Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder.

Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes ∼24 hr rhythms in many behavioral and physiological processes. This system is altered in delayed sleep phase disorder (DSPD), a common form of insomnia in which sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6%, and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population.

Rhythms of life: circadian disruption and brain disorders across the lifespan.

Many processes in the human body - including brain function - are regulated over the 24-hour cycle, and there are strong associations between disrupted circadian rhythms (for example, sleep-wake cycles) and disorders of the CNS. Brain disorders such as autism, depression and Parkinson disease typically develop at certain stages of life, and circadian rhythms are important during each stage of life for the regulation of processes that may influence the development of these disorders. Here, we describe circadian disruptions observed in various brain disorders throughout the human lifespan and highlight emerging evidence suggesting these disruptions affect the brain. Currently, much of the evidence linking brain disorders and circadian dysfunction is correlational, and so whether and what kind of causal relationships might exist are unclear. We therefore identify remaining questions that may direct future research towards a better understanding of the links between circadian disruption and CNS disorders.

Light, sleep and circadian rhythm in critical illness.

PURPOSE OF REVIEW: Sleep and circadian disruption (SCD) are associated with worse outcomes in the ICU population. We discuss sleep, circadian physiology, the role of light in circadian entrainment and its possible role in treating SCD, with special attention to the use of light therapies and ICU design. RECENT FINDINGS: The American Thoracic Society recently published an official research statement highlighting key areas required to define and treat ICU SCD. Recent literature has been predominantly observational, describing how both critical illness and the ICU environment might impair normal sleep and impact circadian rhythm. Emerging consensus guidance outlines the need for standardized light metrics in clinical trials investigating effects of light therapies. A recent proof-of-concept randomized controlled trial (RCT) showed improvement in delirium incidence and circadian alignment from ICU room redesign that included a dynamic lighting system (DLS). SUMMARY: Further investigation is needed to define the optimal physical properties of light therapy in the ICU environment as well as timing and duration of light treatments. Work in this area will inform future circadian-promoting design, as well as multicomponent nonpharmacological protocols, to mitigate ICU SCD with the objective of improving patient outcomes.

Personalized sleep and nutritional strategies to combat adverse effects of night shift work: a controlled intervention protocol.

BACKGROUND: Working during the night interferes with the timing of normal daily activities and is associated with an increased risk of chronic diseases. Under controlled experimental conditions, interventions focusing on sleep and nutrition can mitigate the short-term adverse effects of shift work. However, it is unclear how these results translate to real-life, how they can be targeted to individual conditions, and how they relate to long-term health. Therefore, the current study aims to implement a personalized sleep and nutritional intervention among night shift workers in the field. METHODS: A non-blinded controlled intervention study is used, consisting of a run-in period, an intervention of 3 months, post-intervention measurements, and a follow-up after 12 months. Three study arms are included: sleep intervention, nutritional intervention, and control group (n = 25 each). Participants are healthy 18-60-year male night shift workers, with at least one year of experience in night shift work. Information from the run-in period will be used to personalize the interventions. The main outcomes are sleep measurements and continuous interstitial glucose levels. Furthermore, general health biomarkers and parameters will be determined to further evaluate effects on long-term health. DISCUSSION: This study aims to mitigate negative health consequences associated with night shift work by introducing two personalized preventive interventions. If proven effective, the personalized interventions may serve as practical solutions that can have a meaningful impact on the sustainable health and employability of night shift workers. This study will thereby contribute to the current need for high-quality data on preventative strategies for night shift work in a real-life context. TRIAL REGISTRATION: This trial has been registered under ClinicalTrials.gov Identifier NCT06147089. Registered 27 November 2023.

Sleep duration and quality in permanent night work: an observational field study.

