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.

Obesity and Longer Term Risks of Dementia in 65-74 Year Olds.

BACKGROUND: overweight or obesity at ages <65 years associates with increased dementia incidence, but at ≥65 years estimates are paradoxical. Weight loss before dementia diagnosis, plus smoking and diseases causing weight loss may confound associations. OBJECTIVE: to estimate weight loss before dementia diagnosis, plus short and longer-term body mass index associations with incident dementia in 65-74 year olds within primary care populations in England. METHODS: we studied dementia diagnosis free subjects: 257,523 non-smokers without baseline cancer, heart failure or multi-morbidity (group A) plus 161,927 with these confounders (group B), followed ≤14.9 years. Competing hazard models accounted for mortality. RESULTS: in group A, 9,774 were diagnosed with dementia and in those with repeat weight measures, 54% lost ≥2.5 kg during 10 years pre-diagnosis. During <10 years obesity (≥30.0 kg/m2) or overweight (25.0 to <30.0) were inversely associated with incident dementia (versus 22.5 to <25.0). However, from 10 to 14.9 years, obesity was associated with increased dementia incidence (hazard ratio [HR] 1.17; 95% CI: 1.03-1.32). Overweight protective associations disappeared in longer-term analyses (HR, 1.01; 95% CI: 0.90-1.13). In group B, (n = 6,070 with incident dementia), obesity was associated with lower dementia risks in the short and longer-term. CONCLUSIONS: in 65-74 year olds (free of smoking, cancer, heart failure or multi-morbidity at baseline) obesity associates with higher longer-term incidence of dementia. Paradoxical associations were present short-term and in those with likely confounders. Reports of protective effects of obesity or overweight on dementia risk in older groups may reflect biases, especially weight loss before dementia diagnosis.

Association of blood pressure with clinical outcomes in older adults with chronic kidney disease.

BACKGROUND: in chronic kidney disease (CKD), hypertension is associated with poor outcomes at ages <70 years. At older ages, this association is unclear. We tested 10-year mortality and cardiovascular outcomes by clinical systolic blood pressure (SBP) in older CKD Stages 3 and 4 patients without diabetes or proteinuria. METHODS: retrospective cohort in population representative primary care electronic medical records linked to hospital data from the UK. CKD staged by CKD-EPI equation (≥2 creatinine measurements ≥90 days apart). SBPs were 3-year medians before baseline, with mean follow-up 5.7 years. Cox competing models accounted for mortality. RESULTS: about 158,713 subjects with CKD3 and 6,611 with CKD4 met inclusion criteria. Mortality increased with increasing CKD stage in all subjects aged >60. In the 70 plus group with SBPs 140-169 mmHg, there was no increase in mortality, versus SBP 130-139. Similarly, SBPs 140-169 mmHg were not associated with increased incident heart failure, stroke or myocardial infarctions. SBPs <120 mmHg were associated with increased mortality and cardiovascular risk. At ages 60-69, there was increased mortality at SBP <120 and SBP >150 mmHg.Results were little altered after excluding those with declining SBPs during 5 years before baseline, or for longer-term outcomes (5-10 years after baseline). CONCLUSIONS: in older primary care patients, CKD3 or 4 was the dominant outcome predictor. SBP 140-169 mmHg having little additional predictive value, <120 mmHg was associated with increased mortality. Prospective studies of representative older adults with CKD are required to establish optimum BP targets.

Mediators of the association between childhood body mass index and educational attainment: Analysis of a UK prospective cohort study.

BACKGROUND: Higher body mass index (BMI) in childhood is associated with lower academic achievement. OBJECTIVE: To explore potential pathways linking childhood BMI with educational attainment. METHODS: Using data from the Avon Longitudinal Study of Parents and Children prospective cohort study (N = 6949), we assessed the association between BMI z-scores at 11.7 years and educational attainment at 16 (General Certificate of Secondary Education [GCSE] results). Depressive symptoms, externalizing behaviours, bullying and school enjoyment were considered as potential mediators. Mediators were examined individually and jointly using sequential causal mediation. RESULTS: Higher BMI z-scores were associated with lower GCSE scores (females ß = -3.47 95% CI -5.54, -1.41 males ß = -4.33 95% CI -6.73, -1.94). Together, bullying, externalizing symptoms, depressive symptoms and school enjoyment mediated 41.9% of this association in females, and 23.3% in males. In males, evidence for mediation was weak (confidence intervals for all indirect effects spanned the null). In both females and males, most of the mediation was driven by externalizing symptoms. CONCLUSIONS: The detrimental effect of higher BMI on educational attainment appears to be partly explained by externalizing behaviours, particularly in females. Interventions to support behavioural problems may help the academic achievement of children with a higher body weight.

