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Sarcopenia is associated with adverse health outcomes. This study investigated whether skeletal muscle gene expression was associated with lean mass and grip strength in community-dwelling older men. Utilising a cross-sectional study design, lean muscle mass and grip strength were measured in 88 men aged 68-76 years. Expression profiles of 44 genes implicated in the cellular regulation of skeletal muscle were determined. Serum was analysed for circulating cytokines TNF (tumour necrosis factor), IL-6 (interleukin 6, IFNG (interferon gamma), IL1R1 (interleukin-1 receptor-1). Relationships between skeletal muscle gene expression, circulating cytokines, lean mass and grip strength were examined. Participant groups with higher and lower values of lean muscle mass (n = 18) and strength (n = 20) were used in the analysis of gene expression fold change. Expression of VDR (vitamin D receptor) [fold change (FC) 0.52, standard error for fold change (SE) ± 0.08, p = 0.01] and IFNG mRNA (FC 0.31; SE ± 0.19, p = 0.01) were lower in those with higher lean mass. Expression of IL-6 (FC 0.43; SE ± 0.13, p = 0.02), TNF (FC 0.52; SE ± 0.10, p = 0.02), IL1R1 (FC 0.63; SE ± 0.09, p = 0.04) and MSTN (myostatin) (FC 0.64; SE ± 0.11, p = 0.04) were lower in those with higher grip strength. No other significant changes were observed. Significant negative correlations between serum IL-6 (R = -0.29, p = 0.005), TNF (R = -0.24, p = 0.017) and grip strength were demonstrated. This novel skeletal muscle gene expression study carried out within a well-characterized epidemiological birth cohort has demonstrated that lower expression of VDR and IFNG is associated with higher lean mass, and lower expression of IL-6, TNF, IL1R1 and myostatin is associated with higher grip strength. These findings are consistent with a role of proinflammatory factors in mediating lower muscle strength in community-dwelling older men.

Unhealthy dietary patterns are associated with poor lung function. It is not known whether this is due to low consumption of antioxidant-rich fruit and vegetables, or is a consequence of higher intakes of harmful dietary constituents, such as processed meat. We examined the individual and combined associations of processed meat, fruit and vegetable consumption and dietary total antioxidant capacity (TAC) with lung function among 1551 males and 1391 females in the UK in the Hertfordshire Cohort Study. Diet was assessed using a food frequency questionnaire. After controlling for confounders, processed meat consumption was negatively associated with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio in males and females, while fruit and vegetable consumption and dietary TAC were positively associated with FEV1 and FVC, but not FEV1/FVC ratio. In males, the negative association between processed meat consumption and FEV1 was more marked in those who had low fruit and vegetable consumption (p=0.035 for interaction), and low dietary TAC (p=0.025 for interaction). The deficit in FEV1/FVC associated with processed meat consumption was larger in males who smoked (p=0.022 for interaction). Higher processed meat consumption is associated with poorer lung function, especially in males who have lower fruit and vegetable consumption or dietary TAC, and among current smokers.

Cross-sectional studies show that older people with better cognition tend to walk faster. Whether this association reflects an influence of fluid cognition upon walking speed, vice versa, a bidirectional relationship or the effect of common causes is unclear. We used linear mixed effects models to examine the dynamic relationship between usual walking speed and fluid cognition, as measured by executive function, verbal memory and processing speed, in 2,654 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing. There was a bidirectional relationship between walking speed and fluid cognition. After adjusting for age and sex, better performance on executive function, memory and processing speed was associated with less yearly decline in walking speed over the 6-year follow-up period; faster walking speed was associated with less yearly decline in each cognitive domain; and less yearly decline in each cognitive domain was associated with less yearly decline in walking speed. Effect sizes were small. After further adjustment for other covariates, effect sizes were attenuated but most remained statistically significant. We found some evidence that walking speed and the fluid cognitive domains of executive function and processing speed may change in parallel with increasing age. Investigation of the association between walking speed and cognition earlier in life is needed to better understand the origins of this relation and inform the development and timing of interventions.

