Extracorporeal cardiopulmonary resuscitation versus standard treatment for refractory out-of-hospital cardiac arrest: a Bayesian meta-analysis.

BACKGROUND: The outcomes of several randomized trials on extracorporeal cardiopulmonary resuscitation (ECPR) in patients with refractory out-of-hospital cardiac arrest were examined using frequentist methods, resulting in a dichotomous interpretation of results based on p-values rather than in the probability of clinically relevant treatment effects. To determine such a probability of a clinically relevant ECPR-based treatment effect on neurological outcomes, the authors of these trials performed a Bayesian meta-analysis of the totality of randomized ECPR evidence. METHODS: A systematic search was applied to three electronic databases. Randomized trials that compared ECPR-based treatment with conventional CPR for refractory out-of-hospital cardiac arrest were included. The study was preregistered in INPLASY (INPLASY2023120060). The primary Bayesian hierarchical meta-analysis estimated the difference in 6-month neurologically favorable survival in patients with all rhythms, and a secondary analysis assessed this difference in patients with shockable rhythms (Bayesian hierarchical random-effects model). Primary Bayesian analyses were performed under vague priors. Outcomes were formulated as estimated median relative risks, mean absolute risk differences, and numbers needed to treat with corresponding 95% credible intervals (CrIs). The posterior probabilities of various clinically relevant absolute risk difference thresholds were estimated. RESULTS: Three randomized trials were included in the analysis (ECPR, n = 209 patients; conventional CPR, n = 211 patients). The estimated median relative risk of ECPR for 6-month neurologically favorable survival was 1.47 (95%CrI 0.73-3.32) with a mean absolute risk difference of 8.7% (- 5.0; 42.7%) in patients with all rhythms, and the median relative risk was 1.54 (95%CrI 0.79-3.71) with a mean absolute risk difference of 10.8% (95%CrI - 4.2; 73.9%) in patients with shockable rhythms. The posterior probabilities of an absolute risk difference > 0% and > 5% were 91.0% and 71.1% in patients with all rhythms and 92.4% and 75.8% in patients with shockable rhythms, respectively. CONCLUSION: The current Bayesian meta-analysis found a 71.1% and 75.8% posterior probability of a clinically relevant ECPR-based treatment effect on 6-month neurologically favorable survival in patients with all rhythms and shockable rhythms. These results must be interpreted within the context of the reported credible intervals and varying designs of the randomized trials. REGISTRATION: INPLASY (INPLASY2023120060, December 14th, 2023, https://doi.org/10.37766/inplasy2023.12.0060 ).

Impact of patient selection in clinical trials: application of ROCKET AF and ARISTOTLE criteria in GARFIELD-AF.

BACKGROUND: The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)-the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF-were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry. METHODS: Vitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA. RESULTS: Among patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs. CONCLUSION: Apixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials.

Comparison of the efficacy and safety of ciprofol and propofol in sedating patients in the operating room and outside the operating room: a meta-analysis and systematic review.

BACKGROUND: As a new type of intravenous anesthetic, ciprofol has the advantages of fast onset of action, fast recovery and high clearance rate. This study aimed to investigate the effectiveness and safety of ciprofol versus traditional propofol for anesthesia and sedation in and out of the operating room. METHODS: We searched the literature in PubMed, Web of Science, Cochrane Library, and Embase databases from January 2021 to December 2023. All clinical studies comparing the sedative effects of propofol and ciprofol, both inside and outside the operating room, were included in our trial. The main outcome measures were induction time and incidence of injection-site pain. Data are merged using risk ratio and standardized mean difference with 95% confidence interval. Subgroup analysis, meta-regression, sensitivity analysis, and publication bias were performed. The study protocol was prospectively registered with PROSPERO (CRD42023447747). RESULTS: A total of 15 randomized, controlled trials involving 2002 patients were included in this study. Compared with propofol, ciprofol has a longer induction time in the operating room but a shorter induction time in non-operating room settings. Ciprofol can effectively reduce the risk of injection-site pain and respiratory depression both inside and outside the operating room. In addition, the risk of drug-related hypotension induced with ciprofol in the operating room is lower, but the awakening time is also longer. Meta-regression analysis showed that neither age nor BMI were potential sources of heterogeneity. Funnel plot, egger and begg tests showed no significant publication bias. Sensitivity analyzes indicate that our results are robust and reliable. CONCLUSION: Ciprofol has absolute advantages in reducing the risk of injection-site pain and respiratory depression, both in and outside operating room. Intraoperative use of ciprofol reduces the risk of drug-related hypotension and may also reduce the risk of intraoperative physical movements. However, ciprofol may have longer induction and awakening time than propofol.

