Effectiveness of mRNA COVID-19 Vaccines as First Booster Doses in England: An Observational Study in OpenSAFELY-TPP.

BACKGROUND: The UK delivered its first "booster" COVID-19 vaccine doses in September 2021, initially to individuals at high risk of severe disease, then to all adults. The BNT162b2 Pfizer-BioNTech vaccine was used initially, then also Moderna mRNA-1273. METHODS: With the approval of the National Health Service England, we used routine clinical data to estimate the effectiveness of boosting with BNT162b2 or mRNA-1273 compared with no boosting in eligible adults who had received two primary course vaccine doses. We matched each booster recipient with an unboosted control on factors relating to booster priority status and prior COVID-19 immunization. We adjusted for additional factors in Cox models, estimating hazard ratios up to 182 days (6 months) following booster dose. We estimated hazard ratios overall and within the following periods: 1-14, 15-42, 43-69, 70-97, 98-126, 127-152, and 155-182 days. Outcomes included a positive SARS-CoV-2 test, COVID-19 hospitalization, COVID-19 death, non-COVID-19 death, and fracture. RESULTS: We matched 8,198,643 booster recipients with unboosted controls. Adjusted hazard ratios over 6-month follow-up were: positive SARS-CoV-2 test 0.75 (0.74, 0.75); COVID-19 hospitalization 0.30 (0.29, 0.31); COVID-19 death 0.11 (0.10, 0.14); non-COVID-19 death 0.22 (0.21, 0.23); and fracture 0.77 (0.75, 0.78). Estimated effectiveness of booster vaccines against severe COVID-19-related outcomes peaked during the first 3 months following the booster dose. By 6 months, the cumulative incidence of positive SARS-CoV-2 test was higher in boosted than unboosted individuals. CONCLUSIONS: We estimate that COVID-19 booster vaccination, compared with no booster vaccination, provided substantial protection against COVID-19 hospitalization and COVID-19 death but only limited protection against positive SARS-CoV-2 test. Lower rates of fracture in boosted than unboosted individuals may suggest unmeasured confounding. Observational studies should report estimated vaccine effectiveness against nontarget and negative control outcomes.

The cost of keeping patients waiting: retrospective treatment-control study of additional healthcare utilisation for UK patients awaiting elective treatment.

OBJECTIVE: Long waiting times for elective hospital treatments are common in many countries. This study seeks to address a deficit in the literature concerning the effect of long waits on the wider consumption of healthcare resources. METHODS: We carried out a retrospective treatment-control study in a healthcare system in South West England from 15 June 2021 to 15 December 2021. We compared weekly contacts with health services of patients waiting over 18 weeks for treatment ('Treatments') and people not on a waiting list ('Controls'). Controls were matched to Treatments based on age, sex, deprivation and multimorbidity. Treatments were stratified by the clinical specialty of the awaited hospital treatment, with healthcare usage assessed over various healthcare settings. Wilcoxon signed-rank tests assessed whether there was an increase in healthcare utilisation and bootstrap resampling was used to estimate the magnitude of any differences. RESULTS: A total of 44,616 patients were waiting over 18 weeks (the constitutional target in England) for treatment during the study period. There was an increase (p < 0.0004) in healthcare utilisation for all specialties. Patients in the Cardiothoracic Surgery specialty had the largest increase, with 17.9 [interquartile-range: 4.3, 33.8] additional contacts with secondary care and 17.3 [-1.1, 34.1] additional prescriptions per year. CONCLUSION: People waiting for treatment consume higher levels of healthcare than comparable individuals not on a waiting list. These findings are relevant for clinicians and managers in better understanding patient need and reducing harm. Results also highlight the possible 'false economy' in failing to promptly resolve long elective waits.

The effectiveness of knowledge-sharing techniques and approaches in research funded by the National Institute for Health and Care Research (NIHR): a systematic review.

BACKGROUND: The National Institute of Health and Care Research (NIHR), funds, enables and delivers world-leading health and social care research to improve people's health and wellbeing. To achieve this aim, effective knowledge sharing (two-way knowledge sharing between researchers and stakeholders to create new knowledge and enable change in policy and practice) is needed. To date, it is not known which knowledge sharing techniques and approaches are used or how effective these are in creating new knowledge that can lead to changes in policy and practice in NIHR funded studies. METHODS: In this restricted systematic review, electronic databases [MEDLINE, The Health Management Information Consortium (including the Department of Health's Library and Information Services and King's Fund Information and Library Services)] were searched for published NIHR funded studies that described knowledge sharing between researchers and other stakeholders. One researcher performed title and abstract, full paper screening and quality assessment (Critical Appraisal Skills Programme qualitative checklist) with a 20% sample independently screened by a second reviewer. A narrative synthesis was adopted. RESULTS: In total 9897 records were identified. After screening, 17 studies were included. Five explicit forms of knowledge sharing studies were identified: embedded models, knowledge brokering, stakeholder engagement and involvement of non-researchers in the research or service design process and organisational collaborative partnerships between universities and healthcare organisations. Collectively, the techniques and approaches included five types of stakeholders and worked with them at all stages of the research cycle, except the stage of formation of the research design and preparation of funding application. Seven studies (using four of the approaches) gave examples of new knowledge creation, but only one study (using an embedded model approach) gave an example of a resulting change in practice. The use of a theory, model or framework to explain the knowledge sharing process was identified in six studies. CONCLUSIONS: Five knowledge sharing techniques and approaches were reported in the included NIHR funded studies, and seven studies identified the creation of new knowledge. However, there was little investigation of the effectiveness of these approaches in influencing change in practice or policy.

