Patterns of Sedentary Behavior and Mortality in U.S. Middle-Aged and Older Adults: A National Cohort Study

Background: Excessive sedentary time is ubiquitous in Western societies. Previous studies have relied on self-reporting to evaluate the total volume of sedentary time as a prognostic risk factor for mortality and have not examined whether the manner in which sedentary time is accrued (in short or long bouts) carries prognostic relevance. Objective: To examine the association between objectively measured sedentary behavior (its total volume and accrual in prolonged, uninterrupted bouts) and all-cause mortality. Design: Prospective cohort study. Setting: Contiguous United States. Participants: 7985 black and white adults aged 45 years or older. Measurements: Sedentary time was measured using a hip-mounted accelerometer. Prolonged, uninterrupted sedentariness was expressed as mean sedentary bout length. Hazard ratios (HRs) were calculated comparing quartiles 2 through 4 to quartile 1 for each exposure (quartile cut points: 689.7, 746.5, and 799.4 min/d for total sedentary time; 7.7, 9.6, and 12.4 min/bout for sedentary bout duration) in models that included moderate to vigorous physical activity. Results: Over a median follow-up of 4.0 years, 340 participants died. In multivariable-adjusted models, greater total sedentary time (HR, 1.22 [95% CI, 0.74 to 2.02]; HR, 1.61 [CI, 0.99 to 2.63]; and HR, 2.63 [CI, 1.60 to 4.30]; P for trend < 0.001) and longer sedentary bout duration (HR, 1.03 [CI, 0.67 to 1.60]; HR, 1.22 [CI, 0.80 to 1.85]; and HR, 1.96 [CI, 1.31 to 2.93]; P for trend < 0.001) were both associated with a higher risk for all-cause mortality. Evaluation of their joint association showed that participants classified as high for both sedentary characteristics (high sedentary time [≥12.5 h/d] and high bout duration [≥10 min/bout]) had the greatest risk for death. Limitation: Participants may not be representative of the general U.S. population. Conclusion: Both the total volume of sedentary time and its accrual in prolonged, uninterrupted bouts are associated with all-cause mortality, suggesting that physical activity guidelines should target reducing and interrupting sedentary time to reduce risk for death

Association Between Objectively Measured Physical Activity and Cognitive Function in Older Adults—The Reasons for Geographic and Racial Differences in Stroke Study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116310/1/jgs13829_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/116310/2/jgs13829.pd

Patterns of Sedentary Behavior in US Middle-Age and Older Adults: The REGARDS Study

Purpose The purpose of this study was to examine patterns of objectively-measured sedentary behavior in a national cohort of U.S. middle-aged and older adults and determine factors that influence prolonged sedentary behavior. Methods We studied 8,096 participants from the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study, a population-based study of black and white adults ≥45 years. Seven-day accelerometry was conducted. Prolonged sedentary behavior was defined as accumulating ≥50% of total sedentary time in bouts ≥30 min. Results The number of sedentary bouts ≥20, ≥30, ≥60, and ≥90 min were 8.8 ± 2.3, 5.5 ± 1.9, 1.9 ± 1.1, and 0.8 ± 0.7 bouts/day, respectively. Sedentary bouts ≥20, ≥30, ≥60, and ≥90 min accounted for 60.0 ± 13.9%, 48.0 ± 15.5%, 26.0 ± 15.4%, and 14.2 ± 12.9% of total sedentary time, respectively. Several factors were associated with prolonged sedentary behavior in multivariate-adjusted models (Odds Ratio [95% CI]): older age (65-74 years: 1.99 [1.55-2.57]; ≥75 years: 4.68 [3.61-6.07] vs. 45-54 years), male sex (1.41 [1.28-1.56] vs. female), residence in non-stroke belt/buckle region of U.S. (stroke belt: 0.87 [0.77-0.98]; stroke buckle: 0.86 [0.77-0.95] vs. non-belt/buckle), body mass index (BMI) (overweight: 1.33 [1.18-1.51]; obese: 2.15 [1.89-2.44] vs. normal weight), winter (1.18 [1.03-1.35] vs. summer), and low amounts of moderate-vigorous physical activity (MVPA) [0 min/week: 2.00 [1.66-2.40] vs. ≥150 min/week). Conclusions In this sample of U.S. middle-aged and older adults, a large proportion of total sedentary time was accumulated in prolonged, uninterrupted bouts of sedentary behavior as almost one-half was accumulated in sedentary bouts ≥30 min. Several sociodemographic (age, sex, BMI), behavioral (MVPA), environmental (region), and seasonal factors are associated with patterns of prolonged sedentary behavior

