Association of sleep timing with all-cause and cardiovascular mortality: the Sleep Heart Health Study and the Osteoporotic Fractures in Men Study.

STUDY OBJECTIVES: Previous studies have highlighted the importance of sleep patterns for human health. This study aimed to investigate the association of sleep timing with all-cause and cardiovascular disease mortality. METHODS: Participants were screened from two cohort studies: the Sleep Heart Health Study (SHHS; n = 4,824) and the Osteoporotic Fractures in Men Study (n = 2,658). Sleep timing, including bedtime and wake-up time, was obtained from sleep habit questionnaires at baseline. The sleep midpoint was defined as the halfway point between the bedtime and wake-up time. Restricted cubic splines and Cox proportional hazards regression analyses were used to examine the association between sleep timing and mortality. RESULTS: We observed a U-shaped association between bedtime and all-cause mortality in both the SHHS and Osteoporotic Fractures in Men Study groups. Specifically, bedtime at 11:00 pm and waking up at 7:00 am was the nadir for all-cause and cardiovascular disease mortality risks. Individuals with late bedtime (> 12:00 am) had an increased risk of all-cause mortality in SHHS (hazard ratio 1.53, 95% confidence interval 1.28-1.84) and Osteoporotic Fractures in Men Study (hazard ratio 1.27, 95% confidence interval 1.01-1.58). In the SHHS, late wake-up time (> 8:00 am) was associated with increased all-cause mortality (hazard ratio 1.39, 95% confidence interval 1.13-1.72). No significant association was found between wake-up time and cardiovascular disease mortality. Delaying sleep midpoint (> 4:00 am) was also significantly associated with all-cause mortality in the SHHS and Osteoporotic Fractures in Men Study. CONCLUSIONS: Sleep timing is associated with all-cause and cardiovascular disease mortality. Our findings highlight the importance of appropriate sleep timing in reducing mortality risk. CITATION: Ma M, Fan Y, Peng Y, et al. Association of sleep timing with all-cause and cardiovascular mortality: the Sleep Heart Health Study and the Osteoporotic Fractures in Men Study. J Clin Sleep Med. 2024;20(4):545-553.

Longitudinal Gut Microbiota Dysbiosis Underlies Olanzapine-Induced Weight Gain.

Olanzapine is one of the most effective medicines available for stabilizing schizophrenia spectrum disorders. However, it has been reported to show the greatest propensity for inducing body weight gain and producing metabolic side effects, which cause a great burden in patients with psychiatric disorders. Since the gut microbiota has a profound impact on the initiation and development of metabolic diseases, we conducted a longitudinal study to explore its role in olanzapine-induced obesity and metabolic abnormalities. Female Sprague-Dawley rats were treated with different doses of olanzapine, and metabolic and inflammatory markers were measured. Olanzapine significantly induced body weight gain (up to a 2.1-fold change), which was accompanied by hepatic inflammation and increased plasma triglyceride levels (up to a 2.9-fold change), as well as gut microbiota dysbiosis. Subsequently, fuzzy c-means clustering was used to characterize three clusters of longitudinal trajectories for microbial fluctuations: (i) genera continuing to increase, (ii) genera continuing to decrease, and (iii) genera temporarily changing. Among them, Enterorhabdus (r = 0.38), Parasutterella (r = 0.43), and Prevotellaceae UCG-001 (r = 0.52) positively correlated with body weight gain. In addition, two MetaCyc metabolic pathways were identified as associated with olanzapine-induced body weight gain, including the superpathway of glucose and xylose degradation and the superpathway of l-threonine biosynthesis. In conclusion, we demonstrate that olanzapine can directly alter the gut microbiota and rapidly induce dysbiosis, which is significantly associated with body weight gain. This may suggest gut microbiota targets in future studies on metabolic abnormalities caused by olanzapine. IMPORTANCE Olanzapine is one of the most effective second-generation antipsychotics for stabilizing schizophrenia spectrum disorders. However, olanzapine has multiple drug-induced metabolic side effects, including weight gain. This study provides insight to the gut microbiota target in olanzapine-induced obesity. Specifically, we explored the longitudinal gut microbiota trajectories of female Sprague-Dawley rats undergoing olanzapine treatment. We showed that olanzapine treatment causes a dynamic alteration of gut microbiota diversity. Additionally, we identified three genera, Parasutterella, Enterorhabdus, and Prevotellaceae UCG-001, that may play an important role in olanzapine-induced obesity. In this case, the supply or removal of specific elements of the gut microbiota may represent a promising avenue for treatment of olanzapine-related metabolic side effects.

