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1.
Artigo em Inglês | MEDLINE | ID: mdl-31621207

RESUMO

BACKGROUND: Muscle mass declines with age. However, common assessments used to quantify muscle mass are indirect. The D3 -creatine (D3 Cr) dilution method is a direct assessment of muscle mass; however, longitudinal changes have not been examined in relation to changes in other measures of muscle mass, strength, and performance. METHODS: A convenience sample of 40 men from the Osteoporotic Fractures in Men Study (mean age = 83.3 years, standard deviation = 3.9) underwent repeat assessment of D3 Cr muscle mass, dual-energy X-ray absorptiometry (DXA) lean mass, grip strength, and walking speed at two time points approximately 1.6 years apart (2014-2016). One-sample t-tests and Pearson correlations were used to examine changes in DXA total body lean mass, DXA appendicular lean mass/height2 , DXA appendicular lean mass/weight, D3 Cr muscle mass, D3 Cr muscle mass/weight, grip strength, walking speed, and weight. RESULTS: D3 -creatine muscle mass, D3 Cr muscle mass/weight, grip strength, and walking speed all significantly declined (all P < 0.01). The change in DXA measures of lean mass was moderately correlated with changes in D3 Cr muscle mass. There was no significant correlation between the change in DXA measures of lean mass and change in walking speed (all P > 0.05). The change in D3 Cr muscle mass/weight was moderately correlated with change in walking speed (r = 0.33, P < .05). The change in grip strength was weakly correlated with the change in DXA measures of lean mass and D3 Cr muscle mass (r = 0.19-0.32). CONCLUSIONS: The results of our study provide new insights regarding the decline in muscle strength and D3 Cr muscle mass. The D3 Cr method may be a feasible tool to measure declines in muscle mass over time.

2.
Am J Clin Nutr ; 110(4): 1003-1014, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504105

RESUMO

BACKGROUND: While the gut microbiota is relatively stable through adulthood, its composition is influenced by various host and environmental factors, including changes in health, gastrointestinal processes (e.g., transit time, gastric acidity), medication use, and diet. The association of habitual diet, in the form of a posteriori-derived dietary patterns, and microbiota composition has not been adequately studied, particularly in older men. OBJECTIVE: The objective was to investigate the association of dietary patterns with the composition and diversity of the gut bacterial microbiota in community-dwelling, older men. METHODS: This cross-sectional study included 517 men who were participants in the Osteoporotic Fractures in Men (MrOS) Study (≥65 y of age at baseline in 2000-2002) and who provided a stool sample and completed an FFQ at MrOS Visit 4 in 2014-2016. Dietary patterns were derived by factor analysis. 16S ribosomal RNA target gene sequencing was performed and taxonomy assignments were derived using the Greengenes database. Linear regression and permutational multivariate analysis of variance (PERMANOVA) considered variations in alpha and beta diversity by dietary pattern, and a model that implements a 0-inflated Gaussian distribution of mean group abundance for each taxa (metagenomeSeq) assessed taxonomic variations by dietary pattern. RESULTS: In multivariable-adjusted models, greater adherence to the Western pattern was positively associated with families Mogibacteriaceae and Veillonellaceae and genera Alistipes, Anaerotruncus, CC-115, Collinsella, Coprobacillus, Desulfovibrio, Dorea, Eubacterium, and Ruminococcus, while greater adherence to the prudent pattern was positively associated with order Streptophyta, family Victivallaceae, and genera Cetobacterium, Clostridium, Faecalibacterium, Lachnospira, Paraprevotella, and Veillonella. The relative abundance of the dominant gut bacterial phyla, Bacteroidetes and Firmicutes, did not differ between participants with greater adherence to the Western pattern, compared with those with greater adherence to the prudent pattern. Dietary patterns were not associated with measures of alpha diversity, but beta diversity measures were significantly associated with both Western and prudent patterns. CONCLUSIONS: We observed significant associations between dietary patterns and measures of gut microbial composition in this sample of community-dwelling, older men.

3.
Am J Epidemiol ; 188(6): 991-1012, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31155658

RESUMO

The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).

