Severe COVID-19 outcomes after full vaccination of primary schedule and initial boosters: pooled analysis of national prospective cohort studies of 30 million individuals in England, Northern Ireland, Scotland, and Wales.

BACKGROUND: Current UK vaccination policy is to offer future COVID-19 booster doses to individuals at high risk of serious illness from COVID-19, but it is still uncertain which groups of the population could benefit most. In response to an urgent request from the UK Joint Committee on Vaccination and Immunisation, we aimed to identify risk factors for severe COVID-19 outcomes (ie, COVID-19-related hospitalisation or death) in individuals who had completed their primary COVID-19 vaccination schedule and had received the first booster vaccine. METHODS: We constructed prospective cohorts across all four UK nations through linkages of primary care, RT-PCR testing, vaccination, hospitalisation, and mortality data on 30 million people. We included individuals who received primary vaccine doses of BNT162b2 (tozinameran; Pfizer-BioNTech) or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines in our initial analyses. We then restricted analyses to those given a BNT162b2 or mRNA-1273 (elasomeran; Moderna) booster and had a severe COVID-19 outcome between Dec 20, 2021, and Feb 28, 2022 (when the omicron (B.1.1.529) variant was dominant). We fitted time-dependent Poisson regression models and calculated adjusted rate ratios (aRRs) and 95% CIs for the associations between risk factors and COVID-19-related hospitalisation or death. We adjusted for a range of potential covariates, including age, sex, comorbidities, and previous SARS-CoV-2 infection. Stratified analyses were conducted by vaccine type. We then did pooled analyses across UK nations using fixed-effect meta-analyses. FINDINGS: Between Dec 8, 2020, and Feb 28, 2022, 16 208 600 individuals completed their primary vaccine schedule and 13 836 390 individuals received a booster dose. Between Dec 20, 2021, and Feb 28, 2022, 59 510 (0·4%) of the primary vaccine group and 26 100 (0·2%) of those who received their booster had severe COVID-19 outcomes. The risk of severe COVID-19 outcomes reduced after receiving the booster (rate change: 8·8 events per 1000 person-years to 7·6 events per 1000 person-years). Older adults (≥80 years vs 18-49 years; aRR 3·60 [95% CI 3·45-3·75]), those with comorbidities (≥5 comorbidities vs none; 9·51 [9·07-9·97]), being male (male vs female; 1·23 [1·20-1·26]), and those with certain underlying health conditions-in particular, individuals receiving immunosuppressants (yes vs no; 5·80 [5·53-6·09])-and those with chronic kidney disease (stage 5 vs no; 3·71 [2·90-4·74]) remained at high risk despite the initial booster. Individuals with a history of COVID-19 infection were at reduced risk (infected ≥9 months before booster dose vs no previous infection; aRR 0·41 [95% CI 0·29-0·58]). INTERPRETATION: Older people, those with multimorbidity, and those with specific underlying health conditions remain at increased risk of COVID-19 hospitalisation and death after the initial vaccine booster and should, therefore, be prioritised for additional boosters, including novel optimised versions, and the increasing array of COVID-19 therapeutics. FUNDING: National Core Studies-Immunity, UK Research and Innovation (Medical Research Council), Health Data Research UK, the Scottish Government, and the University of Edinburgh.

Two-dose ChAdOx1 nCoV-19 vaccine protection against COVID-19 hospital admissions and deaths over time: a retrospective, population-based cohort study in Scotland and Brazil.