PURPOSE: Permanent night workers conceivably show better adaptation of circadian rhythms to night work than shift workers and therefore better possibilities of obtaining sufficient sleep of good quality after night shifts. We investigated the effect of night shifts including number of consecutive shifts on sleep among self-selected permanent night workers, and studied if the effect of night shifts differed between morning and evening types and compared with 3-shift workers. METHODS: The study population included 90 permanent night workers followed for 14 days (warehouse workers, 1228 observation days, 80% males). For comparison, we included 70 3-shift workers followed for 26 days (police officers, 1774 observation days, 100% men). Total sleep time (TST), primary sleep duration (PSD), and sleep efficiency were assessed by actigraphy. Measures of sleep quality and diurnal type were self-reported. RESULTS: Among permanent night workers, TST, PSD, difficulties falling asleep, disturbed sleep, and the number of awakenings decreased after night shifts compared with days without night work. Sleep efficiency, difficulties awakening, and non-refreshing sleep increased. More consecutive night shifts were associated with shorter TST and PSD. Sleep outcomes did not differ by diurnal type. Permanent night workers had fewer awakenings after night shifts than 3-shift workers, but no other differences were observed. CONCLUSION: This study does not provide evidence that supports recommendation of permanent night work to reduce adverse effects of night shifts on sleep. A limited number of consecutive night shifts is recommended to reduce accumulation of sleep debt.

The association between shift work, shift work sleep disorders and premature ejaculation in male workers.

OBJECTIVE: Shift work and Shift Work Sleep Disorder (SWSD) are known to affect the secretion of several neurotransmitters and hormones associated with premature ejaculation (PE). However, their specific influence on the regulation of male ejaculation remains unclear. This study explores the relationship between shift work, SWSD, and PE. METHODS: From April to October 2023, a cross-sectional survey was conducted across five regions of China to explore the work schedules, sleep quality, and sexual function of male workers. Participants' sleep quality was evaluated using a validated SWSD questionnaire, and their erectile function and ejaculatory control were assessed with the International Inventory of Erectile Function (IIEF-5) scores and Premature Ejaculation Diagnostic Tool (PEDT) scores, respectively. Univariate and multivariate linear regression analyses were employed to identify risk factors associated with PE. Confounders were controlled using multiple regression models, and clinical prediction models were developed to predict PE onset and assess the contribution of risk factors. RESULTS: The study included 1239 eligible participants, comprising 840 non-shift workers and 399 shift workers (148 with SWSD and 251 without SWSD). Compared to non-shift working males, those involved in shift work (ß 1.58, 95% CI 0.75 - 2.42, p < 0.001) and those suffering from SWSD (ß 2.86, 95% CI 1.86 - 3.85, p < 0.001) they had significantly higher PEDT scores. Additionally, we identified daily sleep of less than six hours, depression, anxiety, diabetes, hyperlipidemia, frequent alcohol consumption (more than twice a week), and erectile dysfunction as risk factors for PE. The predictive model for PE demonstrated commendable efficacy. CONCLUSION: Both shift work and SWSD significantly increase the risk of premature ejaculation, with the risk magnifying in tandem with the duration of shift work. This study reveals the potential impact of shift work and SWSD on PE and provides new theoretical foundations for the risk assessment and prevention of this condition.

Associations Among Social Jet Lag, Sleep-Related Characteristics, and Burnout of Nurses in Tertiary Hospitals.

To investigate the status of social jet lag (SJL) through sociodemographic factors among clinical nurses and examine the correlation with burnout. There has been relatively little research on the possible factors resulting in SJL among nurses in China and its role in burnout. A multicenter cross-sectional study recruited 596 nurses from 7 Chinese hospitals. Online questionnaires were delivered to assess sociodemographics, shift work, SJL, chronotypes, and the burnout of nurses. Nurses had severe levels of SJL. The number of children, forms of employment, specialty area, length of professional service, and chronotypes were the main predictors of SJL. Moreover, SJL affected burnout (emotional exhaustion and deindividuation), and reducing the nurses' SJL could relieve their burnout. Additional evidence-based interventions indicate that reducing the SJL is essential as the nurses are suffering severe job burnout.

Sex Differences in Insomnia and Circadian Rhythm Disorders: A Systematic Review.

