Consistency, completeness and external validity of ethnicity recording in NHS primary care records: a cohort study in 25 million patients' records at source using OpenSAFELY.

BACKGROUND: Ethnicity is known to be an important correlate of health outcomes, particularly during the COVID-19 pandemic, where some ethnic groups were shown to be at higher risk of infection and adverse outcomes. The recording of patients' ethnic groups in primary care can support research and efforts to achieve equity in service provision and outcomes; however, the coding of ethnicity is known to present complex challenges. We therefore set out to describe ethnicity coding in detail with a view to supporting the use of this data in a wide range of settings, as part of wider efforts to robustly describe and define methods of using administrative data. METHODS: We describe the completeness and consistency of primary care ethnicity recording in the OpenSAFELY-TPP database, containing linked primary care and hospital records in > 25 million patients in England. We also compared the ethnic breakdown in OpenSAFELY-TPP with that of the 2021 UK census. RESULTS: 78.2% of patients registered in OpenSAFELY-TPP on 1 January 2022 had their ethnicity recorded in primary care records, rising to 92.5% when supplemented with hospital data. The completeness of ethnicity recording was higher for women than for men. The rate of primary care ethnicity recording ranged from 77% in the South East of England to 82.2% in the West Midlands. Ethnicity recording rates were higher in patients with chronic or other serious health conditions. For each of the five broad ethnicity groups, primary care recorded ethnicity was within 2.9 percentage points of the population rate as recorded in the 2021 Census for England as a whole. For patients with multiple ethnicity records, 98.7% of the latest recorded ethnicities matched the most frequently coded ethnicity. Patients whose latest recorded ethnicity was categorised as Other were most likely to have a discordant ethnicity recording (32.2%). CONCLUSIONS: Primary care ethnicity data in OpenSAFELY is present for over three quarters of all patients, and combined with data from other sources can achieve a high level of completeness. The overall distribution of ethnicities across all English OpenSAFELY-TPP practices was similar to the 2021 Census, with some regional variation. This report identifies the best available codelist for use in OpenSAFELY and similar electronic health record data.

Changes in opioid prescribing during the COVID-19 pandemic in England: an interrupted time-series analysis in the OpenSAFELY-TTP cohort.

BACKGROUND: The COVID-19 pandemic disrupted health-care delivery, including difficulty accessing in-person care, which could have increased the need for strong pharmacological pain relief. Due to the risks associated with overprescribing of opioids, especially to vulnerable populations, we aimed to quantify changes to measures during the COVID-19 pandemic, overall, and by key subgroups. METHODS: For this interrupted time-series analysis study conducted in England, with National Health Service England approval, we used routine clinical data from more than 20 million general practice adult patients in OpenSAFELY-TPP, which is a a secure software platform for analysis of electronic health records. We included all adults registered with a primary care practice using TPP-SystmOne software. Using interrupted time-series analysis, we quantified prevalent and new opioid prescribing before the COVID-19 pandemic (January, 2018-February, 2020), during the lockdown (March, 2020-March, 2021), and recovery periods (April, 2021-June, 2022), overall and stratified by demographics (age, sex, deprivation, ethnicity, and geographical region) and in people in care homes identified via an address-matching algorithm. FINDINGS: There was little change in prevalent prescribing during the pandemic, except for a temporary increase in March, 2020. We observed a 9·8% (95% CI -14·5 to -6·5) reduction in new opioid prescribing from March, 2020, with a levelling of the downward trend, and rebounding slightly after April, 2021 (4·1%, 95% CI -0·9 to 9·4). Opioid prescribing rates varied by demographics, but we found a reduction in new prescribing for all subgroups except people aged 80 years or older. Among care home residents, in April, 2020, parenteral opioid prescribing increased by 186·3% (153·1 to 223·9). INTERPRETATION: Opioid prescribing increased temporarily among older people and care home residents, likely reflecting use to treat end-of-life COVID-19 symptoms. Despite vulnerable populations being more affected by health-care disruptions, disparities in opioid prescribing by most demographic subgroups did not widen during the pandemic. Further research is needed to understand what is driving the changes in new opioid prescribing and its relation to changes to health-care provision during the pandemic. FUNDING: The Wellcome Trust, Medical Research Council, The National Institute for Health and Care Research, UK Research and Innovation, and Health Data Research UK.

