AbstractWe previously reported that the ApoE e4e4 genotype was associated with COVID-19 test positivity (OR=2.31, 95% CI: 1.65 to 3.24, p=1.19×10−6) in the UK Biobank (UKB) cohort, during the epidemic peak in England, from March 16 to April 26, 2020. With more COVID-19 test results (March 16 to May 31, 2020) and mortality data (to April 26, 2020) linked to UKB, we re-evaluated the ApoE e4 allele association with COVID-19 test positivity, and with all-cause mortality following test-confirmed COVID-19. Logistic regression models compared ApoE e4e4 participants (or e3e4s) to e3e3s with adjustment for sex; age on April 26th or age at death; baseline UKB assessment center in England (accounting for geographical differences in viral exposures); genotyping array type; and the top five genetic principal components (accounting for possible population admixture). ApoE e4e4 genotype was associated with increased risks of test positivity (OR=2.24, 95% CI: 1.72 to 2.93, p=3.24×10−9) and of mortality with test-confirmed COVID-19 (OR=4.29, 95% CI: 2.38 to 7.72, p=1.22×10−6), compared to e3e3s. Independent replications are needed to confirm our findings and mechanistic work is needed to understand how ApoE e4e4 results in the marked increase in vulnerability, especially for COVID-19 mortality. These findings also demonstrate that risks for COVID-19 mortality are not simply related to advanced chronological age or the comorbidities commonly seen in aging.

AbstractWith no known treatments or vaccine, COVID-19 presents a major threat, particularly to older adults, who account for the majority of severe illness and deaths. The age-related susceptibility is partly explained by increased comorbidities including dementia and type II diabetes [1]. While it is unclear why these diseases predispose risk, we hypothesize that increased biological age, rather than chronological age, may be driving disease-related trends in COVID-19 severity with age. To test this hypothesis, we applied our previously validated biological age measure (PhenoAge) [2] composed of chronological age and nine clinical chemistry biomarkers to data of 347,751 participants from a large community cohort in the United Kingdom (UK Biobank), recruited between 2006 and 2010. Other data included disease diagnoses (to 2017), mortality data (to 2020), and the UK national COVID-19 test results (to May 31, 2020) [3]. Accelerated aging 10-14 years prior to the start of the COVID-19 pandemic was associated with test positivity (OR=1.15 per 5-year acceleration, 95% CI: 1.08 to 1.21, p=3.2×10−6) and all-cause mortality with test-confirmed COVID-19 (OR=1.25, per 5-year acceleration, 95% CI: 1.09 to 1.44, p=0.002) after adjustment for demographics including current chronological age and pre-existing diseases or conditions. The corresponding areas under the curves were 0.669 and 0.803, respectively. Biological aging, as captured by PhenoAge, is a better predictor of COVID-19 severity than chronological age, and may inform risk stratification initiatives, while also elucidating possible underlying mechanisms, particularly those related to inflammaging.

BACKGROUND: Higher continuity of GP care (CGPC), that is, consulting the same doctor consistently, can improve doctor-patient relationships and increase quality of care; however, its effects on patients with dementia are mostly unknown. AIM: to estimate the associations between CGPC and potentially inappropriate prescribing (PIP), and with the incidence of adverse health outcomes (AHOs) in patients with dementia. DESIGN AND SETTING: a retrospective cohort study with 1 year of follow-up anonymised medical records from 9324 patients with dementia, aged ≥65 years living in England in 2016. METHOD: CGPC measures include the Usual Provider of Care (UPC), Bice-Boxerman Continuity of Care (BB), and Sequential Continuity (SECON) indices. Regression models estimated associations with PIPs and survival analysis with incidence of AHOs during the follow-up adjusted for age, sex, deprivation level, 14 comorbidities, and frailty. RESULTS: the highest quartile (HQ) of UPC (highest continuity) had 34.8% less risk of delirium (odds ratio [OR] 0.65, 95% confidence interval [CI] = 0.51 to 0.84), 57.9% less risk of incontinence (OR 0.42, 95% CI = 0.31 to 0.58), and 9.7% less risk of emergency admissions to hospital (OR 0.90, 95% CI = 0.82 to 0.99) compared with the lowest quartile. Polypharmacy and PIP were identified in 81.6% (n = 7612) and 75.4% (n = 7027) of patients, respectively. The HQ had fewer prescribed medications (HQ: mean 8.5, lowest quartile (LQ): mean 9.7, P

