Journal: BMJ

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Abstract

High flow oxygen and risk of mortality in patients with a suspected acute coronary syndrome: pragmatic, cluster randomised, crossover trial.

Stewart RAH, Jones P, Dicker B, Jiang Y, ... White HD, Devlin G
Objective
To determine the association between high flow supplementary oxygen and 30 day mortality in patients presenting with a suspected acute coronary syndrome (ACS).
Design
Pragmatic, cluster randomised, crossover trial.
Setting
Four geographical regions in New Zealand.
Participants
40 872 patients with suspected or confirmed ACS included in the All New Zealand Acute Coronary Syndrome Quality Improvement registry or ambulance ACS pathway during the study periods. 20 304 patients were managed using the high oxygen protocol and 20 568 were managed using the low oxygen protocol. Final diagnosis of ST elevation myocardial infarction (STEMI) and non-STEMI were determined from the registry and ICD-10 discharge codes.
Interventions
The four geographical regions were randomly allocated to each of two oxygen protocols in six month blocks over two years. The high oxygen protocol recommended oxygen at 6-8 L/min by face mask for ischaemic symptoms or electrocardiographic changes, irrespective of the transcapillary oxygen saturation (SpO2). The low oxygen protocol recommended oxygen only if SpO2 was less than 90%, with a target SpO2 of less than 95%.
Main outcome measure
30 day all cause mortality determined from linkage to administrative data.
Results
Personal and clinical characteristics of patients managed under both oxygen protocols were well matched. For patients with suspected ACS, 30 day mortality for the high and low oxygen groups was 613 (3.0%) and 642 (3.1%), respectively (odds ratio 0.97, 95% confidence interval 0.86 to 1.08). For 4159 (10%) patients with STEMI, 30 day mortality for the high and low oxygen groups was 8.8% (n=178) and 10.6% (n=225), respectively (0.81, 0.66 to 1.00) and for 10 218 (25%) patients with non-STEMI was 3.6% (n=187) and 3.5% (n=176), respectively (1.05, 0.85 to 1.29).
Conclusion
In a large patient cohort presenting with suspected ACS, high flow oxygen was not associated with an increase or decrease in 30 day mortality.
Trial registration
ANZ Clinical Trials ACTRN12616000461493.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 01 Mar 2021; 372:n355
Stewart RAH, Jones P, Dicker B, Jiang Y, ... White HD, Devlin G
BMJ: 01 Mar 2021; 372:n355 | PMID: 33653685
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Abstract

Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis.

Ackley SF, Zimmerman SC, Brenowitz WD, Tchetgen Tchetgen EJ, ... Brickman AM, Glymour MM
Objective
To evaluate trials of drugs that target amyloid to determine whether reductions in amyloid levels are likely to improve cognition.
Design
Instrumental variable meta-analysis.
Setting
14 randomized controlled trials of drugs for the prevention or treatment of Alzheimer\'s disease that targeted an amyloid mechanism, identified from ClinicalTrials.gov.
Population
Adults enrolled in randomized controlled trials of amyloid targeting drugs. Inclusion criteria for trials vary, but typically include adults aged 50 years or older with a diagnosis of mild cognitive impairment or Alzheimer\'s disease, and amyloid positivity at baseline.
Main outcome measures
Analyses included trials for which information could be obtained on both change in brain amyloid levels measured with amyloid positron emission tomography and change in at least one cognitive test score reported for each randomization arm.
Results
Pooled results from the 14 randomized controlled trials were more precise than estimates from any single trial. The pooled estimate for the effect of reducing amyloid levels by 0.1 standardized uptake value ratio units was an improvement in the mini-mental state examination score of 0.03 (95% confidence interval -0.06 to 0.1) points. This study provides a web application that allows for the re-estimation of the results when new data become available and illustrates the magnitude of the new evidence that would be necessary to achieve a pooled estimate supporting the benefit of reducing amyloid levels.
Conclusions
Pooled evidence from available trials reporting both reduction in amyloid levels and change in cognition suggests that amyloid reduction strategies do not substantially improve cognition.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 24 Feb 2021; 372:n156
Ackley SF, Zimmerman SC, Brenowitz WD, Tchetgen Tchetgen EJ, ... Brickman AM, Glymour MM
BMJ: 24 Feb 2021; 372:n156 | PMID: 33632704
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Abstract

Association between human papillomavirus vaccination and serious adverse events in South Korean adolescent girls: nationwide cohort study.

Yoon D, Lee JH, Lee H, Shin JY
Objective
To evaluate the association between human papillomavirus (HPV) vaccination and serious adverse events in adolescent girls in South Korea.
Design
Cohort study.
Setting
A large linked database created by linking the Korea Immunization Registry Information System and the National Health Information Database, between January 2017 and December 2019.
Participants
441 399 girls aged 11-14 years who had been vaccinated in 2017: 382 020 had been vaccinated against HPV and 59 379 had not been vaccinated against HPV.
Main outcome measures
Outcomes were 33 serious adverse events, including endocrine, gastrointestinal, cardiovascular, musculoskeletal, haematological, dermatological, and neurological diseases. A cohort design was used for the primary analysis and a self-controlled risk interval design for the secondary analysis; both analyses used a risk period of one year after HPV vaccination for each outcome. Incidence rate and adjusted rate ratios were estimated using Poisson regression in the primary analysis, comparing the HPV vaccinated group with the HPV unvaccinated group, and adjusted relative risks were estimated using conditional logistic regression in the secondary analysis.
Results
Among the 33 predefined serious adverse events, no associations were found with HPV vaccination in the cohort analysis, including Hashimoto\'s thyroiditis (incidence rate per 100 000 person years: 52.7 v 36.3 for the vaccinated and unvaccinated groups; adjusted rate ratio 1.24, 95% confidence interval 0.78 to 1.94) and rheumatoid arthritis (incidence rate per 100 000 person years: 168.1 v 145.4 for the vaccinated and unvaccinated groups; 0.99, 0.79 to 1.25), with the exception of an increased risk observed for migraine (incidence rate per 100 000 person years: 1235.0 v 920.9 for the vaccinated and unvaccinated groups; 1.11, 1.02 to 1.22). Secondary analysis using self-controlled risk intervals confirmed no associations between HPV vaccination and serious adverse events, including migraine (adjusted relative risk 0.67, 95% confidence interval 0.58 to 0.78). Results were robust to varying follow-up periods and for vaccine subtypes.
Conclusions
In this nationwide cohort study, with more than 500 000 doses of HPV vaccines, no evidence was found to support an association between HPV vaccination and serious adverse events using both cohort analysis and self-controlled risk interval analysis. Inconsistent findings for migraine should be interpreted with caution considering its pathophysiology and the population of interest.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 28 Jan 2021; 372:m4931
Yoon D, Lee JH, Lee H, Shin JY
BMJ: 28 Jan 2021; 372:m4931 | PMID: 33514507
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Abstract

Association between county level cannabis dispensary counts and opioid related mortality rates in the United States: panel data study.

Hsu G, Kovács B
Objective
To examine county level associations between the prevalence of medical and recreational cannabis stores (referred to as dispensaries) and opioid related mortality rates.
Design
Panel regression methods.
Setting
812 counties in the United States in the 23 states that allowed legal forms of cannabis dispensaries to operate by the end of 2017.
Participants
The study used US mortality data from the Centers for Disease Control and Prevention combined with US census data and data from Weedmaps.com on storefront dispensary operations. Data were analyzed at the county level by using panel regression methods.
Main outcome measure
The main outcome measures were the log transformed, age adjusted mortality rates associated with all opioid types combined, and with subcategories of prescription opioids, heroin, and synthetic opioids other than methadone. The associations of medical dispensary and recreational dispensary counts with age adjusted mortality rates were also analyzed.
Results
County level dispensary count (natural logarithm) is negatively related to the log transformed, age adjusted mortality rate associated with all opioid types (β=-0.17, 95% confidence interval -0.23 to -0.11). According to this estimate, an increase from one to two storefront dispensaries in a county is associated with an estimated 17% reduction in all opioid related mortality rates. Dispensary count has a particularly strong negative association with deaths caused by synthetic opioids other than methadone (β=-0.21, 95% confidence interval -0.27 to -0.14), with an estimated 21% reduction in mortality rates associated with an increase from one to two dispensaries. Similar associations were found for medical versus recreational storefront dispensary counts on synthetic (non-methadone) opioid related mortality rates.
Conclusions
Higher medical and recreational storefront dispensary counts are associated with reduced opioid related death rates, particularly deaths associated with synthetic opioids such as fentanyl. While the associations documented cannot be assumed to be causal, they suggest a potential association between increased prevalence of medical and recreational cannabis dispensaries and reduced opioid related mortality rates. This study highlights the importance of considering the complex supply side of related drug markets and how this shapes opioid use and misuse.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 26 Jan 2021; 372:m4957
Hsu G, Kovács B
BMJ: 26 Jan 2021; 372:m4957 | PMID: 33504472
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Abstract

Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials.

