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To assess the association between psychotropic medications and sleep microstructure in large community-based cohorts of older people.We analyzed overnight polysomnograms of 381 women from the Study of Osteoporotic Fractures (SOF) and 2,657 men from the Osteoporotic Fractures in Men Sleep Study (MrOS), who either used no psychotropic medication (n=2,819), only benzodiazepines (n=112), or only selective serotonin reuptake inhibitors (SSRI) (n=107). Sleep microstructure (cyclic alternating pattern, CAP) was compared between the no medication group and psychotropic medication groups using the Mann-Whitney U-test. Significant differences were investigated using multivariable linear regression adjusted for confounders.CAP rate, arousal index, apnea-hypopnea index, and the frequency of slow, low-amplitude electroencephalography activation phases were significantly lower in MrOS participants using benzodiazepines than participants not taking psychotropic medication. SSRI users in MrOS experienced no altered sleep microstructure compared to those with no psychotropic use. SOF participants using benzodiazepines did not show similar associations with sleep microstructure. However, SSRI users from SOF had a significantly higher frequency of rapid, high-amplitude electroencephalography activation phases (A2 + 3) and periodic limb-movement index than participants not taking psychotropic medication. Multivariable linear regression adjusted for demographic, lifestyle, mood disorders, and health variables indicated additional significant associations between CAP rate and A2 + 3 index, respectively, and benzodiazepine usage in older men, and between CAP rate and SSRI usage in older women.We identified significant associations between sleep microstructure and psychotropic drugs in MrOS and SOF highlighting the importance of comprehensive sleep analysis, including CAP. Our results may help to better understand the differences in sleep-wake mechanisms based on psychotropic usage.Registry: ClinicalTrials.gov; Title: Outcomes of Sleep Disorders in Older Men; Identifier: NCT00070681; URL: https://clinicaltrials.gov/ct2/show/record/NCT00070681.

Objective Examine the association between personality measures and perceived mental fatigability. Methods We performed a cross-sectional analysis in N=1670 men, age 84.3±4.1 years. Multivariable linear regression models were used to examine the covariate adjusted association between personality measures (conscientiousness, optimism, goal reengagement, and goal disengagement) and perceived mental fatigability (measured with the validated 10-item Pittsburgh Fatigability Scale, PFS). Results One standard deviation lower conscientiousness (β=−0.91, pDiscussion Lower conscientiousness, optimism, and higher goal reengagement were linked with more severe perceived mental fatigability in older men. Personality traits may potentially contribute to early risk assessment for fatigability in later life. Future work should be longitudinal in nature and include personality assessments to confirm the temporality of the relationships observed.

Insomnia or poor sleep quality with objective short sleep duration (hereafter referred to as ISSD) has been identified as a high-risk phenotype among middle-aged persons. We evaluated the prevalence and clinical correlates of ISSD among community-living older persons.In 3053 men from the Osteoporotic Fractures in Men Sleep Study (MrOS; average age 76.4 ± 5.5 years) and 3044 women from the Study of Osteoporotic Fractures (SOF; average age 83.6 ± 3.8 years), we evaluated the prevalence of ISSD (trouble getting to sleep within 30 minutes, waking up in the middle of the night or early morning, and/or taking a medication to help with sleep ≥3 times per week and actigraphy-estimated sleep duration6 h). Using separate logistic regression models in men and women, we evaluated the cross-sectional associations between predisposing, precipitating, and perpetuating factors for ISSD, as compared with normal sleep (no insomnia and actigraphy-estimated sleep duration of 6-9 h).Overall, 20.6% of older men and 12.8% of older women had insomnia with short sleep duration. Multiple predisposing, precipitating, and perpetuating factors were cross-sectionally associated with ISSD in both men and women. In multivariable models that adjusted for predisposing factors (demographics, multimorbidity, obesity), precipitating (depression, anxiety, central nervous system-active medication use, restless legs syndrome) and perpetuating (napping, falls) factors were significantly associated with ISSD in men and women (adjusted odds ratios ranging 1.63-4.57).In this cross-sectional study of community-living older men and women, ISSD was common and associated with multiple predisposing, precipitating, and perpetuating factors, akin to a multifactorial geriatric health condition. Future work should examine causal pathways and determine whether the identified correlates represent modifiable risk factors.

Growing evidence suggests that impairment in rest-activity rhythms may be a risk factor for cognitive decline and impairment in the aging population. However, previous studies included only a limited set of rest-activity metrics and produced mixed findings. We studied a comprehensive set of parametric and nonparametric characteristics of rest-activity rhythms in relation to mild cognitive impairment (MCI) and probable dementia in a cohort of older women.The prospective analysis included 763 women enrolled in two ancillary studies of the Women's Health Initiative (WHI): the WHI Memory Study-Epidemiology of Cognitive Health Outcomes and Objective Physical Activity and Cardiovascular Health studies. The association between accelerometry-based rest-activity parameters and centrally adjudicated MCI and probable dementia were determined using Cox regression models adjusted for sociodemographic characteristics, lifestyle factors, and comorbidities.Overall, the results support a prospective association between weakened rest-activity rhythms (e.g., reduced amplitude and overall rhythmicity) and adverse cognitive outcomes. Specifically, reduced overall rhythmicity (pseudo F statistic), lower amplitude and activity level (amplitude/relative amplitude, mesor, and activity level during active periods of the day [M10]), and later activity timing (acrophase and midpoint of M10) were associated with a higher risk for MCI and probable dementia. Women with lower amplitude and mesor also exhibited faster cognitive decline over follow-up.Weakened rest-activity rhythms may be predictive markers for cognitive decline, MCI, and dementia among older women.

