Mortality in COVID-19 among women on hormone replacement therapy: a retrospective cohort study.

BACKGROUND: Limited recent observational data have suggested that there may be a protective effect of oestrogen on the severity of COVID-19 disease. Our aim was to investigate the association between hormone replacement therapy (HRT) or combined oral contraceptive pill (COCP) use and the likelihood of death in women with COVID-19. METHODS: We undertook a retrospective cohort study using routinely collected computerized medical records from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) primary care database. We identified a cohort of 1,863,478 women over 18 years of age from 465 general practices in England. Mixed-effects logistic regression models were used to quantify the association between HRT or COCP use and all-cause mortality among women diagnosed with confirmed or suspected COVID-19 in unadjusted and adjusted models. RESULTS: There were 5,451 COVID-19 cases within the cohort. HRT was associated with a reduction in all-cause mortality in COVID-19 (adjusted OR 0.22, 95% CI 0.05 to 0.94). There were no reported events for all-cause mortality in women prescribed COCPs. This prevented further examination of the impact of COCP. CONCLUSIONS: We found that HRT prescription within 6 months of a recorded diagnosis of COVID-19 infection was associated with a reduction in all-cause mortality. Further work is needed in larger cohorts to examine the association of COCP in COVID-19, and to further investigate the hypothesis that oestrogens may contribute a protective effect against COVID-19 severity.

Mortality from angiotensin-converting enzyme-inhibitors and angiotensin receptor blockers in people infected with COVID-19: a cohort study of 3.7 million people.

BACKGROUND: Concerns have been raised that angiotensin-converting enzyme-inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) might facilitate transmission of severe acute respiratory syndrome coronavirus 2 leading to more severe coronavirus disease (COVID-19) disease and an increased risk of mortality. We aimed to investigate the association between ACE-I/ARB treatment and risk of death amongst people with COVID-19 in the first 6 months of the pandemic. METHODS: We identified a cohort of adults diagnosed with either confirmed or probable COVID-19 (from 1 January to 21 June 2020) using computerized medical records from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) primary care database. This comprised 465 general practices in England, United Kingdom with a nationally representative population of 3.7 million people. We constructed mixed-effects logistic regression models to quantify the association between ACE-I/ARBs and all-cause mortality among people with COVID-19, adjusted for sociodemographic factors, comorbidities, concurrent medication, smoking status, practice clustering, and household number. RESULTS: There were 9,586 COVID-19 cases in the sample and 1,463 (15.3%) died during the study period between 1 January 2020 and 21 June 2020. In adjusted analysis ACE-I and ARBs were not associated with all-cause mortality (adjusted odds ratio [OR] 1.02, 95% confidence interval [CI] 0.85-1.21 and OR 0.84, 95% CI 0.67-1.07, respectively). CONCLUSION: Use of ACE-I/ARB, which are commonly used drugs, did not alter the odds of all-cause mortality amongst people diagnosed with COVID-19. Our findings should inform patient and prescriber decisions concerning continued use of these medications during the pandemic.

Waning of first- and second-dose ChAdOx1 and BNT162b2 COVID-19 vaccinations: a pooled target trial study of 12.9 million individuals in England, Northern Ireland, Scotland and Wales.

BACKGROUND: Several SARS-CoV-2 vaccines have been shown to provide protection against COVID-19 hospitalization and death. However, some evidence suggests that notable waning in effectiveness against these outcomes occurs within months of vaccination. We undertook a pooled analysis across the four nations of the UK to investigate waning in vaccine effectiveness (VE) and relative vaccine effectiveness (rVE) against severe COVID-19 outcomes. METHODS: We carried out a target trial design for first/second doses of ChAdOx1(Oxford-AstraZeneca) and BNT162b2 (Pfizer-BioNTech) with a composite outcome of COVID-19 hospitalization or death over the period 8 December 2020 to 30 June 2021. Exposure groups were matched by age, local authority area and propensity for vaccination. We pooled event counts across the four UK nations. RESULTS: For Doses 1 and 2 of ChAdOx1 and Dose 1 of BNT162b2, VE/rVE reached zero by approximately Days 60-80 and then went negative. By Day 70, VE/rVE was -25% (95% CI: -80 to 14) and 10% (95% CI: -32 to 39) for Doses 1 and 2 of ChAdOx1, respectively, and 42% (95% CI: 9 to 64) and 53% (95% CI: 26 to 70) for Doses 1 and 2 of BNT162b2, respectively. rVE for Dose 2 of BNT162b2 remained above zero throughout and reached 46% (95% CI: 13 to 67) after 98 days of follow-up. CONCLUSIONS: We found strong evidence of waning in VE/rVE for Doses 1 and 2 of ChAdOx1, as well as Dose 1 of BNT162b2. This evidence may be used to inform policies on timings of additional doses of vaccine.

