Bias Of Randomized Controlled Trials Research Articles

Effectiveness of virtual and augmented reality for cardiopulmonary resuscitation training: a systematic review and meta-analysis

BackgroundVirtual reality (VR) and augmented reality (AR) are emerging technologies that can be used for cardiopulmonary resuscitation (CPR) training. Compared to traditional face-to-face training, VR/AR-based training has the potential to reach a wider audience, but there is debate regarding its effectiveness in improving CPR quality. Therefore, we conducted a meta-analysis to assess the effectiveness of VR/AR training compared with face-to-face training.MethodsWe searched PubMed, Embase, Cochrane Library, Web of Science, CINAHL, China National Knowledge Infrastructure, and Wanfang databases from the inception of these databases up until December 1, 2023, for randomized controlled trials (RCTs) comparing VR- and AR-based CPR training to traditional face-to-face training. Cochrane's tool for assessing bias in RCTs was used to assess the methodological quality of the included studies. We pooled the data using a random-effects model with Review Manager 5.4, and assessed publication bias with Stata 11.0.ResultsNine RCTs (involving 855 participants) were included, of which three were of low risk of bias. Meta-analyses showed no significant differences between VR/AR-based CPR training and face-to-face CPR training in terms of chest compression depth (mean difference [MD], -0.66 mm; 95% confidence interval [CI], -6.34 to 5.02 mm; P = 0.82), chest compression rate (MD, 3.60 compressions per minute; 95% CI, -1.21 to 8.41 compressions per minute; P = 0.14), overall CPR performance score (standardized mean difference, -0.05; 95% CI, -0.93 to 0.83; P = 0.91), as well as the proportion of participants meeting CPR depth criteria (risk ratio [RR], 0.79; 95% CI, 0.53 to 1.18; P = 0.26) and rate criteria (RR, 0.99; 95% CI, 0.72 to 1.35; P = 0.93). The Egger regression test showed no evidence of publication bias.ConclusionsOur study showed evidence that VR/AR-based training was as effective as traditional face-to-face CPR training. Nevertheless, there was substantial heterogeneity among the included studies, which reduced confidence in the findings. Future studies need to establish standardized VR/AR-based CPR training protocols, evaluate the cost-effectiveness of this approach, and assess its impact on actual CPR performance in real-life scenarios and patient outcomes.Trial registrationCRD42023482286.

Long-term impact of home-based monitoring after an admission for acute decompensated heart failure: a systematic review and meta-analysis of randomised controlled trials

Patients with heart failure have high rehospitalisation rates and poor cardiovascular outcomes. Home-based monitoring (HBM) has emerged with promising results in different settings. However, its long-term effects on patients recently admitted for acute decompensated heart failure (ADHF) remain uncertain. We systematically searched PubMed, Embase, and Cochrane Library for randomised controlled trials (RCTs) comparing HBM with usual care (UC) that were published between database inception and June 24, 2023. We included studies with patients admitted for ADHF in the previous 6 months and with a minimum follow-up of 6 months. We excluded studies with patients hospitalised for reasons other than ADHF and studies with disproportional education interventions between arms. Statistical analyses were performed using R software version 4.3.2. We pooled risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) for categorical and continuous outcomes, respectively. Cochrane Collaboration's tool for assessing risk of bias in RCTs (RoB 2) was used to assess study quality. Publication bias was assessed via funnel plots and Egger's test, and heterogeneity was assessed through I2 statistics and sensitivity analysis. The protocol for this systematic review and meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO, CRD42023465359). We included 16 RCTs comprising 4629 patients, of whom 2393 (51.7%) were randomised to HBM and 3150 (68%) were men. Follow-up ranged from six to fifteen months. As compared with UC, HBM significantly reduced all-cause mortality (RR 0.75; 95% CI 0.61, 0.91; p=0.005), all-cause hospitalisations (RR 0.82; 95% CI 0.70, 0.97; p=0.018), cardiovascular (CV) mortality (RR 0.53; 95% CI 0.36, 0.79; p=0.002), hospitalisations for heart failure (RR 0.75; 95% CI 0.62, 0.91; p=0.004), and CV hospitalisations (RR 0.72; 95% CI 0.55, 0.95; p=0.018). There were no significant differences in length of hospital stay (MD 0.97 days; 95% CI -0.90, 2.84; p=0.308). In patients recently admitted with ADHF, HBM significantly reduces long-term all-cause mortality and hospitalisations, CV mortality and hospitalisations, and hospitalisations for heart failure, as compared with UC. This supports the implementation of HBM as a standard practice to optimise patient outcomes following admissions for ADHF. However, future studies are warranted to evaluate the efficacy and safety of implementing HBM in the real-world setting. None.

