Association of Polymorphisms in Connective Tissue Growth Factor and Epidermal Growth Factor Receptor Genes With Human Longevity.

Growth pathways play key roles in longevity. The present study tested single-nucleotide polymorphisms (SNPs) in the connective tissue growth factor gene (CTGF) and the epidermal growth factor receptor gene (EGFR) for association with longevity. Comparison of allele and genotype frequencies of 12 CTGF SNPs and 41 EGFR SNPs between 440 American men of Japanese ancestry aged ≥95 years and 374 men of average life span revealed association with longevity at the p < .05 level for 2 SNPs in CTGF and 7 in EGFR. Two in CTGF and two in EGFR remained significant after Bonferroni correction. The SNPs of both CTGF and EGFR were in a haplotype block in each respective gene. Haplotype analysis confirmed the suggestive association found by χ2 analysis. We noted an excess of heterozygotes among the longevity cases, consistent with heterozygote advantage in living to extreme old age. No associations of the most significant SNPs were observed in whites or Koreans. In conclusion, the present findings indicate that genetic variation in CTGF and EGFR may contribute to the attainment of extreme old age in Japanese. More research is needed to confirm that genetic variation in CTGF and EGFR contributes to the attainment of extreme old age across human populations.

Longevity-Associated FOXO3 Genotype and its Impact on Coronary Artery Disease Mortality in Japanese, Whites, and Blacks: A Prospective Study of Three American Populations.

BACKGROUND: We recently reported that protection against coronary artery disease (CAD) mortality is the major contributor to longer life associated with FOXO3 genotype. The present study examined this relation in more detail. METHODS: We performed a 15-year observational study of 3,584 older American men of Japanese ancestry from the Kuakini Honolulu Heart Program cohort and 1,595 White and 1,067 Black elderly individuals from the Health Aging and Body Composition study. RESULTS: Multivariate Cox regression models demonstrated that carriage of the longevity-associated G allele of FOXO3 single nucleotide polymorphisms rs2802292 was a protective factor against CAD mortality in all three populations. In Japanese and Whites, but not in Blacks, the protective effect of the G allele was little changed in models adjusted for other major risk factors. Population-attributable risk (PAR) models found that the nonprotective TT genotype contributed 15%, 9%, and 3% to CAD mortality risk in Japanese, White, and Black Americans, respectively, and was one of the top three contributing factors to CAD mortality. In Japanese, this effect size was comparable with hypertension (15%), but in Whites and Blacks PAR for hypertension was higher (29% and 26%, respectively). G-allele carriers had lower plasma TNF-α than noncarriers, suggesting inflammation as a potential mediating factor for CAD mortality risk. CONCLUSION: FOXO3 genotype is an important risk factor for CAD mortality in older populations. More research is needed to identify potential mechanisms and targets for intervention.

Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2.

Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF] = 3%) was associated with higher vBMD (ß = 0.22, p = 1.9 × 10-8 ) and decreased risk of radiographic vertebral fracture (odds ratio [OR] = 0.75; false discovery rate [FDR] p = 0.01). In 1p36.12, rs12742784 (MAF = 21%) was associated with higher vBMD (ß = 0.09, p = 1.2 × 10-10 ) and decreased risk of clinical vertebral fracture (OR = 0.82; FDR p = 7.4 × 10-4 ). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (ß = 0.28, FDR p = 0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (ß = 0.12, FDR p = 1.7 × 10-3 , functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence. © 2016 American Society for Bone and Mineral Research.

The FoxO3 gene and cause-specific mortality.

