Long-term cardiovascular safety of COVID-19 vaccination according to brand, dose and combinations: Cohort study of 46 million adults in England (preprint)

Using longitudinal health records from 45.7 million adults in England followed for a year, our study compared the incidence of thrombotic and cardiovascular complications after first, second and booster doses of brands and combinations of COVID-19 vaccines used during the first two years of the UK vaccination program with the incidence before or without the corresponding vaccination. The incidence of common arterial thrombotic events (mainly acute myocardial infarction and ischaemic stroke) was generally lower after each vaccine dose, brand and combination. Similarly, the incidence of common venous thrombotic events, (mainly pulmonary embolism and lower limb deep venous thrombosis) was lower after vaccination. There was a higher incidence of previously reported rare harms after vaccination: vaccine-induced thrombotic thrombocytopenia after first ChAdOx1 vaccination, and myocarditis and pericarditis after first, second and transiently after booster mRNA vaccination (BNT-162b2 and mRNA- 1273) These findings support the wide uptake of future COVID-19 vaccination programs.

How much did the Covid-19 shielding policy cost in Wales? A Retrospective Cost analysis within the EVITE Immunity study (preprint)

Background: The EVITE Immunity study investigates the effects of shielding Clinically Extremely Vulnerable (CEV) people during the COVID-19 pandemic on health outcomes and healthcare costs in Wales, UK, to help prepare for future pandemics. Shielding was intended to protect those at highest risk of serious harm from COVID-19. We report the cost of implementing shielding in Wales. Methods: The number of people shielding was extracted from the Secure Anonymised Information Linkage Databank. Resources supporting shielding between March and June 2020 were mapped using published reports, web pages, freedom of information requests to Welsh Government and personal communications (e.g. the office of the Chief Medical Officer for Wales). Results: At the beginning of shielding, 117,415 people were on the shielding list. The total additional cost to support those advised to stay home during the initial 14 weeks of the pandemic was £13,307,654 (£113 per person shielded). This included the new resources required to compile the shielding list, inform CEV people of the shielding intervention and provide medicine and food deliveries. The list was adjusted weekly over the 3-month period (130,000 people identified by June 2020) therefore the cost per person shielded lies between £102 and £113. Conclusion: This is the first evaluation of the cost of the measures put in place to support those identified to shield in Wales. However, no data on opportunity cost was available. The true cost of shielding including its budget impact and opportunity costs need to be investigated to decide whether shielding is a worthwhile policy for future health emergencies.

Developing a research ready population-scale linked data ethnicity-spine in Wales (preprint)

Introduction: Ethnicity information is recorded routinely in electronic health records (EHRs); however, to date, there is no national standard or framework for harmonisation of the existing records. Methods and analysis The national ethnicity-spine uses anonymised individual-level population-scale ethnicity data from 26 EHR available through the Secure Anonymised Information Linkage (SAIL) Databank. A total of 46 million ethnicity records for 4,297,694 individuals in Wales-UK over 22 years (between 2000 and 2021) have been compiled in a harmonised, deduplicated longitudinal research ready data asset. We serialised this data and compared distribution of records over time for four selection approaches (Latest, Mode, Weighted-Mode and Composite) across age bands, sex, deprivation quintiles, health board, and residential location, against the ONS census 2011. The distribution of the dominant group (White) is minimally affected based on the four different selection approaches. Across all other ethnicity categorisations, the Mixed group was most susceptible to variation in distribution depending on the selection approach used and varied from a 0.6% prevalence across the Latest and Mode approach to a 1.1% prevalence for the Weighted-Mode, compared to the 3.1% prevalence for the Composite approach. Substantial alignment was observed with ONS census with the Latest group method (kappa= 0.68, 95% CI [0.67,0.71]) across all sub-groups. Conclusion We provides a reproducible EHR based resource enabling the investigation and evaluation of health inequalities related to ethnic groups in Wales. This generalisable method informs opportunities for the transferability of this methodology across the UK to platforms with comparable routine data sources. Ethics and dissemination This work was supported by the Con-COV team funded by Medical Research Council, Health Data Research UK, ADR Wales funded by ADR UK through the Economic and Social Research Council, and the Wales COVID-19 Evidence Centre, funded by Health and Care Research Wales.

