Jennifer C. Palmer

Background: Childhood obesity is a major public health concern worldwide, yet the best way to prevent it remains unknown. Objective(s): To determine what types of intervention strategy are most effective at preventing the development of obesity in children aged 5–18 years, as measured by change in body mass index, and to determine whether interventions work differentially in children with different characteristics associated with inequities. Design: Systematic reviews and statistical evidence syntheses. Eligibility criteria: Randomised controlled trials of dietary and/or activity interventions that aimed to prevent overweight or obesity in children and young people aged 5–18 years and reported outcomes at least 12 weeks after baseline. Non-randomised evidence was identified through an overview of systematic reviews. Sources of inequity of interest were those defined by the PROGRESS (place of residence, race/ethnicity/culture/language, occupation, gender/sex, religion, education, socioeconomic status, social capital) acronym: place, race/ethnicity, occupation (of parents), gender/sex, religion, education (of parents), socioeconomic status and social capital. Data sources: Updating of an existing Cochrane Review, searching bibliographic databases up to February 2023, including MEDLINE, EMBASE, PsycInfo® (American Psychological Association, Washington, DC, USA) and Cochrane Central Register of Controlled Trials on the Cochrane Library, international trial registers and grey literature databases, and examining reference lists. Results subgrouped by inequity factors were sought directly from trialists. Review methods: Cochrane Reviews followed standard Cochrane procedures. The main statistical synthesis was informed by a novel analytic framework developed iteratively through discussions with children and young people, schoolteachers and public health professionals. Methodology was developed to analyse the data using multilevel metaregression. To examine the impact of inequity factors, we performed a two-stage meta-analysis of interactions, based on subgroup-level aggregate data collected directly from the trialists. We collected available information on intervention costs. Results: We included 172 trials in ages 5–11 and 74 in ages 12–18. In the main synthesis, of 204 trials from both reviews, we found interventions were effective on average (mean difference in standardised body mass index −0.037, 95% credible interval −0.053 to −0.022, which would correspond to a reduction in a proportion of 2.3% with obesity to a proportion of approximately 2.1%). Larger effects were associated with physical activity rather than dietary interventions, after 12 months of follow-up and in the older age group. The overview of non-randomised evidence included 24 systematic reviews, yielding mixed results. The investigation of inequity did not identify substantial differences in effectiveness according to place of residence, race/ethnicity/culture/language, occupation, gender/sex, religion, education, socioeconomic status, social capital characteristics, and there was very limited information about costs. Limitations: We were able to examine only the interventions that had been evaluated in studies identified for inclusion in the systematic reviews, which does not cover all possible intervention approaches. Conclusions: Interventions to prevent obesity in children aged 5–18 have a small beneficial effect on body mass index on average but with considerable variation. A novel re-analysis of existing randomised trials failed to identify general intervention characteristics driving this variation. No evidence was identified to suggest that interventions increase (or decrease) health inequities. Future work: Future studies of the effects of interventions to prevent childhood obesity should routinely collect baseline characteristics around potential inequities. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme as award number NIHR131572.

Androgens have been shown to be linked to cancer progression, particularly in hormone-dependent cancers such as prostate and breast cancer, but also other cancers. Amyloid precursor protein (APP), which has primarily been studied in Alzheimer’s disease, is gaining recognition for its role in tumor growth and survival. While APP overexpression and androgen receptor (AR) signaling are each associated with cancer progression, the connection between androgens and APP processing in cancer has not been thoroughly investigated. This systematic review was conducted through a comprehensive search of PubMed, Scopus, Web of Science, and EMBASE between 2000 to 2024 for studies examining the effects of androgens on APP and its cleavage enzymes in cancer. Five experimental studies met the inclusion criteria, covering prostate and breast cancer models. Data were extracted and synthesized narratively due to heterogeneity in methods and outcomes. Three studies reported that dihydrotestosterone (DHT) or AR agonists increased the expression and nuclear translocation of ADAM10, a key α-secretase enzyme in the non-amyloidogenic APP processing pathway. Two studies identified APP as an androgen-responsive gene, showing that androgens upregulated APP expression in prostate and breast cancer cells and promoted the proliferation of cancer cells. Inhibition or knockdown of APP and ADAM10 reduced proliferation, supporting their roles in tumor progression. Androgen signaling modulates APP processing in cancer, particularly through the non-amyloidogenic pathway; however, significant knowledge gaps remain. Further studies are needed to explore the interaction between androgens and APP processing in other cancer types, as well as to elucidate downstream signaling pathways regulated at the gene expression level.