4.
Bone ; 126: 18-26, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30954730

RESUMO

Proteins are an essential part of essentially all biological processes, and there is enormous variation in protein forms and concentrations that is not reflected in DNA or RNA. Recently there have been rapid advances in the ability to measure protein sequence, modification and concentration, particularly with methods based in mass spectrometry. Global measures of proteins in tissues or in the circulation provide a broad assessment of the proteome that can be extremely useful for discovery, and targeted proteomic measures can yield specific and sensitive assessments of specific peptides and proteins. While most proteomic measures are directed at the detection of consensus peptide sequences, mass spectrometry based proteomic methods also allow a detailed examination of the peptide sequence differences that result from genetic variants and that may have important effects on protein function. In evaluating proteomic data, a number of analytical considerations are important, including an understanding of missing data, the challenge of multiple testing and replication, and the use of rapidly evolving methods in systems biology. While proteomics has not yet had a major impact in skeletal research, interesting recent research has used these approaches in the study of bone cell biology and the discovery of biomarkers of skeletal disorders. Proteomics can be expected to have an increasing influence in the study of bone biology and pathophysiology.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30869772

RESUMO

BACKGROUND: Lack of consensus on how to diagnose sarcopenia has limited the ability to diagnose this condition and hindered drug development. The Sarcopenia Definitions and Outcomes Consortium (SDOC) was formed to develop evidence-based diagnostic cut-points for lean mass and/or muscle strength that identify people at increased risk of mobility disability. We describe here the proceedings of a meeting of SDOC and other experts to discuss strategic considerations in the development of evidence-based sarcopenia definition. METHODS: Presentations and panel discussions reviewed the usefulness of sarcopenia as a biomarker, the analytical approach used by SDOC to establish cut-points, preliminary findings, and provided strategic direction to develop an evidence-based definition of sarcopenia. RESULTS: The SDOC assembled data from 8 Epidemiologic Cohorts consisting of 18,831 participants; clinical populations from 10 randomized trials and observational studies; and 2 nationally representative cohorts. In preliminary assessments, grip strength or grip strength/body mass index (BMI) were identified as discriminators of risk for mobility disability (walking speed<0.8 m/sec), while DXA-derived lean mass measures were not good discriminators of mobility disability. Candidate definitions based on grip strength variables were associated with increased risk of mortality, falls, mobility disability and instrumental activities of daily living (IADL) disability. The prevalence of low grip strength increased with age. The attendees recommended the establishment of an International Expert panel to review a series of position statements on sarcopenia definition that are informed by the findings of the SDOC analyses and synthesis of literature. CONCLUSIONS: International consensus on an evidence-based definition of sarcopenia is needed. Grip strength - absolute or adjusted for BMI - is an important discriminator of mobility disability and other endpoints. Additional research is needed to develop a predictive risk model that takes into account sarcopenia components as well as age, sex, and race, and comorbidities.

6.
J Cachexia Sarcopenia Muscle ; 10(1): 14-21, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30900400

RESUMO

Sarcopenia has been described as the age-associated decrease in skeletal muscle mass. However, virtually every study of sarcopenia has measured lean body mass (LBM) or fat free mass (FFM) rather than muscle mass, specifically. In a number of published sarcopenia studies, LBM or FFM is referred to as muscle mass, leading to an incorrect assumption that measuring LBM or FFM is an accurate measure of muscle mass. As a result, the data on the effects of changes in LBM or FFM in older populations on outcomes such as functional capacity, disability, and risk of injurious falls have been inconsistent resulting in the conclusion that muscle mass is only weakly related to these outcomes. We review and describe the assumptions for the most commonly used measurements of body composition. Dual-energy X-ray absorptiometry (DXA) has become an increasingly common tool for the assessment of LBM or FFM and appendicular lean mass as a surrogate, but inaccurate, measurement of muscle mass. Other previously used methods (total body water, bioelectric impedance, and imaging) also have significant limitations. D3 -Creatine (D3 -Cr) dilution provides a direct and accurate measurement of creatine pool size and skeletal muscle mass. In a recent study in older men (MrOS cohort), D3 -Cr muscle mass was associated with functional capacity and risk of injurious falls and disability, while assessments of LBM or appendicular lean mass by DXA were only weakly or not associated with these outcomes. Inaccurate measurements of muscle mass by DXA and other methods have led to inconsistent results and potentially erroneous conclusions about the importance of skeletal muscle mass in health and disease. The assessment of skeletal muscle mass using the D3 -Cr dilution method in prospective cohort studies may reveal sarcopenia as a powerful risk factor for late life disability and chronic disease.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30383210