The G allele of the FOXO3 single nucleotide polymorphism (SNP) rs2802292 exhibits a consistently replicated genetic association with longevity in multiple populations worldwide. The aims of this study were to quantify the mortality risk for the longevity-associated genotype and to discover the particular cause(s) of death associated with this allele in older Americans of diverse ancestry. It involved a 17-year prospective cohort study of 3584 older American men of Japanese ancestry from the Honolulu Heart Program cohort, followed by a 17-year prospective replication study of 1595 white and 1056 black elderly individuals from the Health Aging and Body Composition cohort. The relation between FOXO3 genotype and cause-specific mortality was ascertained for major causes of death including coronary heart disease (CHD), cancer, and stroke. Age-adjusted and multivariable Cox proportional hazards models were used to compute hazard ratios (HRs) for all-cause and cause-specific mortality. We found G allele carriers had a combined (Japanese, white, and black populations) risk reduction of 10% for total (all-cause) mortality (HR = 0.90; 95% CI, 0.84-0.95; P = 0.001). This effect size was consistent across populations and mostly contributed by 26% lower risk for CHD death (HR = 0.74; 95% CI, 0.64-0.86; P = 0.00004). No other causes of death made a significant contribution to the survival advantage for G allele carriers. In conclusion, at older age, there is a large risk reduction in mortality for G allele carriers, mostly due to lower CHD mortality. The findings support further research on FOXO3 and FoxO3 protein as potential targets for therapeutic intervention in aging-related diseases, particularly cardiovascular disease.

Association Analysis of FOXO3 Longevity Variants With Blood Pressure and Essential Hypertension.

BACKGROUND: The minor alleles of 3 FOXO3 single nucleotide polymorphisms (SNPs)- rs2802292 , rs2253310 , and rs2802288 -are associated with human longevity. The aim of the present study was to test these SNPs for association with blood pressure (BP) and essential hypertension (EHT). METHODS: In a primary study involving Americans of Japanese ancestry drawn from the Family Blood Pressure Program II we genotyped 411 female and 432 male subjects aged 40-79 years and tested for statistical association by contingency table analysis and generalized linear models that included logistic regression adjusting for sibling correlation in the data set. Replication of rs2802292 with EHT was attempted in Japanese SONIC study subjects and of each SNP in a meta-analysis of genome-wide association studies of BP in individuals of European ancestry. RESULTS: In Americans of Japanese ancestry, women homozygous for the longevity-associated (minor) allele of each FOXO3 SNP had 6mm Hg lower systolic BP and 3mm Hg lower diastolic BP compared with major allele homozygotes (Bonferroni corrected P < 0.05 and >0.05, respectively). Frequencies of minor allele homozygotes were 3.3-3.9% in women with EHT compared with 9.5-9.6% in normotensive women ( P = 0.03-0.04; haplotype analysis P = 0.0002). No association with BP or EHT was evident in males. An association with EHT was seen for the minor allele of rs2802292 in the Japanese SONIC cohort ( P = 0.03), while in European subjects the minor allele of each SNP was associated with higher systolic and diastolic BP. CONCLUSION: Longevity-associated FOXO3 variants may be associated with lower BP and EHT in Japanese women.

GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.

BACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies. METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity. RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)). CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip.

OBJECTIVES: Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. METHODS: We performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. RESULTS: We accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis). CONCLUSIONS: Novel genetic loci for hip OA were found in this meta-analysis of GWAS.

Estimated GFR and risk of hip fracture in older men: comparison of associations using cystatin C and creatinine.

BACKGROUND: Higher serum cystatin C level is associated with an increased risk of hip fracture in postmenopausal white women, but there is a paucity of data for men. Whether estimated glomerular filtration rate (eGFR) based on cystatin C (eGFRcys) is superior in predicting hip fracture risk to eGFR based on creatinine (eGFRcr) or the combination (eGFR(cr-cys)) also is uncertain. STUDY DESIGN: Nested case-cohort. SETTING & PARTICIPANTS: Participants enrolled in the Osteoporotic Fractures in Men (MrOS) Study (5,994 men aged ≥ 65 years from 6 US centers) including a random subcohort of 1,602 men and 168 men with incident hip fractures (51 of whom were in the subcohort). PREDICTOR: eGFR(cys), eGFR(cr), and eGFR(cr-cys) computed using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations and expressed in categories of <60, 60-74, and ≥ 75 mL/min/1.73 m(2) (referent group). OUTCOME: Incident hip fracture ascertained by participant contacts every 4 months and confirmed with radiographic reports. RESULTS: Median eGFR(cys) was 72.9 (IQR, 60.5-85.7) mL/min/1.73 m(2). In unadjusted models, all measures of eGFR were associated with increased hip fracture risk. However, after adjustment for age, race, site, and body mass index, the association of lower eGFR(cys) (but not lower eGFR(cr) or lower eGFR(cr-cys)) with higher hip fracture risk remained: for <60 versus ≥ 75 mL/min/1.73 m(2), HRs were 1.96 [95% CI, 1.25-3.09], 0.84 [95% CI, 0.52-1.37], and 1.08 [95% CI, 0.66-1.77] for eGFR(cys), eGFR(cr), and eGFR(cr-cys), respectively. Similarly, after adjustment for age, race, site, and body mass index, eGFR < 60 mL/min/1.73 m(2) defined by eGFR(cys), but not eGFR(cr) or eGFR(cr-cys), was associated with higher hip fracture risk. The association between eGFR(cys) and hip fracture was not explained by levels of calciotropic hormones or inflammatory markers, but the relationship was attenuated and no longer reached significance (for <60 vs ≥ 75 mL/min/1.73 m(2): HR, 1.43; 95% CI, 0.88-2.34) after consideration of additional clinical risk factors and bone mineral density. LIMITATIONS: Findings not generalizable to other populations; residual confounding may exist. CONCLUSIONS: Older community-dwelling men with lower eGFR(cys) have an increased risk of hip fracture that is explained in large part by greater burden of risk factors among men with lower eGFR(cys). In contrast, lower eGFR(cr) or lower eGFR(cr-cys) was not associated with a higher age-adjusted hip fracture risk.