BACKGROUND: Reports suggest that COVID-19 vaccine effectiveness is decreasing, but whether this reflects waning or new SARS-CoV-2 variants-especially delta (B.1.617.2)-is unclear. We investigated the association between time since two doses of ChAdOx1 nCoV-19 vaccine and risk of severe COVID-19 outcomes in Scotland (where delta was dominant), with comparative analyses in Brazil (where delta was uncommon). METHODS: In this retrospective, population-based cohort study in Brazil and Scotland, we linked national databases from the EAVE II study in Scotland; and the COVID-19 Vaccination Campaign, Acute Respiratory Infection Suspected Cases, and Severe Acute Respiratory Infection/Illness datasets in Brazil) for vaccination, laboratory testing, clinical, and mortality data. We defined cohorts of adults (aged ≥18 years) who received two doses of ChAdOx1 nCoV-19 and compared rates of severe COVID-19 outcomes (ie, COVID-19 hospital admission or death) across fortnightly periods, relative to 2-3 weeks after the second dose. Entry to the Scotland cohort started from May 19, 2021, and entry to the Brazil cohort started from Jan 18, 2021. Follow-up in both cohorts was until Oct 25, 2021. Poisson regression was used to estimate rate ratios (RRs) and vaccine effectiveness, with 95% CIs. FINDINGS: 1 972 454 adults received two doses of ChAdOx1 nCoV-19 in Scotland and 42 558 839 in Brazil, with longer follow-up in Scotland because two-dose vaccination began earlier in Scotland than in Brazil. In Scotland, RRs for severe COVID-19 increased to 2·01 (95% CI 1·54-2·62) at 10-11 weeks, 3·01 (2·26-3·99) at 14-15 weeks, and 5·43 (4·00-7·38) at 18-19 weeks after the second dose. The pattern of results was similar in Brazil, with RRs of 2·29 (2·01-2·61) at 10-11 weeks, 3·10 (2·63-3·64) at 14-15 weeks, and 4·71 (3·83-5·78) at 18-19 weeks after the second dose. In Scotland, vaccine effectiveness decreased from 83·7% (95% CI 79·7-87·0) at 2-3 weeks, to 75·9% (72·9-78·6) at 14-15 weeks, and 63·7% (59·6-67·4) at 18-19 weeks after the second dose. In Brazil, vaccine effectiveness decreased from 86·4% (85·4-87·3) at 2-3 weeks, to 59·7% (54·6-64·2) at 14-15 weeks, and 42·2% (32·4-50·6) at 18-19 weeks. INTERPRETATION: We found waning vaccine protection of ChAdOx1 nCoV-19 against COVID-19 hospital admissions and deaths in both Scotland and Brazil, this becoming evident within three months of the second vaccine dose. Consideration needs to be given to providing booster vaccine doses for people who have received ChAdOx1 nCoV-19. FUNDING: UK Research and Innovation (Medical Research Council), Scottish Government, Research and Innovation Industrial Strategy Challenge Fund, Health Data Research UK, Fiocruz, Fazer o Bem Faz Bem Programme; Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

Maternal multimorbidity and preterm birth in Scotland: an observational record-linkage study.

BACKGROUND: Multimorbidity is common in women across the life course. Preterm birth is the single biggest cause of neonatal mortality and morbidity. We aim to estimate the prevalence of multimorbidity in pregnant women and to examine the association between maternal multimorbidity and PTB. METHODS: This is a retrospective cohort study using electronic health records from the Scottish Morbidity Records. All pregnancies among women aged 15 to 49 with a conception date between 1 January 2014 and 31 December 2018 were included. Multimorbidity was defined as the presence of two or more pre-existing long-term physical or mental health conditions, and complex multimorbidity as the presence of four or more. It was calculated at the time of conception using a predefined list of 79 conditions published by the MuM-PreDiCT consortium. PTB was defined as babies born alive between 24 and less than 37 completed weeks of gestation. We used Generalised Estimating Equations adjusted for maternal age, socioeconomic status, number of previous pregnancies, BMI, and smoking history to estimate the effect of maternal pre-existing multimorbidity. Absolut rates are reported in the results and tables, whilst Odds Ratios (ORs) are adjusted (aOR). RESULTS: Thirty thousand five hundred fifty-seven singleton births from 27,711 pregnant women were included in the analysis. The prevalence of pre-existing multimorbidity and complex multimorbidity was 16.8% (95% CI: 16.4-17.2) and 3.6% (95% CI: 3.3-3.8), respectively. The prevalence of multimorbidity in the youngest age group was 10.2%(95% CI: 8.8-11.6), while in those 40 to 44, it was 21.4% (95% CI: 18.4-24.4), and in the 45 to 49 age group, it was 20% (95% CI: 8.9-31.1). In women without multimorbidity, the prevalence of PTB was 6.7%; it was 11.6% in women with multimorbidity and 15.6% in women with complex multimorbidity. After adjusting for maternal age, socioeconomic status, number of previous pregnancies, Body Mass Index (BMI), and smoking, multimorbidity was associated with higher odds of PTB (aOR = 1.64, 95% CI: 1.48-1.82). CONCLUSIONS: Multimorbidity at the time of conception was present in one in six women and was associated with an increased risk of preterm birth. Multimorbidity presents a significant health burden to women and their offspring. Routine and comprehensive evaluation of women with multimorbidity before and during pregnancy is urgently needed.

Polypharmacy during pregnancy and associated risk factors: a retrospective analysis of 577 medication exposures among 1.5 million pregnancies in the UK, 2000-2019.