A spatio-temporal framework for modelling wastewater concentration during the COVID-19 pandemic (preprint)

The potential utility of wastewater-based epidemiology as an early warning tool has been explored widely across the globe during the current COVID-19 pandemic. Methods to detect the presence of SARS-CoV-2 RNA in wastewater were developed early in the pandemic, and extensive work has been conducted to evaluate the relationship between viral concentration and COVID-19 case numbers at the catchment areas of sewage treatment works (STWs) over time. However, no attempt has been made to develop a model that predicts wastewater concentration at fine spatio-temporal resolutions covering an entire country, a necessary step towards using wastewater monitoring for the early detection of local outbreaks. We consider weekly averages of flow-normalised viral concentration, reported as the number of SARS-CoV-2 N1 gene copies per litre (gc/L) of wastewater available at 303 STWs over the period between 1 June 2021 and 30 March 2022. We specify a spatially continuous statistical model that quantifies the relationship between weekly viral concentration and a collection of covariates covering socio-demographics, land cover and virus-associated genomic characteristics at STW catchment areas while accounting for spatial and temporal correlation. We evaluate the models predictive performance at the catchment level through 10-fold cross-validation. We predict the weekly viral concentration at the population-weighted centroid of the 32,844 lower super output areas (LSOAs) in England, then aggregate these LSOA predictions to the Lower Tier Local Authority level (LTLA), a geography that is more relevant to public health policy-making. We also use the model outputs to quantify the probability of local changes of direction (increases or decreases) in viral concentration over short periods (e.g. two consecutive weeks). The proposed statistical framework is able to predict SARS-CoV-2 viral concentration in wastewater at high spatio-temporal resolution across England. Additionally, the probabilistic quantification of local changes can be used as an early warning tool for public health surveillance.

Harmonising electronic health records for reproducible research: challenges, solutions and recommendations from a UK-wide COVID-19 research collaboration (preprint)

Background The CVD-COVID-UK consortium was formed to understand the relationship between COVID-19 and cardiovascular diseases through analyses of harmonised electronic health records (EHRs) across the four UK nations. Beyond COVID-19, data harmonisation and common approaches enables analysis within and across independent Trusted Research Environments. Here we describe the reproducible harmonisation method developed using large-scale EHRs in Wales to accommodate the fast and efficient implementation of cross-nation analysis in England and Wales as part of the CVD-COVID-UK programme. We characterise current challenges and share lessons learnt.Methods Serving the scope and scalability of multiple study protocols, we used linked, anonymised individual-level EHR, demographic and administrative data held within the SAIL Databank for the population of Wales. The harmonisation method was implemented as a four-layer reproducible process, starting from raw data in the first layer. Then each of the layers two to four is framed by, but not limited to, the characterised challenges and lessons learnt. We achieved curated data as part of our second layer, followed by extracting phenotyped data in the third layer. We captured any project-specific requirements in the fourth layer.Results Using the implemented four-layer harmonisation method, we retrieved approximately 100 health-related variables for the 3.2 million individuals in Wales, which are harmonised with corresponding variables for > 56 million individuals in England. We processed 13 data sources into the first layer of our harmonisation method: five of these are updated daily or weekly, and the rest at various frequencies providing sufficient data flow updates for frequent capturing of up-to-date demographic, administrative and clinical information.Conclusions We implemented an efficient, transparent, scalable, and reproducible harmonisation method that enables multi-nation collaborative research. With a current focus on COVID-19 and its relationship with cardiovascular outcomes, the harmonised data has supported a wide range of research activities across the UK.

