Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD.

Associations of steps per day and step intensity with the risk of cancer: Findings from the Women's Health Accelerometry Collaboration cohort.

OBJECTIVE: Accumulating more steps/day is associated with a lower risk of cancer mortality and composite cancer outcomes. However, less is known about the relationship of steps/day with the risk of multiple site-specific cancers. METHODS: This study included >22,000 women from the Women's Health Accelerometry Collaboration Cohort (2011-2022), comprised of women from the Women's Health Study and Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study. Steps/day and step intensity were collected with accelerometry. Incident cancer cases and deaths were adjudicated. Stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the associations of steps/day and step intensity with incident breast, colon, endometrial, lung, and ovarian cancers, a composite of 13 physical activity-related cancers, total invasive cancer, and fatal cancer. RESULTS: On average, women were 73.4 years old, accumulated 4993 steps/day, and had 7.9 years of follow-up. There were small nonsignificant inverse associations with the risks of colon cancer (HR = 0.94, 95% CI: 0.83, 1.05), endometrial cancer (HR = 0.91, 95% CI: 0.82, 1.01), and fatal cancer (HR = 0.95 95% CI: 0.90, 1.00) per 1000 steps/day. More minutes at ≥40 steps/min and a faster peak 10- and 30-min step cadence were associated with a lower risk of endometrial cancer, but findings were attenuated after adjustment for body mass index and steps/day. CONCLUSIONS: Among women 62-97 years, there were small nonsignificant inverse associations of colon, endometrial, and fatal cancer with more steps/day. Epidemiologic studies with longer follow-up and updated assessments are needed to further explore these associations.

Accelerometer-measured physical activity and postmenopausal breast cancer incidence in the Women's Health Accelerometry Collaboration.

BACKGROUND: Few studies have examined accelerometer-measured physical activity and incident breast cancer (BC). Thus, this study examined associations between accelerometer-measured vector magnitude counts per 15 seconds (VM/15s) and average daily minutes of light physical activity (LPA), moderate-to-vigorous PA (MVPA), and total PA (TPA) and BC risk among women in the Women's Health Accelerometry Collaboration (WHAC). METHODS: The WHAC comprised 21,089 postmenopausal women (15,375 from the Women's Health Study [WHS]; 5714 from the Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study [OPACH]). Women wore an ActiGraph GT3X+ on the hip for ≥4 days and were followed for 7.4 average years to identify physician-adjudicated in situ (n = 94) or invasive (n = 546) BCs. Multivariable stratified Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for tertiles of physical activity measures in association with incident BC overall and by cohort. Effect measure modification was examined by age, race/ethnicity, and body mass index (BMI). RESULTS: In covariate-adjusted models, the highest (vs. lowest) tertiles of VM/15s, TPA, LPA, and MVPA were associated with BC HRs of 0.80 (95% CI, 0.64-0.99), 0.84 (95% CI, 0.69-1.02), 0.89 (95% CI, 0.73-1.08), and 0.81 (95% CI, 0.64-1.01), respectively. Further adjustment for BMI or physical function attenuated these associations. Associations were more pronounced among OPACH than WHS women for VM/15s, MVPA, and TPA; younger than older women for MVPA; and women with BMI ≥30 than <30 kg/m2 for LPA. CONCLUSION: Greater levels of accelerometer-assessed PA were associated with lower BC risk. Associations varied by age and obesity and were not independent of BMI or physical function.

Physical activity and relationship to physical function, quality of life, and cognitive function in older patients with acute decompensated heart failure.