Herrett E, Williamson E, Brack K, Beaumont D, ... Smeeth L, StatinWISE Trial Group
Objective
To establish the effect of statins on muscle symptoms in people who had previously reported muscle symptoms when taking statins.
Design
Series of randomised, placebo controlled n-of-1 trials.
Setting
Primary care across 50 sites in the United Kingdom, December 2016 to April 2018.
Participants
200 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms.
Interventions
Participants were randomised to a sequence of six double blinded treatment periods (two months each) of atorvastatin 20 mg daily or placebo.
Main outcome measures
At the end of each treatment period, participants rated their muscle symptoms on a visual analogue scale (0-10). The primary analysis compared symptom scores in the statin and placebo periods.
Results
151 participants provided symptoms scores for at least one statin period and one placebo period and were included in the primary analysis. Overall, no difference in muscle symptom scores was found between the statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; P=0.40)). Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long term treatment with statins.
Conclusions
No overall effect of atorvastatin 20 mg on muscle symptoms compared with placebo was found in participants who had previously reported severe muscle symptoms when taking statins. Most people completing the trial intended to restart treatment with statins. N-of-1 trials can assess drug effects at the group level and guide individual treatment.
Trial registration
ISRCTN30952488, EUDRACT 2016-000141-31, NCT02781064.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 23 Jan 2021; 372:n135
Herrett E, Williamson E, Brack K, Beaumont D, ... Smeeth L, StatinWISE Trial Group
BMJ: 23 Jan 2021; 372:n135 | PMID: 33627334
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Abstract

Effect of screening by clinical breast examination on breast cancer incidence and mortality after 20 years: prospective, cluster randomised controlled trial in Mumbai.

Mittra I, Mishra GA, Dikshit RP, Gupta S, ... Pramesh CS, Badwe RA
Objective
To test the efficacy of screening by clinical breast examination in downstaging breast cancer at diagnosis and in reducing mortality from the disease, when compared with no screening.
Design
Prospective, cluster randomised controlled trial.
Setting
20 geographically distinct clusters located in Mumbai, India, randomly allocated to 10 screening and 10 control clusters; total trial duration was 20 years (recruitment began in May 1998; database locked in March 2019 for analysis).
Participants
151 538 women aged 35-64 with no history of breast cancer.
Interventions
Women in the screening arm (n=75 360) received four screening rounds of clinical breast examination (conducted by trained female primary health workers) and cancer awareness every two years, followed by five rounds of active surveillance every two years. Women in the control arm (n=76 178) received one round of cancer awareness followed by eight rounds of active surveillance every two years.
Main outcome measures
Downstaging of breast cancer at diagnosis and reduction in mortality from breast cancer.
Results
Breast cancer was detected at an earlier age in the screening group than in the control group (age 55.18 (standard deviation 9.10) v 56.50 (9.10); P=0.01), with a significant reduction in the proportion of women with stage III or IV disease (37% (n=220) v 47% (n=271), P=0.001). A non-significant 15% reduction in breast cancer mortality was observed in the screening arm versus control arm in the overall study population (age 35-64; 20.82 deaths per 100 000 person years (95% confidence interval 18.25 to 23.97) v 24.62 (21.71 to 28.04); rate ratio 0.85 (95% confidence interval 0.71 to 1.01); P=0.07). However, a post hoc subset analysis showed nearly 30% relative reduction in breast cancer mortality in women aged 50 and older (24.62 (20.62 to 29.76) v 34.68 (27.54 to 44.37); 0.71 (0.54 to 0.94); P=0.02), but no significant reduction in women younger than 50 (19.53 (17.24 to 22.29) v 21.03 (18.97 to 23.44); 0.93 (0.79 to 1.09); P=0.37). A 5% reduction in all cause mortality was seen in the screening arm versus the control arm, but it was not statistically significant (rate ratio 0.95 (95% confidence interval 0.81 to 1.10); P=0.49).
Conclusions
These results indicate that clinical breast examination conducted every two years by primary health workers significantly downstaged breast cancer at diagnosis and led to a non-significant 15% reduction in breast cancer mortality overall (but a significant reduction of nearly 30%in mortality in women aged ≥50). No significant reduction in mortality was seen in women younger than 50 years. Clinical breast examination should be considered for breast cancer screening in low and middle income countries.
Trial registration
Clinical Trials Registry of India CTRI/2010/091/001205; ClinicalTrials.gov NCT00632047.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 23 Jan 2021; 372:n256
Mittra I, Mishra GA, Dikshit RP, Gupta S, ... Pramesh CS, Badwe RA
BMJ: 23 Jan 2021; 372:n256 | PMID: 33627312
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Abstract

Excess mortality in Wuhan city and other parts of China during the three months of the covid-19 outbreak: findings from nationwide mortality registries.

Liu J, Zhang L, Yan Y, Zhou Y, ... Chen Z, Zhou M
Objective
To assess excess all cause and cause specific mortality during the three months (1 January to 31 March 2020) of the coronavirus disease 2019 (covid-19) outbreak in Wuhan city and other parts of China.
Design
Nationwide mortality registries.
Setting
605 urban districts and rural counties in China\'s nationally representative Disease Surveillance Point (DSP) system.
Participants
More than 300 million people of all ages.
Main outcome measures
Observed overall and weekly mortality rates from all cause and cause specific diseases for three months (1 January to 31 March 2020) of the covid-19 outbreak compared with the predicted (or mean rates for 2015-19) in different areas to yield rate ratio.
Results
The DSP system recorded 580 819 deaths from January to March 2020. In Wuhan DSP districts (n=3), the observed total mortality rate was 56% (rate ratio 1.56, 95% confidence interval 1.33 to 1.87) higher than the predicted rate (1147 v 735 per 100 000), chiefly as a result of an eightfold increase in deaths from pneumonia (n=1682; 275 v 33 per 100 000; 8.32, 5.19 to 17.02), mainly covid-19 related, but a more modest increase in deaths from certain other diseases, including cardiovascular disease (n=2347; 408 v 316 per 100 000; 1.29, 1.05 to 1.65) and diabetes (n=262; 46 v 25 per 100 000; 1.83, 1.08 to 4.37). In Wuhan city (n=13 districts), 5954 additional (4573 pneumonia) deaths occurred in 2020 compared with 2019, with excess risks greater in central than in suburban districts (50% v 15%). In other parts of Hubei province (n=19 DSP areas), the observed mortality rates from pneumonia and chronic respiratory diseases were non-significantly 28% and 23% lower than the predicted rates, despite excess deaths from covid-19 related pneumonia. Outside Hubei (n=583 DSP areas), the observed total mortality rate was non-significantly lower than the predicted rate (675 v 715 per 100 000), with significantly lower death rates from pneumonia (0.53, 0.46 to 0.63), chronic respiratory diseases (0.82, 0.71 to 0.96), and road traffic incidents (0.77, 0.68 to 0.88).
Conclusions
Except in Wuhan, no increase in overall mortality was found during the three months of the covid-19 outbreak in other parts of China. The lower death rates from certain non-covid-19 related diseases might be attributable to the associated behaviour changes during lockdown.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 23 Jan 2021; 372:n415
Liu J, Zhang L, Yan Y, Zhou Y, ... Chen Z, Zhou M
BMJ: 23 Jan 2021; 372:n415 | PMID: 33627311
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Abstract

Vaccines for older adults.

Cunningham AL, McIntyre P, Subbarao K, Booy R, Levin MJ
The proportion of the global population aged 65 and older is rapidly increasing. Infections in this age group, most recently with SARS-CoV-2, cause substantial morbidity and mortality. Major improvements have been made in vaccines for older people, either through the addition of novel adjuvants-as in the new recombinant zoster vaccine and an adjuvanted influenza vaccine-or by increasing antigen concentration, as in influenza vaccines. In this article we review improvements in immunization for the three most important vaccine preventable diseases of aging. The recombinant zoster vaccine has an efficacy of 90% that is minimally affected by the age of the person being vaccinated and persists for more than four years. Increasing antigen dose or inclusion of adjuvant has improved the immunogenicity of influenza vaccines in older adults, although the relative effectiveness of the enhanced influenza vaccines and the durability of the immune response are the focus of ongoing clinical trials. Conjugate and polysaccharide pneumococcal vaccines have similar efficacy against invasive pneumococcal disease and pneumococcal pneumonia caused by vaccine serotypes in older adults. Their relative value varies by setting, depending on the prevalence of vaccine serotypes, largely related to conjugate vaccine coverage in children. Improved efficacy will increase public confidence and uptake of these vaccines. Co-administration of these vaccines is feasible and important for maximal uptake in older people. Development of new vaccine platforms has accelerated following the arrival of SARS-CoV-2, and will likely result in new vaccines against other pathogens in the future.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

BMJ: 21 Jan 2021; 372:n188
Cunningham AL, McIntyre P, Subbarao K, Booy R, Levin MJ
BMJ: 21 Jan 2021; 372:n188 | PMID: 33619170
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Abstract

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

Veiga VC, Prats JAGG, Farias DLC, Rosa RG, ... Scheinberg P, Coalition covid-19 Brazil VI Investigators
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.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 19 Jan 2021; 372:n84
Veiga VC, Prats JAGG, Farias DLC, Rosa RG, ... Scheinberg P, Coalition covid-19 Brazil VI Investigators
BMJ: 19 Jan 2021; 372:n84 | PMID: 33472855
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Abstract

Efficacy and safety of antidepressants for the treatment of back pain and osteoarthritis: systematic review and meta-analysis.

