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We investigated thrombocytopenic, thromboembolic and hemorrhagic events following a second dose of ChAdOx1 and BNT162b2 using a self-controlled case series analysis. We used a national prospective cohort with 2.0 million(m) adults vaccinated with two doses of ChAdOx or 1.6 m with BNT162b2. The incidence rate ratio (IRR) for idiopathic thrombocytopenic purpura (ITP) 14–20 days post-ChAdOx1 second dose was 2.14, 95% confidence interval (CI) 0.90–5.08. The incidence of ITP post-second dose ChAdOx1 was 0.59 (0.37–0.89) per 100,000 doses. No evidence of an increased risk of CVST was found for the 0–27 day risk period (IRR 0.83, 95% CI 0.16 to 4.26). However, few (≤5) events arose within this risk period. It is perhaps noteworthy that these events all clustered in the 7–13 day period (IRR 4.06, 95% CI 0.94 to 17.51). No other associations were found for second dose ChAdOx1, or any association for second dose BNT162b2 vaccination. Second dose ChAdOx1 vaccination was associated with increased borderline risks of ITP and CVST events. However, these events were rare thus providing reassurance about the safety of these vaccines. Further analyses including more cases are required to determine more precisely the risk profile for ITP and CVST after a second dose of ChAdOx1 vaccine. Here, Simpson et al. analyze data from 3.6 million COVID-19 vaccine second doses (ChAdOx1 and BNT162b2) in Scotland for risk of thrombocytopenic, thromboembolic and hemorrhagic events. Borderline increased risks of immune thrombocytopenic purpura and cerebral venous sinus thrombosis were found for the ChAdOx1 vaccine. These events were rare and usually short-lived.

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.

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. 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. Between Dec 8, 2020, and Feb 28, 2022, 17 337 580 individuals completed their primary vaccine schedule and 14 698 030 individuals received a booster dose. Between Dec 20, 2021, and Feb 28, 2022, 59 510 (0·3%) 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]). 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. National Core Studies–Immunity, UK Research and Innovation (Medical Research Council), Health Data Research UK, the Scottish Government, and the University of Edinburgh.

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. 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. 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.

•90% vaccine uptake by 30 Sept 2021, but uptake in more deprived areas was lower.•BNT162b2 was 85% effective after 2 weeks from second dose and 52% from 22 weeks.•Equitable effectiveness of BNT162b2 after second dose. 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. 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. 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. 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.

Background: The use of informant rating scales in older adults at risk of dementia may assist with early detection and intervention strategies. This study aims to evaluate whether informants rate greater cognitive change in patients with mild cognitive impairment (MCI) compared to cognitively intact individuals, and to determine the relationship between informant ratings of cognitive change and neuropsychological performance. Methods: One hundred and nine health-seeking older adults underwent clinical and neuropsychological assessments, and informants completed the Cambridge Behavioral Inventory-Revised (CBI-R). Patients were rated according to MCI criteria, including amnestic and non-amnestic subtypes, or as being cognitively intact. CBI-R ratings were evaluated with respect to MCI diagnosis and neuropsychological performance. Results: Compared to cognitively intact individuals, informants rated patients with MCI as having significantly more change in overall functioning (p < 0.05) as well as in specific domains of memory and orientation (p < 0.01), everyday skills (p < 0.05), and motivation (p < 0.05), even after controlling for depressive symptom severity. In further analyses, the non-amnestic MCI subgroup only had more informant-rated mood changes compared to the amnestic subgroup. In relation to neuropsychological performance, informant ratings were related to poorer visual memory, verbal learning and memory, language, and psychomotor speed, with correlations ranging from –0.19 to –0.43 (p < 0.05). Conclusions: These findings indicate that informants are sensitive to subtle early cognitive change in individuals with MCI, and that their ratings are related to objectively measured neuropsychological performance. Thus, the CBI-R may be valuable in assisting early screening and intervention processes.