Context: Maternal 25-hydroxyvitamin D [25(OH)D] status in pregnancy has been associated with offspring bone development and adiposity. Vitamin D has also been implicated in postnatal muscle function, but little is known about a role for antenatal 25(OH)D exposure in programming muscle development., Objective: We investigated the associations between maternal plasma 25(OH)D status at 34 weeks of gestation and offspring lean mass and muscle strength at 4 years of age., Design and Setting: We studied a prospective UK population-based mother-offspring cohort: the Southampton Women's Survey (SWS)., Participants: Initially, 12,583 nonpregnant women were recruited into the SWS, of whom 3159 had singleton pregnancies; 678 mother-child pairs were included in this analysis., Main Outcomes Measured: At 4 years of age, offspring assessments included hand grip strength and whole-body dual-energy x-ray absorptiometry, yielding lean mass and percent lean mass. Physical activity was assessed by 7-day accelerometry in a subset of children (n=326)., Results: The maternal serum 25(OH)D concentration in pregnancy was positively associated with offspring height-adjusted hand grip strength (β=0.10 SD/SD, P=.013), which persisted after adjustment for maternal confounding factors, duration of breastfeeding, and child's physical activity at 4 years (β=0.13 SD/SD, P=.014). Maternal 25(OH)D was also positively associated with offspring percent lean mass (β=0.11 SD/SD, P=.006), but not total lean mass (β=0.06 SD/SD, P=.15). However, this association did not persist after adjustment for confounding factors (β=0.09 SD/SD, P=.11)., Conclusions: This observational study suggests that intrauterine exposure to 25(OH)D during late pregnancy might influence offspring muscle development through an effect primarily on muscle strength rather than on muscle mass.

The APOE ε2/3/4 genotype has been associated with low-density lipoprotein cholesterol (LDL-C) and Alzheimer disease. However, evidence for associations with measures of cognitive performance in adults without dementia has been mixed, as it is for physical performance. Associations may also be evident in other genotypes implicated in LDL-C levels. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, genotypic information was obtained for APOE ε2/3/4, rs515135 (APOB), rs2228671 (LDLR) and rs629301 (SORT1) from eight cohorts of adults aged between 44 and 90 + years. We investigated associations with four measures of cognitive (word recall, phonemic fluency, semantic fluency and search speed) and physical capability (grip strength, get up and go/walk speed, timed chair rises and ability to balance) using meta-analyses. Overall, little evidence for associations between any of the genotypes and measures of cognitive capability was observed (e.g. pooled beta for APOE ε4 effect on semantic fluency z score = -0.02; 95 % CI = -0.05 to 0.02; p value = 0.3; n = 18,796). However, there was borderline evidence within studies that negative effects of APOE ε4 on nonverbal ability measures become more apparent with age. Few genotypic associations were observed with physical capability measures. The findings from our large investigation of middle-aged to older adults in the general population suggest that effects of APOE on cognitive capability are at most modest and are domain- and age-specific, while APOE has little influence on physical capability. In addition, other LDL-C-related genotypes have little impact on these traits.

Cross-sectional studies show that frailty is common in older people with cardiovascular disease. Whether older people at higher risk of developing cardiovascular disease are more likely to become frail is unclear. We used multinomial logistic regression to examine the prospective relation between Framingham cardiovascular disease risk scores and incidence of physical frailty or pre-frailty, defined according to the Fried criteria, in 1,726 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing who had no history of cardiovascular disease at baseline. Men and women with higher Framingham cardiovascular risk scores were more likely to become frail over the 4-year follow-up period. For a standard deviation higher score at baseline, the relative risk ratio (95 % confidence interval) for incident frailty, adjusted for sex and baseline frailty status, was 2.76 (2.18, 3.49). There was a significant association between Framingham cardiovascular risk score and risk of pre-frailty: 1.69 (1.46, 1.95). After further adjustment for other potential confounding factors, the relative risk ratios for frailty and pre-frailty were 2.15 (1.68, 2.75) and 1.50 (1.29, 1.74), respectively. The associations were unchanged after excluding incident cases of cardiovascular disease. Separate adjustment for each component of the risk score suggested that no single component was driving the associations between cardiovascular risk score and incident pre-frailty or frailty. Framingham cardiovascular risk scores may be useful for predicting the development of physical frailty in older people. We now need to understand the biological mechanisms whereby cardiovascular risk increases the risk of frailty.