RESUMO

Background: Physical performance and activity have both been linked to fall risk, but the way they are jointly associated with falls is unclear. We investigated how these two factors are related to incident falls in older men. Methods: In 2741 men (78.8±5 years) we evaluated the associations between activity and physical performance and how they jointly contributed to incident falls. Activity was assessed by accelerometry. Physical performance was measured by gait speed, dynamic balance (narrow walk), chair stand time, grip strength and leg power. Falls were ascertained by tri-annual questionnaires. Results: Men were grouped into four categories based on activity and performance levels. The greatest number of falls (36-43%) and the highest fall rate (4.7-5.4/year among those who fell) (depending on the performance test) occurred in men with low activity/low performance, but most falls (57-64%) and relatively high fall rates (3.0-4.35/year) occurred in the other groups (low activity/high performance, high activity/high performance and high activity/low performance; 70% of men were in these groups). There were interactions between activity, performance (gait speed, narrow walk) and incident falls (p=0.001-0.02); predicted falls/yr. were highest in men with low activity/low performance, but there was also a peak of predicted falls in those with high activity. Conclusions: In community-dwelling older men, many falls occur in those with the lowest activity/worst physical performance but fall risk is also substantial with better activity and performance. Activity/physical performance assessments may improve identification of older men at risk of falls, and allow individualized approaches to prevention.

9.
Artigo em Inglês | MEDLINE | ID: mdl-30401599

RESUMO

OBJECTIVES: There is growing evidence that urine cadmium is a temporally stable biomarker indicative of long-term cadmium exposure; however questions remain with regard to generalizability to older persons, the impact of changes in smoking behavior, and the degree of temporal stability when repeat sample collection spans years instead of weeks or months. METHODS: Using archived samples from cohorts of older men (Osteoporotic Fractures in Men (MrOS-US)) and women (Study of Osteoporotic Fractures (SOF)) (mean age = 80 at study visit 2), we analyzed two morning urine samples each from 39 men and 18 women with a diverse self-reported smoking history. For MrOS, samples were collected approximately 6 years apart, and 4 years apart for SOF. Intra-class correlations were computed to assess temporal stability, and adjusted for age and body mass index. RESULTS: The median creatinine-adjusted urinary cadmium levels (0.39 µg/g for men, 0.89 µg/g for women) were similar to levels expected for these age/sex groups in the US according to the National Health and Nutrition Examination Survey. The overall intra-class correlation was high (ICC = 0.85; 95% CI: 0.76-0.91) and similar between cohorts (MrOS: ICC = 0.74; 95% CI: 0.58-0.86; SOF: ICC = 0.81; 95% CI: 0.59-0.93), but slightly lower among those who stopped smoking between visits of sample collection (ICC = 0.64; 95% CI: 0.31-0.87) or among former smokers who quit prior to the first sample collection (ICC = 0.68; 95% CI: 0.25-0.93). CONCLUSIONS: We report good-to-excellent reproducibility of urine cadmium using morning urine samples collected 4-6 years apart from older men and women, but slightly lower correlations among those with a history of smoking. Single measures of urine cadmium are a reliable biomarker in older men and women.