Grey matter volume and its association with cognitive impairment and peripheral cytokines in excited individuals with schizophrenia.

Although excited behavior in patients with schizophrenia has been linked to brain structural abnormalities, whether cortical abnormalities in this subgroup are related to cognitive impairment or peripheral immune responses is unknown. We included 28 patients with excitability (EC), 28 patients without excitability (NEC), and 48 healthy controls (HCs) to evaluate the associations. Compared with the HC group, the EC and NEC groups showed significant cognitive impairment and increased serum cytokine levels. Analysis of variance in whole-brain grey matter volume (GMV) showed that the volumes of several brain areas, including the superior frontal gyrus (SFG), superior temporal gyrus, and cingulate gyrus, were decreased in patients with schizophrenia. Notably, the left SFG volume was significantly lower in the EC group than in the NEC group. Spearman correlation analysis showed that elevated cytokines were negatively correlated with the GMV of the bilateral SFG, bilateral inferior parietal gyrus, left anterior cingulate gyrus, right fusiform gyrus and parahippocampal gyrus, which were mainly positive correlated with cognitive tests. Moreover, interleukin 4 may contribute to poor scores on Brief Assessment of Cognition and Neuropsychological Assessment Battery by reducing the left SFG volume (17%, Pmediation = 0.044; and 24%, Pmediation = 0.040, respectively). In conclusion, our results confirm GMV changes in excited patients with schizophrenia, and characterize the GMV as an important interface between inflammatory cytokines and cognitive impairment. Therefore, targeted anti-inflammatory adjuvant antipsychotic therapy may improve cognitive function and volumetric brain abnormalities in these patients.

Characterizing serum amino acids in schizophrenic patients: Correlations with gut microbes.

Amino acid abnormalities have been suggested to be a key pathophysiological mechanism in schizophrenia (SZ). Recently, gut microbes were found to be critically involved in mental and metabolic diseases. However, the relationship between serum amino acid levels and gut microbes in SZ is rarely studied. Here, we analyzed serum amino acid levels in 76 untreated SZ patients and 79 healthy controls (HC). Serum levels of 10 amino acids were significantly altered in patients with SZ. We further classified the cut-off values for serum arginine, leucine, glutamine, and methionine levels to distinguish SZ patients from controls. These classifiers were shown to be effective in another validation cohort (49 SZ and 48 HC). The correlation between serum amino acids and clinical symptoms and cognitive functions was also analyzed. Arginine, leucine, glutamine, and methionine levels were significantly correlated with clinical symptoms and cognitive impairments in SZ patients. By metagenome shotgun sequencing of fecal samples, we found that patients with SZ with a low level of serum amino acids have higher richness and evenness of the gut microbiota. At the genus level, the abundances of Mitsuokella and Oscillibacter are significantly abnormal. At the mOTU level, 15 mOTUs in the low-level SZ group were significantly different from the HC group. In addition, Mitsuokella multacida was correlated with glutamine and methionine, respectively. Our research revealed that alterations in serum amino acid levels are critically related to changes in gut microbiota composition in SZ patients. These findings may shed light on new strategies for the diagnosis and treatment of SZ.

Association between plasma proteome and childhood neurodevelopmental disorders: A two-sample Mendelian randomization analysis.

