'A good decision is the one that feels right for me': Codesign with patients to inform theoretical underpinning of a decision aid website.

INTRODUCTION: Patient decision aids (PtDA) complement shared decision-making with healthcare professionals and improve decision quality. However, PtDA often lack theoretical underpinning. We are codesigning a PtDA to help people with increased genetic cancer risks manage choices. The aim of an innovative workshop described here was to engage with the people who will use the PtDA regarding the theoretical underpinning and logic model outlining our hypothesis of how the PtDA would lead to more informed decision-making. METHODS: Short presentations about psychological and behavioural theories by an expert were interspersed with facilitated, small-group discussions led by patients. Patients were asked what is important to them when they make health decisions, what theoretical constructs are most meaningful and how this should be applied to codesign of a PtDA. An artist created a visual summary. Notes from patient discussions and the artwork were analysed using reflexive thematic analysis. RESULTS: The overarching theme was: It's personal. Contextual factors important for decision-making were varied and changed over time. There was no one 'best fit' theory to target support needs in a PtDA, suggesting an inductive, flexible framework approach to programme theory would be most effective. The PtDA logic model was revised based on patient feedback. CONCLUSION: Meaningful codesign of PtDA including discussions about the theoretical mechanisms through which they support decision-making has the potential to lead to improved patient care through understanding the intricately personal nature of health decisions, and tailoring content and format for holistic care. PATIENT CONTRIBUTION: Patients with lived experience were involved in codesign and coproduction of this workshop and analysis as partners and coauthors. Patient discussions were the primary data source. Facilitators provided a semi-structured guide, but they did not influence the patient discussions or provide clinical advice. The premise of this workshop was to prioritise the importance of patient lived experience: to listen, learn, then reflect together to understand and propose ideas to improve patient care through codesign of a PtDA.

Incidence, morbidity, mortality and disparities in dementia: A population linked electronic health records study of 4.3 million individuals.

INTRODUCTION: We report dementia incidence, comorbidities, reasons for health-care visits, mortality, causes of death, and examined dementia patterns by relative deprivation in the UK. METHOD: A longitudinal cohort analysis of linked electronic health records from 4.3 million people in the UK was conducted to investigate dementia incidence and mortality. Reasons for hospitalization and causes of death were compared in individuals with and without dementia. RESULTS: From 1998 to 2016 we observed 145,319 (3.1%) individuals with incident dementia. Repeated hospitalizations among senior adults for infection, unknown morbidity, and multiple primary care visits for chronic pain were observed prior to dementia diagnosis. Multiple long-term conditions are present in half of the individuals at the time of diagnosis. Individuals living in high deprivation areas had higher dementia incidence and high fatality. DISCUSSION: There is a considerable disparity of dementia that informs priorities of prevention and provision of patient care.

Assessing potential shared genetic aetiology between body mass index and sleep duration in 142,209 individuals.

Observational studies find an association between increased body mass index (BMI) and short self-reported sleep duration in adults. However, the underlying biological mechanisms that underpin these associations are unclear. Recent findings from the UK Biobank suggest a weak genetic correlation between BMI and self-reported sleep duration. However, the potential shared genetic aetiology between these traits has not been examined using a comprehensive approach. To investigate this, we created a polygenic risk score (PRS) of BMI and examined its association with self-reported sleep duration in a combination of individual participant data and summary-level data, with a total sample size of 142,209 individuals. Although we observed a nonsignificant genetic correlation between BMI and sleep duration, using LD score regression (rg = -0.067 [SE = 0.039], P = 0.092) we found that a PRS of BMI is associated with a decrease in sleep duration (unstandardized coefficient = -1.75 min [SE = 0.67], P = 6.13 × 10-7 ), but explained only 0.02% of the variance in sleep duration. Our findings suggest that BMI and self-reported sleep duration possess a small amount of shared genetic aetiology and other mechanisms must underpin these associations.

The Consortium of Metabolomics Studies (COMETS): Metabolomics in 47 Prospective Cohort Studies.

The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).

Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies.

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Causal Associations of Adiposity and Body Fat Distribution With Coronary Heart Disease, Stroke Subtypes, and Type 2 Diabetes Mellitus: A Mendelian Randomization Analysis.

