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Objective: It is frequent to find overlapping network meta-analyses (NMAs) on the same topic with differences in terms of both treatments included and effect estimates. We aimed to evaluate the impact on effect estimates of selecting different treatment combinations (ie, network geometries) for inclusion in NMAs., Design: Multiverse analysis, covering all possible NMAs on different combinations of treatments., Setting: Data from a previously published NMA exploring the comparative effectiveness of 22 treatments (21 antidepressants and a placebo) for the treatment of acute major depressive disorder., Participants: Cipriani et al explored a dataset of 116 477 patients included in 522 randomised controlled trials., Main Outcome Measures: For each possible treatment selection, we performed an NMA to estimate comparative effectiveness on treatment response and treatment discontinuation for the treatments included (231 between-treatment comparisons). The distribution of effect estimates of between-treatment comparisons across NMAs was computed, and the direction, magnitude and statistical significance of the 1st and 99th percentiles were compared., Results: 4 116 254 different NMAs concerned treatment response. Among possible network geometries, 172/231 (74%) pairwise comparisons exhibited opposite effects between the 1st and 99th percentiles, 57/231 (25%) comparisons exhibited statistically significant results in opposite directions, 118 of 231 (51%) comparisons derived results that were both significant and non-significant at 5% risk and 56/231 (24%) treatment pairs obtained consistent results with only significant differences (or only non-significant differences) at 5% risk. Comparisons based on indirect evidence only were associated with greater variability in effect estimates. Comparisons with small absolute values observed in the complete NMA more frequently obtained statistically significant results in opposite directions. Similar results were observed for treatment discontinuation., Conclusion: In this multiverse analysis, we observed that the selection of treatments to be included in an NMA could have considerable consequences on treatment effect estimations., Trial Registration: https://osf.io/mb5dy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and declare that FN received funding from the French National Research Agency (ANR-17-CE36-0010), the French ministry of health, and the French ministry of research. He is a work package leader in the OSIRIS project (Open Science to Increase Reproducibility in Science). The OSIRIS project has received funding from the European Union’s Horizon Europe research and innovation program under the grant agreement No. 101094725. He is a work package leader for the doctoral network MSCA-DN SHARE-CTD funded by the EU. Provenance and peer review: Not commissioned; externally peer reviewed.

Objectives: To explore the association between industry funding and network meta-analyses' (NMAs) conclusion, and the use in Clinical Practice Guidelines (CPGs) of NMAs., Study Design and Setting: This was an overview of NMAs and CPGs. We searched PubMed/MEDLINE, Epistemonikos, and several guideline databases up to February 18th 2023. We included CPGs from the last 5 years and NMAs of randomized controlled trials that evaluated targeted therapies in immune-mediated inflammatory diseases. Data extraction and outcome assessments were done in duplicate by independent authors., Results: We included 216 NMAs and 99 CPGs. 31% (67/216) were industry-funded. The proportion of industry-funded NMAs that cited one treatment as being best was 44% (25/57) compared to 26% (30/116) for nonindustry-funded (OR = 2.24 [1.15-4.39]; aOR = 1.76 [0.81-3.81]). The abstract's conclusion of 39/67 (58%) industry-funded and 69/149 (46%) nonindustry-funded NMAs were considered unsupported by the results (OR = 1.61 [0.90-2.89]; aOR = 1.40 [0.71-2.78]). All industry-funded NMAs that cited one treatment as best cited their own sponsored drug. 59/99 (60%) CPGs included at least one NMA, with 23/59 (39%) of them citing industry-funded NMAs., Conclusions: We did not find evidence that industry-funded NMAs were more likely to have unsupported conclusions or to cite only one treatment as being best in their conclusions compared to non-industry-funded NMAs. However, almost all industry-funded NMAs favored their own treatments. Even though 40% of the CPGs did not rely on NMA, over a third of those who did used industry-funded NMAs. Limitations include the possible misclassification due to undisclosed funding and potential confounders that have not been accounted for., Competing Interests: Declaration of competing interest Robin Guelimi reports financial support was provided by Public Assistance Hospitals Paris. and the Association for Interdisciplinary Meta-Research and Open Science. LLC, ES, and SA are co-authors of this work and authors of several studies that are included in the submitted overview. L.L.C., E.S., and S.A. are authors of several studies that are included in this overview. L.L.C. took part in the selection process, but none of them were involved in the extraction of data or in the assessment of the quality of a work they took a part in. L.L.C. and E.S. received a grant from the French Ministry of Health (PHRC-N AOM22145). L.L.C. is the co-ordinating editor of the Cochrane Skin. F.N. received funding from the French National Research Agency (ANR-17-CE36-0010), the French ministry of health and the French ministry of research. He is a work package leader in the OSIRIS project (Open Science to Increase Reproducibility in Science). The OSIRIS project has received funding from the European Union's Horizon Europe research and innovation programme under the grant agreement No. 101094725. He is a work package leader for the doctoral network MSCA-DN SHARE-CTD (HORIZON-MSCA-2022-DN-01 101120360) funded by the EU. YZZN received a grant from the NIHR Manchester Biomedical Research Centre (NIHR203308). R.G., A.M., T.B., and G.P. had no conflict of interest to declare. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: CV is a PhD student in the OSIRIS (Open Science to Increase Reproducibility in Science) project. The OSIRIS project has received funding from the European Union’s Horizon Europe research and innovation programme under the grant agreement number 101094725. SH has received funding from the European Union’s Horizon Europe programme, the German Federal Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection (BMUV) and the LMUExcellent. CP received funding from NIH (NIEHS R01ES0324702 and NIA RF1AG074372). NJD has received funding from the European Union’s Horizon Europe programme, also via the OSIRIS project, the Naji Foundation, the German Federal Ministry of Education and Research (BMBF) and the Fetzer Franklin Memorial Fund, and has been employed on grants from the Mohn-Westlake Foundation, Laura and John Arnold Foundation, Elsevier and the Good Thinking Society in the last 5 years. BT is compensated for consulting with Seed Health and Enzymetrics Biosciences on microbiome study design. FN received funding from the French National Research Agency (ANR-17-CE36-0010), the French Ministry of Health and the French Ministry of Research. He is a work package leader in the OSIRIS project. He is a work package leader for the doctoral network MSCA-DN SHARE-CTD (HORIZON-MSCA-2022-DN-01 101120360), funded by the EU. The work of JPAI has been supported by an unrestricted gift from Sue and Bob O’Donnell to Stanford University.