Cross-sectional studies show that higher blood concentrations of inflammatory markers tend to be more common in frail older people, but longitudinal evidence that these inflammatory markers are risk factors for frailty is sparse and inconsistent. We investigated the prospective relation between baseline concentrations of the inflammatory markers C-reactive protein (CRP) and fibrinogen and risk of incident frailty in 2,146 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing. The relationship between CRP and fibrinogen and risk of incident frailty differed significantly by sex (p for interaction terms <0.05). In age-adjusted logistic regression analyses, for a standard deviation (SD) increase in CRP or fibrinogen, odds ratios (95% confidence intervals) for incident frailty in women were 1.69 (1.32, 2.17) and 1.39 (1.12, 1.72), respectively. Further adjustment for other potential confounding factors attenuated both these estimates. For an SD increase in CRP and fibrinogen, the fully-adjusted odds ratio (95% confidence interval) for incident frailty in women was 1.27 (0.96, 1.69) and 1.31 (1.04, 1.67), respectively. Having a high concentration of both inflammatory markers was more strongly predictive of incident frailty than having a high concentration of either marker alone. In men, there were no significant associations between any of the inflammatory markers and risk of incident frailty. High concentrations of the inflammatory markers CRP and fibrinogen are more strongly predictive of incident frailty in women than in men. Further research is needed to understand the mechanisms underlying this sex difference.

The reduced muscle mass and impaired muscle performance that define sarcopenia in older individuals are associated with increased risk of physical limitation and a variety of chronic diseases. They may also contribute to clinical frailty. A gradual erosion of quality of life (QoL) has been evidenced in these individuals, although much of this research has been done using generic QoL instruments, particularly the SF-36, which may not be ideal in older populations with significant comorbidities. This review and report of an expert meeting presents the current definitions of these geriatric syndromes (sarcopenia and frailty). It then briefly summarizes QoL concepts and specificities in older populations and examines the relevant domains of QoL and what is known concerning QoL decline with these conditions. It calls for a clearer definition of the construct of disability, argues that a disease-specific QoL instrument for sarcopenia/frailty would be an asset for future research, and discusses whether there are available and validated components that could be used to this end and whether the psychometric properties of these instruments are sufficiently tested. It calls also for an approach using utility weighting to provide some cost estimates and suggests that a time trade-off study could be appropriate.

Sarcopenia is the age-related loss of skeletal muscle mass and function. It is now recognised as a major clinical problem for older people and research in the area is expanding exponentially. One of the most important recent developments has been convergence in the operational definition of sarcopenia combining measures of muscle mass and strength or physical performance. This has been accompanied by considerable progress in understanding of pathogenesis from animal models of sarcopenia. Well-described risk factors include age, gender and levels of physical activity and this knowledge is now being translated into effective management strategies including resistance exercise with recent interest in the additional role of nutritional intervention. Sarcopenia is currently a major focus for drug discovery and development although there remains debate about the best primary outcome measure for trials, and various promising avenues to date have proved unsatisfactory. The concept of 'new tricks for old drugs' is, however, promising, for example, there is some evidence that the angiotensin-converting enzyme inhibitors may improve physical performance. Future directions will include a deeper understanding of the molecular and cellular mechanisms of sarcopenia and the application of a lifecourse approach to understanding aetiology as well as to informing the optimal timing of interventions.

Unlabelled: The aim of this study was to examine the prospective association between symptoms of anxiety and depression and risk of fracture in older people. Results showed that men, but not women, with probable anxiety at baseline had an increased risk of fracture., Introduction: The use of psychotropic drugs has been linked with an increased risk of fracture in older people, but there are indications that the conditions for which these drugs were prescribed may themselves influence fracture risk. The aim of this study was to investigate the relation between symptoms of anxiety and depression and risk of fracture in older people. The study design is a prospective cohort study., Methods: One thousand eighty-seven men and 1,050 women aged 59-73 years completed the Hospital Anxiety and Depression Scale (HADS). Data on incident fracture during an average follow-up period of 5.6 years were collected through interview and a postal questionnaire., Results: Compared to men with no or few symptoms of anxiety (score ≤7 on the HADS anxiety subscale), men with probable anxiety (score ≥11) had an increased risk of fracture: After adjustment for age and potential confounding factors, the odds ratio (OR) (95 % confidence interval) was 4.03 (1.55, 10.5). There were no associations between levels of anxiety and fracture risk in women. Few men or women had probable depression at baseline (score ≥11 on the HADS depression subscale). Amongst men with possible depression (score 8-10), there was an increased risk of fracture that was of borderline significance: multivariate-adjusted OR 3.57 (0.99, 12.9). There was no association between possible depression and fracture risk in women., Conclusions: High levels of anxiety in older men may increase their risk of fracture. Future research needs to replicate this finding in other populations and investigate the underlying mechanisms.

