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Emerging reports of rare neurological complications associated with COVID-19 infection and vaccinations are leading to regulatory, clinical and public health concerns. We undertook a self-controlled case series study to investigate hospital admissions from neurological complications in the 28 days after a first dose of ChAdOx1nCoV-19 ( n  = 20,417,752) or BNT162b2 ( n  = 12,134,782), and after a SARS-CoV-2-positive test ( n  = 2,005,280). There was an increased risk of Guillain–Barré syndrome (incidence rate ratio (IRR), 2.90; 95% confidence interval (CI): 2.15–3.92 at 15–21 days after vaccination) and Bell’s palsy (IRR, 1.29; 95% CI: 1.08–1.56 at 15–21 days) with ChAdOx1nCoV-19. There was an increased risk of hemorrhagic stroke (IRR, 1.38; 95% CI: 1.12–1.71 at 15–21 days) with BNT162b2. An independent Scottish cohort provided further support for the association between ChAdOx1nCoV and Guillain–Barré syndrome (IRR, 2.32; 95% CI: 1.08–5.02 at 1–28 days). There was a substantially higher risk of all neurological outcomes in the 28 days after a positive SARS-CoV-2 test including Guillain–Barré syndrome (IRR, 5.25; 95% CI: 3.00–9.18). Overall, we estimated 38 excess cases of Guillain–Barré syndrome per 10 million people receiving ChAdOx1nCoV-19 and 145 excess cases per 10 million people after a positive SARS-CoV-2 test. In summary, although we find an increased risk of neurological complications in those who received COVID-19 vaccines, the risk of these complications is greater following a positive SARS-CoV-2 test. A self-controlled case series analysis of nearly 32 million people in England shows an increased risk of rare neurological complications in those who received COVID-19 vaccines and following SARS-CoV-2 infection. The results highlight 38 excess cases of Guillain–Barré syndrome per 10 million ChAdOx1nCoV-19 vaccinations.

Reports of ChAdOx1 vaccine–associated thrombocytopenia and vascular adverse events have led to some countries restricting its use. Using a national prospective cohort, we estimated associations between exposure to first-dose ChAdOx1 or BNT162b2 vaccination and hematological and vascular adverse events using a nested incident-matched case-control study and a confirmatory self-controlled case series (SCCS) analysis. An association was found between ChAdOx1 vaccination and idiopathic thrombocytopenic purpura (ITP) (0–27 d after vaccination; adjusted rate ratio (aRR) = 5.77, 95% confidence interval (CI), 2.41–13.83), with an estimated incidence of 1.13 (0.62–1.63) cases per 100,000 doses. An SCCS analysis confirmed that this was unlikely due to bias (RR = 1.98 (1.29–3.02)). There was also an increased risk for arterial thromboembolic events (aRR = 1.22, 1.12–1.34) 0–27 d after vaccination, with an SCCS RR of 0.97 (0.93–1.02). For hemorrhagic events 0–27 d after vaccination, the aRR was 1.48 (1.12–1.96), with an SCCS RR of 0.95 (0.82–1.11). A first dose of ChAdOx1 was found to be associated with small increased risks of ITP, with suggestive evidence of an increased risk of arterial thromboembolic and hemorrhagic events. The attenuation of effect found in the SCCS analysis means that there is the potential for overestimation of the reported results, which might indicate the presence of some residual confounding or confounding by indication. Public health authorities should inform their jurisdictions of these relatively small increased risks associated with ChAdOx1. No positive associations were seen between BNT162b2 and thrombocytopenic, thromboembolic and hemorrhagic events. New data from the EAVE II cohort in Scotland suggests that a first dose of the ChAdOx1 nCoV-19 vaccine might be associated with a small increase in the risk of idiopathic thrombocytopenic purpura between 0 and 27 d after vaccination.

