NIHR Bristol Biomedical Research Centre

Assessment of risk of bias is regarded as an essential component of a systematic review on the effects of an intervention. The most commonly used tool for randomised trials is the Cochrane risk-of-bias tool. We updated the tool to respond to developments in understanding how bias arises in randomised trials, and to address user feedback on and limitations of the original tool.

The UK Medical Research Council’s widely used guidance for developing and evaluating complex interventions has been replaced by a new framework, commissioned jointly by the Medical Research Council and the National Institute for Health Research, which takes account of recent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

Importance: Mendelian randomization (MR) studies use genetic variation associated with modifiable exposures to assess their possible causal relationship with outcomes and aim to reduce potential bias from confounding and reverse causation. Objective: To develop the STROBE-MR Statement as a stand-alone extension to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline for the reporting of MR studies. Design, Setting, and Participants: The development of the STROBE-MR Statement followed the Enhancing the Quality and Transparency of Health Research (EQUATOR) framework guidance and used the STROBE Statement as a starting point to draft a checklist tailored to MR studies. The project was initiated in 2018 by reviewing the literature on the reporting of instrumental variable and MR studies. A group of 17 experts, including MR methodologists, MR study design users, developers of previous reporting guidelines, and journal editors, participated in a workshop in May 2019 to define the scope of the Statement and draft the checklist. The draft checklist was published as a preprint in July 2019 and discussed on the preprint platform, in social media, and at the 4th Mendelian Randomization Conference. The checklist was then revised based on comments, further refined through 2020, and finalized in July 2021. Findings: The STROBE-MR checklist is organized into 6 sections (Title and Abstract, Introduction, Methods, Results, Discussion, and Other Information) and includes 20 main items and 30 subitems. It covers both 1-sample and 2-sample MR studies that assess 1 or multiple exposures and outcomes, and addresses MR studies that follow a genome-wide association study and are reported in the same article. The checklist asks authors to justify why MR is a helpful method to address the study question and state prespecified causal hypotheses. The measurement, quality, and selection of genetic variants must be described and attempts to assess validity of MR-specific assumptions should be well reported. An item on data sharing includes reporting when the data and statistical code required to replicate the analyses can be accessed. Conclusions and Relevance: STROBE-MR provides guidelines for reporting MR studies. Improved reporting of these studies could facilitate their evaluation by editors, peer reviewers, researchers, clinicians, and other readers, and enhance the interpretation of their results.

Importance: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support. Objective: To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality. Design, Setting, and Participants: Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance-weighted fixed-effect analysis using risk ratios. Exposures: Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients). Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events. Results: A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as "low" for 6 of the 7 mortality results and as "some concerns" in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo. Conclusions and Relevance: In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

In observational epidemiology, mendelian randomisation (MR) studies provide an opportunity to study the causal association between an exposure and an outcome while reducing the risk of certain biases Little consensus exists around the reporting of MR studies, and the quality of reporting of these studies has been inconsistent; many MR study reports do not state or examine the various assumptions of MR and report insufficient details on the data sources STROBE-MR (strengthening the reporting of observational studies in epidemiology using mendelian randomisation), a checklist of 20 reporting items, has been developed for the communication of MR studies This article explains the rationale of these checklist items and provides examples of transparent reporting MR study authors, reviewers, and journal editors are encouraged to use STROBE-MR to improve the reporting of these studies on 18 July