BACKGROUND: The implications of different adiposity measures on cardiovascular disease etiology remain unclear. In this article, we quantify and contrast causal associations of central adiposity (waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) and general adiposity (body mass index [BMI]) with cardiometabolic disease. METHODS: Ninety-seven independent single-nucleotide polymorphisms for BMI and 49 single-nucleotide polymorphisms for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with coronary heart disease (CHD) data from CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics; combined total 66 842 cases), stroke from METASTROKE (12 389 ischemic stroke cases), type 2 diabetes mellitus from DIAGRAM (Diabetes Genetics Replication and Meta-analysis; 34 840 cases), and lipids from GLGC (Global Lipids Genetic Consortium; 213 500 participants) consortia. Primary outcomes were CHD, type 2 diabetes mellitus, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits. RESULTS: Each one standard deviation (SD) higher WHRadjBMI (1 SD≈0.08 U) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD, 1.48; 95% confidence interval [CI], 1.28-1.71), similar to findings for BMI (1 SD≈4.6 kg/m2; OR for CHD, 1.36; 95% CI, 1.22-1.52). Only WHRadjBMI increased risk of ischemic stroke (OR, 1.32; 95% CI, 1.03-1.70). For type 2 diabetes mellitus, both measures had large effects: OR, 1.82 (95% CI, 1.38-2.42) and OR, 1.98 (95% CI, 1.41-2.78) per 1 SD higher WHRadjBMI and BMI, respectively. Both WHRadjBMI and BMI were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6, and circulating lipids. WHRadjBMI was also associated with higher carotid intima-media thickness (39%; 95% CI, 9%-77% per 1 SD). CONCLUSIONS: Both general and central adiposity have causal effects on CHD and type 2 diabetes mellitus. Central adiposity may have a stronger effect on stroke risk. Future estimates of the burden of adiposity on health should include measures of central and general adiposity.

Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers.

We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00 × 10(-10)), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38 × 10(-5)). An interaction test confirmed that these estimates differed from each other (P = 4.95 × 10(-13)). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.

Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12.

BACKGROUND: Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants. OBJECTIVE: To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation. METHODS: 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10(-5)) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays. RESULTS: Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10(-6), preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10(-6)). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10(-6)). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10(-7)). CONCLUSIONS: This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.

Mendelian randomization of blood lipids for coronary heart disease.

AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

Incident disability in older adults: prediction models based on two British prospective cohort studies.

OBJECTIVE: To develop and validate a prediction model for incident locomotor disability after 7 years in older adults. SETTING: Prospective British cohort studies: British Women's Heart and Health Study (BWHHS) for development and the English Longitudinal Study of Ageing (ELSA) for validation. SUBJECTS: Community-dwelling older adults. METHODS: Multivariable logistic regression models after selection of predictors with backward elimination. Model performance was assessed using metrics of discrimination and calibration. Models were internally and externally validated. RESULTS: Locomotor disability was reported in BWHHS by 861 of 1,786 (48%) women after 7 years. Age, a history of arthritis and low physical activity levels were the most important predictors of locomotor disability. Models using routine measures as predictors had satisfactory calibration and discrimination (c-index 0.73). Addition of 31 blood markers did not increase the predictive performance. External validation in ELSA showed reduced discrimination (c-index 0.65) and an underestimation of disability risks. A web-based calculator for locomotor disability is available (http://www.sealedenvelope.com/trials/bwhhsmodel/). CONCLUSIONS: We developed and externally validated a prediction model for incident locomotor disability in older adults based on routine measures available to general practitioners, patients and public health workers, and showed an adequate discrimination. Addition of blood markers from major biological pathways did not improve the performance of the model. Further replication in additional data sets may lead to further enhancement of the current model.

A cross-sectional observational study for ethno-geographical disparities in sleep quality, brain morphometry and cognition (a SOLACE study) in Indians residing in India, and South Asians and Europeans residing in the UK - a study protocol.

Introduction: As individuals age, their sleep patterns change, and sleep disturbances can increase the risk of dementia. Poor sleep quality can be a risk factor for mild cognitive impairment (MCI) and dementia. Epidemiological studies show a connection between sleep quality and cognitive changes, with brain imaging revealing grey matter volume reduction and amyloid beta accumulation in Alzheimer's disease. However, most research has focused on Europeans, with little attention to other ethnic groups. Methods: This is a cross sectional study comparing effects across countries and ethnicities. Group 1 (n = 193) will be Indians residing in India (new participant recruitment), Group 2 will be South Asians residing in UK and group 3 will be Europeans residing in the UK. For group 2 and 3 (n = 193), data already collected by UK-based Southall and Brent REvisited (SABRE) tri-ethnic study will be used. For group 1, Pittsburgh Sleep Quality Index questionnaire (PSQI) will be used for assessment of sleep quality, Indian Council of Medical Research (Neurocognitive ToolBox) (ICMR-NCTB) for cognition testing and a 3 T MRI cerebral scan for brain morphometry. The data will be compared to sleep, cognitive function and brain MRI parameters from SABRE. Discussion: Racial and ethnic differences can impact the relationships of cognitive function, sleep quality and brain structure in older adults. Earlier studies have highlighted higher prevalence of poor sleep among black individuals compared to white individuals. Genetic or epigenetic mechanisms may contribute to these variations. Socio-cultural and environmental factors, such as neighbourhood, migration, lifestyle, stress and perceived discrimination may influence sleep patterns. The aim of the study is to examine the ethnogeographic variations in sleep quality, cognitive performance and brain morphometry among Indians living in India, and South Asians and Europeans residing in the UK.

