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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.

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.

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

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.

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.

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.

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.

BACKGROUND: Conventional metrics to evaluate sleep-disordered breathing (SDB) have many limitations, including their inability to identify subclinical markers of cardiovascular (CV) dysfunction. RESEARCH QUESTION: Does sleep study-derived circulation time (Ct) predict mortality, independent of CV risks and SDB severity? STUDY DESIGN AND METHODS: We derived average lung to finger Ct (LFCt) from sleep studies in older men enrolled in the multicenter Osteoporotic Fractures in Men (MrOS) Sleep study. LFCt was defined as the average time between end of scored respiratory events and nadir oxygen desaturations associated with those events. We calculated the hazard ratio (HRs) for the CV and all-cause mortality by LFCt quartiles, adjusting for the demographic characteristics, body habitus, baseline CV risk, and CV disease (CVD). Additional models included apnea-hypopnea index (AHI), time with oxygen saturation as measured by pulse oximetry (SpO(2)) < 90% (T90), and hypoxic burden. We also repeated analyses after excluding those with CVD at baseline. RESULTS: A total of 2,631 men (mean ± SD age, 76.4 ± 5.5 years) were included in this study. LFCt median (interquartile range) was 18 (15-22) s. During an average ± SD follow-up of 9.9 ± 3.5 years, 427 men (16%) and 1,205 men (46%) experienced CV death and all-cause death, respectively. In multivariate analysis, men in the fourth quartile of LFCt (22-52 s) had an HR of 1.36 (95% CI, 1.02-1.81) and 1.35 (95% CI, 1.14-1.60) for CV and all-cause mortality, respectively, when compared with men in the first quartile (4-15 s). The results were similar when additionally adjusting for AHI, T90, or hypoxic burden. Results were stronger among men with no history of CVD at baseline. INTERPRETATION: LFCt is associated with both CV and all-cause mortality in older men, independent of baseline CV burden and SDB metrics. LFCt may be a novel physiologic marker for subclinical CVD and adverse outcomes in patients with SDB.

Author(s): Lee, Soomi; Stone, Katie L; Engeland, Christopher G; Lane, Nancy E; Buxton, Orfeu M | Abstract: ObjectiveTo examine the associations of prevalent arthritis with systemic inflammation in older men and to test whether sleep health mediates the associations.MethodsCross-sectional data came from 2,562 community-dwelling older men (all were age 65 years or older; mean age 76 years) in the Osteoporotic Fractures in Men Study who participated in a sleep ancillary study in 2003-2005. Participants were classified as having osteoarthritis (OA) (24%) or rheumatoid arthritis (RA) (0.7%) based on self-reported diagnoses and medication use. We constructed a composite score of multidimensional sleep health (i.e., perceived sleep quality, sleepiness, frequency of daytime napping, wake after sleep onset, and sleep duration) measured by both self-report and actigraphy. We also created binary indicators of elevated inflammation using C-reactive protein (CRP) (g3 mg/liter) and interleukin-6 (IL-6) (g1.08 pg/ml) levels. Analyses controlled for age, diagnosed sleep disorders, body mass index, smoking status, relevant medication use, and comorbidities.ResultsOlder men with OA did not have higher risk of elevated CRP or IL-6 levels. However, indirect associations of OA through sleep health were found. OA was associated with poorer sleep health, which was further associated with 16% higher odds of elevated CRP (P l 0.001) and 12% higher odds of elevated IL-6 (P l 0.01) levels after controlling for OA. Older men with RA had higher odds of elevated CRP and IL-6 levels, but the associations were not mediated by sleep health.ConclusionFindings suggest that promoting sleep health may help reduce the risk of systemic inflammation in older men with OA.

Aims Apnoea-hypopnoea index (AHI), the universal clinical metric of sleep apnoea severity, poorly predicts the adverse outcomes of sleep apnoea, potentially because the AHI, a frequency measure, does not adequately capture disease burden. Therefore, we sought to evaluate whether quantifying the severity of sleep apnoea by the 'hypoxic burden' would predict mortality among adults aged 40 and older. Methods and results The samples were derived from two cohort studies: The Outcomes of Sleep Disorders in Older Men (MrOS), which included 2743 men, age 76.3 ± 5.5 years; and the Sleep Heart Health Study (SHHS), which included 5111 middle-aged and older adults (52.8% women), age: 63.7 ± 10.9 years. The outcomes were all-cause and Cardiovascular disease (CVD)-related mortality. The hypoxic burden was determined by measuring the respiratory event-associated area under the desaturation curve from pre-event baseline. Cox models were used to calculate the adjusted hazard ratios for hypoxic burden. Unlike the AHI, the hypoxic burden strongly predicted CVD mortality and all-cause mortality (only in MrOS). Individuals in the MrOS study with hypoxic burden in the highest two quintiles had hazard ratios of 1.81 [95% confidence interval (CI) 1.25-2.62] and 2.73 (95% CI 1.71-4.36), respectively. Similarly, the group in the SHHS with hypoxic burden in the highest quintile had a hazard ratio of 1.96 (95% CI 1.11-3.43). Conclusion The 'hypoxic burden', an easily derived signal from overnight sleep study, predicts CVD mortality across populations. The findings suggest that not only the frequency but the depth and duration of sleep related upper airway obstructions, are important disease characterizing features.

Background/Objective Many studies have shown a U-shaped association of sleep duration with mortality; however, this association is difficult to interpret owing to possible reverse causation, residual confounding, and measurement issues. We used data from the Women's Health Initiative to examine the associations of sleep duration, insomnia, and use of sleep aids with death from cardiovascular disease (CVD), cancer, “other” causes, and all causes combined. Methods Cox proportional hazards models were used in the analysis of baseline data and in time-dependent analyses of repeated measures to estimate associations of sleep-related factors with mortality. Among 158,203 women with information regarding sleep, 30,400 total deaths, 8857 CVD deaths, 9284 cancer deaths, and 11,928 other deaths were ascertained over a median of 17.8 years. Results In both baseline and time-dependent analyses, both short (≤5 h) and long sleep (≥9 h) durations were associated with increased risk of total, CVD, and “other” deaths, but not with cancer deaths. Insomnia showed no association with mortality, whereas use of sleep medications was associated with an increased mortality risk. Conclusions While our findings showed a small but robust association of sleep duration with mortality in postmenopausal women, studies including objective measurements of sleep quality and efficiency are needed to clarify these associations.