BACKGROUND: Large-scale and contemporary population-based studies of heart failure incidence are needed to inform resource planning and research prioritisation but current evidence is scarce. We aimed to assess temporal trends in incidence and prevalence of heart failure in a large general population cohort from the UK, between 2002 and 2014. METHODS: For this population-based study, we used linked primary and secondary electronic health records of 4 million individuals from the Clinical Practice Research Datalink (CPRD), a cohort that is representative of the UK population in terms of age and sex. Eligible patients were aged 16 years and older, had contributed data between Jan 1, 2002, and Dec 31, 2014, had an acceptable record according to CPRD quality control, were approved for CPRD and Hospital Episodes Statistics linkage, and were registered with their general practice for at least 12 months. For patients with incident heart failure, we extracted the most recent measurement of baseline characteristics (within 2 years of diagnosis) from electronic health records, as well as information about comorbidities, socioeconomic status, ethnicity, and region. We calculated standardised rates by applying direct age and sex standardisation to the 2013 European Standard Population, and we inferred crude rates by applying year-specific, age-specific, and sex-specific incidence to UK census mid-year population estimates. We assumed no heart failure for patients aged 15 years or younger and report total incidence and prevalence for all ages (>0 years). FINDINGS: From 2002 to 2014, heart failure incidence (standardised by age and sex) decreased, similarly for men and women, by 7% (from 358 to 332 per 100 000 person-years; adjusted incidence ratio 0·93, 95% CI 0·91-0·94). However, the estimated absolute number of individuals with newly diagnosed heart failure in the UK increased by 12% (from 170 727 in 2002 to 190 798 in 2014), largely due to an increase in population size and age. The estimated absolute number of prevalent heart failure cases in the UK increased even more, by 23% (from 750 127 to 920 616). Over the study period, patient age and multi-morbidity at first presentation of heart failure increased (mean age 76·5 years [SD 12·0] to 77·0 years [12·9], adjusted difference 0·79 years, 95% CI 0·37-1·20; mean number of comorbidities 3·4 [SD 1·9] vs 5·4 [2·5]; adjusted difference 2·0, 95% CI 1·9-2·1). Socioeconomically deprived individuals were more likely to develop heart failure than were affluent individuals (incidence rate ratio 1·61, 95% CI 1·58-1·64), and did so earlier in life than those from the most affluent group (adjusted difference -3·51 years, 95% CI -3·77 to -3·25). From 2002 to 2014, the socioeconomic gradient in age at first presentation with heart failure widened. Socioeconomically deprived individuals also had more comorbidities, despite their younger age. INTERPRETATION: Despite a moderate decline in standardised incidence of heart failure, the burden of heart failure in the UK is increasing, and is now similar to the four most common causes of cancer combined. The observed socioeconomic disparities in disease incidence and age at onset within the same nation point to a potentially preventable nature of heart failure that still needs to be tackled. FUNDING: British Heart Foundation and National Institute for Health Research.

BACKGROUND: Pulmonary embolism (PE) is frequently cited as a common primary cause of unilateral pleural effusion, but in clinical practice appears to be uncommon. OBJECTIVES: In order to evaluate this observation, CT pulmonary angiography (CTPA) was performed in consecutive patients presenting to a single centre with a new uninvestigated unilateral pleural effusion and no clear cause and was supplemented by delayed-phase thoracic CT, optimized for visualization of the pleura. METHODS: All patients underwent standard clinical assessment and pleural investigations in line with recent national guidelines and were followed up for a minimum of 1 year or until histological/microbiological diagnosis. RESULTS: One hundred and fifty patients were recruited, and of these, 141 had a CTPA. PEs were detected in 9/141 (6.4%) patients, and of these, 8/9 were subsequently diagnosed with pleural malignancy. In only 1 case was PE clinically suspected and in no case was PE the primary cause of effusion; 9.8% (8/82) of patients who were ultimately diagnosed with pleural malignancy had PE at presentation. CONCLUSIONS: This study indicates that PE is a frequent concomitant finding in patients with malignant effusions but uncommon as a primary cause of unilateral effusion. In addition, it highlights the known difficulty of clinical diagnosis of PE in the context of malignancy. In view of this, we recommend that CTPA combined with pleural-phase thoracic CT should be considered at presentation when investigating patients with suspected malignant pleural effusion.

