Exercise-based cardiac rehabilitation for adults with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, disrupts the heart's rhythm through numerous small re-entry circuits in the atrial tissue, leading to irregular atrial contractions. The condition poses significant health risks, including increased stroke risk, heart failure, and reduced quality of life. Given the complexity of AF and its growing incidence globally, exercise-based cardiac rehabilitation (ExCR) may provide additional benefits for people with AF or those undergoing routine treatment for the condition. OBJECTIVES: To assess the benefits and harms of ExCR compared with non-exercise controls for people who currently have AF or who have been treated for AF. SEARCH METHODS: We searched the following electronic databases: CENTRAL in the Cochrane Library, MEDLINE Ovid, Embase Ovid, PsycINFO Ovid, Web of Science Core Collection Thomson Reuters, CINAHL EBSCO, LILACS BIREME, and two clinical trial registers on 24 March 2024. We imposed no language restrictions. SELECTION CRITERIA: We included randomised clinical trials (RCTs) that investigated ExCR interventions compared with any type of non-exercise control. We included adults 18 years of age or older with any subtype of AF or those who had received treatment for AF. DATA COLLECTION AND ANALYSIS: Five review authors independently screened and extracted data in duplicate. We assessed risk of bias using Cochrane's RoB 1 tool as outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We assessed clinical and statistical heterogeneity by visual inspection of the forest plots and by using standard Chi² and I² statistics. We performed meta-analyses using random-effects models for continuous and dichotomised outcomes. We calculated standardised mean differences where different scales were used for the same outcome. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included 20 RCTs involving a total of 2039 participants with AF. All trials were conducted between 2006 and 2024, with a follow-up period ranging from eight weeks to five years. We assessed the certainty of evidence as moderate to very low. Five trials assessed comprehensive ExCR programmes, which included educational or psychological interventions, or both; the remaining 15 trials compared exercise-only cardiac rehabilitation with controls. The overall risk of bias in the included studies was mixed. Details on random sequence generation, allocation concealment, and use of intention-to-treat analysis were typically poorly reported. Evidence from nine trials (n = 1173) suggested little to no difference in mortality between ExCR and non-exercise controls (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.76 to 1.49; I² = 0%; 101 deaths; low-certainty evidence). Based on evidence from 10 trials (n = 825), ExCR may have little to no effect on SAEs (RR 1.30, 95% CI 0.63 to 2.67; I² = 0%; 28 events; low-certainty evidence). Evidence from four trials (n = 378) showed that ExCR likely reduced AF recurrence (measured via Holter monitoring) compared to controls (RR 0.70, 95% CI 0.56 to 0.88; I² = 2%; moderate-certainty evidence). ExCR may reduce AF symptom severity (mean difference (MD) -1.59, 95% CI -2.98 to -0.20; I² = 61%; n = 600; low-certainty evidence); likely reduces AF symptom burden (MD -1.61, 95% CI -2.76 to -0.45; I² = 0%; n = 317; moderate-certainty evidence); may reduce AF episode frequency (MD -1.29, 95% CI -2.50 to -0.07; I² = 75%; n = 368; low-certainty evidence); and likely reduces AF episode duration (MD -0.58, 95% CI -1.14 to -0.03; I² = 0%; n = 317; moderate-certainty evidence), measured via the AF Severity Scale (AFSS) questionnaire. Moderate-certainty evidence from six trials (n = 504) showed that ExCR likely improved the mental component summary measure in health-related quality of life (HRQoL) of the 36-item Short Form Health Survey (SF-36) (MD 2.66, 95% CI 1.22 to 4.11; I² = 2%), but the effect of ExCR on the physical component summary measure was very uncertain (MD 1.75, 95% CI -0.31 to 3.81; I² = 52%; very low-certainty evidence). ExCR also may improve individual components of HRQoL (general health, vitality, emotional role functioning, and mental health) and exercise capacity (peak oxygen uptake (VO2peak) and 6-minute walk test) following ExCR. The effects of ExCR on serious adverse events and exercise capacity were consistent across different models of ExCR delivery: centre compared to home-based, exercise dose, exercise only compared to comprehensive programmes, and aerobic training alone compared to aerobic plus resistance programmes. Using univariate meta-regression, there was evidence of significant association between location of trial and length of longest follow-up on exercise capacity. AUTHORS' CONCLUSIONS: Due to few randomised participants and typically short-term follow-up, the impact of ExCR on all-cause mortality or serious adverse events for people with AF is uncertain. ExCR likely improves AF-specific measures including reduced AF recurrence, symptom burden, and episode duration, as well as the mental components of HRQoL. ExCR may improve AF symptom severity, episode frequency, and VO2peak. Future high-quality RCTs are needed to assess the benefits of ExCR for people with AF on patient-relevant outcomes including AF symptom severity and burden, AF recurrence, AF-specific quality of life, and clinical events such as mortality, readmissions, and serious adverse events. High-quality trials are needed to investigate how AF subtype and clinical setting (i.e. primary and secondary care) may influence ExCR effectiveness.