BACKGROUND: Childhood neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), and Tourette syndrome (TS), comprise a major cause of health-related disabilities in children. However, biomarkers towards pathogenesis or novel drug targets are still limited. Our study aims to provide a comprehensive investigation of the causal effects of the plasma proteome on ASD, ADHD, and TS using the two-sample Mendelian Randomization (MR) approach. METHODS: Genetic associations with 2994 plasma proteins were selected as exposures and genome-wide association data of ASD, ADHD, TS were utilized as outcomes. MR analyses were carried out using the inverse-variance weighted method, and the MR-Egger and weighted median methods were used for sensitivity analysis. FINDINGS: Using single-nucleotide polymorphisms as instruments, the study suggested increased levels of MAPKAPK3 (OR: 1.09; 95% CI: 1.05-1.13; P = 1.43 × 10-6) and MRPL33 (OR: 1.07; 95% CI: 1.04-1.11; P = 5.37 × 10-6) were causally associated with a higher risk of ASD, and increased MANBA level was associated with a lower risk of ADHD (OR: 0.91; 95% CI: 0.88-0.95; P = 8.97 × 10-6). The causal associations were robust in sensitivity analysis, leave-one-out analysis and Multivariable MR, and no pleiotropy was observed. No significant risk protein was identified for TS. INTERPRETATION: The study findings support the idea that the MAPK/ERK signaling pathway and mitochondrial dysfunction are involved in the pathogenesis of ASD, while a deficiency in beta-mannosidase might play a role in the development of ADHD. FUNDING: Natural Science Basic Research Program of Shaanxi (2021JQ-390).

Characteristics of human oral microbiome and its non-invasive diagnostic value in chronic kidney disease.

BACKGROUND: Morbidity of chronic kidney disease (CKD) is increased, with many complications and high mortality rates. The characteristics of oral microbiome in CKD patients have not been reported. This study aims to analyze the oral microbiome, and to demonstrate the potential of microbiome as noninvasive biomarkers for CKD patients. METHODS: The study collected 253 oral samples from different regions of China (Central China and East China) prospectively and finally 235 samples completed Miseq sequencing, including 103 samples from CKD patients and 132 healthy controls (HCs). RESULTS: Compared with HCs (n=88), the oral microbial diversity in CKD patients (n=44) was increased. Fourteen genera including Streptococcus, Actinomyces and Leptotrichia were enriched, while six genera including Prevotella and Haemophilus were decreased in CKD patients. Moreover, 49 predicted microbial gene functions including arginine metabolism and tryptophan metabolism increased, while 55 functions including Ribosome and DNA repair recombination proteins decreased. Furthermore, correlation analysis demonstrated that 38 operational taxonomic units (OTUs) were closely related to 5 clinical indicators of CKD. Notably, 7 optimal biomarkers were identified using random forest model, and the classifier model respectively reached an area under the curve (AUC) of 0.9917 and 0.8026 in the discovery and validation phase, achieving a cross-region validation. CONCLUSIONS: We first illustrated the characteristics of the oral microbiome of patients with CKD, identified the potential of oral microbial makers as noninvasive tools for the diagnosis of CKD and achieved cross-region validation.

Estimation of the bidirectional relationship between schizophrenia and inflammatory bowel disease using the mendelian randomization approach.