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

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

A multi-granular stacked regression for forecasting long-term demand in Emergency Departments.

BACKGROUND: In the United Kingdom, Emergency Departments (EDs) are under significant pressure due to an ever-increasing number of attendances. Understanding how the capacity of other urgent care services and the health of a population may influence ED attendances is imperative for commissioners and policy makers to develop long-term strategies for reducing this pressure and improving quality and safety. METHODS: We developed a novel multi-granular stacked regression (MGSR) model using publicly available data to predict future mean monthly ED attendances within Clinical Commissioning Group regions in England. The MGSR combines measures of population health and health service capacity in other related settings. We assessed model performance using the R-squared statistic, measuring variance explained, and the Mean Absolute Percentage Error (MAPE), measuring forecasting accuracy. We used the MGSR to forecast ED demand over a 4-year period under hypothetical scenarios where service capacity is increased, or population health is improved. RESULTS: Measures of service capacity explain 41 ± 4% of the variance in monthly ED attendances and measures of population health explain 62 ± 22%. The MGSR leads to an overall improvement in performance, with an R-squared of 0.79 ± 0.02 and MAPE of 3% when forecasting mean monthly ED attendances per CCG. Using the MGSR to forecast long-term demand under different scenarios, we found improving population health would reduce peak ED attendances per CCG by approximately 1000 per month after 2 years. CONCLUSION: Combining models of population health and wider urgent care service capacity for predicting monthly ED attendances leads to an improved performance compared to each model individually. Policies designed to improve population health will reduce ED attendances and enhance quality and safety in the long-term.

Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, or thrombocytopenic events: A population-based cohort study of 46 million adults in England.

BACKGROUND: Thromboses in unusual locations after the Coronavirus Disease 2019 (COVID-19) vaccine ChAdOx1-S have been reported, although their frequency with vaccines of different types is uncertain at a population level. The aim of this study was to estimate the population-level risks of hospitalised thrombocytopenia and major arterial and venous thromboses after COVID-19 vaccination. METHODS AND FINDINGS: In this whole-population cohort study, we analysed linked electronic health records from adults living in England, from 8 December 2020 to 18 March 2021. We estimated incidence rates and hazard ratios (HRs) for major arterial, venous, and thrombocytopenic outcomes 1 to 28 and >28 days after first vaccination dose for ChAdOx1-S and BNT162b2 vaccines. Analyses were performed separately for ages <70 and ≥70 years and adjusted for age, age2, sex, ethnicity, and deprivation. We also prespecified adjustment for anticoagulant medication, combined oral contraceptive medication, hormone replacement therapy medication, history of pulmonary embolism or deep vein thrombosis, and history of coronavirus infection in analyses of venous thrombosis; and diabetes, hypertension, smoking, antiplatelet medication, blood pressure lowering medication, lipid lowering medication, anticoagulant medication, history of stroke, and history of myocardial infarction in analyses of arterial thromboses. We selected further covariates with backward selection. Of 46 million adults, 23 million (51%) were women; 39 million (84%) were <70; and 3.7 million (8.1%) Asian or Asian British, 1.6 million (3.5%) Black or Black British, 36 million (79%) White, 0.7 million (1.5%) mixed ethnicity, and 1.5 million (3.2%) were of another ethnicity. Approximately 21 million (46%) adults had their first vaccination between 8 December 2020 and 18 March 2021. The crude incidence rates (per 100,000 person-years) of all venous events were as follows: prevaccination, 140 [95% confidence interval (CI): 138 to 142]; ≤28 days post-ChAdOx1-S, 294 (281 to 307); >28 days post-ChAdOx1-S, 359 (338 to 382), ≤28 days post-BNT162b2-S, 241 (229 to 253); >28 days post-BNT162b2-S 277 (263 to 291). The crude incidence rates (per 100,000 person-years) of all arterial events were as follows: prevaccination, 546 (95% CI: 541 to 555); ≤28 days post-ChAdOx1-S, 1,211 (1,185 to 1,237); >28 days post-ChAdOx1-S, 1678 (1,630 to 1,726), ≤28 days post-BNT162b2-S, 1,242 (1,214 to 1,269); >28 days post-BNT162b2-S, 1,539 (1,507 to 1,572). Adjusted HRs (aHRs) 1 to 28 days after ChAdOx1-S, compared with unvaccinated rates, at ages <70 and ≥70 years, respectively, were 0.97 (95% CI: 0.90 to 1.05) and 0.58 (0.53 to 0.63) for venous thromboses, and 0.90 (0.86 to 0.95) and 0.76 (0.73 to 0.79) for arterial thromboses. Corresponding aHRs for BNT162b2 were 0.81 (0.74 to 0.88) and 0.57 (0.53 to 0.62) for venous thromboses, and 0.94 (0.90 to 0.99) and 0.72 (0.70 to 0.75) for arterial thromboses. aHRs for thrombotic events were higher at younger ages for venous thromboses after ChAdOx1-S, and for arterial thromboses after both vaccines. Rates of intracranial venous thrombosis (ICVT) and of thrombocytopenia in adults aged <70 years were higher 1 to 28 days after ChAdOx1-S (aHRs 2.27, 95% CI: 1.33 to 3.88 and 1.71, 1.35 to 2.16, respectively), but not after BNT162b2 (0.59, 0.24 to 1.45 and 1.00, 0.75 to 1.34) compared with unvaccinated. The corresponding absolute excess risks of ICVT 1 to 28 days after ChAdOx1-S were 0.9 to 3 per million, varying by age and sex. The main limitations of the study are as follows: (i) it relies on the accuracy of coded healthcare data to identify exposures, covariates, and outcomes; (ii) the use of primary reason for hospital admission to measure outcome, which improves the positive predictive value but may lead to an underestimation of incidence; and (iii) potential unmeasured confounding. CONCLUSIONS: In this study, we observed increases in rates of ICVT and thrombocytopenia after ChAdOx1-S vaccination in adults aged <70 years that were small compared with its effect in reducing COVID-19 morbidity and mortality, although more precise estimates for adults aged <40 years are needed. For people aged ≥70 years, rates of arterial or venous thrombotic events were generally lower after either vaccine compared with unvaccinated, suggesting that either vaccine is suitable in this age group.

