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Introduction: Wilms’ tumour is the most common childhood renal malignancy, with 5–10% of cases presenting bilaterally 1. However, there is currently no consensus between centres on optimal management of bilateral Wilms’ tumours. This is an international multi-centre case series comparing management and outcomes of bilateral Wilms’ tumours between low-income centres (LIC) and high-income centres (HIC). Methods: Patients with bilateral Wilms' tumour were identified from four tertiary referral centres internationally. Data were collected on baseline characteristics, disease status, treatment used and clinical outcomes. Results were compared between individual centres as well as between groups of low-income centres (LIC) and high-income centres (HIC). Results: Data were collected for forty patients. Most patients received preoperative chemotherapy ( n = 38, 95%). The most common surgical procedures were bilateral nephron-sparing surgery ( n = 10, 25%) and nephrectomy with partial nephrectomy ( n = 20, 50%). Ten-year survival after treatment was as follows: LIC's n = 13 (65%); HIC's n = 20 (100%) ( p = 0.01). Discussion: Ten-year survival was significantly higher in HIC's. Our results show this may be caused by patient factors such as later presentation with more advanced disease in low-income centres. This comparative case series is the first to report on a large number of cases from multiple international centres, and to compare key outcomes.

Objectives To assess the association between routinely prescribed non-steroidal anti-inflammatory drugs (NSAIDs) and deaths from COVID-19 using OpenSAFELY, a secure analytical platform.Methods We conducted two cohort studies from 1 March to 14 June 2020. Working on behalf of National Health Service England, we used routine clinical data in England linked to death data. In study 1, we identified people with an NSAID prescription in the last 3 years from the general population. In study 2, we identified people with rheumatoid arthritis/osteoarthritis. We defined exposure as current NSAID prescription within the 4 months before 1 March 2020. We used Cox regression to estimate HRs for COVID-19 related death in people currently prescribed NSAIDs, compared with those not currently prescribed NSAIDs, accounting for age, sex, comorbidities, other medications and geographical region.Results In study 1, we included 536 423 current NSAID users and 1 927 284 non-users in the general population. We observed no evidence of difference in risk of COVID-19 related death associated with current use (HR 0.96, 95% CI 0.80 to 1.14) in the multivariable-adjusted model. In study 2, we included 1 708 781 people with rheumatoid arthritis/osteoarthritis, of whom 175 495 (10%) were current NSAID users. In the multivariable-adjusted model, we observed a lower risk of COVID-19 related death (HR 0.78, 95% CI 0.64 to 0.94) associated with current use of NSAID versus non-use.Conclusions We found no evidence of a harmful effect of routinely prescribed NSAIDs on COVID-19 related deaths. Risks of COVID-19 do not need to influence decisions about the routine therapeutic use of NSAIDs.https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.http://dx.doi.org/10.1136/annrheumdis-2020-219517

ObjectiveTo compare the effectiveness of sotrovimab (a neutralising monoclonal antibody) vs. molnupiravir (an antiviral) in preventing severe COVID-19 outcomes in non-hospitalised high-risk COVID-19 adult patients.DesignWith the approval of NHS England, we conducted a real-world cohort study using the OpenSAFELY-TPP platform.SettingPatient-level electronic health record data were obtained from 24 million people registered with a general practice in England that uses TPP software. The primary care data were securely linked with data on COVID-19 infection and therapeutics, hospital admission, and death within the OpenSAFELY-TPP platform, covering a period where both medications were frequently prescribed in community settings.ParticipantsNon-hospitalised adult COVID-19 patients at high risk of severe outcomes treated with sotrovimab or molnupiravir since December 16, 2021.InterventionsSotrovimab or molnupiravir administered in the community by COVID-19 Medicine Delivery Units.Main outcome measureCOVID-19 related hospitalisation or COVID-19 related death within 28 days after treatment initiation.ResultsBetween December 16, 2021 and February 10, 2022, 3331 and 2689 patients were treated with sotrovimab and molnupiravir, with no substantial differences in their baseline characteristics. The mean age of all 6020 patients was 52 (SD=16) years; 59% were female, 89% White and 88% had three or more COVID-19 vaccinations. Within 28 days after treatment initiation, 87 (1.4%) COVID-19 related hospitalisations/deaths were observed (32 treated with sotrovimab and 55 with molnupiravir). Cox proportional hazards models stratified by area showed that after adjusting for demographics, high-risk cohort categories, vaccination status, calendar time, body mass index and other comorbidities, treatment with sotrovimab was associated with a substantially lower risk than treatment with molnupiravir (hazard ratio, HR=0.54, 95% CI: 0.33 to 0.88; P=0.014). Consistent results were obtained from propensity score weighted Cox models (HR=0.50, 95% CI: 0.31 to 0.81; P=0.005) and when restricted to fully vaccinated people (HR=0.53, 95% CI: 0.31 to 0.90; P=0.019). No substantial effect modifications by other characteristics were detected (all P values for interaction>0.10). Findings were similar in an exploratory analysis of patients treated between February 16 and May 1, 2022 when the Omicron BA.2 variant was dominant in England.ConclusionIn routine care of non-hospitalised high-risk adult patients with COVID-19 in England, those who received sotrovimab were at lower risk of severe COVID-19 outcomes than those receiving molnupiravir.

ObjectivesAscertain patient eligibility status and describe coverage of antivirals and neutralising monoclonal antibodies (nMAB) as treatment for COVID-19 in community settings in England.DesignCohort study, approved by NHS England.SettingRoutine clinical data from 23.4m people linked to data on COVID-19 infection and treatment, within the OpenSAFELY-TPP database.ParticipantsNon-hospitalised COVID-19 patients at high-risk of severe outcomes.InterventionsNirmatrelvir/ritonavir (Paxlovid), sotrovimab, molnupiravir, casirivimab or remdesivir, administered in the community by COVID-19 Medicine Delivery Units.ResultsWe identified 102,170 non-hospitalised patients with COVID-19 between 11th December 2021 and 28th April 2022 at high-risk of severe outcomes and therefore potentially eligible for antiviral and/or nMAB treatment. Of these patients, 18,210 (18%) received treatment; sotrovimab, 9,340 (51%); molnupiravir, 4,500 (25%); Paxlovid, 4,290 (24%); casirivimab, 50 (ConclusionsUsing the OpenSAFELY platform we were able to identify patients who were potentially eligible to receive treatment and assess the coverage of these new treatments amongst these patients. Targeted activity may be needed to address apparent lower treatment coverage observed among certain groups, in particular (at present): different NHS regions, socioeconomically deprived areas, and care homes.What is already known about this topicSince the emergence of COVID-19, a number of approaches to treatment have been tried and evaluated. These have mainly consisted of treatments such as dexamethasone, which were used in UK hospitals,from early on in the pandemic to prevent progression to severe disease. Until recently (December 2021), no treatments have been widely used in community settings across England.What this study addsFollowing the rollout of antiviral medicines and neutralising monoclonal antibodies (nMABs) as treatment for patients with COVID-19, we were able to identify patients who were potentially eligible to receive antivirals or nMABs and assess the coverage of these new treatments amongst these patients, in as close to real-time as the available data flows would support. While the proportion of the potentially eligible patients receiving treatment increased over time, rising from 8% (180/2,380) in the first week of the roll out to 22% (420/1870) in the last week of April 2022, there were variations in coverage between key clinical, geographic, and demographic subgroup.How this study might affect research, practice, or policyTargeted activity may therefore be needed to address lower treatment rates observed among certain geographic areas and key groups including ethnic minorities, people living in areas of higher deprivation, and in care homes.