It has been reported that schizophrenia (SCZ) and inflammatory bowel disease (IBD) are related. However, whether there is a bidirectional interaction between them remains unclear. The aim of this study was to conduct a bidirectional Mendelian randomization (MR) analysis to elucidate the causal relationship between SCZ and IBD and its subtypes, including Crohn's disease (CD) and ulcerative colitis (UC). Single-nucleotide polymorphisms (SNPs) extracted from the summary data of genome-wide association studies were used as genetic instruments. MR was performed using the inverse-variance-weighted method. The MR-Egger and weighted median methods were used for sensitivity analyses. Analysis using 70 SNPs as genetic instruments showed that SCZ was associated with an increased risk of IBD (OR = 1.14, 95% CI: 1.09-1.20, P = 9.21 × 10-8), CD (OR = 1.16, 95% CI: 1.07-1.25, P = 1.42 × 10-4), and UC (OR = 1.14, 95% CI: 1.07-1.21, P = 2.72 × 10-5). The results of the sensitivity analyses were robust and no evidence of pleiotropy was observed. Bidirectional MR analyses showed no causal effects of IBD, CD, or UC on SCZ. This study suggests that SCZ has causal effects on IBD and its subtypes, whereas IBD has no effect on SCZ. Brain-gut axis interactions may help clarify the causal relationship between SCZ and IBD. However, further studies are needed to elucidate the biological mechanisms behind the brain-gut interactions.

Multi-Omics Analysis Reveals Aberrant Gut-Metabolome-Immune Network in Schizophrenia.

Schizophrenia (SCZ) is associated with several immune dysfunctions, including elevated levels of pro-inflammatory cytokines. Microorganisms and their metabolites have been found to regulate the immune system, and that intestinal microbiota is significantly disturbed in schizophrenic patients. To systematically investigate aberrant gut-metabolome-immune network in schizophrenia, we performed an integrative analysis of intestinal microbiota, serum metabolome, and serum inflammatory cytokines in 63 SCZ patients and 57 healthy controls using a multi-omics strategy. Eighteen differentially abundant metabolite clusters were altered in patients displayed higher cytokine levels, with a significant increase in pro-inflammatory metabolites and a significant decrease in anti-inflammatory metabolites (such as oleic acid and linolenic acid). The bacterial co-abundance groups in the gut displayed more numerous and stronger correlations with circulating metabolites than with cytokines. By integrating these data, we identified that certain bacteria might affect inflammatory cytokines by modulating host metabolites, such as amino acids and fatty acids. A random forest model was constructed based on omics data, and seven serum metabolites significantly associated with cytokines and α-diversity of intestinal microbiota were able to accurately distinguish the cases from the controls with an area under the receiver operating characteristic curve of 0.99. Our results indicated aberrant gut-metabolome-immune network in SCZ and gut microbiota may influence immune responses by regulating host metabolic processes. These findings suggest a mechanism by which microbial-derived metabolites regulated inflammatory cytokines and insights into the diagnosis and treatment of mental disorders from the microbial-immune system in the future.

Stressful events induce long-term gut microbiota dysbiosis and associated post-traumatic stress symptoms in healthcare workers fighting against COVID-19.

OBJECTIVE: The microbiota-gut-brain axis is a key pathway perturbed by prolonged stressors to produce brain and behavioral disorders. Frontline healthcare workers (FHWs) fighting against COVID-19 typically experience stressful event sequences and manifest some mental symptoms; however, the role of gut microbiota in such stress-induced mental problems remains unclear. We investigated the association between the psychological stress of FHW and gut microbiota. METHODS: We used full-length 16S rRNA gene sequencing to characterize the longitudinal changes in gut microbiota and investigated the impact of microbial changes on FHWs' mental status. RESULTS: Stressful events induced significant depression, anxiety, and stress in FHWs and disrupted the gut microbiome; gut dysbiosis persisted for at least half a year. Different microbes followed discrete trajectories during the half-year of follow-up. Microbes associated with mental health were mainly Faecalibacterium spp. and [Eubacterium] eligens group spp. with anti-inflammatory effects. Of note, the prediction model indicated that low abundance of [Eubacterium] hallii group uncultured bacterium and high abundance of Bacteroides eggerthii at Day 0 (immediately after the two-month frontline work) were significant determinants of the reappearance of post-traumatic stress symptoms in FHWs. LIMITATIONS: The lack of metabolomic evidence and animal experiments result in the unclear mechanism of gut dysbiosis-related stress symptoms. CONCLUSION: The stressful event sequences of fighting against COVID-19 induce characteristic longitudinal changes in gut microbiota, which underlies dynamic mental state changes.