International prescribing patterns and polypharmacy in older people with advanced chronic kidney disease: results from the European Quality study.

BACKGROUND: People with chronic kidney disease (CKD) are at high risk of polypharmacy. However, no previous study has investigated international prescribing patterns in this group. This article aims to examine prescribing and polypharmacy patterns among older people with advanced CKD across the countries involved in the European Quality (EQUAL) study. METHODS: The EQUAL study is an international prospective cohort study of patients ≥65 years of age with advanced CKD. Baseline demographic, clinical and medication data were analysed and reported descriptively. Polypharmacy was defined as ≥5 medications and hyperpolypharmacy as ≥10. Univariable and multivariable linear regressions were used to determine associations between country and the number of prescribed medications. Univariable and multivariable logistic regression were used to determine associations between country and hyperpolypharmacy. RESULTS: Of the 1317 participants from five European countries, 91% were experiencing polypharmacy and 43% were experiencing hyperpolypharmacy. Cardiovascular medications were the most prescribed medications (mean 3.5 per person). There were international differences in prescribing, with significantly greater hyperpolypharmacy in Germany {odds ratio (OR) 2.75 [95% confidence interval (CI) 1.73-4.37]; P < 0.001, reference group UK}, the Netherlands [OR 1.91 (95% CI 1.32-2.76); P = 0.001] and Italy [OR 1.57 (95% CI 1.15-2.15); P = 0.004]. People in Poland experienced the least hyperpolypharmacy [OR 0.39 (95% CI 0.17-0.87); P = 0.021]. CONCLUSIONS: Hyperpolypharmacy is common among older people with advanced CKD, with significant international differences in the number of medications prescribed. Practice variation may represent a lack of consensus regarding appropriate prescribing for this high-risk group for whom pharmacological treatment has great potential for harm as well as benefit.

A multi-stakeholder approach to the co-production of the research agenda for medicines optimisation.

BACKGROUND: Up to 50% of medicines are not used as intended, resulting in poor health and economic outcomes. Medicines optimisation is 'a person-centred approach to safe and effective medicines use, to ensure people obtain the best possible outcomes from their medicines'. The purpose of this exercise was to co-produce a prioritised research agenda for medicines optimisation using a multi-stakeholder (patient, researcher, public and health professionals) approach. METHODS: A three-stage, multiple method process was used including: generation of preliminary research questions (Stage 1) using a modified Nominal Group Technique; electronic consultation and ranking with a wider multi-stakeholder group (Stage 2); a face-to-face, one-day consensus meeting involving representatives from all stakeholder groups (Stage 3). RESULTS: In total, 92 research questions were identified during Stages 1 and 2 and ranked in order of priority during stage 3. Questions were categorised into four areas: 'Patient Concerns' [e.g. is there a shared decision (with patients) about using each medicine?], 'Polypharmacy' [e.g. how to design health services to cope with the challenge of multiple medicines use?], 'Non-Medical Prescribing' [e.g. how can the contribution of non-medical prescribers be optimised in primary care?], and 'Deprescribing' [e.g. what support is needed by prescribers to deprescribe?]. A significant number of the 92 questions were generated by Patient and Public Involvement representatives, which demonstrates the importance of including this stakeholder group when identifying research priorities. CONCLUSIONS: A wide range of research questions was generated reflecting concerns which affect patients, practitioners, the health service, as well the ethical and philosophical aspects of the prescribing and deprescribing of medicines. These questions should be used to set future research agendas and funding commissions.