Amyotrophic lateral sclerosis shares characteristics with some cancers, such as onset being more common in later life, progression usually being rapid, the disease affecting a particular cell type, and showing complex inheritance. We used a model originally applied to cancer epidemiology to investigate the hypothesis that amyotrophic lateral sclerosis is a multistep process. We generated incidence data by age and sex from amyotrophic lateral sclerosis population registers in Ireland (registration dates 1995–2012), the Netherlands (2006–12), Italy (1995–2004), Scotland (1989–98), and England (2002–09), and calculated age and sex-adjusted incidences for each register. We regressed the log of age-specific incidence against the log of age with least squares regression. We did the analyses within each register, and also did a combined analysis, adjusting for register. We identified 6274 cases of amyotrophic lateral sclerosis from a catchment population of about 34 million people. We noted a linear relationship between log incidence and log age in all five registers: England r2=0·95, Ireland r2=0·99, Italy r2=0·95, the Netherlands r2=0·99, and Scotland r2=0·97; overall r2=0·99. All five registers gave similar estimates of the linear slope ranging from 4·5 to 5·1, with overlapping confidence intervals. The combination of all five registers gave an overall slope of 4·8 (95% CI 4·5–5·0), with similar estimates for men (4·6, 4·3–4·9) and women (5·0, 4·5–5·5). A linear relationship between the log incidence and log age of onset of amyotrophic lateral sclerosis is consistent with a multistage model of disease. The slope estimate suggests that amyotrophic lateral sclerosis is a six-step process. Identification of these steps could lead to preventive and therapeutic avenues. UK Medical Research Council; UK Economic and Social Research Council; Ireland Health Research Board; The Netherlands Organisation for Health Research and Development (ZonMw); the Ministry of Health and Ministry of Education, University, and Research in Italy; the Motor Neurone Disease Association of England, Wales, and Northern Ireland; and the European Commission (Seventh Framework Programme).

The benefit of CT coronary angiography (CTCA) in patients presenting with stable chest pain has not been systematically studied. We aimed to assess the effect of CTCA on the diagnosis, management, and outcome of patients referred to the cardiology clinic with suspected angina due to coronary heart disease. In this prospective open-label, parallel-group, multicentre trial, we recruited patients aged 18–75 years referred for the assessment of suspected angina due to coronary heart disease from 12 cardiology chest pain clinics across Scotland. We randomly assigned (1:1) participants to standard care plus CTCA or standard care alone. Randomisation was done with a web-based service to ensure allocation concealment. The primary endpoint was certainty of the diagnosis of angina secondary to coronary heart disease at 6 weeks. All analyses were intention to treat, and patients were analysed in the group they were allocated to, irrespective of compliance with scanning. This study is registered with ClinicalTrials.gov, number NCT01149590. Between Nov 18, 2010, and Sept 24, 2014, we randomly assigned 4146 (42%) of 9849 patients who had been referred for assessment of suspected angina due to coronary heart disease. 47% of participants had a baseline clinic diagnosis of coronary heart disease and 36% had angina due to coronary heart disease. At 6 weeks, CTCA reclassified the diagnosis of coronary heart disease in 558 (27%) patients and the diagnosis of angina due to coronary heart disease in 481 (23%) patients (standard care 22 [1%] and 23 [1%]; p<0·0001). Although both the certainty (relative risk [RR] 2·56, 95% CI 2·33–2·79; p<0·0001) and frequency of coronary heart disease increased (1·09, 1·02–1·17; p=0·0172), the certainty increased (1·79, 1·62–1·96; p<0·0001) and frequency seemed to decrease (0·93, 0·85–1·02; p=0·1289) for the diagnosis of angina due to coronary heart disease. This changed planned investigations (15% vs 1%; p<0·0001) and treatments (23% vs 5%; p<0·0001) but did not affect 6-week symptom severity or subsequent admittances to hospital for chest pain. After 1·7 years, CTCA was associated with a 38% reduction in fatal and non-fatal myocardial infarction (26 vs 42, HR 0·62, 95% CI 0·38–1·01; p=0·0527), but this was not significant. In patients with suspected angina due to coronary heart disease, CTCA clarifies the diagnosis, enables targeting of interventions, and might reduce the future risk of myocardial infarction. The Chief Scientist Office of the Scottish Government Health and Social Care Directorates funded the trial with supplementary awards from Edinburgh and Lothian's Health Foundation Trust and the Heart Diseases Research Fund.

