Journal: BMJ

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Abstract

Hospital policies can create barriers to good management of opioid withdrawal.

Saul H, Gursul D, Deeney B, Harris M, Holland A
The studyHarris M, Holland A, Lewer D, et al. Barriers to management of opioid withdrawal in hospitals in England: a document analysis of hospital policies on the management of substance dependence. BMC Med 2022;20:151.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/many-hospital-policies-create-barriers-to-good-management-of-opioid-withdrawal/.

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BMJ: 02 Dec 2022; 379:o2860
Saul H, Gursul D, Deeney B, Harris M, Holland A
BMJ: 02 Dec 2022; 379:o2860 | PMID: 36460314
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Abstract

Correction for vol. 379, p.


Optimizing Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older Adults (OPERAM): cluster randomised controlled trial.

© 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 Dec 2022; 379:o2859
BMJ: 01 Dec 2022; 379:o2859 | PMID: 36455932
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Abstract

Effectiveness of mRNA-1273, BNT162b2, and BBIBP-CorV vaccines against infection and mortality in children in Argentina, during predominance of delta and omicron covid-19 variants: test negative, case-control study.

Castelli JM, Rearte A, Olszevicki S, Voto C, ... Giovacchini CM, Vizzotti C
Objective
To estimate the effectiveness of a two dose vaccine schedule (mRNA-1273, BNT162b2, and BBIBP-CorV) against SARS-CoV-2 infection and covid-19 related death and short term waning of immunity in children (3-11 years old) and adolescents (12-17 years old) during periods of delta and omicron variant predominance in Argentina.
Design
Test negative, case-control study.
Setting
Database of the National Surveillance System and the Nominalized Federal Vaccination Registry of Argentina.
Participants
844 460 children and adolescents without previous SARS-CoV-2 infection eligible to receive primary vaccination schedule who were tested for SARS-CoV-2 by polymerase chain reaction or rapid antigen test from September 2021 to April 2022. After matching with their corresponding controls, 139 321 (60.3%) of 231 181 cases remained for analysis.
Exposures
Two dose mRNA-1273, BNT162b2, and BBIBP-CorV vaccination schedule.
Main outcome measures
SARS-CoV-2 infection and covid-19 related death. Conditional logistic regression was used to estimate the odds of SARS-CoV-2 infection among two dose vaccinated and unvaccinated participants. Vaccine effectiveness was estimated as (1-odds ratio)×100%.
Results
Estimated vaccine effectiveness against SARS-CoV-2 infection was 61.2% (95% confidence interval 56.4% to 65.5%) in children and 66.8% (63.9% to 69.5%) in adolescents during the delta dominant period and 15.9% (13.2% to 18.6%) and 26.0% (23.2% to 28.8%), respectively, when omicron was dominant. Vaccine effectiveness declined over time, especially during the omicron period, from 37.6% (34.2% to 40.8%) at 15-30 days after vaccination to 2.0% (1.8% to 5.6%) after ≥60 days in children and from 55.8% (52.4% to 59.0%) to 12.4% (8.6% to 16.1%) in adolescents.Vaccine effectiveness against death related to SARS-CoV-2 infection during omicron predominance was 66.9% (6.4% to 89.8%) in children and 97.6% (81.0% to 99.7%) in adolescents.
Conclusions
Vaccine effectiveness in preventing mortality remained high in children and adolescents regardless of the circulating variant. Vaccine effectiveness in preventing SARS-CoV-2 infection in the short term after vaccination was lower during omicron predominance and decreasing sharply over time.
Trial registration
National Registry of Health Research IS003720.

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BMJ: 30 Nov 2022; 379:e073070
Castelli JM, Rearte A, Olszevicki S, Voto C, ... Giovacchini CM, Vizzotti C
BMJ: 30 Nov 2022; 379:e073070 | PMID: 36450402
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Abstract

Oxygen administration during surgery and postoperative organ injury: observational cohort study.

McIlroy DR, Shotwell MS, Lopez MG, Vaughn MT, ... Billings FT, Multicenter Perioperative Outcomes Group
Objective
To examine whether supraphysiological oxygen administration during surgery is associated with lower or higher postoperative kidney, heart, and lung injury.
Design
Observational cohort study.
Setting
42 medical centers across the United States participating in the Multicenter Perioperative Outcomes Group data registry.
Participants
Adult patients undergoing surgical procedures ≥120 minutes\' duration with general anesthesia and endotracheal intubation who were admitted to hospital after surgery between January 2016 and November 2018.
Intervention
Supraphysiological oxygen administration, defined as the area under the curve of the fraction of inspired oxygen above air (21%) during minutes when the hemoglobin oxygen saturation was greater than 92%.
Main outcomes
Primary endpoints were acute kidney injury defined using Kidney Disease Improving Global Outcomes criteria, myocardial injury defined as serum troponin >0.04 ng/mL within 72 hours of surgery, and lung injury defined using international classification of diseases hospital discharge diagnosis codes.
Results
The cohort comprised 350 647 patients with median age 59 years (interquartile range 46-69 years), 180 546 women (51.5%), and median duration of surgery 205 minutes (interquartile range 158-279 minutes). Acute kidney injury was diagnosed in 19 207 of 297 554 patients (6.5%), myocardial injury in 8972 of 320 527 (2.8%), and lung injury in 13 789 of 312 161 (4.4%). The median fraction of inspired oxygen was 54.0% (interquartile range 47.5%-60.0%), and the area under the curve of supraphysiological inspired oxygen was 7951% min (5870-11 107% min), equivalent to an 80% fraction of inspired oxygen throughout a 135 minute procedure, for example. After accounting for baseline covariates and other potential confounding variables, increased oxygen exposure was associated with a higher risk of acute kidney injury, myocardial injury, and lung injury. Patients at the 75th centile for the area under the curve of the fraction of inspired oxygen had 26% greater odds of acute kidney injury (95% confidence interval 22% to 30%), 12% greater odds of myocardial injury (7% to 17%), and 14% greater odds of lung injury (12% to 16%) compared with patients at the 25th centile. Sensitivity analyses evaluating alternative definitions of the exposure, restricting the cohort, and conducting an instrumental variable analysis confirmed these observations.
Conclusions
Increased supraphysiological oxygen administration during surgery was associated with a higher incidence of kidney, myocardial, and lung injury. Residual confounding of these associations cannot be excluded.
Trial registration
Open Science Framework osf.io/cfd2m.

© 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: 30 Nov 2022; 379:e070941
McIlroy DR, Shotwell MS, Lopez MG, Vaughn MT, ... Billings FT, Multicenter Perioperative Outcomes Group
BMJ: 30 Nov 2022; 379:e070941 | PMID: 36450405
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Abstract

Advances in diagnosis and treatment of testicular cancer.

Chovanec M, Cheng L
Testicular cancer is a curable cancer. The success of physicians in curing the disease is underpinned by multidisciplinary advances. Cisplatin-based combination chemotherapy and the refinement of post-chemotherapy surgical procedures and diagnostic strategies have greatly improved long term survival in most patients. Despite such excellent outcomes, several controversial dilemmas exist in the approaches to clinical stage I disease, salvage chemotherapy, post-chemotherapy surgical procedures, and implementing innovative imaging studies. Relapse after salvage chemotherapy has a poor prognosis and the optimal treatment is not apparent. Recent research has provided insight into the molecular mechanisms underlying cisplatin resistance. Phase 2 studies with targeted agents have failed to show adequate efficacy; however, our understanding of cisplatin resistant disease is rapidly expanding. This review summarizes recent advances and discusses relevant issues in the biology and management of testicular cancer.

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BMJ: 28 Nov 2022; 379:e070499
Chovanec M, Cheng L
BMJ: 28 Nov 2022; 379:e070499 | PMID: 36442868
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Abstract

Retracted papers originating from paper mills: cross sectional study.

Candal-Pedreira C, Ross JS, Ruano-Ravina A, Egilman DS, Fernández E, Pérez-Ríos M
Objectives
To describe retracted papers originating from paper mills, including their characteristics, visibility, and impact over time, and the journals in which they were published.
Design
Cross sectional study.
Setting
The Retraction Watch database was used for identification of retracted papers from paper mills, Web of Science was used for the total number of published papers, and data from Journal Citation Reports were collected to show characteristics of journals.
Participants
All paper mill papers retracted from 1 January 2004 to 26 June 2022 were included in the study. Papers bearing an expression of concern were excluded.
Main outcome measures
Descriptive statistics were used to characterise the sample and analyse the trend of retracted paper mill papers over time, and to analyse their impact and visibility by reference to the number of citations received.
Results
1182 retracted paper mill papers were identified. The publication of the first paper mill paper was in 2004 and the first retraction was in 2016; by 2021, paper mill retractions accounted for 772 (21.8%) of the 3544 total retractions. Overall, retracted paper mill papers were mostly published in journals of the second highest Journal Citation Reports quartile for impact factor (n=529 (44.8%)) and listed four to six authors (n=602 (50.9%)). Of the 1182 papers, almost all listed authors of 1143 (96.8%) paper mill retractions came from Chinese institutions and 909 (76.9%) listed a hospital as a primary affiliation. 15 journals accounted for 812 (68.7%) of 1182 paper mill retractions, with one journal accounting for 166 (14.0%). Nearly all (n=1083, 93.8%) paper mill retractions had received at least one citation since publication, with a median of 11 (interquartile range 5-22) citations received.
Conclusions
Papers retracted originating from paper mills are increasing in frequency, posing a problem for the research community. Retracted paper mill papers most commonly originated from China and were published in a small number of journals. Nevertheless, detected paper mill papers might be substantially different from those that are not detected. New mechanisms are needed to identify and avoid this relatively new type of misconduct.

© 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 Nov 2022; 379:e071517
Candal-Pedreira C, Ross JS, Ruano-Ravina A, Egilman DS, Fernández E, Pérez-Ríos M
BMJ: 28 Nov 2022; 379:e071517 | PMID: 36442874
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Abstract

Impact of community asymptomatic rapid antigen testing on covid-19 related hospital admissions: synthetic control study.

Zhang X, Barr B, Green M, Hughes D, ... García-Fiñana M, Buchan I
Objective
To analyse the impact of voluntary rapid testing for SARS-CoV-2 antigen in Liverpool city on covid-19 related hospital admissions.
Design
Synthetic control analysis comparing hospital admissions for small areas in the intervention population with a group of control areas weighted to be similar for past covid-19 related hospital admission rates and sociodemographic factors.
Setting
Liverpool city, UK, 6 November 2020 to 2 January 2021, under the intervention of Covid-SMART (systematic meaningful asymptomatic repeated testing) voluntary, open access supervised self-testing with lateral flow devices, compared with control areas selected from the rest of England.
Population
General population of Liverpool (n=498 042) and a synthetic control population from the rest of England.
Main outcome measure
Weekly covid-19 related hospital admissions for neighbourhoods in England.
Results
The introduction of community testing was associated with a 43% (95% confidence interval 29% to 57%) reduction (146 (96 to 192) in total) in covid-19 related hospital admissions in Liverpool compared with the synthetic control population (non-adjacent set of neighbourhoods with aggregate trends in covid-19 hospital admissions similar to Liverpool) for the initial period of intensive testing with military assistance in national lockdown from 6 November to 3 December 2020. A 25% (11% to 35%) reduction (239 (104 to 333) in total) was estimated across the overall intervention period (6 November 2020 to 2 January 2021), involving fewer testing centres, before England\'s national roll-out of community testing, after adjusting for regional differences in tiers of covid-19 restrictions from 3 December 2020 to 2 January 2021.
Conclusions
The city-wide pilot of community based asymptomatic testing for SARS-CoV-2 was associated with substantially reduced covid-19 related hospital admissions. Large scale asymptomatic rapid testing for SARS-CoV-2 could help reduce transmission and prevent hospital admissions.

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BMJ: 23 Nov 2022; 379:e071374
Zhang X, Barr B, Green M, Hughes D, ... García-Fiñana M, Buchan I
BMJ: 23 Nov 2022; 379:e071374 | PMID: 36418047
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Abstract

Changing patterns in reporting and sharing of review data in systematic reviews with meta-analysis of the effects of interventions: cross sectional meta-research study.

Nguyen PY, Kanukula R, McKenzie JE, Alqaidoom Z, ... Welch VA, Page MJ
Objectives
To examine changes in completeness of reporting and frequency of sharing data, analytical code, and other review materials in systematic reviews over time; and factors associated with these changes.
Design
Cross sectional meta-research study.
Population
Random sample of 300 systematic reviews with meta-analysis of aggregate data on the effects of a health, social, behavioural, or educational intervention. Reviews were indexed in PubMed, Science Citation Index, Social Sciences Citation Index, Scopus, and Education Collection in November 2020.
Main outcome measures
The extent of complete reporting and the frequency of sharing review materials in the systematic reviews indexed in 2020 were compared with 110 systematic reviews indexed in February 2014. Associations between completeness of reporting and various factors (eg, self-reported use of reporting guidelines, journal policies on data sharing) were examined by calculating risk ratios and 95% confidence intervals.
Results
Several items were reported suboptimally among 300 systematic reviews from 2020, such as a registration record for the review (n=113; 38%), a full search strategy for at least one database (n=214; 71%), methods used to assess risk of bias (n=185; 62%), methods used to prepare data for meta-analysis (n=101; 34%), and source of funding for the review (n=215; 72%). Only a few items not already reported at a high frequency in 2014 were reported more frequently in 2020. No evidence indicated that reviews using a reporting guideline were more completely reported than reviews not using a guideline. Reviews published in 2020 in journals that mandated either data sharing or inclusion of data availability statements were more likely to share their review materials (eg, data, code files) than reviews in journals without such mandates (16/87 (18%) v 4/213 (2%)).
Conclusion
Incomplete reporting of several recommended items for systematic reviews persists, even in reviews that claim to have followed a reporting guideline. Journal policies on data sharing might encourage sharing of review materials.

© 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: 22 Nov 2022; 379:e072428
Nguyen PY, Kanukula R, McKenzie JE, Alqaidoom Z, ... Welch VA, Page MJ
BMJ: 22 Nov 2022; 379:e072428 | PMID: 36414269
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Abstract

Little evidence supports gabapentinoid use in bipolar disorder or insomnia.

Saul H, Gursul D, Cassidy S, Harrison P
The studyHong JSW, Atkinson LZ, Al-Juffali N, et al. Gabapentin and pregabalin in bipolar disorder, anxiety states, and insomnia: systematic review, meta-analysis, and rationale. Mol Psychiatry 2022;27:1339-49.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/review-finds-little-evidence-support-gabapentinoid-use-bipolar-disorder-or-insomnia/.

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BMJ: 18 Nov 2022; 379:o2576
Saul H, Gursul D, Cassidy S, Harrison P
BMJ: 18 Nov 2022; 379:o2576 | PMID: 36400449
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Abstract

Maternal mortality in eight European countries with enhanced surveillance systems: descriptive population based study.

Diguisto C, Saucedo M, Kallianidis A, Bloemenkamp K, ... Nyflot LT, Deneux-Tharaux C
Objective
To compare maternal mortality in eight countries with enhanced surveillance systems.
Design
Descriptive multicountry population based study.
Setting
Eight countries with permanent surveillance systems using enhanced methods to identify, document, and review maternal deaths. The most recent available aggregated maternal mortality data were collected for three year periods for France, Italy, and the UK and for five year periods for Denmark, Finland, the Netherlands, Norway, and Slovakia.
Population
297 835 live births in Denmark (2013-17), 301 169 in Finland (2008-12), 2 435 583 in France (2013-15), 1 281 986 in Italy (2013-15), 856 572 in the Netherlands (2014-18), 292 315 in Norway (2014-18), 283 930 in Slovakia (2014-18), and 2 261 090 in the UK (2016-18).
Outcome measures
Maternal mortality ratios from enhanced systems were calculated and compared with those obtained from each country\'s office of vital statistics. Age specific maternal mortality ratios; maternal mortality ratios according to women\'s origin, citizenship, or ethnicity; and cause specific maternal mortality ratios were also calculated.
Results
Methods for identifying and classifying maternal deaths up to 42 days were very similar across countries (except for the Netherlands). Maternal mortality ratios up to 42 days after end of pregnancy varied by a multiplicative factor of four from 2.7 and 3.4 per 100 000 live births in Norway and Denmark to 9.6 in the UK and 10.9 in Slovakia. Vital statistics offices underestimated maternal mortality by 36% or more everywhere but Denmark. Age specific maternal mortality ratios were higher for the youngest and oldest mothers (pooled relative risk 2.17 (95% confidence interval 1.38 to 3.34) for women aged <20 years, 2.10 (1.54 to 2.86) for those aged 35-39, and 3.95 (3.01 to 5.19) for those aged ≥40, compared with women aged 20-29 years). Except in Norway, maternal mortality ratios were ≥50% higher in women born abroad or of minoritised ethnicity, defined variously in different countries. Cardiovascular diseases and suicides were leading causes of maternal deaths in each country. Some other conditions were also major contributors to maternal mortality in only one or two countries: venous thromboembolism in the UK and the Netherlands, hypertensive disorders in the Netherlands, amniotic fluid embolism in France, haemorrhage in Italy, and stroke in Slovakia. Only two countries, France and the UK, had enhanced methods for studying late maternal deaths, those occurring between 43 and 365 days after the end of pregnancy.
Conclusions
Variations in maternal mortality ratios exist between high income European countries with enhanced surveillance systems. In-depth analyses of differences in the quality of care and health system performance at national levels are needed to reduce maternal mortality further by learning from best practices and each other. Cardiovascular diseases and mental health in women during and after pregnancy must be prioritised in all countries.

© 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: 16 Nov 2022; 379:e070621
Diguisto C, Saucedo M, Kallianidis A, Bloemenkamp K, ... Nyflot LT, Deneux-Tharaux C
BMJ: 16 Nov 2022; 379:e070621 | PMID: 36384872
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Abstract

Comparative effectiveness of sotrovimab and molnupiravir for prevention of severe covid-19 outcomes in patients in the community: observational cohort study with the OpenSAFELY platform.

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

© 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 Nov 2022; 379:e071932
Zheng B, Green ACA, Tazare J, Curtis HJ, ... Goldacre B, Tomlinson LA
BMJ: 16 Nov 2022; 379:e071932 | PMID: 36384890
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Abstract

Angiotensin receptor blockers for the treatment of covid-19: pragmatic, adaptive, multicentre, phase 3, randomised controlled trial.

Jardine MJ, Kotwal SS, Bassi A, Hockham C, ... Jha V, CLARITY trial investigators
Objective
To determine whether disrupting the renin angiotensin system with angiotensin receptor blockers will improve clinical outcomes in people with covid-19.
Design
CLARITY was a pragmatic, adaptive, multicentre, phase 3, randomised controlled trial.
Setting
17 hospital sites in India and Australia.
Participants
Participants were at least 18 years old, previously untreated with angiotensin receptor blockers, with a laboratory confirmed diagnosis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection who had been admitted to hospital for management of covid-19.
Intervention
Oral angiotensin receptor blockers (telmisartan in India) or placebo (1:1) for 28 days.
Main outcome measures
The primary endpoint was covid-19 disease severity using a modified World Health Organization Clinical Progression Scale (WHO scale) at day 14. Secondary outcomes were WHO scale scores at day 28, mortality, intensive care unit admission, and respiratory failure. Analyses were evaluated on an ordinal scale in the intention-to-treat population.
Results
Between 3 May 2020 and 13 November 2021, 2930 people were screened for eligibility, with 393 randomly assigned to angiotensin receptor blockers (of which 388 (98.7%) to telmisartan 40 mg/day) and 394 to the control group. 787 participants were randomised: 778 (98.9%) from India and nine (1.1%) from Australia. The median WHO scale score at day 14 was 1 (interquartile range 1-1) in 384 participants assigned angiotensin receptor blockers and 1 (1-1) in 382 participants assigned placebo (adjusted odds ratio 1.51 (95% credible interval 1.02 to 2.23), probability of an odds ratio of >1 (Pr(OR>1)=0.98). WHO scale scores at day 28 showed little evidence of difference between groups (1.02 (0.55 to 1.87), Pr(OR>1)=0.53). The trial was stopped when a prespecified futility rule was met.
Conclusions
In patients admitted to hospital for covid-19, mostly with mild disease, not requiring oxygen, no evidence of benefit, based on disease severity score, was found for treatment with angiotensin receptor blockers, using predominantly 40 mg/day of telmisartan.
Trial registration
ClinicalTrials.gov NCT04394117.

© 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 Nov 2022; 379:e072175
Jardine MJ, Kotwal SS, Bassi A, Hockham C, ... Jha V, CLARITY trial investigators
BMJ: 16 Nov 2022; 379:e072175 | PMID: 36384746
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Abstract

Pathophysiology, diagnosis, and management of endometriosis.

Horne AW, Missmer SA
Endometriosis affects approximately 190 million women and people assigned female at birth worldwide. It is a chronic, inflammatory, gynecologic disease marked by the presence of endometrial-like tissue outside the uterus, which in many patients is associated with debilitating painful symptoms. Patients with endometriosis are also at greater risk of infertility, emergence of fatigue, multisite pain, and other comorbidities. Thus, endometriosis is best understood as a condition with variable presentation and effects at multiple life stages. A long diagnostic delay after symptom onset is common, and persistence and recurrence of symptoms despite treatment is common. This review discusses the potential genetic, hormonal, and immunologic factors that lead to endometriosis, with a focus on current diagnostic and management strategies for gynecologists, general practitioners, and clinicians specializing in conditions for which patients with endometriosis are at higher risk. It examines evidence supporting the different surgical, pharmacologic, and non-pharmacologic approaches to treating patients with endometriosis and presents an easy to adopt step-by-step management strategy. As endometriosis is a multisystem disease, patients with the condition should ideally be offered a personalized, multimodal, interdisciplinary treatment approach. A priority for future discovery is determining clinically informative sub-classifications of endometriosis that predict prognosis and enhance treatment prioritization.

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BMJ: 14 Nov 2022; 379:e070750
Horne AW, Missmer SA
BMJ: 14 Nov 2022; 379:e070750 | PMID: 36375827
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Abstract

More people survived a cardiac arrest when first aiders received an app alert.

Saul H, Gursul D, Cassidy S, Smith C
The studySmith CM, Lall R, Fothergill RT, Spaight R, Perkins GD. The effect of the GoodSAM volunteer first-responder app on survival to hospital discharge following out-of-hospital cardiac arrest. Eur Heart J Acute Cardiovasc Care 2022;11:20-31.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/more-people-survived-cardiac-arrest-first-aiders-goodsam-alert/.

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BMJ: 11 Nov 2022; 379:o2578
Saul H, Gursul D, Cassidy S, Smith C
BMJ: 11 Nov 2022; 379:o2578 | PMID: 36368720
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Impact:
Abstract

Integrating genome-wide polygenic risk scores and non-genetic risk to predict colorectal cancer diagnosis using UK Biobank data: population based cohort study.

Briggs SEW, Law P, East JE, Wordsworth S, ... Hippisley-Cox J, Tomlinson I
Objective
To evaluate the benefit of combining polygenic risk scores with the QCancer-10 (colorectal cancer) prediction model for non-genetic risk to identify people at highest risk of colorectal cancer.
Design
Population based cohort study.
Setting
Data from the UK Biobank study, collected between March 2006 and July 2010.
Participants
434 587 individuals with complete data for genetics and QCancer-10 predictions were included in the QCancer-10 plus polygenic risk score modelling and validation cohorts.
Main outcome measures
Prediction of colorectal cancer diagnosis by genetic, non-genetic, and combined risk models. Using data from UK Biobank, six different polygenic risk scores for colorectal cancer were developed using LDpred2 polygenic risk score software, clumping, and thresholding approaches, and a model based on genome-wide significant polymorphisms. The top performing genome-wide polygenic risk score and the score containing genome-wide significant polymorphisms were combined with QCancer-10 and performance was compared with QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women.
Results
Polygenic risk scores derived using the LDpred2 program performed best, with an odds ratio per standard deviation of 1.584 (95% confidence interval 1.536 to 1.633), and top age and sex adjusted C statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10 plus polygenic risk score models out-performed QCancer-10 alone. In men, the integrated LDpred2 model produced a C statistic of 0.730 (0.720 to 0.741) and explained variation of 28.2% (26.3 to 30.1), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9 to 23.1) for QCancer-10 alone. In women, the C statistic for the integrated LDpred2 model was 0.687 (0.673 to 0.702) and explained variation was 21.0% (18.7 to 23.7), compared with 0.645 (0.631 to 0.659) and 12.4% (10.3 to 14.6) for QCancer-10 alone. In the top 20% of individuals at highest absolute risk, the sensitivity and specificity of the integrated LDpred2 models for predicting colorectal cancer diagnosis was 47.8% and 80.3% respectively in men, and 42.7% and 80.1% respectively in women, with increases in absolute risk in the top 5% of risk in men of 3.47-fold and in women of 2.77-fold compared with the median. Illustrative decision curve analysis indicated a small incremental improvement in net benefit with QCancer-10 plus polygenic risk score models compared with QCancer-10 alone.
Conclusions
Integrating polygenic risk scores with QCancer-10 modestly improves risk prediction over use of QCancer-10 alone. Given that QCancer-10 data can be obtained relatively easily from health records, use of polygenic risk score in risk stratified population screening for colorectal cancer currently has no clear justification. The added benefit, cost effectiveness, and acceptability of polygenic risk scores should be carefully evaluated in a real life screening setting before implementation in the general population.