BACKGROUND: The number of medications prescribed during pregnancy has increased over the past few decades. Few studies have described the prevalence of multiple medication use among pregnant women. This study aims to describe the overall prevalence over the last two decades among all pregnant women and those with multimorbidity and to identify risk factors for polypharmacy in pregnancy. METHODS: A retrospective cohort study was conducted between 2000 and 2019 using the Clinical Practice Research Datalink (CPRD) pregnancy register. Prescription records for 577 medication categories were obtained. Prevalence estimates for polypharmacy (ranging from 2+ to 11+ medications) were presented along with the medications commonly prescribed individually and in pairs during the first trimester and the entire pregnancy period. Logistic regression models were performed to identify risk factors for polypharmacy. RESULTS: During the first trimester (812,354 pregnancies), the prevalence of polypharmacy ranged from 24.6% (2+ medications) to 0.1% (11+ medications). During the entire pregnancy period (774,247 pregnancies), the prevalence ranged from 58.7 to 1.4%. Broad-spectrum penicillin (6.6%), compound analgesics (4.5%) and treatment of candidiasis (4.3%) were commonly prescribed. Pairs of medication prescribed to manage different long-term conditions commonly included selective beta 2 agonists or selective serotonin re-uptake inhibitors (SSRIs). Risk factors for being prescribed 2+ medications during the first trimester of pregnancy include being overweight or obese [aOR: 1.16 (1.14-1.18) and 1.55 (1.53-1.57)], belonging to an ethnic minority group [aOR: 2.40 (2.33-2.47), 1.71 (1.65-1.76), 1.41 (1.35-1.47) and 1.39 (1.30-1.49) among women from South Asian, Black, other and mixed ethnicities compared to white women] and smoking or previously smoking [aOR: 1.19 (1.18-1.20) and 1.05 (1.03-1.06)]. Higher and lower age, higher gravidity, increasing number of comorbidities and increasing level of deprivation were also associated with increased odds of polypharmacy. CONCLUSIONS: The prevalence of polypharmacy during pregnancy has increased over the past two decades and is particularly high in younger and older women; women with high BMI, smokers and ex-smokers; and women with multimorbidity, higher gravidity and higher levels of deprivation. Well-conducted pharmaco-epidemiological research is needed to understand the effects of multiple medication use on the developing foetus.

The development of a core outcome set for studies of pregnant women with multimorbidity.

BACKGROUND: Heterogeneity in reported outcomes can limit the synthesis of research evidence. A core outcome set informs what outcomes are important and should be measured as a minimum in all future studies. We report the development of a core outcome set applicable to observational and interventional studies of pregnant women with multimorbidity. METHODS: We developed the core outcome set in four stages: (i) a systematic literature search, (ii) three focus groups with UK stakeholders, (iii) two rounds of Delphi surveys with international stakeholders and (iv) two international virtual consensus meetings. Stakeholders included women with multimorbidity and experience of pregnancy in the last 5 years, or are planning a pregnancy, their partners, health or social care professionals and researchers. Study adverts were shared through stakeholder charities and organisations. RESULTS: Twenty-six studies were included in the systematic literature search (2017 to 2021) reporting 185 outcomes. Thematic analysis of the focus groups added a further 28 outcomes. Two hundred and nine stakeholders completed the first Delphi survey. One hundred and sixteen stakeholders completed the second Delphi survey where 45 outcomes reached Consensus In (≥70% of all participants rating an outcome as Critically Important). Thirteen stakeholders reviewed 15 Borderline outcomes in the first consensus meeting and included seven additional outcomes. Seventeen stakeholders reviewed these 52 outcomes in a second consensus meeting, the threshold was ≥80% of all participants voting for inclusion. The final core outcome set included 11 outcomes. The five maternal outcomes were as follows: maternal death, severe maternal morbidity, change in existing long-term conditions (physical and mental), quality and experience of care and development of new mental health conditions. The six child outcomes were as follows: survival of baby, gestational age at birth, neurodevelopmental conditions/impairment, quality of life, birth weight and separation of baby from mother for health care needs. CONCLUSIONS: Multimorbidity in pregnancy is a new and complex clinical research area. Following a rigorous process, this complexity was meaningfully reduced to a core outcome set that balances the views of a diverse stakeholder group.

Intranasal steroid use and COVID-19 mortality among patients with asthma and COPD: A retrospective cohort study.