ObjectiveTo ascertain patient eligibility status and describe coverage of antiviral drugs and neutralising monoclonal antibodies (nMAB) as treatment for covid-19 in community settings in England.DesignRetrospective, descriptive cohort study, approved by NHS England.SettingRoutine clinical data from 23.4 million people linked to data on covid-19 infection and treatment, within the OpenSAFELY-TPP database.ParticipantsOutpatients with covid-19 at high risk of severe outcomes.InterventionsNirmatrelvir/ritonavir (paxlovid), sotrovimab, molnupiravir, casirivimab/imdevimab, or remdesivir, used in the community by covid-19 medicine delivery units.Results93 870 outpatients with covid-19 were identified between 11 December 2021 and 28 April 2022 to be at high risk of severe outcomes and therefore potentially eligible for antiviral or nMAB treatment (or both). Of these patients, 19 040 (20%) received treatment (sotrovimab, 9660 (51%); molnupiravir, 4620 (24%); paxlovid, 4680 (25%); casirivimab/imdevimab, 50 (ConclusionsUsing the OpenSAFELY platform, we were able to identify patients with covid-19 at high risk of severe outcomes who were potentially eligible to receive treatment and assess the coverage of these new treatments among these patients. In the context of a rapid deployment of a new service, the NHS analytical code used to determine eligibility could have been over-inclusive and some of the eligibility criteria not fully captured in healthcare data. However targeted activity might be needed to resolve apparent lower treatment coverage observed among certain groups, in particular (at present): different NHS regions, ethnic groups, people aged ≥80 years, those living in socioeconomically deprived areas, and care home residents.

Background On December 8th 2020, NHS England administered the first COVID-19 vaccination as part of an ambitious vaccination programme during a global health emergency. Aims To develop a framework for detailed near-real-time monitoring of COVID-19 vaccine roll-out; to describe trends and variation in coverage by geographic area, and between key clinical and demographic patient groups. Methods Working on behalf of NHS England we used routine clinical data from 23.4 million patients to conduct a retrospective cohort study of comprehensive electronic health record data in NHS England, using the OpenSAFELY-TPP platform which covers approximately 40% of the general population in England with weekly data updates. We developed algorithms to identify key demographic and clinical sub-groups within this population and generated descriptive statistics on proportion of eligible patients receiving the vaccine among key Joint Committee on Vaccination and Immunisation (JCVI) target groups. Results Between December 8th and January 13th 961,580 people out of 23.4m in our dataset received a COVID-19 vaccine. Of 1,160,062 patients aged 80 or over and not living in a care home (currently targeted by JCVI) 476,375 had been vaccinated in total (41.1%). We observed a substantial divergence in vaccination by ethnicity within this group (White 42.5% vaccinated, Black 20.5%) and across rankings of deprivation (least deprived 44.7%, most deprived 37.9%). Patients with pre-existing medical conditions were equally likely, or more likely, to have received a vaccine across most co-morbidity groups with two exceptions: severe mental illness (30.3% vaccinated) and learning disability (28.1%). We identify substantial variation in vaccination among the over-80s between Sustainability and Transformation Partnerships (STPs; Range 12%-74%); lower vaccination rates among ethnic minority and deprived groups was observed in most but not all STPs. In the 70-79 age cohort 74,108 people (3.6%) had been vaccinated. 378,921 vaccine recipients under 70 and not identifiably resident in a care home were presumed to be health or social care workers; 32,174 recipients were identified as older aged care home residents (33.2% coverage). Of all those vaccinated, 169,472 had received a second dose (17.6%). Conclusions The NHS in England has rapidly delivered mass vaccination. We were able to deploy a data monitoring framework across small clinical subgroups using linked patient-level NHS data on 23.4 million people with very short delays from vaccine administration to completed analysis. Targeted activity may be needed to address lower vaccination rates observed among certain key groups: ethnic minorities, people living in areas of higher deprivation, and those with severe mental illness or learning disabilities. However we note that this data is only from the first preliminary weeks of the vaccination programme. Variation in vaccination coverage between groups and regions will have many complex drivers, the figures presented in this manuscript require thoughtful interpretation to support a rapidly evolving NHS vaccination campaign; we are sharing local level data with national and regional NHS teams on request.

Background The COVID-19 pandemic has disrupted healthcare activity globally. The NHS in England stopped most non-urgent work by March 2020, but later recommended that services should be restored to near-normal levels before winter where possible. The authors are developing the OpenSAFELY NHS Service Restoration Observatory , using data to describe changes in service activity during COVID-19, and reviewing signals for action with commissioners, researchers and clinicians. Here we report phase one: generating, managing, and describing the data. Objective To describe the volume and variation of coded clinical activity in English primary care across 23.8 million patients’ records, taking respiratory disease and laboratory procedures as key examples. Methods Working on behalf of NHS England we developed an open source software framework for data management and analysis to describe trends and variation in clinical activity across primary care EHR data on 23.8 million patients; and conducted a population cohort-based study to describe activity using CTV3 coding hierarchy and keyword searches from January 2019-September 2020. Results Much activity recorded in general practice declined to some extent during the pandemic, but largely recovered by September 2020, with some exceptions. There was a large drop in coded activity for commonly used laboratory tests, with broad recovery to pre-pandemic levels by September. One exception was blood coagulation tests such as International Normalised Ratio (INR), with a smaller reduction (median tests per 1000 patients in 2020: February 8.0; April 6.2; September 7.0). The overall pattern of recording for respiratory symptoms was less affected, following an expected seasonal pattern and classified as “no change” from the previous year. Respiratory tract infections exhibited a sustained drop compared with pre-pandemic levels, not returning to pre-pandemic levels by September 2020. Various COVID-19 codes increased through the period. We observed a small decline associated with high level codes for long-term respiratory conditions such as chronic obstructive pulmonary disease (COPD) and asthma. Asthma annual reviews experienced a small drop but since recovered, while COPD annual reviews remain below baseline. Conclusions We successfully delivered an open source software framework to describe trends and variation in clinical activity across an unprecedented scale of primary care data. The COVD-19 pandemic led to a substantial change in healthcare activity. Most laboratory tests showed substantial reduction, largely recovering to near-normal levels by September 2020, with some important tests less affected. Records of respiratory infections decreased with the exception of codes related to COVID-19, whilst activity of other respiratory disease codes was mixed. We are expanding the NHS Service Restoration Observatory in collaboration with clinicians, commissioners and researchers and welcome feedback.

