AbstractObjectiveTo assess the prospective associations of baseline and long term trajectories of physical activity on mortality from all causes, cardiovascular disease, and cancer.DesignPopulation ...based cohort study.SettingAdults from the general population in the UK.Participants14 599 men and women (aged 40 to 79) from the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort, assessed at baseline (1993 to 1997) up to 2004 for lifestyle and other risk factors; then followed to 2016 for mortality (median of 12.5 years of follow-up, after the last exposure assessment).Main exposurePhysical activity energy expenditure (PAEE) derived from questionnaires, calibrated against combined movement and heart rate monitoring.Main outcome measuresMortality from all causes, cardiovascular disease, and cancer. Multivariable proportional hazards regression models were adjusted for age, sex, sociodemographics, and changes in medical history, overall diet quality, body mass index, blood pressure, triglycerides, and cholesterol levels.ResultsDuring 171 277 person years of follow-up, 3148 deaths occurred. Long term increases in PAEE were inversely associated with mortality, independent of baseline PAEE. For each 1 kJ/kg/day per year increase in PAEE (equivalent to a trajectory of being inactive at baseline and gradually, over five years, meeting the World Health Organization minimum physical activity guidelines of 150 minutes/week of moderate-intensity physical activity), hazard ratios were: 0.76 (95% confidence interval 0.71 to 0.82) for all cause mortality, 0.71 (0.62 to 0.82) for cardiovascular disease mortality, and 0.89 (0.79 to 0.99) for cancer mortality, adjusted for baseline PAEE, and established risk factors. Similar results were observed when analyses were stratified by medical history of cardiovascular disease and cancer. Joint analyses with baseline and trajectories of physical activity show that, compared with consistently inactive individuals, those with increasing physical activity trajectories over time experienced lower risks of mortality from all causes, with hazard ratios of 0.76 (0.65 to 0.88), 0.62 (0.53 to 0.72), and 0.58 (0.43 to 0.78) at low, medium, and high baseline physical activity, respectively. At the population level, meeting and maintaining at least the minimum physical activity recommendations would potentially prevent 46% of deaths associated with physical inactivity.ConclusionsMiddle aged and older adults, including those with cardiovascular disease and cancer, can gain substantial longevity benefits by becoming more physically active, irrespective of past physical activity levels and established risk factors. Considerable population health impacts can be attained with consistent engagement in physical activity during mid to late life.
Summary Background No clinical trials have assessed the effects or cost-effectiveness of sequential screening strategies to detect new cases of type 2 diabetes. We used a mathematical model to ...estimate the cost-effectiveness of several screening strategies. Methods We used person-specific data from a representative sample of the US population to create a simulated population of 325 000 people aged 30 years without diabetes. We used the Archimedes model to compare eight simulated screening strategies for type 2 diabetes with a no-screening control strategy. Strategies differed in terms of age at initiation and frequency of screening. Once diagnosed, diabetes treatment was simulated in a standard manner. We calculated the effects of each strategy on the incidence of type 2 diabetes, myocardial infarction, stroke, and microvascular complications in addition to quality of life, costs, and cost per quality-adjusted life-year (QALY). Findings Compared with no screening, all simulated screening strategies reduced the incidence of myocardial infarction (3–9 events prevented per 1000 people screened) and diabetes-related microvascular complications (3–9 events prevented per 1000 people), and increased the number of QALYs (93–194 undiscounted QALYs) added over 50 years. Most strategies prevented a significant number of simulated deaths (2–5 events per 1000 people). There was little or no effect of screening on incidence of stroke (0–1 event prevented per 1000 people). Five screening strategies had costs per QALY of about US$10 500 or less, whereas costs were much higher for screening started at 45 years of age and repeated every year ($15 509), screening started at 60 years of age and repeated every 3 years ($25 738), or a maximum screening strategy (screening started at 30 years of age and repeated every 6 months; $40 778). Several strategies differed substantially in the number of QALYs gained. Costs per QALY were sensitive to the disutility assigned to the state of having diabetes diagnosed with or without symptoms. Interpretation In the US population, screening for type 2 diabetes is cost effective when started between the ages of 30 years and 45 years, with screening repeated every 3–5 years. Funding Novo Nordisk, Bayer HealthCare, and Pfizer.
Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy ...homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEK-ERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.
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•Mutations in KSR2 are associated with obesity in humans•Mutations affect ERK signaling and impair the oxidation of glucose and fatty acids•Patients display hyperphagia, insulin resistance, and a reduced basal metabolic rate•KSR2 is an important regulator of energy intake and expenditure in humans
Mutations in KSR2, a scaffolding protein involved in multiple signaling pathways, lead to severe metabolic alterations that cause early onset obesity in humans.