Abstract Data generated by genome-wide association studies (GWAS) are growing fast with the linkage of biobank samples to health records, and expanding capture of high-dimensional molecular phenotypes. However the utility of these efforts can only be fully realised if their complete results are collected from their heterogeneous sources and formats, harmonised and made programmatically accessible. Here we present the OpenGWAS database, an open source, open access, scalable and high-performance cloud-based data infrastructure that imports and publishes complete GWAS summary datasets and metadata for the scientific community. Our import pipeline harmonises these datasets against dbSNP and the human genome reference sequence, generates summary reports and standardises the format of results and metadata. Users can access the data via a website, an application programming interface, R and Python packages, and also as downloadable files that can be rapidly queried in high performance computing environments. OpenGWAS currently contains 126 billion genetic associations from 14,582 complete GWAS datasets representing a range of different human phenotypes and disease outcomes across different populations. We developed R and Python packages to serve as conduits between these GWAS data sources and a range of available analytical tools, enabling Mendelian randomization, genetic colocalisation analysis, fine mapping, genetic correlation and locus visualisation. OpenGWAS is freely accessible at https://gwas.mrcieu.ac.uk , and has been designed to facilitate integration with third party analytical tools.

Diabetic foot disease results in a major global burden for patients and the health care system. The International Working Group on the Diabetic Foot (IWGDF) has been producing evidence-based guidelines on the prevention and management of diabetic foot disease since 1999. In 2019, all IWGDF Guidelines have been updated based on systematic reviews of the literature and formulation of recommendations by multidisciplinary experts from all over the world. In this document, the IWGDF Practical Guidelines, we describe the basic principles of prevention, classification, and treatment of diabetic foot disease, based on the six IWGDF Guideline chapters. We also describe the organizational levels to successfully prevent and treat diabetic foot disease according to these principles and provide addenda to assist with foot screening. The information in these practical guidelines is aimed at the global community of health care professionals who are involved in the care of persons with diabetes. Many studies around the world support our belief that implementing these prevention and management principles is associated with a decrease in the frequency of diabetes-related lower extremity amputations. We hope that these updated practical guidelines continue to serve as reference document to aid health care providers in reducing the global burden of diabetic foot disease.

Mendelian randomization (MR) is a method of studying the causal effects of modifiable exposures (i.e., potential risk factors) on health, social, and economic outcomes using genetic variants associated with the specific exposures of interest. MR provides a more robust understanding of the influence of these exposures on outcomes because germline genetic variants are randomly inherited from parents to offspring and, as a result, should not be related to potential confounding factors that influence exposure-outcome associations. The genetic variant can therefore be used as a tool to link the proposed risk factor and outcome, and to estimate this effect with less confounding and bias than conventional epidemiological approaches. We describe the scope of MR, highlighting the range of applications being made possible as genetic data sets and resources become larger and more freely available. We outline the MR approach in detail, covering concepts, assumptions, and estimation methods. We cover some common misconceptions, provide strategies for overcoming violation of assumptions, and discuss future prospects for extending the clinical applicability, methodological innovations, robustness, and generalizability of MR findings.

BACKGROUND: Missing data are unavoidable in epidemiological research, potentially leading to bias and loss of precision. Multiple imputation (MI) is widely advocated as an improvement over complete case analysis (CCA). However, contrary to widespread belief, CCA is preferable to MI in some situations. METHODS: We provide guidance on choice of analysis when data are incomplete. Using causal diagrams to depict missingness mechanisms, we describe when CCA will not be biased by missing data and compare MI and CCA, with respect to bias and efficiency, in a range of missing data situations. We illustrate selection of an appropriate method in practice. RESULTS: For most regression models, CCA gives unbiased results when the chance of being a complete case does not depend on the outcome after taking the covariates into consideration, which includes situations where data are missing not at random. Consequently, there are situations in which CCA analyses are unbiased while MI analyses, assuming missing at random (MAR), are biased. By contrast MI, unlike CCA, is valid for all MAR situations and has the potential to use information contained in the incomplete cases and auxiliary variables to reduce bias and/or improve precision. For this reason, MI was preferred over CCA in our real data example. CONCLUSIONS: Choice of method for dealing with missing data is crucial for validity of conclusions, and should be based on careful consideration of the reasons for the missing data, missing data patterns and the availability of auxiliary information.

