Chronic circadian rhythm disorder induces heart failure with preserved ejection fraction-like phenotype through the Clock-sGC-cGMP-PKG1 signaling pathway.

Emerging evidence has documented that circadian rhythm disorders could be related to cardiovascular diseases. However, there is limited knowledge on the direct adverse effects of circadian misalignment on the heart. This study aimed to investigate the effect of chronic circadian rhythm disorder on heart homeostasis in a mouse model of consistent jetlag. The jetlag model was induced in mice by a serial 8-h phase advance of the light cycle using a light-controlled isolation box every 4 days for up to 3 months. Herein, we demonstrated for the first time that chronic circadian rhythm disorder established in the mouse jetlag model could lead to HFpEF-like phenotype such as cardiac hypertrophy, cardiac fibrosis, and cardiac diastolic dysfunction, following the attenuation of the Clock-sGC-cGMP-PKG1 signaling. In addition, clock gene knock down in cardiomyocytes induced hypertrophy via decreased sGC-cGMP-PKG signaling pathway. Furthermore, treatment with an sGC-activator riociguat directly attenuated the adverse effects of jetlag model-induced cardiac hypertrophy, cardiac fibrosis, and cardiac diastolic dysfunction. Our data suggest that circadian rhythm disruption could induce HFpEF-like phenotype through downregulation of the clock-sGC-cGMP-PKG1 signaling pathway. sGC could be one of the molecular targets against circadian rhythm disorder-related heart disease.

The association between circadian syndrome and chronic kidney disease in an aging population: a 4-year follow-up study.

Introduction: Circadian syndrome (CircS) is proposed as a novel risk cluster based on reduced sleep duration, abdominal obesity, depression, hypertension, dyslipidemia and hyperglycemia. However, the association between CircS and chronic kidney disease (CKD) remains unclear. To investigate the cross-sectional and longitudinal association between CircS and CKD, this study was performed. Methods: A national prospective cohort (China Health and Retirement Longitudinal Study, CHARLS) was used in this study. To define CKD, the estimated glomerular filtration rate (eGFR) was calculated based on the 2012 CKD-EPI creatinine-cystatin C equation. Participants with eGFR <60 mL.min-1/1.73/m2 were diagnosed with CKD. Multivariate binary logistic regression was used to assess the cross-sectional association between CircS and CKD. Subgroup and interactive analyses were performed to determine the interactive effects of covariates. In the sensitivity analysis, the obese population was excluded and another method for calculating the eGFR was used to verify the robustness of previous findings. In addition, participants without CKD at baseline were followed up for four years to investigate the longitudinal relationship between CircS and CKD. Results: A total of 6355 participants were included in this study. In the full model, CircS was positively associated with CKD (OR = 1.28, 95% CI = 1.04-1.59, P < 0.05). As per one increase of CircS components, there was a 1.11-fold (95% CI = 1.04-1.18, P < 0.05) risk of prevalent CKD in the full model. A significant interactive effect of hyperuricemia in the CircS-CKD association (P for interaction < 0.01) was observed. Sensitivity analyses excluding the obese population and using the 2009 CKD-EPI creatinine equation to diagnose CKD supported the positive correlation between CircS and CKD. In the 2011-2015 follow-up cohort, the CircS group had a 2.18-fold risk of incident CKD (95% CI = 1.33-3.58, P < 0.01) in the full model. The OR was 1.29 (95% CI = 1.10-1.51, P < 0.001) with per one increase of CircS components. Conclusion: CircS is a risk factor for CKD and may serve as a predictor of CKD for early identification and intervention.

Circadian dysfunction and cardio-metabolic disorders in humans.

The topic of human circadian rhythms is not only attracting the attention of clinical researchers from various fields but also sparking a growing public interest. The circadian system comprises the central clock, located in the suprachiasmatic nucleus of the hypothalamus, and the peripheral clocks in various tissues that are interconnected; together they coordinate many daily activities, including sleep and wakefulness, physical activity, food intake, glucose sensitivity and cardiovascular functions. Disruption of circadian regulation seems to be associated with metabolic disorders (particularly impaired glucose tolerance) and cardiovascular disease. Previous clinical trials revealed that disturbance of the circadian system, specifically due to shift work, is associated with an increased risk of type 2 diabetes mellitus. This review is intended to provide clinicians who wish to implement knowledge of circadian disruption in diagnosis and strategies to avoid cardio-metabolic disease with a general overview of this topic.

The Association between Circadian Syndrome and Frailty in US adults: a cross-sectional study of NHANES Data from 2007 to 2018.

