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Supplemental material, sj-pdf-3-jrs-10.1177_01410768231182389 for COVID-19 risk mitigation in reopening mass cultural events: population-based observational study for the UK Events Research Programme in Liverpool City Region by Girvan Burnside, Christopher P Cheyne, Gary Leeming, Michael Humann, Alistair Darby, Mark A Green, Alexander Crozier, Simon Maskell, Kay O’Halloran, Elena Musi, Elinor Carmi, Naila Khan, Debra Fisher, Rhiannon Corcoran, Jake Dunning, W John Edmunds, Kukatharmini Tharmaratnam, David M Hughes, Liora Malki-Epshtein, Malcolm Cook, Ben M Roberts, Eileen Gallagher, Kate Howell, Meera Chand, Robin Kemp, Matthew Boulter, Tom Fowler, Malcolm G Semple, Emer Coffey, Matt Ashton, The COVID-19 Genomics UK (COG-UK) Consortium, Marta García-Fiñana and Iain E Buchan in Journal of the Royal Society of Medicine

Supplemental material, sj-pdf-3-jrs-10.1177_01410768231182389 for COVID-19 risk mitigation in reopening mass cultural events: population-based observational study for the UK Events Research Programme in Liverpool City Region by Girvan Burnside, Christopher P Cheyne, Gary Leeming, Michael Humann, Alistair Darby, Mark A Green, Alexander Crozier, Simon Maskell, Kay O’Halloran, Elena Musi, Elinor Carmi, Naila Khan, Debra Fisher, Rhiannon Corcoran, Jake Dunning, W John Edmunds, Kukatharmini Tharmaratnam, David M Hughes, Liora Malki-Epshtein, Malcolm Cook, Ben M Roberts, Eileen Gallagher, Kate Howell, Meera Chand, Robin Kemp, Matthew Boulter, Tom Fowler, Malcolm G Semple, Emer Coffey, Matt Ashton, The COVID-19 Genomics UK (COG-UK) Consortium, Marta García-Fiñana and Iain E Buchan in Journal of the Royal Society of Medicine

Supplemental material, sj-pdf-2-jrs-10.1177_01410768231182389 for COVID-19 risk mitigation in reopening mass cultural events: population-based observational study for the UK Events Research Programme in Liverpool City Region by Girvan Burnside, Christopher P Cheyne, Gary Leeming, Michael Humann, Alistair Darby, Mark A Green, Alexander Crozier, Simon Maskell, Kay O’Halloran, Elena Musi, Elinor Carmi, Naila Khan, Debra Fisher, Rhiannon Corcoran, Jake Dunning, W John Edmunds, Kukatharmini Tharmaratnam, David M Hughes, Liora Malki-Epshtein, Malcolm Cook, Ben M Roberts, Eileen Gallagher, Kate Howell, Meera Chand, Robin Kemp, Matthew Boulter, Tom Fowler, Malcolm G Semple, Emer Coffey, Matt Ashton, The COVID-19 Genomics UK (COG-UK) Consortium, Marta García-Fiñana and Iain E Buchan in Journal of the Royal Society of Medicine

Supplemental material, sj-pdf-4-jrs-10.1177_01410768231182389 for COVID-19 risk mitigation in reopening mass cultural events: population-based observational study for the UK Events Research Programme in Liverpool City Region by Girvan Burnside, Christopher P Cheyne, Gary Leeming, Michael Humann, Alistair Darby, Mark A Green, Alexander Crozier, Simon Maskell, Kay O’Halloran, Elena Musi, Elinor Carmi, Naila Khan, Debra Fisher, Rhiannon Corcoran, Jake Dunning, W John Edmunds, Kukatharmini Tharmaratnam, David M Hughes, Liora Malki-Epshtein, Malcolm Cook, Ben M Roberts, Eileen Gallagher, Kate Howell, Meera Chand, Robin Kemp, Matthew Boulter, Tom Fowler, Malcolm G Semple, Emer Coffey, Matt Ashton, The COVID-19 Genomics UK (COG-UK) Consortium, Marta García-Fiñana and Iain E Buchan in Journal of the Royal Society of Medicine

