Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis

ObjectivesTo investigate whether the conclusion of a recent systematic review and network meta-analysis (Ciprianiet al) that antidepressants are more efficacious than placebo for adult depression was supported by the evidence.DesignReanalysis of a systematic review, with meta-analyses.Data sources522 trials (116 477 participants) as reported in the systematic review by Ciprianiet aland clinical study reports for 19 of these trials.AnalysisWe used the Cochrane Handbook’s risk of bias tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to evaluate the risk of bias and the certainty of evidence, respectively. The impact of several study characteristics and publication status was estimated using pairwise subgroup meta-analyses.ResultsSeveral methodological limitations in the evidence base of antidepressants were either unrecognised or underestimated in the systematic review by Ciprianiet al. The effect size for antidepressants versus placebo on investigator-rated depression symptom scales was higher in trials with a ‘placebo run-in’ study design compared with trials without a placebo run-in design (p=0.05). The effect size of antidepressants was higher in published trials compared with unpublished trials (p<0.0001). The outcome data reported by Ciprianiet aldiffered from the clinical study reports in 12 (63%) of 19 trials. The certainty of the evidence for the placebo-controlled comparisons should be very low according to GRADE due to a high risk of bias, indirectness of the evidence and publication bias. The mean difference between antidepressants and placebo on the 17-item Hamilton depression rating scale (range 0–52 points) was 1.97 points (95% CI 1.74 to 2.21).ConclusionsThe evidence does not support definitive conclusions regarding the benefits of antidepressants for depression in adults. It is unclear whether antidepressants are more efficacious than placebo.

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Benefits and harms of the human papillomavirus (HPV) vaccines: comparison of trial data from clinical study reports with corresponding trial register entries and journal publications

Systematic Reviews ◽

10.1186/s13643-020-01300-1 ◽

2020 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Lars Jørgensen ◽

Peter C. Gøtzsche ◽

Tom Jefferson

Keyword(s):

Systematic Review ◽

Clinical Study ◽

Hpv Vaccine ◽

Meta Analysis ◽

Trial Data ◽

Link Type ◽

Trial Register ◽

Journal Publications ◽

Meta Analyses ◽

Clinical Study Reports

Abstract Background No study has looked at differences of pooled estimates—such as meta-analyses—of corresponding study documents of the same intervention. In this study, we compared meta-analyses of human papillomavirus (HPV) vaccine trial data from clinical study reports with trial data from corresponding trial register entries and journal publications. Methods We obtained clinical study reports from the European Medicines Agency and GlaxoSmithKline, corresponding trial register entries from ClinicalTrials.gov and corresponding journal publications via the Cochrane Collaboration’s Central Register of Controlled Trials, Google Scholar and PubMed. Two researchers extracted data. We compared reporting of trial design aspects and 20 prespecified benefit and harm outcomes extracted from each study document type. Risk ratios were calculated with the random effects inverse variance method. Results We included study documents from 22 randomized clinical trials and 2 follow-up studies with 95,670 healthy participants and non-HPV vaccine comparators (placebo, HPV vaccine adjuvants and hepatitis vaccines). We obtained 24 clinical study reports, 24 corresponding trial register entries and 23 corresponding journal publications; the median number of pages was 1351 (range 357 to 11,456), 32 (range 11 to 167) and 11 (range 7 to 83), respectively. All 24 (100%) clinical study reports, no (0%) trial register entries and 9 (39%) journal publications reported on all six major design-related biases defined by the Cochrane Handbook version 2011. The clinical study reports reported more inclusion criteria (mean 7.0 vs. 5.8 [trial register entries] and 4.0 [journal publications]) and exclusion criteria (mean 17.8 vs. 11.7 and 5.0) but fewer primary outcomes (mean 1.6 vs. 3.5 and 1.2) and secondary outcomes (mean 8.8 vs. 13.0 and 3.2) than the trial register entries. Results were posted for 19 trial register entries (79%). Compared to the clinical study reports, the trial register entries and journal publications contained 3% and 44% of the seven assessed benefit data points (6879 vs. 230 and 3015) and 38% and 31% of the 13 assessed harm data points (167,550 vs. 64,143 and 51,899). No meta-analysis estimate differed significantly when we compared pooled risk ratio estimates of corresponding study document data as ratios of relative risk. Conclusion There were no significant differences in the meta-analysis estimates of the assessed outcomes from corresponding study documents. The clinical study reports were the superior study documents in terms of the quantity and the quality of the data they contained and should be used as primary data sources in systematic reviews. Systematic review registration The protocol for our comparison is registered on PROSPERO as an addendum to our systematic review of the benefits and harms of the HPV vaccines: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20180320.pdf: CRD42017056093. Our systematic review protocol was registered on PROSPERO on January 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20170030.pdf. Two protocol amendments were registered on PROSPERO on November 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20171116.pdf. Our index of the HPV vaccine studies was published in Systematic Reviews on January 2018: 10.1186/s13643-018-0675-z. A description of the challenges obtaining the data was published on September 2018: 10.1136/bmj.k3694.

