<div><h4>Recovery and symptom trajectories up to two years after SARS-CoV-2 infection: population based, longitudinal cohort study.</h4><i>Ballouz T, Menges D, Anagnostopoulos A, Domenghino A, ... Fehr JS, Puhan MA</i><br /><b>Objective</b><br />To evaluate longer term symptoms and health outcomes associated with post-covid-19 condition within a cohort of individuals with a SARS-CoV-2 infection.<br /><b>Design</b><br />Population based, longitudinal cohort.<br /><b>Setting</b><br />General population of canton of Zurich, Switzerland.<br /><b>Participants</b><br />1106 adults with a confirmed SARS-CoV-2 infection who were not vaccinated before infection and 628 adults who did not have an infection.<br /><b>Main outcome measures</b><br />Trajectories of self-reported health status and covid-19 related symptoms between months six, 12, 18, and 24 after infection and excess risk of symptoms at six months after infection compared with individuals who had no infection.<br /><b>Results</b><br />22.9% (95% confidence interval 20.4% to 25.6%) of individuals infected with SARS-CoV-2 did not fully recover by six months. The proportion of individuals who had an infection who reported not having recovered decreased to 18.5% (16.2% to 21.1%) at 12 months and 17.2% (14.0% to 20.8%) at 24 months after infection. When assessing changes in self-reported health status, most participants had continued recovery (68.4% (63.8% to 72.6%)) or had an overall improvement (13.5% (10.6% to 17.2%)) over time. Yet, 5.2% (3.5% to 7.7%) had a worsening in health status and 4.4% (2.9% to 6.7%) had alternating periods of recovery and health impairment. The point prevalence and severity of covid-19 related symptoms also decreased over time, with 18.1% (14.8% to 21.9%) reporting symptoms at 24 months. 8.9% (6.5% to 11.2%) of participants reported symptoms at all four follow-up time points, while in 12.5% (9.8% to 15.9%) symptoms were alternatingly absent and present. Symptom prevalence was higher among individuals who were infected compared with those who were not at six months (adjusted risk difference 17.0% (11.5% to 22.4%)). Excess risk (adjusted risk difference) for individual symptoms among those infected ranged from 2% to 10%, with the highest excess risks observed for altered taste or smell (9.8% (7.7% to 11.8%)), post-exertional malaise (9.4% (6.1% to 12.7%)), fatigue (5.4% (1.2% to 9.5%)), dyspnoea (7.8% (5.2% to 10.4%)), and reduced concentration (8.3% (6.0% to 10.7%)) and memory (5.7% (3.5% to 7.9%)).<br /><b>Conclusions</b><br />Up to 18% of individuals who were not vaccinated before infection had post-covid-19 condition up to two years after infection, with evidence of excess symptom risk compared with controls. Effective interventions are needed to reduce the burden of post-covid-19 condition. Use of multiple outcome measures and consideration of the expected rates of recovery and heterogeneity in symptom trajectories are important in the design and interpretation of clinical trials.<br /><b>Registrations</b><br />ISRCTN18181860, .<br /><br />© 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.<br /><br /><small>BMJ: 31 May 2023; 381:e074425</small></div>

<div><h4>Race-free estimated glomerular filtration rate equation in kidney transplant recipients: development and validation study.</h4><i>Raynaud M, Al-Awadhi S, Juric I, Divard G, ... Bentall AJ, Loupy A</i><br /><b>Objective</b><br />To compare the performance of a newly developed race-free kidney recipient specific glomerular filtration rate (GFR) equation with the three current main equations for measuring GFR in kidney transplant recipients.<br /><b>Design</b><br />Development and validation study <br /><b>Setting:</b><br/>17 cohorts in Europe, the United States, and Australia (14 transplant centres, three clinical trials).<br /><b>Participants</b><br />15 489 adults (3622 in development cohort (Necker, Saint Louis, and Toulouse hospitals, France), 11 867 in multiple external validation cohorts) who received kidney transplants between 1 January 2000 and 1 January 2021.<br /><b>Main outcome measure</b><br />The main outcome measure was GFR, measured according to local practice. Performance of the GFR equations was assessed using P<sub>30</sub> (proportion of estimated GFR (eGFR) within 30% of measured GFR (mGFR)) and correct classification (agreement between eGFR and mGFR according to GFR stages). The race-free equation, based on creatinine level, age, and sex, was developed using additive and multiplicative linear regressions, and its performance was compared with the three current main GFR equations: Modification of Diet in Renal Disease (MDRD) equation, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation, and race-free CKD-EPI 2021 equation.<br /><b>Results</b><br />The study included 15 489 participants, with 50 464 mGFR and eGFR values. The mean GFR was 53.18 mL/min/1.73m<sup>2</sup> (SD 17.23) in the development cohort and 55.90 mL/min/1.73m<sup>2</sup> (19.69) in the external validation cohorts. Among the current GFR equations, the race-free CKD-EPI 2021 equation showed the lowest performance compared with the MDRD and CKD-EPI 2009 equations. When race was included in the kidney recipient specific GFR equation, performance did not increase. The race-free kidney recipient specific GFR equation showed significantly improved performance compared with the race-free CKD-EPI 2021 equation and performed well in the external validation cohorts (P<sub>30</sub> ranging from 73.0% to 91.3%). The race-free kidney recipient specific GFR equation performed well in several subpopulations of kidney transplant recipients stratified by race (P<sub>30</sub> 73.0-91.3%), sex (72.7-91.4%), age (70.3-92.0%), body mass index (64.5-100%), donor type (58.5-92.9%), donor age (68.3-94.3%), treatment (78.5-85.2%), creatinine level (72.8-91.3%), GFR measurement method (73.0-91.3%), and timing of GFR measurement post-transplant (72.9-95.5%). An online application was developed that estimates GFR based on recipient\'s creatinine level, age, and sex (https://transplant-prediction-system.shinyapps.io/eGFR_equation_KTX/).<br /><b>Conclusion</b><br />A new race-free kidney recipient specific GFR equation was developed and validated using multiple, large, international cohorts of kidney transplant recipients. The equation showed high accuracy and outperformed the race-free CKD-EPI 2021 equation that was developed in individuals with native kidneys.<br /><b>Trial registration</b><br />ClinicalTrials.gov NCT05229939.<br /><br />© 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.<br /><br /><small>BMJ: 31 May 2023; 381:e073654</small></div>

<div><h4>Risk stratified monitoring for methotrexate toxicity in immune mediated inflammatory diseases: prognostic model development and validation using primary care data from the UK.</h4><i>Nakafero G, Grainge MJ, Williams HC, Card T, ... Riley RD, Abhishek A</i><br /><b>Objective</b><br />To develop and validate a prognostic model to inform risk stratified decisions on frequency of monitoring blood tests during long term methotrexate treatment.<br /><b>Design</b><br />Retrospective cohort study.<br /><b>Setting</b><br />Electronic health records within the UK\'s Clinical Practice Research Datalink (CPRD) Gold and CPRD Aurum.<br /><b>Participants</b><br />Adults (≥18 years) with a diagnosis of an immune mediated inflammatory disease who were prescribed methotrexate by their general practitioner for six months or more during 2007-19.<br /><b>Main outcome measure</b><br />Discontinuation of methotrexate owing to abnormal monitoring blood test result. Patients were followed-up from six months after their first prescription for methotrexate in primary care to the earliest of outcome, drug discontinuation for any other reason, leaving the practice, last data collection from the practice, death, five years, or 31 December 2019. Cox regression was performed to develop the risk equation, with bootstrapping used to shrink predictor effects for optimism. Multiple imputation handled missing predictor data. Model performance was assessed in terms of calibration and discrimination.<br /><b>Results</b><br />Data from 13 110 (854 events) and 23 999 (1486 events) participants were included in the development and validation cohorts, respectively. 11 candidate predictors (17 parameters) were included. In the development dataset, the optimism adjusted R<sup>2</sup> was 0.13 and the optimism adjusted Royston D statistic was 0.79. The calibration slope and Royston D statistic in the validation dataset for the entire follow-up period was 0.94 (95% confidence interval 0.85 to 1.02) and 0.75 (95% confidence interval 0.67 to 0.83), respectively. The prognostic model performed well in predicting outcomes in clinically relevant subgroups defined by age group, type of immune mediated inflammatory disease, and methotrexate dose.<br /><b>Conclusion</b><br />A prognostic model was developed and validated that uses information collected during routine clinical care and may be used to risk stratify the frequency of monitoring blood test during long term methotrexate treatment.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 30 May 2023; 381:e074678</small></div>

<div><h4>Advances in systemic therapies for triple negative breast cancer.</h4><i>Leon-Ferre RA, Goetz MP</i><br /><AbstractText>Triple negative breast cancer (TNBC) continues to be the subtype of breast cancer with the highest rates of recurrence and mortality. The lack of expression of targetable proteins such as the estrogen receptor and absence of HER2 amplification have made relying on cytotoxic chemotherapy necessary for decades. In the operable setting, efforts to improve outcomes have focused on escalation of systemic therapy and a shift toward preoperative delivery followed by a response adapted approach to postoperative systemic therapy. An improved understanding of tumor biology has resulted in the identification of subsets of patients with specific molecular features, leading to testing and approval of multiple new targeted therapies for this disease. Furthermore, advances in drug development have led to the approval of antibody-drug conjugates that are redefining classification schemes for breast cancer. This review focuses on the modern management of TNBC, with particular focus on recent updates in the treatment of operable disease, and an overview of the most recent promising advances in the therapeutic landscape of metastatic disease. It discusses the practical challenges and unanswered questions resulting from the approval of neoadjuvant immunotherapy and shares an approach in the clinic on topics for which evidence is lacking. In addition, it provides a glimpse into the future, highlighting challenges and opportunities for biomarker based right-sizing of preoperative therapy, refining evaluation of response to preoperative therapy after surgery, early diagnosis and detection of relapse, and areas of needed research for metastatic TNBC.</AbstractText><br /><br />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.<br /><br /><small>BMJ: 30 May 2023; 381:e071674</small></div>

<div><h4>Optimising prescribing in older adults with multimorbidity and polypharmacy in primary care (OPTICA): cluster randomised clinical trial.</h4><i>Jungo KT, Ansorg AK, Floriani C, Rozsnyai Z, ... Rodondi N, Streit S</i><br /><b>Objective</b><br />To study the effects of a primary care medication review intervention centred around an electronic clinical decision support system (eCDSS) on appropriateness of medication and the number of prescribing omissions in older adults with multimorbidity and polypharmacy compared with a discussion about medication in line with usual care.<br /><b>Design</b><br />Cluster randomised clinical trial.<br /><b>Setting</b><br />Swiss primary care, between December 2018 and February 2021.<br /><b>Participants</b><br />Eligible patients were ≥65 years of age with three or more chronic conditions and five or more long term medications.<br /><b>Intervention</b><br />The intervention to optimise pharmacotherapy centred around an eCDSS was conducted by general practitioners, followed by shared decision making between general practitioners and patients, and was compared with a discussion about medication in line with usual care between patients and general practitioners.<br /><b>Main outcome measures</b><br />Primary outcomes were improvement in the Medication Appropriateness Index (MAI) and the Assessment of Underutilisation (AOU) at 12 months. Secondary outcomes included number of medications, falls, fractures, and quality of life.<br /><b>Results</b><br />In 43 general practitioner clusters, 323 patients were recruited (median age 77 (interquartile range 73-83) years; 45% (n=146) women). Twenty one general practitioners with 160 patients were assigned to the intervention group and 22 general practitioners with 163 patients to the control group. On average, one recommendation to stop or start a medication was reported to be implemented per patient. At 12 months, the results of the intention-to-treat analysis of the improvement in appropriateness of medication (odds ratio 1.05, 95% confidence interval 0.59 to 1.87) and the number of prescribing omissions (0.90, 0.41 to 1.96) were inconclusive. The same was the case for the per protocol analysis. No clear evidence was found for a difference in safety outcomes at the 12 month follow-up, but fewer safety events were reported in the intervention group than in the control group at six and 12 months.<br /><b>Conclusions</b><br />In this randomised trial of general practitioners and older adults, the results were inconclusive as to whether the medication review intervention centred around the use of an eCDSS led to an improvement in appropriateness of medication or a reduction in prescribing omissions at 12 months compared with a discussion about medication in line with usual care. Nevertheless, the intervention could be safely delivered without causing any harm to patients.<br /><b>Trial registration</b><br />NCT03724539Clinicaltrials.gov NCT03724539.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 24 May 2023; 381:e074054</small></div>

