Safety outcomes following COVID-19 vaccination and infection in 5.1 million children in England.

The risk-benefit profile of COVID-19 vaccination in children remains uncertain. A self-controlled case-series study was conducted using linked data of 5.1 million children in England to compare risks of hospitalisation from vaccine safety outcomes after COVID-19 vaccination and infection. In 5-11-year-olds, we found no increased risks of adverse events 1-42 days following vaccination with BNT162b2, mRNA-1273 or ChAdOX1. In 12-17-year-olds, we estimated 3 (95%CI 0-5) and 5 (95%CI 3-6) additional cases of myocarditis per million following a first and second dose with BNT162b2, respectively. An additional 12 (95%CI 0-23) hospitalisations with epilepsy and 4 (95%CI 0-6) with demyelinating disease (in females only, mainly optic neuritis) were estimated per million following a second dose with BNT162b2. SARS-CoV-2 infection was associated with increased risks of hospitalisation from seven outcomes including multisystem inflammatory syndrome and myocarditis, but these risks were largely absent in those vaccinated prior to infection. We report a favourable safety profile of COVID-19 vaccination in under-18s.

Predicting the risk of pancreatic cancer in adults with new-onset diabetes: development and internal-external validation of a clinical risk prediction model.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) recommends that people aged 60+ years with newly diagnosed diabetes and weight loss undergo abdominal imaging to assess for pancreatic cancer. More nuanced stratification could lead to enrichment of these referral pathways. METHODS: Population-based cohort study of adults aged 30-85 years at type 2 diabetes diagnosis (2010-2021) using the QResearch primary care database in England linked to secondary care data, the national cancer registry and mortality registers. Clinical prediction models were developed to estimate risks of pancreatic cancer diagnosis within 2 years and evaluated using internal-external cross-validation. RESULTS: Seven hundred and sixty-seven of 253,766 individuals were diagnosed with pancreatic cancer within 2 years. Models included age, sex, BMI, prior venous thromboembolism, digoxin prescription, HbA1c, ALT, creatinine, haemoglobin, platelet count; and the presence of abdominal pain, weight loss, jaundice, heartburn, indigestion or nausea (previous 6 months). The Cox model had the highest discrimination (Harrell's C-index 0.802 (95% CI: 0.797-0.817)), the highest clinical utility, and was well calibrated. The model's highest 1% of predicted risks captured 12.51% of pancreatic cancer cases. NICE guidance had 3.95% sensitivity. DISCUSSION: A new prediction model could have clinical utility in identifying individuals with recent onset diabetes suitable for fast-track abdominal imaging.

Effectiveness and safety of COVID-19 vaccination in people with blood cancer.

BACKGROUND: People with blood cancer have increased risk of severe COVID-19 outcomes and poor response to vaccination. We assessed the safety and effectiveness of COVID-19 vaccines in this vulnerable group compared to the general population. METHODS: Individuals aged ≥12 years as of 1st December 2020 in the QResearch primary care database were included. We assessed adjusted COVID-19 vaccine effectiveness (aVE) against COVID-19-related hospitalisation and death in people with blood cancer using a nested matched case-control study. Using the self-controlled case series methodology, we compared the risk of 56 pre-specified adverse events within 1-28 days of a first, second or third COVID-19 vaccine dose in people with and without blood cancer. FINDINGS: The cohort comprised 12,274,948 individuals, of whom 81,793 had blood cancer. COVID-19 vaccines were protective against COVID-19-related hospitalisation and death in people with blood cancer, although they were less effective, particularly against COVID-19-related hospitalisation, compared to the general population. In the blood cancer population, aVE against COVID-19-related hospitalisation was 64% (95% confidence interval [CI] 48%-75%) 14-41 days after a third dose, compared to 80% (95% CI 78%-81%) in the general population. Against COVID-19-related mortality, aVE was >80% in people with blood cancer 14-41 days after a second or third dose. We found no significant difference in risk of adverse events 1-28 days after any vaccine dose between people with and without blood cancer. INTERPRETATION: Our study provides robust evidence which supports the use of COVID-19 vaccinations for people with blood cancer.

Uptake of COVID-19 vaccination in people with blood cancer: Population-level cohort study of 12 million patients in England.