BACKGROUND: Volitional physical activity level is predictive of a variety of health outcomes, but has not been examined in patients recently hospitalized for acute decompensated HF (ADHF). METHODS: Ten to 14 days after index hospitalization for ADHF, 93 participants wore a wrist-mounted triaxial accelerometer (ActiGraph GT3X+) to objectively quantify sedentary behavior, light physical activity, and moderate-to-vigorous physical activity. Levels were compared to 2 groups of age-matched NHANES participants: healthy and chronic, stable HF. The relationship between physical activity levels and physical function [Short Physical Performance Battery (SPPB)], HF-specific quality-of-life (QOL) [Kansas City Cardiomyopathy Questionnaire (KCCQ)], and cognition [Montreal Cognitive Assessment (MOCA)] were examined. RESULTS: ADHF participants accumulated a median 1,008 (IQR 896, 1,109) minutes of sedentary time, 88 (57, 139) minutes of light physical activity, and 10 (6, 25) minutes of moderate-to-vigorous physical activity per day. Sedentary time, light physical activity, or moderate-to-vigorous activity did not differ by sex or EF subtype. ADHF participants spent only 9% of awake time nonsedentary, compared to 34% and 27% for healthy adults and adults with chronic, stable HF, respectively. Among ADHF participants, SPPB, KCCQ, and MOCA scores did not differ among quartiles of total physical activity. CONCLUSIONS: Older patients recently hospitalized for ADHF have very low levels of physical activity and high levels of sedentary time, both of which may be potential targets for interventions in this high-risk population. Physical activity level was not significantly associated with objectively measured physical function, QOL, or cognition, suggesting that this measure provides independent information regarding the patient experience of living with HF. TRIAL REGISTRATION: NCT02196038, https://clinicaltrials.gov/ct2/show/NCT02196038.

Prior psychosocial profile and perceived impact of the COVID-19 pandemic: insights from the Baltimore Longitudinal Study of Aging.

Stress, social isolation, and changes in health behaviors during the COVID-19 pandemic period may have a lasting influence on health. Here, the correlation between current or prior demographic, social and health related characteristics, including psychosocial factors with perceived impact of the COVID-19 pandemic assessed by questionnaire during the early pandemic period is evaluated among 770 participants of the Baltimore Longitudinal Study of Aging. In multinomial logistic regression models participants with higher pre-pandemic personal mastery, a construct related to self-efficacy, were more likely to report "both positive and negative" impact of the pandemic than a solely "negative" impact (OR: 2.17, 95% CI: 1.29-3.65). Higher perceived stress and frequent contact with family prior to the pandemic were also associated with pandemic impact. These observations highlight the relevance of psychosocial factors in the COVID-19 pandemic experience and identify characteristics that may inform interventions in future public health crises.

Physical inactivity and non-communicable disease burden in low-income, middle-income and high-income countries.

OBJECTIVES: Physical inactivity is a risk factor for premature mortality and several non-communicable diseases. The purpose of this study was to estimate the global burden associated with physical inactivity, and to examine differences by country income and region. METHODS: Population-level, prevalence-based population attributable risks (PAR) were calculated for 168 countries to estimate how much disease could be averted if physical inactivity were eliminated. We calculated PARs (percentage of cases attributable to inactivity) for all-cause mortality, cardiovascular disease mortality and non-communicable diseases including coronary heart disease, stroke, hypertension, type 2 diabetes, dementia, depression and cancers of the bladder, breast, colon, endometrium, oesophagus, stomach and kidney. RESULTS: Globally, 7.2% and 7.6% of all-cause and cardiovascular disease deaths, respectively, are attributable to physical inactivity. The proportions of non-communicable diseases attributable to physical inactivity range from 1.6% for hypertension to 8.1% for dementia. There was an increasing gradient across income groups; PARs were more than double in high-income compared with low-income countries. However, 69% of total deaths and 74% of cardiovascular disease deaths associated with physical inactivity are occurring in middle-income countries, given their population size. Regional differences were also observed, with the PARs occurring in Latin America/Caribbean and high-income Western and Asia-Pacific countries, and the lowest burden occurring in Oceania and East/Southeast Asia. CONCLUSION: The global burden associated with physical inactivity is substantial. The relative burden is greatest in high-income countries; however, the greatest number of people (absolute burden) affected by physical inactivity are living in middle-income countries given the size of their populations.

Device-measured physical activity, adiposity and mortality: a harmonised meta-analysis of eight prospective cohort studies.