Supplemental material, sj-pdf-6-jrs-10.1177_01410768231182389 for COVID-19 risk mitigation in reopening mass cultural events: population-based observational study for the UK Events Research Programme in Liverpool City Region by Girvan Burnside, Christopher P Cheyne, Gary Leeming, Michael Humann, Alistair Darby, Mark A Green, Alexander Crozier, Simon Maskell, Kay O’Halloran, Elena Musi, Elinor Carmi, Naila Khan, Debra Fisher, Rhiannon Corcoran, Jake Dunning, W John Edmunds, Kukatharmini Tharmaratnam, David M Hughes, Liora Malki-Epshtein, Malcolm Cook, Ben M Roberts, Eileen Gallagher, Kate Howell, Meera Chand, Robin Kemp, Matthew Boulter, Tom Fowler, Malcolm G Semple, Emer Coffey, Matt Ashton, The COVID-19 Genomics UK (COG-UK) ConsortiumMarta García-Fiñana and Iain E Buchan in Journal of the Royal Society of Medicine

Supplemental material, sj-pdf-5-jrs-10.1177_01410768231182389 for COVID-19 risk mitigation in reopening mass cultural events: population-based observational study for the UK Events Research Programme in Liverpool City Region by Girvan Burnside, Christopher P Cheyne, Gary Leeming, Michael Humann, Alistair Darby, Mark A Green, Alexander Crozier, Simon Maskell, Kay O’Halloran, Elena Musi, Elinor Carmi, Naila Khan, Debra Fisher, Rhiannon Corcoran, Jake Dunning, W John Edmunds, Kukatharmini Tharmaratnam, David M Hughes, Liora Malki-Epshtein, Malcolm Cook, Ben M Roberts, Eileen Gallagher, Kate Howell, Meera Chand, Robin Kemp, Matthew Boulter, Tom Fowler, Malcolm G Semple, Emer Coffey, Matt Ashton, The COVID-19 Genomics UK (COG-UK) Consortium, Marta García-Fiñana and Iain E Buchan in Journal of the Royal Society of Medicine

Supplemental material, sj-pdf-2-jrs-10.1177_01410768231182389 for COVID-19 risk mitigation in reopening mass cultural events: population-based observational study for the UK Events Research Programme in Liverpool City Region by Girvan Burnside, Christopher P Cheyne, Gary Leeming, Michael Humann, Alistair Darby, Mark A Green, Alexander Crozier, Simon Maskell, Kay O’Halloran, Elena Musi, Elinor Carmi, Naila Khan, Debra Fisher, Rhiannon Corcoran, Jake Dunning, W John Edmunds, Kukatharmini Tharmaratnam, David M Hughes, Liora Malki-Epshtein, Malcolm Cook, Ben M Roberts, Eileen Gallagher, Kate Howell, Meera Chand, Robin Kemp, Matthew Boulter, Tom Fowler, Malcolm G Semple, Emer Coffey, Matt Ashton, The COVID-19 Genomics UK (COG-UK) Consortium, Marta García-Fiñana and Iain E Buchan in Journal of the Royal Society of Medicine

Supplemental material, sj-pdf-5-jrs-10.1177_01410768231182389 for COVID-19 risk mitigation in reopening mass cultural events: population-based observational study for the UK Events Research Programme in Liverpool City Region by Girvan Burnside, Christopher P Cheyne, Gary Leeming, Michael Humann, Alistair Darby, Mark A Green, Alexander Crozier, Simon Maskell, Kay O’Halloran, Elena Musi, Elinor Carmi, Naila Khan, Debra Fisher, Rhiannon Corcoran, Jake Dunning, W John Edmunds, Kukatharmini Tharmaratnam, David M Hughes, Liora Malki-Epshtein, Malcolm Cook, Ben M Roberts, Eileen Gallagher, Kate Howell, Meera Chand, Robin Kemp, Matthew Boulter, Tom Fowler, Malcolm G Semple, Emer Coffey, Matt Ashton, The COVID-19 Genomics UK (COG-UK) Consortium, Marta García-Fiñana and Iain E Buchan in Journal of the Royal Society of Medicine