Background Falls occur annually in 25% of adults aged ≥65 years. Fall-related injuries are increasing, highlighting the need to identify modifiable risk factors. Methods Role of fatigability on prospective, recurrent, and injurious fall risk was examined in 1 740 men aged 77–101 years in the Osteoporotic Fractures in Men Study. The 10-item Pittsburgh Fatigability Scale measured perceived physical and mental fatigability (0–50/subscale) at Year 14 (2014–16); established cut-points identified men with more severe perceived physical (≥15, 55.7%), more severe mental (≥13, 23.7%) fatigability, or having both (22.8%). Prospective, recurrent (≥2), and injurious falls were captured by triannual questionnaires ≥1 year after fatigability assessment; risk of any fall was estimated with Poisson generalized estimating equations, and likelihood of recurrent/injurious falls with logistic regression. Models adjusted for age, health conditions, and other confounders. Results Men with more severe physical fatigability had a 20% (p = .03) increased fall risk compared with men with less physical fatigability, with increased odds of recurrent and injurious falls, 37% (p = .04) and 35% (p = .035), respectively. Men with both more severe physical and mental fatigability had a 24% increased risk of a prospective fall (p = .026), and 44% (p = .045) increased odds of recurrent falling compared with men with less severe physical and mental fatigability. Mental fatigability alone was not associated with fall risk. Additional adjustment for previous fall history attenuated associations. Conclusions More severe fatigability may be an early indicator to identify men at high risk for falls. Our findings warrant replication in women, as they have higher rates of fatigability and prospective falls.

Background Lower physical activity (PA) is associated with greater perceived fatigability, a person-centered outcome. The association between change in PA and fatigability with advanced age has yet to be established. Methods Community-dwelling older men (N = 1 113, age = 84.1 ± 3.9 years at Year 14) had free-living PA assessed using SenseWear Armband prospectively at Year 7 (2007–2009) and Year 14 (2014–2016) of Osteoporotic Fractures in Men Study, a longitudinal cohort established in 2000 (baseline). We categorized percent changes in PA into groups (large decline → large increase) for 4 metrics: step count, light intensity PA (LIPA, metabolic equivalents [METs] >1.5 to 1.5). Results Men declined 2 336 ± 2 546 (34%) steps/d, 24 ± 31 (25%) LIPA min/d, 33 ± 58 (19%) MVPA min/d, and increased 40 ± 107 (6%) SB min/d over 7.2 ± 0.7 years. Compared to large decline (% change less than −50%), those that maintained or increased step count had 3–8 points lower PFS Physical scores; those who maintained or increased LIPA and MVPA had 2–3 and 2–4 points lower PFS Physical scores, respectively (all p ≤ .01). Associations were similar, but smaller, for PFS Mental scores. Conclusion Older men who maintained or increased PA had lower fatigability, independent of initial PA. Our findings inform the types and doses of PA that should be targeted to reduce fatigability in older adults.

STUDY OBJECTIVES: Persons > 65 years with short sleep duration (≤ 6 hours) are at risk for adverse outcomes, but the accuracy of self-reported sleep duration may be affected by reduced symptom awareness. We evaluated the performance characteristics of self-reported vs objectively measured sleep duration in this age group. METHODS: In 2,980 men from the Osteoporotic Fractures in Men Sleep Study and 2,855 women from the Study of Osteoporotic Fractures we examined the agreement and accuracy of self-reported vs actigraphy-measured short and normal (> 6 but < 9 hours) sleep duration. We evaluated associations of select factors (demographics; medical, physical, and neuropsychiatric conditions; medication and substance use; and sleep-related measures) with risk of false-negative (normal sleep duration by self-report but short sleep duration by actigraphy) and false-positive (short sleep duration by self-report and normal sleep duration by actigraphy) designations, respectively, using logistic regression. RESULTS: Average ages were 76.3 ± 5.5 and 83.5 ± 3.7 years in men and women, respectively. There was poor agreement between self-reported and actigraphic sleep duration (kappa ≤ 0.24). False negatives occurred in nearly half and false positives in over a quarter of older persons. In multivariable models in men and women, false negatives were independently associated with obesity, daytime sleepiness, and napping, while false positives were significantly lower with obesity. CONCLUSIONS: Under- and overreporting of short sleep is common among older persons. Reliance on self-report may lead to missed opportunities to prevent adverse outcomes or unnecessary interventions. Self-reported sleep duration should be objectively confirmed when evaluating the effect of sleep duration on health outcomes. CITATION: Miner B, Stone KL, Zeitzer JM, et al. Self-reported and actigraphic short sleep duration in older adults. J Clin Sleep Med. 2022;18(2):403–413.

STUDY OBJECTIVES: Subjective insomnia complaints and objective sleep changes are mostly studied outside of clinical trial studies. In this study, we tested whether 240 genetic variants associated with subjectively reported insomnia were also associated with objective insomnia parameters extracted from polysomnographic recordings in three studies. METHODS: The study sample (total n = 2,770) was composed of the Wisconsin Sleep Cohort (n = 1,091) and the Osteoporotic Fractures in Men (n = 1,026) study, two population-based studies, and the Stanford Sleep Cohort, a sleep center patient-based sample (n = 653). Seven objective polysomnographic features related to insomnia defined outcome variables, with each variant allele serving as predictor. Meta-regression was performed, accounting for common confounders as well as variance differences between studies. Additionally, a normalized genetic risk score was generated for each subject to serve as a predictor variable in separate linear mixed models assessing objective insomnia features. RESULTS: After correction for multiple testing, single-nucleotide polymorphisms associated with subjective insomnia were not significantly associated with 6 of 7 objective sleep measures. Only periodic limb movement index was significantly associated with rs113851554 (MEIS1), as found in previous studies. The normalized genetic risk score was only weakly associated with arousal index and duration of wake after sleep onset. CONCLUSIONS: Our findings suggest that subjective insomnia does not have a strong genetic signature mapping onto objective (polysomnographic) sleep variables. CITATION: Foldager J, Peppard PE, Hagen EW, et al. Genetic risk for subjective reports of insomnia associates only weakly with polygraphic measures of insomnia in 2,770 adults. J Clin Sleep Med. 2022;18(1):21-29.