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Comparative efficacy and acceptability of different antihypertensive drug classes for cardiovascular disease prevention: protocol for a systematic review and network meta-analysis

BMJ Open ◽

10.1136/bmjopen-2020-044302 ◽

2021 ◽

Vol 11 (3) ◽

pp. e044302

Author(s):

Heidi Jussil ◽

Anna Chaimani ◽

Bo Carlberg ◽

Mattias Brunström

Keyword(s):

Systematic Review ◽

Antihypertensive Drug ◽

Meta Analysis ◽

Risk Of Bias ◽

Major Adverse Cardiovascular Events ◽

Bias Assessment ◽

Drug Classes ◽

Randomised Controlled ◽

Meta Analyses ◽

The Impact

IntroductionClinical practice guidelines differ in their recommendations on first-line antihypertensive drug classes. No adequately powered randomised controlled trial have assessed all major drug classes against each other, and previous meta-analyses have mainly relied on pairwise meta-analyses for treatment comparisons.Methods and analysisA systematic review and network meta-analysis will be carried out to assess the efficacy and acceptability of all major antihypertensive drug classes. PubMed and CENTRAL were searched on 21 February 2020 to identify randomised controlled trials with at least 1000 person-years of follow-up, assessing any antihypertensive agent against other agents or placebo. All trials fulfilling the inclusion criteria will be assessed for risk of bias using the second version of Cochrane’s risk of bias assessment tool. The study selection process, risk of bias assessment and data extraction are done by two authors in duplicate. Relative risks from individual trials will be combined in pairwise meta-analyses; in the absence of important intransitivity, random-effects network meta-analysis will be performed. The primary outcome for efficacy will be major adverse cardiovascular events, whereas the primary acceptability outcome will be treatment discontinuation for any reason. Additional outcomes include all-cause mortality, cardiovascular mortality, stroke, myocardial infarction, heart failure and acute renal failure. The impact of differences within drug classes will be explored through alternative networks, including analysing thiazide-like and thiazide-type diuretics separately.Ethics and disseminationThis review will only process aggregated study level data and does not require ethical approval. The findings will be published in a peer-reviewed medical journal.PROSPERO registration numberCRD42020205482.

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Physically active lessons in schools and their impact on physical activity, educational, health and cognition outcomes: a systematic review and meta-analysis

British Journal of Sports Medicine ◽

10.1136/bjsports-2018-100502 ◽

2019 ◽

Vol 54 (14) ◽

pp. 826-838 ◽

Cited By ~ 13

Author(s):

Emma Norris ◽

Tommy van Steen ◽

Artur Direito ◽

Emmanuel Stamatakis

Keyword(s):