Supplemental material, sj-pdf-1-jrs-10.1177_01410768231182389 for COVID-19 risk mitigation in reopening mass cultural events: population-based observational study for the UK Events Research Programme in Liverpool City Region by Girvan Burnside, Christopher P Cheyne, Gary Leeming, Michael Humann, Alistair Darby, Mark A Green, Alexander Crozier, Simon Maskell, Kay O’Halloran, Elena Musi, Elinor Carmi, Naila Khan, Debra Fisher, Rhiannon Corcoran, Jake Dunning, W John Edmunds, Kukatharmini Tharmaratnam, David M Hughes, Liora Malki-Epshtein, Malcolm Cook, Ben M Roberts, Eileen Gallagher, Kate Howell, Meera Chand, Robin Kemp, Matthew Boulter, Tom Fowler, Malcolm G Semple, Emer Coffey, Matt Ashton, The COVID-19 Genomics UK (COG-UK) Consortium, Marta García-Fiñana and Iain E Buchan in Journal of the Royal Society of Medicine

Supplemental material, sj-pdf-4-jrs-10.1177_01410768231182389 for COVID-19 risk mitigation in reopening mass cultural events: population-based observational study for the UK Events Research Programme in Liverpool City Region by Girvan Burnside, Christopher P Cheyne, Gary Leeming, Michael Humann, Alistair Darby, Mark A Green, Alexander Crozier, Simon Maskell, Kay O’Halloran, Elena Musi, Elinor Carmi, Naila Khan, Debra Fisher, Rhiannon Corcoran, Jake Dunning, W John Edmunds, Kukatharmini Tharmaratnam, David M Hughes, Liora Malki-Epshtein, Malcolm Cook, Ben M Roberts, Eileen Gallagher, Kate Howell, Meera Chand, Robin Kemp, Matthew Boulter, Tom Fowler, Malcolm G Semple, Emer Coffey, Matt Ashton, The COVID-19 Genomics UK (COG-UK) Consortium, Marta García-Fiñana and Iain E Buchan in Journal of the Royal Society of Medicine

Supplemental material, sj-pdf-6-jrs-10.1177_01410768231182389 for COVID-19 risk mitigation in reopening mass cultural events: population-based observational study for the UK Events Research Programme in Liverpool City Region by Girvan Burnside, Christopher P Cheyne, Gary Leeming, Michael Humann, Alistair Darby, Mark A Green, Alexander Crozier, Simon Maskell, Kay O’Halloran, Elena Musi, Elinor Carmi, Naila Khan, Debra Fisher, Rhiannon Corcoran, Jake Dunning, W John Edmunds, Kukatharmini Tharmaratnam, David M Hughes, Liora Malki-Epshtein, Malcolm Cook, Ben M Roberts, Eileen Gallagher, Kate Howell, Meera Chand, Robin Kemp, Matthew Boulter, Tom Fowler, Malcolm G Semple, Emer Coffey, Matt Ashton, The COVID-19 Genomics UK (COG-UK) ConsortiumMarta García-Fiñana and Iain E Buchan in Journal of the Royal Society of Medicine

Additional file 1. Population demographics, MCMC output (parameter estimates, trace plots and posterior distributions) for all models and log likelihood profile for infectiveness.