PURPOSE: Frailty and Circadian Syndrome (CircS) are prevalent among the elderly, yet the link between them remains underexplored. This study aims to examine the association between CircS and frailty, particularly focusing on the impact of various CircS components on frailty. MATERIALS AND METHODS: We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2018. The 49-item Frailty Index (FI) was employed to assess frailty. To understand the prevalence of CircS in relation to frailty, we applied three multivariate logistic regression models. Additionally, subgroup and interaction analyses were performed to investigate potential modifying factors. RESULTS: The study included 8,569 participants. In fully adjusted models, individuals with CircS showed a significantly higher risk of frailty compared to those without CircS (Odds Ratio [OR] = 2.18, 95% Confidence Interval [CI]: 1.91-2.49, p < 0.001). A trend of increasing frailty risk with greater CircS component was observed (trend test p < 0.001). Age (p = 0.01) and race (p = 0.02) interactions notably influenced this association, although the direction of effect was consistent across subgroups. Sensitivity analysis further confirmed the strength of this relationship. CONCLUSION: This study identifies a strong positive correlation between CircS and frailty in the elderly. The risk of frailty escalates with an increasing number of CircS components. These findings highlight the intricate interplay between circadian syndrome and frailty in older adults, offering valuable insights for developing targeted prevention and intervention strategies.

Gut Microbiota Mediate the Neuroprotective Effect of Oolong Tea Polyphenols in Cognitive Impairment Induced by Circadian Rhythm Disorder.

Oolong tea polyphenols (OTP) have attracted wide attention due to their ability to reduce inflammatory response, regulate gut microbiota, and improve cognitive function. However, exactly how the gut microbiota modulates nervous system activity is still an open question. We previously expounded that supplementing with OTP alleviated neuroinflammation in circadian rhythm disorder (CRD) mice. Here, we showed that OTP can relieve microglia activation by reducing harmful microbial metabolites lipopolysaccharide (LPS) that alleviate CRD-induced cognitive decline. Mechanistically, OTP suppressed the inflammation response by regulating the gut microbiota composition, including upregulating the relative abundance of Muribaculaceae and Clostridia_UCG-014 and downregulating Desulfovibrio, promoting the production of short-chain fatty acids (SCFAs). Moreover, the use of OTP alleviated intestinal barrier damage and decreased the LPS transport to the serum. These results further inhibited the activation of microglia, thus alleviating cognitive impairment by inhibiting neuroinflammation, neuron damage, and neurotoxicity metabolite glutamate elevation. Meanwhile, OTP upregulated the expression of synaptic plasticity-related protein postsynaptic density protein 95 (PSD-95) and synaptophysin (SYN) by elevating the brain-derived neurotrophic factor (BDNF) level. Taken together, our findings suggest that the OTP has the potential to prevent CRD-induced cognition decline by modulating gut microbiota and microbial metabolites.

The relationship between anxiety symptoms and disturbances in biological rhythms in patients with depression.

BACKGROUND: Biological rhythms denote the cyclical patterns of life activities anchored to a 24-hour cycle. Research shows that depression exhibits disturbances in biological rhythms. Yet, the relationship between these biological rhythms and concomitant anxiety symptoms is insufficiently investigated in structured clinical assessments. METHODS: This multicenter study, carried out in four Chinese hospitals, comprehensively examined the relationship between anxiety and disruptions in biological rhythms among patients with depression. The study encompassed 218 patients diagnosed with depression and 205 matched healthy controls. The Chinese version of the Biological Rhythms Interview of Assessment in Neuropsychiatry was utilized to evaluate the participants' biological rhythms, focusing on four dimensions: sleep, activity, social, and diet. RESULTS: In patients with depression, there is a significant positive correlation between the severity of anxiety symptoms and the disturbances in biological rhythms. The severity of anxiety and depression, along with the quality of life, are independently associated with disruptions in biological rhythms. The mediation model reveals that anxiety symptoms mediate the relationship between depressive symptoms and biological rhythms. CONCLUSION: This research highlights the role of anxiety within the spectrum of depressive disorders and the associated disturbances in biological rhythms. Our findings shed light on potential pathways towards more targeted preventive strategies and therapeutic interventions for individuals battling depression and anxiety.

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.

Melatonin attenuates fentanyl - induced behavioral sensitization and circadian rhythm disorders in mice.