Use of antibiotics and asthma medication for acute lower respiratory tract infections in people with and without asthma: retrospective cohort study.

BACKGROUND: Antibiotics are overused in patients with acute lower respiratory tract infections (ALRTIs), but less is known about their use in patients with asthma, or the use of asthma medication for ALRTI in patients without asthma. Our aim was to describe the frequency, variation and drivers in antibiotic and asthma medication prescribing for ALRTI in adults with and without asthma in primary care. METHODS: A retrospective cohort analysis of patients aged ≥12 years, diagnosed with an ALRTI in primary care in 2014-15 was conducted using data from the Clinical Practice Research Datalink. Current asthma status, asthma medication and oral antibiotic use within 3 days of ALRTI infection was determined. Treatment frequency was calculated by asthma status. Mixed-effect regression models were used to explore between-practice variation and treatment determinants. RESULTS: There were 127,976 ALRTIs reported among 110,418 patients during the study period, of whom 17,952 (16%) had asthma. Respectively, 81 and 79% of patients with and without asthma received antibiotics, and 41 and 15% asthma medication. There were significant differences in between-practice prescribing for all treatments, with greatest differences seen for oral steroids (odds ratio (OR) 18; 95% CI 7-82 and OR = 94; 33-363, with and without asthma) and asthma medication only (OR 7; 4-18 and OR = 17; 10-33, with and without asthma). Independent predictors of antibiotic prescribing among patients with asthma included fewer previous ALRTI presentations (≥2 vs. 0 previous ALRTI: OR = 0.25; 0.16-0.39), higher practice (OR = 1.47; 1.35-1.60 per SD) and prior antibiotic prescribing (3+ vs. 1 prescriptions OR = 1.28; 1.04-1.57) and concurrent asthma medication (OR = 1.44; 1.32-1.57). Independent predictors of asthma medication in patients without asthma included higher prior asthma medication prescribing (≥7 vs. 0 prescriptions OR = 2.31; 1.83-2.91) and concurrent antibiotic prescribing (OR = 3.59; 3.22-4.01). CONCLUSION: Findings from the study indicate that antibiotics are over-used for ALRTI, irrespective of asthma status, and asthma medication is over-used in patients without asthma, with between-practice variation suggesting considerable clinical uncertainty. Further research is urgently needed to clarify the role of these medications for ALRTI.

Polypharmacy patterns in the last year of life in patients with dementia.

PURPOSE: To describe prescribing of medicines in primary care in the last year of life in patients with dementia. METHOD: A retrospective cohort analysis in UK primary care using routinely collected data from the Clinical Practice Research Datalink. Number of medications and potentially inappropriate medication prescribed one year prior to, and including death, was ascertained. RESULTS: Dementia patients (n = 6923) aged 86.6 ± 7.3 years (mean ± SD) were prescribed 4.8 ± 4.0 drugs 1 year prior to death, increasing to 5.6 ± 4.0 2 months prior, before falling to 4.9 ± 4.1 at death. One year prior to death, 50% of patients were prescribed a potentially inappropriate medication, falling to 41% at death. Cardiovascular medications were the most common, with decreases in drug count only occurring in the last month prior to death. Prescriptions for gastrointestinal and central nervous system medication increased throughout the year, particularly laxatives/analgaesics, antidepressants and hypnotic/antipsychotics. Women (vs. men) and patients with Alzheimer's (vs. vascular dementia) were prescribed 4.7% (95% CI 2.3%-7%) and 14.6% (11.7-17.3%) fewer medications, respectively. Prescribing decreased with age and increased with additional comorbidities. CONCLUSIONS: Dementia patients are prescribed high levels of medication, many potentially inappropriate, during their last year of life, with reductions occurring relatively late. Improvements to medication optimisation guidelines are needed to inform decision-making around deprescribing of long-term medications in patients with limited life-expectancy.

Growth Trajectories, Breast Size, and Breast-Tissue Composition in a British Prebirth Cohort of Young Women.

