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We are delighted to report on the success of the inaugural David Sackett Fellowship, building on the success of the 2019 Doug Altman Scholarship, with generous funding and support from the McCall MacBain Foundation (MMF). We used the funding for nine forward-thinking future leaders in Evidence-Based Medicine (EBM) to attend the 2022 EBMLive Conference in Oxford. The nine Fellows brought provocative, bold, and constructive contributions on the theme of making research relevant, replicable, and accessible to end-users. From a highly competitive field, we selected the scholars because of their forward-thinking solutions to address the issue of making research evidence relevant, replicable, and accessible to end-users, as set out in the EBM manifesto, building on the legacy of David Sackett. After an unanticipated delay in hosting EBMLive in 2020 due to the COVID-19 pandemic, the return to an in-person meeting in Oxford, where David Sackett first founded the Centre for Evidence-Based Medicine, re-invigorated the EBM movement with their ideas, enthusiasm, and perspectives. This report highlights the contributions of the awardees, their outputs and the work of the CEBM that supports early-mid career researchers and builds capacity in EBM globally.

Emily McFadden,1 Sarah Lay-Flurrie,1,2 Constantinos Koshiaris,1 Georgia C Richards,1,3 Carl Heneghan1,3 1Centre for Evidence Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK; 2EMEA Real World Methods and Evidence Generation, IQVIA, London, UK; 3Global Centre on Healthcare and Urbanisation, Kellogg College, University of Oxford, Oxford, UKCorrespondence: Emily McFaddenCentre for Evidence Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Woodstock Road, Oxford, OX2 6GG, UKTel +44 1865 617940Email emily.mcfadden@phc.ox.ac.ukPurpose: Stress urinary incontinence (SUI) and pelvic organ prolapse (POP) may be treated with surgical mesh devices; evidence of their long-term complications is lacking.Patients and Methods: Rates of diagnoses of depression, anxiety or self-harm (composite measure) and sexual dysfunction, and rates of prescriptions for antibiotics and opioids were estimated in women with and without mesh surgery, with a diagnostic SUI/POP code, registered in the Clinical Practice Research Datalink (CPRD) gold database.Results: There were 220,544 women eligible for inclusion; 74% (n = 162,687) had SUI, 37% (n = 82,123) had POP, and 11% (n = 24,266) had both. Women undergoing mesh surgery for SUI or POP had about 1.1 times higher rates of antibiotic use. Women with no previous history of the outcome, who underwent mesh surgery had 2.43 (95% CI 2.19– 2.70) and 1.47 (95% CI 1.19– 1.81) times higher rates of depression, anxiety, or self-harm, 1.88 (95% CI 1.50– 2.36) and 1.64 (95% CI 1.02– 2.63) times higher rates of sexual dysfunction and 1.40 (95% CI 1.26– 1.56) and 1.23 (95% CI 1.01– 1.49) times higher opioid use for SUI and POP, respectively. Women with a history of depression, anxiety and self-harm had 0.3 times lower rates of these outcomes with SUI or POP mesh surgery (HR for SUI 0.70 (95% CI 0.67-0.73), HR for POP 0.72 (95% CI 0.65-0.79)). Women with a history of opioid use who had POP mesh surgery had about 0.09 times lower rates (HR 0.91 (95% CI 0.86– 0.96)) of prescriptions. Negative control outcome analyses showed no evidence of an association between asthma consultations and mesh surgery in women with POP, but the rate was 0.09 times lower (HR 0.91 (95% CI 0.87– 0.94)) in women with SUI mesh surgery, suggesting that study results are subject to some residual confounding.Conclusion: Mesh surgery was associated with poor mental and sexual health outcomes, alongside increased opioid and antibiotic use, in women with no history of these outcomes and improved mental health, and lower opioid use, in women with a previous history of these outcomes. Although our results suggest an influence of residual confounding, careful consideration of the benefits and risk of mesh surgery for women with SUI or POP on an individual basis is required.Keywords: urinary incontinence, epidemiology, mental health, sexual dysfunction, pain management