<div><h4>Integrating non-communicable disease prevention and control into maternal and child health programmes.</h4><i>Simkovich SM, Foeller ME, Tunçalp Ö, Papageorghiou A, Checkley W</i><br /><AbstractText><b>Suzanne Simkovich and colleagues</b> argue for implementation research to meet the needs of end users and use of open source data to strengthen preventive strategies for non-communicable diseases in women of reproductive age</AbstractText><br /><br /><br /><br /><small>BMJ: 23 May 2023; 381:e071072</small></div>

<div><h4>Building an interdisciplinary workforce for prevention and control of non-communicable diseases: the role of e-learning.</h4><i>Akselrod S, Collins TE, Hoe C, Seyer J, ... Berlina D, Sobel H</i><br /><AbstractText><b>Svetlana Akselrod and colleagues</b> argue that interdisciplinary education for health workers, including through e-learning programmes, can help improve the quality of integrated care for non-communicable diseases</AbstractText><br /><br /><br /><br /><small>BMJ: 23 May 2023; 381:e071071</small></div>

<div><h4>Adverse outcomes of SARS-CoV-2 infection with delta and omicron variants in vaccinated versus unvaccinated US veterans: retrospective cohort study.</h4><i>Bohnert AS, Kumbier K, Rowneki M, Gupta A, ... Dimcheff D, Ioannou GN</i><br /><b>Objectives</b><br />To determine the association between covid-19 vaccination types and doses with adverse outcomes of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection during the periods of delta (B.1.617.2) and omicron (B.1.1.529) variant predominance.<br /><b>Design</b><br />Retrospective cohort.<br /><b>Setting</b><br />US Veterans Affairs healthcare system.<br /><b>Participants</b><br />Adults (≥18 years) who are affiliated to Veterans Affairs with a first documented SARS-CoV-2 infection during the periods of delta (1 July-30 November 2021) or omicron (1 January-30 June 2022) variant predominance. The combined cohorts had a mean age of 59.4 (standard deviation 16.3) and 87% were male.<br /><b>Interventions</b><br />Covid-19 vaccination with mRNA vaccines (BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)) and adenovirus vector vaccine (Ad26.COV2.S (Janssen/Johnson & Johnson)).<br /><b>Main outcome measures</b><br />Stay in hospital, intensive care unit admission, use of ventilation, and mortality measured 30 days after a positive test result for SARS-CoV-2.<br /><b>Results</b><br />In the delta period, 95 336 patients had infections with 47.6% having at least one vaccine dose, compared with 184 653 patients in the omicron period, with 72.6% vaccinated. After adjustment for patient demographic and clinical characteristics, in the delta period, two doses of the mRNA vaccines were associated with lower odds of hospital admission (adjusted odds ratio 0.41 (95% confidence interval 0.39 to 0.43)), intensive care unit admission (0.33 (0.31 to 0.36)), ventilation (0.27 (0.24 to 0.30)), and death (0.21 (0.19 to 0.23)), compared with no vaccination. In the omicron period, receipt of two mRNA doses were associated with lower odds of hospital admission (0.60 (0.57 to 0.63)), intensive care unit admission (0.57 (0.53 to 0.62)), ventilation (0.59 (0.51 to 0.67)), and death (0.43 (0.39 to 0.48)). Additionally, a third mRNA dose was associated with lower odds of all outcomes compared with two doses: hospital admission (0.65 (0.63 to 0.69)), intensive care unit admission (0.65 (0.59 to 0.70)), ventilation (0.70 (0.61 to 0.80)), and death (0.51 (0.46 to 0.57)). The Ad26.COV2.S vaccination was associated with better outcomes relative to no vaccination, but higher odds of hospital stay and intensive care unit admission than with two mRNA doses. BNT162b2 was generally associated with worse outcomes than mRNA-1273 (adjusted odds ratios between 0.97 and 1.42).<br /><b>Conclusions</b><br />In veterans with recent healthcare use and high occurrence of multimorbidity, vaccination was robustly associated with lower odds of 30 day morbidity and mortality compared with no vaccination among patients infected with covid-19. The vaccination type and number of doses had a significant association with outcomes.<br /><br />© 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.<br /><br /><small>BMJ: 23 May 2023; 381:e074521</small></div>

<div><h4>Assisted vaginal births: women who tear or have a surgical cut need prompt antibiotics.</h4><i>Saul H, Deeney B, Cassidy S, Imison C, Knight M</i><br /><AbstractText>The studyHumphries ABC, Linsell L, Knight M. Factors associated with infection after operative vaginal birth-a secondary analysis of a randomized controlled trial of prophylactic antibiotics for the prevention of infection following operative vaginal birth. <i>AJOG</i> 2023;228:328.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/assisted-vaginal-births-women-need-prompt-antibiotics/.</AbstractText><br /><br />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.<br /><br /><small>BMJ: 19 May 2023; 381:p1088</small></div>

<div><h4>Women and non-white people among Lasker Award recipients from 1946 to 2022: cross sectional study.</h4><i>Jacobs JW, Bibb LA, Allen ES, Ward DC, ... Silver JK, Adkins BD</i><br /><b>Objective</b><br />To determine whether gender and racial inequities exist among Lasker Award recipients.<br /><b>Design</b><br />Observational, cross sectional analysis.<br /><b>Setting</b><br />Population based study.<br /><b>Participants</b><br />Recipients of four Lasker Awards from 1946 to 2022.<br /><b>Main outcome measures</b><br />Gender and race (non-white categorized as racialized <i>v</i> white categorized as non-racialized) of all Lasker Award recipients. Personal characteristics of award recipients were categorized by four independent authors using previously established methods and consistency of categorization among authors was analyzed. Women and non-white people were thought to be underrepresented among Lasker Award recipients compared with professional degree recipients overall.<br /><b>Results</b><br />Among 397 Lasker Award recipients since 1946, 92.2% (366/397) were men. Most award recipients were identified as white (95.7%, 380/397). One non-white woman was identified as having received a Lasker Award over the course of seven decades. The proportion of women among award recipients in the most recent decade (2013-22) is similar to the first decade of awards (1946-55; 15.6%, 7/45 <i>v</i> 12.9%, 8/62). The median timeframe from terminal degree receipt to Lasker Award conferral for all award recipients is 30 years. The proportion of women who received a Lasker Award between 2019 and 2022 (7.1%) was less than would be expected based on the proportion of life science doctorates awarded to womenin 1989 (30 years previously; 38.1%).<br /><b>Conclusions</b><br />The number of women and non-white people in academic medicine and biomedical research continues to increase, yet the proportion of women among Lasker Award recipients has not changed in more than 70 years. Additionally, time from terminal degree receipt to Lasker Award conferral does not appear to fully account for the observed inequities. These findings establish the need for further investigation of possible factors that could hinder women and non-white people from entering the pool of eligible award recipients, potentially limiting the diversification of the science and academic biomedical workforce.<br /><br />© 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.<br /><br /><small>BMJ: 17 May 2023; 381:e074968</small></div>

<div><h4>Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial.</h4><i>Santer M, Lawrence M, Renz S, Eminton Z, ... Layton AM, SAFA trial investigators</i><br /><b>Objective</b><br />To assess the effectiveness of oral spironolactone for acne vulgaris in adult women.<br /><b>Design</b><br />Pragmatic, multicentre, phase 3, double blind, randomised controlled trial.<br /><b>Setting</b><br />Primary and secondary healthcare, and advertising in the community and on social media in England and Wales.<br /><b>Participants</b><br />Women (≥18 years) with facial acne for at least six months, judged to warrant oral antibiotics.<br /><b>Interventions</b><br />Participants were randomly assigned (1:1) to either 50 mg/day spironolactone or matched placebo until week six, increasing to 100 mg/day spironolactone or placebo until week 24. Participants could continue using topical treatment.<br /><b>Main outcome measures</b><br />Primary outcome was Acne-Specific Quality of Life (Acne-QoL) symptom subscale score at week 12 (range 0-30, where higher scores reflect improved QoL). Secondary outcomes were Acne-QoL at week 24, participant self-assessed improvement; investigator\'s global assessment (IGA) for treatment success; and adverse reactions.<br /><b>Results</b><br />From 5 June 2019 to 31 August 2021, 1267 women were assessed for eligibility, 410 were randomly assigned to the intervention (n=201) or control group (n=209) and 342 were included in the primary analysis (n=176 in the intervention group and n=166 in the control group). Baseline mean age was 29.2 years (standard deviation 7.2), 28 (7%) of 389 were from ethnicities other than white, with 46% mild, 40% moderate, and 13% severe acne. Mean Acne-QoL symptom scores at baseline were 13.2 (standard deviation 4.9) and at week 12 were 19.2 (6.1) for spironolactone and 12.9 (4.5) and 17.8 (5.6) for placebo (difference favouring spironolactone 1.27 (95% confidence interval 0.07 to 2.46), adjusted for baseline variables). Scores at week 24 were 21.2 (5.9) for spironolactone and 17.4 (5.8) for placebo (difference 3.45 (95% confidence interval 2.16 to 4.75), adjusted). More participants in the spironolactone group reported acne improvement than in the placebo group: no significant difference was reported at week 12 (72% <i>v</i> 68%, odds ratio 1.16 (95% confidence interval 0.70 to 1.91)) but significant difference was noted at week 24 (82% <i>v</i> 63%, 2.72 (1.50 to 4.93)). Treatment success (IGA classified) at week 12 was 31 (19%) of 168 given spironolactone and nine (6%) of 160 given placebo (5.18 (2.18 to 12.28)). Adverse reactions were slightly more common in the spironolactone group with more headaches reported (20% <i>v</i> 12%; p=0.02). No serious adverse reactions were reported.<br /><b>Conclusions</b><br />Spironolactone improved outcomes compared with placebo, with greater differences at week 24 than week 12. Spironolactone is a useful alternative to oral antibiotics for women with acne.<br /><b>Trial registration</b><br />ISRCTN12892056.<br /><br />© 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.<br /><br /><small>BMJ: 16 May 2023; 381:e074349</small></div>

<div><h4>Institutionalising community engagement for quality of care: moving beyond the rhetoric.</h4><i>Gilmore B, Dsane-Aidoo PH, Rosato M, Yaqub NO, Doe R, Baral S</i><br /><AbstractText>Community engagement has the potential to improve quality of care but is poorly represented in policy and the literature; its institutionalisation in health systems must be supported, argue <b>Brynne Gilmore and colleagues</b></AbstractText><br /><br /><br /><br /><small>BMJ: 15 May 2023; 381:e072638</small></div>

<div><h4>Association between inequalities in human resources for health and all cause and cause specific mortality in 172 countries and territories, 1990-2019: observational study.</h4><i>Yan W, Qin C, Tao L, Guo X, ... Liu M, Liu J</i><br /><b>Objective</b><br />To explore inequalities in human resources for health (HRH) in relation to all cause and cause specific mortality globally in 1990-2019.<br /><b>Design</b><br />Observational study.<br /><b>Setting</b><br />172 countries and territories.<br /><b>Data sources</b><br />Databases of the Global Burden of Disease Study 2019, United Nations Statistics, and Our World in Data.<br /><b>Main outcome measures</b><br />The main outcome was age standardized all cause mortality per 100 000 population in relation to HRH density per 10 000 population, and secondary outcome was age standardized cause specific mortality. The Lorenz curve and the concentration index (CCI) were used to assess trends and inequalities in HRH.<br /><b>Results</b><br />Globally, the total HRH density per 10 000 population increased, from 56.0 in 1990 to 142.5 in 2019, whereas age standardized all cause mortality per 100 000 population decreased, from 995.5 in 1990 to 743.8 in 2019. The Lorenz curve lay below the equality line and CCI was 0.43 (P<0.05), indicating that the health workforce was more concentrated among countries and territories ranked high on the human development index. The CCI for HRH was stable, at about 0.42-0.43 between 1990 and 2001 and continued to decline (narrowed inequality), from 0.43 in 2001 to 0.38 in 2019 (P<0.001). In the multivariable generalized estimating equation model, a negative association was found between total HRH level and all cause mortality, with the highest levels of HRH as reference (low: incidence risk ratio 1.15, 95% confidence interval 1.00 to 1.32; middle: 1.14, 1.01 to 1.29; high: 1.18, 1.08 to 1.28). A negative association between total HRH density and mortality rate was more pronounced for some types of cause specific mortality, including neglected tropical diseases and malaria, enteric infections, maternal and neonatal disorders, and diabetes and kidney diseases. The risk of death was more likely to be higher in people from countries and territories with a lower density of doctors, dentistry staff, pharmaceutical staff, aides and emergency medical workers, optometrists, psychologists, personal care workers, physiotherapists, and radiographers.<br /><b>Conclusions</b><br />Inequalities in HRH have been decreasing over the past 30 years globally but persist. All cause mortality and most types of cause specific mortality were relatively higher in countries and territories with a limited health workforce, especially for several specific HRH types among priority diseases. The findings highlight the importance of strengthening political commitment to develop equity oriented health workforce policies, expanding health financing, and implementing targeted measures to reduce deaths related to inadequate HRH to achieve universal health coverage by 2030.<br /><br />© 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.<br /><br /><small>BMJ: 10 May 2023; 381:e073043</small></div>