Mammographic percent density, the proportion of fibroglandular tissue in the breast, is a strong risk factor for breast cancer, but its determinants in young women are unknown. We examined associations of magnetic resonance imaging (MRI) breast-tissue composition at age 21 years with prospectively collected measurements of body size and composition from birth to early adulthood and markers of puberty (all standardized) in a sample of 500 nulliparous women from a prebirth cohort of children born in Avon, United Kingdom, in 1991-1992 and followed up to 2011-2014. Linear models were fitted to estimate relative change in MRI percent water, which is equivalent to mammographic percent density, associated with a 1-standard-deviation increase in the exposure of interest. In mutually adjusted analyses, MRI percent water was positively associated with birth weight (relative change (RC) = 1.03, 95% confidence interval (CI): 1.00, 1.06) and pubertal height growth (RC = 1.07, 95% CI: 1.02, 1.13) but inversely associated with pubertal weight growth (RC = 0.86, 95% CI: 0.84, 0.89) and changes in dual-energy x-ray absorptiometry percent body fat mass (e.g., for change between ages 11 years and 13.5 years, RC = 0.96, 95% CI: 0.93, 0.99). Ages at thelarche and menarche were positively associated with MRI percent water, but these associations did not persist upon adjustment for height and weight growth. These findings support the hypothesis that growth trajectories influence breast-tissue composition in young women, whereas puberty plays no independent role.

Impact of type of full-field digital image on mammographic density assessment and breast cancer risk estimation: a case-control study.

BACKGROUND: Full-field digital mammography, which is gradually being introduced in most clinical and screening settings, produces two types of images: raw and processed. However, the extent to which mammographic density measurements, and their ability to predict breast cancer risk, vary according to type of image is not fully known. METHODS: We compared the performance of the semi-automated Cumulus method on digital raw, "analogue-like" raw and processed images, and the performance of a recently developed method - Laboratory for Breast Radiodensity Assessment (LIBRA) - on digital raw and processed images, in a case-control study (414 patients (cases) and 684 controls) by evaluating the extent to which their measurements were associated with breast cancer risk factors, and by comparing their ability to predict breast cancer risk. RESULTS: Valid Cumulus and LIBRA measurements were obtained from all available images, but the resulting distributions differed according to the method and type of image used. Both Cumulus and LIBRA percent density were inversely associated with age, body mass index (BMI), parity and postmenopausal status, regardless of type of image used. Cumulus percent density was strongly associated with breast cancer risk, but with the magnitude of the association slightly stronger for processed (risk increase per one SD increase in percent density (95 % CI): 1.55 (1.29, 1.85)) and "analogue-like" raw (1.52 (1.28, 1.80)) than for raw (1.35 (1.14, 1.60)) images. LIBRA percent density produced weaker associations with risk, albeit stronger for processed (1.32 (1.08, 1.61)) than raw images (1.17 (0.99, 1.37)). The percent density values yielded by the various density assessment/type of image combinations had similar ability to discriminate between patients and controls (area under the receiving operating curve values for percent density, age, BMI, parity and menopausal status combined ranged from 0.61 and 0.64). CONCLUSIONS: The findings showed that Cumulus can be used to measure density on all types of digital images. They also indicate that LIBRA may provide a valid fully automated alternative to the more labour-intensive Cumulus. However, the same digital image type and assessment method should be used when examining mammographic density across populations, or longitudinal changes in density within a single population.

Pre-natal exposures and breast tissue composition: findings from a British pre-birth cohort of young women and a systematic review.

BACKGROUND: Breast density, the amount of fibroglandular tissue in the adult breast for a women's age and body mass index, is a strong biomarker of susceptibility to breast cancer, which may, like breast cancer risk itself, be influenced by events early in life. In the present study, we investigated the association between pre-natal exposures and breast tissue composition. METHODS: A sample of 500 young, nulliparous women (aged approximately 21 years) from a U.K. pre-birth cohort underwent a magnetic resonance imaging examination of their breasts to estimate percent water, a measure of the relative amount of fibroglandular tissue equivalent to mammographic percent density. Information on pre-natal exposures was collected throughout the mothers' pregnancy and shortly after delivery. Regression models were used to investigate associations between percent water and pre-natal exposures. Mediation analysis, and a systematic review and meta-analysis of the published literature, were also conducted. RESULTS: Adjusted percent water in young women was positively associated with maternal height (p for linear trend [p t] = 0.005), maternal mammographic density in middle age (p t = 0.018) and the participant's birth size (p t < 0.001 for birthweight). A 1-SD increment in weight (473 g), length (2.3 cm), head circumference (1.2 cm) and Ponderal Index (4.1 g/cm3) at birth were associated with 3 % (95 % CI 2-5 %), 2 % (95 % CI 0-3 %), 3 % (95 % CI 1-4 %) and 1 % (95 % CI 0-3 %), respectively, increases in mean adjusted percent water. The effect of maternal height on the participants' percent water was partly mediated through birth size, but there was little evidence that the effect of birthweight was primarily mediated via adult body size. The meta-analysis supported the study findings, with breast density being positively associated with birth size. CONCLUSIONS: These findings provide strong evidence of pre-natal influences on breast tissue composition. The positive association between birth size and relative amount of fibroglandular tissue indicates that breast density and breast cancer risk may share a common pre-natal origin.

Is previous respiratory disease a risk factor for lung cancer?

