Showing papers in "BMJ in 2021"

The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

Abstract: The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.

PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews.

Abstract: The methods and results of systematic reviews should be reported in sufficient detail to allow users to assess the trustworthiness and applicability of the review findings. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement was developed to facilitate transparent and complete reporting of systematic reviews and has been updated (to PRISMA 2020) to reflect recent advances in systematic review methodology and terminology. Here, we present the explanation and elaboration paper for PRISMA 2020, where we explain why reporting of each item is recommended, present bullet points that detail the reporting recommendations, and present examples from published reviews. We hope that changes to the content and structure of PRISMA 2020 will facilitate uptake of the guideline and lead to more transparent, complete, and accurate reporting of systematic reviews.

A new framework for developing and evaluating complex interventions: Update of Medical Research Council guidance

Abstract: The UK Medical Research Council’s widely used guidance for developing and evaluating complex interventions has been replaced by a new framework, commissioned jointly by the Medical Research Council and the National Institute for Health Research, which takes account of recent developments in theory and methods and the need to maximise the efficiency, use, and impact of research.

Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study.

Abstract: Objective To estimate the real world effectiveness of the Pfizer-BioNTech BNT162b2 and Oxford-AstraZeneca ChAdOx1-S vaccines against confirmed covid-19 symptoms (including the UK variant of concern B.1.1.7), admissions to hospital, and deaths. Design Test negative case-control study. Setting Community testing for covid-19 in England. Participants 156 930 adults aged 70 years and older who reported symptoms of covid-19 between 8 December 2020 and 19 February 2021 and were successfully linked to vaccination data in the National Immunisation Management System. Interventions Vaccination with BNT162b2 or ChAdOx1-S. Main outcome measures Primary outcomes were polymerase chain reaction confirmed symptomatic SARS-CoV-2 infections, admissions to hospital for covid-19, and deaths with covid-19. Results Participants aged 80 years and older vaccinated with BNT162b2 before 4 January 2021 had a higher odds of testing positive for covid-19 in the first nine days after vaccination (odds ratio up to 1.48, 95% confidence interval 1.23 to 1.77), indicating that those initially targeted had a higher underlying risk of infection. Vaccine effectiveness was therefore compared with the baseline post-vaccination period. Vaccine effects were noted 10 to 13 days after vaccination, reaching a vaccine effectiveness of 70% (95% confidence interval 59% to 78%), then plateauing. From 14 days after the second dose a vaccination effectiveness of 89% (85% to 93%) was found compared with the increased baseline risk. Participants aged 70 years and older vaccinated from 4 January (when ChAdOx1-S delivery commenced) had a similar underlying risk of covid-19 to unvaccinated individuals. With BNT162b2, vaccine effectiveness reached 61% (51% to 69%) from 28 to 34 days after vaccination, then plateaued. With ChAdOx1-S, effects were seen from 14 to 20 days after vaccination, reaching an effectiveness of 60% (41% to 73%) from 28 to 34 days, increasing to 73% (27% to 90%) from day 35 onwards. On top of the protection against symptomatic disease, a further 43% (33% to 52%) reduced risk of emergency hospital admission and 51% (37% to 62%) reduced risk of death was observed in those who had received one dose of BNT162b2. Participants who had received one dose of ChAdOx1-S had a further 37% (3% to 59%) reduced risk of emergency hospital admission. Follow-up was insufficient to assess the effect of ChAdOx1-S on mortality. Combined with the effect against symptomatic disease, a single dose of either vaccine was about 80% effective at preventing admission to hospital with covid-19 and a single dose of BNT162b2 was 85% effective at preventing death with covid-19. Conclusion Vaccination with either one dose of BNT162b2 or ChAdOx1-S was associated with a significant reduction in symptomatic covid-19 in older adults, and with further protection against severe disease. Both vaccines showed similar effects. Protection was maintained for the duration of follow-up (>6 weeks). A second dose of BNT162b2 was associated with further protection against symptomatic disease. A clear effect of the vaccines against the B.1.1.7 variant was found.

Long covid-mechanisms, risk factors, and management.

Abstract: Since its emergence in Wuhan, China, covid-19 has spread and had a profound effect on the lives and health of people around the globe. As of 4 July 2021, more than 183 million confirmed cases of covid-19 had been recorded worldwide, and 3.97 million deaths. Recent evidence has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-2 infection, and this condition is now coined long covid by recognized research institutes. Studies have shown that long covid can affect the whole spectrum of people with covid-19, from those with very mild acute disease to the most severe forms. Like acute covid-19, long covid can involve multiple organs and can affect many systems including, but not limited to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cognitive impairment, sleep disturbances, symptoms of post-traumatic stress disorder, muscle pain, concentration problems, and headache. This review summarizes studies of the long term effects of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-19 and long covid and possible therapeutic options are also discussed.

Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study.