BACKGROUND: Observational epidemiologic studies provide critical data for the evaluation of the potential effects of environmental, occupational and behavioural exposures on human health. Systematic reviews of these studies play a key role in informing policy and practice. Systematic reviews should incorporate assessments of the risk of bias in results of the included studies. OBJECTIVE: To develop a new tool, Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS-E) to assess risk of bias in estimates from cohort studies of the causal effect of an exposure on an outcome. METHODS AND RESULTS: ROBINS-E was developed by a large group of researchers from diverse research and public health disciplines through a series of working groups, in-person meetings and pilot testing phases. The tool aims to assess the risk of bias in a specific result (exposure effect estimate) from an individual observational study that examines the effect of an exposure on an outcome. A series of preliminary considerations informs the core ROBINS-E assessment, including details of the result being assessed and the causal effect being estimated. The assessment addresses bias within seven domains, through a series of 'signalling questions'. Domain-level judgements about risk of bias are derived from the answers to these questions, then combined to produce an overall risk of bias judgement for the result, together with judgements about the direction of bias. CONCLUSION: ROBINS-E provides a standardized framework for examining potential biases in results from cohort studies. Future work will produce variants of the tool for other epidemiologic study designs (e.g. case-control studies). We believe that ROBINS-E represents an important development in the integration of exposure assessment, evidence synthesis and causal inference.

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.

Abstract Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER +ve ) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.

OBJECTIVE: To conduct a systematic review and meta-analysis of epidemiological studies investigating the association of arsenic, lead, cadmium, mercury, and copper with cardiovascular disease. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, and Web of Science searched up to December 2017. REVIEW METHODS: Studies reporting risk estimates for total cardiovascular disease, coronary heart disease, and stroke for levels of arsenic, lead, cadmium, mercury, or copper were included. Two investigators independently extracted information on study characteristics and outcomes in accordance with PRISMA and MOOSE guidelines. Relative risks were standardised to a common scale and pooled across studies for each marker using random effects meta-analyses. RESULTS: The review identified 37 unique studies comprising 348 259 non-overlapping participants, with 13 033 coronary heart disease, 4205 stroke, and 15 274 cardiovascular disease outcomes in aggregate. Comparing top versus bottom thirds of baseline levels, pooled relative risks for arsenic and lead were 1.30 (95% confidence interval 1.04 to 1.63) and 1.43 (1.16 to 1.76) for cardiovascular disease, 1.23 (1.04 to 1.45) and 1.85 (1.27 to 2.69) for coronary heart disease, and 1.15 (0.92 to 1.43) and 1.63 (1.14 to 2.34) for stroke. Relative risks for cadmium and copper were 1.33 (1.09 to 1.64) and 1.81 (1.05 to 3.11) for cardiovascular disease, 1.29 (0.98 to 1.71) and 2.22 (1.31 to 3.74) for coronary heart disease, and 1.72 (1.29 to 2.28) and 1.29 (0.77 to 2.17) for stroke. Mercury had no distinctive association with cardiovascular outcomes. There was a linear dose-response relation for arsenic, lead, and cadmium with cardiovascular disease outcomes. CONCLUSION: Exposure to arsenic, lead, cadmium, and copper is associated with an increased risk of cardiovascular disease and coronary heart disease. Mercury is not associated with cardiovascular risk. These findings reinforce the importance of environmental toxic metals in cardiovascular risk, beyond the roles of conventional behavioural risk factors.

