San Francisco Coordinating Center

Berry Creek, CA, United States

San Francisco Coordinating Center

Berry Creek, CA, United States
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Yaffe K.,University of California at San Francisco | Yaffe K.,San Francisco Veterans Affairs Medical Center | Laffan A.M.,San Francisco Coordinating Center | Harrison S.L.,San Francisco Coordinating Center | And 5 more authors.
JAMA - Journal of the American Medical Association | Year: 2011

Context: Sleep-disordered breathing (characterized by recurrent arousals from sleep and intermittent hypoxemia) is common among older adults. Cross-sectional studies have linked sleep-disordered breathing to poor cognition; however, it remains unclear whether sleep-disordered breathing precedes cognitive impairment in older adults. Objectives: To determine the prospective relationship between sleep-disordered breathing and cognitive impairment and to investigate potential mechanisms of this association. Design, Setting, and Participants: Prospective sleep and cognition study of 298 women without dementia (mean [SD] age: 82.3 [3.2] years) who had overnight polysomnography measured between January 2002 and April 2004 in a substudy of the Study of Osteoporotic Fractures. Sleep-disordered breathing was defined as an apneahypopnea index of 15 or more events per hour of sleep. Multivariate logistic regression was used to determine the independent association of sleep-disordered breathing with risk of mild cognitive impairment or dementia, adjusting for age, race, body mass index, education level, smoking status, presence of diabetes, presence of hypertension, medication use (antidepressants, benzodiazepines, or nonbenzodiazepine anxiolytics), and baseline cognitive scores. Measures of hypoxia, sleep fragmentation, and sleep duration were investigated as underlying mechanisms for this relationship. Main Outcome Measures: Adjudicated cognitive status (normal, dementia, or mild cognitive impairment) based on data collected between November 2006 and September 2008. Results: Compared with the 193 women without sleep-disordered breathing, the 105 women (35.2%) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (31.1% [n=60] vs 44.8% [n=47]; adjusted odds ratio [AOR], 1.85; 95% confidence interval [CI], 1.11-3.08). Elevated oxygen desaturation index (≥15 events/hour) and high percentage of sleep time (>7%) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR, 1.71 [95% CI, 1.04-2.83] and AOR, 2.04 [95% CI, 1.10-3.78], respectively). Measures of sleep fragmentation (arousal index and wake after sleep onset) or sleep duration (total sleep time) were not associated with risk of cognitive impairment. Conclusion: Among older women, those with sleep-disordered breathing compared with those without sleep-disordered breathing had an increased risk of developing cognitive impairment. ©2011 American Medical Association. All rights reserved.


Arasu A.,University of California at San Francisco | Cawthon P.M.,San Francisco Coordinating Center | Cawthon P.M.,California Pacific Medical Center Research Institute | Lui L.-Y.,San Francisco Coordinating Center | And 7 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Sclerostin, a protein secreted by osteocytes, inhibits bone formation. Individuals with genetic mutations that decrease the availability of sclerostin have very high bone mass. Objective: The aim of this study was to examine the hypothesis that elevated serum sclerostin levels are associated with increased risk of hip fracture in older women. Design, Setting, and Participants: This was a case-cohort study of a prospective, community-based cohort of 9704 women aged 65 yr or older. Sclerostin levels were measured in serum collected in 1989-1990 in 228 women with incident hip fractures and 227 women in a randomly selected sample; average follow-up time was 9.8 yr. Results: Serum sclerostin levels were correlated with total hip bone mineral density (BMD; r=0.27, P<0.001). The risk of hip fracture increased across quartiles of serum sclerostin (test for trend, P< 0.001) and was significantly elevated among those in the fourth quartile (hazard risk 3.4, 95% confidence interval 1.7-7.0) compared with women in the lowest quartile, after adjusting for age, body mass index, estrogen use, history of fracture since age 50 yr, and total hip BMD. When dividing the cohort into eight groups by sclerostin quartile and median hip BMD, women with lower total hip BMD in the highest sclerostin quartile had a 22.3-fold (95% confidence interval 5.8-86.3) increased risk of fracture compared with women with higher total hip BMD in the lowest sclerostin quartile. Conclusions: We conclude that higher serum sclerostin levels are associated with a greater risk of hip fractures in older women. In addition, the risk of hip fracture is amplified when high sclerostin levels are combined with lower BMD. Copyright © 2012 by The Endocrine Society.


