Objective:

To derive a simple score for estimating the long-term risk of osteoporotic and hip fracture in individual patients with MS.

Methods:

Using the UK General Practice Research Database linked to the National Hospital Registry (1997–2008), we identified patients with incident MS (n = 5,494). They were matched 1:6 by year of birth, sex, and practice with patients without MS (control subjects). Cox proportional hazards models were used to calculate the long-term risk of osteoporotic and hip fracture. We fitted the regression model with general and specific risk factors, and the final Cox model was converted into integer risk scores.

Results:

In comparison with the FRAX calculator, our risk score contains several new risk factors that have been linked with fracture, which include MS, use of antidepressants, use of anticonvulsants, history of falling, and history of fatigue. We estimated the 5- and 10-year risks of osteoporotic and hip fracture in relation to the risk score. The C-statistic was moderate (0.67) for the prediction of osteoporotic fracture and excellent (0.89) for the prediction of hip fracture.

Conclusion:

This is the first clinical risk score for fracture risk estimation involving MS as a risk factor.

Objective

To investigate the associations of body mass index (BMI) and grip strength with objective measures of physical performance (chair rise time, walking speed and balance) including an assessment of sex differences and non-linearity.

Methods

Cross-sectional data from eight UK cohort studies (total N = 16 444) participating in the Healthy Ageing across the Life Course (HALCyon) research programme, ranging in age from 50 to 90+ years at the time of physical capability assessment, were used. Regression models were fitted within each study and meta-analysis methods used to pool regression coefficients across studies and to assess the extent of heterogeneity between studies.

Results

Higher BMI was associated with poorer performance on chair rise (N = 10 773), walking speed (N = 9 761) and standing balance (N = 13 921) tests. Higher BMI was associated with stronger grip strength in men only. Stronger grip strength was associated with better performance on all tests with a tendency for the associations to be stronger in women than men; for example, walking speed was higher by 0.43 cm/s (0.14, 0.71) more per kg in women than men. Both BMI and grip strength remained independently related with performance after mutual adjustment, but there was no evidence of effect modification. Both BMI and grip strength exhibited non-linear relations with performance; those in the lowest fifth of grip strength and highest fifth of BMI having particularly poor performance. Findings were similar when waist circumference was examined in place of BMI.

Conclusion

Older men and women with weak muscle strength and high BMI have considerably poorer performance than others and associations were observed even in the youngest cohort (age 53). Although causality cannot be inferred from observational cross-sectional studies, our findings suggest the likely benefit of early assessment and interventions to reduce fat mass and improve muscle strength in the prevention of future functional limitations.

Background

frailty, a multi-dimensional geriatric syndrome, confers a high risk for falls, disability, hospitalisation and mortality. The prevalence and correlates of frailty in the UK are unknown.

Methods

frailty, defined by Fried, was examined among community-dwelling young-old (64-74 years) men (n = 320) and women (n = 318) who participated in the Hertfordshire Cohort Study, UK.

Results

the prevalence of frailty was 8.5% among women and 4.1% among men (P = 0.02). Among men, older age (P = 0.009), younger age of leaving education (P = 0.05), not owning/mortgaging one’s home (odds ratio [OR] for frailty 3.45 [95% confidence interval {CI} 1.01-11.81], P = 0.05, in comparison with owner/mortgage occupiers) and reduced car availability (OR for frailty 3.57 per unit decrease in number of cars available [95% CI 1.32, 10.0], P = 0.01) were associated with increased odds of frailty. Among women, not owning/mortgaging one’s home (P = 0.02) was associated with frailty. With the exception of car availability among men (P = 0.03), all associations were non-significant (P > 0.05) after adjustment for co-morbidity.

Conclusions

frailty is not uncommon even among community-dwelling young-old men and women in the UK. There are social inequalities in frailty which appear to be mediated by co-morbidity.

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.