© 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 Nov 2022; 379:e071707
Briggs SEW, Law P, East JE, Wordsworth S, ... Hippisley-Cox J, Tomlinson I
BMJ: 09 Nov 2022; 379:e071707 | PMID: 36351667
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Impact:
Abstract

Development and external validation of a risk prediction model for falls in patients with an indication for antihypertensive treatment: retrospective cohort study.

Archer L, Koshiaris C, Lay-Flurrie S, Snell KIE, ... Sheppard JP, STRAtifying Treatments In the multi-morbid Frail elderlY (STRATIFY) investigators
Objective
To develop and externally validate the STRAtifying Treatments In the multi-morbid Frail elderlY (STRATIFY)-Falls clinical prediction model to identify the risk of hospital admission or death from a fall in patients with an indication for antihypertensive treatment.
Design
Retrospective cohort study.
Setting
Primary care data from electronic health records contained within the UK Clinical Practice Research Datalink (CPRD).
Participants
Patients aged 40 years or older with at least one blood pressure measurement between 130 mm Hg and 179 mm Hg.
Main outcome measure
First serious fall, defined as hospital admission or death with a primary diagnosis of a fall within 10 years of the index date (12 months after cohort entry). Model development was conducted using a Fine-Gray approach in data from CPRD GOLD, accounting for the competing risk of death from other causes, with subsequent recalibration at one, five, and 10 years using pseudo values. External validation was conducted using data from CPRD Aurum, with performance assessed through calibration curves and the observed to expected ratio, C statistic, and D statistic, pooled across general practices, and clinical utility using decision curve analysis at thresholds around 10%.
Results
Analysis included 1 772 600 patients (experiencing 62 691 serious falls) from CPRD GOLD used in model development, and 3 805 366 (experiencing 206 956 serious falls) from CPRD Aurum in the external validation. The final model consisted of 24 predictors, including age, sex, ethnicity, alcohol consumption, living in an area of high social deprivation, a history of falls, multiple sclerosis, and prescriptions of antihypertensives, antidepressants, hypnotics, and anxiolytics. Upon external validation, the recalibrated model showed good discrimination, with pooled C statistics of 0.833 (95% confidence interval 0.831 to 0.835) and 0.843 (0.841 to 0.844) at five and 10 years, respectively. Original model calibration was poor on visual inspection and although this was improved with recalibration, under-prediction of risk remained (observed to expected ratio at 10 years 1.839, 95% confidence interval 1.811 to 1.865). Nevertheless, decision curve analysis suggests potential clinical utility, with net benefit larger than other strategies.
Conclusions
This prediction model uses commonly recorded clinical characteristics and distinguishes well between patients at high and low risk of falls in the next 1-10 years. Although miscalibration was evident on external validation, the model still had potential clinical utility around risk thresholds of 10% and so could be useful in routine clinical practice to help identify those at high risk of falls who might benefit from closer monitoring or early intervention to prevent future falls. Further studies are needed to explore the appropriate thresholds that maximise the model\'s clinical utility and cost effectiveness.

© 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: 08 Nov 2022; 379:e070918
Archer L, Koshiaris C, Lay-Flurrie S, Snell KIE, ... Sheppard JP, STRAtifying Treatments In the multi-morbid Frail elderlY (STRATIFY) investigators
BMJ: 08 Nov 2022; 379:e070918 | PMID: 36347531
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Impact:
Abstract

Effect of oral antimicrobial prophylaxis on surgical site infection after elective colorectal surgery: multicentre, randomised, double blind, placebo controlled trial.

Futier E, Jaber S, Garot M, Vignaud M, ... Paugam-Burtz C, COMBINE study group
Objective
To investigate whether oral antimicrobial prophylaxis as an adjunct to intravenous antibiotic prophylaxis reduces surgical site infections after elective colorectal surgery.
Design
Multicentre, randomised, double blind, placebo controlled trial.
Setting
11 university and non-university hospitals in France between 25 May 2016 and 8 August 2019.
Participants
926 adults scheduled for elective colorectal surgery.
Intervention
Patients were randomised to receive either a single 1 g dose of ornidazole (n=463) or placebo (n=463) orally 12 hours before surgery, in addition to intravenous antimicrobial prophylaxis before surgical incision.
Main outcome measures
The primary outcome was the proportion of patients with surgical site infection within 30 days after surgery. Secondary outcomes included individual types of surgical site infections and major postoperative complications (Clavien-Dindo classification grade 3 or higher) within 30 days after surgery.
Results
Of the 960 patients who were enrolled, 926 (96%) were included in the analysis. The mean age of participants was 63 years and 554 (60%) were men. Surgical site infection within 30 days after surgery occurred in 60 of 463 patients (13%) in the oral prophylaxis group and 100 of 463 (22%) in the placebo group (absolute difference -8.6%, 95% confidence interval -13.5% to -3.8%; relative risk 0.60, 95% confidence interval 0.45 to 0.80). The proportion of patients with deep infections was 4.8% in the oral prophylaxis group and 8.0% in the placebo group (absolute difference -3.2%, 95% confidence interval -6.4% to -0.1%). The proportion of patients with organ space infections was 5.0% in the oral prophylaxis group and 8.4% in the placebo group (absolute difference -3.4%, -6.7% to -0.2%). Major postoperative complications occurred in 9.1% patients in the oral prophylaxis group and 13.6% in the placebo group (absolute difference -4.5%, -8.6% to -0.5%).
Conclusion
Among adults undergoing elective colorectal surgery, the addition of a single 1 g dose of ornidazole compared with placebo before surgery significantly reduced surgical site infections.
Trial registration
ClinicalTrials.gov NCT02618720.

© 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 Nov 2022; 379:e071476
Futier E, Jaber S, Garot M, Vignaud M, ... Paugam-Burtz C, COMBINE study group
BMJ: 03 Nov 2022; 379:e071476 | PMID: 36328372
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Impact:
Abstract

Transmission dynamics of monkeypox in the United Kingdom: contact tracing study.

Ward T, Christie R, Paton RS, Cumming F, Overton CE
Objective
To analyse the transmission dynamics of the monkeypox outbreak in the UK, declared a Public Health Emergency of International Concern in July 2022.
Design
Contact tracing study, linking data on case-contact pairs and on probable exposure dates.
Setting
Case questionnaires from the UK Health Security Agency (UKHSA), United Kingdom.
Participants
2746 people with polymerase chain reaction confirmed monkeypox virus in the UK between 6 May and 1 August 2022.
Main outcome measures
The incubation period and serial interval of a monkeypox infection using two bayesian time delay models-one corrected for interval censoring (ICC-interval censoring corrected) and one corrected for interval censoring, right truncation, and epidemic phase bias (ICRTC-interval censoring right truncation corrected). Growth rates of cases by reporting date, when monkeypox virus was confirmed and reported to UKHSA, were estimated using generalised additive models.
Results
The mean age of participants was 37.8 years and 95% reported being gay, bisexual, and other men who have sex with men (1160 out of 1213 reporting). The mean incubation period was estimated to be 7.6 days (95% credible interval 6.5 to 9.9) using the ICC model and 7.8 days (6.6 to 9.2) using the ICRTC model. The estimated mean serial interval was 8.0 days (95% credible interval 6.5 to 9.8) using the ICC model and 9.5 days (7.4 to 12.3) using the ICRTC model. Although the mean serial interval was longer than the incubation period for both models, short serial intervals were more common than short incubation periods, with the 25th centile and the median of the serial interval shorter than the incubation period. For the ICC and ICRTC models, the corresponding estimates ranged from 1.8 days (95% credible interval 1.5 to 1.8) to 1.6 days (1.4 to 1.6) shorter at the 25th centile and 1.6 days (1.5 to 1.7) to 0.8 days (0.3 to 1.2) shorter at the median. 10 out of 13 linked patients had documented pre-symptomatic transmission. Doubling times of cases declined from 9.07 days (95% confidence interval 12.63 to 7.08) on the 6 May, when the first case of monkeypox was reported in the UK, to a halving time of 29 days (95% confidence interval 38.02 to 23.44) on 1 August.
Conclusions
Analysis of the instantaneous growth rate of monkeypox incidence indicates that the epidemic peaked in the UK as of 9 July and then started to decline. Short serial intervals were more common than short incubation periods suggesting considerable pre-symptomatic transmission, which was validated through linked patient level records. For patients who could be linked through personally identifiable data, four days was the maximum time that transmission was detected before symptoms manifested. An isolation period of 16 to 23 days would be required to detect 95% of people with a potential infection. The 95th centile of the serial interval was between 23 and 41 days, suggesting long infectious periods.

© 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 Nov 2022; 379:e073153
Ward T, Christie R, Paton RS, Cumming F, Overton CE
BMJ: 02 Nov 2022; 379:e073153 | PMID: 36323407
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Impact:
Abstract

Novel antihyperglycaemic drugs and prevention of chronic obstructive pulmonary disease exacerbations among patients with type 2 diabetes: population based cohort study.

Pradhan R, Lu S, Yin H, Yu OHY, ... Suissa S, Azoulay L
Objective
To determine whether the use of glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, separately, is associated with a decreased risk of exacerbations of chronic obstructive pulmonary disease among patients with chronic obstructive pulmonary disease and type 2 diabetes.
Design
Population based cohort study using an active comparator, new user design.
Setting
The United Kingdom Clinical Practice Research Datalink linked with the Hospital Episode Statistics Admitted Patient Care and Office for National Statistics databases.
Participants
Three active comparator, new user cohorts of patients starting the study drugs (GLP-1 receptor agonists, DPP-4 inhibitors, or SGLT-2 inhibitors) or sulfonylureas with a history of chronic obstructive pulmonary disease. The first cohort included 1252 patients starting GLP-1 receptor agonists and 14 259 starting sulfonylureas, the second cohort included 8731 patients starting DPP-4 inhibitors and 18 204 starting sulfonylureas, and the third cohort included 2956 patients starting SGLT-2 inhibitors and 10 841 starting sulfonylureas.
Main outcome measures
Cox proportional hazards models with propensity score fine stratification weighting were fitted to estimate hazard ratios and 95% confidence intervals of severe exacerbation of chronic obstructive pulmonary disease (defined as hospital admission for chronic obstructive pulmonary disease), separately for GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors. Whether these drugs were associated with a decreased risk of moderate exacerbation (defined as a co-prescription of an oral corticosteroid and an antibiotic along with an outpatient diagnosis of acute chronic obstructive pulmonary disease exacerbation on the same day) was also assessed.
Results
Compared with sulfonylureas, GLP-1 receptor agonists were associated with a 30% decreased risk of severe exacerbation (3.5 v 5.0 events per 100 person years; hazard ratio 0.70, 95% confidence interval 0.49 to 0.99) and moderate exacerbation (0.63, 0.43 to 0.94). DPP-4 inhibitors were associated with a modestly decreased incidence of severe exacerbation (4.6 v. 5.1 events per 100 person years; hazard ratio 0.91, 0.82 to 1.02) and moderate exacerbation (0.93, 0.82 to 1.07), with confidence intervals including the null value. Finally, SGLT-2 inhibitors were associated with a 38% decreased risk of severe exacerbation (2.4 v 3.9 events per 100 person years; hazard ratio 0.62, 0.48 to 0.81) but not moderate exacerbation (1.02, 0.83 to 1.27).
Conclusions
In this population based study, GLP-1 receptor agonists and SGLT-2 inhibitors were associated with a reduced risk of severe exacerbations compared with sulfonylureas in patients with chronic obstructive pulmonary disease and type 2 diabetes. DPP-4 inhibitors were not clearly associated with a decreased risk of chronic obstructive pulmonary disease exacerbations.

© 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 Nov 2022; 379:e071380
Pradhan R, Lu S, Yin H, Yu OHY, ... Suissa S, Azoulay L
BMJ: 01 Nov 2022; 379:e071380 | PMID: 36318979
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Impact:
Abstract

Clinical and cost effectiveness of single stage compared with two stage revision for hip prosthetic joint infection (INFORM): pragmatic, parallel group, open label, randomised controlled trial.

Blom AW, Lenguerrand E, Strange S, Noble SM, ... Whitehouse MR, INFORM trial group
Objectives
To determine whether patient reported outcomes improve after single stage versus two stage revision surgery for prosthetic joint infection of the hip, and to determine the cost effectiveness of these procedures.
Design
Pragmatic, parallel group, open label, randomised controlled trial.
Setting
High volume tertiary referral centres or orthopaedic units in the UK (n=12) and in Sweden (n=3), recruiting from 1 March 2015 to 19 December 2018.
Participants
140 adults (aged ≥18 years) with a prosthetic joint infection of the hip who required revision (65 randomly assigned to single stage and 75 to two stage revision).
Interventions
A computer generated 1:1 randomisation list stratified by hospital was used to allocate participants with prosthetic joint infection of the hip to a single stage or a two stage revision procedure.
Main outcome measures
The primary intention-to-treat outcome was pain, stiffness, and functional limitations 18 months after randomisation, measured by the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) score. Secondary outcomes included surgical complications and joint infection. The economic evaluation (only assessed in UK participants) compared quality adjusted life years and costs between the randomised groups.
Results
The mean age of participants was 71 years (standard deviation 9) and 51 (36%) were women. WOMAC scores did not differ between groups at 18 months (mean difference 0.13 (95% confidence interval -8.20 to 8.46), P=0.98); however, the single stage procedure was better at three months (11.53 (3.89 to 19.17), P=0.003), but not from six months onwards. Intraoperative events occurred in five (8%) participants in the single stage group and 20 (27%) in the two stage group (P=0.01). At 18 months, nine (14%) participants in the single stage group and eight (11%) in the two stage group had at least one marker of possible ongoing infection (P=0.62). From the perspective of healthcare providers and personal social services, single stage revision was cost effective with an incremental net monetary benefit of £11 167 (95% confidence interval £638 to £21 696) at a £20 000 per quality adjusted life years threshold (£1.0; $1.1; €1.4).
Conclusions
At 18 months, single stage revision compared with two stage revision for prosthetic joint infection of the hip showed no superiority by patient reported outcome. Single stage revision had a better outcome at three months, fewer intraoperative complications, and was cost effective. Patients prefer early restoration of function, therefore, when deciding treatment, surgeons should consider patient preferences and the cost effectiveness of single stage surgery.
Trial registration
ISRCTN registry ISRCTN10956306.

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BMJ: 31 Oct 2022; 379:e071281
Blom AW, Lenguerrand E, Strange S, Noble SM, ... Whitehouse MR, INFORM trial group
BMJ: 31 Oct 2022; 379:e071281 | PMID: 36316046
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Impact:
Abstract

Impact of a package of health, nutrition, psychosocial support, and WaSH interventions delivered during preconception, pregnancy, and early childhood periods on birth outcomes and on linear growth at 24 months of age: factorial, individually randomised controlled trial.

Taneja S, Chowdhury R, Dhabhai N, Upadhyay RP, ... Bhandari N, WINGS Study Group
Objective
To determine the effect of integrated and concurrent delivery of health, nutrition, water, sanitation and hygiene (WaSH), and psychosocial care interventions during the preconception period alone, during pregnancy and early childhood, and throughout preconception, pregnancy, and early childhood on birth outcomes and linear growth at 24 months of age compared with routine care.
Design
Individually randomised factorial trial.
Setting
Low and middle income neighbourhoods of Delhi, India.
Participants
13 500 women were randomised to receive preconception interventions (n=6722) or routine care (n=6778). 2652 and 2269 pregnant women were randomised again to receive pregnancy and early childhood interventions or routine care. The analysis of birth outcomes included 1290 live births for the preconception, pregnancy, and early childhood interventions (group A), 1276 for the preconception intervention (group B), 1093 for the pregnancy and early childhood interventions (group C), and 1093 for the control (group D). Children aged 24 months by 30 June 2021 were included in the 24 month outcome analysis (453 in group A, 439 in B, 293 in C, and 271 in D).
Interventions
Health, nutrition, psychosocial care and support, and WaSH interventions were delivered during preconception, pregnancy, and early childhood periods.
Main outcome measures
The primary outcomes were low birth weight, small for gestational age, preterm, and mean birth weight. At 24 months, the outcomes were mean length-for-age z scores and proportion stunted. Three prespecified comparisons were made: preconception intervention groups (A+B) versus no preconception intervention groups (C+D); pregnancy and early childhood intervention groups (A+C) versus routine care during pregnancy and early childhood (B+D) and preconception, pregnancy, and early childhood interventions groups (A) versus control group (D).
Results
The proportion with low birth weight was lower in the preconception intervention groups (506/2235) than in the no preconception intervention groups (502/1889; incidence rate ratio 0.85, 98.3% confidence interval 0.75 to 0.97; absolute risk reduction -3.80%, 98.3% confidence interval -6.99% to -0.60%). The proportion with low birth weight was lower in the pregnancy intervention groups (502/2096) than in the no pregnancy intervention groups (506/2028) but the upper limit of the confidence interval crossed null effect (0.87, 0.76 to 1.01; -1.71%, -4.96% to 1.54%). There was a larger effect on proportion with low birth weight in the group that received interventions in the preconception and pregnancy periods (267/1141) compared with the control group (267/934; 0.76, 0.62 to 0.91; -5.59%, -10.32% to -0.85%). The proportion stunted at 24 months of age was substantially lower in the pregnancy and early childhood intervention groups (79/746) compared with the groups that did not receive these interventions (136/710; 0.51, 0.38 to 0.70; -8.32%, -12.31% to -4.32%), and in the group that received preconception, pregnancy, and early childhood interventions (47/453) compared with the control group (51/271; 0.49, 0.32 to 0.75; -7.98%, -14.24% to -1.71%). No effect on stunting at 24 months was observed in the preconception intervention groups (132/892) compared with the no preconception intervention groups (83/564).
Conclusions
An intervention package delivered during preconception, pregnancy, and early childhood substantially reduced low birth weight and stunting at 24 months. Pregnancy and early childhood interventions alone had lower but important effects on birth outcomes and 24 month outcomes. Preconception interventions alone had an important effect on birth outcomes but not on 24 month outcomes.
Trial registration
Clinical Trial Registry-India CTRI/2017/06/008908.

© 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: 26 Oct 2022; 379:e072046
Taneja S, Chowdhury R, Dhabhai N, Upadhyay RP, ... Bhandari N, WINGS Study Group
BMJ: 26 Oct 2022; 379:e072046 | PMID: 36288808
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Impact:
Abstract

Comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with different covid-19 vaccines: international network cohort study from five European countries and the US.

Li X, Burn E, Duarte-Salles T, Yin C, ... Strauss V, Prieto-Alhambra D
Objective
To quantify the comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with use of adenovirus based covid-19 vaccines versus mRNA based covid-19 vaccines.
Design
International network cohort study.
Setting
Routinely collected health data from contributing datasets in France, Germany, the Netherlands, Spain, the UK, and the US.
Participants
Adults (age ≥18 years) registered at any contributing database and who received at least one dose of a covid-19 vaccine (ChAdOx1-S (Oxford-AstraZeneca), BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), or Ad26.COV2.S (Janssen/Johnson & Johnson)), from December 2020 to mid-2021.
Main outcome measures
Thrombosis with thrombocytopenia syndrome or venous or arterial thromboembolic events within the 28 days after covid-19 vaccination. Incidence rate ratios were estimated after propensity scores matching and were calibrated using negative control outcomes. Estimates specific to the database were pooled by use of random effects meta-analyses.
Results
Overall, 1 332 719 of 3 829 822 first dose ChAdOx1-S recipients were matched to 2 124 339 of 2 149 679 BNT162b2 recipients from Germany and the UK. Additionally, 762 517 of 772 678 people receiving Ad26.COV2.S were matched to 2 851 976 of 7 606 693 receiving BNT162b2 in Germany, Spain, and the US. All 628 164 Ad26.COV2.S recipients from the US were matched to 2 230 157 of 3 923 371 mRNA-1273 recipients. A total of 862 thrombocytopenia events were observed in the matched first dose ChAdOx1-S recipients from Germany and the UK, and 520 events after a first dose of BNT162b2. Comparing ChAdOx1-S with a first dose of BNT162b2 revealed an increased risk of thrombocytopenia (pooled calibrated incidence rate ratio 1.33 (95% confidence interval 1.18 to 1.50) and calibrated incidence rate difference of 1.18 (0.57 to 1.8) per 1000 person years). Additionally, a pooled calibrated incidence rate ratio of 2.26 (0.93 to 5.52) for venous thrombosis with thrombocytopenia syndrome was seen with Ad26.COV2.S compared with BNT162b2.
Conclusions
In this multinational study, a pooled 30% increased risk of thrombocytopenia after a first dose of the ChAdOx1-S vaccine was observed, as was a trend towards an increased risk of venous thrombosis with thrombocytopenia syndrome after Ad26.COV2.S compared with BNT162b2. Although rare, the observed risks after adenovirus based vaccines should be considered when planning further immunisation campaigns and future vaccine development.

© 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: 26 Oct 2022; 379:e071594
Li X, Burn E, Duarte-Salles T, Yin C, ... Strauss V, Prieto-Alhambra D
BMJ: 26 Oct 2022; 379:e071594 | PMID: 36288813
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Impact:
Abstract

Use of linked registry claims data for long term surveillance of devices after endovascular abdominal aortic aneurysm repair: observational surveillance study.

Goodney P, Mao J, Columbo J, Suckow B, ... Sedrakyan A, Society for Vascular Surgery’s Patient Safety Organization
Objective
To evaluate long term outcomes (reintervention and late rupture of abdominal aortic aneurysm) of aortic endografts in real world practice using linked registry claims data.
Design
Observational surveillance study.
Setting
282 centers in the Vascular Quality Initiative Registry linked to United States Medicare claims (2003-18).
Participants
20 489 patients treated with four device types used for endovascular abdominal aortic aneurysm repair (EVAR): 40.6% (n=8310) received the Excluder (Gore), 32.2% (n=6606) the Endurant (Medtronic), 16.0% (n=3281) the Zenith (Cook Medical), and 11.2% (n=2292) the AFX (Endologix). Given modifications to AFX in late 2014, patients who received the AFX device were categorized into two groups: the early AFX group (n=942) and late AFX group (n=1350) and compared with patients who received the other devices, using propensity matched Cox models.
Main outcome measures
Reintervention and rupture of abdominal aortic aneurysm post-EVAR; all patients (100%) had complete follow-up via the registry or claims based outcome assessment, or both.
Results
Median age was 76 years (interquartile range (IQR) 70-82 years), 80.0% (16 386/20 489) of patients were men, and median follow-up was 2.3 years (IQR 0.9-4.1 years). Crude five year reintervention rates were significantly higher for patients who received the early AFX device compared with the other devices: 14.9% (95% confidence interval 13.7% to 16.2%) for Excluder, 19.5% (18.1% to 21.1%) for Endurant, 16.7% (15.0% to 18.6%) for Zenith, and early 27.0% (23.7% to 30.6%) for the early AFX. The risk of reintervention for patients who received the early AFX device was higher compared with the other devices in propensity matched Cox models (hazard ratio 1.61, 95% confidence interval 1.29 to 2.02) and analyses using a surgeon level instrumental variable of >33% AFX grafts used in their practice (1.75, 1.19 to 2.59). The linked registry claims surveillance data identified the increased risk of reintervention with the early AFX device as early as mid-2013, well before the first regulatory warnings were issued in the US in 2017.
Conclusions
The linked registry claims surveillance data identified a device specific risk in long term reintervention after EVAR of abdominal aortic aneurysm. Device manufacturers and regulators can leverage linked data sources to actively monitor long term outcomes in real world practice after cardiovascular interventions.

© 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: 25 Oct 2022; 379:e071452
Goodney P, Mao J, Columbo J, Suckow B, ... Sedrakyan A, Society for Vascular Surgery’s Patient Safety Organization
BMJ: 25 Oct 2022; 379:e071452 | PMID: 36283705
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Impact:
Abstract

Obesity alone should not rule out knee replacement surgery.

Saul H, Gursul D, Evans J
The studyEvans JT, Mouchti S, Blom AW, et al. Obesity and revision surgery, mortality, and patient-reported outcomes after primary knee replacement surgery in the National Joint Registry: a UK cohort study. PLoS Med 2021;18:7.

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BMJ: 25 Oct 2022; 379:o2473
Saul H, Gursul D, Evans J
BMJ: 25 Oct 2022; 379:o2473 | PMID: 36283709
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Impact:
Abstract

Management of psychiatric and cognitive complications in Parkinson\'s disease.

Weintraub D, Aarsland D, Biundo R, Dobkin R, Goldman J, Lewis S
Neuropsychiatric symptoms (NPSs) such as affective disorders, psychosis, behavioral changes, and cognitive impairment are common in Parkinson\'s disease (PD). However, NPSs remain under-recognized and under-treated, often leading to adverse outcomes. Their epidemiology, presentation, risk factors, neural substrate, and management strategies are incompletely understood. While psychological and psychosocial factors may contribute, hallmark PD neuropathophysiological changes, plus the associations between exposure to dopaminergic medications and occurrence of some symptoms, suggest a neurobiological basis for many NPSs. A range of psychotropic medications, psychotherapeutic techniques, stimulation therapies, and other non-pharmacological treatments have been studied, are used clinically, and are beneficial for managing NPSs in PD. Appropriate management of NPSs is critical for comprehensive PD care, from recognizing their presentations and timing throughout the disease course, to the incorporation of different therapeutic strategies (ie, pharmacological and non-pharmacological) that utilize a multidisciplinary approach.