<div><h4>Development and internal-external validation of statistical and machine learning models for breast cancer prognostication: cohort study.</h4><i>Clift AK, Dodwell D, Lord S, Petrou S, ... Collins GS, Hippisley-Cox J</i><br /><b>Objective</b><br />To develop a clinically useful model that estimates the 10 year risk of breast cancer related mortality in women (self-reported female sex) with breast cancer of any stage, comparing results from regression and machine learning approaches.<br /><b>Design</b><br />Population based cohort study.<br /><b>Setting</b><br />QResearch primary care database in England, with individual level linkage to the national cancer registry, Hospital Episodes Statistics, and national mortality registers.<br /><b>Participants</b><br />141 765 women aged 20 years and older with a diagnosis of invasive breast cancer between 1 January 2000 and 31 December 2020.<br /><b>Main outcome measures</b><br />Four model building strategies comprising two regression (Cox proportional hazards and competing risks regression) and two machine learning (XGBoost and an artificial neural network) approaches. Internal-external cross validation was used for model evaluation. Random effects meta-analysis that pooled estimates of discrimination and calibration metrics, calibration plots, and decision curve analysis were used to assess model performance, transportability, and clinical utility.<br /><b>Results</b><br />During a median 4.16 years (interquartile range 1.76-8.26) of follow-up, 21 688 breast cancer related deaths and 11 454 deaths from other causes occurred. Restricting to 10 years maximum follow-up from breast cancer diagnosis, 20 367 breast cancer related deaths occurred during a total of 688 564.81 person years. The crude breast cancer mortality rate was 295.79 per 10 000 person years (95% confidence interval 291.75 to 299.88). Predictors varied for each regression model, but both Cox and competing risks models included age at diagnosis, body mass index, smoking status, route to diagnosis, hormone receptor status, cancer stage, and grade of breast cancer. The Cox model\'s random effects meta-analysis pooled estimate for Harrell\'s C index was the highest of any model at 0.858 (95% confidence interval 0.853 to 0.864, and 95% prediction interval 0.843 to 0.873). It appeared acceptably calibrated on calibration plots. The competing risks regression model had good discrimination: pooled Harrell\'s C index 0.849 (0.839 to 0.859, and 0.821 to 0.876, and evidence of systematic miscalibration on summary metrics was lacking. The machine learning models had acceptable discrimination overall (Harrell\'s C index: XGBoost 0.821 (0.813 to 0.828, and 0.805 to 0.837); neural network 0.847 (0.835 to 0.858, and 0.816 to 0.878)), but had more complex patterns of miscalibration and more variable regional and stage specific performance. Decision curve analysis suggested that the Cox and competing risks regression models tested may have higher clinical utility than the two machine learning approaches.<br /><b>Conclusion</b><br />In women with breast cancer of any stage, using the predictors available in this dataset, regression based methods had better and more consistent performance compared with machine learning approaches and may be worthy of further evaluation for potential clinical use, such as for stratified follow-up.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 10 May 2023; 381:e073800</small></div>

<div><h4>FDA approval, clinical trial evidence, efficacy, epidemiology, and price for non-orphan and ultra-rare, rare, and common orphan cancer drug indications: cross sectional analysis.</h4><i>Michaeli T, Jürges H, Michaeli DT</i><br /><b>Objective</b><br />To analyze the US Food and Drug Administration (FDA) approval, trials, unmet needs, benefit, and pricing of ultra-rare (<6600 affected US citizens), rare (6600-200 000 citizens), and common (>200 000 citizens) orphan cancer drug indications and non-orphan cancer drug indications.<br /><b>Design</b><br />Cross sectional analysis.<br /><b>Setting</b><br />Data from Drugs@FDA, FDA labels, Global Burden of Disease study, and Medicare and Medicaid.<br /><b>Population</b><br />170 FDA approved drugs across 455 cancer indications between 2000 and 2022.<br /><b>Main outcome measures</b><br />Comparison of non-orphan and ultra-rare, rare, and common orphan indications regarding regulatory approval, trials, epidemiology, and price. Hazard ratios for overall survival and progression-free survival were meta-analyzed.<br /><b>Results</b><br />161 non-orphan and 294 orphan cancer drug indications were identified, of which 25 were approved for ultra-rare diseases, 205 for rare diseases, and 64 for common diseases. Drugs for ultra-rare orphan indications were more frequently first in class (76% <i>v</i> 48% <i>v</i> 38% <i>v</i> 42%; P<0.001), monotherapies (88% <i>v</i> 69% <i>v</i> 72% <i>v</i> 55%; P=0.001), for hematologic cancers (76% <i>v</i> 66% <i>v</i> 0% <i>v</i> 0%; P<0.001), and supported by smaller trials (median 85 <i>v</i> 199 <i>v</i> 286 <i>v</i> 521 patients; P<0.001), of single arm (84% <i>v</i> 44% <i>v</i> 28% <i>v</i> 21%; P<0.001) phase 1/2 design (88% <i>v</i> 45% <i>v</i> 45% <i>v</i> 27%; P<0.001) compared with rare and common orphan indications and non-orphan indications. Drugs for common orphan indications were more often biomarker directed (69% <i>v</i> 26% <i>v</i> 12%; P<0.001), first line (77% <i>v</i> 39% <i>v</i> 20%; P<0.001), small molecules (80% <i>v</i> 62% <i>v</i> 48%; P<0.001) benefiting from quicker time to first FDA approval (median 5.7 <i>v</i> 7.1 <i>v</i> 8.9 years; P=0.02) than those for rare and ultra-rare orphan indications. Drugs for ultra-rare, rare, and common orphan indications offered a significantly greater progression-free survival benefit (hazard ratio 0.53 <i>v</i> 0.51 <i>v</i> 0.49 <i>v</i> 0.64; P<0.001), but not overall survival benefit (0.50 <i>v</i> 0.73 <i>v</i> 0.71 <i>v</i> 0.74; P=0.06), than non-orphans. In single arm trials, tumor response rates were greater for drugs for ultra-rare orphan indications than for rare or common orphan indications and non-orphan indications (objective response rate 57% <i>v</i> 48% <i>v</i> 55% <i>v</i> 33%; P<0.001). Disease incidence/prevalence, five year survival, and the number of available treatments were lower, whereas disability adjusted life years per patient were higher, for ultra-rare orphan indications compared with rare or common indications and non-orphan indications. For 147 on-patent drugs with available data in 2023, monthly prices were higher for ultra-rare orphan indications than for rare or common orphan indications and non-orphan indications ($70 128 (£55 971; €63 370) <i>v</i> $33 313 <i>v</i> $16 484 <i>v</i> $14 508; P<0.001). For 48 on-patent drugs with available longitudinal data from 2005 to 2023, prices increased by 94% for drugs for orphan indications and 50% for drugs for non-orphan indications on average.<br /><b>Conclusions</b><br />The Orphan Drug Act of 1983 incentivizes development of drugs not only for rare diseases but also for ultra-rare diseases and subsets of common diseases. These orphan indications fill significant unmet needs, yet their approval is based on small, non-robust trials that could overestimate efficacy outcomes. A distinct ultra-orphan designation with greater financial incentives could encourage and expedite drug development for ultra-rare diseases.<br /><br />© 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.<br /><br /><small>BMJ: 09 May 2023; 381:e073242</small></div>

<div><h4>One-session treatment is as effective as multi-session therapy for young people with phobias.</h4><i>Saul H, Deeney B, Kwint J, Gega L</i><br /><AbstractText>The studyWright B, Tindall L, Scott AJ, et al. One-session treatment compared with multisession CBT in children aged 7-16 years with specific phobias: the ASPECT non-inferiority RCT. <i>Health Technol Assess</i> 2022;26:1-174.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/one-session-cbt-treatment-effective-for-young-people-with-phobias/.</AbstractText><br /><br />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.<br /><br /><small>BMJ: 05 May 2023; 381:p882</small></div>

<div><h4>Facilitators of co-leadership for quality care.</h4><i>Cocoman O, Dohlsten M, Asiedu EK, Taye DB, ... Abramah NM, Sagoe-Moses I</i><br /><AbstractText><b>Olive Cocoman and colleagues</b> argue that national leadership for quality of care requires working in a co-leadership model such that quality and programme units have equal standing and clearly defined individual roles and responsibilities</AbstractText><br /><br /><br /><br /><small>BMJ: 05 May 2023; 381:e071330</small></div>

<div><h4>Association between SARS-CoV-2 vaccination and healthcare contacts for menstrual disturbance and bleeding in women before and after menopause: nationwide, register based cohort study.</h4><i>Ljung R, Xu Y, Sundström A, Leach S, ... Gedeborg R, Nyberg F</i><br /><b>Objectives</b><br />To evaluate the risks of any menstrual disturbance and bleeding following SARS-CoV-2 vaccination in women who are premenopausal or postmenopausal.<br /><b>Design</b><br />A nationwide, register based cohort study.<br /><b>Setting</b><br />All inpatient and specialised outpatient care in Sweden from 27 December 2020 to 28 February 2022. A subset covering primary care for 40% of the Swedish female population was also included.<br /><b>Participants</b><br />2 946 448 Swedish women aged 12-74 years were included. Pregnant women, women living in nursing homes, and women with history of any menstruation or bleeding disorders, breast cancer, cancer of female genital organs, or who underwent a hysterectomy between 1 January 2015 and 26 December 2020 were excluded.<br /><b>Interventions</b><br />SARS-CoV-2 vaccination, by vaccine product (BNT162b2, mRNA-1273, or ChAdOx1 nCoV-19 (AZD1222)) and dose (unvaccinated and first, second, and third dose) over two time windows (one to seven days, considered the control period, and 8-90 days).<br /><b>Main outcome measures</b><br />Healthcare contact (admission to hospital or visit) for menstrual disturbance or bleeding before or after menopause (diagnosed with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes N91, N92, N93, N95).<br /><b>Results</b><br />2 580 007 (87.6%) of 2 946 448 women received at least one SARS-CoV-2 vaccination and 1 652 472 (64.0%) 2 580 007 of vaccinated women received three doses before the end of follow-up. The highest risks for bleeding in women who were postmenopausal were observed after the third dose, in the one to seven days risk window (hazard ratio 1.28 (95% confidence interval 1.01 to 1.62)) and in the 8-90 days risk window (1.25 (1.04 to 1.50)). The impact of adjustment for covariates was modest. Risk of postmenopausal bleeding suggested a 23-33% increased risk after 8-90 days with BNT162b2 and mRNA-1273 after the third dose, but the association with ChAdOx1 nCoV-19 was less clear. For menstrual disturbance or bleeding in women who were premenopausal, adjustment for covariates almost completely removed the weak associations noted in the crude analyses.<br /><b>Conclusions</b><br />Weak and inconsistent associations were observed between SARS-CoV-2 vaccination and healthcare contacts for bleeding in women who are postmenopausal, and even less evidence was recorded of an association for menstrual disturbance or bleeding in women who were premenopausal. These findings do not provide substantial support for a causal association between SARS-CoV-2 vaccination and healthcare contacts related to menstrual or bleeding disorders.<br /><br />© 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.<br /><br /><small>BMJ: 03 May 2023; 381:e074778</small></div>

<div><h4>Transparent reporting of multivariable prediction models for individual prognosis or diagnosis: checklist for systematic reviews and meta-analyses (TRIPOD-SRMA).</h4><i>Snell KIE, Levis B, Damen JAA, Dhiman P, ... Collins GS, Riley RD</i><br /><AbstractText>Most clinical specialties have a plethora of studies that develop or validate one or more prediction models, for example, to inform diagnosis or prognosis. Having many prediction model studies in a particular clinical field motivates the need for systematic reviews and meta-analyses, to evaluate and summarise the overall evidence available from prediction model studies, in particular about the predictive performance of existing models. Such reviews are fast emerging, and should be reported completely, transparently, and accurately. To help ensure this type of reporting, this article describes a new reporting guideline for systematic reviews and meta-analyses of prediction model research.</AbstractText><br /><br /><br /><br /><small>BMJ: 03 May 2023; 381:e073538</small></div>

