Uptake of COVID-19 vaccinations amongst 3,433,483 children and young people: meta-analysis of UK prospective cohorts.

SARS-CoV-2 infection in children and young people (CYP) can lead to life-threatening COVID-19, transmission within households and schools, and the development of long COVID. Using linked health and administrative data, we investigated vaccine uptake among 3,433,483 CYP aged 5-17 years across all UK nations between 4th August 2021 and 31st May 2022. We constructed national cohorts and undertook multi-state modelling and meta-analysis to identify associations between demographic variables and vaccine uptake. We found that uptake of the first COVID-19 vaccine among CYP was low across all four nations compared to other age groups and diminished with subsequent doses. Age and vaccination status of adults living in the same household were identified as important risk factors associated with vaccine uptake in CYP. For example, 5-11 year-olds were less likely to receive their first vaccine compared to 16-17 year-olds (adjusted Hazard Ratio [aHR]: 0.10 (95%CI: 0.06-0.19)), and CYP in unvaccinated households were less likely to receive their first vaccine compared to CYP in partially vaccinated households (aHR: 0.19, 95%CI 0.13-0.29).

Clustering long-term health conditions among 67728 people with multimorbidity using electronic health records in Scotland.

There is still limited understanding of how chronic conditions co-occur in patients with multimorbidity and what are the consequences for patients and the health care system. Most reported clusters of conditions have not considered the demographic characteristics of these patients during the clustering process. The study used data for all registered patients that were resident in Fife or Tayside, Scotland and aged 25 years or more on 1st January 2000 and who were followed up until 31st December 2018. We used linked demographic information, and secondary care electronic health records from 1st January 2000. Individuals with at least two of the 31 Elixhauser Comorbidity Index conditions were identified as having multimorbidity. Market basket analysis was used to cluster the conditions for the whole population and then repeatedly stratified by age, sex and deprivation. 318,235 individuals were included in the analysis, with 67,728 (21·3%) having multimorbidity. We identified five distinct clusters of conditions in the population with multimorbidity: alcohol misuse, cancer, obesity, renal failure, and heart failure. Clusters of long-term conditions differed by age, sex and socioeconomic deprivation, with some clusters not present for specific strata and others including additional conditions. These findings highlight the importance of considering demographic factors during both clustering analysis and intervention planning for individuals with multiple long-term conditions. By taking these factors into account, the healthcare system may be better equipped to develop tailored interventions that address the needs of complex patients.

Adverse events after first and second doses of COVID-19 vaccination in England: a national vaccine surveillance platform self-controlled case series study.

OBJECTIVES: To estimate the incidence of adverse events of interest (AEIs) after receiving their first and second doses of coronavirus disease 2019 (COVID-19) vaccinations, and to report the safety profile differences between the different COVID-19 vaccines. DESIGN: We used a self-controlled case series design to estimate the relative incidence (RI) of AEIs reported to the Oxford-Royal College of General Practitioners national sentinel network. We compared the AEIs that occurred seven days before and after receiving the COVID-19 vaccinations to background levels between 1 October 2020 and 12 September 2021. SETTING: England, UK. PARTICIPANTS: Individuals experiencing AEIs after receiving first and second doses of COVID-19 vaccines. MAIN OUTCOME MEASURES: AEIs determined based on events reported in clinical trials and in primary care during post-license surveillance. RESULTS: A total of 7,952,861 individuals were vaccinated with COVID-19 vaccines within the study period. Among them, 781,200 individuals (9.82%) presented to general practice with 1,482,273 AEIs. Within the first seven days post-vaccination, 4.85% of all the AEIs were reported. There was a 3-7% decrease in the overall RI of AEIs in the seven days after receiving both doses of Pfizer-BioNTech BNT162b2 (RI = 0.93; 95% CI: 0.91-0.94) and 0.96; 95% CI: 0.94-0.98), respectively) and Oxford-AstraZeneca ChAdOx1 (RI = 0.97; 95% CI: 0.95-0.98) for both doses), but a 20% increase after receiving the first dose of Moderna mRNA-1273 (RI = 1.20; 95% CI: 1.00-1.44)). CONCLUSIONS: COVID-19 vaccines are associated with a small decrease in the incidence of medically attended AEIs. Sentinel networks could routinely report common AEI rates, which could contribute to reporting vaccine safety.