Ferreira GE, McLachlan AJ, Lin CC, Zadro JR, ... O\'Keeffe M, Maher CG
Objective
To investigate the efficacy and safety of antidepressants for back and osteoarthritis pain compared with placebo.
Design
Systematic review and meta-analysis.
Data sources
Medline, Embase, Cochrane Central Register of Controlled Trials, CINAHL, International Pharmaceutical Abstracts, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from inception to 15 November and updated on 12 May 2020.
Eligibility criteria for study selection
Randomised controlled trials comparing the efficacy or safety, or both of any antidepressant drug with placebo (active or inert) in participants with low back or neck pain, sciatica, or hip or knee osteoarthritis.
Data extraction and synthesis
Two independent reviewers extracted data. Pain and disability were primary outcomes. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst pain or disability). A random effects model was used to calculate weighted mean differences and 95% confidence intervals. Safety (any adverse event, serious adverse events, and proportion of participants who withdrew from trials owing to adverse events) was a secondary outcome. Risk of bias was assessed with the Cochrane Collaboration\'s tool and certainty of evidence with the grading of recommendations assessment, development and evaluation (GRADE) framework.
Results
33 trials (5318 participants) were included. Moderate certainty evidence showed that serotonin-noradrenaline reuptake inhibitors (SNRIs) reduced back pain (mean difference -5.30, 95% confidence interval -7.31 to -3.30) at 3-13 weeks and low certainty evidence that SNRIs reduced osteoarthritis pain (-9.72, -12.75 to -6.69) at 3-13 weeks. Very low certainty evidence showed that SNRIs reduced sciatica at two weeks or less (-18.60, -31.87 to -5.33) but not at 3-13 weeks (-17.50, -42.90 to 7.89). Low to very low certainty evidence showed that tricyclic antidepressants (TCAs) did not reduce sciatica at two weeks or less (-7.55, -18.25 to 3.15) but did at 3-13 weeks (-15.95, -31.52 to -0.39) and 3-12 months (-27.0, -36.11 to -17.89). Moderate certainty evidence showed that SNRIs reduced disability from back pain at 3-13 weeks (-3.55, -5.22 to -1.88) and disability due to osteoarthritis at two weeks or less (-5.10, -7.31 to -2.89), with low certainty evidence at 3-13 weeks (-6.07, -8.13 to -4.02). TCAs and other antidepressants did not reduce pain or disability from back pain.
Conclusion
Moderate certainty evidence shows that the effect of SNRIs on pain and disability scores is small and not clinically important for back pain, but a clinically important effect cannot be excluded for osteoarthritis. TCAs and SNRIs might be effective for sciatica, but the certainty of evidence ranged from low to very low.
Systematic review registration
PROSPERO CRD42020158521.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 19 Jan 2021; 372:m4825
Ferreira GE, McLachlan AJ, Lin CC, Zadro JR, ... O'Keeffe M, Maher CG
BMJ: 19 Jan 2021; 372:m4825 | PMID: 33472813
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Abstract

Home and Online Management and Evaluation of Blood Pressure (HOME BP) using a digital intervention in poorly controlled hypertension: randomised controlled trial.

McManus RJ, Little P, Stuart B, Morton K, ... Yardley L, HOME BP investigators
Objective
The HOME BP (Home and Online Management and Evaluation of Blood Pressure) trial aimed to test a digital intervention for hypertension management in primary care by combining self-monitoring of blood pressure with guided self-management.
Design
Unmasked randomised controlled trial with automated ascertainment of primary endpoint.
Setting
76 general practices in the United Kingdom.
Participants
622 people with treated but poorly controlled hypertension (>140/90 mm Hg) and access to the internet.
Interventions
Participants were randomised by using a minimisation algorithm to self-monitoring of blood pressure with a digital intervention (305 participants) or usual care (routine hypertension care, with appointments and drug changes made at the discretion of the general practitioner; 317 participants). The digital intervention provided feedback of blood pressure results to patients and professionals with optional lifestyle advice and motivational support. Target blood pressure for hypertension, diabetes, and people aged 80 or older followed UK national guidelines.
Main outcome measures
The primary outcome was the difference in systolic blood pressure (mean of second and third readings) after one year, adjusted for baseline blood pressure, blood pressure target, age, and practice, with multiple imputation for missing values.
Results
After one year, data were available from 552 participants (88.6%) with imputation for the remaining 70 participants (11.4%). Mean blood pressure dropped from 151.7/86.4 to 138.4/80.2 mm Hg in the intervention group and from 151.6/85.3 to 141.8/79.8 mm Hg in the usual care group, giving a mean difference in systolic blood pressure of -3.4 mm Hg (95% confidence interval -6.1 to -0.8 mm Hg) and a mean difference in diastolic blood pressure of -0.5 mm Hg (-1.9 to 0.9 mm Hg). Results were comparable in the complete case analysis and adverse effects were similar between groups. Within trial costs showed an incremental cost effectiveness ratio of £11 ($15, €12; 95% confidence interval £6 to £29) per mm Hg reduction.
Conclusions
The HOME BP digital intervention for the management of hypertension by using self-monitored blood pressure led to better control of systolic blood pressure after one year than usual care, with low incremental costs. Implementation in primary care will require integration into clinical workflows and consideration of people who are digitally excluded.
Trial registration
ISRCTN13790648.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 18 Jan 2021; 372:m4858
McManus RJ, Little P, Stuart B, Morton K, ... Yardley L, HOME BP investigators
BMJ: 18 Jan 2021; 372:m4858 | PMID: 33468518
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Impact:
Abstract

Electronic health record alerts for acute kidney injury: multicenter, randomized clinical trial.

Wilson FP, Martin M, Yamamoto Y, Partridge C, ... Testani J, Ugwuowo U
Objective
To determine whether electronic health record alerts for acute kidney injury would improve patient outcomes of mortality, dialysis, and progression of acute kidney injury.
Design
Double blinded, multicenter, parallel, randomized controlled trial.
Setting
Six hospitals (four teaching and two non-teaching) in the Yale New Haven Health System in Connecticut and Rhode Island, US, ranging from small community hospitals to large tertiary care centers.
Participants
6030 adult inpatients with acute kidney injury, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria.
Interventions
An electronic health record based \"pop-up\" alert for acute kidney injury with an associated acute kidney injury order set upon provider opening of the patient\'s medical record.
Main outcome measures
A composite of progression of acute kidney injury, receipt of dialysis, or death within 14 days of randomization. Prespecified secondary outcomes included outcomes at each hospital and frequency of various care practices for acute kidney injury.
Results
6030 patients were randomized over 22 months. The primary outcome occurred in 653 (21.3%) of 3059 patients with an alert and in 622 (20.9%) of 2971 patients receiving usual care (relative risk 1.02, 95% confidence interval 0.93 to 1.13, P=0.67). Analysis by each hospital showed worse outcomes in the two non-teaching hospitals (n=765, 13%), where alerts were associated with a higher risk of the primary outcome (relative risk 1.49, 95% confidence interval 1.12 to 1.98, P=0.006). More deaths occurred at these centers (15.6% in the alert group v 8.6% in the usual care group, P=0.003). Certain acute kidney injury care practices were increased in the alert group but did not appear to mediate these outcomes.
Conclusions
Alerts did not reduce the risk of our primary outcome among patients in hospital with acute kidney injury. The heterogeneity of effect across clinical centers should lead to a re-evaluation of existing alerting systems for acute kidney injury.
Trial registration
ClinicalTrials.gov NCT02753751.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 17 Jan 2021; 372:m4786
Wilson FP, Martin M, Yamamoto Y, Partridge C, ... Testani J, Ugwuowo U
BMJ: 17 Jan 2021; 372:m4786 | PMID: 33461986
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Impact:
Abstract

Management of non-alcoholic fatty liver disease.

