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Human untargeted metabolomics studies annotate only ~10% of molecular features. We introduce reference-data-driven analysis to match metabolomics tandem mass spectrometry (MS/MS) data against metadata-annotated source data as a pseudo-MS/MS reference library. Applying this approach to food source data, we show that it increases MS/MS spectral usage 5.1-fold over conventional structural MS/MS library matches and allows empirical assessment of dietary patterns from untargeted data.

Younger adults have a biological disposition to sleep and wake at later times that conflict with early morning obligations like work and school; this conflict leads to inadequate sleep duration and a difference in sleep timing between school days and weekends. The COVID-19 pandemic forced universities and workplaces to shut down in person attendance and implement remote learning and meetings that decreased/removed commute times and gave students more flexibility with their sleep timing. To determine the impact of remote learning on the daily sleep–wake cycle we conducted a natural experiment using wrist actimetry monitors to compare activity patterns and light exposure in three cohorts of students: pre-shutdown in-person learning (2019), during-shutdown remote learning (2020), and post-shutdown in-person learning (2021). Our results show that during-shutdown the difference between school day and weekend sleep onset, duration, and midsleep timing was diminished. For instance, midsleep during school days pre-shutdown occurred 50 min later on weekends (5:14 ± 12 min) than school days (4:24 ± 14 min) but it did not differ under COVID restrictions. Additionally, we found that while the interindividual variance in sleep parameters increased under COVID restrictions the intraindividual variance did not change, indicating that the schedule flexibility did not cause more irregular sleep patterns. In line with our sleep timing results, school day vs. weekend differences in the timing of light exposure present pre- and post-shutdown were absent under COVID restrictions. Our results provide further evidence that increased freedom in class scheduling allows university students to better and consistently align sleep behavior between school days and weekends.

The goal of this study was to determine the bone turnover marker (BTM) response to insufficient and subsequent recovery sleep, independent of changes in posture, body weight, and physical activity.Healthy men (N = 12) who habitually slept 7-9 h/night were admitted to an inpatient sleep laboratory for a baseline 8 h/night sleep opportunity followed by six nights of insufficient sleep (5 h/night). Diet, physical activity, and posture were controlled. Serum markers of bone formation (osteocalcin, PINP) and resorption (β-CTX) were obtained over 24 h at baseline and on the last night of sleep restriction, and on fasted samples obtained daily while inpatient and five times after discharge over 3 weeks. Maximum likelihood estimates in a repeated measures model were used to assess the effect of insufficient and subsequent recovery sleep on BTM levels.There was no statistically or clinically significant change in PINP (p = 0.53), osteocalcin (p = 0.66), or β-CTX (p = 0.10) in response to six nights of insufficient sleep. There were no significant changes in BTMs from the inpatient stay through 3 weeks of recovery sleep (all p [Formula: see text] 0.63). On average, body weight was stable during the inpatient stay (Δweight = - 0.55 ± 0.91 kg, p = 0.06).No significant changes in serum BTMs were observed after six nights of insufficient or subsequent recovery sleep in young healthy men. Changes in weight and physical activity may be required to observe significant BTM change in response to sleep and circadian disruptions. Clinical Trials Registration Registered at ClinicalTrials.gov (NCT03733483) on November 7, 2018.