Insomnia and circadian rhythm disorders are increasingly common in modern society and lead to significant challenges for people's health and well-being. Some studies suggests that men and women differ in neurohormonal secretion, biological processes, and brain morphology. Thus, such differences may affect the etiology, manifestation, and course of sleep disorders, including insomnia and circadian rhythm. This systematic review aims to synthesize the existing literature on sex differences in insomnia and circadian rhythm disorders. PubMed, MEDLINE, Epistemonikos, and Cochrane databases were searched for articles published from inception until 5 September 2023, not older than five years. We performed a systematic search using MESH and non-MESH queries: (sex differences) or (male and female differences) or (men and women differences) or (men and women) AND (insomnia) or (sleep wake disorder*) or (sleep wake rhythm disorder*) or (circadian rhythm disorder*) or (sleep cycle disruption) or (sleep cycle disorder*). Out off 2833 articles screened, 11 studies were included. The prevalence of insomnia is higher among women, and their sleep is more regular and stable compared to men. Studies evaluating the impact of the stressful situation associated with the lockdown on women's and men's insomnia present discordant results concerning sex differences. Women's circadian rhythm was found to be more stable and less fragmented than men's. However, the progression of peak activity time with age was more pronounced in men. The current literature suggests that risk factors for insomnia and circadian rhythm disorders affect men and women differently. These include cerebrovascular and cardiometabolic factors, shift work, and infections. The long-term effects of insomnia seem to be more relevant for the male sex, shortening lifespan more than in women. By summarizing and analyzing existing studies, we highlight the need for further research to improve understanding of the interaction between sex and sleep.

Shift Work Sleep Disorder and Mental Health: An Integrative Review of Neurobiological, Sociological, and Psychological Perspectives With Public Policy Implications.

Shift workers support critical 24-hr operations; their health can be impaired by disrupted circadian rhythms and dysfunctional sleep. Shift work sleep disorder (SWSD) is a prevalent condition with significant psychological consequences. Nurse leaders have not yet implemented effective policies to prevent SWSD and optimize shift workers' mental health. The purpose of this integrative review was to examine research about SWSD within the context of neurobiological, sociological, and psychological perspectives that can inform policy changes. The Centers for Disease Control and Prevention Policy Analytic Framework was used to determine the priority recommendations. A search of three databases provided 19 research articles about SWSD and mental health, which illustrated how SWSD is common around the world in many occupations. Backward-rotating schedules and quick returns were risk factors for SWSD. In addition, SWSD was associated with circadian languidity, sleep reactivity, depressive symptoms, and anxiety. Collectively, the studies lacked objective measures of sleep and circadian rhythms, which has hindered the ability to devise interventions that will target the neurobiological causes of SWSD. The research also lacked attention to important sociological factors, such as workers' pay and benefits. Using these findings, nurse leaders can contribute to public policy reforms that increase funding for more rigorous SWSD research. Lawmakers should be advised by nurse leaders to enforce new regulations that provide incentives for employers to create healthier workplaces, such as prohibiting the overuse of schedules that make employees vulnerable to SWSD and providing funds for interventions to prevent SWSD and support mental health.

[Consequences of chronodisruption on body weight regulation and metabolism]. / Konsequenzen von Chronodisruption auf Körpergewichtsregulation und Stoffwechsel.

INTRODUCTION: The prevalence of overweight and obesity has increased dramatically. At the same time, lack of sleep has become a part of the modern lifestyle, as well as shift and night work. As a result, chronodisruption, i. e. a change in physiological processes that are controlled by the internal clock, becomes commonplace. Epidemiological data show that too short but also too long sleep are associated with an increased risk of obesity, also seen for night shift work. Overweight and obesity are associated with metabolic syndrome and data likewise report an increased risk by both short and long sleep. It has not yet been conclusively clarified how chronodisruption influences the metabolic risks. Clinical experimental studies report on neuroendocrine and circadian mechanisms and it has been shown that lack of sleep increases the hunger-promoting hormone ghrelin as well as subjective feelings of hunger and increases leptin levels. Lack of sleep also increases hedonic hunger and food-related reward signals. Through preventive measures, chronodisruption and thus, the risk of obesity can be counteracted. The extent to which smartwatches and fitness trackers, which according to the manufacturer can measure and analyze sleep, provide an objective picture of sleep has not been sufficiently investigated. However, smartwatches and fitness trackers can - probably - increase awareness of sleep in the modern society.

Circadian rhythms and disorders of the timing of sleep.

