagevimab–cilgavimab for early outpatient treatment of COVID-19’ (TACKLE) study for tixagevimab/cilgavimab. Results were presented in terms of incremental cost-effectiveness ratios (ICERs) measured in cost per QALYs gained and also using incremental net monetary benefit (NMB). An advantage of NMB is that interventions can be compared using different assumptions on efficacy for different interventions, and interventions can be omitted without the need to recalculate efficiency frontiers. Results Due to changes between the conditions when the pivotal studies were undertaken and the current conditions in terms of the SoC, the percentage of people who have been vaccinated and a change in the dominant SARS-CoV-2 variant all results should be treated with caution. Caution should also be applied when comparing between interventions. The results also do not incorporate confidential price discounts for baricitinib, sotrovimab and tocilizumab, nor were any cost-effectiveness results presented for casirivimab/imdevimab, molnupiravir and tixagevimab/cilgavimab which had confidential list prices. These analyses were seen by the NICE appraisal committee in a confidential appendix. All treatments used for hospitalised patients, had a median HR for death below one, indicating a benefit, although all CIs crossed unity apart from those for baricitinib, casirivimab/imdevimab and tocilizumab. The overlapping CIs and heterogeneous studies meant that no firm conclusions could be made regarding the relative efficacy of these treatments. There was less data relating to the relative risks (RRs) of clinical improvement at 28 days and the HRs for the time to discharge, although these were generally close to unity and had CIs that crossed unity. No clear conclusions could be made on the relative efficacy of treatments for these two measures compared with SoC. All treatments used in the community had favourable median RRs for hospitalisation and death at 28 days with the upper limit of the CI being below 1 for all drugs except molnupiravir. The median RRs associated with death at 28 days were favourable for all interventions, except for remdesivir where the median estimate was unity as no deaths were observed in the study within COVID-NMA. The CIs were wide and spanned one for all treatments except for molnupiravir and nirmatrelvir/ritonavir. For hospitalised patients requiring supplemental oxygen, all treatments had estimated ICERs compared with SoC below £12,000 in both the mean efficacy and high efficacy scenarios. However, in the low efficacy scenario only baricitinib and tocilizumab generated more QALYs than SoC. Baricitinib had an estimated ICER under £9000, while tocilizumab had an estimated ICER under £29,000. For hospitalised patients not requiring supplemental oxygen, all treatments had estimated ICERs compared with SoC below £12,000 in both the mean efficacy and high efficacy scenarios. However, in the low efficacy scenario, only baricitinib generated more QALYs than SoC with an estimated ICER below £6000. For interventions used in the community, the estimated ICERs compared with SoC were more varied. In the mean efficacy scenario, the estimated ICERs were below £7000 for nirmatrelvir/ritonavir, below £35,000 for sotrovimab and below £91,000 for remdesivir. In the high efficacy scenario, the estimated ICERs were below £5000 for nirmatrelvir/ritonavir, below £19,000 for sotrovimab and below £25,000 for remdesivir. In the low efficacy scenario, the estimated ICER was below £12,000 for nirmatrelvir/ritonavir, with remdesivir and sotrovimab having ICERs in excess of £10,000. Only one of the scenario analyses noticeably changed the ICERs for all interventions, which was changing the proportion of people with COVID-19 in the community at high risk of hospitalisation who are hospitalised when treated with SoC. Treatments became more cost-effective as the admission proportion increased at the mean and high efficacy scenarios. The ranges in the ICERs assuming mean efficacy for the drugs, when using 1%, 10% and 20%, rather than 2.82% as assumed in the base case, were: nirmatrelvir/ritonavir (£25,544, dominant and dominant), remdesivir (£280,819, £16,170 and £1512) and sotrovimab (£111,318, £4870 and dominant). If data from Solidarity are included, the low efficacy scenarios for remdesivir had a positive NMB regardless of the willingness-to-pay threshold and oxygen status assumed. For patients requiring supplemental oxygen the ICER was £25,903; the corresponding ICER was £34,550 for those not requiring supplementary oxygen. Conclusions There is considerable uncertainty in the efficacy of treatments compared to SoC observed in the studies due to the small number of events, which results in wide CIs for HRs and RRs. Some treatments (baricitinib and tocilizumab in the hospitalised setting and casirivimab/imdevimab, molnupiravir and nirmatrelvir/ritonavir in the community setting) were estimated to have a statistically significant benefit related to death due to COVID-19, however, this may also have been shown for other treatments if the pivotal studies had had larger sample sizes. However, the dominant SARS-CoV-2 variant, the SoC and the percentage of people who have had a vaccination, have all changed since the pivotal studies were undertaken meaning that the efficacies for treatments are highly uncertain. This is demonstrated by sotrovimab having favourable median and mean efficacies in prevention hospitalisation, but this drug is not authorised in the USA, as it is unlikely to be effective against the Omicron BA.2 subvariant. Further the World Health Organization has made strong recommendations against the use of sotrovimab. Given potential further changes in the variant, the results presented in this report, and within the confidential appendix, should be treated with caution. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR135564) and will be published in full in Health Technology Assessment; Vol. 27, No. 14. See the NIHR Journals Library website for further project information.

