The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH). Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.

Epidemiologic studies have reported conflicting results on the relationship between daytime napping and mortality risk, and there are few data on the potential association in the British population. We investigated the associations between daytime napping and all-cause or cause-specific mortality in the European Prospective Investigation Into Cancer-Norfolk study, a British population-based cohort study. Among the 16,374 men and women who answered questions on napping habits between 1998 and 2000, a total of 3,251 died during the 13-year follow-up. Daytime napping was associated with an increased risk of all-cause mortality (for napping less than 1 hour per day on average, hazard ratio = 1.14, 95% confidence interval: 1.02, 1.27; for napping 1 hour or longer per day on average, hazard ratio = 1.32, 95% confidence interval: 1.04, 1.68), independent of age, sex, social class, educational level, marital status, employment status, body mass index, physical activity level, smoking status, alcohol intake, depression, self-reported general health, use of hypnotic drugs or other medications, time spent in bed at night, and presence of preexisting health conditions. This association was more pronounced for death from respiratory diseases (for napping less than 1 hour, hazard ratio = 1.40, 95% confidence interval: 0.95, 2.05; for napping 1 hour or more, hazard ratio = 2.56, 95% confidence interval: 1.34, 4.86) and in individuals 65 years of age or younger. Excessive daytime napping might be a useful marker of underlying health risk, particularly of respiratory problems, especially among those 65 years of age or younger. Further research is required to clarify the nature of the observed association.

Refractive error in this predominantly white older UK population was associated with axial biometry and sociodemographic characteristics. Educational status was the strongest determinant of axial length.

Objectives:The relationship between obesity and grip strength, a key indicator of sarcopenia, has been inconsistently reported. We aimed to examine associations between grip strength and both body mass index (BMI), a clinical indicator of total adiposity, and waist circumference (WC), an indicator of central adiposity. Design: Cross-sectional study. Setting and Participants: Data collected from 8,441 men and women, aged 48-92 years old, who attended the third health examination of the European Prospective Investigation into Cancer-Norfolk study was used. Measurements: Maximum grip strength (Smedley dynamometer), BMI (weight/ height 2 ) and WC (measured at the natural waist) were ascertained at a research clinic. The associations between grip strength and adiposity measures were explored using linear regression with adjustment for age, height, social class, physical activity, prevalent disease, smoking status and alcohol intake. Results: Men and women were examined separately and those in the upper quartile of BMI were 2.70kg (95%CI 2.07, 3.33) and 1.46kg (95%CI 1.05, 1.86) stronger respectively than those in the bottom quartile (P trends <0.001). Grip strength also increased weakly with increasing WC. However, including both BMI and WC in the same regression model revealed an inverse association between grip strength and WC, whilst the previously observed association with BMI strengthened. For every 10cm increase in WC, grip strength was 3.56kg (95%CI 3.04, 4.08) lower in men and 1.00kg (95%CI 0.74, 1.24) lower in women. Conclusions: Larger overall body mass, indicated by higher BMI, is associated with stronger grip strength but high WC, a clinical indicator of central obesity, is associated with lower grip strength. Abdominal fat is the most metabolically active adipose tissue and this provides a clue to potential mechanisms underlying relationships between fat and skeletal muscle. Additionally, it reinforces the recommendation to measure WC in clinical practice, especially when BMI is below obese ranges. Key words:Grip strength, central obesity, sarcopenia, aging. The divergent conclusions reported to date reflect the challenging issues in the study of this association. Firstly, the most commonly used marker of obesity is body mass index (BMI), a measure which incorporates both fat and fatfree mass in its calculation. Therefore, increases in BMI indicate increases in lean as well as fat mass (16), which are additionally highly correlated measures (17). Co-variables used to account for lean mass in analyses differ between studies and may contribute to the inconsistency of results (12,14,18). Secondly, BMI does not indicate fat distribution. It is important to consider fat distribution since the properties of adipose tissue are not homogenous throughout the body and different associations of fat with health outcomes have been observed, based on the site of fat accumulation (19,20). Centrally deposited adipose tissue is most closely associated with the metabolic consequences of obesity and increased wai...