The daily alternation between sleep and wakefulness is one of the most dominant features of our lives and is a manifestation of the intrinsic 24 h rhythmicity underlying almost every aspect of our physiology. Circadian rhythms are generated by networks of molecular oscillators in the brain and peripheral tissues that interact with environmental and behavioural cycles to promote the occurrence of sleep during the environmental night. This alignment is often disturbed, however, by contemporary changes to our living environments, work or social schedules, patterns of light exposure, and biological factors, with consequences not only for sleep timing but also for our physical and mental health. Characterised by undesirable or irregular timing of sleep and wakefulness, in this Series paper we critically examine the existing categories of circadian rhythm sleep-wake disorders and the role of the circadian system in their development. We emphasise how not all disruption to daily rhythms is driven solely by an underlying circadian disturbance, and take a broader, dimensional approach to explore how circadian rhythms and sleep homoeostasis interact with behavioural and environmental factors. Very few high-quality epidemiological and intervention studies exist, and wider recognition and treatment of sleep timing disorders are currently hindered by a scarcity of accessible and objective tools for quantifying sleep and circadian physiology and environmental variables. We therefore assess emerging wearable technology, transcriptomics, and mathematical modelling approaches that promise to accelerate the integration of our knowledge in sleep and circadian science into improved human health.

Shine light on sleep: Morning bright light improves nocturnal sleep and next morning alertness among college students.

The relationship between daytime light, especially morning light and sleep, has not been well documented. People who work in an office spend most of their time indoors and thus have less access to high-level daylight. The current study employed a field intervention approach to investigate whether exposure to 1.5 h of bright electric light in the early morning for 1 workweek would benefit sleep among students who spent most of their time in an office at the university. Twelve students (24.92 ± 1.78 years) underwent a 2 workday baseline measurement and two inconsecutive 5 workday interventions (with 1 week washout) with morning bright light and regular office light (1000 lx, 6500 K vs. 300 lx, 4000 K, at eye level). The sleep outcomes were recorded with actigraphy and a sleep diary. In addition, self-ratings of daytime sleepiness, mood, mental fatigue, perceived effort, and next morning sleepiness were measured each workday. The results showed that exposure to morning bright light versus regular office light yielded a higher sleep efficiency (83.82% ± 1.60 vs. 80.35% ± 1.57, p = 0.02), a smaller fragmentation index (15.26% ± 1.31 vs. 17.18% ± 1.28, p = 0.05), and a shorter time in bed (7.12 ± 0.13 vs. 7.51 ± 0.12, p = 0.03). Meanwhile, an earlier sleep onset time, shorter sleep latency, and lower morning sleepiness were observed after a 5 workday morning bright light intervention compared with the baseline (ps <0.05), no such benefit was found for self-ratings (ps >0.05). These findings support existing evidence that morning bright light could function as an enhancer of sleep and alertness for office occupants.

Circadian aspects in the aetiology and pathophysiology of insomnia.

Because the endogenous circadian pacemaker is a very strong determinant of alertness/sleep propensity across the 24 h period, its mistiming may contribute to symptoms of insomnia (e.g., difficulties initiating sleep and maintaining sleep) and to the development of insomnia disorder. Despite the separation of insomnia and circadian rhythm disorders in diagnostic nosology implying independent pathophysiology, there is considerable evidence of co-morbidity and interaction between them. Sleep onset insomnia is associated with later timed circadian rhythms and can be treated with morning bright light to shift rhythms to an earlier timing. It is also possible that the causal link may go in both directions and that having a delayed circadian rhythm can result in enough experiences of delayed sleep onset to lead to some conditioned insomnia or insomnia disorder further exacerbating a delayed circadian rhythm. Early morning awakening insomnia is associated with an advanced circadian phase (early timing) and can be treated with evening bright light resulting in a delay of rhythms and an improved ability to sleep later in the morning and to obtain more sleep. There is some evidence suggesting that sleep maintenance insomnia is associated with a blunted amplitude of circadian rhythm that may be treated with increased regularity of sleep and light exposure timing. However, this is an insomnia phenotype that requires considerably more circadian research as well as further insomnia clinical research with the other insomnia phenotypes incorporating circadian timing measures and treatments.