Background

Malnutrition is common in older people in hospital and is associated with adverse clinical outcomes including increased mortality, morbidity and length of stay. This has raised concerns about the nutrition and diet of hospital in-patients. A number of factors may contribute to low dietary intakes in hospital, including acute illness and cognitive impairment among in-patients. The extent to which other factors influence intake such as a lack of help at mealtimes, for patients who require assistance with eating, is uncertain. This study aims to evaluate the effectiveness of using trained volunteer mealtime assistants to help patients on an acute medical ward for older people at mealtimes.

Methods/design

The study design is quasi-experimental with a before (year one) and after (year two) comparison of patients on the intervention ward and parallel comparison with patients on a control ward in the same department. The intervention in the second year was the provision of trained volunteer mealtime assistance to patients in the intervention ward. There were three components of data collection that were repeated in both years on both wards. The first (primary) outcome was patients’ dietary intake, collected as individual patient records and as ward-level balance data over 24 hour periods. The second was clinical outcome data assessed on admission and discharge from both wards, and 6 and 12 months after discharge. Finally qualitative data on the views and experience of patients, carers, staff and volunteers was collected through interviews and focus groups in both years to allow a mixed-method evaluation of the intervention.

Discussion

The study will describe the effect of provision of trained volunteer mealtime assistants on the dietary intake of older medical in-patients. The association between dietary intake and clinical outcomes including malnutrition risk, body composition, grip strength, length of hospital stay and mortality will also be determined. An important component of the study is the use of qualitative approaches to determine the views of patients, relatives, staff and volunteers on nutrition in hospital and the impact of mealtime assistance.

Trial registration

Trial registered with ClinicalTrials.gov NCTO1647204

Objective This study examined longitudinal relationships between maternal red-cell folate status and dietary intakes of vitamins B6, B12 and folate before and during pregnancy and subsequent postpartum depressive symptoms.

Study design and setting Within a cohort study of women aged 20–34 years (the Southampton Women's Survey) dietary data were obtained before pregnancy and at 11 and 34 weeks' gestation. Red-cell folate was measured before pregnancy and at 11 weeks' gestation. We derived relative risks of postpartum depressive symptoms using an Edinburgh Postnatal Depression Scale (EPDS) score of ≥ 13 administered from 6 months to 1 year postpartum.

Results No significant differences were found between those with postpartum depressive symptoms (n = 905) and those without (n = 1951) in relation to red-cell folate concentration or dietary intake of folate, vitamin B12 and vitamin B6, before or during pregnancy. A prior history of mental illness (relative risk (RR) 1.83; 95% confidence interval (CI) 1.53–2.19) was associated with postpartum depressive symptoms, and women who breastfed until 6 months were less likely to experience postpartum depressive symptoms (RR 0.68; 95% CI 0.55–0.84).

Conclusion This study suggests that folate status and dietary folate, B6 and B12 intakes before and during pregnancy are not associated with postpartum depressive symptoms. A history of mental illness, however, was a strong risk factor.

High bone mass (HBM), detected in 0.2% of DXA scans, is characterised by a mild skeletal dysplasia largely unexplained by known genetic mutations. We conducted the first systematic assessment of the skeletal phenotype in unexplained HBM using pQCT in our unique HBM population identified from screening routine UK NHS DXA scans.

pQCT measurements from the mid and distal tibia and radius in 98 HBM cases were compared with (i) 65 family controls (constituting unaffected relatives and spouses), and (ii) 692 general population controls.

HBM cases had substantially greater trabecular density at the distal tibia (340 [320, 359] mg/cm3), compared to both family (294 [276, 312]) and population controls (290 [281, 299]) (p < 0.001 for both, adjusted for age, gender, weight, height, alcohol, smoking, malignancy, menopause, steroid and estrogen replacement use). Similar results were obtained at the distal radius. Greater cortical bone mineral density (cBMD) was observed in HBM cases, both at the midtibia and radius (adjusted p < 0.001). Total bone area (TBA) was higher in HBM cases, at the distal and mid tibia and radius (adjusted p < 0.05 versus family controls), suggesting greater periosteal apposition. Cortical thickness was increased at the mid tibia and radius (adjusted p < 0.001), implying reduced endosteal expansion. Together, these changes resulted in greater predicted cortical strength (strength strain index [SSI]) in both tibia and radius (p < 0.001). We then examined relationships with age; tibial cBMD remained constant with increasing age amongst HBM cases (adjusted β − 0.01 [− 0.02, 0.01], p = 0.41), but declined in family controls (− 0.05 [− 0.03, − 0.07], p < 0.001) interaction p = 0.002; age-related changes in tibial trabecular BMD, CBA and SSI were also divergent. In contrast, at the radius HBM cases and controls showed parallel age-related declines in cBMD and trabecular BMD.