<div><h4>Association of early life physical and sexual abuse with premature mortality among female nurses: prospective cohort study.</h4><i>Wang YX, Sun Y, Missmer SA, Rexrode KM, ... Chavarro JE, Rich-Edwards JW</i><br /><b>Objective</b><br />To explore associations between early life physical and sexual abuse and subsequent risk of premature mortality (death before age 70 years).<br /><b>Design</b><br />Prospective cohort study.<br /><b>Setting</b><br />The Nurses\' Health Study II (2001-19).<br /><b>Participants</b><br />67 726 female nurses aged 37-54 years when completing a violence victimization questionnaire in 2001.<br /><b>Main outcome measures</b><br />Hazard ratios and 95% confidence intervals for total and cause specific premature mortality by childhood or adolescent physical and sexual abuse, estimated by multivariable Cox proportional hazard models.<br /><b>Results</b><br />2410 premature deaths were identified over 18 years of follow-up. Nurses who experienced severe physical abuse or forced sexual activity in childhood and adolescence had a higher crude premature mortality rate than nurses without such abuse in childhood or adolescence (3.15 <i>v</i> 1.83 and 4.00 <i>v</i> 1.90 per 1000 person years, respectively). The corresponding age adjusted hazard ratios for premature deaths were 1.65 (95% confidence interval 1.45 to 1.87) and 2.04 (1.71 to 2.44), respectively, which were materially unchanged after further adjusting for personal characteristics and early life socioeconomic status (1.53, 1.35 to 1.74, and 1.80, 1.50 to 2.15, respectively). Cause specific analyses indicated that severe physical abuse was associated with a greater risk of mortality due to external causes of injury and poisoning (multivariable adjusted hazard ratio 2.81, 95% confidence interval 1.62 to 4.89), suicide (3.05, 1.41 to 6.60), and diseases of the digestive system (2.40, 1.01 to 5.68). Forced sexual activity as a child and adolescent was associated with greater risk of mortality due to cardiovascular disease (2.48, 1.37 to 4.46), external injury or poisoning (3.25, 1.53 to 6.91), suicide (4.30, 1.74 to 10.61), respiratory disease (3.74, 1.40 to 9.99), and diseases of the digestive system (4.83, 1.77 to 13.21). The association of sexual abuse with premature mortality was stronger among women who smoked or had higher levels of anxiety during adulthood. Smoking, low physical activity, anxiety, and depression each explained 3.9-22.4% of the association between early life abuse and premature mortality.<br /><b>Conclusion</b><br />Early life physical and sexual abuse could be associated with a greater risk of adult premature mortality.<br /><br />© 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.<br /><br /><small>BMJ: 03 May 2023; 381:e073613</small></div>

<div><h4>Fracture risk reduction and safety by osteoporosis treatment compared with placebo or active comparator in postmenopausal women: systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials.</h4><i>Händel MN, Cardoso I, von Bülow C, Rohde JF, ... Langdahl B, Abrahamsen B</i><br /><b>Objective</b><br />To review the comparative effectiveness of osteoporosis treatments, including the bone anabolic agents, abaloparatide and romosozumab, on reducing the risk of fractures in postmenopausal women, and to characterise the effect of antiosteoporosis drug treatments on the risk of fractures according to baseline risk factors.<br /><b>Design</b><br />Systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials.<br /><b>Data sources</b><br />Medline, Embase, and Cochrane Library to identify randomised controlled trials published between 1 January 1996 and 24 November 2021 that examined the effect of bisphosphonates, denosumab, selective oestrogen receptor modulators, parathyroid hormone receptor agonists, and romosozumab compared with placebo or active comparator.<br /><b>Eligibility criteria for selecting studies</b><br />Randomised controlled trials that included non-Asian postmenopausal women with no restriction on age, when interventions looked at bone quality in a broad perspective. The primary outcome was clinical fractures. Secondary outcomes were vertebral, non-vertebral, hip, and major osteoporotic fractures, all cause mortality, adverse events, and serious cardiovascular adverse events.<br /><b>Results</b><br />The results were based on 69 trials (>80 000 patients). For clinical fractures, synthesis of the results showed a protective effect of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab compared with placebo. Compared with parathyroid hormone receptor agonists, bisphosphonates were less effective in reducing clinical fractures (odds ratio 1.49, 95% confidence interval 1.12 to 2.00). Compared with parathyroid hormone receptor agonists and romosozumab, denosumab was less effective in reducing clinical fractures (odds ratio 1.85, 1.18 to 2.92 for denosumab <i>v</i> parathyroid hormone receptor agonists and 1.56, 1.02 to 2.39 for denosumab <i>v</i> romosozumab). An effect of all treatments on vertebral fractures compared with placebo was found. In the active treatment comparisons, denosumab, parathyroid hormone receptor agonists, and romosozumab were more effective than oral bisphosphonates in preventing vertebral fractures. The effect of all treatments was unaffected by baseline risk indicators, except for antiresorptive treatments that showed a greater reduction of clinical fractures compared with placebo with increasing mean age (number of studies=17; β=0.98, 95% confidence interval 0.96 to 0.99). No harm outcomes were seen. The certainty in the effect estimates was moderate to low for all individual outcomes, mainly because of limitations in reporting, nominally indicating a serious risk of bias and imprecision.<br /><b>Conclusions</b><br />The evidence indicated a benefit of a range of treatments for osteoporosis in postmenopausal women for clinical and vertebral fractures. Bone anabolic treatments were more effective than bisphosphonates in the prevention of clinical and vertebral fractures, irrespective of baseline risk indicators. Hence this analysis provided no clinical evidence for restricting the use of anabolic treatment to patients with a very high risk of fractures.<br /><b>Systematic review registration</b><br />PROSPERO CRD42019128391.<br /><br />© 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.<br /><br /><small>BMJ: 02 May 2023; 381:e068033</small></div>

<div><h4>Online support improved eczema symptoms in children and young people.</h4><i>Saul H, Cassidy S, Imison C, Santer M</i><br /><AbstractText>The studySanter M, Muller I, Becque T. Eczema Care Online behavioural interventions to support self-care for children and young people: two independent, pragmatic, randomised controlled trials. <i>BMJ</i> 2022;379:e072007.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/online-support-improved-eczema-symptoms-in-children-and-young-people/.</AbstractText><br /><br />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.<br /><br /><small>BMJ: 28 Apr 2023; 381:p878</small></div>

<div><h4>Multi-faceted intervention to improve management of antibiotics for children presenting to primary care with acute cough and respiratory tract infection (CHICO): efficient cluster randomised controlled trial.</h4><i>Blair PS, Young G, Clement C, Dixon P, ... Bevan S, Hay AD</i><br /><b>Objective</b><br />To assess whether an easy-to-use multifaceted intervention for children presenting to primary care with respiratory tract infections would reduce antibiotic dispensing, without increasing hospital admissions for respiratory tract infection.<br /><b>Design</b><br />Two arm randomised controlled trial clustered by general practice, using routine outcome data, with qualitative and economic evaluations.<br /><b>Setting</b><br />English primary care practices using the EMIS electronic medical record system.<br /><b>Participants</b><br />Children aged 0-9 years presenting with respiratory tract infection at 294 general practices, before and during the covid-19 pandemic.<br /><b>Intervention</b><br />Elicitation of parental concerns during consultation; a clinician focused prognostic algorithm to identify children at very low, normal, or elevated 30 day risk of hospital admission accompanied by antibiotic prescribing guidance; and a leaflet for carers including safety netting advice.<br /><b>Main outcome measures</b><br />Rate of dispensed amoxicillin and macrolide antibiotics (superiority comparison) and hospital admissions for respiratory tract infection (non-inferiority comparison) for children aged 0-9 years over 12 months (same age practice list size as denominator).<br /><b>Results</b><br />Of 310 practices needed, 294 (95%) were randomised (144 intervention and 150 controls) representing 5% of all registered 0-9 year olds in England. Of these, 12 (4%) subsequently withdrew (six owing to the pandemic). Median intervention use per practice was 70 (by a median of 9 clinicians). No evidence was found that antibiotic dispensing differed between intervention practices (155 (95% confidence interval 138 to 174) items/year/1000 children) and control practices (157 (140 to 176) items/year/1000 children) (rate ratio 1.011, 95% confidence interval 0.992 to 1.029; P=0.25). Pre-specified subgroup analyses suggested reduced dispensing in intervention practices with fewer prescribing nurses, in single site (compared with multisite) practices, and in practices located in areas of lower socioeconomic deprivation, which may warrant future investigation. Pre-specified sensitivity analysis suggested reduced dispensing among older children in the intervention arm (P=0.03). A post hoc sensitivity analysis suggested less dispensing in intervention practices before the pandemic (rate ratio 0.967, 0.946 to 0.989; P=0.003). The rate of hospital admission for respiratory tract infections in the intervention practices (13 (95% confidence interval 10 to 18) admissions/1000 children) was non-inferior compared with control practices (15 (12 to 20) admissions/1000 children) (rate ratio 0.952, 0.905 to 1.003).<br /><b>Conclusions</b><br />This multifaceted antibiotic stewardship intervention for children with respiratory tract infections did not reduce overall antibiotic dispensing or increase respiratory tract infection related hospital admissions. Evidence suggested that in some subgroups and situations (for example, under non-pandemic conditions) the intervention slightly reduced prescribing rates but not in a clinically relevant way.<br /><b>Trial registration</b><br />ISRCTN11405239ISRCTN registry ISRCTN11405239.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 26 Apr 2023; 381:e072488</small></div>

<div><h4>Molnupiravir and risk of post-acute sequelae of covid-19: cohort study.</h4><i>Xie Y, Choi T, Al-Aly Z</i><br /><b>Objective</b><br />To examine whether treatment with the antiviral agent molnupiravir during the first five days of SARS-CoV-2 infection is associated with reduced risk of post-acute adverse health outcomes.<br /><b>Design</b><br />Cohort study.<br /><b>Setting</b><br />US Department of Veterans Affairs.<br /><b>Participants</b><br />229 286 participants who tested positive for SARS-CoV-2 between 5 January 2022 and 15 January 2023, had at least one risk factor for progression to severe covid-19, and survived the first 30 days after testing positive were enrolled. 11 472 participants received a prescription for molnupiravir within five days of the positive test result and 217 814 received no covid-19 antiviral or antibody treatment (no treatment group).<br /><b>Main outcome measures</b><br />Risks of post-acute sequelae of SARS-CoV-2 (PASC, defined based on a prespecified set of 13 post-acute sequelae), post-acute death, post-acute hospital admission, and each individual post-acute sequela between the molnupiravir group and no treatment group were examined after application of inverse probability weighting to balance the treatment and no treatment groups. Post-acute outcomes were ascertained from 30 days after the first SARS-CoV-2 positive test result until end of follow-up. Risks on the relative scale (relative risk or hazard ratio) and absolute scale (absolute risk reduction at 180 days) were estimated.<br /><b>Results</b><br />Compared with no treatment, molnupiravir use within five days of a positive SARS-CoV-2 test result was associated with reduced risk of PASC (relative risk 0.86 (95% confidence interval 0.83 to 0.89); absolute risk reduction at 180 days 2.97% (95% confidence interval 2.31% to 3.60%)), post-acute death (hazard ratio 0.62 (0.52 to 0.74); 0.87% (0.62% to 1.13%)), and post-acute hospital admission (0.86 (0.80 to 0.93); 1.32% (0.72% to 1.92%)). Molnupiravir was associated with reduced risk of eight of the 13 post-acute sequelae: dysrhythmia, pulmonary embolism, deep vein thrombosis, fatigue and malaise, liver disease, acute kidney injury, muscle pain, and neurocognitive impairment. Molnupiravir was also associated with reduced risk of PASC in people who had not received a covid-19 vaccine, had received at one or two vaccine doses, and had received a booster dose, and in people with primary SARS-CoV-2 infection and reinfection.<br /><b>Conclusions</b><br />In people with SARS-CoV-2 infection and at least one risk factor for progression to severe covid-19, compared with no treatment, molnupiravir use within five days of infection was associated with reduced risk of PASC in people who had not received a covid-19 vaccine, had received one or two vaccine doses, and had received a booster dose, and in those with primary SARS-CoV-2 infection and reinfection. Among people at high risk of progression to severe covid-19, molnupiravir use within five days of SARS-CoV-2 infection may be a viable approach to reduce the risk of PASC.<br /><br />© 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.<br /><br /><small>BMJ: 25 Apr 2023; 381:e074572</small></div>