Relationships between birthweight and grip strength throughout the life course suggest that early influences on the growth and development of muscle are important for long-term muscle function. However, little is known about parental influences on children's grip strength. We have explored this in the Southampton Women's Survey, a prospective general population cohort study from before conception through childhood. Grip strength was measured using a Jamar handgrip dynamometer in the mother at 19 weeks' gestation and her partner, and in the child at age 4 years. Pre-pregnancy heights and weights were measured in the mothers; reported weights and measured heights were available for the fathers. Complete data on parents and children were available for 444 trios. In univariable analyses, both parents' grip strengths were significantly associated with that of the child (r = 0.17, P < 0.001 for mothers; r = 0.15, P = 0.002 for fathers). These correlations were similar to that between the grip strength of the mothers and the fathers (r = 0.17, P < 0.001). In the multivariable model, after adjustment for child's height and physical activity, the correlations with the child's grip strength were attenuated, being 0.10 (P = 0.02) and 0.11 (P = 0.01) for mothers' and fathers' grip strength respectively. The findings show that grip strength of each parent is associated with that of the child, indicating that heritable influences and the shared family environment influence the development of muscle strength. This contributes to our understanding of the role of heritable and environmental factors on early muscle growth and development, which are important for muscle function across the life course., (© 2011 Blackwell Publishing Ltd.)

Unlabelled: It is unknown whether osteoporosis is socially patterned. Using data from the Hertfordshire Cohort Study we found no consistent evidence for social inequalities in prevalent or incident fracture, bone mineral density or loss rates, or bone strength. Public health strategies for prevention of osteoporosis should focus on the whole population., Introduction: Osteoporosis and osteoporotic fracture are major public health issues for society; the burden for the affected individual is also high. It is unclear whether osteoporosis and osteoporotic fracture are socially patterned., Objective: This study aims to analyse social inequalities in osteoporosis and osteoporotic fracture among the 3,225 community-dwelling men and women, aged 59-73 years, who participated in the Hertfordshire Cohort Study (HCS), UK., Methods: A panel of markers of bone health (fracture since 45 years of age; DXA bone mineral density and loss rate at the total femur; pQCT strength strain indices for the radius and tibia; and incident fracture) were analysed in relation to the social circumstances of the HCS participants (characterised at the individual level by: age left full time education; current social class; housing tenure and car availability)., Results: We found little strong or consistent evidence among men, or women, for social inequalities in prevalent or incident fracture, DXA bone mineral density, bone loss rates, or pQCT bone strength, with or without adjustment for age, anthropometry, lifestyle and clinical characteristics. Reduced car availability at baseline was associated with lower pQCT radius and tibia strength strain indices at follow-up among men only (p = 0.02 radius and p < 0.01 tibia unadjusted; p = 0.05 radius and p = 0.01 tibia, adjusted for age, anthropometry, lifestyle and clinical characteristics)., Conclusions: Our results suggest that fracture and osteoporosis do not have a strong direct social gradient and that public health strategies for prevention and treatment of osteoporosis should continue to focus on the whole population.

Background: Age-related hearing loss is a common disabling condition but its causes are not well understood and the role of inflammation as an influencing factor has received little consideration in the literature., Objective: To investigate the association between inflammatory markers and hearing in community-dwelling older men and women., Design: Cross-sectional analysis within a cohort study., Setting: The Hertfordshire Ageing Study., Participants: A total of 343 men and 268 women aged 63-74 years on whom data on audiometric testing, inflammatory markers and covariates were available at follow-up in 1995., Main Outcome Measures: Average hearing threshold level (across 500-4,000 Hz) of the worst hearing ear and audiometric slope in dB/octave from 500 to 4,000 Hz., Results: Older age, smoking, history of noise exposure and male gender (all P < 0.001) were associated with higher mean hearing threshold in the worse ear in univariate analysis. After adjustment for these factors in multiple regression models, four measures of immune or inflammatory status were significantly associated with hearing threshold, namely white blood cell count (r = 0.13, P = 0.001), neutrophil count (r = 0.13, P = 0.002), IL-6 (r = 0.10, P = 0.05) and C-reactive protein (r = 0.11, P = 0.01). None of the inflammatory markers was associated with maximum audiometric slope in adjusted analyses., Conclusions: Markers of inflammatory status were significantly associated with degree of hearing loss in older people. The findings are consistent with the possibility that inflammatory changes occurring with ageing may be involved in age-related hearing loss. Longitudinal data would enable this hypothesis to be explored further.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance., Competing Interests: DM Waterworth, X Yuan, and VE Mooser are full-time employees of GlaxoSmithKline. P Vollenweider received grant money from GlaxoSmithKline to fund the CoLaus study. The other authors declare no competing financial interests.