The methodological quality of systematic reviews regarding the Core Outcome Set (COS) development

BackgroundThe Core Outcome Measures in Effectiveness Trials (COMET) working group proposed core outcome sets (COS) to address the heterogeneity in outcome measures in clinical studies. According to the recommendations of COMET, performing systematic reviews (SRs) usually was the first step for COS development. However, the SRs that serve as a basis for COS are not specifically appraised by organizations such as COMET regarding their quality. Here, we investigated the status of SRs related to development of COS and evaluated their methodological quality.MethodsWe conducted a search on PubMed to identify SRs related to COS development published from inception to May 2022. We qualitatively summarized the disease included in SR topics, and the studies included in the SRs. We evaluated the methodological quality of the SRs using AMSTAR 2.0 and compared the overall quality of SRs with and without protocols using the Mann-Whitney U test.ResultsWe included 175 SRs from 23 different countries or regions, and they mainly focused on five diseases: musculoskeletal system or connective tissue disease (n = 19, 10.86%), injury, poisoning, or certain other consequences of external causes (n = 18, 10.29%), digestive system disease (n = 16, 9.14%), nervous system disease (n = 15, 8.57%), and genitourinary system disease (n = 15, 8.57%). Although 88.00% of SRs included randomized controlled trials (RCTs), only a few SRs (23.38%) employed appropriate tools to assess the risk of bias in RCTs. The assessment results on the basis of AMSTAR 2.0 indicated that most SRs (93.71%) were rated as ‘’critically low’’ to ‘’low’’ in terms of overall confidence. The overall confidence of SRs with protocols was significantly higher than that without protocols (P <.001). Compared to the SRs with protocols on Core Outcome Measures in Effectiveness Trials (COMET), SRs with protocols on PROSPERO were of better overall confidence (P = .017).ConclusionThe overall quality of published SRs regarding COS development was poor. Our findings emphasize the need for researchers to carefully select the disease topic and strictly adhere to the requirements of optimal methodology when conducting a SR for the establishment of a COS.

Efficacy of adjuvant-associated COVID-19 vaccines against SARS-CoV-2 variants of concern in randomized controlled trials: A systematic review and meta-analysis.

Adjuvants may enhance the efficacy of vaccines. however, the efficacy of adjuvant-associated COVID-19 vaccines (ACVs) remains unclear since the emergence of the COVID-19 pandemic. This study aimed to address this gap by conducting a systematic review and meta-analysis of the efficacy of ACVs against Severe Acute Respiratory Syndrome Coronavirus 2 CoV (SARS-CoV-2) variants of concern (VOC). A systematic search was conducted of randomized controlled trials (RCTs) evaluating the vaccine efficacy (VE) of ACVs against VOC (alpha, beta, gamma, delta, or Omicron), up to May 27, 2023. The DerSimonian-Laird random-effects model was used to assess VE with 95% confidence intervals (CI) through meta-analysis. Cochrane Risk of Bias tools were used to assess the risk of bias in RCTs. Eight RCTs with 113,202 participants were included in the analysis, which incorporated 4 ACVs [Matrix-M (NVX-CoV2373), Alum (BBV152), CpG-1018/Alum (SCB-2019), and AS03 (CoVLP]). The pooled efficacy of full vaccination with ACVs against VOC was 88.0% (95% CI: 83.0-91.5). Full vaccination was effective against Alpha, Beta, Delta, and Gamma variants, with VE values of 93.66% (95% CI: 86.5-100.74), 64.70% (95% CI: 41.87-87.54), 75.95% (95% CI: 67.9-83.99), and 91.26% (95% CI: 84.35-98.17), respectively. Currently, there is a lack of RCT evidence regarding the efficacy of ACVs against the Omicron variant. In this meta-analysis, it should be that full vaccination with ACVs has high efficacy against Alpha or Gamma variants and moderate efficacy against Beta and Delta variants. Notably, with the exception of the aluminum-adjuvanted vaccine, the other ACVs had moderate to high efficacy against the SARS-CoV-2 variant. This raises concerns about the effectiveness of ACVs booster vaccinations against Omicron.

