Melatonin decreases human adipose tissue insulin sensitivity.

Melatonin is a pineal hormone that modulates the circadian system and exerts soporific and phase-shifting effects. It is also involved in many other physiological processes, such as those implicated in cardiovascular, endocrine, immune, and metabolic functions. However, the role of melatonin in glucose metabolism remains contradictory, and its action on human adipose tissue (AT) explants has not been demonstrated. We aimed to assess whether melatonin (a pharmacological dose) influences insulin sensitivity in human AT. This will help better understand melatonin administration's effect on glucose metabolism. Abdominal AT (subcutaneous and visceral) biopsies were obtained from 19 participants with severe obesity (age: 42.84 ± 12.48 years; body mass index: 43.14 ± 8.26 kg/m2) who underwent a laparoscopic gastric bypass. AT biopsies were exposed to four different treatments: control (C), insulin alone (I) (10 nM), melatonin alone (M) (5000 pg/mL), and insulin plus melatonin combined (I + M). All four conditions were repeated in both subcutaneous and visceral AT, and all were performed in the morning at 8 a.m. (n = 19) and the evening at 8 p.m. (in a subsample of n = 12). We used western blot analysis to determine insulin signaling (using the pAKT/tAKT ratio). Furthermore, RNAseq analyses were performed to better understand the metabolic pathways involved in the effect of melatonin on insulin signaling. As expected, insulin treatment (I) increased the pAKT/tAKT ratio compared with control (p < .0001). Furthermore, the addition of melatonin (I + M) resulted in a decrease in insulin signaling as compared with insulin alone (I); this effect was significant only during the evening time (not in the morning time). Further, RNAseq analyses in visceral AT during the evening condition (at 8 p.m.) showed that melatonin resulted in a prompt transcriptome response (around 1 h after melatonin addition), particularly by downregulating the insulin signaling pathway. Our results show that melatonin reduces insulin sensitivity in human AT during the evening. These results may partly explain the previous studies showing a decrease in glucose tolerance after oral melatonin administration in the evening or when eating late when endogenous melatonin is present.

Dietary patterns and insomnia symptoms: A systematic review and meta-analysis.

We aimed to systematically review and synthesize the available evidence regarding the link between dietary patterns and insomnia symptoms among the general population using observational studies. We reviewed 16,455 references, of which 37 studies met inclusion criteria with a total sample size of 591,223. There was a significant association of the Mediterranean diet (OR: 0.86; 95 % CI, 0.79, 0.93; P < 0.001; I2 = 32.68 %), a high-quality diet (OR: 0.66; 95 % CI, 0.48, 0.90; P = 0.010; I2 = 84.62 %), and an empirically-derived healthy dietary pattern (OR: 0.91; 95 % CI, 0.85, 0.98; P = 0.010; I2 = 57.14 %) with a decreased risk of insomnia symptoms. Moreover, the dietary glycemic index (OR: 1.16; 95 % CI, 1.08, 1.25; P < 0.001; I2 = 0.0 %), the dietary glycemic load (OR: 1.10; 95 % CI, 1.01, 1.20; P = 0.032; I2 = 74.36 %), and an empirically-derived unhealthy dietary pattern (OR: 1.20; 95 % CI, 1.01, 1.42; P = 0.040; I2 = 68.38 %) were linked with a higher risk of insomnia symptoms. Most individual studies were of good quality (NOS) but provided very low certainty of evidence (GRADE). Consistent data reveals that following healthy diets is associated with decreased insomnia symptoms prevalence, while adherence to an unhealthy pattern is associated with an increased prevalence of insomnia symptoms.

Longitudinal associations of diurnal rest-activity rhythms with fatigue, insomnia, and health-related quality of life in survivors of colorectal cancer up to 5 years post-treatment.

