PROspective Meta-analysis Of Trials of Initial Oxygen in preterm Newborns (PROMOTION): Protocol for a systematic review and prospective meta-analysis with individual participant data on initial oxygen concentration for resuscitation of preterm infants.

BACKGROUND: Clinicians favour low oxygen concentrations when resuscitating preterm infants immediately after birth despite inconclusive evidence to support this practice. Prospective meta-analysis (PMA) is a novel approach where studies are identified as eligible for inclusion in the meta-analysis before their results are known. AIMS: To explore whether high (60%) or low (30%) oxygen is associated with greater efficacy and safety for the initial resuscitation (immediately after birth) of preterm infants born at <29 weeks' gestation. METHODS: We will conduct a prospective meta-analysis (PMA) with individual participant data (IPD). We will perform a systematic search to identify ongoing RCTs including infants <29 weeks' gestation randomised to high (60%) or low (30%) oxygen for initial resuscitation after birth. IPD will be sought for all infants randomised for the purpose of meta-analysis. We will employ a one-stage random-effects approach to IPD meta-analysis. Potential heterogeneity and the differential effect of high or low oxygen will be explored through subgroup and interaction analyses. The primary outcome of this study is all-cause mortality prior to hospital discharge. There will be a follow-up analysis of neurodevelopmental outcomes once available. RESULTS/CONCLUSION: The results of neonatal outcomes at hospital discharge are expected by 2025, and neurodevelopmental outcomes by 2027.

An overlapping pattern of cerebral cortical thinning is associated with both positive symptoms and aggression in schizophrenia via the ENIGMA consortium.

BACKGROUND: Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample. METHOD: To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls. RESULTS: The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression. CONCLUSION: These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

A Bayesian Reanalysis of the Overall and Sex-Disaggregated Results of the Neonatal Oxygenation Prospective Meta-Analysis (NeOProM).

Data from the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) indicate that targeting a higher (91-95%) versus lower (85-89%) pulse oximeter saturation (SpO2) range may reduce mortality and necrotizing enterocolitis (NEC) and increase retinopathy of prematurity (ROP). Aiming to re-evaluate the strength of this evidence, we conducted a Bayesian reanalysis of the NeOProM data. We used Bayes factors (BFs) to evaluate the likelihood of the data under the combination of models assuming the presence vs. absence of effect, heterogeneity, and moderation by sex. The Bayesian reanalysis showed moderate evidence in favor of no differences between SpO2 targets (BF10 = 0.30) in death or major disability, but moderate evidence (BF10 = 3.60) in favor of a lower mortality in the higher SpO2 group. Evidence in favor of differences was observed for bronchopulmonary dysplasia (BPD) (BF10 = 14.44, lower rate with lower SpO2), severe NEC (BF10 = 9.94), and treated ROP (BF10 = 3.36). The only outcome with moderate evidence in favor of sex differences was BPD. This reanalysis of the NeOProM trials confirmed that exposure to a lower versus higher SpO2 range is associated with a higher mortality and risk of NEC, but a lower risk of ROP and BPD. The Bayesian approach can help in assessing the strength of evidence supporting clinical decisions.

Effectiveness of full Pulpotomy compared with Root canal treatment in managing teeth with signs and symptOms indicative of irreversible pulpitis: a protocol for prospectiVE meta-analysis of individual participant data of linked randomised clinical trials (PROVE).