Impact of General Practitioner Education on Acceptance of an Adjuvanted Seasonal Influenza Vaccine among Older Adults in England.

Seasonal vaccination against influenza and in-pandemic COVID-19 vaccination are top public health priorities; vaccines are the primary means of reducing infections and also controlling pressures on health systems. During the 2018-2019 influenza season, we conducted a study of the knowledge, attitudes, and behaviours of 159 general practitioners (GPs) and 189 patients aged ≥65 years in England using a combination of qualitative and quantitative approaches to document beliefs about seasonal influenza and seasonal influenza vaccine. GPs were surveyed before and after a continuing medical education (CME) module on influenza disease and vaccination with an adjuvanted trivalent influenza vaccine (aTIV) designed for patients aged ≥65 years, and patients were surveyed before and after a routine visit with a GP who participated in the CME portion of the study. The CME course was associated with significantly increased GP confidence in their ability to address patients' questions and concerns about influenza disease and vaccination (p < 0.001). Patients reported significantly increased confidence in the effectiveness and safety of aTIV after meeting their GP. Overall, 82.2% of the study population were vaccinated against influenza (including 137 patients vaccinated during the GP visit and 15 patients who had been previously vaccinated), a rate higher than the English national average vaccine uptake of 72.0% that season. These findings support the value of GP-patient interactions to foster vaccine acceptance.

Adverse events following first and second dose COVID-19 vaccination in England, October 2020 to September 2021: a national vaccine surveillance platform self-controlled case series study.

BackgroundPost-authorisation vaccine safety surveillance is well established for reporting common adverse events of interest (AEIs) following influenza vaccines, but not for COVID-19 vaccines.AimTo estimate the incidence of AEIs presenting to primary care following COVID-19 vaccination in England, and report safety profile differences between vaccine brands.MethodsWe used a self-controlled case series design to estimate relative incidence (RI) of AEIs reported to the national sentinel network, the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub. We compared AEIs (overall and by clinical category) 7 days pre- and post-vaccination to background levels between 1 October 2020 and 12 September 2021.ResultsWithin 7,952,861 records, 781,200 individuals (9.82%) presented to general practice with 1,482,273 AEIs, 4.85% within 7 days post-vaccination. Overall, medically attended AEIs decreased post-vaccination against background levels. There was a 3-7% decrease in incidence within 7 days after both doses of Comirnaty (RI: 0.93; 95% CI: 0.91-0.94 and RI: 0.96; 95% CI: 0.94-0.98, respectively) and Vaxzevria (RI: 0.97; 95% CI: 0.95-0.98). A 20% increase was observed after one dose of Spikevax (RI: 1.20; 95% CI: 1.00-1.44). Fewer AEIs were reported as age increased. Types of AEIs, e.g. increased neurological and psychiatric conditions, varied between brands following two doses of Comirnaty (RI: 1.41; 95% CI: 1.28-1.56) and Vaxzevria (RI: 1.07; 95% CI: 0.97-1.78).ConclusionCOVID-19 vaccines are associated with a small decrease in medically attended AEI incidence. Sentinel networks could routinely report common AEI rates, contributing to reporting vaccine safety.

Severe COVID-19 outcomes after full vaccination of primary schedule and initial boosters: pooled analysis of national prospective cohort studies of 30 million individuals in England, Northern Ireland, Scotland, and Wales.