Study protocol for the MIND-PD study: a randomized controlled trial to investigate clinical and biological effects of mindfulness-based cognitive therapy in people with Parkinson's disease.

BACKGROUND: People with Parkinson's disease (PD) are very sensitive to the effects of stress. The prevalence of stress-related neuropsychiatric symptoms is high, and acute stress worsens motor symptoms. Animal studies suggest that chronic stress may accelerate disease progression, but evidence for this in humans is lacking. Mindfulness-based interventions (MBIs) train participants to focus on the present moment, on purpose and without judgement. Previous studies suggest that MBIs may alleviate stress and reduce depression and anxiety in PD. We aim to demonstrate the efficacy of Mindfulness-Based Cognitive Therapy (MBCT) as a non-pharmacologic treatment strategy for neuropsychiatric (and motor) symptoms in PD, and to identify the mechanisms underlying stress and stress reduction in PD. METHODS: In a prospective randomized controlled trial (RCT), we investigate whether 8 weeks of MBCT, as compared to care as usual, can reduce symptoms of anxiety and depression in people with PD. We aim to include 124 PD patients, who experience mild-moderate symptoms of anxiety and depression, are eligible for magnetic resonance imaging (MRI) and naïve to mindfulness, and who have a disease duration ≤ 10 years. Every participant is followed for 12 months. Clinical and biochemical assessments take place at baseline (T0), after 2 months (T1), and after 12 months (T2); MRI assessments take place at T0 and T2. Our primary outcome is the total score on the Hospital Anxiety and Depression Scale (HADS) at T1, while correcting for the HADS score at T0, age, and gender. Beyond testing the effects of MBCT on symptoms of anxiety and depression in PD, we explore whether MBCT: (1) has an effect on motor symptom severity, (2) influences cerebral and biochemical markers of stress, and (3) leads to a change in biomarkers of PD progression. DISCUSSION: MIND-PD is one of the first RCTs with a 1-year follow-up to investigate the effects of MBCT on symptoms of anxiety and depression in PD, and to explore possible mechanisms underlying stress and stress reduction in PD. Insight into these mechanisms can pave the way to new treatment methods in the future. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05779137. Registered on 12 January 2023.

Recruitment and Retention Strategies for Randomized Clinical Trials Involving Family Members of ICU Patients.

OBJECTIVES: To review recruitment and retention strategies of randomized family-centered interventional studies in adult ICUs. DATA SOURCES: The MEDLINE, Embase, PsycINFO, CINAHL, and the Cochrane Library database from inception to February 2023. STUDY SELECTION: Randomized controlled trials with family-centered interventions in the ICU setting that reported at least one family-centered outcome that were included in our previously published systematic review. DATA EXTRACTION: For recruitment: Number of family members approached and enrolled, type of approach, location, time of day approached, whether medical team approached first, compensation offered, and type of consent. For retention: Number of family members enrolled and completed initial follow-up visit, mode of follow-up, location of follow-up visit, data collection method, timing of follow-up visits, number of follow-up visits, and compensation offered. Recruitment (participants approached/enrolled) and retention (participants enrolled/completed initial follow-up) percentage were calculated. DATA SYNTHESIS: There were 51 studies in the analysis. The mean recruitment percentage was 49.3% ± 24.3%. There were no differences in recruitment percentage by study country, ICU type, recruitment approach, or whether the medical team approached the family member first (all p > 0.05). The mean retention percentage for the initial follow-up visit was 81.6% ± 18.0%. There were no differences in retention percentage by mode of participant contact, data collection type, or follow-up location (all p > 0.05). Minimal data were available to determine the impact of time of day approached and compensation on recruitment and retention outcomes. CONCLUSIONS: About half of family members of ICU patients approached participated in trials and more than eight in ten completed the initial follow-up visit. We did not identify specific factors that impacted family recruitment or retention. There is a strong need for further studies to characterize optimal strategies to ensure family participation in clinical trials.

Critically Ill Older Adults' Representation in Intervention Trials: A Systematic Review.