Background Antimicrobial stewardship (AMS) initiatives in hospitals often include the implementation of clustered intervention components to improve the surveillance and targeting of antibiotics. However, impacts of the individual components of AMS interventions are not well known, especially in low- and lower-middle-income countries (LLMICs). Objective A scoping review was conducted to summarize evidence from systematic reviews (SRs) on the impact of common hospital-implemented healthcare-worker-targeted components of AMS interventions that may be appropriate for LLMICs. Methods Major databases were searched systematically for SRs of AMS interventions that were evaluated in hospitals. For SRs to be eligible, they had to report on at least one intervention that could be categorized according to the Effective Practice and Organisation of Care taxonomy. Clinical and process outcomes were considered. Primary studies from LLMICs were consulted for additional information. Results Eighteen SRs of the evaluation of intervention components met the inclusion criteria. The evidence shows that audit and feedback, and clinical practice guidelines improved several clinical and process outcomes in hospitals. An unintended consequence of interventions was an increase in the use of antibiotics. There was a cumulative total of 547 unique studies, but only 2% (N=12) were conducted in hospitals in LLMICs. Two studies in LLMICs reported that guidelines and educational meetings were effective in hospitals. Conclusion Evidence from high- and upper-middle-income countries suggests that audit and feedback, and clinical practice guidelines have the potential to improve various clinical and process outcomes in hospitals. The lack of evidence in LLMIC settings prevents firm conclusions from being drawn, and highlights the need for further research.

Background: The global burden of cardiovascular disease (CVD) is forecast to increase, and anticoagulants will remain important medicines for its management. Coroners' Prevention of Future Death reports (PFDs) provide valuable insights that may enable safer and more effective use of these agents. Objective: To identify CVD-related PFD reports highlighting the use or lack of anticoagulants as having caused or contributed to deaths. Methods: We conducted a retrospective observational study of coronial case reports in England and Wales between 2013 and 2019. We screened 3037 PFDs for inclusion and used content analysis to assess concerns raised by coroners and who responded to them. Results: We identified 113 CVD-related PFDs (113 deaths) involving anticoagulants. Warfarin (36%), enoxaparin (11%), and rivaroxaban (11%) were the most common anticoagulants reported. In 14 cases, the coroner mentioned that the administration of an anticoagulant may have prevented the death. Concerns most frequently raised by coroners included poor systems (31%), poor communication (25%), and failures to keep accurate medical records (25%). These concerns were most often directed to NHS trusts (29%), hospitals (10%), and general practices (8%), but had national importance. Nearly two-thirds (60%) of PFDs had not received responses from such organisations, which are mandatory under regulation 28 of the Coroners' (Investigations) Regulations 2013. Conclusions: We created a tool (https://preventabledeathstracker.net/) that bring together coroner reports to identify important lessons related to preventable deaths. Here we examined instances of premature deaths from CVD involving anticoagulants. National organisations, healthcare professionals, and prescribers should take actions to address these concerns, to improve the use of anticoagulants in patients with CVD.

SummaryObjectiveto review the evidence from studies comparing SARS-CoV-2 culture, the best indicator of current infection and infectiousness with the results of reverse transcriptase polymerase chain reaction (RT-PCR).MethodsWe searched LitCovid, medRxiv, Google Scholar and the WHO Covid-19 database for Covid-19 using the terms ‘viral culture’ or ‘viral replication’ and associated synonyms up to 10 September 2020. We carried out citation matching and included studies reporting attempts to culture or observe SARS-CoV-2 matching with cutoffs for RT-PCR positivity. One reviewer extracted data for each study and a second reviewer checked end edited the extraction and summarised the narratively by sample: fecal, respiratory, environment or mixed.Where necessary we wrote to corresponding authors of the included or background papers for additional information. We assessed quality using a modified QUADAS 2 risk of bias tool.This review is part of an Open Evidence Review on Transmission Dynamics of COVID-19. Summaries of the included studies and the protocol (v1) are available at: https://www.cebm.net/evidence-synthesis/transmission-dynamics-of-covid-19/. Searches are updated every 2 weeks. This is the fourth version of this review that was first published on the 4th of August and updated on the 21t of AugustResultsWe included 29 studies reporting culturing or observing tissue invasion by SARS-CoV in sputum, naso or oropharyngeal, urine, stool, blood and environmental samples from patients diagnosed with Covid-19. The data are suggestive of a relation between the time from collection of a specimen to test, cycle threshold and symptom severity. The quality of the studies was moderate with lack of standardised reporting.Twelve studies reported that Ct values were significantly lower and log copies higher in samples producing live virus culture. Five studies reported no growth in samples based on a Ct cut-off value. These values ranged from CT > 24 for no growth to Ct ≥ 34. Two studies report a strong relationship between Ct value and ability to recover infectious virus and that the odds of live virus culture reduced by 33% for every one unit increase in Ct. A cut-off RT-PCR Ct > 30 was associated with non-infectious samples. One study that analysed the NSP, N and E gene fragments of the PCR result reported different cut-off thresholds depending on the gene fragment analysed. The duration of RNA shedding detected by PCR was far longer compared to detection of live culture. Six out of eight studies reported RNA shedding for longer than 14 days. Yet, infectivity declines after day 8 even among cases with ongoing high viral loads. A very small proportion of people re-testing positive after hospital discharge or with high Ct are likely to be infectious.ConclusionProspective routine testing of reference and culture specimens are necessary for each country involved in the pandemic to establish the usefulness and reliability of PCR for Covid-19 and its relation to patients’ factors. Infectivity is related to the date of onset of symptoms and cycle threshold level.A binary Yes/No approach to the interpretation RT-PCR unvalidated against viral culture will result in false positives with possible segregation of large numbers of people who are no longer infectious and hence not a threat to public health.

