Seven-year outcomes of venetoclax-ibrutinib therapy in mantle cell lymphoma: durable responses and treatment-free remissions.

In the phase-2 clinical trial (AIM) of venetoclax-ibrutinib, 24 patients with mantle cell lymphoma (MCL; 23 with relapsed/refractory [R/R] disease) received ibrutinib 560mg and venetoclax 400mg both once daily. High complete remission (CR) and measurable residual disease negative (MRD-negative) CR rates were previously reported. With median survivor follow-up now exceeding 7 years, we report long-term results. Treatment was initially continuous, with elective treatment interruption (ETI) allowed after protocol amendment for patients in MRD-negative CR. For R/R MCL, the estimated 7-year progression-free survival (PFS) was 30% [95%CI: 14-49] (median 28 months [95%CI: 13-82]) and overall survival was 43% [95%CI: 23-62] (median 32 months [95%CI: 15-NE]). Eight patients in MRD-negative CR entered ETI for a median of 58 months (95%CI, 37-79), with four experiencing disease recurrence. Two of 3 re-attained CR on retreatment. Time-to-treatment-failure (TTF), which excluded progression in ETI for those reattaining response, was 39% overall and 68% at 7-years for responders. Beyond 56 weeks Grade 3 and serious adverse events were uncommon. Newly emergent or increasing cardiovascular toxicity were not observed beyond 56 weeks. We demonstrate long-term durable responses and acceptable toxicity profile of venetoclax-ibrutinib in R/R MCL and show feasibility of treatment interruption while maintaining ongoing disease control. (NCT02471391).

Identifying the Optimum Strategy for Identifying Adults and Children With Celiac Disease: A Cost-Effectiveness and Value of Information Analysis.

OBJECTIVES: Celiac disease (CD) is thought to affect around 1% of people in the United Kingdom, but only approximately 30% are diagnosed. The aim of this work was to assess the cost-effectiveness of strategies for identifying adults and children with CD in terms of who to test and which tests to use. METHODS: A decision tree and Markov model were used to describe testing strategies and model long-term consequences of CD. The analysis compared a selection of pre-test probabilities of CD above which patients should be screened, as well as the use of different serological tests, with or without genetic testing. Value of information analysis was used to prioritize parameters for future research. RESULTS: Using serological testing alone in adults, immunoglobulin A (IgA) tissue transglutaminase (tTG) at a 1% pre-test probability (equivalent to population screening) was most cost-effective. If combining serological testing with genetic testing, human leukocyte antigen combined with IgA tTG at a 5% pre-test probability was most cost-effective. In children, the most cost-effective strategy was a 10% pre-test probability with human leukocyte antigen plus IgA tTG. Value of information analysis highlighted the probability of late diagnosis of CD and the accuracy of serological tests as important parameters. The analysis also suggested prioritizing research in adult women over adult men or children. CONCLUSIONS: For adults, these cost-effectiveness results suggest UK National Screening Committee Criteria for population-based screening for CD should be explored. Substantial uncertainty in the results indicate a high value in conducting further research.

Virtual wards for people with frailty: what works, for whom, how and why-a rapid realist review.

BACKGROUND: Virtual wards (VWs) deliver multidisciplinary care at home to people with frailty who are at high risk of a crisis or in crisis, aiming to mitigate the risk of acute hospital admission. Different VW models exist, and evidence of effectiveness is inconsistent. AIM: We conducted a rapid realist review to identify different VW models and to develop explanations for how and why VWs could deliver effective frailty management. METHODS: We searched published and grey literature to identify evidence on multidisciplinary VWs. Information on how and why VWs might 'work' was extracted and synthesised into context-mechanism-outcome configurations with input from clinicians and patient/public contributors. RESULTS: We included 17 peer-reviewed and 11 grey literature documents. VWs could be short-term and acute (1-21 days), or longer-term and preventative (typically 3-7 months). Effective VW operation requires common standards agreements, information sharing processes, an appropriate multidisciplinary team that plans patient care remotely, and good co-ordination. VWs may enable delivery of frailty interventions through appropriate selection of patients, comprehensive assessment including medication review, integrated case management and proactive care. Important components for patients and caregivers are good communication with the VW, their experience of care at home, and feeling involved, safe and empowered to manage their condition. CONCLUSIONS: Insights gained from this review could inform implementation or evaluation of VWs for frailty. A combination of acute and longer-term VWs may be needed within a whole system approach. Proactive care is recommended to avoid frailty-related crises.

Interventions to prevent obesity in children aged 5 to 11 years old.