Background: Many interventions, especially those linked to open science, have been proposed to improve reproducibility in science. To what extent these propositions are based on scientific evidence from empirical evaluations is not clear., Aims: The primary objective is to identify Open Science interventions that have been formally investigated regarding their influence on reproducibility and replicability. A secondary objective is to list any facilitators or barriers reported and to identify gaps in the evidence., Methods: We will search broadly by using electronic bibliographic databases, broad internet search, and contacting experts in the field of reproducibility, replicability, and open science. Any study investigating interventions for their influence on the reproducibility and replicability of research will be selected, including those studies additionally investigating drivers and barriers to the implementation and effectiveness of interventions. Studies will first be selected by title and abstract (if available) and then by reading the full text by at least two independent reviewers. We will analyze existing scientific evidence using scoping review and evidence gap mapping methodologies., Results: The results will be presented in interactive evidence maps, summarized in a narrative synthesis, and serve as input for subsequent research., Review Registration: This protocol has been pre-registered on OSF under doi https://doi.org/10.17605/OSF.IO/D65YS., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Dudda LA et al.)

Background: Pain is a non-motor symptom that impairs quality of life in Parkinson's patients. Pathological nociceptive hypersensitivity in patients could be due to changes in the processing of somatosensory information at the level of the basal ganglia, including the subthalamic nucleus (STN), but the underlying mechanisms are not yet defined. Here, we investigated the interaction between the STN and the dorsal horn of the spinal cord (DHSC), by first examining the nature of STN neurons that respond to peripheral nociceptive stimulation and the nature of their responses under normal and pathological conditions. Next, we studied the consequences of deep brain stimulation (DBS) of the STN on the electrical activity of DHSC neurons. Then, we investigated whether the therapeutic effect of STN-DBS would be mediated by the brainstem descending pathway involving the rostral ventromedial medulla (RVM). Finally, to better understand how the STN modulates allodynia, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) expressed in the STN., Methods: The study was carried out on the 6-OHDA rodent model of Parkinson's disease, obtained by stereotactic injection of the neurotoxin into the medial forebrain bundle of rats and mice. In these animals, we used motor and nociceptive behavioral tests, in vivo electrophysiology of STN and wide dynamic range (WDR) DHSC neurons in response to peripheral stimulation, deep brain stimulation of the STN and the selective DREADD approach. Vglut2-ires-cre mice were used to specifically target and inhibit STN glutamatergic neurons., Results: STN neurons are able to detect nociceptive stimuli, encode their intensity and generate windup-like plasticity, like WDR neurons in the DHSC. These phenomena are impaired in dopamine-depleted animals, as the intensity response is altered in both spinal and subthalamic neurons. Furthermore, As with L-Dopa, STN-DBS in rats ameliorated 6-OHDA-induced allodynia, and this effect is mediated by descending brainstem projections leading to normalization of nociceptive integration in DHSC neurons. Furthermore, this therapeutic effect was reproduced by selective inhibition of STN glutamatergic neurons in Vglut2-ires-cre mice., Conclusion: Our study highlights the centrality of the STN in nociceptive circuits, its interaction with the DHSC and its key involvement in pain sensation in Parkinson's disease. Furthermore, our results provide for the first-time evidence that subthalamic DBS produces analgesia by normalizing the responses of spinal WDR neurons via descending brainstem pathways. These effects are due to direct inhibition, rather than activation of glutamatergic neurons in the STN or passage fibers, as shown in the DREADDs experiment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Consensus statements can be very influential in medicine and public health. Some of these statements use systematic evidence synthesis but others fail on this front. Many consensus statements use panels of experts to deduce perceived consensus through Delphi processes. We argue that stacking of panel members towards one