Continuous positive airway pressure as an accurate marker for non-24-hour sleep-wake rhythm disorder.

Non-24-h sleep-wake rhythm disorder is quite rare in sighted patients and frequently associated with psychiatric disorders. We report the case of a 46-year-old man with autism spectrum disorder (ASD) and agoraphobia who had been referred for a suspicion of obstructive sleep apnea syndrome (OSAS). Polysomnography and arterial blood gas confirmed moderate OSAS associated with hypoventilation. Continuous positive airway pressure (CPAP) was started on fixed mode with excellent results. At follow-up, his CPAP report data revealed an irregular sleep-wake rhythm with a progressive offset of sleep schedule and wake time delayed from 1 h from day to day. Melatonin (or agonist) is efficacious and safe for long-term treatment in ASD and circadian rhythm sleep-wake disorder (CRSWD) with light therapy and wakefulness promoting medication. This case underlines the importance to sensitise psychiatrists to sleep and CRSWD, and also that CPAP data offer a possible objective alternative to sleep diary.

Melatonin Treatment of Circadian Rhythm Sleep-Wake Disorder in Obese Children Affects the Brain-Derived Neurotrophic Factor Level.

BACKGROUND: Previous studies proved that the brain-derived neurotrophic factor (BDNF) is correlated with sleep regulation, yet how BDNF functions and reacts in the melatonin treatment of circadian rhythm sleep-wake disorder (CRSWD) among obese children remain enigmatic. Focusing on CRSWD in obese children, this study monitored their sleep efficiency and serum BDNF level changes during the treatment of melatonin. METHODS: In total, 35 obese children diagnosed with CRSWD were included in this study and administrated melatonin (3 mg/night) for 3 months. Blood samples were collected 24 hours before and after the treatment (08:00, 12:00, 16:00, 20:00, 24:00, and 04:00). Subsequently, the plasma melatonin level and serum BDNF level were measured by enzyme-linked immunosorbent assay. Sleep parameters, including sleep quality, Pittsburgh Sleep Quality Index as well as melatonin and BDNF levels before and after treatment, were recorded to profile the effectiveness and safety of melatonin treatment. RESULTS: Melatonin treatment increased plasma melatonin concentration and restored circadian rhythm. Besides, the serum BDNF level showed a significant increase, representing a strong positive correlation with melatonin concentration (p = 0.026). Patients experienced much-improved sleep efficiency (P < 0.001), with longer actual sleep time (P < 0.001), shorter sleep onset latency, and fewer awakenings after treatment (P < 0.001). Besides, melatonin was well tolerated by patients without producing severe side effects. CONCLUSION: Melatonin treatment effectively improved CRSWD among obese children with their serum BDNF levels increased, indicating that BDNF is a key regulator in CRSWD in obese children. This study may offer theoretical support for melatonin treatment of CRSWD in obese children.

Efficacy of agomelatine with cognitive behavioral therapy for delayed sleep-wake phase disorder in young adults: A randomized controlled study.

BACKGROUND: Delayed sleep-wake phase disorder (DSWPD) is common and easily misdiagnosed in young people, and to date, there is no evidence-based treatment. PURPOSE: A nonblinded randomized controlled study evaluated the effect of agomelatine therapy (AT) and cognitive behavior therapy (CBT) on DSWPD in young adults. METHODS: Sixty adolescents and young adults (range = 19-24 years, mean = 22 years, 52% female) diagnosed with DSWPD were randomized to receive 4 weeks of agomelatine therapy with or without cognitive behavior therapy. Sleep diaries, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Insomnia Severity Index (ISI), and World Health Organization wellbeing questionnaire (WHO-5) were measured pre-treatment and post-treatment. RESULTS: Agomelatine therapy for 4 weeks shifted the sleep-wake rhythm (p < .001) forward in both groups at the week 4 assessment. There were no significant differences in sleep onset (p = .099) and sleep offset (p = .959) between the CBT group and the no treatment (NT) group at the follow-up visits. However, significant differences were found in sleep duration (p = .002), sleep quality (p=0.005), sleep difficulties (p < .001), daytime sleepiness (p = .001), and wellbeing (p = .007) between groups. CONCLUSIONS: The improvements were received largely through the sleep-promoting effects of agomelatine therapy, and combining with cognitive behavior therapy on maintenance of altered sleep rhythms might be feasible.