BACKGROUND: Prevention of obesity in children is an international public health priority given the prevalence of the condition (and its significant impact on health, development and well-being). Interventions that aim to prevent obesity involve behavioural change strategies that promote healthy eating or 'activity' levels (physical activity, sedentary behaviour and/or sleep) or both, and work by reducing energy intake and/or increasing energy expenditure, respectively. There is uncertainty over which approaches are more effective and numerous new studies have been published over the last five years, since the previous version of this Cochrane review. OBJECTIVES: To assess the effects of interventions that aim to prevent obesity in children by modifying dietary intake or 'activity' levels, or a combination of both, on changes in BMI, zBMI score and serious adverse events. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was February 2023. SELECTION CRITERIA: Randomised controlled trials in children (mean age 5 years and above but less than 12 years), comparing diet or 'activity' interventions (or both) to prevent obesity with no intervention, usual care, or with another eligible intervention, in any setting. Studies had to measure outcomes at a minimum of 12 weeks post baseline. We excluded interventions designed primarily to improve sporting performance. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our outcomes were body mass index (BMI), zBMI score and serious adverse events, assessed at short- (12 weeks to < 9 months from baseline), medium- (9 months to < 15 months) and long-term (≥ 15 months) follow-up. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: This review includes 172 studies (189,707 participants); 149 studies (160,267 participants) were included in meta-analyses. One hundred forty-six studies were based in high-income countries. The main setting for intervention delivery was schools (111 studies), followed by the community (15 studies), the home (eight studies) and a clinical setting (seven studies); one intervention was conducted by telehealth and 31 studies were conducted in more than one setting. Eighty-six interventions were implemented for less than nine months; the shortest was conducted over one visit and the longest over four years. Non-industry funding was declared by 132 studies; 24 studies were funded in part or wholly by industry. Dietary interventions versus control Dietary interventions, compared with control, may have little to no effect on BMI at short-term follow-up (mean difference (MD) 0, 95% confidence interval (CI) -0.10 to 0.10; 5 studies, 2107 participants; low-certainty evidence) and at medium-term follow-up (MD -0.01, 95% CI -0.15 to 0.12; 9 studies, 6815 participants; low-certainty evidence) or zBMI at long-term follow-up (MD -0.05, 95% CI -0.10 to 0.01; 7 studies, 5285 participants; low-certainty evidence). Dietary interventions, compared with control, probably have little to no effect on BMI at long-term follow-up (MD -0.17, 95% CI -0.48 to 0.13; 2 studies, 945 participants; moderate-certainty evidence) and zBMI at short- or medium-term follow-up (MD -0.06, 95% CI -0.13 to 0.01; 8 studies, 3695 participants; MD -0.04, 95% CI -0.10 to 0.02; 9 studies, 7048 participants; moderate-certainty evidence). Five studies (1913 participants; very low-certainty evidence) reported data on serious adverse events: one reported serious adverse events (e.g. allergy, behavioural problems and abdominal discomfort) that may have occurred as a result of the intervention; four reported no effect. Activity interventions versus control Activity interventions, compared with control, may have little to no effect on BMI and zBMI at short-term or long-term follow-up (BMI short-term: MD -0.02, 95% CI -0.17 to 0.13; 14 studies, 4069 participants; zBMI short-term: MD -0.02, 95% CI -0.07 to 0.02; 6 studies, 3580 participants; low-certainty evidence; BMI long-term: MD -0.07, 95% CI -0.24 to 0.10; 8 studies, 8302 participants; zBMI long-term: MD -0.02, 95% CI -0.09 to 0.04; 6 studies, 6940 participants; low-certainty evidence). Activity interventions likely result in a slight reduction of BMI and zBMI at medium-term follow-up (BMI: MD -0.11, 95% CI -0.18 to -0.05; 16 studies, 21,286 participants; zBMI: MD -0.05, 95% CI -0.09 to -0.02; 13 studies, 20,600 participants; moderate-certainty evidence). Eleven studies (21,278 participants; low-certainty evidence) reported data on serious adverse events; one study reported two minor ankle sprains and one study reported the incident rate of adverse events (e.g. musculoskeletal injuries) that may have occurred as a result of the intervention; nine studies reported no effect. Dietary and activity interventions versus control Dietary and activity interventions, compared with control, may result in a slight reduction in BMI and zBMI at short-term follow-up (BMI: MD -0.11, 95% CI -0.21 to -0.01; 27 studies, 16,066 participants; zBMI: MD -0.03, 95% CI -0.06 to 0.00; 26 studies, 12,784 participants; low-certainty evidence) and likely result in a reduction of BMI and zBMI at medium-term follow-up (BMI: MD -0.11, 95% CI -0.21 to 0.00; 21 studies, 17,547 participants; zBMI: MD -0.05, 95% CI -0.07 to -0.02; 24 studies, 20,998 participants; moderate-certainty evidence). Dietary and activity interventions compared with control may result in little to no difference in BMI and zBMI at long-term follow-up (BMI: MD 0.03, 95% CI -0.11 to 0.16; 16 studies, 22,098 participants; zBMI: MD -0.02, 95% CI -0.06 to 0.01; 22 studies, 23,594 participants; low-certainty evidence). Nineteen studies (27,882 participants; low-certainty evidence) reported data on serious adverse events: four studies reported occurrence of serious adverse events (e.g. injuries, low levels of extreme dieting behaviour); 15 studies reported no effect. Heterogeneity was apparent in the results for all outcomes at the three follow-up times, which could not be explained by the main setting of the interventions (school, home, school and home, other), country income status (high-income versus non-high-income), participants' socioeconomic status (low versus mixed) and duration of the intervention. Most studies excluded children with a mental or physical disability. AUTHORS' CONCLUSIONS: The body of evidence in this review demonstrates that a range of school-based 'activity' interventions, alone or in combination with dietary interventions, may have a modest beneficial effect on obesity in childhood at short- and medium-term, but not at long-term follow-up. Dietary interventions alone may result in little to no difference. Limited evidence of low quality was identified on the effect of dietary and/or activity interventions on severe adverse events and health inequalities; exploratory analyses of these data suggest no meaningful impact. We identified a dearth of evidence for home and community-based settings (e.g. delivered through local youth groups), for children living with disabilities and indicators of health inequities.