The European Prospective Investigation of Cancer (EPIC) is a 10-country collaborative study in which EPIC-Norfolk is one of the UK centres. EPIC-Norfolk examined 25 639 men and women resident in East Anglia (aged 40–79 years), between 1993 and 1997. The EPIC collaboration was set up to examine the dietary determinants of cancer, but the remit in the EPIC-Norfolk cohort was broadened from the outset to include determinants of other health conditions and chronic diseases. EPIC-Norfolk completed a third round of health examinations (EPIC-Norfolk 3 or 3HC) in December 2011, on 8623 participants in the age range 48–92 years. EPIC-Norfolk focused on objective measures of cognitive function, physical capability and visual health, adapting this existing mid-life cohort to the current need to investigate healthy and independent living for ageing societies. With a wealth of longitudinal data and a biobank (including DNA) collected at up to three separate time points, EPIC-Norfolk offers the unique opportunity to investigate the association of lifestyle and biological factors, including genetic exposures, with a range of health outcomes in middle and later life. Information for data access can be found on the study website, details as given in this cohort profile.

Objectives To report the distribution of intraocular pressure (IOP) by age and sex and the prevalence of glaucoma. Design Community based cross sectional observational study. Setting EPIC-Norfolk cohort in Norwich and the surrounding rural and urban areas. Participants 8623 participants aged 48-92 recruited from the community who underwent ocular examination to identify glaucoma. Main outcome measures Prevalence and characteristics of glaucoma, distribution of IOP, and the sensitivity and specificity of IOP for case finding for glaucoma. Results The mean IOP in 8401 participants was 16.3 mm Hg (95% confidence interval 16.2 mm Hg to 16.3 mm Hg; SD 3.6 mm Hg). In 363 participants (4%), glaucoma was present in either eye; 314 (87%) had primary open angle glaucoma. In the remaining participants, glaucoma was suspected in 607 (7%), and 863 (10.0%) had ocular hypertension. Two thirds (242) of those with glaucoma had previously already received the diagnosis. In 76% of patients with newly diagnosed primary open angle glaucoma (83/107), the mean IOP was under the threshold for ocular hypertension (21 mm Hg). No one IOP threshold provided adequately high sensitivity and specificity for diagnosis of glaucoma. Conclusions In this British community, cases of glaucoma, suspected glaucoma, and ocular hypertension represent a large number of potential referrals to the hospital eye service. The use of IOP for detection of those with glaucoma is inaccurate and probably not viable.

Metabolic risk factors showed a graded association with both tortuosity and width of retinal venules, even among people without clinical diabetes, whereas atherosclerotic risk factors correlated more closely with arteriolar width, even excluding those with hypertension and cardiovascular disease. These noninvasive microvasculature measures should be evaluated further as predictors of future cardiometabolic disease.

ObjectiveTo determine the association between systemic medication use and intraocular pressure (IOP) in a population of older British men and women.DesignPopulation-based, cross-sectional study.ParticipantsWe included 7093 participants from the European Prospective Investigation into Cancer–Norfolk Eye Study. Exclusion criteria were a history of glaucoma therapy (medical, laser, or surgical), IOP asymmetry between eyes of >5 mmHg, and missing data for any covariables. The mean age of participants was 68 years (range, 48–92) and 56% were women.MethodsWe measured IOP using the Ocular Response Analyzer. Three readings were taken per eye and the best signal value of the Goldmann-correlated IOP value considered. Participants were asked to bring all their medications and related documentation to the health examination, and these were recorded by the research nurse using an electronic case record form. The medication classes examined were angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, α-blockers, β-blockers, calcium channel blockers, diuretics, nitrates, statins, insulin, biguanides, sulfonylureas, aspirin, and other nonsteroidal anti-inflammatory drugs. We examined associations between medication use and IOP using multivariable linear regression models adjusted for age, sex, and body mass index. Models containing diabetic medication were further adjusted for glycosylated hemoglobin levels.Main Outcome MeasuresMean IOP of the right and left eyes.ResultsUse of systemic β-blockers (−0.92 mmHg; 95% CI, −1.19, −0.65; P<0.001) and nitrates (−0.63 mmHg; 95% CI, −1.12, −0.14; P = 0.011) were independently associated with lower IOP. The observed associations between statin or aspirin use with IOP were no longer significant after adjustment for β-blocker use.ConclusionsThis is the first population-based study to demonstrate and quantify clinically significant differences in IOP among participants using systemic β-blockers or nitrates. Lower IOP observed in participants using statins or aspirin was explained by concurrent systemic β-blocker use. The study findings may have implications for the management of glaucoma patients with comorbidity, and may provide insight into the pathophysiologic processes underlying IOP.