Physical Activity ◽

Systematic Review ◽

Health Outcomes ◽

Educational Outcomes ◽

Meta Analysis ◽

Risk Of Bias ◽

Control Group ◽

Physically Active ◽

Meta Analyses ◽

The Impact

ObjectiveThis review provides the first meta-analysis of the impact of physically active lessons on lesson-time and overall physical activity (PA), as well as health, cognition and educational outcomes.DesignSystematic review and meta-analysis of controlled studies. Six meta-analyses pooled effects on lesson-time PA, overall PA, in-class educational and overall educational outcomes, cognition and health outcomes. Meta-analyses were conducted using the metafor package in R. Risk of bias was assessed using the Cochrane tool for risk of bias.Data sourcesPubMed, Embase, PsycINFO, ERIC and Web of Science, grey literature and reference lists were searched in December 2017 and April 2019.Studies eligibility criteriaPhysically active lessons compared with a control group in a randomised or non-randomised design, within single component interventions in general school populations.Results42 studies (39 in preschool or elementary school settings, 27 randomised controlled trials) were eligible to be included in the systematic review and 37 of them were included across the six meta-analyses (n=12 663). Physically active lessons were found to produce large, significant increases in lesson-time PA (d=2.33; 95% CI 1.42 to 3.25: k=16) and small, increases on overall PA (d=0.32; 95% CI 0.18 to 0.46: k=8), large, improvement in lesson-time educational outcomes (d=0.81; 95% CI 0.47 to 1.14: k=7) and a small improvement in overall educational outcomes (d=0.36; 95% CI 0.09 to 0.63: k=25). No effects were seen on cognitive (k=3) or health outcomes (k=3). 25/42 studies had high risk of bias in at least two domains.ConclusionIn elementary and preschool settings, when physically active lessons were added into the curriculum they had positive impact on both physical activity and educational outcomes. These findings support policy initiatives encouraging the incorporation of physically active lessons into teaching in elementary and preschool setting.Trial registration numberCRD42017076933.

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Comparative efficacy and safety of interventions for treating head lice: a protocol for systematic review and network meta-analysis

BMJ Paediatrics Open ◽

10.1136/bmjpo-2021-001129 ◽

2021 ◽

Vol 5 (1) ◽

pp. e001129

Author(s):

Bill Stevenson ◽

Wubshet Tesfaye ◽

Julia Christenson ◽

Cynthia Mathew ◽

Solomon Abrha ◽

...

Keyword(s):

Systematic Review ◽

Randomised Controlled Trials ◽

Meta Analysis ◽

Grey Literature ◽

Risk Of Bias ◽

Controlled Trials ◽

Head Lice ◽

Efficacy And Safety ◽

Randomised Controlled ◽

Meta Analyses

BackgroundHead lice infestation is a major public health problem around the globe. Its treatment is challenging due to product failures resulting from rapidly emerging resistance to existing treatments, incorrect treatment applications and misdiagnosis. Various head lice treatments with different mechanism of action have been developed and explored over the years, with limited report on systematic assessments of their efficacy and safety. This work aims to present a robust evidence summarising the interventions used in head lice.MethodThis is a systematic review and network meta-analysis which will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement for network meta-analyses. Selected databases, including PubMed, Embase, MEDLINE, Web of Science, CINAHL and Cochrane Central Register of Controlled Trials will be systematically searched for randomised controlled trials exploring head lice treatments. Searches will be limited to trials published in English from database inception till 2021. Grey literature will be identified through Open Grey, AHRQ, Grey Literature Report, Grey Matters, ClinicalTrials.gov, WHO International Clinical Trials Registry and International Standard Randomised Controlled Trials Number registry. Additional studies will be sought from reference lists of included studies. Study screening, selection, data extraction and assessment of methodological quality will be undertaken by two independent reviewers, with disagreements resolved via a third reviewer. The primary outcome measure is the relative risk of cure at 7 and 14 days postinitial treatment. Secondary outcome measures may include adverse drug events, ovicidal activity, treatment compliance and acceptability, and reinfestation. Information from direct and indirect evidence will be used to generate the effect sizes (relative risk) to compare the efficacy and safety of individual head lice treatments against a common comparator (placebo and/or permethrin). Risk of bias assessment will be undertaken by two independent reviewers using the Cochrane Risk of Bias tool and the certainty of evidence assessed using the Grading of Recommendations, Assessment, Development and Evaluations guideline for network meta-analysis. All quantitative analyses will be conducted using STATA V.16.DiscussionThe evidence generated from this systematic review and meta-analysis is intended for use in evidence-driven treatment of head lice infestations and will be instrumental in informing health professionals, public health practitioners and policy-makers.PROSPERO registration numberCRD42017073375.