RATIONALE: Previous respiratory diseases have been associated with increased risk of lung cancer. Respiratory conditions often co-occur and few studies have investigated multiple conditions simultaneously. OBJECTIVES: Investigate lung cancer risk associated with chronic bronchitis, emphysema, tuberculosis, pneumonia, and asthma. METHODS: The SYNERGY project pooled information on previous respiratory diseases from 12,739 case subjects and 14,945 control subjects from 7 case-control studies conducted in Europe and Canada. Multivariate logistic regression models were used to investigate the relationship between individual diseases adjusting for co-occurring conditions, and patterns of respiratory disease diagnoses and lung cancer. Analyses were stratified by sex, and adjusted for age, center, ever-employed in a high-risk occupation, education, smoking status, cigarette pack-years, and time since quitting smoking. MEASUREMENTS AND MAIN RESULTS: Chronic bronchitis and emphysema were positively associated with lung cancer, after accounting for other respiratory diseases and smoking (e.g., in men: odds ratio [OR], 1.33; 95% confidence interval [CI], 1.20-1.48 and OR, 1.50; 95% CI, 1.21-1.87, respectively). A positive relationship was observed between lung cancer and pneumonia diagnosed 2 years or less before lung cancer (OR, 3.31; 95% CI, 2.33-4.70 for men), but not longer. Co-occurrence of chronic bronchitis and emphysema and/or pneumonia had a stronger positive association with lung cancer than chronic bronchitis "only." Asthma had an inverse association with lung cancer, the association being stronger with an asthma diagnosis 5 years or more before lung cancer compared with shorter. CONCLUSIONS: Findings from this large international case-control consortium indicate that after accounting for co-occurring respiratory diseases, chronic bronchitis and emphysema continue to have a positive association with lung cancer.

Can computer simulation support strategic service planning? Modelling a large integrated mental health system on recovery from COVID-19.

BACKGROUND: COVID-19 has had a significant impact on people's mental health and mental health services. During the first year of the pandemic, existing demand was not fully met while new demand was generated, resulting in large numbers of people requiring support. To support mental health services to recover without being overwhelmed, it was important to know where services will experience increased pressure, and what strategies could be implemented to mitigate this. METHODS: We implemented a computer simulation model of patient flow through an integrated mental health service in Southwest England covering General Practice (GP), community-based 'talking therapies' (IAPT), acute hospital care, and specialist care settings. The model was calibrated on data from 1 April 2019 to 1 April 2021. Model parameters included patient demand, service-level length of stay, and probabilities of transitioning to other care settings. We used the model to compare 'do nothing' (baseline) scenarios to 'what if' (mitigation) scenarios, including increasing capacity and reducing length of stay, for two future demand trajectories from 1 April 2021 onwards. RESULTS: The results from the simulation model suggest that, without mitigation, the impact of COVID-19 will be an increase in pressure on GP and specialist community based services by 50% and 50-100% respectively. Simulating the impact of possible mitigation strategies, results show that increasing capacity in lower-acuity services, such as GP, causes a shift in demand to other parts of the mental health system while decreasing length of stay in higher acuity services is insufficient to mitigate the impact of increased demand. CONCLUSION: In capturing the interrelation of patient flow related dynamics between various mental health care settings, we demonstrate the value of computer simulation for assessing the impact of interventions on system flow.

Cohort study of cardiovascular safety of different COVID-19 vaccination doses among 46 million adults in England.

The first dose of COVID-19 vaccines led to an overall reduction in cardiovascular events, and in rare cases, cardiovascular complications. There is less information about the effect of second and booster doses on cardiovascular diseases. Using longitudinal health records from 45.7 million adults in England between December 2020 and January 2022, our study compared the incidence of thrombotic and cardiovascular complications up to 26 weeks after first, second and booster doses of brands and combinations of COVID-19 vaccines used during the UK vaccination program with the incidence before or without the corresponding vaccination. The incidence of common arterial thrombotic events (mainly acute myocardial infarction and ischaemic stroke) was generally lower after each vaccine dose, brand and combination. Similarly, the incidence of common venous thrombotic events, (mainly pulmonary embolism and lower limb deep venous thrombosis) was lower after vaccination. There was a higher incidence of previously reported rare harms after vaccination: vaccine-induced thrombotic thrombocytopenia after first ChAdOx1 vaccination, and myocarditis and pericarditis after first, second and transiently after booster mRNA vaccination (BNT-162b2 and mRNA-1273). These findings support the wide uptake of future COVID-19 vaccination programs.

Acute and long-term outcomes of SARS-CoV-2 infection in school-aged children in England: Study protocol for the joint analysis of the COVID-19 schools infection survey (SIS) and the COVID-19 mapping and mitigation in schools (CoMMinS) study.