Association of serum uric acid and incident nonspine fractures in elderly men: the Osteoporotic Fractures in Men (MrOS) study.

Uric acid (UA) is produced from purines by the enzyme xanthine oxidase, and elevated levels may cause arthritis and kidney stones. Conversely, UA also appears to function as an antioxidant and may protect against the oxidative stress associated with aging and disease. We performed a prospective fracture case-cohort study to understand the relation of UA and fracture risk in older men enrolled in the Osteoporotic Fractures in Men (MrOS) study. In the cohort of 5994 men aged 65 years and older attending the baseline MrOS examination, we evaluated a subgroup 1680 men in a case-cohort study design. The analytic group included 387 men with incident nonspine fractures (73 hip) and a random sample of 1383. Serum UA was measured in baseline serum samples. Modified proportional hazards models that account for case-cohort study design were used to estimate the relative hazards (RH) of hip and nonspine fracture in men for serum UA. Models were adjusted for age, race, clinic site, body mass index, vitamin D, parathyroid hormone, walking speed, Physical Activity Scale for the Elderly (PASE) score, frailty, and total. Subjects with incident nonspine fractures were older, had lower total hip bone mineral density (BMD), and higher serum phosphorus. There was an 18% decreased risk of nonspine fractures (95% confidence interval [CI] 0.71-0.93; p = 0.003) per 1 SD increase of baseline serum and 34% decreased risk of nonspine fractures in quartile 4 of UA versus quartiles 1, 2, and 3 (95% CI 0.49-0.89; p = 0.028) compared with nonfracture cases after multivariate adjustment. Hip fractures were not significantly associated with UA. Total hip BMD was significantly higher in the group of men with high UA levels compared with lower UA levels and increased linearly across quartiles of UA after multivariate adjustment (p for trend = 0.002). In summary, higher serum UA levels were associated with a reduction in risk of incident nonspine fractures but not hip fractures and higher hip BMD.

Sex hormone levels and risk of breast cancer with estrogen plus progestin.

BACKGROUND: Although high endogenous sex hormone levels and estrogen plus progestin (E+P) therapy are associated with increased breast cancer risk, it is unknown whether pretreatment levels of sex hormones modify E+P effect on breast cancer. METHODS: We conducted a nested case-control study within the Women's Health Initiative randomized clinical trial of E+P. The trial enrolled 16608 postmenopausal women aged 50 to 79 years with intact uterus and no breast cancer history. During a mean of 5.6 years of follow-up, 348 incident breast cancer case subjects were identified and matched with 348 control subjects. Case and control subjects had their sex hormone levels measured at baseline (estrogens, testosterone, progesterone, and sex hormone-binding globulin [SHBG]) and year 1 (estrogens and SHBG) using sensitive assays. All statistical tests were two-sided. RESULTS: Statistically significant elevations in breast cancer risk were seen with greater pretreatment levels of total estradiol (P trend = .04), bioavailable estradiol (P trend = .03), estrone (P trend = .007), and estrone sulfate (P trend = .007). E+P increased all measured estrogens and SHGB at year 1 (all P < .001). The effect of E+P on breast cancer risk was strongest in women whose pretreatment levels of total estradiol, bioavailable estradiol, and estrone were in the lowest quartiles. For example, the odds ratio for E+P relative to placebo was 2.47 (95% confidence interval [CI] = 1.28 to 4.79) in the lowest total estradiol quartile, compared with 0.96 (95% CI = 0.44 to 2.09) in the highest total estradiol quartile; P interaction = .04). CONCLUSIONS: Women with lower pr-treatment endogenous estrogen levels were at greater risk of breast cancer during E+P therapy compared with those with higher levels. Further studies are warranted to confirm these findings.