particular position or narrative is a major threat, especially in absence of systematic evidence review. Stacking may involve financial conflicts of interest, but non-financial conflicts of strong advocacy can also cause major bias. Given their emerging importance, we describe here how such consensus statements may be misleading, by analysing in depth a recent high-impact Delphi consensus statement on COVID-19 recommendations as a case example. We demonstrate that many of the selected panel members and at least 35% of the core panel members had advocated towards COVID-19 elimination (zero-COVID) during the pandemic and were leading members of aggressive advocacy groups. These advocacy conflicts were not declared in the Delphi consensus publication, with rare exceptions. Therefore, we propose that consensus statements should always require rigorous evidence synthesis and maximal transparency on potential biases towards advocacy or lobbyist groups to be valid. While advocacy can have many important functions, its biased impact on consensus panels should be carefully avoided., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The dissemination of clinical trial results is an important scientific and ethical endeavour. This survey of completed interventional studies in a French academic center describes their reporting status., Methods: We explored all interventional studies sponsored by Rennes University Hospital identified on the French Open Science Monitor which tracks trials registered on EUCTR or clinicaltrials.gov, and provides an automatic assessment of the reporting of results. For each study, we ascertained the actual reporting of results using systematic searches on the hospital internal database, bibliographic databases (Google Scholar, PubMed), and by contacting all principal investigators (PIs). We describe several features (including total budget and numbers of trial participants) of the studies that did not report any results., Results: The French Open Science Monitor identified 93 interventional studies, among which 10 (11%) reported results. In contrast, our survey identified 36 studies (39%) reporting primary analysis results and an additional 18 (19%) reporting results for secondary analyses (without results for their primary analysis). The overall budget for studies that did not report any results was estimated to be €5,051,253 for a total of 6,735 trial participants. The most frequent reasons for the absence of results reported by PIs were lack of time for 18 (42%), and logistic difficulties (e.g. delay in obtaining results or another blocking factor) for 12 (28%). An association was found between non-publication and negative results (adjusted Odds Ratio = 4.70, 95% Confidence Interval [1.67;14.11])., Conclusions: Even allowing for the fact that automatic searches underestimate the number of studies with published results, the level of reporting was disappointingly low. This amounts to a waste of trial participants' implication and money. Corrective actions are needed., Trial Registration: https://osf.io/q5hcs., (© 2024. The Author(s).)

Competing Interests: Competing interests: DC reports an HIV grant from Janssen (2019-2020), personal fees from Gilead (2020) and Pfizer (2022) for lectures outside the submitted work. RT has been the coordinator of the IMI2 EBOVAC2 project in collaboration with Janssen (2014-2021). Other authors have no competing interests to disclose.

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and have the following interests to declare: FN received funding from the French National Research Agency (ANR-17-CE36-0010), the French Ministry of Health and the French Ministry of Research. He is a work package leader in the OSIRIS project (Open Science to Increase Reproducibility in Science), which has received funding from the European Union’s Horizon Europe research and innovation programme under the grant agreement No. 101094725. He is a work package leader for the doctoral network MSCA-DN SHARE-CTD (HORIZON-MSCA-2022-DN-01 101120360), funded by the EU. CJP received funding from National Institutes for Health (NIEHS R01ES0324702 and NIA RF1AG074372). NJD has received funding from the Horizon Europe programme, the OSIRIS project, the Naji Foundation, the German Federal Ministry of Education and Research, and the Fetzer Franklin Memorial Fund and has been employed on grants from the Mohn-Westlake Foundation, Laura and John Arnold Foundation, Elsevier, and the Good Thinking Society in the past five years. SH has received funding from Horizon Europe, the German Federal Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection, and from LMUExcellent.