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Effects of Sport-Based Interventions on Children’s Executive Function: A Systematic Review and Meta-Analysis

Brain Sciences ◽

10.3390/brainsci11060755 ◽

2021 ◽

Vol 11 (6) ◽

pp. 755

Author(s):

Falonn Contreras-Osorio ◽

Christian Campos-Jara ◽

Cristian Martínez-Salazar ◽

Luis Chirosa-Ríos ◽

Darío Martínez-García

Keyword(s):

Systematic Review ◽

Working Memory ◽

Executive Function ◽

Inhibitory Control ◽

Cognitive Flexibility ◽

Meta Analysis ◽

Scientific Evidence ◽

Healthy Children ◽

Meta Analyses ◽

The Impact

One of the most studied aspects of children’s cognitive development is that of the development of the executive function, and research has shown that physical activity has been demonstrated as a key factor in its enhancement. This meta-analysis aims to assess the impact of specific sports interventions on the executive function of children and teenagers. A systematic review was carried out on 1 November 2020 to search for published scientific evidence that analysed different sports programs that possibly affected executive function in students. Longitudinal studies, which assessed the effects of sports interventions on subjects between 6 and 18 years old, were identified through a systematic search of the four principal electronic databases: Web of Science, PubMed, Scopus, and EBSCO. A total of eight studies, with 424 subjects overall, met the inclusion criteria and were classified based on one or more of the following categories: working memory, inhibitory control, and cognitive flexibility. The random-effects model for meta-analyses was performed with RevMan version 5.3 to facilitate the analysis of the studies. Large effect sizes were found in all categories: working memory (ES −1.25; 95% CI −1.70; −0.79; p < 0.0001); inhibitory control (ES −1.30; 95% CI −1.98; −0.63; p < 0.00001); and cognitive flexibility (ES −1.52; 95% CI −2.20; −0.83; p < 0.00001). Our analysis concluded that healthy children and teenagers should be encouraged to practice sports in order to improve their executive function at every stage of their development.

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Predictability of rotational tooth movement with orthodontic aligners comparing software-based and achieved data: A systematic review and meta-analysis of observational studies

Journal of Orthodontics ◽

10.1177/14653125211027266 ◽

2021 ◽

pp. 146531252110272

Author(s):

Despina Koletsi ◽

Anna Iliadi ◽

Theodore Eliades

Keyword(s):

Effect Size ◽

Tooth Movement ◽

Data Extraction ◽

Meta Analysis ◽

Risk Of Bias ◽

Patient Treatment ◽

Qualitative Synthesis ◽

Meta Analyses ◽

Enamel Reduction

Objective: To evaluate all available evidence on the prediction of rotational tooth movements with aligners. Data sources: Seven databases of published and unpublished literature were searched up to 4 August 2020 for eligible studies. Data selection: Studies were deemed eligible if they included evaluation of rotational tooth movement with any type of aligner, through the comparison of software-based and actually achieved data after patient treatment. Data extraction and data synthesis: Data extraction was done independently and in duplicate and risk of bias assessment was performed with the use of the QUADAS-2 tool. Random effects meta-analyses with effect sizes and their 95% confidence intervals (CIs) were performed and the quality of the evidence was assessed through GRADE. Results: Seven articles were included in the qualitative synthesis, of which three contributed to meta-analyses. Overall results revealed a non-accurate prediction of the outcome for the software-based data, irrespective of the use of attachments or interproximal enamel reduction (IPR). Maxillary canines demonstrated the lowest percentage accuracy for rotational tooth movement (three studies: effect size = 47.9%; 95% CI = 27.2–69.5; P < 0.001), although high levels of heterogeneity were identified (I2: 86.9%; P < 0.001). Contrary, mandibular incisors presented the highest percentage accuracy for predicted rotational movement (two studies: effect size = 70.7%; 95% CI = 58.9–82.5; P < 0.001; I2: 0.0%; P = 0.48). Risk of bias was unclear to low overall, while quality of the evidence ranged from low to moderate. Conclusion: Allowing for all identified caveats, prediction of rotational tooth movements with aligner treatment does not appear accurate, especially for canines. Careful selection of patients and malocclusions for aligner treatment decisions remain challenging.