HBM is characterised by increased trabecular BMD and by alterations in cortical bone density and structure, leading to substantial increments in predicted cortical bone strength. In contrast to the radius, neither trabecular nor cortical BMD declined with age in the tibia of HBM cases, suggesting attenuation of age-related bone loss in weight-bearing limbs contributes to the observed bone phenotype.

Highlights

► High Bone Mass (HBM) is characterised by increased bone size, cortical BMD, cortical thickness and increased strength strain index. ► In HBM, trabecular density is also increased at both the distal radius and tibia. ► Tibial cortical and trabecular BMD decline with age in controls, but not in HBM implying attenuation of age-related loss. ► Similar differences in age-related bone loss are not seen at the radius, suggesting a possible interaction with weight-bearing.

Background

Good bone and joint health is essential for the physical tasks of daily living and poorer indicators of physical capability in older adults have been associated with increased mortality rates. Genetic variants of indicators of bone and joint health may be associated with measures of physical capability.

Methods

As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women aged between 52 and 90 + years from six UK cohorts were genotyped for a polymorphism associated with serum calcium (rs1801725, CASR), two polymorphisms associated with bone mineral density (BMD) (rs2941740, ESR1 and rs9594759, RANKL) and one associated with osteoarthritis risk rs3815148 (COG5). Meta-analysis was used to pool within-study effects of the associations between each of the polymorphisms and measures of physical capability: grip strength, timed walk or get up and go, chair rises and standing balance.

Results

Few important associations were observed among the several tests. We found that carriers of the serum calcium-raising allele had poorer grip strength compared with non-carriers (pooled p = 0.05, n = 11,239) after adjusting for age and sex. Inconsistent results were observed for the two variants associated with BMD and we found no evidence for an association between rs3815148 (COG5) and any of the physical capability measures.

Conclusion

Our findings suggest elevated serum calcium levels may lead to lower grip strength, though this requires further replication. Our results do not provide evidence for a substantial influence of these variants in ESR1, RANKL and COG5 on physical capability in older adults.

Highlights

► We examined associations between bone-related genotypes and physical capability. ► We conducted a meta-analysis on 12,836 middle-age adults. ► We found CASR may be associated with grip strength. ► No substantial support for specific bone mineral density variants and physical capability.

Summary

The association between functioning of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages remains poorly understood. We carried out meta-analyses to test the hypothesis that dysregulation of the HPA axis, as indexed by patterns of diurnal cortisol release, is associated with worse physical performance. Data from six adult cohorts (ages 50–92 years) were included in a two stage meta-analysis of individual participant data. We analysed each study separately using linear and logistic regression models and then used meta-analytic methods to pool the results. Physical performance outcome measures were walking speed, balance time, chair rise time and grip strength. Exposure measures were morning (serum and salivary) and evening (salivary) cortisol. Total sample sizes in meta-analyses ranged from n = 2146 for associations between morning Cortisol Awakening Response and balance to n = 8448 for associations between morning cortisol and walking speed. A larger diurnal drop was associated with faster walking speed (standardised coefficient per SD increase 0.052, 95% confidence interval (CI) 0.029, 0.076, p < 0.001; age and gender adjusted) and a quicker chair rise time (standardised coefficient per SD increase −0.075, 95% CI −0.116, −0.034, p < 0.001; age and gender adjusted). There was little evidence of associations with balance or grip strength. Greater diurnal decline of the HPA axis is associated with better physical performance in later life. This may reflect a causal effect of the HPA axis on performance or that other ageing-related factors are associated with both reduced HPA reactivity and performance.