BACKGROUND: People with blood cancers have increased risk of severe outcomes from COVID-19 and were prioritised for vaccination. METHODS: Individuals in the QResearch database aged 12 years and above on 1st December 2020 were included in the analysis. Kaplan-Meier analysis described time to COVID-19 vaccine uptake in people with blood cancer and other high-risk disorders. Cox regression was used to identify factors associated with vaccine uptake in people with blood cancer. RESULTS: The analysis included 12,274,948 individuals, of whom 97,707 had a blood cancer diagnosis. 92% of people with blood cancer received at least one dose of vaccine, compared to 80% of the general population, but there was lower uptake of each subsequent vaccine dose (31% for fourth dose). Vaccine uptake decreased with social deprivation (HR 0.72, 95% CI 0.70, 0.74 for most deprived versus most affluent quintile for first vaccine). Compared with White groups, uptake of all vaccine doses was significantly lower in people of Pakistani and Black ethnicity, and more people in these groups remain unvaccinated. CONCLUSIONS: COVID-19 vaccine uptake declines following second dose and there are ethnic and social disparities in uptake in blood cancer populations. Enhanced communication of benefits of vaccination to these groups is needed.

Factors influencing influenza, pneumococcal and shingles vaccine uptake and refusal in older adults: a population-based cross-sectional study in England.

OBJECTIVES: Uptake of influenza, pneumococcal and shingles vaccines in older adults vary across regions and socioeconomic backgrounds. In this study, we study the coverage and factors associated with vaccination uptake, as well as refusal in the unvaccinated population and their associations with ethnicity, deprivation, household size and health conditions. DESIGN, SETTING AND PARTICIPANTS: This is a cross-sectional study of adults aged 65 years or older in England, using a large primary care database. Associations of vaccine uptake and refusal in the unvaccinated with ethnicity, deprivation, household size and health conditions were modelled using multivariable logistic regression. OUTCOME MEASURE: Influenza, pneumococcal and shingles vaccine uptake and refusal (in the unvaccinated). RESULTS: This study included 2 054 463 patients from 1318 general practices. 1 711 465 (83.3%) received at least one influenza vaccine, 1 391 228 (67.7%) pneumococcal vaccine and 690 783 (53.4%) shingles vaccine. Compared with White ethnicity, influenza vaccine uptake was lower in Chinese (OR 0.49; 95% CI 0.45 to 0.53), 'Other ethnic' groups (0.63; 95% CI 0.60 to 0.65), black Caribbean (0.68; 95% CI 0.64 to 0.71) and black African (0.72; 95% CI 0.68 to 0.77). There was generally lower vaccination uptake among more deprived individuals, people living in larger household sizes (three or more persons) and those with fewer health conditions. Among those who were unvaccinated, higher odds of refusal were associated with the black Caribbean ethnic group and marginally with increased deprivation, but not associated with higher refusal in those living in large households or those with lesser health conditions. CONCLUSION: Certain ethnic minority groups, deprived populations, large households and 'healthier' individuals were less likely to receive a vaccine, although higher refusal was only associated with ethnicity and deprivation but not larger households nor healthier individuals. Understanding these may inform tailored public health messaging to different communities for equitable implementation of vaccination programmes.

Ethnic disparities in COVID-19 outcomes: a multinational cohort study of 20 million individuals from England and Canada.

BACKGROUND: Heterogeneous studies have demonstrated ethnic inequalities in the risk of SARS-CoV-2 infection and adverse COVID-19 outcomes. This study evaluates the association between ethnicity and COVID-19 outcomes in two large population-based cohorts from England and Canada and investigates potential explanatory factors for ethnic patterning of severe outcomes. METHODS: We identified adults aged 18 to 99 years in the QResearch primary care (England) and Ontario (Canada) healthcare administrative population-based datasets (start of follow-up: 24th and 25th Jan 2020 in England and Canada, respectively; end of follow-up: 31st Oct and 30th Sept 2020, respectively). We harmonised the definitions and the design of two cohorts to investigate associations between ethnicity and COVID-19-related death, hospitalisation, and intensive care (ICU) admission, adjusted for confounders, and combined the estimates obtained from survival analyses. We calculated the 'percentage of excess risk mediated' by these risk factors in the QResearch cohort. RESULTS: There were 9.83 million adults in the QResearch cohort (11,597 deaths; 21,917 hospitalisations; 2932 ICU admissions) and 10.27 million adults in the Ontario cohort (951 deaths; 5132 hospitalisations; 1191 ICU admissions). Compared to the general population, pooled random-effects estimates showed that South Asian ethnicity was associated with an increased risk of COVID-19 death (hazard ratio: 1.63, 95% CI: 1.09-2.44), hospitalisation (1.53; 1.32-1.76), and ICU admission (1.67; 1.23-2.28). Associations with ethnic groups were consistent across levels of deprivation. In QResearch, sociodemographic, lifestyle, and clinical factors accounted for 42.9% (South Asian) and 39.4% (Black) of the excess risk of COVID-19 death. CONCLUSION: International population-level analyses demonstrate clear ethnic inequalities in COVID-19 risks. Policymakers should be cognisant of the increased risks in some ethnic populations and design equitable health policy as the pandemic continues.