Cardiorespiratory Fitness as a Predictor of Fatal and Nonfatal Stroke in Asymptomatic Women and Men

Background and Purpose - Prospective data on the association between cardiorespiratory fitness (CRF) and stroke are largely limited to studies in men or do not separately examine risks for fatal and nonfatal stroke. This study examined the association between CRF and fatal and nonfatal stroke in a large cohort of asymptomatic women and men. Methods - A total of 46,405 men and 15,282 women without known myocardial infarction or stroke at baseline completed a maximal treadmill exercise test between 1970 and 2001. CRF was grouped as quartiles of the sex-specific distribution of maximal metabolic equivalents achieved. Mortality follow-up was through December 31, 2003, using the National Death Index. Nonfatal stroke, defined as physician-diagnosed stroke, was ascertained from surveys during 1982 to 2004. Cox regression models quantified the pattern and magnitude of association between CRF and stroke. Results - There were 692 strokes during 813,944 man-years of exposure and 171 strokes during 248,902 woman-years of exposure. Significant inverse associations between CRF and age-adjusted fatal, nonfatal, and total stroke rates were observed for women and men (Ptrend≤0.05 each). After adjusting for several cardiovascular disease risk factors, the inverse association between CRF and each stroke outcome remained significant (Ptrend\u3c0.05 each) in men. In women, the multivariable-adjusted relationship between CRF and nonfatal and total stroke remained significant (Ptrend≤0.01 each), but not between CRF and fatal stroke (Ptrend=0.18). A CRF threshold of 7 to 8 maximal metabolic equivalents was associated with a substantially reduced rate of total stroke in both men and women. Conclusions - These findings suggest that CRF is an independent determinant of stroke incidence in initially asymptomatic and cardiovascular disease-free adults, and the strength and pattern of the association is similar for men and women

DNA Fragmentation Simulation Method (FSM) and Fragment Size Matching Improve aCGH Performance of FFPE Tissues

Whole-genome copy number analysis platforms, such as array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays, are transformative research discovery tools. In cancer, the identification of genomic aberrations with these approaches has generated important diagnostic and prognostic markers, and critical therapeutic targets. While robust for basic research studies, reliable whole-genome copy number analysis has been unsuccessful in routine clinical practice due to a number of technical limitations. Most important, aCGH results have been suboptimal because of the poor integrity of DNA derived from formalin-fixed paraffin-embedded (FFPE) tissues. Using self-hybridizations of a single DNA sample we observed that aCGH performance is significantly improved by accurate DNA size determination and the matching of test and reference DNA samples so that both possess similar fragment sizes. Based on this observation, we developed a novel DNA fragmentation simulation method (FSM) that allows customized tailoring of the fragment sizes of test and reference samples, thereby lowering array failure rates. To validate our methods, we combined FSM with Universal Linkage System (ULS) labeling to study a cohort of 200 tumor samples using Agilent 1 M feature arrays. Results from FFPE samples were equivalent to results from fresh samples and those available through the glioblastoma Cancer Genome Atlas (TCGA). This study demonstrates that rigorous control of DNA fragment size improves aCGH performance. This methodological advance will permit the routine analysis of FFPE tumor samples for clinical trials and in daily clinical practice

BRAF V600E Mutations Are Common in Pleomorphic Xanthoastrocytoma: Diagnostic and Therapeutic Implications