BACKGROUND: Rapid on-site diagnosis facilitates tuberculosis control. Performing Xpert MTB/RIF (Xpert) at point of care is feasible, even when performed by minimally trained health-care workers, and when compared with point-of-care smear microscopy, reduces time to diagnosis and pretreatment loss to follow-up. However, whether Xpert is cost-effective at point of care remains unclear. METHODS: We empirically collected cost (US$, 2014) and clinical outcome data from participants presenting to primary health-care facilities in four African countries (South Africa, Zambia, Zimbabwe, and Tanzania) during the TB-NEAT trial. Costs were determined using an bottom-up ingredients approach. Effectiveness measures from the trial included number of cases diagnosed, initiated on treatment, and completing treatment. The primary outcome was the incremental cost-effectiveness of point-of-care Xpert relative to smear microscopy. The study was performed from the perspective of the health-care provider. FINDINGS: Using data from 1502 patients, we calculated that the mean Xpert unit cost was lower when performed at a centralised laboratory (Lab Xpert) rather than at point of care ($23·00 [95% CI 22·12-23·88] vs $28·03 [26·19-29·87]). Per 1000 patients screened, and relative to smear microscopy, point-of-care Xpert cost an additional $35 529 (27 054-40 025) and was associated with an additional 24·3 treatment initiations ([-20·0 to 68·5]; $1464 per treatment), 63·4 same-day treatment initiations ([27·3-99·4]; $511 per same-day treatment), and 29·4 treatment completions ([-6·9 to 65·6]; $1211 per completion). Xpert costs were most sensitive to test volume, whereas incremental outcomes were most sensitive to the number of patients initiating and completing treatment. The probability of point-of-care Xpert being cost-effective was 90% at a willingness to pay of $3820 per treatment completion. INTERPRETATION: In southern Africa, although point-of-care Xpert unit cost is higher than Lab Xpert, it is likely to offer good value for money relative to smear microscopy. With the current availability of point-of-care nucleic acid amplification platforms (eg, Xpert Edge), these data inform much needed investment and resource allocation strategies in tuberculosis endemic settings. FUNDING: European Union European and Developing Countries Clinical Trials Partnership.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

BackgroundXpert MTB/RIF, the most widely used automated nucleic acid amplification test for tuberculosis, is available in more than 130 countries. Although diagnostic accuracy is well documented, anticipated improvements in patient outcomes have not been clearly identified. We performed an individual patient data meta-analysis to examine improvements in patient outcomes associated with Xpert MTB/RIF.MethodsWe searched PubMed, Embase, ClinicalTrials.gov, and the Pan African Clinical Trials Registry from inception to Feb 1, 2018, for randomised controlled trials (RCTs) comparing the use of Xpert MTB/RIF with sputum smear microscopy as tests for tuberculosis diagnosis in adults (aged 18 years or older). We excluded studies of patients with extrapulmonary tuberculosis, and studies in which mortality was not assessed. We used a two-stage approach for our primary analysis and a one-stage approach for the sensitivity analysis. To assess the primary outcome of cumulative 6-month all-cause mortality, we first performed logistic regression models (random effects for cluster randomised trials, with robust SEs for multicentre studies) for each trial, and then pooled the odds ratio (OR) estimates by a fixed-effects (inverse variance) or random-effects (Der Simonian Laird) meta-analysis. We adjusted for age and gender, and stratified by HIV status and previous tuberculosis-treatment history. The study protocol has been registered with PROSPERO, number CRD42014013394.FindingsOur search identified 387 studies, of which five RCTs were eligible for analysis. 