Poor mental health is associated with obesity, but existing studies are either cross-sectional or have long time periods between measurements of mental health and weight. It is, therefore, unclear ...how small fluctuations in mental wellbeing within individuals predict bodyweight over short time periods, e.g. within the next month. Studying this could identify modifiable determinants of weight changes and highlight opportunities for early intervention.
2,133 UK adults from a population-based cohort completed monthly mental health and weight measurements using a mobile app over a period of 6-9 months. We used random intercept regression models to examine longitudinal associations of depressive symptoms, anxiety symptoms and stress with subsequent weight. In sub-group analyses, we included interaction terms of mental health variables with baseline characteristics. Mental health variables were split into "between-individual" measurements (= the participant's median score across all timepoints) and "within-individual" measurements (at each timepoint, the difference between the participant's current score and their median).
Within-individual variation in depressive symptoms predicted subsequent weight (0.045kg per unit of depressive symptom severity, 95% CI 0.021-0.069). We found evidence of a moderation effect of baseline BMI on the association between within-individual fluctuation in depressive symptoms and subsequent weight: The association was only apparent in those with overweight/obesity, and it was stronger in those with obesity than those with overweight (BMI<25kg/m2: 0.011kg per unit of depressive symptom severity 95% CI -0.017 to 0.039; BMI 25-29.9kg/m2: 0.052kg per unit of depressive symptom severity 95%CI 0.010-0.094kg; BMI≥30kg/m2: 0.071kg per unit of depressive symptom severity 95%CI 0.013-0.129kg). We found no evidence for other interactions, associations of stress and anxiety with weight, or for a reverse direction of association.
In this exploratory study, individuals with overweight or obesity were more vulnerable to weight gain following higher-than-usual (for that individual) depressive symptoms than individuals with a BMI<25kg/m2.
Abstract
Background
The advent of very large cohort studies (n > 500 000) has given rise to prospective analyses of health outcomes being undertaken after short (<4 years) follow-up periods. However, ...these studies are potentially at risk of reverse causality bias. We investigated differences in the associations between self-reported physical activity and all-cause and cardiovascular disease (CVD) mortality, and incident CVD, using different follow-up time cut-offs and methods to account for reverse causality bias.
Methods
Data were from n = 452 933 UK Biobank participants, aged 38–73 years at baseline. Median available follow-up time was 7 years (for all-cause and CVD mortality) and 6.1 years (for incident CVD). We additionally analysed associations at 1-, 2- and 4-year cut-offs after baseline. We fit up to four models: (1) adjusting for prevalent CVD and cancer, (2) excluding prevalent disease, (3) and (4) Model 2 excluding incident cases in the first 12 and 24 months, respectively.
Results
The strength of associations decreased as follow-up time cut-off increased. For all-cause mortality, Model 1 hazard ratios were 0.73 (0.69–0.78) after 1 year and 0.86 (0.84–0.87) after 7 years. Associations were weaker with increasing control for possible reverse causality. After 7-years follow-up, the hazard ratios were 0.86 (0.84–0.87) and 0.88 (0.86–0.90) for Models 1 and 4, respectively. Associations with CVD outcomes followed similar trends.
Conclusions
As analyses with longer follow-up times and increased control for reverse causality showed weaker associations, there are implications for the decision about when to analyse a cohort study with ongoing data collection, the interpretation of study results and their contribution to meta-analyses.
Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, ...we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
The rising prevalence of obesity has made hepatic steatosis an increasingly common issue. Ultrasound is generally used in clinical practice to assess steatosis, but its accuracy has been inconsistent ...across studies. We aimed to determine the validity of ultrasound to diagnose hepatic steatosis when compared to the criterion method proton magnetic resonance spectroscopy (MRS) in older individuals.
A total of 72 healthy white European individuals (n = 42 men; n = 30 women aged 67-76 years) participating in the Hertfordshire Birth Cohort Physical Activity trial had hepatic steatosis assessed by ultrasound and MRS. The ultrasound scans were graded as normal, mild, moderate and severe steatosis, while hepatic fat content above 5.5% by MRS was used as a cut-off for steatosis.
18 participants (25%) had a level of hepatic fat measured by MRS consistent with diagnosis of steatosis. The sensitivity and specificity of ultrasound in diagnosing hepatic steatosis (mild/moderate/severe vs normal) were 96% (95% CI: 87-99.6%) and 94% (95% CI: 73-100%) respectively, although overlap in MRS hepatic fat content was observed between the ultrasound categories.