OBJECTIVES: Older adults may be under-represented in critical care research, and results may not apply to this specific population. Our primary objective was to evaluate the prevalence of inclusion of older adults across critical care trials focused on common ICU conditions or interventions. Our secondary objective was to evaluate whether older age was used as a stratification variable for randomization or outcome analysis. DESIGN SETTING AND SUBJECTS: We performed a systematic review of previously published systematic reviews of randomized controlled trials (RCTs) in critical care. We searched PubMed, Ovid, CENTRAL, and Cochrane from 2009 to 2022. Systematic reviews of any interventions across five topics: acute respiratory distress syndrome (ARDS), sepsis/shock, nutrition, sedation, and mobilization were eligible. MAIN RESULTS: We identified 216 systematic reviews and included a total of 253 RCTs and 113,090 patients. We extracted baseline characteristics and the reported proportion of older adults. We assessed whether any upper age limit was an exclusion criterion for trials, whether age was used for stratification during randomization or data analysis, and if age-specific subgroup analysis was present. The most prevalent topic was sepsis (78 trials, 31%), followed by nutrition (62 trials, 25%), ARDS (39 trials, 15%), mobilization (38 trials, 15%), and sedation (36 trials, 14%). Eighteen trials (7%) had exclusion criteria based on older age. Age distribution with information on older adults prevalence was given in six trials (2%). Age was considered in the analysis of ten trials (5%) using analytic methods to evaluate the outcome stratified by age. Conclusions: In this systematic review, the proportion of older critically ill patients is undetermined, and it is unclear how age is or is not an effect modifier or to what extent the results are valid for older adult groups. Reporting age is important to guide clinicians in personalizing care. These results highlight the importance of incorporating older critically ill patients in future trials to ensure the results are generalizable to this growing population.

Effect of sodium-glucose co-transporter 2 inhibitors (SGLT2i) on N-terminal pro-B-type natriuretic peptide (NT-proBNP) level and structural changes following myocardial infarction: A systematic review and meta-analysis.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are anti-hyperglycemic drugs and have been proven to have cardiovascular protective effects for patients with heart failure regardless of their diabetes status. However, the benefit of SGLT2i following myocardial infarction (MI) remains incompletely established. This review aimed to investigate the impact of SGLT2i on NT-proBNP levels and structural changes post-MI. METHOD: Medline, ClinicalTrial.gov, Scopus, and Directory of open-access journals were searched to retrieve the relevant articles. Eligible studies were randomized clinical trials that assessed NT-proBNP and cardiac structural changes in patients who received SGLT2i compared to placebo following MI. Two reviewers independently screened articles, extracted data, and assessed study quality. RESULT: Four studies were included in this review, including patients with and without diabetes. While two studies showed no marked decrease from the baseline in NT-proBNP levels between the SGLT2i group and the control group, two studies reported a substantial reduction. The meta-analysis included three of these studies, with a total of 238 participants. The meta-analysis did not find a statistically significant drop in NT-proBNP levels post-MI in the SGLT2 inhibitors group compared to placebo (pooled SMD = 0.16, 95% CI 0.57-0.26, P 0.45). Furthermore, different echocardiographic parameters were reported in the included trials, yet no meta-analysis could be conducted to assess the influence of SGLT2i on cardiac remodeling post-MI. CONCLUSION: SGLT2i did not result in a statistically significant reduction of NT-proBNP level subsequent to myocardial infarction. A knowledge gap exists regarding the impact of these agents on cardiac remodeling post-MI. Future high-quality clinical trials are needed to provide more robust evidence.

Clarifying Causal Effects of Interest and Underlying Assumptions in Randomized and Nonrandomized Clinical Trials in Oncology Using Directed Acyclic Graphs and Single-World Intervention Graphs.

Recent clinical trials in oncology have used increasingly complex methodologies, such as causal inference methods for intercurrent events, external control, and covariate adjustment, posing challenges in clarifying the estimand and underlying assumptions. This article proposes expressing causal structures using graphical tools-directed acyclic graphs (DAGs) and single-world intervention graphs (SWIGs)-in the planning phase of a clinical trial. It presents five rules for selecting a sufficient set of adjustment variables on the basis of a diagram representing the clinical trial, along with three case studies of randomized and single-arm trials and a brief tutorial on DAG and SWIG. Through the case studies, DAGs appear effective in clarifying assumptions for identifying causal effects, although SWIGs should complement DAGs due to their limitations in the presence of intercurrent events in oncology research.