Short sleep duration, recognized as a public health epidemic, is associated with adverse health conditions, yet little is known about the association between sleep and bone health. We tested the associations of usual sleep behavior and bone mineral density (BMD) and osteoporosis. In a sample of 11,084 postmenopausal women from the Women's Health Initiative (WHI; mean age 63.3 years, SD = 7.4), we performed a cross-sectional study of the association of self-reported usual hours of sleep and sleep quality (WHI Insomnia Rating Score) with whole body, total hip, femoral neck, and spine BMD using linear regression models. We also studied the association of sleep duration and quality with dual-energy X-ray absorptiometry (DXA)-defined low bone mass (T-score

Objective Several cross-sectional studies have reported an association between visual contrast sensitivity (a functional measure of low contrast vision) and poor cognitive performance or dementia, but no studies have investigated this association prospectively in a population based cohort with final adjudication of mild cognitive impairment (MCI)/dementia.

Objective The objective of this study was to examine the strength and direction of the association between urinary symptoms and both poor quality sleep and daytime sleepiness among women with urgency urinary incontinence. Methods A planned secondary analysis of baseline characteristics of participants in a multicenter, double-blinded, 12-week randomized controlled trial of pharmacologic therapy for urgency-predominant urinary incontinence in ambulatory women self-diagnosed by the 3 Incontinence Questions was performed. Urinary symptoms were assessed by 3-day voiding diaries. Quality of sleep was assessed using the Pittsburgh Sleep Quality Index (PSQI) and daytime sleepiness using the Epworth Sleepiness Scale. Results Of the 640 participants, mean (SD) age was 56 (±14) years and 68% were white. Participants reported an average of 3.9 (±3.0) urgency incontinence episodes per day and 1.3 (±1.3) episodes of nocturia per night. At baseline, 57% had poor sleep quality (PSQI score, >5) and 17% reported daytime sleepiness (Epworth Sleepiness Scale score, >10). Most women (69%) did not use sleeping medication during the prior month, whereas 13% reported use of sleeping medication 3 or more times per week. An increase in total daily incontinence episodes, total daily urgency incontinence episodes, total daily micturitions, and moderate to severe urge sensations were all associated with higher self-report of poor sleep quality according to the PSQI (all P ≤ 0.01). Higher scores on the Bother Scale and the Health-Related Quality of Life for overactive bladder on the Overactive Bladder Questionnaire were similarly associated with higher rates of poor sleep quality (both P ≤ 0.01). In subgroup analysis of those who took sleeping medications less than twice a week, there was still a significant relationship between incontinence measures and quality of sleep as measured by the PSQI. In multivariable analyses, greater frequency of nighttime urgency incontinence was associated with poor sleep quality (P = 0.03). Conclusions Among ambulatory women with urgency urinary incontinence, poor sleep quality is common and greater frequency of incontinence is associated with a greater degree of sleep dysfunction. Women seeking urgency urinary incontinence treatment should be queried about their sleeping habits so that they can be offered appropriate interventions.

Background Antidepressant use is very common in the elderly, but the effects of antidepressants on cognition in the elderly are controversial with some studies suggesting harm and others protection. We aimed to investigate the association between different antidepressant use and change in cognition and risk of mild cognitive impairment (MCI) or dementia in very old women. Methods We examined 1,234 community-dwelling women (mean age 83.2 years) from the Study of Osteoporotic Fractures. Baseline antidepressant use was reported and verified by medication containers, and medications were coded with computerized dictionary. Cognitive status (normal, MCI, or dementia) was adjudicated by an expert clinical panel 5 years later. Change in a short-form Mini-Mental State Examination and Trails B were evaluated over 5 years. Results Eleven per cent of the women were taking antidepressants. Users of selective serotonin reuptake inhibitors (SSRIs) had the greatest cognitive decline over 5 years, after adjustment for demographics, medical comorbidities, benzodiazepine use, and baseline cognition. Multivariable logistic regression shows that the users of SSRIs were more than twice (OR = 2.69, 95% CI = 1.64-4.41) and trazodone users more than three times (3.48, 1.12-10.81) as likely to develop MCI or dementia compared with the nonusers. Further adjustment for baseline cognition or depressive symptoms did not appreciably alter the results, and the association remained after excluding women with high depressive symptoms. The use of tricyclic antidepressants or other antidepressants was not significantly associated with cognitive outcomes. Conclusions The use of antidepressants, especially SSRIs and trazodone, was associated with an increased risk of cognitive impairment 5 years later among the oldest old women.

Epidemiologic studies have demonstrated an association of elevated plasma homocysteine levels with greater bone resorption and fracture risk. Vitamins B12 , B6 , and folic acid are cofactors in homocysteine metabolism, and supplementation with B vitamins is effective in lowering homocysteine levels in humans. However, randomized trials of supplemental B vitamins for reduction of fracture risk have been limited. Therefore, we performed an ancillary study to the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a large randomized trial of women with preexisting cardiovascular disease or three or more coronary risk factors, to test whether a daily B vitamin intervention including folic acid (2.5 mg/day), vitamin B6 (50 mg/day), and vitamin B12 (1 mg/day) reduces nonspine fracture risk over 7.3 years of treatment and follow-up. Among 4810 women, we confirmed 349 nonspine fracture cases by centralized review of medical records. In a substudy of 300 women (150 in treatment group and 150 controls) with paired plasma samples at randomization and follow-up (7.3 years later), we measured two bone turnover markers, including C-terminal cross-linking telopeptide of type I collagen (CTX) and intact type I procollagen N-propeptide (P1NP). In Cox proportional hazards models based on intention-to-treat, we found no significant effects of B vitamin supplementation on nonspine fracture risk (relative hazard = 1.08; 95% confidence interval, 0.88 to 1.34). In a nested case-cohort analysis, there were no significant effects of B vitamins on fracture risk among women with elevated plasma homocysteine levels, or low levels of vitamins B12 or B6 , or folate at baseline. Furthermore, treatment with B vitamins had no effect on change in markers of bone turnover. We found no evidence that daily supplementation with B vitamins reduces fracture risk or rates of bone metabolism in middle-aged and older women at high risk of cardiovascular disease. © 2017 American Society for Bone and Mineral Research.