Abstract: Objective To establish whether there is any change in mortality from infection with a new variant of SARS-CoV-2, designated a variant of concern (VOC-202012/1) in December 2020, compared with circulating SARS-CoV-2 variants. Design Matched cohort study. Setting Community based (pillar 2) covid-19 testing centres in the UK using the TaqPath assay (a proxy measure of VOC-202012/1 infection). Participants 54 906 matched pairs of participants who tested positive for SARS-CoV-2 in pillar 2 between 1 October 2020 and 29 January 2021, followed-up until 12 February 2021. Participants were matched on age, sex, ethnicity, index of multiple deprivation, lower tier local authority region, and sample date of positive specimens, and differed only by detectability of the spike protein gene using the TaqPath assay. Main outcome measure Death within 28 days of the first positive SARS-CoV-2 test result. Results The mortality hazard ratio associated with infection with VOC-202012/1 compared with infection with previously circulating variants was 1.64 (95% confidence interval 1.32 to 2.04) in patients who tested positive for covid-19 in the community. In this comparatively low risk group, this represents an increase in deaths from 2.5 to 4.1 per 1000 detected cases. Conclusions The probability that the risk of mortality is increased by infection with VOC-202012/01 is high. If this finding is generalisable to other populations, infection with VOC-202012/1 has the potential to cause substantial additional mortality compared with previously circulating variants. Healthcare capacity planning and national and international control policies are all impacted by this finding, with increased mortality lending weight to the argument that further coordinated and stringent measures are justified to reduce deaths from SARS-CoV-2.

Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study.

Abstract: Objective To quantify rates of organ specific dysfunction in individuals with covid-19 after discharge from hospital compared with a matched control group from the general population. Design Retrospective cohort study. Setting NHS hospitals in England. Participants 47 780 individuals (mean age 65, 55% men) in hospital with covid-19 and discharged alive by 31 August 2020, exactly matched to controls from a pool of about 50 million people in England for personal and clinical characteristics from 10 years of electronic health records. Main outcome measures Rates of hospital readmission (or any admission for controls), all cause mortality, and diagnoses of respiratory, cardiovascular, metabolic, kidney, and liver diseases until 30 September 2020. Variations in rate ratios by age, sex, and ethnicity. Results Over a mean follow-up of 140 days, nearly a third of individuals who were discharged from hospital after acute covid-19 were readmitted (14 060 of 47 780) and more than 1 in 10 (5875) died after discharge, with these events occurring at rates four and eight times greater, respectively, than in the matched control group. Rates of respiratory disease (P Conclusions Individuals discharged from hospital after covid-19 had increased rates of multiorgan dysfunction compared with the expected risk in the general population. The increase in risk was not confined to the elderly and was not uniform across ethnicities. The diagnosis, treatment, and prevention of post-covid syndrome requires integrated rather than organ or disease specific approaches, and urgent research is needed to establish the risk factors.

Covid-19 pandemic and the social determinants of health.

Abstract: Lauren Paremoer and colleagues call for action to create a fairer and more sustainable post-covid world

Managing the long term effects of covid-19: summary of NICE, SIGN, and RCGP rapid guideline.

Abstract: ### What you need to know For a proportion of people covid-19 leads to long term effects that can have a significant impact on quality of life. According to the Office for National Statistics, around one in five people testing positive for covid-19 exhibit symptoms for a period of five weeks or more.1 This presents challenges for determining best-practice standards of care. As yet, no commonly agreed clinical definition of long term covid-19 exists, nor a clear definition of treatment pathway. To assist clinicians, the National Institute for Health and Care Excellence (NICE), the Scottish Intercollegiate Guidelines Network (SIGN), and the Royal College of General Practitioners (RCGP) have developed the “COVID-19 rapid guideline: managing the long term effects of COVID-19.”2 It covers care for people with signs and symptoms that continue for more than four weeks, and which developed during or after an infection consistent with covid-19, and which are not explained by alternative diagnoses. The guideline provides clinical definitions of the effects of covid-19 at different times and provides advice on diagnosis and management based on the best available evidence and the knowledge and experience of the expert panel. It will be subject to a “living” approach, which means that targeted areas of the guideline will be reviewed weekly and updated in response to emerging evidence and evolving expert experience. This article summarises the guideline recommendations as published on 18 …

Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial.

Abstract: Objective To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19). Design Randomised, open label trial. Setting Nine hospitals in Brazil, 8 May to 17 July 2020. Participants Adults with confirmed covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the tocilizumab group. Interventions Tocilizumab (single intravenous infusion of 8 mg/kg) plus standard care (n=65) versus standard care alone (n=64). Main outcome measure The primary outcome, clinical status measured at 15 days using a seven level ordinal scale, was analysed as a composite of death or mechanical ventilation because the assumption of odds proportionality was not met. Results A total of 129 patients were enrolled (mean age 57 (SD 14) years; 68% men) and all completed follow-up. All patients in the tocilizumab group and two in the standard care group received tocilizumab. 18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32). Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2). Adverse events were reported in 29 of 67 (43%) patients who received tocilizumab and 21 of 62 (34%) who did not receive tocilizumab. Conclusions In patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality. Trial registration ClinicalTrials.gov NCT04403685.