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

Purpose: To evaluate two psychometric properties of SF-36, namely unidimensionality and reliability., Methods: The data are from three cohorts in the HALCyon collaborative research programme into healthy ageing: Aberdeen Birth Cohort 1936 (n = 428), Hertfordshire Ageing Study (n = 358) and Hertfordshire Cohort Study (n = 3,216). The Mokken scaling model was applied to each sub-scale of SF-36 to evaluate unidimensionality as indicated by scalability. The lower bound for internal consistency reliability was determined by Cronbach's alpha., Results: All six sub-scales of SF-36, with the exception of general health (GH) and mental health (MH), demonstrated strong scalability (0.5 ≤ H < 1). The results were consistent across all 3 cohorts. Both GH and MH showed medium scalability (0.4 ≤ H <0.55), although individual items 'sick easier..', 'as healthy as..' and 'expect to get worse' of the GH sub-scale and 'nervous', 'happy' in the MH sub-scale had low scalability (H < 0.4) in the oldest cohort (aged 73-83). Cronbach's alphas for all sub-scales were between 0.70 and 0.92., Conclusions: The unidimensionality and reliability of the sub-scales of SF-36 are sufficient to make this a useful measure of health-related quality of life in older people. Caution is needed when interpreting the results for GH and MH in the oldest cohort due to the poor unidimensionality.

The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, although not consistently. Our objective was to conduct a meta-analysis of the published literature on athletic status and investigate its associations with physical capability in several new population-based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For life course physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research program, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (P = 0.09, n = 7,672 in males; P = 0.90, n = 7,839 in females), standing balance, timed get up and go, or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population., (© 2011 Wiley-Liss, Inc.)

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Background: A number of studies have shown strong graded positive relationships between size at birth, grip strength, and estimates of muscle mass in older people. However no studies to date have included direct measures of muscle size., Methods: We studied 313 men and 318 women born in Hertfordshire, United Kingdom between 1931 and 1939 who were still resident there and had historical records of growth in early life. Information on lifestyle was collected, and participants underwent peripheral quantitative computed tomography to directly measure forearm and calf muscle size., Results: Birth weight was positively related to forearm muscle area in the men (r = 0.24, p <.0001) and women (r = 0.17, p =.003). There were similar but weaker associations between birth weight and calf muscle area in the men (r = 0.13, p =.03) and in the women (r = 0.17, p =.004). These relationships were all attenuated by adjustment for adult size., Conclusion: We present first evidence that directly measured muscle size in older men and women is associated with size at birth. This may reflect tracking of muscle size and is important because it suggests that benefit may be gained from taking a life course approach both to understanding the etiology of sarcopenia and to developing effective interventions.

High quality coding of hospital activity is important because the data is used for resource allocation and measuring performance. There is little information on the quality of coding of admissions of frail older people who have multiple diagnoses, co-morbidities and functional impairment. Presence or absence of four geriatric syndromes and eight medical conditions was noted on case note review (CNR). Discharge summaries (DS) and hospital coding (HC) were reviewed and compared with the CNR. Forty patients had at least one geriatric syndrome noted in the DS; 16 (40.0%) were captured by the HC. Of 57 patients with at least one medical condition noted in the DS, 52 (91.2%) were captured by the HC (p<0.0001 for difference in HC capture rates). We have demonstrated poor capture of information on geriatric syndromes compared to medical conditions in discharge summaries and hospital coding and propose a problem list bookmark approach to improve this.