The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, though 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 lifecourse physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, 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-value=0.09, n=7672 in males; p-value=0.90, n=7839 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.

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. Hum Mutat 32:1–11, 2011. © 2011 Wiley-Liss, Inc.

Objective

Experts disagree about the optimal classification of upper limb disorders (ULDs). To explore whether differential response to treatments offers a basis for choosing between case definitions, we analysed previously published research.

Methods

We screened 183 randomised controlled trials (RCTs) of treatments for ULDs, identified from the bibliographies of 10 Cochrane reviews, four other systematic reviews, and a search in Medline, Embase, and Google Scholar to June 2010. From these, we selected RCTs which allowed estimates of benefit (expressed as relative risks (RRs)) for >1 case definition to be compared when other variables (treatment, comparison group, follow-up time, outcome measure) were effectively held constant. Comparisons of RRs for paired case definitions were summarised by their ratios, with the RR for the simpler and broader definition as the denominator.

Result

Two RCT reports allowed within-trial comparison of RRs and thirteen others allowed between-trial comparisons. Together these provided 17 ratios of RRs (five for shoulder treatments, 12 for elbow treatments, none for wrist/hand treatments). The median ratio of RRs was 1.0 (range 0.3 to 1.7; interquartile range 0.6 to 1.3).

Conclusion

Although the evidence base is limited, our findings suggest that for musculoskeletal disorders of the shoulder and elbow, clinicians in primary care will often do best to apply simpler and broader case definitions. Researchers should routinely publish secondary analyses for subgroups of patients by different diagnostic features at trial entry, to expand the evidence base on optimal case definitions for patient management.

Variation in exposure to polyunsaturated fatty acids (PUFAs) might influence the development of atopy, asthma, and wheeze. This study aimed to determine whether differences in PUFA concentrations in maternal plasma phosphatidylcholine are associated with the risk of childhood wheeze or atopy. For 865 term-born children, we measured phosphatidylcholine fatty acid composition in maternal plasma collected at 34 weeks' gestation. Wheezing was classified using questionnaires at 6, 12, 24, and 36 months and 6 years. At age of 6 years, the children underwent skin prick testing, fractional exhaled nitric oxide (FENO) measurement, and spirometry. Maternal n-6 fatty acids and the ratio of n-3 to n-6 fatty acids were not associated with childhood wheeze. However, higher maternal eicosapentaenoic acid, docosahexaenoic acid, and total n-3 fatty acids were associated with reduced risk of non-atopic persistent/late wheeze (RR 0.57, 0.67 and 0.69, resp. P = 0.01, 0.015, and 0.021, resp.). Maternal arachidonic acid was positively associated with FENO (P = 0.024). A higher ratio of linoleic acid to its unsaturated metabolic products was associated with reduced risk of skin sensitisation (RR 0.82, P = 0.013). These associations provide some support for the hypothesis that variation in exposure to n-6 and n-3 fatty acids during pregnancy influences the risk of childhood wheeze and atopy.

Background

Experts disagree about the optimal classification of upper limb disorders (ULDs). To explore whether differences in associations with occupational risk factors offer a basis for choosing between case definitions in aetiological research and surveillance, we analysed previously published research.

Methods

Eligible reports (those with estimates of relative risk (RR) for >1 case definition relative to identical exposures were identified from systematic reviews of ULD and occupation and by hand-searching five peer-review journals published between January 1990 and June 2010. We abstracted details by anatomical site of the case and exposure definitions employed and paired estimates of RR, for alternative case definitions with identical occupational exposures. Pairs of case definitions were typically nested, a stricter definition being a subset of a simpler version. Differences in RR between paired definitions were expressed as the ratio of RRs, using that for the simpler definition as the denominator.