Formerly incarcerated people have exceptionally poor health profiles and are at increased risk of preventable mortality when compared with their general population peers. However, not enough is known about the epidemiology of mortality in this population—specifically the rates, causes, and timing of death in specific subgroups and regions—to inform the development of targeted, evidence-based responses. We aimed to document the incidence, timing, causes, and risk factors for mortality after release from incarceration. We analysed linked administrative data from the multi-national Mortality After Release from Incarceration Consortium (MARIC) study. We examined mortality outcomes for 1 471 526 people released from incarceration in eight countries (Australia, Brazil, Canada, New Zealand, Norway, Scotland, Sweden, and the USA) from 1980 to 2018, across 10 534 441 person-years of follow-up (range 0–24 years per person). We combined data from 18 cohort studies using two-step individual participant data meta-analyses to estimate pooled all-cause and cause-specific crude mortality rates (CMRs) per 100 000 person-years, for specific time periods (first, daily from days 1–14; second, weekly from weeks 3–12; third, weeks 13–52 combined; fourth, weeks 53 and over combined; and fifth, total follow-up) after release, overall and stratified by age, sex, and region. 75 427 deaths were recorded. The all-cause CMR during the first week following release (1612 [95% CI 1048–2287]) was higher than during all other time periods (incidence rate ratio [IRR] compared with week 2: 1·5 [95% CI 1·2–1·8], I2=26·0%, weeks 3–4: 2·0 [1·5–2·6], I2=53·0%, and weeks 9–12: 2·2 [1·6–3·0], I2=70·5%). The highest cause-specific mortality rates during the first week were due to alcohol and other drug poisoning (CMR 657 [95% CI 332–1076]), suicide (135 [36–277]), and cardiovascular disease (71 [16–153]). We observed considerable variation in cause-specific CMRs over time since release and across regions. Pooled all-cause CMRs were similar between males (731 [95% CI 630–839]) and females (660 [560–767]) and were higher in older age groups. The markedly elevated rate of death in the first week post-release underscores an urgent need for investment in evidence-based, coordinated transitional healthcare, including treatment for mental illness and substance use disorders to prevent post-release deaths due to suicide and overdose. Temporal variations in rates and causes of death highlight the need for routine monitoring of post-release mortality. Australia's National Health and Medical Research Council.

The Cox regression analysis for time to hospital admission found that S gene-positive cases were associated with an increased risk of COVID-19 hospital admission: hazard ratio (HR) 1·85 (95% CI 1·39–2·47) when compared to S gene-negative cases, after adjusting for age, sex, deprivation, temporal trend, and comorbidities. The corresponding hazard ratio for risk of hospital admission for S gene-positive cases was 0·38 (95% CI 0·24–0·58), with an interaction test p value of 0·19, suggesting that there was no evidence of a differential vaccine effect on hospital admissions among those first testing positive (appendix p 4). Considering the whole population cohort (rather than just hospital cases), the test-negative analysis to estimate vaccine effectiveness in preventing RT-PCR-confirmed SARS-CoV-2 infection showed that, compared to those unvaccinated, at least 14 days after the second dose, BNT162b2 (Pfizer–BioNTech vaccine) offered very good protection: 92% (95% CI 90–93) S gene-negative, 79% (75–82) S gene-positive.

AbstractObjectiveTo assess the risk of hospital admission for coronavirus disease 2019 (covid-19) among patient facing and non-patient facing healthcare workers and their household members.DesignNationwide linkage cohort study.SettingScotland, UK, 1 March to 6 June 2020.ParticipantsHealthcare workers aged 18-65 years, their households, and other members of the general population.Main outcome measureAdmission to hospital with covid-19.ResultsThe cohort comprised 158 445 healthcare workers, most of them (90 733; 57.3%) being patient facing, and 229 905 household members. Of all hospital admissions for covid-19 in the working age population (18-65 year olds), 17.2% (360/2097) were in healthcare workers or their households. After adjustment for age, sex, ethnicity, socioeconomic deprivation, and comorbidity, the risk of admission due to covid-19 in non-patient facing healthcare workers and their households was similar to the risk in the general population (hazard ratio 0.81 (95% confidence interval 0.52 to 1.26) and 0.86 (0.49 to 1.51), respectively). In models adjusting for the same covariates, however, patient facing healthcare workers, compared with non-patient facing healthcare workers, were at higher risk (hazard ratio 3.30, 2.13 to 5.13), as were household members of patient facing healthcare workers (1.79, 1.10 to 2.91). After sub-division of patient facing healthcare workers into those who worked in “front door,” intensive care, and non-intensive care aerosol generating settings and other, those in front door roles were at higher risk (hazard ratio 2.09, 1.49 to 2.94). For most patient facing healthcare workers and their households, the estimated absolute risk of hospital admission with covid-19 was less than 0.5%, but it was 1% and above in older men with comorbidity.ConclusionsHealthcare workers and their households contributed a sixth of covid-19 cases admitted to hospital. Although the absolute risk of admission was low overall, patient facing healthcare workers and their household members had threefold and twofold increased risks of admission with covid-19.