Chronic disruption of rhythms (CDR) impacts sleep and can result in circadian misalignment of physiological systems which, in turn, is associated with increased disease risk. Exposure to repeated or severe stressors also disturbs sleep and diurnal rhythms. Prebiotic nutrients produce favorable changes in gut microbial ecology, the gut metabolome, and reduce several negative impacts of acute severe stressor exposure, including disturbed sleep, core body temperature rhythmicity, and gut microbial dysbiosis. In light of previous compelling evidence that prebiotic diet broadly reduces negative impacts of acute, severe stressors, we hypothesize that prebiotic diet will also effectively mitigate the negative impacts of chronic disruption of circadian rhythms on physiology and sleep/wake behavior. Male, Sprague Dawley rats were fed diets enriched in prebiotic substrates or calorically matched control chow. After 5 weeks on diet, rats were exposed to CDR (12 h light/dark reversal, weekly for 8 weeks) or remained on undisturbed normal light/dark cycles (NLD). Sleep EEG, core body temperature, and locomotor activity were recorded via biotelemetry in freely moving rats. Fecal samples were collected on experimental days –33, 0 (day of onset of CDR), and 42. Taxonomic identification and relative abundances of gut microbes were measured in fecal samples using 16S rRNA gene sequencing and shotgun metagenomics. Fecal primary, bacterially modified secondary, and conjugated bile acids were measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Prebiotic diet produced rapid and stable increases in the relative abundances of Parabacteroides distasonis and Ruminiclostridium 5. Shotgun metagenomics analyses confirmed reliable increases in relative abundances of Parabacteroides distasonis and Clostridium leptum, a member of the Ruminiclostridium genus. Prebiotic diet also modified fecal bile acid profiles; and based on correlational and step-wise regression analyses, Parabacteroides distasonis and Ruminiclostridium 5 were positively associated with each other and negatively associated with secondary and conjugated bile acids. Prebiotic diet, but not CDR, impacted beta diversity. Measures of alpha diversity evenness were decreased by CDR and prebiotic diet prevented that effect. Rats exposed to CDR while eating prebiotic, compared to control diet, more quickly realigned NREM sleep and core body temperature (ClockLab) diurnal rhythms to the altered light/dark cycle. Finally, both cholic acid and Ruminiclostridium 5 prior to CDR were associated with time to realign CBT rhythms to the new light/dark cycle after CDR; whereas both Ruminiclostridium 5 and taurocholic acid prior to CDR were associated with NREM sleep recovery after CDR. These results support our hypothesis and suggest that ingestion of prebiotic substrates is an effective strategy to increase the relative abundance of health promoting microbes, alter the fecal bile acid profile, and facilitate the recovery and realignment of sleep and diurnal rhythms after circadian disruption.

Late sleep timing is prevalent in early childhood and a risk factor for poor behavioral and health outcomes. Sleep timing is influenced by the phase of the circadian clock, with later circadian timing linked to delayed sleep onset in young children. Light is the strongest zeitgeber of circadian timing and, in adults, evening light produces circadian phase delay in an intensity-dependent manner. The intensity-dependent circadian phase-shifting response to evening light in children, however, is currently unknown. In the present study, 33 healthy, good-sleeping children aged 3.0 to 4.9 years (M = 4.14 years, 39% male) completed a 10-day between-subjects protocol. Following 7 days of a stable sleep schedule, an in-home dim-light circadian assessment was performed. Children remained in dim-light across 3 days (55 h), with salivary melatonin collected in regular intervals throughout each evening. Phase-shifting effects of light exposure were determined via changes in the timing of the dim-light melatonin onset (DLMO) prior to (Day 8) and following (Day 10) a light exposure stimulus. On Day 9, children were exposed to a 1 h light stimulus in the hour before their habitual bedtime. Each child was randomly assigned to one intensity between 5 and 5000 lux (4.5-3276 melanopic EDI). Across light intensities, children showed significant circadian phase delays, with an average phase delay of 56.1 min (SD = 33.6 min), and large inter-individual variability. No relationship between light intensity and magnitude of the phase shift was observed. However, a greater percentage of melatonin suppression during the light exposure was associated with a greater phase delay ( r = −0.73, p < 0.01). These findings demonstrate that some young children may be highly sensitive to light exposure in the hour before bedtime and suggest that the home lighting environment and its impact on circadian timing should be considered a possible contributor to behavioral sleep difficulties.

In the absence of electric light, sleep for humans typically starts soon after dusk and at higher latitudes daily sleep timing changes seasonally as photoperiod changes. However, access to electric light shields humans from natural photoperiod changes, and whether seasonal changes in sleep occur despite this isolation from the natural light-dark cycle remains a matter of controversy. We measured sleep timing in over 500 university students living in the city of Seattle, WA (47.6°N) throughout the four seasons; we show that even when students are following a school schedule, sleep timing is delayed during the fall and winter. For instance, during the winter school days, students fell asleep 35 min later and woke up 27 min later (under daylight-savings time) than students during the summer school days, a change that is an hour larger relative to solar midnight. Furthermore, chronotype defined by mid-sleep on free days corrected for oversleep (MSFc), an indirect estimate of circadian phase, was more than 30 min later in the winter compared with the summer. Analysis of the effect of light exposure showed that the number of hours of light exposure to at least 50 lux during the daytime was a stronger predictor of MSFc than the exposure time to this illuminance after dusk. Specifically, MSFc was advanced by 30 min for each additional hour of light exposure during daytime and delayed by only 15 min for each additional hour of postdusk exposure to light. Additionally, the time of the day of exposure to high light intensities was more predictive of MSFc when daytime exposure was considered than when exposure for the full 24-h day was considered. Our results show that although sleep time is highly synchronized to social time, a delayed timing of sleep is evident during the winter months. They also suggest that daily exposure to daylight is key to prevent this delayed phase of the circadian clock and thus circadian disruption that is typically exacerbated in high-latitude winters.