Molecular mediators of the association between child obesity and mental health.

Biological mechanisms underlying the association between obesity and depression remain unclear. We investigated the role of metabolites and DNA methylation as mediators of the relationship between childhood obesity and subsequent poor mental health in the English Avon Longitudinal Study of Parents and Children. Obesity was defined according to United Kingdom Growth charts at age 7 years and mental health through the Short Mood and Feelings Questionnaire (SMFQ) completed at age 11 years. Metabolites and DNA methylation were measured by nuclear magnetic resonance spectroscopy and Illumina array in blood at the age of 7 years. The associations between obesity and SMFQ score, as continuous count data or using cut-offs to define depressive symptoms (SMFQ >7) or depression (SMFQ >11), were tested using adjusted Poisson and logistic regression. Candidate metabolite mediators were identified through metabolome-wide association scans for obesity and SMFQ score, correcting for false-discovery rate. Candidate DNA methylation mediators were identified through testing the association of putative BMI-associated CpG sites with SMFQ scores, correcting for look-up false-discovery rate. Mediation by candidate molecular markers was tested. Two-sample Mendelian randomization (MR) analyses were additionally applied to test causal associations of metabolites with depression in independent adult samples. 4,018 and 768 children were included for metabolomics and epigenetics analyses, respectively. Obesity at 7 years was associated with a 14% increase in SMFQ score (95% CI: 1.04, 1.25) and greater odds of depression (OR: 1.46 (95% CI: 0.78, 2.38) at 11 years. Natural indirect effects (mediating pathways) between obesity and depression for tyrosine, leucine and conjugated linoleic acid were 1.06 (95% CI: 1.00, 1.13, proportion mediated (PM): 15%), 1.04 (95% CI: 0.99, 1.10, PM: 9.6%) and 1.06 (95% CI: 1.00, 1.12, PM: 13.9%) respectively. In MR analysis, one unit increase in tyrosine was associated with 0.13 higher log odds of depression (p = 0.1). Methylation at cg17128312, located in the FBXW9 gene, had a natural indirect effect of 1.05 (95% CI: 1.01,1.13, PM: 27%) as a mediator of obesity and SMFQ score. Potential biologically plausible mechanisms involving these identified molecular features include neurotransmitter regulation, inflammation, and gut microbiome modulation. These results require replication in further observational and mechanistic studies.

Potentially inappropriate prescribing in dementia: a state-of-the-art review since 2007.

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.

Vitamin D levels and risk of delirium: A mendelian randomization study in the UK Biobank.

OBJECTIVE: To estimate effects of vitamin D levels on incident delirium hospital admissions using inherited genetic variants in mendelian randomization models, which minimize confounding and exclude reverse causation. METHODS: Longitudinal analysis using the UK Biobank, community-based, volunteer cohort (2006-2010) with incident hospital-diagnosed delirium (ICD-10 F05) ascertained during ≤9.9 years of follow-up of hospitalization records (to early 2016). We included volunteers of European descent aged 60-plus years by end of follow-up. We used single-nucleotide polymorphisms previously shown to increase circulating vitamin D levels, and APOE variants. Cox competing models accounting for mortality were used. RESULTS: Of 313,121 participants included, 544 were hospitalized with delirium during follow-up. Vitamin D variants were protective for incident delirium: hazard ratio = 0.74 per 10 nmol/L (95% confidence interval 0.62-0.87, p = 0.0004) increase in genetically instrumented vitamin D, with no evidence for pleiotropy (mendelian randomization-Egger p > 0.05). Participants with ≥1 APOE ε4 allele were more likely to develop delirium (e.g., ε4ε4 hazard ratio = 3.73, 95% confidence interval 2.68-5.21, p = 8.0 × 10-15 compared to ε3ε3), but there was no interaction with vitamin D variants. CONCLUSIONS AND RELEVANCE: In a large community-based cohort, there is genetic evidence supporting a causal role for vitamin D levels in incident delirium. Trials of correction of low vitamin D levels in the prevention of delirium are needed.

Impact of Low Cardiovascular Risk Profiles on Geriatric Outcomes: Evidence From 421,000 Participants in Two Cohorts.