Multi-arm multi-stage (MAMS) randomised selection designs: impact of treatment selection rules on the operating characteristics.

BACKGROUND: Multi-arm multi-stage (MAMS) randomised trial designs have been proposed to evaluate multiple research questions in the confirmatory setting. In designs with several interventions, such as the 8-arm 3-stage ROSSINI-2 trial for preventing surgical wound infection, there are likely to be strict limits on the number of individuals that can be recruited or the funds available to support the protocol. These limitations may mean that not all research treatments can continue to accrue the required sample size for the definitive analysis of the primary outcome measure at the final stage. In these cases, an additional treatment selection rule can be applied at the early stages of the trial to restrict the maximum number of research arms that can progress to the subsequent stage(s). This article provides guidelines on how to implement treatment selection within the MAMS framework. It explores the impact of treatment selection rules, interim lack-of-benefit stopping boundaries and the timing of treatment selection on the operating characteristics of the MAMS selection design. METHODS: We outline the steps to design a MAMS selection trial. Extensive simulation studies are used to explore the maximum/expected sample sizes, familywise type I error rate (FWER), and overall power of the design under both binding and non-binding interim stopping boundaries for lack-of-benefit. RESULTS: Pre-specification of a treatment selection rule reduces the maximum sample size by approximately 25% in our simulations. The familywise type I error rate of a MAMS selection design is smaller than that of the standard MAMS design with similar design specifications without the additional treatment selection rule. In designs with strict selection rules - for example, when only one research arm is selected from 7 arms - the final stage significance levels can be relaxed for the primary analyses to ensure that the overall type I error for the trial is not underspent. When conducting treatment selection from several treatment arms, it is important to select a large enough subset of research arms (that is, more than one research arm) at early stages to maintain the overall power at the pre-specified level. CONCLUSIONS: Multi-arm multi-stage selection designs gain efficiency over the standard MAMS design by reducing the overall sample size. Diligent pre-specification of the treatment selection rule, final stage significance level and interim stopping boundaries for lack-of-benefit are key to controlling the operating characteristics of a MAMS selection design. We provide guidance on these design features to ensure control of the operating characteristics.

An evaluation of dexmedetomidine in combination with midazolam in pediatric sedation: a systematic review and meta-analysis.

BACKGROUND: Dexmedetomidine and midazolam are commonly used sedatives in children. We conducted a systematic review and meta-analysis to compare the safety and effectiveness of sedation provided by dexmedetomidine combined with midazolam versus other sedatives including chloral hydrate, midazolam and other sedatives in pediatric sedation. METHODS: The Embase, Web of Science, Cochrane Library, and PubMed databases, and Clinicaltrials.gov register of controlled trials were searched from inception to June 2022. All randomized controlled trials used dexmedetomidine-midazolam in pediatric sedation were enrolled. The articles search, data extraction, and quality assessment of included studies were performed independently by two researchers. The success rate of sedation was considered as the primary outcome. The secondary outcomes included onset time of sedation, recovery time of sedation and occurrence of adverse events. RESULTS: A total of 522 studies were screened and 6 RCTs were identified; 859 patients were analyzed. The administration of dexmedetomidine combined with midazolam was associated with a higher sedation success rate and a lower incidence of nausea and vomiting in computed tomography, magnetic resonance imaging, Auditory Brainstem Response test or fiberoptic bronchoscopy examinations than the other sedatives did (OR = 2.92; 95% CI: 1.39-6.13, P = 0.005, I2 = 51%; OR = 0.23, 95% CI: 0.07-0.68, P = 0.008, I2 = 0%, respectively). Two groups did not differ significantly in recovery time and the occurrence of adverse reactions (WMD = - 0.27, 95% CI: - 0.93 to - 0.39, P = 0.42; OR 0.70; 95% CI: 0.48-1.02, P = 0.06, I2 = 45%. respectively). However, the results of the subgroup analysis of ASA I-II children showed a quicker onset time in dexmedetomidine-midazolam group than the other sedatives (WMD=-3.08; 95% CI: -4.66 to - 1.49, P = 0.0001, I2 = 30%). CONCLUSIONS: This meta-analysis showed that compared with the control group, dexmedetomidine combined with midazolam group provided higher sedation success rates and caused a lower incidence of nausea and vomiting in completing examinations, indicating a prospective outpatient clinical application for procedural sedation.