Predictors of patterns of change in health-related quality of life in older women over 7 years: evidence from a prospective cohort study.

BACKGROUND: the evaluation of the determinants of change over time in health-related quality of life (HR-QoL) in older people is limited. This study aims to identify patterns of change in HR-QoL over 7 years and their determinants using data from the British Women's Heart and Health Study, a representative sample of older women (n = 4286). METHODS: longitudinal latent class analysis was used to identify subpopulations of women with similar HR-QoL trajectories from 1999-2000 to 2007. HR-QoL was measured using the EQ-5D. Multivariate multinomial logistic regression was used to model the association of identified trajectories with baseline predictors after multiple imputation of missing data. RESULTS: four distinct EQ-5D trajectories were suggested: high (19% of women), high decline (22%), intermediate (42%) and low decline (16%). Prevalent arthritis (OR = 13.4; 95% CI: 8.8, 20.5), diabetes (OR = 4.6; 95% CI: 1.5, 14.2) and obesity (OR = 3.9; 95% CI: 2.5, 6.0) were the strongest predicting health conditions of adverse changes in HR-QoL and physical activity the strongest predicting lifestyle factor (OR = 2.8; 95% CI: 2.0, 3.9). CONCLUSIONS: findings suggest that older women without obesity or pre-existing health conditions who undertake more physical activity are more likely to experience high HR-QoL, reinforcing the importance of these factors for healthy ageing.

Effect of changes in moderate or vigorous physical activity on changes in health-related quality of life of elderly British women over seven years.

PURPOSE: This study investigates the effect of changes in moderate or vigorous physical activity (MVPA) on trajectories in health-related quality of life (HR-QoL) over 7 years in British elderly women. METHODS: A total of 1,926 women from the British Women's Heart and Health Study with information on MVPA and HR-QoL [measured using Euro quality of life 5 dimension (EQ-5D)] at baseline and at 7 years of follow-up were included in the analysis. Baseline and 7-year follow-up MVPA values were categorised into 3 groups, generating 9 categories of change in MVPA. Logistic regression was used to obtain odds ratios (ORs) of maintaining or improving HR-QoL according to different patterns of change in MVPA level. RESULTS: Women who remained inactive over the 7 years of follow-up had the largest reduction in their EQ-5D scores. Compared to these women, women that increased their MPVA level from "inactive" to "low" or to "moderate-high" were more likely to maintain or improve their HR-QoL over 7 years (ORs 1.65 or 2.70, respectively, p value for trend <0.001). After adjustment for baseline EQ-5D score and a wide range of potential confounders, results remained largely unchanged, though precision of the estimates generally decreased. CONCLUSIONS: Our findings suggest that relatively regular MVPA, even taken up later in life, can help older women prevent a decline in HR-QoL and even improve their enjoyment of life.

Prevalence of chronic pain or analgesic use in children and young people and its long-term impact on substance misuse, mental illness, and prescription opioid use: a retrospective longitudinal cohort study.