Black D.M.,University of California at San Francisco | Reid I.R.,University of Auckland | Cauley J.A.,University of Pittsburgh | Cosman F.,Helen Hayes Hospital | And 9 more authors.
Journal of Bone and Mineral Research | Year: 2015

While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double-blind study, 190 women were randomized to Z9 (n = 95) and Z6P3 (n = 95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: -0.37%, 1.93%; p = 0.183). BTMs showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits. © 2015 American Society for Bone and Mineral Research. © 2014 American Society for Bone and Mineral Research.


Lang T.,University of California at San Francisco | Cauley J.A.,University of Pittsburgh | Tylavsky F.,University of Tennessee Health Science Center | Bauer D.,University of California at San Francisco | And 2 more authors.
Journal of Bone and Mineral Research | Year: 2010

Fatty infiltration of muscle, myosteatosis, increases with age and results in reduced muscle strength and function and increased fall risk. However, it is unknown if increased fatty infiltration of muscle predisposes to hip fracture. We measured the mean Hounsfield unit (HU) of the lean tissue within the midthigh muscle bundle (thigh muscle HU, an indicator of intramuscular fat), its cross-sectional area (CSA, a measure of muscle mass) by computed tomography (CT), bone mineral density (BMD) of the hip and total-body percent fat by dual X-ray absorptiometry (DXA), isokinetic leg extensor strength, and the Short Physical Performance Battery (SPPB) in 2941 white and black women and men aged 70 to 79 years. Sixty-three hip fractures were validated during 6.6 years of follow-up. Proportional hazards regression analysis was used to assess the relative risk (RR) of hip fracture across variations in thigh muscle attenuation, CSA, muscle strength, and physical function for hip fracture. In models adjusted by age, race, gender, body mass index, and percentage fat, decreased thigh muscle HU resulted in increased risk of hip fracture [RR/SD=1.58; 95% confidence interval (CI) 1.10-1.99], an association that continued to be significant after further adjustment for BMD. In models additionally adjusted by CSA, muscle strength, and SPPB score, decreased thigh muscle HU but none of the other muscle parameters continued to be associated with an increased risk of hip fracture (RR/SD=1.42; 95% CI 1.03-1.97). Decreased thigh muscle HU, a measure of fatty infiltration of muscle, is associated with increased risk of hip fracture and appears to account for the association between reduced muscle strength, physical performance, and muscle mass and risk of hip fracture. This characteristic captures a physical characteristic of muscle tissue that may have importance in hip fracture etiology. © 2010 American Society for Bone and Mineral Research.


Wang X.,University of California at Berkeley | Sanyal A.,University of California at Berkeley | Cawthon P.M.,San Francisco Coordinating Center | Palermo L.,University of California at San Francisco | And 7 more authors.
Journal of Bone and Mineral Research | Year: 2012

Vertebral strength, as estimated by finite element analysis of computed tomography (CT) scans, has not yet been compared against areal bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) for prospectively assessing the risk of new clinical vertebral fractures. To do so, we conducted a case-cohort analysis of 306 men aged 65 years and older, which included 63 men who developed new clinically-identified vertebral fractures and 243 men who did not, all observed over an average of 6.5 years. Nonlinear finite element analysis was performed on the baseline CT scans, blinded to fracture status, to estimate L1 vertebral compressive strength and a load-to-strength ratio. Volumetric BMD by quantitative CT and areal BMD by DXA were also evaluated. We found that, for the risk of new clinical vertebral fracture, the age-adjusted hazard ratio per standard deviation change for areal BMD (3.2; 95% confidence interval [CI], 2.0-5.2) was significantly lower (p<0.005) than for strength (7.2; 95% CI, 3.6-14.1), numerically lower than for volumetric BMD (5.7; 95% CI, 3.1-10.3), and similar for the load-to-strength ratio (3.0; 95% CI, 2.1-4.3). After also adjusting for race, body mass index (BMI), clinical center, and areal BMD, all these hazard ratios remained highly statistically significant, particularly those for strength (8.5; 95% CI, 3.6-20.1) and volumetric BMD (9.4; 95% CI, 4.1-21.6). The area-under-the-curve for areal BMD (AUC=0.76) was significantly lower than for strength (AUC=0.83, p=0.02), volumetric BMD (AUC=0.82, p=0.05), and the load-to-strength ratio (AUC=0.82, p=0.05). We conclude that, compared to areal BMD by DXA, vertebral compressive strength and volumetric BMD consistently improved vertebral fracture risk assessment in this cohort of elderly men. Copyright © 2012 American Society for Bone and Mineral Research.