Effectiveness of exercise for improving physical and renal function in older adults with pre-dialysis chronic kidney disease: A systematic review and meta-analysis

Purpose : Exercise may prevent the worsening of chronic kidney disease (CKD) and progression of cardiovascular diseases in patients with CKD. This review aims to identify the best type of exercise modality and summarizes the beneficial effects of exercise on physical and renal function among older adults with pre-dialysis CKD.Methods : A systematic search of PubMed, Embase, CINAHL, Cochrane Library, Web of Science, SCOPUS, and domestic database was performed for randomized controlled trials (RCTs) assessing the effect of exercise intervention on older adults with pre-dialysis CKD published until February 2023. A random-effects metaanalysis was conducted. The risk of bias was assessed using a Cochrane tool for assessing the risk of bias in RCTs (RoB 2.0).Results : The systematic review included 11 RCTs (n = 591, average age 60.2–76), of which 8 could be included for meta-analysis. Exercise was significant in increasing peak oxygen consumption and knee muscle strength among physical functions, and also in improving glomerular filtration rate among kidney functions.Conclusion : Exercise has beneficial effects on physical and renal function among older adults with pre-dialysis CKD. In the future, it is necessary to verify the effectiveness of exercise by subdividing it by type, intensity, duration, and delivery.

Quality evaluation of the literature on randomized controlled clinical trials of traditional Chinese medicine for treatment of gastric precancerous lesions in last 20 years.

To evaluate the methodological quality of randomized controlled trials (RCTs) of traditional Chinese medicines for the treatment of gastric precancerous lesions in the past 20 years. The studies of RCTs on traditional Chinese medicines for gastric precancerous lesions were searched from the Chinese full-text journal database, Wanfang database, VIP database, PubMed, and Embase from January 2001 to December 2021. The retrieved articles were screened, extracted and evaluated based on the 2010 edition of CONSORT statement, Cochrane Risk of Bias Assessment Scale and additional indicators. A total of 840 papers were included. According to the Cochrane Risk of Bias Assessment Scale, the high risk of bias in the application of randomized methods was 5.95%; the concealed risk of uncertainty in the allocation scheme was 98.93%; the low risk of bias for blinding of patients or testers was 1.30%; the risk of bias for blinding of the outcome assessor was 100.00%; the risk of bias for completeness of the outcome data was 2.86%; and the risk of uncertainty for selective reporting was 98.44%. The CONSORT statement evaluating the quality of reporting showed that 100.00% of the RCT articles reported the 8 entries of introduction, objectives and interventions; 36.79% of the literature mentioned the method of randomized sequence generation, but only 27.62% of the literature implemented a randomized program, 1.07% of the literature hid the randomized program and 1.31% of the literature was blinded; 36.67% of the literature reported adverse reactions; no literature reported sample size prediction methods; additional evaluation indicators showed that 17.02% of the studies had ethical approval; 43.81% of the literature specified Chinese medicine evidence; 16.55% of the studies excluded severe heterotrophic hyperplasia; 7.26% of the studies conducted follow-up; and 65.12% of the literature used composite efficacy indicators; 46.67% of the literature applied pathological histological evaluation; 2.62% of the literature applied quality of life evaluation, etc. The overall risk of bias in RCTs of traditional Chinese medicines for gastric precancerous lesions is high, and the quality of most of the study reports needs to be improved. In the future, it is necessary to strengthen the study design of RCTs and refer to appropriate traditional Chinese medicines evidence grading standards, select study protocols according to different purposes, provide objective and strong evidence of clinical studies on traditional Chinese medicines, and carry out clinical study design and result reporting suitable for traditional Chinese medicines according to the CONSORT principle.

Peripheral Nerve Block and Peri-operative Neurocognitive Disorders in Older Patients With Hip Fractures: A Systematic Review With Meta-analysis.

Poor pain control and opioid use are risk factors for perioperative neurocognitive disorders (PND). The peripheral nerve block (PNB) can reduce pain and opioid consumption. This systematic review aimed to investigate the effects of PNB on PND in older patients with hip fractures. The PubMed, Cochrane Central Registers of Controlled Trial, Embase and ClinicalTrials.gov databases were searched from inception until November 19, 2021 for all randomized controlled trials (RCTs) comparing PNB with analgesics. The quality of the selected studies was assessed according to Version 2 of the Cochrane tool for assessing the risk of bias in RCTs. The primary outcome was the incidence of PND. Secondary outcomes included pain intensity and the incidence of postoperative nausea and vomiting. Subgroup analyses were based on population characteristics, type and infusion method of local anesthetics, and type of PNB. Eight RCTs comprising 1015 older patients with hip fractures were included. Compared with analgesics, PNB did not reduce the incidence of PND in the elderly hip fracture population comprising patients with intact cognition and those with pre-existing dementia or cognitive impairment (risk ratio [RR] = .67; 95% confidence interval [CI] = .42 to 1.08; P = .10; I2 = 64%). However, PNB reduced the incidence of PND in older patients with intact cognition (RR = .61; 95% CI = .41 to .91; P = .02; I2 = 0%). Fascia iliaca compartment block, bupivacaine, and continuous infusion of local anesthetics were found to reduce the incidence of PND. PNB effectively reduced PND in older patients with hip fractures and intact cognition. When the study population included patients with intact cognition and those with pre-existing dementia or cognitive impairment, PNB showed no reduction in the incidence of PND. These conclusions should be confirmed with larger, higher-quality RCTs.