BACKGROUND: The joint associations of total and intensity-specific physical activity with obesity in relation to all-cause mortality risk are unclear. METHODS: We included 34 492 adults (72% women, median age 62.1 years, 2034 deaths during follow-up) in a harmonised meta-analysis of eight population-based prospective cohort studies with mean follow-up ranging from 6.0 to 14.5 years. Standard body mass index categories were cross-classified with sample tertiles of device-measured total, light-to-vigorous and moderate-to-vigorous physical activity and sedentary time. In five cohorts with waist circumference available, high and low waist circumference was combined with tertiles of moderate-to-vigorous physical activity. RESULTS: There was an inverse dose-response relationship between higher levels of total and intensity-specific physical activity and mortality risk in those who were normal weight and overweight. In individuals with obesity, the inverse dose-response relationship was only observed for total physical activity. Similarly, lower levels of sedentary time were associated with lower mortality risk in normal weight and overweight individuals but there was no association between sedentary time and risk of mortality in those who were obese. Compared with the obese-low total physical activity reference, the HRs were 0.59 (95% CI 0.44 to 0.79) for normal weight-high total activity and 0.67 (95% CI 0.48 to 0.94) for obese-high total activity. In contrast, normal weight-low total physical activity was associated with a higher risk of mortality compared with the obese-low total physical activity reference (1.28; 95% CI 0.99 to 1.67). CONCLUSIONS: Higher levels of physical activity were associated with lower risk of mortality irrespective of weight status. Compared with obesity-low physical activity, there was no survival benefit of being normal weight if physical activity levels were low.

Changes in Body Composition Before and After Parkinson's Disease Diagnosis.

BACKGROUND: Weight loss is common in Parkinson's disease (PD). However, little is known about when it starts, how PD changes as it progresses, and whether there is a differential loss of lean or fat mass. The objective of this study was to examine how body composition changes before and after PD diagnosis. METHODS: In the Health, Aging, and Body Composition study (n = 3075; age range, 70-79 years), body composition was assessed using dual-energy x-ray absorptiometry on an annual or biennial basis from year 1 to year 10. For each PD case each year, we calculated the difference between their actual body composition measures and expected values had they not developed PD. Using linear mixed models with crossed random effects, we further examined the trend of change in body composition measures before and after PD diagnosis. RESULTS: A total of 80 PD cases were identified in this cohort. Compared with their expected values, PD cases began to lose total and fat mass about 6-7 years before diagnosis, although the differences were not statistically significant until 3-5 years after diagnosis. The loss was substantial and persistent, with statistically significant trends of loss for total body mass (P = 0.008), fat mass (P = 0.001), and percentage fat (P < 0.001). In comparison, lean mass was stable throughout the follow-up (P = 0.16). Overall, 96% of the body mass loss in PD cases was from the loss of fat mass. CONCLUSIONS: In this longitudinal analysis with objective measures of body composition, we found persistent weight loss in PD cases, predominantly in fat mass, starting a few years before diagnosis. © 2021 International Parkinson and Movement Disorder Society.

Relationships Between Level and Change in Sarcopenia and Other Body Composition Components and Adverse Health Outcomes: Findings from the Health, Aging, and Body Composition Study.

We investigated how baseline values and rates of decline in components of sarcopenia and other body composition parameters relate to adverse clinical outcomes using the Health, Aging, and Body Composition Study. 2689 participants aged 70-79 years were studied. Appendicular lean mass, whole body fat mass, and total hip BMD were ascertained using DXA; muscle strength by grip dynamometry; and muscle function by gait speed. Baseline values and 2-3 year conditional changes (independent of baseline) in each characteristic were examined as predictors of mortality, hospital admission, low trauma fracture, and recurrent falls in the subsequent 10-14 years using Cox regression (generalized estimating equations used for recurrent falls) with adjustment for sex, ethnicity, age, and potential confounders. Lower levels and greater declines in all parameters (excluding hip BMD level) were associated (p < 0.05) with increased rates of mortality; fully-adjusted hazard ratios per SD lower gait speed and grip strength were 1.27 (95% CI 1.19, 1.36) and 1.14 (1.07, 1.21), respectively. Risk factors of hospital admission included lower levels and greater declines in gait speed and grip strength, and greater declines in hip BMD. Lower levels and greater declines in fat mass and hip BMD were associated with low trauma fracture. Lower gait speed, higher fat mass, and both lower levels and greater declines in grip strength were related to recurrent falls. Lower baseline levels and greater declines in musculoskeletal parameters were related to adverse outcomes. Interventions to maximize peak levels in earlier life and reduce rates of age-related decline may reduce the burden of disease in this age group.

Revisiting the association of sedentary behavior and physical activity with all-cause mortality using a compositional approach: the Women's Health Study.