Effectiveness of mRNA COVID-19 Vaccines as First Booster Doses in England: An Observational Study in OpenSAFELY-TPP.

BACKGROUND: The UK delivered its first "booster" COVID-19 vaccine doses in September 2021, initially to individuals at high risk of severe disease, then to all adults. The BNT162b2 Pfizer-BioNTech vaccine was used initially, then also Moderna mRNA-1273. METHODS: With the approval of the National Health Service England, we used routine clinical data to estimate the effectiveness of boosting with BNT162b2 or mRNA-1273 compared with no boosting in eligible adults who had received two primary course vaccine doses. We matched each booster recipient with an unboosted control on factors relating to booster priority status and prior COVID-19 immunization. We adjusted for additional factors in Cox models, estimating hazard ratios up to 182 days (6 months) following booster dose. We estimated hazard ratios overall and within the following periods: 1-14, 15-42, 43-69, 70-97, 98-126, 127-152, and 155-182 days. Outcomes included a positive SARS-CoV-2 test, COVID-19 hospitalization, COVID-19 death, non-COVID-19 death, and fracture. RESULTS: We matched 8,198,643 booster recipients with unboosted controls. Adjusted hazard ratios over 6-month follow-up were: positive SARS-CoV-2 test 0.75 (0.74, 0.75); COVID-19 hospitalization 0.30 (0.29, 0.31); COVID-19 death 0.11 (0.10, 0.14); non-COVID-19 death 0.22 (0.21, 0.23); and fracture 0.77 (0.75, 0.78). Estimated effectiveness of booster vaccines against severe COVID-19-related outcomes peaked during the first 3 months following the booster dose. By 6 months, the cumulative incidence of positive SARS-CoV-2 test was higher in boosted than unboosted individuals. CONCLUSIONS: We estimate that COVID-19 booster vaccination, compared with no booster vaccination, provided substantial protection against COVID-19 hospitalization and COVID-19 death but only limited protection against positive SARS-CoV-2 test. Lower rates of fracture in boosted than unboosted individuals may suggest unmeasured confounding. Observational studies should report estimated vaccine effectiveness against nontarget and negative control outcomes.

OpenSAFELY: A platform for analysing electronic health records designed for reproducible research.

Electronic health records (EHRs) and other administrative health data are increasingly used in research to generate evidence on the effectiveness, safety, and utilisation of medical products and services, and to inform public health guidance and policy. Reproducibility is a fundamental step for research credibility and promotes trust in evidence generated from EHRs. At present, ensuring research using EHRs is reproducible can be challenging for researchers. Research software platforms can provide technical solutions to enhance the reproducibility of research conducted using EHRs. In response to the COVID-19 pandemic, we developed the secure, transparent, analytic open-source software platform OpenSAFELY designed with reproducible research in mind. OpenSAFELY mitigates common barriers to reproducible research by: standardising key workflows around data preparation; removing barriers to code-sharing in secure analysis environments; enforcing public sharing of programming code and codelists; ensuring the same computational environment is used everywhere; integrating new and existing tools that encourage and enable the use of reproducible working practices; and providing an audit trail for all code that is run against the real data to increase transparency. This paper describes OpenSAFELY's reproducibility-by-design approach in detail.

The impact of COVID-19 on medication reviews in English primary care. An OpenSAFELY-TPP analysis of 20 million adult electronic health records.

AIMS: The COVID-19 pandemic caused significant disruption to routine activity in primary care. Medication reviews are an important primary care activity ensuring safety and appropriateness of prescribing. A disruption could have significant negative implications for patient care. Using routinely collected data, our aim was first to describe codes used to record medication review activity and then to report the impact of COVID-19 on the rates of medication reviews. METHODS: With the approval of NHS England, we conducted a cohort study of 20 million adult patient records in general practice, in-situ using the OpenSAFELY platform. For each month, between April 2019 and March 2022, we report the percentage of patients with a medication review coded monthly and in the previous 12 months with breakdowns by regional, clinical and demographic subgroups and those prescribed high-risk medications. RESULTS: In April 2019, 32.3% of patients had a medication review coded in the previous 12 months. During the first COVID-19 lockdown, monthly activity decreased (-21.1% April 2020), but the 12-month rate was not substantially impacted (-10.5% March 2021). The rate of structured medication review in the last 12 months reached 2.9% by March 2022, with higher percentages in high-risk groups (care home residents 34.1%, age 90+ years 13.1%, high-risk medications 10.2%). The most used medication review code was Medication review done 314530002 (59.5%). CONCLUSIONS: There was a substantial reduction in the monthly rate of medication reviews during the pandemic but rates recovered by the end of the study period. Structured medication reviews were prioritized for high-risk patients.