Risk of myocarditis and pericarditis following COVID-19 vaccination in England and Wales (preprint)

We describe our analyses of data from over 52 million people in England and Wales, representing near-complete coverage of the relevant population, to assess the risk of myocarditis and pericarditis following COVID-19 vaccination. A self-controlled case series (SCCS) design has previously reported increased risk of myocarditis after first doses of ChAdOx1, BNT162b2, and mRNA-1273 vaccinations and after second doses of the mRNA COVID-19 vaccinations in England. Here, we use a cohort design to estimate hazard ratios for hospitalised or fatal myocarditis/pericarditis and excess events after first and second doses of BNT162b2 and ChAdOx1 vaccinations. SCCS and cohort designs are subject to different assumptions and biases and therefore provide the opportunity for triangulation of evidence. In contrast to the findings from the SCCS approach previously reported for England, we found evidence of lower incidence of hospitalised or fatal myocarditis/pericarditis after first dose ChAdOx1 and BNT162b2 vaccination.

Pre-COVID-19 pandemic health-related behaviours in children (2018-2020) and association with being tested for SARS-CoV-2 and testing positive for SARS-CoV-2 (2020-2021): a retrospective cohort study using survey data linked with routine health data in Wales, UK (preprint)

ABSTRACT Objectives Examine if pre-COVID-19 pandemic (prior March 2020) health-related behaviours during primary school are associated with i) being tested for SARS-CoV-2 and ii) testing positive between 1 March 2020 to 31 August 2021. Design Retrospective cohort study using an online cohort survey (January 2018 to February 2020) linked to routine PCR SARS-CoV-2 test results. Setting Children attending primary schools in Wales (2018-2020), UK who were part of the HAPPEN school network. Participants Complete linked records of eligible participants were obtained for n=7,062 individuals. 39.1% (n=2,764) were tested (age 10.6±0.9, 48.9% girls) and 8.1% (n=569) tested positive for SARS-CoV-2 (age 10.6±1.0, 54.5% girls). Main outcome measures Logistic regression of health-related behaviours and demographics were used to determine Odds Ratios (OR) of factors associated with i) being tested for SARS-CoV-2 and ii) testing positive for SARS-CoV-2. Results Consuming sugary snacks (1-2 days/week OR=1.24, 95% CI 1.04 – 1.49; 5-6 days/week 1.31, 1.07 – 1.61; reference 0 days) can swim 25m (1.21, 1.06 – 1.39) and age (1.25, 1.16 – 1.35) were associated with an increased likelihood of being tested for SARS-CoV-2. Eating breakfast (1.52, 1.01 – 2.27), weekly physical activity ≥ 60 mins (1-2 days 1.69, 1.04 – 2.74; 3-4 days 1.76, 1.10 – 2.82, reference 0 days), out of school club participation (1.06, 1.02 – 1.10), can ride a bike (1.39, 1.00 – 1.93), age (1.16, 1.05 – 1.28) and girls (1.21, 1.00 – 1.46) were associated with an increased likelihood of testing positive for SARS-CoV-2. Living in least deprived quintiles 4 (0.64, 0.46 – 0.90) and 5 (0.64, 0.46 – 0.89) compared to the most deprived quintile was associated with a decreased likelihood. Conclusions Associations may be related to parental health literacy and monitoring behaviours. Physically active behaviours may include co-participation with others, and exposure to SARS-CoV-2. A risk versus benefit approach must be considered given the importance of health-related behaviours for development. STRENGTHS AND LIMITATIONS Investigation of the association of pre-pandemic child health-related behaviour measures with subsequent SARS-CoV-2 testing and infection. Reporting of multiple child health behaviours linked at an individual-level to routine records of SARS-CoV-2 testing data through the SAIL Databank. Child-reported health behaviours were measured before the COVID-19 pandemic (1 January 2018 to 28 February 2020) which may not reflect behaviours during COVID-19. Health behaviours captured through the national-scale HAPPEN survey represent children attending schools that engaged with the HAPPEN Wales primary school network and may not be representative of the whole population of Wales. The period of study for PCR-testing for and testing positive for SARS-CoV-2 includes a time frame with varying prevalence rates, approaches to testing children (targeted and mass testing) and restrictions which were not measured in this study.