Interventions to prevent obesity in children aged 12 to 18 years old.

BACKGROUND: Prevention of obesity in adolescents is an international public health priority. The prevalence of overweight and obesity is over 25% in North and South America, Australia, most of Europe, and the Gulf region. Interventions that aim to prevent obesity involve strategies that promote healthy diets or 'activity' levels (physical activity, sedentary behaviour and/or sleep) or both, and work by reducing energy intake and/or increasing energy expenditure, respectively. There is uncertainty over which approaches are more effective, and numerous new studies have been published over the last five years since the previous version of this Cochrane Review. OBJECTIVES: To assess the effects of interventions that aim to prevent obesity in adolescents by modifying dietary intake or 'activity' levels, or a combination of both, on changes in BMI, zBMI score and serious adverse events. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was February 2023. SELECTION CRITERIA: Randomised controlled trials in adolescents (mean age 12 years and above but less than 19 years), comparing diet or 'activity' interventions (or both) to prevent obesity with no intervention, usual care, or with another eligible intervention, in any setting. Studies had to measure outcomes at a minimum of 12 weeks post baseline. We excluded interventions designed primarily to improve sporting performance. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our outcomes were BMI, zBMI score and serious adverse events, assessed at short- (12 weeks to < 9 months from baseline), medium- (9 months to < 15 months) and long-term (≥ 15 months) follow-up. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: This review includes 74 studies (83,407 participants); 54 studies (46,358 participants) were included in meta-analyses. Sixty studies were based in high-income countries. The main setting for intervention delivery was schools (57 studies), followed by home (nine studies), the community (five studies) and a primary care setting (three studies). Fifty-one interventions were implemented for less than nine months; the shortest was conducted over one visit and the longest over 28 months. Sixty-two studies declared non-industry funding; five were funded in part by industry. Dietary interventions versus control The evidence is very uncertain about the effects of dietary interventions on body mass index (BMI) at short-term follow-up (mean difference (MD) -0.18, 95% confidence interval (CI) -0.41 to 0.06; 3 studies, 605 participants), medium-term follow-up (MD -0.65, 95% CI -1.18 to -0.11; 3 studies, 900 participants), and standardised BMI (zBMI) at long-term follow-up (MD -0.14, 95% CI -0.38 to 0.10; 2 studies, 1089 participants); all very low-certainty evidence. Compared with control, dietary interventions may have little to no effect on BMI at long-term follow-up (MD -0.30, 95% CI -1.67 to 1.07; 1 study, 44 participants); zBMI at short-term (MD -0.06, 95% CI -0.12 to 0.01; 5 studies, 3154 participants); and zBMI at medium-term (MD 0.02, 95% CI -0.17 to 0.21; 1 study, 112 participants) follow-up; all low-certainty evidence. Dietary interventions may have little to no effect on serious adverse events (two studies, 377 participants; low-certainty evidence). Activity interventions versus control Compared with control, activity interventions do not reduce BMI at short-term follow-up (MD -0.64, 95% CI -1.86 to 0.58; 6 studies, 1780 participants; low-certainty evidence) and probably do not reduce zBMI at medium- (MD 0, 95% CI -0.04 to 0.05; 6 studies, 5335 participants) or long-term (MD -0.05, 95% CI -0.12 to 0.02; 1 study, 985 participants) follow-up; both moderate-certainty evidence. Activity interventions do not reduce zBMI at short-term follow-up (MD 0.02, 95% CI -0.01 to 0.05; 7 studies, 4718 participants; high-certainty evidence), but may reduce BMI slightly at medium-term (MD -0.32, 95% CI -0.53 to -0.11; 3 studies, 2143 participants) and long-term (MD -0.28, 95% CI -0.51 to -0.05; 1 study, 985 participants) follow-up; both low-certainty evidence. Seven studies (5428 participants; low-certainty evidence) reported data on serious adverse events: two reported injuries relating to the exercise component of the intervention and five reported no effect of intervention on reported serious adverse events. Dietary and activity interventions versus control Dietary and activity interventions, compared with control, do not reduce BMI at short-term follow-up (MD 0.03, 95% CI -0.07 to 0.13; 11 studies, 3429 participants; high-certainty evidence), and probably do not reduce BMI at medium-term (MD 0.01, 95% CI -0.09 to 0.11; 8 studies, 5612 participants; moderate-certainty evidence) or long-term (MD 0.06, 95% CI -0.04 to 0.16; 6 studies, 8736 participants; moderate-certainty evidence) follow-up. They may have little to no effect on zBMI in the short term, but the evidence is very uncertain (MD -0.09, 95% CI -0.2 to 0.02; 3 studies, 515 participants; very low-certainty evidence), and they may not reduce zBMI at medium-term (MD -0.05, 95% CI -0.1 to 0.01; 6 studies, 3511 participants; low-certainty evidence) or long-term (MD -0.02, 95% CI -0.05 to 0.01; 7 studies, 8430 participants; low-certainty evidence) follow-up. Four studies (2394 participants) reported data on serious adverse events (very low-certainty evidence): one reported an increase in weight concern in a few adolescents and three reported no effect. AUTHORS' CONCLUSIONS: The evidence demonstrates that dietary interventions may have little to no effect on obesity in adolescents. There is low-certainty evidence that activity interventions may have a small beneficial effect on BMI at medium- and long-term follow-up. Diet plus activity interventions may result in little to no difference. Importantly, this updated review also suggests that interventions to prevent obesity in this age group may result in little to no difference in serious adverse effects. Limitations of the evidence include inconsistent results across studies, lack of methodological rigour in some studies and small sample sizes. Further research is justified to investigate the effects of diet and activity interventions to prevent childhood obesity in community settings, and in young people with disabilities, since very few ongoing studies are likely to address these. Further randomised trials to address the remaining uncertainty about the effects of diet, activity interventions, or both, to prevent childhood obesity in schools (ideally with zBMI as the measured outcome) would need to have larger samples.