Effectiveness of public health measures in reducing the incidence of covid-19, SARS-CoV-2 transmission, and covid-19 mortality: systematic review and meta-analysis

Abstract: Objective To review the evidence on the effectiveness of public health measures in reducing the incidence of covid-19, SARS-CoV-2 transmission, and covid-19 mortality. Design Systematic review and meta-analysis. Data sources Medline, Embase, CINAHL, Biosis, Joanna Briggs, Global Health, and World Health Organization COVID-19 database (preprints). Eligibility criteria for study selection Observational and interventional studies that assessed the effectiveness of public health measures in reducing the incidence of covid-19, SARS-CoV-2 transmission, and covid-19 mortality. Main outcome measures The main outcome measure was incidence of covid-19. Secondary outcomes included SARS-CoV-2 transmission and covid-19 mortality. Data synthesis DerSimonian Laird random effects meta-analysis was performed to investigate the effect of mask wearing, handwashing, and physical distancing measures on incidence of covid-19. Pooled effect estimates with corresponding 95% confidence intervals were computed, and heterogeneity among studies was assessed using Cochran’s Q test and the I2 metrics, with two tailed P values. Results 72 studies met the inclusion criteria, of which 35 evaluated individual public health measures and 37 assessed multiple public health measures as a “package of interventions.” Eight of 35 studies were included in the meta-analysis, which indicated a reduction in incidence of covid-19 associated with handwashing (relative risk 0.47, 95% confidence interval 0.19 to 1.12, I2=12%), mask wearing (0.47, 0.29 to 0.75, I2=84%), and physical distancing (0.75, 0.59 to 0.95, I2=87%). Owing to heterogeneity of the studies, meta-analysis was not possible for the outcomes of quarantine and isolation, universal lockdowns, and closures of borders, schools, and workplaces. The effects of these interventions were synthesised descriptively. Conclusions This systematic review and meta-analysis suggests that several personal protective and social measures, including handwashing, mask wearing, and physical distancing are associated with reductions in the incidence covid-19. Public health efforts to implement public health measures should consider community health and sociocultural needs, and future research is needed to better understand the effectiveness of public health measures in the context of covid-19 vaccination. Systematic review registration PROSPERO CRD42020178692.

Covid-19: Pfizer's paxlovid is 89% effective in patients at risk of serious illness, company reports.

Abstract: Pfizer’s oral antiviral drug paxlovid significantly reduces hospital admissions and deaths among people with covid-19 who are at high risk of severe illness, when compared with placebo, the company has reported. The interim analysis of the phase II-III data, outlined in a press release, included 1219 adults who were enrolled by 29 September 2021. It found that, among participants who received treatments within three days of covid-19 symptoms starting, the risk of covid related hospital admission or death from any cause was 89% lower in the paxlovid group than the placebo group. The UK government has purchased 250 000 courses …

Arterial events, venous thromboembolism, thrombocytopenia, and bleeding after vaccination with Oxford-AstraZeneca ChAdOx1-S in Denmark and Norway: population based cohort study.

Abstract: Objective To assess rates of cardiovascular and haemostatic events in the first 28 days after vaccination with the Oxford-AstraZeneca vaccine ChAdOx1-S in Denmark and Norway and to compare them with rates observed in the general populations. Design Population based cohort study. Setting Nationwide healthcare registers in Denmark and Norway. Participants All people aged 18-65 years who received a first vaccination with ChAdOx1-S from 9 February 2021 to 11 March 2021. The general populations of Denmark (2016-18) and Norway (2018-19) served as comparator cohorts. Main outcome measures Observed 28 day rates of hospital contacts for incident arterial events, venous thromboembolism, thrombocytopenia/coagulation disorders, and bleeding among vaccinated people compared with expected rates, based on national age and sex specific background rates from the general populations of the two countries. Results The vaccinated cohorts comprised 148 792 people in Denmark (median age 45 years, 80% women) and 132 472 in Norway (median age 44 years, 78% women), who received their first dose of ChAdOx1-S. Among 281 264 people who received ChAdOx1-S, the standardised morbidity ratio for arterial events was 0.97 (95% confidence interval 0.77 to 1.20). 59 venous thromboembolic events were observed in the vaccinated cohort compared with 30 expected based on the incidence rates in the general population, corresponding to a standardised morbidity ratio of 1.97 (1.50 to 2.54) and 11 (5.6 to 17.0) excess events per 100 000 vaccinations. A higher than expected rate of cerebral venous thrombosis was observed: standardised morbidity ratio 20.25 (8.14 to 41.73); an excess of 2.5 (0.9 to 5.2) events per 100 000 vaccinations. The standardised morbidity ratio for any thrombocytopenia/coagulation disorders was 1.52 (0.97 to 2.25) and for any bleeding was 1.23 (0.97 to 1.55). 15 deaths were observed in the vaccine cohort compared with 44 expected. Conclusions Among recipients of ChAdOx1-S, increased rates of venous thromboembolic events, including cerebral venous thrombosis, were observed. For the remaining safety outcomes, results were largely reassuring, with slightly higher rates of thrombocytopenia/coagulation disorders and bleeding, which could be influenced by increased surveillance of vaccine recipients. The absolute risks of venous thromboembolic events were, however, small, and the findings should be interpreted in the light of the proven beneficial effects of the vaccine, the context of the given country, and the limitations to the generalisability of the study findings.

Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials

Abstract: Objective To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk. Design Network meta-analysis. Data sources Medline, Embase, and Cochrane CENTRAL up to 11 August 2020. Eligibility criteria for selecting studies Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias. Main outcome measures Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review. Results 764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced mortality and admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 5 to 48 fewer deaths in 1000 patients over five years; see interactive decision support tool (https://magicevidence.org/match-it/200820dist/#!/) for all outcomes. Conclusions In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with notable differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review. Systematic review registration PROSPERO CRD42019153180.

Covid-19: European countries suspend use of Oxford-AstraZeneca vaccine after reports of blood clots.

Abstract: Denmark has temporarily suspended use of the Oxford-AstraZeneca covid-19 vaccine as a precautionary move after reports of blood clots and one death. However, the European Medicines Agency (EMA) and the UK’s regulatory body have said that there is no indication that vaccination is linked to thromboembolic events. Eight other countries—Norway, Iceland, Austria, Estonia, Lithuania, Luxembourg, Italy, and Latvia—have also suspended use of AstraZeneca’s vaccine. The decisions are a further setback for Europe’s vaccination campaign, which has struggled to pick up speed, partly because of delays in delivering the AstraZeneca vaccine. The Danish Health Authority said that one person in Denmark had died after receiving the AstraZeneca vaccine and that it would suspend the drug’s use for two weeks while the case was investigated. “It is important to point out that we have not terminated the use of the AstraZeneca vaccine—we are just pausing its use,” said the Danish Health Authority’s director, Soren Brostrom. On 10 …

Excess deaths associated with covid-19 pandemic in 2020: age and sex disaggregated time series analysis in 29 high income countries.

Abstract: Objective To estimate the direct and indirect effects of the covid-19 pandemic on mortality in 2020 in 29 high income countries with reliable and complete age and sex disaggregated mortality data. Design Time series study of high income countries. Setting Austria, Belgium, Czech Republic, Denmark, England and Wales, Estonia, Finland, France, Germany, Greece, Hungary, Israel, Italy, Latvia, Lithuania, the Netherlands, New Zealand, Northern Ireland, Norway, Poland, Portugal, Scotland, Slovakia, Slovenia, South Korea, Spain, Sweden, Switzerland, and United States. Participants Mortality data from the Short-term Mortality Fluctuations data series of the Human Mortality Database for 2016-20, harmonised and disaggregated by age and sex. Interventions Covid-19 pandemic and associated policy measures. Main outcome measures Weekly excess deaths (observed deaths versus expected deaths predicted by model) in 2020, by sex and age (0-14, 15-64, 65-74, 75-84, and ≥85 years), estimated using an over-dispersed Poisson regression model that accounts for temporal trends and seasonal variability in mortality. Results An estimated 979 000 (95% confidence interval 954 000 to 1 001 000) excess deaths occurred in 2020 in the 29 high income countries analysed. All countries had excess deaths in 2020, except New Zealand, Norway, and Denmark. The five countries with the highest absolute number of excess deaths were the US (458 000, 454 000 to 461 000), Italy (89 100, 87 500 to 90 700), England and Wales (85 400, 83 900 to 86 800), Spain (84 100, 82 800 to 85 300), and Poland (60 100, 58 800 to 61 300). New Zealand had lower overall mortality than expected (−2500, −2900 to −2100). In many countries, the estimated number of excess deaths substantially exceeded the number of reported deaths from covid-19. The highest excess death rates (per 100 000) in men were in Lithuania (285, 259 to 311), Poland (191, 184 to 197), Spain (179, 174 to 184), Hungary (174, 161 to 188), and Italy (168, 163 to 173); the highest rates in women were in Lithuania (210, 185 to 234), Spain (180, 175 to 185), Hungary (169, 156 to 182), Slovenia (158, 132 to 184), and Belgium (151, 141 to 162). Little evidence was found of subsequent compensatory reductions following excess mortality. Conclusion Approximately one million excess deaths occurred in 2020 in these 29 high income countries. Age standardised excess death rates were higher in men than women in almost all countries. Excess deaths substantially exceeded reported deaths from covid-19 in many countries, indicating that determining the full impact of the pandemic on mortality requires assessment of excess deaths. Many countries had lower deaths than expected in children

Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial.

Abstract: Objective To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. Design Randomised controlled, adaptive, open label clinical trial. Setting 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. Participants 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). Interventions Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. Main outcome measures The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. Results The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m2. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). Conclusions In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. Trial registration ClinicalTrials.gov NCT04362085.

