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1.  When, Where and How Osteoporosis-Associated Fractures Occur: An Analysis from the Global Longitudinal Study of Osteoporosis in Women (GLOW) 
PLoS ONE  2013;8(12):e83306.
Objective
To examine when, where and how fractures occur in postmenopausal women.
Methods
We analyzed data from the Global Longitudinal Study of Osteoporosis in Women (GLOW), including women aged ≥55 years from the United States of America, Canada, Australia and seven European countries. Women completed questionnaires including fracture data at baseline and years 1, 2 and 3.
Results
Among 60,393 postmenopausal women, 4122 incident fractures were reported (86% non-hip, non-vertebral [NHNV], 8% presumably clinical vertebral and 6% hip). Hip fractures were more likely to occur in spring, with little seasonal variation for NHNV or spine fractures. Hip fractures occurred equally inside or outside the home, whereas 65% of NHNV fractures occurred outside and 61% of vertebral fractures occurred inside the home. Falls preceded 68–86% of NHNV and 68–83% of hip fractures among women aged ≤64 to ≥85 years, increasing with age. About 45% of vertebral fractures were associated with falls in all age groups except those ≥85 years, when only 24% occurred after falling.
Conclusion
In this multi-national cohort, fractures occurred throughout the year, with only hip fracture having a seasonal variation, with a higher proportion in spring. Hip fractures occurred equally within and outside the home, spine fractures more often in the home, and NHNV fractures outside the home. Falls were a proximate cause of most hip and NHNV fractures. Postmenopausal women at risk for fracture need counseling about reducing potentially modifiable fracture risk factors, particularly falls both inside and outside the home and during all seasons of the year.
doi:10.1371/journal.pone.0083306
PMCID: PMC3859637  PMID: 24349484
2.  Telomere Length and Physical Performance at Older Ages: An Individual Participant Meta-Analysis 
PLoS ONE  2013;8(7):e69526.
Background
Telomeres are involved in cellular ageing and shorten with increasing age. If telomere length is a valuable biomarker of ageing, then telomere shortening should be associated with worse physical performance, an ageing trait, but evidence for such an association is lacking. The purpose of this study was to examine whether change in telomere length is associated with physical performance.
Methods
Using data from four UK adult cohorts (ages 53–80 years at baseline), we undertook cross-sectional and longitudinal analyses. We analysed each study separately and then used meta-analytic methods to pool the results. Physical performance was measured using walking and chair rise speed, standing balance time and grip strength. Telomere length was measured by quantitative real-time polymerase chain reaction (PCR) in whole blood at baseline and follow-up (time 1, time 2).
Results
Total sample sizes in meta-analyses ranged from 1,217 to 3,707. There was little evidence that telomere length was associated with walking speed, balance or grip strength, though weak associations were seen with chair rise speed and grip strength at baseline (p = 0.02 and 0.01 respectively). Faster chair rise speed at follow-up, was associated with a smaller decline in telomere length between time 1 and time 2 (standardised coefficient per SD increase 0.061, 95% CI 0.006, 0.115, p = 0.03) but this was consistent with chance (p = 0.08) after further adjustment.
Conclusions
Whereas shortening of leukocyte telomeres might be an important measure of cellular ageing, there is little evidence that it is a strong biomarker for physical performance.
doi:10.1371/journal.pone.0069526
PMCID: PMC3724915  PMID: 23922731
3.  Body Mass Index, Muscle Strength and Physical Performance in Older Adults from Eight Cohort Studies: The HALCyon Programme 
PLoS ONE  2013;8(2):e56483.
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.
doi:10.1371/journal.pone.0056483
PMCID: PMC3577921  PMID: 23437142
4.  Fetal Liver Blood Flow Distribution: Role in Human Developmental Strategy to Prioritize Fat Deposition versus Brain Development 
PLoS ONE  2012;7(8):e41759.
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.
doi:10.1371/journal.pone.0041759
PMCID: PMC3425554  PMID: 22927915
5.  A Multi-Cohort Study of Polymorphisms in the GH/IGF Axis and Physical Capability: The HALCyon Programme 
PLoS ONE  2012;7(1):e29883.
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.
doi:10.1371/journal.pone.0029883
PMCID: PMC3254646  PMID: 22253814
6.  Age and Gender Differences in Physical Capability Levels from Mid-Life Onwards: The Harmonisation and Meta-Analysis of Data from Eight UK Cohort Studies 
PLoS ONE  2011;6(11):e27899.
Using data from eight UK cohorts participating in the Healthy Ageing across the Life Course (HALCyon) research programme, with ages at physical capability assessment ranging from 50 to 90+ years, we harmonised data on objective measures of physical capability (i.e. grip strength, chair rising ability, walking speed, timed get up and go, and standing balance performance) and investigated the cross-sectional age and gender differences in these measures. Levels of physical capability were generally lower in study participants of older ages, and men performed better than women (for example, results from meta-analyses (N = 14,213 (5 studies)), found that men had 12.62 kg (11.34, 13.90) higher grip strength than women after adjustment for age and body size), although for walking speed, this gender difference was attenuated after adjustment for body size. There was also evidence that the gender difference in grip strength diminished with increasing age,whereas the gender difference in walking speed widened (p<0.01 for interactions between age and gender in both cases). This study highlights not only the presence of age and gender differences in objective measures of physical capability but provides a demonstration that harmonisation of data from several large cohort studies is possible. These harmonised data are now being used within HALCyon to understand the lifetime social and biological determinants of physical capability and its changes with age.
doi:10.1371/journal.pone.0027899
PMCID: PMC3218057  PMID: 22114723
7.  Large Scale Replication Study of the Association between HLA Class II/BTNL2 Variants and Osteoarthritis of the Knee in European-Descent Populations 
PLoS ONE  2011;6(8):e23371.
Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR)  = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the meta-analysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r2 = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r2<0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals.
doi:10.1371/journal.pone.0023371
PMCID: PMC3154440  PMID: 21853121
8.  Childhood Socioeconomic Position and Objectively Measured Physical Capability Levels in Adulthood: A Systematic Review and Meta-Analysis 
PLoS ONE  2011;6(1):e15564.
Background
Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood.
Methods and Findings
Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta-analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations.
Conclusions
Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life.
doi:10.1371/journal.pone.0015564
PMCID: PMC3027621  PMID: 21297868

Results 1-8 (8)