Cystatin C and risk of hip fractures in older women.

To test the hypothesis that older women with higher cystatin C are at increased risk of hip fracture independent of traditional risk factors including hip bone mineral density (BMD), we performed a case-cohort analysis nested in a cohort of 4709 white women attending a Year 10 (1997-1998) examination of the Study of Osteoporotic Fractures that included a random sample of 1170 women and the first 300 women with incident hip fracture occurring after Year 10 examination. Serum cystatin C and creatinine were measured in Year 10 sera. In a model adjusted for age, clinical site, body mass index, and total hip BMD, higher cystatin C was associated with an increased risk of hip fracture (p for linear trend 0.008) with women in quartile 4 having a 1.9-fold higher risk (hazard ratio [HR] 1.91; 95% confidence interval [CI], 1.24-2.95) compared with those in quartile 1 (referent group). Further adjustment for additional risk factors only slightly attenuated the association; the risk for hip fracture was 1.7-fold higher (HR 1.74; 95% CI, 1.11-2.72) in women in quartile 4 compared with those in quartile 1. In contrast, neither serum creatinine nor creatinine-based estimated glomerular filtration rate (eGFRCr ) were associated with risk of hip fracture. Older women with higher cystatin C, but not higher serum creatinine or lower eGFRCr , have an increased risk of hip fracture independent of traditional risk factors. These findings suggest that cystatin C may be a promising biomarker for identification of older adults at high risk of hip fracture.

Sex hormone levels and risks of estrogen receptor-negative and estrogen receptor-positive breast cancers.

BACKGROUND: Endogenous sex hormone levels are associated with risks of breast cancer overall and estrogen receptor (ER)-positive breast tumors; however, their associations with ER-negative tumors remain unclear. METHODS: In a case-cohort study within the Women's Health Initiative Observational Study among postmenopausal women aged 50-79 years, we examined associations between endogenous testosterone and estradiol levels and the risks of ER-negative and ER-positive breast cancers. Serum levels of bioavailable testosterone and estradiol were assessed at the baseline visit in 317 invasive breast cancer case subjects and in a subcohort of 594 women. Bioavailable sex hormone levels were calculated using the total hormone level and the sex hormone-binding globulin concentration (measured by radioimmunoassays and a chemiluminescent immunoassay, respectively). Cox proportional hazards regression was used for statistical analysis. All statistical tests were two-sided. RESULT: The unadjusted absolute rates of ER-negative breast cancer for testosterone quartiles 1-4 were 0.34, 0.20, 0.23, and 0.21 per 10,000 person-years, respectively. Compared with women in the lowest quartile of testosterone level, those in quartile 2 had a 56% lower risk of ER-negative cancer (hazard ratio [HR] = 0.44, 95% confidence interval [CI] = 0.23 to 0.85), those in quartile 3 had a 45% lower risk (HR = 0.55, 95% CI = 0.30 to 1.01), and those in quartile 4 had a 49% lower risk (HR = 0.51, 95% CI = 0.28 to 0.94), independent of other risk factors. Estradiol level was not associated with ER-negative breast cancer. ER-positive breast cancer risk increased with higher testosterone levels (P(trend) = .04), but this trend was not statistically significant after adjustment for estradiol (P(trend) = .15). ER-positive cancer risk was approximately twofold higher in women with estradiol levels in quartiles 2-4 compared with women in quartile 1, independent of risk factors. CONCLUSION: Higher serum levels of bioavailable testosterone are associated with lower risks of ER-negative breast cancer in postmenopausal women.

Does surgically induced weight loss improve daytime sleepiness?