Measuring individual circadian phase is important to diagnose and treat circadian rhythm sleep-wake disorders and circadian misalignment, inform chronotherapy, and advance circadian science. Initial findings using blood transcriptomics to predict the circadian phase marker dim-light melatonin onset (DLMO) show promise. Alternatively, there are limited attempts using metabolomics to predict DLMO and no known omics-based biomarkers predict dim-light melatonin offset (DLMOff). We analyzed the human plasma metabolome during adequate and insufficient sleep to predict DLMO and DLMOff using one blood sample. Sixteen (8 male/8 female) healthy participants aged 22.4 ± 4.8 years (mean ± SD) completed an in-laboratory study with 3 baseline days (9 h sleep opportunity/night), followed by a randomized cross-over protocol with 9-h adequate sleep and 5-h insufficient sleep conditions, each lasting 5 days. Blood was collected hourly during the final 24 h of each condition to independently determine DLMO and DLMOff. Blood samples collected every 4 h were analyzed by untargeted metabolomics and were randomly split into training (68%) and test (32%) sets for biomarker analyses. DLMO and DLMOff biomarker models were developed using partial least squares regression in the training set followed by performance assessments using the test set. At baseline, the DLMOff model showed the highest performance (0.91 R2 and 1.1 ± 1.1 h median absolute error ± interquartile range [MdAE ± IQR]), with significantly ( p < 0.01) lower prediction error versus the DLMO model. When all conditions (baseline, 9 h, and 5 h) were included in performance analyses, the DLMO (0.60 R2; 2.2 ± 2.8 h MdAE; 44% of the samples with an error under 2 h) and DLMOff (0.62 R2; 1.8 ± 2.6 h MdAE; 51% of the samples with an error under 2 h) models were not statistically different. These findings show promise for metabolomics-based biomarkers of circadian phase and highlight the need to test biomarkers that predict multiple circadian phase markers under different physiological conditions.

Traditional risk factors for obesity and the metabolic syndrome, such as excess energy intake and lack of physical activity, cannot fully explain the high prevalence of these conditions. Insufficient sleep and circadian misalignment predispose individuals to poor metabolic health and promote weight gain and have received increased research attention in the past 10 years. Insufficient sleep is defined as sleeping less than recommended for health benefits, whereas circadian misalignment is defined as wakefulness and food intake occurring when the internal circadian system is promoting sleep. This Review discusses the impact of insufficient sleep and circadian misalignment in humans on appetite hormones (focusing on ghrelin, leptin and peptide-YY), energy expenditure, food intake and choice, and risk of obesity. Some potential strategies to reduce the adverse effects of sleep disruption on metabolic health are provided and future research priorities are highlighted. Millions of individuals worldwide do not obtain sufficient sleep for healthy metabolic functions. Furthermore, modern working patterns, lifestyles and technologies are often not conducive to adequate sleep at times when the internal physiological clock is promoting it (for example, late-night screen time, shift work and nocturnal social activities). Efforts are needed to highlight the importance of optimal sleep and circadian health in the maintenance of metabolic health and body weight regulation.

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

In adults, recent evidence demonstrates that sleep and circadian physiology change across lunar phases, including findings that endogenous melatonin levels are lower near the full moon compared to the new moon. Here, we extend these results to early childhood by examining circalunar fluctuations in children's evening melatonin levels. We analysed extant data on young children's circadian rhythms (n = 46, aged 3.0-5.9 years, 59% female). After following a strict sleep schedule for 5-7 days, children completed an in-home, dim-light circadian assessment (10 lux). Salivary melatonin was assessed at regular 20- to 30-min intervals until 1 h past each child's scheduled bedtime. Melatonin levels varied significantly across lunar phases, such that melatonin was lower in participants assessed near the full moon as compared to near the new moon. Significant differences were observed at 50 min (mean