Background: Epidemiological studies suggest chronic and recurrent pain affects around a quarter of children, while 8% report intense and frequent pain. The long-term implications of chronic pain in childhood are uncertain. Using electronic health records (EHRs) we used both disease codes and medicines prescription records to investigate the scale of chronic pain and long-term analgesic use in children and young people (CYP), and if chronic pain and/or use of analgesic medicines at an early age is associated with substance misuse, use of prescription opioids, and poor mental health in adulthood. Methods: We conducted a cohort study using data from IQVIA Medical Research Data UK. We identified individuals aged 2-24 with exposure to either a diagnostic code indicating chronic pain (diagnosis-exposed), repeat prescription for medicines commonly used to treat pain (prescription-exposed), or both. Follow-up began at 25, and the unexposed population acted as comparators. We calculated hazard ratios (HR) for mental health and substance misuse outcomes, and rate ratios (RR) for opioid prescriptions in adulthood. Additionally, we investigated which diagnoses, if any, were over-represented in the prescription-exposed subgroup. Findings: The cohort constituted 853,625 individuals; 146,431 had one or more of the exposures of interest (diagnosis-exposed = 115,101, prescription-exposed = 20,298, both-exposed = 11,032), leaving 707,194 as comparators. Median age at index exposure was 18.7 years (IQR 14.7-22.3). On average during follow-up, the pooled exposed group had, respectively, a 31% and 17% higher risk of adverse mental health and substance misuse outcomes (adjusted HR [95% CI] of 1.31 [1.29-1.32] and 1.17 [1.11-1.24]). Exposed individuals also received prescription opioids at double the rate of unexposed individuals on average during follow-up (adjusted RR 2.01 [95% CI 1.95-2.10]). Outcomes varied between exposure subgroups, with prescription- and both-exposure tending to have worse outcomes. Unlike these two subgroups, in the diagnosis-exposed subgroup we did not detect a greater risk of substance misuse. Interpretation: Chronic pain in CYP is associated with increased prescription opioid use and adverse mental health outcomes in adulthood, as is repeat prescription for analgesic medicines, but only the latter is also associated with substance misuse in adulthood. It is essential to avoid the harms of under-treating pain in CYP while giving due consideration to the risks posed by analgesic medicines. Early recognition of chronic pain in CYP and utilising non-pharmacological management options may help minimise overprescribing, and long-term reliance on dependence-forming-drugs. Funding: AL is an NIHR funded academic clinical fellow, and was supported by funding from UCLH Charities while carrying out this work. RS and DS are part of the Advanced Pain Discovery Platform and were supported by a UKRI and Versus Arthritis grant (MR/W002566/1) as part of the Consortium Against Pain Inequality. AW was supported by the Wellcome Trust (220558/Z/20/Z).

Antipsychotic drug prescribing and mortality in people with dementia before and during the COVID-19 pandemic: a retrospective cohort study in Wales, UK.

BACKGROUND: Concerns have been raised that antipsychotic drug prescribing, which has been associated with increased mortality in people with dementia, might have increased during the COVID-19 pandemic due to social restrictions imposed to limit the spread of SARS-CoV-2. We used multisource, routinely collected health-care data from Wales, UK to investigate prescribing and mortality variations in people with dementia before and during the COVID-19 pandemic. METHODS: In this retrospective cohort study, we used individual-level, anonymised, population-scale linked health data to identify adults aged 60 years and older with a diagnosis of dementia in Wales, UK. We used the CVD-COVID-UK initiative to access Welsh routinely collected electronic health record data from the Secure Anonymised Information Linkage (SAIL) Databank. Patients who were alive and registered with a SAIL general practice on Jan 1, 2016, and who received a dementia diagnosis before the age of 60 years and before or during the study period were included. We explored antipsychotic drug prescribing rate changes over 67 months, between Jan 1, 2016, and Aug 1, 2021, overall and stratified by age and dementia subtype. We used time-series analyses to examine all-cause and myocardial infarction and stroke mortality over the study period and identified the leading causes of death in people with dementia between Jan 1, 2020, and Aug 1, 2021. FINDINGS: Of 3 106 690 participants in SAIL between Jan 1, 2016 and Aug 1, 2021, 57 396 people (35 148 [61·2%] women and 22 248 [38·8%] men) met inclusion criteria for this study and contributed 101 428 person-years of follow-up. Of the 57 396 people with dementia, 11 929 (20·8%) were prescribed an antipsychotic drug at any point during follow-up. Accounting for seasonality, antipsychotic drug prescribing increased during the second half of 2019 and throughout 2020. However, the absolute difference in prescribing rates was small, ranging from 1253 prescriptions per 10 000 person-months in March, 2019, to 1305 per 10 000 person-months in September, 2020. All-cause mortality and stroke mortality increased throughout 2020, while myocardial infarction mortality declined. From Jan 1, 2020, to Aug 1, 2021, 1286 (17·1%) of 7508 participants who died had COVID-19 recorded as the underlying cause of death. INTERPRETATION: During the COVID-19 pandemic, antipsychotic drug prescribing in people with dementia in the UK increased slightly; however, it is unlikely that this was solely related to the pandemic and this increase was unlikely to be a major factor in the substantial increase in mortality during 2020. The long-term increase in antipsychotic drug prescribing in younger people and in those with Alzheimer's disease warrants further investigation using resources with access to more granular clinical data. Although deprescribing antipsychotic medications remains an essential aspect of dementia care, the results of this study suggest that changes in prescribing and deprescribing practices as a result of the COVID-19 pandemic are not required. FUNDING: British Heart Foundation (via the British Heart Foundation Data Science Centre led by Health Data Research UK), and the Scottish Neurological Research Fund.