Melatonin is a neurohormone synthesized by the pineal gland to regulate the circadian rhythms and has proven to be effective in treating drug addiction and dependence. However, the effects of melatonin to modulate the drug-seeking behavior of fentanyl and its underlying molecular mechanism is elusive. This study was designed to investigate the effects of melatonin on fentanyl - induced behavioral sensitization and circadian rhythm disorders in mice. The accompanying changes in the expression of Brain and Muscle Arnt-Like (BMAL1), tyrosine hydroxylase (TH), and monoamine oxidase A (MAO-A) in relevant brain regions including the suprachiasmatic nucleus (SCN), nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus (Hip) were investigated by western blot assays to dissect the mechanism by which melatonin modulates fentanyl - induced behavioral sensitization and circadian rhythm disorders. The present study suggest that fentanyl (0.05, 0.1 and 0.2 mg/kg) could induce behavioral sensitization and melatonin (30.0 mg/kg) could attenuate the behavioral sensitization and circadian rhythm disorders in mice. Fentanyl treatment reduced the expression of BMAL1 and MAO-A and increased that of TH in relevant brain regions. Furthermore, melatonin treatment could reverse the expression levels of BMAL1, MAO-A, and TH. In conclusion, our study demonstrate for the first time that melatonin has therapeutic potential for fentanyl addiction.

Circadian clock-related genome-wide mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity.

BACKGROUND: Circadian rhythm is crucial to the function of the immune system. Disorders of the circadian rhythm can contribute to inflammatory diseases such as Ulcerative colitis (UC). This Mendelian Randomization (MR) analysis applies genetic tools to represent the aggregated statistical results of exposure to circadian rhythm disorders and UC and its comorbidities, allowing for causal inferences. METHODS: Summary statistics of protein, DNA methylation and gene expression quantitative trait loci in individuals of European ancestry (pQTL, mQTL, and eQTL, respectively) were used. Genetic variants located within or near 152 circadian clock-related genes and closely related to circadian rhythm disorders were selected as instrumental variables. Causal relationships with UC and its comorbidities were then estimated through employed Summary data-based Mendelian Randomization (SMR) and Inverse-Variance-Weighted MR (IVW-MR). RESULTS: Through preliminary SMR analysis, we identified a potential causal relationship between circadian clock-related genes and UC along with its comorbidities, which was further confirmed by IVW-MR analysis. Our study identified strong evidence of positive correlation involving seven overlapping genes (CSNK1E, OPRL1, PIWIL2, RORC, MAX, PPP5C, and AANAT) through MWAS and TWAS in UC, four overlapping genes (OPRL1, CHRNB2, FBXL17, and SIRT1) in UC with PSC, and three overlapping genes (ARNTL, USP7, and KRAS) in UC with arthropathy. CONCLUSIONS: This SMR study demonstrates the causal effect of circadian rhythm disorders in UC and its comorbidities. Furthermore, our investigation pinpointed candidate genes that could potentially serve as drug targets.

VX-765 Alleviates Circadian Rhythm Disorder in a Rodent Model of Traumatic Brain Injury Plus Hemorrhagic Shock and Resuscitation.

Severe traumatic brain injury (TBI) can result in persistent complications, including circadian rhythm disorder, that substantially affect not only the injured people, but also the mood and social interactions with the family and the community. Pyroptosis in GFAP-positive astrocytes plays a vital role in inflammatory changes post-TBI. We determined whether VX-765, a low molecular weight caspase-1 inhibitor, has potential therapeutic value against astrocytic inflammation and pyroptosis in a rodent model of TBI plus hemorrhagic shock and resuscitation (HSR). A weight-drop plus bleeding and refusion model was used to establish traumatic exposure in rats. VX-765 (50 mg/kg) was injected via the femoral vein after resuscitation. Wheel-running activity was assessed, brain magnetic resonance images were evaluated, the expression of pyroptosis-associated molecules including cleaved caspase-1, gasdermin D (GSDMD), and interleukin-18 (IL-18) in astrocytes in the region of anterior hypothalamus, were explored 30 days post-trauma. VX-765-treated rats had significant improvement in circadian rhythm disorder, decreased mean diffusivity (MD) and mean kurtosis (MK), increased fractional anisotropy (FA), an elevated number and branches of astrocytes, and lower cleaved caspase-1, GSDMD, and IL-18 expression in astrocytes than TBI + HSR-treated rats. These results demonstrated that inhibition of pyroptosis-associated astrocytic activations in the anterior hypothalamus using VX-765 may ameliorate circadian rhythm disorder after trauma. In conclusion, we suggest that interventions targeting caspase-1-induced astrocytic pyroptosis by VX-765 are promising strategies to alleviate circadian rhythm disorder post-TBI.