BACKGROUND: Current UK vaccination policy is to offer future COVID-19 booster doses to individuals at high risk of serious illness from COVID-19, but it is still uncertain which groups of the population could benefit most. In response to an urgent request from the UK Joint Committee on Vaccination and Immunisation, we aimed to identify risk factors for severe COVID-19 outcomes (ie, COVID-19-related hospitalisation or death) in individuals who had completed their primary COVID-19 vaccination schedule and had received the first booster vaccine. METHODS: We constructed prospective cohorts across all four UK nations through linkages of primary care, RT-PCR testing, vaccination, hospitalisation, and mortality data on 30 million people. We included individuals who received primary vaccine doses of BNT162b2 (tozinameran; Pfizer-BioNTech) or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines in our initial analyses. We then restricted analyses to those given a BNT162b2 or mRNA-1273 (elasomeran; Moderna) booster and had a severe COVID-19 outcome between Dec 20, 2021, and Feb 28, 2022 (when the omicron (B.1.1.529) variant was dominant). We fitted time-dependent Poisson regression models and calculated adjusted rate ratios (aRRs) and 95% CIs for the associations between risk factors and COVID-19-related hospitalisation or death. We adjusted for a range of potential covariates, including age, sex, comorbidities, and previous SARS-CoV-2 infection. Stratified analyses were conducted by vaccine type. We then did pooled analyses across UK nations using fixed-effect meta-analyses. FINDINGS: Between Dec 8, 2020, and Feb 28, 2022, 16 208 600 individuals completed their primary vaccine schedule and 13 836 390 individuals received a booster dose. Between Dec 20, 2021, and Feb 28, 2022, 59 510 (0·4%) of the primary vaccine group and 26 100 (0·2%) of those who received their booster had severe COVID-19 outcomes. The risk of severe COVID-19 outcomes reduced after receiving the booster (rate change: 8·8 events per 1000 person-years to 7·6 events per 1000 person-years). Older adults (≥80 years vs 18-49 years; aRR 3·60 [95% CI 3·45-3·75]), those with comorbidities (≥5 comorbidities vs none; 9·51 [9·07-9·97]), being male (male vs female; 1·23 [1·20-1·26]), and those with certain underlying health conditions-in particular, individuals receiving immunosuppressants (yes vs no; 5·80 [5·53-6·09])-and those with chronic kidney disease (stage 5 vs no; 3·71 [2·90-4·74]) remained at high risk despite the initial booster. Individuals with a history of COVID-19 infection were at reduced risk (infected ≥9 months before booster dose vs no previous infection; aRR 0·41 [95% CI 0·29-0·58]). INTERPRETATION: Older people, those with multimorbidity, and those with specific underlying health conditions remain at increased risk of COVID-19 hospitalisation and death after the initial vaccine booster and should, therefore, be prioritised for additional boosters, including novel optimised versions, and the increasing array of COVID-19 therapeutics. FUNDING: National Core Studies-Immunity, UK Research and Innovation (Medical Research Council), Health Data Research UK, the Scottish Government, and the University of Edinburgh.

Interdisciplinary Informatics to Support Primary Care Sentinel Surveillance of Respiratory Infectious Disease Including COVID-19: Donabedian Evaluation.

The Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) is one of Europe's oldest sentinel systems, providing sentinel surveillance since 1967. We report the interdisciplinary informatics required to run such a system. We used the Donabedian framework to describe the interdisciplinary informatics roles that support the structures, processes and outcomes of the RSC. Over the course of the COVID-19 pandemic University, RCGP, information technology specialists, SQL developers, analysts, practice liaison team, network member primary care providers, and their registered patients have nearly quadrupled the size of the RSC from working with 5 million to 19 million peoples pseudonymised health data. We have produced outputs used by the UK Health Security Agency to describe the epidemiology of COVID-19 and report vaccine effectiveness. We have also supported a trial of community-based therapies for COVID-19 and other observational studies. The home of the primary care sentinel surveillance network is with a clinical informatics research group. Interdisciplinary informatics teamwork was required to support primary care sentinel surveillance; such teams can accelerate the scale, scope and digital maturity of surveillance systems as demonstrated by the RSC across the COVID-19 pandemic.

Differences in Clinical Presentation With Long COVID After Community and Hospital Infection and Associations With All-Cause Mortality: English Sentinel Network Database Study.