10.
J Am Heart Assoc ; 7(16): e009172, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30369326

RESUMO

Background Visceral adipose tissue ( VAT ) and other measures of central obesity predict incident atherosclerotic cardiovascular disease ( ASCVD ) events in middle-aged individuals, but these associations are less certain in older individuals age 70 years and older. Our objective was to estimate the associations of VAT and the android-gynoid fat mass ratio, another measure of central obesity, with incident ASCVD events among a large cohort of older men. Methods and Results Two thousand eight hundred ninety-nine men (mean [ SD ] age 76.3 [5.5] years) enrolled in the Outcomes of Sleep Disorders in Older Men study had rigorous adjudication of incident ASCVD events (myocardial infarction, coronary heart disease death, or fatal or nonfatal stroke). We used proportional hazards models to estimate the hazard ratios for incident ASCVD per SD increase of VAT or android-gynoid fat mass ratio (measured at baseline with dual-energy absorptiometry), adjusted for age, race, education, systolic blood pressure, smoking status, oxidized low-density lipoprotein level, treatment for hypertension, statin use, aspirin use, presence of diabetes mellitus, and study enrollment site. Over a mean ( SD ) follow-up period of 7.9 (3.4) years, 424 men (14.6%) had an incident ASCVD event. Neither VAT nor android-gynoid fat mass ratio were associated with incident ASCVD events, either unadjusted or after multivariable-adjustment (hazard ratios [95% confidence interval ] per SD increase 1.02 [0.92-1.13] and 1.05 [0.95-1.17], respectively). Conclusions Central adipose tissue, as measured by VAT or android-gynoid fat mass ratio, was not associated with incident ASCVD events in this study of older men.

11.
Bone ; 120: 70-74, 2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30290234

RESUMO

Osteogenesis imperfecta [1] is a rare disorder of connective tissue caused by abnormalities in the synthesis or processing of type I collagen. Type I collagen is the most abundant type of collagen and is expressed in almost all connective tissues. Given that type I collagen interacts with other collagens based in the extracellular matrix (ECM), we hypothesized changes in type I collagen in OI would result in perturbations in the homeostasis of other collagen types. We measured serum biomarkers of several non-type I collagens in patients with mild (type I) and moderate-to-severe (type III/IV) OI. Compared to controls, those with moderate-to severe OI had a higher mean level of the synthesis markers of collagen III (ProC3) (P = 0.02), and levels of collagen V (ProC5) (P = 0.07) were slightly, but not significantly, higher. Degradation markers of collage type IV (C4M2) (P = 0.04) and type VI (C6M) (P = 0.003) were also higher. In each case, a test for trend suggested levels were higher in moderate-to-severe OI, intermediate in mild OI, and lowest in controls (P = 0.06-0.002). These changes supports the hypothesis that mutations in type I collagen induce a widespread alteration in the ECM, and that the diverse clinical manifestations of OI reflect an extensive disruption in ECM biology.

12.
J Bone Miner Res ; 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30320955

RESUMO

We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2 > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

13.
PLoS Genet ; 14(9): e1007601, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30261039

RESUMO

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10-8. Suggestive (p<5×10-7) and genome-wide significant (p<5×10-8) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10-10). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10-11), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10-19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10-13), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10-10). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

14.
J Bone Miner Res ; 33(12): 2150-2157, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30011086

RESUMO

Measures of muscle mass, strength, and function predict risk of incident fractures, but it is not known whether this risk information is additive to that from FRAX (fracture risk assessment tool) probability. In the Osteoporotic Fractures in Men (MrOS) Study cohorts (Sweden, Hong Kong, United States), we investigated whether measures of physical performance/appendicular lean mass (ALM) by DXA predicted incident fractures in older men, independently of FRAX probability. Baseline information included falls history, clinical risk factors for falls and fractures, femoral neck aBMD, and calculated FRAX probabilities. An extension of Poisson regression was used to investigate the relationship between time for five chair stands, walking speed over a 6 m distance, grip strength, ALM adjusted for body size (ALM/height2 ), FRAX probability (major osteoporotic fracture [MOF]) with or without femoral neck aBMD, available in a subset of n = 7531), and incident MOF (hip, clinical vertebral, wrist, or proximal humerus). Associations were adjusted for age and time since baseline, and are reported as hazard ratios (HRs) for first incident fracture per SD increment in predictor using meta-analysis. 5660 men in the United States (mean age 73.5 years), 2764 men in Sweden (75.4 years), and 1987 men in Hong Kong (72.4 years) were studied. Mean follow-up time was 8.7 to 10.9 years. Greater time for five chair stands was associated with greater risk of MOF (HR 1.26; 95% CI, 1.19 to 1.34), whereas greater walking speed (HR 0.85; 95% CI, 0.79 to 0.90), grip strength (HR 0.77; 95% CI, 0.72 to 0.82), and ALM/height2 (HR 0.85; 95% CI, 0.80 to 0.90) were associated with lower risk of incident MOF. Associations remained largely similar after adjustment for FRAX, but associations between ALM/height2 and MOF were weakened (HR 0.92; 95% CI, 0.85 to 0.99). Inclusion of femoral neck aBMD markedly attenuated the association between ALM/height2 and MOF (HR 1.02; 95% CI, 0.96 to 1.10). Measures of physical performance predicted incident fractures independently of FRAX probability. Whilst the predictive value of ALM/height2 was substantially reduced by inclusion of aBMD requires further study, these findings support the consideration of physical performance in fracture risk assessment. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