[How to: correctly read scientific articles : Research design and methodology]. / How to: einen wissenschaftlichen Artikel richtig lesen : Forschungsdesign und Methodik.

Criteria for assessment of the significance of scientific articles are presented. The focus is on research design and methodology, illustrated by the classical study on prehospital volume treatment of severely injured individuals with penetrating torso injuries by Bickell et al. (1994). A well-thought out research design is crucial for the success of a scientific study and is documented in a study protocol beforehand. A hypothesis is a provisional explanation or prediction and must be testable, falsifiable, precise, and relevant. There are various types of randomization methods, with the randomized controlled trial being the gold standard for clinical interventional studies. When reading a scientific article it is important to verify whether the research design and setting align with the research question and whether potential sources of error have been considered and controlled. Critical scrutiny should also be applied to references, the funding and expertise of the researchers.

Accounting for center-level effects in multicenter randomized controlled trials.

Investigators often conduct randomized controlled trials (RCTs) at multiple centers/sites when determining the effect of a treatment or an intervention. Diversifying recruitment across multiple institutions allows investigators to make recruitment go faster within a shorter timeframe and allows generalizing the study results across diverse populations. Despite having a common study protocol across multiple centers, the eligible participants may be heterogeneous, site policies and practices may vary, and the investigators' experience, training, and expertise may also vary across sites. These factors may contribute to the heterogeneity in effect estimates across centers. As a result, we usually observe some degree of heterogeneity in effect estimates across centers, despite all centers following the same study protocol. During the analysis of such a trial, investigators typically ignore center effects, but some have suggested considering centers as fixed or random effects in the model. It is not clear how considering the effects of centers, either as fixed or random effects, impacts the test of the primary hypothesis. In this article, we first review the practice of accounting for center effects in the analyses of published RCTs and illustrate the extent of heterogeneity observed in a few preexisting multicenter RCTs. To determine the impact of heterogeneity on the test of a primary hypothesis of an RCT, we considered continuous and binary outcomes and the corresponding appropriate model, namely, a simple linear regression model for a continuous outcome and a logistic regression model for the binary outcome. For each model type, we considered three methods: (a) ignore the center effect, (b) account for centers as fixed effects, or (c) account for centers as random effects. Based on simulation studies of these models, we then examine whether considering the center as a fixed or random effect in the model helps to preserve or reduce the type I and type II error rates during the analysis phase of an RCT. Finally, we outline the threshold at which center-level effects are negligible and thus negligible and provide recommendations on when it may be necessary to account for center effects during the analyses of multicenter randomized controlled trials.

Comparative effectiveness of alternative spontaneous breathing trial techniques: a systematic review and network meta-analysis of randomized trials.

BACKGROUND: The spontaneous breathing trial (SBT) technique that best balance successful extubation with the risk for reintubation is unknown. We sought to determine the comparative efficacy and safety of alternative SBT techniques. METHODS: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to February 2023 for randomized or quasi-randomized trials comparing SBT techniques in critically ill adults and children and reported initial SBT success, successful extubation, reintubation (primary outcomes) and mortality (ICU, hospital, most protracted; secondary outcome) rates. Two reviewers screened, reviewed full-texts, and abstracted data. We performed frequentist random-effects network meta-analysis. RESULTS: We included 40 RCTs (6716 patients). Pressure Support (PS) versus T-piece SBTs was the most common comparison. Initial successful SBT rates were increased with PS [risk ratio (RR) 1.08, 95% confidence interval (CI) (1.05-1.11)], PS/automatic tube compensation (ATC) [1.12 (1.01 -1.25), high flow nasal cannulae (HFNC) [1.07 (1.00-1.13) (all moderate certainty), and ATC [RR 1.11, (1.03-1.20); low certainty] SBTs compared to T-piece SBTs. Similarly, initial successful SBT rates were increased with PS, ATC, and PS/ATC SBTs compared to continuous positive airway pressure (CPAP) SBTs. Successful extubation rates were increased with PS [RR 1.06, (1.03-1.09); high certainty], ATC [RR 1.13, (1.05-1.21); moderate certainty], and HFNC [RR 1.06, (1.02-1.11); high certainty] SBTs, compared to T-piece SBTs. There was little to no difference in reintubation rates with PS (vs. T-piece) SBTs [RR 1.05, (0.91-1.21); low certainty], but increased reintubation rates with PS [RR 2.84, (1.61-5.03); moderate certainty] and ATC [RR 2.95 (1.57-5.56); moderate certainty] SBTs compared to HFNC SBTs. CONCLUSIONS: SBTs conducted with pressure augmentation (PS, ATC, PS/ATC) versus without (T-piece, CPAP) increased initial successful SBT and successful extubation rates. Although SBTs conducted with PS or ATC versus HFNC increased reintubation rates, this was not the case for PS versus T-piece SBTs.

