Sleep and long COVID: Preexisting sleep issues and the risk of PASC in a large general population using 3 different model definitions.

Study Objectives: Insomnia, poor sleep quality and extremes of sleep duration are associated with COVID-19 infection. This study assessed whether these factors are related to Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Methods: Cross-sectional survey of a general population of 24,803 U.S. adults to determine the association of insomnia, poor sleep quality and sleep duration with PASC. Results: Prevalence rates of PASC among previously COVID-19 infected participants for three definitions of PASC were COPE (21.9%), NICE (38.9%) and RECOVER PASC Score (15.3%). PASC was associated with insomnia in all 3 models in fully adjusted models with adjusted odds ratios (aORs) and 95% confidence intervals (CI) ranging from 1.30 (95% CI: 1.11-1.52, p≤0.05, PASC Score) to 1.52 (95% CI: 1.34-1.71, p≤0.001, (NICE). Poor sleep quality was related to PASC in all models with aORs ranging from 1.77 (95% CI: 1.60-1.97, p≤0.001, NICE) to 2.00 (95% CI: 1.77-2.26, p≤0.001, COPE). Sleep <6 hours was associated with PASC with aORs between 1.59 (95% CI: 1.40-1.80, p≤0.001, PASC Score) to 1.70 (95% CI: 1.53-1.89, p≤0.001, COPE). Sleep > 9 hours was not associated with PASC in any model. Although vaccination with COVID-19 booster decreased the likelihood of developing PASC, it did not attenuate associations between insomnia, poor sleep quality and short sleep duration with PASC in any of the models. Conclusions: Insomnia, poor sleep quality and short sleep duration are potential risk factors for PASC. Interventions to improve sleep may decrease the development of PASC. Brief Summary: Current Knowledge/Study Rationale: Insomnia, poor sleep quality, and extremes of sleep duration have been associated with a higher likelihood of COVID-19 infection. However, evidence implicating an association with the development of Post-Acute Sequelae of SARS-CoV-2 infection (PASC) is scant.Study Impact: Results indicate that insomnia, poor sleep quality and sleep duration < 6 hours are associated with an increase in the prevalence of PASC among persons who have previously had a COVID-19 infection. The findings provide support for employing interventions to improve sleep as a means to decrease the development of PASC.

Time of Day and Sleep Deprivation Effects on Risky Decision Making.

Previous research has revealed that daily variations in human neurobehavioral functions are driven in part by the endogenous circadian system. The objective of this study was to explore whether there exists a circadian influence on performance regarding a risky decision-making task and to determine whether the performance changes with sleep deprivation (SD). Thirteen participants underwent a 39 h constant routine (CR) protocol, during which they remained awake in constant conditions and performed the BART (balloon analogue risk task) every two hours. The mean pumps (gains) (p < 0.001) and balloons popped (losses) (p = 0.003) exhibited variation during the CR. The reaction time (RT) also showed significant variation across the CR (p < 0.001), with slower mean RTs in the morning hours following SD. A greater risk propensity was observed around midday before SD and a lower risk propensity after 29.5 h of being awake. The sensitivity to punishment varied during the CR, but did not follow a predictable trend. Further research using real monetary incentives and neurophysiological measures is warranted to elucidate these findings.

The effect of a dynamic lighting schedule on neurobehavioral performance during a 45-day simulated space mission.