BACKGROUND: There is a growing population of survivors of colorectal cancer (CRC). Fatigue and insomnia are common symptoms after CRC, negatively influencing health-related quality of life (HRQoL). Besides increasing physical activity and decreasing sedentary behavior, the timing and patterns of physical activity and rest over the 24-h day (i.e. diurnal rest-activity rhythms) could also play a role in alleviating these symptoms and improving HRQoL. We investigated longitudinal associations of the diurnal rest-activity rhythm (RAR) with fatigue, insomnia, and HRQoL in survivors of CRC. METHODS: In a prospective cohort study among survivors of stage I-III CRC, 5 repeated measurements were performed from 6 weeks up to 5 years post-treatment. Parameters of RAR, including mesor, amplitude, acrophase, circadian quotient, dichotomy index, and 24-h autocorrelation coefficient, were assessed by a custom MATLAB program using data from tri-axial accelerometers worn on the upper thigh for 7 consecutive days. Fatigue, insomnia, and HRQoL were measured by validated questionnaires. Confounder-adjusted linear mixed models were applied to analyze longitudinal associations of RAR with fatigue, insomnia, and HRQoL from 6 weeks until 5 years post-treatment. Additionally, intra-individual and inter-individual associations over time were separated. RESULTS: Data were available from 289 survivors of CRC. All RAR parameters except for 24-h autocorrelation increased from 6 weeks to 6 months post-treatment, after which they remained relatively stable. A higher mesor, amplitude, circadian quotient, dichotomy index, and 24-h autocorrelation were statistically significantly associated with less fatigue and better HRQoL over time. A higher amplitude and circadian quotient were associated with lower insomnia. Most of these associations appeared driven by both within-person changes over time and between-person differences in RAR parameters. No significant associations were observed for acrophase. CONCLUSIONS: In the first five years after CRC treatment, adhering to a generally more active (mesor) and consistent (24-h autocorrelation) RAR, with a pronounced peak activity (amplitude) and a marked difference between daytime and nighttime activity (dichotomy index) was found to be associated with lower fatigue, lower insomnia, and a better HRQoL. Future intervention studies are needed to investigate if restoring RAR among survivors of CRC could help to alleviate symptoms of fatigue and insomnia while enhancing their HRQoL. TRIAL REGISTRATION: EnCoRe study NL6904 ( https://www.onderzoekmetmensen.nl/ ).

Hypertension: Causes and Consequences of Circadian Rhythms in Blood Pressure.

Hypertension is extremely common, affecting approximately 1 in every 2 adults globally. Chronic hypertension is the leading modifiable risk factor for cardiovascular disease and premature mortality worldwide. Despite considerable efforts to define mechanisms that underlie hypertension, a potentially major component of the disease, the role of circadian biology has been relatively overlooked in both preclinical models and humans. Although the presence of daily and circadian patterns has been observed from the level of the genome to the whole organism, the functional and structural impact of biological rhythms, including mechanisms such as circadian misalignment, remains relatively poorly defined. Here, we review the impact of daily rhythms and circadian systems in regulating blood pressure and the onset, progression, and consequences of hypertension. There is an emphasis on the impact of circadian biology in relation to vascular disease and end-organ effects that, individually or in combination, contribute to complex phenotypes such as cognitive decline and the loss of cardiac and brain health. Despite effective treatment options for some individuals, control of blood pressure remains inadequate in a substantial portion of the hypertensive population. Greater insight into circadian biology may form a foundation for novel and more widely effective molecular therapies or interventions to help in the prevention, treatment, and management of hypertension and its related pathophysiology.

The sleep-circadian interface: A window into mental disorders.

Sleep, circadian rhythms, and mental health are reciprocally interlinked. Disruption to the quality, continuity, and timing of sleep can precipitate or exacerbate psychiatric symptoms in susceptible individuals, while treatments that target sleep-circadian disturbances can alleviate psychopathology. Conversely, psychiatric symptoms can reciprocally exacerbate poor sleep and disrupt clock-controlled processes. Despite progress in elucidating underlying mechanisms, a cohesive approach that integrates the dynamic interactions between psychiatric disorder with both sleep and circadian processes is lacking. This review synthesizes recent evidence for sleep-circadian dysfunction as a transdiagnostic contributor to a range of psychiatric disorders, with an emphasis on biological mechanisms. We highlight observations from adolescent and young adults, who are at greatest risk of developing mental disorders, and for whom early detection and intervention promise the greatest benefit. In particular, we aim to a) integrate sleep and circadian factors implicated in the pathophysiology and treatment of mood, anxiety, and psychosis spectrum disorders, with a transdiagnostic perspective; b) highlight the need to reframe existing knowledge and adopt an integrated approach which recognizes the interaction between sleep and circadian factors; and c) identify important gaps and opportunities for further research.

