A spatio-temporal framework for modelling wastewater concentration during the COVID-19 pandemic.

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-2N1 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 model's 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 can 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.

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.

Using national electronic health records for pandemic preparedness: validation of a parsimonious model for predicting excess deaths among those with COVID-19-a data-driven retrospective cohort study.

OBJECTIVES: To use national, pre- and post-pandemic electronic health records (EHR) to develop and validate a scenario-based model incorporating baseline mortality risk, infection rate (IR) and relative risk (RR) of death for prediction of excess deaths. DESIGN: An EHR-based, retrospective cohort study. SETTING: Linked EHR in Clinical Practice Research Datalink (CPRD); and linked EHR and COVID-19 data in England provided in NHS Digital Trusted Research Environment (TRE). PARTICIPANTS: In the development (CPRD) and validation (TRE) cohorts, we included 3.8 million and 35.1 million individuals aged ≥30 years, respectively. MAIN OUTCOME MEASURES: One-year all-cause excess deaths related to COVID-19 from March 2020 to March 2021. RESULTS: From 1 March 2020 to 1 March 2021, there were 127,020 observed excess deaths. Observed RR was 4.34% (95% CI, 4.31-4.38) and IR was 6.27% (95% CI, 6.26-6.28). In the validation cohort, predicted one-year excess deaths were 100,338 compared with the observed 127,020 deaths with a ratio of predicted to observed excess deaths of 0.79. CONCLUSIONS: We show that a simple, parsimonious model incorporating baseline mortality risk, one-year IR and RR of the pandemic can be used for scenario-based prediction of excess deaths in the early stages of a pandemic. Our analyses show that EHR could inform pandemic planning and surveillance, despite limited use in emergency preparedness to date. Although infection dynamics are important in the prediction of mortality, future models should take greater account of underlying conditions.

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

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 enable 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.

The impact of the COVID-19 pandemic on cardiovascular disease prevention and management.

How the Coronavirus Disease 2019 (COVID-19) pandemic has affected prevention and management of cardiovascular disease (CVD) is not fully understood. In this study, we used medication data as a proxy for CVD management using routinely collected, de-identified, individual-level data comprising 1.32 billion records of community-dispensed CVD medications from England, Scotland and Wales between April 2018 and July 2021. Here we describe monthly counts of prevalent and incident medications dispensed, as well as percentage changes compared to the previous year, for several CVD-related indications, focusing on hypertension, hypercholesterolemia and diabetes. We observed a decline in the dispensing of antihypertensive medications between March 2020 and July 2021, with 491,306 fewer individuals initiating treatment than expected. This decline was predicted to result in 13,662 additional CVD events, including 2,281 cases of myocardial infarction and 3,474 cases of stroke, should individuals remain untreated over their lifecourse. Incident use of lipid-lowering medications decreased by 16,744 patients per month during the first half of 2021 as compared to 2019. By contrast, incident use of medications to treat type 2 diabetes mellitus, other than insulin, increased by approximately 623 patients per month for the same time period. In light of these results, methods to identify and treat individuals who have missed treatment for CVD risk factors and remain undiagnosed are urgently required to avoid large numbers of excess future CVD events, an indirect impact of the COVID-19 pandemic.

COVID-19 booster vaccination uptake and infection breakthrough amongst health care workers in Wales: A national prospective cohort study.