BACKGROUND: The symptom profiles of acute SARS-CoV-2 infection and long-COVID in children and young people (CYP), risk factors, and associated healthcare needs, are poorly defined. The Schools Infection Survey 1 (SIS-1) was a nationwide study of SARS-CoV-2 infection in primary and secondary schools in England during the 2020/21 school year. The Covid-19 Mapping and Mitigation in Schools (CoMMinS) study was conducted in schools in the Bristol area over a similar period. Both studies conducted testing to identify current and previous SARS-CoV-2 infection, and recorded symptoms and school attendance. These research data have been linked to routine electronic health record (EHR) data. AIMS: To better understand the short- and long-term consequences of SARS-CoV-2 infection, and their risk factors, in CYP. METHODS: Retrospective cohort and nested case-control analyses will be conducted for SIS-1 and CoMMinS data linked to EHR data for the association between (1) acute symptomatic SARS-CoV-2 infection and risk factors; (2) SARS-CoV-2 infection and long-term effects on health: (a) persistent symptoms; (b) any new diagnosis; (c) a new prescription in primary care; (d) health service attendance; (e) a high rate of school absence. RESULTS: Our study will improve understanding of long-COVID in CYP by characterising the trajectory of long-COVID in CYP in terms of things like symptoms and diagnoses of conditions. The research will inform which groups of CYP are more likely to get acute- and long-term outcomes of SARS-CoV-2 infection, and patterns of related healthcare-seeking behaviour, relevant for healthcare service planning. Digested information will be produced for affected families, doctors, schools, and the public, as appropriate. CONCLUSION: Linked SIS-1 and CoMMinS data represent a unique and rich resource for understanding the impact of SARS-CoV-2 infection on children's health, benefiting from enhanced SARS-CoV-2 testing and ability to assess a wide range of outcomes.

COVID-19 diagnosis, vaccination during pregnancy, and adverse pregnancy outcomes of 865,654 women in England and Wales: a population-based cohort study.

Background: The extent to which COVID-19 diagnosis and vaccination during pregnancy are associated with risks of common and rare adverse pregnancy outcomes remains uncertain. We compared the incidence of adverse pregnancy outcomes in women with and without COVID-19 diagnosis and vaccination during pregnancy. Methods: We studied population-scale linked electronic health records for women with singleton pregnancies in England and Wales from 1 August 2019 to 31 December 2021. This time period was divided at 8th December 2020 into pre-vaccination and vaccination roll-out eras. We calculated adjusted hazard ratios (HRs) for common and rare pregnancy outcomes according to the time since COVID-19 diagnosis and vaccination and by pregnancy trimester and COVID-19 variant. Findings: Amongst 865,654 pregnant women, we recorded 60,134 (7%) COVID-19 diagnoses and 182,120 (21%) adverse pregnancy outcomes. COVID-19 diagnosis was associated with a higher risk of gestational diabetes (adjusted HR 1.22, 95% CI 1.18-1.26), gestational hypertension (1.16, 1.10-1.22), pre-eclampsia (1.20, 1.12-1.28), preterm birth (1.63, 1.57-1.69, and 1.68, 1.61-1.75 for spontaneous preterm), very preterm birth (2.04, 1.86-2.23), small for gestational age (1.12, 1.07-1.18), thrombotic venous events (1.85, 1.56-2.20) and stillbirth (only within 14-days since COVID-19 diagnosis, 3.39, 2.23-5.15). HRs were more pronounced in the pre-vaccination era, within 14-days since COVID-19 diagnosis, when COVID-19 diagnosis occurred in the 3rd trimester, and in the original variant era. There was no evidence to suggest COVID-19 vaccination during pregnancy was associated with a higher risk of adverse pregnancy outcomes. Instead, dose 1 of COVID-19 vaccine was associated with lower risks of preterm birth (0.90, 0.86-0.95), very preterm birth (0.84, 0.76-0.94), small for gestational age (0.93, 0.88-0.99), and stillbirth (0.67, 0.49-0.92). Interpretation: Pregnant women with a COVID-19 diagnosis have higher risks of adverse pregnancy outcomes. These findings support recommendations towards high-priority vaccination against COVID-19 in pregnant women. Funding: BHF, ESRC, Forte, HDR-UK, MRC, NIHR and VR.

Incidence of diabetes after SARS-CoV-2 infection in England and the implications of COVID-19 vaccination: a retrospective cohort study of 16 million people.