First dose COVID-19 vaccine coverage amongst adolescents and children in England: an analysis of 3.21 million patients' primary care records in situ using OpenSAFELY.

Background: The coronavirus disease 2019 (COVID-19) vaccination programme in England was extended to include all adolescents and children by April 2022. The aim of this paper is to describe trends and variation in vaccine coverage in different clinical and demographic groups amongst adolescents and children in England by August 2022. Methods: With the approval of NHS England, a cohort study was conducted of 3.21 million children and adolescents' records in general practice in England,  in situ and within the infrastructure of the electronic health record software vendor TPP using OpenSAFELY. Vaccine coverage across various demographic (sex, deprivation index and ethnicity) and clinical (risk status) populations is described. Results: Coverage is higher amongst adolescents than it is amongst children, with 53.5% adolescents and 10.8% children having received their first dose of the COVID-19 vaccine. Within those groups, coverage varies by ethnicity, deprivation index and risk status; there is no evidence of variation by sex. Conclusion: First dose COVID-19 vaccine coverage is shown to vary amongst various demographic and clinical groups of children and adolescents.

Changes in COVID-19-related mortality across key demographic and clinical subgroups in England from 2020 to 2022: a retrospective cohort study using the OpenSAFELY platform.

BACKGROUND: COVID-19 has been shown to differently affect various demographic and clinical population subgroups. We aimed to describe trends in absolute and relative COVID-19-related mortality risks across clinical and demographic population subgroups during successive SARS-CoV-2 pandemic waves. METHODS: We did a retrospective cohort study in England using the OpenSAFELY platform with the approval of National Health Service England, covering the first five SARS-CoV-2 pandemic waves (wave one [wild-type] from March 23 to May 30, 2020; wave two [alpha (B.1.1.7)] from Sept 7, 2020, to April 24, 2021; wave three [delta (B.1.617.2)] from May 28 to Dec 14, 2021; wave four [omicron (B.1.1.529)] from Dec 15, 2021, to April 29, 2022; and wave five [omicron] from June 24 to Aug 3, 2022). In each wave, we included people aged 18-110 years who were registered with a general practice on the first day of the wave and who had at least 3 months of continuous general practice registration up to this date. We estimated crude and sex-standardised and age-standardised wave-specific COVID-19-related death rates and relative risks of COVID-19-related death in population subgroups. FINDINGS: 18 895 870 adults were included in wave one, 19 014 720 in wave two, 18 932 050 in wave three, 19 097 970 in wave four, and 19 226 475 in wave five. Crude COVID-19-related death rates per 1000 person-years decreased from 4·48 deaths (95% CI 4·41-4·55) in wave one to 2·69 (2·66-2·72) in wave two, 0·64 (0·63-0·66) in wave three, 1·01 (0·99-1·03) in wave four, and 0·67 (0·64-0·71) in wave five. In wave one, the standardised COVID-19-related death rates were highest in people aged 80 years or older, people with chronic kidney disease stage 5 or 4, people receiving dialysis, people with dementia or learning disability, and people who had received a kidney transplant (ranging from 19·85 deaths per 1000 person-years to 44·41 deaths per 1000 person-years, compared with from 0·05 deaths per 1000 person-years to 15·93 deaths per 1000 person-years in other subgroups). In wave two compared with wave one, in a largely unvaccinated population, the decrease in COVID-19-related mortality was evenly distributed across population subgroups. In wave three compared with wave one, larger decreases in COVID-19-related death rates were seen in groups prioritised for primary SARS-CoV-2 vaccination, including people aged 80 years or older and people with neurological disease, learning disability, or severe mental illness (90-91% decrease). Conversely, smaller decreases in COVID-19-related death rates were observed in younger age groups, people who had received organ transplants, and people with chronic kidney disease, haematological malignancies, or immunosuppressive conditions (0-25% decrease). In wave four compared with wave one, the decrease in COVID-19-related death rates was smaller in groups with lower vaccination coverage (including younger age groups) and conditions associated with impaired vaccine response, including people who had received organ transplants and people with immunosuppressive conditions (26-61% decrease). INTERPRETATION: There was a substantial decrease in absolute COVID-19-related death rates over time in the overall population, but demographic and clinical relative risk profiles persisted and worsened for people with lower vaccination coverage or impaired immune response. Our findings provide an evidence base to inform UK public health policy for protecting these vulnerable population subgroups. FUNDING: UK Research and Innovation, Wellcome Trust, UK Medical Research Council, National Institute for Health and Care Research, and Health Data Research UK.