Major mistakes or errors in the use of trial sequential analysis in systematic reviews or meta-analyses - the METSA systematic review.

BACKGROUND: Systematic reviews and data synthesis of randomised clinical trials play a crucial role in clinical practice, research, and health policy. Trial sequential analysis can be used in systematic reviews to control type I and type II errors, but methodological errors including lack of protocols and transparency are cause for concern. We assessed the reporting of trial sequential analysis. METHODS: We searched Medline and the Cochrane Database of Systematic Reviews from 1 January 2018 to 31 December 2021 for systematic reviews and meta-analysis reports that include a trial sequential analysis. Only studies with at least two randomised clinical trials analysed in a forest plot and a trial sequential analysis were included. Two independent investigators assessed the studies. We evaluated protocolisation, reporting, and interpretation of the analyses, including their effect on any GRADE evaluation of imprecision. RESULTS: We included 270 systematic reviews and 274 meta-analysis reports and extracted data from 624 trial sequential analyses. Only 134/270 (50%) systematic reviews planned the trial sequential analysis in the protocol. For analyses on dichotomous outcomes, the proportion of events in the control group was missing in 181/439 (41%), relative risk reduction in 105/439 (24%), alpha in 30/439 (7%), beta in 128/439 (29%), and heterogeneity in 232/439 (53%). For analyses on continuous outcomes, the minimally relevant difference was missing in 125/185 (68%), variance (or standard deviation) in 144/185 (78%), alpha in 23/185 (12%), beta in 63/185 (34%), and heterogeneity in 105/185 (57%). Graphical illustration of the trial sequential analysis was present in 93% of the analyses, however, the Z-curve was wrongly displayed in 135/624 (22%) and 227/624 (36%) did not include futility boundaries. The overall transparency of all 624 analyses was very poor in 236 (38%) and poor in 173 (28%). CONCLUSIONS: The majority of trial sequential analyses are not transparent when preparing or presenting the required parameters, partly due to missing or poorly conducted protocols. This hampers interpretation, reproducibility, and validity. STUDY REGISTRATION: PROSPERO CRD42021273811.

Beneficial and harmful effects of tricyclic antidepressants for adults with major depressive disorder: a systematic review with meta-analysis and trial sequential analysis.

QUESTION: Tricyclic antidepressants are used to treat depression worldwide, but the adverse effects have not been systematically assessed. Our objective was to assess the beneficial and harmful effects of all tricyclic antidepressants for adults with major depressive disorder. STUDY SELECTION AND ANALYSIS: We conducted a systematic review with meta-analysis and trial sequential analysis. We searched CENTRAL, MEDLINE, Embase, LILACS and other sources from inception to January 2023 for randomised clinical trials comparing tricyclic antidepressants versus placebo or 'active placebo' for adults with major depressive disorder. The primary outcomes were depressive symptoms measured on the 17-item Hamilton Depression Rating Scale (HDRS-17), serious adverse events and quality of life. The minimal important difference was defined as three points on the HDRS-17. FINDINGS: We included 103 trials randomising 10 590 participants. All results were at high risk of bias, and the certainty of the evidence was very low or low. All trials only assessed outcomes at the end of the treatment period at a maximum of 12 weeks after randomisation. Meta-analysis and trial sequential analysis showed evidence of a beneficial effect of tricyclic antidepressants compared with placebo (mean difference -3.77 HDRS-17 points; 95% CI -5.91 to -1.63; 17 trials). Meta-analysis showed evidence of a harmful effect of tricyclic antidepressants compared with placebo on serious adverse events (OR 2.78; 95% CI 2.18 to 3.55; 35 trials), but the required information size was not reached. Only 2 out of 103 trials reported on quality of life and t-tests showed no evidence of a difference. CONCLUSIONS: The long-term effects of tricyclic antidepressants and the effects on quality of life are unknown. Short-term results suggest that tricyclic antidepressants may reduce depressive symptoms while also increasing the risks of serious adverse events, but these results were based on low and very low certainty evidence. PROSPERO REGISTRATION NUMBER: CRD42021226161.