Results

We found 21 reports, yielding 320 pairs of RRs (82, 75 and 163 respectively at the shoulder, elbow, and distal arm). Ratios of RRs were frequently ≤1 (46%), the median ratio overall and by anatomical site being close to unity. In only 2% of comparisons did ratios reach ≥4.

Conclusion

Complex ULD case definitions (e.g. involving physical signs, more specific symptom patterns, and investigations) yield similar associations with occupational risk factors to those using simpler definitions. Thus, in population-based aetiological research and surveillance, simple case definitions should normally suffice. Data on risk factors can justifiably be pooled in meta-analyses, despite differences in case definition.

Objectives

To explore the relationship between occupational exposures and lateral and medial epicondylitis and the effect of epicondylitis on sickness absence in a population sample of working aged adults.

Methods

This was a cross-sectional study of 9696 randomly selected adults aged 25-64 years involving a screening questionnaire and standardised physical examination. Age- and sex-specific prevalence rates of epicondylitis were estimated and associations with occupational risk factors explored.

Results

Among 6038 respondents, 636 (11%) reported elbow pain in the last week. 0.7% of those surveyed were diagnosed with lateral epicondylitis and 0.6% with medial epicondylitis. Lateral epicondylitis was associated with manual work (OR 4.0, 95% CI 1.9-8.4). In multivariate analyses, repetitive bending/straightening elbow > 1 hour day was independently associated with lateral (OR 2.5, 95% CI 1.2-5.5) and medial epicondylitis (OR 5.1, 95% CI 1.8-14.3). 5% of adults with epicondylitis took sickness absence because of their elbow symptoms in the past 12 months (median 29 days).

Conclusions

Repetitive exposure to bending/straightening the elbow was a significant risk factor for medial and lateral epicondylitis. Epicondylitis is associated with prolonged sickness absence in 5% of affected working-aged adults.

Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother's adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P<0.001) and at age 4 years (r = 0.16, P = 0.02). In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02). This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04). We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fat.

This systematic review assesses the effectiveness of interventions in community and workplace settings to reduce sickness absence and job loss in workers with musculoskeletal disorders (MSDs). Relevant studies (randomised controlled trials (RCTs) and cohort studies published since 1990) were identified by screening citations in 35 earlier systematic reviews and from searches of Medline and Embase to April 2010. Among 42 studies (54 reports) including 34 RCTs, 27 assessed return to work, 21 duration of sickness absence, and five job loss. Interventions included exercise therapy, behavioural change techniques, workplace adaptations and provision of additional services. Studies were typically small (median sample size 107 (inter-quartile range (IQR) 77 to 148) and limited in quality. Most interventions were reported as beneficial: the median relative risk (RR) for return to work was 1.21 (IQR 1.00 – 1.60) and that for avoiding MSD-related job loss, 1.25 (IQR 1.06-1.71); the median reduction in sickness absence was 1.11 (IQR 0.32 to 3.20) days/month. However, effects were smaller in the larger and better quality studies, suggesting publication bias. No intervention was clearly superior to others, although effort-intensive interventions were less effective than simple ones. No cost-benefit analyses established statistically significant net economic benefits. Given that benefits are small and of doubtful cost-effectiveness, employers’ practice should be guided by their value judgements about the uncertainties. Expensive interventions should be implemented only with rigorous cost-benefit evaluation planned from the outset. Future research should focus on the cost-effectiveness of simple low cost interventions, and further explore impacts on job retention.

Summary

Background

Several age-related traits are associated with shorter telomeres, the structures that cap the end of linear chromosomes. A common polymorphism near the telomere maintenance gene TERT has been associated with several cancers, but relationships with other ageing traits such as physical capability have not been reported.

Methods

As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women aged between 44 and 90 years from 9 UK cohorts were genotyped for the single nucleotide polymorphism (SNP) rs401681. We then investigated relationships between the SNP and 30 age-related phenotypes, including cognitive and physical capability, blood lipid levels and lung function, pooling within-study genotypic effects in meta-analyses.