<div><h4>Suicide in young people: screening, risk assessment, and intervention.</h4><i>Hughes JL, Horowitz LM, Ackerman JP, Adrian MC, Campo JV, Bridge JA</i><br /><AbstractText>Suicide is the fourth leading cause of death among young people worldwide and the third leading cause of death among those in the US. This review outlines the epidemiology of suicide and suicidal behavior in young people. It discusses intersectionality as an emerging framework to guide research on prevention of suicide in young people and highlights several clinical and community settings that are prime targets for implementation of effective treatment programs and interventions aimed at rapidly reducing the suicide rate in young people. It provides an overview of current approaches to screening and assessment of suicide risk in young people and the commonly used screening tools and assessment measures. It discusses universal, selective, and indicated evidence based suicide focused interventions and highlights components of psychosocial interventions with the strongest evidence for reducing risk. Finally, the review discusses suicide prevention strategies in community settings and considers future research directions and questions challenging the field.</AbstractText><br /><br />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.<br /><br /><small>BMJ: 24 Apr 2023; 381:e070630</small></div>

<div><h4>Combination therapy for painful diabetic neuropathy is safe and effective.</h4><i>Saul H, Deeney B, Imison C, Tesfaye S</i><br /><AbstractText>The studyTesfaye S, Sloan G, Petrie J, et al. Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial. <i>Lancet</i> 2022;400:680-90.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/combination-therapy-for-painful-diabetic-neuropathy-is-safe-and-effective/.</AbstractText><br /><br />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.<br /><br /><small>BMJ: 21 Apr 2023; 381:p866</small></div>

<div><h4>Surgical versus non-surgical treatment for sciatica: systematic review and meta-analysis of randomised controlled trials.</h4><i>Liu C, Ferreira GE, Abdel Shaheed C, Chen Q, ... Koes B, Lin CC</i><br /><b>Objective</b><br />To investigate the effectiveness and safety of surgery compared with non-surgical treatment for sciatica.<br /><b>Design</b><br />Systematic review and meta-analysis.<br /><b>Data sources</b><br />Medline, Embase, CINAHL, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the World Health Organisation International Clinical Trials Registry Platform from database inception to June 2022.<br /><b>Eligibility criteria for selecting studies</b><br />Randomised controlled trials comparing any surgical treatment with non-surgical treatment, epidural steroid injections, or placebo or sham surgery, in people with sciatica of any duration due to lumbar disc herniation (diagnosed by radiological imaging).<br /><b>Data extraction and synthesis</b><br />Two independent reviewers extracted data. Leg pain and disability were the primary outcomes. Adverse events, back pain, quality of life, and satisfaction with treatment were the secondary outcomes. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst pain or disability). Data were pooled using a random effects model. Risk of bias was assessed with the Cochrane Collaboration\'s tool and certainty of evidence with the grading of recommendations assessment, development, and evaluation (GRADE) framework. Follow-up times were into immediate term (≤six weeks), short term (>six weeks and ≤three months), medium term (>three and <12 months), and long term (at 12 months).<br /><b>Results</b><br />24 trials were included, half of these investigated the effectiveness of discectomy compared with non-surgical treatment or epidural steroid injections (1711 participants). Very low to low certainty evidence showed that discectomy, compared with non-surgical treatment, reduced leg pain: the effect size was moderate at immediate term (mean difference -12.1 (95% confidence interval -23.6 to -0.5)) and short term (-11.7 (-18.6 to -4.7)), and small at medium term (-6.5 (-11.0 to -2.1)). Negligible effects were noted at long term (-2.3 (-4.5 to -0.2)). For disability, small, negligible, or no effects were found. A similar effect on leg pain was found when comparing discectomy with epidural steroid injections. For disability, a moderate effect was found at short term, but no effect was observed at medium and long term. The risk of any adverse events was similar between discectomy and non-surgical treatment (risk ratio 1.34 (95% confidence interval 0.91 to 1.98)).<br /><b>Conclusion</b><br />Very low to low certainty evidence suggests that discectomy was superior to non-surgical treatment or epidural steroid injections in reducing leg pain and disability in people with sciatica with a surgical indication, but the benefits declined over time. Discectomy might be an option for people with sciatica who feel that the rapid relief offered by discectomy outweighs the risks and costs associated with surgery.<br /><b>Systematic review registration</b><br />PROSPERO CRD42021269997.<br /><br />© 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.<br /><br /><small>BMJ: 19 Apr 2023; 381:e070730</small></div>

<div><h4>Beverage consumption and mortality among adults with type 2 diabetes: prospective cohort study.</h4><i>Ma L, Hu Y, Alperet DJ, Liu G, ... Hu FB, Sun Q</i><br /><b>Objective</b><br />To investigate the intake of specific types of beverages in relation to mortality and cardiovascular disease (CVD) outcomes among adults with type 2 diabetes.<br /><b>Design</b><br />Prospective cohort study.<br /><b>Setting</b><br />Health professionals in the United States.<br /><b>Participants</b><br />15 486 men and women with a diagnosis of type 2 diabetes at baseline and during follow-up (Nurses\' Health Study: 1980-2018; and Health Professionals Follow-Up Study: 1986-2018). Beverage consumption was assessed using a validated food frequency questionnaire and updated every two to four years.<br /><b>Main outcome measures</b><br />The main outcome was all cause mortality. Secondary outcomes were CVD incidence and mortality.<br /><b>Results</b><br />During an average of 18.5 years of follow-up, 3447 (22.3%) participants with incident CVD and 7638 (49.3%) deaths were documented. After multivariable adjustment, when comparing the categories of lowest intake of beverages with the highest intake, the pooled hazard ratios for all cause mortality were 1.20 (95% confidence interval 1.04 to 1.37) for sugar sweetened beverages (SSBs), 0.96 (0.86 to 1.07) for artificially sweetened beverages (ASBs), 0.98 (0.90 to 1.06) for fruit juice, 0.74 (0.63 to 0.86) for coffee, 0.79 (0.71 to 0.89) for tea, 0.77 (0.70 to 0.85) for plain water, 0.88 (0.80 to 0.96) for low fat milk, and 1.20 (0.99 to 1.44) for full fat milk. Similar associations were observed between the individual beverages and CVD incidence and mortality. In particular, SSB intake was associated with a higher risk of incident CVD (hazard ratio 1.25, 95% confidence interval 1.03 to 1.51) and CVD mortality (1.29, 1.02 to 1.63), whereas significant inverse associations were observed between intake of coffee and low fat milk and CVD incidence. Additionally, compared with those who did not change their consumption of coffee in the period after a diabetes diagnosis, a lower all cause mortality was observed in those who increased their consumption of coffee. A similar pattern of association with all cause mortality was also observed for tea, and low fat milk. Replacing SSBs with ABSs was significantly associated with lower all cause mortality and CVD mortality, and replacing SSBs, ASBs, fruit juice, or full fat milk with coffee, tea, or plain water was consistently associated with lower all cause mortality.<br /><b>Conclusions</b><br />Individual beverages showed divergent associations with all cause mortality and CVD outcomes among adults with type 2 diabetes. Higher intake of SSBs was associated with higher all cause mortality and CVD incidence and mortality, whereas intakes of coffee, tea, plain water, and low fat milk were inversely associated with all cause mortality. These findings emphasize the potential role of healthy choices of beverages in managing the risk of CVD and premature death overall in adults with type 2 diabetes.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 19 Apr 2023; 381:e073406</small></div>

<div><h4>Denosumab and incidence of type 2 diabetes among adults with osteoporosis: population based cohort study.</h4><i>Lyu H, Zhao SS, Zhang L, Wei J, ... Tang P, Solomon DH</i><br /><b>Objective</b><br />To estimate the effect of denosumab compared with oral bisphosphonates on reducing the risk of type 2 diabetes in adults with osteoporosis.<br /><b>Design</b><br />Population based study involving emulation of a randomized target trial using electronic health records.<br /><b>Setting</b><br />IQVIA Medical Research Data primary care database in the United Kingdom, 1995-2021.<br /><b>Participants</b><br />Adults aged 45 years or older who used denosumab or an oral bisphosphonate for osteoporosis.<br /><b>Main outcome measures</b><br />The primary outcome was incident type 2 diabetes, as defined by diagnostic codes. Cox proportional hazards models were used to estimate adjusted hazard ratios and 95% confidence intervals, comparing denosumab with oral bisphosphonates using an as treated approach.<br /><b>Results</b><br />4301 new users of denosumab were matched on propensity score to 21 038 users of an oral bisphosphonate and followed for a mean of 2.2 years. The incidence rate of type 2 diabetes in denosumab users was 5.7 (95% confidence interval 4.3 to 7.3) per 1000 person years and in oral bisphosphonate users was 8.3 (7.4 to 9.2) per 1000 person years. Initiation of denosumab was associated with a reduced risk of type 2 diabetes (hazard ratio 0.68, 95% confidence interval 0.52 to 0.89). Participants with prediabetes appeared to benefit more from denosumab compared with an oral bisphosphonate (hazard ratio 0.54, 0.35 to 0.82), as did those with a body mass index ≥30 (0.65, 0.40 to 1.06).<br /><b>Conclusions</b><br />In this population based study, denosumab use was associated with a lower risk of incident type 2 diabetes compared with oral bisphosphonate use in adults with osteoporosis. This study provides evidence at a population level that denosumab may have added benefits for glucose metabolism compared with oral bisphosphonates.<br /><br />© 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.<br /><br /><small>BMJ: 18 Apr 2023; 381:e073435</small></div>

<div><h4>Diagnosis and management of bipolar disorders.</h4><i>Goes FS</i><br /><AbstractText>Bipolar disorders (BDs) are recurrent and sometimes chronic disorders of mood that affect around 2% of the world\'s population and encompass a spectrum between severe elevated and excitable mood states (mania) to the dysphoria, low energy, and despondency of depressive episodes. The illness commonly starts in young adults and is a leading cause of disability and premature mortality. The clinical manifestations of bipolar disorder can be markedly varied between and within individuals across their lifespan. Early diagnosis is challenging and misdiagnoses are frequent, potentially resulting in missed early intervention and increasing the risk of iatrogenic harm. Over 15 approved treatments exist for the various phases of bipolar disorder, but outcomes are often suboptimal owing to insufficient efficacy, side effects, or lack of availability. Lithium, the first approved treatment for bipolar disorder, continues to be the most effective drug overall, although full remission is only seen in a subset of patients. Newer atypical antipsychotics are increasingly being found to be effective in the treatment of bipolar depression; however, their long term tolerability and safety are uncertain. For many with bipolar disorder, combination therapy and adjunctive psychotherapy might be necessary to treat symptoms across different phases of illness. Several classes of medications exist for treating bipolar disorder but predicting which medication is likely to be most effective or tolerable is not yet possible. As pathophysiological insights into the causes of bipolar disorders are revealed, a new era of targeted treatments aimed at causal mechanisms, be they pharmacological or psychosocial, will hopefully be developed. For the time being, however, clinical judgment, shared decision making, and empirical follow-up remain essential elements of clinical care. This review provides an overview of the clinical features, diagnostic subtypes, and major treatment modalities available to treat people with bipolar disorder, highlighting recent advances and ongoing therapeutic challenges.</AbstractText><br /><br />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.<br /><br /><small>BMJ: 12 Apr 2023; 381:e073591</small></div>