Factors associated with repeat emergency department visits for mental health care in adolescents: A scoping review.

OBJECTIVES: The aim of this review was to identify factors associated with multiple visits to emergency department (ED) services for mental health care in adolescents. METHODS: Electronic databases (MEDLINE, PsycINFO, Embase, CINAHL, Web of Science and ProQuest Dissertations & Thesis Global) were searched for evidence that presented an association between risk factors or correlates of multiple visits to the emergency departmental for mental health care by 10-24 year olds. High impact use was defined as at least one return ED visit for mental health care. Primary studies of any quantitative design were included, with no exclusions based on language or country and all possible risk factors were considered. Data were extracted and synthesised using quantitative methods; frequencies of positive, negative and null associations were summarised for categories of potential risk factors. RESULTS: Sixty-five studies were included in the review. Most studies were from North America and reported a wide range of measures of high impact ED use, the most common being a binary indicator of multiple ED visits. Sex/gender and age were the most frequently reported risk factors. Measure of previous or concurrent access to mental health care was consistently positively associated with high impact use. Having private health insurance, compared with public or no insurance, was generally negatively associated with high impact use. Proxy measures of socioeconomic position (SEP) showed associations between lower SEP and more high impact use in a small number of studies. No other factors were consistently or uniformly associated with high impact use. CONCLUSIONS: The review identified a substantial evidence base but due to the variability in study design and measurement of both risk factors and outcomes, no consistent risk factors emerged. More research is needed, particularly outside North America, using robust methods and high quality routinely collected data.

Defining usual care comparators when designing pragmatic trials of complex health interventions: a methodology review.