Effectiveness of BNT162b2 and mRNA-1273 covid-19 vaccines against symptomatic SARS-CoV-2 infection and severe covid-19 outcomes in Ontario, Canada: test negative design study.

Abstract: Objective To estimate the effectiveness of mRNA covid-19 vaccines against symptomatic infection and severe outcomes (hospital admission or death). Design Test negative design study. Setting Ontario, Canada between 14 December 2020 and 19 April 2021. Participants 324 033 community dwelling people aged ≥16 years who had symptoms of covid-19 and were tested for SARS-CoV-2. Interventions BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine. Main outcome measures Laboratory confirmed SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR) and hospital admissions and deaths associated with SARS-CoV-2 infection. Multivariable logistic regression was adjusted for personal and clinical characteristics associated with SARS-CoV-2 and vaccine receipt to estimate vaccine effectiveness against symptomatic infection and severe outcomes. Results Of 324 033 people with symptoms, 53 270 (16.4%) were positive for SARS-CoV-2 and 21 272 (6.6%) received at least one dose of vaccine. Among participants who tested positive, 2479 (4.7%) were admitted to hospital or died. Vaccine effectiveness against symptomatic infection observed ≥14 days after one dose was 60% (95% confidence interval 57% to 64%), increasing from 48% (41% to 54%) at 14-20 days after one dose to 71% (63% to 78%) at 35-41 days. Vaccine effectiveness observed ≥7 days after two doses was 91% (89% to 93%). Vaccine effectiveness against hospital admission or death observed ≥14 days after one dose was 70% (60% to 77%), increasing from 62% (44% to 75%) at 14-20 days to 91% (73% to 97%) at ≥35 days, whereas vaccine effectiveness observed ≥7 days after two doses was 98% (88% to 100%). For adults aged ≥70 years, vaccine effectiveness estimates were observed to be lower for intervals shortly after one dose but were comparable to those for younger people for all intervals after 28 days. After two doses, high vaccine effectiveness was observed against variants with the E484K mutation. Conclusions Two doses of mRNA covid-19 vaccines were observed to be highly effective against symptomatic infection and severe outcomes. Vaccine effectiveness of one dose was observed to be lower, particularly for older adults shortly after the first dose.

Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study.

Abstract: Objective To evaluate the excess risk and relative hazards for developing incident clinical sequelae after the acute phase of SARS-CoV-2 infection in adults aged 18-65. Design Retrospective cohort study. Setting Three merged data sources from a large United States health plan: a large national administrative claims database, an outpatient laboratory testing database, and an inpatient hospital admissions database. Participants Individuals aged 18-65 with continuous enrollment in the health plan from January 2019 to the date of a diagnosis of SARS-CoV-2 infection. Three comparator groups, matched by propensity score, to individuals infected with SARS-CoV-2: a 2020 comparator group, an historical 2019 comparator group, and an historical comparator group with viral lower respiratory tract illness. Main outcome measures More than 50 clinical sequelae after the acute phase of SARS-CoV-2 infection (defined as the date of first SARS-CoV-2 diagnosis (index date) plus 21 days) were identified using ICD-10 (international classification of diseases, 10th revision) codes. Excess risk in the four months after acute infection and hazard ratios with Bonferroni corrected 95% confidence intervals were calculated. Results 14% of adults aged ≤65 who were infected with SARS-CoV-2 (27 074 of 193 113) had at least one new type of clinical sequelae that required medical care after the acute phase of the illness, which was 4.95% higher than in the 2020 comparator group. The risk for specific new sequelae attributable to SARS-Cov-2 infection after the acute phase, including chronic respiratory failure, cardiac arrythmia, hypercoagulability, encephalopathy, peripheral neuropathy, amnesia (memory difficulty), diabetes, liver test abnormalities, myocarditis, anxiety, and fatigue, was significantly greater than in the three comparator groups (2020, 2019, and viral lower respiratory tract illness groups) (all P Conclusions The results indicate the excess risk of developing new clinical sequelae after the acute phase of SARS-CoV-2 infection, including specific types of sequelae less commonly seen in other viral illnesses. Although individuals who were older, had pre-existing conditions, and were admitted to hospital because of covid-19 were at greatest excess risk, younger adults (aged ≤50), those with no pre-existing conditions, or those not admitted to hospital for covid-19 also had an increased risk of developing new clinical sequelae. The greater risk for incident sequelae after the acute phase of SARS-CoV-2 infection is relevant for healthcare planning.