BACKGROUND: Full pulpotomy has been proposed as an alternative to root canal treatment in teeth with signs and symptoms indicative of irreversible pulpitis (IRP), but the evidence is limited, relying on underpowered studies with a high risk of bias. The aim of this study is to conduct a prospective meta-analysis (PMA) of individual participant data of a series of individual randomised trials to provide robust evidence on the clinical and cost-effectiveness of pulpotomy compared with root canal treatment. METHODS: Individual participant data will be obtained from a series of randomised trials designed and conducted by a consortium of multi-national investigators with an interest in vital pulp treatment. These individualised trials will be conducted using a specified protocol, defined outcomes, and outcome measures. Ten parallel-group randomised trials currently being conducted in 10 countries will provide data from more than 500 participants. The primary outcome is a composite measure defined as (1) the absence of pain indicative of IRP, (2) the absence of signs and symptoms indicative of acute or chronic apical periodontitis, and (3) the absence of radiographic evidence of failure including radiolucency or resorption. Individual participant data will be obtained, assessed, and checked for quality by two independent reviewers prior to the PMA. Pooled estimates on treatment effects will be generated using a 2-stage meta-analysis approach. The first stage involves a standard regression analysis in each trial to produce aggregate data on treatment effect estimates followed by an inverse variance weighted meta-analysis to combine these aggregate data and produce summary statistics and forest plots. Cost-effectiveness analysis based on the composite outcome will be undertaken as a process evaluation to evaluate treatment fidelity and acceptability by patients and dentists. RESULTS: The research question and trial protocol were developed and approved by investigators in all 10 sites. All sites use shared resources including study protocols, data collection forms, participant information leaflets, and consent forms in order to improve flow, consistency, and reproducibility. Each site obtained its own Institutional Review Board approval, and trials were registered in appropriate open access platforms. Patient recruitment has started in most sites, as of July 2023. DISCUSSION: PMA offers a rigorous, flexible, and efficient methodology to answer this important research question and provide results with improved generalisability and external validity compared with traditional trials and retrospective meta-analyses. The results of this study will have implications for both the delivery of clinical practice and structured clinical guidelines' development. TRIAL REGISTRATION: PROSPERO CRD42023446809. Registered on 08 February 2023.

Effects of the Informed Health Choices secondary school intervention: A prospective meta-analysis.

AIM: The aim of this prospective meta-analysis was to synthesize the results of three cluster-randomized trials of an intervention designed to teach lower-secondary school students (age 14-16) to think critically about health choices. METHODS: We conducted the trials in Kenya, Rwanda, and Uganda. The intervention included a 2- to 3-day teacher training workshop, digital resources, and ten 40-min lessons. The lessons focused on nine key concepts. We did not intervene in control schools. The primary outcome was a passing score on a test (≥9 of 18 multiple-choice questions answered correctly). We performed random effects meta-analyses to estimate the overall adjusted odds ratios. Secondary outcomes included effects of the intervention on teachers. RESULTS: Altogether, 244 schools (11,344 students) took part in the three trials. The overall adjusted odds ratio was 5.5 (95% CI: 3.0-10.2; p < 0.0001) in favor of the intervention (high certainty evidence). This corresponds to 33% (95% CI: 25-40%) more students in the intervention schools passing the test. Overall, 3397 (58%) of 5846 students in intervention schools had a passing score. The overall adjusted odds ratio for teachers was 13.7(95% CI: 4.6-40.4; p < 0.0001), corresponding to 32% (95% CI: 6%-57%) more teachers in the intervention schools passing the test (moderate certainty evidence). Overall, 118 (97%) of 122 teachers in intervention schools had a passing score. CONCLUSIONS: The intervention led to a large improvement in the ability of students and teachers to think critically about health choices, but 42% of students in the intervention schools did not achieve a passing score.