Morbid obesity is associated with excessive daytime sleepiness and reduced health-related quality of life. We prospectively evaluated the pre- and postoperative responses of bariatric surgery recipients with the Epworth Sleepiness Scale (ESS) and the Short Form-12. Participants (n = 223; 79% women) with a mean body mass index (BMI) and ESS of 44.8 ± 7.9 kg/m(2) and 7.9 ± 4.5, respectively, received a vertical gastrectomy (76%) or Roux-en-Y gastric bypass (12%). Preoperatively, 30% of patients complained of excessive daytime sleepiness (ESS > 10). Patients with preoperative excessive daytime sleepiness were more obese (p = 0.002), had higher fasting glucose levels (p = 0.02), more likely to have a diagnosis of sleep-disordered breathing (p < 0.001), report snoring (p < 0.001), and had lower health-related quality of life measures particularly physical function (p < 0.001), depression (p = 0.006), and sexual satisfaction (p = 0.04) than non-sleepy patients. At 12-months postoperatively, most patients experienced a significant reduction in BMI (28.6 ± 5.5 kg/m(2), p < 0.001) and excessive daytime sleepiness (mean ESS 5.3 ± 3.3, p < 0.001). Patients with a clinically relevant improvement in the ESS at 12-months post-operatively had greater improvements in physical function (p = 0.009) and snoring (p = 0.010) and were more likely still using positive airway pressure therapy (p = 0.032) than patients without a clinically relevant improvement. Statistically and clinically significant improvements in all health-related quality of life measures were noted at 24 months. Bariatric surgery is associated with dramatic weight loss and improvements in physical functioning and daytime sleepiness.

High prevalence of vitamin D deficiency in patients with basal cell nevus syndrome.

OBJECTIVES: To evaluate vitamin D status in patients with basal cell nevus syndrome (BCNS) who practice photoprotection because of their genetic predisposition to skin cancer and to determine risk factors for deficiency. DESIGN: Retrospective cohort study. SETTING: Academic medical centers. PATIENTS: Forty-one ambulatory patients with BCNS who participated in a 2-year chemoprevention clinical trial. Population-based controls (n = 360) were selected and matched by age, sex, Fitzpatrick skin type, and season/geography. MAIN OUTCOME MEASURES: Levels of 25-hydroxyvitamin D (25[OH]D) and vitamin D deficiency (defined as a 25[OH]D level of ≤20 ng/mL). RESULTS: Twenty-three patients with BCNS (56%) were vitamin D deficient. Patients with BCNS had mean 25(OH)D levels below those of the general population (-3 ng/mL; P = .02) and were 3 times more likely to be vitamin D deficient (56% vs 18%; P < .001). Levels of 25(OH)D were lower in patients who were overweight (-3.0 ng/mL; P = .04) and who had blood collected in the winter compared with the summer (-7.1 ng/mL; P < .001). CONCLUSION: Patients with BCNS may be at increased risk for vitamin D deficiency, depending on their adherence to photoprotection practices.

Serum 25-hydroxyvitamin D, parathyroid hormone, and mortality in older men.

CONTEXT: Low 25-hydroxyvitamin D [25(OH)D] and high PTH may contribute to increased mortality risk in older adults. OBJECTIVE: The aim of the study was to test the association between 25(OH)D, PTH, and mortality in older men. DESIGN AND SETTING: The prospective Osteoporotic Fractures in Men (MrOS) study was conducted at six U.S. clinical centers. PARTICIPANTS: We studied community-dwelling men at least 65 yr old (n = 1490). MAIN OUTCOME MEASURE: Multivariate-adjusted proportional hazards models estimated the hazard ratio (HR) for mortality; cause of death was classified as cancer, cardiovascular, and other by central review of death certificates. RESULTS: During 7.3 yr of follow-up, 330 (22.2%) participants died: 97 from cancer, 110 from cardiovascular disease, and 106 from other causes. The adjusted HR per sd decrease in 25(OH)D for all-cause mortality was 1.01 (95% CI, 0.89, 1.14); no association between 25(OH)D and cardiovascular or other-cause mortality was seen. Unexpectedly, lower 25(OH)D levels were modestly associated with a decreased risk of cancer mortality (adjusted HR per sd decrease, 0.80; 95% CI, 0.64, 0.99). Analyzing 25(OH)D as a categorical variable did not alter these results. Higher PTH levels (log-transformed) were associated with an increased risk of all-cause mortality (adjusted HR per sd increase, 1.15; 95% CI, 1.03, 1.29) and cardiovascular mortality (adjusted HR per sd increase in PTH, 1.21; 95% CI, 1.00, 1.45). CONCLUSIONS: In contrast to previous studies, lower 25(OH)D levels were not associated with an increased risk of all-cause or cause-specific mortality in older men. Higher PTH levels were associated with a modest increase in mortality risk.