Background Sleep disturbances are commonly reported by people with multiple sclerosis (PwMS). However, optimal management of sleep disturbances is uncertain, and objective studies of sleep quality in PwMS are scarce. Objectives To determine the effect of exogenous melatonin on sleep quality and sleep disturbances in PwMS. Methods Thirty adult PwMS reporting sleep difficulties were recruited in a randomized, controlled, double-blind cross-over study. They took either melatonin or placebo for 2 weeks, and the opposite for the following 2 weeks. During weeks 2 and 4, an actigraph was used to capture mean total sleep time and sleep efficiency. Patient-reported outcomes (PROs) were collected at weeks 0, 2 and 4. Results Melatonin use significantly improved mean total sleep time ( p = 0.03), with a trend towards higher sleep efficiency ( p = 0.06). No PROs were significantly different; there was a trend for melatonin use to decrease mean Insomnia Severity Index score ( p = 0.07), improve Pittsburgh Sleep Quality Index sleep quality component ( p = 0.07), and improve NeuroQoL-Fatigue ( p = 0.06). No other PROs showed differences between melatonin and placebo; nor did step count measured by actigraphy (all p > 0.45). Conclusion These results provide preliminary evidence that melatonin, a low-cost, over-the-counter supplement, could improve objective measures of sleep quality in PwMS.

Objectives The authors hypothesized that polysomnogram-based heart rate variability autonomic function biomarkers are associated with incident atrial fibrillation (AF) and these associations are modified by measures of sleep-disordered breathing. Background Autonomic dysfunction contributes to AF. Methods A total of 2,350 participants of a multicenter prospective study (Outcomes of Sleep Disorders in Older Men Study) without baseline AF underwent sleep studies with incident adjudicated AF follow-up (8.0 ± 2.6 years). Cox proportional hazard models were used to analyze sleep study–electrocardiogram spectral heart rate variability indices (low- and high-frequency power [LF/HF]) and time domain indices (mean of normal to normal beats and short- and long-term variability) and premature atrial contractions and incident AF (hazard ratio and 95% confidence interval). Statistical interactions between heart rate variability and sleep-disordered breathing were examined. Models were adjusted for age, race, body mass index, waist circumference, cardiac medications, comorbid diseases, alcohol use, and study site. Results Lower LF/HF and lower LF were associated with higher AF incidence (LF/HF Q1 vs. Q4: 1.46; 1.02 to 2.08; LF Q1 vs. Q4: 1.46; 1.02 to 2.10). Higher short- and long-term variability was associated with an increased risk of AF (p trend = 0.028). The highest premature atrial contractions quartile had a 3-fold increased AF risk (2.99; 1.94 to 4.62) compared with the lowest quartile. A significant interaction of obstructive apnea was observed in the LF-AF relationship (p = 0.045). Conclusions Sleep-related reduced sympathovagal balance (LF/HF) and increased atrial ectopy are independently associated with future AF, a relationship modified by obstructive apnea.

Background Despite the widespread belief that napping is common among older adults, little is known about the correlates of napping. We examined the prevalence and correlates of self-reported and objectively measured napping among very old women. Methods We studied 2,675 community-dwelling women (mean age 84.5 ± 3.7 years; range 79-96). Self-reported napping was defined as a report of regular napping for ≥1 hour per day. Individual objective naps were defined as ≥5 consecutive minutes of inactivity as measured by actigraphy and women were characterized as "objective nappers" if they had at least 60 minutes of naps per day. Results Seven percent of the women only had self-reported napping, 29% only had objective napping, and 14% met the criteria for both. Multinomial logistic regression showed that the independent correlates of "both subjective and objective napping" were age (per 5 year odds ratio [OR] = 1.59; 95% CI: 1.31-1.93), depressive symptoms (per SD of score, OR = 1.53; 1.32-1.77), obesity (OR =1.93; 1.42-2.61), current smoking (OR = 3.37; 1.56-7.30), heavier alcohol drinking (OR = 0.49; 0.34-0.71), history of stroke (OR = 1.56; 1.08-2.26), diabetes (OR = 2.40; 1.61-3.57), dementia (OR = 3.31; 1.27-8.62), and Parkinson's disease (OR = 7.43; 1.87-29.50). Besides, having objective napping alone was associated with age and diabetes, whereas subjective napping was associated with stroke and myocardial infarction. These associations were independent of nighttime sleep duration and fragmentation. Conclusions Daytime napping is very common in women living in their ninth decade and both subjective and objective napping were significantly related to age and comorbidities. Future studies are needed to better understand napping and its health implications.