Importance: Deprescribing of antihypertensive medications is recommended for some older patients with polypharmacy and multi-morbidity where the benefits of continued treatment may not outweigh the harms. Objective: This study aimed to establish whether antihypertensive medication reduction is possible without significant changes in systolic blood pressure control or adverse events during a 12-week follow-up period. Design, Setting, and Participants: The OPtimising Treatment for MIld Systolic hypertension in the Elderly (OPTIMISE) study was a randomized, unblinded, non-inferiority trial conducted in 69 primary care sites in England. Participants were aged ≥80 years with systolic blood pressure, This work received joint funding from the National Institute for Health Research (NIHR) Oxford Collaboration for Leadership in Applied Health Research and Care (CLAHRC) at Oxford Health NHS Foundation Trust (ref: P2-501) and the NIHR School for Primary Care Research (SPCR; ref 335).

A response by Cochrane’s Editor in Chief1 to an article by Jorgensen at al published in BMJ Evidence Based Medicine (BMJ EBM) asks questions about the journal’s peer review and editorial processes. The article, ‘The Cochrane HPV vaccine review was incomplete and ignored important evidence of bias,’2 was submitted to BMJ EBM on 24th May 2018 for the ‘Debate, analysis and opinion’ section of the journal. The handling editor, Dr Igho Onakpoya (Research Editor, BMJ EBM) sent it for external peer review to an expert in HPV vaccines and for internal peer review to Professor Carl Heneghan, Editor in Chief of BMJ EBM, who is an expert in evidence synthesis and systematic review methods. Peer reviewers reports were returned by 19th June and were sent to the authors, who were invited to make revisions. The revised version was submitted on 3 July, accepted by the handling editor on 7 July and published online on the 27July 2018.2 With permission …

In recent years, national and international guidelines have recommended the use of out-of-office blood pressure monitoring for diagnosing hypertension. Despite evidence of cost effectiveness, critics expressed concerns this would increase cardiovascular morbidity. We assessed the impact of these changes on the incidence of hypertension, out-of-office monitoring and cardiovascular morbidity using routine clinical data from English general practices, linked to inpatient hospital, mortality and socio-economic status data. We studied 3,937,191 adults with median follow-up of 4.2 years (49% men, mean age = 39.7 years) between 1/4/2006 and 31/3/2017. Interrupted time series analysis was used to examine the impact of changes to English hypertension guidelines in 2011 on incidence of hypertension (primary outcome). Secondary outcomes included rate of out-of-office monitoring and cardiovascular events. Across the study period, incidence of hypertension fell from 2.1 to 1.4 per 100 person-years. The change in guidance in 2011 was not associated with an immediate change in incidence (change in rate = 0.01; 95% CI [-0.18 to 0.20]) but did result in a levelling out of the downward trend (change in yearly trend = 0.09; 95% CI [0.04 to 0.15]). Ambulatory monitoring increased significantly in 2011/12 (change in rate = 0.52; 95% CI [0.43 to 0.60]). The rate of cardiovascular events remained unchanged (change in rate = -0.02, 95% CI [-0.05 to 0.02]). In summary, changes to hypertension guidelines in 2011 were associated with a stabilisation in incidence and no increase in cardiovascular events. Guidelines should continue to recommend out-of-office monitoring for diagnosis of hypertension.