BACKGROUND: While physical activity has consistently been associated with decreased mortality rates, it remains unknown if there is a single "ideal" combination of time in physical activities of different intensities and sedentary behavior (SB) associated with the lowest rate. This study examined the associations of combinations of time in moderate-to-vigorous intensity (MVPA), higher-light intensity (HLPA), lower-light intensity activities (LLPA), and SB with mortality rates in older women. METHODS: This prospective cohort study included 16,676 older women from throughout the United States enrolled in the Women's Health Study. Women wore accelerometers on their hip from 2011 to 2015 and were followed through 2017 (mean (SD) of 4.3 (1.1) years). Deaths were confirmed with medical records, death certificates, or the National Death Index. Compositional Cox regression models were used. RESULTS: The mean (SD) age was 72 (5.7) years at accelerometer wear; 503 women died. Compared to the least active women (mean, 3 min/day MVPA, 27 min/day HLPA, 162 min/day LLPA, and 701 min/day SB): compositional models showed an inverse L-shaped dose-response association of MVPA replacing other behaviors with mortality rates mortality rates (P = .02); SB relative to LLPA, HLPA, and MVPA was directly associated with mortality rates in a curvilinear dose-response manner (P < .001); replacing 10 min of SB for MVPA (HR (95% CI) = .86 (.73-.98)) or for HLPA (HR (95% CI.94 (.88-1.00)) associated with 14 and 6% lower mortality rates, respectively; a 47% risk reduction (HR [95% CI] = .53 [.42-.64]) was observed among women meeting physical activity guidelines (mean, 36 min/day MVPA, 79 min/day HLPA, 227 min/day LLPA and 549 min/day SB); and similar mortality rate reductions of 43% (HR (95% CI) = .57 (.41-.73)) were observed with increases in HLPA and LLPA without increasing MVPA, e.g., reallocating SB to 90 min/day of HLPA plus 120 min/day of LLPA. CONCLUSIONS: There was no "ideal" combination of physical activities of different intensities and SB associated with the lowest mortality rates. Of particular relevance to older women, replacing SB with light intensity activity was associated with lower mortality rates, and "mixing and matching" times in different intensities yielded equivalent mortality risk reductions.

Joint association between accelerometry-measured daily combination of time spent in physical activity, sedentary behaviour and sleep and all-cause mortality: a pooled analysis of six prospective cohorts using compositional analysis.

OBJECTIVE: To examine the joint associations of daily time spent in different intensities of physical activity, sedentary behaviour and sleep with all-cause mortality. METHODS: Federated pooled analysis of six prospective cohorts with device-measured time spent in different intensities of physical activity, sedentary behaviour and sleep following a standardised compositional Cox regression analysis. PARTICIPANTS: 130 239 people from general population samples of adults (average age 54 years) from the UK, USA and Sweden. MAIN OUTCOME: All-cause mortality (follow-up 4.3-14.5 years). RESULTS: Studies using wrist and hip accelerometer provided statistically different results (I2=92.2%, Q-test p<0.001). There was no association between duration of sleep and all-cause mortality, HR=0.96 (95% CI 0.67 to 1.12). The proportion of time spent in moderate to vigorous physical activity was significantly associated with lower risk of all-cause mortality (HR=0.63 (95% CI 0.55 to 0.71) wrist; HR=0.93 (95% CI 0.87 to 0.98) hip). A significant association for the ratio of time spent in light physical activity and sedentary time was only found in hip accelerometer-based studies (HR=0.5, 95% CI 0.42 to 0.62). In studies based on hip accelerometer, the association between moderate to vigorous physical activity and mortality was modified by the balance of time spent in light physical activity and sedentary time. CONCLUSION: This federated analysis shows a joint dose-response association between the daily balance of time spent in physical activity of different intensities and sedentary behaviour with all-cause mortality, while sleep duration does not appear to be significant. The strongest association is with time spent in moderate to vigorous physical activity, but it is modified by the balance of time spent in light physical activity relative to sedentary behaviour.

Profiles of Accelerometry-Derived Physical Activity Are Related to Perceived Physical Fatigability in Older Adults.

