APOE e4 genotype predicts severe COVID-19 in the UK Biobank community cohort

This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.C.L.K., L.C.P., G.A.K., and D.M. are supported in part by an R21 grant (R21AG060018) funded by National Institute on Aging, National Instute of Health, USA, UK Medical Research Council award MR/S009892/1 (PI Melzer) supports J.L.A. J.A.H.M. is supported by National Institute for Health Research, UK Doctoral Research Fellowship DRF-2014-07-177.published version, accepted version (12 month embargo), submitted versio

Long-term effects of allergen sensitization and exposure in adult asthma: a prospective study.

BACKGROUND: : We investigated the effects of sensitization and exposure to common domestic allergens on longitudinal changes in lung function and bronchial hyperresponsiveness. METHODS: : Subjects attended 2 visits that were 4 years apart. Skin prick testing was performed and household dust samples were collected for quantification of mite, dog, and cat allergens at baseline. Measurements of lung function, exhaled nitric oxide, and bronchial hyperresponsiveness were completed at both visits. RESULTS: : Dust samples were collected in 165 of the 200 subjects completing both visits. Mean length of follow-up was 47 months. Bronchial hyperresponsiveness, measured at both visits in 86 subjects, deteriorated in those exposed to high mite allergen levels compared with those not exposed [mean (95% CI) doubling dose change PD20 = -0.44 (-1.07 to 0.19) vs 0.82 (0.27 to 1.36)], but improved in those exposed to high dog allergen levels compared with those not exposed [1.10 (0.33 to 1.86) vs 0.10 (-0.39 to 0.58)]. The associations were significant in the multivariate models. Cat allergen exposure was not associated with any changes in lung function, exhaled nitric oxide, or bronchial hyperresponsiveness. CONCLUSIONS: : In a 4-year prospective cohort of persons with asthma, exposure to high levels of dust mite allergens at baseline was associated with a subsequent increase in bronchial hyperresponsiveness

Low Vitamin D Levels and Risk of Incident Delirium in 351,000 Older UK Biobank Participants

This is the final version. Available on open access from Wiley via the DOI in this recordBACKGROUND/OBJECTIVES Delirium is common in older adults, especially following hospitalization. Because low vitamin D levels may be associated with increased delirium risk, we aimed to determine the prognostic value of blood vitamin D levels, extending our previous genetic analyses of this relationship. DESIGN Prospective cohort analysis. SETTING Community‐based cohort study of adults from 22 cities across the United Kingdom (the UK Biobank). PARTICIPANTS Adults aged 60 and older by the end of follow‐up in the linked hospital inpatient admissions data, up to 14 years after baseline (n = 351,320). MEASUREMENTS At baseline, serum vitamin D (25‐OH‐D) levels were measured. We used time‐to‐event models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between vitamin D deficiency and incident hospital‐diagnosed delirium, adjusted for age, sex, assessment month, assessment center, and ethnicity. We performed Mendelian randomization genetic analysis in European participants to further investigate vitamin D and delirium risk. RESULTS A total of 3,634 (1.03%) participants had at least one incident hospital‐diagnosed delirium episode. Vitamin D deficiency (50 nmol/L). Increased risk was not limited to the deficient group: insufficient levels (25–50 nmol/L) were also at increased risk (HR = 1.38; 95% CI = 1.28–1.49; P = 4*10−18). The association was independent of calcium levels, hospital‐diagnosed fractures, dementia, and other relevant cofactors. In genetic analysis, participants carrying more vitamin D–increasing variants had a reduced likelihood of incident delirium diagnosis (HR = .80 per standard deviation increase in genetically instrumented vitamin D: .73–.87; P = 2*10−7). CONCLUSION Progressively lower vitamin D levels predicted increased risks of incident hospital‐diagnosed delirium, and genetic evidence supports a shared causal pathway. Because low vitamin D levels are simple to detect and inexpensive and safe to correct, an intervention trial to confirm these results is urgently needed.Alzheimer’s SocietyMedical Research Council (MRC)National Institute on Agin

Predicting incident delirium diagnoses using data from primary-care electronic health records