<div><h4>Nirmatrelvir and risk of hospital admission or death in adults with covid-19: emulation of a randomized target trial using electronic health records.</h4><i>Xie Y, Bowe B, Al-Aly Z</i><br /><b>Objective</b><br />To estimate the effectiveness of nirmatrelvir, compared with no treatment, in reducing admission to hospital or death at 30 days in people infected with the SARS-CoV-2 virus and at risk of developing severe disease, according to vaccination status and history of previous SARS-CoV-2 infection.<br /><b>Design</b><br />Emulation of a randomized target trial with electronic health records.<br /><b>Setting</b><br />Healthcare databases of the US Department of Veterans Affairs <br /><b>Participants:</b><br/>256 288 participants with a SARS-CoV-2 positive test result and at least one risk factor for developing severe covid-19 disease, between 3 January and 30 November 2022. 31 524 were treated with nirmatrelvir within five days of testing positive for SARS-CoV-2 and 224 764 received no treatment.<br /><b>Main outcome measures</b><br />The effectiveness of starting nirmatrelvir within five days of a positive SARS-CoV-2 test result versus no treatment in reducing the risk of admission to hospital or death at 30 days was estimated in those who were not vaccinated, in those who received one or two doses of vaccine, and those who received a vaccine booster and, separately, in participants with a primary SARS-CoV-2 infection or reinfection. The inverse probability weighting method was used to balance personal and health characteristics between the groups. Relative risk and absolute risk reduction were computed from cumulative incidence at 30 days, estimated by weighted Kaplan-Meier estimator.<br /><b>Results</b><br />Among people who were not vaccinated (n=76 763; 5338 nirmatrelvir and 71 425 no treatment), compared with no treatment, the relative risk of nirmatrelvir in reducing admission to hospital or death at 30 days was 0.60 (95% confidence interval 0.50 to 0.71); the absolute risk reduction was 1.83% (95% confidence interval 1.29% to 2.49%). The relative risk and absolute risk reduction, compared with no treatment, were 0.65 (0.57 to 0.74) and 1.27% (0.90% to 1.61%), respectively, in people who received one or two doses of vaccine (n=84 620; 7989 nirmatrelvir and 76 631 no treatment); 0.64 (0.58 to 0.71) and 1.05% (0.85% to 1.27%) in individuals who received a booster dose of vaccine (n=94 905; 18 197 nirmatrelvir and 76 708 no treatment); 0.61 (0.57 to 0.65) and 1.36% (1.19% to 1.53%) in participants with a primary SARS-CoV-2 infection (n=228 081; 26 350 nirmatrelvir and 201 731 no treatment); and 0.74 (0.63 to 0.87) and 0.79% (0.36% to 1.18%) in participants who were reinfected with the SARS-CoV-2 virus (n=28 207; 5174 nirmatrelvir and 23 033 no treatment). Nirmatrelvir was associated with a reduced risk of admission to hospital or death in those aged ≤65 years and > 65 years; in men and women; in black and white participants; in those with 1-2, 3-4, and ≥5 risk factors for progression to severe covid-19 illness; and in those infected during the omicron BA.1 or BA.2 predominant era, and the BA.5 predominant era.<br /><b>Conclusions</b><br />In people with SARS-CoV-2 infection who were at risk of developing severe disease, compared with no treatment, nirmatrelvir was associated with a reduced risk of admission to hospital or death at 30 days in people who were not vaccinated, vaccinated, and had received a booster vaccine, and in those with a primary SARS-CoV-2 infection and reinfection.<br /><br />© 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.<br /><br /><small>BMJ: 11 Apr 2023; 381:e073312</small></div>

<div><h4>Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.</h4><i>Shi Q, Nong K, Vandvik PO, Guyatt GH, ... Tian H, Li S</i><br /><b>Objective</b><br />To compare the benefits and harms of drug treatments for adults with type 2 diabetes, adding non-steroidal mineralocorticoid receptor antagonists (including finerenone) and tirzepatide (a dual glucose dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist) to previously existing treatment options.<br /><b>Design</b><br />Systematic review and network meta-analysis.<br /><b>Data sources</b><br />Ovid Medline, Embase, and Cochrane Central up to 14 October 2022.<br /><b>Eligibility criteria for selecting studies</b><br />Eligible randomised controlled trials compared drugs of interest in adults with type 2 diabetes. Eligible trials had a follow-up of 24 weeks or longer. Trials systematically comparing combinations of more than one drug treatment class with no drug, subgroup analyses of randomised controlled trials, and non-English language studies were deemed ineligible. Certainty of evidence was assessed following the GRADE (grading of recommendations, assessment, development and evaluation) approach.<br /><b>Results</b><br />The analysis identified 816 trials with 471 038 patients, together evaluating 13 different drug classes; all subsequent estimates refer to the comparison with standard treatments. Sodium glucose cotransporter-2 (SGLT-2) inhibitors (odds ratio 0.88, 95% confidence interval 0.83 to 0.94; high certainty) and GLP-1 receptor agonists (0.88, 0.82 to 0.93; high certainty) reduce all cause death; non-steroidal mineralocorticoid receptor antagonists, so far tested only with finerenone in patients with chronic kidney disease, probably reduce mortality (0.89, 0.79 to 1.00; moderate certainty); other drugs may not. The study confirmed the benefits of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing cardiovascular death, non-fatal myocardial infarction, admission to hospital for heart failure, and end stage kidney disease. Finerenone probably reduces admissions to hospital for heart failure and end stage kidney disease, and possibly cardiovascular death. Only GLP-1 receptor agonists reduce non-fatal stroke; SGLT-2 inhibitors are superior to other drugs in reducing end stage kidney disease. GLP-1 receptor agonists and probably SGLT-2 inhibitors and tirzepatide improve quality of life. Reported harms were largely specific to drug class (eg, genital infections with SGLT-2 inhibitors, severe gastrointestinal adverse events with tirzepatide and GLP-1 receptor agonists, hyperkalaemia leading to admission to hospital with finerenone). Tirzepatide probably results in the largest reduction in body weight (mean difference -8.57 kg; moderate certainty). Basal insulin (mean difference 2.15 kg; moderate certainty) and thiazolidinediones (mean difference 2.81 kg; moderate certainty) probably result in the largest increases in body weight. Absolute benefits of SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone vary in people with type 2 diabetes, depending on baseline risks for cardiovascular and kidney outcomes (https://matchit.magicevidence.org/230125dist-diabetes).<br /><b>Conclusions</b><br />This network meta-analysis extends knowledge beyond confirming the substantial benefits with the use of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing adverse cardiovascular and kidney outcomes and death by adding information on finerenone and tirzepatide. These findings highlight the need for continuous assessment of scientific progress to introduce cutting edge updates in clinical practice guidelines for people with type 2 diabetes.<br /><b>Systematic review registration</b><br />PROSPERO CRD42022325948.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 06 Apr 2023; 381:e074068</small></div>

<div><h4>Dietary sugar consumption and health: umbrella review.</h4><i>Huang Y, Chen Z, Chen B, Li J, ... Cao D, Liu L</i><br /><b>Objective</b><br />To evaluate the quality of evidence, potential biases, and validity of all available studies on dietary sugar consumption and health outcomes.<br /><b>Design</b><br />Umbrella review of existing meta-analyses.<br /><b>Data sources</b><br />PubMed, Embase, Web of Science, Cochrane Database of Systematic Reviews, and hand searching of reference lists.<br /><b>Inclusion criteria</b><br />Systematic reviews and meta-analyses of randomised controlled trials, cohort studies, case-control studies, or cross sectional studies that evaluated the effect of dietary sugar consumption on any health outcomes in humans free from acute or chronic diseases.<br /><b>Results</b><br />The search identified 73 meta-analyses and 83 health outcomes from 8601 unique articles, including 74 unique outcomes in meta-analyses of observational studies and nine unique outcomes in meta-analyses of randomised controlled trials. Significant harmful associations between dietary sugar consumption and 18 endocrine/metabolic outcomes, 10 cardiovascular outcomes, seven cancer outcomes, and 10 other outcomes (neuropsychiatric, dental, hepatic, osteal, and allergic) were detected. Moderate quality evidence suggested that the highest versus lowest dietary sugar consumption was associated with increased body weight (sugar sweetened beverages) (class IV evidence) and ectopic fatty accumulation (added sugars) (class IV evidence). Low quality evidence indicated that each serving/week increment of sugar sweetened beverage consumption was associated with a 4% higher risk of gout (class III evidence) and each 250 mL/day increment of sugar sweetened beverage consumption was associated with a 17% and 4% higher risk of coronary heart disease (class II evidence) and all cause mortality (class III evidence), respectively. In addition, low quality evidence suggested that every 25 g/day increment of fructose consumption was associated with a 22% higher risk of pancreatic cancer (class III evidence).<br /><b>Conclusions</b><br />High dietary sugar consumption is generally more harmful than beneficial for health, especially in cardiometabolic disease. Reducing the consumption of free sugars or added sugars to below 25 g/day (approximately 6 teaspoons/day) and limiting the consumption of sugar sweetened beverages to less than one serving/week (approximately 200-355 mL/week) are recommended to reduce the adverse effect of sugars on health.<br /><b>Systematic review registration</b><br />PROSPERO CRD42022300982.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 05 Apr 2023; 381:e071609</small></div>

<div><h4>Ambient air pollution and clinical dementia: systematic review and meta-analysis.</h4><i>Wilker EH, Osman M, Weisskopf MG</i><br /><b>Objective</b><br />To investigate the role of air pollutants in risk of dementia, considering differences by study factors that could influence findings.<br /><b>Design</b><br />Systematic review and meta-analysis.<br /><b>Data sources</b><br />EMBASE, PubMed, Web of Science, Psycinfo, and OVID Medline from database inception through July 2022.<br /><b>Eligibility criteria for selecting studies</b><br />Studies that included adults (≥18 years), a longitudinal follow-up, considered US Environmental Protection Agency criteria air pollutants and proxies of traffic pollution, averaged exposure over a year or more, and reported associations between ambient pollutants and clinical dementia. Two authors independently extracted data using a predefined data extraction form and assessed risk of bias using the Risk of Bias In Non-randomised Studies of Exposures (ROBINS-E) tool. A meta-analysis with Knapp-Hartung standard errors was done when at least three studies for a given pollutant used comparable approaches.<br /><b>Results</b><br />2080 records identified 51 studies for inclusion. Most studies were at high risk of bias, although in many cases bias was towards the null. 14 studies could be meta-analysed for particulate matter <2.5 µm in diameter (PM<sub>2.5</sub>). The overall hazard ratio per 2 μg/m<sup>3</sup> PM<sub>2.5</sub> was 1.04 (95% confidence interval 0.99 to 1.09). The hazard ratio among seven studies that used active case ascertainment was 1.42 (1.00 to 2.02) and among seven studies that used passive case ascertainment was 1.03 (0.98 to 1.07). The overall hazard ratio per 10 μg/m<sup>3</sup> nitrogen dioxide was 1.02 ((0.98 to 1.06); nine studies) and per 10 μg/m<sup>3</sup> nitrogen oxide was 1.05 ((0.98 to 1.13); five studies). Ozone had no clear association with dementia (hazard ratio per 5 μg/m<sup>3</sup> was 1.00 (0.98 to 1.05); four studies).<br /><b>Conclusion</b><br />PM<sub>2.5</sub> might be a risk factor for dementia, as well as nitrogen dioxide and nitrogen oxide, although with more limited data. The meta-analysed hazard ratios are subject to limitations that require interpretation with caution. Outcome ascertainment approaches differ across studies and each exposure assessment approach likely is only a proxy for causally relevant exposure in relation to clinical dementia outcomes. Studies that evaluate critical periods of exposure and pollutants other than PM<sub>2.5</sub>, and studies that actively assess all participants for outcomes are needed. Nonetheless, our results can provide current best estimates for use in burden of disease and regulatory setting efforts.<br /><b>Systematic review registration</b><br />PROSPERO CRD42021277083.<br /><br />© 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.<br /><br /><small>BMJ: 05 Apr 2023; 381:e071620</small></div>

<div><h4>Comparison of seven popular structured dietary programmes and risk of mortality and major cardiovascular events in patients at increased cardiovascular risk: systematic review and network meta-analysis.</h4><i>Karam G, Agarwal A, Sadeghirad B, Jalink M, ... Boyce E, Johnston BC</i><br /><b>Objective</b><br />To determine the relative efficacy of structured named diet and health behaviour programmes (dietary programmes) for prevention of mortality and major cardiovascular events in patients at increased risk of cardiovascular disease.<br /><b>Design</b><br />Systematic review and network meta-analysis of randomised controlled trials.<br /><b>Data sources</b><br />AMED (Allied and Complementary Medicine Database), CENTRAL (Cochrane Central Register of Controlled Trials), Embase, Medline, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and ClinicalTrials.gov were searched up to September 2021.<br /><b>Study selection</b><br />Randomised trials of patients at increased risk of cardiovascular disease that compared dietary programmes with minimal intervention (eg, healthy diet brochure) or alternative programmes with at least nine months of follow-up and reporting on mortality or major cardiovascular events (such as stroke or non-fatal myocardial infarction). In addition to dietary intervention, dietary programmes could also include exercise, behavioural support, and other secondary interventions such as drug treatment.<br /><b>Outcomes and measures</b><br />All cause mortality, cardiovascular mortality, and individual cardiovascular events (stroke, non-fatal myocardial infarction, and unplanned cardiovascular interventions).<br /><b>Review methods</b><br />Pairs of reviewers independently extracted data and assessed risk of bias. A random effects network meta-analysis was performed using a frequentist approach and grading of recommendations assessment, development and evaluation (GRADE) methods to determine the certainty of evidence for each outcome.<br /><b>Results</b><br />40 eligible trials were identified with 35 548 participants across seven named dietary programmes (low fat, 18 studies; Mediterranean, 12; very low fat, 6; modified fat, 4; combined low fat and low sodium, 3; Ornish, 3; Pritikin, 1). At last reported follow-up, based on moderate certainty evidence, Mediterranean dietary programmes proved superior to minimal intervention for the prevention of all cause mortality (odds ratio 0.72, 95% confidence interval 0.56 to 0.92; patients at intermediate risk: risk difference 17 fewer per 1000 followed over five years), cardiovascular mortality (0.55, 0.39 to 0.78; 13 fewer per 1000), stroke (0.65, 0.46 to 0.93; 7 fewer per 1000), and non-fatal myocardial infarction (0.48, 0.36 to 0.65; 17 fewer per 1000). Based on moderate certainty evidence, low fat programmes proved superior to minimal intervention for prevention of all cause mortality (0.84, 0.74 to 0.95; 9 fewer per 1000) and non-fatal myocardial infarction (0.77, 0.61 to 0.96; 7 fewer per 1000). The absolute effects for both dietary programmes were more pronounced for patients at high risk. There were no convincing differences between Mediterranean and low fat programmes for mortality or non-fatal myocardial infarction. The five remaining dietary programmes generally had little or no benefit compared with minimal intervention typically based on low to moderate certainty evidence.<br /><b>Conclusions</b><br />Moderate certainty evidence shows that programmes promoting Mediterranean and low fat diets, with or without physical activity or other interventions, reduce all cause mortality and non-fatal myocardial infarction in patients with increased cardiovascular risk. Mediterranean programmes are also likely to reduce stroke risk. Generally, other named dietary programmes were not superior to minimal intervention.<br /><b>Systematic review registration</b><br />PROSPERO CRD42016047939.<br /><br />© 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.<br /><br /><small>BMJ: 29 Mar 2023; 380:e072003</small></div>