Background: The effect of sleep medications on cognition in older adults is controversial, possibly dependent upon sleep quality, and may differ by race. Objective: To determine the longitudinal association between sleep medication use and incident dementia over 15 years, and to explore whether the association is independent of nighttime sleep disturbances and if it differs by race. Methods: We examined 3,068 community-dwelling older adults (aged 74.1±2.9 years, 41.7% Black, 51.5% female) without dementia. Sleep medication use was recorded three times by asking “Do you take sleeping pills or other medications to help you sleep?” with the response options: “Never (0)”, “Rarely (≤1/month)”, “Sometimes (2–4/month)”, “Often (5–15/month)”, or “Almost Always (16–30/month)”. Incident dementia was defined using hospitalization records, dementia medication prescription or clinically significant decline in global cognition. Results: 138 (7.71%) of Whites and 34 (2.66%) of Blacks reported taking sleep medications “often or almost always”. Whites were almost twice as likely to take all prescription hypnotics. 617 participants developed dementia over the follow-up. After adjustment for all covariates, participants who reported taking sleep medications ≥ 5/month versus ≤1/month were significantly more likely to develop dementia, and the association was only observed among Whites (HR = 1.79,1.21–2.66) but not Blacks (HR = 0.84,0.38–1.83); p for interaction = 0.048. Further adjustment for nighttime sleep did not appreciably alter the results. The association was similar for the cumulative frequency of sleep medication use and remained after introducing a time lag of 3 years. Conclusion: Frequent sleep medication use was associated with an increased risk of dementia in White older adults. Further research is needed to determine underlying mechanisms.

Background Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing. Methods The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation Results We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10−8) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways. Conclusions We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.

Background Older men with the worse alignment of activity and light may have lower levels of cognition and increased rates of cognitive decline. Methods This cohort consisted of 1 036 older men (81.1 ± 4.6 years) from the MrOS Sleep Study (2009–2012). Light and activity levels were gathered by wrist actigraphy. Phasor analysis was used to quantify the alignment of light–dark and rest-activity patterns (magnitude) and their temporal relationship (angle). Global cognitive function (Modified Mini-Mental State examination [3MS]) and executive function (Trails B test) were measured, then repeated 4.2 ± 0.8 years later. Linear regression models examined the associations of phasor magnitude and angle with cognition and cognitive decline. Models were adjusted for age, clinic, race, education, and season. Results Smaller phasor magnitude (worse aligned light and activity patterns) was associated with lower initial level and increased decline in executive function. Compared to those with higher phasor magnitude, those with lower magnitude took an average of 11.1 seconds longer to complete the Trails B test (quartile 1 vs quartile 4, p = .02). After follow-up, Trails B completion time increased an average of 5.5 seconds per standard deviation decrease in phasor magnitude (95% confidence interval [CI] 0.7–10.4, p = .03). There were no associations with phasor angle, and none with magnitude and global cognition (3MS). Conclusion Among older men, worse alignment of light and activity patterns was associated with worse initial performance and increased decline in executive function, but not related to global cognition. Interventions that improve the alignment of light and activity may slow cognitive decline in older adults.

There is emerging evidence that obstructive sleep apnea (OSA) is a risk factor for preclinical Alzheimer's disease (AD). An American Thoracic Society workshop was convened that included clinicians, basic scientists, and epidemiologists with expertise in OSA, cognition, and dementia, with the overall objectives of summarizing the state of knowledge in the field, identifying important research gaps, and identifying potential directions for future research. Although currently available cognitive screening tests may allow for identification of cognitive impairment in patients with OSA, they should be interpreted with caution. Neuroimaging in OSA can provide surrogate measures of disease chronicity, but it has methodological limitations. Most data on the impact of OSA treatment on cognition are for continuous positive airway pressure (CPAP), with limited data for other treatments. The cognitive domains improving with CPAP show considerable heterogeneity across studies. OSA can negatively influence risk, manifestations, and possibly progression of AD and other forms of dementia. Sleep-dependent memory tasks need greater incorporation into OSA testing, with better delineation of sleep fragmentation versus intermittent hypoxia effects. Plasma biomarkers may prove to be sensitive, feasible, and scalable biomarkers for use in clinical trials. There is strong biological plausibility, but insufficient data, to prove bidirectional causality of the associations between OSA and aging pathology. Engaging, recruiting, and retaining diverse populations in health care and research may help to decrease racial and ethnic disparities in OSA and AD. Key recommendations from the workshop include research aimed at underlying mechanisms; longer-term longitudinal studies with objective assessment of OSA, sensitive cognitive markers, and sleep-dependent cognitive tasks; and pragmatic study designs for interventional studies that control for other factors that may impact cognitive outcomes and use novel biomarkers.