Clinical Efficacy of Deep Transcranial Magnetic Stimulation in Psychiatric and Cognitive Disorders: Protocol for a Systematic Review.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a widely used noninvasive brain stimulation technique for psychiatric and cognitive disorders. In recent years, deep TMS (dTMS) has shown promise as an enhanced form of TMS able to stimulate deeper brain structures and target broader networks. Various magnetic Hesed-coil (H-coil) designs-a novel feature of dTMS-have been used to stimulate brain regions implicated in the pathophysiology of specific psychiatric and cognitive disorders, thereby producing therapeutic effects. Given the novelty of dTMS in psychiatry, little is known about the clinical efficacy of dTMS across psychiatric and cognitive disorders-that is, whether dTMS performs superiorly to sham or control. OBJECTIVE: In this paper, we outline a protocol for a systematic review investigating the clinical efficacy of dTMS. The primary objective is to conduct a systematic review of the literature on dTMS for psychiatric and cognitive disorders and, if feasible, a meta-analysis to compare the efficacy of active dTMS versus sham/control for psychiatric disorders. Dementia and related cognitive disorders will also be examined. A secondary objective will be to examine subgroup differences (by age, sex, H-coil design, and dTMS parameters [ie, pulses per session, percentage of motor threshold, etc]) to evaluate whether dTMS differentially influences clinical outcomes based on these factors. METHODS: A comprehensive search of the APA PsycINFO, Embase, MEDLINE, and PubMed databases will be conducted using keywords such as "H-coil" and "dTMS." Two authors (AD and MD) will be responsible for screening relevant articles, assessing article eligibility (according to predetermined inclusion and exclusion criteria), and data extraction. All included articles will undergo a quality and risk of bias assessment. Data from included articles will be summarized qualitatively in a systematic review. If a sufficient number of equivalent studies are available, a meta-analysis will be performed to (1) determine the effect of active versus sham dTMS (or another control arm) across psychiatric and cognitive disorders, and (2) examine subgroup effects of clinical outcomes. RESULTS: The preliminary search rendered a total of 1134 articles from the APA PsycINFO, Embase, and MEDLINE databases. After full-text screening, 21 eligible articles remained. One additional article was identified from the references section of an existing systematic review. In total, 22 eligible articles were included. Data extraction and quality of assessment procedures are ongoing. CONCLUSIONS: We will outline the evidence relating to the clinical efficacy of dTMS in various psychiatric and cognitive disorders. The results of the prospective systematic review will provide clinicians with valuable insight into the clinical (ie, participant age, sex, psychiatric or cognitive disorder, etc) and methodological factors (ie, H-coil design, dTMS parameters, etc) which may contribute to dTMS efficacy, and thereby may assist clinicians in their decision to prescribe dTMS for specific psychiatric and cognitive disorders. TRIAL REGISTRATION: PROSPERO CRD42022360066; https://tinyurl.com/5ev6byrn. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/45213.

Examining the sustainability of effects of early childhood obesity prevention interventions: Follow-up of the EPOCH individual participant data prospective meta-analysis.

BACKGROUND: Although early childhood obesity prevention has become an important issue internationally, little evidence exists regarding longer term effects (i.e., sustainability) of early interventions. OBJECTIVE: To determine whether intervention benefits at 2 years of age were sustained at 3.5 and 5 years. METHODS: Follow-up of the Early Prevention of Obesity in Children (EPOCH) individual participant data prospective meta-analysis of four randomized controlled trials including 2196 mother-child dyads at baseline. Interventions were home- or community-based, commenced within 6 months of birth, ended by 2 years of age, and comprised multiple sessions. Controls received standard care. BMI z-score (primary outcome), other anthropometric measures and weight-related behaviours were initially measured at 1.5-2 years and followed up at 3.5 and 5 years. RESULTS: Positive intervention effects on BMI z-scores at 1.5-2 years of age were not apparent by 3.5 years (-0.04 adjusted mean difference; 95% CI:-0.14, 0.06; p = 0.424), and 5 years (0.03; 95% CI: -0.08, 0.14; p = 0.60). While prolonged intervention benefits were detected for a few, but not the majority of, weight-related behaviours at 3.5 years, these effects diminished over time. CONCLUSION: This meta-analysis found that initial positive effects of childhood obesity interventions faded out after interventions ended, pointing toward the importance of a suite of interventions implemented at multiple stages across childhood.