The adverse impact of COVID-19 pandemic on cardiovascular disease prevention and management in England, Scotland and Wales: A population-scale descriptive analysis of trends in medication data (preprint)

Objectives: To estimate the impact of the COVID-19 pandemic on cardiovascular disease (CVD) and CVD management using routinely collected medication data as a proxy. Design: Descriptive and interrupted time series analysis using anonymised individual-level population-scale data for 1.32 billion records of dispensed CVD medications across 15.8 million individuals in England, Scotland and Wales. Setting: Community dispensed CVD medications with 100% coverage from England, Scotland and Wales, plus primary care prescribed CVD medications from England (including 98% English general practices). Participants: 15.8 million individuals aged 18+ years alive on 1st April 2018 dispensed at least one CVD medicine in a year from England, Scotland and Wales. Main outcome measures: Monthly counts, percent annual change (1st April 2018 to 31st July 2021) and annual rates (1st March 2018 to 28th February 2021) of medicines dispensed by CVD/ CVD risk factor; prevalent and incident use. Results: Year-on-year change in dispensed CVD medicines by month were observed, with notable uplifts ahead of the first (11.8% higher in March 2020) but not subsequent national lockdowns. Using hypertension as one example of the indirect impact of the pandemic, we observed 491,203 fewer individuals initiated antihypertensive treatment across England, Scotland and Wales during the period March 2020 to end May 2021 than would have been expected compared to 2019. We estimated that this missed antihypertension treatment could result in 13,659 additional CVD events should individuals remain untreated, including 2,281 additional myocardial infarctions (MIs) and 3,474 additional strokes. Incident use of lipid-lowering medicines decreased by an average 14,793 per month in early 2021 compared with the equivalent months prior to the pandemic in 2019. In contrast, the use of incident medicines to treat type-2 diabetes (T2DM) increased by approximately 1,642 patients per month. Conclusions: Management of key CVD risk factors as proxied by incident use of CVD medicines has not returned to pre-pandemic levels in the UK. Novel methods to identify and treat individuals who have missed treatment are urgently required to avoid large numbers of additional future CVD events, further adding indirect cost of the COVID-19 pandemic.

Association of COVID-19 with arterial and venous vascular diseases: a population-wide cohort study of 48 million adults in England and Wales (preprint)

Importance: The long-term effects of COVID-19 on the incidence of vascular diseases are unclear. Objective: To quantify the association between time since diagnosis of COVID-19 and vascular disease, overall and by age, sex, ethnicity, and pre-existing disease. Design: Cohort study based on population-wide linked electronic health records, with follow up from January 1st to December 7th 2020. Setting and participants: Adults registered with an NHS general practice in England or Wales and alive on January 1st 2020. Exposures: Time since diagnosis of COVID-19 (categorised as 0-6 days, 1-2 weeks, 3-4, 5-8, 9-12, 13-26 and 27-49 weeks since diagnosis), with and without hospitalisation within 28 days of diagnosis. Main outcomes and measures: Primary outcomes were arterial thromboses (mainly acute myocardial infarction and ischaemic stroke) and venous thromboembolic events (VTE, mainly pulmonary embolism and lower limb deep vein thrombosis). We also studied other vascular events (transient ischaemic attack, haemorrhagic stroke, heart failure and angina). Hazard ratios were adjusted for demographic characteristics, previous disease diagnoses, comorbidities and medications. Results: Among 48 million adults, 130,930 were and 1,315,471 were not hospitalised within 28 days of COVID-19. In England, there were 259,742 first arterial thromboses and 60,066 first VTE during 41.6 million person-years follow-up. Adjusted hazard ratios (aHRs) for first arterial thrombosis compared with no COVID-19 declined rapidly from 21.7 (95% CI 21.0-22.4) to 3.87 (3.58-4.19) in weeks 1 and 2 after COVID-19, 2.80 (2.61-3.01) during weeks 3-4 then to 1.34 (1.21-1.48) during weeks 27-49. aHRs for first VTE declined from 33.2 (31.3-35.2) and 8.52 (7.59-9.58) in weeks 1 and 2 to 7.95 (7.28-8.68) and 4.26 (3.86-4.69) during weeks 3-4 and 5-8, then 2.20 (1.99-2.44) and 1.80 (1.50-2.17) during weeks 13-26 and 27-49 respectively. aHRs were higher, for longer after diagnosis, after hospitalised than non-hospitalised COVID-19. aHRs were also higher among people of Black and Asian than White ethnicity and among people without than with a previous event. Across the whole population estimated increases in risk of arterial thromboses and VTEs were 2.5% and 0.6% respectively 49 weeks after COVID-19, corresponding to 7,197 and 3,517 additional events respectively after 1.4 million COVID-19 diagnoses. Conclusions and Relevance: High rates of vascular disease early after COVID-19 diagnosis decline more rapidly for arterial thromboses than VTEs but rates remain elevated up to 49 weeks after COVID-19. These results support continued policies to avoid COVID-19 infection with effective COVID-19 vaccines and use of secondary preventive agents in high-risk patients.