Since its emergence in November, 2021, in southern Africa, the SARS-CoV-2 omicron variant of concern (VOC) has rapidly spread across the world. We aimed to investigate the severity of omicron and the extent to which booster vaccines are effective in preventing symptomatic infection. In this study, using the Scotland-wide Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) platform, we did a cohort analysis with a nested test-negative design incident case-control study covering the period Nov 1–Dec 19, 2021, to provide initial estimates of omicron severity and the effectiveness of vaccine boosters against symptomatic disease relative to 25 weeks or more after the second vaccine dose. Primary care data derived from 940 general practices across Scotland were linked to laboratory data and hospital admission data. We compared outcomes between infection with the delta VOC (defined as S-gene positive) and the omicron VOC (defined as S-gene negative). We assessed effectiveness against symptomatic SARS-CoV-2 infection, with infection confirmed through a positive RT-PCR. By Dec 19, 2021, there were 23 840 S-gene-negative cases in Scotland, which were predominantly among those aged 20–39 years (11 732 [49·2%]). The proportion of S-gene-negative cases that were possible reinfections was more than ten times that of S-gene-positive cases (7·6% vs 0·7%; p<0·0001). There were 15 hospital admissions in S-gene-negative individuals, giving an adjusted observed-to-expected admissions ratio of 0·32 (95% CI 0·19–0·52). The booster vaccine dose was associated with a 57% (54–60) reduction in the risk of symptomatic S-gene-negative infection relative to individuals who tested positive 25 weeks or more after the second vaccine dose. These early national data suggest that omicron is associated with a two-thirds reduction in the risk of COVID-19 hospitalisation compared with delta. Although offering the greatest protection against delta, the booster dose of vaccination offers substantial additional protection against the risk of symptomatic COVID-19 for omicron compared with 25 weeks or more after the second vaccine dose. Health Data Research UK, National Core Studies, Public Health Scotland, Scottish Government, UK Research and Innovation, and University of Edinburgh.

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

There is a growing concern about the mental health of children and young people (CYP) in the UK, with increasing demand for counselling services, admissions for self-harm and referrals to mental health services. We investigated whether there have been similar recent trends in selected mental health outcomes among CYP in national health surveys from England, Scotland and Wales. Data were analysed from 140 830 participants (4-24 years, stratified into 4-12, 13-15, 16-24 years) in 36 national surveys in England, Scotland and Wales, 1995-2014. Regression models were used to examine time trends in seven parent/self-reported variables: general health, any long-standing health condition, long-standing mental health condition; Warwick-Edinburgh Mental Wellbeing Score (WEMWBS), above-threshold Strengths and Difficulties Questionnaire Total (SDQT) score, SDQ Emotion (SDQE) score, General Health Questionnaire (GHQ) score. Across all participants aged 4-24, long-standing mental health conditions increased in England (0.8-4.8% over 19 years), Scotland (2.3-6.0%, 11 years) and Wales (2.6-4.1%, 7 years) (all p < 0.001). Among young children (4-12 years), the proportion reporting high SDQT and SDQE scores decreased significantly among both boys and girls in England [SDQE: odds ratio (OR) 0.97 (0.96-0.98), p < 0.001] and girls in Scotland [SDQE: OR 0.96 (0.93-0.99), p = 0.005]. The proportion with high SDQE scores (13-15 years) decreased in England [OR 0.98 (0.96-0.99), p = 0.006] but increased in Wales [OR 1.07 (1.03-1.10), p < 0.001]. The proportion with high GHQ scores decreased among English women (16-24 years) [OR 0.98 (0.98-0.99), p = 0.002]. Despite a striking increase in the reported prevalence of long-standing mental health conditions among UK CYP, there was relatively little change in questionnaire scores reflecting psychological distress and emotional well-being.