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

To investigate the influence of fasting during the night shift on eating behavior, hunger, glucose and insulin levels the following day.Study with 10 male police officers who have been working at night. Participants were tested under three different conditions separated by at least 6 days of washout in a randomized, crossover design: "Night Shift Fasting" (NSF)-two nights of fasting during the night shift; "Night Shift Eating" (NSE)-two nights with the consumption of a standardized meal during the night shift (678 ± 42 kcal consumed at ~ 0200 h); and "Nighttime Sleep" (NS)-two nights of sleep. The morning after, blood glucose and insulin and hunger ratings were assessed, and food intake was assessed with an ad libitum test meal. Food intake was also assessed throughout the remainder of the day using a food record. Generalized Estimating Equations were used to analyze the effect of experimental condition.Food intake during the test meal, especially of proteins and fats, was higher after fasting during the night shift compared to the other conditions (p 0.05), whereas desire to eat scores were lower after the NSF compared to NSE condition (p = 0.043). Hunger levels were lower after the NSF compared to the NS condition (p = 0.012). Insulin and HOMA-IR were also lower in the morning after NSF (p 0.001).Fasting during the night shift leads to not only a higher intake of energy and macronutrients both in the early morning after work and throughout the next day, but also lower insulin levels and HOMA-IR in the morning.NCT03800732. Initial release: 01/09/2019. Last release: 02/23/2022.

Cellular circadian rhythms confer daily temporal organisation upon behaviour and physiology that is fundamental to human health and disease. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body. Being naturally anucleate, RBC circadian rhythms share key elements of post-translational, but not transcriptional, regulation with other cell types. The physiological function and developmental regulation of RBC circadian rhythms is poorly understood, however, partly due to the small number of appropriate techniques available. Here, we extend the RBC circadian toolkit with a novel biochemical assay for haemoglobin oxidation status, termed “Bloody Blotting”. Our approach relies on a redox-sensitive covalent haem-haemoglobin linkage that forms during cell lysis. Formation of this linkage exhibits daily rhythms in vitro, which are unaffected by mutations that affect the timing of circadian rhythms in nucleated cells. In vivo, haemoglobin oxidation rhythms demonstrate daily variation in the oxygen-carrying and nitrite reductase capacity of the blood, and are seen in human subjects under controlled laboratory conditions as well as in freely-behaving humans. These results extend our molecular understanding of RBC circadian rhythms and suggest they serve an important physiological role in gas transport.

Circadian clocks drive cyclic variations in many aspects of physiology, but some daily variations are evoked by periodic changes in the environment or sleep-wake state and associated behaviors, such as changes in posture, light levels, fasting or eating, rest or activity and social interactions; thus, it is often important to quantify the relative contributions of these factors. Yet, circadian rhythms and these evoked effects cannot be separated under typical 24-h day conditions, because circadian phase and the length of time awake or asleep co-vary. Nathaniel Kleitman's forced desynchrony (FD) protocol was designed to assess endogenous circadian rhythmicity and to separate circadian from evoked components of daily rhythms in multiple parameters. Under FD protocol conditions, light intensity is kept low to minimize its impact on the circadian pacemaker, and participants have sleep-wake state and associated behaviors scheduled to an imposed non-24-h cycle. The period of this imposed cycle, Τ, is chosen so that the circadian pacemaker cannot entrain to it and therefore continues to oscillate at its intrinsic period (τ, ~24.15 h), ensuring circadian components are separated from evoked components of daily rhythms. Here we provide detailed instructions and troubleshooting techniques on how to design, implement and analyze the data from an FD protocol. We provide two procedures: one with general guidance for designing an FD study and another with more precise instructions for replicating one of our previous FD studies. We discuss estimating circadian parameters and quantifying the separate contributions of circadian rhythmicity and the sleep-wake cycle, including statistical analysis procedures and an R package for conducting the non-orthogonal spectral analysis method that enables an accurate estimation of period, amplitude and phase.

We describe the time course of bone formation marker (P1NP) decline in men exposed to ~ 3 weeks of sleep restriction with concurrent circadian disruption. P1NP declined within 10 days and remained lower with ongoing exposure. These data suggest even brief exposure to sleep and circadian disruptions may disrupt bone metabolism. A serum bone formation marker (procollagen type 1 N-terminal, P1NP) was lower after ~ 3 weeks of sleep restriction combined with circadian disruption. We now describe the time course of decline. The ~ 3-week protocol included two segments: “baseline,” ≥ 10-h sleep opportunity/day × 5 days; “forced desynchrony” (FD), recurring 28 h day (circadian disruption) with sleep restriction (~ 5.6-h sleep per 24 h). Fasted plasma P1NP was measured throughout the protocol in nine men (20–59 years old). We tested the hypothesis that PINP would steadily decline across the FD intervention because the magnitude of sleep loss and circadian misalignment accrued as the protocol progressed. A piecewise linear regression model was used to estimate the slope (β) as ΔP1NP per 24 h with a change point mid-protocol to estimate the initial vs. prolonged effects of FD exposure. Plasma P1NP levels declined significantly within the first 10 days of FD ($$ \hat{\beta} $$ = − 1.33 μg/L per 24 h, p