Social and circadian rhythm dysregulation and suicide: A systematic review and meta-analysis.

This systematic review of 52 studies provides a quantitative synthesis of the empirical literature on social and circadian rhythm correlates of suicidal thoughts and behaviors (STB). Small-to-medium pooled effect sizes were observed for associations between evening chronotype and STB and suicidal ideation (SI), although the pooled effect size diminished when accounting for publication bias. Three studies employed longitudinal designs and suggested eveningness was predictive of future STB, with a small-to-medium effect size. Social rhythm irregularity was also a significant correlate of STB with pooled effect sizes in the medium range. Overall circadian rhythm disruption was not associated with STB, although certain circadian rhythm metrics, including mean daytime activity, circadian rhythm sleep-wake disorder diagnosis, and actigraphy-assessed amplitude were associated with STB. Pooled effect sizes for these indices were in the medium to large range. There is a need for additional longitudinal research on actigraphy-based circadian parameters and objective markers of circadian phase (i.e., dim-light melatonin onset) to gain a clearer understanding of associations of endogenous circadian function and STB beyond that which can be captured via self-report.

The efficacy of a transdiagnostic sleep intervention for outpatients with sleep problems and depression, bipolar disorder, or attention deficit disorder: study protocol for a randomized controlled trial.

BACKGROUND: Patients with mental disorders have a higher prevalence of sleep problems than the general population. Sleep problems may include insomnia, circadian rhythm disorders, or hypersomnia. A transdiagnostic approach combining cognitive behavioral therapy for insomnia (CBT-I) with chronotherapy addressing a broad range of sleep problems has shown promising results in a limited number of studies. The aim of the study is to investigate the efficacy of a transdiagnostic sleep intervention for patients with sleep problems comorbid to bipolar disorder, unipolar depression, or attention deficit disorders. The primary hypothesis is that the intervention improves sleep quality compared with a control group. The secondary hypotheses are that the intervention increases subjective and objective sleep efficiency, reduces sleep onset latency, wake after sleep onset, number of awakenings, and severity of insomnia; and that it improves well-being, personal recovery, work ability, and consumption of sleep medication compared with a control group. METHODS: The study is a randomized controlled trial enrolling 88 outpatients with bipolar disorder, major depression, or attention deficit disorder with symptoms of various sleep problems (insomnia, circadian rhythm disorders, or hypersomnia). Patients are allocated to either an intervention group receiving six sessions of transdiagnostic sleep treatment or to a control group receiving a single session of sleep hygiene education. Assessments are made at baseline, at week two, and after 6 weeks in both groups. Actigraphy is performed continuously throughout the 6-week study period for all patients. The primary outcome is changes in the subjective appraisal of sleep quality (Pittsburgh Sleep Quality Index). The secondary outcomes are changes in sleep efficiency, sleep onset latency, wake after sleep onset, number of nocturnal awakenings (based on actigraph and sleep diary data), changes in insomnia severity (Insomnia Severity Index), well-being (WHO-5 Well-Being Index), personal recovery (INSPIRE-O), work ability (Work Ability Index), and consumption of sleep medication (sleep-diaries). DISCUSSION: The study was initiated in 2022 and the inclusion period will continue until mid-2024. The results may have implications for the development and implementation of additional treatment options for patients with mental disorders and comorbid sleep problems. TRIAL REGISTRATION: ClinicalTrials.gov. NCT05406414. Registered on June 6, 2022.

Loss of Dec1 inhibits alcohol-induced hepatic lipid accumulation and circadian rhythm disorder.

Chronic alcohol exposure increases liver damage such as lipid accumulation and hepatitis, resulting in hepatic cirrhosis. Chronic alcohol intake is known to disturb circadian rhythms in humans and animals. DEC1, a basic helix-loop-helix transcription factor, plays an important role in the circadian rhythm, inflammation, immune responses, and tumor progression. We have previously shown that Dec1 deficiency inhibits stresses such as periodontal inflammation and perivascular fibrosis of the heart. However, the significance of Dec1 deficiency in chronic alcohol consumption remains unclear. In the present study, we investigated whether the biological stress caused by chronic alcohol intake is inhibited in Dec1 knockout mice. We treated control and Dec1 knockout mice for three months by providing free access to 10% alcohol. The Dec1 knockout mice consumed more alcohol than control mice, however, we observed severe hepatic lipid accumulation and circadian rhythm disturbance in control mice. In contrast, Dec1 knockout mice exhibited little effect on these outcomes. We also investigated the expression of peroxisome proliferator-activated receptors (PPARs) and AMP-activated protein kinase (AMPK), which are involved in the regulation of fatty acid metabolism. Immunohistochemical analysis revealed increases of phosphorylation AMPK and PPARa but decreases PPARg in Dec1 knockout mice compared to that in control mice. This indicates a molecular basis for the inhibition of hepatic lipid accumulation in alcohol-treated Dec1 knockout mice. These results suggest a novel function of Dec1 in alcohol-induced hepatic lipid accumulation and circadian rhythm disorders.