Objective: To explore differences between published reviews and their respective protocols in a sample of 97 non-Cochrane Systematic Reviews (non-CSRs) and 97 Cochrane Systematic Reviews (CSRs) in terms of PICOS (Patients/Population, Intervention, Comparison/Control, Outcome, Study type) elements and the extent to which they were reported., Study Design and Setting: We searched PubMed and Cochrane databases to identify non-CSRs and CSRs that were published in 2018. We then searched for their corresponding Cochrane or PROSPERO protocols. The published reviews were compared to their protocols. The primary outcome was changes from protocol to review in terms of PICOS elements., Results: We identified a total of 227 changes from protocol to review in PICOS elements, 1.11 (Standard Deviation (SD), 1.22) changes per review for CSRs and 1.23 (SD, 1.12) for non-CSRs per review. More than half of each sub-sample (54.6% of CSRs and 67.0% of non-CSRs) (Absolute Risk Reduction (ARR) 12.4% [-1.3%; 26.0%]) had changes in PICOS elements. For both subsamples, approximately a third of all changes corresponded to changes related to primary outcomes. Marked differences were found between the sub-samples for the reporting of changes. 95.8% of the changes in PICOS items were not reported in the non-CSRs compared to 42.6% in the CSRs (ARR 53.2% [43.2%; 63.2%])., Conclusion: CSRs showed better results than non-CSRs in terms of the reporting of changes. Reporting of changes from protocol needs to be promoted and requires general improvement. The limitations of this study lie in its observational design. Registration: https://osf.io/6j8gd/., Competing Interests: Marta Roqué, Roberto Acosta-Dighero & Meisser Madera are members of Cochrane. Maximilian Siebert did a 2-month internship at the Iberoamerican Cochrane Center in 2019., (©2023 Siebert et al.)

Competing Interests: Declaration of competing interest None declared. The Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB) is supported by the Foundation Clinical Neuroimmunology and Neuroscience Basel (Switzerland).

Objectives: This descriptive study of registered trials aimed to identify large clinical trials on antidepressants for mental disorders: (1) to assess what proportion could be labelled as 'seeding trials' (trials for marketing purposes) and (2) to describe their methodological characteristics and outcomes., Design: A search was conducted across all trials registered on ClinicalTrials.gov by drug name in March 2017., Setting: All trials registered in the database of ClinicalTrials.gov were screened. Large registered studies were received and studies focusing prospectively on the effects of antidepressants in mental health disorders. Specific data items were extracted automatically, and subsequently inspected, corrected and completed by hand., Participants: Prospective studies were selected focusing on the effects of antidepressants in any mental health disorder with 800 participants or more planned for inclusion., Main Outcome Measures: Three members from the study team independently assessed the following 'seeding trial' characteristics in each registered study: a high level of involvement of the product manufacturer in the study design, in the data analysis and reporting of the study, an abnormally low ratio of patient numbers to study site, spin and/or omissions of clinically relevant findings in the abstracts, and conclusions that focused on secondary endpoints and surrogate markers. Secondary outcomes were the exploration of a functional outcome and suicidality., Results: 31 trials were identified from clinical trials database. 18/31 were published (58%). 8 of these 18 (44%) studies were identified as possible seeding trials. 13/31 (42%) large trials planned to explore functioning and 5/31 (16%) suicidality., Conclusions: Large trials are rare in the field of antidepressant research. Some could be 'seeding trials'. Few explored suicidality. Identifying seeding trials from incomplete data entries in registries, especially when almost half of the studies were still unpublished, posed considerable challenges. The delay between our research and publication limits the strength of our conclusions., Prospero Registration Number: CRD42017065591., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Registered reports (RR) are a publication format implying a peer-review of the protocol before the start of the study, followed by an in-principle acceptance (IPA) by the journal before the study starts. We aimed to describe randomized controlled trials (RCTs) in the clinical field published as RR., Study Design and Setting: This cross-sectional study included RR results for RCTs, identified on PubMed/Medline and on a list compiled by the Center for Open Science. It explored the proportion of reports that received IPA (and/or published a protocol before inclusion of the first patient) and changes in the primary outcome., Results: A total of 93 RCTs publications identified as RR were included. All but one were published in the same journal group. The date of the IPA was never documented. For most of these reports (79/93, 84.9%), a protocol was published after the date of inclusion of the first patient. A change in the primary outcome was noted in 40/93 (44%) of them. Thirteen of the 40 (33%) mentioned this change., Conclusions: RCTs in the clinical field identified as RR were rare, originated from a single journal group, and did not comply with the basic features of this format., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023. Published by Elsevier Inc.)

Competing Interests: Declaration of competing interest The authors declare that they have no competing interests.