8567 adult clinic attendees (4490 [63·5%] of 7074 participants for whom data were available were HIV-positive) were tested for tuberculosis with Xpert MTB/RIF (Xpert group) versus sputum smear microscopy (sputum smear group), across five low-income and middle-income countries (South Africa, Brazil, Zimbabwe, Zambia, and Tanzania). The primary outcome (reported in three studies) occurred in 182 (4·5%) of 4050 patients in the Xpert group and 217 (5·3%) of 4093 patients in the smear group (pooled adjusted OR 0·88, 95% CI 0·68-1·14 [p=0·34]; for HIV-positive individuals OR 0·83, 0·65-1·05 [p=0·12]). Kaplan-Meier estimates showed a lower rate of death (12·73 per 100 person-years in the Xpert group vs 16·38 per 100 person-years in the sputum smear group) for HIV-positive patients (hazard ratio 0·76, 95% CI 0·60-0·97; p=0·03). The risk of bias was assessed as reasonable and the statistical heterogeneity across studies was low (I2

​​​​​​​Late Paleocene deposition of an organic-rich sedimentary facies on the continental shelf and slope of New Zealand and eastern Australia has been linked to short-lived climatic cooling and terrestrial denudation following sea level fall. Recent studies confirm that the organic matter in this facies, termed “Waipawa organofacies”, is primarily of terrestrial origin, with a minor marine component. It is also unusually enriched in 13C. In this study we address the cause of this enrichment. For Waipawa organofacies and its bounding facies in the Taylor White section, Hawke's Bay, paired palynofacies and carbon isotope analysis of heavy liquid-separated density fractions indicate that the heaviest δ13C values are associated with degraded phytoclasts (woody plant matter) and that the 13C enrichment may be partly due to lignin degradation. Compound-specific stable carbon isotope analyses of samples from the Taylor White and mid-Waipara (Canterbury) sections display similar trends and further reveal a residual 13C enrichment of ∼ 2.5 ‰ in higher plant biomarkers (long chain n-alkanes and fatty acids) and a ∼ 2 ‰–5 ‰ change in subordinate marine biomarkers. Using the relationship between atmospheric CO2 and C3 plant tissue δ13C values, we determine that the 3 ‰ increase in terrestrial δ13C may represent a ∼ 35 % decrease in atmospheric CO2. Refined age control for Waipawa organofacies indicates that deposition occurred between 59.2 and 58.5 Ma, which coincides with an interval of carbonate dissolution in the deep sea that is associated with a Paleocene oxygen isotope maximum (POIM, 59.7–58.1 Ma) and the onset of the Paleocene carbon isotope maximum (PCIM, 59.3–57.4 Ma). This association suggests that Waipawa deposition occurred during a time of cool climatic conditions and increased carbon burial. This relationship is further supported by published TEX86-based sea surface temperatures that indicate a pronounced regional cooling during deposition. We suggest that reduced greenhouse gas emissions from volcanism and accelerated carbon burial, due to tectonic factors, resulted in short-lived global cooling, growth of ephemeral ice sheets and a global fall in sea level. Accompanying erosion and carbonate dissolution in deep-sea sediment archives may have hidden the evidence of this “hypothermal” event until now.

G-quadruplexes (G4s) have been identified as a potential alternative chemotherapy target. A series of eight β-amino acid derived naphthalenediimides (NDI) were screened against a series of oncogenic G4 sequences: c-KIT1, h-TELO, and TBA. Three sets of enantiomers were investigated to further our understanding of the effect of point chirality on G4 stabilisation. Enantioselective binding behaviour was observed with both c-KIT1 and h-TELO. Docking studies using GNINA and UV-vis titrations were employed to better understand this selective binding behaviour.