Pleomorphic xanthoastrocytoma (PXA) is low-grade glial neoplasm principally affecting children and young adults. Approximately 40% of PXA are reported to recur within 10 years of primary resection. Upon recurrence, patients receive radiation therapy and conventional chemotherapeutics designed for high-grade gliomas. Genetic changes that can be targeted by selective therapeutics have not been extensively evaluated in PXA and ancillary diagnostic tests to help discriminate PXA from other pleomorphic and often more aggressive astrocytic malignancies are limited. In this study, we apply the SNaPshot multiplexed targeted sequencing platform in the analysis of brain tumors to interrogate 60 genetic loci that are frequently mutated in 15 cancer genes. In our analysis we detect BRAF V600E mutations in 12 of 20 (60%) WHO grade II PXA, in 1 of 6 (17%) PXA with anaplasia and in 1 glioblastoma arising in a PXA. Phospho-ERK was detected in all tumors independent of the BRAF mutation status. BRAF duplication was not detected in any of the PXA cases. BRAF V600E mutations were identified in only 2 of 71 (2.8%) glioblastoma (GBM) analyzed, including 1 of 9 (11.1%) giant cell GBM (gcGBM). The finding that BRAF V600E mutations are common in the majority of PXA has important therapeutic implications and may help in differentiating less aggressive PXAs from lethal gcGBMs and GBMs

BRAF V600E Mutations Are Common in Pleomorphic Xanthoastrocytoma: Diagnostic and Therapeutic Implications

Pleomorphic xanthoastrocytoma (PXA) is low-grade glial neoplasm principally affecting children and young adults. Approximately 40% of PXA are reported to recur within 10 years of primary resection. Upon recurrence, patients receive radiation therapy and conventional chemotherapeutics designed for high-grade gliomas. Genetic changes that can be targeted by selective therapeutics have not been extensively evaluated in PXA and ancillary diagnostic tests to help discriminate PXA from other pleomorphic and often more aggressive astrocytic malignancies are limited. In this study, we apply the SNaPshot multiplexed targeted sequencing platform in the analysis of brain tumors to interrogate 60 genetic loci that are frequently mutated in 15 cancer genes. In our analysis we detect BRAF V600E mutations in 12 of 20 (60%) WHO grade II PXA, in 1 of 6 (17%) PXA with anaplasia and in 1 glioblastoma arising in a PXA. Phospho-ERK was detected in all tumors independent of the BRAF mutation status. BRAF duplication was not detected in any of the PXA cases. BRAF V600E mutations were identified in only 2 of 71 (2.8%) glioblastoma (GBM) analyzed, including 1 of 9 (11.1%) giant cell GBM (gcGBM). The finding that BRAF V600E mutations are common in the majority of PXA has important therapeutic implications and may help in differentiating less aggressive PXAs from lethal gcGBMs and GBMs

Pilot Study of Return of Genetic Results to Patients in Adult Nephrology

Background and objectives: Actionable genetic findings have implications for care of patients with kidney disease, and genetic testing is an emerging tool in nephrology practice. However, there are scarce data regarding best practices for return of results and clinical application of actionable genetic findings for kidney patients. Design, setting, participants and measurements: We developed a Return of Results workflow in collaborations with clinicians for the retrospective re-contact of adult nephrology patients who had been recruited into a biobank research study for exome sequencing and were identified to have medically actionable genetic findings. Results: Using this workflow, we attempted to re-contact a diverse pilot cohort of 104 nephrology research participants with actionable genetic findings encompassing 34 different monogenic etiologies of nephropathy and five single-gene disorders recommended by the American College of Medical Genetics and Genomics for return as medically actionable secondary findings. We successfully re-contacted 64 (62%) participants and returned results to 41 (39%) individuals. In each case, the genetic diagnosis had meaningful implications for the patients’ nephrology care. Through implementation efforts and qualitative interviews with providers, we identified over 20 key challenges associated with returning results to study participants, and found that physician knowledge gaps in genomics was a recurrent theme. We iteratively addressed these challenges to yield an optimized workflow, which included standardized consultation notes with tailored management recommendations, monthly educational conferences on core topics in genomics, and a curated list of expert clinicians for cases requiring extra-nephrologic referrals. Conclusions: Developing the infrastructure to support return of genetic results in nephrology was resource-intensive, but presented potential opportunities for improving patient care