Journal: BMJ

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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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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.

© 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: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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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.

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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.

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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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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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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.

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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/.

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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/.

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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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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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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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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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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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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/.

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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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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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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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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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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/.

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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:

This program is still in alpha version.