Introduction Sleep disorders and sleep characteristics have been linked to higher risk of mortality. Despite the emerging evidence of a sleep-mortality association, the relationship between sleep architecture and mortality aren’t well understood. We hypothesize that reduced REM is associated with increased mortality risk. Methods The Osteoporotic Fractures in Men (MrOS) study is a population-based study of 2,675 older men. Cox regression was used to evaluate the association between %REM and mortality rate. Potential covariates were evaluated using 6-fold cross validation. Sensitivity analyses were performed to rule out alternative explanations. Wisconsin Sleep Cohort (WSC) and Sleep Heart Health Study (SHHS) data were used to replicate the findings. Results The MrOS sample mean age was 76.3 years (SD=5.51) and the median follow-up time was 12.1 years. There was a 13% higher rate of mortality for every absolute 5% reduction in REM sleep (HR=1.13, 95%CI, 1.08–1.19) after adjusting for multiple demographic, sleep, and health covariates. The association persisted for cardiovascular disease-related mortality (CVD) (HR=1.18, 95%CI, 1.09–1.28), cancer-related mortality (HR=1.14, 95%CI, 1.03–1.26), and other mortality (HR=1.19, 95%CI, 1.10–1.28). The WSC included 45.7% women. The mean age of the 1,388 individuals analyzed was 51.5 (SD=8.5); the median follow-up time was 20.8 years. The effect size for 5% reduction in REM on rate of all-cause mortality was similar in this cohort despite the younger age, inclusion of women, and longer follow-up period (HR=1.17, 95%CI, 1.03–1.34). SHHS data is still being analyzed; however the unadjusted model is consistent with the other cohorts. Conclusion We found an association between reduced REM and mortality in two, possibly three independent cohorts, which persisted across different causes of death and multiple sensitivity analyses. Mechanistic studies are needed and strategies to preserve REM may influence clinical therapies and reduce mortality risk. Support NHLBI provides funding for the MrOS Sleep ancillary study “Outcomes of Sleep Disorders in Older Men” under grant numbers: R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838, and R01 HL070839. Wisconsin Sleep Cohort was supported by R01HL62252, RR03186, and R01AG14124 from the NIH. Dr. Redline was partially supported by NHLBI R35 HL135818.

Objective To investigate an association between restless legs syndrome (RLS) and depression and to what extent sleep disturbance, periodic limb movements during sleep (PLMS), and antidepressant medication mediate this relationship. Methods A cross-sectional analysis was conducted of the Osteoporotic Fractures in Older Men Study data in 982 men assessed for RLS (International RLS Study Group scale [IRLSS]) and depression (Geriatric Depression Scale [GDS]), who underwent actigraphy (for sleep latency/efficiency) and polysomnography (for PLMS). Men were split into three groups: no RLS (N = 815), mild RLS (IRLSS ≤ 12, N = 85), moderate-to-severe RLS (IRLSS > 12, N = 82). Depression was defined as GDS score ≥ 6. Logistic and linear regression assessed associations of RLS and depression or number depressive symptoms, respectively. Models were adjusted for age, site, race, education, body mass index, personal habits, benzodiazepine/dopaminergic medication, physical activity, cardiovascular risk factors, and apnea-hypopnea index. Results Of 982 men, 167 (17.0%) had RLS. Depression was significantly associated with moderate-to-severe RLS after adjustment (versus no RLS: OR [95% CI] 2.85 [1.23, 6.64]). Further adjustment for potential mediators attenuated effect size modestly, most for sleep efficiency (OR: 2.85–2.55). Compared with no RLS, moderate-to-severe RLS was associated with the number of depressive symptoms after adjustment (adjusted means [95% CI]; no RLS: 1.14 [1.05, 1.24] versus IRLSS > 12: 1.69 [1.32, 2.11]). Further adjustment for potential mediators did not alter effect size. For men with PLMS index at least median, number of depressive symptoms significantly increased as RLS category became more severe. Conclusion Depression is more common as RLS severity worsens. The RLS–depression relationship is modestly explained by sleep disturbance and PLMS.

Study Objectives To determine the associations of sleep-disordered breathing (SDB) with subsequent healthcare costs and utilization including inpatient and post-acute care facility stays among community-dwelling older men. Methods Participants were 1,316 men (mean age 76.1 [SD = 5.7] years) in the Outcomes of Sleep Disorders in Older Men (MrOS sleep) study (from December 2003 to March 2005), who were enrolled in a Medicare Fee-For-Service plan. Primary SDB measures including apnea hypopnea index (AHI) and oxygen desaturation index (ODI) were collected using in-home level 2 polysomnography. Incident healthcare costs and utilization were determined from claims data in the subsequent 3-year period post-MrOS sleep visit. Results Five hundred and twenty-nine (40.2%) men had at least one hospitalization in the 3-year period. Compared with those without sleep apnea (AHI < 5/hour), men with moderate to severe sleep apnea (AHI ≥ 15/hour) had a higher odds of all-cause hospitalization (odds ratio [OR] adjusted for age and site 1.43, 95% confidence interval [CI]: 1.07–1.90). This association was slightly attenuated after further adjustment for traditional prognostic factors including education, body mass index, comorbid medical conditions, and health status (OR = 1.36; 95% CI: 1.01–1.83). Similar associations were observed for ODI. However, measures of SDB were not related to subsequent healthcare costs (total or outpatient) or odds of post-acute skilled nursing facility stay. Conclusions Older men with SDB have an increased risk of hospitalization, not entirely explained by the greater prevalence of comorbid conditions, but not higher subsequent total healthcare costs. These findings indicate a need to evaluate the impact of SDB treatment on subsequent healthcare utilization.

Background Evidence suggests that short and long sleep durations are potential lifestyle factors associated with cardiovascular disease (CVD). Research on sleep duration and CVD risk is limited by use of self-report sleep measures, homogeneous populations, and studies on individual CVD risk factors. For women, risk of CVD and inadequate sleep duration increases with age. We hypothesized that accelerometer-measured sleep duration was associated with 10-year predicted probability of future CVD risk in a cohort of aging women. Methods This cross-sectional analysis included 3,367 older women (mean age 78.9 years; 53.3% White), from the Objective Physical Activity and Cardiovascular Health Study, ancillary study to the Women’s Health Initiative. Women wore ActiGraph GT3X+ accelerometers on the hip for 24 hours/7 days. A 10-year predicted probability of future CVD risk, the Reynolds Risk Score (RRS), was computed using age, systolic blood pressure, high-sensitivity C-reactive protein (CRP), total and HDL cholesterol, diabetes mellitus status, smoking status, and family history of CVD. Average nightly sleep duration was derived from accelerometer data. Adjusted linear regression models investigated the association between sleep duration and RRS. Results Results suggested a U-shaped relationship between sleep duration and RRS, with both short and long sleep associated with higher RRS (p < .001). The association remained significant after adjustments for race/ethnicity, education, lifestyle factors, and health status indicators. Conclusion In older women, actigraphy-ascertained sleep duration was associated with a 10-year predicted probability of future CVD risk. This study supports sleep duration as a modifiable risk factor for CVD in older women.