Impact of polygenic score for BMI on weight loss effectiveness and genome-wide association analysis.

BACKGROUND: While environmental factors play an important role in weight loss effectiveness, genetics may also influence its success. We examined whether a genome-wide polygenic score for BMI was associated with weight loss effectiveness and aimed to identify common genetic variants associated with weight loss. METHODS: Participants in the ONTIME study (n = 1210) followed a uniform, multimodal behavioral weight-loss intervention. We first tested associations between a genome-wide polygenic score for higher BMI and weight loss effectiveness (total weight loss, rate of weight loss, and attrition). We then conducted a genome-wide association study (GWAS) for weight loss in the ONTIME study and performed the largest weight loss meta-analysis with earlier studies (n = 3056). Lastly, we ran exploratory GWAS in the ONTIME study for other weight loss outcomes and related factors. RESULTS: We found that each standard deviation increment in the polygenic score was associated with a decrease in the rate of weight loss (Beta (95% CI) = -0.04 kg per week (-0.06, -0.01); P = 3.7 × 10-03) and with higher attrition after adjusting by treatment duration. No associations reached genome-wide significance in meta-analysis with previous GWAS studies for weight loss. However, associations in the ONTIME study showed effects consistent with published studies for rs545936 (MIR486/NKX6.3/ANK1), a previously noted weight loss locus. In the meta-analysis, each copy of the minor A allele was associated with 0.12 (0.03) kg/m2 higher BMI at week five of treatment (P = 3.9 × 10-06). In the ONTIME study, we also identified two genome-wide significant (P < 5×10-08) loci for the rate of weight loss near genes implicated in lipolysis, body weight, and metabolic regulation: rs146905606 near NFIP1/SPRY4/FGF1; and rs151313458 near LSAMP. CONCLUSION: Our findings are expected to help in developing personalized weight loss approaches based on genetics. CLINICAL TRIAL REGISTRATION: Obesity, Nutrigenetics, Timing, and Mediterranean (ONTIME; clinicaltrials.gov: NCT02829619) study.

Endogenous circadian rhythms in mood and well-being.

OBJECTIVES: We examined whether the endogenous circadian timing system modulates proxies of mood vulnerability and well-being. METHODS: Nineteen healthy participants (mean age: 26.6 years [23.0-30.2], seven females, body-mass index: 22.8 kg/m2 [21.1-25]) completed a laboratory protocol with a 32-hour Constant Routine, a stringently controlled protocol designed to isolate assessment of endogenous circadian rhythms. We assessed hourly anxiety- and depression-like mood (i.e., those typically observed in depression and anxiety) and well-being (i.e., associated with mental fatigue and physical comfort). RESULTS: Significant endogenous circadian rhythms were observed in anxiety-like and depression-like mood, as well as well-being (p values from the mixed-model analysis using false discovery rates < .001). Post-hoc comparisons revealed more anxiety-like and depression-like mood during the circadian phase 60°-75° (∼8-9 a.m.), and more mental fatigue and less physical comfort during the circadian phase 30°-60° (∼6-8 a.m.). CONCLUSIONS: Our data indicate endogenous circadian rhythms in anxiety-like and depression-like mood and well-being in healthy young adults. Future studies will help establish circadian-based therapeutics for individuals experiencing mood and anxiety disorders.

Social jetlag and obesity: A systematic review and meta-analysis.