<div><h4>Communication of anticancer drug benefits and related uncertainties to patients and clinicians: document analysis of regulated information on prescription drugs in Europe.</h4><i>Davis C, Wagner AK, Salcher-Konrad M, Scowcroft H, ... Lew J, Naci H</i><br /><b>Objective</b><br />To evaluate the frequency with which relevant and accurate information about the benefits and related uncertainties of anticancer drugs are communicated to patients and clinicians in regulated information sources in Europe.<br /><b>Design</b><br />Document content analysis.<br /><b>Setting</b><br />European Medicines Agency.<br /><b>Participants</b><br />Anticancer drugs granted a first marketing authorisation by the European Medicines Agency, 2017-19.<br /><b>Main outcome measures</b><br />Whether written information on a product addressed patients\' commonly asked questions about: who and what the drug is used for; how the drug was studied; types of drug benefit expected; and the extent of weak, uncertain, or missing evidence for drug benefits. Information on drug benefits in written sources for clinicians (summaries of product characteristics), patients (patient information leaflets), and the public (public summaries) was compared with information reported in regulatory assessment documents (European public assessment reports).<br /><b>Results</b><br />29 anticancer drugs that received a first marketing authorisation for 32 separate cancer indications in 2017-19 were included. General information about the drug (including information on approved indications and how the drug works) was frequently reported across regulated information sources aimed at both clinicians and patients. Nearly all summaries of product characteristics communicated full information to clinicians about the number and design of the main studies, the control arm (if any), study sample size, and primary measures of drug benefit. None of the patient information leaflets communicated information to patients about how drugs were studied. 31 (97%) summaries of product characteristics and 25 (78%) public summaries contained information about drug benefits that was accurate and consistent with information in regulatory assessment documents. The presence or absence of evidence that a drug extended survival was reported in 23 (72%) summaries of product characteristics and four (13%) public summaries. None of the patient information leaflets communicated information about the drug benefits that patients might expect based on study findings. Scientific concerns about the reliability of evidence on drug benefits, which were raised by European regulatory assessors for almost all drugs in the study sample, were rarely communicated to clinicians, patients, or the public.<br /><b>Conclusions</b><br />The findings of this study highlight the need to improve the communication of the benefits and related uncertainties of anticancer drugs in regulated information sources in Europe to support evidence informed decision making by patients and their clinicians.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 29 Mar 2023; 380:e073711</small></div>

<div><h4>Comparative effectiveness and safety of analgesic medicines for adults with acute non-specific low back pain: systematic review and network meta-analysis.</h4><i>Wewege MA, Bagg MK, Jones MD, Ferraro MC, ... Gustin SM, McAuley JH</i><br /><b>Objective</b><br />To evaluate the comparative effectiveness and safety of analgesic medicines for acute non-specific low back pain.<br /><b>Design</b><br />Systematic review and network meta-analysis.<br /><b>Data sources</b><br />Medline, PubMed, Embase, CINAHL, CENTRAL, ClinicalTrials.gov, clinicialtrialsregister.eu, and World Health Organization\'s International Clinical Trials Registry Platform from database inception to 20 February 2022.<br /><b>Eligibility criteria for study selection</b><br />Randomised controlled trials of analgesic medicines (eg, non-steroidal anti-inflammatory drugs, paracetamol, opioids, anti-convulsant drugs, skeletal muscle relaxants, or corticosteroids) compared with another analgesic medicine, placebo, or no treatment. Adults (≥18 years) who reported acute non-specific low back pain (for less than six weeks).<br /><b>Data extraction and synthesis</b><br />Primary outcomes were low back pain intensity (0-100 scale) at end of treatment and safety (number of participants who reported any adverse event during treatment). Secondary outcomes were low back specific function, serious adverse events, and discontinuation from treatment. Two reviewers independently identified studies, extracted data, and assessed risk of bias. A random effects network meta-analysis was done and confidence was evaluated by the Confidence in Network Meta-Analysis method.<br /><b>Results</b><br />98 randomised controlled trials (15 134 participants, 49% women) included 69 different medicines or combinations. Low or very low confidence was noted in evidence for reduced pain intensity after treatment with tolperisone (mean difference -26.1 (95% confidence intervals -34.0 to -18.2)), aceclofenac plus tizanidine (-26.1 (-38.5 to -13.6)), pregabalin (-24.7 (-34.6 to -14.7)), and 14 other medicines compared with placebo. Low or very low confidence was noted for no difference between the effects of several of these medicines. Increased adverse events had moderate to very low confidence with tramadol (risk ratio 2.6 (95% confidence interval 1.5 to 4.5)), paracetamol plus sustained release tramadol (2.4 (1.5 to 3.8)), baclofen (2.3 (1.5 to 3.4)), and paracetamol plus tramadol (2.1 (1.3 to 3.4)) compared with placebo. These medicines could increase the risk of adverse events compared with other medicines with moderate to low confidence. Moderate to low confidence was also noted for secondary outcomes and secondary analysis of medicine classes.<br /><b>Conclusions</b><br />The comparative effectiveness and safety of analgesic medicines for acute non-specific low back pain are uncertain. Until higher quality randomised controlled trials of head-to-head comparisons are published, clinicians and patients are recommended to take a cautious approach to manage acute non-specific low back pain with analgesic medicines.<br /><b>Systematic review registration</b><br />PROSPERO CRD42019145257.<br /><br />© 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.<br /><br /><small>BMJ: 22 Mar 2023; 380:e072962</small></div>

<div><h4>Estimated impact from the withdrawal of primary care financial incentives on selected indicators of quality of care in Scotland: controlled interrupted time series analysis.</h4><i>Morales DR, Minchin M, Kontopantelis E, Roland M, Sutton M, Guthrie B</i><br /><b>Objective</b><br />To determine whether the withdrawal of the Quality and Outcomes Framework (QOF) scheme in primary care in Scotland in 2016 had an impact on selected recorded quality of care, compared with England where the scheme continued.<br /><b>Design</b><br />Controlled interrupted time series regression analysis.<br /><b>Setting</b><br />General practices in Scotland and England.<br /><b>Participants</b><br />979 practices with 5 599 171 registered patients in Scotland, and 7921 practices with 56 270 628 registered patients in England in 2013-14, decreasing to 864 practices in Scotland and 6873 in England in 2018-19, mainly due to practice mergers.<br /><b>Main outcome measures</b><br />Changes in quality of care at one year and three years after withdrawal of QOF financial incentives in Scotland at the end of the 2015-16 financial year for 16 indicators (two complex processes, nine intermediate outcomes, and five treatments) measured annually for financial years from 2013-14 to 2018-19.<br /><b>Results</b><br />A significant decrease in performance was observed for 12 of the 16 quality of care indicators in Scotland one year after QOF was abolished and for 10 of the 16 indicators three years after QOF was abolished, compared with England. At three years, the absolute percentage point difference between Scotland and England was largest for recording (by tick box) of mental health care planning (-40.2 percentage points, 95% confidence interval -45.5 to -35.0) and diabetic foot screening (-22.8, -33.9 to -11.7). Substantial reductions were, however, also observed for intermediate outcomes, including blood pressure control in patients with peripheral arterial disease (-18.5, -22.1 to -14.9), stroke or transient ischaemic attack (-16.6, -20.6 to -12.7), hypertension (-13.7, -19.4 to -7.9), diabetes (-12.7, -15.0 to -12.4), or coronary heart disease (-12.8, -14.9 to -10.8), and for glycated haemoglobin control in people with HbA<sub>1c</sub> levels ≤75 mmol/mol (-5.0, -8.4 to -1.5). No significant differences were observed between Scotland and England for influenza immunisation and antiplatelet or anticoagulant treatment for coronary heart disease three years after withdrawal of incentives.<br /><b>Conclusion</b><br />The abolition of financial incentives in Scotland was associated with reductions in recorded quality of care for most performance indicators. Changes to pay for performance should be carefully designed and implemented to monitor and respond to any reductions in care quality.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 22 Mar 2023; 380:e072098</small></div>

<div><h4>Optimising adolescent wellbeing in a digital age.</h4><i>Holly L, Wong BLH, van Kessel R, Awah I, Agrawal A, Ndili N</i><br /><AbstractText>Empowering adolescents and strengthening governance of digital media are among the urgent actions required to tackle the digital determinants of adolescent wellbeing, argue <b>Louise Holly</b> and <b>colleagues</b></AbstractText><br /><br /><br /><br /><small>BMJ: 20 Mar 2023; 380:e068279</small></div>

<div><h4>Comparative effectiveness of BNT162b2 versus mRNA-1273 covid-19 vaccine boosting in England: matched cohort study in OpenSAFELY-TPP.</h4><i>Hulme WJ, Horne EMF, Parker EPK, Keogh RH, ... Hernán MA, Sterne JAC</i><br /><b>Objective</b><br />To compare the effectiveness of the BNT162b2 mRNA (Pfizer-BioNTech) and mRNA-1273 (Moderna) covid-19 vaccines during the booster programme in England.<br /><b>Design</b><br />Matched cohort study, emulating a comparative effectiveness trial.<br /><b>Setting</b><br />Linked primary care, hospital, and covid-19 surveillance records available within the OpenSAFELY-TPP research platform, covering a period when the SARS-CoV-2 delta and omicron variants were dominant.<br /><b>Participants</b><br />3 237 918 adults who received a booster dose of either vaccine between 29 October 2021 and 25 February 2022 as part of the national booster programme in England and who received a primary course of BNT162b2 or ChAdOx1.<br /><b>Intervention</b><br />Vaccination with either BNT162b2 or mRNA-1273 as a booster vaccine dose.<br /><b>Main outcome measures</b><br />Recorded SARS-CoV-2 positive test, covid-19 related hospital admission, covid-19 related death, and non-covid-19 related death at 20 weeks after receipt of the booster dose.<br /><b>Results</b><br />1 618 959 people were matched in each vaccine group, contributing a total 64 546 391 person weeks of follow-up. The 20 week risks per 1000 for a positive SARS-CoV-2 test were 164.2 (95% confidence interval 163.3 to 165.1) for BNT162b2 and 159.9 (159.0 to 160.8) for mRNA-1273; the hazard ratio comparing mRNA-1273 with BNT162b2 was 0.95 (95% confidence interval 0.95 to 0.96). The 20 week risks per 1000 for hospital admission with covid-19 were 0.75 (0.71 to 0.79) for BNT162b2 and 0.65 (0.61 to 0.69) for mRNA-1273; the hazard ratio was 0.89 (0.82 to 0.95). Covid-19 related deaths were rare: the 20 week risks per 1000 were 0.028 (0.021 to 0.037) for BNT162b2 and 0.024 (0.018 to 0.033) for mRNA-1273; hazard ratio 0.83 (0.58 to 1.19). Comparative effectiveness was generally similar within subgroups defined by the primary course vaccine brand, age, previous SARS-CoV-2 infection, and clinical vulnerability. Relative benefit was similar when vaccines were compared separately in the delta and omicron variant eras.<br /><b>Conclusions</b><br />This matched observational study of adults estimated a modest benefit of booster vaccination with mRNA-1273 compared with BNT162b2 in preventing positive SARS-CoV-2 tests and hospital admission with covid-19 20 weeks after vaccination, during a period of delta followed by omicron variant dominance.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 15 Mar 2023; 380:e072808</small></div>