BACKGROUND: From September 2021, Health Care Workers (HCWs) in Wales began receiving a COVID-19 booster vaccination. This is the first dose beyond the primary vaccination schedule. Given the emergence of new variants, vaccine waning vaccine, and increasing vaccination hesitancy, there is a need to understand booster vaccine uptake and subsequent breakthrough in this high-risk population. METHODS: We conducted a prospective, national-scale, observational cohort study of HCWs in Wales using anonymised, linked data from the SAIL Databank. We analysed uptake of COVID-19 booster vaccinations from September 2021 to February 2022, with comparisons against uptake of the initial primary vaccination schedule. We also analysed booster breakthrough, in the form of PCR-confirmed SARS-Cov-2 infection, comparing to the second primary dose. Cox proportional hazard models were used to estimate associations for vaccination uptake and breakthrough regarding staff roles, socio-demographics, household composition, and other factors. RESULTS: We derived a cohort of 73,030 HCWs living in Wales (78% female, 60% 18-49 years old). Uptake was quickest amongst HCWs aged 60 + years old (aHR 2.54, 95%CI 2.45-2.63), compared with those aged 18-29. Asian HCWs had quicker uptake (aHR 1.18, 95%CI 1.14-1.22), whilst Black HCWs had slower uptake (aHR 0.67, 95%CI 0.61-0.74), compared to white HCWs. HCWs residing in the least deprived areas were slightly quicker to have received a booster dose (aHR 1.12, 95%CI 1.09-1.16), compared with those in the most deprived areas. Strongest associations with breakthrough infections were found for those living with children (aHR 1.52, 95%CI 1.41-1.63), compared to two-adult only households. HCWs aged 60 + years old were less likely to get breakthrough infections, compared to those aged 18-29 (aHR 0.42, 95%CI 0.38-0.47). CONCLUSION: Vaccination uptake was consistently lower among black HCWs, as well as those from deprived areas. Whilst breakthrough infections were highest in households with children.

Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales.

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a prothrombotic state, but long-term effects of COVID-19 on incidence of vascular diseases are unclear. METHODS: We studied vascular diseases after COVID-19 diagnosis in population-wide anonymized linked English and Welsh electronic health records from January 1 to December 7, 2020. We estimated adjusted hazard ratios comparing the incidence of arterial thromboses and venous thromboembolic events (VTEs) after diagnosis of COVID-19 with the incidence in people without a COVID-19 diagnosis. We conducted subgroup analyses by COVID-19 severity, demographic characteristics, and previous history. RESULTS: Among 48 million adults, 125 985 were hospitalized and 1 319 789 were not hospitalized within 28 days of COVID-19 diagnosis. In England, there were 260 279 first arterial thromboses and 59 421 first VTEs during 41.6 million person-years of follow-up. Adjusted hazard ratios for first arterial thrombosis after COVID-19 diagnosis compared with no COVID-19 diagnosis declined from 21.7 (95% CI, 21.0-22.4) in week 1 after COVID-19 diagnosis to 1.34 (95% CI, 1.21-1.48) during weeks 27 to 49. Adjusted hazard ratios for first VTE after COVID-19 diagnosis declined from 33.2 (95% CI, 31.3-35.2) in week 1 to 1.80 (95% CI, 1.50-2.17) during weeks 27 to 49. Adjusted hazard ratios were higher, for longer after diagnosis, after hospitalized versus nonhospitalized COVID-19, among Black or Asian versus White people, and among people without versus with a previous event. The estimated whole-population increases in risk of arterial thromboses and VTEs 49 weeks after COVID-19 diagnosis were 0.5% and 0.25%, respectively, corresponding to 7200 and 3500 additional events, respectively, after 1.4 million COVID-19 diagnoses. CONCLUSIONS: High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients.

Comparative risk of cerebral venous sinus thrombosis (CVST) following COVID-19 vaccination or infection: A national cohort study using linked electronic health records.

To inform the public and policy makers, we investigated and compared the risk of cerebral venous sinus thrombosis (CVST) after SARS-Cov-2 vaccination or infection using a national cohort of 2,643,699 individuals aged 17 y and above, alive, and resident in Wales on 1 January 2020 followed up through multiple linked data sources until 28 March 2021. Exposures were first dose of Oxford-ChAdOx1 or Pfizer-BioNTech vaccine or polymerase chain reaction (PCR)-confirmed SARS-Cov-2 infection. The outcome was an incident record of CVST. Hazard ratios (HR) were calculated using multivariable Cox regression, adjusted for confounders. HR from SARS-Cov-2 infection was compared with that for SARS-Cov-2 vaccination. We identified 910,556 (34.4%) records of first SARS-Cov-2 vaccination and 165,862 (6.3%) of SARS-Cov-2 infection. A total of 1,372 CVST events were recorded during the study period, of which 52 (3.8%) and 48 (3.5%) occurred within 28 d after vaccination and infection, respectively. We observed slight non-significant risk of CVST within 28 d of vaccination [aHR: 1.34, 95% CI: 0.95-1.90], which remained after stratifying by vaccine [BNT162b2, aHR: 1.18 (95% CI: 0.63-2.21); ChAdOx1, aHR: 1.40 (95% CI: 0.95-2.05)]. Three times the number of CVST events is observed within 28 d of a positive SARS-Cov-2 test [aHR: 3.02 (95% CI: 2.17-4.21)]. The risk of CVST following SARS-Cov-2 infection is 2.3 times that following SARS-Cov-2 vaccine. This is important information both for those designing COVID-19 vaccination programs and for individuals making their own informed decisions on the risk-benefit of vaccination. This record-linkage approach will be useful in monitoring the safety of future vaccine programs.