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A protocol for the systematic review and meta-analysis of thigmotactic behaviour in the open field test in rodent models associated with persistent pain

BMJ Open Science ◽

10.1136/bmjos-2020-100135 ◽

2021 ◽

Vol 5 (1) ◽

pp. e100135

Author(s):

Xue Ying Zhang ◽

Jan Vollert ◽

Emily S Sena ◽

Andrew SC Rice ◽

Nadia Soliman

Keyword(s):

Systematic Review ◽

Outcome Measure ◽

Meta Analysis ◽

Persistent Pain ◽

Effect Sizes ◽

Bias Assessment ◽

Animal Pain ◽

Trim And Fill ◽

Meta Analyses ◽

The Impact

ObjectiveThigmotaxis is an innate predator avoidance behaviour of rodents and is enhanced when animals are under stress. It is characterised by the preference of a rodent to seek shelter, rather than expose itself to the aversive open area. The behaviour has been proposed to be a measurable construct that can address the impact of pain on rodent behaviour. This systematic review will assess whether thigmotaxis can be influenced by experimental persistent pain and attenuated by pharmacological interventions in rodents.Search strategyWe will conduct search on three electronic databases to identify studies in which thigmotaxis was used as an outcome measure contextualised to a rodent model associated with persistent pain. All studies published until the date of the search will be considered.Screening and annotationTwo independent reviewers will screen studies based on the order of (1) titles and abstracts, and (2) full texts.Data management and reportingFor meta-analysis, we will extract thigmotactic behavioural data and calculate effect sizes. Effect sizes will be combined using a random-effects model. We will assess heterogeneity and identify sources of heterogeneity. A risk-of-bias assessment will be conducted to evaluate study quality. Publication bias will be assessed using funnel plots, Egger’s regression and trim-and-fill analysis. We will also extract stimulus-evoked limb withdrawal data to assess its correlation with thigmotaxis in the same animals. The evidence obtained will provide a comprehensive understanding of the strengths and limitations of using thigmotactic outcome measure in animal pain research so that future experimental designs can be optimised. We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines and disseminate the review findings through publication and conference presentation.

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Influence of Coronal Preflaring on the Accuracy of Electronic Working Length Determination: Systematic Review and Meta-Analysis

Journal of Clinical Medicine ◽

10.3390/jcm10132760 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2760

Author(s):

María León-López ◽

Daniel Cabanillas-Balsera ◽

Victoria Areal-Quecuty ◽

Jenifer Martín-González ◽

María C. Jiménez-Sánchez ◽

...

Keyword(s):

Systematic Review ◽

Science Studies ◽

Meta Analysis ◽

Experimental Studies ◽

Risk Of Bias ◽

Permanent Teeth ◽

Total Risk ◽

Human Teeth ◽

Working Length ◽

Meta Analyses

Aim. To conduct a systematic review and meta-analysis according to the following PICO question: in extracted human permanent teeth, does preflaring, compared with unflared canals, influence the accuracy of WL determination with EAL? Material and Methods. A systematic review was conducted according to the PRISMA checklist, using the following databases: PubMed, Science Direct, Scopus, and Web of Science. Studies related to WL determination using EAL both in preflared and unflared root canals of extracted human teeth were included. The outcome of interest was the accuracy of the electronic WL determination. A quality assessment of the included studies was performed, determining the risk of bias. The meta-analyses were calculated with the 5.4 RevMan software using the inverse variance method with random effects. PROSPERO registration: CRD42021243412. Results. Ten experimental studies fulfilled the inclusion criteria, and most of them found that preflaring increases the accuracy of the EALs in WL determination. The calculated OR was 1.98 (95% CI = 1.65–2.37; p < 0.00001; I2 = 10%), indicating that the determination of WL by EALs is almost twice as accurate in preflared canals. The accuracy of Root ZX in WL determination increases more than three times (OR = 3.25; p < 0.00001). Preflaring with Protaper files significantly increases the accuracy of EALs (OR = 1.76; p < 0.00001). The total risk of bias of the included studies was low. No obvious publication bias was observed. Conclusions. The results indicate a significant increase in the accuracy of WL determination with EAL after preflaring, doubling the percentage of exact measurements. Preflaring should be recommended as an important step during mechanical enlargement of the root canal, not only because it improves the access of the files to the canal, but also because it allows one to obtain more accurate electronic determinations of WL.