AIMS Systematic annual screening to detect sight-threatening diabetic retinopathy (STDR) is established in the United Kingdom. We designed an observational cohort study to provide up-to-date data for policy makers and clinical researchers on incidence of key screening endpoints in people with diabetes attending one screening programme running for over 30 years. METHODS All people with diabetes aged ≥12 years registered with general practices in the Liverpool health district were offered inclusion. Data sources comprised: primary care (demographics, systemic risk factors), Liverpool Diabetes Eye Screening Programme (retinopathy grading), Hospital Eye Services (slit lamp biomicroscopy assessment of screen positives). RESULTS 133,366 screening episodes occurred in 28,384 people over 11 years. Overall incidences were: screen positive 6.7% (95% CI 6.5-6.8), screen positive for retinopathy 3.1% (3.0-3.1), unassessable images 2.6% (2.5-2.7), other significant eye diseases 1.0% (1.0-1.1). 1.6% (1.6-1.7) had sight-threatening retinopathy confirmed by slit lamp biomicroscopy. The annual incidence of screen positive and screen positive for retinopathy showed consistent declines from 8.8%-10.6% and 4.4%-4.6% in 2007/09 to 4.4%-6.8% and 2.3%-2.9% in 2013/17, respectively. Rates of STDR (true positive) were consistently below 2% after 2008/09. Screen positive rates were higher in first time attenders (9.9% [9.4-10.2] vs. 6.1% [6.0-6.2]) in part due to ungradeable images (4.1% vs. 2.3%) and other eye disease (2.4% vs. 0.8%). 4.5% (3.9-5.2) of previous non-attenders had sight-threatening retinopathy. Compared with people with type 2 diabetes, those with type 1 disease demonstrated higher rates of screen positive (11.9% vs. 6.0%) and STDR (6.4% vs. 1.2%). Overall prevalence of any retinopathy was 27.2% (27.0-27.4). CONCLUSIONS In an established screening programme with a stable population screen, positive rates show a consistent fall over time to a low level. Of those who are screen positive, fewer than 50% are screen positive for diabetic retinopathy. Most are due to sight threatening maculopathy. The annual incidence of STDR is under 2% suggesting future work on redefining screen positive and supporting extended intervals for people at low risk. Higher rates of screen positive and STDR are seen in first time attenders. Those who have never attended for screening should be specifically targeted.

BACKGROUND: Mortality rates in hospitalised patients with COVID-19 in the UK appeared to decline during the first wave of the pandemic. We aimed to quantify potential drivers of this change and identify groups of patients who remain at high risk of dying in hospital. METHODS: In this multicentre prospective observational cohort study, the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK recruited a prospective cohort of patients with COVID-19 admitted to 247 acute hospitals in England, Scotland, and Wales during the first wave of the pandemic (between March 9 and Aug 2, 2020). We included all patients aged 18 years and older with clinical signs and symptoms of COVID-19 or confirmed COVID-19 (by RT-PCR test) from assumed community-acquired infection. We did a three-way decomposition mediation analysis using natural effects models to explore associations between week of admission and in-hospital mortality, adjusting for confounders (demographics, comorbidities, and severity of illness) and quantifying potential mediators (level of respiratory support and steroid treatment). The primary outcome was weekly in-hospital mortality at 28 days, defined as the proportion of patients who had died within 28 days of admission of all patients admitted in the observed week, and it was assessed in all patients with an outcome. This study is registered with the ISRCTN Registry, ISRCTN66726260. FINDINGS: Between March 9, and Aug 2, 2020, we recruited 80 713 patients, of whom 63 972 were eligible and included in the study. Unadjusted weekly in-hospital mortality declined from 32·3% (95% CI 31·8-32·7) in March 9 to April 26, 2020, to 16·4% (15·0-17·8) in June 15 to Aug 2, 2020. Reductions in mortality were observed in all age groups, in all ethnic groups, for both sexes, and in patients with and without comorbidities. After adjustment, there was a 32% reduction in the risk of mortality per 7-week period (odds ratio [OR] 0·68 [95% CI 0·65-0·71]). The higher proportions of patients with severe disease and comorbidities earlier in the first wave (March and April) than in June and July accounted for 10·2% of this reduction. The use of respiratory support changed during the first wave, with gradually increased use of non-invasive ventilation over the first wave. Changes in respiratory support and use of steroids accounted for 22·2%, OR 0·95 (0·94-0·95) of the reduction in in-hospital mortality. INTERPRETATION: The reduction in in-hospital mortality in patients with COVID-19 during the first wave in the UK was partly accounted for by changes in the case-mix and illness severity. A significant reduction in in-hospital mortality was associated with differences in respiratory support and critical care use, which could partly reflect accrual of clinical knowledge. The remaining improvement in in-hospital mortality is not explained by these factors, and could be associated with changes in community behaviour, inoculum dose, and hospital capacity strain. FUNDING: National Institute for Health Research and the Medical Research Council.