BACKGROUND: Some studies have shown that the incidence of type 2 diabetes increases after a diagnosis of COVID-19, although the evidence is not conclusive. However, the effects of the COVID-19 vaccine on this association, or the effect on other diabetes subtypes, are not clear. We aimed to investigate the association between COVID-19 and incidence of type 2, type 1, gestational and non-specific diabetes, and the effect of COVID- 19 vaccination, up to 52 weeks after diagnosis. METHODS: In this retrospective cohort study, we investigated the diagnoses of incident diabetes following COVID-19 diagnosis in England in a pre-vaccination, vaccinated, and unvaccinated cohort using linked electronic health records. People alive and aged between 18 years and 110 years, registered with a general practitioner for at least 6 months before baseline, and with available data for sex, region, and area deprivation were included. Those with a previous COVID-19 diagnosis were excluded. We estimated adjusted hazard ratios (aHRs) comparing diabetes incidence after COVID-19 diagnosis with diabetes incidence before or in the absence of COVID-19 up to 102 weeks after diagnosis. Results were stratified by COVID-19 severity (categorised as hospitalised or non-hospitalised) and diabetes type. FINDINGS: 16 669 943 people were included in the pre-vaccination cohort (Jan 1, 2020-Dec 14, 2021), 12 279 669 in the vaccinated cohort, and 3 076 953 in the unvaccinated cohort (both June 1-Dec 14, 2021). In the pre-vaccination cohort, aHRs for the incidence of type 2 diabetes after COVID-19 (compared with before or in the absence of diagnosis) declined from 4·30 (95% CI 4·06-4·55) in weeks 1-4 to 1·24 (1·14-1.35) in weeks 53-102. aHRs were higher in unvaccinated people (8·76 [7·49-10·25]) than in vaccinated people (1·66 [1·50-1·84]) in weeks 1-4 and in patients hospitalised with COVID-19 (pre-vaccination cohort 28·3 [26·2-30·5]) in weeks 1-4 declining to 2·04 [1·72-2·42] in weeks 53-102) than in those who were not hospitalised (1·95 [1·78-2·13] in weeks 1-4 declining to 1·11 [1·01-1·22] in weeks 53-102). Type 2 diabetes persisted for 4 months after COVID-19 in around 60% of those diagnosed. Patterns were similar for type 1 diabetes, although excess incidence did not persist beyond 1 year after a COVID-19 diagnosis. INTERPRETATION: Elevated incidence of type 2 diabetes after COVID-19 is greater, and persists for longer, in people who were hospitalised with COVID-19 than in those who were not, and is markedly less apparent in people who have been vaccinated against COVID-19. Testing for type 2 diabetes after severe COVID-19 and the promotion of vaccination are important tools in addressing this public health problem. FUNDING: UK National Institute for Health and Care Research, UK Research and Innovation (UKRI) Medical Research Council, UKRI Engineering and Physical Sciences Research Council, Health Data Research UK, Diabetes UK, British Heart Foundation, and the Stroke Association.

COVID-19 and Mental Illnesses in Vaccinated and Unvaccinated People.

Importance: Associations have been found between COVID-19 and subsequent mental illness in both hospital- and population-based studies. However, evidence regarding which mental illnesses are associated with COVID-19 by vaccination status in these populations is limited. Objective: To determine which mental illnesses are associated with diagnosed COVID-19 by vaccination status in both hospitalized patients and the general population. Design, Setting, and Participants: This study was conducted in 3 cohorts, 1 before vaccine availability followed during the wild-type/Alpha variant eras (January 2020-June 2021) and 2 (vaccinated and unvaccinated) during the Delta variant era (June-December 2021). With National Health Service England approval, OpenSAFELY-TPP was used to access linked data from 24 million people registered with general practices in England using TPP SystmOne. People registered with a GP in England for at least 6 months and alive with known age between 18 and 110 years, sex, deprivation index information, and region at baseline were included. People were excluded if they had COVID-19 before baseline. Data were analyzed from July 2022 to June 2024. Exposure: Confirmed COVID-19 diagnosis recorded in primary care secondary care, testing data, or the death registry. Main Outcomes and Measures: Adjusted hazard ratios (aHRs) comparing the incidence of mental illnesses after diagnosis of COVID-19 with the incidence before or without COVID-19 for depression, serious mental illness, general anxiety, posttraumatic stress disorder, eating disorders, addiction, self-harm, and suicide. Results: The largest cohort, the pre-vaccine availability cohort, included 18 648 606 people (9 363 710 [50.2%] female and 9 284 896 [49.8%] male) with a median (IQR) age of 49 (34-64) years. The vaccinated cohort included 14 035 286 individuals (7 308 556 [52.1%] female and 6 726 730 [47.9%] male) with a median (IQR) age of 53 (38-67) years. The unvaccinated cohort included 3 242 215 individuals (1 363 401 [42.1%] female and 1 878 814 [57.9%] male) with a median (IQR) age of 35 (27-46) years. Incidence of most outcomes was elevated during weeks 1 through 4 after COVID-19 diagnosis, compared with before or without COVID-19, in each cohort. Incidence of mental illnesses was lower in the vaccinated cohort compared with the pre-vaccine availability and unvaccinated cohorts: aHRs for depression and serious mental illness during weeks 1 through 4 after COVID-19 were 1.93 (95% CI, 1.88-1.98) and 1.49 (95% CI, 1.41-1.57) in the pre-vaccine availability cohort and 1.79 (95% CI, 1.68-1.90) and 1.45 (95% CI, 1.27-1.65) in the unvaccinated cohort compared with 1.16 (95% CI, 1.12-1.20) and 0.91 (95% CI, 0.85-0.98) in the vaccinated cohort. Elevation in incidence was higher and persisted longer after hospitalization for COVID-19. Conclusions and Relevance: In this study, incidence of mental illnesses was elevated for up to a year following severe COVID-19 in unvaccinated people. These findings suggest that vaccination may mitigate the adverse effects of COVID-19 on mental health.