Publications

STUDY OBJECTIVES: To describe racial/ethnic differences in sleep duration, continuity, and perceived sleep quality in postmenopausal women and to identify statistical mediators of differences in sleep characteristics.

METHODS: Recruited from the observational Study of Women's Health Across the Nation (SWAN), 1,203 (548 white, 303 black, 147 Chinese, 132 Japanese, and 73 Hispanic; mean age 65 years, 97% postmenopausal) women participated in a week-long actigraphy and daily diary study in 2013-2015. Actigraphic measures of sleep duration and wake after sleep onset (WASO), and diary-rated sleep quality were averaged across the week. Candidate mediators included health-related variables; stress; and emotional well-being assessed up to 13 times across 18 years from baseline to sleep study.

RESULTS: Whites slept longer than other groups; the significant mediators were concurrent financial hardship and increasing number of stressors for Hispanics or Japanese versus whites. Whites had less WASO than blacks and Hispanics; significant mediators were concurrent number of health problems, physical inactivity, waist circumference, vasomotor symptoms, number of life stressors, and financial hardship, and increasing number of health problems from baseline to sleep study. Whites reported better sleep quality than blacks, Chinese, and Japanese; significant mediators were concurrent physical inactivity, vasomotor symptoms, positive affect, and depressive symptoms.

CONCLUSIONS: Sleep differences between blacks or Hispanics versus whites were mediated by health problems, number of stressors, and financial hardship, whereas sleep differences between Chinese or Japanese versus whites were mediated by emotional well-being. This is the first study using formal mediational approaches.

In humans, circulating levels of the hormone melatonin and the initiation of spontaneous labor are both higher at night than during the day. Since activation of uterine melatonin receptors can stimulate human in vitro uterine contractions and these receptors are only expressed on the uterine tissue of women in labor, we hypothesized that circulating melatonin concentrations would affect uterine contractions in vivo. We evaluated the impact of light-induced modulation of melatonin secretion on uterine contractions in women during late third trimester ( 36-39 weeks) of pregnancy in two inpatient protocols. We found a significant (P < 0.05) positive linear association between circulating melatonin concentrations and the number of uterine contractions under both protocols. On average, uterine contractions increased between 1.4 and 2.1 contractions per 30 minutes for every 10 pg/mL*h increase in melatonin concentration. These findings have both basic science and clinical implications for pregnant women, since endogenous melatonin levels and melatonin receptor activity can be altered by light and/or pharmaceutical agents.

Establishing circadian and wake-dependent changes in the human metabolome are critical for understanding and treating human diseases due to circadian misalignment or extended wake. Here, we assessed endogenous circadian rhythms and wake-dependent changes in plasma metabolites in 13 participants (4 females) studied during 40-hours of wakefulness. Four-hourly plasma samples were analyzed by hydrophilic interaction liquid chromatography (HILIC)-LC-MS for 1,740 metabolite signals. Group-averaged (relative to DLMO) and individual participant metabolite profiles were fitted with a combined cosinor and linear regression model. In group-level analyses, 22% of metabolites were rhythmic and 8% were linear, whereas in individual-level analyses, 14% of profiles were rhythmic and 4% were linear. We observed metabolites that were significant at the group-level but not significant in a single individual, and metabolites that were significant in approximately half of individuals but not group-significant. Of the group-rhythmic and group-linear metabolites, only 7% and 12% were also significantly rhythmic or linear, respectively, in ≥50% of participants. Owing to large inter-individual variation in rhythm timing and the magnitude and direction of linear change, acrophase and slope estimates also differed between group- and individual-level analyses. These preliminary findings have important implications for biomarker development and understanding of sleep and circadian regulation of metabolism.

There is a new appreciation of the perimenopause-defined as the early and late menopause transition stages as well as the early postmenopause-as a window of vulnerability for the development of both depressive symptoms and major depressive episodes. However, clinical recommendations on how to identify, characterize and treat clinical depression are lacking. To address this gap, an expert panel was convened to systematically review the published literature and develop guidelines on the evaluation and management of perimenopausal depression. The areas addressed included: (1) epidemiology; (2) clinical presentation; (3) therapeutic effects of antidepressants; (4) effects of hormone therapy; and (5) efficacy of other therapies (e.g., psychotherapy, exercise, and natural health products). Overall, evidence generally suggests that most midlife women who experience a major depressive episode during the perimenopause have experienced a prior episode of depression. Midlife depression presents with classic depressive symptoms commonly in combination with menopause symptoms (i.e., vasomotor symptoms, sleep disturbance), and psychosocial challenges. Menopause symptoms complicate, co-occur, and overlap with the presentation of depression. Diagnosis involves identification of menopausal stage, assessment of co-occurring psychiatric and menopause symptoms, appreciation of the psychosocial factors common in midlife, differential diagnoses, and the use of validated screening instruments. Proven therapeutic options for depression (i.e., antidepressants, psychotherapy) are the front-line treatments for perimenopausal depression. Although estrogen therapy is not approved to treat perimenopausal depression, there is evidence that it has antidepressant effects in perimenopausal women, particularly those with concomitant vasomotor symptoms. Data on estrogen plus progestin are sparse and inconclusive.