Aims/hypothesis Using variable diabetic retinopathy screening intervals, informed by personal risk levels, offers improved engagement of people with diabetes and reallocation of resources to high-risk groups, while addressing the increasing prevalence of diabetes. However, safety data on extending screening intervals are minimal. The aim of this study was to evaluate the safety and cost-effectiveness of individualised, variable-interval, risk-based population screening compared with usual care, with wide-ranging input from individuals with diabetes. Methods This was a two-arm, parallel-assignment, equivalence RCT (minimum 2 year follow-up) in individuals with diabetes aged 12 years or older registered with a single English screening programme. Participants were randomly allocated 1:1 at baseline to individualised screening at 6, 12 or 24 months for those at high, medium and low risk, respectively, as determined at each screening episode by a risk-calculation engine using local demographic, screening and clinical data, or to annual screening (control group). Screening staff and investigators were observer-masked to allocation and interval. Data were collected within the screening programme. The primary outcome was attendance (safety). A secondary safety outcome was the development of sight-threatening diabetic retinopathy. Cost-effectiveness was evaluated within a 2 year time horizon from National Health Service and societal perspectives. Results A total of 4534 participants were randomised. After withdrawals, there were 2097 participants in the individualised screening arm and 2224 in the control arm. Attendance rates at first follow-up were equivalent between the two arms (individualised screening 83.6%; control arm 84.7%; difference −1.0 [95% CI −3.2, 1.2]), while sight-threatening diabetic retinopathy detection rates were non-inferior in the individualised screening arm (individualised screening 1.4%, control arm 1.7%; difference −0.3 [95% CI −1.1, 0.5]). Sensitivity analyses confirmed these findings. No important adverse events were observed. Mean differences in complete case quality-adjusted life-years (EuroQol Five-Dimension Questionnaire, Health Utilities Index Mark 3) did not significantly differ from zero; multiple imputation supported the dominance of individualised screening. Incremental cost savings per person with individualised screening were £17.34 (95% CI 17.02, 17.67) from the National Health Service perspective and £23.11 (95% CI 22.73, 23.53) from the societal perspective, representing a 21% reduction in overall programme costs. Overall, 43.2% fewer screening appointments were required in the individualised arm. Conclusions/interpretation Stakeholders involved in diabetes care can be reassured by this study, which is the largest ophthalmic RCT in diabetic retinopathy screening to date, that extended and individualised, variable-interval, risk-based screening is feasible and can be safely and cost-effectively introduced in established systematic programmes. Because of the 2 year time horizon of the trial and the long time frame of the disease, robust monitoring of attendance and retinopathy rates should be included in any future implementation. Trial registration ISRCTN 87561257 Funding The study was funded by the UK National Institute for Health Research.

