A novel method to visualise and quantify circadian misalignment

The circadian clock governs virtually all processes in the human body, including sleep-wake behaviour. Circadian misalignment describes the off-set between sleep-wake cycles and clock-regulated physiology. This strain is predominantly caused by external (societal) demands including shift work, early school start times and fast travels across time zones. Sleeping at the 'wrong' internal time can jeopardise health and safety, and we therefore need a good quantification of this phenomenon. Here, we propose a novel method to quantify the mistiming of sleep-wake rhythms and demonstrate its versatility in day workers and shift workers. Based on a single time series, our Composite Phase Deviation method unveils distinct, subject-and schedule-specific geometries ('islands and pancakes') that illustrate how modern work times interfere with sleep. With increasing levels of circadian strain, the resulting shapes change systematically from small, connected forms to large and fragmented patterns. Our method shows good congruence with published measures of circadian misalignment (i.e., Inter-daily Stability and 'Behavioural Entrainment'), but offers added value as to its requirements, e.g., being computable for sleep logs and questionnaires. Composite Phase Deviations will help to understand the mechanisms that link 'living against the clock' with health and disease on an individual basis

Chronotype Modulates Sleep Duration, Sleep Quality, and Social Jet Lag in Shift-Workers

This study explores chronotype-dependent tolerance to the demands of working morning, evening, and night shifts in terms of social jet lag, sleep duration, and sleep disturbance. A total of 238 shift-workers were chronotyped with the Munich ChronoType Questionnaire for shift-workers (MCTQ(Shift)), which collects information about shift-dependent sleep duration and sleep timing. Additionally, 94 shift-workers also completed those items of the Sleep Questionnaire from the Standard Shift-Work Index (SSI) that assess sleep disturbances. Although all participants worked morning, evening, and night shifts, subsamples differed in rotation direction and speed. Sleep duration, social jet lag, and sleep disturbance were all significantly modulated by the interaction of chronotype and shift (mixed-model ANOVAs). Earlier chronotypes showed shortened sleep duration during night shifts, high social jet lag, as well as higher levels of sleep disturbance. A similar pattern was observed for later chronotypes during early shifts. Age itself only influenced sleep duration and quality per se, without showing interactions with shifts. We found that workers slept longer in fast, rotating shift schedules. Since chronotype changes with age, investigations on sleep behavior and circadian misalignment in shift-workers have to consider chronotype to fully understand interindividual and intraindividual variability, especially in view of the current demographic changes. Given the impact of sleep on health, our results stress the importance of chronotype both in understanding the effects of shift-work on sleep and in devising solutions to reduce shift-work-related health problems

The Munich ChronoType Questionnaire for Shift-Workers (MCTQ(Shift))

Sleep is systematically modulated by chronotype in day-workers. Therefore, investigations into how shift-work affects sleep, health, and cognition may provide more reliable insights if they consider individual circadian time (chronotype). The Munich ChronoType Questionnaire (MCTQ) is a useful tool for determining chronotype. It assesses chronotype based on sleep behavior, specifically on the local time of mid-sleep on free days corrected for sleep debt accumulated over the workweek (MSFsc). Because the original MCTQ addresses people working standard hours, we developed an extended version that accommodates shift-work (MCTQ(Shift)). We first present the validation of this new version with daily sleep logs (n = 52) and actimetry (n = 27). Next, we evaluated 371 MCTQ(Shift) entries of shift-workers (rotating through 8-h shifts starting at 0600 h, 1400 h, and 2200 h). Our results support experimental findings showing that sleep is difficult to initiate and to maintain under the constraints of shift-work. Sleep times are remarkably stable on free days (on average between midnight and 0900 h), so that chronotype of shift-workers can be assessed by means of MSF-similar to that of day-workers. Sleep times on free-days are, however, slightly influenced by the preceding shift (displacements < 1 h), which are smallest after evening shifts. We therefore chose this shift-specific mid-sleep time (MSFE) to assess chronotype in shift-workers. The distribution of MSFE in our sample is identical to that of MSF in day-workers. We propose conversion algorithms for chronotyping shift-workers whose schedules do not include free days after evening shifts

Shift work and cognitive impairment in later life - results of a cross-sectional pilot study testing the feasibility of a large-scale epidemiologic investigation