Systems biological assessment of altered cytokine responses to bacteria and fungi reveals impaired immune functionality in schizophrenia.

Evidence suggests that complex interactions between the immune system and brain have important etiological and therapeutic implications in schizophrenia. However, the detailed cellular and molecular basis of immune dysfunction in schizophrenia remains poorly characterized. To better understand the immune changes and molecular pathways, we systemically compared the cytokine responses of peripheral blood mononuclear cells (PBMCs) derived from patients with schizophrenia and controls against bacterial, fungal, and purified microbial ligands, and identified aberrant cytokine response patterns to various pathogens, as well as reduced cytokine production after stimulation with muramyl dipeptide (MDP) in schizophrenia. Subsequently, we performed single-cell RNA sequencing on unstimulated and stimulated PBMCs from patients and controls and revealed widespread suppression of antiviral and inflammatory programs as well as impaired chemokine/cytokine-receptor interaction networks in various immune cell subpopulations of schizophrenic patients after MDP stimulation. Moreover, serum MDP levels were elevated in these patients and correlated with the course of the disease, suggesting increased bacterial translocation along with disease progression. In vitro assays revealed that MDP pretreatment altered the functional response of normal PBMCs to its re-stimulation, which partially recapitulated the impaired immune function in schizophrenia. In conclusion, we delineated the molecular and cellular landscape of impaired immune function in schizophrenia, and proposed a mutual interplay between innate immune impairment, reduced pathogen clearance, increased MDP translocation along schizophrenia development, and blunted innate immune response. These findings provide new insights into the pathogenic mechanisms that drive systemic immune activation, neuroinflammation, and brain abnormalities in schizophrenia.

Mendelian randomization analyses reveal novel drug targets for anorexia nervosa.

Among all psychiatric disorders, anorexia nervosa (AN) has the highest mortality rate. However, there is still no pharmacological therapy for AN. The human plasma proteome may be a great cornerstone for the development of new drugs against AN. Here we performed a Mendelian randomization (MR) analysis to identify causal risk proteins for AN. Exposure data were extracted from a large genome-wide association study (GWAS) of 2994 plasma proteins in 3301 subjects of European descent, while outcome data were obtained from another GWAS of AN (16,992 cases and 55,525 controls of European descent). MR analyses were performed using the inverse-variance weighted (IVW) method and other sensitivity analysis methods. Using single nucleotide polymorphisms as instruments, this study suggested that high TXNDC12 levels were associated with a higher risk of AN (IVW Odd's ratio [OR]: 1.12; 95% confidence interval [CI]: 1.08-1.16; P = 2.35 × 10-10), while another protein ADH1B showed the opposite effect (IVW OR: 0.89; 95% CI: 0.85-0.93; P = 2.99 × 10-7). The causal associations were robust in multivariable models, genome-wide significant models, and with additional MR methods. No pleiotropy was observed. Our findings suggest that TXNDC12 was associated with a high risk of AN, while AHD1B was associated with a low risk of AN. They might both have implications in AN by regulating the brain dopamine reward system. In combination with existing knowledge on AN, these proteins may be novel drug targets for AN treatment.

Sleeping Late Increases the Risk of Myocardial Infarction in the Middle-Aged and Older Populations.