Convalescent plasma therapy for COVID-19 patients: a protocol of a prospective meta-analysis of randomized controlled trials.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an infection with possible serious consequences. The plasma of recovered patients might serve as treatment, which we aim to assess in the form of a prospective meta-analysis focusing on mortality, multi-organ failure, duration of intensive care unit stay, and adverse events. METHODS: A systematic search was conducted to find relevant registered randomized controlled trials in five trial registries. A comprehensive search will be done continuously on a monthly basis in MEDLINE (via PubMed), Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science to find the results of previously registered randomized controlled trials. The selection will be done by two independent authors. Data extraction will be carried out by two other independent reviewers. Disagreements will be resolved by a third investigator. An update of the search of the registries and the first search of the databases will be done on the 21st of July. Data synthesis will be performed following the recommendations of the Cochrane Collaboration. In the case of dichotomous outcomes (mortality and organ failure), we will calculate pooled risk ratios with a 95% confidence interval (CI) from two-by-two tables (treatment Y/N, outcome Y/N). Data from models with multivariate adjustment (hazard ratios, odds ratio, risk ratio) will be preferred for the analysis. P less than 0.05 will be considered statistically significant. In the case of ICU stay, weighted mean difference with a 95% confidence interval will be calculated. Heterogeneity will be tested with I2, and χ2 tests. Meta-analysis will be performed if at least 3 studies report on the same outcome and population. DISCUSSION: Convalescent plasma therapy is a considerable alternative in COVID-19, which we aim to investigate in a prospective meta-analysis.

Quantifying the advantages of conducting a prospective meta-analysis (PMA): a case study of early childhood obesity prevention.

BACKGROUND: For prospective meta-analyses (PMAs), eligible studies are identified, and the PMA hypotheses, selection criteria, and analysis methods are pre-specified before the results of any of the studies are known. This reduces publication bias and selective outcome reporting and provides a unique opportunity for outcome standardisation/harmonisation. We conducted a world-first PMA of four trials investigating interventions to prevent early childhood obesity. The aims of this study were to quantitatively analyse the effects of prospective planning on variations across trials, outcome harmonisation, and the power to detect intervention effects, and to derive recommendations for future PMA. METHODS: We examined intervention design, participant characteristics, and outcomes collected across the four trials included in the EPOCH PMA using their registration records, protocol publications, and variable lists. The outcomes that trials planned to collect prior to inclusion in the PMA were compared to the outcomes that trials collected after PMA inclusion. We analysed the proportion of matching outcome definitions across trials, the number of outcomes per trial, and how collaboration increased the statistical power to detect intervention effects. RESULTS: The included trials varied in intervention design and participants, this improved external validity and the ability to perform subgroup analyses for the meta-analysis. While individual trials had limited power to detect the main intervention effect (BMI z-score), synthesising data substantially increased statistical power. Prospective planning led to an increase in the number of collected outcome categories (e.g. weight, child's diet, sleep), and greater outcome harmonisation. Prior to PMA inclusion, only 18% of outcome categories were included in all trials. After PMA inclusion, this increased to 91% of outcome categories. However, while trials mostly collected the same outcome categories after PMA inclusion, some inconsistencies in how the outcomes were measured remained (such as measuring physical activity by hours of outside play versus using an activity monitor). CONCLUSION: Prospective planning led to greater outcome harmonisation and greater power to detect intervention effects, while maintaining acceptable variation in trial designs and populations, which improved external validity. Recommendations for future PMA include more detailed harmonisation of outcome measures and careful pre-specification of analyses to avoid research waste by unnecessary over-collection of data.

Interventions commenced by early infancy to prevent childhood obesity-The EPOCH Collaboration: An individual participant data prospective meta-analysis of four randomized controlled trials.

BACKGROUND: Childhood obesity is a significant global problem. Childhood obesity prevention interventions may be more effective when started very early in life before metabolic and behavioural patterns are established. METHODS AND FINDINGS: A prospectively planned, individual participant data meta-analysis of four randomized controlled trials. Participants were first-time mothers of term infants. Trial interventions commenced during pregnancy or early infancy and comprised education and support delivered via group sessions and/or home visits. Control group families accessed existing local well-child health care. The primary outcome was body mass index (BMI) z score at 18 to 24 months; 2196 mother-child dyads were available for analysis. Intervention children had lower BMI z scores at 18 to 24 months than control children (-0.12 adjusted mean; 95% confidence interval, -0.22 to -0.02, P = .017). There was some evidence that the BMI z score reduction was greater in settings with limited well-child health care programmes (interaction P value = .03). Improvements were also detected in television viewing time, feeding practices, and breastfeeding duration. CONCLUSIONS: Parent-focused intervention programmes that commence by early infancy and which aim to establish a trajectory of healthy lifestyle behaviours produced a modest but statistically significant reduction in BMI z score, which if replicated on a wider scale may have important public health implications.