Aims/hypothesis: Using variable diabetic retinopathy screening intervals, informed by personal risk levels, offers improved engagement of people with diabetes and reallocation of resources to high-risk groups, while addressing the increasing prevalence of diabetes. However, safety data on extending screening intervals are minimal. The aim of this study was to evaluate the safety and cost-effectiveness of individualised, variable-interval, risk-based population screening compared with usual care, with wide-ranging input from individuals with diabetes. Methods: This was a two-arm, parallel-assignment, equivalence RCT (minimum 2year follow-up) in individuals with diabetes aged 12years or older registered with a single English screening programme. Participants were randomly allocated 1:1 at baseline to individualised screening at 6, 12 or 24months for those at high, medium and low risk, respectively, as determined at each screening episode by a risk-calculation engine using local demographic, screening and clinical data, or to annual screening (control group). Screening staff and investigators were observer-masked to allocation and interval. Data were collected within the screening programme. The primary outcome was attendance (safety). A secondary safety outcome was the development of sight-threatening diabetic retinopathy. Cost-effectiveness was evaluated within a 2year time horizon from National Health Service and societal perspectives. Results: A total of 4534 participants were randomised. After withdrawals, there were 2097 participants in the individualised screening arm and 2224 in the control arm. Attendance rates at first follow-up were equivalent between the two arms (individualised screening 83.6%; control arm 84.7%; difference −1.0 [95% CI −3.2, 1.2]), while sight-threatening diabetic retinopathy detection rates were non-inferior in the individualised screening arm (individualised screening 1.4%, control arm 1.7%; difference −0.3 [95% CI −1.1, 0.5]). Sensitivity analyses confirmed these findings. No important adverse events were observed. Mean differences in complete case quality-adjusted life-years (EuroQol Five-Dimension Questionnaire, Health Utilities Index Mark 3) did not significantly differ from zero; multiple imputation supported the dominance of individualised screening. Incremental cost savings per person with individualised screening were £17.34 (95% CI 17.02, 17.67) from the National Health Service perspective and £23.11 (95% CI 22.73, 23.53) from the societal perspective, representing a 21% reduction in overall programme costs. Overall, 43.2% fewer screening appointments were required in the individualised arm. Conclusions/interpretation: Stakeholders involved in diabetes care can be reassured by this study, which is the largest ophthalmic RCT in diabetic retinopathy screening to date, that extended and individualised, variable-interval, risk-based screening is feasible and can be safely and cost-effectively introduced in established systematic programmes. Because of the 2year time horizon of the trial and the long time frame of the disease, robust monitoring of attendance and retinopathy rates should be included in any future implementation. Trial registration: ISRCTN 87561257 Funding: The study was funded by the UK National Institute for Health Research. [Figure not available: see fulltext.]

IntroductionCurrently, all people with diabetes (PWD) aged 12 years and over in the UK are invited for screening for diabetic retinopathy (DR) annually. Resources are not increasing despite a 5% increase in the numbers of PWD nationwide each year. We describe the rationale, design and methodology for a randomised controlled trial (RCT) evaluating the safety, acceptability and cost-effectiveness of personalised variable-interval risk-based screening for DR. This is the first randomised trial of personalised screening for DR and the largest ophthalmic RCT in the UK.Methods and analysisPWD attending seven screening clinics in the Liverpool Diabetic Eye Screening Programme were recruited into a single site RCT with a 1:1 allocation to individualised risk-based variable-interval or annual screening intervals. A risk calculation engine developed for the trial estimates the probability that an individual will develop referable disease (screen positive DR) within the next 6, 12 or 24 months using demographic, retinopathy and systemic risk factor data from primary care and screening programme records. Dynamic, secure, real-time data connections have been developed. The primary outcome is attendance for follow-up screening. We will test for equivalence in attendance rates between the two arms. Secondary outcomes are rates and severity of DR, visual outcomes, cost-effectiveness and health-related quality of life. The required sample size was 4460 PWD. Recruitment is complete, and the trial is in follow-up.Ethics and disseminationEthical approval was obtained from National Research Ethics Service Committee North West – Preston, reference 14/NW/0034. Results will be presented at international meetings and published in peer-reviewed journals. This pragmatic RCT will inform screening policy in the UK and elsewhere.Trial registration numberISRCTN87561257; Pre-results.

OBJECTIVE: To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs. METHODS: Children born to women with epilepsy (n = 243) and women without epilepsy (n = 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models. RESULTS: The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] -4.9 to -14.6; p 800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5-19.7; p