Background and Aims: Cocaine use disorder (CUD) is an increasingly widespread concern worldwide. Various pharmacological treatments have been investigated for CUD, but their efficacy remains unclear, and none have been licensed for treatment. Therefore, we assessed the comparative effectiveness, safety, and acceptability of pharmacological interventions for the treatment of CUD and prevention of relapse. Design: Systematic review and network meta-analyses of double-blind randomized controlled trials (RCTs). PROSPERO (CRD42024596434). We assessed risk of bias using the Cochrane Risk of Bias 2 tool and certainty of evidence was assessed using the Confidence in Network Meta-analysis framework. Setting: Any in/outpatient setting, with no restriction on geographic location. Participants: Adults with diagnosed CUD. Participants with co-occurring substance use disorders and/or common mental health conditions were eligible. Interventions: Pharmacologicalinterventions specifically tested for the treatment of CUD with a minimum follow-up of 4 weeks. Measurements: We assessed 12 effectiveness, three acceptability, and two safety outcomes. Our primary outcomes were continuous abstinence, point abstinence, dropout for any reason, and serious adverse events. We also examined longest duration of continuous abstinence, extent of cocaine use, craving, severity of dependence, dropout due to adverse events, adherence, and mortality. Findings: We included 218 reports of 163 studies (14871 participants) assessing 89 unique medications, grouped into 8 categories. Most study results had some concerns or high risk of bias, and the results of syntheses were generally judged to be very low certainty evidence. As such, the findings ought to be interpreted with caution. No single treatment type showed consistent beneficial effects across all effectiveness outcomes and there was limited evidence that results varied by intervention type or presence of co-occurring comorbidity. Conclusions: Despite continued work in this area, effective pharmacological treatments for CUD remain elusive.

Background: Recent systematic reviews and meta-analyses on the effects of interventions to prevent obesity in children aged 5–18 years identified over 200 randomised trials. Interventions targeting diet, activity (including physical activity and sedentary behaviours) and both diet and activity appear to have small but beneficial effects on average. However, these effects varied between studies and might be explained by variation in characteristics of the interventions, for example, by the extent to which the children enjoyed the intervention or whether they aim to modify behaviour through education or physical changes to the environment. Here we develop a novel analytic framework to identify key intervention characteristics considered likely to explain differential effects. Objectives: To describe the development of the analytic framework, including the involvement of school-aged children, parents, teachers and other stakeholders, and to present the content of the finalised analytic framework and the results of the coding of the interventions. Design and methods: We first conducted a literature review to find out from the existing literature what different types of characteristics of interventions we should be thinking about and why. This information helped us to develop a comprehensive map (called a logic model) of these characteristics. We then used this logic model to develop a list of possible intervention characteristics. We held a series of workshops with children, parents, teachers and public health professionals to refine the list into a coding scheme. We then used this to code the characteristics of each intervention in all the trials which aimed to prevent obesity in children aged 5–18 years. Findings: Our finalised analytic framework included 25 questions across 12 characteristics. These addressed aspects such as the setting of the intervention (e.g. at school, at home or in the community), mode of delivery (e.g. to individuals or to groups of children), whether the intervention targeted diet and/or activity, complexity (e.g. focused on a single swap of juice for water or aimed to change all aspects of the diet), intensity, flexibility, choice, mechanism of action (e.g. through participation, education, change in the social environment, change in the physical environment), resonance (e.g. credibility of the person delivering the intervention), commercial involvement and the ‘fun factor’ (as perceived by children). We coded 255 interventions from 210 randomised trials. Conclusions: Our evidence-based analytic framework, refined by consulting with stakeholders, allowed us to code 255 interventions aiming to prevent obesity in children aged 5–18 years. Our confidence in the validity of the framework and coding results is increased by our rigorous methods and, especially, the involvement of children at multiple stages. Future work: Future work will include the development of statistical methods for the synthesis and its application to the data coded according to the analytic framework. Limitations: The coding results depend on the level of detail provided to describe the interventions, and the applicability of the analytic framework may be limited by demographic profile of the children and young people involved in the project. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme as award number NIHR131572.