Effects of Daily Zinc Alone or in Combination with Other Nutrient Supplements on the Risk of Malaria Parasitaemia: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Zinc supplementation has been explored as a potential intervention to reduce the risk of malaria parasitaemia in randomised controlled trials (RCTs). However, inconsistent evidence has been obtained regarding the efficacy of zinc supplementation in the context of malaria prevention. This systematic review was implemented to survey the existing literature to determine the effects of the daily oral administration of zinc, either alone or in combination with other nutrient supplements, on the risk of malaria parasitaemia. The systematic review was prospectively registered in the PROSPERO database CRD42023424345 and followed PRISMA protocols. A comprehensive search was conducted across multiple databases, including Embase, MEDLINE, Ovid, PubMed, Scopus, ProQuest, and Google Scholar, from their inception until 6 May 2023. The risk of bias in RCTs was assessed using the Cochrane Risk of Bias Tool 2 (RoB 2). The effect sizes, represented as risk ratios (RRs) with 95% confidence intervals (CIs), were standardised by transforming them into log RRs and then pooling them using a fixed-effects or random-effects model depending on the heterogeneity across studies. Comparisons were made between individuals who received zinc alone or zinc in combination with other micronutrient supplements and those who did not receive zinc. A total of 1339 articles were identified through the database searches, and after the screening and selection process, 10 studies were included in the final synthesis. The meta-analysis revealed that zinc supplementation alone did not significantly affect the risk of malaria parasitaemia compared with placebo (p = 0.30, log RR = 0.05, 95% CI: -0.05-0.15, I2 = 0.00%, with 566 malaria cases in the zinc intake group and 521 malaria cases in the placebo group). However, the analysis demonstrated a borderline significant effect of zinc supplementation in combination with other micronutrients on the risk of malaria parasitaemia compared with placebo (p = 0.05, log RR = 1.31, 95% CI: 0.03-2.59, I2 = 99.22%, with 8904 malaria cases in the zinc intake group and 522 malaria cases in the placebo group). The findings of this systematic review indicate that zinc supplementation, either alone or combined with the supplementation of other micronutrients such as vitamin A, iron, or multiple nutrients, does not significantly alter the risk of malaria parasitaemia. Further research with larger sample sizes is warranted to explore the potential effects of multi-nutrient supplementation and to identify more specific micronutrients and additional factors associated with the risk of malaria, rather than just zinc alone, among individuals in different malaria-endemic areas.

Efficacy and safety of intranasal midazolam versus intranasal ketamine as sedative premedication in pediatric patients: a meta-analysis of randomized controlled trials

BackgroundIntranasal midazolam and ketamine have been widely used as sedative premedication in children. It is difficult to determine which one yields better sedative effects for clinical practice. We conducted the present meta-analysis by summarizing the evidences to evaluate the efficacy and safety of intranasal midazolam versus intranasal ketamine as sedative premedication in pediatric patients.MethodsWe searched PubMed, Embase, and Cochrane Library from inception to April 2022. All randomized controlled trials (RCTs) used intranasal midazolam and ketamine as sedatives in children were enrolled. The risk of bias in RCTs was assessed by Cochrane risk of bias tool. Condition of parental separation, anesthesia induction or facemask acceptance, sedation level, different hemodynamic parameters and adverse events were considered as the outcomes in our study.ResultsA total of 16 studies with 1066 patients were enrolled. Compared with midazolam, administration of intranasal ketamine might be associated with severer changes in hemodynamics parameters including mean blood pressure (SMD = -0.53, with 95% CI [-0.93, -0.13]) and heart rate (HR) (SMD = -1.39, with 95% CI [-2.84, 0.06]). Meanwhile, administration of intranasal midazolam was associated with more satisfactory sedation level (61.76% vs 40.74%, RR = 1.53, with 95%CI [1.28, 1.83]), more rapid onset of sedation (SMD = -0.59, with 95%CI [-0.90, -0.28]) and more rapid recovery (SMD = -1.06, with 95%CI [-1.83, -0.28]). Current evidences also indicated that the differences of various adverse effects between two groups were not significant.ConclusionsGiven that administration of midazolam via intranasal route provides more satisfactory sedative level with less fluctuation of hemodynamics parameters and more rapid onset and recovery, it might be considered as the preferred sedative premedication for pediatric patients compared to ketamine. However, the widespread evidences with low or moderate quality indicated that superiority of intranasal midazolam in pediatric sedation needs to be confirmed by more studies with high quality and large sample size in future.Trial registrationThe protocol of present study was registered with PROSPERO (CRD42022321348).

