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This collaborative meta-analysis was supported by the Swiss National Science Foundation and the Laura and John Arnold Foundation (grant supporting the post-doctoral fellowship at the Meta-Research Innovation Center at Stanford (METRICS), Stanford University). The funders had no role in the design of this collaborative meta-analysis; in the collection, analysis, and interpretation of data; or in the report writing., We would like to express our warm gratitude to all participating patients and convalescent plasma donors. We thank Katja Suter and Sina Ullrich, University of Basel, for their administrative assistance. For their helpful contribution to individual trials, we thank Erica Wood, Iain Gosbell, Richard Charlewood, Thomas Hills, Veronica Hoad, Kristina Kairaitis, Aikaj Jindal, John Gerrard, Hong Foo, Adam Stewart, and Nanette Trask (ASCOT trial); Amalia Bravo-Lindoro, Ral Carrillo-Esper, Karla Maldonado-Silva, Catalina Casillas-Suárez, Orlando Carrillo-Torres, Sandra Murrieta, Elizabeth Diaz-Padilla, Eli Omar Zavaleta, Yadira Bejar-Ramirez, and Evelyn Cortina-de la Rosa (CPC-SARS trial); Sheri Renaud, Roel Rolando-Almario, and Jacqueline Day (NCT04385199 trial); Sandra Tingsgrd, MD, Karen Brorup Heje Pedersen, MD, Michaela Tinggaard, MD, Louise Thorlacius-Ussing, MD, Clara Lundetoft Clausen, MD, Nichlas Hovmand, MD, Simone Bastrup Israelsen, MD, Cecilie Leding, MD, Katrine Iversen, MD, Maria Engel Miller, MD, Hkon Sandholdt, MSc biostatistician (CCAP-2 trial). On behalf of the IRCT20200310046736N1 trial, we thank the Khuzestan Blood Transfusion Organization for specialized assistance in the preparation and maintenance of plasma samples. On behalf of the NCT04332835 trial, we thank all the members of the "PC-COVID-19 Group" at the Clinica del Occidente and Hospital Universitario Mayor Mederi in Bogota, and Clinica CES in Medellin. On behalf of the NCT04403477 trial, we thank Miles Carroll for his support regarding the antibody testing in Bangladesh. The Co-CLARITY team would like to extend their gratitude to the Department of Science and Technology Philippine Council for Health Research and Development and the UP-Philippine General Hospital for all their support in the setting up and conduct of the trial. For helpfully communicating details of their trial, we thank members of the PlasmAr trial, NCT04359810 trial (Max O´Donnell), NCT04468009 trial, and CTRI/2020/05/025299 trial. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute (https://www.cancer.gov/)., During the conduct of the study, the following is reported: Dr. Berry reports being employee with ownership role at Berry Consultants (receives payments for statistical modeling and design of REMAP-CAP). Dr. Castillo reports grants from DOST PCHRD. Dr. Daly reports grants from Medical Research Future Fund (Australian Govt) and RBWH. Dr. Denkinger reports grants from German Ministry for Education and Research. Dr. Dumagay reports grants from Philippine Council for Health Research and Development. Dr. Dunachie reports grants from UK Department of Health and Social Care, grants from UK National Institute of Health Research. Dr. Gauiran reports grants from Department of Science and Technology—Philippine Council for Health Research and Development. Dr. Gordon reports grants from NIHR, grants from NIHR Research Professorship (RP-2015-06-18), and non-financial support from NIHR Clinical Research Network. Dr. Higgins reports grants from NHMRC and from the Minderoo Foundation. Dr. Hills reports grants from Health Research Council of New Zealand. Dr. Holm reports grants from Swedish Government Funds for Clinical Research (ALF). Dr. Janssen and Dr. Müller-Tidow report grants from the Federal Ministry of Education and Research in Germany (BMBF) to the RECOVER clinical trial. Dr. Krapp reports grants from Department of Foreign Affairs, Trade, and Development of Canada, grants from Fundación Telefónica del Perú. Dr. J. Lim reports grants from the Department of Science and Technology, Philippine Council for Health Research and Development. Dr. Lucero