IntroductionLittle is known about the longitudinal association between napping and cognitive impairment in older adults.MethodsWe used wrist actigraphy to measure naps in 2751 community-dwelling older men. Cognition was assessed repeatedly over 12years, and clinically significant cognitive impairment was determined by physician diagnosis, Alzheimer's medication use or a significant cognitive decline.ResultsAfter adjustment for all covariates, men with longer napping duration had greater cognitive decline and higher risk of cognitive impairment. Men who napped for ≥120min/day (vs.

In this issue of Blood, Zhang et al report on the treatment of newly diagnosed idiopathic multicentric Castleman disease (iMCD) with the combination of oral thalidomide, cyclophosphamide, and prednisone (TCP), providing an alternative to anti–interleukin-6 (IL-6) monoclonal antibodies (mAbs), especially when these are not readily available.1

Study ObjectivesBoth periodic limb movements during sleep (PLMS) and arousals are associated with sympathetic nervous system activation and may be arrhythmogenic. We hypothesize a temporal relationship exists between individual PLMS, particularly with arousal, and nonsustained ventricular tachycardia (NSVT) events.MethodsA bidirectional time-stratified case-crossover design was used to assess temporal associations between PLMS and NSVT during sleep in 49 Osteoporotic Fractures in Men Sleep Study participants with NSVT in a community-based cohort (n = 2,911). Sleep time was divided into approximate 30-min segments. For each NSVT (n = 141), we selected a preceding 30-s hazard period and three randomly chosen 30-s control periods from sleep within the same segment and evaluated for PLMS, respiratory events, minimum saturation, and arousals. Odds ratios and 95% confidence intervals—OR (95% CI)—were determined by conditional logistic regression; covariates included EEG arousals, minimum saturation, and respiratory events in the same hazard/control period.ResultsParticipants with NSVT were 79.5 ± 6.2 years with a PLMS index of 32.1 (IQR: 10.1, 61.4) and apnea–hypopnea index of 17.1 (IQR: 9.4, 26.1). PLMS without arousal were not significantly associated with NSVT (OR = 0.80, 95% CI: 0.41–1.59). PLMS with arousal were associated with NSVT in unadjusted analyses (OR = 2.50, 95% CI: 1.11–5.65) and after adjustment (OR = 2.31, 95% CI: 1.02–5.25). Arousals associated with PLMS were associated with NSVT in unadjusted (OR = 2.84, 95% CI: 1.23–6.56) and adjusted analyses (OR = 2.61, 95% CI: 1.13–6.05).ConclusionsPLMS with (but not without) arousals are temporally associated with a greater than twofold higher odds of subsequent NSVT episodes. PLMS-related arousals may be physiologically important ventricular arrhythmia triggers.Clinical Trial RegistrationClinicalTrials.gov, NCT00070681.

Sleep disturbances are common and may influence falls and fracture directly by influencing bone turnover and muscle strength or indirectly through high comorbidity or poor physical function. To investigate the association between self‐reported sleep and falls and fractures, we prospectively studied 157,306 women in the Women's Health Initiative (WHI) using information on sleep quality, sleep duration, and insomnia from questionnaires. Annual self‐report of falling two or more times (ie, “recurrent falling”) during each year of follow‐up was modeled with repeated measures logistic regression models fit by generalized estimating equations. Cox proportional hazards models were used to investigate sleep disturbance and time to first fracture. We examined the risks of recurrent falls and fracture by sleep duration with 7 hours as referent. We examined the risks across categories of sleep disturbance, insomnia status, and sleep quality. The average follow‐up time was 7.6 years for falls and 12.0 years for fractures. In multivariable adjusted models, including adjustment for comorbidity, medications, and physical function, women who were short (≤5 hours) and long (≥10 hours) sleepers had increased odds of recurrent falls (odds ratio [OR] 1.28; 95% confidence interval [CI], 1.23 to 1.34 and OR 1.25; 95% CI, 1.09 to 1.43, respectively). Poor sleep quality, insomnia, and more sleep disturbances were also associated with an increased odds of recurrent falls. Short sleep was associated with an increased risk of all fractures, and upper limb, lower limb, and central body fractures, but not hip fractures, with hazard ratios ranging from 1.10 to 1.13 (p

Background The association between diabetes and dementia may be explained in part by elevated levels of glycated peptides; we sought to determine whether serum-glycated peptides predicted cognitive decline in nondiabetic older adults. Methods We prospectively studied 525 community-dwelling nondiabetic women, mean age of 82 years, and analyzed baseline glycated peptides (serum level of fructosamine and glycated albumin). Cognitive outcomes included 5-year decline on the short Mini-Mental State Examination (sMMSE), Trails B, and performance on a battery of five other cognitive tests at the follow-up visit. Generalized linear models were adjusted for education, age, race, physical activity, body mass index, and vascular disease. Results Women with higher level of fructosamine (upper two tertiles) had greater 5-year decline in Trails B performance compared with women in the lowest tertile (adjusted mean change = 67 vs 50 seconds, p = .046), but change in sMMSE was not different between groups. Higher fructosamine was also associated with worse cognitive function 5 years later: adjusted mean score for the California Verbal Learning Test-II Short Form was 22.7 versus 23.9 (p = .010) and for Category Fluency was 10.1 versus 11.1 (p = .003). Higher glycated albumin was also associated with worse performance on Category Fluency (10.1 vs 11.1, p = .003) but not on any other test. Conclusions Among older nondiabetic women, higher concentrations of glycated peptides may be associated with greater cognitive decline, especially in measures of executive function. These associations may present new opportunities for targeted prevention and therapeutic strategies in cognitive aging.