BACKGROUND: Most studies of long COVID (symptoms of COVID-19 infection beyond 4 weeks) have focused on people hospitalized in their initial illness. Long COVID is thought to be underrecorded in UK primary care electronic records. OBJECTIVE: We sought to determine which symptoms people present to primary care after COVID-19 infection and whether presentation differs in people who were not hospitalized, as well as post-long COVID mortality rates. METHODS: We used routine data from the nationally representative primary care sentinel cohort of the Oxford-Royal College of General Practitioners Research and Surveillance Centre (N=7,396,702), applying a predefined long COVID phenotype and grouped by whether the index infection occurred in hospital or in the community. We included COVID-19 infection cases from March 1, 2020, to April 1, 2021. We conducted a before-and-after analysis of long COVID symptoms prespecified by the Office of National Statistics, comparing symptoms presented between 1 and 6 months after the index infection matched with the same months 1 year previously. We conducted logistic regression analysis, quoting odds ratios (ORs) with 95% CIs. RESULTS: In total, 5.63% (416,505/7,396,702) and 1.83% (7623/416,505) of the patients had received a coded diagnosis of COVID-19 infection and diagnosis of, or referral for, long COVID, respectively. People with diagnosis or referral of long COVID had higher odds of presenting the prespecified symptoms after versus before COVID-19 infection (OR 2.66, 95% CI 2.46-2.88, for those with index community infection and OR 2.42, 95% CI 2.03-2.89, for those hospitalized). After an index community infection, patients were more likely to present with nonspecific symptoms (OR 3.44, 95% CI 3.00-3.95; P<.001) compared with after a hospital admission (OR 2.09, 95% CI 1.56-2.80; P<.001). Mental health sequelae were more strongly associated with index hospital infections (OR 2.21, 95% CI 1.64-2.96) than with index community infections (OR 1.36, 95% CI 1.21-1.53; P<.001). People presenting to primary care after hospital infection were more likely to be men (OR 1.43, 95% CI 1.25-1.64; P<.001), more socioeconomically deprived (OR 1.42, 95% CI 1.24-1.63; P<.001), and with higher multimorbidity scores (OR 1.41, 95% CI 1.26-1.57; P<.001) than those presenting after an index community infection. All-cause mortality in people with long COVID was associated with increasing age, male sex (OR 3.32, 95% CI 1.34-9.24; P=.01), and higher multimorbidity score (OR 2.11, 95% CI 1.34-3.29; P<.001). Vaccination was associated with reduced odds of mortality (OR 0.10, 95% CI 0.03-0.35; P<.001). CONCLUSIONS: The low percentage of people recorded as having long COVID after COVID-19 infection reflects either low prevalence or underrecording. The characteristics and comorbidities of those presenting with long COVID after a community infection are different from those hospitalized. This study provides insights into the presentation of long COVID in primary care and implications for workload.

Developing a Long COVID Phenotype for Postacute COVID-19 in a National Primary Care Sentinel Cohort: Observational Retrospective Database Analysis.

BACKGROUND: Following COVID-19, up to 40% of people have ongoing health problems, referred to as postacute COVID-19 or long COVID (LC). LC varies from a single persisting symptom to a complex multisystem disease. Research has flagged that this condition is underrecorded in primary care records, and seeks to better define its clinical characteristics and management. Phenotypes provide a standard method for case definition and identification from routine data and are usually machine-processable. An LC phenotype can underpin research into this condition. OBJECTIVE: This study aims to develop a phenotype for LC to inform the epidemiology and future research into this condition. We compared clinical symptoms in people with LC before and after their index infection, recorded from March 1, 2020, to April 1, 2021. We also compared people recorded as having acute infection with those with LC who were hospitalized and those who were not. METHODS: We used data from the Primary Care Sentinel Cohort (PCSC) of the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database. This network was recruited to be nationally representative of the English population. We developed an LC phenotype using our established 3-step ontological method: (1) ontological step (defining the reasoning process underpinning the phenotype, (2) coding step (exploring what clinical terms are available, and (3) logical extract model (testing performance). We created a version of this phenotype using Protégé in the ontology web language for BioPortal and using PhenoFlow. Next, we used the phenotype to compare people with LC (1) with regard to their symptoms in the year prior to acquiring COVID-19 and (2) with people with acute COVID-19. We also compared hospitalized people with LC with those not hospitalized. We compared sociodemographic details, comorbidities, and Office of National Statistics-defined LC symptoms between groups. We used descriptive statistics and logistic regression. RESULTS: The long-COVID phenotype differentiated people hospitalized with LC from people who were not and where no index infection was identified. The PCSC (N=7.4 million) includes 428,479 patients with acute COVID-19 diagnosis confirmed by a laboratory test and 10,772 patients with clinically diagnosed COVID-19. A total of 7471 (1.74%, 95% CI 1.70-1.78) people were coded as having LC, 1009 (13.5%, 95% CI 12.7-14.3) had a hospital admission related to acute COVID-19, and 6462 (86.5%, 95% CI 85.7-87.3) were not hospitalized, of whom 2728 (42.2%) had no COVID-19 index date recorded. In addition, 1009 (13.5%, 95% CI 12.73-14.28) people with LC were hospitalized compared to 17,993 (4.5%, 95% CI 4.48-4.61; P<.001) with uncomplicated COVID-19. CONCLUSIONS: Our LC phenotype enables the identification of individuals with the condition in routine data sets, facilitating their comparison with unaffected people through retrospective research. This phenotype and study protocol to explore its face validity contributes to a better understanding of LC.