Ketamine for Critically Ill Patients with Severe Acute Brain Injury: A Systematic Review with Meta-analysis and Trial Sequential Analysis of Randomized Clinical Trials.

BACKGROUND: Patients with severe acute brain injury have a high risk of a poor clinical outcome due to primary and secondary brain injury. Ketamine reportedly inhibits cortical spreading depolarization, an electrophysiological phenomenon that has been associated with secondary brain injury, making ketamine potentially attractive for patients with severe acute brain injury. The aim of this systematic review is to explore the current literature regarding ketamine for patients with severe acute brain injury. METHODS: We systematically searched international databases for randomized clinical trials comparing ketamine by any regimen versus placebo, no intervention, or any control drug for patients with severe acute brain injury. Two authors independently reviewed and selected trials for inclusion, extracted data, assessed risk of bias, and performed analysis using Review Manager and Trial Sequential Analysis. Evidence certainty was assessed using Grading of Recommendations Assessment, Development and Evaluation. The primary outcomes were the proportion of participants with an unfavorable functional outcome, the proportion of participants with one or more serious adverse events, and quality of life. RESULTS: We identified five randomized trials comparing ketamine versus sufentanil, fentanyl, other sedatives, or saline (total N = 149 participants). All outcomes were at overall high risk of bias. The proportions of participants with one or more serious adverse events did not differ between ketamine and sufentanil or fentanyl (relative risk 1.45, 95% confidence interval 0.81-2.58; very low certainty). Trial sequential analysis showed that further trials are needed. CONCLUSIONS: The level of evidence regarding the effects of ketamine on functional outcome and serious adverse events in patients with severe acute brain injury is very low. Ketamine may markedly, modestly, or not at all affect these outcomes. Large randomized clinical trials at low risk of bias are needed.

Prompt closure versus gradual weaning of external ventricular drain for hydrocephalus following aneurysmal subarachnoid haemorrhage: a statistical analysis plan for the DRAIN randomised clinical trial.

BACKGROUND: Insertion of an external ventricular drain (EVD) is a first-line treatment of acute hydrocephalus caused by aneurysmal subarachnoid haemorrhage (aSAH). Once the patient is clinically stable, the EVD is either removed or replaced by a permanent internal shunt. The optimal strategy for cessation of the EVD is unknown. Prompt closure carries a risk of acute hydrocephalus or redundant shunt implantations, whereas gradual weaning may increase the risk of EVD-related infections. METHODS: DRAIN (Danish RAndomised Trial of External Ventricular Drainage Cessation IN Aneurysmal Subarachnoid Haemorrhage) is an international multicentre randomised clinical trial comparing prompt closure versus gradual weaning of the EVD after aSAH. The primary outcome is a composite of VP-shunt implantation, all-cause mortality, or EVD-related infection. Secondary outcomes are serious adverse events excluding mortality and health-related quality of life (EQ-5D-5L). Exploratory outcomes are modified Rankin Scale, Fatigue Severity Scale, Glasgow Outcome Scale Extended, and length of stay in the neurointensive care unit and hospital. Outcome assessment will be performed 6 months after ictus. Based on the sample size calculation (event proportion 80% in the gradual weaning group, relative risk reduction 20%, alpha 5%, power 80%), 122 participants are required in each intervention group. Outcome assessment for the primary outcome, statistical analyses, and conclusion drawing will be blinded. Two independent statistical analyses and reports will be tracked using a version control system, and both will be published. Based on the final statistical report, the blinded steering group will formulate two abstracts. CONCLUSION: We present a pre-defined statistical analysis plan for the randomised DRAIN trial, which limits bias, p-hacking, and data-driven interpretations. This statistical analysis plan is accompanied by tables with simulated data, which increases transparency and reproducibility. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03948256. Registered on May 13, 2019.