BACKGROUND: The Medical Research Council published the second edition of its framework in 2006 on developing and evaluating complex interventions. Since then, there have been considerable developments in the field of complex intervention research. The objective of this project was to update the framework in the light of these developments. The framework aims to help research teams prioritise research questions and design, and conduct research with an appropriate choice of methods, rather than to provide detailed guidance on the use of specific methods. METHODS: There were four stages to the update: (1) gap analysis to identify developments in the methods and practice since the previous framework was published; (2) an expert workshop of 36 participants to discuss the topics identified in the gap analysis; (3) an open consultation process to seek comments on a first draft of the new framework; and (4) findings from the previous stages were used to redraft the framework, and final expert review was obtained. The process was overseen by a Scientific Advisory Group representing the range of relevant National Institute for Health Research and Medical Research Council research investments. RESULTS: Key changes to the previous framework include (1) an updated definition of complex interventions, highlighting the dynamic relationship between the intervention and its context; (2) an emphasis on the use of diverse research perspectives: efficacy, effectiveness, theory-based and systems perspectives; (3) a focus on the usefulness of evidence as the basis for determining research perspective and questions; (4) an increased focus on interventions developed outside research teams, for example changes in policy or health services delivery; and (5) the identification of six 'core elements' that should guide all phases of complex intervention research: consider context; develop, refine and test programme theory; engage stakeholders; identify key uncertainties; refine the intervention; and economic considerations. We divide the research process into four phases: development, feasibility, evaluation and implementation. For each phase we provide a concise summary of recent developments, key points to address and signposts to further reading. We also present case studies to illustrate the points being made throughout. LIMITATIONS: The framework aims to help research teams prioritise research questions and design and conduct research with an appropriate choice of methods, rather than to provide detailed guidance on the use of specific methods. In many of the areas of innovation that we highlight, such as the use of systems approaches, there are still only a few practical examples. We refer to more specific and detailed guidance where available and note where promising approaches require further development. CONCLUSIONS: This new framework incorporates developments in complex intervention research published since the previous edition was written in 2006. As well as taking account of established practice and recent refinements, we draw attention to new approaches and place greater emphasis on economic considerations in complex intervention research. We have introduced a new emphasis on the importance of context and the value of understanding interventions as 'events in systems' that produce effects through interactions with features of the contexts in which they are implemented. The framework adopts a pluralist approach, encouraging researchers and research funders to adopt diverse research perspectives and to select research questions and methods pragmatically, with the aim of providing evidence that is useful to decision-makers. FUTURE WORK: We call for further work to develop relevant methods and provide examples in practice. The use of this framework should be monitored and the move should be made to a more fluid resource in the future, for example a web-based format that can be frequently updated to incorporate new material and links to emerging resources. FUNDING: This project was jointly funded by the Medical Research Council (MRC) and the National Institute for Health Research (Department of Health and Social Care 73514).

BACKGROUND: The COVID-19 pandemic and mitigation measures are likely to have a marked effect on mental health. It is important to use longitudinal data to improve inferences. AIMS: To quantify the prevalence of depression, anxiety and mental well-being before and during the COVID-19 pandemic. Also, to identify groups at risk of depression and/or anxiety during the pandemic. METHOD: Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC) index generation (n = 2850, mean age 28 years) and parent generation (n = 3720, mean age 59 years), and Generation Scotland (n = 4233, mean age 59 years). Depression was measured with the Short Mood and Feelings Questionnaire in ALSPAC and the Patient Health Questionnaire-9 in Generation Scotland. Anxiety and mental well-being were measured with the Generalised Anxiety Disorder Assessment-7 and the Short Warwick Edinburgh Mental Wellbeing Scale. RESULTS: Depression during the pandemic was similar to pre-pandemic levels in the ALSPAC index generation, but those experiencing anxiety had almost doubled, at 24% (95% CI 23-26%) compared with a pre-pandemic level of 13% (95% CI 12-14%). In both studies, anxiety and depression during the pandemic was greater in younger members, women, those with pre-existing mental/physical health conditions and individuals in socioeconomic adversity, even when controlling for pre-pandemic anxiety and depression. CONCLUSIONS: These results provide evidence for increased anxiety in young people that is coincident with the pandemic. Specific groups are at elevated risk of depression and anxiety during the COVID-19 pandemic. This is important for planning current mental health provisions and for long-term impact beyond this pandemic.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