Sodium-Glucose Cotransporter-2 Inhibitor and Glucagon-Like Peptide-1 Receptor Agonist Combination Therapy in Type 2 Diabetes: Protocol for a Kidney End Points Real-world Study (COMBi-KID Study).

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are both considered to be part of standard care in the management of glycemia in type 2 diabetes. Recent trial evidence has indicated benefits on primary kidney end points for individual drugs within each medication class. Despite the potential benefits of combining SGLT2is and GLP-1RAs for glycemia management, according to national and international guideline recommendations, there is currently limited data on kidney end points for this drug combination. OBJECTIVE: The aims of the study are to assess the real-world effects of combination SGLT2i and GLP-1RA therapies for diabetes management on kidney end points, glycemic control, and weight in people with type 2 diabetes who are being treated with renin-angiotensin system blockade medication. METHODS: This retrospective cohort study will use the electronic health records of people with type 2 diabetes that are registered with general practices covering over 15 million people in England and Wales and are included in the Oxford-Royal College of General Practitioners Research and Surveillance Centre network. A propensity score-matched cohort of prevalent new users of SGLT2is and GLP-1RAs and those who have been prescribed SGLT2is and GLP-1RAs in combination will be identified. They will be matched based on drug histories, comorbidities, and demographics. A repeated-measures, multilevel, linear regression analysis will be performed to compare the mean change (from baseline) in estimated glomerular filtration rate at 12 and 24 months between those who switched to combined therapy and those continuing monotherapy with an SGLT2i or GLP-1RA. The secondary end points will be albuminuria, serum creatinine level, glycated hemoglobin level, and BMI. These will also be assessed for change at the 12- and 24-month follow-ups. RESULTS: The study is due to commence in March 2022 and is expected to be complete by September 2022. CONCLUSIONS: Our study will be the first to assess the impact of combination SGLT2i and GLP-1RA therapy in type 2 diabetes on primary kidney end points from a real-world perspective. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/34206.

Methodological Issues in Using a Common Data Model of COVID-19 Vaccine Uptake and Important Adverse Events of Interest: Feasibility Study of Data and Connectivity COVID-19 Vaccines Pharmacovigilance in the United Kingdom.