Social jetlag, the weekly variation in sleep timing, is proposed to contribute to increased obesity risk, potentially because of the misalignment of behavioral cycles relative to the endogenous circadian timing system. This systematic review and meta-analysis aim to determine the association between social jetlag and adiposity-related measures using observational studies. We reviewed 477 references, of which 43 studies met inclusion criteria with a total sample size of 231,648. There was a positive association between social jetlag and body mass index (correlation coefficient [r]: 0.12; 95%CI, 0.07, 0.17; P < 0.001; I2  = 94.99%), fat mass (r: 0.10; 95%CI, 0.05, 0.15; P < 0.001; I2  = 0.00%), fat mass index (fat mass divided by height in meter squared, ß: 0.14 kg/m2 ; 95%CI, 0.05, 0.23; P < 0.001; I2  = 56.50%), percent of body fat (r: 0.37; 95%CI, 0.33, 0.41; P < 0.001; I2  = 96.17%), waist circumference (r: 0.15; 95%CI, 0.06, 0.24; P = 0.001; I2  = 90.83%), and the risk of having overweight/obesity (odds ratio: 1.20; 95%CI, 1.02, 1.140; P = 0.039; I2  = 98.25%). Social jetlag is positively and consistently associated with multiple obesity-related anthropometric measures. Further studies are needed to test causality, underlying mechanisms, and whether obesity interventions based on increasing regularity of the sleep/wake cycle can aid in the battle against the obesity pandemic.

The Negative Effects of Travel on Student Athletes Through Sleep and Circadian Disruption.

Collegiate athletes must satisfy the academic obligations common to all undergraduates, but they have the additional structural and social stressors of extensive practice time, competition schedules, and frequent travel away from their home campus. Clearly such stressors can have negative impacts on both their academic and athletic performances as well as on their health. These concerns are made more acute by recent proposals and decisions to reorganize major collegiate athletic conferences. These rearrangements will require more multi-day travel that interferes with the academic work and personal schedules of athletes. Of particular concern is additional east-west travel that results in circadian rhythm disruptions commonly called jet lag that contribute to the loss of amount as well as quality of sleep. Circadian misalignment and sleep deprivation and/or sleep disturbances have profound effects on physical and mental health and performance. We, as concerned scientists and physicians with relevant expertise, developed this white paper to raise awareness of these challenges to the wellbeing of our student-athletes and their co-travelers. We also offer practical steps to mitigate the negative consequences of collegiate travel schedules. We discuss the importance of bedtime protocols, the availability of early afternoon naps, and adherence to scheduled lighting exposure protocols before, during, and after travel, with support from wearables and apps. We call upon departments of athletics to engage with sleep and circadian experts to advise and help design tailored implementation of these mitigating practices that could contribute to the current and long-term health and wellbeing of their students and their staff members.

Light exposure during sleep is bidirectionally associated with irregular sleep timing: The multi-ethnic study of atherosclerosis (MESA).

Exposure to light at night (LAN) may influence sleep timing and regularity. Here, we test whether greater light exposure during sleep (LEDS) is bidirectionally associated with greater irregularity in sleep onset timing in a large cohort of older adults in cross-sectional and short-term longitudinal (days) analyses. Light exposure and activity patterns, measured via wrist-worn actigraphy (ActiWatch Spectrum), were analyzed in 1933 participants with 6+ valid days of data in the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 5 Sleep Study. Summary measures of LEDS averaged across nights were evaluated in linear and logistic regression analyses to test the association with standard deviation (SD) in sleep onset timing (continuous variable) and irregular sleep onset timing (SD > 90 min, binary). Night-to-night associations between LEDS and absolute differences in nightly sleep onset timing were also evaluated with distributed lag non-linear models and mixed models. In between-individual linear and logistic models adjusted for demographic, health, and seasonal factors, every 5-lux unit increase in LEDS was associated with a 7.8-min increase in sleep onset SD (ß = 0.13 h, 95%CI:0.09-0.17) and 32% greater odds (OR = 1.32, 95%CI:1.17-1.50) of irregular sleep onset. In within-individual night-to-night mixed model analyses, every 5-lux unit increase in LEDS the night prior was associated with a 2.2-min greater deviation of sleep onset the next night (ß = 0.036 h, p < 0.05). Conversely, every 1-h increase in sleep deviation was associated with a 0.35-lux increase in future LEDS (ß = 0.348 lux, p < 0.05). LEDS was associated with greater irregularity in sleep onset in between-individual analyses and subsequent deviation in sleep timing in within-individual analyses, supporting a role for LEDS in irregular sleep onset timing. Greater deviation in sleep onset was also associated with greater future LEDS, suggesting a bidirectional relationship. Maintaining a dark sleeping environment and preventing LEDS may promote sleep regularity and following a regular sleep schedule may limit LEDS.