Background: Evidence suggests there may be a bidirectional relationship between high blood pressure (BP) and Alzheimer’s disease (AD). It is hypothesised that this is due to cerebral changes during pre-clinical AD that cause elevation of systemic BP. We aimed to test this by exploring the effect of risk of pre-clinical AD on blood pressure. Methods: We used data from the UK Biobank, including adults without prevalent or incident (within first 5 years of follow-up) clinical AD (N = 501,420, mean age 56.6, SD 8 years). We used two instrumental variables, an age-weighted parental dementia instrument score and a participant genetic instrument score, that are vulnerable to differing biases, to instrument risk of pre-clinical AD (the exposure). We tested the association of both instrument scores with systolic BP (SBP), diastolic BP (DBP), and hypertension. Sensitivity analyses were undertaken to explore different biases. Results: Both the higher parental dementia instrument and participant genetic instrument score were associated with higher mean SBP (difference in mean SBP mmHg per 1SD higher score: 0.12, 95% CI 0.06 to 0.17, p < 0.0001, and 0.07, 95% CI 0.00 to 0.13, p=0.037, respectively) but not DBP. Sensitivity analyses were largely consistent with these findings. Conclusions: Our findings provide preliminary evidence that pre-clinical AD increases SBP. Further research is required to determine whether this increase in SBP is due to increased cerebrovascular resistance as a result of pre-clinical AD. Obtaining a better understanding of the changing relationship with BP at different stages of AD may enable effective optimisation and targeting of therapies.

Introduction: We aim to identify effective characteristics of behavioural change (physical activity and diet) interventions that prevent obesity in children aged 5 to 18 years. Methods: We re-analysed data from two Cochrane systematic reviews published in 2024 using a Bayesian multi-level meta-regression analysis with intervention and trial characteristics coded according to an analytic framework co-developed with stakeholders. Results: We included 204 trials (255 intervention arms) reporting data on body mass index (BMI), either unstandardised or measured as a z-score (zBMI) or percentile. Interventions were effective on average (MD in zBMI −0.037, 95% credible interval −0.053 to −0.022). The greatest effects were associated with medium-term follow-up (nine to <15 months) and older children (12 to 18 years). We found evidence of small beneficial effects for interventions targeting physical activity alone compared with diet alone (difference in MDs −0.227,–0.362 to −0.090) and small unfavourable effects for interventions that involved a change to the structural environment (typically the school food environment) (difference in MDs 0.05, 0.017 to 0.085). Accounting for interactions between covariates, the most effective combination of intervention characteristics was to intervene in the school setting, with an individualised element to delivery, targeting physical activity, using multiple strategies of short duration and high intensity and involving modification of behaviour through participation in activities. Conclusions: The most effective characteristic to include in a behavioural change intervention to prevent obesity in children aged 5–18 years was targeting of physical activity. This should not be interpreted as evidence that attempts to modify diet are not beneficial. Being physically active and consuming a healthy diet during childhood offer many important benefits beyond contributing to healthy weight and growth. Our findings suggest that interventions to prevent obesity in children should consider increasing their focus on the promotion of physical activity and consider other effective characteristics we identify here.

Background and Aims: Evidence suggests there may be a bidirectional relationship between high blood pressure (BP) and Alzheimer’s disease (AD). It is hypothesised that this is due to cerebral changes during pre-clinical AD that cause elevation of systemic BP. We aimed to test this by exploring the effect of risk of pre-clinical AD on blood pressure. Methods: We used data from the UK Biobank, including adults without prevalent or incident (within first 5-years of follow-up) clinical AD (N = 501,420, mean age 56.6, SD 8 years). We used two instrumental variables, an age-weighted parental dementia instrument score and a participant genetic instrument score, that are vulnerable to differing biases, to instrument risk of pre-clinical AD (the exposure). We tested the association of both instrument scores with systolic BP (SBP), diastolic BP (DBP) and hypertension. Sensitivity analyses were undertaken to explore different biases. Results: Both the higher parental dementia instrument and participant genetic instrument score were associated with higher mean SBP (difference in mean SBP mmHg per 1SD higher score: 0.12, 95% CI: 0.06 to 0.17, and 0.07, 95% CI: 0.00 to 0.13, respectively) but not DBP. Sensitivity analyses were largely consistent with these findings. Conclusions: Our findings provide preliminary evidence that pre-clinical AD increases SBP. Further research is required to determine whether this increase in SBP is due to increased cerebrovascular resistance in pre-clinical AD. Obtaining a better understanding of the changing relationship with BP at different stages of AD may enable effective optimisation and targeting of therapies.