Exploring the interface between adolescent dysmenorrhoea and endometriosis: a protocol for a cohort and nested case-control study within the QResearch Database.

INTRODUCTION: Dysmenorrhoea affects up to 70%-91% of adolescents who menstruate, with approximately one-third experiencing severe symptoms with impacts on education, work and leisure. Dysmenorrhoea can occur without identifiable pathology, but can indicate underlying conditions, including congenital genital tract anomalies or endometriosis. There is a need for evidence about the management and incidence of dysmenorrhoea in primary care, the impact of treatments in adolescence on long-term outcomes and when to consider the possibility of endometriosis in adolescence. METHODS AND ANALYSIS: This study aims to improve the evidence base for adolescents presenting to primary care with dysmenorrhoea. It comprises three interlinked studies. Using the QResearch Database, the study population includes all female at birth participants aged 10-19 years any time between 1 January 2000 and 30 June 2021. We will undertake (1) a descriptive study documenting the prevalence of coded dysmenorrhoea in primary care, stratified by demographic variables, reported using descriptive statistics; (2) a prospective open cohort study following an index cohort of all adolescents recorded as attending primary care with dysmenorrhoea and a comparator cohort of five times as many who have not, to determine the HR for a diagnosis of endometriosis, adenomyosis, ongoing menstrual pain or subfertility (considered singly and in combination) anytime during the study period; and (3) a nested case-control study for adolescents diagnosed with endometriosis, using conditional logistic regression, to determine the OR for symptom(s) preceding this diagnosis. ETHICS AND DISSEMINATION: The project has been independently peer reviewed and received ethics approval from the QResearch Scientific Board (reference OX46 under REC 18/EM/0400).In addition to publication in peer-reviewed academic journals, we will use the combined findings to generate a resource and infographic to support shared decision-making about dysmenorrhoea in community health settings. Additionally, the findings will be used to inform a subsequent qualitative study, exploring adolescents' experiences of menstrual pain.

Temporality of body mass index, blood tests, comorbidities and medication use as early markers for pancreatic ductal adenocarcinoma (PDAC): a nested case-control study.

OBJECTIVE: Prior studies identified clinical factors associated with increased risk of pancreatic ductal adenocarcinoma (PDAC). However, little is known regarding their time-varying nature, which could inform earlier diagnosis. This study assessed temporality of body mass index (BMI), blood-based markers, comorbidities and medication use with PDAC risk . DESIGN: We performed a population-based nested case-control study of 28 137 PDAC cases and 261 219 matched-controls in England. We described the associations of biomarkers with risk of PDAC using fractional polynomials and 5-year time trends using joinpoint regression. Associations with comorbidities and medication use were evaluated using conditional logistic regression. RESULTS: Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while following a U-shaped relationship for BMI and haemoglobin. Five-year trends showed biphasic BMI decrease and HbA1c increase prior to PDAC; early-gradual changes 2-3 years prior, followed by late-rapid changes 1-2 years prior. Liver markers and blood counts (white blood cell, platelets) showed monophasic rapid-increase approximately 1 year prior. Recent diagnosis of pancreatic cyst, pancreatitis, type 2 diabetes and initiation of certain glucose-lowering and acid-regulating therapies were associated with highest risk of PDAC. CONCLUSION: Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while followed a U-shaped relationship for BMI and haemoglobin. BMI and HbA1c derange biphasically approximately 3 years prior while liver markers and blood counts (white blood cell, platelets) derange monophasically approximately 1 year prior to PDAC. Profiling these in combination with their temporality could inform earlier PDAC diagnosis.