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BMJ: 24 Oct 2022; 379:e068718
Weintraub D, Aarsland D, Biundo R, Dobkin R, Goldman J, Lewis S
BMJ: 24 Oct 2022; 379:e068718 | PMID: 36280256
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Impact:
Abstract

Maternal hypertensive disorder of pregnancy and mortality in offspring from birth to young adulthood: national population based cohort study.

Huang C, Wei K, Lee PMY, Qin G, Yu Y, Li J
Objective
To examine the association of maternal hypertensive disorder of pregnancy (HDP) with overall and cause specific mortality in offspring from birth to young adulthood.
Design
Nationwide population based cohort study.
Setting
Danish national health registers.
Participants
All 2 437 718 individuals live born in Denmark, 1978-2018, with follow-up from date of birth until date of death, emigration, or 31 December 2018, whichever came first.
Main outcome measures
The primary outcome was all cause mortality. Secondary outcomes were 13 specific causes of death in offspring from birth to young adulthood (age 41 years). Cox regression was used to assess the association, taking into consideration several potential confounders. The role of timing of onset and severity of pre-eclampsia, maternal history of diabetes, and maternal education were also studied.
Results
102 095 mothers had HDP: 67 683 with pre-eclampsia, 679 with eclampsia, and 33 733 with hypertension. During follow-up to 41 years (median 19.4 (interquartile range 9.7-28.7) years), deaths occurred in 781 (58.94 per 100 000 person years) offspring born to mothers with pre-eclampsia, 17 (133.73 per 100 000 person years) born to mothers with eclampsia, 223 (44.38 per 100 000 person years) born to mothers with hypertension, and 19 119 (41.99 per 100 000 person years) born to mothers with no HDP. The difference in cumulative incidence in overall mortality between cohorts exposed and unexposed to maternal HDP was 0.37% (95% confidence interval 0.11% to 0.64%), and the population attributable fraction for maternal HDP was estimated as 1.09% (95% confidence interval 0.77% to 1.41%). Maternal HDP was associated with a 26% (hazard ratio 1.26, 95% confidence interval 1.18 to 1.34) higher risk of all cause mortality in offspring. The corresponding estimates for maternal pre-eclampsia, eclampsia, and hypertension were 1.29 (1.20 to 1.38), 2.88 (1.79 to 4.63), and 1.12 (0.98 to 1.28). Increased risks were also observed for several cause specific mortalities, such as deaths from conditions originating in the perinatal period (2.04, 1.81 to 2.30), cardiovascular diseases (1.52, 1.08 to 2.13), digestive system diseases (2.09, 1.27 to 3.43), and endocrine, nutritional, and metabolic diseases (1.56, 1.08 to 2.27). The increased risks were more pronounced among offspring of mothers with early onset and severe pre-eclampsia (6.06, 5.35 to 6.86) or with both HDP and diabetes history (1.57, 1.16 to 2.14) or HDP and low education level (1.49, 1.34 to 1.66).
Conclusion
Maternal HDP, particularly eclampsia and severe pre-eclampsia, is associated with increased risks of overall mortality and various cause specific mortalities in offspring from birth to young adulthood.

© 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 Oct 2022; 379:e072157
Huang C, Wei K, Lee PMY, Qin G, Yu Y, Li J
BMJ: 19 Oct 2022; 379:e072157 | PMID: 36261141
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Impact:
Abstract

Effect of financial voucher incentives provided with UK stop smoking services on the cessation of smoking in pregnant women (CPIT III): pragmatic, multicentre, single blinded, phase 3, randomised controlled trial.

Tappin D, Sinclair L, Kee F, McFadden M, ... Ussher M, Bauld L
Objective
To examine effectiveness, cost effectiveness, generalisability, and acceptability of financial incentives for smoking cessation during pregnancy in addition to variously organised UK stop smoking services.
Design
Pragmatic, multicentre, single blinded, phase 3, randomised controlled trial (Cessation in Pregnancy Incentives Trial phase 3 (CPIT III)).
Setting
Seven UK stop smoking services provided in primary and secondary care facilities in Scotland, Northern Ireland, and England.
Participants
944 pregnant women (age ≥16 years) who self-reported as being smokers (at least one cigarette in the past week) when asked at first maternity visit, less than 24 weeks\' gestation, and notified to the trial team by routine stop smoking services.
Interventions
Participants in the control group were offered the standard stop smoking services, which includes the offer of counselling by specially trained workers using withdrawal orientated therapy and the offer of free nicotine replacement therapy. The intervention was the offer of usual support from the stop smoking services and the addition of up to £400 ($440; €455) of LoveToShop financial voucher incentives for engaging with current stop smoking services or to stop smoking, or both, during pregnancy.
Main outcome measures
Self-reported smoking cessation in late pregnancy (between 34 and 38 weeks\' gestation) corroborated by saliva cotinine (and anabasine if using nicotine replacement products). Results were adjusted for age, smoking years, index of multiple deprivation, Fagerström score, before or after covid, and recruitment site. Secondary outcomes included point and continuous abstinence six months after expected date of delivery, engagement with stop smoking services, biochemically validated abstinence from smoking at four weeks after stop smoking date, birth weight of baby, cost effectiveness, generalisability documenting formats of stop smoking services, and acceptability to pregnant women and their carers.
Results
From 9 January 2018 to 4 April 2020, of 4032 women screened by stop smoking services, 944 people were randomly assigned to the intervention group (n=471) or the control group (n=470). Three people asked for their data to be removed. 126 (27%) of 471 participants stopped smoking from the intervention group and 58 (12%) of 470 from the control group (adjusted odds ratio 2.78 (1.94 to 3.97) P<0.001). Serious adverse events were miscarriages and other expected pregnancy events requiring hospital admission; all serious adverse events were unrelated to the intervention. Most people who stopped smoking from both groups relapsed after their baby was born.
Conclusions
The offer of up to £400 of financial voucher incentives to stop smoking during pregnancy as an addition to current UK stop smoking services is highly effective. This bolt-on intervention supports new guidance from the UK National Institute for Health and Care Excellence, which includes the addition of financial incentives to support pregnant women to stop smoking. Continuing incentives to 12 months after birth is being examined to prevent relapse.
Trial registration
ISRCTN Registry ISRCTN15236311.

© 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: 19 Oct 2022; 379:e071522
Tappin D, Sinclair L, Kee F, McFadden M, ... Ussher M, Bauld L
BMJ: 19 Oct 2022; 379:e071522 | PMID: 36261162
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Impact:
Abstract

Comparative effectiveness of initial computed tomography and invasive coronary angiography in women and men with stable chest pain and suspected coronary artery disease: multicentre randomised trial.

DISCHARGE Trial Group
Objective
To assess the comparative effectiveness of computed tomography and invasive coronary angiography in women and men with stable chest pain suspected to be caused by coronary artery disease.
Design
Prospective, multicentre, randomised pragmatic trial.
Setting
Hospitals at 26 sites in 16 European countries.
Participants
2002 (56.2%) women and 1559 (43.8%) men (total of 3561 patients) with suspected coronary artery disease referred for invasive coronary angiography on the basis of stable chest pain and a pre-test probability of obstructive coronary artery disease of 10-60%.
Intervention
Both women and men were randomised 1:1 (with stratification by gender and centre) to a strategy of either computed tomography or invasive coronary angiography as the initial diagnostic test (1019 and 983 women, and 789 and 770 men, respectively), and an intention-to-treat analysis was performed. Randomised allocation could not be blinded, but outcomes were assessed by investigators blinded to randomisation group.
Main outcome measures
The primary endpoint was major adverse cardiovascular events (MACE; cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). Key secondary endpoints were an expanded MACE composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, transient ischaemic attack, or major procedure related complication) and major procedure related complications.
Results
Follow-up at a median of 3.5 years was available in 98.9% (1979/2002) of women and in 99.0% (1544/1559) of men. No statistically significant gender interaction was found for MACE (P=0.29), the expanded MACE composite (P=0.45), or major procedure related complications (P=0.11). In both genders, the rate of MACE did not differ between the computed tomography and invasive coronary angiography groups. In men, the expanded MACE composite endpoint occurred less frequently in the computed tomography group than in the invasive coronary angiography group (22 (2.8%) v 41 (5.3%); hazard ratio 0.52, 95% confidence interval 0.31 to 0.87). In women, the risk of having a major procedure related complication was lower in the computed tomography group than in the invasive coronary angiography group (3 (0.3%) v 21 (2.1%); hazard ratio 0.14, 0.04 to 0.46).
Conclusion
This study found no evidence for a difference between women and men in the benefit of using computed tomography rather than invasive coronary angiography as the initial diagnostic test for the management of stable chest pain in patients with an intermediate pre-test probability of coronary artery disease. An initial computed tomography scan was associated with fewer major procedure related complications in women and a lower frequency of the expanded MACE composite in men.
Trial registration
NCT02400229ClinicalTrials.gov NCT02400229.

© 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 Oct 2022; 379:e071133
DISCHARGE Trial Group
BMJ: 19 Oct 2022; 379:e071133 | PMID: 36261169
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Impact:
Abstract

Post-acute sequelae of covid-19 six to 12 months after infection: population based study.

Peter RS, Nieters A, Kräusslich HG, Brockmann SO, ... Kern WV, EPILOC Phase 1 Study Group
Objectives
To describe symptoms and symptom clusters of post-covid syndrome six to 12 months after acute infection, describe risk factors, and examine the association of symptom clusters with general health and working capacity.
Design
Population based, cross sectional study
Setting:
Adults aged 18-65 years with confirmed SARS-CoV-2 infection between October 2020 and March 2021 notified to health authorities in four geographically defined regions in southern Germany.
Participants
50 457 patients were invited to participate in the study, of whom 12 053 (24%) responded and 11 710 (58.8% (n=6881) female; mean age 44.1 years; 3.6% (412/11 602) previously admitted with covid-19; mean follow-up time 8.5 months) could be included in the analyses.
Main outcome measures
Symptom frequencies (six to 12 months after versus before acute infection), symptom severity and clustering, risk factors, and associations with general health recovery and working capacity.
Results
The symptom clusters fatigue (37.2% (4213/11 312), 95% confidence interval 36.4% to 38.1%) and neurocognitive impairment (31.3% (3561/11 361), 30.5% to 32.2%) contributed most to reduced health recovery and working capacity, but chest symptoms, anxiety/depression, headache/dizziness, and pain syndromes were also prevalent and relevant for working capacity, with some differences according to sex and age. Considering new symptoms with at least moderate impairment of daily life and ≤80% recovered general health or working capacity, the overall estimate for post-covid syndrome was 28.5% (3289/11 536, 27.7% to 29.3%) among participants or at least 6.5% (3289/50 457) in the infected adult population (assuming that all non-responders had completely recovered). The true value is likely to be between these estimates.
Conclusions
Despite the limitation of a low response rate and possible selection and recall biases, this study suggests a considerable burden of self-reported post-acute symptom clusters and possible sequelae, notably fatigue and neurocognitive impairment, six to 12 months after acute SARS-CoV-2 infection, even among young and middle aged adults after mild infection, with a substantial impact on general health and working capacity.
Trial registration
German registry of clinical studies DRKS 00027012.

© 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: 13 Oct 2022; 379:e071050
Peter RS, Nieters A, Kräusslich HG, Brockmann SO, ... Kern WV, EPILOC Phase 1 Study Group
BMJ: 13 Oct 2022; 379:e071050 | PMID: 36229057
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Impact:
Abstract

Vaccine effectiveness of primary series and booster doses against covid-19 associated hospital admissions in the United States: living test negative design study.

Adams K, Rhoads JP, Surie D, Gaglani M, ... Self WH, Influenza and other Viruses in the AcutelY ill (IVY) Network
Objective
To compare the effectiveness of a primary covid-19 vaccine series plus booster doses with a primary series alone for the prevention of hospital admission with omicron related covid-19 in the United States.
Design
Multicenter observational case-control study with a test negative design.
Setting
Hospitals in 18 US states.
Participants
4760 adults admitted to one of 21 hospitals with acute respiratory symptoms between 26 December 2021 and 30 June 2022, a period when the omicron variant was dominant. Participants included 2385 (50.1%) patients with laboratory confirmed covid-19 (cases) and 2375 (49.9%) patients who tested negative for SARS-CoV-2 (controls).
Main outcome measures
The main outcome was vaccine effectiveness against hospital admission with covid-19 for a primary series plus booster doses and a primary series alone by comparing the odds of being vaccinated with each of these regimens versus being unvaccinated among cases versus controls. Vaccine effectiveness analyses were stratified by immunosuppression status (immunocompetent, immunocompromised). The primary analysis evaluated all covid-19 vaccine types combined, and secondary analyses evaluated specific vaccine products.
Results
Overall, median age of participants was 64 years (interquartile range 52-75 years), 994 (20.8%) were immunocompromised, 85 (1.8%) were vaccinated with a primary series plus two boosters, 1367 (28.7%) with a primary series plus one booster, and 1875 (39.3%) with a primary series alone, and 1433 (30.1%) were unvaccinated. Among immunocompetent participants, vaccine effectiveness for prevention of hospital admission with omicron related covid-19 for a primary series plus two boosters was 63% (95% confidence interval 37% to 78%), a primary series plus one booster was 65% (58% to 71%), and for a primary series alone was 37% (25% to 47%) (P<0.001 for the pooled boosted regimens compared with a primary series alone). Vaccine effectiveness was higher for a boosted regimen than for a primary series alone for both mRNA vaccines (BNT162b2 (Pfizer-BioNTech): 73% (44% to 87%) for primary series plus two boosters, 64% (55% to 72%) for primary series plus one booster, and 36% (21% to 48%) for primary series alone (P<0.001); mRNA-1273 (Moderna): 68% (17% to 88%) for primary series plus two boosters, 65% (55% to 73%) for primary series plus one booster, and 41% (25% to 54%) for primary series alone (P=0.001)). Among immunocompromised patients, vaccine effectiveness for a primary series plus one booster was 69% (31% to 86%) and for a primary series alone was 49% (30% to 63%) (P=0.04).
Conclusion
During the first six months of 2022 in the US, booster doses of a covid-19 vaccine provided additional benefit beyond a primary vaccine series alone for preventing hospital admissions with omicron related covid-19.
Readers\' note
This article is a living test negative design study that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

© 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: 11 Oct 2022; 379:e072065
Adams K, Rhoads JP, Surie D, Gaglani M, ... Self WH, Influenza and other Viruses in the AcutelY ill (IVY) Network
BMJ: 11 Oct 2022; 379:e072065 | PMID: 36220174
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Impact:
Abstract

Management of chronic migraine.

Hovaguimian A, Roth J
Chronic migraine is a neurologic disorder associated with considerable disability, lost productivity, and a profound economic burden worldwide. The past five years have seen a dramatic expansion in new treatments for this often challenging condition, among them calcitonin gene related peptide antagonists and neuromodulatory devices. This review outlines the epidemiology of and diagnostic criteria and risk factors for chronic migraine. It discusses evidence based drug and non-drug treatments, their advantages and disadvantages, and the principles of patient centered care for adults with chronic migraine, with attention to differential diagnosis and comorbidities, clinical reasoning, initiation and monitoring, cost, and availability. It discusses the international guidelines on drug treatment for chronic migraine and evaluates non-drug treatments including behavioral and complementary therapies and lifestyle modifications. Finally, it discusses the management of chronic migraine in special populations, including pediatrics, pregnancy, and older people, and considers future questions and emerging research in the field.

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BMJ: 10 Oct 2022; 379:e067670
Hovaguimian A, Roth J
BMJ: 10 Oct 2022; 379:e067670 | PMID: 36216384
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Impact:
Abstract

Maternal consumption of ultra-processed foods and subsequent risk of offspring overweight or obesity: results from three prospective cohort studies.

Wang Y, Wang K, Du M, Khandpur N, ... Nguyen LH, Chan AT
Objective
To assess whether maternal ultra-processed food intake during peripregnancy and during the child rearing period is associated with offspring risk of overweight or obesity during childhood and adolescence.
Design
Population based prospective cohort study.
Setting
The Nurses\' Health Study II (NHSII) and the Growing Up Today Study (GUTS I and II) in the United States.
Participants
19 958 mother-child (45% boys, aged 7-17 years at study enrollment) pairs with a median follow-up of 4 years (interquartile range 2-5 years) until age 18 or the onset of overweight or obesity, including a subsample of 2925 mother-child pairs with information on peripregnancy diet.
Main outcome measures
Multivariable adjusted, log binomial models with generalized estimating equations and an exchangeable correlation structure were used to account for correlations between siblings and to estimate the relative risk of offspring overweight or obesity defined by the International Obesity Task Force.
Results
2471 (12.4%) offspring developed overweight or obesity in the full analytic cohort. After adjusting for established maternal risk factors and offspring\'s ultra-processed food intake, physical activity, and sedentary time, maternal consumption of ultra-processed foods during the child rearing period was associated with overweight or obesity in offspring, with a 26% higher risk in the group with the highest maternal ultra-processed food consumption (group 5) versus the lowest consumption group (group 1; relative risk 1.26, 95% confidence interval 1.08 to 1.47, P for trend<0.001). In the subsample with information on peripregnancy diet, while rates were higher, peripregnancy ultra-processed food intake was not significantly associated with an increased risk of offspring overweight or obesity (n=845 (28.9%); group 5 v group 1: relative risk 1.17, 95% confidence interval 0.89 to 1.53, P fortrend=0.07). These associations were not modified by age, sex, birth weight, and gestational age of offspring or maternal body weight.
Conclusions
Maternal consumption of ultra-processed food during the child rearing period was associated with an increased risk of overweight or obesity in offspring, independent of maternal and offspring lifestyle risk factors. Further study is needed to confirm these findings and to understand the underlying biological mechanisms and environmental determinants. These data support the importance of refining dietary recommendations and the development of programs to improve nutrition for women of reproductive age to promote offspring health.

© 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: 05 Oct 2022; 379:e071767
Wang Y, Wang K, Du M, Khandpur N, ... Nguyen LH, Chan AT
BMJ: 05 Oct 2022; 379:e071767 | PMID: 36198411
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Impact:
Abstract

Characterization and corroboration of safety signals identified from the US Food and Drug Administration Adverse Event Reporting System, 2008-19: cross sectional study.

Dhodapkar MM, Shi X, Ramachandran R, Chen EM, Wallach JD, Ross JS
Objective
To characterize potential drug safety signals identified from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), from 2008 to 2019, to determine how often these signals resulted in regulatory action by the FDA and whether these actions were corroborated by published research findings or public assessments by the Sentinel Initiative.
Design
Cross sectional study.
Setting
USA.
Population
Safety signals identified from the FAERS and publicly reported by the FDA between 2008 and 2019; and review of the relevant literature published before and after safety signals were reported in 2014-15. Literature searches were performed in November 2019, Sentinel Initiative assessments were searched in December 2021, and data analysis was finalized in December 2021.
Main outcome measures
Safety signals and resulting regulatory actions; number and characteristics of published studies, including corroboration of regulatory action as evidenced by significant associations (or no associations) between the drug related to the signal and the adverse event.
Results
From 2008 to 2019, 603 potential safety signals identified from the FAERS were reported by the FDA (median 48 annually, interquartile range 41-61), of which 413 (68.5%) were resolved as of December 2021 (372 of 399 (93.2%) signals ≥3 years old were resolved). Among the resolved safety signals, 91 (22.0%) led to no regulatory action and 322 (78.0%) resulted in regulatory action, including 319 (77.2%) changes to drug labeling and 59 (14.3%) drug safety communications or other public communications from the FDA. For a subset of 82 potential safety signals reported in 2014-15, a literature search identified 1712 relevant publications; 1201 (70.2%) were case reports or case series. Among these 82 safety signals, 76 (92.7%) were resolved, of which relevant published research was identified for 57 (75.0%) signals and relevant Sentinel Initiative assessments for four (5.3%) signals. Regulatory actions by the FDA were corroborated by at least one relevant published research study for 17 of the 57 (29.8%) resolved safety signals; none of the relevant Sentinel Initiative assessments corroborated FDA regulatory action.
Conclusions
Most potential safety signals identified from the FAERS led to regulatory action by the FDA. Only a third of regulatory actions were corroborated by published research, however, and none by public assessments from the Sentinel Initiative. These findings suggest that either the FDA is taking regulatory actions based on evidence not made publicly available or more comprehensive safety evaluations might be needed when potential safety signals are identified.

© 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: 05 Oct 2022; 379:e071752
Dhodapkar MM, Shi X, Ramachandran R, Chen EM, Wallach JD, Ross JS
BMJ: 05 Oct 2022; 379:e071752 | PMID: 36198428
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Impact:
Abstract

How to improve discussions about osteoarthritis in primary care.

Saul H, Gursul D, Deeney B, Vennik J
The studyVennik J, Hughes S, Smith KA, et al. Patient and practitioner priorities and concerns about primary healthcare interactions for osteoarthritis: a meta-ethnography. Patient Educ Couns 2022;105:1865-77.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/discussions-about-osteoarthritis-in-primary-care/.

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BMJ: 04 Oct 2022; 379:o2234
Saul H, Gursul D, Deeney B, Vennik J
BMJ: 04 Oct 2022; 379:o2234 | PMID: 36195322
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Impact:
Abstract

Association between initiation of fluoroquinolones and hospital admission or emergency department visit for suicidality: population based cohort study.

Wang J, Gagne JJ, Kattinakere-Sreedhara S, Fischer MA, Bykov K
Objective
To evaluate the association between initiation of fluoroquinolones and hospital admission or emergency department visit for suicidality.
Design
Population based cohort study.
Setting
IBM MarketScan database, USA.
Participants
2 756 268 adults (≥18 years) who initiated an oral fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin, gemifloxacin, ofloxacin, gatifloxacin, norfloxacin, lomefloxacin, besifloxacin) or comparator antibiotic (January 2003 to September 2015) and had at least six months of continuous health plan enrollment and a diagnosis of pneumonia or urinary tract infection (UTI) three days or less before the drug initiation date. Comparator antibiotics were azithromycin in the pneumonia cohort and trimethoprim-sulfamethoxazole in the UTI cohort. Participants were matched 1:1 within each cohort on a propensity score, calculated from a multivariable logistic regression model that included 57 baseline covariates.
Main outcomes measure
Primary outcome was hospital admission or emergency department visit for suicidal ideation or self-harm within 60 days after treatment initiation. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals.
Results
The pneumonia cohort included 551 042 individuals, and the UTI cohort included 2 205 526 individuals. During the 60 day follow-up, 181 events were observed in the pneumonia cohort and 966 in the UTI cohort. The adjusted hazard ratios for fluoroquinolones were 1.01 (95% confidence interval 0.76 to 1.36) versus azithromycin in the pneumonia cohort and 1.03 (0.91 to 1.17) versus trimethoprim-sulfamethoxazole in the UTI cohort. Results were consistent across sensitivity analyses and subgroups of sex, age, or history of mental illnesses.
Conclusion
Initiation of fluoroquinolones was not associated with a substantially increased risk of admission to hospital or emergency department visits for suicidality compared with azithromycin or trimethoprim-sulfamethoxazole.

© 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: 04 Oct 2022; 379:e069931
Wang J, Gagne JJ, Kattinakere-Sreedhara S, Fischer MA, Bykov K
BMJ: 04 Oct 2022; 379:e069931 | PMID: 36195324
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Impact:
Abstract

Waning of vaccine effectiveness against moderate and severe covid-19 among adults in the US from the VISION network: test negative, case-control study.

Ferdinands JM, Rao S, Dixon BE, Mitchell PK, ... Thompson MG, Fireman B
Objective
To estimate the effectiveness of mRNA vaccines against moderate and severe covid-19 in adults by time since second, third, or fourth doses, and by age and immunocompromised status.
Design
Test negative case-control study.
Setting
Hospitals, emergency departments, and urgent care clinics in 10 US states, 17 January 2021 to 12 July 2022.
Participants
893 461 adults (≥18 years) admitted to one of 261 hospitals or to one of 272 emergency department or 119 urgent care centers for covid-like illness tested for SARS-CoV-2.
Main outcome measures
The main outcome was waning of vaccine effectiveness with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine during the omicron and delta periods, and the period before delta was dominant using logistic regression conditioned on calendar week and geographic area while adjusting for age, race, ethnicity, local virus circulation, immunocompromised status, and likelihood of being vaccinated.
Results
45 903 people admitted to hospital with covid-19 (cases) were compared with 213 103 people with covid-like illness who tested negative for SARS-CoV-2 (controls), and 103 287 people admitted to emergency department or urgent care with covid-19 (cases) were compared with 531 168 people with covid-like illness who tested negative for SARS-CoV-2. In the omicron period, vaccine effectiveness against covid-19 requiring admission to hospital was 89% (95% confidence interval 88% to 90%) within two months after dose 3 but waned to 66% (63% to 68%) by four to five months. Vaccine effectiveness of three doses against emergency department or urgent care visits was 83% (82% to 84%) initially but waned to 46% (44% to 49%) by four to five months. Waning was evident in all subgroups, including young adults and individuals who were not immunocompromised; although waning was morein people who were immunocompromised. Vaccine effectiveness increased among most groups after a fourth dose in whom this booster was recommended.
Conclusions
Effectiveness of mRNA vaccines against moderate and severe covid-19 waned with time after vaccination. The findings support recommendations for a booster dose after a primary series and consideration of additional booster doses.