Functional Characterization of Circadian Nuclear Receptors REV-ERBα and REV-ERBß in Human Osteosarcoma Cell Cultures.

REV-ERBα and its paralog, REV-ERBß, encoded by NR1D1 and NR1D2 genes, are key nuclear receptors that link the circadian timing system and metabolic homeostasis. Since heme is an endogenous ligand, REV-ERBs have been considered key components of the circadian molecular clock and can be pharmacologically targeted to treat various circadian rhythm-related diseases, such as cardiometabolic, inflammatory, and neuropsychiatric diseases, as well as cancer. REV-ERBs are believed to be functionally redundant and compensatory, although they often affect the expression of gene subsets in an isoform-specific manner. Therefore, this study aimed to identify the redundant and distinct roles of each isoform in controlling its target genes by comparing the transcriptome profiles of a panel of mutant U2OS human osteosarcoma cells in which either NR1D1 or NR1D2 was ablated. Indeed, our transcriptomic analyses revealed that most REV-ERB-regulated genes are controlled by redundant or even additive actions. However, the RNA expression profiles of each single mutant cell line also provide strong evidence for isoform-dependent actions. For example, REV-ERBα is more responsible for regulating the NF-κΒ signaling pathway, whereas a group of extracellular matrix components requires REV-ERBß to maintain their expression. We found that REV-ERBs have isoform-selective functions in the regulation of certain circadian output pathways despite their overlapping roles in the circadian molecular clock. Thus, the development of isoform-selective REV-ERB modulators can help treat metabolic disturbances and certain types of cancer.

Pressure Building Against the Clock: The Impact of Circadian Misalignment on Blood Pressure.

PURPOSE OF REVIEW: Misalignment between the endogenous biological timing system and behavioral activities (i.e., sleep/wake, eating, activity) contributes to adverse cardiovascular health. In this review, we discuss the effects of recurring circadian misalignment on blood pressure regulation and the implications for hypertension development. Additionally, we highlight emerging therapeutic approaches designed to mitigate the negative cardiovascular consequences elicited by circadian disruption. RECENT FINDINGS: Circadian misalignment elicited by work schedules that require individuals to be awake during the biological night (i.e., shift work) alters 24-h blood pressure rhythms. Mechanistically, circadian misalignment appears to alter blood pressure via changes in autonomic nervous system balance, variations to sodium retention, dysregulation of endothelial vasodilatory responsiveness, and activation of proinflammatory mechanisms. Recurring circadian misalignment produced by a mismatch in sleep timing on free days vs. work days (i.e., social jetlag) appears to have no direct effects on prevailing blood pressure levels in healthy adults; though, circadian disruptions resulting from social jetlag may increase the risk of hypertension through enhanced sympathetic activation and/or obesity. Furthermore, social jetlag assessment may be a useful metric in shift work populations where the magnitude of circadian misalignment may be greater than in the general population. Circadian misalignment promotes unfavorable changes to 24-h blood pressure rhythms, most notably in shift working populations. While light therapy, melatonin supplementation, and the timing of drug administration may improve cardiovascular outcomes, interventions designed to target the effects of circadian misalignment on blood pressure regulation are warranted.

Guanxin V alleviates ventricular remodeling after acute myocardial infarction with circadian disruption by regulating mitochondrial dynamics.