Trends, variation, and clinical characteristics of recipients of antiviral drugs and neutralising monoclonal antibodies for covid-19 in community settings: retrospective, descriptive cohort study of 23.4 million people in OpenSAFELY.

Objective: To ascertain patient eligibility status and describe coverage of antiviral drugs and neutralising monoclonal antibodies (nMAB) as treatment for covid-19 in community settings in England. Design: Retrospective, descriptive cohort study, approved by NHS England. Setting: Routine clinical data from 23.4 million people linked to data on covid-19 infection and treatment, within the OpenSAFELY-TPP database. Participants: Outpatients with covid-19 at high risk of severe outcomes. Interventions: Nirmatrelvir/ritonavir (paxlovid), sotrovimab, molnupiravir, casirivimab/imdevimab, or remdesivir, used in the community by covid-19 medicine delivery units. Results: 93 870 outpatients with covid-19 were identified between 11 December 2021 and 28 April 2022 to be at high risk of severe outcomes and therefore potentially eligible for antiviral or nMAB treatment (or both). Of these patients, 19 040 (20%) received treatment (sotrovimab, 9660 (51%); molnupiravir, 4620 (24%); paxlovid, 4680 (25%); casirivimab/imdevimab, 50 (<1%); and remdesivir, 30 (<1%)). The proportion of patients treated increased from 9% (190/2220) in the first week of treatment availability to 29% (460/1600) in the latest week. The proportion treated varied by high risk group, being lowest in those with liver disease (16%; 95% confidence interval 15% to 17%); by treatment type, with sotrovimab favoured over molnupiravir and paxlovid in all but three high risk groups (Down's syndrome (35%; 30% to 39%), rare neurological conditions (45%; 43% to 47%), and immune deficiencies (48%; 47% to 50%)); by age, ranging from ≥80 years (13%; 12% to 14%) to 50-59 years (23%; 22% to 23%); by ethnic group, ranging from black (11%; 10% to 12%) to white (21%; 21% to 21%); by NHS region, ranging from 13% (12% to 14%) in Yorkshire and the Humber to 25% (24% to 25%) in the East of England); and by deprivation level, ranging from 15% (14% to 15%) in the most deprived areas to 23% (23% to 24%) in the least deprived areas. Groups that also had lower coverage included unvaccinated patients (7%; 6% to 9%), those with dementia (6%; 5% to 7%), and care home residents (6%; 6% to 7%). Conclusions: Using the OpenSAFELY platform, we were able to identify patients with covid-19 at high risk of severe outcomes who were potentially eligible to receive treatment and assess the coverage of these new treatments among these patients. In the context of a rapid deployment of a new service, the NHS analytical code used to determine eligibility could have been over-inclusive and some of the eligibility criteria not fully captured in healthcare data. However targeted activity might be needed to resolve apparent lower treatment coverage observed among certain groups, in particular (at present): different NHS regions, ethnic groups, people aged ≥80 years, those living in socioeconomically deprived areas, and care home residents.

Comparative effectiveness of BNT162b2 versus mRNA-1273 covid-19 vaccine boosting in England: matched cohort study in OpenSAFELY-TPP.

OBJECTIVE: To compare the effectiveness of the BNT162b2 mRNA (Pfizer-BioNTech) and mRNA-1273 (Moderna) covid-19 vaccines during the booster programme in England. DESIGN: Matched cohort study, emulating a comparative effectiveness trial. SETTING: 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. PARTICIPANTS: 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. INTERVENTION: Vaccination with either BNT162b2 or mRNA-1273 as a booster vaccine dose. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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.

Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: a collaborative analysis of 20 prospective studies and Mendelian randomization analysis.

BACKGROUND: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer. METHODS: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium. RESULTS: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I. CONCLUSIONS: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.

Gout incidence and management during the COVID-19 pandemic in England, UK: a nationwide observational study using OpenSAFELY.

BACKGROUND: Gout is the most prevalent inflammatory arthritis, yet one of the worst managed. Our objective was to assess how the COVID-19 pandemic impacted incidence and quality of care for people with gout in England, UK. METHODS: With the approval of National Health Service England, we did a population-level cohort study using primary care and hospital electronic health record data for 17·9 million adults registered with general practices using TPP health record software, via the OpenSAFELY platform. The study period was from March 1, 2015, to Feb 28, 2023. Individuals aged 18-110 years were defined as having incident gout if they were assigned index diagnostic codes for gout, were registered with TPP practices in England for at least 12 months before diagnosis, did not receive prescriptions for urate-lowering therapy more than 30 days before diagnosis, and had not been admitted to hospital or attended an emergency department for gout flares more than 30 days before diagnosis. Outcomes assessed were incidence and prevalence of people with recorded gout diagnoses, incidence of gout hospitalisations, initiation of urate-lowering therapy, and attainment of serum urate targets (≤360 µmol/L). FINDINGS: From a reference population of 17 865 145 adults, 246 695 individuals were diagnosed with incident gout. The mean age of individuals with incident gout was 61·3 years (SD 16·2). 66 265 (26·9%) of 246 695 individuals were female, 180 430 (73·1%) were male, and 189 035 (90·9%) of 208 050 individuals with available ethnicity data were White. Incident gout diagnoses decreased by 30·9% in the year beginning March, 2020, compared with the preceding year (1·23 diagnoses vs 1·78 diagnoses per 1000 adults). Gout prevalence was 3·07% in 2015-16, and 3·21% in 2022-23. Gout hospitalisations decreased by 30·1% in the year commencing March, 2020, compared with the preceding year (9·6 admissions vs 13·7 admissions per 100 000 adults). Of 228 095 people with incident gout and available follow-up, 66 560 (29·2%) were prescribed urate-lowering therapy within 6 months. Of 65 305 individuals who initiated urate-lowering therapy with available follow-up, 16 790 (25·7%) attained a serum urate concentration of 360 µmol/L or less within 6 months of urate-lowering therapy initiation. In interrupted time-series analyses, urate-lowering therapy prescribing improved modestly during the pandemic, compared with pre-pandemic, whereas urate target attainment was similar. INTERPRETATION: Using gout as an exemplar disease, we showed the complexity of how health care was impacted during the COVID-19 pandemic. We observed a reduction in gout diagnoses but no effect on treatment metrics. We showed how country-wide, routinely collected data can be used to map disease epidemiology and monitor care quality. FUNDING: None.

Incidence and management of inflammatory arthritis in England before and during the COVID-19 pandemic: a population-level cohort study using OpenSAFELY.

Background: The impact of the COVID-19 pandemic on the incidence and management of inflammatory arthritis is not understood. Routinely captured data in secure platforms, such as OpenSAFELY, offer unique opportunities to understand how care for patients with inflammatory arthritis was impacted upon by the pandemic. Our objective was to use OpenSAFELY to assess the effects of the pandemic on diagnostic incidence and care delivery for inflammatory arthritis in England and to replicate key metrics from the National Early Inflammatory Arthritis Audit. Methods: In this population-level cohort study, we used primary care and hospital data for 17·7 million adults registered with general practices using TPP health record software, to explore the following outcomes between April 1, 2019, and March 31, 2022: (1) incidence of inflammatory arthritis diagnoses (rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and undifferentiated inflammatory arthritis) recorded in primary care; (2) time to first rheumatology assessment; (3) time to first prescription of a disease-modifying antirheumatic drug (DMARD) in primary care; and (4) choice of first DMARD. Findings: Among 17 683 500 adults, there were 31 280 incident inflammatory arthritis diagnoses recorded between April 1, 2019, and March 31, 2022. The mean age of diagnosed patients was 55·4 years (SD 16·6), 18 615 (59·5%) were female, 12 665 (40·5%) were male, and 22 925 (88·3%) of 25 960 with available ethnicity data were White. New inflammatory arthritis diagnoses decreased by 20·3% in the year commencing April, 2020, relative to the preceding year (5·1 vs 6·4 diagnoses per 10 000 adults). The median time to first rheumatology assessment was shorter during the pandemic (18 days; IQR 8-35) than before (21 days; 9-41). The proportion of patients prescribed DMARDs in primary care was similar before and during the pandemic; however, during the pandemic, fewer people were prescribed methotrexate or leflunomide, and more were prescribed sulfasalazine or hydroxychloroquine. Interpretation: Inflammatory arthritis diagnoses decreased markedly during the early phase of the pandemic. The impact on rheumatology assessment times and DMARD prescribing in primary care was less marked than might have been anticipated. This study demonstrates the feasibility of using routinely captured, near real-time data in the secure OpenSAFELY platform to benchmark care quality on a national scale, without the need for manual data collection. Funding: None.