Objective: Sleep has a significant influence on the incidence of myocardial infarction (MI). The purpose of this study was to investigate the association between sleep timing including bedtime, wake-up time and sleep midpoint, and the incidence of MI. Methods: A total of 4,576 patients (2,065 men, 2,511 women; age 63.4 ± 11.0 years) were selected from the Sleep Heart Health Study. Sleep timings on weekdays and weekends were recorded or calculated based on the sleep habits questionnaire completed by the participants at baseline. Bedtime was divided into 10:00 PM and before, 10:01 PM-11:00 PM, 11:01 PM-12:00 AM, and later than 12:00 AM. Cox proportional hazards regression analysis was used to examine the relationship between sleep timings and MI. Results: Participants with a weekday bedtime later than 12:00 AM, between 11:01 PM-12:00 AM, and 10:00 PM or before had a higher incidence of MI than those with a bedtime between 10:01 PM and 11:00 PM (9.2% vs. 7.0% vs. 6.9% vs. 5.1%, respectively; P = 0.008). Multivariable Cox regression analysis showed that sleeping on weekdays later than 12:00 AM was associated with an increased risk of incident MI after adjusting for potential covariates (hazard ratio, 1.628; 95% confidence interval, 1.092-2.427; P = 0.017). However, there was no significant association between late bedtime on weekends and MI. In addition, no significant association of late wake-up time and delayed sleep midpoint on both weekdays and weekends with the incidence of MI was observed. Conclusion: Sleeping late on weekday (>12:00 AM) independently increased the risk of MI. This finding emphasizes the importance of a proper bedtime for the maintenance of the health of the cardiovascular system.

Methylation quantitative trait locus rs5326 is associated with susceptibility and effective dosage of methadone maintenance treatment for heroin use disorder.

RATIONALE: Opioid use disorder is a complicated brain disease with high heritability. The underlying mechanisms of the genetic underpinnings in the susceptibility and treatment response of opioid use disorder remain elusive. OBJECTIVES: To reveal the potential associations of genotypes and gene methylations of dopaminergic system genes, as well as roles of them in opioid use disorder. In the present study, we detected the DNA methylation in the promoter regions of five representative dopaminergic system genes (DRD1, DRD2, SLC6A3, TH, and COMT) between 120 patients with heroin use disorder in methadone maintenance treatment (MMT) program and 111 healthy controls. The associations of 25 SNPs in the above genes and methylation of 237 CpG sites, known as methylation quantitative trait loci (mQTLs), were determined. Then, the correlations of the above mQTLs and traits of heroin use disorder were analyzed in a sample set of 801 patients with heroin use disorder and 930 healthy controls. RESULTS: Our results demonstrated that several mQTLs in the DRD1 and DRD2 genes were identified both in the heroin use disorder and healthy control groups. Interestingly, rs4867798-CpG_174872884 and rs5326-CpG_174872884 in the DRD1 gene were the unique SNP-CpG pairs in the patients with heroin use disorder. Furthermore, mQTL rs5326 was associated with the susceptibility and effective dosage of MMT for heroin use disorder, and demonstrated allele-specific correlation with the expression of the DRD1 gene in the human caudate. CONCLUSIONS: Our findings suggest that some mQTLs may be associated with traits of opioid use disorder by implicating the DNA methylation and gene expression.

The chromosome-level reference genome assembly for Dendrobium officinale and its utility of functional genomics research and molecular breeding study.

Dendrobium officinale, an important medicinal plant of the genus Dendrobium in Orchidaceae family, has been used as traditional Chinese medicine (TCM) for nearly thousands of years. Here, we report the first chromosome-level reference genome of D. officinale, based on PacBio long-reads, Illumina short-reads and Hi-C data. The high-quality assembled genome is 1.23 Gb long, with contig N50 of 1.44 Mb. A total of 93.53% genome sequences were assembled into 19 pseudochromosomes with a super scaffold N50 of 63.07 Mb. Through comparative genomic analysis, we explored the expanded gene families of D. officinale, and also their impact on environmental adaptation and biosynthesis of secondary metabolites. We further performed detailed transcriptional analysis of D. officinale, and identified the candidate genes involved in the biosynthesis of three main active ingredients, including polysaccharides, alkaloids and flavonoids. In addition, the MODIFYING WALL LIGNIN-1 (MWL1) gene, which inferred from Genome-Wide Association Studies (GWAS) based on the resequencing date from D. officinale and five related species and their morphologic features, may contribute to the plant production (yield of stems) of D. officinale. Therefore, the high-quality reference genome reported in this study could benefits functional genomics research and molecular breeding of D. officinale.