Effective dosage and mode of exercise for enhancing cognitive function in Alzheimer's disease and dementia: a systematic review and Bayesian Model-Based Network Meta-analysis of RCTs.

OBJECTIVE: Research the dose-response relationship between overall and certain types of exercise and cognitive function in older adults with Alzheimer's disease and dementia. DESIGN: Systemic and Bayesian Model-Based Network Meta-Analysis. METHODS: In our study, we analyzed data from randomized controlled trials investigating the effects of different exercises on cognitive outcomes in older adults with AD. We searched the Web of Science, PubMed, Cochrane Central Register of Controlled Trials, and Embase up to November 2023. Using the Cochrane Risk of Bias tool (Rob2) for quality assessment and R software with the MBNMA package for data analysis, we determined standard mean differences (SMDs) and 95% confidence intervals (95%CrI) to evaluate exercise's impact on cognitive function in AD. RESULTS: Twenty-seven studies with 2,242 AD patients revealed a nonlinear relationship between exercise and cognitive improvement in AD patients. We observed significant cognitive enhancements at an effective exercise dose of up to 1000 METs-min/week (SMDs: 0.535, SD: 0.269, 95% CrI: 0.023 to 1.092). The optimal dose was found to be 650 METs-min/week (SMDs: 0.691, SD: 0.169, 95% CrI: 0.373 to 1.039), with AE (Aerobic exercise) being particularly effective. For AE, the optimal cognitive enhancement dose was determined to be 660 METs-min/week (SMDs: 0.909, SD: 0.219, 95% CrI: 0.495 to 1.362). CONCLUSION: Nonlinear dose-response relationship between exercise and cognitive improvement in Alzheimer's disease, with the optimal AE dose identified at 660 METs-min/week for enhancing cognitive function in AD.

On exact randomization-based covariate-adjusted confidence intervals.

Randomization-based inference using the Fisher randomization test allows for the computation of Fisher-exact P-values, making it an attractive option for the analysis of small, randomized experiments with non-normal outcomes. Two common test statistics used to perform Fisher randomization tests are the difference-in-means between the treatment and control groups and the covariate-adjusted version of the difference-in-means using analysis of covariance. Modern computing allows for fast computation of the Fisher-exact P-value, but confidence intervals have typically been obtained by inverting the Fisher randomization test over a range of possible effect sizes. The test inversion procedure is computationally expensive, limiting the usage of randomization-based inference in applied work. A recent paper by Zhu and Liu developed a closed form expression for the randomization-based confidence interval using the difference-in-means statistic. We develop an important extension of Zhu and Liu to obtain a closed form expression for the randomization-based covariate-adjusted confidence interval and give practitioners a sufficiency condition that can be checked using observed data and that guarantees that these confidence intervals have correct coverage. Simulations show that our procedure generates randomization-based covariate-adjusted confidence intervals that are robust to non-normality and that can be calculated in nearly the same time as it takes to calculate the Fisher-exact P-value, thus removing the computational barrier to performing randomization-based inference when adjusting for covariates. We also demonstrate our method on a re-analysis of phase I clinical trial data.

Adaptive designs were primarily used but inadequately reported in early phase drug trials.