BACKGROUND: Psychosocial and health-related risk factors for depressive symptoms are known. It is unclear if these are associated with depressive symptom patterns over time. We identified trajectories of depressive symptoms and their risk factors among midlife women followed over 15 years.

METHODS: Participants were 3300 multiracial/ethnic women enrolled in a multisite longitudinal menopause and aging study, Study of Women's Health Across the Nation. Biological, psychosocial, and depressive symptom data were collected approximately annually. Group-based trajectory modeling identified women with similar longitudinal patterns of depressive symptoms. Trajectory groups were compared on time-invariant and varying characteristics using multivariable multinomial analyses and pairwise comparisons.

RESULTS: Five symptom trajectories were compared (50% very low; 29% low; 5% increasing; 11% decreasing; 5% high). Relative to whites, blacks were less likely to be in the increasing trajectory and more likely to be in the decreasing symptom trajectory and Hispanics were more likely to have a high symptom trajectory than an increasing trajectory. Psychosocial/health factors varied between groups. A rise in sleep problems was associated with higher odds of having an increasing trajectory and a rise in social support was associated with lower odds. Women with low role functioning for 50% or more visits had three times the odds of being in the increasing symptom group.

CONCLUSIONS: Changes in psychosocial and health characteristics were related to changing depressive symptom trajectories. Health care providers need to evaluate women's sleep quality, social support, life events, and role functioning repeatedly during midlife to monitor changes in these and depressive symptoms.

STUDY OBJECTIVES: We compared resident physician work hours and sleep in a multicenter clustered-randomized crossover clinical trial that randomized resident physicians to an Extended Duration Work Roster (EDWR) with extended-duration (≥24 hr) shifts or a Rapidly Cycling Work Roster (RCWR), in which scheduled shift lengths were limited to 16 or fewer consecutive hours.

METHODS: Three hundred two resident physicians were enrolled and completed 370 1 month pediatric intensive care unit rotations in six US academic medical centers. Sleep was objectively estimated with wrist-worn actigraphs. Work hours and subjective sleep data were collected via daily electronic diary.

RESULTS: Resident physicians worked fewer total hours per week during the RCWR compared with the EDWR (61.9 ± 4.8 versus 68.4 ± 7.4, respectively; p < 0.0001). During the RCWR, 73% of work hours occurred within shifts of ≤16 consecutive hours. In contrast, during the EDWR, 38% of work hours occurred on shifts of ≤16 consecutive hours. Resident physicians obtained significantly more sleep per week on the RCWR (52.9 ± 6.0 hr) compared with the EDWR (49.1 ± 5.8 hr, p < 0.0001). The percentage of 24 hr intervals with less than 4 hr of actigraphically measured sleep was 9% on the RCWR and 25% on the EDWR (p < 0.0001).

CONCLUSIONS: RCWRs were effective in reducing weekly work hours and the occurrence of >16 consecutive hour shifts, and improving sleep duration of resident physicians. Although inclusion of the six operational healthcare sites increases the generalizability of these findings, there was heterogeneity in schedule implementation. Additional research is needed to optimize scheduling practices allowing for sufficient sleep prior to all work shifts.Clinical Trial: Multicenter Clinical Trial of Limiting Resident Work Hours on ICU Patient Safety (ROSTERS), https://clinicaltrials.gov/ct2/show/NCT02134847.

OBJECTIVE: Women's sleep at menopause is widely reported to be problematic. The Insomnia Severity Index (ISI) is a commonly used tool for quantifying sleep problems in clinical and research settings, but psychometric properties in postmenopausal women have not been reported. Our study aim was to examine the factor structure of the ISI in a large and diverse sample of midlife women with hot flashes.

METHODS: Baseline data were from 899 women enrolled in one of the three clinical trials using similar entry criteria conducted by the Menopause Strategies Finding Lasting Answers to Symptoms and Health research network. We conducted confirmatory factor analyses for the total sample and within strata defined by race/ethnicity (black and white women).

RESULTS: The ISI had two factors in the total sample. The two-factor structure was consistent across black and white women, with the exception of one item "difficulty falling asleep."

CONCLUSIONS: The ISI in midlife women with hot flashes is composed of two factors that capture dimensions of the insomnia severity and daytime impact. The instrument is a psychometrically sound scale appropriate for use in research and clinical practice to capture the severity and daytime impact of insomnia symptoms in diverse samples of midlife women with hot flashes. An abbreviated screening of two items could be considered to determine if further evaluation is needed of sleep complaints.