Study Objectives: We previously reported that during a 45-day simulated space mission, a dynamic lighting schedule (DLS) improved circadian phase alignment and performance assessed once on selected days. This study aimed to evaluate how DLS affected performance on a 5-minute psychomotor vigilance task (PVT) administered multiple times per day on selected days. Methods: Sixteen crewmembers (37.4 ±â€…6.7 years; 5F) underwent six cycles of 2 × 8-hour/night followed by 5 × 5-hour/night sleep opportunities. During the DLS (n = 8), daytime white light exposure was blue-enriched (~6000 K; Level 1: 1079, Level 2: 76 melanopic equivalent daytime illuminance (melEDI) lux) and blue-depleted (~3000-4000 K; L1: 21, L2: 2 melEDI lux) 3 hours before bed. In the standard lighting schedule (SLS; n = 8), lighting remained constant (~4500K; L1: 284, L2 62 melEDI lux). Effects of lighting condition (DLS/SLS), sleep condition (5/8 hours), time into mission, and their interactions, and time awake on PVT performance were analyzed using generalized linear mixed models. Results: The DLS was associated with fewer attentional lapses (reaction time [RT] > 500 milliseconds) compared to SLS. Lapses, mean RT, and 10% fastest/slowest RTs were worse following 5 compared to 8 hours of sleep but not between lighting conditions. There was an effect of time into mission on RTs, likely due to sleep loss. Overall performance differed by time of day, with longer RTs at the beginning and end of the day. There were more lapses and slower RTs in the afternoon in the SLS compared to the DLS condition. Conclusions: Future missions should incorporate DLS to enhance circadian alignment and performance. This paper is part of the Sleep and Circadian Rhythms: Management of Fatigue in Occupational Settings Collection.

Association of Chronotype and Shiftwork with COVID-19 Infection.

OBJECTIVE: This study assesses whether chronotype is related to COVID-19 infection and whether there is an interaction with shift work. METHODS: Cross-sectional survey of 19,821 U.S. adults. RESULTS: COVID-19 infection occurred in 40% of participants, 32.6% morning and 17.2% evening chronotypes. After adjusting for demographic and socioeconomic factors, shift/remote work, sleep duration and comorbidities, morning chronotype was associated with a higher (aOR: 1.15, 95% CI 1.10-1.21) and evening chronotype with a lower (aOR: 0.82, 95% CI: 0.78-0.87) prevalence of COVID-19 infection in comparison to an intermediate chronotype. Working exclusively night shifts was not associated with higher prevalence of COVID-19. Morning chronotype and working some evening shifts was associated with the highest prevalence of previous COVID-19 infection (aOR: 1.87, 95% CI: 1.28-2.74). CONCLUSION: Morning chronotype and working a mixture of shifts increase risk of COVID-19 infection.

Association of Obstructive Sleep Apnea with Post-Acute Sequelae of SARS-CoV-2 Infection.

BACKGROUND: Obstructive sleep apnea is associated with COVID-19 infection. Less clear is whether obstructive sleep apnea is a risk factor for the development of post-acute sequelae of SARS-CoV-2 infection (PASC). STUDY DESIGN: Cross-sectional survey of a general population of 24,803 US adults to determine the association of obstructive sleep apnea with PASC. RESULTS: COVID-19 infection occurred in 10,324 (41.6%) participants. Prevalence of persistent (>3 months post infection) putative PASC-related physical and mental health symptoms ranged from 6.5% (peripheral edema) to 19.6% (nervous/anxious). In logistic regression models, obstructive sleep apnea was associated with all putative PASC-related symptoms with the highest adjusted odds ratios being fever (2.053) and nervous/anxious (1.939). In 4 logistic regression models of overall PASC derived from elastic net regression, obstructive sleep apnea was associated with PASC (range of adjusted odds ratios: 1.934-2.071); this association was mitigated in those with treated obstructive sleep apnea. In the best fitting overall model requiring ≥3 symptoms, PASC prevalence was 21.9%. CONCLUSION: In a general population sample, obstructive sleep apnea is associated with the development of PASC-related symptoms and a global definition of PASC. Treated obstructive sleep apnea mitigates the latter risk. The presence of 3 or more PASC symptoms may be useful in identifying cases and for future research.

Circadian protein expression patterns in healthy young adults.