Premaor M.O.,Federal University of Santa Maria | Ensrud K.,University of Minnesota | Lui L.,California Pacific Medical Center Research Institute | Parker R.A.,University of Cambridge | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: A high prevalence of obesity has recently been reported in postmenopausal women with low trauma fracture, suggesting that higher bone mineral density (BMD) in obese individuals may not be protective against fracture. Objective: The aim of this study was to compare BMD and other risk factors for nonvertebral fracture in 1377 obese postmenopausal women. Design: Characteristics of obese women with and without incident nonvertebral fracture were investigated among the prospective cohort in the Study of Osteoporotic Fractures. Setting: The Study of Osteoporotic Fractures is a multicenter study of 9704 women (>99% Caucasian) aged 65 yr and over who were recruited between September 1986 and October 1988 from population-based listings at four U.S. clinical centers. Main Outcome Measure: The main outcome measure was nonvertebral fracture. Results: BMDT-scores in the spine, femoral neck, and total hip were significantly lower in obese women who experienced fractures than in obese women without fracture: mean differences, -0.56 [95% confidence interval (CI) = -0.73 to -0.39], -0.46 (95% CI = -0.57 to -0.36), and -0.51 (95% CI = -0.62 to -0.39), respectively (P < 0.0001 for all). A previous history of fracture [odds ratio = 1.69 (95% CI = 1.33-2.14); P < 0.0001] and femoral neck BMD [1.62 (95% CI = 1.42-1.85) per SD decrease in BMD; P < 0.0001] were independently associated with incident nonvertebral fracture. Conclusions: Obese postmenopausal women who sustain nonvertebral fractures have significantly lower BMD on average than obese women without fracture and are more likely to have a past history of fracture. Fractures in obese postmenopausal women thus exhibit some characteristics of fragility fractures. Copyright © 2011 by The Endocrine Society.


Premaor M.,Federal University of Santa Maria | Parker R.A.,University of Cambridge | Cummings S.,San Francisco Coordinating Center | Ensrud K.,University of Minnesota | And 4 more authors.
Journal of Bone and Mineral Research | Year: 2013

Recent studies indicate that obesity is not protective against fracture in postmenopausal women and increases the risk of fracture at some sites. Risk factors for fracture in obese women may differ from those in the nonobese. We aimed to compare the ability of FRAX with and without bone mineral density (BMD) to predict fractures in obese and nonobese older postmenopausal women who were participants in the Study of Osteoporotic Fractures. Data for FRAX clinical risk factors and femoral neck BMD were available in 6049 women, of whom 18.5% were obese. Hip fractures, major osteoporotic fractures, and any clinical fractures were ascertained during a mean follow-up period of 9.03 years. Receiving operator curve (ROC) analysis, model calibration, and decision curve analysis were used to compare fracture prediction in obese and nonobese women. ROC analysis revealed no significant differences between obese and nonobese women in fracture prediction by FRAX, with or without BMD. Predicted hip fracture risk was lower than observed risk in both groups of women, particularly when FRAX + BMD was used, but there was good calibration for FRAX + BMD in prediction of major osteoporotic fracture in both groups. Decision curve analysis demonstrated that both FRAX models were useful for hip fracture prediction in obese and nonobese women for threshold 10-year fracture probabilities in the range of 4% to 10%, although in obese women FRAX + BMD was superior to FRAX alone. For major osteoporotic fracture, both FRAX models were useful in both groups of women for threshold probabilities in the range of 10% to 30%. For all clinical fractures, the FRAX models were not useful at threshold probabilities below 30%. We conclude that FRAX is of value in predicting hip and major osteoporotic fractures in obese postmenopausal women, particularly when used with BMD. © 2013 American Society for Bone and Mineral Research.


Scheuermaier K.,Brigham and Women's Hospital | Scheuermaier K.,Harvard University | Laffan A.M.,Brigham and Women's Hospital | Laffan A.M.,San Francisco Coordinating Center | Duffy J.F.,Brigham and Women's Hospital
Journal of Biological Rhythms | Year: 2010