Objective: to investigate the relationship between grip strength and health-related quality of life (HRQoL)., Design: cross-sectional survey within a cohort study design., Setting: the county of Hertfordshire in the UK., Participants: a total of 2,987 community-dwelling men and women aged 59-73 years of age., Measurements: grip strength was used as a marker of sarcopaenia and measured using a Jamar dynamometer. HRQoL was assessed using the eight domain scores of the Short Form-36 (SF-36) questionnaire, and subjects in the lowest sex-specific fifth of the distribution were classified as having 'poor' status for each domain., Results: men and women with lower grip strength were significantly more likely to report a poor as opposed to excellent to fair overall opinion of their general health (GH) [odds ratio (OR) per kilogram decrease in grip strength = 1.13, 95% CI = 1.06-1.19, P < 0.001 in men, 1.13, 95% CI = 1.07-1.20, P < 0.001 in women]. Among men, after adjustment for age, size, physical activity and known co-morbidity, decreased grip strength was associated with increased prevalence of poor SF-36 scores for the physical functioning (PF) (OR per kilogram decrease in grip strength = 1.03, 95% CI = 1.01-1.06, P = 0.007) and GH domains (OR = 1.03, 95% CI = 1.01-1.05, P = 0.01). Similar associations were seen in women., Conclusions: our findings suggest that lower grip strength is associated with reduced HRQoL in older men and women. This does not appear to be explained by age, size, physical activity or co-morbidity and may reflect the link between sarcopaenia and generalised frailty. Individuals with sarcopaenia may benefit from interventions to improve muscle mass and strength before the onset of chronic disorders usually associated with impaired HRQoL.

Objective: to determine the resources required to carry out the single assessment process in primary care., Design: prospective descriptive study., Setting: one urban primary care practice, Southampton., Participants: nine hundred and forty-four people aged 70+ years, registered with the practice, not living in a residential/nursing home, or terminally ill., Intervention: participants were sent the six-item Sherbrooke questionnaire (case-finding tool). Non-responders were re-mailed after 4 weeks. All those scoring 4, 5 or 6 and a randomly selected half of those scoring 2 or 3 were offered overview assessment and comprehensive assessment as indicated by the Minimum Data Set for Home Care protocol. The nurse assessor identified unmet needs and agreed an action plan with participants. Another researcher conducted semi-structured interviews with a purposive sample of 26 participants to elicit their views of the process., Main Outcome Measures: response rates/scores of Sherbrooke questionnaire; numbers/characteristics of people requiring overview and comprehensive assessments; nature of resulting recommendations/referrals and impact on other agencies; resources required; views of service users., Results: eight hundred and sixty-three (91%) participants replied. Five hundred and seven (54%) scored 2+, triggering an overview assessment, which was offered to 307. One hundred and twenty-four participants (40%) accepted; 64 (52%) had unmet needs (median 8 each, range 2-18), resulting in 34 referrals within the practice including four case conferences, and 21 to community/secondary health services. Few participants with a Sherbrooke score of 2 required comprehensive assessment. Users perceived the process as acceptable and useful, but not always relevant to their current needs., Conclusion: targeting those scoring 3+ on the Sherbrooke questionnaire (28% of sample) may improve the identification of patients who would benefit from further assessment. A contact approach rather than a case-finding one may improve the relevance of this process to older people.

Objective: To estimate the number of people worldwide requiring daily assistance from another person in carrying out health, domestic or personal tasks., Methods: Data from the Global Burden of Disease Study were used to calculate the prevalence of severe levels of disability, and consequently, to estimate dependency. Population projections were used to forecast changes over the next 50 years., Findings: The greatest burden of dependency currently falls in sub-Saharan Africa, where the "dependency ratio" (ratio of dependent people to the population of working age) is about 10%, compared with 7-8% elsewhere. Large increases in prevalence are predicted in sub-Saharan Africa, the Middle East, Asia and Latin America of up to 5-fold or 6-fold in some cases. These increases will occur in the context of generally increasing populations, and dependency ratios will increase modestly to about 10%. The dependency ratio will increase more in China (14%) and India (12%) than in other areas with large prevalence increases. Established market economies, especially Europe and Japan, will experience modest increases in the prevalence of dependency (30%), and in the dependency ratio (up to 10%). Former Socialist economies of Europe will have static or declining numbers of dependent people, but will have large increases in the dependency ratio (up to 13%)., Conclusion: Many countries will be greatly affected by the increasing number of dependent people and will need to identify the human and financial resources to support them. Much improved collection of data on disability and on the needs of caregivers is required. The prevention of disability and provision of support for caregivers needs greater priority.