Petroni ML, Brodosi L, Bugianesi E, Marchesini G
Non-alcoholic fatty liver disease is a very common medical condition, driven by a combination of genetic and lifestyle factors, ultimately producing a severe chronic liver disease and increased cardiovascular risk. Most people are asymptomatic for a long time, and their daily life is unaffected, leading to difficulty in identifying and managing people who slowly progress to non-alcoholic steatohepatitis (NASH), NASH-cirrhosis, and eventually hepatocellular carcinoma. Despite advances in the understanding of pathogenic mechanisms and the identification of liver fibrosis as the strongest factor in predicting disease progression, no specific treatments have been approved by regulatory agencies. Outside controlled trials, treatment is generally limited to lifestyle intervention aimed at weight loss. Pioglitazone remains the drug of choice to reduce progression of fibrosis in people with diabetes, although it is often used off-label in the absence of diabetes. Vitamin E is mainly used in children and may be considered in adults without diabetes. Several drugs are under investigation according to the agreed targets of reduced NASH activity without worsening of fibrosis or improving fibrosis without worsening of NASH. Anti-inflammatory, anti-fibrotic agents and metabolism modulators have been tested in either phase III or phase IIb randomized controlled trials; a few failed, and others have produced marginally positive results, but only a few are being tested in extension studies. The development of non-invasive, easily repeatable surrogate biomarkers and/or imaging tools is crucial to facilitate clinical studies and limit liver biopsy.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

BMJ: 17 Jan 2021; 372:m4747
Petroni ML, Brodosi L, Bugianesi E, Marchesini G
BMJ: 17 Jan 2021; 372:m4747 | PMID: 33461969
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Abstract

Correction for vol. 372, p.


Arthroscopic hip surgery compared with physiotherapy and activity modification for the treatment of symptomatic femoroacetabular impingement: multicentre randomised controlled trial.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 17 Jan 2021; 372:m3715
BMJ: 17 Jan 2021; 372:m3715 | PMID: 33461966
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Abstract

Food anaphylaxis in the United Kingdom: analysis of national data, 1998-2018.

Baseggio Conrado A, Ierodiakonou D, Gowland MH, Boyle RJ, Turner PJ
Objective
To describe time trends for hospital admissions due to food anaphylaxis in the United Kingdom over the past 20 years.
Design
Analysis of national data, 1998-2018.
Setting
Data relating to hospital admissions for anaphylaxis and deaths, and prescription data for adrenaline autoinjector devices.
Participants
UK population as a whole and devolved nations (England, Scotland, Wales, and Northern Ireland).
Main outcome measures
Time trends, age, and sex distributions for hospital admissions for anaphylaxis due to food and non-food triggers, and how these admission rates compare with the case fatality rate (number of fatalities as a proportion of hospital admissions).
Results
Between 1998 and 2018, 101 891 people were admitted to hospital for anaphylaxis. Of these admissions, 30 700 (30.1%) were coded as due to a food trigger. Food anaphylaxis admissions increased from 1.23 to 4.04 per 100 000 population per year (from 1998 to 2018), an annual increase of 5.7% (95% confidence interval 5.5% to 5.9%, P<0.001). The largest increase in hospital admissions was observed in children younger than 15 years, with an increase from 2.1 to 9.2 admissions per 100 000 population per year (an annual increase of 6.6%, 95% confidence interval 6.3% to 7.0%). For comparison, the annual increase was 5.9% (5.6% to 6.2%) in people aged 15-59 years and 2.1% (1.8% to 3.1%) in those aged 60 years and older. 152 deaths were identified where the fatal event was probably caused by food induced anaphylaxis. The case fatality rate decreased from 0.7% to 0.19% for confirmed fatal food anaphylaxis (rate ratio 0.931, 95% confidence interval 0.904 to 0.959, P<0.001) and to 0.30% for suspected fatal food anaphylaxis (0.970, 0.945 to 0.996, P=0.024). At least 46% (86 of 187, which also includes 35 deaths in 1992-98) of deaths were triggered by peanut or tree nut. Cow\'s milk was responsible for 17 of 66 (26%) deaths in school aged children. Over the same time period, prescriptions for adrenaline autoinjectors increased by 336% (estimated rate ratio 1.113, 95% confidence interval 1.112 to 1.113; an increase of 11% per year).
Conclusions
Hospital admissions for food induced anaphylaxis have increased from 1998 to 2018, however the case fatality rate has decreased. In school aged children, cow\'s milk is now the most common single cause of fatal anaphylaxis.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 16 Jan 2021; 372:n251
Baseggio Conrado A, Ierodiakonou D, Gowland MH, Boyle RJ, Turner PJ
BMJ: 16 Jan 2021; 372:n251 | PMID: 33597169
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Abstract

Covid-19 deaths in Africa: prospective systematic postmortem surveillance study.

Mwananyanda L, Gill CJ, MacLeod W, Kwenda G, ... Etter L, Thea D
Objective
To directly measure the fatal impact of coronavirus disease 2019 (covid-19) in an urban African population.
Design
Prospective systematic postmortem surveillance study.
Setting
Zambia\'s largest tertiary care referral hospital.
Participants
Deceased people of all ages at the University Teaching Hospital morgue in Lusaka, Zambia, enrolled within 48 hours of death.
Main outcome measure
Postmortem nasopharyngeal swabs were tested via reverse transcriptase quantitative polymerase chain reaction (PCR) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Deaths were stratified by covis-19 status, location, age, sex, and underlying risk factors.
Results
372 participants were enrolled between June and September 2020; PCR results were available for 364 (97.8%). SARS-CoV-2 was detected in 58/364 (15.9%) according to the recommended cycle threshold value of <40 and in 70/364 (19.2%) when expanded to any level of PCR detection. The median age at death among people with a positive test for SARS-CoV-2 was 48 (interquartile range 36-72) years, and 69% (n=48) were male. Most deaths in people with covid-19 (51/70; 73%) occurred in the community; none had been tested for SARS-CoV-2 before death. Among the 19/70 people who died in hospital, six were tested before death. Among the 52/70 people with data on symptoms, 44/52 had typical symptoms of covid-19 (cough, fever, shortness of breath), of whom only five were tested before death. Covid-19 was identified in seven children, only one of whom had been tested before death. The proportion of deaths with covid-19 increased with age, but 76% (n=53) of people who died were aged under 60 years. The five most common comorbidities among people who died with covid-19 were tuberculosis (22; 31%), hypertension (19; 27%), HIV/AIDS (16; 23%), alcohol misuse (12; 17%), and diabetes (9; 13%).
Conclusions
Contrary to expectations, deaths with covid-19 were common in Lusaka. Most occurred in the community, where testing capacity is lacking. However, few people who died at facilities were tested, despite presenting with typical symptoms of covid-19. Therefore, cases of covid-19 were under-reported because testing was rarely done not because covid-19 was rare. If these data are generalizable, the impact of covid-19 in Africa has been vastly underestimated.

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BMJ: 16 Jan 2021; 372:n334
Mwananyanda L, Gill CJ, MacLeod W, Kwenda G, ... Etter L, Thea D
BMJ: 16 Jan 2021; 372:n334 | PMID: 33597166
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Abstract

Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation.

Mn W, L J, Jw H, Ks R, ... At H, Cf W
Objective
To determine whether the sensitivity and specificity of SNP chips are adequate for detecting rare pathogenic variants in a clinically unselected population.
Design
Retrospective, population based diagnostic evaluation.
Participants
49 908 people recruited to the UK Biobank with SNP chip and next generation sequencing data, and an additional 21 people who purchased consumer genetic tests and shared their data online via the Personal Genome Project.
Main outcome measures
Genotyping (that is, identification of the correct DNA base at a specific genomic location) using SNP chips versus sequencing, with results split by frequency of that genotype in the population. Rare pathogenic variants in the BRCA1 and BRCA2 genes were selected as an exemplar for detailed analysis of clinically actionable variants in the UK Biobank, and BRCA related cancers (breast, ovarian, prostate, and pancreatic) were assessed in participants through use of cancer registry data.
Results
Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. However, the likelihood of a true positive result decreased dramatically with decreasing variant frequency; for variants that are very rare in the population, with a frequency below 0.001% in UK Biobank, the positive predictive value was very low and only 16% of 4757 heterozygous genotypes from the SNP chips were confirmed with sequencing data. Results were similar for SNP chip data from the Personal Genome Project, and 20/21 individuals analysed had at least one false positive rare pathogenic variant that had been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, which are individually very rare, the overall performance metrics for the SNP chips versus sequencing in the UK Biobank were: sensitivity 34.6%, specificity 98.3%, positive predictive value 4.2%, and negative predictive value 99.9%. Rates of BRCA related cancers in UK Biobank participants with a positive SNP chip result were similar to those for age matched controls (odds ratio 1.31, 95% confidence interval 0.99 to 1.71) because the vast majority of variants were false positives, whereas sequence positive participants had a significantly increased risk (odds ratio 4.05, 2.72 to 6.03).
Conclusions
SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 14 Jan 2021; 372:n214
Mn W, L J, Jw H, Ks R, ... At H, Cf W
BMJ: 14 Jan 2021; 372:n214 | PMID: 33589468
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Abstract

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.