Network Meta-Analysis of Trials Testing If Home Exercise Programs Informed by Wearables Measuring Activity Improve Peripheral Artery Disease Related Walking Impairment.

Background: This study aimed to investigate whether home exercise programs informed by wearable activity monitors improved walking ability of patients with peripheral artery disease (PAD). Methods: A systematic literature search was performed to identify randomised controlled trials (RCT) testing home exercise that were or were not informed by wearable activity monitors. The primary outcome was the change in walking distance measured by a six-minute walking test or treadmill test over the course of the trial. Network meta-analysis (NMA) was performed using the gemtc R statistical package. The risk of bias was assessed using Cochrane tool for assessing risk of bias in RCTs (RoB 2.0). Results: A total of 14 RCTs involving 1544 participants were included. Nine trials used wearable activity monitors to inform the home exercise program tested, while five trials did not use wearable activity monitors to inform the home exercise program tested. Overall quality assessment showed 12 trials to be at low risk of bias and two trials at high risk of bias. Home exercise programs informed by wearable activity monitors significantly improved walking distance compared to non-exercise controls (Mean difference, MD: 32.8 m [95% credible interval, CrI: 6.1, 71.0]) but not compared to home exercise programs not informed by wearable activity monitors (MD: 4.7 m [95% CrI: −38.5, 55.4]). Conclusions: Home exercise informed by wearable activity monitors improve walking ability of patients with PAD. It is, however, unclear if activity monitoring informed exercise programs are more effective than exercise programs not using activity monitors.

Ketogenic therapy for Parkinson's disease: A systematic review and synthesis without meta-analysis of animal and human trials

ObjectiveThe aim of the present systematic review was to assess the efficacy of ketogenic therapy in Parkinson's disease (PD), using all available data from randomized controlled trials (RCTs) on humans and animal studies with PD models. DesignSystematic review of in vivo studies. MethodsStudies related to the research question were identified through searches in PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, clinicaltrials.gov and the gray literature, from inception until November 2021. Rayyan was employed to screen and identify all studies fulfilling the inclusion criteria. Cochrane's revised Risk of Bias 2.0 and SYRCLE tools evaluated bias in RCTs and animal studies, respectively. An effect direction plot was developed to synthesize the evidence of the RCTs. ResultsTwelve studies were identified and included in the qualitative synthesis (4 RCTs and 8 animal trials). Interventions included ketogenic diets (KDs), supplementation with medium-chain triglyceride (MCT) oil, caprylic acid administration and ketone ester drinks. The animal research used zebrafish and rodents, and PD was toxin-induced. Based on the available RCTs, ketogenic therapy does not improve motor coordination and functioning, cognitive impairment, anthropometrics, blood lipids and glycemic control, exercise performance or voice disorders in patients with PD. The evidence is scattered and heterogenous, with single trials assessing different outcomes; thus, a synthesis of the evidence cannot be conclusive regarding the efficacy of ketogenic therapy. On the other hand, animal studies tend to demonstrate more promising results, with marked improvements in locomotor activity, dopaminergic activity, redox status, and inflammatory markers. ConclusionsAlthough animal studies indicate promising results, research on the effect of ketogenic therapy in PD is still in its infancy, with RCTs conducted on humans being heterogeneous and lacking PD-specific outcomes. More studies are required to recommend or refute the use of ketogenic therapy in PD.

Safety and Efficacy of Vinpocetine as a Neuroprotective Agent in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

BackgroundVinpocetine as a neuroprotective agent is effective in acute ischemic stroke in some randomized controlled trials (RCTs). Since the last systematic review has been published in 2008, which didn’t find conclusive evidence favoring its use, two more RCTs have also been completed.MethodsRelevant electronic databases were searched with a suitable combination of Medical Subject Headings terms to detect publications describing RCTs exploring the safety and efficacy of vinpocetine in patients with acute ischemic stroke. The risk of bias was determined by using the Cochrane Collaboration’s tool for assessing the risk of bias in RCTs after full-text review and relevant data extraction. Higgins and Thompson’s I2 method was used to assess heterogeneity in studies. The presence of publication bias was assessed by Egger’s test. We used a random effect model when I2 was more than 50% and a fixed-effect model for other parameters.ResultsFour placebo-controlled RCTs enrolling a total of 601 and 236 patients in vinpocetine and placebo groups, respectively, were included. The number of patients with death or significant disability was lower in the vinpocetine group than that in the placebo group at both 1 and 3 months (relative risk 0.80, 95% confidence interval [CI] 0.65–0.99 and relative risk 0.67, CI 0.48–0.92, p = 0.04 and 0.02, respectively). The degree of disability in participants at 1 month and 3 months was also lower in vinpocetine group than that in the placebo group (standardized mean difference (SMD) 0.49, 95% CI 0.03–0.95 and SMD 1.22, CI 0.23–2.24, p = 0.001 and 0.04, respectively). Change in mini-mental state examination score compared with baseline at trial enrolment was also better in the vinpocetine group than in the placebo group (pooled weighted mean difference 0.92, 95% CI 0.02–1.82, p = 0.04).ConclusionsVinpocetine has some promising efficacy in patients with ischemic stroke when used in the acute stage in reducing the disability, but presently there is not enough evidence to suggest that it also reduces case fatality. More double-blind, placebo-controlled RCTs of adequate sample size are needed before making recommendations for the routine administration of vinpocetine for all patients with acute ischemic stroke.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12028-022-01499-y.