Sleep is an important indicator of a person’s health, and its accurate and cost-effective quantification is of great value in healthcare. The gold standard for sleep assessment and the clinical diagnosis of sleep disorders is polysomnography (PSG). However, PSG requires an overnight clinic visit and trained technicians to score the obtained multimodality data. Wrist-worn consumer devices, such as smartwatches, are a promising alternative to PSG because of their small form factor, continuous monitoring capability, and popularity. Unlike PSG, however, wearables-derived data are noisier and far less information-rich because of the fewer number of modalities and less accurate measurements due to their small form factor. Given these challenges, most consumer devices perform two-stage (i.e., sleep-wake) classification, which is inadequate for deep insights into a person’s sleep health. The challenging multi-class (three, four, or five-class) staging of sleep using data from wrist-worn wearables remains unresolved. The difference in the data quality between consumer-grade wearables and lab-grade clinical equipment is the motivation behind this study. In this paper, we present an artificial intelligence (AI) technique termed sequence-to-sequence LSTM for automated mobile sleep staging (SLAMSS), which can perform three-class (wake, NREM, REM) and four-class (wake, light, deep, REM) sleep classification from activity (i.e., wrist-accelerometry-derived locomotion) and two coarse heart rate measures—both of which can be reliably obtained from a consumer-grade wrist-wearable device. Our method relies on raw time-series datasets and obviates the need for manual feature selection. We validated our model using actigraphy and coarse heart rate data from two independent study populations: the Multi-Ethnic Study of Atherosclerosis (MESA; N = 808) cohort and the Osteoporotic Fractures in Men (MrOS; N = 817) cohort. SLAMSS achieves an overall accuracy of 79%, weighted F1 score of 0.80, 77% sensitivity, and 89% specificity for three-class sleep staging and an overall accuracy of 70-72%, weighted F1 score of 0.72-0.73, 64-66% sensitivity, and 89-90% specificity for four-class sleep staging in the MESA cohort. It yielded an overall accuracy of 77%, weighted F1 score of 0.77, 74% sensitivity, and 88% specificity for three-class sleep staging and an overall accuracy of 68-69%, weighted F1 score of 0.68-0.69, 60-63% sensitivity, and 88-89% specificity for four-class sleep staging in the MrOS cohort. These results were achieved with feature-poor inputs with a low temporal resolution. In addition, we extended our three-class staging model to an unrelated Apple Watch dataset. Importantly, SLAMSS predicts the duration of each sleep stage with high accuracy. This is especially significant for four-class sleep staging, where deep sleep is severely underrepresented. We show that, by appropriately choosing the loss function to address the inherent class imbalance, our method can accurately estimate deep sleep time (SLAMSS/MESA: 0.61±0.69 hours, PSG/MESA ground truth: 0.60±0.60 hours; SLAMSS/MrOS: 0.53±0.66 hours, PSG/MrOS ground truth: 0.55±0.57 hours;). Deep sleep quality and quantity are vital metrics and early indicators for a number of diseases. Our method, which enables accurate deep sleep estimation from wearables-derived data, is therefore promising for a variety of clinical applications requiring long-term deep sleep monitoring.

OBJECTIVES: Back pain and poor mental health are interrelated issues in older men. Evidence suggests that socioeconomic status moderates this relationship, but less is known about the role of subjective social status (SSS). This study examined if the association between back pain and mental health is moderated by SSS. METHOD: We used a sample of community-dwelling older men (≥65 years) from the Osteoporotic Fractures in Men Study (N=5994). Participants self-reported their back pain severity and frequency over the past 12 months. SSS was assessed with the MacArthur Scale of SSS. Mental health was assessed with the SF-12 Mental Component Summary (MCS). RESULTS: Severe back pain was associated with lower SF-12 MCS scores (p = .03). Back pain frequency was not associated with SF-12 MCS scores. SSS moderated the back pain and mental health relationship. Among men with higher national or community SSS, the association between back pain severity and SF-12 MCS scores was not significant. However, among men with lower national or community SSS, more severe back pain was associated with lower SF-12 MCS scores (p’s < .001). Among those with lower national or community SSS, greater back pain frequency was also associated with lower SF-12 MCS scores (p’s < .05). CONCLUSION: Where one ranks oneself within their nation or community matters for the back pain and mental health relationship. Higher SSS may be a psychosocial resource that buffers the negative associations of severe and frequent back pain on mental health in older men.

ObjectiveTo determine whether high school start time is associated with headache frequency in adolescents with migraine.BackgroundAdolescence is marked by a physiologic delayed circadian phase, characterized by later bedtimes and wake times. The American Academy of Pediatrics (AAP) recommends that high schools start no earlier than 8:30a.m., but most high schools in the United States start earlier. The study hypothesis was that adolescents with migraine whose high schools start at 8:30a.m. or later (late group) would have lower headache frequency than those whose schools start earlier than 8:30a.m. (early group).MethodsThis was a cross-sectional Internet survey study of US high schoolers with migraine recruited online through social media. Comparisons were made between the late group and the early group. The primary outcome measure was self-reported headache days/month.ResultsIn total, 1012 respondents constituted the analytic set: n=503 in the late group versus n=509 in the early group. Mean (SD) self-reported headache days/month was 4.8 (4.6) versus 7.7 (6.1) in the late and early groups, respectively (p&nbsp

We sought to determine which facets of sleep neurophysiology were most strongly linked to cognitive performance in 3,819 older adults from two independent cohorts, using whole-night electroencephalography. From over 150 objective sleep metrics, we identified 23 that predicted cognitive performance, and processing speed in particular, with effects that were broadly independent of gross changes in sleep quality and quantity. These metrics included rapid eye movement duration, features of the electroencephalography power spectra derived from multivariate analysis, and spindle and slow oscillation morphology and coupling. These metrics were further embedded within broader associative networks linking sleep with aging and cardiometabolic disease: individuals who, compared with similarly aged peers, had better cognitive performance tended to have profiles of sleep metrics more often seen in younger, healthier individuals. Taken together, our results point to multiple facets of sleep neurophysiology that track coherently with underlying, age-dependent determinants of cognitive and physical health trajectories in older adults.

Short and long sleep duration are associated with adverse metabolic outcomes, such as obesity and diabetes. We evaluated cross-sectional differences in metabolite levels between women with self-reported habitual short (

The associations between objective measures of sleep duration and bone outcomes in older men are unknown. No consistent, significant association was identified between sleep duration and bone mineral density (BMD) in the current analysis. However, future research should determine if vitamin D status modifies this relationship. Prior studies, predominantly in women, reported that long and short self-reported sleep duration are associated with lower BMD. Associations between actigraphy-determined sleep duration and BMD or bone turnover markers (BTMs) in older men are unknown. Men in The Osteoporotic Fractures in Men (MrOS) Study with wrist actigraphy and concurrent BMD assessment but without comorbidities affecting bone health were included. Sleep duration was considered as a continuous (N = 1926) and dichotomized variable where men were classified as getting the recommended (7–8 h/night; N = 478) or short (< 6 h/night; N = 577) sleep. The cross-sectional association between BMD, BTMs, and sleep duration was examined using a t test or linear regression, where appropriate, in unadjusted and adjusted models. There were no clinically or statistically significant differences in BMD at the L-spine, total hip, or femoral neck between men getting the recommended vs. short sleep duration, using actigraphy or self-reported sleep duration (all p ≥ 0.07). When sleep duration was considered as a continuous variable, femoral neck BMD was higher in men with longer self-reported sleep duration (β = 0.006 ±0.003, p = 0.02), but this was not significant after further adjustment. In men with low 25OHD (< 20 ng/mL), longer actigraphy-determined sleep duration was associated with higher total hip BMD (β = 0.016 ± 0.008; p = 0.04). Sleep duration and BTMs were not associated. Sleep duration was not associated with hip or L-spine BMD or BTMs in older men. Future research should determine if vitamin D status or other factors modify this relationship.