Results

No significant associations were found between the SNP and any of the cognitive performance tests (e.g. pooled beta per T allele for word recall z-score=0.02, 95% CI: -0.01- 0.04, p-value=0.12, n=18,737), physical performance tests (e.g. pooled beta for grip strength=-0.02, 95% CI:-0.045- 0.006, p-value=0.14, n=11,711), blood pressure, lung function or blood test measures. Similarly, no differences in observations were found when considering follow-up measures of cognitive or physical performance after adjusting for its measure at an earlier assessment.

Conclusion

The lack of associations between SNP rs401681 and a wide range of age-related phenotypes investigated in this large multi-cohort study suggests that whilst this SNP may be associated with cancer, it is not an important contributor to other markers of ageing.

Background

National initiatives to prevent and/or manage sickness absence require a database from which trends can be monitored.

Aims

To evaluate the information provided by surveillance schemes and publicly available datasets on sickness absence nationally from musculoskeletal disorders (MSDs).

Methods

A grey literature search was undertaken using the search engine Google, supplemented by leads from consultees from academia, industry, employers, lay interest groups and government. We abstracted data on the outcomes and populations covered, and made quantitative estimates of MSD-related sickness absence, overall and, where distinguishable, by sub-diagnosis. The coverage and limitations of each source were evaluated.

Results

Sources included the Labour Force Survey (LFS) and its Self-reported Work-related Illness survey module; the THOR-GP surveillance scheme; surveys by national and local government; surveys by employers’ organisations; and a database of benefit statistics. Each highlighted MSDs as a leading cause of sickness absence. Data limitations varied by source, but typically included lack of diagnostic detail and restriction of focus to selected subgroups (e.g. work-ascribed or benefit-awarded cases, specific employment sectors). Additionally, some surveys had very low response rates, were completed only by proxy respondents, or ranked only the perceived importance of MSD-related sickness absence, rather than measuring it.

Conclusions

National statistics on MSD-related sickness absence are piecemeal and incomplete. This limits capacity to plan and monitor national policies in an important area of public health. Simple low-cost additions to the LFS would improve the situation.

OBJECTIVE

Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans.

RESEARCH DESIGN AND METHODS

Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5′ from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ≥5% and a 5–95% range ≥10%, we related methylation status to maternal pregnancy diet and to child’s adiposity at age 9 years. Replication was sought in a second independent cohort.

RESULTS

In cohort 1, retinoid X receptor-α (RXRA) chr9:136355885+ and endothelial nitric oxide synthase (eNOS) chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient [β] 17% per SD change in methylation [95% CI 4–31], P = 0.009, n = 64, and β = 20% [9–32], P < 0.001, n = 66, respectively) and %fat mass (β = 10% [1–19], P = 0.023, n = 64 and β =12% [4–20], P = 0.002, n = 66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (β = 6% [2–10] and β = 4% [1–7], respectively, both P = 0.002, n = 239).

CONCLUSIONS

Our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease.

The use of thiazolidinediones (TZDs) has been associated with an increased fracture risk. In addition, type 2 diabetes mellitus (T2DM) has been linked with fracture. We evaluated to what extent the association between TZD use and fracture risk is related to the drug or to the underlying disease. We conducted a population-based cohort study using the Danish National Health Registers (1996–2007), which link pharmacy data to the national hospital registry. Oral antidiabetic users (n = 180,049) were matched 1:3 by year of birth and sex to nonusers. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture. Time-dependent adjustments were made for age, comorbidity, and drug use. We created a proxy indicator for the severity of disease. The first stage was defined as current use of either a biguanide or a sulfonyluerum, the second stage as current use of a biguanide and a sulfonyluerum at the same time, the third stage as patients using TZDs, and the fourth stage as patients using insulin. The risk of osteoporotic fracture was increased 1.3-fold for stages 3 and 4 compared with controls. Risk with current TZD use (stage 3 HR = 1.27, 95 % CI 1.06–1.52) and risk with current use of insulin (stage 4 HR = 1.25, 95 % CI 1.20–1.31) were similar. In the first (HR = 1.15, 95 % CI 1.13–1.18) and second (HR = 1.00, 95 % CI 0.96–1.04) stages risks were lower. Risk of osteoporotic fracture was similar for TZD users and insulin users. When studying fracture risk with TZDs, the underlying T2DM should be taken into account.