Covid-19: Omicron may be more transmissible than other variants and partly resistant to existing vaccines, scientists fear

Abstract: Omicron, the SARS-CoV-2 variant responsible for a cluster of cases in South Africa and that is now spreading around the world, is the most heavily mutated variant to emerge so far and carries mutations similar to changes seen in previous variants of concern associated with enhanced transmissibility and partial resistance to vaccine induced immunity. Daily case numbers in South Africa had been fairly low but then rose rapidly from 273 on 16 November to more than 1200 by 25 November, more than 80% of which were in the northern province of Gauteng, where the first cases were seen. Europe’s first case of the variant was confirmed in Belgium on 26 November in a person who tested positive for covid-19 on 22 November. By 29 November cases had been reported in the Netherlands, France, Germany, Portugal, and Italy. The UK had recorded nine cases by the morning of 29 November, six of them in Scotland. Elsewhere in the world cases have been reported in Botswana, Hong Kong, Canada, and Australia, which has had extremely tight border controls through the pandemic. Some countries, including Japan and Israel, were quick to close their borders to all foreign travellers, while others, such as the UK and EU countries, enforced quarantine for travellers from South …

Effectiveness of the CoronaVac vaccine in older adults during a gamma variant associated epidemic of covid-19 in Brazil: test negative case-control study.

Abstract: Objective To estimate the effectiveness of the inactivated whole virus vaccine, CoronaVac (Sinovac Biotech), against symptomatic covid-19 in the elderly population of Sao Paulo state, Brazil during widespread circulation of the gamma variant. Design Test negative case-control study. Setting Community testing for covid-19 in Sao Paulo state, Brazil. Participants 43 774 adults aged ≥70 years who were residents of Sao Paulo state and underwent reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 from 17 January to 29 April 2021. 26 433 cases with symptomatic covid-19 and 17 622 test negative controls with covid-19 symptoms were formed into 13 283 matched sets, one case with to up to five controls, according to age, sex, self-reported race, municipality of residence, previous covid-19 status, and date of RT-PCR test (±3 days). Intervention Vaccination with a two dose regimen of CoronaVac. Main outcome measures RT-PCR confirmed symptomatic covid-19 and associated hospital admissions and deaths. Results Adjusted vaccine effectiveness against symptomatic covid-19 was 24.7% (95% confidence interval 14.7% to 33.4%) at 0-13 days and 46.8% (38.7% to 53.8%) at ≥14 days after the second dose. Adjusted vaccine effectiveness against hospital admissions was 55.5% (46.5% to 62.9%) and against deaths was 61.2% (48.9% to 70.5%) at ≥14 days after the second dose. Vaccine effectiveness ≥14 days after the second dose was highest for the youngest age group (70-74 years)—59.0% (43.7% to 70.2%) against symptomatic disease, 77.6% (62.5% to 86.7%) against hospital admissions, and 83.9% (59.2% to 93.7%) against deaths—and declined with increasing age. Conclusions Vaccination with CoronaVac was associated with a reduction in symptomatic covid-19, hospital admissions, and deaths in adults aged ≥70 years in a setting with extensive transmission of the gamma variant. Vaccine protection was, however, low until completion of the two dose regimen, and vaccine effectiveness was observe to decline with increasing age among this elderly population.

Covid-19: Novavax vaccine efficacy is 86% against UK variant and 60% against South African variant

Abstract: The SARS-CoV-2 vaccine produced by the US biotechnology company Novavax is 956% effective against the original variant of SARS-CoV-2 but also provides protection against the newer variants B117 (856%) and B1351 (60%), preliminary data from clinical trials show Interim results have been released from a phase III trial carried out in the UK with more than 15 000 participants aged between 18 and 84, including 27% over the age of 65 The trial tested two doses of the vaccine administered three weeks apart and reported 62 symptomatic cases of covid-19, of which 56 were in the placebo group (saline) and six in the vaccine group Of the 62 cases, only one was severe (in the placebo group), and 32 were with the UK variant A phase II trial of the Novavax vaccine is also ongoing in South Africa with 4400 volunteers, in which …

Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study.