15.
Artigo em Inglês | MEDLINE | ID: mdl-29897420

RESUMO

Background: Direct assessment of skeletal muscle mass in older adults is clinically challenging. Relationships between lean mass and late-life outcomes have been inconsistent. The D3-creatine dilution method provides a direct assessment of muscle mass. Methods: Muscle mass was assessed by D3-creatine (D3Cr) dilution in 1,382 men (mean age, 84.2 yrs). Participants completed the Short Physical Performance Battery (SPPB); usual walking speed (6 meters); and DXA lean mass. Men self-reported mobility limitations (difficulty walking 2-3 blocks or climbing 10 steps); recurrent falls (2+); and serious injurious falls in the subsequent year. Across quartiles of D3Cr muscle mass/body mass, multivariate linear models calculated means for SPPB and gait speed; multivariate logistic models calculated odds ratios for incident mobility limitations or falls. Results: Compared to men in the highest quartile, those in the lowest quartile of D3Cr muscle mass/body mass had slower gait speed (Q1: 1.04 vs Q4: 1.17 m/s); lower SPPB (Q1: 8.4 vs Q4: 10.4 points); greater likelihood of incident serious injurious falls (OR Q1 vs Q4: 2.49, 95% CI: 1.37, 4.54); prevalent mobility limitation (OR Q1 vs Q4,: 6.1, 95%CI: 3.7, 10.3) and incident mobility limitation (OR Q1 vs Q4: 2.15 95% CI: 1.42, 3.26); p for trend <.001 for all. Results for incident recurrent falls were in the similar direction (p=0.156). DXA lean mass had weaker associations with the outcomes. Conclusions: Unlike DXA lean mass, low D3Cr muscle mass/body mass is strongly related to physical performance, mobility and incident injurious falls in older me.

16.
J Clin Endocrinol Metab ; 103(9): 3278-3288, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29955795

RESUMO

Context: The optimal measure of vitamin D status is unknown. Objective: To directly measure circulating free 25-hydroxyvitamin D [25(OH)D] concentrations and relationships to total 25(OH)D in a clinically diverse sample of humans. Design: Cross-sectional analysis. Setting: Seven academic sites. Patients: A total of 1661 adults: healthy (n = 279), prediabetic (n = 479), outpatients (n = 714), cirrhotic (n = 90), pregnant (n = 20), nursing home resident (n = 79). Interventions: Merge research data on circulating free 25(OH)D (directly-measured immunoassay), total 25(OH)D (liquid chromatography/tandem mass spectrometry), D-binding protein [DBP; by radial (polyclonal) immunodiffusion assay], albumin, creatinine, intact parathyroid hormone, and DBP haplotype. Main outcome measures: Distribution of free 25(OH)D (ANOVA with Bonferroni correction for post hoc comparisons) and relationships between free and total 25(OH)D (mixed-effects modeling incorporating clinical condition, DBP haplotype with sex, race, estimated glomerular filtration rate (eGFR), body mass index (BMI), and other covariates). Results: Free 25(OH)D was 4.7 ± 1.8 pg/mL (mean ± SD) in healthy persons and 4.3 ± 1.9 pg/mL in outpatients, with levels of 0.5 to 8.1 pg/mL and 0.9 to 8.1 pg/mL encompassing 95% of healthy persons and outpatients, respectively. Free 25(OH)D was higher in patients with cirrhosis (7.1 ± 3.0 pg/mL; P < 0.0033) and nursing home residents (7.9 ± 2.1 pg/mL; P < 0.0033) than in other groups and differed between whites and blacks (P < 0.0033) and between DBP haplotypes (P < 0.0001). Mixed-effects modeling of relationships between free and total 25(OH)D identified clinical conditions (patients with cirrhosis > nursing home residents > patients with prediabetes > outpatients > pregnant women) and BMI (lesser effect) as covariates affecting relationships but not eGFR, sex, race, or DBP haplotype. Conclusions: Total 25(OH)D, health condition, race, and DBP haplotype affected free 25(OH)D, but only health conditions and BMI affected relationships between total and free 25(OH)D. Clinical importance of free 25(OH)D needs to be established in studies assessing outcomes.