reports grants from Philippine Council for Health Research and Development. Dr Manrique reports economic support from Grupo ISA Intercolombia for the project development of trial NCT04332835. Drs. McQuilten and Wood report grants from Medical Research Future Fund. Dr. McVerry reports grants from The Pittsburgh Foundation, Translational Breast Cancer Research Consortium, and from UPMC Learning While Doing Program. Mr. Mouncey reports grants from National Institute for Health Research and from the European Union FP7: PREPARE. Dr. Najdovski reports payment from KUL Leuven to Belgian Red Cross for supply of convalescent plasma. Dr. Nichol reports grants from Health Research Board of Ireland. Dr. D. Roberts reports grants from the National Institute for Health (UKRIDHSC COVID-19 Rapid Response Rolling Call—Grant Reference Number COV19-RECPLAS) and the European Commission (SUPPORT-E #101015756). Dr. Rowan reports grants from the European Commission and from the UK National Institute for Health Research. Dr. Shankar-Hari reports grants from National Institute for Health Research UK, grants from UKRI-National Institute for Health Research UK. Dr. Turgeon reports grants from Canadian Institutes of Health Research. Dr. Venkatesh reports grants from Baxter. Dr. Webb reports grants from National Health and Medical Research Council, grants from Minderoo Foundation. Dr. Zacharowski reports grants from EU Horizon 2020. The ASCOT trial team (Drs Bowen, Daly, Davis, Denholm, Hammond, Jha, L. Lim, McQuilten, Molton, Morpeth, O’Sullivan, Paterson, Perry, Price, Rees, Roberts, Rogers, Sasadeusz, Snelling, Tong, Venkatesh, Wood) is funded by grants from from Royal Brisbane and Women’s Hospital Foundation, Pratt Foundation, Minderoo Foundation, BHP Foundation, Hospital Research Foundation, Macquarie Group Foundation, Health Research Council of New Zealand, Australian Partnership for Preparedness Research on Infectious Disease Emergencies (APPRISE), and the collection and supply of convalescent plasma was conducted within Lifeblood’s funding arrangements. The CONFIDENT trial is funded by the Belgian KCE (blood establishments received payment for the convalescent plasma supplied in the clinical trial). REMAP-CAP was supported in part by funding from UKRIDHSC COVID-19 Rapid Response Rolling Call (Grant Reference Number COV19-RECPLAS). Collection of convalescent plasma for REMAP-CAP was funded by the Department of Health and Social Care, UK. The IRCT20200310046736N1 trial was supported by the Ahvaz Jundishapur University of Medical Sciences (Grant No. R.AJUMS.REC.1399.003, Dr. Pouladzadeh). The PC-COVID-19 Group is supported by the Universidad del Rosario, IDCBIS, ISA Group and Suramericana (Colombia). Outside the submitted work, the following is reported: Dr. Axfors reports postdoctoral grants from the Knut and Alice Wallenberg Foundation, Uppsala University, the Swedish Society of Medicine, the Blanceflor Foundation, and the Sweden-America Foundation. Dr. Aomar reports personal fees from SOBI, GEDEON RICHTER, and GSK. Dr. Benfield reports grants from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Hansen Foundation, Erik and Susanna Olesen’s Charitable Fund; grants and personal fees from GSK, Pfizer, Gilead; and personal fees from Boehringer Ingelheim, MSD, and Pentabase ApS. Dr. Estcourt reports being an investigator on the RECOVERY trial. Dr. Gordon reports personal fees from GlaxoSmithKline, Bristol Myers Squibb, and 30 Respiratory. Dr. Jha reports grants and personal fees from Baxter Healthcare, personal fees from Astra Zeneca, grants from NephroPlus. Dr. Laterre reports personal fees from Adrenomed. Dr. McVerry reports grants from NIH/NHLBI and Bayer Pharmaceuticals, Inc. Dr. Mondragon reports financial activities outside the submitted work (employment at Johnson & Johnson). Dr. Perry reports partner being employed at CSL and owning shares in CSL. Dr. Paterson reports involvement with ALLIANCE trial of COVID-19 treatments. Dr. J. Roberts reports other COVID-19 related trials (in different patient groups): tocilizumab in ICU patients; hydroxychloroquine dosing in ICU patients; planned study of remdesivir pharmacokinetics in patients during expanded access program; and in silico evaluation of ivermectin dosing. Dr Sasadeusz reports grants from various Pharma companies including Gilead Sciences, Abvvie, Merck, and Takeda. Dr. Zacharowski reports personal fees from Biotest AG, CSL Behring, GE Heathcare, and is President of the ESAIC., Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX). Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care., Amalia Bravo-Lindoro, BHP Foundation, Blanceflor Foundation, Department of Foreign Affairs, Trade, and Development of Canada, Eli Omar Zavaleta, Erik and Susanna Olesen’s Charitable Fund, Federal Ministry of Education and Research in Germany, Fundación Telefónica del Perú, IDCBIS, ISA Group and Suramericana, Kai Hansen Foundation, Katja Suter and Sina Ullrich, Khuzestan Blood Transfusion Organization, Macquarie Group Foundation, Medical Research Future Fund, NephroPlus, RBWH, Roel Rolando-Almario NCT04385199, Royal Brisbane, Sheri Renaud, Simonsen Foundation, UKRI-National Institute for Health Research UK, UKRIDHSC COV19-RECPLAS, UP-Philippine General Hospital CTRI/2020/05/025299, NCT04359810, NCT04468009, Women’s Hospital Foundation, National Institutes of Health, National Heart, Lung, and Blood Institute, Pittsburgh Foundation, Pfizer, Baxter International, Stanford University, Gilead Sciences, National Institute on Handicapped Research RP-2015-06-18, Meso Scale Diagnostics, Universität Basel, Laura and John Arnold Foundation, Health Research Board, Pratt Foundation, Canadian Institutes of Health Research, National Institute for Health Research, Department of Health and Social Care, European Commission 101015756, National Health and Medical Research Council, Department of Science and Technology, Ministry of Science and Technology, India, Health Research Council of New Zealand, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Sweden-America Foundation, Bundesministerium für Bildung und Forschung, Lundbeckfonden, Knut och Alice Wallenbergs Stiftelse, Seventh Framework Programme, Ahvaz Jundishapur University of Medical Sciences, Université Pierre et Marie Curie, Uppsala Universitet, Horizon 2020, Svenska Läkaresällskapet, Universidad del Rosario, Pharmaceuticals Bayer, Novo Nordisk Fonden, Department of Science and Technology, Philippines, Philippine Council for Health Research and Development, Minderoo Foundation

To study the association between detection of the Clostridioides difficile gene encoding the binary toxin (CDT) and direct detection of toxinB (TcdB) from feces with the appearance of serious disease, complications, or recurrence in a prospective series of cases. A total of 220 confirmed cases were included, using a two-step algorithm: an initial study to detect the enzyme, glutamate dehydrogenase (GDH), followed, in cases of positivity, by detection of the tcdB. tcdB-positive patients were investigated for the presence of CDT and TcdB. Outcome variables were severe disease, the modified Illinois C. difficile infection (CDI) prognostic risk index (ZAR score), the appearance of complications (need for colectomy, CDI-related death, or toxic megacolon) and recurrence. Patients who tested positive for the presence of TcdB in feces were found to have greater disease severity than those who tested negative, with a ZAR score of 35.4% vs. 23% (p = .048), a higher recurrence rate (14.6% vs. 5.9%, p = .032), and a tendency for higher number of complications (20.7% vs. 11.5%), although without reaching statistical significance (p = .053). When presence of CDT was analyzed, higher frequencies of severe disease (39.2% vs. 21.2%, p = .005), complications and recurrence (21.6% vs. 10.9%, p = .037 and 14.9% vs. 5.8%, p = .029; respectively) were observed in patients where CDT was detected. TcdB and CDT act as prognostic markers of the appearance of serious disease, complications or recurrence in cases of CDI. Simultaneous detection of both markers, TcdB and CDT, had a greater impact on the prognosis than when they were detected separately.