Adverse effects with semaglutide: a protocol for a systematic review with meta-analysis and trial sequential analysis.

INTRODUCTION: Semaglutide is increasingly used for the treatment of type 2 diabetes mellitus, overweight and other conditions. It is well known that semaglutide lowers blood glucose levels and leads to significant weight loss. Still, a systematic review has yet to investigate the adverse effects with semaglutide for all patient groups. METHODS AND ANALYSIS: We will conduct a systematic review and search major medical databases (Cochrane Central Register of Controlled Trials, Medline, Embase, Latin American and Caribbean Health Sciences Literature, Science Citation Index Expanded, Conference Proceedings Citation Index-Science) and clinical trial registries from their inception and onwards to identify relevant randomised clinical trials. We expect to conduct the literature search in July 2024. Two review authors will independently extract data and perform risk-of-bias assessments. We will include randomised clinical trials comparing oral or subcutaneous semaglutide versus placebo. Primary outcomes will be all-cause mortality and serious adverse events. Secondary outcomes will be myocardial infarction, stroke, all-cause hospitalisation and non-serious adverse events. Data will be synthesised by meta-analyses and trial sequential analysis; risk of bias will be assessed with Cochrane Risk of Bias tool-version 2, an eight-step procedure will be used to assess if the thresholds for statistical and clinical significance are crossed, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations. ETHICS AND DISSEMINATION: This protocol does not present any results. Findings of this systematic review will be published in international peer-reviewed scientific journals. PROSPERO REGISTRATION NUMBER: CRD42024499511.

Heterologous versus homologous COVID-19 booster vaccinations for adults: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials.

BACKGROUND: To combat coronavirus disease 2019 (COVID-19), booster vaccination strategies are important. However, the optimal administration of booster vaccine platforms remains unclear. Herein, we aimed to assess the benefits and harms of three or four heterologous versus homologous booster regimens. METHODS: From November 3 2022 to December 21, 2023, we searched five databases for randomised clinical trials (RCT). Reviewers screened, extracted data, and assessed bias risks independently with the Cochrane risk-of-bias 2 tool. We conducted meta-analyses and trial sequential analyses (TSA) on our primary (all-cause mortality; laboratory confirmed symptomatic and severe COVID-19; serious adverse events [SAE]) and secondary outcomes (quality of life [QoL]; adverse events [AE] considered non-serious). We assessed the evidence with the GRADE approach. Subgroup analyses were stratified for trials before and after 2023, three or four boosters, immunocompromised status, follow-up, risk of bias, heterologous booster vaccine platforms, and valency of booster. RESULTS: We included 29 RCTs with 43 comparisons (12,538 participants). Heterologous booster regimens may not reduce the relative risk (RR) of all-cause mortality (11 trials; RR 0.86; 95% CI 0.33 to 2.26; I2 0%; very low certainty evidence); laboratory-confirmed symptomatic COVID-19 (14 trials; RR 0.95; 95% CI 0.72 to 1.25; I2 0%; very low certainty); or severe COVID-19 (10 trials; RR 0.51; 95% CI 0.20 to 1.33; I2 0%; very low certainty). For safety outcomes, heterologous booster regimens may have no effect on SAE (27 trials; RR 1.15; 95% CI 0.68 to 1.95; I2 0%; very low certainty) but may raise AE considered non-serious (20 trials; RR 1.19; 95% CI 1.08 to 1.32; I2 64.4%; very low certainty). No data on QoL was available. Our TSAs showed that the cumulative Z curves did not reach futility for any outcome. CONCLUSIONS: With our current sample sizes, we were not able to infer differences of effects for any outcomes, but heterologous booster regimens seem to cause more non-serious AE. Furthermore, more robust data are instrumental to update this review.