BACKGROUND: Pragmatic trials evaluating complex health interventions often compare them to usual care. This comparator should resemble care as provided in everyday practice. However, usual care can differ for the same condition, between patients and practitioners, across clinical sites and over time. Heterogeneity within a usual care arm can raise methodological and ethical issues. To address these it may be necessary to standardise what usual care entails, although doing so may compromise a trial's external validity. Currently, there is no guidance detailing how researchers should decide the content of their usual care comparators. We conducted a methodology review to summarise current thinking about what should inform this decision. METHODS: MEDLINE, Embase, CINAHL and PsycINFO were searched from inception to January 2022. Articles and book chapters that discussed how to identify or develop usual care comparators were included. Experts in the field were also contacted. Reference lists and forward citation searches of included articles were screened. Data were analysed using a narrative synthesis approach. RESULTS: One thousand nine hundred thirty records were identified, 1611 titles and abstracts screened, 112 full texts screened, and 16 articles included in the review. Results indicated that the content of a usual care comparator should be informed by the aims of the trial, existing care practices, clinical guidelines, and characteristics of the target population. Its content should also be driven by the trial's requirements to protect participants, inform practice, and be methodologically robust, efficient, feasible and acceptable to stakeholders. When deciding the content of usual care, researchers will need to gather information about these drivers, balance tensions that might occur when responding to different trial objectives, and decide how usual care will be described and monitored in the trial. DISCUSSION: When deciding the content of a usual care arm, researchers need to understand the context in which a trial will be implemented and what the trial needs to achieve to address its aim and remain ethical. This is a complex decision-making process and trade-offs might need to be made. It also requires research and engagement with stakeholders, and therefore time and funding during the trial's design phase. TRIAL REGISTRATION: PROSPERO CRD42022307324.

Primary care-based interventions for secondary prevention of opioid dependence in chronic non-cancer pain patients on pharmaceutical opioids: systematic review.

BACKGROUND: Globally almost one third of adults with chronic non-cancer pain (CNCP) are prescribed opioids. Prevention of opioid dependence among these patients is a public health priority. AIM: Synthesise the evidence on the effectiveness of primary care-based interventions for secondary prevention of opioid dependence in CNCP patients on pharmaceutical opioids. DESIGN & SETTING: Systematic review of randomised controlled trials (RCTs) and comparative non-randomised studies of interventions from high-income countries. METHOD: We searched five databases for studies on non-tapering secondary prevention interventions such as tools for predicting dependence, screening tools for early recognition of dependence, prescribing/medication monitoring, and specialist support. We examined multiple outcomes, including reduction in opioid dosage. Primary analyses were restricted to RCTs with data synthesised using an effect direction plot. Risk of bias was assessed using the Cochrane risk of bias (RoB2) tool. RESULTS: Of 7,102 identified reports, 18 studies were eligible (8 RCTs). Most used multiple interventions/components. Of the seven RCTs at low risk of bias or 'some concerns', five showed a positive intervention effect on at least one relevant outcome, four of which included a nurse care manager and/or other specialist support. The remaining two RCTs showed no positive effect of automated symptom monitoring and optimised analgesic management by a nurse care manager/physician pain specialist team, or of a mobile opioid management app. CONCLUSION: We identify a clear need for further adequately powered high quality studies. The conclusions that can be drawn on intervention effectiveness are limited by the sparsity and inconsistency of available data.

Disciplinary behaviour management strategies in schools and their impact on student psychosocial outcomes: A systematic review.

Background: Disciplinary behaviour management strategies are implemented in schools to manage pupil behaviour. There is limited evidence of their intended impact on behaviour but there is growing concern around the potential negative impacts on pupil wellbeing. Methods: We carried out a systematic review to examine the impact of these strategies on psychosocial outcomes in pupils (PROSPERO Registration: CRD42021285427). We searched multiple sources and double-screened titles, abstracts, and full texts. Data extraction and risk of bias assessment were done by one reviewer and checked by another. Results were narratively synthesised. Results: We included 14 studies, from 5375 citations, assessing temporary suspension (n=10), verbal reprimand (n=2), and mixed strategies (n=2). Depression was the most common outcome (n=7), followed by academic grades (n=4) and behaviour in class (n=4). All except one study were at high risk of bias. We found a recurring pattern in the evidence of disciplinary strategies associated with poor mental wellbeing and behaviour in pupils. The effect on academic attainment was unclear. Conclusions: Disciplinary behaviour management strategies may have negative impact on pupil mental wellbeing and class behaviour. These important consequences should be assessed in better designed studies before these strategies are implemented.

How does school discipline affect pupil mental health and wellbeing? A systematic review In England, a variety of approaches are used in schools to manage pupils' behaviour. There isn't much evidence about their impact on behaviour, but there's growing concern they might negatively affect pupils' wellbeing. We systematically reviewed the published research to understand the impact of these behaviour management strategies on pupils' wellbeing. We searched multiple sources and two people looked at titles, abstracts and full papers. One reviewer extracted the data and assessed the studies for risk of bias, while another checked this work. Results from all studies were combined together in text and tables. We included 14 studies from the 5,375 papers that we looked at. Included studies explored at a range of strategies, including temporary suspension (10 studies), verbal reprimand or being told off (2 studies), and a combination of strategies (2 studies). Seven studies looked at whether these strategies led to depression, four looked at the impact on exam grades and four on behaviour in class. All except one study were at high risk of bias, meaning we can't fully trust their findings. Many of the studies showed these disciplinary strategies were linked to poor mental wellbeing and behaviour in pupils. The effect on exam results wasn't clear. It appears pupil mental wellbeing and class behaviour was made worse by these strategies. These are important impacts and should be researched in high quality studies before these strategies are used further.