Compliance of RCTs in endodontic instrumentation with the CONSORT Statement: A systematic review

This systematic review aimed to evaluate the adherence to the CONSORT Statement in clinical studies comparing different instrumentation techniques in Endodontics. Methodology: A systematic search was carried out through Medline databases. There was no restriction on publication year or idiom. Solely randomized controlled trials (RCTs) were included. The articles were evaluated in compliance with CONSORT. Descriptive analyses of the number of studies by journal, country, and quality assessments were performed with RoB 2.0 Cochrane Collaboration’s tool for assessing risk of bias in RCTs. A total of 6779 studies were identified, and only 33 meet the eligibility criteria. In relation to the overall risk of bias, eight out of 33 were classified as at ‘low’ risk of bias. The overall CONSORT score for the included studies in this review was 22 ± 6.2 points. Significant differences among countries were observed (p = 0.03). The range of years had a significant influence on the average CONSORT score (p = 0.01). The adherence of RCTs of endodontic instrumentation to the CONSORT Statement requires improvements. Adherence to the CONSORT statement will also reduce the high or some concerns risk of bias of studies in the field. CRD42020160552

The methodological quality of 176,620 randomized controlled trials published between 1966 and 2018 reveals a positive trend but also an urgent need for improvement.

Many randomized controlled trials (RCTs) are biased and difficult to reproduce due to methodological flaws and poor reporting. There is increasing attention for responsible research practices and implementation of reporting guidelines, but whether these efforts have improved the methodological quality of RCTs (e.g., lower risk of bias) is unknown. We, therefore, mapped risk-of-bias trends over time in RCT publications in relation to journal and author characteristics. Meta-information of 176,620 RCTs published between 1966 and 2018 was extracted. The risk-of-bias probability (random sequence generation, allocation concealment, blinding of patients/personnel, and blinding of outcome assessment) was assessed using a risk-of-bias machine learning tool. This tool was simultaneously validated using 63,327 human risk-of-bias assessments obtained from 17,394 RCTs evaluated in the Cochrane Database of Systematic Reviews (CDSR). Moreover, RCT registration and CONSORT Statement reporting were assessed using automated searches. Publication characteristics included the number of authors, journal impact factor (JIF), and medical discipline. The annual number of published RCTs substantially increased over 4 decades, accompanied by increases in authors (5.2 to 7.8) and institutions (2.9 to 4.8). The risk of bias remained present in most RCTs but decreased over time for allocation concealment (63% to 51%), random sequence generation (57% to 36%), and blinding of outcome assessment (58% to 52%). Trial registration (37% to 47%) and the use of the CONSORT Statement (1% to 20%) also rapidly increased. In journals with a higher impact factor (>10), the risk of bias was consistently lower with higher levels of RCT registration and the use of the CONSORT Statement. Automated risk-of-bias predictions had accuracies above 70% for allocation concealment (70.7%), random sequence generation (72.1%), and blinding of patients/personnel (79.8%), but not for blinding of outcome assessment (62.7%). In conclusion, the likelihood of bias in RCTs has generally decreased over the last decades. This optimistic trend may be driven by increased knowledge augmented by mandatory trial registration and more stringent reporting guidelines and journal requirements. Nevertheless, relatively high probabilities of bias remain, particularly in journals with lower impact factors. This emphasizes that further improvement of RCT registration, conduct, and reporting is still urgently needed.

Misreporting of Results of Research in Psychiatry.