BACKGROUND: Faced with the high cost and limited efficiency of classical randomized controlled trials, researchers are increasingly applying adaptive designs to speed up the development of new drugs. However, the application of adaptive design to drug randomized controlled trials (RCTs) and whether the reporting is adequate are unclear. Thus, this study aimed to summarize the epidemiological characteristics of the relevant trials and assess their reporting quality by the Adaptive designs CONSORT Extension (ACE) checklist. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov from inception to January 2020. We included drug RCTs that explicitly claimed to be adaptive trials or used any type of adaptative design. We extracted the epidemiological characteristics of included studies to summarize their adaptive design application. We assessed the reporting quality of the trials by Adaptive designs CONSORT Extension (ACE) checklist. Univariable and multivariable linear regression models were used to the association of four prespecified factors with the quality of reporting. RESULTS: Our survey included 108 adaptive trials. We found that adaptive design has been increasingly applied over the years, and was commonly used in phase II trials (n = 45, 41.7%). The primary reasons for using adaptive design were to speed the trial and facilitate decision-making (n = 24, 22.2%), maximize the benefit of participants (n = 21, 19.4%), and reduce the total sample size (n = 15, 13.9%). Group sequential design (n = 63, 58.3%) was the most frequently applied method, followed by adaptive randomization design (n = 26, 24.1%), and adaptive dose-finding design (n = 24, 22.2%). The proportion of adherence to the ACE checklist of 26 topics ranged from 7.4 to 99.1%, with eight topics being adequately reported (i.e., level of adherence ≥ 80%), and eight others being poorly reported (i.e., level of adherence ≤ 30%). In addition, among the seven items specific for adaptive trials, three were poorly reported: accessibility to statistical analysis plan (n = 8, 7.4%), measures for confidentiality (n = 14, 13.0%), and assessments of similarity between interim stages (n = 25, 23.1%). The mean score of the ACE checklist was 13.9 (standard deviation [SD], 3.5) out of 26. According to our multivariable regression analysis, later published trials (estimated ß = 0.14, p < 0.01) and the multicenter trials (estimated ß = 2.22, p < 0.01) were associated with better reporting. CONCLUSION: Adaptive design has shown an increasing use over the years, and was primarily applied to early phase drug trials. However, the reporting quality of adaptive trials is suboptimal, and substantial efforts are needed to improve the reporting.

Optimal dose and type of exercise to improve depressive symptoms in older adults: a systematic review and network meta-analysis.

BACKGROUND: Depression is a prevalent issue among older adults, affecting their quality of life and overall well-being. Exercise is an effective means of relieving depressive symptoms in older adults, but the optimal dose for different exercise types remains unclear. As such, the aim of this meta-analysis was to examine the dose-response relationship between overall and specific types of exercise with depression symptoms in older adults. METHODS: This systematic review and network meta-analysis included a search of PubMed, Medline, Embase, PsycINFO, Cochrane library, and Web of Science for randomized controlled trials of exercise in older adults with depression symptoms from inception to 15 July 2023. Comprehensive data extraction covered dose, treatment regimen, demographics and study duration. Dosage metrics, encompassing METs-min/week, were scrutinized in correlation with the Minimal Clinically Importance Difference (MCID). RESULTS: A total of 47 studies involving 2895 participants and 7 kinds of exercise were included in the review. Without considering the dose, the results of our network meta-analysis indicated that Walking was the most effective in alleviating depression in older adults, in addition to Aerobic exercise (AE), Yoga, Qigong, Resistance training (RT), and Tai Chi (TC), which were equally effective. However, the results of the dose-response analysis found that Aerobic exercise was most effective at a dose of 1000 METs-min/week. It is noteworthy that Walking is significantly effective in alleviating depressive symptoms in older adults at very low doses. In terms of clinical benefits, we found that overall exercise doses in the range of 600 ~ 970 METs-min/week were clinically effective. Considering the specific types of exercise, Aerobic exercise, Resistance training, Walking, and Yoga were found to be effective at doses ranging from 820 ~ 1000 METs-min/week, 520 ~ 1000 METs-min/week, 650 ~ 1000 METs-min/week, 680 ~ 1000 METs-min/week, respectively. At the same time, we found that when the age exceeded 81 years, even when participating in exercise, it did not achieve the effect of alleviating depressive symptoms in older adults. CONCLUSIONS: In conclusion, including Walking, AE, Yoga, Qigong, RT, and TC, effectively alleviate depressive symptoms in older adults. Furthermore, we established statistically and clinically significant threshold doses for various exercise types. Early initiation of exercise is beneficial, but its efficacy diminishes from the age of 80, and beyond 81, exercise no longer significantly alleviates depressive symptoms.

Cerebellar transcranial magnetic stimulation for improving balance capacity and activity of daily living in stroke patients: a systematic review and meta-analysis.