Individual participant data from digital sources informed and improved precision in the evaluation of predictive biomarkers in Bayesian network meta-analysis.

OBJECTIVES: We aimed to develop a network meta-analytic model for the evaluation of treatment effectiveness within predictive biomarker subgroups, by combining evidence from individual participant data (IPD) from digital sources (in the absence of randomized controlled trials) and aggregate data (AD). STUDY DESIGN AND SETTING: A Bayesian framework was developed for modeling time-to-event data to evaluate predictive biomarkers. IPD were sourced from electronic health records, using a target trial emulation approach, or digitized Kaplan-Meier curves. The model is illustrated using two examples: breast cancer with a hormone receptor biomarker, and metastatic colorectal cancer with the Kirsten Rat Sarcoma (KRAS) biomarker. RESULTS: The model allowed for the estimation of treatment effects in two subgroups of patients defined by their biomarker status. Effectiveness of taxanes did not differ in hormone receptor positive and negative breast cancer patients. Epidermal growth factor receptor inhibitors were more effective than chemotherapy in KRAS wild type colorectal cancer patients but not in patients with KRAS mutant status. Use of IPD reduced uncertainty of the subgroup-specific treatment effect estimates by up to 49%. CONCLUSION: Utilization of IPD allowed for more detailed evaluation of predictive biomarkers and cancer therapies and improved precision of the estimates compared to use of AD alone.

Multidisciplinary ecosystem to study lifecourse determinants and prevention of early-onset burdensome multimorbidity (MELD-B) - protocol for a research collaboration.

Background: Most people living with multiple long-term condition multimorbidity (MLTC-M) are under 65 (defined as 'early onset'). Earlier and greater accrual of long-term conditions (LTCs) may be influenced by the timing and nature of exposure to key risk factors, wider determinants or other LTCs at different life stages. We have established a research collaboration titled 'MELD-B' to understand how wider determinants, sentinel conditions (the first LTC in the lifecourse) and LTC accrual sequence affect risk of early-onset, burdensome MLTC-M, and to inform prevention interventions. Aim: Our aim is to identify critical periods in the lifecourse for prevention of early-onset, burdensome MLTC-M, identified through the analysis of birth cohorts and electronic health records, including artificial intelligence (AI)-enhanced analyses. Design: We will develop deeper understanding of 'burdensomeness' and 'complexity' through a qualitative evidence synthesis and a consensus study. Using safe data environments for analyses across large, representative routine healthcare datasets and birth cohorts, we will apply AI methods to identify early-onset, burdensome MLTC-M clusters and sentinel conditions, develop semi-supervised learning to match individuals across datasets, identify determinants of burdensome clusters, and model trajectories of LTC and burden accrual. We will characterise early-life (under 18 years) risk factors for early-onset, burdensome MLTC-M and sentinel conditions. Finally, using AI and causal inference modelling, we will model potential 'preventable moments', defined as time periods in the life course where there is an opportunity for intervention on risk factors and early determinants to prevent the development of MLTC-M. Patient and public involvement is integrated throughout.

Effect on life expectancy of temporal sequence in a multimorbidity cluster of psychosis, diabetes, and congestive heart failure among 1·7 million individuals in Wales with 20-year follow-up: a retrospective cohort study using linked data.