Palmer SC, Tendal B, Mustafa RA, Vandvik PO, ... Guyatt G, Strippoli GFM
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.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 12 Jan 2021; 372:m4573
Palmer SC, Tendal B, Mustafa RA, Vandvik PO, ... Guyatt G, Strippoli GFM
BMJ: 12 Jan 2021; 372:m4573 | PMID: 33441402
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Abstract

Efficacy and safety of low and very low carbohydrate diets for type 2 diabetes remission: systematic review and meta-analysis of published and unpublished randomized trial data.

Goldenberg JZ, Day A, Brinkworth GD, Sato J, ... Thabane L, Johnston BC
Objective
To determine the efficacy and safety of low carbohydrate diets (LCDs) and very low carbohydrate diets (VLCDs) for people with type 2 diabetes.
Design
Systematic review and meta-analysis.
Data sources
Searches of CENTRAL, Medline, Embase, CINAHL, CAB, and grey literature sources from inception to 25 August 2020.
Study selection
Randomized clinical trials evaluating LCDs (<130 g/day or <26% of a 2000 kcal/day diet) and VLCDs (<10% calories from carbohydrates) for at least 12 weeks in adults with type 2 diabetes were eligible.
Data extraction
Primary outcomes were remission of diabetes (HbA1c <6.5% or fasting glucose <7.0 mmol/L, with or without the use of diabetes medication), weight loss, HbA1c, fasting glucose, and adverse events. Secondary outcomes included health related quality of life and biochemical laboratory data. All articles and outcomes were independently screened, extracted, and assessed for risk of bias and GRADE certainty of evidence at six and 12 month follow-up. Risk estimates and 95% confidence intervals were calculated using random effects meta-analysis. Outcomes were assessed according to a priori determined minimal important differences to determine clinical importance, and heterogeneity was investigated on the basis of risk of bias and seven a priori subgroups. Any subgroup effects with a statistically significant test of interaction were subjected to a five point credibility checklist.
Results
Searches identified 14 759 citations yielding 23 trials (1357 participants), and 40.6% of outcomes were judged to be at low risk of bias. At six months, compared with control diets, LCDs achieved higher rates of diabetes remission (defined as HbA1c <6.5%) (76/133 (57%) v 41/131 (31%); risk difference 0.32, 95% confidence interval 0.17 to 0.47; 8 studies, n=264, I2=58%). Conversely, smaller, non-significant effect sizes occurred when a remission definition of HbA1c <6.5% without medication was used. Subgroup assessments determined as meeting credibility criteria indicated that remission with LCDs markedly decreased in studies that included patients using insulin. At 12 months, data on remission were sparse, ranging from a small effect to a trivial increased risk of diabetes. Large clinically important improvements were seen in weight loss, triglycerides, and insulin sensitivity at six months, which diminished at 12 months. On the basis of subgroup assessments deemed credible, VLCDs were less effective than less restrictive LCDs for weight loss at six months. However, this effect was explained by diet adherence. That is, among highly adherent patients on VLCDs, a clinically important reduction in weight was seen compared with studies with less adherent patients on VLCDs. Participants experienced no significant difference in quality of life at six months but did experience clinically important, but not statistically significant, worsening of quality of life and low density lipoprotein cholesterol at 12 months. Otherwise, no significant or clinically important between group differences were found in terms of adverse events or blood lipids at six and 12 months.
Conclusions
On the basis of moderate to low certainty evidence, patients adhering to an LCD for six months may experience remission of diabetes without adverse consequences. Limitations include continued debate around what constitutes remission of diabetes, as well as the efficacy, safety, and dietary satisfaction of longer term LCDs.
Systematic review registration
PROSPERO CRD42020161795.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 12 Jan 2021; 372:m4743
Goldenberg JZ, Day A, Brinkworth GD, Sato J, ... Thabane L, Johnston BC
BMJ: 12 Jan 2021; 372:m4743 | PMID: 33441384
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Abstract

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

Rentsch CT, Beckman JA, Tomlinson L, Gellad WF, ... Justice AC, Freiberg MS
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 (84.4%) 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 14.3% (95% confidence interval 13.1% to 15.5%) among those who received prophylactic anticoagulation and 18.7% (15.1% to 22.9%) 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 0.73, 95% confidence interval 0.66 to 0.81). 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 0.87, 0.71 to 1.05). Quantitative bias analysis showed that results were robust to unmeasured confounding (e-value lower 95% confidence interval 1.77 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.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 10 Jan 2021; 372:n311
Rentsch CT, Beckman JA, Tomlinson L, Gellad WF, ... Justice AC, Freiberg MS
BMJ: 10 Jan 2021; 372:n311 | PMID: 33574135
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Abstract

Association of first trimester prescription opioid use with congenital malformations in the offspring: population based cohort study.

Bateman BT, Hernandez-Diaz S, Straub L, Zhu Y, ... Gautam N, Huybrechts KF
Objective
To evaluate the risk of first trimester exposure to prescription opioids for major congenital malformations, previously reported to be associated with such exposure.
Design
Population based cohort study.
Setting
Nationwide sample of publicly and commercially insured pregnant women linked to their liveborn infants, nested in the Medicaid Analytic eXtract (MAX, 2000-14) and the MarketScan Research Database (MarketScan, 2003-15).
Participants
1 602 580 publicly insured (MAX) and 1 177 676 commercially insured (MarketScan) pregnant women with eligibility from at least three months before pregnancy to one month after delivery; infants with eligibility for at least three months after birth.
Interventions
Use of prescription opioids was ascertained by requiring two or more dispensations of any opioid during the first trimester.
Main outcomes measures
Major malformations overall, cardiac malformations overall, ventricular septal defect, secundum atrial septal defect/patent foramen ovale, neural tube defect, clubfoot, and oral cleft, defined based on validated algorithms. Propensity score stratification was used to adjust for potential confounders and/or proxies for confounders. Estimates from each database were combined using meta-analysis.
Results
70 447 (4.4%) of 1 602 580 publicly insured and 12 454 (1.1%) of 1 177 676 commercially insured pregnant women had two or more dispensations of an opioid during the first trimester. Absolute risk of malformations overall was 41.0 (95% confidence interval 39.5 to 42.5) per 1000 pregnancies exposed to opioids versus 32.0 (31.7 to 32.3) per 1000 unexposed pregnancies in the MAX cohort, and 42.6 (39.0 to 46.1) and 37.3 (37.0 to 37.7) per 1000, respectively, in the MarketScan cohort. Pooled unadjusted relative risk estimates were raised for all outcomes but shifted substantially toward the null after adjustment; for malformations overall (relative risk 1.06, 95% confidence interval 1.02 to 1.10), cardiovascular malformations (1.09, 1.00 to 1.18), ventricular septal defect (1.07, 0.95 to 1.21), atrial septal defect/patent foramen ovale (1.04, 0.88 to 1.24), neural tube defect (0.82, 0.53 to 1.27), and clubfoot (1.06, 0.88 to 1.28). The relative risk for oral clefts remained raised after adjustment (1.21, 0.98 to 1.50), with a higher risk of cleft palate (1.62, 1.23 to 2.14).
Conclusions
Prescription opioids used in early pregnancy are not associated with a substantial increase in risk for most of the malformation types considered, although a small increase in the risk of oral clefts associated with their use is possible.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 09 Jan 2021; 372:n102
Bateman BT, Hernandez-Diaz S, Straub L, Zhu Y, ... Gautam N, Huybrechts KF
BMJ: 09 Jan 2021; 372:n102 | PMID: 33568363
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Abstract

Association between use of macrolides in pregnancy and risk of major birth defects: nationwide, register based cohort study.