Physical activity (PA) is associated with greater fatigability in older adults; little is known about magnitude, shape, timing and variability of the entire 24-h rest-activity rhythm (RAR) associated with fatigability. We identified which features of the 24-h RAR pattern were independently and jointly associated with greater perceived physical fatigability (Pittsburgh Fatigability Scale, PFS, 0-50) in older adults (n = 181, 71.3 ± 6.7 years). RARs were characterized using anti-logistic extended cosine models and 4-h intervals of PA means and standard deviations across days. A K-means clustering algorithm approach identified four profiles of RAR features: "Less Active/Robust", "Earlier Risers", "More Active/Robust" and "Later RAR". Quantile regression tested associations of each RAR feature/profile on median PFS adjusted for age, sex, race, body mass index and depression symptomatology. Later rise times (up mesor; ß = 1.38, p = 0.01) and timing of midpoint of activity (acrophase; ß = 1.29, p = 0.01) were associated with higher PFS scores. Lower PA between 4 a.m. and 8 a.m. was associated with higher PFS scores (ß = -4.50, p = 0.03). "Less Active/Robust" (ß = 6.14, p = 0.01) and "Later RAR" (ß = 3.53, p = 0.01) patterns were associated with higher PFS scores compared to "Earlier Risers". Greater physical fatigability in older adults was associated with dampened, more variable, and later RARs. This work can guide development of interventions aimed at modifying RARs to reduce fatigability in older adults.

Calibration and Cross-Validation of Accelerometer Cut-Points to Classify Sedentary Time and Physical Activity from Hip and Non-Dominant and Dominant Wrists in Older Adults.

Accelerometers' accuracy for sedentary time (ST) and moderate-to-vigorous physical activity (MVPA) classification depends on accelerometer placement, data processing, activities, and sample characteristics. As intensities differ by age, this study sought to determine intensity cut-points at various wear locations people more than 70 years old. Data from 59 older adults were used for calibration and from 21 independent participants for cross-validation purposes. Participants wore accelerometers on their hip and wrists while performing activities and having their energy expenditure measured with portable calorimetry. ST and MVPA were defined as ≤1.5 metabolic equivalents (METs) and ≥3 METs (1 MET = 2.8 mL/kg/min), respectively. Receiver operator characteristic (ROC) analyses showed fair-to-good accuracy (area under the curve [AUC] = 0.62-0.89). ST cut-points were 7 mg (cross-validation: sensitivity = 0.88, specificity = 0.80) and 1 count/5 s (cross-validation: sensitivity = 0.91, specificity = 0.96) for the hip; 18 mg (cross-validation: sensitivity = 0.86, specificity = 0.86) and 102 counts/5 s (cross-validation: sensitivity = 0.91, specificity = 0.92) for the non-dominant wrist; and 22 mg and 175 counts/5 s (not cross-validated) for the dominant wrist. MVPA cut-points were 14 mg (cross-validation: sensitivity = 0.70, specificity = 0.99) and 54 count/5 s (cross-validation: sensitivity = 1.00, specificity = 0.96) for the hip; 60 mg (cross-validation: sensitivity = 0.83, specificity = 0.99) and 182 counts/5 s (cross-validation: sensitivity = 1.00, specificity = 0.89) for the non-dominant wrist; and 64 mg and 268 counts/5 s (not cross-validated) for the dominant wrist. These cut-points can classify ST and MVPA in older adults from hip- and wrist-worn accelerometers.

Long-term rates of change in musculoskeletal aging and body composition: findings from the Health, Aging and Body Composition Study.

Musculoskeletal disorders are common among older people. Preventive strategies require understanding of age-related changes in strength, function and body composition, including how they interrelate. We have described, and examined associations between, 9-year changes in these parameters among 2917 Health, Aging and Body Composition Study participants (aged 70-79 years). Appendicular lean mass (ALM), whole body fat mass and total hip BMD were ascertained using DXA; muscle strength by grip dynamometry; and muscle function by gait speed. For each characteristic annualised percentage changes were calculated; measures of conditional change (independent of baseline) were derived and their interrelationships were examined using Pearson correlations; proportion of variance at 9-year follow-up explained by baseline level was estimated; and mean trajectories in relation to age were estimated using linear mixed models. Analyses were stratified by sex. Median [lower quartile, upper quartile] annual percentage declines were grip strength (1.5 [0.0, 2.9]), gait speed (2.0 [0.6, 3.7]), ALM (0.7 [0.1, 1.4]), fat mass (0.4 [- 1.1, 1.9]) and hip BMD (0.5 [0.0, 1.1]). Declines were linear for ALM and accelerated over time for other characteristics. Most conditional change measures were positively correlated, most strongly between ALM, fat mass and hip BMD (r > 0.28). Proportion of variation at follow-up explained by baseline was lower for grip strength and gait speed (39-52%) than other characteristics (69-86%). Strength and function declined more rapidly, and were less correlated between baseline and follow-up, than measures of body composition. Therefore, broader intervention strategies to prevent loss of strength and function in later life are required as those targeting body composition alone may be insufficient.