BACKGROUND: To inform targeted public health strategies, it is crucial to understand how coexisting diseases develop over time and their associated impacts on patient outcomes and health-care resources. This study aimed to examine how psychosis, diabetes, and congestive heart failure, in a cluster of physical-mental health multimorbidity, develop and coexist over time, and to assess the associated effects of different temporal sequences of these diseases on life expectancy in Wales. METHODS: In this retrospective cohort study, we used population-scale, individual-level, anonymised, linked, demographic, administrative, and electronic health record data from the Wales Multimorbidity e-Cohort. We included data on all individuals aged 25 years and older who were living in Wales on Jan 1, 2000 (the start of follow-up), with follow-up continuing until Dec 31, 2019, first break in Welsh residency, or death. Multistate models were applied to these data to model trajectories of disease in multimorbidity and their associated effect on all-cause mortality, accounting for competing risks. Life expectancy was calculated as the restricted mean survival time (bound by the maximum follow-up of 20 years) for each of the transitions from the health states to death. Cox regression models were used to estimate baseline hazards for transitions between health states, adjusted for sex, age, and area-level deprivation (Welsh Index of Multiple Deprivation [WIMD] quintile). FINDINGS: Our analyses included data for 1 675 585 individuals (811 393 [48·4%] men and 864 192 [51·6%] women) with a median age of 51·0 years (IQR 37·0-65·0) at cohort entry. The order of disease acquisition in cases of multimorbidity had an important and complex association with patient life expectancy. Individuals who developed diabetes, psychosis, and congestive heart failure, in that order (DPC), had reduced life expectancy compared with people who developed the same three conditions in a different order: for a 50-year-old man in the third quintile of the WIMD (on which we based our main analyses to allow comparability), DPC was associated with a loss in life expectancy of 13·23 years (SD 0·80) compared with the general otherwise healthy or otherwise diseased population. Congestive heart failure as a single condition was associated with mean a loss in life expectancy of 12·38 years (0·00), and with a loss of 12·95 years (0·06) when preceded by psychosis and 13·45 years (0·13) when followed by psychosis. Findings were robust in people of older ages, more deprived populations, and women, except that the trajectory of psychosis, congestive heart failure, and diabetes was associated with higher mortality in women than men. Within 5 years of an initial diagnosis of diabetes, the risk of developing psychosis or congestive heart failure, or both, was increased. INTERPRETATION: The order in which individuals develop psychosis, diabetes, and congestive heart failure as combinations of conditions can substantially affect life expectancy. Multistate models offer a flexible framework to assess temporal sequences of diseases and allow identification of periods of increased risk of developing subsequent conditions and death. FUNDING: Health Data Research UK.

Maternal Mental Health and Children's Problem Behaviours: A Bi-directional Relationship?

Transactional theory and the coercive family process model have illustrated how the parent-child relationship is reciprocal. Emerging research using advanced statistical methods has examined these theories, but further investigations are necessary. In this study, we utilised linked health data on maternal mental health disorders and explored their relationship with child problem behaviours via the Strengths and Difficulties Questionnaire for over 13 years. We accessed data from the Millennium Cohort Study, linked to anonymised individual-level population-scale health and administrative data within the Secure Anonymised Information Linkage (SAIL) Databank. We used Bayesian Structural Equation Modelling, specifically Random-Intercept Cross-Lagged Panel Models, to analyse the relationships between mothers and their children. We then explored these models with the addition of time-invariant covariates. We found that a mother's mental health was strongly associated over time, as were children's problem behaviours. We found mixed evidence for bi-directional relationships, with only emotional problems showing bi-directional associations in mid to late childhood. Only child-to-mother pathways were identified for the overall problem behaviour score and peer problems; no associations were found for conduct problems or hyperactivity. All models had strong between-effects and clear socioeconomic and sex differences. We encourage the use of whole family-based support for mental health and problem behaviours, and recommend that socioeconomic, sex and wider differences should be considered as factors in tailoring family-based interventions and support.

Trajectories in chronic disease accrual and mortality across the lifespan in Wales, UK (2005-2019), by area deprivation profile: linked electronic health records cohort study on 965,905 individuals.