Context To our knowledge, circadian rhythms have not been examined in girls with polycystic ovarian syndrome (PCOS), despite the typical delayed circadian timing of adolescence, which is an emerging link between circadian health and insulin sensitivity (SI), and decreased SI in PCOS. Objective To examine differences in the circadian melatonin rhythm between obese adolescent girls with PCOS and control subjects, and evaluate relationships between circadian variables and SI. Design Cross-sectional study. Participants Obese adolescent girls with PCOS (n = 59) or without PCOS (n = 33). Outcome Measures Estimated sleep duration and timing from home actigraphy monitoring, in-laboratory hourly sampled dim-light, salivary-melatonin and fasting hormone analysis. Results All participants obtained insufficient sleep. Girls with PCOS had later clock-hour of melatonin offset, later melatonin offset relative to sleep timing, and longer duration of melatonin secretion than control subjects. A later melatonin offset after wake time (i.e., morning wakefulness occurring during the biological night) was associated with higher serum free testosterone levels and worse SI regardless of group. Analyses remained significant after controlling for daytime sleepiness and sleep-disordered breathing. Conclusion Circadian misalignment in girls with PCOS is characterized by later melatonin offset relative to clock time and sleep timing. Morning circadian misalignment was associated with metabolic dysregulation in girls with PCOS and obesity. Clinical care of girls with PCOS and obesity would benefit from assessment of sleep and circadian health. Additional research is needed to understand mechanisms underlying the relationship between morning circadian misalignment and SI in this population.

Human untargeted metabolomics studies succeed in annotating only ~10% of molecular features. We, therefore, introduce reference data-driven analysis that uses the source data as a pseudo-MS/MS reference library to match against human metabolomics MS/MS data. We demonstrate this approach with food source data, allowing an empirical assessment of dietary patterns from untargeted data but is broadly applicable and provides an additional layer of interpretability to metabolomics data.

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

Purpose of Review This paper presents a review of the current literature in support of a model explaining the relationships between sleep health and risk for type 2 diabetes in adolescents. Recent Findings Short sleep duration is associated with risk of developing obesity in youth. Sleep restriction increases energy expenditure, but also increases hunger, appetite, and food intake, causing positive energy balance, impacting appetite-regulating hormones, and leading to increased eating late at night. Insufficient sleep may lead to reduced physical activity and greater sedentary behaviors. In addition, short sleep duration is associated with reduced insulin sensitivity. The cumulative negative consequences of insufficient sleep increase risk for type 2 diabetes. Applications to clinical care, public policy, and future research are discussed. Summary Insufficient sleep in adolescence increases risk for type 2 diabetes directly through impact on insulin sensitivity and indirectly through increased dietary intake, sedentary activity, and weight gain.

Study Objectives Sleep deprivation induces systemic inflammation that may contribute to stress vulnerability and other pathologies. We tested the hypothesis that immunization with heat-killed Mycobacterium vaccae NCTC 11659 (MV), an environmental bacterium with immunoregulatory and anti-inflammatory properties, prevents the negative impacts of 5 days of sleep disruption on stress-induced changes in sleep, behavior, and physiology in mice. Methods In a 2 × 2 × 2 experimental design, male C57BL/6N mice were given injections of either MV or vehicle on days –17, –10, and –3. On days 1–5, mice were exposed to intermittent sleep disruption, whereby sleep was disrupted for 20 h per day. Immediately following sleep disruption, mice were exposed to 1-h social defeat stress or novel cage (control) conditions. Object location memory (OLM) testing was conducted 24 h after social defeat, and tissues were collected 6 days later to measure inflammatory markers. Sleep was recorded using electroencephalography (EEG) and electromyography (EMG) throughout the experiment. Results In vehicle-treated mice, only the combination of sleep disruption followed by social defeat (double hit): (1) increased brief arousals and NREM beta (15–30 Hz) EEG power in sleep immediately post-social defeat compared to baseline; (2) induced an increase in the proportion of rapid-eye-movement (REM) sleep and number of state shifts for at least 5 days post-social defeat; and (3) induced hyperlocomotion and lack of habituation in the OLM task. Immunization with MV prevented most of these sleep and behavioral changes. Conclusions Immunization with MV ameliorates a stress-induced sleep and behavioral phenotype that shares features with human posttraumatic stress disorder.