The impact of the COVID-19 pandemic on cardiovascular disease prevention and management.

How the Coronavirus Disease 2019 (COVID-19) pandemic has affected prevention and management of cardiovascular disease (CVD) is not fully understood. In this study, we used medication data as a proxy for CVD management using routinely collected, de-identified, individual-level data comprising 1.32 billion records of community-dispensed CVD medications from England, Scotland and Wales between April 2018 and July 2021. Here we describe monthly counts of prevalent and incident medications dispensed, as well as percentage changes compared to the previous year, for several CVD-related indications, focusing on hypertension, hypercholesterolemia and diabetes. We observed a decline in the dispensing of antihypertensive medications between March 2020 and July 2021, with 491,306 fewer individuals initiating treatment than expected. This decline was predicted to result in 13,662 additional CVD events, including 2,281 cases of myocardial infarction and 3,474 cases of stroke, should individuals remain untreated over their lifecourse. Incident use of lipid-lowering medications decreased by 16,744 patients per month during the first half of 2021 as compared to 2019. By contrast, incident use of medications to treat type 2 diabetes mellitus, other than insulin, increased by approximately 623 patients per month for the same time period. In light of these results, methods to identify and treat individuals who have missed treatment for CVD risk factors and remain undiagnosed are urgently required to avoid large numbers of excess future CVD events, an indirect impact of the COVID-19 pandemic.

Inflammation, coagulation and risk of locomotor disability in elderly women: findings from the British Women's Heart and Health Study.

This study investigated associations between chronic inflammation and coagulation and incident locomotor disability using prospective data from the British Women's Heart and Health Study. Locomotor disability was assessed using self-reported questionnaires in 1999/2000, and 3 and 7 years later. Scores for inflammation and coagulation were obtained from summation of quartile categories of all available biomarkers from blood samples taken at baseline. 534 women developed locomotor disability after 3 years, 260 women after 7 years, while 871 women remained free of locomotor disability over the whole study period. After adjustment for demographic characteristics, lifestyle factors and health conditions, we found associations between inflammation and incident locomotor disability after three (OR per unit increase in score = 1.08, 95 % confidence interval (CI): 1.03, 1.13) and 7 years (OR = 1.10, 95 % CI: 1.03, 1.18) and between coagulation and incident locomotor disability after 3 (OR = 1.06, 95 % CI: 0.98, 1.14) and 7 years (OR = 1.09, 95 % CI: 1.00, 1.18). This corresponds to ORs between 1.8 and 2.4 comparing women with highest to lowest inflammation or coagulation scores. These results support the role of inflammation and coagulation in the development of locomotor disability in elderly women irrespective of their lifestyle factors and underlying age-related chronic diseases.

Evaluation of antithrombotic use and COVID-19 outcomes in a nationwide atrial fibrillation cohort.

OBJECTIVE: To evaluate antithrombotic (AT) use in individuals with atrial fibrillation (AF) and at high risk of stroke (CHA2DS2-VASc score ≥2) and investigate whether pre-existing AT use may improve COVID-19 outcomes. METHODS: Individuals with AF and CHA2DS2-VASc score ≥2 on 1 January 2020 were identified using electronic health records for 56 million people in England and were followed up until 1 May 2021. Factors associated with pre-existing AT use were analysed using logistic regression. Differences in COVID-19-related hospitalisation and death were analysed using logistic and Cox regression in individuals with pre-existing AT use versus no AT use, anticoagulants (AC) versus antiplatelets (AP), and direct oral anticoagulants (DOACs) versus warfarin. RESULTS: From 972 971 individuals with AF (age 79 (±9.3), female 46.2%) and CHA2DS2-VASc score ≥2, 88.0% (n=856 336) had pre-existing AT use, 3.8% (n=37 418) had a COVID-19 hospitalisation and 2.2% (n=21 116) died, followed up to 1 May 2021. Factors associated with no AT use included comorbidities that may contraindicate AT use (liver disease and history of falls) and demographics (socioeconomic status and ethnicity). Pre-existing AT use was associated with lower odds of death (OR=0.92, 95% CI 0.87 to 0.96), but higher odds of hospitalisation (OR=1.20, 95% CI 1.15 to 1.26). AC versus AP was associated with lower odds of death (OR=0.93, 95% CI 0.87 to 0.98) and higher hospitalisation (OR=1.17, 95% CI 1.11 to 1.24). For DOACs versus warfarin, lower odds were observed for hospitalisation (OR=0.86, 95% CI 0.82 to 0.89) but not for death (OR=1.00, 95% CI 0.95 to 1.05). CONCLUSIONS: Pre-existing AT use may be associated with lower odds of COVID-19 death and, while not evidence of causality, provides further incentive to improve AT coverage for eligible individuals with AF.