Abstract: Objective To assess the association between covid-19 vaccines and risk of thrombocytopenia and thromboembolic events in England among adults. Design Self-controlled case series study using national data on covid-19 vaccination and hospital admissions. Setting Patient level data were obtained for approximately 30 million people vaccinated in England between 1 December 2020 and 24 April 2021. Electronic health records were linked with death data from the Office for National Statistics, SARS-CoV-2 positive test data, and hospital admission data from the United Kingdom’s health service (NHS). Participants 29 121 633 people were vaccinated with first doses (19 608 008 with Oxford-AstraZeneca (ChAdOx1 nCoV-19) and 9 513 625 with Pfizer-BioNTech (BNT162b2 mRNA)) and 1 758 095 people had a positive SARS-CoV-2 test. People aged ≥16 years who had first doses of the ChAdOx1 nCoV-19 or BNT162b2 mRNA vaccines and any outcome of interest were included in the study. Main outcome measures The primary outcomes were hospital admission or death associated with thrombocytopenia, venous thromboembolism, and arterial thromboembolism within 28 days of three exposures: first dose of the ChAdOx1 nCoV-19 vaccine; first dose of the BNT162b2 mRNA vaccine; and a SARS-CoV-2 positive test. Secondary outcomes were subsets of the primary outcomes: cerebral venous sinus thrombosis (CVST), ischaemic stroke, myocardial infarction, and other rare arterial thrombotic events. Results The study found increased risk of thrombocytopenia after ChAdOx1 nCoV-19 vaccination (incidence rate ratio 1.33, 95% confidence interval 1.19 to 1.47 at 8-14 days) and after a positive SARS-CoV-2 test (5.27, 4.34 to 6.40 at 8-14 days); increased risk of venous thromboembolism after ChAdOx1 nCoV-19 vaccination (1.10, 1.02 to 1.18 at 8-14 days) and after SARS-CoV-2 infection (13.86, 12.76 to 15.05 at 8-14 days); and increased risk of arterial thromboembolism after BNT162b2 mRNA vaccination (1.06, 1.01 to 1.10 at 15-21 days) and after SARS-CoV-2 infection (2.02, 1.82 to 2.24 at 15-21 days). Secondary analyses found increased risk of CVST after ChAdOx1 nCoV-19 vaccination (4.01, 2.08 to 7.71 at 8-14 days), after BNT162b2 mRNA vaccination (3.58, 1.39 to 9.27 at 15-21 days), and after a positive SARS-CoV-2 test; increased risk of ischaemic stroke after BNT162b2 mRNA vaccination (1.12, 1.04 to 1.20 at 15-21 days) and after a positive SARS-CoV-2 test; and increased risk of other rare arterial thrombotic events after ChAdOx1 nCoV-19 vaccination (1.21, 1.02 to 1.43 at 8-14 days) and after a positive SARS-CoV-2 test. Conclusion Increased risks of haematological and vascular events that led to hospital admission or death were observed for short time intervals after first doses of the ChAdOx1 nCoV-19 and BNT162b2 mRNA vaccines. The risks of most of these events were substantially higher and more prolonged after SARS-CoV-2 infection than after vaccination in the same population.

Covid-19 vaccination hesitancy.

Abstract: ### What you need to know Rollout of covid-19 vaccination is well underway, with more than 700 million doses given worldwide as of April 2021.1 Vaccination is highly effective at reducing severe illness and death from covid-19. Vaccines for covid-19 are also safe, with extremely low risks of severe adverse events.234 A major threat to the impact of vaccination in preventing disease and death from covid-19 is low uptake of vaccines. In this practice pointer we offer on overview of vaccine hesitancy and some approaches that clinicians and policymakers can adopt at the individual and community levels to help people make informed decisions about covid-19 vaccination. The World Health Organization defines vaccine hesitancy as a “delay in acceptance or refusal of safe vaccines despite availability of vaccine services.”5 It is caused by complex, context specific factors that vary across time, place, and different vaccines, and is influenced by issues such as complacency, convenience, confidence, and sociodemographic contexts.6 Vaccine hesitancy may also be related to misinformation and conspiracy theories which are often spread online, including through social media.78 In addition, structural factors such as health inequalities, socioeconomic disadvantages, systemic racism, and barriers to access are key drivers of …

Severe covid-19 pneumonia: pathogenesis and clinical management.

Abstract: Severe covid-19 pneumonia has posed critical challenges for the research and medical communities. Older age, male sex, and comorbidities increase the risk for severe disease. For people hospitalized with covid-19, 15-30% will go on to develop covid-19 associated acute respiratory distress syndrome (CARDS). Autopsy studies of patients who died of severe SARS CoV-2 infection reveal presence of diffuse alveolar damage consistent with ARDS but with a higher thrombus burden in pulmonary capillaries. When used appropriately, high flow nasal cannula (HFNC) may allow CARDS patients to avoid intubation, and does not increase risk for disease transmission. During invasive mechanical ventilation, low tidal volume ventilation and positive end expiratory pressure (PEEP) titration to optimize oxygenation are recommended. Dexamethasone treatment improves mortality for the treatment of severe and critical covid-19, while remdesivir may have modest benefit in time to recovery in patients with severe disease but shows no statistically significant benefit in mortality or other clinical outcomes. Covid-19 survivors, especially patients with ARDS, are at high risk for long term physical and mental impairments, and an interdisciplinary approach is essential for critical illness recovery.

Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration

Abstract: Mendelian randomisation (MR) studies allow a better understanding of the causal effects of modifiable exposures on health outcomes, but the published evidence is often hampered by inadequate reporting. Reporting guidelines help authors effectively communicate all critical information about what was done and what was found. STROBE-MR (strengthening the reporting of observational studies in epidemiology using mendelian randomisation) assists authors in reporting their MR research clearly and transparently. Adopting STROBE-MR should help readers, reviewers, and journal editors evaluate the quality of published MR studies. This article explains the 20 items of the STROBE-MR checklist, along with their meaning and rationale, using terms defined in a glossary. Examples of transparent reporting are used for each item to illustrate best practices.

Risk prediction of covid-19 related death and hospital admission in adults after covid-19 vaccination: national prospective cohort study.