Andersson NW, Olsen RH, Andersen JT
Objective
To examine the association between the use of macrolide antibiotics in pregnancy and the risk of major birth defects.
Design
Nationwide, register based cohort study.
Setting
Denmark, 1997-2016.
Participants
Of 1 192 539 live birth pregnancies, pregnancies during which macrolides had been used (13 019) were compared with those during which penicillin (that is, phenoxymethylpenicillin) had been used (matched in a 1:1 ratio on propensity scores). Other comparative groups were pregnancies when macrolides had been used recently but before pregnancy (matched 1:1) and pregnancies where no antibiotics had been used (matched 1:4).
Main outcome measures
Association with an outcome of any major birth defect and specific subgroups of birth defects were assessed by relative risk ratios and absolute risk differences.
Results
In matched comparisons, 457 infants were born with major birth defects to women who had used macrolides during pregnancy (35.1 per 1000 pregnancies) compared with 481 infants (37.0 per 1000 pregnancies) to women who had used penicillin (relative risk ratio 0.95; 95% confidence interval 0.84 to 1.08), corresponding to an absolute risk difference of -1.8 (95% confidence interval -6.4 to 2.7) per 1000 pregnancies. The risk of major birth defects was not significantly increased for women who had used macrolides during pregnancy compared with those who had used macrolides recently but before becoming pregnant (relative risk ratio 1.00 (95% confidence interval 0.88 to 1.14); absolute risk difference -0.1 (95% confidence interval -4.8 to 4.7) per 1000 pregnancies) or compared with women who did not use any antibiotics (1.05 (0.95 to 1.17); 1.8 (-1.7 to 5.3) per 1000 pregnancies). For all three comparative group analyses and in the analyses of use of individual macrolides, no significant increased risk of specific subgroups of birth defects associated with the use of macrolides was found.
Conclusions
In this nationwide cohort study, the use of macrolide antibiotics in pregnancy was not associated with an increased risk of major birth defects. Analyses of the associated risk of 12 specific subgroups of birth defects with the use of macrolides in pregnancy were not significant.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 09 Jan 2021; 372:n107
Andersson NW, Olsen RH, Andersen JT
BMJ: 09 Jan 2021; 372:n107 | PMID: 33568349
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Abstract

Association between antihypertensive treatment and adverse events: systematic review and meta-analysis.

Albasri A, Hattle M, Koshiaris C, Dunnigan A, ... Sheppard JP, STRATIFY investigators
Objective
To examine the association between antihypertensive treatment and specific adverse events.
Design
Systematic review and meta-analysis.
Eligibility criteria
Randomised controlled trials of adults receiving antihypertensives compared with placebo or no treatment, more antihypertensive drugs compared with fewer antihypertensive drugs, or higher blood pressure targets compared with lower targets. To avoid small early phase trials, studies were required to have at least 650 patient years of follow-up.
Information sources
Searches were conducted in Embase, Medline, CENTRAL, and the Science Citation Index databases from inception until 14 April 2020.
Main outcome measures
The primary outcome was falls during trial follow-up. Secondary outcomes were acute kidney injury, fractures, gout, hyperkalaemia, hypokalaemia, hypotension, and syncope. Additional outcomes related to death and major cardiovascular events were extracted. Risk of bias was assessed using the Cochrane risk of bias tool, and random effects meta-analysis was used to pool rate ratios, odds ratios, and hazard ratios across studies, allowing for between study heterogeneity (τ2).
Results
Of 15 023 articles screened for inclusion, 58 randomised controlled trials were identified, including 280 638 participants followed up for a median of 3 (interquartile range 2-4) years. Most of the trials (n=40, 69%) had a low risk of bias. Among seven trials reporting data for falls, no evidence was found of an association with antihypertensive treatment (summary risk ratio 1.05, 95% confidence interval 0.89 to 1.24, τ2=0.009). Antihypertensives were associated with an increased risk of acute kidney injury (1.18, 95% confidence interval 1.01 to 1.39, τ2=0.037, n=15), hyperkalaemia (1.89, 1.56 to 2.30, τ2=0.122, n=26), hypotension (1.97, 1.67 to 2.32, τ2=0.132, n=35), and syncope (1.28, 1.03 to 1.59, τ2=0.050, n=16). The heterogeneity between studies assessing acute kidney injury and hyperkalaemia events was reduced when focusing on drugs that affect the renin angiotensin-aldosterone system. Results were robust to sensitivity analyses focusing on adverse events leading to withdrawal from each trial. Antihypertensive treatment was associated with a reduced risk of all cause mortality, cardiovascular death, and stroke, but not of myocardial infarction.
Conclusions
This meta-analysis found no evidence to suggest that antihypertensive treatment is associated with falls but found evidence of an association with mild (hyperkalaemia, hypotension) and severe adverse events (acute kidney injury, syncope). These data could be used to inform shared decision making between doctors and patients about initiation and continuation of antihypertensive treatment, especially in patients at high risk of harm because of previous adverse events or poor renal function.
Registration
PROSPERO CRD42018116860.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 09 Jan 2021; 372:n189
Albasri A, Hattle M, Koshiaris C, Dunnigan A, ... Sheppard JP, STRATIFY investigators
BMJ: 09 Jan 2021; 372:n189 | PMID: 33568342
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Abstract

Use of proton pump inhibitors to treat persistent throat symptoms: multicentre, double blind, randomised, placebo controlled trial.

O\'Hara J, Stocken DD, Watson GC, Fouweather T, ... Wood R, Wilson JA
Objective
To assess the use of proton pump inhibitors (PPIs) to treat persistent throat symptoms.
Design
Pragmatic, double blind, placebo controlled, randomised trial.
Setting
Eight ear, nose, and throat outpatient clinics, United Kingdom.
Participants
346 patients aged 18 years or older with persistent throat symptoms who were randomised according to recruiting centre and baseline severity of symptoms (mild or severe): 172 to lansoprazole and 174 to placebo.
Intervention
Random blinded allocation (1:1) to either 30 mg lansoprazole twice daily or matched placebo twice daily for 16 weeks.
Main outcome measures
Primary outcome was symptomatic response at 16 weeks measured using the total reflux symptom index (RSI) score. Secondary outcomes included symptom response at 12 months, quality of life, and throat appearances.
Results
Of 1427 patients initially screened for eligibility, 346 were recruited. The mean age of the study sample was 52.2 (SD 13.7) years, 196 (57%) were women, and 162 (47%) had severe symptoms at presentation; these characteristics were balanced across treatment arms. The primary analysis was performed on 220 patients who completed the primary outcome measure within a window of 14-20 weeks. Mean RSI scores were similar between treatment arms at baseline: lansoprazole 22.0 (95% confidence interval 20.4 to 23.6) and placebo 21.7 (20.5 to 23.0). Improvements (reduction in RSI score) were observed in both groups-score at 16 weeks: lansoprazole 17.4 (15.5 to19.4) and placebo 15.6 (13.8 to 17.3). No statistically significant difference was found between the treatment arms: estimated difference 1.9 points (95% confidence interval -0.3 to 4.2 points; P=0.096) adjusted for site and baseline symptom severity. Lansoprazole showed no benefits over placebo for any secondary outcome measure, including RSI scores at 12 months: lansoprazole 16.0 (13.6 to 18.4) and placebo 13.6 (11.7 to 15.5): estimated difference 2.4 points (-0.6 to 5.4 points).
Conclusions
No evidence was found of benefit from PPI treatment in patients with persistent throat symptoms. RSI scores were similar between the lansoprazole and placebo groups after 16 weeks of treatment and at the 12 month follow-up.
Trial registration
ISRCTN Registry ISRCTN38578686 and EudraCT 2013-004249-17.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 06 Jan 2021; 372:m4903
O'Hara J, Stocken DD, Watson GC, Fouweather T, ... Wood R, Wilson JA
BMJ: 06 Jan 2021; 372:m4903 | PMID: 33414239
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Abstract

Axial spondyloarthritis: new advances in diagnosis and management.

Ritchlin C, Adamopoulos IE
Axial spondyloarthritis (axSpA) is an inflammatory disease of the axial skeleton associated with significant pain and disability. Previously, the diagnosis of ankylosing spondylitis required advanced changes on plain radiographs of the sacroiliac joints. Classification criteria released in 2009, however, identified a subset of patients, under the age of 45, with back pain for more than three months in the absence of radiographic sacroiliitis who were classified as axSpA based on a positive magnetic resonance imaging or HLAB27 positivity and specific clinical features. This subgroup was labeled non-radiographic (nr)-axSpA. These patients, compared with those identified by the older New York criteria, contained a larger percentage of women and demonstrated less structural damage. However, their clinical manifestations and response to biologics were similar to radiographic axSpA. The discovery of the interleukin (IL) IL-23/IL-17 pathway revealed key molecules involved in the pathophysiology of axSpA. This discovery propelled the generation of antibodies directed toward IL-17A, which are highly effective and demonstrate treatment responses in axSpA that are similar to those observed with anti-TNF agents. The finding that agents that block IL-23 were not effective in axSpA came as a surprise and the potential underlying mechanisms underlying this lack of response are discussed. New agents with dual inhibition of the IL-17A and F isoforms and some oral small molecule agents that target the Jak-STAT pathway, have also shown efficacy in axSpA.

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BMJ: 03 Jan 2021; 372:m4447
Ritchlin C, Adamopoulos IE
BMJ: 03 Jan 2021; 372:m4447 | PMID: 33397652
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Abstract

Prospective validation of Canadian TIA Score and comparison with ABCD2 and ABCD2i for subsequent stroke risk after transient ischaemic attack: multicentre prospective cohort study.