Background: Health literacy is the ability to find information, understand information, know how to act on information and know which services to use. Having higher levels of health literacy may help patients to look after minor problems themselves (self-care). It may also help to reduce patients’ perceived need for contacting health services for minor health problems, to reduce the perceived urgency of problems or to improve patients’ ability to identify and choose from the range of available services. Interventions to improve health literacy for minor health problems have been evaluated, but their effectiveness at reducing use of primary care and emergency services has not been synthesised. Objectives: The key objectives were as follows: (1) to construct a typology of interventions that aim to reduce primary or emergency care use, (2) to synthesise evidence of the effectiveness of different types of health literacy interventions and (3) to consider how stakeholders in the UK could operationalise the evidence. Interventions: The interventions being reviewed were initiatives that help members of the population to self-care or make decisions about whether or not and where to seek health care for minor health problems. Design: This study was a systematic review with stakeholder involvement. Data sources and review methods: A meeting was held with 14 stakeholders (including patients, carers and the public) to guide the systematic review. This was followed by a multicomponent review of quantitative and qualitative research. Database literature searches were undertaken in Ovid MEDLINE, The Cochrane Library (via Wiley Interscience), EMBASE (via OVID), the Cumulative Index to Nursing and Allied Health Literature (via EBSCO), PsycINFO (via OVID), Web of Science and Sociological Abstracts. The search was limited to English-language publications from 1990–2020. To assess study quality, the Cochrane Risk of Bias tool was used for randomised controlled trials and the Newcastle–Ottawa Scale was used for non-randomised studies. A narrative synthesis was undertaken. The review was followed by a meeting with 16 stakeholders to interpret the results. Results: A total of 67 articles (64 studies) were included: 37 from the USA, 16 from the UK, 12 from the rest of Europe and two from the rest of the world. There were seven intervention types: navigation tools directing people to the range of services available (n = 7); written education about managing minor health problems in booklet or website format (n = 17); person-delivered education (n = 5); written education with person-delivered education (n = 17); multicomponent of written education, person-delivered education and mass media campaign (n = 5); self-triage (n = 9); and other (n = 7). Our team assessed the readability and user-friendliness of interventions, and found that these varied widely. When assessed, most studies measuring satisfaction with the intervention, enablement and perceived changes to behaviour showed positive results. Of 30 articles reporting impact on emergency department attendances, 19 (63%) showed a reduction, and 16/27 (59%) articles measuring impact on general practice consultations showed a reduction. Variation in the evidence base was not explained by any research, context or intervention characteristics. Only eight articles measured safety: these identified no problems. Limitations: There was inconsistency in how the outcomes were measured, so a meta-analysis was not possible. Conclusions: Health literacy interventions have potential to affect emergency and primary care use, but the evidence base is inconsistent. Future research: It is important to continue to evaluate these types of initiatives. Study registration: This study is registered as PROSPERO CRD42020214206. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 10, No. 38. See the NIHR Journals Library website for further project information.

Objectives To assess the comparative accuracy of risk assessment models (RAMs) to identify women during pregnancy and the early postnatal period who are at increased risk of venous thromboembolism (VTE).Design Systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.Data sources MEDLINE, Embase, Cochrane Library and two research registers were searched until February 2021.Eligibility criteria All validation studies that examined the accuracy of a multivariable RAM (or scoring system) for predicting the risk of developing VTE in women who are pregnant or in the puerperium (within 6 weeks post-delivery).Data extraction and synthesis Two authors independently selected and extracted data. Risk of bias was appraised using PROBAST (Prediction model Risk Of Bias ASsessment Tool). Data were synthesised without meta-analysis.Results Seventeen studies, comprising 19 externally validated RAMs and 1 internally validated model, met the inclusion criteria. The most widely evaluated RAMs were the Royal College of Obstetricians and Gynaecologists guidelines (six studies), American College of Obstetricians and Gynecologists guidelines (two studies), Swedish Society of Obstetrics and Gynecology guidelines (two studies) and the Lyon score (two studies). In general, estimates of sensitivity and specificity were highly variable with sensitivity estimates ranging from 0% to 100% for RAMs that were applied to antepartum women to predict antepartum or postpartum VTE and 0% to 100% for RAMs applied postpartum to predict postpartum VTE. Specificity estimates were similarly diverse ranging from 28% to 98% and 5% to 100%, respectively.Conclusions Available data suggest that external validation studies have weak designs and limited generalisability, so estimates of prognostic accuracy are very uncertain.PROSPERO registration number CRD42020221094.