Abstract: Objectives To derive and validate risk prediction algorithms to estimate the risk of covid-19 related mortality and hospital admission in UK adults after one or two doses of covid-19 vaccination. Design Prospective, population based cohort study using the QResearch database linked to data on covid-19 vaccination, SARS-CoV-2 results, hospital admissions, systemic anticancer treatment, radiotherapy, and the national death and cancer registries. Settings Adults aged 19-100 years with one or two doses of covid-19 vaccination between 8 December 2020 and 15 June 2021. Main outcome measures Primary outcome was covid-19 related death. Secondary outcome was covid-19 related hospital admission. Outcomes were assessed from 14 days after each vaccination dose. Models were fitted in the derivation cohort to derive risk equations using a range of predictor variables. Performance was evaluated in a separate validation cohort of general practices. Results Of 6 952 440 vaccinated patients in the derivation cohort, 5 150 310 (74.1%) had two vaccine doses. Of 2031 covid-19 deaths and 1929 covid-19 hospital admissions, 81 deaths (4.0%) and 71 admissions (3.7%) occurred 14 days or more after the second vaccine dose. The risk algorithms included age, sex, ethnic origin, deprivation, body mass index, a range of comorbidities, and SARS-CoV-2 infection rate. Incidence of covid-19 mortality increased with age and deprivation, male sex, and Indian and Pakistani ethnic origin. Cause specific hazard ratios were highest for patients with Down’s syndrome (12.7-fold increase), kidney transplantation (8.1-fold), sickle cell disease (7.7-fold), care home residency (4.1-fold), chemotherapy (4.3-fold), HIV/AIDS (3.3-fold), liver cirrhosis (3.0-fold), neurological conditions (2.6-fold), recent bone marrow transplantation or a solid organ transplantation ever (2.5-fold), dementia (2.2-fold), and Parkinson’s disease (2.2-fold). Other conditions with increased risk (ranging from 1.2-fold to 2.0-fold increases) included chronic kidney disease, blood cancer, epilepsy, chronic obstructive pulmonary disease, coronary heart disease, stroke, atrial fibrillation, heart failure, thromboembolism, peripheral vascular disease, and type 2 diabetes. A similar pattern of associations was seen for covid-19 related hospital admissions. No evidence indicated that associations differed after the second dose, although absolute risks were reduced. The risk algorithm explained 74.1% (95% confidence interval 71.1% to 77.0%) of the variation in time to covid-19 death in the validation cohort. Discrimination was high, with a D statistic of 3.46 (95% confidence interval 3.19 to 3.73) and C statistic of 92.5. Performance was similar after each vaccine dose. In the top 5% of patients with the highest predicted covid-19 mortality risk, sensitivity for identifying covid-19 deaths within 70 days was 78.7%. Conclusion This population based risk algorithm performed well showing high levels of discrimination for identifying those patients at highest risk of covid-19 related death and hospital admission after vaccination.

Covid-19: The E484K mutation and the risks it poses.

Abstract: The mutation E484K, first identified in the South African SARS-CoV-2 variant, has now been identified in the UK fast-spreading variant, prompting fears the virus is evolving further and could become resistant to vaccines. Jacqui Wise looks at what we know so far

Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study.

Abstract: OBJECTIVE: To evaluate whether early initiation of prophylactic anticoagulation compared with no anticoagulation was associated with decreased risk of death among patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United States DESIGN: Observational cohort study SETTING: Nationwide cohort of patients receiving care in the Department of Veterans Affairs, a large integrated national healthcare system PARTICIPANTS: All 4297 patients admitted to hospital from 1 March to 31 July 2020 with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and without a history of anticoagulation MAIN OUTCOME MEASURES: The main outcome was 30 day mortality Secondary outcomes were inpatient mortality, initiating therapeutic anticoagulation (a proxy for clinical deterioration, including thromboembolic events), and bleeding that required transfusion RESULTS: Of 4297 patients admitted to hospital with covid-19, 3627 (844%) received prophylactic anticoagulation within 24 hours of admission More than 99% (n=3600) of treated patients received subcutaneous heparin or enoxaparin 622 deaths occurred within 30 days of hospital admission, 513 among those who received prophylactic anticoagulation Most deaths (510/622, 82%) occurred during hospital stay Using inverse probability of treatment weighted analyses, the cumulative incidence of mortality at 30 days was 143% (95% confidence interval 131% to 155%) among those who received prophylactic anticoagulation and 187% (151% to 229%) among those who did not Compared with patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30 day mortality (hazard ratio 073, 95% confidence interval 066 to 081) Similar associations were found for inpatient mortality and initiation of therapeutic anticoagulation Receipt of prophylactic anticoagulation was not associated with increased risk of bleeding that required transfusion (hazard ratio 087, 071 to 105) Quantitative bias analysis showed that results were robust to unmeasured confounding (e-value lower 95% confidence interval 177 for 30 day mortality) Results persisted in several sensitivity analyses CONCLUSIONS: Early initiation of prophylactic anticoagulation compared with no anticoagulation among patients admitted to hospital with covid-19 was associated with a decreased risk of 30 day mortality and no increased risk of serious bleeding events These findings provide strong real world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial treatment for patients with covid-19 on hospital admission