Background: The effect of shift work on impairment of cognition in later life has not yet been sufficiently investigated. Therefore, we aimed at testing the feasibility of a large-scale epidemiologic study examining this putative association in a pilot study. Methods: Between January and April 2017, a cross-sectional study invited a random sample of 425 former and current employees of a German university hospital aged 55 years and older to undergo a cognitive test battery (including the Repeatable Battery for the Assessment of Neuropsychological Status, Trail Making Test, Letter-Number Span, and Vocabulary Test) and to complete a self-administered questionnaire on socio-demographic characteristics, chronotype, sleep, occupational history including shift work, and medical history. Fifty percent of the invitees were registered in the hospital's occupational records as currently working or having worked in a shift system. The feasibility of a large-scale study was evaluated by the response of the study sample and the completeness of data. In addition, we calculated the prevalence of shift work and cognitive impairment in the study population. Results: Seventy five subjects (18%) completed the questionnaire, of whom 47 (11% of the total sample) participated in cognitive testing. In all but four items assessed in the questionnaire, the proportion of missing data was below 10 %, suggesting that the quality of collected data can be considered as high. Eighty percent of the participants reported that they ever worked in a shift system, indicating selective participation by exposure to shift work. With respect to chronotype, the majority of the study subjects rated themselves as rather evening type, while a quarter considered themselves as definite morning type. All cognitive tests could be carried out completely. We observed slight difficulties in at least one of the cognitive tests in 17 participants (36%) while two participants (4%) showed more pronounced signs of cognitive impairment. Conclusion: The present pilot study only partially supported the feasibility of the planned large-scale study. As response rates were low and depended on exposure to shift work, a better way of sampling and recruitment needs to be identified. The questionnaire and the test battery appear to be viable instruments

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Chronotype Modulates Sleep Duration, Sleep Quality, and Social Jet Lag in Shift-Workers

This study explores chronotype-dependent tolerance to the demands of working morning, evening, and night shifts in terms of social jet lag, sleep duration, and sleep disturbance. A total of 238 shift-workers were chronotyped with the Munich ChronoType Questionnaire for shift-workers (MCTQ(Shift)), which collects information about shift-dependent sleep duration and sleep timing. Additionally, 94 shift-workers also completed those items of the Sleep Questionnaire from the Standard Shift-Work Index (SSI) that assess sleep disturbances. Although all participants worked morning, evening, and night shifts, subsamples differed in rotation direction and speed. Sleep duration, social jet lag, and sleep disturbance were all significantly modulated by the interaction of chronotype and shift (mixed-model ANOVAs). Earlier chronotypes showed shortened sleep duration during night shifts, high social jet lag, as well as higher levels of sleep disturbance. A similar pattern was observed for later chronotypes during early shifts. Age itself only influenced sleep duration and quality per se, without showing interactions with shifts. We found that workers slept longer in fast, rotating shift schedules. Since chronotype changes with age, investigations on sleep behavior and circadian misalignment in shift-workers have to consider chronotype to fully understand interindividual and intraindividual variability, especially in view of the current demographic changes. Given the impact of sleep on health, our results stress the importance of chronotype both in understanding the effects of shift-work on sleep and in devising solutions to reduce shift-work-related health problems

Exogenous melatonin decreases circadian misalignment and body weight among early types

Shift workers experience chronic circadian misalignment, which can manifest itself in reduced melatonin production, and has been associated with metabolic disorders. In addition, chronotype modulates the effect of night shift work, with early types presenting greater circadian misalignment when working night shift as compared to late types. Melatonin supplementation has shown positive results reducing weight gain in animal models, but the effect of exogenous melatonin in humans on body weight in the context of shift work remains inconsistent. The aim of this study was thus to evaluate the effects of exogenous melatonin on circadian misalignment and body weight among overweight night shift workers, according to chronotype, under real life conditions. We conducted a double-blind, randomized, placebo-controlled, crossover trial where melatonin (3 mg) or placebo was administered on non-night shift nights for 12 weeks in 27 female nurses (37.1 yo, ±5.9 yo; BMI 29.9 kg/m2, ±3.3 kg/m2). Melatonin (or placebo) was only taken on nights when the participants did not work night shifts, that is, on nights when they slept (between night shifts and on days-off). Composite Phase Deviations (CPD) of actigraphy-based midsleep timing were calculated to measure circadian misalignment. The analyses were performed for the whole group and by chronotype. We found approximately 20% reduction of circadian misalignment after exogenous melatonin administration considering all chronotypes. Moreover, melatonin supplementation in those who presented high circadian misalignment, as observed in early chronotypes, reduced body weight, BMI, waist circumference, and hip circumference, without any change in the participants’ calorie intake or physical activity levels

Sleep Timing in Patients with Precocious and Delayed Pubertal Development

Previous studies have reported a shift in the timing of sleep during adolescence toward a later time. To date, it is unclear whether hormonal changes during puberty might contribute to this change in sleeping behavior. We systematically assessed pubertal development and sleep timing in a cross-sectional case-control study in girls with precocious (n = 42) and boys with delayed pubertal development (n = 19). We used the Munich ChronoType Questionnaire and the Children’s ChronoType Questionnaire to assess sleep timing in patients and age- and sex-matched controls (n = 309) and used the midpoint of sleep on free days, corrected for potential sleep debt accumulated during the school week, as a marker for sleep timing. Compared to the controls, girls with central precocious puberty showed a delay in sleep timing of 54 min, and girls with premature pubarche slept on average 30 min later. Male adolescents with delayed pubertal development showed an average sleep midpoint that was 40 min earlier compared to the control group. The results of this pilot study suggest an association between pubertal onset and shifts in sleep timing, which is a novel finding in human sleep behavior. Prospective studies in larger cohorts will be needed to examine the robustness and generalizability of the findings