Dysfunction of Prkcaa Links Social Behavior Defects with Disturbed Circadian Rhythm in Zebrafish.

Protein kinase Cα (PKCα/PRKCA) is a crucial regulator of circadian rhythm and is associated with human mental illnesses such as autism spectrum disorders and schizophrenia. However, the roles of PRKCA in modulating animal social behavior and the underlying mechanisms remain to be explored. Here we report the generation and characterization of prkcaa-deficient zebrafish (Danio rerio). The results of behavioral tests indicate that a deficiency in Prkcaa led to anxiety-like behavior and impaired social preference in zebrafish. RNA-sequencing analyses revealed the significant effects of the prkcaa mutation on the expression of the morning-preferring circadian genes. The representatives are the immediate early genes, including egr2a, egr4, fosaa, fosab and npas4a. The downregulation of these genes at night was attenuated by Prkcaa dysfunction. Consistently, the mutants demonstrated reversed day-night locomotor rhythm, which are more active at night than in the morning. Our data show the roles of PRKCA in regulating animal social interactions and link the social behavior defects with a disturbed circadian rhythm.

Exercise, diet, and sleep habits of nurses working full-time during the COVID-19 pandemic: An observational study.

BACKGROUND: Healthy diet, exercise, and sleep practices may mitigate stress and prevent illness. However, lifestyle behaviors of acute care nurses working during stressful COVID-19 surges are unclear. PURPOSE: To quantify sleep, diet, and exercise practices of 12-hour acute care nurses working day or night shift during COVID-19-related surges. METHODS: Nurses across 10 hospitals in the United States wore wrist actigraphs and pedometers to quantify sleep and steps and completed electronic diaries documenting diet over 7-days. FINDINGS: Participant average sleep quantity did not meet national recommendations; night shift nurses (n = 23) slept significantly less before on-duty days when compared to day shift nurses (n = 34). Proportionally more night shift nurses did not meet daily step recommendations. Diet quality was low on average among participants. DISCUSSION: Nurses, especially those on night shift, may require resources to support healthy sleep hygiene, physical activity practices, and diet quality to mitigate stressful work environments.

Changes in menstrual cycle length and in sleep-wake behaviors during COVID-19 related lockdown in Israel.

COVID-19 related lockdowns changed our life. Studies report that young women are more susceptible to lockdown-induced adverse effects and stress. As stress and menstrual cycle are associated, we hypothesized that menstrual cycle length might change during lockdown. We examined menstrual cycle length, and sleep-wake behaviors during lockdown in Israel. Participants were 97 women in their fertile years who used Tempdrop fertility sensor™ to track cycles. Data were collected before, during and after lockdown in Israel. Our main finding is that lockdown was associated with changes in menstrual cycle length of most participants, with either increased of decreased length. Changes were reversed when lockdown was terminated. Sleep duration increased during lockdown but we found no relationship between sleep and menstrual cycle. We suggest these findings contribute to the understanding of the relationship between stress, sleep, and menstrual cycle. Further studies should explore the sources for differential effects in sub-groups of women.

Wake-up Call: Night Shifts Adversely Affect Nurse Health and Retention, Patient and Public Safety, and Costs.

The purpose of this mini review is to (1) summarize the findings on the impact of night shift on nurses' health and wellness, patient and public safety, and implications on organizational costs and (2) provide strategies to promote night shift nurses' health and improve organizational costs. The night shift, compared with day shift, results in poorer physical and mental health through its adverse effects on sleep, circadian rhythms, and dietary and beverage consumption, along with impaired cognitive function that increases nurse errors. Nurse administrators and health care organizations have opportunities to improve nurse and patient safety on night shifts. Low-, moderate-, and higher-cost measures that promote night nurses' health and well-being can help mitigate these negative outcomes. The provided individual and organizational recommendations and innovations support night shift nurses' health, patient and public safety, and organizational success.