OBJECTIVES: Given the neurocognitive hyperarousal observed in patients with insomnia disorder and associations of nocturnal hot flashes with cardiovascular disease risk, we examined whether women with hot flash-associated insomnia disorder demonstrate exaggerated cardiovascular responsivity to acute stressors, and also a profile of psychological hyperarousal.

METHODS: Peri and postmenopausal women with and without hot flash-associated insomnia disorder underwent assessments of cardiovascular autonomic responsivity to acute stress paradigms and psychological hyperarousal. Hemodynamic responses (heart rate, blood pressure) to nociceptive, social-evaluative, and cognitive stress paradigms were measured in the morning. Psychological hyperarousal was evaluated using questionnaires assessing daytime and presleep hyperarousal, anxiety, and sleep-related cognitions.

RESULTS: Women (25 with and 15 without hot flash-associated insomnia) aged 53.4 ± 4.8 years reported a range of insomnia symptoms. Resting-state hemodynamics were similar between groups. Heart rate and blood pressure responses to stress paradigms did not differ by group nor did they correlate with insomnia severity. Women with insomnia disorder had higher generalized anxiety disorder scores (mean 2.7 ± 3.0 vs 1.0 ± 1.4; P = 0.05) and sleep-related cognitions than those without insomnia (P ≤ 0.05). Insomnia symptom severity was moderately correlated with presleep and daytime hyperarousal, anxiety, and sleep-related cognition (all r ≥ 0.43).

CONCLUSIONS: Though hot flash-associated insomnia is characterized by psychological hyperarousal before sleep and during the daytime, it does not relate to cardiovascular responsiveness to acute stressors. Our findings do not support the hypothesis that altered cardiovascular control is a potential mechanism by which hot flash-associated insomnia confers higher cardiovascular disease risk.

INTRODUCTION: While the Accreditation Council for Graduate Medical Education limited first year resident-physicians to 16 consecutive work hours from 2011 to 2017, resident-physicians in their second year or higher were permitted to work up to 28 h consecutively. This paper describes the Randomized Order Safety Trial Evaluating Resident-physician Schedules (ROSTERS) study, a clustered-randomized crossover clinical trial designed to evaluate the effectiveness of eliminating traditional shifts of 24 h or longer for second year or higher resident-physicians in pediatric intensive care units (PICUs).

METHODS: ROSTERS was a multi-center non-blinded trial in 6 PICUs at US academic medical centers. The primary aim was to compare patient safety between the extended duration work roster (EDWR), which included shifts ≥24 h, and a rapidly cycling work roster (RCWR), where shifts were limited to a maximum of 16 h. Information on potential medical errors was gathered and used for classification by centrally trained physician reviewers who were blinded to the study arm. Secondary aims were to assess the relationship of the study arm to resident-physician sleep duration, work hours and neurobehavioral performance.

RESULTS: The study involved 6577 patients with a total of 38,821 patient days (n = 18,749 EDWR, n = 20,072 RCWR). There were 413 resident-physician rotations included in the study (n = 203 EDWR, n = 210 RCWR). Resident-physician questionnaire data were over 95% complete.

CONCLUSIONS: Results from data collected in the ROSTERS study will be evaluated for the impact of resident-physician schedule roster on patient safety outcomes in PICUs, and will allow for examination of a number of secondary outcome measures. ClinicalTrials.gov Identifier: NCT02134847.

Light is the most effective environmental stimulus for shifting the mammalian circadian pacemaker. Numerous studies have been conducted across multiple species to delineate wavelength, intensity, duration, and timing contributions to the response of the circadian pacemaker to light. Recent studies have revealed a surprising sensitivity of the human circadian pacemaker to short pulses of light. Such responses have challenged photon counting-based theories of the temporal dynamics of the mammalian circadian system to both short- and long-duration light stimuli. Here, we collate published light exposure data from multiple species, including gerbil, hamster, mouse, and human, to investigate these temporal dynamics and explore how the circadian system integrates light information at both short- and long-duration time scales to produce phase shifts. Based on our investigation of these data sets, we propose 3 new interpretations: (1) intensity and duration are independent factors of total phase shift magnitude, (2) the possibility of a linear/log temporal function of light duration that is universal for all intensities for durations less than approximately 12 min, and (3) a potential universal minimum light duration of  0.7 sec that describes a "dead zone" of light stimulus. We show that these properties appear to be consistent across mammalian species. These interpretations, if confirmed by further experiments, have important practical implications in terms of understanding the underlying physiology and for the design of lighting regimens to reset the mammalian circadian pacemaker.