© 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 Oct 2022; 379:e072141
Ferdinands JM, Rao S, Dixon BE, Mitchell PK, ... Thompson MG, Fireman B
BMJ: 03 Oct 2022; 379:e072141 | PMID: 36191948
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Impact:
Abstract

Emulating the GRADE trial using real world data: retrospective comparative effectiveness study.

Deng Y, Polley EC, Wallach JD, Dhruva SS, ... Ross JS, McCoy RG
Objective
To emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly compared second line glucose lowering drugs for their ability to lower glycated hemoglobin A1c (HbA1c).
Design
Observational study.
Setting
OptumLabs® Data Warehouse (OLDW), a nationwide claims database in the US, 25 January 2010 to 30 June 2019.
Participants
Adults with type 2 diabetes and HbA1c 6.8-8.5% while using metformin monotherapy, identified according to the GRADE trial specifications, who also used glimepiride, liraglutide, sitagliptin, or insulin glargine.
Main outcome measures
The primary outcome was time to HbA1c ≥7.0%. Secondary outcomes were time to HbA1c >7.5%, incident microvascular complications, incident macrovascular complications, adverse events, all cause hospital admissions, and all cause mortality. Propensity scores were estimated using the gradient boosting machine method, and inverse propensity score weighting was used to emulate randomization of the treatment groups, which were then compared using Cox proportional hazards regression.
Results
8252 people were identified (19.7% of adults starting the study drugs in OLDW) who met eligibility criteria for the GRADE trial (glimepiride arm=4318, liraglutide arm=690, sitagliptin arm=2993, glargine arm=251). The glargine arm was excluded from analyses owing to small sample size. Median times to HbA1c ≥7.0% were 442 days (95% confidence interval 394 to 480 days) for glimepiride, 764 (741 to not calculable) days for liraglutide, and 427 (380 to 483) days for sitagliptin. Liraglutide was associated with lower risk of reaching HbA1c ≥7.0% compared with glimepiride (hazard ratio 0.57, 95% confidence interval 0.43 to 0.75) and sitagliptin (0.55, 0.41 to 0.73). Results were consistent for the secondary outcome of time to HbA1c >7.5%. No significant differences were observed among treatment groups for the remaining secondary outcomes.
Conclusions
In this emulation of the GRADE trial, liraglutide was statistically significantly more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy. Generating timely evidence on medical treatments using real world data as a complement to prospective trials is of value.

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BMJ: 03 Oct 2022; 379:e070717
Deng Y, Polley EC, Wallach JD, Dhruva SS, ... Ross JS, McCoy RG
BMJ: 03 Oct 2022; 379:e070717 | PMID: 36191949
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Abstract

Comparison of short term surgical outcomes of male and female gastrointestinal surgeons in Japan: retrospective cohort study.

Okoshi K, Endo H, Nomura S, Kono E, ... Kakeji Y, Kitagawa Y
Objective
To compare short term surgical outcomes between male and female gastrointestinal surgeons in Japan.
Design
Retrospective cohort study.
Setting
Data from the Japanese National Clinical Database (includes data on >95% of surgeries performed in Japan) (2013-17) and the Japanese Society of Gastroenterological Surgery.
Participants
Male and female surgeons who performed distal gastrectomy, total gastrectomy, and low anterior resection.
Main outcome measures
Surgical mortality, surgical mortality combined with postoperative complications, pancreatic fistula (distal gastrectomy/total gastrectomy only), and anastomotic leakage (low anterior resection only). The association of surgeons\' gender with surgery related mortality and surgical complications was examined using multivariable logistic regression models adjusted for patient, surgeon, and hospital characteristics.
Results
A total of 149 193 distal gastrectomy surgeries (male surgeons: 140 971 (94.5%); female surgeons: 8222 (5.5%)); 63 417 gastrectomy surgeries (male surgeons: 59 915 (94.5%); female surgeons: 3502 (5.5%)); and 81 593 low anterior resection procedures (male surgeons: 77 864 (95.4%);female surgeons: 3729 (4.6%)) were done. On average, female surgeons had fewer post-registration years, operated on patients at higher risk, and did fewer laparoscopic surgeries than male surgeons. No significant difference was found between male and female surgeons in the adjusted risk for surgical mortality (adjusted odds ratio 0.98 (95% confidence interval 0.74 to 1.29) for distal gastrectomy; 0.83 (0.57 to 1.19) for total gastrectomy; 0.56 (0.30 to 1.05) for low anterior resection), surgical mortality combined with Clavien-Dindo grade ≥3 complications (adjusted odds ratio 1.03 (0.93 to 1.14) for distal gastrectomy; 0.92 (0.81 to 1.05) for total gastrectomy; 1.02 (0.91 to 1.15) for low anterior resection), pancreatic fistula (adjusted odds ratio 1.16 (0.97 to 1.38) for distal gastrectomy; 1.02 (0.84 to 1.23) for total gastrectomy), and anastomotic leakage (adjusted odds ratio 1.04 (0.92 to 1.18) for low anterior resection).
Conclusion
This study found no significant adjusted risk difference in the outcomes of surgeries performed by male versus female gastrointestinal surgeons. Despite disadvantages, female surgeons take on patients at high risk. Greater access to surgical training for female physicians is warranted in Japan.

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BMJ: 28 Sep 2022; 378:e070568
Okoshi K, Endo H, Nomura S, Kono E, ... Kakeji Y, Kitagawa Y
BMJ: 28 Sep 2022; 378:e070568 | PMID: 36170985
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Abstract

Effectiveness of a behavioural intervention delivered by text messages (safetxt) on sexually transmitted reinfections in people aged 16-24 years: randomised controlled trial.

Free C, Palmer MJ, McCarthy OL, Jerome L, ... Turner KME, Potter K
Objective
To quantify the effects of a series of text messages (safetxt) delivered in the community on incidence of chlamydia and gonorrhoea reinfection at one year in people aged 16-24 years.
Design
Parallel group randomised controlled trial.
Setting
92 sexual health clinics in the United Kingdom.
Participants
People aged 16-24 years with a diagnosis of, or treatment for, chlamydia, gonorrhoea, or non-specific urethritis in the past two weeks who owned a mobile phone.
Interventions
3123 participants assigned to the safetxt intervention received a series of text messages to improve sex behaviours: four texts daily for days 1-3, one or two daily for days 4-28, two or three weekly for month 2, and 2-5 monthly for months 3-12. 3125 control participants received a monthly text message for one year asking for any change to postal or email address. It was hypothesised that safetxt would reduce the risk of chlamydia and gonorrhoea reinfection at one year by improving three key safer sex behaviours: partner notification at one month, condom use, and sexually transmitted infection testing before unprotected sex with a new partner. Care providers and outcome assessors were blind to allocation.
Main outcome measures
The primary outcome was the cumulative incidence of chlamydia or gonorrhoea reinfection at one year, assessed by nucleic acid amplification tests. Safety outcomes were self-reported road traffic incidents and partner violence. All analyses were by intention to treat.
Results
6248 of 20 476 people assessed for eligibility between 1 April 2016 and 23 November 2018 were randomised. Primary outcome data were available for 4675/6248 (74.8%). At one year, the cumulative incidence of chlamydia or gonorrhoea reinfection was 22.2% (693/3123) in the safetxt arm versus 20.3% (633/3125) in the control arm (odds ratio 1.13, 95% confidence interval 0.98 to 1.31). The number needed to harm was 64 (95% confidence interval number needed to benefit 334 to ∞ to number needed to harm 24) The risk of road traffic incidents and partner violence was similar between the groups.
Conclusions
The safetxt intervention did not reduce chlamydia and gonorrhoea reinfections at one year in people aged 16-24 years. More reinfections occurred in the safetxt group. The results highlight the need for rigorous evaluation of health communication interventions.
Trial registration
ISRCTN registry ISRCTN64390461.

© 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: 28 Sep 2022; 378:e070351
Free C, Palmer MJ, McCarthy OL, Jerome L, ... Turner KME, Potter K
BMJ: 28 Sep 2022; 378:e070351 | PMID: 36170988
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Abstract

Association of gestational diabetes mellitus with overall and type specific cardiovascular and cerebrovascular diseases: systematic review and meta-analysis.

Xie W, Wang Y, Xiao S, Qiu L, Yu Y, Zhang Z
Objective
To quantify the risk of overall and type specific cardiovascular and cerebrovascular diseases as well as venous thromboembolism in women with a history of gestational diabetes mellitus.
Design
Systematic review and meta-analyses.
Data sources
PubMed, Embase, and the Cochrane Library from inception to 1 November 2021 and updated on 26 May 2022.
Review methods
Observational studies reporting the association between gestational diabetes mellitus and incident cardiovascular and cerebrovascular diseases were eligible. Data, pooled by random effects models, are presented as risk ratios (95% confidence intervals). Certainty of evidence was appraised by the Grading of Recommendations, Assessment, Development, and Evaluations.
Results
15 studies rated as moderate or serious risk of bias were included. Of 513 324 women with gestational diabetes mellitus, 9507 had cardiovascular and cerebrovascular disease. Of more than eight million control women without gestational diabetes, 78 895 had cardiovascular and cerebrovascular disease. Compared with women without gestational diabetes mellitus, women with a history of gestational diabetes mellitus showed a 45% increased risk of overall cardiovascular and cerebrovascular diseases (risk ratio 1.45, 95% confidence interval 1.36 to 1.53), 72% for cardiovascular diseases (1.72, 1.40 to 2.11), and 40% for cerebrovascular diseases (1.40, 1.29 to 1.51). Women with gestational diabetes mellitus showed increased risks of incident coronary artery diseases (1.40, 1.18 to 1.65), myocardial infarction (1.74, 1.37 to 2.20), heart failure (1.62, 1.29 to 2.05), angina pectoris (2.27, 1.79 to 2.87), cardiovascular procedures (1.87, 1.34 to 2.62), stroke (1.45, 1.29 to 1.63), and ischaemic stroke (1.49, 1.29 to 1.71). The risk of venous thromboembolism was observed to increase by 28% in women with previous gestational diabetes mellitus (1.28, 1.13 to 1.46). Subgroup analyses of cardiovascular and cerebrovascular disease outcomes stratified by study characteristics and adjustments showed significant differences by region (P=0.078), study design (P=0.02), source of data (P=0.005), and study quality (P=0.04), adjustment for smoking (P=0.03), body mass index (P=0.01), and socioeconomic status (P=0.006), and comorbidities (P=0.05). The risk of cardiovascular and cerebrovascular diseases was, however, attenuated but remained significant when restricted to women who did not develop subsequent overt diabetes (all gestational diabetes mellitus: 1.45, 1.33 to 1.59, gestational diabetes mellitus without subsequent diabetes: 1.09, 1.06 to 1.13). Certainty of evidence was judged as low or very low quality.
Conclusions
Gestational diabetes mellitus is associated with increased risks of overall and type specific cardiovascular and cerebrovascular diseases that cannot be solely attributed to conventional cardiovascular risk factors or subsequent diabetes.

© 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: 21 Sep 2022; 378:e070244
Xie W, Wang Y, Xiao S, Qiu L, Yu Y, Zhang Z
BMJ: 21 Sep 2022; 378:e070244 | PMID: 36130740
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Impact:
Abstract

Margin status and survival outcomes after breast cancer conservation surgery: prospectively registered systematic review and meta-analysis.

Bundred JR, Michael S, Stuart B, Cutress RI, ... Dodwell D, Bundred NJ
Objective
To determine if margin involvement is associated with distant recurrence and to determine the required margin to minimise both local recurrence and distant recurrence in early stage invasive breast cancer.
Design
Prospectively registered systematic review and meta-analysis of literature.
Data sources
Medline (PubMed), Embase, and Proquest online databases. Unpublished data were sought from study authors.
Eligibility criteria
Eligible studies reported on patients undergoing breast conserving surgery (for stages I-III breast cancer), allowed an estimation of outcomes in relation to margin status, and followed up patients for a minimum of 60 months. Patients with ductal carcinoma in situ only or treated with neoadjuvant chemotherapy or by mastectomy were excluded. Where applicable, margins were categorised as tumour on ink (involved), close margins (no tumour on ink but <2 mm), and negative margins (≥2 mm).
Results
68 studies from 1 January 1980 to 31 December 2021, comprising 112 140 patients with breast cancer, were included. Across all studies, 9.4% (95% confidence interval 6.8% to 12.8%) of patients had involved (tumour on ink) margins and 17.8% (13.0% to 23.9%) had tumour on ink or a close margin. The rate of distant recurrence was 25.4% (14.5% to 40.6%) in patients with tumour on ink, 8.4% (4.4% to 15.5%) in patients with tumour on ink or close, and 7.4% (3.9% to 13.6%) in patients with negative margins. Compared with negative margins, tumour on ink margins were associated with increased distant recurrence (hazard ratio 2.10, 95% confidence interval 1.65 to 2.69, P<0.001) and local recurrence (1.98, 1.66 to 2.36, P<0.001). Close margins were associated with increased distant recurrence (1.38, 1.13 to 1.69, P<0.001) and local recurrence (2.09, 1.39 to 3.13, P<0.001) compared with negative margins, after adjusting for receipt of adjuvant chemotherapy and radiotherapy. In five studies published since 2010, tumour on ink margins were associated with increased distant recurrence (2.41, 1.81 to 3.21, P<0.001) as were tumour on ink and close margins (1.44, 1.22 to 1.71, P<0.001) compared with negative margins.
Conclusions
Involved or close pathological margins after breast conserving surgery for early stage, invasive breast cancer are associated with increased distant recurrence and local recurrence. Surgeons should aim to achieve a minimum clear margin of at least 1 mm. On the basis of current evidence, international guidelines should be revised.
Systematic review registration
CRD42021232115.

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BMJ: 21 Sep 2022; 378:e070346
Bundred JR, Michael S, Stuart B, Cutress RI, ... Dodwell D, Bundred NJ
BMJ: 21 Sep 2022; 378:e070346 | PMID: 36130770
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Abstract

External validation of a prediction model for estimating fat mass in children and adolescents in 19 countries: individual participant data meta-analysis.

Hudda MT, Wells JCK, Adair LS, Alvero-Cruz JRA, ... Whincup PH, Nightingale CM
Objective
To evaluate the performance of a UK based prediction model for estimating fat-free mass (and indirectly fat mass) in children and adolescents in non-UK settings.
Design
Individual participant data meta-analysis.
Setting
19 countries.
Participants
5693 children and adolescents (49.7% boys) aged 4 to 15 years with complete data on the predictors included in the UK based model (weight, height, age, sex, and ethnicity) and on the independently assessed outcome measure (fat-free mass determined by deuterium dilution assessment).
Main outcome measures
The outcome of the UK based prediction model was natural log transformed fat-free mass (lnFFM). Predictive performance statistics of R2, calibration slope, calibration-in-the-large, and root mean square error were assessed in each of the 19 countries and then pooled through random effects meta-analysis. Calibration plots were also derived for each country, including flexible calibration curves.
Results
The model showed good predictive ability in non-UK populations of children and adolescents, providing R2 values of >75% in all countries and >90% in 11 of the 19 countries, and with good calibration (ie, agreement) of observed and predicted values. Root mean square error values (on fat-free mass scale) were <4 kg in 17 of the 19 settings. Pooled values (95% confidence intervals) of R2, calibration slope, and calibration-in-the-large were 88.7% (85.9% to 91.4%), 0.98 (0.97 to 1.00), and 0.01 (-0.02 to 0.04), respectively. Heterogeneity was evident in the R2 and calibration-in-the-large values across settings, but not in the calibration slope. Model performance did not vary markedly between boys and girls, age, ethnicity, and national income groups. To further improve the accuracy of the predictions, the model equation was recalibrated for the intercept in each setting so that country specific equations are available for future use.
Conclusion
The UK based prediction model, which is based on readily available measures, provides predictions of childhood fat-free mass, and hence fat mass, in a range of non-UK settings that explain a large proportion of the variability in observed fat-free mass, and exhibit good calibration performance, especially after recalibration of the intercept for each population. The model demonstrates good generalisability in both low-middle income and high income populations of healthy children and adolescents aged 4-15 years.

© 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: 21 Sep 2022; 378:e071185
Hudda MT, Wells JCK, Adair LS, Alvero-Cruz JRA, ... Whincup PH, Nightingale CM
BMJ: 21 Sep 2022; 378:e071185 | PMID: 36130780
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Abstract

Modifiable risk factors and long term risk of type 2 diabetes among individuals with a history of gestational diabetes mellitus: prospective cohort study.

Yang J, Qian F, Chavarro JE, Ley SH, ... Hu FB, Zhang C
Objectives
To evaluate the individual and combined associations of five modifiable risk factors with risk of type 2 diabetes among women with a history of gestational diabetes mellitus and examine whether these associations differ by obesity and genetic predisposition to type 2 diabetes.
Design
Prospective cohort study.
Setting
Nurses\' Health Study II, US.
Participants
4275 women with a history of gestational diabetes mellitus, with repeated measurements of weight and lifestyle factors and followed up between 1991 and 2009.
Main outcome measure
Self-reported, clinically diagnosed type 2 diabetes. Five modifiable risk factors were assessed, including not being overweight or obese (body mass index <25.0), high quality diet (top two fifthsof the modified Alternate Healthy Eating Index), regular exercise (≥150 min/week of moderate intensity or ≥75 min/week of vigorous intensity), moderate alcohol consumption (5.0-14.9 g/day), and no current smoking. Genetic susceptibility for type 2 diabetes was characterised by a genetic risk score based on 59 single nucleotide polymorphisms associated with type 2 diabetes in a subset of participants (n=1372).
Results
Over a median 27.9 years of follow-up, 924 women developed type 2 diabetes. Compared with participants who did not have optimal levels of any of the risk factors for the development of type 2 diabetes, those who had optimal levels of all five factors had >90% lower risk of the disorder. Hazard ratios of type 2 diabetes for those with one, two, three, four, and five optimal levels of modifiable factors compared with none was 0.94 (95% confidence interval 0.59 to 1.49), 0.61 (0.38 to 0.96), 0.32 (0.20 to 0.51), 0.15 (0.09 to 0.26), and 0.08 (0.03 to 0.23), respectively (Ptrend<0.001). The inverse association of the number of optimal modifiable factors with risk of type 2 diabetes was seen even in participants who were overweight/obese or with higher genetic susceptibility (Ptrend<0.001). Among women with body mass index ≥25 (n=2227), the hazard ratio for achieving optimal levels of all the other four risk factors was 0.40 (95% confidence interval 0.18 to 0.91). Among women with higher genetic susceptibility, the hazard ratio of developing type 2 diabetes for having four optimal factors was 0.11 (0.04 to 0.29); in the group with optimal levels of all five factors, no type 2 diabetes events were observed.
Conclusions
Among women with a history of gestational diabetes mellitus, each additional optimal modifiable factor was associated with an incrementally lower risk of type 2 diabetes. These associations were seen even among individuals who were overweight/obese or were at greater genetic susceptibility.

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BMJ: 21 Sep 2022; 378:e070312
Yang J, Qian F, Chavarro JE, Ley SH, ... Hu FB, Zhang C
BMJ: 21 Sep 2022; 378:e070312 | PMID: 36130782
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Abstract

Unemployment and insecure housing are linked to less successful treatment for depression.

Saul H, Gursul D, Hoskin L, Buckman J
The studyBuckman JEJ, Saunders R, Stott J, et al. Socioeconomic indicators of treatment prognosis for adults with depression: a systematic review and individual patient data meta-analysis. JAMA Psychiatry 2022;79:5.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/unemployment-insecure-housing-linked-less-successful-depression-treatment/.

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BMJ: 16 Sep 2022; 378:o2182
Saul H, Gursul D, Hoskin L, Buckman J
BMJ: 16 Sep 2022; 378:o2182 | PMID: 36113881
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Impact:
Abstract

Associations of physician burnout with career engagement and quality of patient care: systematic review and meta-analysis.

Hodkinson A, Zhou A, Johnson J, Geraghty K, ... Esmail A, Panagioti M
Objective
To examine the association of physician burnout with the career engagement and the quality of patient care globally.
Design
Systematic review and meta-analysis.
Data sources
Medline, PsycINFO, Embase, and CINAHL were searched from database inception until May 2021.
Eligibility criteria for selecting studies
Observational studies assessing the association of physician burnout (including a feeling of overwhelming emotional exhaustion, feelings of cynicism and detachment from job defined as depersonalisation, and a sense of ineffectiveness and little personal accomplishment) with career engagement (job satisfaction, career choice regret, turnover intention, career development, and productivity loss) and the quality of patient care (patient safety incidents, low professionalism, and patient satisfaction). Data were double extracted by independent reviewers and checked through contacting all authors, 84 (49%) of 170 of whom confirmed their data. Random-effect models were used to calculate the pooled odds ratio, prediction intervals expressed the amount of heterogeneity, and meta-regressions assessed for potential moderators with significance set using a conservative level of P<0.10.
Results
4732 articles were identified, of which 170 observational studies of 239 246 physicians were included in the meta-analysis. Overall burnout in physicians was associated with an almost four times decrease in job satisfaction compared with increased job satisfaction (odds ratio 3.79, 95% confidence interval 3.24 to 4.43, I2=97%, k=73 studies, n=146 980 physicians). Career choice regret increased by more than threefold compared with being satisfied with their career choice (3.49, 2.43 to 5.00, I2=97%, k=16, n=33 871). Turnover intention also increased by more than threefold compared with retention (3.10, 2.30 to 4.17, I2=97%, k=25, n=32 271). Productivity had a small but significant effect (1.82, 1.08 to 3.07, I2=83%, k=7, n=9581) and burnout also affected career development from a pooled association of two studies (3.77, 2.77 to 5.14, I2=0%, n=3411). Overall physician burnout doubled patient safety incidents compared with no patient safety incidents (2.04, 1.69 to 2.45, I2=87%, k=35, n=41 059). Low professionalism was twice as likely compared with maintained professionalism (2.33, 1.96 to 2.70, I2=96%, k=40, n=32 321), as was patient dissatisfaction compared with patient satisfaction (2.22, 1.38 to 3.57, I2=75%, k=8, n=1002). Burnout and poorer job satisfaction was greatest in hospital settings (1.88, 0.91 to 3.86, P=0.09), physicians aged 31-50 years (2.41, 1.02 to 5.64, P=0.04), and working in emergency medicine and intensive care (2.16, 0.98 to 4.76, P=0.06); burnout was lowest in general practitioners (0.16, 0.03 to 0.88, P=0.04). However, these associations did not remain significant in the multivariable regressions. Burnout and patient safety incidents were greatest in physicians aged 20-30 years (1.88, 1.07 to 3.29, P=0.03), and people working in emergency medicine (2.10, 1.09 to 3.56, P=0.02). The association of burnout with low professionalism was smallest in physicians older than 50 years (0.36, 0.19 to 0.69, P=0.003) and greatest in physicians still in training or residency (2.27, 1.45 to 3.60, P=0.001), in those who worked in a hospital (2.16, 1.46 to 3.19, P<0.001), specifically in emergency medicine specialty (1.48, 1.01 to 2.34, P=0.042), or situated in a low to middle income country (1.68, 0.94 to 2.97, P=0.08).
Conclusions
This meta-analysis provides compelling evidence that physician burnout is associated with poor function and sustainability of healthcare organisations primarily by contributing to the career disengagement and turnover of physicians and secondarily by reducing the quality of patient care. Healthcare organisations should invest more time and effort in implementing evidence-based strategies to mitigate physician burnout across specialties, and particularly in emergency medicine and for physicians in training or residency.
Systematic review registration
PROSPERO number CRD42021249492.

© 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 Sep 2022; 378:e070442
Hodkinson A, Zhou A, Johnson J, Geraghty K, ... Esmail A, Panagioti M
BMJ: 14 Sep 2022; 378:e070442 | PMID: 36104064
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Abstract

Diagnostic accuracy of covid-19 rapid antigen tests with unsupervised self-sampling in people with symptoms in the omicron period: cross sectional study.