Objective To compare the effectiveness of sotrovimab (a neutralising monoclonal antibody) with molnupiravir (an antiviral) in preventing severe outcomes of covid-19 in adult patients infected with SARS-CoV-2 in the community and at high risk of severe outcomes from covid-19. Design Observational cohort study with the OpenSAFELY platform. Setting With the approval of NHS England, a real world cohort study was conducted with the OpenSAFELY-TPP platform (a secure, transparent, open source software platform for analysis of NHS electronic health records), and patient level electronic health record data were obtained from 24 million people registered with a general practice in England that uses TPP software. The primary care data were securely linked with data on SARS-CoV-2 infection and treatments, hospital admission, and death, over a period when both drug treatments were frequently prescribed in community settings. Participants Adult patients with covid-19 in the community at high risk of severe outcomes from covid-19, treated with sotrovimab or molnupiravir from 16 December 2021. Interventions Sotrovimab or molnupiravir given in the community by covid-19 medicine delivery units. Main outcome measures Admission to hospital with covid-19 (ie, with covid-19 as the primary diagnosis) or death from covid-19 (ie, with covid-19 as the underlying or contributing cause of death) within 28 days of the start of treatment. Results Between 16 December 2021 and 10 February 2022, 3331 and 2689 patients were treated with sotrovimab and molnupiravir, respectively, with no substantial differences in baseline characteristics. Mean age of all 6020 patients was 52 (standard deviation 16) years; 59% were women, 89% were white, and 88% had received three or more covid-19 vaccinations. Within 28 days of the start of treatment, 87 (1.4%) patients were admitted to hospital or died of infection from SARS-CoV-2 (32 treated with sotrovimab and 55 with molnupiravir). Cox proportional hazards models stratified by area showed that after adjusting for demographic information, high risk cohort categories, vaccination status, calendar time, body mass index, and other comorbidities, treatment with sotrovimab was associated with a substantially lower risk than treatment with molnupiravir (hazard ratio 0.54, 95% confidence interval 0.33 to 0.88, P=0.01). Consistent results were found from propensity score weighted Cox models (0.50, 0.31 to 0.81, P=0.005) and when restricted to people who were fully vaccinated (0.53, 0.31 to 0.90, P=0.02). No substantial effect modifications by other characteristics were detected (all P values for interaction >0.10). The findings were similar in an exploratory analysis of patients treated between 16 February and 1 May 2022 when omicron BA.2 was the predominant variant in England. Conclusions In routine care of adult patients in England with covid-19 in the community, at high risk of severe outcomes from covid-19, those who received sotrovimab were at lower risk of severe outcomes of covid-19 than those treated with molnupiravir.

BackgroundCOVID-19 has disproportionately affected minority ethnic populations in the UK. Our aim was to quantify ethnic differences in SARS-CoV-2 infection and COVID-19 outcomes during the first and second waves of the COVID-19 pandemic in England.MethodsWe conducted an observational cohort study of adults (aged ≥18 years) registered with primary care practices in England for whom electronic health records were available through the OpenSAFELY platform, and who had at least 1 year of continuous registration at the start of each study period (Feb 1 to Aug 3, 2020 [wave 1], and Sept 1 to Dec 31, 2020 [wave 2]). Individual-level primary care data were linked to data from other sources on the outcomes of interest: SARS-CoV-2 testing and positive test results and COVID-19-related hospital admissions, intensive care unit (ICU) admissions, and death. The exposure was self-reported ethnicity as captured on the primary care record, grouped into five high-level census categories (White, South Asian, Black, other, and mixed) and 16 subcategories across these five categories, as well as an unknown ethnicity category. We used multivariable Cox regression to examine ethnic differences in the outcomes of interest. Models were adjusted for age, sex, deprivation, clinical factors and comorbidities, and household size, with stratification by geographical region.FindingsOf 17 288 532 adults included in the study (excluding care home residents), 10 877 978 (62·9%) were White, 1 025 319 (5·9%) were South Asian, 340 912 (2·0%) were Black, 170 484 (1·0%) were of mixed ethnicity, 320 788 (1·9%) were of other ethnicity, and 4 553 051 (26·3%) were of unknown ethnicity. In wave 1, the likelihood of being tested for SARS-CoV-2 infection was slightly higher in the South Asian group (adjusted hazard ratio 1·08 [95% CI 1·07-1·09]), Black group (1·08 [1·06-1·09]), and mixed ethnicity group (1·04 [1·02-1·05]) and was decreased in the other ethnicity group (0·77 [0·76-0·78]) relative to the White group. The risk of testing positive for SARS-CoV-2 infection was higher in the South Asian group (1·99 [1·94-2·04]), Black group (1·69 [1·62-1·77]), mixed ethnicity group (1·49 [1·39-1·59]), and other ethnicity group (1·20 [1·14-1·28]). Compared with the White group, the four remaining high-level ethnic groups had an increased risk of COVID-19-related hospitalisation (South Asian group 1·48 [1·41-1·55], Black group 1·78 [1·67-1·90], mixed ethnicity group 1·63 [1·45-1·83], other ethnicity group 1·54 [1·41-1·69]), COVID-19-related ICU admission (2·18 [1·92-2·48], 3·12 [2·65-3·67], 2·96 [2·26-3·87], 3·18 [2·58-3·93]), and death (1·26 [1·15-1·37], 1·51 [1·31-1·71], 1·41 [1·11-1·81], 1·22 [1·00-1·48]). In wave 2, the risks of hospitalisation, ICU admission, and death relative to the White group were increased in the South Asian group but attenuated for the Black group compared with these risks in wave 1. Disaggregation into 16 ethnicity groups showed important heterogeneity within the five broader categories.InterpretationSome minority ethnic populations in England have excess risks of testing positive for SARS-CoV-2 and of adverse COVID-19 outcomes compared with the White population, even after accounting for differences in sociodemographic, clinical, and household characteristics. Causes are likely to be multifactorial, and delineating the exact mechanisms is crucial. Tackling ethnic inequalities will require action across many fronts, including reducing structural inequalities, addressing barriers to equitable care, and improving uptake of testing and vaccination.FundingMedical Research Council.

Objective To investigate whether risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and outcomes of coronavirus disease 2019 (covid-19) differed between adults living with and without children during the first two waves of the UK pandemic. Design Population based cohort study, on behalf of NHS England. Setting Primary care data and pseudonymously linked hospital and intensive care admissions and death records from England, during wave 1 (1 February to 31 August 2020) and wave 2 (1 September to 18 December 2020). Participants Two cohorts of adults (18 years and over) registered at a general practice on 1 February 2020 and 1 September 2020. Main outcome measures Adjusted hazard ratios for SARS-CoV-2 infection, covid-19 related admission to hospital or intensive care, or death from covid-19, by presence of children in the household. Results Among 9 334 392 adults aged 65 years and under, during wave 1, living with children was not associated with materially increased risks of recorded SARS-CoV-2 infection, covid-19 related hospital or intensive care admission, or death from covid-19. In wave 2, among adults aged 65 years and under, living with children of any age was associated with an increased risk of recorded SARS-CoV-2 infection (hazard ratio 1.06 (95% confidence interval 1.05 to 1.08) for living with children aged 0-11 years; 1.22 (1.20 to 1.24) for living with children aged 12-18 years) and covid-19 related hospital admission (1.18 (1.06 to 1.31) for living with children aged 0-11; 1.26 (1.12 to 1.40) for living with children aged 12-18). Living with children aged 0-11 was associated with reduced risk of death from both covid-19 and non-covid-19 causes in both waves; living with children of any age was also associated with lower risk of dying from non-covid-19 causes. For adults 65 years and under during wave 2, living with children aged 0-11 years was associated with an increased absolute risk of having SARS-CoV-2 infection recorded of 40-60 per 10 000 people, from 810 to between 850 and 870, and an increase in the number of hospital admissions of 1-5 per 10 000 people, from 160 to between 161 and 165. Living with children aged 12-18 years was associated with an increase of 160-190 per 10 000 in the number of SARS-CoV-2 infections and an increase of 2-6 per 10 000 in the number of hospital admissions. Conclusions In contrast to wave 1, evidence existed of increased risk of reported SARS-CoV-2 infection and covid-19 outcomes among adults living with children during wave 2. However, this did not translate into a materially increased risk of covid-19 mortality, and absolute increases in risk were small.