Rapid Quantification of the Binocular Visual Field for Clinical Trials: Performance of a Modified Esterman Supra-Threshold Test Implemented with the Open Perimetry Interface.

Purpose: We aimed to assess the performance of the modified-Esterman test (mET) as a rapid suprathreshold binocular quantification tool for the assessment of peripheral visual fields. The mET consists of an even spread of test points across the visual field. Materials and Methods: The mET was implemented on the Octopus 0900 perimeter using the Open Perimetry Interface (OPI) and consisted of 160 points. Patients with choroideremia, a rod-cone dystrophy, Stargardt disease, a cone-rod dystrophy, and healthy volunteers underwent both the mET and the standard Esterman tests twice. Disease severity (mild/moderate/severe) was graded on both tests independently. Voronoi tessellation was utilised to compare the tests. Results: The Voronoi visualisation was able to demonstrate that the mET was able to provide more information about the disease state at all stages of diseases. This was confirmed by the agreement statistic, which showed that the mET detected 27% more points of visual field loss compared to the Esterman test, being most useful in patients with rod-cone dystrophies. Conclusion: The mET provides a speedy quantitative measure of the peripheral visual field loss, which can be used in clinical trials to monitor longitudinal assessment of peripheral visual function. The mET provides a more even coverage across the visual field compared to the Esterman test points, making it more suitable for this purpose. This is a key part of safety monitoring in retinal clinical trials. The mET can easily be implemented on commercially available perimeters that allow Open Perimetry.

Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomisation analyses in international consortia.

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; Phet  = .0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.

Long-term efficacy and tolerability of TNFα inhibitors in the treatment of non-infectious ocular inflammation: an 8-year prospective surveillance study.

BACKGROUND/AIM: To report the efficacy and tolerability of antitumour necrosis factor-alpha therapy (TNF inhibitors [TNFi]) in the management of non-infectious ocular inflammation, including uveitis and scleritis, in adult patients over an 8-year period. MATERIALS AND METHODS: This is a prospective cohort study of infliximab and adalimumab in the treatment of non-infectious ocular inflammatory disease. 43 of 85 adult patients on TNFi (34 infliximab, 9 adalimumab) for ≥1 year with non-infectious uveitis or scleritis were followed from 2006 to 2014. Clinical assessments, medication, adverse events and history of steroid rescues were collected at 6 monthly intervals. General quality of life (Short Form Health Survey (SF-36)) and visual quality of life (Vision-related quality of life Core Measure (VCM1)) were assessed annually. Outcome measures included rate of sustained remission, rate of relapse, systemic corticosteroid reduction, adverse events, and VCM1 and SF-36 scores. RESULTS: The median time on infliximab was 3.2 years (IQR 4.3) and on adalimumab was 2.4 years (IQR 1.8). Sustained remission was induced in 39 patients (91%) (0.5 per patient year) after a median of 1.2 years on a TNFi. 22 (51%) experienced one relapse, and 5 (12%) had two relapses. 23 (54%) had at least one adverse event; serious adverse events necessitating hospitalisation or cessation of medication occurred in four (9%) patients. 10 patients (23%) switched from the initiation of TNFi, at 1.7 years after starting, to another TNFi or another class of biologic therapy. CONCLUSION: TNFi treatment is associated with long-term drug-induced remission of ocular inflammation, visual stability and corticosteroid reduction. Adverse events were common and no new safety signals occurred. Relapse of inflammation occurs in half of the treated population.