BACKGROUND: Systemic corticosteroids have been widely used for treating patients with severe acute respiratory distress syndrome. Inhaled corticosteroids may have a protective effect for treating acute coronavirus disease 2019 (COVID-19); however, little is known about the potential effect of intranasal corticosteroids (INCS) on COVID-19 outcomes and severity. OBJECTIVE: To assess the impact of prior long-term INCS exposure on COVID-19 mortality among patients with chronic respiratory disease and in the general population. METHODS: A retrospective cohort study was conducted. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between INCS exposure and all-cause and COVID-19 mortality, adjusted by age, sex, deprivation, exacerbations in the last year, and comorbidities. RESULTS: Exposure to INCS did not have a significant association with COVID-19 mortality among the general population or cohorts with chronic obstructive pulmonary disease or asthma, with HRs of 0.8 (95% CI, 0.6-1.0, P = .06), 0.6 (95% CI, 0.3-1.1, P = .1), and 0.9 (95% CI, 0.2-3.9, P = .9), respectively. Exposure to INCS was, however, significantly associated with reduction in all-cause mortality in all groups, which was 40% lower (HR, 0.6 [95% CI, 0.5-0.6, P < .001]) among the general population, 30% lower (HR, 0.7; 95% CI, 0.6-0.8, P < .001) among patients with chronic obstructive pulmonary disease, and 50% lower (HR, 0.5; 95% CI, 0.3-0.7, P = .003) among patients with asthma. CONCLUSION: The role of INCS in COVID-19 is still unclear, but exposure to INCS does not adversely affect COVID-19 mortality. Further studies are needed to explore the association between their use and inflammatory activation, viral load, angiotensin-converting enzyme 2 gene expression, and outcomes, exploring different types and doses of INCS.

Key outcomes for reporting in studies of pregnant women with multiple long-term conditions: a qualitative study.

BACKGROUND: Maternal multiple long-term conditions are associated with adverse outcomes for mother and child. We conducted a qualitative study to inform a core outcome set for studies of pregnant women with multiple long-term conditions. METHODS: Women with two or more pre-existing long-term physical or mental health conditions, who had been pregnant in the last five years or planning a pregnancy, their partners and health care professionals were eligible. Recruitment was through social media, patients and health care professionals' organisations and personal contacts. Participants who contacted the study team were purposively sampled for maximum variation. Three virtual focus groups were conducted from December 2021 to March 2022 in the United Kingdom: (i) health care professionals (n = 8), (ii) women with multiple long-term conditions (n = 6), and (iii) women with multiple long-term conditions (n = 6) and partners (n = 2). There was representation from women with 20 different physical health conditions and four mental health conditions; health care professionals from obstetrics, obstetric/maternal medicine, midwifery, neonatology, perinatal psychiatry, and general practice. Participants were asked what outcomes should be reported in all studies of pregnant women with multiple long-term conditions. Inductive thematic analysis was conducted. Outcomes identified in the focus groups were mapped to those identified in a systematic literature search in the core outcome set development. RESULTS: The focus groups identified 63 outcomes, including maternal (n = 43), children's (n = 16) and health care utilisation (n = 4) outcomes. Twenty-eight outcomes were new when mapped to the systematic literature search. Outcomes considered important were generally similar across stakeholder groups. Women emphasised outcomes related to care processes, such as information sharing when transitioning between health care teams and stages of pregnancy (continuity of care). Both women and partners wanted to be involved in care decisions and to feel informed of the risks to the pregnancy and baby. Health care professionals additionally prioritised non-clinical outcomes, including quality of life and financial implications for the women; and longer-term outcomes, such as children's developmental outcomes. CONCLUSIONS: The findings will inform the design of a core outcome set. Participants' experiences provided useful insights of how maternity care for pregnant women with multiple long-term conditions can be improved.

Prevalence and demographic variation of cardiovascular, renal, metabolic, and mental health conditions in 12 million english primary care records.

BACKGROUND: Primary care electronic health records (EHR) are widely used to study long-term conditions in epidemiological and health services research. Therefore, it is important to understand how well the recorded prevalence of these conditions in EHRs, compares to other reliable sources overall, and varies by socio-demographic characteristics. We aimed to describe the prevalence and socio-demographic variation of cardiovascular, renal, and metabolic (CRM) and mental health (MH) conditions in a large, nationally representative, English primary care database and compare with prevalence estimates from other population-based studies. METHODS: This was a cross-sectional study using the Clinical Practice Research Datalink (CPRD) Aurum primary care database. We calculated prevalence of 18 conditions and used logistic regression to assess how this varied by age, sex, ethnicity, and socio-economic status. We searched the literature for population prevalence estimates from other sources for comparison with the prevalences in CPRD Aurum. RESULTS: Depression (16.0%, 95%CI 16.0-16.0%) and hypertension (15.3%, 95%CI 15.2-15.3%) were the most prevalent conditions among 12.4 million patients. Prevalence of most conditions increased with socio-economic deprivation and age. CRM conditions, schizophrenia and substance misuse were higher in men, whilst anxiety, depression, bipolar and eating disorders were more common in women. Cardiovascular risk factors (hypertension and diabetes) were more prevalent in black and Asian patients compared with white, but the trends in prevalence of cardiovascular diseases by ethnicity were more variable. The recorded prevalences of mental health conditions were typically twice as high in white patients compared with other ethnic groups. However, PTSD and schizophrenia were more prevalent in black patients. The prevalence of most conditions was similar or higher in the primary care database than diagnosed disease prevalence reported in national health surveys. However, screening studies typically reported higher prevalence estimates than primary care data, especially for PTSD, bipolar disorder and eating disorders. CONCLUSIONS: The prevalence of many clinically diagnosed conditions in primary care records closely matched that of other sources. However, we found important variations by sex and ethnicity, which may reflect true variation in prevalence or systematic differences in clinical presentation and practice. Primary care data may underrepresent the prevalence of undiagnosed conditions, particularly in mental health.