Evidence-based medicine is the cornerstone of shared-decision making in healthcare today. The public deserves clear, transparent and trust-worthy information on drug efficacy. Yet today, many drugs are prescribed and used without solid evidence of efficacy. Clinical trials and randomised clinical trials (RCTs) are the best method to evaluate drug efficacy and side effects. In a shared medical decision-making approach, general practitioners need drug assessment based on patient-important outcomes. The aim of project rebuild the evidence base (REB) is to bridge the gap between the data needed in clinical practice and the data available from clinical research. The drugs will be assessed on clinical patient important outcomes and for a population. Using the Cochrane tools, we propose to analyse for each population and outcome: 1) a meta-analysis based on RCTs with a low risk of bias overall; 2) an evaluation of results of confirmatory RCTs; 3) a statistical analysis of heterrogeneity between RCTs and 4) an analysis of publication bias. Depending on the results of these analyses, the evidence will be categorized in 4 different levels: firm evidence, evidence (to be confirmed), signal or absence of evidence. Project REB proposes a method for reading and interpreting RCTs and their meta-analysis to produce quality data for general practitioners to focus on risk-benefit assessment in the interest of patients. If this data does not exist, it could enable clinical research to better its aim., (Copyright © 2022 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Clinical trial data-sharing is seen as an imperative for research integrity and is becoming increasingly encouraged or even required by funders, journals, and other stakeholders. However, early experiences with data-sharing have been disappointing because they are not always conducted properly. Health data is indeed sensitive and not always easy to share in a responsible way. We propose 10 rules for researchers wishing to share their data. These rules cover the majority of elements to be considered in order to start the commendable process of clinical trial data-sharing: Rule 1: Abide by local legal and regulatory data protection requirementsRule 2: Anticipate the possibility of clinical trial data-sharing before obtaining fundingRule 3: Declare your intent to share data in the registration stepRule 4: Involve research participantsRule 5: Determine the method of data accessRule 6: Remember there are several other elements to shareRule 7: Do not proceed aloneRule 8: Deploy optimal data management to ensure that the data shared is usefulRule 9: Minimize risksRule 10: Strive for excellence., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Pellen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: We declare no competing interests.