OBJECTIVES: To explore how the blood plasma proteome fluctuates across the 24-hour day and identify a subset of proteins that show endogenous circadian rhythmicity. METHODS: Plasma samples from 17 healthy adults were collected hourly under controlled conditions designed to unmask endogenous circadian rhythmicity; in a subset of 8 participants, we also collected samples across a day on a typical sleep-wake schedule. A total of 6916 proteins were analyzed from each sample using the SomaScan aptamer-based multiplexed platform. We used differential rhythmicity analysis based on a cosinor model with mixed effects to identify a subset of proteins that showed circadian rhythmicity in their abundance. RESULTS: One thousand and sixty-three (15%) proteins exhibited significant daily rhythmicity. Of those, 431 (6.2%) proteins displayed consistent endogenous circadian rhythms on both a sleep-wake schedule and under controlled conditions: it included both known and novel proteins. When models were fitted with two harmonics, an additional 259 (3.7%) proteins exhibited significant endogenous circadian rhythmicity, indicating that some rhythmic proteins cannot be solely captured by a simple sinusoidal model. Overall, we found that the largest number of proteins had their peak levels in the late afternoon/evening, with another smaller group peaking in the early morning. CONCLUSIONS: This study reveals that hundreds of plasma proteins exhibit endogenous circadian rhythmicity in humans. Future analyses will likely reveal novel physiological pathways regulated by circadian clocks and pave the way for improved diagnosis and treatment for patients with circadian disorders and other pathologies. It will also advance efforts to include knowledge about time-of-day, thereby incorporating circadian medicine into personalized medicine.

Eating during the biological night is associated with nausea.

OBJECTIVES: This study assessed whether there was a time-of-day effect on nausea reports in participants during studies employing circadian protocols. METHODS: Visual-analog-scales of nausea ratings were recorded from 34 participants (18-70years; 18 women) during forced desynchrony studies, where meals were scheduled at different circadian phases. Subjective nausea reports from a further 81 participants (18-35years; 36 women) were recorded during constant routine studies, where they ate identical isocaloric hourly snacks for 36-40 hours. RESULTS: Feelings of nausea varied by circadian phase in the forced desynchrony studies, peaking during the biological night. Nausea during the constant routine was reported by 27% of participants, commencing 2.9 ± 5.2 hours after the midpoint of usual sleep timing, but was never reported to start in the evening (4-9 PM). CONCLUSIONS: Nausea occurred more often during the biological night and early morning hours. This timing is relevant to overnight and early morning shift workers and suggests that a strategy to counteract that is to pay careful attention to meal timing.

Public opinion of resident physician work hours in 2022.

OBJECTIVE: The purpose of this study was to characterize public awareness and opinion regarding resident physician work hours in the United States. METHODS: We conducted a nationally representative cross-sectional survey among adults in the United States. Demographic quota-based sampling was conducted by Qualtrics to match 2020 United States Census estimates of age, sex, race, and ethnicity. Descriptive statistics are presented. Hypothesis testing was conducted to identify characteristics associated with agreement with current resident physician work-hour policies. RESULTS: 4763 adults in the United States participated in the study. 97.1% of the public believes that resident physicians should not work 24-hour shifts and 95.6% believe the current 80 hours resident work week is too long. 66.4% of the participants reported that the maximum shift duration should be 12 consecutive hours or fewer, including 22.9% who recommended a maximum shift length of 8 hours. Similarly, 66.4% reported that maximum weekly work hours should be 59 or fewer, including 24.9% who recommended a maximum of 40 weekly work hours. CONCLUSIONS: Nearly all US adults disagree with current work-hour policies for resident physicians. Public opinion supports limiting shifts to no more than 12 consecutive hours and weekly work to no more than 60 hours, which is in sharp contrast to current regulations that permit of 28 hours shifts and 80 hours of work per week.

Circadian- and wake-dependent influences on face-name memory in healthy men and women over 3weeks of chronic sleep restriction.

OBJECTIVES: Facial recognition is one of the key functions of the human brain, and linking a face to a name is critical in many social and occupational settings. This study assessed circadian- and wake-dependent effects on face-name recognition in healthy adults. METHODS: Thirteen healthy adults (20-70years; 7 F) were studied in a 39-day inpatient protocol that included 3weeks of 28 hours forced desynchrony with sleep restriction (6.5:21.5 hours sleep:wake). Starting 3 hours after scheduled wake, 6 novel face-name pairs were presented every 4 waking hours; recognition was tested 2 hours later. Performance data were averaged across ∼4 hours circadian phase or time-awake bins. RESULTS: Face-name recognition deteriorated with increased time awake (p < .0001) and exhibited significant circadian variation (p < .0001), with worst performance shortly after the core temperature nadir. There was a significant interaction between sex and circadian phase (p = .0177), with women performing significantly better than men at all circadian phases except 60° and 120°. Women exhibited a significantly higher amplitude than men during the third week of forced desynchrony (p < .01). CONCLUSIONS: Like many other aspects of neurobehavioral performance, recalling face-name associations is impacted by both duration of time awake and circadian phase. These results have implications for face recognition testing in medical contexts, such as in testing for dementia, because performance may be impacted by sleep deficiency and the time of testing.