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.

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.

OBJECTIVES: Examine if pre-COVID-19 pandemic (prior March 2020) health-related behaviours during primary school are associated with (1) being tested for SARS-CoV-2 and (2) testing positive between 1 March 2020 and 31 August 2021. DESIGN: Retrospective cohort study using an online cohort survey (January 2018 to February 2020) linked with routine PCR SARS-CoV-2 test results. SETTING: Children attending primary schools in Wales (2018-2020), UK, who were part of the Health and Attainment of Pupils in a Primary Education Network (HAPPEN)_school network. PARTICIPANTS: Complete linked records of eligible participants were obtained for n=7062 individuals. 39.1% (n=2764) 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 the ORs of factors associated with (1) being tested for SARS-CoV-2 and (2) testing positive for SARS-CoV-2. RESULTS: Consuming sugary snacks (1-2 days/week OR=1.24, 95% CI 1.04 to 1.49; 5-6 days/week OR=1.31, 95% CI 1.07 to 1.61; reference 0 days), can swim 25 m (OR=1.21, 95% CI 1.06 to 1.39) and age (OR=1.25, 95% CI 1.16 to 1.35) were associated with an increased likelihood of being tested for SARS-CoV-2. Eating breakfast (OR=1.52, 95% CI 1.01 to 2.27), weekly physical activity ≥60 min (1-2 days OR=1.69, 95% CI 1.04 to 2.74; 3-4 days OR=1.76, 95% CI 1.10 to 2.82; reference 0 days), out-of-school club participation (OR=1.06, 95% CI 1.02 to 1.10), can ride a bike (OR=1.39, 95% CI 1.00 to 1.93), age (OR=1.16, 95% CI 1.05 to 1.28) and girls (OR=1.21, 95% CI 1.00 to 1.46) were associated with an increased likelihood of testing positive for SARS-CoV-2. Living in least deprived areas (quintile 4 OR=0.64, 95% CI 0.46 to 0.90; quintile 5 OR=0.64, 95% CI 0.46 to 0.89) compared with the most deprived (quintile 1) was associated with a decreased likelihood. CONCLUSIONS: Associations may be related to parental health literacy and monitoring behaviours. Physically active behaviours may include coparticipation with others and exposure to SARS-CoV-2. A risk-versus-benefit approach must be considered in relation to promoting these health behaviours, given the importance of health-related behaviours such as childhood physical activity for development.

Risk of thrombocytopenic, haemorrhagic and thromboembolic disorders following COVID-19 vaccination and positive test: a self-controlled case series analysis in Wales.