Objective: To explore the impact of methodological choices on the results of meta-analyses (MAs), with acupuncture for smoking cessation as a case study., Study Design and Setting: After performing an umbrella review (using MEDLINE, the COCHRANE Library, the Wan Fang database, and the Chinese Journal Full-text Database/March 2018) of MAs exploring the use of acupuncture for smoking cessation, we extracted all randomized controlled trials. Numerous MAs were performed as per every possible combination of various methodological choices (e.g., characteristics of the intervention and control procedures, outcome, publication status, language) to assess their vibration of effects or more precisely the existence of a Janus effect, that is, whether the 10th and 90th percentiles in the distribution of effect sizes were in opposite directions., Results: After including 7 MAs and 39 randomized controlled trials, we performed 496,528 MAs. The effect size was negative at the 10th percentile (-0.1, favoring controls) and positive at the 90th percentile (1.17, favoring acupuncture). In all, 104,491 MAs showed a statistically significant difference in favor of acupuncture, whereas 392,037 failed to demonstrate the efficacy of acupuncture (including 96 that showed a statistically significant difference in favor of the control)., Conclusion: The methodological choices made in performing pairwise MAs can result in substantial vibration of effects, occasionally leading to opposite results., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To evaluate the impact of conducting all possible pooled analyses across different combinations of randomised controlled trials and endpoints., Design: Multiverse analysis, consisting of numerous pooled analyses of individual participant data., Setting: Individual patient data from 12 randomised controlled trials comparing canagliflozin treatment with placebo, shared on the Yale University Open Data Access project (https://yoda.yale.edu/) platform, up to 16 April 2021., Participants: 15 094 people with type 2 diabetes mellitus., Main Outcome Measures: Pooled analyses estimated changes in serum glycated haemoglobin (HbA1c), major adverse cardiovascular events, and serious adverse events at weeks 12, 18, 26, and 52. The distribution of effect estimates was calculated for all possible combinations, and the direction and magnitude of the first and 99th centiles of effect estimates were compared., Results: Across 16 332 distinct pooled analyses comparing canagliflozin with placebo for changes in HbA1c, standardised effect estimates were in favour of canagliflozin treatment at both the first centile (-0.75%) and 99th centile (-0.48%); 15 994 (97.93%) analyses showed significant results (P<0.05) in favour of canagliflozin. For major adverse cardiovascular events, estimated hazard ratios were 0.20 at the first centile and 0.90 at the 99th centile; 2705 of 8144 analyses (33.21%) were significant, all of which were in favour of canagliflozin treatment. For serious adverse events, estimated hazard ratios were 0.59 at the first centile and 1.14 at the 99th centile; 5793 of 16 332 (35.47%) analyses were significant, with 5754 in favour of canagliflozin and 39 in favour of placebo., Conclusion: Results from pooled analyses can be subject to vibration of effects and should be critically appraised, especially regarding the risk for selection and availability bias in individual participant data retrieved., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Agence Nationale de la Recherche for the submitted work. JDW currently receives research support from the US Food and Drug Administration and the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under award K01AA028258. JSR currently receives research support through Yale University from Johnson and Johnson to establish the YODA project and develop methods of clinical trial data sharing; from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology; from the FDA for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation program (U01FD005938); from the Agency for Healthcare Research and Quality (R01HS022882); from the National Heart, Lung, and Blood Institute of the National Institutes of Health (R01HS025164, R01HL144644); and from the Laura and John Arnold Foundation to establish the Good Pharma Scorecard at Bioethics International; JSR is an expert witness at the request of Relator's attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen; JSR is an associate editor at The BMJ and an editorial board member at BMJ Medicine; he was not involved in BMJ Medicine’s handling of this manuscript., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Under-representation of women in high academic and medical positions is reported in many countries. This study aims to compare degrees and careers between men and women tenured as Full Professors of Medicine in recent years in France., Methods: We identified all new tenured French Full Professors between 2017 and 2021 and collected the publicly available data (gender, year of birth, curriculum) from the Bibliographic Agency for Higher Education, a public institution under the aegis of the Ministry for Higher Education Research and Innovation. The primary outcome was the gender difference in age appointment of Full Professors. Secondary outcomes were gender differences in career development., Results: Among 820 Full Professors, only 266 (32.4%) were women. They were tenured at a later age than men (43.7 vs 42.4 years, p<0.001), while they graduated for the MD (29.5 vs 29.9 years, p<0.005) or PhD (35.3 vs 36.0 years, p<0.05) several months earlier. Women were also more often Associate Professors than men before becoming Full Professors (67.3% vs 59.2%, p<0.05).  Before achieving Full professor tenure, the average delay is longer for women from MD graduation (14.6 vs 12.5 years), PhD graduation (8.7 vs 6.4 years), or Associate Professor nomination (7.5 vs 5.5 years), with a difference of 2.2, 2.4 and 2.0 years respectively (p<0.001 for all comparisons)., Conclusion: Gender inequalities remain in regards to access to Full Professor status, the highest position in the medical fields., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Data sharing is gradually becoming a requirement across all fields of science, owing to its key benefits in verifying the reproducibility of findings and reusing existent data for new purposes. Although metaresearch studies are complex, time-consuming, and hinge on the availability of data produced and curated by others, there has been little focus on how they make their own data available. This is in stark contrast to the heightened attention data sharing has received in clinical research. Yet, as secondary data users par excellence, metaresearchers are ethically bound to both improving and evaluating data sharing practices and correctly sharing their own data. We contrast particularities of data sharing in metaresearch and clinical research, such as benefits, barriers, and inadequate and potentially pervasive sharing practices. We conclude with an array of concrete and tailored recommendations for improvement., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aim: The placebo effect and the specific effect are often thought to add up (additive model). Whether additivity holds can dramatically influence the external validity of a trial. This assumption of additivity was tested by Kleijnen et al in 1994 but the data produced since then have not been synthetized. In this review, we aimed to systematically review the literature to determine whether additivity held., Methods: We searched Medline and PsychInfo up to 10 January 2019. Studies using the balanced placebo design (BPD), testing two different strengths of placebos, were included. The presence of interaction was evaluated by comparing each group in the BPD with analysis of variance or covariance., Results: Thirty studies were included and the overall risk of bias was high: four found evidence of additivity and 16 studies found evidence of interaction (seven had evidence of positive additivity)., Conclusion: Evidence of additivity between placebo and specific features of treatments was rare in included studies. We suggest interventions for placebo-sensitive ailments should be tested in trials designed to take interactions seriously once an exploratory RCTs has proven their efficacy with sufficient internal validity., (© 2022 British Pharmacological Society.)