COVID-19 mitigation measures in primary schools and association with infection and school staff wellbeing: an observational survey linked with routine data in Wales, UK (preprint)

IntroductionSchool-based COVID-19 mitigation strategies have greatly impacted the primary school day (children aged 3-11) including: wearing face coverings, 2-metre distancing, no mixing of children, and no breakfast clubs or extra-curricular activities. This study examines these mitigation methods and association with COVID-19 infection, respiratory infection, and school staff wellbeing between October to December 2020 in Wales, UK. MethodsA school staff survey captured self-reported COVID-19 mitigation measures in the school, participant anxiety and depression, and open-text responses regarding experiences of teaching and implementing measures. These survey responses were linked to national-scale COVID-19 test results data to examine association of measures in the school and the likelihood of a positive (staff or pupil) COVID-19 case in the school (clustered by school, adjusted for school size and free school meals using logistic regression). Linkage was conducted through the SAIL (Secure Anonymised Information Linkage) Databank. ResultsResponses were obtained from 353 participants from 59 primary schools within 15 of 22 local authorities. Having more direct non-household contacts was associated with a higher likelihood of COVID-19 positive case in the school (1-5 contacts compared to none, OR 2.89 (1.01, 8.31)) and a trend to more self-reported cold symptoms. Staff face covering was not associated with a lower odds of school COVID-19 cases (mask vs. no covering OR 2.82 (1.11, 7.14)) and was associated with higher self-reported cold symptoms. School staff reported the impacts of wearing face coverings on teaching, including having to stand closer to pupils and raise their voices to be heard. 67.1% were not able to implement 2-metre social distancing from pupils. We did not find evidence that maintaining a 2-metre distance was associated with lower rates of COVID-19 in the school. ConclusionsImplementing, adhering to and evaluating COVID-19 mitigation guidelines is challenging in primary school settings. Our findings suggest that reducing non-household direct contacts lowers infection rates. There was no evidence that face coverings, 2-metre social distancing or stopping children mixing was associated with lower odds of COVID-19 or cold infection rates in the school. Primary school staff found teaching challenging during COVID-19 restrictions, especially for younger learners and those with additional learning needs.

Intensity of COVID-19 in care homes following Hospital Discharge in the early stages of the UK epidemic (preprint)