Effects of primary or secondary prevention with vitamin A supplementation on clinically important outcomes: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.

OBJECTIVES: This systematic review with meta-analyses of randomised trials evaluated the preventive effects of vitamin A supplements versus placebo or no intervention on clinically important outcomes, in people of any age. METHODS: We searched different electronic databases and other resources for randomised clinical trials that had compared vitamin A supplements versus placebo or no intervention (last search 16 April 2024). We used Cochrane methodology. We used the random-effects model to calculate risk ratios (RRs), with 95% CIs. We analysed individually and cluster randomised trials separately. Our primary outcomes were mortality, adverse events and quality of life. We assessed risks of bias in the trials and used Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) to assess the certainty of the evidence. RESULTS: We included 120 randomised trials (1 671 672 participants); 105 trials allocated individuals and 15 allocated clusters. 92 trials included children (78 individually; 14 cluster randomised) and 28 adults (27 individually; 1 cluster randomised). 14/105 individually randomised trials (13%) and none of the cluster randomised trials were at overall low risk of bias. Vitamin A did not reduce mortality in individually randomised trials (RR 0.99, 95% CI 0.93 to 1.05; I²=32%; p=0.19; 105 trials; moderate certainty), and this effect was not affected by the risk of bias. In individually randomised trials, vitamin A had no effect on mortality in children (RR 0.96, 95% CI 0.88 to 1.04; I²=24%; p=0.28; 78 trials, 178 094 participants) nor in adults (RR 1.04, 95% CI 0.97 to 1.13; I²=24%; p=0.27; 27 trials, 61 880 participants). Vitamin A reduced mortality in the cluster randomised trials (0.84, 95% CI 0.76 to 0.93; I²=66%; p=0.0008; 15 trials, 14 in children and 1 in adults; 364 343 participants; very low certainty). No trial reported serious adverse events or quality of life. Vitamin A slightly increased bulging fontanelle of neonates and infants. We are uncertain whether vitamin A influences blindness under the conditions examined. CONCLUSIONS: Based on moderate certainty of evidence, vitamin A had no effect on mortality in the individually randomised trials. Very low certainty evidence obtained from cluster randomised trials suggested a beneficial effect of vitamin A on mortality. If preventive vitamin A programmes are to be continued, supporting evidence should come from randomised trials allocating individuals and assessing patient-meaningful outcomes. PROSPERO REGISTRATION NUMBER: CRD42018104347.

Furosemide versus placebo for fluid overload in intensive care patients-The randomised GODIF trial second version: Statistical analysis plan.

BACKGROUND: Fluid overload is associated with increased mortality in intensive care unit (ICU) patients. The GODIF trial aims to assess the benefits and harms of fluid removal with furosemide versus placebo in stable adult patients with moderate to severe fluid overload in the ICU. This article describes the detailed statistical analysis plan for the primary results of the second version of the GODIF trial. METHODS: The GODIF trial is an international, multi-centre, randomised, stratified, blinded, parallel-group, pragmatic clinical trial, allocating 1000 adult ICU patients with moderate to severe fluid overload 1:1 to furosemide versus placebo. The primary outcome is days alive and out of hospital within 90 days post-randomisation. With a power of 90% and an alpha level of 5%, we may reject or detect an improvement of 8%. The primary analyses of all outcomes will be performed in the intention-to-treat population. For the primary outcome, the Kryger Jensen and Lange method will be used to compare the two treatment groups adjusted for stratification variables supplemented with sensitivity analyses in the per-protocol population and with further adjustments for prognostic variables. Secondary outcomes will be analysed with multiple linear regressions, logistic regressions or the Kryger Jensen and Lange method as suitable with adjustment for stratification variables. CONCLUSION: The GODIF trial data will increase the certainty about the effects of fluid removal using furosemide in adult ICU patients with fluid overload. TRIAL REGISTRATIONS: EudraCT identifier: 2019-004292-40 and ClinicalTrials.org: NCT04180397.