BACKGROUND: To reduce contagion of COVID-19, in March 2020 UK general practices implemented predominantly remote consulting via telephone, video, or online consultation platforms. AIM: To investigate the rapid implementation of remote consulting and explore impact over the initial months of the COVID-19 pandemic. DESIGN AND SETTING: Mixed-methods study in 21 general practices in Bristol, North Somerset and South Gloucestershire. METHOD: Longitudinal observational quantitative analysis compared volume and type of consultation in April to July 2020 with April to July 2019. Negative binomial models were used to identify if changes differed among different groups of patients. Qualitative data from 87 longitudinal interviews with practice staff in four rounds investigated practices' experience of the move to remote consulting, challenges faced, and solutions. A thematic analysis utilised Normalisation Process Theory. RESULTS: There was universal consensus that remote consulting was necessary. This drove a rapid change to 90% remote GP consulting (46% for nurses) by April 2020. Consultation rates reduced in April to July 2020 compared to 2019; GPs and nurses maintained a focus on older patients, shielding patients, and patients with poor mental health. Telephone consulting was sufficient for many patient problems, video consulting was used more rarely, and was less essential as lockdown eased. SMS-messaging increased more than three-fold. GPs were concerned about increased clinical risk and some had difficulties setting thresholds for seeing patients face-to-face as lockdown eased. CONCLUSION: The shift to remote consulting was successful and a focus maintained on vulnerable patients. It was driven by the imperative to reduce contagion and may have risks; post-pandemic, the model will need adjustment.

BACKGROUND: The life expectancy of people with HIV taking antiretroviral therapy (ART) has increased substantially over the past 25 years. Most previous studies of life expectancy were based on data from the first few years after starting ART, when mortality is highest. However, many people with HIV have been successfully treated with ART for many years, and up-to-date prognosis data are needed. We aimed to estimate life expectancy in adults with HIV on ART for at least 1 year in Europe and North America from 2015 onwards. METHODS: We used data for people with HIV taking ART from the Antiretroviral Therapy Cohort Collaboration and the UK Collaborative HIV Cohort Study. Included participants started ART between 1996 and 2014 and had been on ART for at least 1 year by 2015, or started ART between 2015 and 2019 and survived for at least 1 year; all participants were aged at least 16 years at ART initiation. We used Poisson models to estimate the associations between mortality and demographic and clinical characteristics, including CD4 cell count at the start of follow-up. We also estimated the remaining years of life left for people with HIV aged 40 years who were taking ART, and stratified these estimates by variables associated with mortality. These estimates were compared with estimates for years of life remaining in a corresponding multi-country general population. FINDINGS: Among 206 891 people with HIV included, 5780 deaths were recorded since 2015. We estimated that women with HIV at age 40 years had 35·8 years (95% CI 35·2-36·4) of life left if they started ART before 2015, and 39·0 years (38·5-39·5) left if they started ART after 2015. For men with HIV, the corresponding estimates were 34·5 years (33·8-35·2) and 37·0 (36·5-37·6). Women with CD4 counts of fewer than 49 cells per μL at the start of follow-up had an estimated 19·4 years (18·2-20·5) of life left at age 40 years if they started ART before 2015 and 24·9 years (23·9-25·9) left if they started ART after 2015. The corresponding estimates for men were 18·2 years (17·1-19·4) and 23·7 years (22·7-24·8). Women with CD4 counts of at least 500 cells per μL at the start of follow-up had an estimated 40·2 years (39·7-40·6) of life left at age 40 years if they started ART before 2015 and 42·0 years (41·7-42·3) left if they started ART after 2015. The corresponding estimates for men were 38·0 years (37·5-38·5) and 39·2 years (38·7-39·7). INTERPRETATION: For people with HIV on ART and with high CD4 cell counts who survived to 2015 or started ART after 2015, life expectancy was only a few years lower than that in the general population, irrespective of when ART was started. However, for people with low CD4 counts at the start of follow-up, life-expectancy estimates were substantially lower, emphasising the continuing importance of early diagnosis and sustained treatment of HIV. FUNDING: US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council.