BACKGROUND: The application of cerebellar transcranial magnetic stimulation (TMS) in stroke patients has received increasing attention due to its neuromodulation mechanisms. However, studies on the effect and safety of cerebellar TMS to improve balance capacity and activity of daily living (ADL) for stroke patients are limited. This systematic review and meta-analysis aimed to investigate the effect and safety of cerebellar TMS on balance capacity and ADL in stroke patients. METHOD: A systematic search of seven electronic databases (PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Wanfang and Chinese Scientific Journal) were conducted from their inception to October 20, 2023. The randomized controlled trials (RCTs) of cerebellar TMS on balance capacity and/or ADL in stroke patients were enrolled. The quality of included studies were assessed by Physiotherapy Evidence Database (PEDro) scale. RESULTS: A total of 13 studies involving 542 participants were eligible. The pooled results from 8 studies with 357 participants showed that cerebellar TMS could significantly improve the post-intervention Berg balance scale (BBS) score (MD = 4.24, 95%CI = 2.19 to 6.29, P < 0.00001; heterogeneity, I2 = 74%, P = 0.0003). The pooled results from 4 studies with 173 participants showed that cerebellar TMS could significantly improve the post-intervention Time Up and Go (TUG) (MD=-1.51, 95%CI=-2.8 to -0.22, P = 0.02; heterogeneity, I2 = 0%, P = 0.41). The pooled results from 6 studies with 280 participants showed that cerebellar TMS could significantly improve the post-intervention ADL (MD = 7.75, 95%CI = 4.33 to 11.17, P < 0.00001; heterogeneity, I2 = 56%, P = 0.04). The subgroup analysis showed that cerebellar TMS could improve BBS post-intervention and ADL post-intervention for both subacute and chronic stage stroke patients. Cerebellar high frequency TMS could improve BBS post-intervention and ADL post-intervention. Cerebellar TMS could still improve BBS post-intervention and ADL post-intervention despite of different cerebellar TMS sessions (less and more than 10 TMS sessions), different total cerebellar TMS pulse per week (less and more than 4500 pulse/week), and different cerebellar TMS modes (repetitive TMS and Theta Burst Stimulation). None of the studies reported severe adverse events except mild side effects in three studies. CONCLUSIONS: Cerebellar TMS is an effective and safe technique for improving balance capacity and ADL in stroke patients. Further larger-sample, higher-quality, and longer follow-up RCTs are needed to explore the more reliable evidence of cerebellar TMS in the balance capacity and ADL, and clarify potential mechanisms.

Therapeutic options for neurocardiogenic syncope: a meta-analysis of randomised trials with and without blinding.

BACKGROUND: Neurocardiogenic syncope is a common condition with significant associated psychological and physical morbidity. The effectiveness of therapeutic options for neurocardiogenic syncope beyond placebo remains uncertain. METHODS: The primary endpoint was the risk ratio (RR) of spontaneously recurring syncope following any therapeutic intervention. We also examined the effect of blinding on treatment efficacy. We identified all randomised trials which evaluated the effect of any pharmacological, device-based or supportive intervention on patients with a history of syncope. A systematic search was conducted on Medline, Embase, PubMed databases and Cochrane Central Register for Controlled Trials from 1950 to 25 April 2023. Event rates, their RRs and 95% CIs were calculated, and a random-effects meta-analysis was conducted for each intervention. Data analysis was performed in R using RStudio. RESULTS: We identified 47 eligible trials randomising 3518 patients. Blinded trials assessing syncope recurrence were neutral for beta blockers, fludrocortisone and conventional dual-chamber pacing but were favourable for selective serotonin reuptake inhibitors (SSRIs) (RR 0.40, 95% CI 0.26 to 0.63, p<0.001), midodrine (RR 0.70, 95% CI 0.53 to 0.94, p=0.016) and closed-loop stimulation (CLS) pacing (RR 0.15, 95% CI 0.07 to 0.35, p<0.001). Unblinded trials reported significant benefits for all therapy categories other than beta blockers and consistently showed larger benefits than blinded trials. CONCLUSIONS: Under blinded conditions, SSRIs, midodrine and CLS pacing significantly reduced syncope recurrence. Future trials for syncope should be blinded to avoid overestimating treatment effects. PROSPERO REGISTRATION NUMBER: CRD42022330148.