BACKGROUND: The Data and Connectivity COVID-19 Vaccines Pharmacovigilance (DaC-VaP) UK-wide collaboration was created to monitor vaccine uptake and effectiveness and provide pharmacovigilance using routine clinical and administrative data. To monitor these, pooled analyses may be needed. However, variation in terminologies present a barrier as England uses the Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT), while the rest of the United Kingdom uses the Read v2 terminology in primary care. The availability of data sources is not uniform across the United Kingdom. OBJECTIVE: This study aims to use the concept mappings in the Observational Medical Outcomes Partnership (OMOP) common data model (CDM) to identify common concepts recorded and to report these in a repeated cross-sectional study. We planned to do this for vaccine coverage and 2 adverse events of interest (AEIs), cerebral venous sinus thrombosis (CVST) and anaphylaxis. We identified concept mappings to SNOMED CT, Read v2, the World Health Organization's International Classification of Disease Tenth Revision (ICD-10) terminology, and the UK Dictionary of Medicines and Devices (dm+d). METHODS: Exposures and outcomes of interest to DaC-VaP for pharmacovigilance studies were selected. Mappings of these variables to different terminologies used across the United Kingdom's devolved nations' health services were identified from the Observational Health Data Sciences and Informatics (OHDSI) Automated Terminology Harmonization, Extraction, and Normalization for Analytics (ATHENA) online browser. Lead analysts from each nation then confirmed or added to the mappings identified. These mappings were then used to report AEIs in a common format. We reported rates for windows of 0-2 and 3-28 days postvaccine every 28 days. RESULTS: We listed the mappings between Read v2, SNOMED CT, ICD-10, and dm+d. For vaccine exposure, we found clear mapping from OMOP to our clinical terminologies, though dm+d had codes not listed by OMOP at the time of searching. We found a list of CVST and anaphylaxis codes. For CVST, we had to use a broader cerebral venous thrombosis conceptual approach to include Read v2. We identified 56 SNOMED CT codes, of which we selected 47 (84%), and 15 Read v2 codes. For anaphylaxis, our refined search identified 60 SNOMED CT codes and 9 Read v2 codes, of which we selected 10 (17%) and 4 (44%), respectively, to include in our repeated cross-sectional studies. CONCLUSIONS: This approach enables the use of mappings to different terminologies within the OMOP CDM without the need to catalogue an entire database. However, Read v2 has less granular concepts than some terminologies, such as SNOMED CT. Additionally, the OMOP CDM cannot compensate for limitations in the clinical coding system. Neither Read v2 nor ICD-10 is sufficiently granular to enable CVST to be specifically flagged. Hence, any pooled analysis will have to be at the less specific level of cerebrovascular venous thrombosis. Overall, the mappings within this CDM are useful, and our method could be used for rapid collaborations where there are only a limited number of concepts to pool.

The Effect of the COVID-19 Pandemic on Glycemic Monitoring and Other Processes of Care for Type 2 Diabetes: Protocol for a Retrospective Cohort Study.

BACKGROUND: Social distancing and other nonpharmaceutical interventions to reduce the spread of COVID-19 infection in the United Kingdom have led to substantial changes in delivering ongoing care for patients with chronic conditions, including type 2 diabetes mellitus (T2DM). Clinical guidelines for the management and prevention of complications for people with T2DM delivered in primary care services advise routine annual reviews and were developed when face-to-face consultations were the norm. The shift in consultations from face-to-face to remote consultations caused a reduction in direct clinical contact and may impact the process of care for people with T2DM. OBJECTIVE: The aim of this study is to explore the impact of the COVID-19 pandemic's first year on the monitoring of people with T2DM using routine annual reviews from a national primary care perspective in England. METHODS: A retrospective cohort study of adults with T2DM will be performed using routinely collected primary care data from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC). We will describe the change in the rate of monitoring of hemoglobin A1c (HbA1c) between the first year of the COVID-19 pandemic (2020) and the preceding year (2019). We will also report any change in the eight checks that make up the components of these reviews. The change in HbA1c monitoring rates will be determined using a multilevel logistic regression model, adjusting for patient and practice characteristics, and similarly, the change in a composite measure of the completeness of all eight checks will be modeled using ordinal regression. The models will be adjusted for the following patient-level variables: age, gender, socioeconomic status, ethnicity, COVID-19 shielding status, duration of diabetes, and comorbidities. The model will also be adjusted for the following practice-level variables: urban versus rural, practice size, Quality and Outcomes Framework achievement, the National Health Service region, and the proportion of face-to-face consultations. Ethical approval was provided by the University of Oxford Medical Sciences Interdivisional Research Ethics Committee (September 2, 2021, reference R77306/RE001). RESULTS: The analysis of the data extract will include 3.96 million patients with T2DM across 700 practices, which is 6% of the available Oxford-RCGP RSC adult population. The preliminary results will be submitted to a conference under the domain of primary care. The resulting publication will be submitted to a peer-reviewed journal on diabetes and endocrinology. CONCLUSIONS: The COVID-19 pandemic has impacted the delivery of care, but little is known about the process of caring for people with T2DM. This study will report the impact of the COVID-19 pandemic on these processes of care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35971.

National rates and disparities in childhood vaccination and vaccine-preventable disease during the COVID-19 pandemic: English sentinel network retrospective database study.