There is a need for better understanding of the risk of thrombocytopenic, haemorrhagic, thromboembolic disorders following first, second and booster vaccination doses and testing positive for SARS-CoV-2. Self-controlled cases series analysis of 2.1 million linked patient records in Wales between 7th December 2020 and 31st December 2021. Outcomes were the first diagnosis of thrombocytopenic, haemorrhagic and thromboembolic events in primary or secondary care datasets, exposure was defined as 0-28 days post-vaccination or a positive reverse transcription polymerase chain reaction test for SARS-CoV-2. 36,136 individuals experienced either a thrombocytopenic, haemorrhagic or thromboembolic event during the study period. Relative to baseline, our observations show greater risk of outcomes in the periods post-first dose of BNT162b2 for haemorrhagic (IRR 1.47, 95%CI: 1.04-2.08) and idiopathic thrombocytopenic purpura (IRR 2.80, 95%CI: 1.21-6.49) events; post-second dose of ChAdOx1 for arterial thrombosis (IRR 1.14, 95%CI: 1.01-1.29); post-booster greater risk of venous thromboembolic (VTE) (IRR-Moderna 3.62, 95%CI: 0.99-13.17) (IRR-BNT162b2 1.39, 95%CI: 1.04-1.87) and arterial thrombosis (IRR-Moderna 3.14, 95%CI: 1.14-8.64) (IRR-BNT162b2 1.34, 95%CI: 1.15-1.58). Similarly, post SARS-CoV-2 infection the risk was increased for haemorrhagic (IRR 1.49, 95%CI: 1.15-1.92), VTE (IRR 5.63, 95%CI: 4.91, 6.4), arterial thrombosis (IRR 2.46, 95%CI: 2.22-2.71). We found that there was a measurable risk of thrombocytopenic, haemorrhagic, thromboembolic events after COVID-19 vaccination and infection.

Impact of the SARS-CoV-2 pandemic on female breast, colorectal and non-small cell lung cancer incidence, stage and healthcare pathway to diagnosis during 2020 in Wales, UK, using a national cancer clinical record system.

BACKGROUND: COVID-19 pandemic responses impacted behaviour and health services. We estimated the impact on incidence, stage and healthcare pathway to diagnosis for female breast, colorectal and non-small cell lung cancers at population level in Wales. METHODS: Cancer e-record and hospital admission data linkage identified adult cases, stage and healthcare pathway to diagnosis (population ~2.5 million). Using multivariate Poisson regressions, we compared 2019 and 2020 counts and estimated incidence rate ratios (IRR). RESULTS: Cases decreased 15.2% (n = -1011) overall. Female breast annual IRR was 0.81 (95% CI: 0.76-0.86, p < 0.001), colorectal 0.80 (95% CI: 0.79-0.81, p < 0.001) and non-small cell lung 0.91 (95% CI: 0.90-0.92, p < 0.001). Decreases were largest in 50-69 year olds for female breast and 80+ year olds for all cancers. Stage I female breast cancer declined 41.6%, but unknown stage increased 55.8%. Colorectal stages I-IV declined (range 26.6-29.9%), while unknown stage increased 803.6%. Colorectal Q2-2020 GP-urgent suspected cancer diagnoses decreased 50.0%, and 53.9% for non-small cell lung cancer. Annual screen-detected female breast and colorectal cancers fell 47.8% and 13.3%, respectively. Non-smal -cell lung cancer emergency presentation diagnoses increased 9.5% (Q2-2020) and 16.3% (Q3-2020). CONCLUSION: Significantly fewer cases of three common cancers were diagnosed in 2020. Detrimental impacts on outcomes varied between cancers. Ongoing surveillance with health service optimisation will be needed to mitigate impacts.

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.

SARS-CoV-2 infection risk among 77,587 healthcare workers: a national observational longitudinal cohort study in Wales, United Kingdom, April to November 2020.

OBJECTIVES: To better understand the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among healthcare workers, leading to recommendations for the prioritisation of personal protective equipment, testing, training and vaccination. DESIGN: Observational, longitudinal, national cohort study. SETTING: Our cohort were secondary care (hospital-based) healthcare workers employed by NHS Wales (United Kingdom) organisations from 1 April 2020 to 30 November 2020. PARTICIPANTS: We included 577,756 monthly observations among 77,587 healthcare workers. Using linked anonymised datasets, participants were grouped into 20 staff roles. Additionally, each role was deemed either patient-facing, non-patient-facing or undetermined. This was linked to individual demographic details and dates of positive SARS-CoV-2 PCR tests. MAIN OUTCOME MEASURES: We used univariable and multivariable logistic regression models to determine odds ratios (ORs) for the risk of a positive SARS-CoV-2 PCR test. RESULTS: Patient-facing healthcare workers were at the highest risk of SARS-CoV-2 infection with an adjusted OR (95% confidence interval [CI]) of 2.28 (95% CI 2.10-2.47). We found that after adjustment, foundation year doctors (OR 1.83 [95% CI 1.47-2.27]), healthcare support workers [OR 1.36 [95% CI 1.20-1.54]) and hospital nurses (OR 1.27 [95% CI 1.12-1.44]) were at the highest risk of infection among all staff groups. Younger healthcare workers and those living in more deprived areas were at a higher risk of infection. We also observed that infection rates varied over time and by organisation. CONCLUSIONS: These findings have important policy implications for the prioritisation of vaccination, testing, training and personal protective equipment provision for patient-facing roles and the higher risk staff groups.