Concentrations, Number of Doses, and Formulations of Aluminium Adjuvants in Vaccines: A Systematic Review with Meta-Analysis and Trial Sequential Analysis of Randomized Clinical Trials.

Aluminium adjuvants are commonly used in vaccines to boost the effects of vaccination. Here, we assessed the benefits and harms of different aluminium adjuvants vs. other aluminium adjuvants or vs. the same aluminium adjuvant at other concentrations, administered a different number of doses, or at different particle sizes used in vaccines or vaccine excipients. We conducted a systematic review with meta-analysis and Trial Sequential Analysis to assess the certainty of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). We obtained data from major medical databases until 20 January 2023 and included 10 randomized clinical trials of healthy volunteers. The comparisons assessed higher vs. lower aluminium adjuvant concentrations; higher vs. lower number of doses of aluminium adjuvant; and aluminium phosphate adjuvant vs. aluminium hydroxide adjuvant. For all three comparisons, meta-analyses showed no evidence of a difference on all-cause mortality, serious adverse events, and adverse events considered non-serious. The certainty of evidence was low to very low. None of the included trials reported on quality of life or proportion of participants who developed the disease being vaccinated against. The benefits and harms of different types of aluminium adjuvants, different aluminium concentrations, different number of doses, or different particle sizes, therefore, remain uncertain.

Detailed statistical analysis plan for a secondary Bayesian analysis of the SafeBoosC-III trial: a multinational, randomised clinical trial assessing treatment guided by cerebral oximetry monitoring versus usual care in extremely preterm infants.

BACKGROUND: Extremely preterm infants have a high mortality and morbidity. Here, we present a statistical analysis plan for secondary Bayesian analyses of the pragmatic, sufficiently powered multinational, trial-SafeBoosC III-evaluating the benefits and harms of cerebral oximetry monitoring plus a treatment guideline versus usual care for such infants. METHODS: The SafeBoosC-III trial is an investigator-initiated, open-label, randomised, multinational, pragmatic, phase III clinical trial with a parallel-group design. The trial randomised 1601 infants, and the frequentist analyses were published in April 2023. The primary outcome is a dichotomous composite outcome of death or severe brain injury. The exploratory outcomes are major neonatal morbidities associated with neurodevelopmental impairment later in life: (1) bronchopulmonary dysplasia; (2) retinopathy of prematurity; (3) late-onset sepsis; (4) necrotising enterocolitis; and (5) number of major neonatal morbidities (count of bronchopulmonary dysplasia, retinopathy of prematurity, and severe brain injury). The primary Bayesian analyses will use non-informed priors including all plausible effects. The models will use a Hamiltonian Monte Carlo sampler with 1 chain, a sampling of 10,000, and at least 25,000 iterations for the burn-in period. In Bayesian statistics, such analyses are referred to as 'posteriors' and will be presented as point estimates with 95% credibility intervals (CrIs), encompassing the most probable results based on the data, model, and priors selected. The results will be presented as probability of any benefit or any harm, Bayes factor, and the probability of clinical important benefit or harm. Two statisticians will analyse the blinded data independently following this protocol. DISCUSSION: This statistical analysis plan presents a secondary Bayesian analysis of the SafeBoosC-III trial. The analysis and the final manuscript will be carried out and written after we publicise the primary frequentist trial report. Thus, we can interpret the findings from both the frequentists and Bayesian perspective. This approach should provide a better foundation for interpreting of our findings. TRIAL REGISTRATION: ClinicalTrials.org, NCT03770741. Registered on 10 December 2018.

Critical reading of articles on randomised clinical trials.

The randomised clinical trial is the most reliable study design to compare the effects of different interventions, however, the methodological quality of randomised clinical trials varies. In this review, the central considerations for critically appraising a randomised clinical trial are described along with an example, terminological references, description of design variants and reporting guidelines and appraisal tools. This review aims at helping clinicians and other users of randomised clinical trials to assess the trustworthiness and relevance of trial results for their own practice.

The effects of cerebral oximetry in mechanically ventilated newborns: a protocol for the SafeBoosC-IIIv randomised clinical trial.