Preexisting Neuropsychiatric Conditions and Associated Risk of Severe COVID-19 Infection and Other Acute Respiratory Infections.

Importance: Evidence indicates that preexisting neuropsychiatric conditions confer increased risks of severe outcomes from COVID-19 infection. It is unclear how this increased risk compares with risks associated with other severe acute respiratory infections (SARIs). Objective: To determine whether preexisting diagnosis of and/or treatment for a neuropsychiatric condition is associated with severe outcomes from COVID-19 infection and other SARIs and whether any observed association is similar between the 2 outcomes. Design, Setting, and Participants: Prepandemic (2015-2020) and contemporary (2020-2021) longitudinal cohorts were derived from the QResearch database of English primary care records. Adjusted hazard ratios (HRs) with 99% CIs were estimated in April 2022 using flexible parametric survival models clustered by primary care clinic. This study included a population-based sample, including all adults in the database who had been registered with a primary care clinic for at least 1 year. Analysis of routinely collected primary care electronic medical records was performed. Exposures: Diagnosis of and/or medication for anxiety, mood, or psychotic disorders and diagnosis of dementia, depression, schizophrenia, or bipolar disorder. Main Outcomes and Measures: COVID-19-related mortality, or hospital or intensive care unit admission; SARI-related mortality, or hospital or intensive care unit admission. Results: The prepandemic cohort comprised 11 134 789 adults (223 569 SARI cases [2.0%]) with a median (IQR) age of 42 (29-58) years, of which 5 644 525 (50.7%) were female. The contemporary cohort comprised 8 388 956 adults (58 203 severe COVID-19 cases [0.7%]) with a median (IQR) age of 48 (34-63) years, of which 4 207 192 were male (50.2%). Diagnosis and/or treatment for neuropsychiatric conditions other than dementia was associated with an increased likelihood of a severe outcome from SARI (anxiety diagnosis: HR, 1.16; 99% CI, 1.13-1.18; psychotic disorder diagnosis and treatment: HR, 2.56; 99% CI, 2.40-2.72) and COVID-19 (anxiety diagnosis: HR, 1.16; 99% CI, 1.12-1.20; psychotic disorder treatment: HR, 2.37; 99% CI, 2.20-2.55). The effect estimate for severe outcome with dementia was higher for those with COVID-19 than SARI (HR, 2.85; 99% CI, 2.71-3.00 vs HR, 2.13; 99% CI, 2.07-2.19). Conclusions and Relevance: In this longitudinal cohort study, UK patients with preexisting neuropsychiatric conditions and treatments were associated with similarly increased risks of severe outcome from COVID-19 infection and SARIs, except for dementia.

Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex.

BACKGROUND: Myocarditis is more common after severe acute respiratory syndrome coronavirus 2 infection than after COVID-19 vaccination, but the risks in younger people and after sequential vaccine doses are less certain. METHODS: A self-controlled case series study of people ages 13 years or older vaccinated for COVID-19 in England between December 1, 2020, and December 15, 2021, evaluated the association between vaccination and myocarditis, stratified by age and sex. The incidence rate ratio and excess number of hospital admissions or deaths from myocarditis per million people were estimated for the 1 to 28 days after sequential doses of adenovirus (ChAdOx1) or mRNA-based (BNT162b2, mRNA-1273) vaccines, or after a positive SARS-CoV-2 test. RESULTS: In 42 842 345 people receiving at least 1 dose of vaccine, 21 242 629 received 3 doses, and 5 934 153 had SARS-CoV-2 infection before or after vaccination. Myocarditis occurred in 2861 (0.007%) people, with 617 events 1 to 28 days after vaccination. Risk of myocarditis was increased in the 1 to 28 days after a first dose of ChAdOx1 (incidence rate ratio, 1.33 [95% CI, 1.09-1.62]) and a first, second, and booster dose of BNT162b2 (1.52 [95% CI, 1.24-1.85]; 1.57 [95% CI, 1.28-1.92], and 1.72 [95% CI, 1.33-2.22], respectively) but was lower than the risks after a positive SARS-CoV-2 test before or after vaccination (11.14 [95% CI, 8.64-14.36] and 5.97 [95% CI, 4.54-7.87], respectively). The risk of myocarditis was higher 1 to 28 days after a second dose of mRNA-1273 (11.76 [95% CI, 7.25-19.08]) and persisted after a booster dose (2.64 [95% CI, 1.25-5.58]). Associations were stronger in men younger than 40 years for all vaccines. In men younger than 40 years old, the number of excess myocarditis events per million people was higher after a second dose of mRNA-1273 than after a positive SARS-CoV-2 test (97 [95% CI, 91-99] versus 16 [95% CI, 12-18]). In women younger than 40 years, the number of excess events per million was similar after a second dose of mRNA-1273 and a positive test (7 [95% CI, 1-9] versus 8 [95% CI, 6-8]). CONCLUSIONS: Overall, the risk of myocarditis is greater after SARS-CoV-2 infection than after COVID-19 vaccination and remains modest after sequential doses including a booster dose of BNT162b2 mRNA vaccine. However, the risk of myocarditis after vaccination is higher in younger men, particularly after a second dose of the mRNA-1273 vaccine.