OBJECTIVE Disruption of rest-activity rhythms is cross-sectionally associated with metabolic disorders, including type 2 diabetes, yet it remains unclear whether it predicts impaired glucose metabolism and homeostasis. The aim of this study is to examine the cross-sectional and prospective associations between rest-activity rhythm characteristics and glycemic measures in a cohort of older men. RESEARCH DESIGN AND METHODS Baseline rest-activity rhythms were derived from actigraphy with use of extended cosine model analysis. With subjects fasting, glucose, insulin, and HOMA of insulin resistance (HOMA-IR) were measured from blood at baseline and after ∼3.5 years. Type 2 diabetes was defined based on self-report, medication use, and fasting glucose. RESULTS In the cross-sectional analysis (n = 2,450), lower 24-h amplitude-to-mesor ratio (i.e., mean activity-adjusted rhythm amplitude) and reduced overall rhythmicity were associated with higher fasting insulin and HOMA-IR (all Ptrend < 0.0001), indicating increased insulin resistance. The odds of baseline type 2 diabetes were significantly higher among those in the lowest quartile of amplitude (Q1) (odds ratio [OR]Q1 vs. Q4 1.63 [95% CI 1.14, 2.30]) and late acrophase group (ORlate vs. normal 1.46 [95% CI 1.04, 2.04]). In the prospective analysis (n = 861), multiple rest-activity characteristics predicted a two- to threefold increase in type 2 diabetes risk, including a lower amplitude (ORQ1 vs. Q4 3.81 [95% CI 1.45, 10.00]) and amplitude-to-mesor ratio (OR 2.79 [95% CI 1.10, 7.07]), reduced overall rhythmicity (OR 3.49 [95% CI 1.34, 9.10]), and a late acrophase (OR 2.44 [1.09, 5.47]). CONCLUSIONS Rest-activity rhythm characteristics are associated with impaired glycemic metabolism and homeostasis and higher risk of incident type 2 diabetes.

Background Heart failure (HF) is a leading cause of morbidity and mortality and although it is linked to sleep apnea, which physiological stressors most strongly associate with incident disease is unclear. We tested whether sleep apnea-specific hypoxic burden (SASHB) predicts incident HF in two independent cohort studies. Research Question In comparison with apnea-hypopnea index (AHI), how does sleep apnea-specific hypoxic burden predict incident HF? Study Design and Methods The samples were derived from two cohort studies: The Sleep Heart Health Study (SHHS), which included 4,881 middle-aged and older adults (54.4% women), age 63.6 ± 11.1 years; and the Outcomes of Sleep Disorders in Older Men (MrOS), which included 2,653 men, age 76.2 ± 5.4 years. We computed SASHB as the sleep apnea-specific area under the desaturation curve from pre-event baseline. We used Cox models for incident HF to estimate the adjusted hazard ratios (HRs) for natural log-transformed SASHB and AHI adjusting for multiple confounders. Results The SASHB predicted incident HF in men in both cohorts, whereas AHI did not. Men in SHHS and MrOS had adjusted HRs (per 1SD increase in SASHB) of 1.18 (95% CI, 1.02-1.37) and 1.22 (95% CI, 1.02-1.45), respectively. Associations with SASHB were observed in men with both low and high AHI levels. Associations were not significant in women. Interpretation In men, the hypoxic burden of sleep apnea was associated with incident HF after accounting for demographic factors, smoking, and co-morbidities. The findings Suggest that quantification of an easily measured index of sleep apnea-related hypoxias may be useful for identifying individuals at risk for heart disease, while also suggesting targets for intervention.

OBJECTIVES: Our aim was to determine the association between protein intake (overall and by source) and all-cause and cause-specific mortality among older men. DESIGN: Prospective cohort study. SETTING: 5790 ambulatory community-dwelling older men from multicenter Osteoporotic Fractures in Men (MrOS) study. MEASUREMENTS: Total energy and protein intake, and protein intake by source (dairy, non-dairy animal, plant) were assessed using a 69-item food frequency questionnaire. We included up to 10-year follow-up with adjudicated cardiovascular, cancer and other mortality outcomes. We used time-to-event analysis with protein exposures, mortality outcome, and adjusted for possible confounders including age, center, education, race, smoking, alcohol use, physical activity, weight, total energy intake (TEI), and comorbidities. Hazard ratios were expressed per each unit=2.9% TEI decrement for all protein intake variables. RESULTS: The mean (SD) baseline age of 5790 men was 73.6 (5.8) y. There were 1611 deaths and 211 drop-outs prior to 10 years, and 3868 men who were alive at the 10-year follow-up. The mean (SD) total protein intake was 64.7 (25.8) g/d, while the mean (SD) intake expressed as percent of total energy intake (%TEI) was 16.1 (2.9) %TEI. Lower protein intake was associated with an increased risk of death, with unadjusted HR=1.11 (95% CI: 1.06, 1.17) and adjusted HR=1.09 (95% CI: 1.04, 1.14) and the associations for protein intake by source were similar. The adjusted HR for cancer mortality was HR=1.13 (95% CI: 1.03, 1.25) while the association for CVD mortality was HR=1.08 (95% CI: 0.99, 1.18). CONCLUSIONS: Low protein intake, irrespective of source, was associated with a modest increase in risk of all-cause and cause-specific mortality among older men. Special consideration should be given to level of protein intake among older adults.