Physical activity interventions in European primary schools: a scoping review to create a framework for the design of tailored interventions in European countries.

Introduction: Schools provide a unique environment to facilitate physical activity for children. However, many school-based physical activity interventions have not been effective. We propose a new approach, which allows schools to tailor interventions to their specific context. This scoping review aimed to identify intervention components from previous school-based physical activity interventions to form the basis of a tailored approach in a European setting. Methods: Joanna Briggs Institute guidelines for conducting scoping reviews were followed. European school-based intervention studies aimed at increasing physical activity in children aged 7-11 years published in English since 2015 were included. Databases searched were Ovid Medline, Embase, PsycINFO, Web of Science Social Sciences Citation Index, ERIC and British Education Index. Data was extracted on intervention components, context-related factors (geographical location, school size, child socioeconomic status and ethnicity), feasibility, acceptability and cost-effectiveness. A data-driven framework was developed to summarize the identified intervention components. Results: 79 articles were included, constituting 45 intervention studies. We identified 177 intervention components, which were synthesized into a framework of 60 intervention component types across 11 activity opportunities: six within the school day, three within the extended school day and two within the wider school environment. Interventions most frequently targeted physical education (21%), active and outdoor learning (16%), active breaks (15%), and school-level environmewnt (12%). Of the intervention components, 41% were delivered by school staff, 31% by the research team, and 24% by external organizations. Only 19% of intervention studies reported geographical location and only 10% reported school size. Participant ethnicity and socioeconomic information was reported by 15% and 25%, respectively. Intervention acceptability was reported in 51% of studies, feasibility in 49%, and cost effectiveness in 2%. Discussion: This review offers a first step in developing a future framework to help schools to develop context-specific, tailored interventions. However, there was a lack of reporting of contextual factors within the included studies, making it difficult to understand the role of context. Future research should seek to measure and report contextual factors, and to better understand the important aspects of context within school-based physical activity.

Facilitators and barriers to community pharmacy PrEP delivery: a scoping review.

INTRODUCTION: Pre-exposure prophylaxis (PrEP) is an effective medication to reduce the risk of acquiring HIV. PrEP is available free of charge in the UK from sexual health clinics. Expanding PrEP delivery to community pharmacies holds promise and aligns with UK government goals to eliminate new cases of HIV by 2030. The aim of this scoping review was to describe the existing evidence about the barriers to and facilitators of community pharmacy oral PrEP delivery, for pharmacists and pharmacy clients, as aligned with the Capacity Opportunity, Motivation Behaviour (COM-B) Model. METHODS: Five bibliographic and five review databases were searched from inception to August 2023. Literature of any study design was included if it discussed barriers and facilitators of community pharmacy PrEP delivery. Trial registrations, protocols and news articles were excluded. RESULTS: A total of 649 records were identified, 73 full texts were reviewed and 56 met the inclusion criteria, predominantly from high-income/westernized settings. Most of the included literature was original research (55%), from the United States (77%) conducted during or after the year 2020 (63%). Barriers to PrEP delivery for pharmacists included lack of knowledge, training and skills (capability), not having the necessary facilities (opportunity), concern about the costs of PrEP and believing that PrEP use could lead to risk behaviours and sexually transmitted infections (motivation). Facilitators included staff training (capability), time, the right facilities (opportunity), believing PrEP could be a source of profit and could reduce new HIV acquisitions (motivation). For clients, barriers included a lack of PrEP awareness (capability), pharmacy facilities (opportunity) and not considering pharmacists as healthcare providers (motivation). Facilitators included awareness of PrEP and pharmacist's training to deliver it (capability), the accessibility of pharmacies (opportunity) and having an interest in PrEP (motivation). DISCUSSION: To effectively enhance oral PrEP delivery in UK community pharmacies, the identified barriers and facilitators should be explored for UK relevance, addressed and leveraged at the pharmacy team, client and care pathway level. CONCLUSIONS: By comprehensively considering all aspects of the COM-B framework, community pharmacies could become crucial providers in expanding PrEP accessibility, contributing significantly to HIV prevention efforts.

Systematic review and meta-analysis of the accuracy of McIsaac and Centor score in patients presenting to secondary care with pharyngitis.