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial [CHEST-2]). Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified. © 2020 The Authors Eli Lilly and Company; Pfizer; Bayer; GlaxoSmithKline; Merck; Actelion Pharmaceuticals; Meso Scale Diagnostics; United Therapeutics Corporation; Novartis Pharma; Merck Sharp and Dohme; GlaxoSmithKline Australia; Deutsche Forschungsgemeinschaft; Grupo Ferrer Internacional, S.A The EXPERT registry was funded by Bayer AG (Berlin, Germany) and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA. The authors acknowledge the database administration by Torsten Tille, Dresden, and the project administration of Mrs Romy Hoppenz and Mrs Linda Kottke at GWT-TUD GmbH, Dresden. Medical writing services provided by Richard Murphy PhD of Adelphi Communications Ltd, Macclesfield, UK were funded by Bayer AG in accordance with Good Publication Practice (GPP3) guidelines. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof Marius M. Hoeper reports personal fees from Bayer AG, during the conduct of the study; personal fees from Actelion, personal fees from Acceleron, personal fees from MSD, personal fees from Jansen, personal fees from Pfizer, outside the submitted work. Dr Hans Klose reports speaker and consultancy fees from Actelion, Bayer AG, GSK, Novartis, Pfizer, and United Therapeutics and research support from Actelion, Bayer AG, GSK, Pfizer, and MSD. Dr Michael Halank reports personal fees and non-financial support from Actelion, AstraZeneca, Bayer AG, Berlin-Chemie, GSK, OMT, MSD, and Novartis. Dr George Giannakoulas reports speaker and consultancy fees from Actelion, Bayer, ELPEN Pharmaceuticals, GSK, Pfizer, Lilly, and United Therapeutics, and research support from GSK, ELPEN Pharmaceuticals, and Galenica. Dr Henning Gall has received honoraria and/or other support from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. Dr Pavel Jansa reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Prof Ekkehard Grünig reports research grants and speaker honoraria/consultancy fees from Actelion and Bayer/MSD, research grants from GSK, United Therapeutics, Bellerophon, OMT GmbH, Pfizer, Reata, and Novartis, and speaker honoraria from Bial, Medscape, and OrPha Swiss GmbH. Prof David Pittrow reports personal fees from Actelion, Bayer AG, Aspen, Boehringer Ingelheim, Sanofi, Biogen, Shire, and MSD outside the submitted work. Silvia Ulrich reports research grants and personal fees from Actelion, Bayer, MSD, and Orpha Swiss. Tobias J. Lange has received personal fees from Actelion, MSD, Pfizer, and OMT orphan. Dr Iraklis Tsangaris reports speaker and consultancy fees from Actelion, Bayer AG, ELPEN, GSK, MSD, Pfizer, and United Therapeutics. Stephan Rosenkranz reports remunerations for lectures and/or consultancy from Abbott, Actelion, Arena, Bayer, Ferrer, GSK, MSD, Novartis, Pfizer, and United Therapeutics; and research support to his institution from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. Repke J. Snijder reports grants from Pfizer and Actelion Pharmaceuticals. Prof Iveta Šimková reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Dr Marc Humbert reports grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck, and United Therapeutics. Marion Delcroix has received investigator, speaker, consultant, and steering committee member fees from Actelion, Bayer AG, Bellerophon, Eli Lilly, GlaxoSmithKline, MSD, Pfizer, and Reata, and research grants from Actelion. Joan A. Barberà reports receipt of honoraria for consultation or speaker fees from Actelion and Merck; and research support through his institution from Actelion, Merck, GlaxoSmithKline, and Ferrer. Joanna Pepke-Zaba reports research grants and speaker honoraria/consultancy fees from Actelion, Bayer/MSD, and GSK. Jean-Luc Vachiéry reports ongoing consultancies to Actelion, Sonnivie, Arena Pharma, Bial Portela, and Respira Therapeutics, past consultancies to AstraZeneca, BayerShering, CardioMEMS, GlaxoSmithKline, Pfizer, Merck, and United Therapeutics, and current membership of an advisory board or similar group for Actelion and GlaxoSmithKline. Jean-Luc Vachiéry's institution receives funding from Actelion Pharmaceuticals for performing clinical studies. Regina Steringer-Mascherbauer, Jens Klotsche, and Miguel-Angel