Importance risk factors for delirium in hospital inpatients are well established, but less is known about whether delirium occurring in the community or during an emergency admission to hospital care might be predicted from routine primary-care records. Objectives identify risk factors in primary-care electronic health records (PC-EHR) predictive of delirium occurring in the community or recorded in the initial episode in emergency hospitalisation. Test predictive performance against the cumulative frailty index. Design Stage 1: case-control; Stages 2 and 3: retrospective cohort. Setting clinical practice research datalink: PC-EHR linked to hospital discharge data from England. Subjects Stage 1: 17,286 patients with delirium aged ≥60 years plus 85,607 controls. Stages 2 and 3: patients ≥ 60 years (n = 429,548 in 2015), split into calibration and validation groups. Methods Stage 1: logistic regression to identify associations of 110 candidate risk measures with delirium. Stage 2: calibrating risk factor weights. Stage 3: validation in independent sample using area under the curve (AUC) receiver operating characteristic. Results fifty-five risk factors were predictive, in domains including: cognitive impairment or mental illness, psychoactive drugs, frailty, infection, hyponatraemia and anticholinergic drugs. The derived model predicted 1-year incident delirium (AUC = 0.867, 0.852:0.881) and mortality (AUC = 0.846, 0.842:0.853), outperforming the frailty index (AUC = 0.761, 0.740:0.782). Individuals with the highest 10% of predicted delirium risk accounted for 55% of incident delirium over 1 year. Conclusions a risk factor model for delirium using data in PC-EHR performed well, identifying individuals at risk of new onsets of delirium. This model has potential for supporting preventive interventions

Vitamin D and COVID-19 in older age: evidence versus expectations

This is the author accepted manuscript. The final version is available from the Royal College of General Practitioners via the DOI in this recordThe current global pandemic of SARS-CoV-2 coronavirus infection originated in Wuhan, China, during December 2019; over 50 million cases have been diagnosed to date. Older age and comorbidity have proven to be key markers of risk for severity of COVID-19 and mortality,1,2 and residents of care homes have been proven to be at high risk. The Office for National Statistics has recorded 16 111 deaths related to COVID-19 in care home residents in England up to 20 November 2020.3 In the first wave of the pandemic, 46% of all excess deaths in England and Wales up to 7 August occurred in care homes.4 Older age is associated with increasing prevalence of vitamin D deficiency, which can affect up to 40% of care home residents.5 There is considerable overlap between the non-modifiable risk factors for severe SARS-CoV-2 infection and those associated with deficiency of vitamin D. For example, age, ethnicity, diabetes, and chronic pulmonary and cardiac diseases; in addition, there is the observed trend towards greater severity of disease in northern latitudes. While these could imply an association between reduced vitamin D levels and susceptibility to SARS-CoV-2 infection this may simply be an ecological fallacy.6 Therefore, it is important to understand the strength of evidence provided by epidemiological and observational studies of COVID-19, and compare it with what is known from clinical trials of the impact of vitamin D supplementation on acute respiratory infections, including those due to SARS-CoV-2.National Institute for Health Research (NIHR

Outcomes of Treated Hypertension at Age 80 and Older: Cohort Analysis of 79,376 Individuals

This is the final version of the article. Available from Wiley via the DOI in this record.OBJECTIVES: To estimate outcomes according to attained blood pressure (BP) in the oldest adults treated for hypertension in routine family practice. DESIGN: Cohort analysis of primary care inpatient and death certificate data for individuals with hypertension. SETTING: Primary care practices in England (Clinical Practice Research Datalink). PARTICIPANTS: Individuals aged 80 and older taking antihypertensive medication and free of dementia, cancer, coronary heart disease, stroke, heart failure, and end-stage renal failure at baseline. MEASUREMENTS: Outcomes were mortality, cardiovascular events, and fragility fractures. Systolic BP (SBP) was grouped in 10-mmHg increments from less than 125 to 185 mmHg or more (reference 145–154 mmHg). RESULTS: Myocardial infarction hazards increased linearly with increasing SBP, and stroke hazards increased for SBP of 145 mmHg or greater, although lowest mortality was in individuals with SBP of 135 to 154 mmHg. Mortality of the 13.1% of patients with SBP less than 135 mmHg was higher than that of the reference group (Cox hazard ratio=1.25, 95% confidence interval=1.19–1.31; equating to one extra death per 12.6 participants). This difference in mortality was consistent over short- and long-term follow-up; adjusting for diastolic BP did not change the risk. Incident heart failure rates were higher in those with SBP less than 125 mmHg than in the reference group. CONCLUSION: In routine primary care, SBP less than 135 mmHg was associated with greater mortality in the oldest adults with hypertension and free of selected potentially confounding comorbidities. Although important confounders were accounted for, observational studies cannot exclude residual confounding. More work is needed to establish whether unplanned SBPs less than 135 mmHg in older adults with hypertension may be a useful clinical sign of poor prognosis, perhaps requiring clinical review of overall care.This work was supported in part by the National Institute for Health Research (NIHR) School for Public Health Research Ageing Well programme