Rationale: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied.

Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP.

Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD.

Measurements and Main Results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10–12 risk alleles was associated with a reduction in FEV1 (β = –72.21 ml, P = 3.90 × 10−4) and FEV1/FVC (β = –1.53%, P = 6.35 × 10−6), and with COPD (odds ratio = 1.63, P = 1.46 × 10−5).

Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.

MAVIDOS is a randomised, double-blind, placebo-controlled trial (ISRCTN82927713, registered 2008 Apr 11), funded by Arthritis Research UK, MRC, Bupa Foundation and NIHR.

Background

Osteoporosis is a major public health problem as a result of associated fragility fractures. Skeletal strength increases from birth to a peak in early adulthood. This peak predicts osteoporosis risk in later life. Vitamin D insufficiency in pregnancy is common (31% in a recent Southampton cohort) and predicts reduced bone mass in the offspring. In this study we aim to test whether offspring of mothers supplemented with vitamin D in pregnancy have higher bone mass at birth than those whose mothers were not supplemented.

Methods/Design

Women have their vitamin D status assessed after ultrasound scanning in the twelfth week of pregnancy at 3 trial centres (Southampton, Sheffield, Oxford). Women with circulating 25(OH)-vitamin D levels 25-100 nmol/l are randomised in a double-blind design to either oral vitamin D supplement (1000 IU cholecalciferol/day, n = 477) or placebo at 14 weeks (n = 477). Questionnaire data include parity, sunlight exposure, dietary information, and cigarette and alcohol consumption. At 19 and 34 weeks maternal anthropometry is assessed and blood samples taken to measure 25(OH)-vitamin D, PTH and biochemistry. At delivery venous umbilical cord blood is collected, together with umbilical cord and placental tissue. The babies undergo DXA assessment of bone mass within the first 14 days after birth, with the primary outcome being whole body bone mineral content adjusted for gestational age and age. Children are then followed up with yearly assessment of health, diet, physical activity and anthropometric measures, with repeat assessment of bone mass by DXA at age 4 years.

Discussion

As far as we are aware, this randomised trial is one of the first ever tests of the early life origins hypothesis in human participants and has the potential to inform public health policy regarding vitamin D supplementation in pregnancy. It will also provide a valuable resource in which to study the influence of maternal vitamin D status on other childhood outcomes such as glucose tolerance, blood pressure, cardiovascular function, IQ and immunology.

Background

Low muscle mass and function have been associated with poorer indicators of physical capability in older people, which are in-turn associated with increased mortality rates. The growth hormone/insulin-like growth factor (GH/IGF) axis is involved in muscle function and genetic variants in genes in the axis may influence measures of physical capability.

Methods

As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women from seven UK cohorts aged between 52 and 90 years old were genotyped for six polymorphisms: rs35767 (IGF1), rs7127900 (IGF2), rs2854744 (IGFBP3), rs2943641 (IRS1), rs2665802 (GH1) and the exon-3 deletion of GHR. The polymorphisms have previously been robustly associated with age-related traits or are potentially functional. Meta-analysis was used to pool within-study genotypic effects of the associations between the polymorphisms and four measures of physical capability: grip strength, timed walk or get up and go, chair rises and standing balance.

Results

Few important associations were observed among the several tests. We found evidence that rs2665802 in GH1 was associated with inability to balance for 5 s (pooled odds ratio per minor allele = 0.90, 95% CI: 0.82–0.98, p-value = 0.01, n = 10,748), after adjusting for age and sex. We found no evidence for other associations between the polymorphisms and physical capability traits.

Conclusion

Our findings do not provide evidence for a substantial influence of these common polymorphisms in the GH/IGF axis on objectively measured physical capability levels in older adults.