Background A defining feature of the COVID-19 pandemic in many countries was the tragic extent to which care home residents were affected, and the difficulty preventing introduction and subsequent spread of infection. Management of risk in care homes requires good evidence on the most important transmission pathways. One hypothesised route at the start of the pandemic, prior to widespread testing, was transfer of patients from hospitals, which were experiencing high levels of nosocomial events. Methods We tested the hypothesis that hospital discharge events increased the intensity of care home cases using a national individually linked health record cohort in Wales, UK. We monitored 186,772 hospital discharge events over the period March to July 2020, tracking individuals to 923 care homes and recording the daily case rate in the homes populated by 15,772 residents. We estimated the risk of an increase in cases rates following exposure to a hospital discharge using multi-level hierarchical logistic regression, and a novel stochastic Hawkes process outbreak model. Findings In regression analysis, after adjusting for care home size, we found no significant association between hospital discharge and subsequent increases in care home case numbers (odds ratio: 0.99, 95% CI 0.82, 1.90). Risk factors for increased cases included care home size, care home resident density, and provision of nursing care. Using our outbreak model, we found a significant effect of hospital discharge on the subsequent intensity of cases. However, the effect was small, and considerably less than the effect of care home size, suggesting the highest risk of introduction came from interaction with the community. We estimated approximately 1.8% of hospital discharged patients may have been infected. Interpretation There is growing evidence in the UK that the risk of transfer of COVID-19 from the high-risk hospital setting to the high-risk care home setting during the early stages of the pandemic was relatively small. Although access to testing was limited to initial symptomatic cases in each care home at this time, our results suggest that reduced numbers of discharges, selection of patients, and action taken within care homes following transfer all may have contributed to mitigation. The precise key transmission routes from the community remain to be quantified.

Surgical activity in England and Wales during the COVID-19 pandemic: a nationwide observational cohort study (preprint)

ObjectivesTo report the volume of surgical activity and the number of cancelled surgical procedures during the COVID-19 pandemic. Design and settingAnalysis of electronic health record data from the National Health Service (NHS) in England and Wales. MethodsWe used hospital episode statistics for all adult patients undergoing surgery between 1st January 2020 and 31st December 2020. We identified surgical procedures using a previously published list of procedure codes. Procedures were stratified by urgency of surgery as defined by NHS England. We calculated the deficit of surgical activity by comparing the expected number of procedures from the years 2016-2019 with the actual number of procedures in 2020. We estimated the cumulative number of cancelled procedures by 31st December 2021 according patterns of activity in 2020. ResultsThe total number of surgical procedures carried out in England and Wales in 2020 was 3,102,674 compared to the predicted number of 4,671,338. This represents a 33.6% reduction in the national volume of surgical activity. There were 763,730 emergency surgical procedures (13.4% reduction), compared to 2,338,944 elective surgical procedures (38.6% reduction). The cumulative number of cancelled or postponed procedures was 1,568,664. We estimate that this will increase to 2,358,420 by 31st December 2021. ConclusionsThe volume of surgical activity in England and Wales was reduced by 33.6% in 2020, resulting in over 1,568,664 cancelled operations. This deficit will continue to grow in 2021. Summary boxesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIThe COVID-19 pandemic necessitated a rapid change in the provision of care, including the suspension of a large proportion of surgical activity C_LIO_LISurgical activity has yet to return to normal and has been further impacted by subsequent waves of the pandemic C_LIO_LIThis will lead to a large backlog of cases C_LI What this study addsO_LI3,102,674 surgical procedures were performed in England and Wales during 2020, a 33.6% reduction on the expected yearly surgical activity C_LIO_LIOver 1.5 million procedures were not performed, with this deficit likely to continue to grow to 2.3 million by the end of 2021 C_LIO_LIThis deficit is the equivalent of more than 6 months of pre-pandemic surgical activity, requiring a monumental financial and logistic challenge to manage C_LI

Evaluating the effect of COVID-19 on dispensing patterns: a national cohort analysis (preprint)