Perry JJ, Sivilotti MLA, Émond M, Stiell IG, ... Wells GA, Sharma M
Objective
To validate the previously derived Canadian TIA Score to stratify subsequent stroke risk in a new cohort of emergency department patients with transient ischaemic attack.
Design
Prospective cohort study.
Setting
13 Canadian emergency departments over five years.
Participants
7607 consecutively enrolled adult patients attending the emergency department with transient ischaemic attack or minor stroke.
Main outcome measures
The primary outcome was subsequent stroke or carotid endarterectomy/carotid artery stenting within seven days. The secondary outcome was subsequent stroke within seven days (with or without carotid endarterectomy/carotid artery stenting). Telephone follow-up used the validated Questionnaire for Verifying Stroke Free Status at seven and 90 days. All outcomes were adjudicated by panels of three stroke experts, blinded to the index emergency department visit.
Results
Of the 7607 patients, 108 (1.4%) had a subsequent stroke within seven days, 83 (1.1%) had carotid endarterectomy/carotid artery stenting within seven days, and nine had both. The Canadian TIA Score stratified the risk of stroke, carotid endarterectomy/carotid artery stenting, or both within seven days as low (risk ≤0.5%; interval likelihood ratio 0.20, 95% confidence interval 0.09 to 0.44), medium (risk 2.3%; interval likelihood ratio 0.94, 0.85 to 1.04), and high (risk 5.9% interval likelihood ratio 2.56, 2.02 to 3.25) more accurately (area under the curve 0.70, 95% confidence interval 0.66 to 0.73) than did the ABCD2 (0.60, 0.55 to 0.64) or ABCD2i (0.64, 0.59 to 0.68). Results were similar for subsequent stroke regardless of carotid endarterectomy/carotid artery stenting within seven days.
Conclusion
The Canadian TIA Score stratifies patients\' seven day risk for stroke, with or without carotid endarterectomy/carotid artery stenting, and is now ready for clinical use. Incorporating this validated risk estimate into management plans should improve early decision making at the index emergency visit regarding benefits of hospital admission, timing of investigations, and prioritisation of specialist referral.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 03 Jan 2021; 372:n49
Perry JJ, Sivilotti MLA, Émond M, Stiell IG, ... Wells GA, Sharma M
BMJ: 03 Jan 2021; 372:n49 | PMID: 33541890
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Abstract

Associations of cereal grains intake with cardiovascular disease and mortality across 21 countries in Prospective Urban and Rural Epidemiology study: prospective cohort study.

Swaminathan S, Dehghan M, Raj JM, Thomas T, ... Teo K, Yusuf S
Objective
To evaluate the association between intakes of refined grains, whole grains, and white rice with cardiovascular disease, total mortality, blood lipids, and blood pressure in the Prospective Urban and Rural Epidemiology (PURE) study.
Design
Prospective cohort study.
Setting
PURE study in 21 countries.
Participants
148 858 participants with median follow-up of 9.5 years.
Exposures
Country specific validated food frequency questionnaires were used to assess intakes of refined grains, whole grains, and white rice.
Main outcome measure
Composite of mortality or major cardiovascular events (defined as death from cardiovascular causes, non-fatal myocardial infarction, stroke, or heart failure). Hazard ratios were estimated for associations of grain intakes with mortality, major cardiovascular events, and their composite by using multivariable Cox frailty models with random intercepts to account for clustering by centre.
Results
Analyses were based on 137 130 participants after exclusion of those with baseline cardiovascular disease. During follow-up, 9.2% (n=12 668) of these participants had a composite outcome event. The highest category of intake of refined grains (≥350 g/day or about 7 servings/day) was associated with higher risk of total mortality (hazard ratio 1.27, 95% confidence interval 1.11 to 1.46; P for trend=0.004), major cardiovascular disease events (1.33, 1.16 to 1.52; P for trend<0.001), and their composite (1.28, 1.15 to 1.42; P for trend<0.001) compared with the lowest category of intake (<50 g/day). Higher intakes of refined grains were associated with higher systolic blood pressure. No significant associations were found between intakes of whole grains or white rice and health outcomes.
Conclusion
High intake of refined grains was associated with higher risk of mortality and major cardiovascular disease events. Globally, lower consumption of refined grains should be considered.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 02 Jan 2021; 372:m4948
Swaminathan S, Dehghan M, Raj JM, Thomas T, ... Teo K, Yusuf S
BMJ: 02 Jan 2021; 372:m4948 | PMID: 33536317
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Abstract

Uveitis for the non-ophthalmologist.

Burkholder BM, Jabs DA
The uveitides are a heterogeneous group of diseases characterized by inflammation inside the eye. The uveitides are classified as infectious or non-infectious. The non-infectious uveitides, which are presumed to be immune mediated, can be further divided into those that are associated with a known systemic disease and those that are eye limited,-ie, not associated with a systemic disease. The ophthalmologist identifies the specific uveitic entity by medical history, clinical examination, and ocular imaging, as well as supplemental laboratory testing, if indicated. Treatment of the infectious uveitides is tailored to the particular infectious organism and may include regional and/or systemic medication. First line treatment for non-infectious uveitides is corticosteroids that can be administered topically, as regional injections or surgical implants, or systemically. Systemic immunosuppressive therapy is used in patients with severe disease who cannot tolerate corticosteroids, require chronic corticosteroids at >7.5 mg/day prednisone, or in whom the disease is known to respond better to immunosuppression. Management of many of these diseases is optimized by coordination between the ophthalmologist and rheumatologist or internist.

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BMJ: 02 Jan 2021; 372:m4979
Burkholder BM, Jabs DA
BMJ: 02 Jan 2021; 372:m4979 | PMID: 33536186
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Abstract

Use of high dose cyproterone acetate and risk of intracranial meningioma in women: cohort study.

Weill A, Nguyen P, Labidi M, Cadier B, ... Froelich S, Coste J
Objective
To assess the risk of meningioma associated with use of high dose cyproterone acetate, a progestogen indicated for clinical hyperandrogenism.
Design
Observational cohort study.
Setting
Data from SNDS, the French administrative healthcare database, between 2007 and 2015.
Participants
253 777 girls and women aged 7-70 years living in France who started cyproterone acetate between 2007 and 2014. Participants had at least one reimbursement for high dose cyproterone acetate and no history of meningioma or benign brain tumour, or long term disease status. Participants were considered to be exposed when they had received a cumulative dose of at least 3 g during the first six months (139 222 participants) and very slightly exposed (control group) when they had received a cumulative dose of less than 3 g (114 555 participants). 10 876 transgender participants (male to female) were included in an additional analysis.
Main outcome measure
Surgery (resection or decompression) or radiotherapy for one or more intracranial meningiomas.
Results
Overall, 69 meningiomas in the exposed group (during 289 544 person years of follow-up) and 20 meningiomas in the control group (during 439 949 person years of follow-up) were treated by surgery or radiotherapy. The incidence of meningioma in the two groups was 23.8 and 4.5 per 100 000 person years, respectively (crude relative risk 5.2, 95% confidence interval 3.2 to 8.6; adjusted hazard ratio 6.6, 95% confidence interval 4.0 to 11.1). The adjusted hazard ratio for a cumulative dose of cyproterone acetate of more than 60 g was 21.7 (10.8 to 43.5). After discontinuation of cyproterone acetate for one year, the risk of meningioma in the exposed group was 1.8-fold higher (1.0 to 3.2) than in the control group. In a complementary analysis, 463 women with meningioma were observed among 123 997 already using cyproterone acetate in 2006 (risk of 383 per 100 000 person years in the group with the highest exposure in terms of cumulative dose). Meningiomas located in the anterior skull base and middle skull base, particularly the medial third of the middle skull base, involving the spheno-orbital region, appeared to be specific to cyproterone acetate. An additional analysis of transgender participants showed a high risk of meningioma (three per 14 460 person years; 20.7 per 100 000 person years).
Conclusions
A strong dose-effect relation was observed between use of cyproterone acetate and risk of intracranial meningiomas. A noticeable reduction in risk was observed after discontinuation of treatment.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 02 Jan 2021; 372:n37
Weill A, Nguyen P, Labidi M, Cadier B, ... Froelich S, Coste J
BMJ: 02 Jan 2021; 372:n37 | PMID: 33536184
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Abstract

Treatment effects in randomised trials using routinely collected data for outcome assessment versus traditional trials: meta-research study.