Schuit E, Venekamp RP, Hooft L, Veldhuijzen IK, ... van de Wijgert JHHM, Moons KGM
Objective
To assess the performance of rapid antigen tests with unsupervised nasal and combined oropharyngeal and nasal self-sampling during the omicron period.
Design
Prospective cross sectional diagnostic test accuracy study.
Setting
Three public health service covid-19 test sites in the Netherlands, 21 December 2021 to 10 February 2022.
Participants
6497 people with covid-19 symptoms aged ≥16 years presenting for testing.
Interventions
Participants had a swab sample taken for reverse transcription polymerase chain reaction (RT-PCR, reference test) and received one rapid antigen test to perform unsupervised using either nasal self-sampling (during the emergence of omicron, and when omicron accounted for >90% of infections, phase 1) or with combined oropharyngeal and nasal self-sampling in a subsequent (phase 2; when omicron accounted for >99% of infections). The evaluated tests were Flowflex (Acon Laboratories; phase 1 only), MPBio (MP Biomedicals), and Clinitest (Siemens-Healthineers).
Main outcome measures
The main outcomes were sensitivity, specificity, and positive and negative predictive values of each self-test, with RT-PCR testing as the reference standard.
Results
During phase 1, 45.0% (n=279) of participants in the Flowflex group, 29.1% (n=239) in the MPBio group, and 35.4% ((n=257) in the Clinitest group were confirmatory testers (previously tested positive by a self-test at own initiative). Overall sensitivities with nasal self-sampling were 79.0% (95% confidence interval 74.7% to 82.8%) for Flowflex, 69.9% (65.1% to 74.4%) for MPBio, and 70.2% (65.6% to 74.5%) for Clinitest. Sensitivities were substantially higher in confirmatory testers (93.6%, 83.6%, and 85.7%, respectively) than in those who tested for other reasons (52.4%, 51.5%, and 49.5%, respectively). Sensitivities decreased from 87.0% to 80.9% (P=0.16 by χ2 test), 80.0% to 73.0% (P=0.60), and 83.1% to 70.3% (P=0.03), respectively, when transitioning from omicron accounting for 29% of infections to >95% of infections. During phase 2, 53.0% (n=288) of participants in the MPBio group and 44.4% (n=290) in the Clinitest group were confirmatory testers. Overall sensitivities with combined oropharyngeal and nasal self-sampling were 83.0% (78.8% to 86.7%) for MPBio and 77.3% (72.9% to 81.2%) for Clinitest. When combined oropharyngeal and nasal self-sampling was compared with nasal self-sampling, sensitivities were found to be slightly higher in confirmatory testers (87.4% and 86.1%, respectively) and substantially higher in those testing for other reasons (69.3% and 59.9%, respectively).
Conclusions
Sensitivities of three rapid antigen tests with nasal self-sampling decreased during the emergence of omicron but was only statistically significant for Clinitest. Sensitivities appeared to be substantially influenced by the proportion of confirmatory testers. Sensitivities of MPBio and Clinitest improved after the addition of oropharyngeal to nasal self-sampling. A positive self-test result justifies prompt self-isolation without the need for confirmatory testing. Individuals with a negative self-test result should adhere to general preventive measures because a false negative result cannot be ruled out. Manufacturers of MPBio and Clinitest may consider extending their instructions for use to include combined oropharyngeal and nasal self-sampling, and other manufacturers of rapid antigen tests should consider evaluating this as well.

© 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 Sep 2022; 378:e071215
Schuit E, Venekamp RP, Hooft L, Veldhuijzen IK, ... van de Wijgert JHHM, Moons KGM
BMJ: 14 Sep 2022; 378:e071215 | PMID: 36104069
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Impact:
Abstract

Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial.

Auer RC, Ott M, Karanicolas P, Brackstone MR, ... Carrier M, PERIOP-01 investigators
Objective
To determine the efficacy and safety of extended duration perioperative thromboprophylaxis by low molecular weight heparin when assessing disease-free survival in patients undergoing resection for colorectal cancer.
Design
Multicentre, open label, randomised controlled trial.
Settings
12 hospitals in Quebec and Ontario, Canada, between 25 October 2011 and 31 December 2020.
Participants
614 adults (age ≥18 years) were eligible with pathologically confirmed invasive adenocarcinoma of the colon or rectum, no evidence of metastatic disease, a haemoglobin concentration of ≥8 g/dL, and were scheduled to undergo surgical resection.
Interventions
Random assignment to extended duration thromboprophylaxis using daily subcutaneous tinzaparin at 4500 IU, beginning at decision to operate and continuing for 56 days postoperatively, compared with in-patient postoperative thromboprophylaxis only.
Main outcome measures
Primary outcome was disease-free survival at three years, defined as survival without locoregional recurrence, distant metastases, second primary (same cancer), second primary (other cancer), or death. Secondary outcomes included venous thromboembolism, postoperative major bleeding complications, and five year overall survival. Analyses were done in the intention-to-treat population.
Results
The trial stopped recruitment prematurely after the interim analysis for futility. The primary outcome occurred in 235 (77%) of 307 patients in the extended duration group and in 243 (79%) of 307 patients in the in-hospital thromboprophylaxis group (hazard ratio 1.1, 95% confidence interval 0.90 to 1.33; P=0.4). Postoperative venous thromboembolism occurred in five patients (2%) in the extended duration group and in four patients (1%) in the in-hospital thromboprophylaxis group (P=0.8). Major surgery related bleeding in the first postoperative week was reported in one person (<1%) in the extended duration and in six people (2%) in the in-hospital thromboprophylaxis group (P=0.1). No difference was noted for overall survival at five years in 272 (89%) patients in the extended duration group and 280 (91%) patients in the in-hospital thromboprophylaxis group (hazard ratio 1.12; 95% confidence interval 0.72 to 1.76; P=0.1).
Conclusions
Extended duration to perioperative anticoagulation with tinzaparin did not improve disease-free survival or overall survival in patients with colorectal cancer undergoing surgical resection compared with in-patient postoperative thromboprophylaxis alone. The incidences of venous thromboembolism and postoperative major bleeding were low and similar between groups.
Trial registration
ClinicalTrials.gov NCT01455831.

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BMJ: 13 Sep 2022; 378:e071375
Auer RC, Ott M, Karanicolas P, Brackstone MR, ... Carrier M, PERIOP-01 investigators
BMJ: 13 Sep 2022; 378:e071375 | PMID: 36100263
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Impact:
Abstract

Prevention of covid-19 and other acute respiratory infections with cod liver oil supplementation, a low dose vitamin D supplement: quadruple blinded, randomised placebo controlled trial.

Brunvoll SH, Nygaard AB, Ellingjord-Dale M, Holland P, ... Meyer HE, Søraas A
Objective
To determine if daily supplementation with cod liver oil, a low dose vitamin D supplement, in winter, prevents SARS-CoV-2 infection, serious covid-19, or other acute respiratory infections in adults in Norway.
Design
Quadruple blinded, randomised placebo controlled trial.
Setting
Norway, 10 November 2020 to 2 June 2021.
Participants
34 601 adults (aged 18-75 years), not taking daily vitamin D supplements.
Intervention
5 mL/day of cod liver oil (10 µg of vitamin D, n=17 278) or placebo (n=17 323) for up to six months.
Main outcome measures
Four co-primary endpoints were predefined: the first was a positive SARS-CoV-2 test result determined by reverse transcriptase-quantitative polymerase chain reaction and the second was serious covid-19, defined as self-reported dyspnoea, admission to hospital, or death. Other acute respiratory infections were indicated by the third and fourth co-primary endpoints: a negative SARS-CoV-2 test result and self-reported symptoms. Side effects related to the supplementation were self-reported. The fallback method was used to handle multiple comparisons.
Results
Supplementation with cod liver oil was not associated with a reduced risk of any of the co-primary endpoints. Participants took the supplement (cod liver oil or placebo) for a median of 164 days, and 227 (1.31%) participants in the cod liver oil group and 228 (1.32%) participants in the placebo group had a positive SARS-CoV-2 test result (relative risk 1.00, multiple comparison adjusted confidence interval 0.82 to 1.22). Serious covid-19 was identified in 121 (0.70%) participants in the cod liver oil group and in 101 (0.58%) participants in the placebo group (1.20, 0.87 to 1.65). 8546 (49.46%) and 8565 (49.44%) participants in the cod liver oil and placebo groups, respectively, had ≥1 negative SARS-CoV-2 test results (1.00, 0.97 to 1.04). 3964 (22.94%) and 3834 (22.13%) participants in the cod liver oil and placebo groups, respectively, reported ≥1 acute respiratory infections (1.04, 0.97 to 1.11). Only low grade side effects were reported in the cod liver oil and placebo groups.
Conclusion
Supplementation with cod liver oil in the winter did not reduce the incidence of SARS-CoV-2 infection, serious covid-19, or other acute respiratory infections compared with placebo.
Trial registration
ClinicalTrials.gov NCT04609423.

© 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: 07 Sep 2022; 378:e071245
Brunvoll SH, Nygaard AB, Ellingjord-Dale M, Holland P, ... Meyer HE, Søraas A
BMJ: 07 Sep 2022; 378:e071245 | PMID: 36215222
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Impact:
Abstract

Effect of a test-and-treat approach to vitamin D supplementation on risk of all cause acute respiratory tract infection and covid-19: phase 3 randomised controlled trial (CORONAVIT).

Jolliffe DA, Holt H, Greenig M, Talaei M, ... Relton C, Martineau AR
Objective
To determine the effect of population level implementation of a test-and-treat approach to correction of suboptimal vitamin D status (25-hydroxyvitamin D (25(OH)D) <75 nmol/L) on risk of all cause acute respiratory tract infection and covid 19.
Design
Phase 3 open label randomised controlled trial.
Setting
United Kingdom.
Participants
6200 people aged ≥16 years who were not taking vitamin D supplements at baseline.
Interventions
Offer of a postal finger prick test of blood 25(OH)D concentration with provision of a six month supply of lower dose vitamin D (800 IU/day, n=1550) or higher dose vitamin D (3200 IU/day, n=1550) to those with blood 25(OH)D concentration <75 nmol/L, compared with no offer of testing or supplementation (n=3100). Follow-up was for six months.
Main outcome measures
The primary outcome was the proportion of participants with at least one swab test or doctor confirmed acute respiratory tract infection of any cause. A secondary outcome was the proportion of participants with swab test confirmed covid-19. Logistic regression was used to calculate odds ratios and associated 95% confidence intervals. The primary analysis was conducted by intention to treat.
Results
Of 3100 participants offered a vitamin D test, 2958 (95.4%) accepted and 2674 (86.3%) had 25(OH)D concentrations <75 nmol/L and received vitamin D supplements (n=1328 lower dose, n=1346 higher dose). Compared with 136/2949 (4.6%) participants in the no offer group, at least one acute respiratory tract infection of any cause occurred in 87/1515 (5.7%) in the lower dose group (odds ratio 1.26, 95% confidence interval 0.96 to 1.66) and 76/1515 (5.0%) in the higher dose group (1.09, 0.82 to 1.46). Compared with 78/2949 (2.6%) participants in the no offer group, 55/1515 (3.6%) developed covid-19 in the lower dose group (1.39, 0.98 to 1.97) and 45/1515 (3.0%) in the higher dose group (1.13, 0.78 to 1.63).
Conclusions
Among people aged 16 years and older with a high baseline prevalence of suboptimal vitamin D status, implementation of a population level test-and-treat approach to vitamin D supplementation was not associated with a reduction in risk of all cause acute respiratory tract infection or covid-19.
Trial registration
ClinicalTrials.gov NCT04579640.

© 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: 07 Sep 2022; 378:e071230
Jolliffe DA, Holt H, Greenig M, Talaei M, ... Relton C, Martineau AR
BMJ: 07 Sep 2022; 378:e071230 | PMID: 36215226
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Impact:
Abstract

Joint association of food nutritional profile by Nutri-Score front-of-pack label and ultra-processed food intake with mortality: Moli-sani prospective cohort study.

Bonaccio M, Di Castelnuovo A, Ruggiero E, Costanzo S, ... Iacoviello L, Moli-sani Study Investigators
Objective
To jointly analyse two food dimensions, the Food Standards Agency Nutrient Profiling System (FSAm-NPS), used to derive the Nutri-Score front-of-pack label, and the NOVA classification in relation to mortality.
Design
Prospective cohort study.
Setting
Moli-sani Study, Italy 2005-10.
Participants
22 895 participants (mean age 55 (SD 12) years; 48% men).
Main outcomes measures
Associations between dietary exposures and mortality risk, assessed using multivariable cause specific Cox proportional hazard models controlled for known risk factors.
Results
A total of 2205 deaths occurred during 272 960 person years of follow-up. In the highest quarter of the FSAm-NPS index compared with the lowest quarter, multivariable adjusted hazard ratios for all cause and cardiovascular mortality were 1.19 (95% confidence interval 1.04 to 1.35; absolute risk difference 4.3%, 95% confidence interval 1.4% to 7.2%) and 1.32 (1.06 to 1.64; 2.6%, 0.3% to 4.9%), respectively. The hazard ratios were 1.19 (1.05 to 1.36; absolute risk difference 9.7%, 5.0% to 14.3%) and 1.27 (1.02 to 1.58; 5.0%, 1.2% to 8.8%), respectively, for all cause and cardiovascular mortality when the two extreme categories of ultra-processed food intake were compared. When these two indices were analysed jointly, the magnitude of the association of the FSAm-NPS dietary index with all cause and cardiovascular mortality was attenuated by 22.3% and 15.4%, respectively, whereas mortality risks associated with high ultra-processed food intake were not altered.
Conclusions
Adults with the lowest quality diet, as measured using the FSAm-NPS dietary index (underpinning the Nutri-Score), and the highest ultra-processed food consumption (NOVA classification) were at the highest risk for all cause and cardiovascular mortality. A significant proportion of the higher mortality risk associated with an elevated intake of nutrient poor foods was explained by a high degree of food processing. In contrast, the relation between a high ultra-processed food intake and mortality was not explained by the poor quality of these foods.

© 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: 31 Aug 2022; 378:e070688
Bonaccio M, Di Castelnuovo A, Ruggiero E, Costanzo S, ... Iacoviello L, Moli-sani Study Investigators
BMJ: 31 Aug 2022; 378:e070688 | PMID: 36450651
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Impact:
Abstract

Patterns of tobacco use in low and middle income countries by tobacco product and sociodemographic characteristics: nationally representative survey data from 82 countries.

Theilmann M, Lemp JM, Winkler V, Manne-Goehler J, ... Vollmer S, Geldsetzer P
Objectives
To determine the prevalence and frequency of using any tobacco product and each of a detailed set of tobacco products, how tobacco use and frequency of use vary across countries, world regions, and World Bank country income groups, and the socioeconomic and demographic gradients of tobacco use and frequency of use within countries.
Design
Secondary analysis of nationally representative, cross-sectional, household survey data from 82 low and middle income countries collected between 1 January 2015 and 31 December 2020.
Setting
Population based survey data.
Participants
1 231 068 individuals aged 15 years and older.
Main outcome measures
Self-reported current smoking, current daily smoking, current smokeless tobacco use, current daily smokeless tobacco use, pack years, and current use and use frequencies of each tobacco product. Products were any type of cigarette, manufactured cigarette, hand rolled cigarette, water pipe, cigar, oral snuff, nasal snuff, chewing tobacco, and betel nut (with and without tobacco).
Results
The smoking prevalence in the study sample was 16.5% (95% confidence interval 16.1% to 16.9%) and ranged from 1.1% (0.9% to 1.3%) in Ghana to 50.6% (45.2% to 56.1%) in Kiribati. The user prevalence of smokeless tobacco was 7.7% (7.5% to 8.0%) and prevalence was highest in Papua New Guinea (daily user prevalence of 65.4% (63.3% to 67.5%)). Although variation was wide between countries and by tobacco product, for many low and middle income countries, the highest prevalence and cigarette smoking frequency was reported in men, those with lower education, less household wealth, living in rural areas, and higher age.
Conclusions
Both smoked and smokeless tobacco use and frequency of use vary widely across tobacco products in low and middle income countries. This study can inform the design and targeting of efforts to reduce tobacco use in low and middle income countries and serve as a benchmark for monitoring progress towards national and international goals.

© 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: 30 Aug 2022; 378:e067582
Theilmann M, Lemp JM, Winkler V, Manne-Goehler J, ... Vollmer S, Geldsetzer P
BMJ: 30 Aug 2022; 378:e067582 | PMID: 36041745
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Impact:
Abstract

Evaluating how clear the questions being investigated in randomised trials are: systematic review of estimands.

Cro S, Kahan BC, Rehal S, Chis Ster A, ... White IR, Cornelius VR
Objectives
To evaluate how often the precise research question being addressed about an intervention (the estimand) is stated or can be determined from reported methods, and to identify what types of questions are being investigated in phase 2-4 randomised trials.
Design
Systematic review of the clarity of research questions being investigated in randomised trials in 2020 in six leading general medical journals.
Data source
PubMed search in February 2021.
Eligibility criteria for selecting studies
Phase 2-4 randomised trials, with no restrictions on medical conditions or interventions. Cluster randomised, crossover, non-inferiority, and equivalence trials were excluded.
Main outcome measures
Number of trials that stated the precise primary question being addressed about an intervention (ie, the primary estimand), or for which the primary estimand could be determined unambiguously from the reported methods using statistical knowledge. Strategies used to handle post-randomisation events that affect the interpretation or existence of patient outcomes, such as intervention discontinuations or uses of additional drug treatments (known as intercurrent events), and the corresponding types of questions being investigated.
Results
255 eligible randomised trials were identified. No trials clearly stated all the attributes of the estimand. In 117 (46%) of 255 trials, the primary estimand could be determined from the reported methods. Intercurrent events were reported in 242 (95%) of 255 trials; but the handling of these could only be determined in 125 (49%) of 255 trials. Most trials that provided this information considered the occurrence of intercurrent events as irrelevant in the calculation of the treatment effect and assessed the effect of the intervention regardless (96/125, 77%)-that is, they used a treatment policy strategy. Four (4%) of 99 trials with treatment non-adherence owing to adverse events estimated the treatment effect in a hypothetical setting (ie, the effect as if participants continued treatment despite adverse events), and 19 (79%) of 24 trials where some patients died estimated the treatment effect in a hypothetical setting (ie, the effect as if participants did not die).
Conclusions
The precise research question being investigated in most trials is unclear, mainly because of a lack of clarity on the approach to handling intercurrent events. Clear reporting of estimands is necessary in trial reports so that all stakeholders, including clinicians, patients and policy makers, can make fully informed decisions about medical interventions.
Systematic review registration
PROSPERO CRD42021238053.

© 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 Aug 2022; 378:e070146
Cro S, Kahan BC, Rehal S, Chis Ster A, ... White IR, Cornelius VR
BMJ: 23 Aug 2022; 378:e070146 | PMID: 35998928
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Impact:
Abstract

Effectiveness of an intervention for reducing sitting time and improving health in office workers: three arm cluster randomised controlled trial.

Edwardson CL, Biddle SJH, Clemes SA, Davies MJ, ... Yates T, Clarke-Cornwell AM
Objectives
To evaluate the effectiveness of an intervention, with and without a height adjustable desk, on daily sitting time, and to investigate the relative effectiveness of the two interventions, and the effectiveness of both interventions on physical behaviours and physical, biochemical, psychological, and work related health and performance outcomes.
Design
Cluster three arm randomised controlled trial with follow-up at three and 12 months.
Setting
Local government councils in Leicester, Liverpool, and Greater Manchester, UK.
Participants
78 clusters including 756 desk based employees in defined offices, departments, or teams from two councils in Leicester, three in Greater Manchester, and one in Liverpool.
Interventions
Clusters were randomised to one of three conditions: the SMART Work and Life (SWAL) intervention, the SWAL intervention with a height adjustable desk (SWAL plus desk), or control (usual practice).
Main outcomes measures
The primary outcome measure was daily sitting time, assessed by accelerometry, at 12 month follow-up. Secondary outcomes were accelerometer assessed sitting, prolonged sitting, standing and stepping time, and physical activity calculated over any valid day, work hours, workdays, and non-workdays, self-reported lifestyle behaviours, musculoskeletal problems, cardiometabolic health markers, work related health and performance, fatigue, and psychological measures.
Results
Mean age of participants was 44.7 years, 72.4% (n=547) were women, and 74.9% (n=566) were white. Daily sitting time at 12 months was significantly lower in the intervention groups (SWAL -22.2 min/day, 95% confidence interval -38.8 to -5.7 min/day, P=0.003; SWAL plus desk -63.7 min/day, -80.1 to -47.4 min/day, P<0.001) compared with the control group. The SWAL plus desk intervention was found to be more effective than SWAL at changing sitting time (-41.7 min/day, -56.3 to -27.0 min/day, P<0.001). Favourable differences in sitting and prolonged sitting time at three and 12 month follow-ups for both intervention groups and for standing time for the SWAL plus desk group were observed during work hours and on workdays. Both intervention groups were associated with small improvements in stress, wellbeing, and vigour, and the SWAL plus desk group was associated with improvements in pain in the lower extremity, social norms for sitting and standing at work, and support.
Conclusions
Both SWAL and SWAL plus desk were associated with a reduction in sitting time, although the addition of a height adjustable desk was found to be threefold more effective.
Trial registration
ISRCTN Registry ISRCTN11618007.

© 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 Aug 2022; 378:e069288
Edwardson CL, Biddle SJH, Clemes SA, Davies MJ, ... Yates T, Clarke-Cornwell AM
BMJ: 17 Aug 2022; 378:e069288 | PMID: 35977732
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Impact:
Abstract

Risk of preterm birth, small for gestational age at birth, and stillbirth after covid-19 vaccination during pregnancy: population based retrospective cohort study.

Fell DB, Dimanlig-Cruz S, Regan AK, Håberg SE, ... MacDonald SE, Dougan SD
Objective
To assess the risk of preterm birth, small for gestational age at birth, and stillbirth after covid-19 vaccination during pregnancy.
Design
Population based retrospective cohort study.
Setting
Ontario, Canada, 1 May to 31 December 2021.
Participants
All liveborn and stillborn infants from pregnancies conceived at least 42 weeks before the end of the study period and with gestational age ≥20 weeks or birth weight ≥500 g.
Main outcome measures
Using Cox regression, hazard ratios and 95% confidence intervals were estimated for preterm birth before 37 weeks (overall and spontaneous preterm birth), very preterm birth (<32 weeks), small for gestational age at birth (<10th centile), and stillbirth. Vaccination against covid-19 was treated as a time varying exposure in the outcome specific risk window, and propensity score weighting was used to adjust hazard ratios for potential confounding.
Results
Among 85 162 births, 43 099 (50.6%) occurred in individuals who received one dose or more of a covid-19 vaccine during pregnancy-42 979 (99.7%) received an mRNA vaccine. Vaccination during pregnancy was not associated with any increased risk of overall preterm birth (6.5% among vaccinated v 6.9% among unvaccinated; adjusted hazard ratio 1.02, 95% confidence interval 0.96 to 1.08), spontaneous preterm birth (3.7% v 4.4%; 0.96, 0.90 to 1.03), or very preterm birth (0.59% v 0.89%; 0.80, 0.67 to 0.95). No increase was found in risk of small for gestational age at birth (9.1% v 9.2%; 0.98, 0.93 to 1.03) or stillbirth (0.25% v 0.44%; 0.65, 0.51 to 0.84). Findings were similar by trimester of vaccination, mRNA vaccine product, and number of doses received during pregnancy.
Conclusion
The findings suggest that vaccination against covid-19 during pregnancy is not associated with a higher risk of preterm birth, small for gestational age at birth, or stillbirth.

© 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 Aug 2022; 378:e071416
Fell DB, Dimanlig-Cruz S, Regan AK, Håberg SE, ... MacDonald SE, Dougan SD
BMJ: 17 Aug 2022; 378:e071416 | PMID: 35977737
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Impact:
Abstract

Covid-19 vaccination in pregnancy.

Badell ML, Dude CM, Rasmussen SA, Jamieson DJ
Pregnancy is an independent risk factor for severe covid-19. Vaccination is the best way to reduce the risk for SARS-CoV-2 infection and limit its morbidity and mortality. The current recommendations from the World Health Organization, Centers for Disease Control and Prevention, and professional organizations are for pregnant, postpartum, and lactating women to receive covid-19 vaccination. Pregnancy specific considerations involve potential effects of vaccination on fetal development, placental transfer of antibodies, and safety of maternal vaccination. Although pregnancy was an exclusion criterion in initial clinical trials of covid-19 vaccines, observational data have been rapidly accumulating and thus far confirm that the benefits of vaccination outweigh the potential risks. This review examines the evidence supporting the effectiveness, immunogenicity, placental transfer, side effects, and perinatal outcomes of maternal covid-19 vaccination. Additionally, it describes factors associated with vaccine hesitancy in pregnancy. Overall, studies monitoring people who have received covid-19 vaccines during pregnancy have not identified any pregnancy specific safety concerns. Additional information on non-mRNA vaccines, vaccination early in pregnancy, and longer term outcomes in infants are needed. To collect this information, vaccination during pregnancy must be prioritized in vaccine research.

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: 10 Aug 2022; 378:e069741
Badell ML, Dude CM, Rasmussen SA, Jamieson DJ
BMJ: 10 Aug 2022; 378:e069741 | PMID: 35948352
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Impact:
Abstract

Reporting guideline for overviews of reviews of healthcare interventions: development of the PRIOR statement.

Gates M, Gates A, Pieper D, Fernandes RM, ... Moss SJ, Hartling L
Objective
To develop a reporting guideline for overviews of reviews of healthcare interventions.
Design
Development of the preferred reporting items for overviews of reviews (PRIOR) statement.
Participants
Core team (seven individuals) led day-to-day operations, and an expert advisory group (three individuals) provided methodological advice. A panel of 100 experts (authors, editors, readers including members of the public or patients) was invited to participate in a modified Delphi exercise. 11 expert panellists (chosen on the basis of expertise, and representing relevant stakeholder groups) were invited to take part in a virtual face-to-face meeting to reach agreement (≥70%) on final checklist items. 21 authors of recently published overviews were invited to pilot test the checklist.
Setting
International consensus.
Intervention
Four stage process established by the EQUATOR Network for developing reporting guidelines in health research: project launch (establish a core team and expert advisory group, register intent), evidence reviews (systematic review of published overviews to describe reporting quality, scoping review of methodological guidance and author reported challenges related to undertaking overviews of reviews), modified Delphi exercise (two online Delphi surveys to reach agreement (≥70%) on relevant reporting items followed by a virtual face-to-face meeting), and development of the reporting guideline.
Results
From the evidence reviews, we drafted an initial list of 47 potentially relevant reporting items. An international group of 52 experts participated in the first Delphi survey (52% participation rate); agreement was reached for inclusion of 43 (91%) items. 44 experts (85% retention rate) completed the second Delphi survey, which included the four items lacking agreement from the first survey and five new items based on respondent comments. During the second round, agreement was not reached for the inclusion or exclusion of the nine remaining items. 19 individuals (6 core team and 3 expert advisory group members, and 10 expert panellists) attended the virtual face-to-face meeting. Among the nine items discussed, high agreement was reached for the inclusion of three and exclusion of six. Six authors participated in pilot testing, resulting in minor wording changes. The final checklist includes 27 main items (with 19 sub-items) across all stages of an overview of reviews.
Conclusions
PRIOR fills an important gap in reporting guidance for overviews of reviews of healthcare interventions. The checklist, along with rationale and example for each item, provides guidance for authors that will facilitate complete and transparent reporting. This will allow readers to assess the methods used in overviews of reviews of healthcare interventions and understand the trustworthiness and applicability of their findings.