BackgroundMedication prescribing and dispensing often regarded as one of the most effective ways to manage and improve population health. Prescribed and dispensed medications can be monitored through data linkage for each patient. We hypothesised that changes in patient care resulting from COVID-19, changed the way patients access their prescribed medication. ObjectiveTo develop an efficient approach for evaluation of the impact of COVID-19 on drug dispensing patterns. MethodsRetrospective observational study using national patient-level dispensing records in Wales-UK. Total dispensed drug items between 01-Jan-2016 and 31-Dec-2019 (counterfactual pre-COVID-19) were compared to 2020 (COVID-19 year). We compared trends of dispensed items in three main British National Formulary (BNF) sections(Cardiovascular system, Central Nervous System, Immunological & Vaccine) using European Age-Standardized rates. We developed an online tool to enable monitoring of changes in dispensing as the pandemic evolves. ResultAmongst all BNF chapters, 52,357,639 items were dispensed in 2020 compared to 49,747,141 items in 2019 demonstrating a relative increase of 5.25% in 2020(95%CI[5.21,5.29]). Comparison of monthly patterns of 2020 and 2019 dispensed items showed a notable difference between the total number of dispensed drug items each month, with an average difference (D) of +290,055 and average Relative Change (RC) of +5.52%. The greatest RC was observed in a substantial March-2020 increase (D=+1,501,242 and RC=+28%), followed by second peak in June (D=+565,004, RC=+10.97%). May was characterised by lower dispensing (D=-399,244, RC=-5.9%). Cardiovascular categories were characterised, across all age groups, by dramatic March-2020 increases, at the epidemic peak, followed by months of lower than expected dispensing, and gradual recovery by September. The Central Nervous System category was similar, but with only a short decline in May, and quicker recovery. A stand-out grouping was Immunological and Vaccine, which dropped to very low levels across all age groups, and all months (including the March dispensing peak). ConclusionsAberration in clinical service delivery during COVID-19 led to substantial changes in community pharmacy drug dispensing. This change may contribute to a long-term burden of COVID-19, raising the importance of a comprehensive and timely monitoring of changes for evaluation of the potential impact on clinical care and outcomes

Effectiveness of First Dose of COVID-19 Vaccines Against Hospital Admissions in Scotland: National Prospective Cohort Study of 5.4 Million People (preprint)

Background: The BNT162b2 mRNA (Pfizer-BioNTech) and ChAdOx1 (Oxford-AstraZeneca) COVID-19 vaccines have demonstrated high efficacy against infection in phase 3 clinical trials and are now being used in national vaccination programmes in the UK and several other countries. There is an urgent need to study the ‘real-world’ effects of these vaccines. The aim of our study was to estimate the effectiveness of the first dose of these COVID-19 vaccines in preventing hospital admissions.Methods: We conducted a prospective cohort study using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) database comprising of linked vaccination, primary care, Real-Time Polymerase Chain Reaction (RT-PCR) testing, hospitalisation and mortality records for 5.4 million people in Scotland (covering ~99% of population). A time-dependent Cox model and Poisson regression models were fitted to estimate effectiveness against COVID-19 related hospitalisation (defined as 1- Adjusted Hazard Ratio) following the first dose of vaccine.Findings: The first dose of the BNT162b2 vaccine was associated with a vaccine effect of 85% (95% confidence interval [CI] 76 to 91) for COVID-19 related hospitalisation at 28-34 days post-vaccination. Vaccine effect at the same time interval for the ChAdOx1 vaccine was 94% (95% CI 73 to 99). Results of combined vaccine effect for prevention of COVID-19 related hospitalisation were comparable when restricting the analysis to those aged ≥80 years (81%; 95% CI 65 to 90 at 28-34 days post-vaccination).Interpretation: A single dose of the BNT162b2 mRNA and ChAdOx1 vaccines resulted in substantial reductions in the risk of COVID-19 related hospitalisation in Scotland.Funding: UK Research and Innovation (Medical Research Council); Research and Innovation Industrial Strategy Challenge Fund; Health Data Research UK.Conflict of Interest: AS is a member of the Scottish Government Chief Medical Officer’s COVID-19Advisory Group and the New and Emerging Respiratory Virus Threats (NERVTAG) Risk Stratification Subgroup. CRS declares funding from the MRC, NIHR, CSO and New Zealand Ministry for Business, Innovation and Employment and Health Research Council during the conduct of this study. SVK is co-chair of the Scottish Government’s Expert Reference Group on COVID-19 and ethnicity, is a member of the Scientific Advisory Group on Emergencies (SAGE) subgroup on ethnicity and acknowledges funding from a NRS Senior Clinical Fellowship, MRC and CSO. All other authors report no conflicts of interest.Ethical Approval: Approvals were obtained from the National Research Ethics Service Committee, Southeast Scotland 02 (reference number: 12/SS/0201) and Public Benefit and Privacy Panel for Health and Social Care (reference number: 1920-0279).