Accuracy of self-reported diagnosis of hip replacement.

OBJECTIVE: To examine the accuracy and validity of self-report of hip replacement for osteoarthritis (OA). METHODS: We compared self-reported hip replacement and the reason for surgery in elderly, white women age > or =65 years from the Study for Osteoporotic Fractures cohort with medical records and pelvis radiographs. Women, followed for an average of 8 years at the fifth clinic visit, were asked about any hip replacements since baseline. RESULTS: Among 7,421 women attending the fifth clinic visit, 347 reported 387 hip replacements. Radiographs and/or medical records were available for 316 self-reported hip replacements. Participants accurately reported that hip replacements were for arthritis or fracture, with 94.5% and 97.2% of these self-reported diagnoses, respectively, confirmed from medical records. However, 1 in 8 self-reported hip replacements were not attributed by participants to either arthritis or a fracture; of these, medical records indicated that 88% were for OA. Overall, 302 self-reported hip replacements (95.6%) were confirmed as hip replacements (for agreement with self-report, kappa = 0.95 [95% confidence interval 0.92-0.96]). Under-reporting of hip replacements compared with hip replacements seen on radiographs was minimal (0.28%). CONCLUSION: Elderly women accurately reported hip replacements and whether the surgery was for arthritis or a hip fracture, although a small number of hip replacements for arthritis were not attributed to this diagnosis by the women. Because hip OA and hip fracture have very different determinants, epidemiologic studies that use self-reported hip replacement as an indicator for the presence of hip OA or as an outcome of hip OA should verify the underlying cause by asking about the reason for surgery.

Inverse association between serum 25(OH) vitamin D levels and non-melanoma skin cancer in elderly men.

To determine the relationship between 25(OH) vitamin D levels and non-melanoma skin cancer (NMSC), we performed a nested case-control study in ambulatory, elderly men enrolled in the Osteoporotic Fractures in Men (MrOS) Study. Health habit and medical history, including self-reported history of NMSC were recorded and 25(OH)D levels were measured on serum collected at baseline from a random sample of Caucasian MrOS subjects. Mean age (73 +/- 5), BMI, daily vitamin D and calcium intake were similar in the men with (n = 178) and without NMSC (n = 930), but higher levels of 25(OH)D were associated with a decreased risk of having a history of NMSC (P(trend) = 0.04). Men in the highest quintile of 25(OH)D (>30 ng/mL) had 47% lower odds of NMSC (95% CI: 0.30-0.93, p = 0.026) compared to those in the lowest quintile. Our results suggest that a diagnosis of NMSC is not a surrogate for adequate 25(OH)D levels or increased UV exposure, and high 25(OH)D levels may be associated with a reduced risk of NMSC.

The general public's perceptions and use of antimicrobials in Trinidad and Tobago / Las percepciones del público general y el uso de antimicrobianos en Trinidad y Tabago