Mc Cord KA, Ewald H, Agarwal A, Glinz D, ... Ioannidis JPA, Hemkens LG
Objective
To compare effect estimates of randomised clinical trials that use routinely collected data (RCD-RCT) for outcome ascertainment with traditional trials not using routinely collected data.
Design
Meta-research study.
Data source
Studies included in the same meta-analysis in a Cochrane review.
Eligibility criteria for study selection
Randomised clinical trials using any type of routinely collected data for outcome ascertainment, including from registries, electronic health records, and administrative databases, that were included in a meta-analysis of a Cochrane review on any clinical question and any health outcome together with traditional trials not using routinely collected data for outcome measurement.
Review methods
Effect estimates from trials using or not using routinely collected data were summarised in random effects meta-analyses. Agreement of (summary) treatment effect estimates from trials using routinely collected data and those not using such data was expressed as the ratio of odds ratios. Subgroup analyses explored effects in trials based on different types of routinely collected data. Two investigators independently assessed the quality of each data source.
Results
84 RCD-RCTs and 463 traditional trials on 22 clinical questions were included. Trials using routinely collected data for outcome ascertainment showed 20% less favourable treatment effect estimates than traditional trials (ratio of odds ratios 0.80, 95% confidence interval 0.70 to 0.91, I2=14%). Results were similar across various types of outcomes (mortality outcomes: 0.92, 0.74 to 1.15, I2=12%; non-mortality outcomes: 0.71, 0.60 to 0.84, I2=8%), data sources (electronic health records: 0.81, 0.59 to 1.11, I2=28%; registries: 0.86, 0.75 to 0.99, I2=20%; administrative data: 0.84, 0.72 to 0.99, I2=0%), and data quality (high data quality: 0.82, 0.72 to 0.93, I2=0%).
Conclusions
Randomised clinical trials using routinely collected data for outcome ascertainment show smaller treatment benefits than traditional trials not using routinely collected data. These differences could have implications for healthcare decision making and the application of real world evidence.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 02 Jan 2021; 372:n450
Mc Cord KA, Ewald H, Agarwal A, Glinz D, ... Ioannidis JPA, Hemkens LG
BMJ: 02 Jan 2021; 372:n450 | PMID: 33658187
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Abstract

Effect of redundant clinical trials from mainland China evaluating statins in patients with coronary artery disease: cross sectional study.

Jia Y, Wen J, Qureshi R, Ehrhardt S, ... Wen Y, Robinson KA
Objective
To identify redundant clinical trials evaluating statin treatment in patients with coronary artery disease from mainland China, and to estimate the number of extra major adverse cardiac events (MACEs) experienced by participants not treated with statins in those trials.
Design
Cross sectional study.
Setting
2577 randomized clinical trials comparing statin treatment with placebo or no treatment in patients with coronary artery disease from mainland China, searched from bibliographic databases to December 2019.
Participants
250 810 patients with any type of coronary artery disease who were enrolled in the 2577 randomized clinical trials.
Main outcome measures
Redundant clinical trials were defined as randomized clinical trials that initiated or continued recruiting after 2008 (ie, one year after statin treatment was strongly recommended by clinical practice guidelines). The primary outcome is the number of extra MACEs that were attributable to the deprivation of statins among patients in the control groups of redundant clinical trials-that is, the number of extra MACEs that could have been prevented if patients were given statins. Cumulative meta-analyses were also conducted to establish the time points when statins were shown to have a statistically significant effect on coronary artery disease.
Results
2045 redundant clinical trials were identified published between 2008 and 2019, comprising 101 486 patients in the control groups not treated with statins for 24 638 person years. 3470 (95% confidence interval 3230 to 3619) extra MACEs were reported, including 559 (95% confidence interval 506 to 612) deaths, 973 (95% confidence interval 897 to 1052) patients with new or recurrent myocardial infarction, 161 (132 to 190) patients with stroke, 83 (58 to 105) patients requiring revascularization, 398 (352 to 448) patients with heart failure, 1197 (1110 to 1282) patients with recurrent or deteriorated angina pectoris, and 99 (95% confidence interval 69 to 129) unspecified MACEs.
Conclusions
Of more than 2000 redundant clinical trials on statins in patients with coronary artery disease identified from mainland China, an extra 3000 MACEs, including nearly 600 deaths, were experienced by participants not treated with statins in these trials. The scale of redundancy necessitates urgent reform to protect patients.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 01 Jan 2021; 372:n48
Jia Y, Wen J, Qureshi R, Ehrhardt S, ... Wen Y, Robinson KA
BMJ: 01 Jan 2021; 372:n48 | PMID: 33531350
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Abstract

SARS-CoV-2 lateral flow assays for possible use in national covid-19 seroprevalence surveys (React 2): diagnostic accuracy study.

Moshe M, Daunt A, Flower B, Simmons B, ... Barclay WS, React study team
Objective
To evaluate the performance of new lateral flow immunoassays (LFIAs) suitable for use in a national coronavirus disease 2019 (covid-19) seroprevalence programme (real time assessment of community transmission 2-React 2).
Design
Diagnostic accuracy study.
Setting
Laboratory analyses were performed in the United Kingdom at Imperial College, London and university facilities in London. Research clinics for finger prick sampling were run in two affiliated NHS trusts.
Participants
Sensitivity analyses were performed on sera stored from 320 previous participants in the React 2 programme with confirmed previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Specificity analyses were performed on 1000 prepandemic serum samples. 100 new participants with confirmed previous SARS-CoV-2 infection attended study clinics for finger prick testing.
Interventions
Laboratory sensitivity and specificity analyses were performed for seven LFIAs on a minimum of 200 serum samples from participants with confirmed SARS-CoV-2 infection and 500 prepandemic serum samples, respectively. Three LFIAs were found to have a laboratory sensitivity superior to the finger prick sensitivity of the LFIA currently used in React 2 seroprevalence studies (84%). These LFIAs were then further evaluated through finger prick testing on participants with confirmed previous SARS-CoV-2 infection: two LFIAs (Surescreen, Panbio) were evaluated in clinics in June-July 2020 and the third LFIA (AbC-19) in September 2020. A spike protein enzyme linked immunoassay and hybrid double antigen binding assay were used as laboratory reference standards.
Main outcome measures
The accuracy of LFIAs in detecting immunoglobulin G (IgG) antibodies to SARS-CoV-2 compared with two reference standards.
Results
The sensitivity and specificity of seven new LFIAs that were analysed using sera varied from 69% to 100%, and from 98.6% to 100%, respectively (compared with the two reference standards). Sensitivity on finger prick testing was 77% (95% confidence interval 61.4% to 88.2%) for Panbio, 86% (72.7% to 94.8%) for Surescreen, and 69% (53.8% to 81.3%) for AbC-19 compared with the reference standards. Sensitivity for sera from matched clinical samples performed on AbC-19 was significantly higher with serum than finger prick at 92% (80.0% to 97.7%, P=0.01). Antibody titres varied considerably among cohorts. The numbers of positive samples identified by finger prick in the lowest antibody titre quarter varied among LFIAs.
Conclusions
One new LFIA was identified with clinical performance suitable for potential inclusion in seroprevalence studies. However, none of the LFIAs tested had clearly superior performance to the LFIA currently used in React 2 seroprevalence surveys, and none showed sufficient sensitivity and specificity to be considered for routine clinical use.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 01 Jan 2021; 372:n423
Moshe M, Daunt A, Flower B, Simmons B, ... Barclay WS, React study team
BMJ: 01 Jan 2021; 372:n423 | PMID: 33653694
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Abstract

A living WHO guideline on drugs to prevent covid-19.

Lamontagne F, Agoritsas T, Siemieniuk R, Rochwerg B, ... Vandvik PO, Jacobs M
Clinical question
What is the role of drugs in preventing covid-19? WHY DOES THIS MATTER?: There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. The first version of this living guideline focuses on the evidence for hydroxychloroquine. Subsequent updates will cover other drugs being investigated for their role in the prevention of covid-19.
Recommendation
The guideline development panel made a strong recommendation against the use of hydroxychloroquine for individuals who do not have covid-19 (high certainty).
How this guideline was created
This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development panel of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Understanding the new recommendation
The linked systematic review and network meta-analysis (6 trials and 6059 participants) found that hydroxychloroquine had a small or no effect on mortality and admission to hospital (high certainty evidence). There was a small or no effect on laboratory confirmed SARS-CoV-2 infection (moderate certainty evidence) but probably increased adverse events leading to discontinuation (moderate certainty evidence). The panel judged that almost all people would not consider this drug worthwhile. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation. The panel considers that this drug is no longer a research priority and that resources should rather be oriented to evaluate other more promising drugs to prevent covid-19.
Updates
This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline.
Readers note
This is the first version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19. When citing this article, please consider adding the update number and date of access for clarity.

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BMJ: 31 Dec 2020; 372:n526
Lamontagne F, Agoritsas T, Siemieniuk R, Rochwerg B, ... Vandvik PO, Jacobs M
BMJ: 31 Dec 2020; 372:n526 | PMID: 33649077
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Impact:

This program is still in alpha version.