Background: Network meta-analyses (NMAs) have become successful in addressing gaps in the comparative effectiveness of systemic treatments in moderate-to-severe psoriasis. However, their increasing number carries both a risk of overlap and reproducibility issues that can hamper clinical decision-making., Objectives: In this overview, we aimed to assess redundancy across these NMAs and to describe their characteristics., Materials and Methods: We considered all systematic reviews with NMAs of randomized controlled trials that included adult patients with moderate-to-severe psoriasis and that evaluated the efficacy and/or safety of systemic treatments compared with placebo or with an active comparator. PubMed/MEDLINE, Epistemonikos, PROSPERO and the Evidence update of the Centre of Evidence-Based Dermatology of the University of Nottingham were searched up to 25 February 2021. Our main outcome was the number per year of redundant NMAs and the extent of their overlap. We also described their features, especially, the confidence in the results of the reviews, the funding of the studies and the presence of spin (a description that overstates efficacy and/or understates harm), reporting issues and methodological characteristics., Results: In total, 47 redundant NMAs were included. Only two of 47 (4%) included all available treatments. Both efficacy and safety were evaluated in 14 of 47 (30%) NMAs and both short- and long-term evaluations were assessed in five of 47 (11%). Confidence in the results was critically low for 39 of 47 (83%) NMAs and only 10 of 47 (21·3%) registered a protocol. Twenty-six of 47 NMAs (55%) received pharmaceutical funding. Contract research organizations were involved in 19 of 47 (40%) NMAs. Reporting was poor across most of the NMA abstracts and spin was present in all of the abstracts. Almost half of the NMAs failed to consider important limitations such as heterogeneity (considered in 32%) or consistency (considered in 66%)., Conclusions: In addition to a duplication of efforts, our overview showed heterogeneous methods and poor confidence in the results in a majority of the included NMAs, further distorted by reporting issues and spin. Clinicians need to interpret NMAs with caution when looking for the most reliable and comprehensive evidence., (© 2022 British Association of Dermatologists.)

Importance: Clinical trial data sharing holds promise for maximizing the value of clinical research. The International Committee of Medical Journal Editors (ICMJE) adopted a policy promoting data sharing in July 2018., Objective: To evaluate the association of the ICMJE data sharing policy with data availability and reproducibility of main conclusions among leading surgical journals., Design, Setting, and Participants: This cross-sectional study, conducted in October 2021, examined randomized clinical trials (RCTs) in 10 leading surgical journals before and after the implementation of the ICMJE data sharing policy in July 2018., Exposure: Implementation of the ICMJE data sharing policy., Main Outcomes and Measures: To demonstrate a pre-post increase in data availability from 5% to 25% (α = .05; β = 0.1), 65 RCTs published before and 65 RCTs published after the policy was issued were included, and their data were requested. The primary outcome was data availability (ie, the receipt of sufficient data to enable reanalysis of the primary outcome). When data sharing was available, the primary outcomes reported in the journal articles were reanalyzed to explore reproducibility. The reproducibility features of these studies were detailed., Results: Data were available for 2 of 65 RCTs (3.1%) published before the ICMJE policy and for 2 of 65 RCTs (3.1%) published after the policy was issued (odds ratio, 1.00; 95% CI, 0.07-14.19; P > .99). A data sharing statement was observed in 11 of 65 RCTs (16.9%) published after the policy vs none before the policy (risk ratio, 2.20; 95% CI, 1.81-2.68; P = .001). Data obtained for reanalysis (n = 4) were not from RCTs published with a data sharing statement. Of the 4 RCTs with available data, all of them had primary outcomes that were fully reproduced. However, discrepancies or inaccuracies that were not associated with study conclusions were identified in 3 RCTs. These concerned the number of patients included in 1 RCT, the management of missing values in another RCT, and discrepant timing for the principal outcome declared in the study registration and reported in the third RCT., Conclusions and Relevance: This cross-sectional study suggests that data sharing practices are rare in surgical journals despite the ICMJE policy and that most RCTs published in these journals lack transparency. The results of these studies may not be reproducible by external researchers.

During the COVID-19 pandemic, the rush to scientific and political judgements on the merits of hydroxychloroquine was fuelled by dubious papers which may have been published because the authors were not independent from the practices of the journals in which they appeared. This example leads us to consider a new type of illegitimate publishing entity, 'self-promotion journals' which could be deployed to serve the instrumentalisation of productivity-based metrics, with a ripple effect on decisions about promotion, tenure and grant funding, but also on the quality of manuscripts that are disseminated to the medical community and form the foundation of evidence-based medicine., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Transparency and reproducibility are expected to be normative practices in clinical trials used for decision-making on marketing authorisations for new medicines. This registered report introduces a cross-sectional study aiming to assess inferential reproducibility for main trials assessed by the European Medicines Agency., Methods: Two researchers independently identified all studies on new medicines, biosimilars and orphan medicines given approval by the European Commission between January 2017 and December 2019, categorised as 'main studies' in the European Public Assessment Reports (EPARs). Sixty-two of these studies were randomly sampled. One researcher retrieved the individual patient data (IPD) for these studies and prepared a dossier for each study, containing the IPD, the protocol and information on the conduct of the study. A second researcher who had no access to study reports used the dossier to run an independent re-analysis of each trial. All results of these re-analyses were reported in terms of each study's conclusions, p-values, effect sizes and changes from the initial protocol. A team of two researchers not involved in the re-analysis compared results of the re-analyses with published results of the trial., Results: Two hundred ninety-two main studies in 173 EPARs were identified. Among the 62 studies randomly sampled, we received IPD for 10 trials. The median number of days between data request and data receipt was 253 [interquartile range 182-469]. For these ten trials, we identified 23 distinct primary outcomes for which the conclusions were reproduced in all re-analyses. Therefore, 10/62 trials (16% [95% confidence interval 8% to 28%]) were reproduced, as the 52 studies without available data were considered non-reproducible. There was no change from the original study protocol regarding the primary outcome in any of these ten studies. Spin was observed in the report of one study., Conclusions: Despite their results supporting decisions that affect millions of people's health across the European Union, most main studies used in EPARs lack transparency and their results are not reproducible for external researchers. Re-analyses of the few trials with available data showed very good inferential reproducibility., Trial Registration: https://osf.io/mcw3t/., (© 2022. The Author(s).)