Predicting neurobehavioral performance of resident physicians in a Randomized Order Safety Trial Evaluating Resident-Physician Schedules (ROSTERS).

OBJECTIVES: Mathematical models of human neurobehavioral performance that include the effects of acute and chronic sleep restriction can be key tools in assessment and comparison of work schedules, allowing quantitative predictions of performance when empirical assessment is impractical. METHODS: Using such a model, we tested the hypothesis that resident physicians working an extended duration work roster, including 24-28 hours of continuous duty and up to 88 hours per week averaged over 4weeks, would have worse predicted performance than resident physicians working a rapidly cycling work roster intervention designed to reduce the duration of extended shifts. The performance metric used was attentional failures (ie, Psychomotor Vigilance Task lapses). Model input was 169 actual work and sleep schedules. Outcomes were predicted hours per week during work hours spent at moderate (equivalent to 16-20 hours of continuous wakefulness) or high (equivalent to ≥20 hours of continuous wakefulness) performance impairment. RESULTS: The model predicted that resident physicians working an extended duration work roster would spend significantly more time at moderate impairment (p = .02, effect size=0.2) than those working a rapidly cycling work roster; this difference was most pronounced during the circadian night (p < .001). On both schedules, performance was predicted to decline from weeks 1 + 2 to weeks 3 + 4 (p < .001), but the rate of decline was significantly greater on extended duration work roster (p < .01). Predicted performance impairment was inversely related to prior sleep duration (p < .001). CONCLUSIONS: These findings demonstrate the utility of a mathematical model to evaluate the predicted performance profile of schedules for resident physicians and others who experience chronic sleep restriction and circadian misalignment.

Influence of circadian phase and extended wakefulness on glucose levels during forced desynchrony.

OBJECTIVES: Circadian misalignment and sleep deprivation often occur in tandem, and both negatively impact glucose homeostasis and metabolic health. The present study employed a forced desynchrony protocol to examine the influence of extended wakefulness and circadian misalignment on hourly glucose levels. METHODS: Nine healthy adults (4F/5M; 26 ± 4years) completed a 31-day in-laboratory protocol. After three 24 hour baseline days with 8 hours scheduled sleep opportunities, participants were scheduled to 14 consecutive 42.85 hour sleep-wake cycles, with 28.57 hours extended wakefulness and 14.28 hours sleep opportunities each cycle. Blood was sampled hourly across the forced desynchrony and over 600 plasma samples per participant were analyzed for glucose levels. RESULTS: Both hours into the 42.85 hours forced desynchrony day and circadian phase modulated glucose levels (p < .0001). Glucose peaked after each meal during scheduled wakefulness and decreased during scheduled sleep/fasting. Glucose levels were, on average, lowest during the biological daytime and rose throughout the biological night, peaking in the biological morning. When analyzed separately for scheduled sleep vs. wakefulness, the peak timing of the circadian rhythm in glucose was later during sleep (p < .05). Glucose area under the curve levels increased rapidly from the beginning of the forced desynchrony protocol and were highest on the second forced desynchrony day (p < .01), returning towards forced desynchrony day 1 levels thereafter. CONCLUSIONS: These findings have important implications for understanding factors contributing to altered glucose metabolism during sleep loss and circadian misalignment, and for potential physiological adaptation of metabolism in healthy adults, who are increasingly exposed to such conditions in our society.

Entrainment to gradual vs. immediate 8-hour phase advance shifts with and without short-wavelength enriched polychromatic green light.