© 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 Aug 2022; 378:e070849
Gates M, Gates A, Pieper D, Fernandes RM, ... Moss SJ, Hartling L
BMJ: 09 Aug 2022; 378:e070849 | PMID: 35944924
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Impact:
Abstract

Role of human papillomavirus (HPV) vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment: systematic review and meta-analysis.

Kechagias KS, Kalliala I, Bowden SJ, Athanasiou A, ... Veroniki AA, Kyrgiou M
Objective
To explore the efficacy of human papillomavirus (HPV) vaccination on the risk of HPV infection and recurrent diseases related to HPV infection in individuals undergoing local surgical treatment.
Design
Systematic review and meta-analysis DATA SOURCES: PubMed (Medline), Scopus, Cochrane, Web of Science, and ClinicalTrials.gov were screened from inception to 31 March 2021.
Review methods
Studies reporting on the risk of HPV infection and recurrence of disease related to HPV infection after local surgical treatment of preinvasive genital disease in individuals who were vaccinated were included. The primary outcome measure was risk of recurrence of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) after local surgical treatment, with follow-up as reported by individual studies. Secondary outcome measures were risk of HPV infection or other lesions related to HPV infection. Independent and in duplicate data extraction and quality assessment were performed with ROBINS-I and RoB-2 tools for observational studies and randomised controlled trials, respectively. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was implemented for the primary outcome. Observational studies and randomised controlled trials were analysed separately from post hoc analyses of randomised controlled trials. Pooled risk ratios and 95% confidence intervals were calculated with a random effects meta-analysis model. The restricted maximum likelihood was used as an estimator for heterogeneity, and the Hartung-Knapp-Sidik-Jonkman method was used to derive confidence intervals.
Results
22 articles met the inclusion criteria of the review; 18 of these studies also reported data from a non-vaccinated group and were included in the meta-analyses (12 observational studies, two randomised controlled trials, and four post hoc analyses of randomised controlled trials). The risk of recurrence of CIN2+ was reduced in individuals who were vaccinated compared with those who were not vaccinated (11 studies, 19 909 participants; risk ratio 0.43, 95% confidence interval 0.30 to 0.60; I2=58%, τ2=0.14, median follow-up 36 months, interquartile range 24-43.5). The effect estimate was even stronger when the risk of recurrence of CIN2+ was assessed for disease related to HPV subtypes HPV16 or HPV18 (six studies, 1879 participants; risk ratio 0.26, 95% confidence interval 0.16 to 0.43; I2=0%, τ2=0). Confidence in the meta-analysis for CIN2+ overall and CIN2+ related to HPV16 or HPV18, assessed by GRADE, ranged from very low to moderate, probably because of publication bias and inconsistency in the studies included in the meta-analysis. The risk of recurrence of CIN3 was also reduced in patients who were vaccinated but uncertainty was large (three studies, 17 757 participants; 0.28, 0.01 to 6.37; I2=71%, τ2=1.23). Evidence of benefit was lacking for recurrence of vulvar, vaginal, and anal intraepithelial neoplasia, genital warts, and persistent and incident HPV infections, although the number of studies and participants in each outcome was low.
Conclusion
HPV vaccination might reduce the risk of recurrence of CIN, in particular when related to HPV16 or HPV18, in women treated with local excision. GRADE assessment for the quality of evidence indicated that the data were inconclusive. Large scale, high quality randomised controlled trials are required to establish the level of effectiveness and cost of HPV vaccination in women undergoing treatment for diseases related to HPV infection.
Systematic review registration
PROSPERO CRD42021237350.

© 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 Aug 2022; 378:e070135
Kechagias KS, Kalliala I, Bowden SJ, Athanasiou A, ... Veroniki AA, Kyrgiou M
BMJ: 03 Aug 2022; 378:e070135 | PMID: 35922074
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Impact:
Abstract

Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis.

Stone MB, Yaseen ZS, Miller BJ, Richardville K, Kalaria SN, Kirsch I
Objectives
To characterize individual participant level response distributions to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration from 1979 to 2016.
Design
Individual participant data analysis.
Population
232 randomized, double blind, placebo controlled trials of drug monotherapy for major depressive disorder submitted by drug developers to the FDA between 1979 and 2016, comprising 73 388 adult and child participants meeting the inclusion criteria for efficacy studies on antidepressants.
Main outcome measures
Responses were converted to Hamilton Rating Scale for Depression (HAMD17) equivalent scores where other measures were used to assess efficacy. Multivariable analyses examined the effects of age, sex, baseline severity, and year of the study on improvements in depressive symptoms in the antidepressant and placebo groups. Response distributions were analyzed with finite mixture models.
Results
The random effects mean difference between drug and placebo favored drug (1.75 points, 95% confidence interval 1.63 to 1.86). Differences between drug and placebo increased significantly (P<0.001) with greater baseline severity. After controlling for participant characteristics at baseline, no trends in treatment effect or placebo response over time were found. The best fitting model of response distributions was three normal distributions, with mean improvements from baseline to end of treatment of 16.0, 8.9, and 1.7 points. These distributions were designated Large, Non-specific, and Minimal responses, respectively. Participants who were treated with a drug were more likely to have a Large response (24.5% v 9.6%) and less likely to have a Minimal response (12.2.% v 21.5%).
Conclusions
The trimodal response distributions suggests that about 15% of participants have a substantial antidepressant effect beyond a placebo effect in clinical trials, highlighting the need for predictors of meaningful responses specific to drug treatment.

© 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 Aug 2022; 378:e067606
Stone MB, Yaseen ZS, Miller BJ, Richardville K, Kalaria SN, Kirsch I
BMJ: 02 Aug 2022; 378:e067606 | PMID: 35918097
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Impact:
Abstract

Risk of covid-19 related deaths for SARS-CoV-2 omicron (B.1.1.529) compared with delta (B.1.617.2): retrospective cohort study.

Ward IL, Bermingham C, Ayoubkhani D, Gethings OJ, ... Walker AS, Nafilyan V
Objective
To assess the risk of covid-19 death after infection with omicron BA.1 compared with delta (B.1.617.2).
Design
Retrospective cohort study.
Setting
England, United Kingdom, from 1 December 2021 to 30 December 2021.
Participants
1 035 149 people aged 18-100 years who tested positive for SARS-CoV-2 under the national surveillance programme and had an infection identified as omicron BA.1 or delta compatible.
Main outcome measures
The main outcome measure was covid-19 death as identified from death certification records. The exposure of interest was the SARS-CoV-2 variant identified from NHS Test and Trace PCR positive tests taken in the community (pillar 2) and analysed by Lighthouse laboratories. Cause specific Cox proportional hazard regression models (censoring non-covid-19 deaths) were adjusted for sex, age, vaccination status, previous infection, calendar time, ethnicity, index of multiple deprivation rank, household deprivation, university degree, keyworker status, country of birth, main language, region, disability, and comorbidities. Interactions between variant and sex, age, vaccination status, and comorbidities were also investigated.
Results
The risk of covid-19 death was 66% lower (95% confidence interval 54% to 75%) for omicron BA.1 compared with delta after adjusting for a wide range of potential confounders. The reduction in the risk of covid-19 death for omicron compared with delta was more pronounced in people aged 18-59 years (number of deaths: delta=46, omicron=11; hazard ratio 0.14, 95% confidence interval 0.07 to 0.27) than in those aged ≥70 years (number of deaths: delta=113, omicron=135; hazard ratio 0.44, 95% confidence interval 0.32 to 0.61, P<0.0001). No evidence of a difference in risk was found between variant and number of comorbidities.
Conclusions
The results support earlier studies showing a reduction in severity of infection with omicron BA.1 compared with delta in terms of hospital admission. This study extends the research to also show a reduction in the risk of covid-19 death for the omicron variant compared with the delta variant.

© 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 Aug 2022; 378:e070695
Ward IL, Bermingham C, Ayoubkhani D, Gethings OJ, ... Walker AS, Nafilyan V
BMJ: 02 Aug 2022; 378:e070695 | PMID: 35918098
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Impact:
Abstract

One-off physiotherapy and at-home exercise are effective in treating shoulder pain.

Saul H, Gursul D, Hopewell S
The studyHopewell S, Keene DJ, Marian IR, et al. Progressive exercise compared with best practice advice, with or without corticosteroid injection, for the treatment of patients with rotator cuff disorders (GRASP): a multicentre, pragmatic, 2 × 2 factorial, randomised controlled trial. Lancet 2021;398:416-28.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/one-off-physiotherapy-session-effective-for-shoulder-pain/.

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: 29 Jul 2022; 378:o1776
Saul H, Gursul D, Hopewell S
BMJ: 29 Jul 2022; 378:o1776 | PMID: 35905985
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Impact:
Abstract

Prognosis and persistence of smell and taste dysfunction in patients with covid-19: meta-analysis with parametric cure modelling of recovery curves.

Tan BKJ, Han R, Zhao JJ, Tan NKW, ... Hopkins C, Toh ST
Objective
To clarify in patients with covid-19 the recovery rate of smell and taste, proportion with persistent dysfunction of smell and taste, and prognostic factors associated with recovery of smell and taste.
Design
Systematic review and meta-analysis.
Data sources
PubMed, Embase, Scopus, Cochrane Library, and medRxiv from inception to 3 October 2021.
Review methods
Two blinded reviewers selected observational studies of adults (≥18 years) with covid-19 related dysfunction of smell or taste. Descriptive prognosis studies with time-to-event curves and prognostic association studies of any prognostic factor were included.
Data extraction and synthesis
Two reviewers extracted data, evaluated study bias using QUIPS, and appraised evidence quality using GRADE, following PRISMA and MOOSE reporting guidelines. Using iterative numerical algorithms, time-to-event individual patient data (IPD) were reconstructed and pooled to retrieve distribution-free summary survival curves, with recovery rates reported at 30 day intervals for participants who remained alive. To estimate the proportion with persistent smell and taste dysfunction, cure fractions from Weibull non-mixture cure models of plateaued survival curves were logit transformed and pooled in a two stage meta-analysis. Conventional aggregate data meta-analysis was performed to explore unadjusted associations of prognostic factors with recovery.
Main outcome measures
The primary outcomes were the proportions of patients remaining with smell or taste dysfunction. Secondary outcomes were the odds ratios of prognostic variables associated with recovery of smell and taste.
Results
18 studies (3699 patients) from 4180 records were included in reconstructed IPD meta-analyses. Risk of bias was low to moderate; conclusions remained unaltered after exclusion of four high risk studies. Evidence quality was moderate to high. Based on parametric cure modelling, persistent self-reported smell and taste dysfunction could develop in an estimated 5.6% (95% confidence interval 2.7% to 11.0%, I2=70%, τ2=0.756, 95% prediction interval 0.7% to 33.5%) and 4.4% (1.2% to 14.6%, I2=67%, τ2=0.684, 95% prediction interval 0.0% to 49.0%) of patients, respectively. Sensitivity analyses suggest these could be underestimates. At 30, 60, 90, and 180 days, respectively, 74.1% (95% confidence interval 64.0% to 81.3%), 85.8% (77.6% to 90.9%), 90.0% (83.3% to 94.0%), and 95.7% (89.5% to 98.3%) of patients recovered their sense of smell (I2=0.0-77.2%, τ2=0.006-0.050) and 78.8% (70.5% to 84.7%), 87.7% (82.0% to 91.6%), 90.3% (83.5% to 94.3%), and 98.0% (92.2% to 95.5%) recovered their sense of taste (range of I2=0.0-72.1%, τ2=0.000-0.015). Women were less likely to recover their sense of smell (odds ratio 0.52, 95% confidence interval 0.37 to 0.72, seven studies, I2=20%, τ2=0.0224) and taste (0.31, 0.13 to 0.72, seven studies, I2=78%, τ2=0.5121) than men, and patients with greater initial severity of dysfunction (0.48, 0.31 to 0.73, five studies, I2=10%, τ2<0.001) or nasal congestion (0.42, 0.18 to 0.97, three studies, I2=0%, τ2<0.001) were less likely to recover their sense of smell.
Conclusions
A substantial proportion of patients with covid-19 might develop long lasting change in their sense of smell or taste. This could contribute to the growing burden of long covid.
Systematic review registration
PROSPERO CRD42021283922.

© 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: 27 Jul 2022; 378:e069503
Tan BKJ, Han R, Zhao JJ, Tan NKW, ... Hopkins C, Toh ST
BMJ: 27 Jul 2022; 378:e069503 | PMID: 35896188
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Impact:
Abstract

Burden of chronic obstructive pulmonary disease and its attributable risk factors in 204 countries and territories, 1990-2019: results from the Global Burden of Disease Study 2019.

Safiri S, Carson-Chahhoud K, Noori M, Nejadghaderi SA, ... Kolahi AA, Kaufman JS
Objective
To report the global, regional, and national burden of chronic obstructive pulmonary disease (COPD) and its attributable risk factors between 1990 and 2019, by age, sex, and sociodemographic index.
Design
Systematic analysis.
Data source
Global Burden of Disease Study 2019.
Main outcome measures
Data on the prevalence, deaths, and disability adjusted life years (DALYs) of COPD, and its attributable risk factors, were retrieved from the Global Burden of Disease 2019 project for 204 countries and territories, between 1990 and 2019. The counts and rates per 100 000 population, along with 95% uncertainty intervals, were presented for each estimate.
Results
In 2019, 212.3 million prevalent cases of COPD were reported globally, with COPD accounting for 3.3 million deaths and 74.4 million DALYs. The global age standardised point prevalence, death, and DALY rates for COPD were 2638.2 (95% uncertainty intervals 2492.2 to 2796.1), 42.5 (37.6 to 46.3), and 926.1 (848.8 to 997.7) per 100 000 population, which were 8.7%, 41.7%, and 39.8% lower than in 1990, respectively. In 2019, Denmark (4299.5), Myanmar (3963.7), and Belgium (3927.7) had the highest age standardised point prevalence of COPD. Egypt (62.0%), Georgia (54.9%), and Nicaragua (51.6%) showed the largest increases in age standardised point prevalence across the study period. In 2019, Nepal (182.5) and Japan (7.4) had the highest and lowest age standardised death rates per 100 000, respectively, and Nepal (3318.4) and Barbados (177.7) had the highest and lowest age standardised DALY rates per 100 000, respectively. In men, the global DALY rate of COPD increased up to age 85-89 years and then decreased with advancing age, whereas for women the rate increased up to the oldest age group (≥95 years). Regionally, an overall reversed V shaped association was found between sociodemographic index and the age standardised DALY rate of COPD. Factors contributing most to the DALYs rates for COPD were smoking (46.0%), pollution from ambient particulate matter (20.7%), and occupational exposure to particulate matter, gases, and fumes (15.6%).
Conclusions
Despite the decreasing burden of COPD, this disease remains a major public health problem, especially in countries with a low sociodemographic index. Preventive programmes should focus on smoking cessation, improving air quality, and reducing occupational exposures to further reduce the burden of COPD.

© 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: 27 Jul 2022; 378:e069679
Safiri S, Carson-Chahhoud K, Noori M, Nejadghaderi SA, ... Kolahi AA, Kaufman JS
BMJ: 27 Jul 2022; 378:e069679 | PMID: 35896191
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Impact:
Abstract

Open spaces and a sense of belonging improve wellbeing.

Saul H, Gursul D, Cassidy S, Corcoran R
The studyMcElroy E, Ashton M, Bagnall AM, et al. The individual, place, and wellbeing-a network analysis. BMC Public Health 2021;21:1621.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/open-spaces-and-community-cohesion-improve-wellbeing/.

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: 22 Jul 2022; 378:o1663
Saul H, Gursul D, Cassidy S, Corcoran R
BMJ: 22 Jul 2022; 378:o1663 | PMID: 35868651
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Impact:
Abstract

Incidence, risk factors, natural history, and hypothesised mechanisms of myocarditis and pericarditis following covid-19 vaccination: living evidence syntheses and review.

Pillay J, Gaudet L, Wingert A, Bialy L, ... Paterson DI, Hartling L
Objectives
To synthesise evidence on incidence rates and risk factors for myocarditis and pericarditis after use of mRNA vaccination against covid-19, clinical presentation, short term and longer term outcomes of cases, and proposed mechanisms.
Design
Living evidence syntheses and review.
Data sources
Medline, Embase, and the Cochrane Library were searched from 6 October 2020 to 10 January 2022; reference lists and grey literature (to 13 January 2021). One reviewer completed screening and another verified 50% of exclusions, using a machine learning program to prioritise records. A second reviewer verified all exclusions at full text, extracted data, and (for incidence and risk factors) risk of bias assessments using modified Joanna Briggs Institute tools. Team consensus determined certainty of evidence ratings for incidence and risk factors using GRADE (Grading of Recommendations, Assessment, Development and Evaluation).
Eligibility criteria for selecting studies
Large (>10 000 participants) or population based or multisite observational studies and surveillance data (incidence and risk factors) reporting on confirmed myocarditis or pericarditis after covid-19 mRNA vaccination; case series (n≥5, presentation, short term clinical course and longer term outcomes); opinions, letters, reviews, and primary studies focused on describing or supporting hypothesised mechanisms.
Results
46 studies were included (14 on incidence, seven on risk factors, 11 on characteristics and short term course, three on longer term outcomes, and 21 on mechanisms). Incidence of myocarditis after mRNA vaccines was highest in male adolescents and male young adults (age 12-17 years, range 50-139 cases per million (low certainty); 18-29 years, 28-147 per million (moderate certainty)). For girls and boys aged 5-11 years and women aged 18-29 years, incidence of myocarditis after vaccination with BNT162b2 (Pfizer/BioNTech) could be fewer than 20 cases per million (low certainty). Incidence after a third dose of an mRNA vaccine had very low certainty evidence. For individuals of 18-29 years, incidence of myocarditis is probably higher after vaccination with mRNA-1273 (Moderna) compared with Pfizer (moderate certainty). Among individuals aged 12-17, 18-29, or 18-39 years, incidence of myocarditis or pericarditis after dose two of an mRNA vaccine for covid-19 might be lower when administered ≥31 days compared with ≤30 days after dose one (low certainty). Data specific to men aged 18-29 years indicated that the dosing interval might need to increase to ≥56 days to substantially drop myocarditis or pericarditis incidence. For clinical course and short term outcomes, only one small case series (n=8) was found for 5-11 year olds. In adolescents and adults, most (>90%) myocarditis cases involved men of a median 20-30 years of age and with symptom onset two to four days after a second dose (71-100%). Most people were admitted to hospital (≥84%) for a short duration (two to four days). For pericarditis, data were limited but more variation than myocarditis has been reported in patient age, sex, onset timing, and rate of admission to hospital. Three case series with longer term (3 months; n=38) follow-up suggested persistent echocardiogram abnormalities, as well as ongoing symptoms or a need for drug treatments or restriction from activities in >50% of patients. Sixteen hypothesised mechanisms were described, with little direct supporting or refuting evidence.
Conclusions
These findings indicate that adolescent and young adult men are at the highest risk of myocarditis after mRNA vaccination. Use of a Pfizer vaccine over a Moderna vaccine and waiting for more than 30 days between doses might be preferred for this population. Incidence of myocarditis in children aged 5-11 years is very rare but certainty was low. Data for clinical risk factors were very limited. A clinical course of mRNA related myocarditis appeared to be benign, although longer term follow-up data were limited. Prospective studies with appropriate testing (eg, biopsy and tissue morphology) will enhance understanding of mechanism.

© 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: 13 Jul 2022; 378:e069445
Pillay J, Gaudet L, Wingert A, Bialy L, ... Paterson DI, Hartling L
BMJ: 13 Jul 2022; 378:e069445 | PMID: 35830976
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Impact:
Abstract

Safety of heterologous primary and booster schedules with ChAdOx1-S and BNT162b2 or mRNA-1273 vaccines: nationwide cohort study.

Andersson NW, Thiesson EM, Laursen MV, Mogensen SH, Kjær J, Hviid A
Objective
To assess the risk of adverse events associated with heterologous primary (two dose) and booster (three dose) vaccine schedules for covid-19 with Oxford-AstraZeneca\'s ChAdOx1-S priming followed by mRNA vaccines (Pfizer-BioNTech\'s BNT162b2 or Moderna\'s mRNA-1273) as compared with homologous mRNA vaccine schedules for covid-19.
Design
Nationwide cohort study.
Setting
Denmark, 1 January 2021 to 26 March 2022.
Participants
Adults aged 18-65 years who received a heterologous vaccine schedule of priming with ChAdOx1-S and one or two mRNA booster doses (with either the BNT162b2 or mRNA-1273 vaccine) were compared with adults who received a homologous BNT162b2 or mRNA-1273 vaccine schedule (ie, two dose v two dose, and three dose v three dose schedule).
Main outcome measures
The incidence of hospital contacts for a range of adverse cardiovascular and haemostatic events within 28 days after the second or third vaccine dose, comparing heterologous versus homologous vaccine schedules. Secondary outcomes included additional prioritised adverse events of special interest. Poisson regression was used to estimate incidence rate ratios with adjustment for selected covariates.
Results
Individuals who had had a heterologous primary vaccine (n=137 495) or a homologous vaccine (n=2 688 142) were identified, in addition to those who had had a heterologous booster (n=129 770) or a homologous booster (n=2 197 213). Adjusted incidence rate ratios of adverse cardiovascular and haemostatic events within 28 days for the heterologous primary and booster vaccine schedules in comparison with the homologous mRNA vaccine schedules were 1.22 (95% confidence interval 0.79 to 1.91) and 1.00 (0.58 to 1.72) for ischaemic cardiac events, 0.74 (0.40 to 1.34) and 0.72 (0.37 to 1.42) for cerebrovascular events, 1.12 (0.13 to 9.58) and 4.74 (0.94 to 24.01) for arterial thromboembolisms, 0.79 (0.45 to 1.38) and 1.09 (0.60 to 1.98) for venous thromboembolisms, 0.84 (0.18 to 3.96) and 1.04 (0.60 to 4.55) for myocarditis or pericarditis, 0.97 (0.45 to 2.10) and 0.89 (0.21 to 3.77) for thrombocytopenia and coagulative disorders, and 1.39 (1.01 to 1.91) and 1.02 (0.70 to 1.47) for other bleeding events, respectively. No associations with any of the outcomes were found when restricting to serious adverse events defined as stay in hospital for more than 24 h.
Conclusion
Heterologous primary and booster covid-19 vaccine schedules of ChAdOx1-S priming and mRNA booster doses as both second and third doses were not associated with increased risk of serious adverse events compared with homologous mRNA vaccine schedules. These results are reassuring but given the rarity of some of the adverse events, associations cannot be excluded.

© 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: 13 Jul 2022; 378:e070483
Andersson NW, Thiesson EM, Laursen MV, Mogensen SH, Kjær J, Hviid A
BMJ: 13 Jul 2022; 378:e070483 | PMID: 35831006
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Impact:
Abstract

Fever therapy in febrile adults: systematic review with meta-analyses and trial sequential analyses.

Holgersson J, Ceric A, Sethi N, Nielsen N, Jakobsen JC
Objective
To investigate the effects of fever therapy compared with no fever therapy in a wide population of febrile adults.
Design
Systematic review with meta-analyses and trial sequential analyses of randomised clinical trials.
Data sources
CENTRAL, BIOSIS, CINAHL, MEDLINE, Embase, LILACS, Scopus, and Web of Science Core Collection, searched from their inception to 2 July 2021.
Eligibility criteria
Randomised clinical trials in adults diagnosed as having fever of any origin. Included experimental interventions were any fever therapy, and the control intervention had to be no fever therapy (with or without placebo/sham).
Data extraction and synthesis
Two authors independently selected studies, extracted data, and assessed the risk of bias. Primary outcomes were all cause mortality and serious adverse events. Secondary outcomes were quality of life and non-serious adverse events. Aggregate data were synthesised with meta-analyses, subgroup analyses, and trial sequential analyses, and the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.
Results
Forty two trials assessing 5140 participants were included. Twenty three trials assessed 11 different antipyretic drugs, 11 trials assessed physical cooling, and eight trials assessed a combination of antipyretic drugs and physical cooling. Of the participants, 3007 were critically ill, 1892 were non-critically ill, 3277 had infectious fever, and 1139 had non-infectious fever. All trials were assessed as being at high risk of bias. Meta-analysis and trial sequential analysis showed that the hypothesis that fever therapy reduces the risk of death (risk ratio 1.04, 95% confidence interval 0.90 to 1.19; I2=0%; P=0.62; 16 trials; high certainty evidence) and the risk of serious adverse events (risk ratio 1.02, 0.89 to 1.17; I2=0%; P=0.78; 16 trials; high certainty evidence) could be rejected. One trial assessing quality of life was included, showing no difference between fever therapy and control. Meta-analysis and trial sequential analysis showed that the hypothesis that fever therapy reduces the risk of non-serious adverse events could be neither confirmed nor rejected (risk ratio 0.92, 0.67 to 1.25; I2=66.5%; P=0.58; four trials; very low certainty evidence).
Conclusions
Fever therapy does not seem to affect the risk of death and serious adverse events.
Systematic review registration
PROSPERO CRD42019134006.