BACKGROUND: Individuals with low cardiovascular risk factor profiles experience lower rates of cardiovascular diseases, but associations with geriatric syndromes are unclear. We tested whether individuals with low cardiovascular disease risk, aged 60-69 years old at baseline in two large cohorts, were less likely to develop aging-related adverse health outcomes. METHODS: Data were from population representative medical records (Clinical Practice Research Datalink [CPRD] England, n = 239,591) and healthy volunteers (UK Biobank [UKB], n = 181,820), followed for ≤10 years. A cardiovascular disease risk score (CRS) summarized smoking status, LDL-cholesterol, blood pressure, body mass index, fasting glucose and physical activity, grouping individuals as low (ie, all factors near ideal), moderate, or high CRS. Logistic regression, Cox models, and Fine and Grey risk models tested the associations between the CRS and health outcomes. RESULTS: Low CRS individuals had less chronic pain (UKB: baseline odds ratio = 0.52, confidence interval [CI] = 0.50-0.54), lower incidence of incontinence (CPRD: subhazard ratio [sub-HR] = 0.75, 0.63-0.91), falls (sub-HR = 0.82, CI = 0.73-0.91), fragility fractures (sub-HR = 0.78, CI = 0.65-0.93), and dementia (vs. high risks; UKB: sub-HR = 0.67, CI = 0.50-0.89; CPRD: sub-HR = 0.79, CI = 0.56-1.12). Only 5.4% in CPRD with low CRS became frail (Rockwood index) versus 24.2% with high CRS. All-cause mortality was markedly lower in the low CRS group (vs. high CRS; HR = 0.40, 95% CI = 0.35-0.47). All associations showed dose-response relationships, and results were similar in both cohorts. CONCLUSIONS: 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.

Global and regional child deaths due to injuries: an assessment of the evidence.

BACKGROUND: Injuries 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. METHODS: We 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. RESULTS: Twenty-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). CONCLUSIONS: Varying 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 and relevant strategies globally.

Blood Pressure Trajectories in the 20 Years Before Death.

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.

Central adiposity and the overweight risk paradox in aging: follow-up of 130,473 UK Biobank participants.

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.

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

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.

Safety and Effectiveness of Statins for Prevention of Recurrent Myocardial Infarction in 12 156 Typical Older Patients: A Quasi-Experimental Study.

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.

Obesity in Older People With and Without Conditions Associated With Weight Loss: Follow-up of 955,000 Primary Care Patients.

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.

Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants.

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=5.7x10-3). 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.

Causes of accidental childhood deaths in China in 2010: A systematic review and analysis.

BACKGROUND: Infectious causes of childhood deaths in the world have decreased substantially in the 21st century. This trend has exposed accidental deaths as an increasingly important future challenge. Presently, little is known about the cause structure of accidental childhood deaths in low- and middle-income country (LMIC) settings. In this paper, we aim to establish cause structure for accidental deaths in children aged 0-4 years in China in the year 2010. METHODS: In this paper, we explored the database of 208 multi-cause child mortality studies in Chinese that formed a basis for the first published estimate of the causes of child deaths in China (for the year 2008). Only five of those studies identified specific causes of accidental deaths. Because of this, we searched the Chinese medical literature databases CNKI and WanFang for single-cause mortality studies that were focused on accidental deaths. We identified 71 further studies that provided specific causes for accidental deaths. We used epidemiological modeling to estimate the number of accidental child deaths in China in 2010 and to assign those deaths to specific causes. RESULTS: In 2010, we estimated 314 581 deaths in children 0-4 years in China, of which 31 633 (10.1%) were accidental. Accidental deaths contributed 7240 (4.0%) of all deaths in neonatal period, 8838 (10.5%) among all post-neonatal infant deaths, and 15 554 (31.7%) among children with 1-4 years of age. Among four tested models, the most predictive was used to establish the likely cause structure of accidental deaths in China. We estimated that asphyxia caused 9490 (95% confidence interval (CI) 8224-11 072), drowning 5694 (95% CI 5061-6327), traffic accidents 3796 (95% CI 3163-4745), poisoning 3163 (95% CI 2531-3796) and falls 2531 (95% CI 2214-3163) deaths. Based on medians from a few rare studies, we also predict 633 (95% CI 316-1265) deaths to be due to burns and 316 (95% CI 0-633) due to falling objects. Together, these 7 causes explain more than 80% of all accidental deaths when modeling is primarily used, and more than 95% when the analysis is based purely on medians from the 76 available studies. CONCLUSIONS: Reduction in global child mortality is a leading political priority and accidental deaths will soon emerge as one of the main challenges. In this paper we provided a detailed breakdown of causes of these deaths in a large middle-income country. We noted that, wherever the share of accidental deaths among all child deaths is increased, drowning is more likely to be the leading cause; asphyxia seems to be equally important in all contexts, while traffic accidents, poisoning and falls are relatively more important in contexts where the overall share of accidents to all child deaths is low.