PURPOSE: Circadian disruption has been a common issue due to modern lifestyles. Ventricular remodeling (VR) is a pivotal progressive pathologic change after acute myocardial infarction (AMI) and circadian disruption may have a negative influence on VR according to the latest research. Whether or not Guanxin V (GXV) has a positive effect on VR after AMI with circadian disruption drew our interest. METHODS: Rats were randomly divided into a sham group, an AMI group, an AMI with circadian disruption group, and an AMI with circadian disruption treated with the GXV group according to a random number table. RNA sequencing (RNA-Seq) was utilized to confirm the different expressed genes regulated by circadian disruption. Cardiac function, inflammation factors, pathological evaluation, and mitochondrial dynamics after the intervention were conducted to reveal the mechanism by which GXV regulated VR after AMI with circadian disruption. RESULTS: RNA-Seq demonstrated that NF-κB was up-regulated by circadian disruption in rats with AMI. Functional and pathological evaluation indicated that compared with the AMI group, circadian disruption was associcataed with deteriorated cardiac function, expanded infarcted size, and exacerbated fibrosis and cardiomyocyte apoptosis. Further investigation demonstrated that mitochondrial dynamics imbalance was induced by circadian disruption. GXV intervention reversed the inflammatory status including down-regulation of NF-κB. Reserved cardiac function, limited infarct size, and ameliorated fibrosis and apoptosis were also observed in the GXV treated group. GXV maintained mitochondrial fission/fusion imbalance through suppressed expression of mitochondrial fission-associated proteins. CONCLUSION: The study findings suggest that identified mitochondrial dysfunctions may underlie the link between circadian disruption and VR. GXV may exert cardioprotection after AMI with circadian disruption through regulating mitochondrial dynamics.

Pediatric Intensive Care Unit related Sleep and Circadian Dysregulation: a focused review.

The pediatric intensive care unit (PICU) is bright, loud, and disruptive to children. Strategies to improve the sleep of adults in the ICU have improved delirium and mortality rates. Children need more sleep than adults for active growth, healing, and development when well; this is likely true when they are critically ill. This review was performed to describe what we know in this area to date with the intent to identify future directions for research in this field. Since the 1990s, 16 articles on 14 observational trials have been published investigating the sleep on a total of 312 critically ill children and the melatonin levels of an additional 144. Sleep measurements occurred in 9 studies through bedside observation (n = 2), actigraphy (n = 2), electroencephalogram (n = 1) and polysomnography (n = 4), of which polysomnography is the most reliable. Children in the PICU sleep more during the day, have fragmented sleep and disturbed sleep architecture. Melatonin levels may be elevated and peak later in critically ill children. Early data suggest there are at-risk subgroups for sleep and circadian disruption in the PICU including those with sepsis, burns, traumatic brain injury and after cardiothoracic surgery. The available literature describing the sleep of critically ill children is limited to small single-center observational studies with varying measurements of sleep and inconsistent findings. Future studies should use validated measurements and standardized definitions to begin to harmonize this area of medicine to build toward pragmatic interventional trials that may shift the paradigm of care in the pediatric intensive care unit.

[Association between circadian rhythm disorder and comorbidity of anxiety and depression in adolescents].

Adolescents are in a transition period from children to adults, during which they are prone to a variety of emotional disorders, with anxiety and depression being the most common disorders. Anxiety and depressive symptoms are highly correlated and the comorbidity of anxiety and depression is common. At the same time, the most prominent behavioral changes in adolescence are the emergence of getting up late and sleeping late, and the circadian rhythm begins to delay. Previous studies have shown that circadian rhythm is closely related to anxiety and depression, but the association between circadian rhythm disorder and comorbidity of anxiety and depression remains unclear. This article reviews the prevalence, association and potential biological mechanism of circadian rhythm disorder and comorbidity of anxiety and depression in adolescents, so as to provide a possible reference for the prevention and control of comorbidity of anxiety and depression in adolescents.

Circadian Rhythm Sleep-Wake Disorders.

OBJECTIVE: This article provides an overview of advances in the understanding of circadian rhythms and the health implications of circadian disruption. LATEST DEVELOPMENTS: Circadian medicine is a relatively new concept, with widespread overlap with many other areas of medicine. Circadian clocks rely on feedback loops that control the expression of many genes. Functional circadian oscillators exist at multiple physiologic levels and facilitate a multimodal clock mechanism. The suprachiasmatic nucleus is the central circadian pacemaker. Peripheral tissues can be entrained by other stimuli (such as food intake) and can uncouple from the suprachiasmatic nucleus pacemaker; this discovery may provide new therapeutic options for circadian rhythm disorders. Numerous modern developments have altered our circadian clocks and these changes are associated with poor health outcomes. ESSENTIAL POINTS: Circadian clocks are ubiquitous throughout our body and regulate multiple body functions. Several studies have highlighted that circadian disruption can result in significant negative mental and physical health consequences. A deeper understanding of the effects of misalignment between our circadian clocks and the external environment may ultimately have therapeutic implications for our health.