Understanding, comparing and learning from the four EPOCH early childhood obesity prevention interventions: A multi-methods study.

BACKGROUND: Childhood obesity is a global problem. Early obesity prevention interventions are complex and differ in effectiveness. Novel frameworks, taxonomies and experience from the Early Prevention of Obesity in CHildren (EPOCH) trials were applied to unpack interventions. OBJECTIVES: Deconstruct interventions into their components (target behaviours, delivery features and behaviour change techniques [BCTs]). Identify lessons learned and future recommendations for intervention planning, delivery, evaluation and implementation. METHODS: This multi-methods study deconstructed the four EPOCH interventions into target behaviours, delivery features and BCTs from unpublished and published materials using systematic frameworks. Additionally, semi-structured interviews were conducted with intervention facilitators and principal investigators. RESULTS: Each trial targeted between 10 and 14 obesity-related behaviours. Key variations in delivery features related to intensity, delivery mode and tailoring. BCTs consistently used across trials included goal-setting, social support, shaping knowledge, role-modelling and credible source. Recommendations from interview analyses include the importance of stakeholder collaboration and consideration of implementation throughout the study process. CONCLUSIONS: The combination of frameworks, methodologies and interviews used in this study is a major step towards understanding complex early obesity prevention interventions. Future work will link systematic intervention deconstruction with quantitative models to identify which intervention components are most effective and for whom.

Systematic review and network meta-analysis with individual participant data on cord management at preterm birth (iCOMP): study protocol.

INTRODUCTION: Timing of cord clamping and other cord management strategies may improve outcomes at preterm birth. However, it is unclear whether benefits apply to all preterm subgroups. Previous and current trials compare various policies, including time-based or physiology-based deferred cord clamping, and cord milking. Individual participant data (IPD) enable exploration of different strategies within subgroups. Network meta-analysis (NMA) enables comparison and ranking of all available interventions using a combination of direct and indirect comparisons. OBJECTIVES: (1) To evaluate the effectiveness of cord management strategies for preterm infants on neonatal mortality and morbidity overall and for different participant characteristics using IPD meta-analysis. (2) To evaluate and rank the effect of different cord management strategies for preterm births on mortality and other key outcomes using NMA. METHODS AND ANALYSIS: Systematic searches of Medline, Embase, clinical trial registries, and other sources for all ongoing and completed randomised controlled trials comparing cord management strategies at preterm birth (before 37 weeks' gestation) have been completed up to 13 February 2019, but will be updated regularly to include additional trials. IPD will be sought for all trials; aggregate summary data will be included where IPD are unavailable. First, deferred clamping and cord milking will be compared with immediate clamping in pairwise IPD meta-analyses. The primary outcome will be death prior to hospital discharge. Effect differences will be explored for prespecified participant subgroups. Second, all identified cord management strategies will be compared and ranked in an IPD NMA for the primary outcome and the key secondary outcomes. Treatment effect differences by participant characteristics will be identified. Inconsistency and heterogeneity will be explored. ETHICS AND DISSEMINATION: Ethics approval for this project has been granted by the University of Sydney Human Research Ethics Committee (2018/886). Results will be relevant to clinicians, guideline developers and policy-makers, and will be disseminated via publications, presentations and media releases. REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12619001305112) and International Prospective Register of Systematic Reviews (PROSPERO, CRD42019136640).

Meta-analysis of Oxygenation Saturation Targeting Trials: Do Infant Subgroups Matter?

Participant data from approximately 5000 infants have been meta-analyzed to guide oxygen saturation policy for extremely preterm infants. The Neonatal Oxygenation Prospective Meta-analysis showed that targeting a higher oxygen saturation range compared with a lower range resulted in decreased death and necrotizing enterocolitis and no difference in major disability but increased treated retinopathy of prematurity (ROP) and supplemental oxygen use at 36 weeks' postmenstrual age. The 91% to 95% range can be recommended for all extremely preterm infants from birth but should be accompanied by stringent surveillance for the prevention and early treatment of ROP.