Stroke events increase the risk of developing dementia, 10% for a first-ever stroke and 30% for recurrent strokes. However, the effects of stroke on global cognition, leading up to dementia, remain poorly understood. We investigated: (i) post-stroke trajectories of cognitive change, (ii) trajectories of cognitive decline in those who develop dementia over periods of follow-up length and (iii) risk factors precipitating the onset of dementia. Prospective cohort of hospital-based stroke survivors in North-East England was followed for up to 12 years. In this study, we included 355 stroke survivors of ≥75 years of age, not demented 3 months post-stroke, who had had annual assessments during follow-up. Global cognition was measured annually and characterized using standardized tests: Cambridge Cognition Examination-Revised and Mini-Mental State Examination. Demographic data and risk factors were recorded at baseline. Mixed-effects models were used to study trajectories in global cognition, and logistic models to test associations between the onset of dementia and key risk factors, adjusted for age and sex. of the 355 participants, 91 (25.6%) developed dementia during follow-up. The dementia group had a sharper decline in Cambridge Cognition Examination-Revised (coeff. = -1.91, 95% confidence interval = -2.23 to -1.59, P 

Abstract
.
. Background
. Age and disease prevalence are the 2 biggest risk factors for Coronavirus disease 2019 (COVID-19) symptom severity and death. We therefore hypothesized that increased biological age, beyond chronological age, may be driving disease-related trends in COVID-19 severity.
.
.
. Methods
. Using the UK Biobank England data, we tested whether a biological age estimate (PhenoAge) measured more than a decade prior to the COVID-19 pandemic was predictive of 2 COVID-19 severity outcomes (inpatient test positivity and COVID-19-related mortality with inpatient test-confirmed COVID-19). Logistic regression models were used with adjustment for age at the pandemic, sex, ethnicity, baseline assessment centers, and preexisting diseases/conditions.
.
.
. Results
. Six hundred and thirteen participants tested positive at inpatient settings between March 16 and April 27, 2020, 154 of whom succumbed to COVID-19. PhenoAge was associated with increased risks of inpatient test positivity and COVID-19-related mortality (ORMortality = 1.63 per 5 years, 95% CI: 1.43–1.86, p = 4.7 × 10−13) adjusting for demographics including age at the pandemic. Further adjustment for preexisting diseases/conditions at baseline (ORM = 1.50, 95% CI: 1.30–1.73 per 5 years, p = 3.1 × 10−8) and at the early pandemic (ORM = 1.21, 95% CI: 1.04–1.40 per 5 years, p =. 011) decreased the association.
.
.
. Conclusions
. PhenoAge measured in 2006–2010 was associated with COVID-19 severity outcomes more than 10 years later. These associations were partly accounted for by prevalent chronic diseases proximate to COVID-19 infection. Overall, our results suggest that aging biomarkers, like PhenoAge may capture long-term vulnerability to diseases like COVID-19, even before the accumulation of age-related comorbid conditions.
.

High blood pressure (BP) affects 75% of people aged over 70. Ageing alters BP homeostasis, resulting in postural hypotension and increased BP variability. Co-morbidity and frailty add complexity to understanding BP changes in later life. Longitudinal BP declines are likely driven by accumulating co-morbidity and are accelerated in both frailty and dementia. This narrative review summarises what is known about the association between BP and frailty, the clinical management of BP in frailty and the association between BP, cognitive decline and dementia.

IMPORTANCE: treatment of dementia in individuals with comorbidities is complex, leading to potentially inappropriate prescribing (PIP). The impact of PIP in this population is unknown. OBJECTIVE: to estimate the rate of PIP and its effect on adverse health outcomes (AHO). DESIGN: retrospective cohort. SETTING: primary care electronic health records linked to hospital discharge data from England. SUBJECTS: 11,175 individuals with dementia aged over 65 years in 2016 and 43,463 age- and sex-matched controls. METHODS: Screening Tool of Older Persons' Prescriptions V2 defined PIP. Logistic regression tested associations with comorbidities at baseline, and survival analyses risk of incident AHO, adjusted for age, gender, deprivation and 14 comorbidities. RESULTS: the dementia group had increased risk of PIP (73% prevalence; odds ratio [OR]: 1.92; confidence interval [CI]: 83-103%; P 