Background: Understanding and quantifying the differences in disease development in different socioeconomic groups of people across the lifespan is important for planning healthcare and preventive services. The study aimed to measure chronic disease accrual, and examine the differences in time to individual morbidities, multimorbidity, and mortality between socioeconomic groups in Wales, UK. Methods: Population-wide electronic linked cohort study, following Welsh residents for up to 20 years (2000-2019). Chronic disease diagnoses were obtained from general practice and hospitalisation records using the CALIBER disease phenotype register. Multi-state models were used to examine trajectories of accrual of 132 diseases and mortality, adjusted for sex, age and area-level deprivation. Restricted mean survival time was calculated to measure time spent free of chronic disease(s) or mortality between socioeconomic groups. Findings: In total, 965,905 individuals aged 5-104 were included, from a possible 2.9 m individuals following a 5-year clearance period, with an average follow-up of 13.2 years (12.7 million person-years). Some 673,189 (69.7%) individuals developed at least one chronic disease or died within the study period. From ages 10 years upwards, the individuals living in the most deprived areas consistently experienced reduced time between health states, demonstrating accelerated transitions to first and subsequent morbidities and death compared to their demographic equivalent living in the least deprived areas. The largest difference were observed in 10 and 20 year old males developing multimorbidity (-0.45 years (99% CI: -0.45, -0.44)) and in 70 year old males dying after developing multimorbidity (-1.98 years (99% CI: -2.01, -1.95)). Interpretation: This study adds to the existing literature on health inequalities by demonstrating that individuals living in more deprived areas consistently experience accelerated time to diagnosis of chronic disease and death across all ages, accounting for competing risks. Funding: UK Medical Research Council, Health Data Research UK, and Administrative Data Research Wales.

Trends in SARS-CoV-2 infection and vaccination in school staff, students and their household members from 2020 to 2022 in Wales, UK: an electronic cohort study.

OBJECTIVES: We investigated SARS-CoV-2 infection trends, risk of SARS-CoV-2 infection and COVID-19 vaccination uptake among school staff, students and their household members in Wales, UK. DESIGN: Seven-day average of SARS-CoV-2 infections and polymerase chain reaction tests per 1000 people daily, cumulative incidence of COVID-19 vaccination uptake and multi-level Poisson models with time-varying covariates. SETTING: National electronic cohort between September 2020 and May 2022 when several variants were predominant in the UK (Alpha, Delta and Omicron). PARTICIPANTS: School students aged 4 to 10/11 years (primary school and younger middle school, n = 238,163), and 11 to 15/16 years (secondary school and older middle school, n = 182,775), school staff in Wales (n = 47,963) and the household members of students and staff (n = 697,659). MAIN OUTCOME MEASURES: SARS-CoV-2 infection and COVID-19 vaccination uptake. RESULTS: School students had a sustained period of high infection rates compared with household members after August 2021. Primary schedule vaccination uptake was highest among staff (96.3%) but lower for household members (72.2%), secondary and older middle school students (59.8%), and primary and younger middle school students (3.3%). Multi-level Poisson models showed that vaccination was associated with a lower risk of SARS-CoV-2 infection. The Delta variant posed a greater infection risk for students than the Alpha variant. However, Omicron was a larger risk for staff and household members. CONCLUSIONS: Public health bodies should be informed of the protection COVID-19 vaccines afford, with more research being required for younger populations. Furthermore, schools require additional support in managing new, highly transmissible variants. Further research should examine the mechanisms between child deprivation and SARS-CoV-2 infection.

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.

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.

The Hospital Frailty Risk Score (HFRS) applied to primary data: protocol for a systematic review.

INTRODUCTION: Frailty is characterised by vulnerability to adverse health outcomes and increases with age. Many frailty risk scores have been developed. One important example is the Hospital Frailty Risk Score (HFRS) which has the potential to be widely used and automatically calculated which will provide accurate assessment of frailty in a time/cost-effective manner. This systematic review, therefore, seeks to describe the HFRS use since its publication in 2018. METHODS AND ANALYSIS: The proposed systematic review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We will include published original peer-reviewed articles, preprints, conference proceedings and letters to the editor reporting primary data where there is an English language abstract available from 1 January 2018 to 30 June 2022. Databases to be searched are MEDLINE, EMBASE and Web of Science. Additional studies from, for example, the reference of the included studies will be identified and assessed for potential inclusion. Two independent reviewers will perform and assess the following: (1) eligibility of the included studies, (2) critical appraisal using the Cochrane Risk of Bias in Non-randomized Studies of Interventions tool, and (3) data extraction using a predefined form. Disagreements will be resolved through discussions or by involvement of a third reviewer. It may be possible to undertake a meta-analysis if there are sufficient studies reporting effect measures in homogenous populations and/or settings. Effect sizes will be calculated using meta-analysis methods and expressed as risk ratios or ORs with 95% CIs. ETHICS AND DISSEMINATION: No ethical approval is required for this systematic review as it will use secondary data only. The results of the systematic review will be submitted for publication in recognised peer-reviewed journals related to frailty and geriatric care and will be widely disseminated through conferences, congresses, seminars, symposia and scientific meetings.