Associations of BMI with COVID-19 vaccine uptake, vaccine effectiveness, and risk of severe COVID-19 outcomes after vaccination in England: a population-based cohort study.

BACKGROUND: A high BMI has been associated with a reduced immune response to vaccination against influenza. We aimed to investigate the association between BMI and COVID-19 vaccine uptake, vaccine effectiveness, and risk of severe COVID-19 outcomes after vaccination by using a large, representative population-based cohort from England. METHODS: In this population-based cohort study, we used the QResearch database of general practice records and included patients aged 18 years or older who were registered at a practice that was part of the database in England between Dec 8, 2020 (date of the first vaccination in the UK), to Nov 17, 2021, with available data on BMI. Uptake was calculated as the proportion of people with zero, one, two, or three doses of the vaccine across BMI categories. Effectiveness was assessed through a nested matched case-control design to estimate odds ratios (OR) for severe COVID-19 outcomes (ie, admission to hospital or death) in people who had been vaccinated versus those who had not, considering vaccine dose and time periods since vaccination. Vaccine effectiveness against infection with SARS-CoV-2 was also investigated. Multivariable Cox proportional hazard models estimated the risk of severe COVID-19 outcomes associated with BMI (reference BMI 23 kg/m2) after vaccination. FINDINGS: Among 9 171 524 participants (mean age 52 [SD 19] years; BMI 26·7 [5·6] kg/m2), 566 461 tested positive for SARS-CoV-2 during follow-up, of whom 32 808 were admitted to hospital and 14 389 died. Of the total study sample, 19·2% (1 758 689) were unvaccinated, 3·1% (287 246) had one vaccine dose, 52·6% (4 828 327) had two doses, and 25·0% (2 297 262) had three doses. In people aged 40 years and older, uptake of two or three vaccine doses was more than 80% among people with overweight or obesity, which was slightly lower in people with underweight (70-83%). Although significant heterogeneity was found across BMI groups, protection against severe COVID-19 disease (comparing people who were vaccinated vs those who were not) was high after 14 days or more from the second dose for hospital admission (underweight: OR 0·51 [95% CI 0·41-0·63]; healthy weight: 0·34 [0·32-0·36]; overweight: 0·32 [0·30-0·34]; and obesity: 0·32 [0·30-0·34]) and death (underweight: 0·60 [0·36-0·98]; healthy weight: 0·39 [0·33-0·47]; overweight: 0·30 [0·25-0·35]; and obesity: 0·26 [0·22-0·30]). In the vaccinated cohort, there were significant linear associations between BMI and COVID-19 hospitalisation and death after the first dose, and J-shaped associations after the second dose. INTERPRETATION: Using BMI categories, there is evidence of protection against severe COVID-19 in people with overweight or obesity who have been vaccinated, which was of a similar magnitude to that of people of healthy weight. Vaccine effectiveness was slightly lower in people with underweight, in whom vaccine uptake was also the lowest for all ages. In the vaccinated cohort, there were increased risks of severe COVID-19 outcomes for people with underweight or obesity compared with the vaccinated population with a healthy weight. These results suggest the need for targeted efforts to increase uptake in people with low BMI (<18·5 kg/m2), in whom uptake is lower and vaccine effectiveness seems to be reduced. Strategies to achieve and maintain a healthy weight should be prioritised at the population level, which could help reduce the burden of COVID-19 disease. FUNDING: UK Research and Innovation and National Institute for Health Research Oxford Biomedical Research Centre.