Light exposure during sleep is associated with irregular sleep timing: the Multi-Ethnic Study of Atherosclerosis (MESA).

Objective: Exposure to light at night (LAN) may influence sleep timing and regularity. Here, we test whether greater light exposure during sleep (LEDS) associates with greater irregularity in sleep onset timing in a large cohort of older adults. Methods: Light exposure and activity patterns, measured via wrist-worn actigraphy (ActiWatch Spectrum), were analyzed in 1,933 participants with 6+ valid days of data in the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 5 Sleep Study. Summary measures of LEDS averaged across nights were evaluated in linear and logistic regression analyses to test the association with standard deviation (SD) in sleep onset timing (continuous variable) and irregular sleep onset timing (SD≥1.36 hours, binary). Night-to-night associations between LEDS and absolute differences in nightly sleep onset timing were also evaluated with distributed lag non-linear models and mixed models. Results: In between-individual linear and logistic models adjusted for demographic, health, and seasonal factors, every 5-lux unit increase in LEDS was associated with an increase of 7.8 minutes in sleep onset SD (ß=0.13 hours, 95%CI:0.09-0.17) and 40% greater odds (OR=1.40, 95%CI:1.24-1.60) of irregular sleep onset. In within-individual night-to-night mixed model analyses, every 5-lux unit increase in LEDS the night prior (lag0) was associated with a 2.2-minute greater deviation of sleep onset the next night (ß=0.036 hours, p<0.05). Conversely, every 1-hour increase in sleep deviation (lag0) was associated with a 0.35-lux increase in future LEDS (ß=0.347 lux, p<0.05). Conclusion: LEDS was associated with greater irregularity in sleep onset in between-individual analyses and subsequent deviation in sleep timing in within-individual analyses, supporting a role for LEDS in exacerbating irregular sleep onset timing. Greater deviation in sleep onset was also associated with greater future LEDS, suggesting a bidirectional relationship. Maintaining a dark sleeping environment and preventing LEDS may promote sleep regularity and following a regular sleep schedule may limit LEDS.

CIRCUST: A novel methodology for temporal order reconstruction of molecular rhythms; validation and application towards a daily rhythm gene expression atlas in humans.

The circadian system drives near-24-h oscillations in behaviors and biological processes. The underlying core molecular clock regulates the expression of other genes, and it has been shown that the expression of more than 50 percent of genes in mammals displays 24-h rhythmic patterns, with the specific genes that cycle varying from one tissue to another. Determining rhythmic gene expression patterns in human tissues sampled as single timepoints has several challenges, including the reconstruction of temporal order of highly noisy data. Previous methodologies have attempted to address these challenges in one or a small number of tissues for which rhythmic gene evolutionary conservation is assumed to be preserved. Here we introduce CIRCUST, a novel CIRCular-robUST methodology for analyzing molecular rhythms, that relies on circular statistics, is robust against noise, and requires fewer assumptions than existing methodologies. Next, we validated the method against four controlled experiments in which sampling times were known, and finally, CIRCUST was applied to 34 tissues from the Genotype-Tissue Expression (GTEx) dataset with the aim towards building a comprehensive daily rhythm gene expression atlas in humans. The validation and application shown here indicate that CIRCUST provides a flexible framework to formulate and solve the issues related to the analysis of molecular rhythms in human tissues. CIRCUST methodology is publicly available at https://github.com/yolandalago/CIRCUST/.

Circadian misalignment increases 24-hour acylated ghrelin in chronic shift workers: a randomized crossover trial.