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

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

Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: UK Research and Innovation (Medical Research Council), Research and Innovation Industrial Strategy Challenge Fund, Health Data Research UK.

External validation of the QCovid risk prediction algorithm for risk of COVID-19 hospitalisation and mortality in adults: national validation cohort study in Scotland.

BACKGROUND: The QCovid algorithm is a risk prediction tool that can be used to stratify individuals by risk of COVID-19 hospitalisation and mortality. Version 1 of the algorithm was trained using data covering 10.5 million patients in England in the period 24 January 2020 to 30 April 2020. We carried out an external validation of version 1 of the QCovid algorithm in Scotland. METHODS: We established a national COVID-19 data platform using individual level data for the population of Scotland (5.4 million residents). Primary care data were linked to reverse-transcription PCR (RT-PCR) virology testing, hospitalisation and mortality data. We assessed the performance of the QCovid algorithm in predicting COVID-19 hospitalisations and deaths in our dataset for two time periods matching the original study: 1 March 2020 to 30 April 2020, and 1 May 2020 to 30 June 2020. RESULTS: Our dataset comprised 5 384 819 individuals, representing 99% of the estimated population (5 463 300) resident in Scotland in 2020. The algorithm showed good calibration in the first period, but systematic overestimation of risk in the second period, prior to temporal recalibration. Harrell's C for deaths in females and males in the first period was 0.95 (95% CI 0.94 to 0.95) and 0.93 (95% CI 0.92 to 0.93), respectively. Harrell's C for hospitalisations in females and males in the first period was 0.81 (95% CI 0.80 to 0.82) and 0.82 (95% CI 0.81 to 0.82), respectively. CONCLUSIONS: Version 1 of the QCovid algorithm showed high levels of discrimination in predicting the risk of COVID-19 hospitalisations and deaths in adults resident in Scotland for the original two time periods studied, but is likely to need ongoing recalibration prospectively.

E. coli bacteraemia and antimicrobial resistance following antimicrobial prescribing for urinary tract infection in the community.

BACKGROUND: Urinary tract infections are one of the most common infections in primary and secondary care, with the majority of antimicrobial therapy initiated empirically before culture results are available. In some cases, however, over 40% of the bacteria that cause UTIs are resistant to some of the antimicrobials used, yet we do not know how the patient outcome is affected in terms of relapse, treatment failure, progression to more serious illness (bacteraemia) requiring hospitalization, and ultimately death. This study analyzed the current patterns of antimicrobial use for UTI in the community in Scotland, and factors for poor outcomes. OBJECTIVES: To explore antimicrobial use for UTI in the community in Scotland, and the relationship with patient characteristics and antimicrobial resistance in E. coli bloodstream infections and subsequent mortality. METHODS: We included all adult patients in Scotland with a positive blood culture with E. coli growth, receiving at least one UTI-related antimicrobial (amoxicillin, amoxicillin/clavulanic acid, ciprofloxacin, trimethoprim, and nitrofurantoin) between 1st January 2009 and 31st December 2012. Univariate and multivariate logistic regression analysis was performed to understand the impact of age, gender, socioeconomic status, previous community antimicrobial exposure (including long-term use), prior treatment failure, and multi-morbidity, on the occurrence of E. coli bacteraemia, trimethoprim and nitrofurantoin resistance, and mortality. RESULTS: There were 1,093,227 patients aged 16 to 100 years old identified as receiving at least one prescription for the 5 UTI-related antimicrobials during the study period. Antimicrobial use was particularly prevalent in the female elderly population, and 10% study population was on long-term antimicrobials. The greatest predictor for trimethoprim resistance in E. coli bacteraemia was increasing age (OR 7.18, 95% CI 5.70 to 9.04 for the 65 years old and over group), followed by multi-morbidity (OR 5.42, 95% CI 4.82 to 6.09 for Charlson Index 3+). Prior antimicrobial use, along with prior treatment failure, male gender, and higher deprivation were also associated with a greater likelihood of a resistant E. coli bacteraemia. Mortality was significantly associated with both having an E. coli bloodstream infection, and those with resistant growth. CONCLUSION: Increasing age, increasing co-morbidity, lower socioeconomic status, and prior community antibiotic exposure were significantly associated with a resistant E. coli bacteraemia, which leads to increased mortality.

Epidemiology of pre-existing multimorbidity in pregnant women in the UK in 2018: a population-based cross-sectional study.