Objective To identify effective characteristics of behaviour change (physical activity and diet) interventions that prevent obesity in children aged 5 to 18 years. Design A Bayesian multi-level meta-regression analysis of randomized trial results, with intervention and trial characteristics coded according to an analytic framework co-developed with stakeholders. Data source Two Cochrane systematic reviews of the effects of interventions to prevent obesity in children, 5 to 11 years and 12 to 18 years, both updated in 2024. Main outcome measures Mean difference (MD) in change from baseline in age- and sex-standardized BMI measured as a Z-score (zBMI). Results that had been reported as (unstandardized) BMI or BMI percentile were converted to zBMI using bespoke mapping techniques. Results We included 204 trials (255 intervention arms) reporting data on at least one of the main outcome scales. Interventions were effective on average (MD in zBMI −0.037, 95% credible interval −0.053 to −0.022). The greatest effects were associated with medium term follow-up (9 to Conclusions The most effective characteristic to include in a behaviour change intervention to prevent obesity in children aged 5-18 years was targeting of physical activity. This should not be interpreted as evidence that attempts to modify diet are not beneficial. Being physically active and consuming a healthy diet during childhood offer many important benefits beyond contributing to healthy weight and growth. Our findings suggest that interventions to prevent obesity in children should consider focusing primarily on the promotion of physical activity and consider other effective characteristics we identify here. What is already known on this topic Rising population levels of childhood overweight and obesity present a global challenge. Many interventions have been developed and evaluated to try and prevent obesity in children and young people. The most effective characteristics of these interventions are not well understood. What this study adds This re-analysis of the results of 204 randomized trials of diverse interventions seeks to identify effective characteristics of behaviour change (physical activity and diet) interventions. The most effective characteristic to include in a behaviour change intervention may be targeting physical activity. Other useful features of interventions appear to be individualized delivery, using multiple strategies, being intense and of short duration, and involving participation in activities.

Background: Public health attempts to prevent obesity in children and young people should aim to minimize health inequalities. We aimed to assess whether there were differences in the effectiveness of the interventions included in two Cochrane reviews according to the eight PROGRESS inequity factors. Methods: We collected data on change in BMI (standardized or unstandardized), subgrouped by baseline measures of PROGRESS factors, for intervention and control groups, from trial authors. We calculated the intervention effect per subgroup (mean difference), then contrasted these to estimate interactions between intervention and the baseline factors. We combined interaction estimates for each factor across trials using standard procedures for meta-analysis. Findings: Our analysis of interventions from 81 trials found no substantial differences in effectiveness for different subgroups in most scenarios. However, in the younger age group (5-11 years), the effect of interventions on standardized BMI appeared to be higher in boys. Interpretation: The Cochrane reviews found that interventions promoting physical activity (only) have a beneficial effect on BMI (compared with a control group) for children and young people aged 5-18 years, as well as interventions promoting physical activity alongside healthy eating for 5-11 year olds. Although these beneficial effects were small, when delivered at scale, they may have the potential to contribute meaningfully to reducing the prevalence of childhood obesity. Our findings suggest that those responsible for public health can promote these beneficial interventions without major concerns about increasing inequalities. Because many of the interventions studied, including school-based interventions, provide building blocks of ‘whole systems approaches’, the findings are relevant to policy and practice. Funding: National Institute for Health and Care Research (NIHR). Research in context: Evidence before this study: A core principle of any public health guidance is to minimize health inequalities. Two previous studies of the effects of interventions aiming to prevent obesity in children and young people, by promoting physical activity or a healthy diet, found that such interventions do not increase health inequalities. However, these studies used secondary data published in trial reports, limiting the data available for analysis. Two recent Cochrane systematic reviews and meta-analyses of over 200 randomized trials of interventions to prevent obesity in children and young people, found, on average , small beneficial effects of physical activity interventions in 5-18 year olds on (standardized and unstandardized) BMI and of combined physical activity and dietary interventions in 5-11 year olds. A previous modelling study found that small beneficial benefits such as these, when delivered at scale, have the potential to contribute meaningfully to reducing the prevalence of childhood obesity. However, average effects may mask differential effects on health equity. Our objective was to collect primary trial results (not previously reported) to examine whether effects of interventions vary according to factors related to inequity as represented by the PROGRESS acronym: place, race/ethnicity, occupation, gender/sex, religion, education, socio-economic status, and social capital. Added value of this study: To the best of our knowledge, this is the first large-scale meta-analysis to assess the impact of interventions to prevent obesity in children and young people on health equity using primary data from randomized trials. Data from 81 trials were included, collected directly from the trialists as aggregate data by intervention and by subgroup, and combined in meta-analyses. We found no substantial impact of the interventions on inequalities, although in the younger age group (5-11 years), the effect of interventions (n=45) on standardized BMI was greater in boys. Implications of all the available evidence: Those responsible for public health can be confident in promoting the types of interventions included in this meta-analysis to prevent obesity in children and young people (5-18 years), knowing they are unlikely to increase inequalities. One exception was that interventions for younger children may benefit from being equally engaging and enjoyable for females and males. We regard ‘whole systems approaches’ to comprise separate interventions (components) interconnected via a programme theory and logic model, including the types of interventions included in this meta-analysis. As such, our findings are relevant to those providing guidance on a whole systems approach to reducing the prevalence of obesity in children and young people alongside promoting health equity.