ObjectivesTo compare approaches for obtaining relative and absolute estimates of risk of 28-day COVID-19 mortality for adults in the general population of England in the context of changing levels of circulating infection.DesignThree designs were compared. (A) case-cohort which does not explicitly account for the time-changing prevalence of COVID-19 infection, (B) 28-day landmarking, a series of sequential overlapping sub-studies incorporating time-updating proxy measures of the prevalence of infection, and (C) daily landmarking. Regression models were fitted to predict 28-day COVID-19 mortality.SettingWorking on behalf of NHS England, we used clinical data from adult patients from all regions of England held in the TPP SystmOne electronic health record system, linked to Office for National Statistics (ONS) mortality data, using the OpenSAFELY platform.ParticipantsEligible participants were adults aged 18 or over, registered at a general practice using TPP software on 1st March 2020 with recorded sex, postcode and ethnicity. 11,972,947 individuals were included, and 7,999 participants experienced a COVID-19 related death. The study period lasted 100 days, ending 8th June 2020.PredictorsA range of demographic characteristics and comorbidities were used as potential predictors. Local infection prevalence was estimated with three proxies: modelled based on local prevalence and other key factors; rate of A&E COVID-19 related attendances; and rate of suspected COVID-19 cases in primary care.Main outcome measuresCOVID-19 related death.ResultsAll models discriminated well between patients who did and did not experience COVID-19 related death, with C-statistics ranging from 0.92-0.94. Accurate estimates of absolute risk required data on local infection prevalence, with modelled estimates providing the best performance.ConclusionsReliable estimates of absolute risk need to incorporate changing local prevalence of infection. Simple models can provide very good discrimination and may simplify implementation of risk prediction tools in practice.

SummaryBlack and minority ethnic groups were at raised risk of dying from COVID-19 during the first few months of the COVID-19 epidemic in England. We aimed to investigate whether ethnic inequalities in COVID-19 deaths were similar in the more recent “second wave” of the epidemic. Working on behalf of NHS England, we used primary care and linked ONS mortality data within the OpenSAFELY platform. All adults in the database at 1st September 2020 and with at least 1 year of prior follow-up and a record of ethnicity were included. The outcome was COVID-19-related death (death with COVID-19 listed as a cause of death on the death certificate). Follow-up was to 9th November 2020. Hazard ratios for ethnicity were calculated using Cox regression models adjusted for age and sex, and then further adjusted for deprivation. 13,223,154 people were included. During the study period, people of South Asian ethnicity were at higher risk of death due to COVID-19 than white people after adjusting for age and sex (HR = 3.47, 95% CI 2.99-4.03); the association attenuated somewhat on further adjustment for index of multiple deprivation (HR = 2.86, 2.46-3.33, Table 2). In contrast with the first wave of the epidemic, we found little evidence of a raised risk in black or other ethnic groups compared to white (HR for black vs white = 1.28, 0.87-1.88 adjusted for age and sex; and 1.01, 0.69-1.49 further adjusted for deprivation). Our findings suggest that ethnic inequalities in the risk of dying COVID-19-related death have changed between the first and early second wave of the epidemic in England.

BackgroundThe COVID-19 pandemic has disrupted healthcare activity globally. The NHS in England stopped most non-urgent work by March 2020, but later recommended that services should be restored to near-normal levels before winter where possible. The authors are developing the OpenSAFELY NHS Service Restoration Observatory, using data to describe changes in service activity during COVID-19, and reviewing signals for action with commissioners, researchers and clinicians. Here we report phase one: generating, managing, and describing the data.ObjectiveTo describe the volume and variation of coded clinical activity in English primary care across 23.8 million patients’ records, taking respiratory disease and laboratory procedures as key examples.MethodsWorking on behalf of NHS England we developed an open source software framework for data management and analysis to describe trends and variation in clinical activity across primary care EHR data on 23.8 million patients; and conducted a population cohort-based study to describe activity using CTV3 coding hierarchy and keyword searches from January 2019-September 2020.ResultsMuch activity recorded in general practice declined to some extent during the pandemic, but largely recovered by September 2020, with some exceptions. There was a large drop in coded activity for commonly used laboratory tests, with broad recovery to pre-pandemic levels by September. One exception was blood coagulation tests such as International Normalised Ratio (INR), with a smaller reduction (median tests per 1000 patients in 2020: February 8.0; April 6.2; September 7.0). The overall pattern of recording for respiratory symptoms was less affected, following an expected seasonal pattern and classified as “no change” from the previous year. Respiratory tract infections exhibited a sustained drop compared with pre-pandemic levels, not returning to pre-pandemic levels by September 2020. Various COVID-19 codes increased through the period. We observed a small decline associated with high level codes for long-term respiratory conditions such as chronic obstructive pulmonary disease (COPD) and asthma. Asthma annual reviews experienced a small drop but since recovered, while COPD annual reviews remain below baseline.ConclusionsWe successfully delivered an open source software framework to describe trends and variation in clinical activity across an unprecedented scale of primary care data. The COVD-19 pandemic led to a substantial change in healthcare activity. Most laboratory tests showed substantial reduction, largely recovering to near-normal levels by September 2020, with some important tests less affected. Records of respiratory infections decreased with the exception of codes related to COVID-19, whilst activity of other respiratory disease codes was mixed. We are expanding the NHS Service Restoration Observatory in collaboration with clinicians, commissioners and researchers and welcome feedback.

BackgroundEarly in the COVID-19 pandemic the NHS recommended that appropriate patients anticoagulated with warfarin should be switched to direct acting oral anticoagulants (DOACs), requiring less frequent blood testing. Subsequently, a national safety alert was issued regarding patients being inappropriately co-prescribed two anticoagulants following a medication change, and associated monitoring.ObjectiveTo describe which people were switched from warfarin to DOACs; identify potentially unsafe co-prescribing of anticoagulants; and assess whether abnormal clotting results have become more frequent during the pandemic.MethodsWorking on behalf of NHS England we conducted a population cohort based study using routine clinical data from >17 million adults in England.Results20,000 of 164,000 warfarin patients (12.2%) switched to DOACs between March and May 2020, most commonly to edoxaban and apixaban. Factors associated with switching included: older age, recent renal function test, higher number of recent INR tests recorded, atrial fibrillation diagnosis and care home residency. There was a sharp rise in co-prescribing of warfarin and DOACs from typically 50-100 per month to 246 in April 2020, 0.06% of all people receiving a DOAC or warfarin. INR testing fell by 14% to 506.8 patients tested per 1000 warfarin patients each month. We observed a very small increase in elevated INRs (n=470) during April compared with January (n=420).ConclusionsIncreased switching of anticoagulants from warfarin to DOACs was observed at the outset of the COVID-19 pandemic in England following national guidance. There was a small but substantial number of people co-prescribed warfarin and DOACs during this period. Despite a national safety alert on the issue, a widespread rise in elevated INR test results was not found. Primary care has responded rapidly to changes in patient care during the COVID-19 pandemic.