Average arterial oxyhemoglobin saturation during sleep (AvSpO(2)S) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23,1, 2 we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpO(2)S and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10(−7)). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpO(2)S variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpO(2)S. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpO(2)S.

Genetic association studies of many heritable traits resulting from physiological testing often have modest sample sizes due to the cost and burden of the required phenotyping. This reduces statistical power and limits discovery of multiple genetic associations. We present a strategy to leverage pleiotropy between traits to both discover new loci and to provide mechanistic hypotheses of the underlying pathophysiology. Specifically, we combine a colocalization test with a locus-level test of pleiotropy. In simulations, we show that this approach is highly selective for identifying true pleiotropy driven by the same causative variant, thereby improves the chance to replicate the associations in underpowered validation cohorts and leads to higher interpretability. Here, as an exemplar, we use Obstructive Sleep Apnea (OSA), a common disorder diagnosed using overnight multi-channel physiological testing. We leverage pleiotropy with relevant cellular and cardio-metabolic phenotypes and gene expression traits to map new risk loci in an underpowered OSA GWAS. We identify several pleiotropic loci harboring suggestive associations to OSA and genome-wide significant associations to other traits, and show that their OSA association replicates in independent cohorts of diverse ancestries. By investigating pleiotropic loci, our strategy allows proposing new hypotheses about OSA pathobiology across many physiological layers. For example, we identify and replicate the pleiotropy across the plateletcrit, OSA and an eQTL of DNA primase subunit 1 (PRIM1) in immune cells. We find suggestive links between OSA, a measure of lung function (FEV1/FVC), and an eQTL of matrix metallopeptidase 15 (MMP15) in lung tissue. We also link a previously known genome-wide significant peak for OSA in the hexokinase 1 (HK1) locus to hematocrit and other red blood cell related traits. Thus, the analysis of pleiotropic associations has the potential to assemble diverse phenotypes into a chain of mechanistic hypotheses that provide insight into the pathogenesis of complex human diseases.

Altered 24-hour rest–activity rhythms may be associated with cognitive impairment in older adults, but evidence from prospective studies is limited. Nonparametric methods were used to assess actigraphy-based activity patterns in 2 496 older men. Incident cognitive impairment was assessed 4 times over 12 years using the Modified Mini-Mental State Examination (3MS) and Trails B tests, self-reported medication use, and clinical diagnosis. The highest quartile (vs the lowest) of intradaily variability and the lowest quartiles (vs the highest) of interdaily stability and relative amplitude were associated with incident cognitive impairment (hazard ratio [95% confidence interval]: 1.82 [1.31–2.53], 1.36 [0.99–1.86], and 1.85 [1.33–2.56], respectively). A larger increase in intradaily variability over 7.5 years was associated with a greater subsequent decline in 3MS scores but not in Trails B performance. In conclusion, less stable and more variable rest–activity rhythms may represent early biomarkers of cognitive impairment in older men.

Importance The burden of fractures among postmenopausal women is high. Although nontraumatic fractures are strong risk factors for future fracture, current clinical guidelines do not address traumatic fractures. Objective To determine how future fracture risk varies according to whether an initial fracture is traumatic or nontraumatic. Design, Setting, and Participants We conducted a prospective observational study using data from the Women’s Health Initiative Study (WHI) (enrollment, September 1994-December 1998; data analysis, September 2020 to March 2021), which enrolled postmenopausal women aged 50 to 79 years at baseline at 40 US clinical centers. The WHI Clinical Trials and WHI Bone Density Substudy, conducted at 3 of the clinical centers, asked participants to report the mechanism of incident fractures. Of 75 335 participants, information regarding incident fracture and covariates was available for 66 874 participants (88.8%), who comprised the analytic sample of this study. Mean (SD) follow-up was 8.1 (1.6) years. Interventions None. Main Outcomes and Measures Incident clinical fractures were self-reported at least annually and confirmed using medical records. Participants reported the mechanism of incident fracture as traumatic or nontraumatic. Results Among the 66 874 participants in the analytic sample (mean [SD] age, 63.1 [7.0] years and 65.3 [7.2] years among women without and with clinical fracture, respectively), 7142 participants (10.7%) experienced incident fracture during the study follow-up period. The adjusted hazard ratio (aHR) of subsequent fracture after initial fracture was 1.49 (95% CI, 1.38-1.61). Among women whose initial fracture was traumatic, the association between initial fracture and subsequent fracture was significantly increased (aHR, 1.25; 95% CI, 1.06-1.48). Among women whose initial fracture was nontraumatic, the association between initial fracture and subsequent fracture was also increased (aHR, 1.52; 95% CI, 1.37-1.68). Confidence intervals for associations between initial fracture and subsequent fracture were overlapping for traumatic and nontraumatic initial fracture strata. Conclusions and Relevance In this cohort study, among postmenopausal women older than 50 years, fracture was associated with a greater risk of subsequent fracture regardless of whether the fracture was traumatic or nontraumatic. These findings suggest that clinical osteoporosis assessment should include high-trauma as well as low-trauma fractures.