Ocular light exposure has important influences on human health and well-being through modulation of circadian rhythms and sleep, as well as neuroendocrine and cognitive functions. Current patterns of light exposure do not optimally engage these actions for many individuals, but advances in our understanding of the underpinning mechanisms and emerging lighting technologies now present opportunities to adjust lighting to promote optimal physical and mental health and performance. A newly developed, SI-compliant standard provides a way of quantifying the influence of light on the intrinsically photosensitive, melanopsin-expressing, retinal neurons that mediate these effects. The present report provides recommendations for lighting, based on an expert-scientific consensus and expressed according to this new measurement standard. These recommendations are supported by a comprehensive analysis of the sensitivity of human ‘non-visual’ responses to ocular light, are centred on an easily measured quantity (melanopic equivalent daylight (D65) illuminance), and provide a straightforward framework to inform lighting design and practice.

The response to a zeitgeber, particularly the light/dark cycle, may vary phenotypically. Phenotypic plasticity can be defined as the ability of one genome to express different phenotypes in response to environmental variation. In this opinion paper, we present some evidence that one of the most prominent effects of the introduction of electric light to the everyday life of humans is a significant increase in phenotypic plasticity and differences in interindividual phases of entrainment. We propose that the healthy limits of phenotypic plasticity have been surpassed in contemporary society., Highlights • Electric light increased phenotypic plasticity in humans and differences in interindividual phases of entrainment. • Healthy limits of phenotypic plasticity have been surpassed in contemporary society. • The correlation between biological time (DLMO) and behavioral time (MSFsc) is reduced in the population without access to electrical light.

Study Objectives Insufficient sleep is believed to promote positive energy balance (EB) and weight gain. Increasing weekend sleep duration to “recover” from weekday sleep loss is common, yet little is known regarding how weekend recovery sleep influences EB. We conducted a randomized controlled trial to assess how: (1) 2 days and 8 days of insufficient sleep and (2) ad libitum weekend recovery sleep impact EB (energy intake [EI] – energy expenditure [EE]). Methods Following ten baseline days with 9 h per night sleep opportunities, participants completed one of three 10-day experimental protocols with ad libitum EI: control (9 h sleep opportunities; n = 8; 23 ± 5 years [mean ± SD]); sleep restriction (SR; 5 h sleep opportunities; n = 14; 25 ± 5 years); sleep restriction with weekend recovery sleep (SR + WR; 5 days insufficient sleep, 2 days ad libitum weekend recovery sleep, 3 days recurrent insufficient sleep; n = 14; 27 ± 4 years). Results Twenty-four hour EB increased (p < 0.001; main effect) by an average of 797.7 ± 96.7 (±SEM) kcal during the 10-day experimental protocol versus baseline with no significant differences between groups. Percent change from baseline in 24 h-EE was higher (p < 0.05) on day 2 of insufficient sleep (SR and SR + WR groups; 10 ± 1%) versus adequate sleep (control group; 4 ± 3%). Conclusions In this between-group study, the effects of adequate sleep and insufficient sleep, with or without or weekend recovery sleep, on 24 h-EB were similar. Examining EB and body weight changes using within-subject cross-over designs and “free-living” conditions outside the laboratory (e.g. sleep extension) are needed to advance our understanding of the links between insufficient sleep, weekend recovery sleep and weight-gain.

SummaryThe human metabolome has remained largely unknown, with most studies annotating ∼10% of features. In nucleic acid sequencing, annotating transcripts by source has proven essential for understanding gene function. Here we generalize this concept to stool, plasma, urine and other human metabolomes, discovering that food-based annotations increase the interpreted fraction of molecular features 7-fold, providing a general framework for expanding the interpretability of human metabolomic “dark matter.”

BACKGROUND: The effects on patient safety of eliminating extended-duration work shifts for resident physicians remain controversial. METHODS: We conducted a multicenter, cluster-randomized, crossover trial comparing two schedules for pediatric resident physicians during their intensive care unit (ICU) rotations: extended-duration work schedules that included shifts of 24 hours or more (control schedules) and schedules that eliminated extended shifts and cycled resident physicians through day and night shifts of 16 hours or less (intervention schedules). The primary outcome was serious medical errors made by resident physicians, assessed by intensive surveillance, including direct observation and chart review. RESULTS: The characteristics of ICU patients during the two work schedules were similar, but resident physician workload, described as the mean (±SD) number of ICU patients per resident physician, was higher during the intervention schedules than during the control schedules (8.8±2.8 vs. 6.7±2.2). Resident physicians made more serious errors during the intervention schedules than during the control schedules (97.1 vs. 79.0 per 1000 patient-days; relative risk, 1.53; 95% confidence interval [CI], 1.37 to 1.72; P