Gomez Sanchez have no conflicts of interest relevant to the EXPERT study. Hossein-Ardeschir Ghofrani reports personal fees for advisory board work, and payment for lectures including service on speaker bureaus, from Actelion, Bayer, GSK, Novartis, and Pfizer; consultancy fees from Actelion, Bayer, Bellerophon Pulse Technologies, GSK, MSD, Novartis, and Pfizer; and grants from Deutsche Forschungsgemeinschaft (DFG). Pilar Escribano Subias reports personal fees from Actelion, Bayer AG, GlaxoSmithKline, and Merck Sharp & Dohme, and grants from Actelion, Bayer AG, GlaxoSmithKline, and Ferrer, outside the submitted work. Gérald Simonneau reports personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees and non-financial support from MSD, outside the submitted work. Douglas S. Helmersen reports industry-sponsored research with Bayer AG, United Therapeutics, and Gilead Sciences, Inc., and advisory board/speaker fees from Bayer AG and Actelion. David Langleben reports honoraria, consultation fees, research support, and/or travel expenses from Actelion, Arena, Bayer AG, Northern Therapeutics, PhaseBio, Acceleron, Janssen, and United Therapeutics. Anco Boonstra reports consultancy fees from Pfizer BV and hospitality from Teva Nederland. Lisa M. Mielniczuk reports speaker fees and honoraria from Bayer AG, and speaker fees, consultancy fees, and travel fees from Actelion. Evgenia Williams and Christian Meier are employees of Bayer AG.

[Introduction] Ceftaroline, tedizolid, dalbavancin, ceftazidime-avibactam and ceftolozane-tazobactam are novel antibiotics used to treat infections caused by multidrug-resistant pathogens (MDR). Their use should be supervised and monitored as part of an antimicrobial stewardship programme (ASP). Appropriate use of the new antibiotics will be improved by including consensual indications for their use in local antibiotic guidelines, together with educational interventions providing advice to prescribers to ensure that the recommendations are clearly understood., [Methods and analysis] This study will be implemented in two phases. First, a preliminary historical cohort (2017–2019) of patients from 13 Andalusian hospitals treated with novel antibiotics will be analysed. Second, a quasiexperimental intervention study will be developed with an interrupted time-series analysis (2020–2021). The intervention will consist of an educational interview between prescribers and ASP leaders at each hospital to reinforce the proper use of novel antibiotics. The educational intervention will be based on a consensus guideline designed and disseminated by leaders after the retrospective cohort data have been analysed. The outcomes will be acceptance of the intervention and appropriateness of prescription. Incidence of infection and colonisation with MDR organisms as well as incidence of Clostridioides difficile infection will also be analysed. Changes in prescription quality between periods and the safety profile of the antibiotics in terms of mortality rate and readmissions will also be measured., [Ethics and dissemination] Ethical approval will be obtained from the Andalusian Coordinating Institutional Review Board. The study is being conducted in compliance with the protocol and regulatory requirements consistent with International Council of Harmonisation E6 Good Clinical Practice and the ethical principles of the latest version of the Declaration of Helsinki. The results will be published in peer-reviewed journals and disseminated at national and international conferences., [Trial registration number] NCT03941951; Pre-results., The study is funded by the Consejería de Salud, Junta de Andalucía, grant PI-0077-2018. The investigators also receive funds for research from the Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001) through the Plan Nacional de I+D+ i 2013‐2016, cofinanced by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014‐2020.

Primary meningococcal meningitis is an infrequent but known disease. However, the infection of a prosthetic joint withNeisseria meningitidisis rare. We hereby describe the second case of an arthroplasty infected withNeisseria meningitidisthat responded favourably to prosthesis retention with surgical debridement, in combination with antibiotics treatment.