Methodological limitations preclude determination of the association between sleep duration and bone mineral density (BMD) from existing literature. This was the first study to use objective sleep duration to determine its association with BMD. Nocturnal sleep duration, assessed objectively (actigraphy) or subjectively (questionnaire), was not independently associated with BMD in postmenopausal women. Both long and short self-reported sleep durations are associated with low bone mineral density (BMD) in men and women. The association between sleep duration measured by actigraphy and BMD in postmenopausal women is unknown. The Study of Osteoporotic Fractures (SOF) ancillary sleep study was used to determine the association between sleep duration and BMD at the total hip and femoral neck in postmenopausal women ≥ 75 years old. Sleep duration was assessed by wrist actigraphy (average 4 nights) and questionnaire. BMD was compared between postmenopausal women with short (

Castleman disease (CD) describes a spectrum of heterogeneous disorders defined by characteristic lymph node histopathology. Enlarged lymph nodes demonstrating CD histopathology can occur in isolation (unicentric CD; UCD) sometimes accompanied by mild symptoms, or at multiple sites (multicentric CD, MCD) with systemic inflammation and cytokine-driven multi-organ dysfunction. The discovery that Kaposi sarcoma herpesvirus/human herpesvirus (HHV)-8 drives MCD in a subset of patients has led to the hypotheses that UCD and MCD patients with negative HHV-8 testing by conventional methods may represent false negatives, or that these cases are driven by another virus, known or unknown. To investigate these hypotheses, the virome capture sequencing for vertebrate viruses (VirCapSeq-VERT) platform was employed to detect RNA transcripts from known and novel viruses in fresh frozen lymph node tissue from CD patients (12 UCD, 11 HHV-8-negative MCD [idiopathic MCD; iMCD], and two HHV-8-positive MCD) and related diseases (three T cell lymphoma and three Hodgkin lymphoma). This assay detected HHV-8 in both HHV-8-positive cases; however, HHV-8 was not found in clinically HHV-8-negative iMCD or UCD cases. Additionally, no novel viruses were discovered, and no single known virus was detected with apparent association to HHV-8-negative CD cases. Herpesviridae family members, notably including Epstein-Barr virus (EBV), were detected in 7 out of 12 UCD and 5 of 11 iMCD cases with apparent correlations with markers of disease severity in iMCD. Analysis of a separate cohort of archival formalin-fixed, paraffin-embedded lymph node tissue by In situ hybridization revealed significantly fewer EBV-positive cells in UCD and iMCD compared to tissue from HHV-8-positive MCD and EBV-associated lymphoproliferative disorder. In an additional cohort, quantitative testing for EBV by PCR in peripheral blood during disease flare did not detect systemic EBV viremia, suggesting detection lymph node tissue is due to occult, local reactivation in UCD and iMCD. This study confirms that HHV-8 is not present in UCD and iMCD patients. Further, it fails to establish a clear association between any single virus, novel or known, and CD in HHV-8-negative cases. Given that distinct forms of CD exist with viral and non-viral etiological drivers, CD should be considered a group of distinct and separate diseases with heterogeneous causes worthy of further study.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

We examined the association of arthritis with sleep health in older men, and whether sleep health mediates the associations of arthritis with systemic inflammation. Data came from 2,560 community-dwelling older men. Participants reported whether they had osteoarthritis (OA) or rheumatoid arthritis (RA). We constructed sleep health index (self-reported sleep quality, sleepiness; actigraphy-assessed wake-after-sleep-onset, sleep duration, and napping, Range=0–5) and binary indicators of elevated inflammation using C-reactive protein (CRP) and interleukin-6 (IL-6). Analyses adjusted for age, sleep disorders, comorbidities, BMI, smoking status, and relevant medication use. Older men with OA or RA had poorer sleep health. Poorer sleep health was associated with 16%-15% higher risk of elevated CRP and 12%-11% higher risk of elevated IL-6, respectively, after controlling separately for OA or RA. The associations of OA or RA with inflammation were mediated by poorer sleep health. Promoting sleep health may reduce associations between older men’s arthritis and high systemic inflammation.

This study aimed to examine relationship between periodic limb movements during sleep (PLMS) and incident atrial fibrillation/flutter (AF).Prospective multicenter cohort (n = 2273: adjudicated AF group; n = 843: self-reported AF group) of community-dwelling men without prevalent AF were followed for an average of 8.3 years (adjudicated) and 6.5 years (self-reported). PLMS index (PLMI,5 (ref), ≥5 to30, ≥30) and PLM arousal index (PLMAI,1 (ref), ≥1 to5, ≥5) were measured by polysomnography. Incident adjudicated and self-reported AF were analyzed by Cox proportional hazards and logistic regression, respectively, and adjusted for age, clinic, race, body mass index (BMI), alcohol use, cholesterol level, cardiac medications, pacemaker, apnea-hypopnea index, renal function, and cardiac risk. The interaction of age and PLMS was examined.In this primarily Caucasian (89.8%) cohort of older men (mean age 76.1 ± 5.5 years) with BMI of 27.2 ± 3.7, there were 261 cases (11.5%) of adjudicated and 85 cases (10.1%) of self-reported incident AF. In the overall cohort, PLMI and PLMAI were not associated with adjudicated or self-reported AF. There was some evidence of an interaction of age and PLMI (p = 0.08, adjudicated AF) and PLMAI (p ≤ 0.06, both outcomes). Among men aged ≥76 years, the highest PLMI tertile was at increased risk of adjudicated AF (≥30 vs.5; hazard ratio (HR) = 1.63, 1.01-2.63) and the middle PLMAI tertile predicted increased risk of both outcomes (1 to5 vs.1; adjudicated, HR = 1.65, 1.05-2.58; self-reported HR = 5.76, 1.76-18.84). No such associations were found in men aged76 years.Although PLMS do not predict AF incidence in the overall cohort, the findings suggest PLMS increases incident AF risk in the older subgroup.