Preexisting comorbidities predicting Covid-19 and mortality in the UK biobank community cohort

This is the author accepted manuscript. The final version is available on open access from Oxford University Press via the DOI in this recordBackground: Hospitalized COVID-19 patients tend to be older and frequently have hypertension, diabetes or coronary heart disease (CHD), but whether these co-morbidities are true risk factors (i.e. more common than in the general older population) is unclear. We estimated associations between pre-existing diagnoses and hospitalized COVID-19 alone or with mortality, in a large community cohort. Methods: UK Biobank (England) participants with baseline assessment 2006 to 2010, followed in hospital discharge records to 2017 and death records to 2020. Demographic and pre-existing common diagnoses association tested with hospitalized laboratory confirmed COVID-19 (16th March to 26th April 2020), alone or with mortality, in logistic models. Results: Of 269,070 participants aged 65+, 507 (0.2%) became COVID-19 hospital inpatients, of which 141 (27.8%) died. Common co-morbidities in hospitalized inpatients were hypertension (59.6%), history of fall or fragility fractures (29.4%), coronary heart disease (CHD, 21.5%), type 2 diabetes (type 2, 19. 9%) and asthma (17.6%). However, in models adjusted for comorbidities, age-group, sex, ethnicity and education, pre-existing diagnoses of dementia, type 2 diabetes, COPD, pneumonia, depression, atrial fibrillation and hypertension emerged as independent risk factors for COVID-19 hospitalization, the first five remaining statistically significant for related mortality. Chronic Kidney Disease and asthma were risk factors for COVID-19 hospitalization in women but not men. Conclusion: There are specific high risk pre-existing co-morbidities for COVID-19 hospitalization and related deaths in community based older men and women. These results do not support simple age-based targeting of the older population to prevent severe COVID-19 infections.Medical Research Council (MRC)University of Connecticut School of Medicine.National Institute for Health Research (NIHR

Statin treatment effectiveness and the SLCO1B1*5 reduced function genotype: Long-term outcomes in women and men

This is the final version. Available from British Pharmacological Society / Wiley via the DOI in this record. The genetic and phenotypic UK Biobank data are available upon application to the UK Biobank (www.ukbiobank.ac.uk/register-apply). The derived data fields used in our analysis will be available via the UK Biobank, search for application number 14631. We are not able to share these directly.OBJECTIVE: To estimate the effect of rs4149056 (SLCO1B1*5) genotype (decreases statin transport) on cholesterol control and treatment duration in male and female primary care patients prescribed common statin medications. METHODS AND ANALYSIS: This study comprised 69 185 European-ancestry UK Biobank cohort participants prescribed simvastatin or atorvastatin (aged 40-79 years at first prescription, treatment duration 1 month to 29 years, mean 5.7 years). Principal outcomes were clinically high total cholesterol (>5 mmol/L) at baseline, plus treatment discontinuation. RESULTS: A total of 48.4% of 591 females homozygous for SLCO1B1*5 decreased function genotype had raised cholesterol vs 41.7% of those with functioning SLCO1B1 (odds ratio 1.31, 95% confidence interval [CI] 1.1-1.55, P = .001). Fewer males had high cholesterol and the genotype effect was attenuated. In primary care prescribing, females homozygous for SLCO1B1*5 were more likely to stop receiving these statins (29.5%) than women with normal SLCO1B1 (25.7%) (hazard ratio [HR] 1.19, 95% CI 1.03-1.37, P = .01), amounting to five discontinuations per 100 statin-years in the SLCO1B1*5 group vs four in the normal SLCO1B1 function group. This remained significant after the first year of treatment (HR for discontinuing >1 year after first prescription 1.3, 95% CI 1.08-1.56, P = .006). In men SLCO1B1*5 was only associated with treatment discontinuation in the first year. CONCLUSIONS: In this large community sample of patients on commonly prescribed statins, the SLCO1B1*5 decreased function variant had much larger effects on cholesterol control and treatment duration in women than in men. Efforts to improve the effectiveness of statin therapy in women may need to include SLCO1B1*5 genotype-guided statin selection.National Institute for Health ResearchMinistry of National Education, Republic of TurkeyExpanding Excellence in EnglandUniversity of Exeter Medical Schoo