OBJECTIVES: For optimal health and well-being the sleep episode and the circadian timing system should be properly aligned. We evaluated the effectiveness of different dynamic light and sleep/wake shift schedules for rapid circadian entrainment following an 8-hour advance of sleep. METHODS: Forty-three healthy participants completed an 8-day inpatient protocol in which the 8-hour sleep episode was advanced by 8 hours. Participants were assigned to one of five conditions: (1) dim ambient WHITE light and GRADUAL shift in which the sleep episode was incrementally advanced over 5days; (2) dim GREEN, short-wavelength (∼504 nm) polychromatic light and GRADUAL shift; (3) dim WHITE light and SLAM shift, including an abrupt 8-hour advance on day 3 following an extended 32-hour wake episode; (4) GREEN light and SLAM shift; or (5) COMBINED (higher illuminance WHITE plus GREEN) light and modified SLAM shift with 2 short naps scheduled on the day prior to the abrupt advance. Phase shifts of the plasma dim light melatonin onset and sleep measures were compared to examine effects of protocol condition. RESULTS: After 5days, the COMBINED light/modified SLAM shift condition showed larger phase advances of dim light melatonin onset (4.02 ± 1.13 hours) compared to the other 4 conditions (range 1.50 ± 0.96-2.83 ± 2.23 hours; p < .05) and resulted in increased REM sleep duration and fewer sleep disruptions. CONCLUSIONS: Consideration of the type of shift and the illuminance and wavelength of light may assist in designing lighting countermeasures to sleep and circadian disruption, which has implications for jetlag, shiftwork, and circadian rhythm sleep disorders.

A pilot study of light exposure as a countermeasure for menstrual phase-dependent neurobehavioral performance impairment in women.

OBJECTIVE: To examine effects of menstrual phase and nighttime light exposure on subjective sleepiness and auditory Psychomotor Vigilance Task performance. METHODS: Twenty-nine premenopausal women (12 =Follicular; 17 =Luteal) completed a 6.5-hour nighttime monochromatic light exposure with varying wavelengths (420-620 nm) and irradiances (1.03-14.12 µW/cm2). Subjective sleepiness, reaction time, and attentional lapses were compared between menstrual phases in women with minimal (<33%) or substantial (≥33%) light-induced melatonin suppression. RESULTS: When melatonin was not suppressed, women in the follicular phase had significantly worse reaction time (mean difference=145.1 ms, 95% CI 51.8-238.3, p < .001, Cohen's D=1.9) and lapses (mean difference=12.9 lapses, 95% CI 4.37-21.41, p < .001, Cohen's D=1.7) compared to women in the luteal phase. When melatonin was suppressed, women in the follicular phase had significantly better reaction time (mean difference=152.1 ms, 95% CI 43.88-260.3, p < .001, Cohen's D=1.7) and lapses (mean difference=12.3 lapses, 95% CI 1.14-25.6, p < .01, Cohen's D=1.6) compared to when melatonin was not suppressed, such that their performance was not different (p > .9) from women in the luteal phase. Subjective sleepiness did not differ by menstrual phase (mean difference=0.6, p > .08) or melatonin suppression (mean difference=0.2, p > .4). CONCLUSIONS: Nighttime light exposure sufficient to suppress melatonin can also mitigate neurobehavioral performance deficits associated with the follicular phase. Despite the relatively small sample size, these data suggest that nighttime light may be a valuable strategy to help reduce errors and accidents in female shift workers.

Sleep and mental health among unpaid caregivers of children, adults, and both: United States, 2022.

OBJECTIVES: We sought to characterize sleep and mental health, and their relationship, among unpaid caregivers. METHODS: During March through August 2022, four waves of cross-sectional surveys were administered to US adults using demographic quota sampling and weighting to improve representativeness of the US adult population. RESULTS: Among 19,767 respondents, 6260 (31.7%) identified as serving one or more unpaid caregiving roles. Compared to people without caregiving roles, caregivers more commonly reported sleep duration outside the healthy range (7-9 hours), insomnia symptoms, diagnosed sleep disorders, and more commonly screened positive for anxiety, depression, and burnout symptoms. Multivariable analyses adjusted for demographics characteristics revealed unpaid caregivers had several-fold elevated odds of adverse mental health symptoms; associations were attenuated but remained significant after adjusting for impaired and nonoptimal sleep. CONCLUSIONS: Both sleep and mental health challenges are disproportionately experienced by and commonly co-occur among unpaid caregivers, especially those who care for both children and adults. These populations, which serve critical societal roles, may benefit from enhanced support services to address sleep and mental health.