OBJECTIVES: To describe rates and variation in uptake of pneumococcal and measles, mumps and rubella (MMR) vaccines in children and associated change in vaccine-preventable diseases (VPDs) across the first and second waves of the COVID-19 pandemic. METHODS: Retrospective database study of all children aged <19 registered with a general practice in the Oxford Royal College of General Practitioners Research and Surveillance Centre English national sentinel surveillance network between 2 November 2015 and 18 July 2021. RESULTS: Coverage of booster dose of pneumococcal vaccine decreased from 94.5% (95% CI 94.3% to 94.7%) at its height on International Organization for Standardization (ISO) week 47 (2020) to 93.6% (95% CI 93.4% to 93.8%) by the end of the study. Coverage of second dose of MMR decreased from 85.0% (95% CI 84.7% to 85.3%) at its height on ISO week 37 (2020) to 84.1% (95% CI 83.8% to 84.4%) by the end of the study. The break point in trends for MMR was at ISO week 34 (2020) (95% CI weeks 32-37 (2020)), while for pneumococcal vaccine the break point was later at ISO week 3 (2021) (95% CI week 53 (2020) to week 8 (2021)). Vaccination coverage for children of white ethnicity was less likely to decrease than other ethnicities. Rates of consultation for VPDs fell and remained low since August 2020. CONCLUSION: Childhood vaccination rates started to fall ahead of the onset of the second wave; this fall is accentuating ethnic, socioeconomic and geographical disparities in vaccine uptake and risks widening health disparities. Social distancing and school closures may have contributed to lower rates of associated VPDs, but there may be increased risk as these measures are removed.

PRINCIPLE trial demonstrates scope for in-pandemic improvement in primary care antibiotic stewardship: a retrospective sentinel network cohort study.

BACKGROUND: The Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE) has provided in-pandemic evidence that azithromycin and doxycycline were not beneficial in the early primary care management of coronavirus 2019 disease (COVID-19). AIM: To explore the extent of in-pandemic azithromycin and doxycycline use, and the scope for trial findings impacting on practice. DESIGN & SETTING: Crude rates of prescribing and respiratory tract infections (RTI) in 2020 were compared with 2019, using the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC). METHOD: Negative binomial models were used to compare azithromycin and doxycycline prescribing, lower respiratory tract infections (LRTI), upper respiratory tract infections (URTI), and influenza-like illness (ILI) in 2020 with 2019; reporting incident rate ratios (IRR) between years, and 95% confidence intervals (95% CI). RESULTS: Azithromycin prescriptions increased 7% in 2020 compared with 2019, whereas doxycycline decreased by 7%. Concurrently, LRTI and URTI incidence fell by over half (58.3% and 54.4%, respectively) while ILI rose slightly (6.4%). The overall percentage of RTI-prescribed azithromycin rose from 0.51% in 2019 to 0.72% in 2020 (risk difference 0.214%; 95% CI = 0.211 to 0.217); doxycycline rose from 11.86% in 2019 to 15.79% in 2020 (risk difference 3.93%; 95% CI = 3.73 to 4.14). The adjusted IRR showed azithromycin prescribing was 22% higher in 2020 (IRR = 1.22; 95% CI = 1.19 to 1.26; P<0.0001). For every unit rise in confirmed COVID-19 there was an associated 3% rise in prescription (IRR = 1.03; 95% CI = 1.02 to 1.03; P<0.0001); whereas these measures were static for doxycycline. CONCLUSION: PRINCIPLE demonstrates scope for improved antimicrobial stewardship during a pandemic.

The impact of primary care supported shielding on the risk of mortality in people vulnerable to COVID-19: English sentinel network matched cohort study.

OBJECTIVES: To mitigate risk of mortality from coronavirus 2019 infection (COVID-19), the UK government recommended 'shielding' of vulnerable people through self-isolation for 12 weeks. METHODS: A retrospective cohort study using a nationally representative English primary care database comparing people aged >= 40 years who were recorded as being advised to shield using a fixed ratio of 1:1, matching to people with the same diagnoses not advised to shield (n = 77,360 per group). Time-to-death was compared using Cox regression, reporting the hazard ratio (HR) of mortality between groups. A sensitivity analysis compared exact matched cohorts (n = 24,752 shielded, n = 61,566 exact matches). RESULTS: We found a time-varying HR of mortality between groups. In the first 21 days, the mortality risk in people shielding was half those not (HR = 0.50, 95%CI:0.41-0.59. p < 0.0001). Over the remaining nine weeks, mortality risk was 54% higher in the shielded group (HR=1.54, 95%CI:1.41-1.70, p < 0.0001). Beyond the shielding period, mortality risk was over two-and-a-half times higher in the shielded group (HR=2.61, 95%CI:2.38-2.87, p < 0.0001). CONCLUSIONS: Shielding halved the risk of mortality for 21 days. Mortality risk became higher across the remainder of the shielding period, rising to two-and-a-half times greater post-shielding. Shielding may be beneficial in the next wave of COVID-19.

Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study.

BACKGROUND: The BNT162b2 mRNA (Pfizer-BioNTech) and ChAdOx1 nCoV-19 (Oxford-AstraZeneca) COVID-19 vaccines have shown high efficacy against disease in phase 3 clinical trials and are now being used in national vaccination programmes in the UK and several other countries. Studying the real-world effects of these vaccines is an urgent requirement. The aim of our study was to investigate the association between the mass roll-out of the first doses of these COVID-19 vaccines and hospital admissions for COVID-19. METHODS: We did a prospective cohort study using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19-EAVE II-database comprising linked vaccination, primary care, real-time reverse transcription-PCR testing, and hospital admission patient records for 5·4 million people in Scotland (about 99% of the population) registered at 940 general practices. Individuals who had previously tested positive were excluded from the analysis. A time-dependent Cox model and Poisson regression models with inverse propensity weights were fitted to estimate effectiveness against COVID-19 hospital admission (defined as 1-adjusted rate ratio) following the first dose of vaccine. FINDINGS: Between Dec 8, 2020, and Feb 22, 2021, a total of 1 331 993 people were vaccinated over the study period. The mean age of those vaccinated was 65·0 years (SD 16·2). The first dose of the BNT162b2 mRNA vaccine was associated with a vaccine effect of 91% (95% CI 85-94) for reduced COVID-19 hospital admission at 28-34 days post-vaccination. Vaccine effect at the same time interval for the ChAdOx1 vaccine was 88% (95% CI 75-94). Results of combined vaccine effects against hospital admission due to COVID-19 were similar when restricting the analysis to those aged 80 years and older (83%, 95% CI 72-89 at 28-34 days post-vaccination). INTERPRETATION: Mass roll-out of the first doses of the BNT162b2 mRNA and ChAdOx1 vaccines was associated with substantial reductions in the risk of hospital admission due to COVID-19 in Scotland. There remains the possibility that some of the observed effects might have been due to residual confounding. FUNDING: UK Research and Innovation (Medical Research Council), Research and Innovation Industrial Strategy Challenge Fund, Health Data Research UK.

The impact of social and physical distancing measures on COVID-19 activity in England: findings from a multi-tiered surveillance system.

BackgroundA multi-tiered surveillance system based on influenza surveillance was adopted in the United Kingdom in the early stages of the coronavirus disease (COVID-19) epidemic to monitor different stages of the disease. Mandatory social and physical distancing measures (SPDM) were introduced on 23 March 2020 to attempt to limit transmission.AimTo describe the impact of SPDM on COVID-19 activity as detected through the different surveillance systems.MethodsData from national population surveys, web-based indicators, syndromic surveillance, sentinel swabbing, respiratory outbreaks, secondary care admissions and mortality indicators from the start of the epidemic to week 18 2020 were used to identify the timing of peaks in surveillance indicators relative to the introduction of SPDM. This timing was compared with median time from symptom onset to different stages of illness and levels of care or interactions with healthcare services.ResultsThe impact of SPDM was detected within 1 week through population surveys, web search indicators and sentinel swabbing reported by onset date. There were detectable impacts on syndromic surveillance indicators for difficulty breathing, influenza-like illness and COVID-19 coding at 2, 7 and 12 days respectively, hospitalisations and critical care admissions (both 12 days), laboratory positivity (14 days), deaths (17 days) and nursing home outbreaks (4 weeks).ConclusionThe impact of SPDM on COVID-19 activity was detectable within 1 week through community surveillance indicators, highlighting their importance in early detection of changes in activity. Community swabbing surveillance may be increasingly important as a specific indicator, should circulation of seasonal respiratory viruses increase.