BackgroundHydroxychloroquine has been shown to inhibit entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into epithelial cells in vitro, but clinical studies found no evidence of reduced mortality when treating patients with COVID-19. We aimed to evaluate the effectiveness of hydroxychloroquine for prevention of COVID-19 mortality, as opposed to treatment for the disease.MethodsWe did a prespecified observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, which covers approximately 40% of the general population in England, UK. We included all adults aged 18 years and older registered with a general practice for 1 year or more on March 1, 2020. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use before the COVID-19 outbreak in England (considered as March 1, 2020) compared with non-users of hydroxychloroquine and risk of COVID-19 mortality among people with rheumatoid arthritis or systemic lupus erythematosus. Model adjustment was informed by a directed acyclic graph.FindingsBetween Sept 1, 2019, and March 1, 2020, of 194 637 people with rheumatoid arthritis or systemic lupus erythematosus, 30 569 (15·7%) received two or more prescriptions of hydroxychloroquine. Between March 1 and July 13, 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0·23% (95% CI 0·18 to 0·29) among users and 0·22% (0·20 to 0·25) among non-users; an absolute difference of 0·008% (−0·051 to 0·066). After accounting for age, sex, ethnicity, use of other immunosuppressive drugs, and geographical region, no association with COVID-19 mortality was observed (HR 1·03, 95% CI 0·80 to 1·33). We found no evidence of interactions with age or other immunosuppressive drugs. Quantitative bias analyses indicated that our observed associations were robust to missing information for additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality.InterpretationWe found no evidence of a difference in COVID-19 mortality among people who received hydroxychloroquine for treatment of rheumatological disease before the COVID-19 outbreak in England. Therefore, completion of randomised trials investigating pre-exposure prophylactic use of hydroxychloroquine for prevention of severe outcomes from COVID-19 are warranted.FundingMedical Research Council.

BackgroundHydroxychloroquine has been shown to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, but early clinical studies found no benefit treating patients with coronavirus disease 2019 (COVID-19). We set out to evaluate the effectiveness of hydroxychloroquine for prevention, as opposed to treatment, of COVID-19 mortality.MethodsWe pre-specified and conducted an observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, representing 40% of the general population in England. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use prior to the COVID-19 outbreak in England and risk of COVID-19 mortality among people with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Model adjustment was informed by a directed acyclic graph.ResultsOf 194,637 patients with RA or SLE, 30,569 (15.7%) received ≥ 2 prescriptions of hydroxychloroquine in the six months prior to 1 March 2020. Between 1 March 2020 and 13 July 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0.23% (95% CI 0.18–0.29) among users and 0.22% (95% CI 0.20–0.25) among non-users; an absolute difference of 0.008% (95% CI –0.051-0.066). After accounting for age, sex, ethnicity, use of other immunuosuppressives, and geographic region, no association with COVID-19 mortality was observed (HR 1.03, 95% CI 0.80–1.33). We found no evidence of interactions with age or other immunosuppressives. Quantitative bias analyses indicated observed associations were robust to missing information regarding additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality.ConclusionWe found no evidence of a difference in COVID-19 mortality among patients who received hydroxychloroquine for treatment of rheumatological disease prior to the COVID-19 outbreak in England.Research in contextEvidence before this studyPublished trials and observational studies to date have shown no evidence of benefit of hydroxychloroquine as a treatment for hospitalised patients who already have COVID-19. A separate question remains: whether routine ongoing use of hydroxychloroquine in people without COVID-19 protects against new infections or severe outcomes. We searched MEDLINE/PubMed for pharmacoepidemiological studies evaluating hydroxychloroquine for prevention of severe COVID-19 outcomes. The keywords “hydroxychloroquine AND (COVID OR coronavirus OR SARS-CoV-2) AND (prophyl* OR prevent*) AND (rate OR hazard OR odds OR risk)” were used and results were filtered to articles from the last year with abstracts available. 109 papers were identified for screening; none investigated pre-exposure prophylactic use of hydroxychloroquine for prevention of severe COVID-19 outcomes. Clinical trials of prophylactic use of hydroxychloroquine are ongoing; however, the largest trial does not expect to meet recruitment targets due to “…unjustified extrapolation and exaggerated safety concerns together with intense politicisation and negative publicity.” In the absence of reported clinical trials, evidence can be generated from real-world data to support the need for randomised clinical trials.Added value of this studyIn this cohort study representing 40% of the population of England, we investigated whether routine use of hydroxychloroquine prior to the COVID-19 outbreak prevented COVID-19 mortality. Using robust pharmacoepidemiological methods, we found no evidence to support a substantial benefit of hydroxychloroquine in preventing COVID-19 mortality. At the same time, we have shown no significant harm, and this generates the equipoise to justify continuing randomised trials. We have demonstrated in this study that it is feasible to address specific hypotheses about medicines in a rapid and transparent manner to inform interim clinical decision making and support the need for large-scale, randomised trial data.Implications of all the available evidenceThis is the first study to investigate the ongoing routine use of hydroxychloroquine and risk of COVID-19 mortality in a general population. While we found no evidence of any protective benefit, due to the observational nature of the study, residual confounding remains a possibility. Completion of trials for prevention of severe outcomes is warranted, but prior to the completion of these, we found no evidence to support the use of hydroxychloroquine for prevention of COVID-19 mortality.