Electronic health care databases are widely used for epidemiological studies. However, they may contain inactive records of individuals no longer participating in the health care system. These inactive records create a methodological challenge as they systematically appear as unexposed with no recorded outcomes. Given the widespread health care system engagement during the COVID-19 pandemic, the English National Health Service (NHS), which hosts a national pandemic planning and research dataset with linkage to COVID-19 vaccination and emergency care data, makes it an ideal setting to identify the extent of overrepresentation due to inactive health care records and assess ways to mitigate them. The objective of this study is to report any differences between the general practitioner-registered adult population size based on health care records compared to census estimates for England and to apply methodology that could be used to correct for such differences. We compared the number of adult patients within the General Practice Extraction Service Data for Pandemic Planning and Research (GDPPR) with a valid general practitioner registration as of 1st October 2021, with estimates published by the Office for National Statistics (ONS) for the English population. We used an approach adapted from a weighting method to correct for non-response bias in surveys and down-weighted individuals with no evidence of recent activity in their records. There were 61,194,033 registered NHS patients (in the GDPPR) compared with 56,550,138 in the ONS census-based population. De-duplication on NHS number reduced the population to 57,876,641, including 46,835,968 adults, with the biggest overrepresented group aged 30-45 years. Of the 46,835,986, 1,121,954 (2.4%) individuals had their initial weights down-weighted due to non-engagement with the health care system since January 2019. The down-weighting removed most of the differences between NHS and ONS populations. There are notable differences in the adult population size as per GDPPR when compared to census estimates. While the overall population size in the GDPPR data was seen to be inflated when compared to ONS census estimates, this was differential with respect to sociodemographic variables. A weighting-based approach can be applied to correct for the inflated denominator. Not correcting for it in large health care datasets, including the English NHS data, could introduce selection bias in epidemiological studies.

Vaccination is the most effective form of prevention of seasonal influenza; the United Kingdom has a national influenza vaccination program to cover targeted population groups. Influenza vaccines are known to be associated with some common minor adverse events of interest (AEIs), but it is not known if the adjuvanted trivalent influenza vaccine (aTIV), first offered in the 2018/2019 season, would be associated with more AEIs than other types of vaccines. We aim to compare the incidence of AEIs associated with different types of seasonal influenza vaccines offered in the 2018/2019 season. We carried out a retrospective cohort study using computerized medical record data from the Royal College of General Practitioners Research and Surveillance Centre sentinel network database. We extracted data on vaccine exposure and consultations for European Medicines Agency-specified AEIs for the 2018/2019 influenza season. We used a self-controlled case series design; computed relative incidence (RI) of AEIs following vaccination; and compared the incidence of AEIs associated with aTIV, the quadrivalent influenza vaccine, and the live attenuated influenza vaccine. We also compared the incidence of AEIs for vaccinations that took place in a practice with those that took place elsewhere. A total of 1,024,160 individuals received a seasonal influenza vaccine, of which 165,723 individuals reported a total of 283,355 compatible symptoms in the 2018/2019 season. Most AEIs occurred within 7 days following vaccination, with a seasonal effect observed. Using aTIV as the reference group, the quadrivalent influenza vaccine was associated with a higher incidence of AEIs (RI 1.46, 95% CI 1.41-1.52), whereas the live attenuated influenza vaccine was associated with a lower incidence of AEIs (RI 0.79, 95% CI 0.73-0.83). No effect of vaccination setting on the incidence of AEIs was observed. Routine sentinel network data offer an opportunity to make comparisons between safety profiles of different vaccines. Evidence that supports the safety of newer types of vaccines may be reassuring for patients and could help improve uptake in the future.

Individuals with depression are often found to perform worse on cognitive tests and to have an increased risk of dementia. The causes and the direction of these associations are however not well understood. We looked at two specific hypotheses, the aetiological risk factor hypothesis and the reverse causality hypothesis. We analysed observational data from two cohorts, English Longitudinal Study of Ageing (ELSA) and Health and Retirement Study (HRS), using cross-lagged panel models with unit fixed effects. Each model was run once with depression and repeated with cognition as the dependent variable and the other variable as the main explanatory variable. All models were estimated separately for contemporaneous effects and lagged effects up to 8 years in the past. We contrasted the results with models making the random effects assumption. Evidence from the fixed effects models is mixed. We find no evidence for the reverse causality hypothesis in ELSA and HRS. While there is no evidence for the aetiological risk factors hypothesis in ELSA, results from HRS indicate some effects. Our findings suggest that current levels of cognitive function do not influence future levels of depression. Results in HRS provide some evidence that current levels of depressive symptoms influence future cognition.

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. 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). 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. 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. 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.