BACKGROUND: The SafeBoosC project aims to test the clinical value of non-invasive cerebral oximetry by near-infrared spectroscopy in newborn infants. The purpose is to establish whether cerebral oximetry can be used to save newborn infants' lives and brains or not. Newborns contribute heavily to total childhood mortality and neonatal brain damage is the cause of a large part of handicaps such as cerebral palsy. The objective of the SafeBoosC-IIIv trial is to evaluate the benefits and harms of cerebral oximetry added to usual care versus usual care in mechanically ventilated newborns. METHODS/DESIGN: SafeBoosC-IIIv is an investigator-initiated, multinational, randomised, pragmatic phase-III clinical trial. The inclusion criteria will be newborns with a gestational age more than 28 + 0 weeks, postnatal age less than 28 days, predicted to require mechanical ventilation for at least 24 h, and prior informed consent from the parents or deferred consent or absence of opt-out. The exclusion criteria will be no available cerebral oximeter, suspicion of or confirmed brain injury or disorder, or congenital heart disease likely to require surgery. A total of 3000 participants will be randomised in 60 neonatal intensive care units from 16 countries, in a 1:1 allocation ratio to cerebral oximetry versus usual care. Participants in the cerebral oximetry group will undergo cerebral oximetry monitoring during mechanical ventilation in the neonatal intensive care unit for as long as deemed useful by the treating physician or until 28 days of life. The participants in the cerebral oximetry group will be treated according to the SafeBoosC treatment guideline. Participants in the usual care group will not receive cerebral oximetry and will receive usual care. We use two co-primary outcomes: (1) a composite of death from any cause or moderate to severe neurodevelopmental disability at 2 years of corrected age and (2) the non-verbal cognitive score of the Parent Report of Children's Abilities-Revised (PARCA-R) at 2 years of corrected age. DISCUSSION: There is need for a randomised clinical trial to evaluate cerebral oximetry added to usual care versus usual care in mechanically ventilated newborns. TRIAL REGISTRATION: The protocol is registered at www. CLINICALTRIALS: gov (NCT05907317; registered 18 June 2023).

Cerebral oximetry monitoring versus usual care for extremely preterm infants: a study protocol for the 2-year follow-up of the SafeBoosC-III randomised clinical trial.

BACKGROUND: In the SafeBoosC-III trial, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth did not reduce the incidence of death or severe brain injury in extremely preterm infants at 36 weeks' postmenstrual age, as compared with usual care. Despite an association between severe brain injury diagnosed in the neonatal period and later neurodevelopmental disability, this relationship is not always strong. The objective of the SafeBoosC-III follow-up study is to assess mortality, neurodevelopmental disability, or any harm in trial participants at 2 years of corrected age. One important challenge is the lack of funding for local costs for a trial-specific assessment. METHODS: Of the 1601 infants randomised in the SafeBoosC-III trial, 1276 infants were alive at 36 weeks' postmenstrual age and will potentially be available for the 2-year follow-up. Inclusion criteria will be enrollment in a neonatal intensive care unit taking part in the follow-up study and parental consent if required by local regulations. We aim to collect data from routine follow-up programmes between the ages of 18 and 30 months of corrected age. If no routine follow-up has been conducted, we will collect informal assessments from other health care records from the age of at least 12 months. A local co-investigator blinded to group allocation will classify outcomes based on these records. We will supplement this with parental questionnaires including the Parent Report of Children's Abilities-Revised. There will be two co-primary outcomes: the composite of death or moderate or severe neurodevelopmental disability and mean Bayley-III/IV cognitive score. We will use a 3-tier model for prioritisation, based on the quality of data. This approach has been chosen to minimise loss to follow-up assuming that little data is better than no data at all. DISCUSSION: Follow-up at the age of 2 years is important for intervention trials in the newborn period as only time can show real benefits and harms later in childhood. To decrease the risk of generalisation and data-driven biased conclusions, we present a detailed description of the methodology for the SafeBoosC-III follow-up study. As funding is limited, a pragmatic approach is necessary. TRIAL REGISTRATION: ClinicalTrials.gov NCT05134116 . Registered on 24 November 2021.