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Evaluating the effectiveness of interventions to reducing screen time in children: meta-analysis of randomized controlled trials

Journal of Public Mental Health ◽

10.1108/jpmh-03-2021-0039 ◽

2021 ◽

Vol ahead-of-print (ahead-of-print) ◽

Author(s):

Duygu Akçay ◽

Nuray Barış

Keyword(s):

Effect Size ◽

Subgroup Analysis ◽

Screen Time ◽

Meta Analysis ◽

Intervention Group ◽

Evidence Base ◽

Control Group ◽

Content Type ◽

Mean Differences ◽

The Impact

Purpose The purpose of this paper is to evaluate the impact of interventions focused on reducing screen time in children. Design/methodology/approach Studies that aim to investigate the effects of interventions aimed at reducing the time spent in front of the screen (i.e. screen time). A Random-effects model was used to calculate the pooled standard mean differences. The outcome was to evaluate the screen time in children in the 0–18 age range. A subgroup analysis was performed to reveal the extent to which the overall effect size varied by subgroups (participant age, duration of intervention and follow). Findings For the outcome, the meta-analysis included 21 studies, and the standard difference in mean change in screen time in the intervention group compared with the control group was −0.16 (95% confidence interval [CI], −0.21 to −0.12) (p < 0.001). The effect size was found to be higher in long-term (=7 months) interventions and follow-ups (p < 0.05). Originality/value Subgroup analysis showed that a significant effect of screen time reduction was observed in studies in which the duration of intervention and follow-up was =7 months. As the evidence base grows, future researchers can contribute to these findings by conducting a more comprehensive analysis of effect modifiers and optimizing interventions to reduce screen time.

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The Effect of Plantago major on Wound Healing in Preclinical Studies: A Systematic Review

Wound Management & Prevention ◽

10.25270/wmp.2021.1.2734 ◽

2021 ◽

Vol 67 (1) ◽

pp. 27-34

Author(s):

Fernanda Cardoso ◽

Jéssica Breder ◽

Priscila Apolinário ◽

Henrique Oliveia ◽

Maria Saidel ◽

...

Keyword(s):

Systematic Review ◽

Wound Healing ◽

Meta Analysis ◽

Experimental Studies ◽

Risk Of Bias ◽

Preclinical Studies ◽

Plantago Major ◽

Best Response ◽

Meta Analyses

BACKGROUND: Plantago major is a medicinal plant that has been used for centuries to treat various health conditions including wounds. PURPOSE: To investigate the effectiveness of the topical use of P major in healing skin wounds in animal models. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review was conducted. Seven (7) electronic databases (Virtual Health Library, Public/Publisher MEDLINE, Scopus, Web of Science, Embase, Cumulative Index of Nursing and Allied Health Literature, and CAB Direct) were searched for controlled studies published in English from January 2006 to March 2020. The Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies tools guided the evaluation of the studies and determined their quality. The Systematic Review Center for Laboratory Animal Experimentation was used to assess the risk of bias. RESULTS: Of the 176 publications identified, 4 met the inclusion criteria. Studies included 20 to 100 animals and varying concentrations of P major. There were no reports of losses during research. Wound healing was assessed between 17 and 21 days following wounding. The best response in terms of wound contraction rate occurred with 10%, 20%, and 50% concentrations when compared with control groups. One (1) study did not have an animal ethics committee review. All studies had a high risk of bias and a lack of methodological rigor. CONCLUSION: The results of this review did not find evidence about the in vivo effectiveness of P major for wound healing. More rigorous preclinical studies with adequate sample sizes are required to identify the best concentrations and formulations as well as increase understanding about the mechanisms of action of P major in wound healing.

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