BACKGROUND: Blood pressure (BP) management in frail older people is challenging. An randomised controlled trial of largely non-frail older people found cardiovascular and mortality benefit with systolic (S) BP target 150 mmHg. Associations with mortality varied between non-frail

OBJECTIVES: Dementia frequently occurs alongside comorbidities. Coexisting conditions are often managed with multiple medications, leading to increased risk of potentially inappropriate medication and adverse drug reactions. We aimed to estimate prevalence of, and identify factors reported to be associated with, potentially inappropriate prescribing (PIP) for older individuals diagnosed with dementia. DESIGN: We used a state-of-the-art review approach, selecting papers written in English and published from 2007 to January 2018. Publications were retrieved from Scopus and Web of Science databases. Inclusion criteria included a formal diagnosis of dementia, a formal classification of PIP and reported prevalence of PIP as an outcome. Random effects models were used to provide a pooled estimate of prevalence of PIP. The Appraisal tool for Cross-Sectional Studies (AXIS tool) was used to assess bias in the included studies. RESULTS: the bibliographic search yielded 221 citations, with 12 studies meeting the inclusion criteria. The estimates of PIP prevalence for people living with dementia ranged from 14% to 64%. Prevalence was 31% (95% CI 9 to 52) in the community, and 42% (95% CI 30 to 55) in nursing/care homes. PIP included prescribing likely related to dementia (eg, hypnotics and sedative and cholinesterase inhibitors) and prescribing related to treatment of comorbidities (eg, cardiovascular drugs and non-steroidal anti-inflammatory medication). Higher levels of comorbidity were associated with increased risk of PIP; however, only one study investigated associations with specific comorbidities of dementia. CONCLUSION: PIP remains a significant issue in healthcare management for people living with dementia. Higher levels of comorbidity are associated with increased prevalence of PIP, but the specific conditions driving this increase remain unknown. Further work is necessary to investigate PIP related to the presence of common comorbidities in patients living with dementia.

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.

Background: Physicians' adherence to guideline-recommended therapy is associated with short-term clinical outcomes in heart failure (HF) with reduced ejection fraction (HFrEF). However, its impact on longer-term outcomes is poorly documented. Here, we present results from the 18-month follow-up of the QUALIFY registry. Methods and results: Data at 18 months were available for 6118 ambulatory HFrEF patients from this international prospective observational survey. Adherence was measured as a continuous variable, ranging from 0 to 1, and was assessed for five classes of recommended HF medications and dosages. Most deaths were cardiovascular (CV) (228/394) and HF-related (191/394) and the same was true for unplanned hospitalizations (1175 CV and 861 HF-related hospitalizations, out of a total of 1541). According to univariable analysis, CV and HF deaths were significantly associated with physician adherence to guidelines. In multivariable analysis, HF death was associated with adherence level [subdistribution hazard ratio (SHR) 0.93, 95% confidence interval (CI) 0.87–0.99 per 0.1 unit adherence level increase; P = 0.034] as was composite of HF hospitalization or CV death (SHR 0.97, 95% CI 0.94–0.99 per 0.1 unit adherence level increase; P = 0.043), whereas unplanned all-cause, CV or HF hospitalizations were not (all-cause: SHR 0.99, 95% CI 0.9–1.02; CV: SHR 0.98, 95% CI 0.96–1.01; and HF: SHR 0.99, 95% CI 0.96–1.02 per 0.1 unit change in adherence score; P = 0.52, P = 0.2, and P = 0.4, respectively). Conclusion: These results suggest that physicians' adherence to guideline-recommended HF therapies is associated with improved outcomes in HFrEF. Practical strategies should be established to improve physicians' adherence to guidelines.