Are there educational disparities in health and functioning among the oldest old? Evidence from the Nordic countries.

With the ageing of the population and recent pressures on important welfare state arrangements, updated knowledge on the linkage between socioeconomic status and health in old age is pertinent for shedding light on emerging patterns of health inequalities in the Nordic countries. This study examined self-rated health (SRH), mobility and activities of daily living (ADL) according to level of education in the three oldest old age groups 75-84, 85-94, and 95+, in four Nordic countries. Altogether, 6132 individuals from Danish Longitudinal Study of Ageing, Norwegian Life Course, Ageing and Generation study, Swedish Panel Study of Living Conditions of the Oldest Old, the 5-Country Oldest Old (Sweden) and Vitality 90 + Study were analysed. First, associations of education level with SRH, mobility, and ADL were estimated for each individual study by means of age- and gender-adjusted logistic regression. Second, results from individual studies were synthesized in a meta-analysis. Older adults with higher education level were more likely to report good SRH, and they were more often independent in mobility and ADL than those with basic education when all age groups were combined. In mobility and ADL, differences between education groups remained stable across the age groups but for SRH, differences seemed to be weaker in older ages. With only a few exceptions, in all age groups, individuals with higher education had more favourable health and functioning than those with basic education. This study shows remarkable persistence of health and functioning inequalities in the Nordic countries throughout later life.

VESPRO: An Individual Patient Data Prospective Meta-Analysis of Selective Internal Radiation Therapy Versus Sorafenib for Advanced, Locally Advanced, or Recurrent Hepatocellular Carcinoma of the SARAH and SIRveNIB Trials.

BACKGROUND: Untreated advanced hepatocellular carcinoma (HCC) has an overall poor prognosis. Currently there are 2 ongoing prospective randomized controlled trials that are evaluating the efficacy and safety of sorafenib and selective internal radiation therapy (SIRT) with yttrium-90 resin microspheres in patients with advanced HCC. The SorAfenib versus Radioembolisation in Advanced Hepatocellular carcinoma (SARAH; 459 patients) trial is being performed in Europe and the SIRt VErsus SorafeNIB (SIRveNIB; 360 patients) trial in the Asia Pacific region. Prospectively combining the results, these trials will not only allow for increased precision to estimate efficacy (in terms of survival), but will also provide increased statistical power for subgroup analyses. OBJECTIVE: To ensure the prospectivity and transparency of the meta-analysis. METHODS: The sirVEnib and SARAH merge PROject (VESPRO) is an individual, patient-data prospective meta-analysis of the SIRveNIB and SARAH randomized trials. The VESPRO protocol includes prespecified hypotheses, inclusion criteria, and outcome measures. The primary outcome measure is overall survival and secondary outcomes include tumor response rate, progression-free survival, progression in the liver as first event, and disease control in the liver. Pooling of toxicity results will allow for robust safety profiles to be established for both therapies, and provides increased statistical power to investigate treatment effects in key subgroups. Analyses will be performed in the intent-to-treat population stratified by trial. RESULTS: Both studies are expected to demonstrate a survival benefit for SIRT together with a better toxicity profile compared with sorafenib. It is also anticipated that liver progression as the first event would be longer in the intervention compared with the control. CONCLUSIONS: As the results of the 2 trials are not yet known, the methodological strength is enhanced, as biases inherent in conventional meta-analyses are avoided. This has the effect of providing this meta-analysis with the advantages of a single, large,randomized study of 819 patients. It is anticipated that the SARAH and SIRveNIB trial results will be published separately and together with the combined meta-analysis results from VESPRO. The combined dataset will allow the effect of the interventions to be explored with improved reliability/precision with respect to prespecified patient and intervention-level characteristics. TRIAL REGISTRATION: Australian New Zealand Trials Registry: ACTRN12617000030370.