Fitness and Body Mass Index During Adolescence and Disability Later in Life: A Cohort Study.

Background: Low physical fitness, obesity, and the combination of the two in adolescence may be related to risk for disability in adulthood, but this has rarely been studied. Objective: To examine individual and combined associations of cardiorespiratory fitness and obesity in male adolescents with later receipt of a disability pension due to all and specific causes. Design: Population-based cohort study. Setting: Sweden. Participants: 1 079 128 Swedish adolescents aged 16 to 19 years who were conscripted into the military between 1972 and 1994. Measurements: Cardiorespiratory fitness and body mass index (BMI) were measured at conscription and were related to information on later receipt of a disability pension obtained from the Social Insurance Agency. Results: Over a median follow-up of 28.3 years, 54 304 men were granted a disability pension. Low cardiorespiratory fitness was strongly associated with later receipt of a disability pension due to all causes (hazard ratio, 3.74 [95% CI, 3.55 to 3.95] for lowest vs. highest fitness decile) and specific causes (psychiatric, musculoskeletal, injuries, nervous system, circulatory, and tumors). Obesity was associated with greater risk for receipt of a disability pension due to all and specific causes, with the greatest risks observed for class II and III obesity. Compared with being unfit, being moderately or highly fit was associated with attenuated risk for receipt of a disability pension across BMI categories. Limitation: The cohort did not include women, had data on smoking and alcohol intake only in a subsample, and lacked repeated measures of exposures and covariates. Conclusion: Low cardiorespiratory fitness, obesity, and the combination of the two were strongly associated with later chronic disability due to a wide range of diseases and causes. Although additional well-designed studies are required, these findings support the importance of high cardiorespiratory fitness and healthy body weight during adolescence to prevent later chronic disease. Primary Funding Source: Karolinska Institutet.

Relationship Between Poor Olfaction and Mortality Among Community-Dwelling Older Adults: A Cohort Study.

Background: Poor olfaction is common among older adults and has been linked to higher mortality. However, most studies have had a relatively short follow-up and have not explored potential explanations. Objective: To assess poor olfaction in relation to mortality in older adults and to investigate potential explanations. Design: Community-based prospective cohort study. Setting: 2 U.S. communities. Participants: 2289 adults aged 71 to 82 years at baseline (37.7% black persons and 51.9% women). Measurements: Brief Smell Identification Test in 1999 or 2000 (baseline) and all-cause and cause-specific mortality at 3, 5, 10, and 13 years after baseline. Results: During follow-up, 1211 participants died by year 13. Compared with participants with good olfaction, those with poor olfaction had a 46% higher cumulative risk for death at year 10 (risk ratio, 1.46 [95% CI, 1.27 to 1.67]) and a 30% higher risk at year 13 (risk ratio, 1.30 [CI, 1.18 to 1.42]). Similar associations were found in men and women and in white and black persons. However, the association was evident among participants who reported excellent to good health at baseline (for example, 10-year mortality risk ratio, 1.62 [CI, 1.37 to 1.90]) but not among those who reported fair to poor health (10-year mortality risk ratio, 1.06 [CI, 0.82 to 1.37]). In analyses of cause-specific mortality, poor olfaction was associated with higher mortality from neurodegenerative and cardiovascular diseases. Mediation analyses showed that neurodegenerative diseases explained 22% and weight loss explained 6% of the higher 10-year mortality among participants with poor olfaction. Limitation: No data were collected on change in olfaction and its relationship to mortality. Conclusion: Poor olfaction is associated with higher long-term mortality among older adults, particularly those with excellent to good health at baseline. Neurodegenerative diseases and weight loss explain only part of the increased mortality. Primary Funding Source: National Institutes of Health and Michigan State University.

Joint associations of accelero-meter measured physical activity and sedentary time with all-cause mortality: a harmonised meta-analysis in more than 44 000 middle-aged and older individuals.