The organization of sleep-wake patterns around daily schedules in college students.

Time is a zero-sum game, and consequently, sleep is often sacrificed for waking activities. For college students, daily activities, comprised of scheduled classes, work, study, social and other extracurricular events, are major contributors to insufficient and poor-quality sleep. We investigated the impact of daily schedules on sleep-wake timing in 223 undergraduate students (age: 18-27 years, 37% females) from a United States (U.S.) university, monitored for approximately 30 days. Sleep-wake timing and daily recorded activities (attendance at academic, studying, exercise-based and/or extracurricular activities) were captured by a twice-daily internet-based diary. Wrist-worn actigraphy was conducted to confirm sleep-wake timing. Linear mixed models were used to quantify associations between daily schedule and sleep-wake timing at between-person and within-person levels. Later schedule start time predicted later sleep onset (between and within: p<.001), longer sleep duration on the previous night (within: p<.001), and later wake time (between and within: p<.001). Later schedule end time predicted later sleep onset (between: p<.05, within: p<.001) and shorter sleep duration that night (within: p<.001). For every 1 hour that recorded activities extended beyond 10pm, sleep onset was delayed by 15 minutes at the within-person level and 45 minutes at the between-person level, and sleep duration was shortened by 5 and 23 minutes, respectively. Increased daily documented total activity time predicted earlier wake (between and within: p<.001), later sleep onset that night (within: p<.05), and shorter sleep duration (within: p<.001). These results indicate that daily schedules are an important factor in shaping sleep timing and duration in college students.

The importance of sleep regularity: a consensus statement of the National Sleep Foundation sleep timing and variability panel.

OBJECTIVE: To develop and present consensus findings of the National Sleep Foundation sleep timing and variability panel regarding the impact of sleep timing variability on health and performance. METHODS: The National Sleep Foundation assembled a panel of sleep and circadian experts to evaluate the scientific evidence and conduct a formal consensus and voting procedure. A systematic literature review was conducted using the NIH National Library of Medicine PubMed database, and panelists voted on the appropriateness of 3 questions using a modified Delphi RAND/UCLA Appropriateness Method with 2 rounds of voting. RESULTS: The literature search and panel review identified 63 full text publications to inform consensus voting. Panelists achieved consensus on each question: (1) is daily regularity in sleep timing important for (a) health or (b) performance? and (2) when sleep is of insufficient duration during the week (or work days), is catch-up sleep on weekends (or non-work days) important for health? Based on the evidence currently available, panelists agreed to an affirmative response to all 3 questions. CONCLUSIONS: Consistency of sleep onset and offset timing is important for health, safety, and performance. Nonetheless, when insufficient sleep is obtained during the week/work days, weekend/non-work day catch-up sleep may be beneficial.

Age-related changes in circadian regulation of the human plasma lipidome.

Aging alters the amplitude and phase of centrally regulated circadian rhythms. Here we evaluate whether peripheral circadian rhythmicity in the plasma lipidome is altered by aging through retrospective lipidomics analysis on plasma samples collected in 24 healthy individuals (9 females; mean ± SD age: 40.9 ± 18.2 years) including 12 younger (4 females, 23.5 ± 3.9 years) and 12 middle-aged older, (5 females, 58.3 ± 4.2 years) individuals every 3 h throughout a 27-h constant routine (CR) protocol, which allows separating evoked changes from endogenously generated oscillations in physiology. Cosinor regression shows circadian rhythmicity in 25% of lipids in both groups. On average, the older group has a ~14% lower amplitude and a ~2.1 h earlier acrophase of the lipid circadian rhythms (both, p ≤ 0.001). Additionally, more rhythmic circadian lipids have a significant linear component in addition to the sinusoidal across the 27-h CR in the older group (44/56) compared to the younger group (18/58, p < 0.0001). Results from individual-level data are consistent with group-average results. Results indicate that prevalence of endogenous circadian rhythms of the human plasma lipidome is preserved with healthy aging into middle-age, but significant changes in rhythmicity include a reduction in amplitude, earlier acrophase, and an altered temporal relationship between central and lipid rhythms.