BackgroundClose contact with children may provide cross-reactive immunity to SARs-CoV-2 due to more frequent prior coryzal infections from seasonal coronaviruses. Alternatively, close contact with children may increase risk of SARs-CoV-2 infection. We investigated whether risk of infection with SARs-CoV-2 and severe outcomes differed between adults living with and without children.MethodsWorking on behalf of NHS England, we conducted a population-based cohort study using primary care data and pseudonymously-linked hospital and intensive care admissions, and death records, from patients registered in general practices representing 40% of England. Using multivariable Cox regression, we calculated fully-adjusted hazard ratios (HR) of outcomes from 1st February-3rd August 2020 comparing adults living with and without children in the household.FindingsAmong 9,157,814 adults ≤65 years, living with children 0-11 years was not associated with increased risks of recorded SARS-CoV-2 infection, COVID-19 related hospital or ICU admission but was associated with reduced risk of COVID-19 death (HR 0.75, 95%CI 0.62-0.92). Living with children aged 12-18 years was associated with a small increased risk of recorded SARS-CoV-2 infection (HR 1.08, 95%CI 1.03-1.13), but not associated with other COVID-19 outcomes. Living with children of any age was also associated with lower risk of dying from non-COVID-19 causes. Among 2,567,671 adults >65 years there was no association between living with children and outcomes related to SARS-CoV-2. We observed no consistent changes in risk following school closure.InterpretationFor adults living with children there is no evidence of an increased risk of severe COVID-19 outcomes. These findings have implications for determining the benefit-harm balance of children attending school in the COVID-19 pandemic.FundingThis work was supported by the Medical Research Council MR/V015737/1.Research in contextEvidence before this studyWe searched MEDLINE on 19th October 2020 for population-based epidemiological studies comparing the risk of SARS-CoV-2 infection and COVID-19 disease in people living with and without children. We searched for articles published in 2020, with abstracts available, and terms “(children or parents or dependants) AND (COVID or SARS-CoV-2 or coronavirus) AND (rate or hazard or odds or risk), in the title, abstract or keywords. 244 papers were identified for screening but none were relevant. One additional study in preprint was identified on medRxiv and found a reduced risk of hospitalisation for COVID-19 and a positive SARS-CoV-2 infection among adult healthcare workers living with children.Added value of this studyThis is the first population-based study to investigate whether the risk of recorded SARS-CoV-2 infection and severe outcomes from COVID-19 differ between adults living in households with and without school-aged children during the UK pandemic. Our findings show that for adults living with children there is no evidence of an increased risk of severe COVID-19 outcomes although there may be a slightly increased risk of recorded SARS-CoV-2 infection for working-age adults living with children aged 12 to 18 years. Working-age adults living with children 0 to 11 years have a lower risk of death from COVID-19 compared to adults living without children, with the effect size being comparable to their lower risk of death from any cause. We observed no consistent changes in risk of recorded SARS-CoV-2 infection and severe outcomes from COVID-19 comparing periods before and after school closure.Implications of all the available evidenceOur results demonstrate no evidence of serious harms from COVID-19 to adults in close contact with children, compared to those living in households without children. This has implications for determining the benefit-harm balance of children attending school in the COVID-19 pandemic.

BackgroundCOVID-19 has had a disproportionate impact on ethnic minority populations, both in the UK and internationally. To date, much of the evidence has been derived from studies within single healthcare settings, mainly those hospitalised with COVID-19. Working on behalf of NHS England, the aim of this study was to identify ethnic differences in the risk of COVID-19 infection, hospitalisation and mortality using a large general population cohort in England.MethodsWe conducted an observational cohort study using linked primary care records of 17.5 million adults between 1 February 2020 and 3 August 2020. Exposure was self-reported ethnicity collapsed into the 5 and 16 ethnicity categories of the English Census. Multivariable Cox proportional hazards regression was used to identify ethnic differences in the risk of being tested and testing positive for SARS-CoV-2 infection, COVID-19 related intensive care unit (ICU) admission, and COVID-19 mortality, adjusted for socio-demographic factors, clinical co-morbidities, geographic region, care home residency, and household size.ResultsA total of 17,510,002 adults were included in the study; 63% white (n=11,030,673), 6% south Asian (n=1,034,337), 2% black (n=344,889), 2% other (n=324,730), 1% mixed (n=172,551), and 26% unknown (n=4,602,822). After adjusting for measured explanatory factors, south Asian, black, and mixed groups were marginally more likely to be tested (south Asian HR 1.08, 95%CI 1.07-1.09; black HR 1.08; 95%CI 1.06-1.09, mixed HR 1.03, 95%CI 1.01-1.05), and substantially more likely to test positive for SARS-CoV-2 compared with white adults (south Asian HR 2.02. 95% CI 1.97-2.07; black HR 1.68, 95%CI 1.61-1.76; mixed HR 1.46, 95%CI 1.36-1.56). The risk of being admitted to ICU for COVID-19 was substantially increased in all ethnic minority groups compared with white adults (south Asian HR 2.22, 95%CI 1.96-2.52; black HR 3.07, 95%CI 2.61-3.61; mixed HR 2.86, 95%CI 2.19-3.75, other HR 2.86, 95%CI 2.31-3.63). Risk of COVID-19 mortality was increased by 25-56% in ethnic minority groups compared with white adults (south Asian HR 1.27, 95%CI 1.17-1.38; black HR 1.55, 95%CI 1.38-1.75; mixed HR 1.40, 95%CI 1.12-1.76; other HR 1.25, 95%CI 1.05-1.49).We observed heterogeneity of associations after disaggregation into detailed ethnic groupings; Indian and African groups were at higher risk of all outcomes; Pakistani, Bangladeshi and Caribbean groups were less or equally likely to be tested for SARS-CoV-2, but at higher risk of all other outcomes, Chinese groups were less likely to be tested for and test positive for SARS-CoV-2, more likely to be admitted to ICU, and equally likely to die from COVID-19.ConclusionsWe found evidence of substantial ethnic inequalities in the risk of testing positive for SARS-CoV-2, ICU admission, and mortality, which persisted after accounting for explanatory factors, including household size. It is likely that some of this excess risk is related to factors not captured in clinical records such as occupation, experiences of structural discrimination, or inequitable access to health and social services. Prioritizing linkage between health, social care, and employment data and engaging with ethnic minority communities to better understand their lived experiences is essential for generating evidence to prevent further widening of inequalities in a timely and actionable manner.

ImportanceThere has been speculation that non-steroidal anti-inflammatory drugs (NSAIDs) may negatively affect coronavirus disease 2019 (COVID-19) outcomes, yet clinical evidence is limited.ObjectiveTo assess the association between NSAID use and deaths from COVID-19 using OpenSAFELY, a secure analytical platform.DesignTwo cohort studies (1stMarch-14thJune 2020).SettingWorking on behalf of NHS England, we used routine clinical data from >17 million patients in England linked to death data from the Office for National Statistics.ParticipantsStudy 1: General population (people with an NSAID prescription in the last three years). Study 2: people with rheumatoid arthritis/osteoarthritis.ExposuresCurrent NSAID prescription within the 4 months before 1stMarch 2020.Main Outcome and MeasureWe used Cox regression to estimate hazard ratios (HRs) for COVID-19 related death in people currently prescribed NSAIDs, compared with those not currently prescribed NSAIDs, adjusting for age, sex, comorbidities and other medications.ResultsIn Study 1, we included 535,519 current NSAID users and 1,924,095 non-users in the general population. The crude HR for current use was 1.25 (95% CI, 1.07–1.46), versus non-use. We observed no evidence of difference in risk of COVID-19 related death associated with current use (HR, 0.95, 95% CI, 0.80–1.13) in the fully adjusted model.In Study 2, we included 1,711,052 people with rheumatoid arthritis/osteoarthritis, of whom 175,631 (10%) were current NSAID users. The crude HR for current use was 0.43 (95% CI, 0.36–0.52), versus non-use. In the fully adjusted model, we observed a lower risk of COVID-19 related death (HR, 0.78, 95% CI, 0.65–0.94) associated with current use of NSAID versus non-use.Conclusion and RelevanceWe found no evidence of a harmful effect of NSAIDs on COVID-19 related deaths. Risks of COVID-19 do not need to influence decisions about therapeutic use of NSAIDs.