Background: Chronic insomnia is common in post-menopausal women and is associated with higher cardiovascular disease (CVD) risk. Hypnotics are a second-line therapy after cognitive behavioral therapy for management of chronic insomnia. Among the hypnotics, nonbenzodiazepine GABA agonists (Z-drugs) are commonly prescribed. However, it is unclear whether Z-drug use and other hypnotic use is associated with risk of incident CVD and mortality in older people with sleep disturbances. Objectives: Among post-menopausal women with sleep disturbances, to evaluate the association of Z-drug use compared with use of other prescription hypnotics, and with non-use of any prescription hypnotics with CVD and mortality. Methods: The population studied were post-menopausal women from the Women’s Health Initiative (WHI) Observational Study and Clinical Trials who, at baseline, scored >=9 with the WHI Insomnia Rating Scale (N=40,728). Hypnotic use was ascertained from prescription medications scanned into the Medi-Span database at baseline and first follow-up clinic visit. Frequency of use was ascertained from self-report. Participants were categorized as users of Z-drugs, users of other prescription hypnotics or non-users. Outcomes were composite CVD (congestive heart failure, stroke, and fatal/non-fatal myocardial infarction) and mortality, centrally adjudicated with review of medical records and death certificates. Hazard ratios were estimated from Cox proportional hazards regression models adjusted for demographic, medical history, and sleep measures. To address potential confounding by indication, we also adjusted for propensity to be prescribed hypnotics. Results: At the first follow-up visit 1.1% (424 of 38,979) of participants were users of Z-drugs, 4.2% (1,653 of 38,979) were users of other prescription hypnotics, 3.1% (1,187 of 38,979) had discontinued prescription hypnotic use, and 91.6% (35,715 of 38,979) were non-users at both baseline and first follow-up visit. The mean age of our cohort was 63.6 years (SD = 7.2) and mean follow-up time after the initial follow-up visit was 14.0 years (SD = 6.3). Z-drug use was significantly associated with an increased risk of composite CVD (HR= 1.35, 95%CI: 1.02-1.79) and all-cause mortality (HR= 1.38, 95%CI: 1.13-1.69). Use of other prescription hypnotics and casual use ( Conclusion: Use of Z-drugs three or more times a week was associated with an increased risk of death and cardiovascular disease in post-menopausal women being treated for insomnia. Additional research is needed to evaluate association between frequency of hypnotic use and these outcomes and to investigate possible mechanisms.

Clarifying whether physiological sleep measures predict mortality could inform risk screening; however, such investigations should account for complex and potentially non-linear relationships among health risk factors. We aimed to establish the predictive utility of polysomnography-assessed sleep measures for mortality using a novel Permutation Random Forest machine learning framework. Data collected from years 1995 – present are from the Sleep Heart Health Study (SHHS; n=5734) and the Wisconsin Sleep cohort study (WSCS; n=1015) and include initial assessments of sleep and heath and up to 15 years of follow-up for all-cause mortality. We applied Permutation Random Forest models to quantify the predictive abilities of 24 measures grouped into 5 domains: polysomnography-assessed sleep (4 measures), self-reported sleep (3), health (8), health behaviors (4), and sociodemographic factors (5). Ten-fold repeated internal validation (WSCS and SHHS combined) and external validation (training in SHHS; testing in WSCS) were used to compute unbiased variable importance metrics and associated p-values. We observed that health, sociodemographic factors, and polysomnography-assessed sleep domains predicted mortality using both External Validation and repeated Internal Validation. Polysomnography-assessed sleep efficiency and the percentage of sleep time with oxygen saturation < 90% (T90) were among the most predictive individual measures. Multivariable Cox regression also revealed the polysomnography-assessed sleep domain to be predictive, with very low sleep efficiency and high hypoxemia conferring the highest risk. These findings, coupled with the emergence of new low-burden technologies for objectively assessing sleep and overnight oxygen saturation, suggest that consideration of physiological sleep measures may improve risk screening.

Study Objectives Disrupted daily rhythms are associated with mild cognitive impairment (MCI) and dementia. The specific nature of how rhythms and cognition are related, however, is unknown. We hypothesized characteristics from a nonparametric estimate of circadian rest-activity rhythm patterns would be associated to the development of MCI or dementia. Methods Wrist actigraphy from 1232 cognitively healthy, community-dwelling women (mean age 82.6 years) from the Study of Osteoporotic Fractures was used to estimate rest-activity patterns, including intradaily variability (IV), interdaily stability (IS), most active 10-hour period (M10), least active 5-hour period (L5), and relative amplitude (RA). Logistic regression examined associations of these predictors with 5-year incidence of MCI or dementia. Models were adjusted for potential confounders. Results Women with earlier sleep/wake times had higher risk of dementia, but not MCI, (early vs. average L5 midpoint: OR, 1.66; 95% CI, 1.08–2.55) as did women with smaller day/night activity differentials (low vs. high RA: OR, 1.96; 95% CI, 1.14–3.35). IV, IS, and M10 were not associated with MCI or dementia. Conclusion The timing and difference in day/night amplitude, but not variability of activity, may be useful as predictors of dementia.

Background The locations of subsequent fractures after initial fracture in postmenopausal women are poorly characterized. Methods We conducted a prospective analysis of subsequent fractures after initial fracture in Women's Health Initiative (1993–2018) participants who provided follow-up (mean 15.4 years, SD 6.2 years) data (n = 157,282 participants; baseline age 50–79; 47,458 participants with incident fracture). Cox proportional hazards models were adjusted for age, race/ethnicity, body mass index, and other covariates. Findings The risk of each type of subsequent fracture was increased after each type of initial fracture. Incident lower arm/wrist fracture was associated with significantly elevated risks of subsequent fractures at the upper arm/shoulder, upper leg, knee, lower leg/ankle, hip/pelvis, and spine (adjusted hazard ratios [aHRs] ranging 2·63–5·68). The risk of hip fracture was increased after initial lower arm or wrist fracture (aHR 4·80, 95% CI 4·29–5·36), initial upper arm or shoulder fracture (aHR 5·06, 95% CI 4·39–5·82), initial upper leg fracture (aHR 5·11, 95% CI 3·91–6·67), initial knee fracture (aHR 5·03, 95% CI 4·20–6·03), initial lower leg/ankle fracture (aHR 4·10, 95% CI 3·58–4·68), and initial spine fracture (aHR 6·69, 95% CI 5·95–7·53). Associations were significant in all age groups, even women aged 50–59 years. Risks of subsequent fracture were more pronounced among non-Hispanic Black, Hispanic/Latina, and Asian/Pacific Islander than among non-Hispanic White women. Interpretation Increased risk of subsequent fracture is observed for all fracture types across all ages. Women who experience any of these fractures should be targeted for interventions to prevent subsequent fractures. Funding National Institutes of Health HHSN268201600018C,HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C.