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.

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.

First dose ChAdOx1 and BNT162b2 COVID-19 vaccinations and cerebral venous sinus thrombosis: A pooled self-controlled case series study of 11.6 million individuals in England, Scotland, and Wales.

BACKGROUND: Several countries restricted the administration of ChAdOx1 to older age groups in 2021 over safety concerns following case reports and observed versus expected analyses suggesting a possible association with cerebral venous sinus thrombosis (CVST). Large datasets are required to precisely estimate the association between Coronavirus Disease 2019 (COVID-19) vaccination and CVST due to the extreme rarity of this event. We aimed to accomplish this by combining national data from England, Scotland, and Wales. METHODS AND FINDINGS: We created data platforms consisting of linked primary care, secondary care, mortality, and virological testing data in each of England, Scotland, and Wales, with a combined cohort of 11,637,157 people and 6,808,293 person years of follow-up. The cohort start date was December 8, 2020, and the end date was June 30, 2021. The outcome measure we examined was incident CVST events recorded in either primary or secondary care records. We carried out a self-controlled case series (SCCS) analysis of this outcome following first dose vaccination with ChAdOx1 and BNT162b2. The observation period consisted of an initial 90-day reference period, followed by a 2-week prerisk period directly prior to vaccination, and a 4-week risk period following vaccination. Counts of CVST cases from each country were tallied, then expanded into a full dataset with 1 row for each individual and observation time period. There was a combined total of 201 incident CVST events in the cohorts (29.5 per million person years). There were 81 CVST events in the observation period among those who a received first dose of ChAdOx1 (approximately 16.34 per million doses) and 40 for those who received a first dose of BNT162b2 (approximately 12.60 per million doses). We fitted conditional Poisson models to estimate incidence rate ratios (IRRs). Vaccination with ChAdOx1 was associated with an elevated risk of incident CVST events in the 28 days following vaccination, IRR = 1.93 (95% confidence interval (CI) 1.20 to 3.11). We did not find an association between BNT162b2 and CVST in the 28 days following vaccination, IRR = 0.78 (95% CI 0.34 to 1.77). Our study had some limitations. The SCCS study design implicitly controls for variables that are constant over the observation period, but also assumes that outcome events are independent of exposure. This assumption may not be satisfied in the case of CVST, firstly because it is a serious adverse event, and secondly because the vaccination programme in the United Kingdom prioritised the clinically extremely vulnerable and those with underlying health conditions, which may have caused a selection effect for individuals more prone to CVST. Although we pooled data from several large datasets, there was still a low number of events, which may have caused imprecision in our estimates. CONCLUSIONS: In this study, we observed a small elevated risk of CVST events following vaccination with ChAdOx1, but not BNT162b2. Our analysis pooled information from large datasets from England, Scotland, and Wales. This evidence may be useful in risk-benefit analyses of vaccine policies and in providing quantification of risks associated with vaccination to the general public.

COVID-19 vaccine uptake, effectiveness, and waning in 82,959 health care workers: A national prospective cohort study in Wales.