Courses to help medical students pass ‘Finals’ already exist but are typically expensive or can only be attended by a limited number of students. We describe the success of ‘The National Finals Revision Day' (NFRD) course, which we believe is sustainable and unique in terms of its combined scale and cost (£10 per person). The course was organised and taught by 12 junior doctors. In total, 300 students attended from 55% of UK medical schools. Attendees found the course both relevant (96.4%) and cost-effective (97%), whilst the 11 medical and surgical talks were of a high standard (90.1%). The organising committee felt confident to organise their own teaching course in the future with 100% having already run a course themselves since the NFRD course. The NFRD course was also used by 11/12 (91.7%) of the organising committee to achieve their Annual Review of Competency Progression (ARCP) and 12/12 (100%) of the organising committee to obtain jobs on training programmes in the UK. We provide guidance about how to organise similar large-scale events for those interested. Moving forward, the teaching course will be run at: (i) multiple times; (ii) multiple UK venues; (iii) run over two days to cover more medical and surgical topics; and (iv) include the option of attending via video link.

BackgroundEarly descriptions of the coronavirus outbreak showed a lower prevalence of asthma and COPD than was expected for people diagnosed with COVID-19, leading to speculation that inhaled corticosteroids (ICS) may protect against infection with SARS-CoV-2, and development of serious sequelae. We evaluated the association between ICS and COVID-19 related death using linked electronic health records in the UK.MethodsWe conducted cohort studies on two groups of people (COPD and asthma) using the OpenSAFELY platform to analyse data from primary care practices linked to national death registrations. People receiving an ICS were compared to those receiving alternative respiratory medications. Our primary outcome was COVID-19 related death.FindingsWe identified 148,588 people with COPD and 817,973 people with asthma receiving relevant respiratory medications in the four months prior to 01 March 2020. People with COPD receiving ICS were at a greater risk of COVID-19 related death compared to those receiving a long-acting beta agonist (LABA) and a long-acting muscarinic antagonist (LAMA) (adjusted HR = 1.38, 95% CI = 1.08 – 1.75). People with asthma receiving high dose ICS were at an increased risk of death compared to those receiving a short-acting beta agonist (SABA) only (adjusted HR = 1.52, 95%CI = 1.08 – 2.14); the adjusted HR for those receiving low-medium dose ICS was 1.10 (95% CI = 0.82 – 1.49). Quantitative bias analyses indicated that an unmeasured confounder of only moderate strength of association with exposure and outcome could explain the observed associations in both populations.InterpretationThese results do not support a major role of ICS in protecting against COVID-19 related deaths. Observed increased risks of COVID-19 related death among people with COPD and asthma receiving ICS can be plausibly explained by unmeasured confounding due to disease severity.FundingThis work was supported by the Medical Research Council MR/V015737/1.

Background Ankle fractures are one of the most common fractures in adults aged 20–65 years. The British Orthopaedic Association (BOA) and British Orthopaedic Foot and Ankle Society (BOFAS) jointly produced Standards for Trauma (BOAST) BOAST 12, with the aim of reducing morbidity by standardising care of these injuries. The primary aim of the AUGMENT study was to determine the extent and clinical effect of variation from BOAST 12. Methods AUGMENT was a multi-centre prospective trainee led audit of consecutive patients presenting with an ankle fracture within a four-week period. Data were collected on patient demographics, comorbidities, management and 12-week outcome. The BOAST 12 standards were divided into four subgroups; documentation, imaging, management and follow-up. Percentage compliance with each subgroup was analysed. A multivariate logistic regression analysis was used to determine impact of overall compliance on likelihood of discharge in follow-up period. Findings 971 patients were included across 52 sites. The overall rate of BOAST 12 compliance was 41.7%. Variations in practice were observed in clinical documentation, especially of neurovascular status, (40.7%) and VTE assessment (61.5%). Patient management compliance with all 16 of the BOAST 12 standards was associated with a higher rate of discharge during the 12-week follow-up period (p = 0.005). Conclusion AUGMENT has demonstrated that the management of ankle fractures is variable across the UK. Over half of patients had aspects of their care that were not BOAST 12 compliant. When compliance was observed, it was associated with earlier discharge from orthopaedic care.

Fixing Evidence-Based Medicine requires transparency, strategic campaigning, and education When patients ask their doctor about the benefits and harms of a treatment, the doctor can only say what is likely to be true based on the volume and quality of evidence available. Poor research integrity misleads doctors, meaning what we tell our patients might simply be wrong. In 2001 a single misreported trial, study 329, led to millions of adolescents being prescribed an antidepressant that didn’t work, and caused suicidal behaviour. This was entirely avoidable. I believe there are three fixes to such problems in evidence-based medicine: transparency; strategic campaigning; and education. Transparency so we know about missing data and poor methodology Half of all clinical trial results are never reported, and positive trials are twice as likely to be published as negative trials. This means we often don’t learn about harms data, and the data we have are biased. Hidden documents mean we don’t know when publication bias is happening: readers accept biased results, because they trust journals and authors to maintain reporting integrity. Transparent reporting fixes publication bias, allowing us to see the most accurate picture of the evidence available. Transparent trial registration, protocols, and editorial practices allow us to detect poor methodology and interpret the evidence accordingly. Such transparency has very real consequences: If all data had been transparently reported, study 329 would have shown the lack of efficacy and increases in harm of paroxetine, and thousands of lives may have been saved. Strategic campaigning to effect real-world change Outcome switching and publication bias remain prevalent, showing decades of prevalence studies do not in themselves solve these problems. Guardians of evidence-based medicine must be more strategic in fixing its flaws. There are strong financial, academic and personal incentives for trialists to comply with requests from journal editors. Appealing to editors to require full registration and transparent reporting is therefore likely to motivate trial authors in good practice. Incentives such as CONSORT and ICMJE do just this and provide a standard to which journals can be held accountable. Funding is arguably the biggest barrier to research. Plan S sets out 10 principles to improve research funded by public grants, including funders’ research integrity requirements. Future projects should learn from this: researchers are likely to comply with such requirements to secure funding. Education so people know what to do Responses to correction letters in the COMPare project showed widespread misunderstandings around the reporting of trial outcomes. Education is needed to show doctors and patients what good trial reporting looks like, so they can make informed clinical decisions with the evidence available. In COMPare we did this through journal correspondence, leading to policy changes and extensive discussion in the clinical trials community. Education should be considered more broadly: teaching EBM at schools sets standards for the next generation of leaders; educating the public creates appropriate intolerance to poor research practice; and open discussion of existing research educates doctors and patients about poor research practice affecting clinical decisions.