BACKGROUND: Although maternal death is rare in the United Kingdom, 90% of these women had multiple health/social problems. This study aims to estimate the prevalence of pre-existing multimorbidity (two or more long-term physical or mental health conditions) in pregnant women in the United Kingdom (England, Northern Ireland, Wales and Scotland). STUDY DESIGN: Pregnant women aged 15-49 years with a conception date 1/1/2018 to 31/12/2018 were included in this population-based cross-sectional study, using routine healthcare datasets from primary care: Clinical Practice Research Datalink (CPRD, United Kingdom, n = 37,641) and Secure Anonymized Information Linkage databank (SAIL, Wales, n = 27,782), and secondary care: Scottish Morbidity Records with linked community prescribing data (SMR, Tayside and Fife, n = 6099). Pre-existing multimorbidity preconception was defined from 79 long-term health conditions prioritised through a workshop with patient representatives and clinicians. RESULTS: The prevalence of multimorbidity was 44.2% (95% CI 43.7-44.7%), 46.2% (45.6-46.8%) and 19.8% (18.8-20.8%) in CPRD, SAIL and SMR respectively. When limited to health conditions that were active in the year before pregnancy, the prevalence of multimorbidity was still high (24.2% [23.8-24.6%], 23.5% [23.0-24.0%] and 17.0% [16.0 to 17.9%] in the respective datasets). Mental health conditions were highly prevalent and involved 70% of multimorbidity CPRD: multimorbidity with ≥one mental health condition/s 31.3% [30.8-31.8%]). After adjusting for age, ethnicity, gravidity, index of multiple deprivation, body mass index and smoking, logistic regression showed that pregnant women with multimorbidity were more likely to be older (CPRD England, adjusted OR 1.81 [95% CI 1.04-3.17] 45-49 years vs 15-19 years), multigravid (1.68 [1.50-1.89] gravidity ≥ five vs one), have raised body mass index (1.59 [1.44-1.76], body mass index 30+ vs body mass index 18.5-24.9) and smoked preconception (1.61 [1.46-1.77) vs non-smoker). CONCLUSION: Multimorbidity is prevalent in pregnant women in the United Kingdom, they are more likely to be older, multigravid, have raised body mass index and smoked preconception. Secondary care and community prescribing dataset may only capture the severe spectrum of health conditions. Research is needed urgently to quantify the consequences of maternal multimorbidity for both mothers and children.

Earlier diagnosis of lung cancer in a randomised trial of an autoantibody blood test followed by imaging.

The EarlyCDT-Lung test is a high-specificity blood-based autoantibody biomarker that could contribute to predicting lung cancer risk. We report on the results of a phase IV biomarker evaluation of whether using the EarlyCDT-Lung test and any subsequent computed tomography (CT) scanning to identify those at high risk of lung cancer reduces the incidence of patients with stage III/IV/unspecified lung cancer at diagnosis compared with the standard clinical practice at the time the study began.The Early Diagnosis of Lung Cancer Scotland (ECLS) trial was a randomised controlled trial of 12 208 participants at risk of developing lung cancer in Scotland in the UK. The intervention arm received the EarlyCDT-Lung test and, if test-positive, low-dose CT scanning 6-monthly for up to 2 years. EarlyCDT-Lung test-negative and control arm participants received standard clinical care. Outcomes were assessed at 2 years post-randomisation using validated data on cancer occurrence, cancer staging, mortality and comorbidities.At 2 years, 127 lung cancers were detected in the study population (1.0%). In the intervention arm, 33 out of 56 (58.9%) lung cancers were diagnosed at stage III/IV compared with 52 out of 71 (73.2%) in the control arm. The hazard ratio for stage III/IV presentation was 0.64 (95% CI 0.41-0.99). There were nonsignificant differences in lung cancer and all-cause mortality after 2 years.ECLS compared EarlyCDT-Lung plus CT screening to standard clinical care (symptomatic presentation) and was not designed to assess the incremental contribution of the EarlyCDT-Lung test. The observation of a stage shift towards earlier-stage lung cancer diagnosis merits further investigations to evaluate whether the EarlyCDT-Lung test adds anything to the emerging standard of low-dose CT.

Medication adherence, utilization of healthcare services, and mortality of patients with epilepsy on opiate replacement therapy: A retrospective cohort study.