Self-determination theory interventions versus usual care in people with diabetes: a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Autonomy-supporting interventions, such as self-determination theory and guided self-determination interventions, may improve self-management and clinical and psychosocial outcomes in people with diabetes. Such interventions have never been systematically reviewed assessing both benefits and harms and concurrently controlling the risks of random errors using trial sequential analysis methodology. This systematic review investigates the benefits and harms of self-determination theory-based interventions compared to usual care in people with diabetes. METHODS: We used the Cochrane methodology. Randomized clinical trials assessing interventions theoretically based on guided self-determination or self-determination theory in any setting were eligible. A comprehensive search (latest search April 2022) was undertaken in CENTRAL, MEDLINE, Embase, LILACS, PsycINFO, SCI-EXPANDED, CINAHL, SSCI, CPCI-S, and CPCI-SSH to identify relevant trials. Two authors independently screened, extracted data, and performed risk-of-bias assessment of included trials using the Cochrane risk-of-bias tool 1.0. Our primary outcomes were quality of life, all-cause mortality, and serious adverse events. Our secondary outcomes were diabetes distress, depressive symptoms, and nonserious adverse events not considered serious. Exploratory outcomes were glycated hemoglobin and motivation (autonomy, controlled, amotivation). Outcomes were assessed at the end of the intervention (primary time point) and at maximum follow-up. The analyses were conducted using Review Manager 5.4 and Trial Sequential Analysis 0.9.5.10. Certainty of the evidence was assessed by GRADE. RESULTS: Our search identified 5578 potentially eligible studies of which 11 randomized trials (6059 participants) were included. All trials were assessed at overall high risk of bias. We found no effect of self-determination theory-based interventions compared with usual care on quality of life (mean difference 0.00 points, 95% CI -4.85, 4.86, I2 = 0%; 225 participants, 3 trials, TSA-adjusted CI -11.83, 11.83), all-cause mortality, serious adverse events, diabetes distress, depressive symptoms, adverse events, glycated hemoglobulin A1c, or motivation (controlled). The certainty of the evidence was low to very low for all outcomes. We found beneficial effect on motivation (autonomous and amotivation; low certainty evidence). CONCLUSIONS: We found no effect of self-determination-based interventions on our primary or secondary outcomes. The evidence was of very low certainty. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020181144.

Adverse events in cognitive behavioral therapy and relaxation training for children and adolescents with obsessive-compulsive disorder: A mixed methods study and analysis plan for the TECTO trial.

Background: Knowledge on adverse events in psychotherapy for youth with OCD is sparse. No official guidelines exist for defining or monitoring adverse events in psychotherapy. Recent recommendations call for more qualitative and quantitative assessment of adverse events in psychotherapy trials. This mixed methods study aims to expand knowledge on adverse events in psychotherapy for youth with OCD. Methods: This is an analysis plan for a convergent mixed methods study within a randomized clinical trial (the TECTO trial). We include at least 128 youth aged 8-17 years with obsessive-compulsive disorder (OCD). Participants are randomized to either family-based cognitive behavioral therapy (FCBT) or family-based psychoeducation and relaxation training (FPRT). Adverse events are monitored quantitatively with the Negative Effects Questionnaire. Furthermore, we assess psychiatric symptoms, global functioning, quality of life, and family factors to investigate predictors for adverse events. We conduct semi-structured qualitative interviews with all youths and their parents on their experience of adverse events in FCBT or FPRT. For the mixed methods analysis, we will merge 1) a qualitative content analysis with descriptive statistics comparing the types, frequencies, and severity of adverse events; 2) a qualitative content analysis of the perceived causes for adverse events with prediction models for adverse events; and 3) a thematic analysis of the participants' treatment evaluation with a correlational analysis of adverse events and OCD severity. Discussion: The in-depth mixed methods analysis can inform 1) safer and more effective psychotherapy for OCD; 2) instruments and guidelines for monitoring adverse events; and 3) patient information on potential adverse events. The main limitation is risk of missing data. Trial registration: ClinicalTrials.gov identifier: NCT03595098. Registered on July 23, 2018.