Background: For older groups, being overweight [body mass index (BMI; in kg/m2): 25 to <30] is reportedly associated with a lower or similar risk of mortality than being normal weight (BMI: 18.5 to <25). However, this “risk paradox” is partly explained by smoking and disease-associated weight loss. This paradox may also arise from BMI failing to measure fat redistribution to a centralized position in later life.Objective: This study aimed to estimate associations between combined measurements of BMI and waist-to-hip ratio (WHR) with mortality and incident coronary artery disease (CAD).Design: This study followed 130,473 UK Biobank participants aged 60–69 y (baseline 2006–2010) for ≤8.3 y (n = 2974 deaths). Current smokers and individuals with recent or disease-associated (e.g., from dementia, heart failure, or cancer) weight loss were excluded, yielding a “healthier agers” group. Survival models were adjusted for age, sex, alcohol intake, smoking history, and educational attainment. Population and sex-specific lower and higher WHR tertiles were <0.91 and ≥0.96 for men and <0.79 and ≥0.85 for women, respectively.Results: Ignoring WHR, the risk of mortality for overweight subjects was similar to that for normal-weight subjects (HR: 1.09; 95% CI: 0.99, 1.19; P = 0.066). However, among normal-weight subjects, mortality increased for those with a higher WHR (HR: 1.33; 95% CI: 1.08, 1.65) compared with a lower WHR. Being overweight with a higher WHR was associated with substantial excess mortality (HR: 1.41; 95% CI: 1.25, 1.61) and greatly increased CAD incidence (sub-HR: 1.64; 95% CI: 1.39, 1.93) compared with being normal weight with a lower WHR. There was no interaction between physical activity and BMI plus WHR groups with respect to mortality.Conclusions: For healthier agers (i.e., nonsmokers without disease-associated weight loss), having central adiposity and a BMI corresponding to normal weight or overweight is associated with substantial excess mortality. The claimed BMI-defined overweight risk paradox may result in part from failing to account for central adiposity, rather than reflecting a protective physiologic effect of higher body-fat content in later life.

Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus (CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7×10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.

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 PARTICIPANTSWe 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.

Variation in human lifespan is 20 to 30% heritable but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested.Genotyped variants (n=845,997) explained 10.2% (SD=1.3%) of combined parental longevity. In GWAS, a locus in the nicotine receptor CHRNA3 -previously associated with increased smoking and lung cancer -was associated with paternal age at death, with each protective allele (rs1051730[G]) being associated with 0.03 years later age at father's death (p=3x10 -8 ). Offspring of longer lived parents had more protective alleles (lower genetic risk scores) for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate gene analyses, variants in the TOMM40/APOE locus were associated with longevity (including rs429358, p=3x10 -5 ), but FOXO variants were not associated.These results support a multiple protective factors model for achieving longer lifespans in humans, with a prominent role for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.

Background:Moderate obesity in later life may improve survival, prompting calls to revise obesity control policies. However, this obesity paradox may be due to confounding from smoking, diseases causing weight-loss, plus varying follow-up periods. We aimed to estimate body mass index (BMI) associations with mortality, incident type 2 diabetes, and coronary heart disease in older people with and without the above confounders.Methods:Cohort analysis in Clinical Practice Research Datalink primary care, hospital and death certificate electronic medical records in England for ages 60 to more than 85 years. Models were adjusted for age, gender, alcohol use, smoking, calendar year, and socioeconomic status.Results:Overall, BMI 30–34.9 (obesity class 1) was associated with lower overall death rates in all age groups. However, after excluding the specific confounders and follow-up less than 4 years, BMI mortality risk curves at age 65–69 were U-shaped, with raised risks at lower BMIs, a nadir between 23 and 26.9 and steeply rising risks above. In older age groups, mortality nadirs were at modestly higher BMIs (all <30) and risk slopes at higher BMIs were less marked, becoming nonsignificant at age 85 and older. Incidence of diabetes was raised for obesity-1 at all ages and for coronary heart disease to age 84.Conclusions:Obesity is associated with shorter survival plus higher incidence of coronary heart disease and type 2 diabetes in older populations after accounting for the studied confounders, at least to age 84. These results cast doubt on calls to revise obesity control policies based on the claimed risk paradox at older ages.

ObjectivesDementia 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.DesignWe 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.ResultsThe 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.ConclusionPIP 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.

BackgroundInjuries result in substantial number of deaths among children globally. The burden across many settings is largely unknown. We estimated global and regional child deaths due to injuries from publicly available evidence.MethodsWe searched for community-based studies and nationally representative data reporting on child injury deaths published after year 1990 from CINAHL, EMBASE, IndMed, LILACS, Global Health, MEDLINE, SCOPUS, and Web of Science. Specific and all-cause mortality due to injuries were extracted for three age groups (0-11 months, 1-4 years, and 0-4 years). We conducted random-effects meta-analysis on extracted crude estimates, and developed a meta-regression model to determine the number of deaths due to injuries among children aged 0-4 years globally and across the World Health Organization (WHO) regions.ResultsTwenty-nine studies from 16 countries met the selection criteria. A total of 230 data-points on 15 causes of injury deaths were retrieved from all studies. Eighteen studies were rated as high quality, although heterogeneity was high (I2 = 99.7%, P < 0.001) reflecting variable data sources and study designs. For children aged 0-11 months, the pooled crude injury mortality rate was 29.6 (95% confidence interval (CI) = 21.1-38.1) per 100 000 child population, with asphyxiation being the leading cause of death (neonatal) at 189.1 (95% CI = 142.7-235.4) per 100 000 followed by suffocation (post-neonatal) at 18.7 (95% CI = 11.8-25.7) per 100 000. Among children aged 1-4 years, the pooled crude injury mortality rate was 32.7 (95% CI = 27.3-38.1) per 100 000, with traffic injuries and drowning the leading causes of deaths at 10.8 (95% CI = 8.9-12.8) and 8.8 (95% CI = 7.5-10.2) per 100 000, respectively. Among children under five years, the pooled injury mortality rate was 37.7 (95% CI = 32.7-42.7) per 100 000, with traffic injuries and drowning also the leading causes of deaths at 10.3 (95% CI = 8.8-11.8) and 8.9 (95% CI = 7.8-9.9) per 100 000 respectively. When crude mortality changes over age, WHO regions, and study period were accounted for in our model, we estimated that in 2015 there were 522 167 (95% CI = 395 823-648 630) deaths among children aged 0-4 years, with South East Asia (SEARO) recording the highest number of deaths at 195 084 (95% CI = 159476-230502), closely followed by the Africa region (AFRO) with 176523 (95% CI = 115 040-237 831) deaths. Globally, traffic injuries and drowning were the leading causes of under-five injury fatalities in 2015 with 142 661 (22.0/100 000) and 123 270 (19.0/100 000) child deaths, respectively. The exception being burns in AFRO with 57 784 deaths (38.6/100 000).ConclusionsVarying study designs, case definitions, and particularly limited country representation from Africa and South-East Asia (where we reported higher estimates), imply a need for more studies for better population representative estimates. This study may have however provided improved understanding on child injury death profiles needed to guide further research, policy reforms an...

Persons aged 60-69 years with near-ideal cardiovascular risk factor profiles have substantially lower incidence of geriatric conditions and frailty. Optimizing cardiovascular disease risk factors may substantially reduce the burden of morbidity in later life.