Background Discrepancies between pre-specified and reported outcomes are an important source of bias in trials. Despite legislation, guidelines and public commitments on correct reporting from journals, outcome misreporting continues to be prevalent. We aimed to document the extent of misreporting, establish whether it was possible to publish correction letters on all misreported trials as they were published, and monitor responses from editors and trialists to understand why outcome misreporting persists despite public commitments to address it. Methods We identified five high-impact journals endorsing Consolidated Standards of Reporting Trials (CONSORT) (New England Journal of Medicine, The Lancet, Journal of the American Medical Association, British Medical Journal, and Annals of Internal Medicine) and assessed all trials over a six-week period to identify every correctly and incorrectly reported outcome, comparing published reports against published protocols or registry entries, using CONSORT as the gold standard. A correction letter describing all discrepancies was submitted to the journal for all misreported trials, and detailed coding sheets were shared publicly. The proportion of letters published and delay to publication were assessed over 12 months of follow-up. Correspondence received from journals and authors was documented and themes were extracted. Results Sixty-seven trials were assessed in total. Outcome reporting was poor overall and there was wide variation between journals on pre-specified primary outcomes (mean 76% correctly reported, journal range 25–96%), secondary outcomes (mean 55%, range 31–72%), and number of undeclared additional outcomes per trial (mean 5.4, range 2.9–8.3). Fifty-eight trials had discrepancies requiring a correction letter (87%, journal range 67–100%). Twenty-three letters were published (40%) with extensive variation between journals (range 0–100%). Where letters were published, there were delays (median 99 days, range 0–257 days). Twenty-nine studies had a pre-trial protocol publicly available (43%, range 0–86%). Qualitative analysis demonstrated extensive misunderstandings among journal editors about correct outcome reporting and CONSORT. Some journals did not engage positively when provided correspondence that identified misreporting; we identified possible breaches of ethics and publishing guidelines. Conclusions All five journals were listed as endorsing CONSORT, but all exhibited extensive breaches of this guidance, and most rejected correction letters documenting shortcomings. Readers are likely to be misled by this discrepancy. We discuss the advantages of prospective methodology research sharing all data openly and pro-actively in real time as feedback on critiqued studies. This is the first empirical study of major academic journals’ willingness to publish a cohort of comparable and objective correction letters on misreported high-impact studies. Suggested improvements include changes to correspondence processes at journals, alternatives for indexed post-publication peer review, changes to CONSORT’s mechanisms for enforcement, and novel strategies for research on methods and reporting. Electronic supplementary material The online version of this article (10.1186/s13063-019-3173-2) contains supplementary material, which is available to authorized users.

Background Discrepancies between pre-specified and reported outcomes are an important and prevalent source of bias in clinical trials. COMPare (Centre for Evidence-Based Medicine Outcome Monitoring Project) monitored all trials in five leading journals for correct outcome reporting, submitted correction letters on all misreported trials in real time, and then monitored responses from editors and trialists. From the trialists’ responses, we aimed to answer two related questions. First, what can trialists’ responses to corrections on their own misreported trials tell us about trialists’ knowledge of correct outcome reporting? Second, what can a cohort of responses to a standardised correction letter tell us about how researchers respond to systematic critical post-publication peer review? Methods All correspondence from trialists, published by journals in response to a correction letter from COMPare, was filed and indexed. We analysed the letters qualitatively and identified key themes in researchers’ errors about correct outcome reporting, and approaches taken by researchers when their work was criticised. Results Trialists frequently expressed views that contradicted the CONSORT (Consolidated Standards of Reporting Trials) guidelines or made inaccurate statements about correct outcome reporting. Common themes were: stating that pre-specification after trial commencement is acceptable; incorrect statements about registries; incorrect statements around the handling of multiple time points; and failure to recognise the need to report changes to pre-specified outcomes in the trial report. We identified additional themes in the approaches taken by researchers when responding to critical correspondence, including the following: ad hominem criticism; arguing that trialists should be trusted, rather than follow guidelines for trial reporting; appealing to the existence of a novel category of outcomes whose results need not necessarily be reported; incorrect statements by researchers about their own paper; and statements undermining transparency infrastructure, such as trial registers. Conclusions Researchers commonly make incorrect statements about correct trial reporting. There are recurring themes in researchers’ responses when their work is criticised, some of which fall short of the scientific ideal. Research on methodological shortcomings is now common, typically in the form of retrospective cohort studies describing the overall prevalence of a problem. We argue that prospective cohort studies which additionally issue correction letters in real time on each individual flawed study—and then follow-up responses from trialists and journals—are more impactful, more informative for those consuming the studies critiqued, more informative on the causes of shortcomings in research, and a better use of research resources. Electronic supplementary material The online version of this article (10.1186/s13063-019-3172-3) contains supplementary material, which is available to authorized users.

1 Abraham WT, Stevenson LW, Bourge RC, et al. Sustained effi cacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: complete follow-up results from the CHAMPION randomised trial. Lancet 2016; 387: 453–61. 2 Adamson PB, Abraham WT, Aaron M, et al. CHAMPION trial rationale and design: the long-term safety and clinical effi cacy of a wireless pulmonary artery pressure monitoring system. J Card Fail 2011; 17: 3–10. its consequences were not adequately considered before the introduction of abdominal aortic aneurysm screening. The letter by Paraskevas and others illustrates that such unidirectional focus on benefi ts is still a problem.

OBJECTIVE To determine if maternal country of birth is associated with the risk of antepartum stillbirth in late pregnancy. DESIGN, SETTING AND PARTICIPANTS Retrospective cross-sectional study of all singleton births at 37-42 weeks' gestation, excluding those with congenital abnormalities and intrapartum stillbirths, between 1 June 2001 and 31 May 2011 at Southern Health, a large metropolitan maternity service in Melbourne, Australia. MAIN OUTCOME MEASURE Rate of late-pregnancy antepartum stillbirth, analysed by maternal country of birth. RESULTS Among 44 326 births, there was a significant difference in the stillbirth rate by maternal country of birth (P < 0.001). The rate of stillbirth per 1000 births was 1.48 among Australian-born women, 3.55 among South Asian-born women and 1.06 among South-East-East Asian-born women. Women born in South Asia were 2.4 (95% CI, 1.4-4.0) times more likely to have a late-pregnancy stillbirth than women born in Australia (P < 0.001). There was no significant difference between women born in Australia and women born in South-East-East Asia (P = 0.34). Adjusting for potential confounding factors, South Asian maternal birth remained an independent risk factor for stillbirth (adjusted odds ratio, 2.5; 95% CI, 1.3-5.1; P = 0.009). CONCLUSION Women born in South Asia have an increased risk of antepartum stillbirth in late pregnancy, compared with other women. This observation may have implications for the delivery of pregnancy care in Australia.

After completing undergraduate degrees in physics, Henry Drysdale, Ioan Milosevic and Eirion Slade decided their futures lay in medicine

1 Morris JM, Roberts CL, Bowen JR, et al. Immediate delivery compared with expectant management after preterm pre-labour rupture of the membranes close to term (PPROMT trial): a randomised controlled trial. Lancet 2016, 387: 444–52. 2 Algert CS, Lain S, Patterson J. The Preterm Prelabour Rupture of Membranes close to Term (PPROMT) Trial: statistical analysis plan. Sydney, Australia. http://ses.library.usyd.edu.au/ handle/2123/10336 (accessed April 7, 2016).

1 Morris JM, Roberts CL, Bowen JR, et al. Immediate delivery compared with expectant management after preterm pre-labour rupture of the membranes close to term (PPROMT trial): a randomised controlled trial. Lancet 2016, 387: 444–52. 2 Algert CS, Lain S, Patterson J. The Preterm Prelabour Rupture of Membranes close to Term (PPROMT) Trial: statistical analysis plan. Sydney, Australia. http://ses.library.usyd.edu.au/ handle/2123/10336 (accessed April 7, 2016).