17.
J Bone Miner Res ; 33(10): 1859-1869, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29750848

RESUMO

Accelerated bone loss (ABL) shown on routine dual-energy X-ray absorptiometry (DXA) may be accompanied by microarchitectural changes, increased cortical porosity, and lower bone strength. To test this hypothesis, we performed a cross-sectional study and used high-resolution peripheral quantitative computed tomography (HR-pQCT) scans (Scanco Medical AG, Brüttisellen, Switzerland) to measure estimated bone strength and microarchitecture in the distal radius and distal and diaphyseal tibia. We studied 1628 men who attended the year 14 exam of the Osteoporotic Fractures in Men (MrOS) study. We retrospectively characterized areal bone mineral density (aBMD) change from the year 7 to year 14 exam in three categories: "accelerated" loss, ≥10% loss at either the total hip or femoral neck (n = 299, 18.4%); "expected" loss, <10% (n = 1061, 65.2%), and "maintained" BMD, ≥0% (n = 268, 16.5%). The ABL cut-off was a safety alert established for MrOS. We used regression models to calculate adjusted mean HR-pQCT parameters in men with ABL, expected loss, or maintained BMD. Men who experienced ABL were older and had a lower body mass index and aBMD and experienced greater weight loss compared with other men. Total volumetric BMD and trabecular and cortical volumetric BMD were lower in men with ABL compared with the expected or maintained group. Men with ABL had significantly lower trabecular bone volume fraction (BV/TV), fewer trabeculae, and greater trabecular separation at both the distal radius and tibia than men with expected loss or who maintained aBMD, all p trend <0.001. Men with ABL had lower cortical thickness and lower estimated bone strength, but there was no difference in cortical porosity except at the tibia diaphyseal site. In summary, men with ABL have lower estimated bone strength, poorer trabecular microarchitecture, and thinner cortices than men without ABL but have similar cortical porosity. These impairments may lead to an increased risk of fracture. © 2018 American Society for Bone and Mineral Research.

18.
Bone ; 113: 49-56, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29751130

RESUMO

High-resolution peripheral quantitative computed tomography (HR-pQCT) assesses both volumetric bone mineral density (vBMD) and trabecular and cortical microarchitecture. However, studies of the association of HR-pQCT parameters with fracture history have been small, predominantly limited to postmenopausal women, often performed limited adjustment for potential confounders including for BMD, and infrequently assessed strength or failure measures. We used data from the Osteoporotic Fractures in Men (MrOS) study, a prospective cohort study of community-dwelling men aged ≥65 years, to evaluate the association of distal radius, proximal (diaphyseal) tibia and distal tibia HR-pQCT parameters measured at the Year 14 (Y14) study visit with prior clinical fracture. The primary HR-pQCT exposure variables were finite element analysis estimated failure loads (EFL) for each skeletal site; secondary exposure variables were total vBMD, total bone area, trabecular vBMD, trabecular bone area, trabecular thickness, trabecular number, cortical vBMD, cortical bone area, cortical thickness, and cortical porosity. Clinical fractures were ascertained from questionnaires administered every 4 months between MrOS study baseline and the Y14 visit and centrally adjudicated by masked review of radiographic reports. We used multivariate-adjusted logistic regression to estimate the odds of prior clinical fracture per 1 SD decrement for each Y14 HR-pQCT parameter. Three hundred forty-four (19.2%) of the 1794 men with available HR-pQCT measures had a confirmed clinical fracture between baseline and Y14. After multivariable adjustment, including for total hip areal BMD, decreased HR-pQCT finite element analysis EFL for each site was associated with significantly greater odds of prior confirmed clinical fracture and major osteoporotic fracture. Among other HR-pQCT parameters, decreased cortical area appeared to have the strongest independent association with prior clinical fracture. Future studies should explore associations of HR-pQCT parameters with specific fracture types and risk of incident fractures and the impact of age and sex on these relationships.