INTRODUCTION: Substance misuse is not uncommonly recognized in people with epilepsy (PWE). Mortality is significantly greater in those with comorbid substance misuse, but it remains unclear whether epilepsy care and management contribute to this. This cohort study aimed to compare the rates of mortality in PWE receiving opiate replacement therapy (ORT) and PWE alone, as well as evaluate their medication adherence, levels of engagement with epilepsy services as currently delivered, and utilization of unscheduled hospital care. MATERIAL AND METHODS: A 5-year historical cohort for PWE was identified and manually validated using electronic patient records registered with NHS Tayside. Overall incidence rates for mortality and contact with emergency health care services were calculated for PWE receiving ORT and PWE alone. Engagement with outpatient epilepsy services was also noted. Adherence to antiepileptic drugs (AEDs) was expressed in terms of medication possession ratio (MPR). RESULTS: Of the 1297 PWE attending a tertiary care epilepsy service, 68 (5.3%) PWE were receiving ORT. The mortality rate was significantly greater in PWE on ORT in comparison to PWE only (7.4% vs 1.7 %; P < 0.05; relative risk of death: 4.34, 95% CI 1.19-15.7), as well as the incidence of emergency healthcare services contact being higher (24.5% vs 17.7%; P < 0.05; incidence rate ratio: 1.39, 95% CI: 1.12-1.71). Poor adherence to AEDs was also more common in PWE on ORT (28.4% vs 23.5%; P = 0.02), as well as failure to engage with elective outpatient services (8.4% vs 3.0%; P < 0.05; rate ratio 2.77, 95% CI: 1.86-4.1). CONCLUSION: People with epilepsy on ORT are less likely to engage with elective epilepsy services as currently delivered or take AEDs as prescribed despite most of these patients having daily attendance at a community pharmacist. This may contribute to the significantly increased rates of mortality and unscheduled hospital care. Clinicians and policymakers should consider service redesign to meet the demands of this high-risk population in an attempt to reduce mortality and morbidity.

Linkage of national health and social care data: a cross-sectional study of multimorbidity and social care use in people aged over 65 years in Scotland.

BACKGROUND: little is known about the relationship between multimorbidity and social care use (also known as long-term care). The aim of this study was to assess the relationship between receipt of formal social care services and multimorbidity. METHODS: this retrospective data linkage, observational study included all individuals over the age of 65 in the population of Scotland in financial years 2014-15 and 2015-16 (n = 975,265). The main outcome was receipt of social care measured by presence in the Scottish Social Care Survey. Logistic regression models were used to assess the influence of multimorbidity, age, sex and socioeconomic position on the outcome reporting average marginal effects (AME). FINDINGS: 93.3% of those receiving social care had multimorbidity, 16.2% of those with multimorbidity received social care compared with 3.7% of those without. The strongest magnitudes of AME for receiving social care were seen for age and multimorbidity (respectively, 50 and 18% increased probability comparing oldest to youngest and most severe multimorbidity to none). A 5.5% increased probability of receiving social care was observed for the most-deprived compared with the least-deprived. INTERPRETATION: higher levels of social care receipt are observed in those with increasing age, severe multimorbidity and living in more deprived areas. Multimorbidity does not fully moderate the relationship between social care receipt and either age or deprivation.

Changes over time in the management of long-term conditions in primary health care for adults with intellectual disabilities, and the healthcare inequality gap.

BACKGROUND: Quality of primary healthcare impacts on health outcomes. This study aimed to quantify trends in good practice and the healthcare inequalities gap. METHOD: Indicators of best-practice management of long-term conditions and health promotion were extracted from primary healthcare records on 721 adults with intellectual disabilities in 2007-2010, and 3638 in 2014. They were compared over time, and with the general population in 2014, using Fisher's Exact test and ordinal regression. RESULTS: Management improved for adults with intellectual disabilities over time (OR = 5.32; CI = 2.69-10.55), but not for the general population (OR = 0.74; CI = 0.34-1.64). However, it remained poorer, but to a lesser extent, compared with the general population (OR = 0.38; CI = 0.20-0.73 in 2014, and OR = 0.05; CI = 0.02-0.12 in 2007-2010). In 2014, health care was comparable to the general population on 49/78 (62.8%) indicators. CONCLUSIONS: The extent of the healthcare inequality gap reduced over this period, but remaining inequalities highlight that further action is still necessary.

Risk factors associated with biochemically detected and hospitalised acute kidney injury in patients prescribed renin angiotensin system inhibitors.