Association between sleep quality and type 2 diabetes at 20-year follow-up in the Southall and Brent REvisited (SABRE) cohort: a triethnic analysis.

BACKGROUND: The risk of developing type 2 diabetes associated with poor sleep quality is comparable to other lifestyle factors (eg, overweight, physical inactivity). In the UK, these risk factors could not explain the two to three-fold excess risks in South-Asian and African-Caribbean men compared with Europeans. This study investigates (1) the association between mid-life sleep quality and later-life type 2 diabetes risk and (2) the potential modifying effect of ethnicity. METHODS: The Southall and Brent REvisited cohort is composed of Europeans, South-Asians and African-Caribbeans (median follow-up 19 years). Complete-case analysis was performed on 2189 participants without diabetes at baseline (age=51.7±7 SD). Competing risks regressions were used to estimate the HRs of developing diabetes associated with self-reported baseline sleep (difficulty falling asleep, early morning waking, waking up tired, snoring and a composite sleep score), adjusting for confounders. Modifying effects of ethnicity were analysed by conducting interaction tests and ethnicity-stratified analyses. RESULTS: There were 484 occurrences of incident type 2 diabetes (22%). Overall, there were no associations between sleep exposures and diabetes risk. Interaction tests suggested a possible modifying effect for South-Asians compared with Europeans for snoring only (p=0.056). The ethnicity-stratified analysis found an association with snoring among South-Asians (HR 1.41, 95% CI 1.08 to 1.85), comparing those who snored often/always versus occasionally/never. There were no elevated risks for the other sleep exposures. CONCLUSION: The association between snoring and type 2 diabetes appeared to be modified by ethnicity, and was strongest in South-Asians.

Circulating Fatty Acids and Risk of Coronary Heart Disease and Stroke: Individual Participant Data Meta-Analysis in Up to 16 126 Participants.

Background We aimed at investigating the association of circulating fatty acids with coronary heart disease (CHD) and stroke risk. Methods and Results We conducted an individual-participant data meta-analysis of 5 UK-based cohorts and 1 matched case-control study. Fatty acids (ie, omega-3 docosahexaenoic acid, omega-6 linoleic acid, monounsaturated and saturated fatty acids) were measured at baseline using an automated high-throughput serum nuclear magnetic resonance metabolomics platform. Data from 3022 incident CHD cases (13 104 controls) and 1606 incident stroke cases (13 369 controls) were included. Logistic regression was used to model the relation between fatty acids and odds of CHD and stroke, adjusting for demographic and lifestyle variables only (ie, minimally adjusted model) or with further adjustment for other fatty acids (ie, fully adjusted model). Although circulating docosahexaenoic acid, but not linoleic acid, was related to lower CHD risk in the fully adjusted model (odds ratio, 0.85; 95% CI, 0.76-0.95 per standard unit of docosahexaenoic acid), there was evidence of high between-study heterogeneity and effect modification by study design. Stroke risk was consistently lower with increasing circulating linoleic acid (odds ratio for fully adjusted model, 0.82; 95% CI, 0.75-0.90). Circulating monounsaturated fatty acids were associated with higher CHD risk across all models and with stroke risk in the fully adjusted model (odds ratio, 1.22; 95% CI, 1.03-1.44). Saturated fatty acids were not related to increased CHD risk in the fully adjusted model (odds ratio, 0.94; 95% CI, 0.82-1.09), or stroke risk. Conclusions We found consistent evidence that linoleic acid was associated with decreased risk of stroke and that monounsaturated fatty acids were associated with increased risk of CHD. The different pattern between CHD and stroke in terms of fatty acids risk profile suggests future studies should be cautious about using composite events. Different study designs are needed to assess which, if any, of the associations observed is causal.