BACKGROUND: Centor and McIsaac scores are clinical prediction rules for diagnosing group A streptococcus (GAS) infection in patients with pharyngitis. Their recommended thresholds vary between guidelines. OBJECTIVES: To estimate the sensitivity and specificity of the McIsaac and Centor scores to diagnose GAS pharyngitis and evaluate their impact on antibiotic prescribing at each threshold in patients presenting to secondary care. DATA SOURCES: MEDLINE, Embase, and Web of Science were searched from inception to September 2022. STUDY ELIGIBILITY CRITERIA: Studies of patients presenting with acute pharyngitis to emergency or outpatient clinics that estimated the accuracy of McIsaac or Centor scores against throat cultures and/or rapid antigen detection tests (RADT) as reference standards. TESTS: Centor or McIsaac score. REFERENCE STANDARD: Throat cultures and/or RADT. ASSESSMENT OF RISK OF BIAS: Quality Assessment of Diagnostic Accuracy Studies. METHODS OF DATA SYNTHESIS: The sensitivities and specificities of the McIsaac and Centor scores were pooled at each threshold using bivariate random effects meta-analysis. RESULTS: Fourteen studies were included (eight McIsaac and six Centor scores). Eight studies had unclear and six had a high risk of bias. The McIsaac score had higher estimated sensitivity and lower specificity relative to Centor scores at equivalent thresholds but with wide and overlapping confidence regions. Using either score as a triage to RADT to decide antibiotic treatment would reduce antibiotic prescription to patients with non-GAS pharyngitis relative to RADT test for everyone, but also reduce antibiotic prescription to patients with GAS. DISCUSSION: Centor and McIsaac scores are equally ineffective at triaging patients who need antibiotics presenting with pharyngitis at hospitals. At high thresholds, too many true positive cases are missed, whereas at low thresholds, too many false positives are treated, leading to the over prescription of antibiotics. The former may be compensated by adequate safety netting by clinicians, ensuring that patients can seek help if symptoms worsen.

Dose-response relationship in cognitive behavioral therapy for depression: A nonlinear metaregression analysis.

OBJECTIVE: Evidence on the optimal "dose" of cognitive behavioral therapy (CBT) for treating major depressive disorder is sparse. This analysis aimed to evaluate the dose-response curve in CBT using a nonlinear approach, whereby "dose" was defined as number of treatment sessions. The dose-response curve of CBT was compared to other psychotherapies and pharmacological treatments for depression. METHOD: A systematic review and metaregression analysis of randomized controlled trials (RCTs) examining the efficacy of CBT in adults with acute depression was conducted. Treatment arms examining other psychosocial or pharmacological interventions were also analyzed. Cubic spline metaregression techniques were used to model nonlinear dose-response curves. RESULTS: Seventy-two studies and 7,377 participants were included. Modeling the dose-response curve between change of depression symptom severity and the number of CBT sessions resulted in a nonlinear curve characterized by a strong improvement in symptom severity from baseline within the first eight sessions. Symptom reduction continues in the further course of the treatment, but at a slower pace. A similar pattern of symptom development was found for other therapies as well, although the prominence of early improvement and overall effect sizes vary across treatment arms. CONCLUSION: Results imply a general tendency for the strongest alleviation of depressive symptom severity in early stages of CBT treatment, thus, if aiming at symptom alleviation, speak for short CBT interventions. However, these findings have to be discussed in the light of the limited data regarding the sustainability of treatment effects in short-term therapies and effects beyond symptomatic changes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Prevalence of problematic pharmaceutical opioid use in patients with chronic non-cancer pain: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Chronic non-cancer pain (CNCP) is one of the most common causes of disability globally. Opioid prescribing to treat CNCP remains widespread, despite limited evidence of long-term clinical benefit and evidence of harm such as problematic pharmaceutical opioid use (POU) and overdose. The study aimed to measure the prevalence of POU in CNCP patients treated with opioid analgesics. METHOD: A comprehensive systematic literature review and meta-analysis was undertaken using MEDLINE, Embase and PsycINFO databases from inception to 27 January 2021. We included studies from all settings with participants aged ≥ 12 with non-cancer pain of ≥ 3 months duration, treated with opioid analgesics. We excluded case-control studies, as they cannot be used to generate prevalence estimates. POU was defined using four categories: dependence and opioid use disorder (D&OUD), signs and symptoms of D&OUD (S&S), aberrant behaviour (AB) and at risk of D&OUD. We used a random-effects multi-level meta-analytical model. We evaluated inconsistency using the I2 statistic and explored heterogeneity using subgroup analyses and meta-regressions. RESULTS: A total of 148 studies were included with > 4.3 million participants; 1% of studies were classified as high risk of bias. The pooled prevalence was 9.3% [95% confidence interval (CI) = 5.7-14.8%; I2 = 99.9%] for D&OUD, 29.6% (95% CI = 22.1-38.3%, I2 = 99.3%) for S&S and 22% (95% CI = 17.4-27.3%, I2 = 99.8%) for AB. The prevalence of those at risk of D&OUD was 12.4% (95% CI = 4.3-30.7%, I2 = 99.6%). Prevalence was affected by study setting, study design and diagnostic tool. Due to the high heterogeneity, the findings should be interpreted with caution. CONCLUSIONS: Problematic pharmaceutical opioid use appears to be common in chronic pain patients treated with opioid analgesics, with nearly one in 10 experiencing dependence and opioid use disorder, one in three showing signs and symptoms of dependence and opioid use disorder and one in five showing aberrant behaviour.