OBJECTIVE: Shift workers typically experience misalignment between their circadian system and behavioral/environmental cycles and have an increased risk for obesity. Experimental studies in non-shift workers have suggested that circadian misalignment can disrupt energy balance regulation. This study examined the impact of circadian misalignment in the most relevant population, i.e., chronic shift workers. METHODS: Seven healthy chronic night shift workers underwent a randomized crossover study with two 3-day laboratory protocols: a night work protocol including 12-hour inverted behavioral/environmental cycles (circadian misalignment) and a day work protocol (circadian alignment). RESULTS: Circadian misalignment led to a ~17% increase in 24-hour acylated ghrelin levels in the chronic shift workers (p = 0.009). Consistently, circadian misalignment resulted in ~14% higher hunger at breakfast in the night shift (p = 0.04). Circadian misalignment did not significantly change fasting and postprandial energy expenditure or respiratory exchange ratio (all p > 0.32). Unexpectedly, 24-hour behavioral activity levels were ~38% higher (p < 0.0001) during circadian misalignment, despite a concurrent increase in sleepiness (p = 0.03). CONCLUSIONS: These results reveal that circadian misalignment, while carefully controlling for dietary intake, increases acylated ghrelin in chronic shift workers. Further studies should test whether the observed acute effects of circadian misalignment in chronic shift workers contribute to their increased obesity risk in the long term.

A Novel Home-Based Study of Circadian Rhythms: Design, Rationale, and Methods for the Circadia Study.

The Circadia Study (Circadia) is a novel "direct-to-participant" research study investigating the genetics of circadian rhythm disorders of advanced and delayed sleep phase and non-24 hour rhythms. The goals of the Circadia Study are twofold: (i) to create an easy-to-use toolkit for at-home circadian phase assessment for patients with circadian rhythm disorders through the use of novel in-home based surveys, tests, and collection kits; and (ii) create a richly phenotyped patient resource for genetic studies that will lead to new genetic loci associated with circadian rhythm disorders revealing possible loci of interest to target in the development of therapeutics for circadian rhythm disorders. Through these goals, we aim to broaden our understanding and elucidate the genetics of circadian rhythm disorders across a diverse patient population while increasing accessibility to circadian rhythm disorder diagnostics reducing health disparities through self-directed at-home dim light melatonin onset (DLMO) collections.

Social jetlag and dietary intake: A systematic review.

The objective of the current systematic review was to critically review the available evidence regarding the link between social jetlag and diet among the general population using observational studies. Electronic databases, including PubMed, Scopus, and ISI Web of Sciences were searched systematically. We reviewed 348 references, of which 17 studies met inclusion criteria with a total sample size of 28,905. Qualitative analysis indicated a negative association between social jetlag and adherence to healthy eating habits, including a negative association with empirically-derived healthy dietary patterns, Japanese dietary patterns, Baltic Sea dietary patterns, and the Mediterranean diet, as well as a positive association with Meat and Starchy dietary pattern. On the other hand, the findings on the link of social jetlag with food groups and nutrients were mixed and controversial, except for a more consistent increase in sugar-sweetened beverages, total fat, and saturated fat intake. Our results indicate a possible link between social jetlag and dietary intake. Research suggests that individuals experiencing greater social jetlag exhibit reduced adherence to a healthy eating pattern. However, it is important to note that the reported association lacks consensus, emphasizing the need for additional longitudinal studies to gain further insights into this matter."

Habitual nappers and non-nappers differ in circadian rhythms of LIPE expression in abdominal adipose tissue explants.

Background and purpose: Napping is a widespread practice worldwide and has in recent years been linked to increased abdominal adiposity. Lipase E or LIPE encodes the protein hormone-sensitive lipase (HSL), an enzyme that plays an important role in lipid mobilization and exhibits a circadian expression rhythm in human adipose tissue. We hypothesized that habitual napping may impact the circadian expression pattern of LIPE, which in turn may attenuate lipid mobilization and induce abdominal fat accumulation. Methods: Abdominal adipose tissue explants from participants with obesity (n = 17) were cultured for a 24-h duration and analyzed every 4 h. Habitual nappers (n = 8) were selected to match non-nappers (n = 9) in age, sex, BMI, adiposity, and metabolic syndrome traits. Circadian LIPE expression rhythmicity was analyzed using the cosinor method. Results: Adipose tissue explants exhibited robust circadian rhythms in LIPE expression in non-nappers. In contrast, nappers had a flattened rhythm. LIPE amplitude was decreased in nappers as compared with non-nappers (71% lower). The decrease in amplitude among nappers was related to the frequency of napping (times per week) where a lower rhythm amplitude was associated with a higher napping frequency (r = -0.80; P = 0.018). Confirmatory analyses in the activity of LIPE's protein (i.e., HSL) also showed a significant rhythm in non-nappers, whereas significance in the activity of HSL was lost among nappers. Conclusion: Our results suggest that nappers display dysregulated circadian LIPE expression as well as dysregulated circadian HSL activity, which may alter lipid mobilization and contribute to increased abdominal obesity in habitual nappers.