Background: Duloxetine is an antidepressant that benefits from a wide range of approval in the elderly population, while its safety for use compared to non-elderly is not clearly assessed. This protocol outlines a systematic review and individual participant data meta-analysis comparing the tolerability of duloxetine between elderly and non-elderly., Methods: Searches will be conducted in PubMed, ClinicalTrials.gov , Clinicaltrialsregister.eu, data sharing platforms, FDA drug approval packages, European public assessment reports and withdrawn applications from the EMA website. The review will be performed on studies available in electronic databases from their date of inception to the 31 March 2022. Only randomized controlled clinical trials, comparing duloxetine to placebo, will be included in this meta-analysis. The studies will be selected if they comprise both elderly and non-elderly adults, in conditions of use of duloxetine approved by the European Medical Agency (EMA) and the Food and Drug Administration (FDA). The primary outcome will be the rate ratio of serious adverse events under duloxetine compared to placebo, between participants at least 65 years old and non-elderly. Second, the number of any adverse events, clinical efficacy and quality of life will be compared between elderly and non-elderly under both interventions. The quality of evidence in the tolerability of duloxetine will be assessed using the GRADE system. A one or two-stage individual participant data random effect meta-analysis will be conducted depending on the availability of the data., Discussion: This meta-analysis will investigate the tolerability safety of duloxetine in the elderly population across all conditions approved by European and American regulatory authorities. The results from this meta-analysis are intended to help prescribers to provide better care for the elderly population., Systematic Review Registration: The protocol has been registered at the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42019130488 )., (© 2022. The Author(s).)

Background: Tivozanib (Fotivda) is an anti-angiogenic tyrosine kinase inhibitor that was denied access to the US market by the Food and Drug Administration (FDA). In contrast, it was granted approval by the European Medicines Agency (EMA) for the treatment of Renal Cell Carcinoma in adults. Given the conflicting decisions from these regulatory agencies, the objectives of the following study are (i) to critically review the evidence supporting the approval of tivozanib; (ii) to analyse the dissemination of this evidence in the literature by way of a citation analysis., Methods: Pivotal trials were searched by two independent reviewers using Medline, Cochrane Library, ClinicalTrials.gov and the European Public Assessment Report. The risk of bias for each trial was then inductively assessed. Articles citing any of these trials were identified using Web of Sciences. Finally, the quality of the citations was evaluated by two independent reviewers according to standard data extraction methods., Results: The search for primary evidence identified two pivotal studies: TIVO-1 upon which the FDA and the EMA decisions were based, and TIVO-3 which was conducted after the agencies' decisions had been issued. The TIVO-1 trial presented several limitations that compromised causal inference, in relation to (i) design (absence of blinding, inappropriate comparator, and one-way crossover), (ii) poor internal consistency in the results for the primary endpoint, (iii) a discrepancy between a benefit observed for progression-free survival (HR: 0.80, 95% CI [0.64-0.99]) and the absence of difference for overall survival (HR: 1.25, 95% CI [0.95 - 1.62]). Our citation search protocol identified 229 articles that cited TIVO-1 in the 7 years following its publication, among which 151 (65.9%) citing articles discussing efficacy. Presence of spin was identified in 64 (42.4%) of these 151 citing articles, and 39 (25.8%) additional articles citing results without providing enough elements to interpret the TIVO-1 results., Conclusion: EMA's approval was based on a single pivotal trial presenting critical limitations, rendering the results from the trial potentially inconclusive. The broad dissemination of TIVO-1 results in the scientific literature may have been affected by spin or results were presented in an inadequate critical manner., (© 2022. The Author(s).)