19.
mSystems ; 3(3)2018 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29719869

RESUMO

Recent algorithmic advances in amplicon-based microbiome studies enable the inference of exact amplicon sequence fragments. These new methods enable the investigation of sub-operational taxonomic units (sOTU) by removing erroneous sequences. However, short (e.g., 150-nucleotide [nt]) DNA sequence fragments do not contain sufficient phylogenetic signal to reproduce a reasonable tree, introducing a barrier in the utilization of critical phylogenetically aware metrics such as Faith's PD or UniFrac. Although fragment insertion methods do exist, those methods have not been tested for sOTUs from high-throughput amplicon studies in insertions against a broad reference phylogeny. We benchmarked the SATé-enabled phylogenetic placement (SEPP) technique explicitly against 16S V4 sequence fragments and showed that it outperforms the conceptually problematic but often-used practice of reconstructing de novo phylogenies. In addition, we provide a BSD-licensed QIIME2 plugin (https://github.com/biocore/q2-fragment-insertion) for SEPP and integration into the microbial study management platform QIITA. IMPORTANCE The move from OTU-based to sOTU-based analysis, while providing additional resolution, also introduces computational challenges. We demonstrate that one popular method of dealing with sOTUs (building a de novo tree from the short sequences) can provide incorrect results in human gut metagenomic studies and show that phylogenetic placement of the new sequences with SEPP resolves this problem while also yielding other benefits over existing methods.

20.
J Bone Miner Res ; 33(7): 1291-1301, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29665068

RESUMO

Methods now exist for analyzing previously taken clinical computed tomography (CT) scans to measure a dual-energy X-ray absorptiometry (DXA)-equivalent bone mineral density (BMD) at the hip and a finite element analysis-derived femoral strength. We assessed the efficacy of this "biomechanical CT" (BCT) approach for identifying patients at high risk of incident hip fracture in a large clinical setting. Using a case-cohort design sampled from 111,694 women and men aged 65 or older who had a prior hip CT scan, a DXA within 3 years of the CT, and no prior hip fracture, we compared those with subsequent hip fracture (n = 1959) with randomly selected sex-stratified controls (n = 1979) and analyzed their CT scans blinded to all other data. We found that the age-, race-, and body mass index (BMI)-adjusted hazard ratio (HR; per standard deviation) for femoral strength was significant before (women: HR = 2.8, 95% confidence interval [CI] 2.2-3.5; men: 2.8, 2.1-3.7) and after adjusting also for the (lowest) hip BMD T-score by BCT (women: 2.1, 1.4-3.2; men: 2.7, 1.6-4.6). The hazard ratio for the hip BMD T-score was similar between BCT and DXA for both sexes (women: 2.1, 1.8-2.5 BCT versus 2.1, 1.7-2.5 DXA; men: 2.8, 2.1-3.8 BCT versus 2.5, 2.0-3.2 DXA) and was higher than for the (lowest) spine/hip BMD T-score by DXA (women: 1.6, 1.4-1.9; men: 2.1, 1.6-2.7). Compared with the latter as a clinical-practice reference and using both femoral strength and the hip BMD T-score from BCT, sensitivity for predicting hip fracture was higher for BCT (women: 0.66 versus 0.59; men: 0.56 versus 0.48), with comparable respective specificity (women: 0.66 versus 0.67; men: 0.76 versus 0.78). We conclude that BCT analysis of previously acquired routine abdominal or pelvic CT scans is at least as effective as DXA testing for identifying patients at high risk of hip fracture. © 2018 American Society for Bone and Mineral Research.

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