Few studies address publication and outcome reporting biases of randomized controlled trials (RCTs) in psychiatry. The objective of this study was to determine publication and outcome reporting bias in RCTs funded by the Stanley Medical Research Institute (SMRI), a U.S. based, non-profit organization funding RCTs in schizophrenia and bipolar disorder. We identified all RCTs (n = 280) funded by SMRI between 2000 and 2011, and using non-public, final study reports and published manuscripts, we classified the results as positive or negative in terms of the drug compared to placebo. Design, outcome measures and statistical methods specified in the original protocol were compared to the published manuscript. Of 280 RCTs funded by SMRI between 2000 and 2011, at the time of this writing, three RCTs were ongoing and 39 were not performed. Among the 238 completed RCTs, 86 (36.1%) reported positive and 152 (63.9%) reported negative results: 86% (74/86) of those with positive findings were published in contrast to 53% (80/152) of those with negative findings (P < .001). In 70% of the manuscripts published, there were major discrepancies between the published manuscript and the original RCT protocol (change in the primary outcome measure or statistics, change in a number of patient groups, 25% or more reduction in sample size). We conclude that publication bias and outcome reporting bias is common in papers reporting RCTs in schizophrenia and bipolar disorder. These data have major implications regarding the validity of the reports of clinical trials published in the literature.

The Effect of a Combined Gluten- and Casein-Free Diet on Children and Adolescents with Autism Spectrum Disorders: A Systematic Review and Meta-Analysis.

There has been a growing interest in the gastrointestinal system and its significance for autism spectrum disorder (ASD), including the significance of adopting a gluten-free and casein-free (GFCF) diet. The objective was to investigate beneficial and safety of a GFCF diet among children with a diagnosis of ASD. We performed a systematic literature search in Medline, Embase, Cinahl, and the Cochrane Library up to January 2020 for existing systematic reviews and individual randomized controlled trials (RCTs). Studies were included if they investigated a GFCF diet compared to a regular diet in children aged 3 to 17 years diagnosed with ASD, with or without comorbidities. The quality of the identified existing reviews was assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR). The risk of bias in RCTs was assessed using the Cochrane Risk of Bias Tool, and overall quality of evidence was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). We identified six relevant RCTs, which included 143 participants. The results from a random effect model showed no effect of a GFCF diet on clinician-reported autism core symptoms (standardized mean difference (SMD) −0.31 (95% Cl. −0.89, 0.27)), parent-reported functional level (mean difference (MD) 0.61 (95% Cl −5.92, 7.14)) or behavioral difficulties (MD 0.80 (95% Cl −6.56, 10.16)). On the contrary, a GFCF diet might trigger gastrointestinal adverse effects (relative risk (RR) 2.33 (95% Cl 0.69, 7.90)). The quality of evidence ranged from low to very low due to serious risk of bias, serious risk of inconsistency, and serious risk of imprecision. Clinical implications of the present findings may be careful consideration of introducing a GFCF diet to children with ASD. However, the limitations of the current literature hinder the possibility of drawing any solid conclusion, and more high-quality RCTs are needed. The protocol is registered at the Danish Health Authority website.

Efficacy and harms of remdesivir for the treatment of COVID-19: A systematic review and meta-analysis.

BackgroundEfficacy and safety of treatments for hospitalized COVID-19 are uncertain. We systematically reviewed efficacy and safety of remdesivir for the treatment of COVID-19.MethodsStudies evaluating remdesivir in adults with hospitalized COVID-19 were searched in several engines until August 21, 2020. Primary outcomes included all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAEs). Inverse variance random effects meta-analyses were performed.ResultsWe included four randomized controlled trials (RCTs) (n = 2296) [two vs. placebo (n = 1299) and two comparing 5-day vs. 10-day regimens (n = 997)], and two case series (n = 88). Studies used intravenous remdesivir 200mg the first day and 100mg for four or nine more days. One RCT (n = 236) was stopped early due to AEs; the other three RCTs reported outcomes between 11 and 15 days. Time to recovery was decreased by 4 days with remdesivir vs. placebo in one RCT (n = 1063), and by 0.8 days with 5-days vs. 10-days of therapy in another RCT (n = 397). Clinical improvement was better for 5-days regimen vs. standard of care in one RCT (n = 600). Remdesivir did not decrease all-cause mortality (RR 0.71, 95%CI 0.39 to 1.28, I2 = 43%) and need for invasive ventilation (RR 0.57, 95%CI 0.23 to 1.42, I2 = 60%) vs. placebo at 14 days but had fewer SAEs; 5-day decreased need for invasive ventilation and SAEs vs. 10-day in one RCT (n = 397). No differences in all-cause mortality or SAEs were seen among 5-day, 10-day and standard of care. There were some concerns of bias to high risk of bias in RCTs. Heterogeneity between studies could be due to different severities of disease, days of therapy before outcome determination, and how ordinal data was analyzed.ConclusionsThere is paucity of adequately powered and fully reported RCTs evaluating effects of remdesivir in hospitalized COVID-19 patients. Until stronger evidence emerges, we cannot conclude that remdesivir is efficacious for treating COVID-19.