STUDY OBJECTIVES To evaluate the association between obstructive airway disease (OAD) and sleep apnea in older men. METHODS A community-based cross-sectional study of 853 community-dwelling older men (mean age 80.7 ± 4.1 years [range 73 to 90]) across 6 centers in the United States from the Outcomes of Sleep Disorders in Older Men Study. Sleep was objectively measured using full in-home polysomnography and lung function was objectively measured using spirometry. The association of OAD (pre-bronchodilator FEV1/FVC ratio < 0.7 and FEV1 < 80% predicted) and sleep apnea (apnea-hypopnea index [AHI] ≥ 15 events/hour) was assessed using logistic regression. RESULTS OAD and sleep apnea were identified in 111 (13.0%) and 247 (29.0%) men, respectively. In univariate analysis, participants with OAD had a lower AHI (mean ± SD; 8.7 ± 11.7 vs. 12.7 ± 13.8, P = 0.0009) and a lower prevalence of sleep apnea (14.4 vs. 31.1%, P = 0.0003) compared to participants without OAD. OAD remained independently associated with a lower odds of sleep apnea (odds ratio 0.30, 95% CI 0.16 to 0.55, P = 0.0001) after adjustment for demographics, body composition, smoking, and potential mediators (arousal index, time spent in rapid eye movement sleep). Individuals with OAD and sleep apnea (n = 16) had an increased arousal index and lower oxygen saturation level as compared to individuals with OAD alone (P values < 0.05). CONCLUSIONS Obstructive airway disease was associated with a lower prevalence of sleep apnea in a cohort of community-dwelling elderly men, and unexplained by differences in adiposity or sleep architecture. Although uncommon in this cohort, coexisting sleep apnea and OAD was associated with increased sleep fragmentation and nocturnal oxygen desaturation compared to OAD alone.

Background Prior studies suggested an association between bisphosphonates and atrial fibrillation/flutter (AF) in women. This relationship in men, including those with sleep-disordered breathing (SDB), remains unclear. This study evaluated the relationship between bisphosphonate use and prevalent (nocturnal) and incident (clinically relevant) AF in a population of community-dwelling older men. Methods A total of 2,911 male participants (mean age, 76 years) of the prospective observational Osteoporotic Fractures in Men Study sleep cohort with overnight in-home polysomnography (PSG) constituted the analytic cohort. Nocturnal AF from ECGs during PSG and incident AF events were centrally adjudicated. The association of bisphosphonate use and AF was examined using multivariable-adjusted logistic regression for prevalent AF and Cox proportional hazards regression for incident AF. Results A total of 123 (4.2%) men were current bisphosphonate users. Prevalent nocturnal AF was present in 138 participants (4.6%). After multivariable adjustment, there was a significant association between current bisphosphonate use and prevalent AF (OR, 2.33; 95% CI, 1.13-4.79). In the subset of men with moderate to severe SDB, this association was even more pronounced (OR, 3.22; 95% CI, 1.29-8.03). However, the multivariable-adjusted relationship between bisphosphonate use and incident AF did not reach statistical significance (adjusted hazard ratio, 1.53; 95% CI, 0.96-2.45). Conclusions These results support an association between bisphosphonate use and prevalent nocturnal AF in community-dwelling older men. The data further suggest that those with moderate to severe SDB may be a particularly vulnerable group susceptible to bisphosphonate-related AF. Similar associations were not seen for bisphosphonate use and clinically relevant incident AF.

Seasonal nadirs in 25-hydroxyvitamin D (25[OH]D) concentrations overlap with increased incidence and severity of obstructive sleep apnea (OSA) in winter. We hypothesized that, because lower 25(OH)D concentrations might lead to upper airway muscle dysfunction, low 25(OH)D would be associated with higher apnea-hypopnea index (AHI), a measure of OSA severity.To determine if lower 25(OH)D concentration is associated with greater prevalence and increased severity of OSA, independent of established OSA risk factors.Using unconditional logistic regression, we performed a cross-sectional analysis in the Outcomes of Sleep Disorders in Older Men study, which included in-home overnight polysomnography, serum 25(OH)D measurement, and collection of demographic and comorbidity data. The primary outcome was severe sleep apnea, as defined by AHI of 30/h or more.Among 2,827 community-dwelling, largely white (92.2%), elderly (aged 76.4 ± 5.5 yr [mean±SD]) males, mean 25(OH)D concentration was 28.8 (±8.8) ng/ml. Subjects within the lowest quartile of 25(OH)D (6-23 ng/ml) had greater odds of severe sleep apnea in unadjusted analyses (odds ratio = 1.45; 95% confidence interval = 1.02-2.07) when compared with the highest 25(OH)D quartile (35-84 ng/ml). However, further adjustment for established OSA risk factors strongly attenuated this association (multivariable adjusted odds ratio = 1.05; 95% confidence interval = 0.72-1.52), with body mass index and neck circumference as the main confounders. There was also no evidence of an independent association between lower 25(OH)D levels and increased odds of mild (AHI = 5.0-14.9/h) or moderate (AHI = 15.0-29.9/h) sleep apnea.Among community-dwelling older men, the association between lower 25(OH)D and sleep apnea was largely explained by confounding by larger body mass index and neck circumference.

