Variants of the IL-10 gene associate with muscle strength in elderly from rural Africa: A candidate gene study

Recently, it has been shown that the capacity of the innate immune system to produce cytokines relates to skeletal muscle mass and strength in older persons. The interleukin-10 (IL-10) gene regulates the production capacities of IL-10 and tumour necrosis factor-α (TNF-α). In rural Ghana, IL-10 gene variants associated with different production capacities of IL-10 and TNF-α are enriched compared with Caucasian populations. In this setting, we explored the association between these gene variants and muscle strength. Among 554 Ghanaians aged 50 years and older, we determined 20 single nucleotide polymorphisms in the IL-10 gene, production capacities of IL-10 and TNF-α in whole blood upon stimulation with lipopolysaccharide (LPS) and handgrip strength as a proxy for skeletal muscle strength. We distinguished pro-inflammatory haplotypes associated with low IL-10 production capacity and anti-inflammatory haplotypes with high IL-10 production capacity. We found that distinct haplotypes of the IL-10 gene associated with handgrip strength. A pro-inflammatory haplotype with a population frequency of 43.2% was associated with higher handgrip strength (P = 0.015). An anti-inflammatory haplotype with a population frequency of 7.9% was associated with lower handgrip strength (P = 0.006). In conclusion, variants of the IL-10 gene contributing to a pro-inflammatory cytokine response associate with higher muscle strength, whereas those with anti-inflammatory response associate with lower muscle strength. Future research needs to elucidate whether these effects of variation in the IL-10 gene are exerted directly through its role in the repair of muscle tissue or indirectly through its role in the defence against infectious diseases

Optimal screening for increased risk for adverse outcomes in hospitalised older adults

Background: screening for frailty might help to prevent adverse outcomes in hospitalised older adults. Objective: to identify the most predictive and efficient screening tool for frailty. Design and setting: two consecutive observational prospective cohorts in four hospitals in the Netherlands. Subjects: patients aged ≥70 years, electively or acutely hospitalised for ≥2 days. Methods: screening instruments included in the Dutch Safety Management Programme [VeiligheidsManagementSysteem (VMS)] on four geriatric domains (ADL, falls, undernutrition and delirium) were used and the Identification of Seniors At Risk, the 6-item Cognitive Impairment Test and the Mini-Mental State Examination were assessed. Three months later, adverse outcomes including functional decline, high-healthcare demand or death were determined. Correlation and regression tree analyses were performed and predictive capacities were assessed. Results: follow-up data were available of 883 patients. All screening instruments were similarly predictive for adverse outcome ( predictive power 0.58–0.66), but the percentage of positively screened patients (13–72%), sensitivity (24–89%) and specificity (35–91%) highly differed. The strongest predictive model for frailty was scoring positive on ≥3 VMS domains if aged 70–80 years; or being aged ≥80 years and scoring positive on ≥1 VMS domains. This tool classified 34% of the patients as frail with a sensitivity of 68% and a specificity of 74%. Comparable results were found in the validation cohort. Conclusions: the VMS-tool plus age (VMS+ ) offers an efficient instrument to identify frail hospitalised older adults at risk for adverse outcome. In clinical practice, it is important to weigh costs and benefits of screening given the rather low-predictive power of screening instruments

Study protocol: A randomised controlled trial on the clinical effects of levothyroxine treatment for subclinical hypothyroidism in people aged 80 years and over

Background: Subclinical hypothyroidism is common in older people and its contribution to health and disease needs to be elucidated further. Observational and clinical trial data on the clinical effects of subclinical hypothyroidism in persons aged 80 years and over is inconclusive, with some studies suggesting harm and some suggesting benefits, translating into equipoise whether levothyroxine therapy provides clinical benefits. This manuscript describes the study protocol for the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus thyroid trial to generate the necessary evidence base. Methods: The IEMO 80-plus thyroid trial was explicitly designed as an ancillary experiment to the Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism randomised placebo controlled Trial (TRUST) with a ne