Sleep health has multiple dimensions including duration, regularity, timing, and quality [1-4]. The Coronavirus 2019 (COVID-19) outbreak led to Stay-at-Home orders and Social Distancing Requirements in countries throughout the world to limit the spread of COVID-19. We investigated sleep behaviors prior to and during Stay-at-Home orders in 139 university students (aged 22.2 ± 1.7 years old [±SD]) while respectively taking the same classes in-person and remotely. During Stay-at-Home, nightly time in bed devoted to sleep (TIB, a proxy for sleep duration with regard to public health recommendations [5]) increased by ∼30 min during weekdays and by ∼24 mins on weekends and regularity of sleep timing improved by ∼12 min. Sleep timing became later by ∼50 min during weekdays and ∼25 min on weekends, and thus the difference between weekend and weekday sleep timing decreased - hence reducing the amount of social jetlag [6,7]. Further, we find individual differences in the change of TIB devoted to sleep such that students with shorter TIB at baseline before the first COVID-19 cases emerged locally had larger increases in weekday and weekend TIB during Stay-at-Home. The percentage of participants that reported 7 h or more sleep per night, the minimum recommended sleep duration for adults to maintain health [5] - including immune health - increased from 84% to 92% for weekdays during Stay-at-Home versus baseline. Understanding the factors underlying such changes in sleep health behaviors could help inform public health recommendations with the goal of improving sleep health during and following the Stay-at-Home orders of the COVID-19 pandemic.

Objective The circadian system provides an organism with the ability to anticipate daily food availability and appropriately coordinate metabolic responses. Few studies have simultaneously assessed factors involved in both the anticipation of energy availability (i.e., hormones involved in appetite regulation) and subsequent metabolic responses (such as energy expenditure and substrate oxidation) under conditions designed to reveal circadian rhythmicity. Methods Eight healthy adults (four females; age: 28.0 ± 2.3 years; BMI: 24.3 ± 2.9 kg/m2 ) participated in a 26-hour constant routine protocol involving continuous wakefulness with constant posture, temperature, dim light, and hourly isocaloric snacks. Indirect calorimetry was performed every 3 hours for measurement of energy expenditure and substrate oxidation. Subjective hunger was obtained hourly using questionnaires. Saliva and plasma were obtained hourly to assess melatonin (circadian phase marker) and hormones (leptin, ghrelin, and peptide YY). Results Fat and carbohydrate oxidation was highest in the biological evening and morning, respectively. Subjective hunger ratings peaked during the middle of the biological day. Significant circadian rhythms were identified for ghrelin and peptide YY with peaks in the biological evening and morning, respectively. Conclusions These findings support a role for the circadian system in the modulation of nutrient oxidation, subjective measures of appetite, and appetitive hormones.

Because regular sleep disruption can increase vulnerability to stress-related psychiatric disorders, there is a need to explore novel countermeasures to increase stress resilience after inadequate sleep. In this study, we explored the impact of 5 days of intermittent sleep disruption on vulnerability to acute social defeat stress in mice, and investigated the ability of the environmental, immunomodulatory bacterium Mycobacterium vaccae NCTC 11659 (MV) to promote stress resilience in that context. We found that mice receiving sleep disruption plus acute stress developed sleep and behavioral phenotypes that had some features of human posttraumatic stress disorder (PTSD) including reduced NREM delta power and increased NREM beta power in post-stress sleep EEG, persistent increases in sleep fragmentation and the REM:Sleep ratio, and behavioral changes. Importantly, immunization with heat-killed MV prevented the development of this phenotype. These results support further research into novel, microbial-based countermeasures to improve health and increase resilience to sleep disruption.