Although research supports a sleep-disordered breathing and atrial fibrillation association, prospective data examining sleep-disordered breathing predicting incident atrial fibrillation are lacking.To investigate sleep-disordered breathing indices as predictors of incident atrial fibrillation.A cohort (n = 843) of ambulatory older men without prevalent atrial fibrillation was assessed for baseline sleep indices: apnea-hypopnea index, central sleep apnea (central apnea index, ≥5 vs.5), central sleep apnea or Cheyne-Stokes respiration, obstructive apnea-hypopnea index, and percentage of sleep time with less than 90% oxygen saturation. Incident clinically symptomatic adjudicated or self-reported atrial fibrillation outcome was ascertained (mean follow-up, 6.5 ± 0.7 yr). We used logistic regression models adjusted for age, race, body mass index, cardiopulmonary disease, alcohol use, pacemaker, cholesterol, cardiac medications, and alternate apnea type for obstructive and central apnea. Age interaction terms and median age-stratified analyses were performed.Central sleep apnea (odds ratio [OR], 2.58; 95% confidence interval [CI], 1.18-5.66) and Cheyne-Stokes respiration with central sleep apnea (OR, 2.27; 95% CI, 1.13-4.56), but not obstructive apnea or hypoxemia, predicted incident atrial fibrillation. Central apnea, Cheyne-Stokes respiration, and sleep-disordered breathing-age interaction terms were significant (P 0.05). Unlike the case with younger participants, among participants aged 76 years or older (albeit with small atrial fibrillation counts), atrial fibrillation was related to central apnea (OR, 9.97; 95% CI, 2.72-36.50), Cheyne-Stokes respiration with central apnea (OR, 6.31; 95% CI, 1.94-20.51), and apnea-hypopnea index (OR, 1.22; 95% CI, 1.08-1.39 [per 5-unit increase]).In older men, central apnea and Cheyne-Stokes respiration predicted increased atrial fibrillation risk, with findings being strongest in older participants in whom overall sleep-disordered breathing also increased atrial fibrillation risk.

Nocturnal cardiac conduction abnormalities are commonly observed in patients with sleep-disordered breathing (SDB). However, few population-based studies have examined the association between SDB and daytime cardiac conduction abnormalities. We examined a random sample of 471 community-dwelling men, aged ≥67 years, enrolled in the multi-center Outcomes of Sleep Disorders in Older Men (MrOS Sleep) study. SDB severity was categorized using percent of total sleep time with oxygen saturation

Study objectives Men with sleep disordered breathing (SDB) may be at increased stroke risk, due to nocturnal hypoxemia, sleep loss or fragmentation, or other mechanisms. We examined the association of SDB with risk of incident stroke in a large cohort of older men. Methods Participants were 2,872 community-dwelling men (mean age 76 years) enrolled in the MrOS Sleep Study, which gathered data from 2003 to 2005 at six clinical sites in the Unites States. SDB predictors (obstructive apnea-hypopnea index, apnea-hypopnea index, central apnea index, and nocturnal hypoxemia) were measured using overnight polysomnography. Incident stroke over an average follow-up of 7.3 years was centrally adjudicated by physician review of medical records. Results One hundred fifty-six men (5.4%) had a stroke during follow-up. After adjustment for age, clinic site, race, body mass index, and smoking status, older men with severe nocturnal hypoxemia (≥ 10% of the night with SpO2 levels below 90%) had a 1.8-fold increased risk of incident stroke compared to those without nocturnal hypoxemia (relative hazard = 1.83; 95% confidence interval 1.12-2.98; P trend = 0.02). Results were similar after further adjustment for other potential covariates and after excluding men with a history of stroke. Other indices of SDB were not associated with incident stroke. Conclusions Older men with severe nocturnal hypoxemia are at significantly increased risk of incident stroke. Measures of overnight oxygen saturation may better identify older men at risk for stroke than measures of apnea frequency.

Sleep disturbances are common in older adults. Little is known about the sleep of cognitively intact older adults and its relationship to subsequent cognitive impairment. The objective of this study was to examine the association between objective sleep-wake measures and risk of incident cognitive impairment.In this prospective cohort study encompassing four U.S. sites, 1,245 women (mean age: 82.6 years) without dementia participated in the Study of Osteoporotic Fractures and completed actigraphy at the baseline visit and comprehensive cognitive assessment at follow-up. The association between sleep-wake patterns measured by actigraphy and risk of incident mild cognitive impairment (MCI) and dementia was examined.A total of 473 women (38%) developed cognitive impairment during an average (SD) follow-up of 4.9 (0.6) years; 290 (23.3%) developed MCI and 183 (14.7%) developed dementia. After controlling for multiple potential confounders, women in the lowest quartile of average sleep efficiency (74%) had a 1.5-fold higher odds of developing MCI or dementia compared with women in the highest quartile of sleep efficiency (86%) (odds ratio: Q1 versus Q4 1.53; 95% CI: 1.07, 2.19; Wald χ(2) [1, N = 1,223] = 5.34 for p for trend = 0.03). Longer average sleep latency, but not total sleep time, was also associated with higher odds of developing cognitive impairment. Greater variability in both sleep efficiency and total sleep time was associated with an increased odds of developing MCI or dementia.Lower average sleep efficiency, longer average sleep latency, and greater variability in sleep efficiency and total sleep time are associated with increased odds of developing cognitive impairment. Further research is needed to explore the mechanisms underlying these associations.

No systematic review of epidemiological evidence has examined risk factors for sleep disturbances among older adults. We searched the PUBMED database combining search terms targeting the following domains (1) prospective, (2) sleep, and (3) aging, and identified 21 relevant population-based studies with prospective sleep outcome data. Only two studies utilized objective measures of sleep disturbance, while six used the Pittsburgh Sleep Quality Index (PSQI) and thirteen used insomnia symptoms or other sleep complaints as the outcome measure. Female gender, depressed mood, and physical illness were most consistently identified as risks for future sleep disturbances. Less robust evidence implicated the following as potentially relevant predictors: lower physical activity levels, African-American race, lower economic status, previous manual occupation, widowhood, marital quality, loneliness and perceived stress, preclinical dementia, long-term benzodiazepine and sedative use, low testosterone levels, and inflammatory markers. Chronological age was not identified as a consistent, independent predictor of future sleep disturbances. In conclusion, prospective studies have identified female gender, depressed mood, and physical illness as general risk factors for future sleep disturbances in later life, although specific physiological pathways have not yet been established. Research is needed to determine the precise mechanisms through which these factors influence sleep over time.