Neuropsychiatric Ramifications of Severe COVID-19 and Other Severe Acute Respiratory Infections.

Importance: Individuals surviving severe COVID-19 may be at increased risk of neuropsychiatric sequelae. Robust assessment of these risks may help improve clinical understanding of the post-COVID syndrome, aid clinical care during the ongoing pandemic, and inform postpandemic planning. Objective: To quantify the risks of new-onset neuropsychiatric conditions and new neuropsychiatric medication prescriptions after discharge from a COVID-19-related hospitalization, and to compare these with risks after discharge from hospitalization for other severe acute respiratory infections (SARI) during the COVID-19 pandemic. Design, Setting, and Participants: In this cohort study, adults (≥18 years of age) were identified from QResearch primary care and linked electronic health record databases, including national SARS-CoV-2 testing, hospital episode statistics, intensive care admissions data, and mortality registers in England, from January 24, 2020, to July 7, 2021. Exposures: COVID-19-related or SARI-related hospital admission (including intensive care admission). Main Outcomes and Measures: New-onset diagnoses of neuropsychiatric conditions (anxiety, dementia, psychosis, depression, bipolar disorder) or first prescription for relevant medications (antidepressants, hypnotics/anxiolytics, antipsychotics) during 12 months of follow-up from hospital discharge. Maximally adjusted hazard ratios (HR) with 95% CIs were estimated using flexible parametric survival models. Results: In this cohort study of data from 8.38 million adults (4.18 million women, 4.20 million men; mean [SD] age 49.18 [18.45] years); 16 679 (0.02%) survived a hospital admission for SARI, and 32 525 (0.03%) survived a hospital admission for COVID-19. Compared with the remaining population, survivors of SARI and COVID-19 hospitalization had higher risks of subsequent neuropsychiatric diagnoses. For example, the HR for anxiety in survivors of SARI was 1.86 (95% CI, 1.56-2.21) and for survivors of COVID-19 infection was 2.36 (95% CI, 2.03-2.74); the HR for dementia for survivors of SARI was 2.55 (95% CI, 2.17-3.00) and for survivors of COVID-19 infection was 2.63 (95% CI, 2.21-3.14). Similar findings were observed for all medications analyzed; for example, the HR for first prescriptions of antidepressants in survivors of SARI was 2.55 (95% CI, 2.24-2.90) and for survivors of COVID-19 infection was 3.24 (95% CI, 2.91-3.61). There were no significant differences observed when directly comparing the COVID-19 group with the SARI group apart from a lower risk of antipsychotic prescriptions in the former (HR, 0.80; 95% CI, 0.69-0.92). Conclusions and Relevance: In this cohort study, the neuropsychiatric sequelae of severe COVID-19 infection were found to be similar to those for other SARI. This finding may inform postdischarge support for people surviving SARI.

Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection.

Although myocarditis and pericarditis were not observed as adverse events in coronavirus disease 2019 (COVID-19) vaccine trials, there have been numerous reports of suspected cases following vaccination in the general population. We undertook a self-controlled case series study of people aged 16 or older vaccinated for COVID-19 in England between 1 December 2020 and 24 August 2021 to investigate hospital admission or death from myocarditis, pericarditis and cardiac arrhythmias in the 1-28 days following adenovirus (ChAdOx1, n = 20,615,911) or messenger RNA-based (BNT162b2, n = 16,993,389; mRNA-1273, n = 1,006,191) vaccines or a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (n = 3,028,867). We found increased risks of myocarditis associated with the first dose of ChAdOx1 and BNT162b2 vaccines and the first and second doses of the mRNA-1273 vaccine over the 1-28 days postvaccination period, and after a SARS-CoV-2 positive test. We estimated an extra two (95% confidence interval (CI) 0, 3), one (95% CI 0, 2) and six (95% CI 2, 8) myocarditis events per 1 million people vaccinated with ChAdOx1, BNT162b2 and mRNA-1273, respectively, in the 28 days following a first dose and an extra ten (95% CI 7, 11) myocarditis events per 1 million vaccinated in the 28 days after a second dose of mRNA-1273. This compares with an extra 40 (95% CI 38, 41) myocarditis events per 1 million patients in the 28 days following a SARS-CoV-2 positive test. We also observed increased risks of pericarditis and cardiac arrhythmias following a positive SARS-CoV-2 test. Similar associations were not observed with any of the COVID-19 vaccines, apart from an increased risk of arrhythmia following a second dose of mRNA-1273. Subgroup analyses by age showed the increased risk of myocarditis associated with the two mRNA vaccines was present only in those younger than 40.

Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection.

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.

Identifying symptoms associated with diagnosis of pancreatic exocrine and neuroendocrine neoplasms: a nested case-control study of the UK primary care population.

BACKGROUND: Pancreatic cancer has the worst survival rate among all cancers. Almost 70% of patients in the UK were diagnosed at Stage IV. AIM: This study aimed to investigate the symptoms associated with the diagnoses of pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine neoplasms (PNEN), and comparatively characterise the symptomatology between the two tumour types to inform earlier diagnosis. DESIGN AND SETTING: A nested case-control study in primary care was conducted using data from the QResearch® database. Patients aged ≥25 years and diagnosed with PDAC or PNEN during 2000 to 2019 were included as cases. Up to 10 controls from the same general practice were matched with each case by age, sex, and calendar year using incidence density sampling. METHOD: Conditional logistic regression was used to investigate the association between the 42 shortlisted symptoms and the diagnoses of PDAC and (or) PNEN in different timeframes relative to the index date, adjusting for patients' sociodemographic characteristics, lifestyle, and relevant comorbidities. RESULTS: A total of 23 640 patients were identified as diagnosed with PDAC and 596 with PNEN. Of the symptoms identified, 23 were significantly associated with PDAC, and nine symptoms with PNEN. The two alarm symptoms for both tumours were jaundice and gastrointestinal bleeding. The two newly identified symptoms for PDAC were thirst and dark urine. The risk of unintentional weight loss may be longer than 2 years before the diagnosis of PNEN. CONCLUSION: PDAC and PNEN have overlapping symptom profiles. The QCancer® (pancreas) risk prediction model could be updated by including the newly identified symptoms and comorbidities, which could help GPs identify high-risk patients for timely investigation in primary care.

Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study.

OBJECTIVE: To assess the association between covid-19 vaccines and risk of thrombocytopenia and thromboembolic events in England among adults. DESIGN: Self-controlled case series study using national data on covid-19 vaccination and hospital admissions. SETTING: Patient level data were obtained for approximately 30 million people vaccinated in England between 1 December 2020 and 24 April 2021. Electronic health records were linked with death data from the Office for National Statistics, SARS-CoV-2 positive test data, and hospital admission data from the United Kingdom's health service (NHS). PARTICIPANTS: 29 121 633 people were vaccinated with first doses (19 608 008 with Oxford-AstraZeneca (ChAdOx1 nCoV-19) and 9 513 625 with Pfizer-BioNTech (BNT162b2 mRNA)) and 1 758 095 people had a positive SARS-CoV-2 test. People aged ≥16 years who had first doses of the ChAdOx1 nCoV-19 or BNT162b2 mRNA vaccines and any outcome of interest were included in the study. MAIN OUTCOME MEASURES: The primary outcomes were hospital admission or death associated with thrombocytopenia, venous thromboembolism, and arterial thromboembolism within 28 days of three exposures: first dose of the ChAdOx1 nCoV-19 vaccine; first dose of the BNT162b2 mRNA vaccine; and a SARS-CoV-2 positive test. Secondary outcomes were subsets of the primary outcomes: cerebral venous sinus thrombosis (CVST), ischaemic stroke, myocardial infarction, and other rare arterial thrombotic events. RESULTS: The study found increased risk of thrombocytopenia after ChAdOx1 nCoV-19 vaccination (incidence rate ratio 1.33, 95% confidence interval 1.19 to 1.47 at 8-14 days) and after a positive SARS-CoV-2 test (5.27, 4.34 to 6.40 at 8-14 days); increased risk of venous thromboembolism after ChAdOx1 nCoV-19 vaccination (1.10, 1.02 to 1.18 at 8-14 days) and after SARS-CoV-2 infection (13.86, 12.76 to 15.05 at 8-14 days); and increased risk of arterial thromboembolism after BNT162b2 mRNA vaccination (1.06, 1.01 to 1.10 at 15-21 days) and after SARS-CoV-2 infection (2.02, 1.82 to 2.24 at 15-21 days). Secondary analyses found increased risk of CVST after ChAdOx1 nCoV-19 vaccination (4.01, 2.08 to 7.71 at 8-14 days), after BNT162b2 mRNA vaccination (3.58, 1.39 to 9.27 at 15-21 days), and after a positive SARS-CoV-2 test; increased risk of ischaemic stroke after BNT162b2 mRNA vaccination (1.12, 1.04 to 1.20 at 15-21 days) and after a positive SARS-CoV-2 test; and increased risk of other rare arterial thrombotic events after ChAdOx1 nCoV-19 vaccination (1.21, 1.02 to 1.43 at 8-14 days) and after a positive SARS-CoV-2 test. CONCLUSION: Increased risks of haematological and vascular events that led to hospital admission or death were observed for short time intervals after first doses of the ChAdOx1 nCoV-19 and BNT162b2 mRNA vaccines. The risks of most of these events were substantially higher and more prolonged after SARS-CoV-2 infection than after vaccination in the same population.