A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE.

In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5-55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.

Membrane Proteome-Wide Screening of Autoantibodies in CIDP Using Human Cell Microarray Technology.

BACKGROUND AND OBJECTIVES: Autoantibody discovery in complex autoimmune diseases is challenging. Diverse successful antigen identification strategies are available, but, so far, have often been unsuccessful, especially in the discovery of protein antigens in which conformational and post-translational modification are critical. Our study assesses the utility of a human membrane and secreted protein microarray technology to detect autoantibodies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: A cell microarray consisting of human embryonic kidney-293 cells expressing >5,000 human proteins was used. First, a validation step was performed with 4 serum samples from patients with autoimmune nodopathy (AN) to assess the ability of this technology to detect circulating known autoantibodies. The ability of the cell microarray technology to discover novel IgG autoantibodies was assessed incubating the array with 8 CIDP serum samples. Identified autoantibodies were subsequently validated using cell-based assays (CBAs), ELISA, and/or tissue immunohistochemistry and analyzed in a cohort of CIDP and AN (n = 96) and control (n = 100) samples. RESULTS: Serum anti-contactin-1 and anti-neurofascin-155 were detected by the human cell microarray technology. Nine potentially relevant antigens were found in patients with CIDP without other detectable antibodies; confirmation was possible in six of them: ephrin type-A receptor 7 (EPHA7); potassium-transporting ATPase alpha chain 1 and subunit beta (ATP4A/4B); leukemia-inhibitory factor (LIF); and interferon lambda 1, 2, and 3 (IFNL1, IFNL2, IFNL3). Anti-ATP4A/4B and anti-EPHA7 antibodies were detected in patients and controls and considered unrelated to CIDP. Both anti-LIF and anti-IFNL antibodies were found in the same 2 patients and were not detected in any control. Both patients showed the same staining pattern against myelinating fibers of peripheral nerve tissue and of myelinating neuron-Schwann cell cocultures. Clinically relevant correlations could not be established for anti-LIF and anti-IFNL3 antibodies. DISCUSSION: Our work demonstrates the utility of human cell microarray technology to detect known and discover unknown autoantibodies in human serum samples. Despite potential CIDP-associated autoantibodies (anti-LIF and anti-IFNL3) being identified, their clinical and pathogenic relevance needs to be elucidated in bigger cohorts.

Genomic landscape and actionable mutations of brain metastases derived from non-small cell lung cancer: A systematic review.

Background: Brain metastases derived from non-small cell lung cancer (NSCLC) represent a significant clinical problem. We aim to characterize the genomic landscape of brain metastases derived from NSCLC and assess clinical actionability. Methods: We searched Embase, MEDLINE, Web of Science, and BIOSIS from inception to 18/19 May 2022. We extracted information on patient demographics, smoking status, genomic data, matched primary NSCLC, and programmed cell death ligand 1 expression. Results: We found 72 included papers and data on 2346 patients. The most frequently mutated genes from our data were EGFR (n = 559), TP53 (n = 331), KRAS (n = 328), CDKN2A (n = 97), and STK11 (n = 72). Common missense mutations included EGFR L858R (n = 80) and KRAS G12C (n = 17). Brain metastases of ever versus never smokers had differing missense mutations in TP53 and EGFR, except for L858R and T790M in EGFR, which were seen in both subgroups. Of the top 10 frequently mutated genes that had primary NSCLC data, we found 37% of the specific mutations assessed to be discordant between the primary NSCLC and brain metastases. Conclusions: To our knowledge, this is the first systematic review to describe the genomic landscape of brain metastases derived from NSCLC. These results provide a comprehensive outline of frequently mutated genes and missense mutations that could be clinically actionable. These data also provide evidence of differing genomic landscapes between ever versus never smokers and primary NSCLC compared to the BM. This information could have important consequences for the selection and development of targeted drugs for these patients.