© 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 Jul 2022; 378:e069620
Holgersson J, Ceric A, Sethi N, Nielsen N, Jakobsen JC
BMJ: 12 Jul 2022; 378:e069620 | PMID: 35820685
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Impact:
Abstract

Clinical prediction models for mortality in patients with covid-19: external validation and individual participant data meta-analysis.

de Jong VMT, Rousset RZ, Antonio-Villa NE, Buenen AG, ... Moons KGM, Debray TPA
Objective
To externally validate various prognostic models and scoring rules for predicting short term mortality in patients admitted to hospital for covid-19.
Design
Two stage individual participant data meta-analysis.
Setting
Secondary and tertiary care.
Participants
46 914 patients across 18 countries, admitted to a hospital with polymerase chain reaction confirmed covid-19 from November 2019 to April 2021.
Data sources
Multiple (clustered) cohorts in Brazil, Belgium, China, Czech Republic, Egypt, France, Iran, Israel, Italy, Mexico, Netherlands, Portugal, Russia, Saudi Arabia, Spain, Sweden, United Kingdom, and United States previously identified by a living systematic review of covid-19 prediction models published in The BMJ, and through PROSPERO, reference checking, and expert knowledge.
Model selection and eligibility criteria
Prognostic models identified by the living systematic review and through contacting experts. A priori models were excluded that had a high risk of bias in the participant domain of PROBAST (prediction model study risk of bias assessment tool) or for which the applicability was deemed poor.
Methods
Eight prognostic models with diverse predictors were identified and validated. A two stage individual participant data meta-analysis was performed of the estimated model concordance (C) statistic, calibration slope, calibration-in-the-large, and observed to expected ratio (O:E) across the included clusters.
Main outcome measures
30 day mortality or in-hospital mortality.
Results
Datasets included 27 clusters from 18 different countries and contained data on 46 914patients. The pooled estimates ranged from 0.67 to 0.80 (C statistic), 0.22 to 1.22 (calibration slope), and 0.18 to 2.59 (O:E ratio) and were prone to substantial between study heterogeneity. The 4C Mortality Score by Knight et al (pooled C statistic 0.80, 95% confidence interval 0.75 to 0.84, 95% prediction interval 0.72 to 0.86) and clinical model by Wang et al (0.77, 0.73 to 0.80, 0.63 to 0.87) had the highest discriminative ability. On average, 29% fewer deaths were observed than predicted by the 4C Mortality Score (pooled O:E 0.71, 95% confidence interval 0.45 to 1.11, 95% prediction interval 0.21 to 2.39), 35% fewer than predicted by the Wang clinical model (0.65, 0.52 to 0.82, 0.23 to 1.89), and 4% fewer than predicted by Xie et al\'s model (0.96, 0.59 to 1.55, 0.21 to 4.28).
Conclusion
The prognostic value of the included models varied greatly between the data sources. Although the Knight 4C Mortality Score and Wang clinical model appeared most promising, recalibration (intercept and slope updates) is needed before implementation in routine care.

© 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: 12 Jul 2022; 378:e069881
de Jong VMT, Rousset RZ, Antonio-Villa NE, Buenen AG, ... Moons KGM, Debray TPA
BMJ: 12 Jul 2022; 378:e069881 | PMID: 35820692
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Impact:
Abstract

People of all ages benefit from drugs to lower blood pressure.

Saul H, Gursul D, Cassidy S, Rahini K
The studyThe Blood Pressure Lowering Treatment Trialists\' Collaboration. Age-stratified and blood-pressure-stratified effects of blood-pressure-lowering pharmacotherapy for the prevention of cardiovascular disease and death: an individual participant-level data meta-analysis. Lancet 2021;398:1053-64.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/people-of-all-ages-benefit-from-drugs-to-lower-blood-pressure/.

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: 11 Jul 2022; 378:o1375
Saul H, Gursul D, Cassidy S, Rahini K
BMJ: 11 Jul 2022; 378:o1375 | PMID: 35817423
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Impact:
Abstract

Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis.

Pereira TV, Jüni P, Saadat P, Xing D, ... Hincapié CA, da Costa BR
Objective
To evaluate the effectiveness and safety of viscosupplementation for pain and function in patients with knee osteoarthritis.
Design
Systematic review and meta-analysis of randomised trials.
Data sources
Searches were conducted of Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to 11 September 2021. Unpublished trials were identified from the grey literature and trial registries.
Eligibility criteria for study selection
Randomised trials comparing viscosupplementation with placebo or no intervention for knee osteoarthritis treatment.
Main outcome measures
The prespecified primary outcome was pain intensity. Secondary outcomes were function and serious adverse events. Pain and function were analysed as standardised mean differences (SMDs). The prespecified minimal clinically important between group difference was -0.37 SMD. Serious adverse events were analysed as relative risks.
Methods
Two reviewers independently extracted relevant data and assessed the risk of bias of trials using the Cochrane risk of bias tool. The predefined main analysis was based only on large, placebo controlled trials with ≥100 participants per group. Summary results were obtained through a random effects meta-analysis model. Cumulative meta-analysis and trial sequential analysis under a random effects model were also performed.
Results
169 trials provided data on 21 163 randomised participants. Evidence of small study effects and publication biases was observed for pain and function (Egger\'s tests with P<0.001 and asymmetric funnel plots). Twenty four large, placebo controlled trials (8997 randomised participants) included in the main analysis of pain indicated that viscosupplementation was associated with a small reduction in pain intensity compared with placebo (SMD -0.08, 95% confidence interval -0.15 to -0.02), with the lower bound of the 95% confidence interval excluding the minimal clinically important between group difference. This effect corresponds to a difference in pain scores of -2.0 mm (95% confidence interval -3.8 to -0.5 mm) on a 100 mm visual analogue scale. Trial sequential analysis for pain indicated that since 2009 there has been conclusive evidence of clinical equivalence between viscosupplementation and placebo. Similar conclusions were obtained for function. Based on 15 large, placebo controlled trials on 6462 randomised participants, viscosupplementation was associated with a statistically significant higher risk of serious adverse events than placebo (relative risk 1.49, 95% confidence interval 1.12 to 1.98).
Conclusion
Strong conclusive evidence indicates that viscosupplementation leads to a small reduction in knee osteoarthritis pain compared with placebo, but the difference is less than the minimal clinically important between group difference. Strong conclusive evidence indicates that viscosupplementation is also associated with an increased risk of serious adverse events compared with placebo. The findings do not support broad use of viscosupplementation for the treatment of knee osteoarthritis.
Systematic review registration
PROSPERO CRD42021236894.

© 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: 06 Jul 2022; 378:e069722
Pereira TV, Jüni P, Saadat P, Xing D, ... Hincapié CA, da Costa BR
BMJ: 06 Jul 2022; 378:e069722 | PMID: 36333100
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Impact:
Abstract

Racial bias and reproducibility in pulse oximetry among medical and surgical inpatients in general care in the Veterans Health Administration 2013-19: multicenter, retrospective cohort study.

Valbuena VSM, Seelye S, Sjoding MW, Valley TS, ... Prescott HC, Iwashyna TJ
Objectives
To evaluate measurement discrepancies by race between pulse oximetry and arterial oxygen saturation (as measured in arterial blood gas) among inpatients not in intensive care.
Design
Multicenter, retrospective cohort study using electronic medical records from general care medical and surgical inpatients.
Setting
Veteran Health Administration, a national and racially diverse integrated health system in the United States, from 2013 to 2019.
Participants
Adult inpatients in general care (medical and surgical), in Veteran Health Administration medical centers.
Main outcomes measures
Occult hypoxemia (defined as arterial blood oxygen saturation (SaO2) of <88% despite a pulse oximetry (SpO2) reading of ≥92%), and whether rates of occult hypoxemia varied by race and ethnic origin.
Results
A total of 30 039 pairs of SpO2-SaO2 readings made within 10 minutes of each other were identified during the study. These pairs were predominantly among non-Hispanic white (21 918 (73.0%)) patients; non-Hispanic black patients and Hispanic or Latino patients accounted for 6498 (21.6%) and 1623 (5.4%) pairs in the sample, respectively. Among SpO2 values greater or equal to 92%, unadjusted probabilities of occult hypoxemia were 15.6% (95% confidence interval 15.0% to 16.1%) in white patients, 19.6% (18.6% to 20.6%) in black patients (P<0.001 v white patients, with similar P values in adjusted models), and 16.2% (14.4% to 18.1%) in Hispanic or Latino patients (P=0.53 v white patients, P<0.05 in adjusted models). This result was consistent in SpO2-SaO2 pairs restricted to occur within 5 minutes and 2 minutes. In white patients, an initial SpO2-SaO2 pair with little difference in saturation was associated with a 2.7% (95% confidence interval -0.1% to 5.5%) probability of SaO2 <88% on a later paired SpO2-SaO2 reading showing an SpO2 of 92%, but black patients had a higher probability (12.9% (-3.3% to 29.0%)).
Conclusions
In general care inpatient settings across the Veterans Health Administration where paired readings of arterial blood gas (SaO2) and pulse oximetry (SpO2) were obtained, black patients had higher odds than white patients of having occult hypoxemia noted on arterial blood gas but not detected by pulse oximetry. This difference could limit access to supplemental oxygen and other more intensive support and treatments for black patients.

© 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 Jul 2022; 378:e069775
Valbuena VSM, Seelye S, Sjoding MW, Valley TS, ... Prescott HC, Iwashyna TJ
BMJ: 06 Jul 2022; 378:e069775 | PMID: 35793817
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Impact:
Abstract

Effectiveness of a fourth dose of covid-19 mRNA vaccine against the omicron variant among long term care residents in Ontario, Canada: test negative design study.

Grewal R, Kitchen SA, Nguyen L, Buchan SA, ... Costa AP, Kwong JC
Objectives
To estimate the marginal effectiveness of a fourth versus third dose and the vaccine effectiveness of mRNA covid-19 vaccines BNT162b2 and mRNA-1273 against any infection, symptomatic infection, and severe outcomes (hospital admission or death) related to the omicron variant.
Design
Test negative design.
Setting
Long term care facilities in Ontario, Canada, 30 December 2021 to 27 April 2022.
Participants
After exclusions, 61 344 residents aged 60 years or older across 626 long term care facilities in Ontario, Canada who were tested for SARS-CoV-2 were included.
Main outcome measures
Laboratory confirmed omicron SARS-CoV-2 infection (any and symptomatic) by reverse transcription polymerase chain reaction (RT-PCR), and hospital admission or death. Multivariable logistic regression was used to estimate marginal effectiveness (four versus three doses) and vaccine effectiveness (two, three, or four doses versus no doses) while adjusting for personal characteristics, comorbidities, week of test, and previous positive SARS-CoV-2 test result more than 90 days previously.
Results
13 654 residents who tested positive for omicron SARS-CoV-2 infection and 205 862 test negative controls were included. The marginal effectiveness of a fourth dose (95% of vaccine recipients received mRNA-1273 as the fourth dose) seven days or more after vaccination versus a third dose received 84 or more days previously was 19% (95% confidence interval 12% to 26%) against infection, 31% (20% to 41%) against symptomatic infection, and 40% (24% to 52%) against severe outcomes. Vaccine effectiveness in vaccine recipients (compared with unvaccinated) increased with each additional dose, and for a fourth dose was 49% (95% confidence interval 43% to 54%) against infection, 69% (61% to 76%) against symptomatic infection, and 86% (81% to 90%) against severe outcomes.
Conclusions
The findings suggest that compared with a third dose of mRNA covid-19 vaccine, a fourth dose improved protection against infection, symptomatic infection, and severe outcomes among long term care residents during an omicron dominant period. A fourth vaccine dose was associated with strong protection against severe outcomes in vaccinated residents compared with unvaccinated residents, although the duration of protection remains unknown.

© 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: 06 Jul 2022; 378:e071502
Grewal R, Kitchen SA, Nguyen L, Buchan SA, ... Costa AP, Kwong JC
BMJ: 06 Jul 2022; 378:e071502 | PMID: 35793826
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Impact:
Abstract

Anticoagulants for thrombosis prophylaxis in acutely ill patients admitted to hospital: systematic review and network meta-analysis.

Eck RJ, Elling T, Sutton AJ, Wetterslev J, ... Meijer K, Keus F
Objective
To assess the benefits and harms of different types and doses of anticoagulant drugs for the prevention of venous thromboembolism in patients who are acutely ill and admitted to hospital.
Design
Systematic review and network meta-analysis.
Data sources
Cochrane CENTRAL, PubMed/Medline, Embase, Web of Science, clinical trial registries, and national health authority databases. The search was last updated on 16 November 2021.
Eligibility criteria for selecting studies
Published and unpublished randomised controlled trials that evaluated low or intermediate dose low-molecular-weight heparin, low or intermediate dose unfractionated heparin, direct oral anticoagulants, pentasaccharides, placebo, or no intervention for the prevention of venous thromboembolism in acutely ill adult patients in hospital.
Main outcome measures
Random effects, bayesian network meta-analyses used four co-primary outcomes: all cause mortality, symptomatic venous thromboembolism, major bleeding, and serious adverse events at or closest timing to 90 days. Risk of bias was also assessed using the Cochrane risk-of-bias 2.0 tool. The quality of evidence was graded using the Confidence in Network Meta-Analysis framework.
Results
44 randomised controlled trials that randomly assigned 90 095 participants were included in the main analysis. Evidence of low to moderate quality suggested none of the interventions reduced all cause mortality compared with placebo. Pentasaccharides (odds ratio 0.32, 95% credible interval 0.08 to 1.07), intermediate dose low-molecular-weight heparin (0.66, 0.46 to 0.93), direct oral anticoagulants (0.68, 0.33 to 1.34), and intermediate dose unfractionated heparin (0.71, 0.43 to 1.19) were most likely to reduce symptomatic venous thromboembolism (very low to low quality evidence). Intermediate dose unfractionated heparin (2.63, 1.00 to 6.21) and direct oral anticoagulants (2.31, 0.82 to 6.47) were most likely to increase major bleeding (low to moderate quality evidence). No conclusive differences were noted between interventions regarding serious adverse events (very low to low quality evidence). When compared with no intervention instead of placebo, all active interventions did more favourably with regard to risk of venous thromboembolism and mortality, and less favourably with regard to risk of major bleeding. The results were robust in prespecified sensitivity and subgroup analyses.
Conclusions
Low-molecular-weight heparin in an intermediate dose appears to confer the best balance of benefits and harms for prevention of venous thromboembolism. Unfractionated heparin, in particular the intermediate dose, and direct oral anticoagulants had the least favourable profile. A systematic discrepancy was noted in intervention effects that depended on whether placebo or no intervention was the reference treatment. Main limitations of this study include the quality of the evidence, which was generally low to moderate due to imprecision and within-study bias, and statistical inconsistency, which was addressed post hoc.
Systematic review registration
PROSPERO CRD42020173088.

© 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: 04 Jul 2022; 378:e070022
Eck RJ, Elling T, Sutton AJ, Wetterslev J, ... Meijer K, Keus F
BMJ: 04 Jul 2022; 378:e070022 | PMID: 35788047
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Impact:
Abstract

Frail older people and those in deprived areas remain at risk from covid-19, even after vaccination.

Saul H, Gursul D, Antonelli M, Steves C
The studyAntonelli M, Penfold RS, Merino J, et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. Lancet Infect Dis 2022;22:1.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/older-people-at-risk-from-covid-even-after-vaccine/.

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: 04 Jul 2022; 378:o1313
Saul H, Gursul D, Antonelli M, Steves C
BMJ: 04 Jul 2022; 378:o1313 | PMID: 35787513
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Impact:
Abstract

Long distance airborne transmission of SARS-CoV-2: rapid systematic review.

Duval D, Palmer JC, Tudge I, Pearce-Smith N, ... Bennett A, Clark R
Objectives
To evaluate the potential for long distance airborne transmission of SARS-CoV-2 in indoor community settings and to investigate factors that might influence transmission.
Design
Rapid systematic review and narrative synthesis.
Data sources
Medline, Embase, medRxiv, Arxiv, and WHO COVID-19 Research Database for studies published from 27 July 2020 to 19 January 2022; existing relevant rapid systematic review for studies published from 1 January 2020 to 27 July 2020; and citation analysis in Web of Science and Cocites.
Eligibility criteria for study selection
Observational studies reporting on transmission events in indoor community (non-healthcare) settings in which long distance airborne transmission of SARS-CoV-2 was the most likely route. Studies such as those of household transmission where the main transmission route was likely to be close contact or fomite transmission were excluded.
Data extraction and synthesis
Data extraction was done by one reviewer and independently checked by a second reviewer. Primary outcomes were SARS-CoV-2 infections through long distance airborne transmission (>2 m) and any modifying factors. Methodological quality of included studies was rated using the quality criteria checklist, and certainty of primary outcomes was determined using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. Narrative synthesis was themed by setting.
Results
22 reports relating to 18 studies were identified (methodological quality was high in three, medium in five, and low in 10); all the studies were outbreak investigations. Long distance airborne transmission was likely to have occurred for some or all transmission events in 16 studies and was unclear in two studies (GRADE: very low certainty). In the 16 studies, one or more factors plausibly increased the likelihood of long distance airborne transmission, particularly insufficient air replacement (very low certainty), directional air flow (very low certainty), and activities associated with increased emission of aerosols, such as singing or speaking loudly (very low certainty). In 13 studies, the primary cases were reported as being asymptomatic, presymptomatic, or around symptom onset at the time of transmission. Although some of the included studies were well conducted outbreak investigations, they remain at risk of bias owing to study design and do not always provide the level of detail needed to fully assess transmission routes.
Conclusion
This rapid systematic review found evidence suggesting that long distance airborne transmission of SARS-CoV-2 might occur in indoor settings such as restaurants, workplaces, and venues for choirs, and identified factors such as insufficient air replacement that probably contributed to transmission. These results strengthen the need for mitigation measures in indoor settings, particularly the use of adequate ventilation.
Systematic review registration
PROSPERO CRD42021236762.

© 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: 29 Jun 2022; 377:e068743
Duval D, Palmer JC, Tudge I, Pearce-Smith N, ... Bennett A, Clark R
BMJ: 29 Jun 2022; 377:e068743 | PMID: 35768139
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Impact:
Abstract

Almost half of people on long term antidepressants can stop without relapsing.

Saul H, Gursul D, Cassidy S, Duffy L, Lewis G, Lewis G
The studyDuffy L, Clarke CS, Lewis G, et al. Antidepressant medication to prevent depression relapse in primary care: the ANTLER RCT. Health Technol Assess 2021;25:69.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/almost-half-people-long-term-antidepressants-stop-without-relapse/.

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BMJ: 28 Jun 2022; 377:o1362
Saul H, Gursul D, Cassidy S, Duffy L, Lewis G, Lewis G
BMJ: 28 Jun 2022; 377:o1362 | PMID: 35764321
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Impact:
Abstract

Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials.

He L, Wang J, Ping F, Yang N, ... Zhang H, Li Y
Objective
To examine the association between dipeptidyl peptidase-4 inhibitors and gallbladder or biliary diseases.
Design
Systematic review and pairwise and network meta-analysis.
Data sources
PubMed, EMBASE, Web of Science, and CENTRAL from inception until 31 July 2021.
Eligibility criteria
Randomised controlled trials of adult patients with type 2 diabetes who received dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors compared with placebo or other antidiabetes drugs.
Main outcome measures
Composite of gallbladder or biliary diseases, cholecystitis, cholelithiasis, and biliary diseases.
Data extraction and data synthesis
Two reviewers independently extracted the data and assessed the quality of the studies. The quality of the evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development and Evaluations framework (GRADE) approach. The meta-analysis used pooled odds ratios and 95% confidence intervals.
Results
A total of 82 randomised controlled trials with 104 833 participants were included in the pairwise meta-analysis. Compared with placebo or non-incretin drugs, dipeptidyl peptidase-4 inhibitors were significantly associated with an increased risk of the composite of gallbladder or biliary diseases (odds ratio 1.22 (95%confidence interval 1.04 to 1.43); risk difference 11 (2 to 21) more events per 10 000 person years) and cholecystitis (odds ratio 1.43 (1.14 to 1.79); risk difference 15 (5 to 27) more events per 10 000 person years) but not with the risk of cholelithiasis and biliary diseases. The associations tended to be observed in patients with a longer duration of dipeptidyl peptidase-4 inhibitor treatment. In the network meta-analysis of 184 trials, dipeptidyl peptidase-4 inhibitors increased the risk of the composite of gallbladder or biliary diseases and cholecystitis compared with sodium-glucose cotransporter-2 inhibitors but not compared with glucagon-like peptide-1 receptor agonists.
Conclusions
Dipeptidyl peptidase-4 inhibitors increased the risk of cholecystitis in randomised controlled trials, especially with a longer treatment duration, which requires more attention from physicians in clinical practice.
Systematic review registration
PROSPERO CRD42021271647.

© 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 Jun 2022; 377:e068882
He L, Wang J, Ping F, Yang N, ... Zhang H, Li Y
BMJ: 28 Jun 2022; 377:e068882 | PMID: 35764326
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Impact:
Abstract

User centered clinical decision support to implement initiation of buprenorphine for opioid use disorder in the emergency department: EMBED pragmatic cluster randomized controlled trial.

Melnick ER, Nath B, Dziura JD, Casey MF, ... Hess EP, D\'Onofrio G
Objective
To determine the effect of a user centered clinical decision support tool versus usual care on rates of initiation of buprenorphine in the routine emergency care of individuals with opioid use disorder.
Design
Pragmatic cluster randomized controlled trial (EMBED).
Setting
18 emergency department clusters across five healthcare systems in five states representing the north east, south east, and western regions of the US, ranging from community hospitals to tertiary care centers, using either the Epic or Cerner electronic health record platform.
Participants
599 attending emergency physicians caring for 5047 adult patients presenting with opioid use disorder.
Intervention
A user centered, physician facing clinical decision support system seamlessly integrated into user workflows in the electronic health record to support initiating buprenorphine in the emergency department by helping clinicians to diagnose opioid use disorder, assess the severity of withdrawal, motivate patients to accept treatment, and complete electronic health record tasks by automating clinical and after visit documentation, order entry, prescribing, and referral.
Main outcome measures
Rate of initiation of buprenorphine (administration or prescription of buprenorphine) in the emergency department among patients with opioid use disorder. Secondary implementation outcomes were measured with the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework.
Results
1 413 693 visits to the emergency department (775 873 in the intervention arm and 637 820 in the usual care arm) from November 2019 to May 2021 were assessed for eligibility, resulting in 5047 patients with opioid use disorder (2787 intervention arm, 2260 usual care arm) under the care of 599 attending physicians (340 intervention arm, 259 usual care arm) for analysis. Buprenorphine was initiated in 347 (12.5%) patients in the intervention arm and in 271 (12.0%) patients in the usual care arm (adjusted generalized estimating equations odds ratio 1.22, 95% confidence interval 0.61 to 2.43, P=0.58). Buprenorphine was initiated at least once by 151 (44.4%) physicians in the intervention arm and by 88 (34.0%) in the usual care arm (1.83, 1.16 to 2.89, P=0.01).
Conclusions
User centered clinical decision support did not increase patient level rates of initiating buprenorphine in the emergency department. Although streamlining and automating electronic health record workflows can potentially increase adoption of complex, unfamiliar evidence based practices, more interventions are needed to look at other barriers to the treatment of addiction and increase the rate of initiating buprenorphine in the emergency department in patients with opioid use disorder.
Trial registration
ClinicalTrials.gov NCT03658642.

© 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: 27 Jun 2022; 377:e069271
Melnick ER, Nath B, Dziura JD, Casey MF, ... Hess EP, D'Onofrio G
BMJ: 27 Jun 2022; 377:e069271 | PMID: 35760423
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Impact:
Abstract

The evidence base for US joint commission hospital accreditation standards: cross sectional study.

Ibrahim SA, Reynolds KA, Poon E, Alam M
Objective
To evaluate the evidence upon which standards for hospital accreditation by The Joint Commission on Accreditation of Healthcare Organizations (the Joint Commission) are based.
Design
Cross sectional study.
Setting
United States.
Participants
Four Joint Commission R3 (requirement, rationale, and reference) reports released by July 2018 and intended to become effective between 1 July 2018 and 1 July 2019.
Interventions
From each R3 report the associated standard and its specific elements of performance (or actionable standards) were extracted. If an actionable standard enumerated multiple requirements, these were separated into distinct components. Two investigators reviewed full text references, and each actionable standard was classified as either completely supported, partly supported, or not supported; Oxford evidence quality ratings were assigned; and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was used to assess the strength of recommendations.
Main outcome measure
Strengths of recommendation for actionable standards.
Results
20 actionable standards with 76 distinct components were accompanied by 48 references. Of the 20 actionable standards, six (30%) were completely supported by cited references, six were partly supported (30%), and eight (40%) were not supported. Of the six directly supported actionable standards, one (17%) cited at least one reference of level 1 or 2 evidence, none cited at least one reference of level 3 evidence, and five (83%) cited references of level 4 or 5 evidence. Of the completely supported actionable standards, strength of recommendation in five was deemed GRADE D and in one was GRADE B.
Conclusions
In general, recent actionable standards issued by The Joint Commission are seldom supported by high quality data referenced within the issuing documents. The Joint Commission might consider being more transparent about the quality of evidence and underlying rationale supporting each of its recommendations, including clarifying when and why in certain instances it determines that lower level evidence is sufficient.