BACKGROUND: While population estimates suggest high vaccine effectiveness against SARS-CoV-2 infection, the protection for health care workers, who are at higher risk of SARS-CoV-2 exposure, is less understood. METHODS: We conducted a national cohort study of health care workers in Wales (UK) from 7 December 2020 to 30 September 2021. We examined uptake of any COVID-19 vaccine, and the effectiveness of BNT162b2 mRNA (Pfizer-BioNTech) against polymerase chain reaction (PCR) confirmed SARS-CoV-2 infection. We used linked and routinely collected national-scale data within the SAIL Databank. Data were available on 82,959 health care workers in Wales, with exposure extending to 26 weeks after second doses. RESULTS: Overall vaccine uptake was high (90%), with most health care workers receiving theBNT162b2 vaccine (79%). Vaccine uptake differed by age, staff role, socioeconomic status; those aged 50-59 and 60+ years old were 1.6 times more likely to get vaccinated than those aged 16-29. Medical and dental staff, and Allied Health Practitioners were 1.5 and 1.1 times more likely to get vaccinated, compared to nursing and midwifery staff. The effectiveness of the BNT162b2 vaccine was found to be strong and consistent across the characteristics considered; 52% three to six weeks after first dose, 86% from two weeks after second dose, though this declined to 53% from 22 weeks after the second dose. CONCLUSIONS: With some variation in rate of uptake, those who were vaccinated had a reduced risk of PCR-confirmed SARS-CoV-2 infection, compared to those unvaccinated. Second dose has provided stronger protection for longer than first dose but our study is consistent with waning from seven weeks onwards.

Comparing associations between frailty and mortality in hospitalised older adults with or without COVID-19 infection: a retrospective observational study using electronic health records.

BACKGROUND: The aim of this study was to describe outcomes in hospitalised older people with different levels of frailty and COVID-19 infection. METHODS: We undertook a single-centre, retrospective cohort study examining COVID-19-related mortality using electronic health records, for older people (65 and over) with frailty, hospitalised with or without COVID-19 infection. Baseline covariates included demographics, early warning scores, Charlson Comorbidity Indices and frailty (Clinical Frailty Scale, CFS), linked to COVID-19 status. FINDINGS: We analysed outcomes on 1,071 patients with COVID-19 test results (285 (27%) were positive for COVID-19). The mean age at ED arrival was 79.7 and 49.4% were female. All-cause mortality (by 30 days) rose from 9 (not frail) to 33% (severely frail) in the COVID-negative cohort but was around 60% for all frailty categories in the COVID-positive cohort. In adjusted analyses, the hazard ratio for death in those with COVID-19 compared to those without COVID-19 was 7.3 (95% CI: 3.00, 18.0) with age, comorbidities and illness severity making small additional contributions. INTERPRETATION: In this study, frailty measured using the CFS appeared to make little incremental contribution to the hazard of dying in older people hospitalised with COVID-19 infection; illness severity and comorbidity had a modest association with the overall adjusted hazard of death, whereas confirmed COVID-19 infection dominated, with a sevenfold hazard for death.

Multivariate network meta-analysis incorporating class effects.

BACKGROUND: Network meta-analysis synthesises data from a number of clinical trials in order to assess the comparative efficacy of multiple healthcare interventions in similar patient populations. In situations where clinical trial data are heterogeneously reported i.e. data are missing for one or more outcomes of interest, synthesising such data can lead to disconnected networks of evidence, increased uncertainty, and potentially biased estimates which can have severe implications for decision-making. To overcome this issue, strength can be borrowed between outcomes of interest in multivariate network meta-analyses. Furthermore, in situations where there are relatively few trials informing each treatment comparison, there is a potential issue with the sparsity of data in the treatment networks, which can lead to substantial parameter uncertainty. A multivariate network meta-analysis approach can be further extended to borrow strength between interventions of the same class using hierarchical models. METHODS: We extend the trivariate network meta-analysis model to incorporate the exchangeability between treatment effects belonging to the same class of intervention to increase precision in treatment effect estimates. We further incorporate a missing data framework to estimate uncertainty in trials that did not report measures of variability in order to maximise the use of all available information for healthcare decision-making. The methods are applied to a motivating dataset in overactive bladder syndrome. The outcomes of interest were mean change from baseline in incontinence, voiding and urgency episodes. All models were fitted using Bayesian Markov Chain Monte Carlo (MCMC) methods in WinBUGS. RESULTS: All models (univariate, multivariate, and multivariate models incorporating class effects) produced similar point estimates for all treatment effects. Incorporating class effects in multivariate models often increased precision in treatment effect estimates. CONCLUSIONS: Multivariate network meta-analysis incorporating class effects allowed for the comparison of all interventions across all outcome measures to ameliorate the potential impact of outcome reporting bias, and further borrowed strength between interventions belonging to the same class of treatment to increase the precision in treatment effect estimates for healthcare policy and decision-making.