Impact of COVID-19 pandemic on community medication dispensing: a national cohort analysis in Wales, UK.

Background: Population-level information on dispensed medication provides insight on the distribution of treated morbidities, particularly if linked to other population-scale data at an individual-level. Objective: To evaluate the impact of COVID-19 on dispensing patterns of medications. Methods: Retrospective observational study using population-scale, individual-level dispensing records in Wales, UK. Total dispensed drug items for the population between 1 st January 2016 and 31 st December 2019 (3-years, pre-COVID-19) were compared to 2020 with follow up until 27 th July 2021 (COVID-19 period). We compared trends across all years and British National Formulary (BNF) chapters and highlighted the trends in three major chapters for 2019-21: 1-Cardiovascular system (CVD); 2-Central Nervous System (CNS); 3-Immunological & Vaccine. We developed an interactive dashboard to enable monitoring of changes as the pandemic evolves. Result: Amongst all BNF chapters, 73,410,543 items were dispensed in 2020 compared to 74,121,180 items in 2019 demonstrating -0.96% relative decrease in 2020. Comparison of monthly patterns showed average difference (D) of -59,220 and average Relative Change (RC) of -0.74% between the number of dispensed items in 2020 and 2019. Maximum RC was observed in March 2020 (D = +1,224,909 and RC = +20.62), followed by second peak in June 2020 (D = +257,920, RC = +4.50%). A third peak was observed in September 2020 (D = +264,138, RC = +4.35%). Large increases in March 2020 were observed for CVD and CNS medications across all age groups. The Immunological and Vaccine products dropped to very low levels across all age groups and all months (including the March dispensing peak). Conclusions: Reconfiguration of routine clinical services 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.

Validating the QCOVID risk prediction algorithm for risk of mortality from COVID-19 in the adult population in Wales, UK.

Introduction: COVID-19 risk prediction algorithms can be used to identify at-risk individuals from short-term serious adverse COVID-19 outcomes such as hospitalisation and death. It is important to validate these algorithms in different and diverse populations to help guide risk management decisions and target vaccination and treatment programs to the most vulnerable individuals in society. Objectives: To validate externally the QCOVID risk prediction algorithm that predicts mortality outcomes from COVID-19 in the adult population of Wales, UK. Methods: We conducted a retrospective cohort study using routinely collected individual-level data held in the Secure Anonymised Information Linkage (SAIL) Databank. The cohort included individuals aged between 19 and 100 years, living in Wales on 24th January 2020, registered with a SAIL-providing general practice, and followed-up to death or study end (28th July 2020). Demographic, primary and secondary healthcare, and dispensing data were used to derive all the predictor variables used to develop the published QCOVID algorithm. Mortality data were used to define time to confirmed or suspected COVID-19 death. Performance metrics, including R2 values (explained variation), Brier scores, and measures of discrimination and calibration were calculated for two periods (24th January-30th April 2020 and 1st May-28th July 2020) to assess algorithm performance. Results: 1,956,760 individuals were included. 1,192 (0.06%) and 610 (0.03%) COVID-19 deaths occurred in the first and second time periods, respectively. The algorithms fitted the Welsh data and population well, explaining 68.8% (95% CI: 66.9-70.4) of the variation in time to death, Harrell's C statistic: 0.929 (95% CI: 0.921-0.937) and D statistic: 3.036 (95% CI: 2.913-3.159) for males in the first period. Similar results were found for females and in the second time period for both sexes. Conclusions: The QCOVID algorithm developed in England can be used for public health risk management for the adult Welsh population.