IMPORTANCE: There is mixed evidence that blood pressure (BP) stabilizes or decreases in later life. It is also unclear whether BP trajectories reflect advancing age, proximity to end of life, or selective survival of persons free from hypertension. OBJECTIVE: to estimate individual patient BP for each of the 20 years before death and identify potential mechanisms that may explain trajectories. DESIGN, STUDY, AND PARTICIPANTS: We analyzed population-based Clinical Practice Research Datalink primary care and linked hospitalization electronic medical records from the United Kingdom, using retrospective cohort approaches with generalized linear mixed-effects modeling. Participants were all available individuals with BP measures over 20 years, yielding 46 634 participants dying aged at least 60 years, from 2010 to 2014. We also compared BP slopes from 10 to 3 years before death for 20 207 participants who died, plus 20 207 birth-year and sex-matched participants surviving longer than 9 years. MAIN OUTCOMES AND MEASURES: Clinically recorded individual patient repeated systolic BP (SBP) and diastolic BP (DBP). RESULTS: in 46 634 participants (51.7% female; mean [SD] age at death, 82.4 [9.0] years), SBPs and DBPs peaked 18 to 14 years before death and then decreased progressively. Mean changes in SBP from peak values ranged from -8.5 mm Hg (95% CI, -9.4 to -7.7) for those dying aged 60 to 69 years to -22.0 mm Hg (95% CI, -22.6 to -21.4) for those dying at 90 years or older; overall, 64.0% of individuals had SBP changes of greater than -10 mm Hg. Decreases in BP appeared linear from 10 to 3 years before death, with steeper decreases in the last 2 years of life. Decreases in SBP from 10 to 3 years before death were present in individuals not treated with antihypertensive medications, but mean yearly changes were steepest in patients with hypertension (-1.58; 95% CI, -1.56 to -1.60 mm Hg vs -0.70; 95% CI, -0.65 to -0.76 mm Hg), dementia (-1.81; 95% CI, -1.77 to -1.87 mm Hg vs -1.41; 95% CI, -1.38 to -1.43 mm Hg), heart failure (-1.66; 95% CI, -1.62 to -1.69 mm Hg vs -1.37; 95% CI, -1.34 to -1.39 mm Hg), and late-life weight loss. CONCLUSIONS AND RELEVANCE: Mean SBP and DBP decreased for more than a decade before death in patients dying at 60 years and older. These BP decreases are not simply attributable to age, treatment of hypertension, or better survival without hypertension. Late-life BP decreases may have implications for risk estimation, treatment monitoring, and trial design.

OBJECTIVES: to estimate associations between long-term use of proton pump inhibitors (PPIs) and pneumonia incidence in older adults in primary care. DESIGN: Longitudinal analyses of electronic medical records. SETTING: England PARTICIPANTS: Individuals aged 60 and older in primary care receiving PPIs for 1 year or longer (N=75,050) and age- and sex-matched controls (N=75,050). MEASUREMENTS: Net hazard ratios for pneumonia incidence in Year 2 of treatment were estimated using the prior event rate ratio (PERR), which adjusts for pneumonia incidence differences before initiation of treatment. Inverse probability weighted models adjusted for 78 demographic, disease, medication, and healthcare usage measures. RESULTS: During the second year after initiating treatment, PPIs were associated with greater hazard of incident pneumonia (PERR-adjusted hazard ratio=1.82, 95% confidence interval=1.27-2.54), accounting for pretreatment pneumonia rates. Estimates were similar across age and comorbidity subgroups. Similar results were also obtained from propensity score- and inverse probability-weighted models. CONCLUSION: in a large cohort of older adults in primary care, PPI prescription was associated with greater risk of pneumonia in the second year of treatment. Results were robust across alternative analysis approaches. Controversies about the validity of reported short-term harms of PPIs should not divert attention from potential long-term effects of PPI prescriptions on older adults.

Background: for older groups, being overweight [body mass index (BMI; in kg/m2): 25 to

BACKGROUND: There is limited evidence on statin risk and effectiveness for patients aged 80+. We estimated risk of recurrent myocardial infarction, muscle-related and other adverse events, and statin-related incremental costs in "real-world" older patients treated with statins versus no statins. METHODS: We used primary care electronic medical records from the UK Clinical Practice Research Datalink. Subhazard ratios (competing risk of death) for myocardial infarction recurrence (primary end point), falls, fractures, ischemic stroke, and dementia, and hazard ratios (Cox) for all-cause mortality were used to compare older (60+) statin users and 1:1 propensity-score-matched controls (n = 12,156). Participants were followed-up for 10 years. RESULTS: Mean age was 76.5±9.2 years; 45.5% were women. Statins were associated with near significant reduction in myocardial infarction recurrence (subhazard ratio = 0.84, 0.69-1.02, p =. 073), with protective effect in the 60-79 age group (0.73, 0.57-0.94) but a nonsignificant result in the 80+ group (1.06, 0.78-1.44; age interaction p =. 094). No significant associations were found for stroke or dementia. Data suggest an increased risk of falls (1.36, 1.17-1.60) and fractures (1.33, 1.04-1.69) in the first 2 years of treatment, particularly in the 80+ group. Treatment was associated with lower all-cause mortality. Statin use was associated with health care cost savings in the 60-79 group but higher costs in the 80+ group. CONCLUSIONS: Estimates of statin effectiveness for the prevention of recurrent myocardial infarction in patients aged 60-79 years were similar to trial results, but more evidence is needed in the older group. There may be an excess of falls and fractures in very old patients, which deserves further investigation.