Ultrasound is a valid method for detecting the presence or absence of hepatic steatosis in older adults and can be used as an alternative tool in both clinical investigations and epidemiological studies, when other imaging techniques are not feasible.
Little is known about the combined associations of cardiorespiratory fitness (CRF) and hand grip strength (GS) with mortality in general adult populations. The purpose of this study was to compare ...the relative risk of mortality for CRF, GS, and their combination. In UK Biobank, a prospective cohort of > 0.5 million adults aged 40-69 years, CRF was measured through submaximal bike tests; GS was measured using a hand-dynamometer. This analysis is based on data from 70,913 men and women (832 all-cause, 177 cardiovascular and 503 cancer deaths over 5.7-year follow-up) who provided valid CRF and GS data, and with no history of heart attack/stroke/cancer at baseline. Compared with the lowest CRF category, the hazard ratio (HR) for all-cause mortality was 0.76 95% confidence interval (CI) 0.64-0.89 and 0.65 (95% CI 0.55-0.78) for the middle and highest CRF categories, respectively, after adjustment for confounders and GS. The highest GS category had an HR of 0.79 (95% CI 0.66-0.95) for all-cause mortality compared with the lowest, after adjustment for confounders and CRF. Similar results were found for cardiovascular and cancer mortality. The HRs for the combination of highest CRF and GS were 0.53 (95% CI 0.39-0.72) for all-cause mortality and 0.31 (95% CI 0.14-0.67) for cardiovascular mortality, compared with the reference category of lowest CRF and GS: no significant association for cancer mortality (HR 0.70; 95% CI 0.48-1.02). CRF and GS are both independent predictors of mortality. Improving both CRF and muscle strength, as opposed to either of the two alone, may be the most effective behavioral strategy to reduce all-cause and cardiovascular mortality risk.
Serum biomarker levels are associated with the risk of complex diseases. Here, we aimed to gain insights into the genetic architecture of biomarker traits which can reflect health status. We ...performed genome-wide association analyses for twenty serum biomarkers involved in organ function and reproductive health. 9,961 individuals from the UK Household Longitudinal Study were genotyped using the Illumina HumanCoreExome array and variants imputed to the 1000 Genomes Project and UK10K haplotypes. We establish a polygenic heritability for all biomarkers, confirm associations of fifty-four established loci, and identify five novel, replicating associations at genome-wide significance. A low-frequency variant, rs28929474, (beta = 0.04, P = 2 × 10
) was associated with levels of alanine transaminase, an indicator of liver damage. The variant is located in the gene encoding serine protease inhibitor, low levels of which are associated with alpha-1 antitrypsin deficiency which leads to liver disease. We identified novel associations (rs78900934, beta = 0.05, P = 6 × 10
; rs2911280, beta = 0.09, P = 6 × 10
) for dihydroepiandrosterone sulphate, a precursor to major sex-hormones, and for glycated haemoglobin (rs12819124, beta = -0.03, P = 4 × 10
; rs761772, beta = 0.05, P = 5 × 10
). rs12819124 is nominally associated with risk of type 2 diabetes. Our study offers insights into the genetic architecture of well-known and less well-studied biomarkers.
Application of metabolite profiling could expand the etiological knowledge of type 2 diabetes mellitus (T2D). However, few prospective studies apply broad untargeted metabolite profiling to reveal ...the comprehensive metabolic alterations preceding the onset of T2D.
We applied untargeted metabolite profiling in serum samples obtained from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort comprising 300 individuals who developed T2D after a median follow-up time of 6 years and 300 matched controls. For that purpose, we used ultraperformance LC-MS with a protocol specifically designed for large-scale metabolomics studies with regard to robustness and repeatability. After multivariate classification to select metabolites with the strongest contribution to disease classification, we applied multivariable-adjusted conditional logistic regression to assess the association of these metabolites with T2D.
Among several alterations in lipid metabolism, there was an inverse association with T2D for metabolites chemically annotated as lysophosphatidylcholine(dm16:0) and phosphatidylcholine(O-20:0/O-20:0). Hexose sugars were positively associated with T2D, whereas higher concentrations of a sugar alcohol and a deoxyhexose sugar reduced the odds of diabetes by approximately 60% and 70%, respectively. Furthermore, there was suggestive evidence for a positive association of the circulating purine nucleotide isopentenyladenosine-5'-monophosphate with incident T2D.
This study constitutes one of the largest metabolite profiling approaches of T2D biomarkers in a prospective study population. The findings might help generate new hypotheses about diabetes etiology and develop further targeted studies of a smaller number of potentially important metabolites.
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