Mortality and critical care unit admission associated with the SARS-CoV-2 lineage B.1.1.7 in England: an observational cohort study.

BACKGROUND: A more transmissible variant of SARS-CoV-2, the variant of concern 202012/01 or lineage B.1.1.7, has emerged in the UK. We aimed to estimate the risk of critical care admission, mortality in patients who are critically ill, and overall mortality associated with lineage B.1.1.7 compared with non-B.1.1.7. We also compared clinical outcomes between these two groups. METHODS: For this observational cohort study, we linked large primary care (QResearch), national critical care (Intensive Care National Audit & Research Centre Case Mix Programme), and national COVID-19 testing (Public Health England) databases. We used SARS-CoV-2 positive samples with S-gene molecular diagnostic assay failure (SGTF) as a proxy for the presence of lineage B.1.1.7. We extracted two cohorts from the data: the primary care cohort, comprising patients in primary care with a positive community COVID-19 test reported between Nov 1, 2020, and Jan 26, 2021, and known SGTF status; and the critical care cohort, comprising patients admitted for critical care with a positive community COVID-19 test reported between Nov 1, 2020, and Jan 27, 2021, and known SGTF status. We explored the associations between SARS-CoV-2 infection with and without lineage B.1.1.7 and admission to a critical care unit (CCU), 28-day mortality, and 28-day mortality following CCU admission. We used Royston-Parmar models adjusted for age, sex, geographical region, other sociodemographic factors (deprivation index, ethnicity, household housing category, and smoking status for the primary care cohort; and ethnicity, body-mass index, deprivation index, and dependency before admission to acute hospital for the CCU cohort), and comorbidities (asthma, chronic obstructive pulmonary disease, type 1 and 2 diabetes, and hypertension for the primary care cohort; and cardiovascular disease, respiratory disease, metastatic disease, and immunocompromised conditions for the CCU cohort). We reported information on types and duration of organ support for the B.1.1.7 and non-B.1.1.7 groups. FINDINGS: The primary care cohort included 198 420 patients with SARS-CoV-2 infection. Of these, 117 926 (59·4%) had lineage B.1.1.7, 836 (0·4%) were admitted to CCU, and 899 (0·4%) died within 28 days. The critical care cohort included 4272 patients admitted to CCU. Of these, 2685 (62·8%) had lineage B.1.1.7 and 662 (15·5%) died at the end of critical care. In the primary care cohort, we estimated adjusted hazard ratios (HRs) of 2·15 (95% CI 1·75-2·65) for CCU admission and 1·65 (1·36-2·01) for 28-day mortality for patients with lineage B.1.1.7 compared with the non-B.1.1.7 group. The adjusted HR for mortality in critical care, estimated with the critical care cohort, was 0·91 (0·76-1·09) for patients with lineage B.1.1.7 compared with those with non-B.1.1.7 infection. INTERPRETATION: Patients with lineage B.1.1.7 were at increased risk of CCU admission and 28-day mortality compared with patients with non-B.1.1.7 SARS-CoV-2. For patients receiving critical care, mortality appeared to be independent of virus strain. Our findings emphasise the importance of measures to control exposure to and infection with COVID-19. FUNDING: Wellcome Trust, National Institute for Health Research Oxford Biomedical Research Centre, and the Medical Sciences Division of the University of Oxford.