<div><h4>Cognitive impairment after cancer treatment: mechanisms, clinical characterization, and management.</h4><i>Fleming B, Edison P, Kenny L</i><br /><AbstractText>Cognitive impairment is a debilitating side effect experienced by patients with cancer treated with systemically administered anticancer therapies. With around 19.3 million new cases of cancer worldwide in 2020 and the five year survival rate growing from 50% in 1970 to 67% in 2013, an urgent need exists to understand enduring side effects with severe implications for quality of life. Whereas cognitive impairment associated with chemotherapy is recognized in patients with breast cancer, researchers have started to identify cognitive impairment associated with other treatments such as immune, endocrine, and targeted therapies only recently. The underlying mechanisms are diverse and therapy specific, so further evaluation is needed to develop effective therapeutic interventions. Drug and non-drug management strategies are emerging that target mechanistic pathways or the cognitive deficits themselves, but they need to be rigorously evaluated. Clinically, consistent use of objective diagnostic tools is necessary for accurate diagnosis and clinical characterization of cognitive impairment in patients treated with anticancer therapies. This should be supplemented with clinical guidelines that could be implemented in daily practice. This review summarizes the recent advances in the mechanisms, clinical characterization, and novel management strategies of cognitive impairment associated with treatment of non-central nervous system cancers.</AbstractText><br /><br />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.<br /><br /><small>BMJ: 15 Mar 2023; 380:e071726</small></div>

<div><h4>Maternal opioid treatment after delivery and risk of adverse infant outcomes: population based cohort study.</h4><i>Zipursky JS, Gomes T, Everett K, Calzavara A, ... Ray JG, Juurlink DN</i><br /><b>Objective</b><br />To examine whether maternal opioid treatment after delivery is associated with an increased risk of adverse infant outcomes.<br /><b>Design</b><br />Population based cohort study.<br /><b>Setting</b><br />Ontario, Canada.<br /><b>Participants</b><br />865 691 mother-infant pairs discharged from hospital alive within seven days of delivery from 1 September 2012 to 31 March 2020. Each mother who filled an opioid prescription within seven days of discharge was propensity score matched to a mother who did not.<br /><b>Main outcome measures</b><br />The primary outcome was hospital readmission of infants for any reason within 30 days of their mother filling an opioid prescription (index date). Infant related secondary outcomes were any emergency department visit, hospital admission for all cause injury, admission to a neonatal intensive care unit, admission with resuscitation or assisted ventilation, and all cause death.<br /><b>Results</b><br />85 675 mothers (99.8% of the 85 852 mothers prescribed an opioid) who filled an opioid prescription within seven days of discharge after delivery were propensity score matched to 85 675 mothers who did not. Of the infants admitted to hospital within 30 days, 2962 (3.5%) were born to mothers who filled an opioid prescription compared with 3038 (3.5%) born to mothers who did not. Infants of mothers who were prescribed an opioid were no more likely to be admitted to hospital for any reason than infants of mothers who were not prescribed an opioid (hazard ratio 0.98, 95% confidence interval 0.93 to 1.03) and marginally more likely to be taken to an emergency department in the subsequent 30 days (1.04, 1.01 to 1.08), but no differences were found for any other adverse infant outcomes and there were no infant deaths.<br /><b>Conclusions</b><br />Findings from this study suggest no association between maternal opioid prescription after delivery and adverse infant outcomes, including death.<br /><br />© 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.<br /><br /><small>BMJ: 15 Mar 2023; 380:e074005</small></div>

<div><h4>Regular measurement is essential but insufficient to improve quality of healthcare.</h4><i>Agweyu A, Hill K, Diaz T, Jackson D, Hailu BG, Muzigaba M</i><br /><AbstractText><b>Ambrose Agweyu and colleagues</b> argue that large scale improvements in quality of healthcare require strong change management as well as health information systems that can provide continuous and rapid feedback</AbstractText><br /><br /><br /><br /><small>BMJ: 13 Mar 2023; 380:e073412</small></div>

<div><h4>Ionising radiation and cardiovascular disease: systematic review and meta-analysis.</h4><i>Little MP, Azizova TV, Richardson DB, Tapio S, ... Einstein AJ, Hamada N</i><br /><b>Objective</b><br />To systematically review and perform a meta-analysis of radiation associated risks of cardiovascular disease in all groups exposed to radiation with individual radiation dose estimates.<br /><b>Design</b><br />Systematic review and meta-analysis.<br /><b>Main outcome measures</b><br />Excess relative risk per unit dose (Gy), estimated by restricted maximum likelihood methods.<br /><b>Data sources</b><br />PubMed and Medline, Embase, Scopus, Web of Science Core collection databases.<br /><b>Eligibility criteria for selecting studies</b><br />Databases were searched on 6 October 2022, with no limits on date of publication or language. Animal studies and studies without an abstract were excluded.<br /><b>Results</b><br />The meta-analysis yielded 93 relevant studies. Relative risk per Gy increased for all cardiovascular disease (excess relative risk per Gy of 0.11 (95% confidence interval 0.08 to 0.14)) and for the four major subtypes of cardiovascular disease (ischaemic heart disease, other heart disease, cerebrovascular disease, all other cardiovascular disease). However, interstudy heterogeneity was noted (P<0.05 for all endpoints except for other heart disease), possibly resulting from interstudy variation in unmeasured confounders or effect modifiers, which is markedly reduced if attention is restricted to higher quality studies or those at moderate doses (<0.5 Gy) or low dose rates (<5 mGy/h). For ischaemic heart disease and all cardiovascular disease, risks were larger per unit dose for lower dose (inverse dose effect) and for fractionated exposures (inverse dose fractionation effect). Population based excess absolute risks are estimated for a number of national populations (Canada, England and Wales, France, Germany, Japan, USA) and range from 2.33% per Gy (95% confidence interval 1.69% to 2.98%) for England and Wales to 3.66% per Gy (2.65% to 4.68%) for Germany, largely reflecting the underlying rates of cardiovascular disease mortality in these populations. Estimated risk of mortality from cardiovascular disease are generally dominated by cerebrovascular disease (around 0.94-1.26% per Gy), with the next largest contribution from ischaemic heart disease (around 0.30-1.20% per Gy).<br /><b>Conclusions</b><br />Results provide evidence supporting a causal association between radiation exposure and cardiovascular disease at high dose, and to a lesser extent at low dose, with some indications of differences in risk between acute and chronic exposures, which require further investigation. The observed heterogeneity complicates a causal interpretation of these findings, although this heterogeneity is much reduced if only higher quality studies or those at moderate doses or low dose rates are considered. Studies are needed to assess in more detail modifications of radiation effect by lifestyle and medical risk factors.<br /><b>Systematic review registration</b><br />PROSPERO CRD42020202036.<br /><br />© 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.<br /><br /><small>BMJ: 08 Mar 2023; 380:e072924</small></div>

<div><h4>Comparison of mental health symptoms before and during the covid-19 pandemic: evidence from a systematic review and meta-analysis of 134 cohorts.</h4><i>Sun Y, Wu Y, Fan S, Dal Santo T, ... Benedetti A, Thombs BD</i><br /><b>Objective</b><br />To synthesise results of mental health outcomes in cohorts before and during the covid-19 pandemic.<br /><b>Design</b><br />Systematic review.<br /><b>Data sources</b><br />Medline, PsycINFO, CINAHL, Embase, Web of Science, China National Knowledge Infrastructure, Wanfang, medRxiv, and Open Science Framework Preprints.<br /><b>Eligibility criteria for selecting studies</b><br />Studies comparing general mental health, anxiety symptoms, or depression symptoms assessed from 1 January 2020 or later with outcomes collected from 1 January 2018 to 31 December 2019 in any population, and comprising ≥90% of the same participants before and during the covid-19 pandemic or using statistical methods to account for missing data. Restricted maximum likelihood random effects meta-analyses (worse covid-19 outcomes representing positive change) were performed. Risk of bias was assessed using an adapted Joanna Briggs Institute Checklist for Prevalence Studies.<br /><b>Results</b><br />As of 11 April 2022, 94 411 unique titles and abstracts including 137 unique studies from 134 cohorts were reviewed. Most of the studies were from high income (n=105, 77%) or upper middle income (n=28, 20%) countries. Among general population studies, no changes were found for general mental health (standardised mean difference (SMD)<sub>change</sub> 0.11, 95% confidence interval -0.00 to 0.22) or anxiety symptoms (0.05, -0.04 to 0.13), but depression symptoms worsened minimally (0.12, 0.01 to 0.24). Among women or female participants, general mental health (0.22, 0.08 to 0.35), anxiety symptoms (0.20, 0.12 to 0.29), and depression symptoms (0.22, 0.05 to 0.40) worsened by minimal to small amounts. In 27 other analyses across outcome domains among subgroups other than women or female participants, five analyses suggested that symptoms worsened by minimal or small amounts, and two suggested minimal or small improvements. No other subgroup experienced changes across all outcome domains. In three studies with data from March to April 2020 and late 2020, symptoms were unchanged from pre-covid-19 levels at both assessments or increased initially then returned to pre-covid-19 levels. Substantial heterogeneity and risk of bias were present across analyses.<br /><b>Conclusions</b><br />High risk of bias in many studies and substantial heterogeneity suggest caution in interpreting results. Nonetheless, most symptom change estimates for general mental health, anxiety symptoms, and depression symptoms were close to zero and not statistically significant, and significant changes were of minimal to small magnitudes. Small negative changes occurred for women or female participants in all domains. The authors will update the results of this systematic review as more evidence accrues, with study results posted online (https://www.depressd.ca/covid-19-mental-health).<br /><b>Review registration</b><br />PROSPERO CRD42020179703.<br /><br />© 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.<br /><br /><small>BMJ: 08 Mar 2023; 380:e074224</small></div>

<div><h4>Molnupiravir and risk of hospital admission or death in adults with covid-19: emulation of a randomized target trial using electronic health records.</h4><i>Xie Y, Bowe B, Al-Aly Z</i><br /><b>Objective</b><br />To emulate a randomized target trial to estimate the association between the antiviral drug molnupiravir and hospital admission or death in adults with SARS-CoV-2 infection in the community during the omicron predominant era who were at high risk of progression to severe covid-19.<br /><b>Design</b><br />Emulation of a randomized target trial using electronic health records.<br /><b>Setting</b><br />US Department of Veterans Affairs.<br /><b>Participants</b><br />85 998 adults with SARS-CoV-2 infection between 5 January and 30 September 2022 and at least one risk factor for progression to severe covid-19: 7818 participants were eligible for and treated with molnupiravir and 78 180 received no treatment.<br /><b>Main outcomes measure</b><br />The primary outcome was a composite of hospital admission or death at 30 days. The clone method with inverse probability of censoring weighting was used to adjust for informative censoring and balance baseline characteristics between the groups. The cumulative incidence function was used to estimate the relative risk and the absolute risk reduction at 30 days.<br /><b>Results</b><br />Molnupiravir was associated with a reduction in hospital admissions or death at 30 days (relative risk 0.72 (95% confidence interval 0.64 to 0.79)) compared with no treatment; the event rates for hospital admission or death at 30 days were 2.7% (95% confidence interval 2.5% to 3.0%) for molnupiravir and 3.8% (3.7% to 3.9%) for no treatment; the absolute risk reduction was 1.1% (95% confidence interval 0.8% to 1.4%). Molnupiravir appeared to be effective in those who had not been vaccinated against covid-19 (relative risk 0.83 (0.70 to 0.97) and absolute risk reduction 0.9% (0.2% to 1.9%)), had received one or two vaccine doses (0.69 (0.56 to 0.83) and 1.3% (0.7% to 1.9%)), and had received a booster dose (0.71 (0.58 to 0.83) and 1.0% (0.5% to 1.4%)); in those infected during the era when the omicron subvariant BA.1 or BA.2 was predominant (0.72 (0.62 to 0.83) and 1.2% (0.7% to 1.6%)) and when BA.5 was predominant (0.75 (0.66 to 0.86) and 0.9% (0.5% to 1.3%)); and in those with no history of SARS-CoV-2 infection (0.72 (0.64 to 0.81) and 1.1% (0.8% to 1.4%)) and with a history of SARS-CoV-2 infection (0.75 (0.58 to 0.97) and 1.1% (0.1% to 1.8%)).<br /><b>Conclusions</b><br />The findings of this emulation of a randomized target trial suggest that molnupiravir might have reduced hospital admission or death at 30 days in adults with SARS-CoV-2 infection in the community during the recent omicron predominant era who were at high risk of progression to severe covid-19 and eligible for treatment with molnupiravir.<br /><br />© 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.<br /><br /><small>BMJ: 07 Mar 2023; 380:e072705</small></div>