Objective. To determine the general public's perceptions and use of antibiotics in Trinidad and Tobago, a two-island republic in the Caribbean. Methods. This prospective study surveyed 824 randomly selected households listed in the telephone directory, from November 1998 to January 1999. Through telephone interviews we determined knowledge about antibiotics and beliefs concerning their safety and efficacy. We studied the influence of age, gender, education, and having private health insurance on knowledge, self-medication, storing medication at home for emergency use ("hoarding"), and asking a private doctor to prescribe antibiotics ("demand prescribing"). Results. For the 824 telephone calls that the interviewers completed, 753 of the households agreed to participate (91.4% response rate). Of those 753 participants, 699 of them (93%) knew the term "antibiotic," 29% (206/699) said it was a drug for bacterial infections, and 25% (170/690) had asked a doctor for an antibiotic prescription. Penicillin was correctly identified as an antibiotic across age, gender, and education categories, but 36% of respondents incorrectly said Benadryl (diphenhydramine), a common over-the-counter cough and cold formulation, was an antibiotic. Gender was not significantly associated with knowledge of antibiotic safety, with self-medication, or with hoarding antibiotics. On the other hand, completion of tertiary (university) education was significantly associated with correct knowledge of the safety of antibiotics and whether or not they could cure all infections. Of the various antimicrobials, beta-lactams were the ones that survey respondents had used most frequently in the preceding year, and 20% of antibiotics users had used multiple antibiotics in that period. In comparison to persons with private health insurance, more individuals without private health insurance said that antibiotics are safe and do not have side effects, and more of them also incorrectly called aspirin and Benadryl antibiotics. Conclusions. In Trinidad and Tobago, inappropriate use of antimicrobials results from self-medication, over-the-counter availability at the community pharmacy, prescribing on demand, and lack of regulatory control. In order to contain antibiotic abuse, both the Drug Inspectorate of the Ministry of Health and the Pharmacy Board should exert stricter control on the dispensing of antibiotics at private pharmacies. Further, education of the general public and of health care professionals on antibiotic misuse and appropriate use must be instituted, along with community-based surveillance of antimicrobial resistance trends

Objetivo. Investigar las percepciones del público general y el uso de antimicrobianos en Trinidad y Tabago, una república caribeña formada por dos islas. Métodos. En este estudio prospectivo se encuestaron, entre noviembre de 1998 y enero de 1999, 824 domicilios seleccionados aleatoriamente que figuraban en la lista telefónica. En las entrevistas, realizadas por teléfono, se investigaron los conocimientos sobre los antimicrobianos y las creencias de los entrevistados acerca de su eficacia y seguridad. Se estudió la influencia de la edad, del sexo, de la educación y del hecho de disponer de seguro de salud privado sobre los conocimientos, la automedicación, el almacenamiento de medicamentos en casa para utilizarlos en caso de urgencia ("acumulación") y la petición de prescripción de antimicrobianos a médicos privados ("demanda de prescripción"). Resultados. De los 824 contactos telefónicos realizados por los entrevistadores, en 753 (91,4%) se obtuvo una respuesta favorable a la participación en la encuesta. De estos 753 participantes, 699 (93%) conocían el término "antibióticos", 29% (206/699) dijeron que se trataba de fármacos para las infecciones bacterianas, y 25% (170/690) le habían pedido al médico prescripciones de antibióticos. La penicilina fue identificada correctamente como un antibiótico por personas de diferentes edades, sexos y niveles educacionales, pero el 36% de los entrevistados dijeron que el Benadryl (difenhidramina), un fármaco muy utilizado en el resfriado y que no necesita receta médica, era un antibiótico. El sexo no se asoció de forma significativa a los conocimientos sobre la seguridad de los antibióticos, a la automedicación ni a la "acumulación" de antibióticos. Por otra parte, el haber completado estudios universitarios se asoció de forma significativa a un buen conocimiento de la seguridad de los antibióticos y del hecho de que no curan todas las infecciones. Los beta-lactámicos fueron los antimicrobianos que los encuestados habían usado con mayor frecuencia el año anterior, período durante el cual el 20% de ellos habían usado múltiples antibióticos. En comparación con las personas que disponían de seguro de salud privado, las que no lo tenían afirmaron con más frecuencia que los antibióticos son seguros y no tienen efectos colaterales y que la aspirina y el Benadryl son antibióticos. Conclusiones. En Trinidad y Tobago, el uso inapropiado de los antimicrobianos se debe a la automedicación, a la posibilidad de adquirirlos en las farmacias sin necesidad de receta médica, a la "demanda de prescripción" y a la ausencia de normas de control. Con el fin de reducir el abuso de antibióticos, la Inspección de Medicamentos del Ministerio de Salud y el Consejo de Farmacéuticos deben ejercer un control más estricto sobre la dispensación de antibióticos en las farmacias privadas. Además, se debe informar mejor al público en general y a los profesionales sanitarios acerca del uso de los antibióticos e instaurar un sistema basado en la comunidad para vigilar las tendencias de la resistencia a los antimicrobianos