Drug-gene interactions of antihypertensive medications and risk of incident cardiovascular disease: A pharmacogenomics study from the CHARGE consortium

Background Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk ofmajor cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regressionmodels to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genom

Elderly postmenopausal patients with breast cancer are at increased risk for distant recurrence: A Tamoxifen Exemestane Adjuvant Multinational Study Analysis

Introduction. For postmenopausal patients with hormonesensitive breast cancer, outcome is worse with increasing age at diagnosis. The aim of this study was to assess the incidenceof breast cancer recurrence (locoregionalanddistant), and contralateral breast cancer by age at diagnosis. Methods. Patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were included. Primary endpoints were locoregional recurrence, distant recurrence, and contralateralbreastcancer.Ageatdiagnosiswascategorizedas younger than 65 years, 65-74 years, and 75 years or older. Results. Overall, 9,766 patients were included, of which 5,349 were younger than 65 years (reference group), 3,060 were 65-74 years, and 1,357 were 75 years or older. With increasing age, a decreased administration of radiotherapy after breast conserving surgery (94%, 92%, and 88%, respectively) and adjuvant chemotherapy (51%, 23%, and 5%, respectively) was observed. Risk of distant recurrence increased with age at diagnosis; multivariable hazard ratio for p

Thyroid function within the normal range and risk of coronary heart disease an individual participant data analysis of 14 cohorts

IMPORTANCE Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD). OBJECTIVE To assess the association between differences in thyroid function within the reference range and CHD risk. DESIGN, SETTING, AND

Thyroid function tests in the reference range and fracture: Individual participant analysis of prospective cohorts

Context: Hyperthyroidism is associated with increased fracture risk, but it is not clear if lower thyroid-stimulating hormone (TSH) and higher free thyroxine (FT4) in euthyroid individuals are associated with fracture risk. Objective: To evaluate the association of TSH and FT4 with incident fractures in euthyroid individuals. Design: Individual participant data analysis. Setting: Thirteen prospective cohort studies with baseline examinations between 1981 and 2002. Participants: Adults with baseline TSH 0.45 to 4.49 mIU/L. Main Outcome Measures: Primary outcome was incident hip fracture. Secondary outcomes were any, nonvertebral, and vertebral fractures. Results were presented as hazard ratios (HRs) with 95% confidence interval (CI) adjusted for age and sex. For clinical relevance, we studied TSH according to five categories: 0.45 to 0.99 mIU/L; 1.00 to 1.49 mIU/L; 1.50 to 2.49 mIU/L; 2.50 to 3.49 mIU/L; and 3.50 to 4.49 mIU/L (reference). FT4 was assessed as study-specific standard deviation increase, because assays varied between cohorts. Results: During 659,059 person-years, 2,565 out of 56,835 participants had hip fracture (4.5%; 12 studies with data on hip fracture). The pooled adjusted HR (95% CI) for hip fracture was 1.25 (1.05 to 1.49) for TSH 0.45 to 0.99 mIU/L, 1.19 (1.01 to 1.41) for TSH 1.00 to 1.49 mIU/L, 1.09 (0.93 to 1.28) for TSH 1.50 to 2.49 mIU/L, and 1.12 (0.94 to 1.33) for TSH 2.50 to 3.49 mIU/L (P for trend = 0.004). Hip fracture was also associated with FT4 [HR (95% CI) 1.22 (1.11 to 1.35) per one standard deviation increase in FT4]. FT4 only was associated with any and nonvertebral fractures. Results remained similar in sensitivity analyses. Conclusions: Among euthyroid adults, lower TSH and higher FT4 are associated with an increased risk of hip fracture. These findings may help refine the definition of optimal ranges of thyroid function tests

Subclinical hypothyroidism and the risk of stroke events and fatal stroke: An individual participant data analysis

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Thyroid function within the reference range and the risk of stroke: An individual participant data analysis

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