Intensity of COVID-19 in care homes following hospital discharge in the early stages of the UK epidemic.

BACKGROUND: defining features of the COVID-19 pandemic in many countries were the tragic extent to which care home residents were affected and the difficulty in preventing the 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 the transfer of patients from hospitals that 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 from 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 case 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 that 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 the mitigation. The precise key transmission routes from the community remain to be quantified.

Variations in COVID-19 vaccination uptake among people in receipt of psychotropic drugs: cross-sectional analysis of a national population-based prospective cohort.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has disproportionately affected people with mental health conditions. AIMS: We investigated the association between receiving psychotropic drugs, as an indicator of mental health conditions, and COVID-19 vaccine uptake. METHOD: We conducted a cross-sectional analysis of a prospective cohort of the Northern Ireland adult population using national linked primary care registration, vaccination, secondary care and pharmacy dispensing data. Univariable and multivariable logistic regression analyses investigated the association between anxiolytic, antidepressant, antipsychotic, and hypnotic use and COVID-19 vaccination status, accounting for age, gender, deprivation and comorbidities. Receiving any COVID-19 vaccine was the primary outcome. RESULTS: There were 1 433 814 individuals, of whom 1 166 917 received a COVID-19 vaccination. Psychotropic medications were dispensed to 267 049 people. In univariable analysis, people who received any psychotropic medication had greater odds of receiving COVID-19 vaccination: odds ratio (OR) = 1.42 (95% CI 1.41-1.44). However, after adjustment, psychotropic medication use was associated with reduced odds of vaccination (ORadj = 0.90, 95% CI 0.89-0.91). People who received anxiolytics (ORadj = 0.63, 95% CI 0.61-0.65), antipsychotics (ORadj = 0.75, 95% CI 0.73-0.78) and hypnotics (ORadj = 0.90, 95% CI 0.87-0.93) had reduced odds of being vaccinated. Antidepressant use was not associated with vaccination (ORadj = 1.02, 95% CI 1.00-1.03). CONCLUSIONS: We found significantly lower odds of vaccination in people who were receiving treatment with anxiolytic and antipsychotic medications. There is an urgent need for evidence-based, tailored vaccine support for people with mental health conditions.

COVID-19 vaccine uptake and effectiveness in adults aged 50 years and older in Wales UK: a 1.2m population data-linkage cohort approach.

Vaccination programs against COVID-19 vary globally with estimates of vaccine effectiveness (VE) affected by vaccine type, schedule, strain, outcome, and recipient characteristics. This study assessed VE of BNT162b2 and ChAdOx1 vaccines against PCR positive SARS-CoV-2 infection, hospital admission, and death among adults aged 50 years and older in Wales, UK during the period 7 December 2020 to 18 July 2021, when Alpha, followed by Delta, were the predominant variants. We used individual-level linked routinely collected data within the Secure Anonymized Information Linkage (SAIL) Databank. Data were available for 1,262,689 adults aged 50 years and over; coverage of one dose of any COVID-19 vaccine in this population was 92.6%, with coverage of two doses 90.4%. VE against PCR positive infection at 28-days or more post first dose of any COVID-19 vaccine was 16.0% (95%CI 9.6-22.0), and 42.0% (95%CI 36.5-47.1) seven or more days after a second dose. VE against hospital admission was higher at 72.9% (95%CI 63.6-79.8) 28 days or more post vaccination with one dose of any vaccine type, and 84.9% (95%CI 78.2-89.5) at 7 or more days post two doses. VE for one dose against death was estimated to be 80.9% (95%CI 72.1-86.9). VE against PCR positive infection and hospital admission was higher for BNT162b2 compared to ChAdOx1. In conclusion, vaccine uptake has been high among adults in Wales and VE estimates are encouraging, with two doses providing considerable protection against severe outcomes. Continued roll-out of the vaccination programme within Wales, and globally, is crucial in our fight against COVID-19.