BACKGROUND Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6 (IL-6) blockade–refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6 blockade–refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype.

Chronic increases in pro-inflammatory cytokines in older adults, known as inflammaging, are an important risk factor for morbidity and mortality in the aging population. It has been suggested that circadian disruption may play a role in chronic inflammation, but there has been limited study that investigated the overall profile of 24-hour rest–activity rhythms in relation to inflammation using longitudinal data. In the Outcomes of Sleep Disorders in Older Men Study, we applied the extended cosine model to derive multiple rest–activity rhythm characteristics using multiday actigraphy, and examined their associations with 6 inflammatory markers (ie, C-reactive protein [CRP], interleukin 6 [IL-6], tumor necrosis factor alpha [TNF-α], tumor necrosis factor alpha soluble receptor II [TNF-α-sRII], interleukin-1β [IL-1β], interferon gamma [IFN-γ]) measured from fasting blood. We assessed both the cross-sectional association between rest–activity rhythms and inflammatory markers measured at baseline, and the prospective association between baseline rest–activity rhythms and changes in inflammatory markers over 3.5 years of follow-up. We found that multiple rest–activity characteristics, including lower amplitude and relative amplitude, and decreased overall rhythmicity, were associated with higher levels of CRP, IL-6, TNF-α, and TNF-α-sRII, but not IL-1β and IFN-γ at baseline. Moreover, the lowest quartile of these 3 rest–activity characteristics was associated with an approximately 2-fold increase in the odds of having elevated inflammation (ie, having 3 or more markers in the highest quartile) at baseline. However, we found little evidence supporting a relationship between rest–activity rhythm characteristics and changes in inflammatory markers. Future studies should clarify the dynamic relationship between rest–activity rhythms and inflammation in different populations, and evaluate the effects of improving rest–activity profiles on inflammation and related disease outcomes.

Discrepancies between actigraphicand self-reported sleep measures are common. Studies of people with insomnia, in whom both sleep disturbances and discrepancy are common, suggest disturbances and discrepancy reflect differences in the sleeping brain's activity measurable using spectral electroencephalogram (EEG). Disentangling effects of discrepancy and disturbance on sleep EEG could help target research on the consequences and treatments of different sleep phenotypes. We therefore categorized participants in a cohort study including 2,850 men (average age=76years, standard deviation=5.5) into four groups using median splits on actigraphic and self-reported sleep efficiency (SE). We compared spectral power between these groups in 1-Hz bins up to 24Hz. Compared with the concordant-high SE group: (a) the group with high actigraphic and low self-reported SE had higher spectral power from 11-15Hz across the night; (b) both groups with low actigraphic SE had higher power across the 15-24Hz range, predominantly in early cycles, and greater slow frequency power in later cycles. These findings suggest that perceived wakefulness undetected by actigraphy may result from or drive activity corresponding to spindles. We also found, consistent with hyperarousal models, that low SE detectable via actigraphy was related to higher frequency power in the beta range; actigraph-measured inefficiency was also associated with later slow oscillations, potentially representing attempts to dissipate homeostatic drive elevated from earlier hyperarousal. These distinct spectral EEG markers (of low SE measured with actigraphy vs. low perceived SE that is not captured by actigraphy) may have different causes or consequences.

OBJECTIVES: Extended-duration work rosters (EDWRs) with shifts of 24+ hours impair performance compared with rapid cycling work rosters (RCWRs) that limit shifts to 16 hours in postgraduate year (PGY) 1 resident-physicians. We examined the impact of a RCWR on PGY 2 and PGY 3 resident-physicians. METHODS: Data from 294 resident-physicians were analyzed from a multicenter clinical trial of 6 US PICUs. Resident-physicians worked 4-week EDWRs with shifts of 24+ hours every third or fourth shift, or an RCWR in which most shifts were ≤16 consecutive hours. Participants completed a daily sleep and work log and the 10-minute Psychomotor Vigilance Task and Karolinska Sleepiness Scale 2 to 5 times per shift approximately once per week as operational demands allowed. RESULTS: Overall, the mean (± SE) number of attentional failures was significantly higher (P =.01) on the EDWR (6.8 ± 1.0) compared with RCWR (2.9 ± 0.7). Reaction time and subjective alertness were also significantly higher, by ∼18% and ∼9%, respectively (both P CONCLUSIONS: Performance impairment due to EDWR is improved by limiting shift duration. These data and their correlation with SME rates highlight the impairment of neurobehavioral performance due to extended-duration shifts and have important implications for patient safety.

Background/Objective Insomnia is common in older women and is associated with higher cardiovascular disease (CVD) risk. Nonbenzodiazepine GABA agonists (Z-drugs) are the most commonly prescribed sleep aids. The study objective was to determine whether the use of Z-drugs is associated with the risk of developing CVD and mortality in older women with sleep disturbances. Patients/Methods The study cohort included post-menopausal women who, at baseline, scored ≥9 with the Women's Health Initiative Insomnia Rating Scale (N = 40,728). Members of the cohort were categorized as users of Z-drugs, users of other prescription hypnotics, or non-users. Outcomes were composite CVD (congestive heart failure, stroke, and fatal/non-fatal myocardial infarction) and mortality. Hazard ratios were estimated from Cox proportional hazards regression models adjusted for demographics, medical history, and sleep measures. To address potential confounding by indication, we also adjusted for propensity to be prescribed hypnotics. Results The mean age of our cohort was 63.57 years (SD = 7.23) and mean follow-up time after the initial follow-up visit was 14.0 years (SD = 6.3). Z-drug use was significantly associated with an increased risk of composite CVD (HR = 1.35, 95%CI: 1.02–1.79) and all-cause mortality (HR = 1.38, 95%CI: 1.13–1.69). When groups were divided by heavy and casual use, only heavy users (≥3 times per week) had an increased risk of mortality. Conclusions Z-drugs use was associated with an increased risk for death and CVD in post-menopausal women being treated for sleep disturbances. Additional research is needed to evaluate both frequency and duration of Z-drug use.