Society gets numerous benefits from the water environment. It is crucial to ensure that water management practices deliver these benefits over the long-term in a sustainable and cost-effective way. Currently, hydromorphological alterations and nutrient enrichment pose the greatest challenges in European water bodies. The rapidly changing climatic and socio-economic boundary conditions pose further challenges to water management decisions and the achievement of policy goals. Scenarios are a strategic tool useful in conducting systematic investigations of future uncertainties pertaining to water management. In this study, the use of scenarios revealed water management challenges for England and Wales to 2050. A set of existing scenarios relevant to river basin management were elaborated through stakeholder workshops and interviews, relying on expert knowledge to identify drivers of change, their interdependencies, and influence on system dynamics. In a set of four plausible alternative futures, the causal chain from driving forces through pressures to states, impacts and responses (DPSIR framework) was explored. The findings suggest that scenarios driven by short-term economic growth and competitiveness undermine current environmental legislative requirements and exacerbate the negative impacts of climate change, producing a general deterioration of water quality and physical habitats, as well as reduced water availability with adverse implications for the environment, society and economy. Conversely, there are substantial environmental improvements under the scenarios characterised by long-term sustainability, though achieving currently desired environmental outcomes still poses challenges. The impacts vary across contrasting generic catchment types that exhibit distinct future water management challenges. The findings suggest the need to address hydromorphological alterations, nutrient enrichment and nitrates in drinking water, which are all likely to be exacerbated in the future. Future-proofing river basin management measures that deal with these challenges is crucial moving forward. The use of scenarios to future-proof strategy, policy and delivery mechanisms is discussed to inform next steps.

An enhanced methodology for the policy-level prioritization of intervention options during carcass disposal is presented. Pareto charts provide a semiquantitative analysis of opportunities for multiple exposures to human health, animal health, and the wider environment during carcass disposal; they identify critical control points for risk management and assist in waste technology assessment. Eighty percent of the total availability of more than 1300 potential exposures to human, animal, or environmental receptors is represented by 16 processes, these being dominated by on-farm collection and carcass processing, reinforcing the criticality of effective controls during early stages of animal culling and waste processing. Exposures during mass burials are dominated by ground- and surface-water exposures with noise and odor nuisance prevalent for mass pyres, consistent with U.K. experience. Pareto charts are discussed in the context of other visualization formats for policy officials and promoted as a communication tool for informing the site-specific risk assessments required during the operational phases of exotic disease outbreaks. © 2010 American Chemical Society.

BACKGROUND/AIMS: Midlife hypertension is associated with an increased risk for dementia, but the association between blood pressure and dementia in very old age is unclear. METHODS: in a population-based cohort study, a total of 102 individuals aged 85, 90 or ≥ 95 years participated in 2 examinations with a 5-year interval. The investigations consisted of a structured interview, blood pressure measurement, rating scales such as the Mini-Mental State Examination (MMSE) and an investigation of medical charts. RESULTS: the majority of participants exhibited a decline in blood pressure. Baseline systolic blood pressure (SBP), diastolic blood pressure or pulse pressure (PP) were not associated with incident dementia or with decline in MMSE scores in multiple regression analyses adjusted for age and sex. However, incident dementia cases exhibited a greater decline in SBP (p = 0.02) and PP (p = 0.04), and decline in SBP was associated with a decline in MMSE score (p = 0.008). CONCLUSION: in this small longitudinal study on the very old, no association between baseline blood pressure and incident dementia was found, but individuals who developed dementia exhibited a greater blood pressure decline. Low blood pressure could be an effect of dementia in the very old.