Effects of Melissa officinalis (Lemon Balm) on cardio-metabolic outcomes: A systematic review and meta-analysis.

Recent evidence indicates a beneficial effect of Melissa officinalis (MO) intake on several chronic diseases. However, the effects of MO intake have not yet been systematically reviewed. Therefore, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of MO intake and focused on several cardiometabolic outcomes. MEDLINE, Scopus, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials were searched for MO-RCTs evaluating cardiometabolic outcomes. Random-effects meta-analyses estimated the pooled standardized mean differences (SMD) between intervention and control groups. Risk of bias was assessed with the Cochrane Collaboration's tool for assessing the risk of bias in RCTs. Seven RCTs were finally deemed eligible. MO intake was associated with a reduced total cholesterol (TC) (SMD: -0.26; 95% CI: -0.52, -0.01; I2 = 13.7%; k = 6) and a reduced systolic blood pressure (SBP) (SMD: -0.56; 95% CI: -0.85, -0.27; I2 = 00.0%; k = 3). MO intake was not associated with statistically significant changes in triglycerides, low-density lipoprotein, diastolic blood pressure, high sensitivity c-reactive protein levels, fasting blood sugar, HbA1c, insulin or high-density lipoprotein levels. No serious adverse events were reported. The risk of bias was high in a considerable amount of studies. Our study suggests that MO is a safe supplement with beneficial effects on TC and SBP. However, the findings of our study must be seen in the light of major limitations such as a low number of included studies and a serious risk of bias. High-quality RCTs are needed for firm conclusions concerning the effects of MO on cardiometabolic outcomes.

Exercise-Based Strategies to Prevent Muscle Injury in Elite Footballers: A Systematic Review and Best Evidence Synthesis

Exercise-based strategies are used to prevent muscle injuries in football and studies on different competitive-level populations may provide different results. To evaluate the effectiveness of exercise-based muscle injury prevention strategies in adult elite football. A systematic search was conducted in PubMed (MEDLINE), Web of Science, Cochrane Library, and SPORTDiscuss (EBSCO). We considered only elite adult (> 16year-old) football players with no distinction for gender; the intervention to be any exercise/s performed with the target to prevent lower-limb muscle injuries; the comparison to be no injury prevention exercise undertaken; the outcome to be the number of injuries, injury incidence, and severity. We searched systematic reviews, randomized-controlled trials (RCTs), and non-randomized-controlled trials (NRCTs), limited for English language. Risk of bias was assessed using the Risk of Bias in Systematic Reviews tool, the Cochrane Collaboration's Tool for assessing risk of bias in RCTs, and the Risk of Bias in NRCTs of Interventions tool. 15 studies were included. Three systematic reviews showed inconsistent results, with one supporting (high risk of bias) and two showing insufficient evidence (low risk of bias) to support exercise-based strategies to prevent muscle injuries in elite players. Five RCTs and seven NRCTs support eccentric exercise, proprioception exercises, and a multi-dimensional component to aninjury prevention program; however, all were deemed to be at high/critical risk of bias. Only one RCT was found at low risk of bias and supported eccentric exercise for preventing groin problems. We found limited scientific evidence to support exercise-based strategies to prevent muscle injury in elite footballers. PROSPERO CRD42017077705.

The use of journal clubs to teach evidence-based medicine to health professionals: A systematic review and meta-analysis.

Journal clubs are an educational activity in which individuals meet to critique and discuss research articles. They are an established part of the medical education system and are considered to be a practical way to improve the content knowledge of health professionals. To determine the effectiveness of journal clubs for increasing health professionals' competency in EBM. A systematic review of randomized controlled trials (RCTs) was performed. Electronic searches were conducted in October 2019 across MEDLINE, ERIC and Scopus databases. Two authors independently reviewed articles, and extracted data. A risk-of-bias tool, based on the Cochrane Collaboration's tool for assessing risk of bias in RCTs, was used to assess internal validity. A total of 151 citations were returned, from which five studies (n=378 individuals) were included in the final review. No overall statistical difference in knowledge scores was observed between health professionals participating in journal clubs compared to other professional education modes (SMD 0.15, 95% CI -0.09, 0.39). Similarly, no significant difference in attitudes or implementation of evidence-based medicine practices was observed across studies. There is insufficient evidence to support the effectiveness of journal clubs in improving the knowledge, attitudes, and implementation of evidence-based skills by health professionals in clinical practice. Further research is needed to test the effectiveness of other interventions to increase uptake of EBM in real world settings. Such interventions may include interactive components with auditing and feedback to facilitate more effective learning.