Purpose The purpose of this work is to determine whether an uncoupling of bone turnover markers (BTMs) occurs in women exposed to the combination of sleep restriction with circadian disruption (SRCD), as previously reported in men. Methods Four bone biomarkers (N-terminal propeptide of type I procollagen [P1NP] and osteocalcin = bone formation; C-telopeptide [CTX] = bone resorption; sclerostin = bone formation inhibitor) were measured in bihourly samples over 24 hours at baseline and after approximately 3 weeks of sleep restriction (~5.6 hours of sleep/24 hours) with concurrent circadian disruption (SRCD, recurring 28-hour “day” in dim light). Maximum likelihood estimation in a repeated-measures model was used to assess the effects of SRCD and age on bone biomarkers. Results Five women were young (22 ± 2.8 years) and four were older (58 ± 1.8 years). Baseline bone biomarker levels did not differ by age (all P ≥ .07). Bone formation markers were lower after SRCD (estimate ± SEE, ΔP1NP = –9.5 ± 2.8 μg/L, P = .01; Δosteocalcin = –2.3 ± 0.9 ng/mL, P = .04). The P1NP decline was greater in young women (ΔP1NP = –12.9 ± 3.7 μg/L, P = .01). After SRCD, CTX was significantly higher in young women (0.182 ± 0.069 ng/mL, P = .04) but did not change in older women. Conclusions These pilot data are similar to previous findings in men and suggest that SRCD negatively altered bone metabolism in women by decreasing markers of bone formation and, in young women, increasing a marker of bone resorption. If sustained, this pattern of BTM uncoupling may lead to bone loss and lower bone mineral density.

Elevated blood pressure (BP ≥130/80 mmHg) is associated with increased risk for myocardial infarction, heart failure, stroke and vascular disease. Insufficient nightly sleep (G -monomethyl-L-arginine (L-NMMA) and the antioxidant vitamin C were determined by venous occlusion plethysmography. The FBF response to ACh was significantly lower (~20%) in the short sleep (from 3.8±0.2 to 11.0±0.6 ml/100 ml tissue/min) compared with the normal sleep duration group (from 4.2±0.2 to 13.6±0.6 ml/100 ml tissue/min). L-NMMA significantly reduced (~25%) the FBF response to ACh in the normal sleep but not the short sleep group. Vitamin C markedly increased (~35%; P

Increased risk of obesity and diabetes in shift workers may be related to food intake at adverse circadian times. Early morning shiftwork represents the largest proportion of shift workers in the United States, yet little is known about the impact of food intake in the early morning on metabolism. Eighteen participants (9 female) completed a counterbalanced 16 day design with two conditions separated by ~1 week: 8 h sleep opportunity at habitual time and simulated early morning shiftwork with 6.5 h sleep opportunity starting ~1 h earlier than habitual time. After wake time, resting energy expenditure (REE) was measured and blood was sampled for melatonin and fasting glucose and insulin. Following breakfast, post-prandial blood samples were collected every 40 min for 2 h and the thermic effect of food (TEF) was assessed for 3.25 h. Total sleep time was decreased by ~85 min (p &lt, 0.0001), melatonin levels were higher (p &lt, 0.0001) and post-prandial glucose levels were higher (p &lt, 0.05) after one day of simulated early morning shiftwork compared with habitual wake time. REE was lower after simulated early morning shiftwork, however, TEF after breakfast was similar to habitual wake time. Insufficient sleep and caloric intake during a circadian phase of high melatonin levels may contribute to metabolic dysregulation in early morning shift workers.

Background Depressive symptoms often manifest in adolescence and predict worsening insulin sensitivity, a key precursor in the path to β-cell failure and type 2 diabetes (T2D). Objective To assess the efficacy of a six-week cognitive-behavioral group versus six-week health education group for improving insulin sensitivity and preserving β-cell function in adolescent girls at-risk for T2D with depressive symptoms and evaluate mechanisms underlying the association between depression and insulin dynamics. Design Randomized controlled trial of N = 150 12–17-year-old girls with overweight/obesity (body mass index [BMI; kg/m2] ≥85th percentile), elevated depressive symptoms (Center for Epidemiologic Studies-Depression Scale [CES-D] total score > 20), and diabetes family history. Methods Girls at-risk for T2D with elevated depressive symptoms are recruited from the Denver-metropolitan area and randomized to participate in one of two six-week interventions. The cognitive-behavioral group is a depression prevention program involving psycho-education, restructuring negative thoughts, and behavioral activation. The health education group is a didactic control that provides knowledge about healthy living. Participants are assessed at baseline, immediate post-intervention, and one-year follow-up. Primary outcomes are insulin sensitivity and β-cell function from oral glucose tolerance tests. Secondary outcomes are disinhibited eating, physical activity, sleep, and cortisol. Summary Results from this adequately powered randomized controlled trial will determine whether decreasing depressive symptoms with a behavioral health program preventatively alters insulin sensitivity and β-cell function trajectories in adolescents at-risk for T2D. Results from the MIND Project will add to knowledge of the contribution of depressive symptoms to T2D risk.