OBJECTIVES: To examine the joint associations of accelerometer-measured physical activity and sedentary time with all-cause mortality. METHODS: We conducted a harmonised meta-analysis including nine prospective cohort studies from four countries. 44 370 men and women were followed for 4.0 to 14.5 years during which 3451 participants died (7.8% mortality rate). Associations between different combinations of moderate-to-vigorous intensity physical activity (MVPA) and sedentary time were analysed at study level using Cox proportional hazards regression analysis and summarised using random effects meta-analysis. RESULTS: Across cohorts, the average time spent sedentary ranged from 8.5 hours/day to 10.5 hours/day and 8 min/day to 35 min/day for MVPA. Compared with the referent group (highest physical activity/lowest sedentary time), the risk of death increased with lower levels of MVPA and greater amounts of sedentary time. Among those in the highest third of MVPA, the risk of death was not statistically different from the referent for those in the middle (16%; 95% CI 0.87% to 1.54%) and highest (40%; 95% CI 0.87% to 2.26%) thirds of sedentary time. Those in the lowest third of MVPA had a greater risk of death in all combinations with sedentary time; 65% (95% CI 1.25% to 2.19%), 65% (95% CI 1.24% to 2.21%) and 263% (95% CI 1.93% to 3.57%), respectively. CONCLUSION: Higher sedentary time is associated with higher mortality in less active individuals when measured by accelerometry. About 30-40 min of MVPA per day attenuate the association between sedentary time and risk of death, which is lower than previous estimates from self-reported data.

Association of Daily Step Count and Step Intensity With Mortality Among US Adults.

Importance: It is unclear whether the number of steps per day and the intensity of stepping are associated with lower mortality. Objective: Describe the dose-response relationship between step count and intensity and mortality. Design, Setting, and Participants: Representative sample of US adults aged at least 40 years in the National Health and Nutrition Examination Survey who wore an accelerometer for up to 7 days ( from 2003-2006). Mortality was ascertained through December 2015. Exposures: Accelerometer-measured number of steps per day and 3 step intensity measures (extended bout cadence, peak 30-minute cadence, and peak 1-minute cadence [steps/min]). Accelerometer data were based on measurements obtained during a 7-day period at baseline. Main Outcomes and Measures: The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular disease (CVD) and cancer mortality. Hazard ratios (HRs), mortality rates, and 95% CIs were estimated using cubic splines and quartile classifications adjusting for age; sex; race/ethnicity; education; diet; smoking status; body mass index; self-reported health; mobility limitations; and diagnoses of diabetes, stroke, heart disease, heart failure, cancer, chronic bronchitis, and emphysema. Results: A total of 4840 participants (mean age, 56.8 years; 2435 [54%] women; 1732 [36%] individuals with obesity) wore accelerometers for a mean of 5.7 days for a mean of 14.4 hours per day. The mean number of steps per day was 9124. There were 1165 deaths over a mean 10.1 years of follow-up, including 406 CVD and 283 cancer deaths. The unadjusted incidence density for all-cause mortality was 76.7 per 1000 person-years (419 deaths) for the 655 individuals who took less than 4000 steps per day; 21.4 per 1000 person-years (488 deaths) for the 1727 individuals who took 4000 to 7999 steps per day; 6.9 per 1000 person-years (176 deaths) for the 1539 individuals who took 8000 to 11 999 steps per day; and 4.8 per 1000 person-years (82 deaths) for the 919 individuals who took at least 12 000 steps per day. Compared with taking 4000 steps per day, taking 8000 steps per day was associated with significantly lower all-cause mortality (HR, 0.49 [95% CI, 0.44-0.55]), as was taking 12 000 steps per day (HR, 0.35 [95% CI, 0.28-0.45]). Unadjusted incidence density for all-cause mortality by peak 30 cadence was 32.9 per 1000 person-years (406 deaths) for the 1080 individuals who took 18.5 to 56.0 steps per minute; 12.6 per 1000 person-years (207 deaths) for the 1153 individuals who took 56.1 to 69.2 steps per minute; 6.8 per 1000 person-years (124 deaths) for the 1074 individuals who took 69.3 to 82.8 steps per minute; and 5.3 per 1000 person-years (108 deaths) for the 1037 individuals who took 82.9 to 149.5 steps per minute. Greater step intensity was not significantly associated with lower mortality after adjustment for total steps per day (eg, highest vs lowest quartile of peak 30 cadence: HR, 0.90 [95% CI, 0.65-1.27]; P value for trend = .34). Conclusions and Relevance: Based on a representative sample of US adults, a greater number of daily steps was significantly associated with lower all-cause mortality. There was no significant association between step intensity and mortality after adjusting for total steps per day.