AIMS: Therapy with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is a mainstay of treatment for heart failure (HF), diabetes mellitus (DM) and chronic kidney disease (CKD). These agents have been associated with development of acute kidney injury (AKI) during intercurrent illness. Risk factors for AKI in patients prescribed ACEi/ARB therapy are not well described. METHODS: We captured the incidence of AKI in patients commencing ACEi/ARB during 2009-2015 using anonymised patient records. Hospital-coded AKI was defined from hospital episode statistics; biochemical AKI was ascertained from laboratory data. Risk factors for biochemically detected and hospitalised AKI were investigated. RESULTS: Of 61,318 patients prescribed ACEi/ARB, with 132 885 person years (py) follow-up, there were 1070 hospitalisations with AKI as a diagnosis recorded and a total of 4645 AKI events, including AKI episodes indicated by biochemical KDIGO-based creatinine change criteria. Incidence of any AKI event was 35.0 per 1000-py, hospital-coded AKI was 7.8 per 1000-py and biochemical AKI was 33.7 per 1000-py. Independent risk factors in a multivariable model for hospital-coded AKI events were age, male gender, HF, diabetes, cerebrovascular disease, lower estimated glomerular filtration rate, socioeconomic deprivation, diuretic or non-steroidal anti-inflammatory use (all P < 0.001). CONCLUSION: In patients prescribed ACEi/ARB, the highest risk of AKI is associated with conditions which are considered strong evidence-based indications for their prescription. Socio-economic status is an under-reported risk factor for AKI with these agents. Strategies targeted at prevention of AKI may be of benefit, such as enhanced awareness based on higher risk comorbidities.

Comparing uptake across breast, cervical and bowel screening at an individual level: a retrospective cohort study.

BACKGROUND: We investigated demographic and clinical predictors of lower participation in bowel screening relative to breast and cervical screening. METHODS: Data linkage study of routinely collected clinical data from 430,591 women registered with general practices in the Greater Glasgow & Clyde Health Board. Participation in the screening programmes was measured by attendance at breast or cervical screening or the return of a bowel screening kit. RESULTS: 72.6% of 159,993 women invited attended breast screening, 80.7% of 309,899 women invited attended cervical screening and 61.7% of 180,408 women invited completed bowel screening. Of the 68,324 women invited to participate in all three screening programmes during the study period, 52.1% participated in all three while 7.2% participated in none. Women who participated in breast (OR = 3.34 (3.21, 3.47), p < 0.001) or cervical (OR = 3.48 (3.32, 3.65), p < 0.001) were more likely to participate in bowel screening. CONCLUSION: Participation in bowel screening was lower than breast or cervical for this population although the same demographic factors were associated with uptake, namely lower social deprivation, increasing age, low levels of comorbidity and prior non-malignant neoplasms. As women who complete breast and cervical are more likely to also complete bowel screening, interventions at these procedures to encourage bowel screening participation should be explored.

Safer Prescribing--A Trial of Education, Informatics, and Financial Incentives.

BACKGROUND: High-risk prescribing and preventable drug-related complications are common in primary care. We evaluated whether the rates of high-risk prescribing by primary care clinicians and the related clinical outcomes would be reduced by a complex intervention. METHODS: In this cluster-randomized, stepped-wedge trial conducted in Tayside, Scotland, we randomly assigned participating primary care practices to various start dates for a 48-week intervention comprising professional education, informatics to facilitate review, and financial incentives for practices to review patients' charts to assess appropriateness. The primary outcome was patient-level exposure to any of nine measures of high-risk prescribing of nonsteroidal antiinflammatory drugs (NSAIDs) or selected antiplatelet agents (e.g., NSAID prescription in a patient with chronic kidney disease or coprescription of an NSAID and an oral anticoagulant without gastroprotection). Prespecified secondary outcomes included the incidence of related hospital admissions. Analyses were performed according to the intention-to-treat principle, with the use of mixed-effect models to account for clustering in the data. RESULTS: A total of 34 practices underwent randomization, 33 of which completed the study. Data were analyzed for 33,334 patients at risk at one or more points in the preintervention period and for 33,060 at risk at one or more points in the intervention period. Targeted high-risk prescribing was significantly reduced, from a rate of 3.7% (1102 of 29,537 patients at risk) immediately before the intervention to 2.2% (674 of 30,187) at the end of the intervention (adjusted odds ratio, 0.63; 95% confidence interval [CI], 0.57 to 0.68; P<0.001). The rate of hospital admissions for gastrointestinal ulcer or bleeding was significantly reduced from the preintervention period to the intervention period (from 55.7 to 37.0 admissions per 10,000 person-years; rate ratio, 0.66; 95% CI, 0.51 to 0.86; P=0.002), as was the rate of admissions for heart failure (from 707.7 to 513.5 admissions per 10,000 person-years; rate ratio, 0.73; 95% CI, 0.56 to 0.95; P=0.02), but admissions for acute kidney injury were not (101.9 and 86.0 admissions per 10,000 person-years, respectively; rate ratio, 0.84; 95% CI, 0.68 to 1.09; P=0.19). CONCLUSIONS: A complex intervention combining professional education, informatics, and financial incentives reduced the rate of high-risk prescribing of antiplatelet medications and NSAIDs and may have improved clinical outcomes. (Funded by the Scottish Government Chief Scientist Office; ClinicalTrials.gov number, NCT01425502.).