Aging is associated with an earlier timing of circadian rhythms and a shorter phase angle between wake time and the timing of melatonin secretion or the core body temperature nadir. Light has a phase-dependent effect on the circadian pacemaker, and modifications of habitual light exposure in older people could contribute to a change in the timing of circadian rhythms or in the phase angle of entrainment. In this study, we compare natural light exposure of community-dwelling older and young subjects studied at the same time of year, focusing on the pattern of light exposure across the waking day. We recorded light exposure data for 3 to 8 days from 22 older (aged 66.01 ± 5.83) and 22 young subjects (aged 23.41 ± 4.57), living at home on self-selected sleepwake schedules, and matched for time of year. All subjects were from New England (latitude 42.3° N to 43° N). We compared the percentage of the waking day spent by older and young subjects at 4 different light levels (from very dim to very bright). We compared hourly averaged light exposure data in each group according to clock time and with respect to each subjects daily sleepwake times. Although both age groups spent more than half of their waking hours in dim or moderate room light intensity (<100 lux), we found that the older subjects spent a significantly greater percentage of their waking day in the brighter light levels (≥1000 lux); their hourly averaged light exposure levels were also significantly greater whether we examined the data with respect to absolute clock time, to wake time, or to bed time, and this was true across all seasons. We found that healthy older people were exposed to significantly higher levels of light throughout their waking day than young people. Differences in natural light exposure may contribute to the age-related phase advance of the circadian pacemaker and its later timing relative to the sleepwake cycle. This hypothesis should be explored further in carefully designed prospective studies. © 2010 SAGE Publications.


Rowbotham M.C.,California Pacific Medical Center Research Institute | Astin J.,California Pacific Medical Center Research Institute | Greene K.,California Pacific Medical Center Research Institute | Cummings S.R.,California Pacific Medical Center Research Institute | Cummings S.R.,San Francisco Coordinating Center
PLoS ONE | Year: 2013

Informed consent is the cornerstone of human research subject protection. Many subjects sign consent documents without understanding the study purpose, procedures, risks, benefits, and their rights. Proof of comprehension is not required and rarely obtained. Understanding might improve by using an interactive system with multiple options for hearing, viewing and reading about the study and the consent form at the subject's own pace with testing and immediate feedback. This prospective randomized study compared the IRB-approved paper ICF for an actual clinical research study with an interactive presentation of the same study and its associated consent form using an iPad device in two populations: clinical research professionals, and patients drawn from a variety of outpatient practice settings. Of the 90 participants, 69 completed the online test and survey questions the day after the session (maximum 36 hours post-session). Among research professionals (n = 14), there was a trend (p =. 07) in the direction of iPad subjects testing better on the online test (mean correct = 77%) compared with paper subjects (mean correct = 57%). Among patients (n = 55), iPad subjects had significantly higher test scores than standard paper consent subjects (mean correct = 75% vs 58%, p <. 001). For all subjects, the total time spent reviewing the paper consent was 13.2 minutes, significantly less than the average of 22.7 minutes total on the three components to be reviewed using the iPad (introductory video, consent form, interactive quiz). Overall satisfaction and overall enjoyment slightly favored the interactive iPad presentation. This study demonstrates that combining an introductory video, standard consent language, and an interactive quiz on a tablet-based system improves comprehension of research study procedures and risks. © 2013 Rowbotham et al.


Kahn A.J.,San Francisco Coordinating Center | Kahn A.J.,Buck Institute for Research on Aging
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2015

In June 2013, a workshop was convened in San Francisco to explore, in depth, the role of the Forkhead transcription factor FOXO3 (and related FOXOs) in development, aging, and, in particular, exceptional longevity. The presentations covered results derived from model systems, computational analysis and bioinformatics, and genomics and genome-wide association studies of a number of cohorts. Although the data collectively strongly reinforce FOXO3 and the FOXO/FOXO3 pathway as very important determinants in aging and life span, much of the detail of how the latter is achieved still remains unknown, in part, because of the very large number of genes (∼2,200 in Caenorhabditis elegans) the transcription factor is involved in helping regulate. Particularly challenging at the present time is understanding the association of apparently nonfunctional specific variants (single nucleotide polymorphisms) of FOXO3 and exceptional longevity in humans, a finding replicated in a number of studies. Nonetheless, as summarized in this report, valuable information and insights were presented at the workshop on the transcription factor including but not limited to its role in determining longevity in C elegans and Drosophila (in flies, eg, an important interaction in aging occurs between dFOXO and the transforming growth factor-β/activin pathway), stem cell function and aging (notably in hematopoiesis), downstream regulatory activity (eg, by binding near sites of RNAse occupancy and altering chromatin structure), and as a potential target for the development a healthy aging drug (in this example, using compounds developed and screened to effect FOXO function in cancer cells). © 2014 The Author.

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