Associations of rest-activity rhythm disturbances with stroke risk and post-stroke adverse outcomes.

Background: Almost all biological and disease processes are influenced by circadian clocks and display ∼24-hour rhythms. Disruption of these rhythms may be an important novel risk factor for stroke. We evaluated the association between 24-h rest-activity rhythm measures, stroke risk, and major post-stroke adverse outcomes. Methods: In this cohort study, we examined ∼100,000 participants in the UK Biobank (44-79 years old; ∼57% females) who underwent an actigraphy (6-7 days) and 5-year median follow-up. We derived: (1) most active 10 hours activity counts ( M10 ) across the 24-h cycle and the timing of its midpoint ( M10 midpoint ); (2) the least active 5 hours counts ( L5 ) and its midpoint timing ( L5 midpoint ); (3) relative amplitude ( RA ) - (M10-L5)/(M10+L5); (4) interdaily stability (IS): stability and (5) intradaily variability (IV), fragmentation of the rhythm. Cox proportional hazard models were constructed for time to (i) incident stroke (n=1,652); and (ii) post-stroke adverse outcomes (dementia, depression, disability, or death). Results: Suppressed RA (lower M10 and higher L5) was associated with stroke risk after adjusting for demographics; the risk was highest in the lowest quartile [Q1] for RA (HR=1.62; 95% CI:1.36-1.93, p <0.001) compared to the top quartile [Q4]. Participants with later M10 midpoint timing (14:00-15:26, HR=1.26, CI:1.07-1.49, p =0.007) also had a higher risk for stroke than earlier (12:17-13:10) participants. A fragmented rhythm (IV) was also associated with a higher risk for stroke (Q4 vs. Q1; HR=1.27; CI:1.06-1.50, p =0.008), but differences in the stability of rhythms (IS) were not. Suppressed RA was associated with an increased risk of unfavorable post-stroke outcomes (Q1 vs. Q4; 1.78 [1.29-2.47]; p <0.001). All the associations were independent of age, sex, race, obesity, sleep disorders, cardiovascular diseases or risks, and other morbidity burdens. Conclusion: Suppressed 24-h rest-activity rhythm may be a risk factor for stroke and an early indicator of major post-stroke adverse outcomes.

Association of Timing of Moderate-to-Vigorous Physical Activity With Changes in Glycemic Control Over 4 Years in Adults With Type 2 Diabetes From the Look AHEAD Trial.

OBJECTIVE: We aimed to determine the association of the time-of-day of bout-related moderate-to-vigorous physical activity (bMVPA) with changes in glycemic control across 4 years in adults with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS: Among 2,416 participants (57% women; mean age, 59 years) with 7-day waist-worn accelerometry recording at year 1 or 4, we assigned bMVPA timing groups based on the participants' temporal distribution of bMVPA at year 1 and recategorized them at year 4. The time-varying exposure of bMVPA (≥10-min bout) timing was defined as ≥50% of bMVPA occurring during the same time period (morning, midday, afternoon, or evening), <50% of bMVPA in any time period (mixed), and ≤1 day with bMVPA per week (inactive). RESULTS: HbA1c reduction at year 1 varied among bMVPA timing groups (P = 0.02), independent of weekly bMVPA volume and intensity. The afternoon group had the greatest HbA1c reduction versus inactive (-0.22% [95%CI -0.39%, -0.06%]), the magnitude of which was 30-50% larger than the other groups. The odds of discontinuation versus maintaining or initiating glucose-lowering medications at year 1 differed by bMVPA timing (P = 0.04). The afternoon group had the highest odds (odds ratio 2.13 [95% CI 1.29, 3.52]). For all the year-4 bMVPA timing groups, there were no significant changes in HbA1c between year 1 and 4. CONCLUSIONS: bMVPA performed in the afternoon is associated with improvements in glycemic control in adults with diabetes, especially within the initial 12 months of an intervention. Experimental studies are needed to examine causality.