Evaluating the effect of COVID-19 on dispensing patterns: a national cohort analysis (preprint)

BackgroundMedication prescribing and dispensing often regarded as one of the most effective ways to manage and improve population health. Prescribed and dispensed medications can be monitored through data linkage for each patient. We hypothesised that changes in patient care resulting from COVID-19, changed the way patients access their prescribed medication.Objective To develop an efficient approach for evaluation of the impact of COVID-19 on drug dispensing patterns.MethodsRetrospective observational study using national patient-level dispensing records in Wales-UK. Total dispensed drug items between 01-Jan-2016 and 31-Dec-2019 (counterfactual pre-COVID-19) were compared to 2020 (COVID-19 year). We compared trends of dispensed items in three main British National Formulary (BNF) sections(Cardiovascular system, Central Nervous System, Immunological & Vaccine) using European Age-Standardized rates. We developed an online tool to enable monitoring of changes in dispensing as the pandemic evolves.ResultAmongst all BNF chapters, 52,357,639 items were dispensed in 2020 compared to 49,747,141 items in 2019 demonstrating a relative increase of 5.25% in 2020(95%CI[5.21,5.29]). Comparison of monthly patterns of 2020 and 2019 dispensed items showed a notable difference between the total number of dispensed drug items each month, with an average difference (D) of +290,055 and average Relative Change (RC) of +5.52%. The greatest RC was observed in a substantial March-2020 increase (D=+1,501,242 and RC=+28%), followed by second peak in June (D=+565,004, RC=+10.97%). May was characterised by lower dispensing (D=-399,244, RC=-5.9%). Cardiovascular categories were characterised, across all age groups, by dramatic March-2020 increases, at the epidemic peak, followed by months of lower than expected dispensing, and gradual recovery by September. The Central Nervous System category was similar, but with only a short decline in May, and quicker recovery. A stand-out grouping was Immunological and Vaccine, which dropped to very low levels across all age groups, and all months (including the March dispensing peak).ConclusionsAberration in clinical service delivery during COVID-19 led to substantial changes in community pharmacy drug dispensing. This change may contribute to a long-term burden of COVID-19, raising the importance of a comprehensive and timely monitoring of changes for evaluation of the potential impact on clinical care and outcomes

Staff-Pupil SARS-CoV-2 Infection Pathways in Schools: A Population Level Linked Data Approach (preprint)

Abstract Background: Better understanding of the role that children and school staff play in the transmission of SARS-CoV-2 is essential to guide policy development on controlling infection whilst minimising disruption to children's education and wellbeing. Methods: Our national e-cohort (n=500,779) study used anonymised linked data for pupils, staff and associated households linked via educational settings. We estimated the risk of testing positive for SARS-CoV-2 infection for staff and pupils over the period August-December 2020, dependent on measures of recent exposure to known cases linked to their educational settings. Results: The total number of cases in a school was not associated with a subsequent increase in the risk of testing positive (Staff OR per case 0.92, 95%CI 0.85, 1.00; Pupils OR per case 0.98, 95%CI 0.93, 1.02). Amongst pupils, the number of recent cases within the same year group was significantly associated with subsequent increased risk of testing positive (OR per case 1.12, 95%CI 1.08 - 1.15). These effects were adjusted for a range of demographic covariates, and in particular any known cases within the same household, which had the strongest association with testing positive (Staff OR 39.86, 95%CI 35.01, 45.38, pupil OR 9.39, 95%CI 8.94 - 9.88). Conclusions: In a national school cohort, the odds of staff testing positive for SARS-CoV-2 infection were not significantly increased in the 14-day period after case detection in the school. However, pupils were found to be at increased risk, following cases appearing within their own year group, where most of their contacts occur. Strong mitigation measures over the whole of the study period may have reduced wider spread within the school environment.