© 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: 23 Jun 2022; 377:e063064
Ibrahim SA, Reynolds KA, Poon E, Alam M
BMJ: 23 Jun 2022; 377:e063064 | PMID: 35738660
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Impact:
Abstract

Industry sponsorship bias in cost effectiveness analysis: registry based analysis.

Xie F, Zhou T
Objective
To assess the association between industry sponsorship (drug, medical device, and biotechnology companies) and cost effectiveness results in cost effectiveness analysis (CEA).
Design
Registry based analysis DATA SOURCE: The Tufts Cost-Effectiveness Analysis Registry was used to identify all CEAs published in Medline between 1976 and 2021.
Eligibility criteria for selecting studies
CEAs that reported incremental cost effectiveness ratio (ICER) using quality adjusted life year and provided sufficient information about the magnitude or location of the ICER.
Methods
Descriptive analyses were used to describe and compare the characteristics of CEAs with and without industry sponsorship. Logistic regression was used to identify the association between industry sponsorship and the cost effective conclusion using selected threshold values ($50 000 (£40 511; €47 405), $100 000, and $150 000). Robust linear regression was used to assess the association between industry sponsorship and the magnitude of ICER. All regression analyses were adjusted for disease and study design characteristics.
Results
8192 CEAs were eligible and included in the analysis, with 2437 (29.7%) sponsored by industry. Industry sponsored CEAs were more likely to publish ICERs below $50 000 (adjusted odds ratio 2.06, 95% confidence interval 1.82 to 2.33), $100 000 (2.95, 2.52 to 3.44), and $150 000 (3.34, 2.80 to 3.99) than non-industry sponsored studies. Among 5877 CEAs that reported positive incremental costs and quality adjusted life years, ICERs from industry sponsored studies were 33% lower (95% confidence interval -40 to -26) than those from non-industry sponsored studies.
Conclusions
Sponsorship bias in CEAs is significant, systemic, and present across a range of diseases and study designs. Use of CEAs conducted by independent bodies could provide payers with more ability to negotiate lower prices. This impartiality is especially important for countries that rely on published CEAs to inform policy making for insurance coverage because of limited capacity for independent economic analysis.

© 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: 22 Jun 2022; 377:e069573
Xie F, Zhou T
BMJ: 22 Jun 2022; 377:e069573 | PMID: 35732297
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Impact:
Abstract

Infertility, recurrent pregnancy loss, and risk of stroke: pooled analysis of individual patient data of 618 851 women.

Liang C, Chung HF, Dobson AJ, Hayashi K, ... Weiderpass E, Mishra GD
Objective
To examine the associations of infertility, recurrent miscarriage, and stillbirth with the risk of first non-fatal and fatal stroke, further stratified by stroke subtypes.
Design
Individual participant pooled analysis of eight prospective cohort studies.
Setting
Cohort studies across seven countries (Australia, China, Japan, Netherlands, Sweden, the United Kingdom, and the United States) participating in the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium, which was established in June 2012.
Participants
618 851 women aged 32.0-73.0 years at baseline with data on infertility, miscarriage, or stillbirth, at least one outcome event (non-fatal or fatal stroke), and information on covariates were included; 93 119 women were excluded. Of the participants, 275 863 had data on non-fatal and fatal stroke, 54 716 only had data on non-fatal stroke, and 288 272 only had data on fatal stroke.
Main outcome and measures
Non-fatal strokes were identified through self-reported questionnaires, linked hospital data, or national patient registers. Fatal strokes were identified through death registry data.
Results
The median follow-up for non-fatal stroke and fatal stroke was 13.0 years (interquartile range 12.0-14.0) and 9.4 years (7.6-13.0), respectively. A first non-fatal stroke was experienced by 9265 (2.8%) women and 4003 (0.7%) experienced a fatal stroke. Hazard ratios for non-fatal or fatal stroke were stratified by hypertension and adjusted for race or ethnicity, body mass index, smoking status, education level, and study. Infertility was associated with an increased risk of non-fatal stroke (hazard ratio 1.14, 95% confidence interval 1.08 to 1.20). Recurrent miscarriage (at least three) was associated with higher risk of non-fatal and fatal stroke (1.35, 1.27 to 1.44, and 1.82, 1.58 to 2.10, respectively). Women with stillbirth were at 31% higher risk of non-fatal stroke (1.31, 1.10 to 1.57) and women with recurrent stillbirth were at 26% higher risk of fatal stroke (1.26, 1.15 to 1.39). The increased risk of stroke (non-fatal or fatal) associated with infertility or recurrent stillbirths was mainly driven by a single stroke subtype (non-fatal ischaemic stroke and fatal haemorrhagic stroke), while the increased risk of stroke (non-fatal or fatal) associated with recurrent miscarriages was driven by both subtypes.
Conclusion
A history of recurrent miscarriages and death or loss of a baby before or during birth could be considered a female specific risk factor for stroke, with differences in risk according to stroke subtypes. These findings could contribute to improved monitoring and stroke prevention for women with such a history.

© 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: 22 Jun 2022; 377:e070603
Liang C, Chung HF, Dobson AJ, Hayashi K, ... Weiderpass E, Mishra GD
BMJ: 22 Jun 2022; 377:e070603 | PMID: 35732311
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Impact:
Abstract

Revascularization in stable coronary artery disease.

Al-Lamee RK, Foley M, Rajkumar CA, Francis DP
Management of stable coronary artery disease (CAD) centers on medication to prevent myocardial infarction and death. Many anti-anginal medications also have benefit for reducing symptoms, and have been proven to be effective against placebo control. Before effective preventive medications were available, patients with stable CAD often underwent revascularization with coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), on the plausible assumption that these procedures would prevent adverse events and reduce symptoms. However, recent randomized controlled trials have cast doubt on these assumptions.Considering results from the recent ISCHEMIA trial, we discuss the evidence base that underpins revascularization for stable CAD in contemporary practice. We also focus on patient groups at high risk of myocardial infarction and death, for whom revascularization is often recommended. We outline the areas of uncertainty, unanswered research questions, and key areas of potential miscommunication in doctor-patient consultations.

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BMJ: 13 Jun 2022; 377:e067085
Al-Lamee RK, Foley M, Rajkumar CA, Francis DP
BMJ: 13 Jun 2022; 377:e067085 | PMID: 35697356
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Impact:
Abstract

Change in covid-19 risk over time following vaccination with CoronaVac: test negative case-control study.

Hitchings MDT, Ranzani OT, Lind ML, Dorion M, ... Ko AI, Croda J
Objective
To estimate the change in odds of covid-19 over time following primary series completion of the inactivated whole virus vaccine CoronaVac (Sinovac Biotech) in São Paulo State, Brazil.
Design
Test negative case-control study.
Setting
Community testing for covid-19 in São Paulo State, Brazil.
Participants
Adults aged ≥18 years who were residents of São Paulo state, had received two doses of CoronaVac, did not have a laboratory confirmed SARS-CoV-2 infection before vaccination, and underwent reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 from 17 January to 14 December 2021. Cases were matched to test negative controls by age (in 5 year bands), municipality of residence, healthcare worker status, and epidemiological week of RT-PCR test.
Main outcome measures
RT-PCR confirmed symptomatic covid-19 and associated hospital admissions and deaths. Conditional logistic regression was adjusted for sex, number of covid-19 associated comorbidities, race, and previous acute respiratory illness.
Results
From 202 741 eligible people, 52 170 cases with symptomatic covid-19 and 69 115 test negative controls with covid-19 symptoms were formed into 43 257 matched sets. Adjusted odds ratios of symptomatic covid-19 increased with time since completion of the vaccination series. The increase in odds was greater in younger people and among healthcare workers, although sensitivity analyses suggested that this was in part due to bias. In addition, the adjusted odds ratios of covid-19 related hospital admission or death significantly increased with time compared with the odds 14-41 days after series completion: from 1.25 (95% confidence interval 1.04 to 1.51) at 70-97 days up to 1.94 (1.41 to 2.67) from 182 days onwards.
Conclusions
Significant increases in the risk of moderate and severe covid-19 outcomes occurred three months after primary vaccination with CoronaVac among people aged 65 and older. These findings provide supportive evidence for the implementation of vaccine boosters in these populations who received this inactivated vaccine. Studies of waning should include analyses designed to uncover common biases.

© 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: 13 Jun 2022; 377:e070102
Hitchings MDT, Ranzani OT, Lind ML, Dorion M, ... Ko AI, Croda J
BMJ: 13 Jun 2022; 377:e070102 | PMID: 35697361
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Impact:
Abstract

Development and validation of a decision support tool for the diagnosis of acute heart failure: systematic review, meta-analysis, and modelling study.

Lee KK, Doudesis D, Anwar M, Astengo F, ... Mills NL, CoDE-HF investigators
Objectives
To evaluate the diagnostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) thresholds for acute heart failure and to develop and validate a decision support tool that combines NT-proBNP concentrations with clinical characteristics.
Design
Individual patient level data meta-analysis and modelling study.
Setting
Fourteen studies from 13 countries, including randomised controlled trials and prospective observational studies.
Participants
Individual patient level data for 10 369 patients with suspected acute heart failure were pooled for the meta-analysis to evaluate NT-proBNP thresholds. A decision support tool (Collaboration for the Diagnosis and Evaluation of Heart Failure (CoDE-HF)) that combines NT-proBNP with clinical variables to report the probability of acute heart failure for an individual patient was developed and validated.
Main outcome measure
Adjudicated diagnosis of acute heart failure.
Results
Overall, 43.9% (4549/10 369) of patients had an adjudicated diagnosis of acute heart failure (73.3% (2286/3119) and 29.0% (1802/6208) in those with and without previous heart failure, respectively). The negative predictive value of the guideline recommended rule-out threshold of 300 pg/mL was 94.6% (95% confidence interval 91.9% to 96.4%); despite use of age specific rule-in thresholds, the positive predictive value varied at 61.0% (55.3% to 66.4%), 73.5% (62.3% to 82.3%), and 80.2% (70.9% to 87.1%), in patients aged <50 years, 50-75 years, and >75 years, respectively. Performance varied in most subgroups, particularly patients with obesity, renal impairment, or previous heart failure. CoDE-HF was well calibrated, with excellent discrimination in patients with and without previous heart failure (area under the receiver operator curve 0.846 (0.830 to 0.862) and 0.925 (0.919 to 0.932) and Brier scores of 0.130 and 0.099, respectively). In patients without previous heart failure, the diagnostic performance was consistent across all subgroups, with 40.3% (2502/6208) identified at low probability (negative predictive value of 98.6%, 97.8% to 99.1%) and 28.0% (1737/6208) at high probability (positive predictive value of 75.0%, 65.7% to 82.5%) of having acute heart failure.
Conclusions
In an international, collaborative evaluation of the diagnostic performance of NT-proBNP, guideline recommended thresholds to diagnose acute heart failure varied substantially in important patient subgroups. The CoDE-HF decision support tool incorporating NT-proBNP as a continuous measure and other clinical variables provides a more consistent, accurate, and individualised approach.
Study registration
PROSPERO CRD42019159407.

© 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: 13 Jun 2022; 377:e068424
Lee KK, Doudesis D, Anwar M, Astengo F, ... Mills NL, CoDE-HF investigators
BMJ: 13 Jun 2022; 377:e068424 | PMID: 35697365
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Abstract

Dexamethasone should not be given to people with a chronic subdural haematoma.

Saul H, Gursul D, Cassidy S, Hutchinson P, Kolias A
The studyHutchinson P, Edlmann E, Bulters D, et al. Trial of dexamethasone for chronic subdural haematoma. N Engl J Med 2020;383:2616-27.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/dexamethasone-should-not-be-used-chronic-subdural-haematoma/.

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BMJ: 10 Jun 2022; 377:o1302
Saul H, Gursul D, Cassidy S, Hutchinson P, Kolias A
BMJ: 10 Jun 2022; 377:o1302 | PMID: 35688460
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Abstract

Approach for reporting master protocol study designs on ClinicalTrials.gov: qualitative analysis.

Williams RJ, Dobbins HD, Tse T, Chon SD, ... Rockhold FW, Zarin DA
Objective
To describe an approach for reporting master protocol research programs (MPRPs) that is consistent with existing good reporting practices and that uses structured information to convey the overall master protocol and design of each substudy.
Design
Qualitative analysis.
Data sources
ClinicalTrials.gov trial registry.
Main outcome measures
Established goals and related practices of the trial reporting system were outlined, examples and key characteristics of MPRPs were reviewed, and specific challenges in registering and reporting summary results to databases designed for traditional clinical trial designs that rely on a model of one study per protocol were identified.
Results
A reporting approach is proposed that accommodates the complex study design of MPRPs and their results. This approach involves the use of separate registration records for each substudy within one MPRP protocol (with potential exceptions noted).
Conclusions
How the proposed approach allows for clear, descriptive, structured information about each substudy\'s prespecified design and supports timely reporting of results after completion of each substudy is described and illustrated. Although the focus is on reporting to ClinicalTrials.gov, the approach supports broader application across trial registries and results databases. This paper is intended to stimulate further discussion of this approach among stakeholders, build awareness about the need to improve reporting of MPRPs, and encourage harmonization across trial registries globally.

© 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 Jun 2022; 377:e067745
Williams RJ, Dobbins HD, Tse T, Chon SD, ... Rockhold FW, Zarin DA
BMJ: 10 Jun 2022; 377:e067745 | PMID: 35688481
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Abstract

Political environment and mortality rates in the United States, 2001-19: population based cross sectional analysis.

Warraich HJ, Kumar P, Nasir K, Joynt Maddox KE, Wadhera RK
Objective
To assess recent trends in age adjusted mortality rates (AAMRs) in the United States based on county level presidential voting patterns.
Design
Cross sectional study.
Setting
USA, 2001-19.
Participants
99.8% of the US population.
Main outcome measures
AAMR per 100 000 population and average annual percentage change (APC).
Methods
The Centers for Disease Control and Prevention WONDER database was linked to county level data on US presidential elections. County political environment was classified as either Democratic or Republican for the four years that followed a November presidential election. Additional sensitivity analyses analyzed AAMR trends for counties that voted only for one party throughout the study, and county level gubernatorial election results and state level AAMR trends. Joinpoint analysis was used to assess for an inflection point in APC trends.
Results
The study period covered five presidential elections from 2000 to 2019. From 2001 to 2019, the AAMR per 100 000 population decreased by 22% in Democratic counties, from 850.3 to 664.0 (average APC -1.4%, 95% confidence interval -1.5% to -1.2%), but by only 11% in Republican counties, from 867.0 to 771.1 (average APC -0.7%, -0.9% to -0.5%). The gap in AAMR between Democratic and Republican counties therefore widened from 16.7 (95% confidence interval 16.6 to 16.8) to 107.1 (106.5 to 107.7). Statistically significant inflection points in APC occurred for Democratic counties between periods 2001-09 (APC -2.1%, -2.3% to -1.9%) and 2009-19 (APC -0.8%, -1.0% to -0.6%). For Republican counties between 2001 and 2008 the APC was -1.4% (-1.8% to -1.0%), slowing to near zero between 2008 and 2019 (APC -0.2%, -0.4% to 0.0%). Male and female residents of Democratic counties experienced both lower AAMR and twice the relative decrease in AAMR than did those in Republican counties. Black Americans experienced largely similar improvement in AAMR in both Democratic and Republican counties. However, the AAMR gap between white residents in Democratic versus Republican counties increased fourfold, from 24.7 (95% confidence interval 24.6 to 24.8) to 101.3 (101.0 to 101.6). Rural Republican counties experienced the highest AAMR and the least improvement. All trends were similar when comparing counties that did not switch political environment throughout the period and when gubernatorial election results were used. The greatest contributors to the widening AAMR gap between Republican and Democratic counties were heart disease (difference in AAMRs 27.6), cancer (17.3), and chronic lower respiratory tract diseases (8.3), followed by unintentional injuries (3.3) and suicide (3.0).
Conclusion
The mortality gap in Republican voting counties compared with Democratic voting counties has grown over time, especially for white populations, and that gap began to widen after 2008.

© 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: 07 Jun 2022; 377:e069308
Warraich HJ, Kumar P, Nasir K, Joynt Maddox KE, Wadhera RK
BMJ: 07 Jun 2022; 377:e069308 | PMID: 35672032
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Abstract

Effectiveness of heterologous and homologous covid-19 vaccine regimens: living systematic review with network meta-analysis.

Au WY, Cheung PP
Objective
To evaluate the effectiveness of heterologous and homologous covid-19 vaccine regimens with and without boosting in preventing covid-19 related infection, hospital admission, and death.
Design
Living systematic review and network meta-analysis.
Data sources
World Health Organization covid-19 databases, including 38 sources of published studies and preprints.
Study selection
Randomised controlled trials, cohort studies, and case-control studies.
Methods
38 WHO covid-19 databases were searched on a weekly basis from 8 March 2022. Studies that assessed the effectiveness of heterologous and homologous covid-19 vaccine regimens with or without a booster were identified. Studies were eligible when they reported the number of documented, symptomatic, severe covid-19 infections, covid-19 related hospital admissions, or covid-19 related deaths among populations that were vaccinated and unvaccinated. The primary measure was vaccine effectiveness calculated as 1-odds ratio. Secondary measures were surface under the cumulative ranking curve (SUCRA) scores and the relative effects for pairwise comparisons. The risk of bias was evaluated by using the risk of bias in non-randomised studies of interventions (ROBINS-I) tool for all cohort and case-control studies. The Cochrane risk of bias tool (version 2; ROB-2) was used to assess randomised controlled trials.
Results
The first round of the analysis comprised 53 studies. 24 combinations of covid-19 vaccine regimens were identified, of which a three dose mRNA regimen was found to be the most effective against asymptomatic and symptomatic covid-19 infections (vaccine effectiveness 96%, 95% credible interval 72% to 99%). Heterologous boosting using two dose adenovirus vector vaccines with one mRNA vaccine has a satisfactory vaccine effectiveness of 88% (59% to 97%). A homologous two dose mRNA regimen has a vaccine effectiveness of 99% (79% to 100%) in the prevention of severe covid-19 infections. Three dose mRNA is the most effective in reducing covid-19 related hospital admission (95%, 90% to 97%). The vaccine effectiveness against death in people who received three doses of mRNA vaccine remains uncertain owing to confounders. In the subgroup analyses, a three dose regimen is similarly effective in all age groups, even in the older population (≥65 years). A three dose mRNA regimen works comparably well in patients who are immunocompromised and those who are non-immunocompromised. Homologous and heterologous three dose regimens are effective in preventing infection by covid-19 variants (alpha, delta, and omicron).
Conclusion
An mRNA booster is recommended to supplement any primary vaccine course. Heterologous and homologous three dose regimens work comparably well in preventing covid-19 infections, even against different variants. The effectiveness of three dose vaccine regimens against covid-19 related death remains uncertain.
Systematic review registration
This review was not registered. The protocol is included in the supplementary document.
Readers\' note
This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

© 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: 31 May 2022; 377:e069989
Au WY, Cheung PP
BMJ: 31 May 2022; 377:e069989 | PMID: 35640925
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Abstract

Extension of cervical screening intervals with primary human papillomavirus testing: observational study of English screening pilot data.

Rebolj M, Cuschieri K, Mathews CS, Pesola F, ... Kitchener H, HPV pilot steering group
Objectives
To provide updated evidence about the risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) and cervical cancer after a negative human papillomavirus (HPV) test in primary cervical screening, by age group and test assay.
Design
Observational study.
Setting
Real world data from the English HPV screening pilot\'s first and second rounds (2013-16, follow-up to end of 2019).
Participants
1 341 584 women.
Interventions
Cervical screening with HPV testing or liquid based cytological testing (cytology or smear tests). Women screened with cytology were referred to colposcopy after high grade cytological abnormalities or after borderline or low grade abnormalities combined with a positive HPV triage test. Women screened with HPV testing who were positive were referred at baseline if their cytology triage test showed at least borderline abnormalities or after a retest (early recall) at 12 and 24 months if they had persistent abnormalities.
Main outcome measures
Detection of CIN3+ and cervical cancer after a negative HPV test.
Results
For women younger than 50 years, second round detection of CIN3+ in this study was significantly lower after a negative HPV screen in the first round than after cytology testing (1.21/1000 v 4.52/1000 women screened, adjusted odds ratio 0.26, 95% confidence interval 0.23 to 0.30), as was the risk of interval cervical cancer (1.31/100 000 v 2.90/100 000 woman years, adjusted hazard ratio 0.44, 0.23 to 0.84). Risk of an incident CIN3+ detected at the second screening round in the pilot five years after a negative HPV test was even lower in women older than 50 years, than in three years in women younger than 50 years (0.57/1000 v 1.21/1000 women screened, adjusted odds ratio 0.46, 0.27 to 0.79). Women with negative HPV tests at early recall after a positive HPV screening test without cytological abnormalities had a higher detection rate of CIN3+ at the second routine recall than women who initially tested HPV negative (5.39/1000 v 1.21/1000 women screened, adjusted odds ratio 3.27, 95% confidence interval 2.21 to 4.84). Detection after a negative result on a clinically validated APTIMA mRNA HPV test was similar to that after clinically validated cobas and RealTime DNA tests (for CIN3+ at the second round 1.32/1000 v 1.14/1000 women screened, adjusted odds ratio 1.05, 0.73 to 1.50).
Conclusions
These data support an extension of the screening intervals, regardless of the test assay used: to five years after a negative HPV test in women aged 25-49 years, and even longer for women aged 50 years and older. The screening interval for HPV positive women who have negative HPV tests at early recall should be kept at three years.

© 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: 31 May 2022; 377:e068776
Rebolj M, Cuschieri K, Mathews CS, Pesola F, ... Kitchener H, HPV pilot steering group
BMJ: 31 May 2022; 377:e068776 | PMID: 35640960
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Abstract

Effectiveness of weight management interventions for adults delivered in primary care: systematic review and meta-analysis of randomised controlled trials.

Madigan CD, Graham HE, Sturgiss E, Kettle VE, ... Taylor GMJ, Daley AJ
Objective
To examine the effectiveness of behavioural weight management interventions for adults with obesity delivered in primary care.
Design
Systematic review and meta-analysis of randomised controlled trials.
Eligibility criteria for selection of studies
Randomised controlled trials of behavioural weight management interventions for adults with a body mass index ≥25 delivered in primary care compared with no treatment, attention control, or minimal intervention and weight change at ≥12 months follow-up.
Data sources
Trials from a previous systematic review were extracted and the search completed using the Cochrane Central Register of Controlled Trials, Medline, PubMed, and PsychINFO from 1 January 2018 to 19 August 2021.
Data extraction and synthesis
Two reviewers independently identified eligible studies, extracted data, and assessed risk of bias using the Cochrane risk of bias tool. Meta-analyses were conducted with random effects models, and a pooled mean difference for both weight (kg) and waist circumference (cm) were calculated.
Main outcome measures
Primary outcome was weight change from baseline to 12 months. Secondary outcome was weight change from baseline to ≥24 months. Change in waist circumference was assessed at 12 months.
Results
34 trials were included: 14 were additional, from a previous review. 27 trials (n=8000) were included in the primary outcome of weight change at 12 month follow-up. The mean difference between the intervention and comparator groups at 12 months was -2.3 kg (95% confidence interval -3.0 to -1.6 kg, I2=88%, P<0.001), favouring the intervention group. At ≥24 months (13 trials, n=5011) the mean difference in weight change was -1.8 kg (-2.8 to -0.8 kg, I2=88%, P<0.001) favouring the intervention. The mean difference in waist circumference (18 trials, n=5288) was -2.5 cm (-3.2 to -1.8 cm, I2=69%, P<0.001) in favour of the intervention at 12 months.
Conclusions
Behavioural weight management interventions for adults with obesity delivered in primary care are effective for weight loss and could be offered to members of the public.
Systematic review registration
PROSPERO CRD42021275529.

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BMJ: 30 May 2022; 377:e069719
Madigan CD, Graham HE, Sturgiss E, Kettle VE, ... Taylor GMJ, Daley AJ
BMJ: 30 May 2022; 377:e069719 | PMID: 35636762
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Abstract

Children with tics can be helped by a new online treatment.

Saul H, Gursul D, Kwint J, Hollis C
The studyHollis C, Hall CL, Jones R, et al. Therapist supported online remote behavioural intervention for tics in children and adolescents in England (ORBIT): a multicentre, parallel group, single-blind, randomised controlled trial. Lancet Psychiatry 2021;8:P871-82.

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BMJ: 30 May 2022; 377:o1217
Saul H, Gursul D, Kwint J, Hollis C
BMJ: 30 May 2022; 377:o1217 | PMID: 35636772
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Older ...

This program is still in alpha version.