Low-contrast visual acuity versus low-luminance visual acuity in choroideremia.

CLINICAL RELEVANCE: Choroideremia is a progressive X-linked inherited rod-cone dystrophy. Patients present with nyctalopia and progressive visual field loss, but visual acuity remains well preserved early on. This study showed that low-luminance visual acuity may be a useful clinical outcome measure during earlier disease stages. BACKGROUND: Choroideremia is a progressive X-linked inherited rod-cone dystrophy. Patients present with nyctalopia and progressive visual field loss. However, visual acuity remains well preserved until late in the disease process, limiting its usefulness as a clinical trial endpoint across the disease spectrum. Visual acuity measurements under low-luminance and low-contrast conditions may be affected sooner and have been suggested as early markers in other ocular diseases. This study assesses whether low-luminance visual acuity and low-contrast visual acuity provide useful endpoints in choroideremia clinical trials. METHOD: Standard high-contrast and low-luminance visual acuity was obtained on 29 choroideremia subjects and 16 healthy controls, using a logMAR chart, set at four metres. Low-luminance visual acuity was tested using a 2.0-log unit neutral density filter, with the same chart set-up, without formal dark adaptation. This was followed by low-contrast visual acuity measured using 1.25 per cent and 2.5 per cent low-contrast logMAR charts placed also at four metres. Data from the right eyes only were analysed using non-parametric statistics. High-contrast visual acuity minus low-luminance and low-contrast visual acuity provided the low-luminance and low-contrast difference scores. RESULTS: A higher number of choroideremia subjects were able to complete the low-luminance test than the low-contrast visual acuity tests. Choroideremia subjects had significantly higher low luminance, 2.5 per cent low-contrast and 1.25 per cent low-contrast difference scores compared with controls (p < 0.01, Mann-Whitney U-test); 1.25 per cent low-contrast visual acuity revealed the poorest performance. A strong positive correlation was found between low-luminance and high-contrast visual acuities (ρ = 0.818, p < 0.001) and 2.5 per cent low-contrast and high-contrast visual acuities (ρ = 0.671, p < 0.001). CONCLUSION: The low-luminance visual acuity test may be a useful additional clinical trial outcome measure for early-to-moderate disease, when high-contrast visual acuity is preserved.

Sleep-Wake Disturbance Related to Ocular Disease: A Systematic Review of Phase-Shifting Pharmaceutical Therapies.

PURPOSE: Light input, via the eyes, is essential for regulating circadian rhythms. Eye diseases can cause disruption of vital biological rhythms. Of totally blind people, 87% report sleep problems. There are no UK guidelines for visual disturbance-related circadian rhythm disruption. Our objective was to systematically review the literature to determine the effectiveness of pharmacological agents on the sleep quality of patients with sleep disturbance related to ocular disease. METHODS: We searched CENTRAL, MEDLINE, EMBASE, PsycINFO, and CINAHL alongside protocol registries and citation searches. We assessed the risk of bias using the Cochrane Risk of Bias Assessment Tool and assessed the strength of overall evidence using GRADE criteria. RESULTS: Four studies (n=116) met the inclusion criteria. Low-quality evidence showed that melatonin can cause entrainment (1 study), increases in total sleep time (all 3 studies), and reduction in sleep latency (1 study). Low-to-moderate quality evidence showed tasimelteon causes a significant improvement in entrainment, midpoint of sleep timing, lower-quartile of night-time sleep, and upper-quartile of daytime sleep. CONCLUSIONS: Results should be treated with caution as the melatonin studies had risks of bias due to inadequate reporting of randomization and masking procedures. The tasimelteon trial had a risk of reporting bias due to changing the outcomes after enrolling participants. Despite the paucity of trials, melatonin and tasimelteon may cause entrainment and improve subjective sleep measures with limited side effects. TRANSLATIONAL RELEVANCE: Given the relative cost melatonin may be a viable choice for treatment of circadian rhythm sleep disorders in the blind and warrants further research.