Oral Microbiome Characteristics in Patients With Autoimmune Hepatitis.

Autoimmune hepatitis (AIH) is a common cause of liver cirrhosis. To identify the characteristics of the oral microbiome in patients with AIH, we collected 204 saliva samples including 68 AIH patients and 136 healthy controls and performed microbial MiSeq sequencing after screening. All samples were randomly divided into discovery cohorts (46 AIH and 92 HCs) and validation cohorts (22 AIH and 44 HCs). Moreover, we collected samples of 12 AIH patients from Hangzhou for cross-regional validation. We described the oral microbiome characteristics of AIH patients and established a diagnostic model. In the AIH group, the oral microbiome diversity was significantly increased. The microbial communities remarkably differed between the two groups. Seven genera, mainly Fusobacterium, Actinomyces and Capnocytophaga, were dominant in the HC group, while 51 genera, Streptococcus, Veillonella and Leptotrichia, were enriched in the AIH group. Notably, we found 23 gene functions, including Membrane Transport, Carbohydrate Metabolism, and Glycerolipid metabolism that were dominant in AIH and 31 gene functions that prevailed in HCs. We further investigated the correlation between the oral microbiome and clinical parameters. The optimal 5 microbial markers were figured out through a random forest model, and the distinguishing potential achieved 99.88% between 46 AIH and 92 HCs in the discovery cohort and 100% in the validation cohort. Importantly, the distinguishing potential reached 95.55% in the cross-regional validation cohort. In conclusion, this study is the first to characterize the oral microbiome in AIH patients and to report the successful establishment of a diagnostic model and the cross-regional validation of microbial markers for AIH. Importantly, oral microbiota-targeted biomarkers may be able to serve as powerful and noninvasive diagnostic tools for AIH.

Objective Sleep Efficiency Predicts Cardiovascular Disease in a Community Population: The Sleep Heart Health Study.

Background There was little evidence about the role of objective sleep efficiency (SE) in the incidence of major cardiovascular disease (CVD) events. The purpose of this study was to investigate the correlation between objective SE and CVD based on polysomnography. Methods and Results A total of 3810 participants from the SHHS (Sleep Heart Health Study) were selected in the current study. CVD was assessed during an almost 11-year follow-up period. The primary composite cardiovascular outcome was major adverse cardiovascular events, defined as CVD mortality, congestive heart failure, myocardial infarction, and stroke. The secondary composite cardiovascular outcome was major adverse cardiovascular event plus revascularization. Objective measured SE, including SE and wake after sleep onset, was based on in-home polysomnography records. Cox regression analysis was used to explore the association between SE and CVD. After multivariate Cox regression analysis, poor SE (<80%) was significantly associated with primary (hazard ratio [HR], 1.338; 95% CI, 1.025-1.745; P=0.032) and secondary composite cardiovascular outcomes (HR, 1.250; 95% CI, 1.027-1.521; P=0.026); it was also found to be a predictor of CVD mortality (HR, 1.887; 95% CI, 1.224-2.909; P=0.004). Moreover, wake after sleep onset of fourth quartile (>78.0 minutes) was closely correlated with primary (HR, 1.436; 95% CI, 1.066-1.934; P=0.017), secondary composite cardiovascular outcomes (HR, 1.374; 95% CI, 1.103-1.712; P=0.005), and CVD mortality (HR, 2.240; 95% CI, 1.377-3.642; P=0.001). Conclusions Poor SE and long wake after sleep onset, objectively measured by polysomnography, were associated with the increased risk of incident CVD.

Later bedtime is associated with angina pectoris in middle-aged and older adults: results from the Sleep Heart Health Study.

OBJECTIVES: Sleep timing is related to several risk factors for angina pectoris (AP), such as obesity and diabetes. This study was designed to evaluate the relationship between sleep timing and AP, specifically whether later bedtime was associated with AP in middle-aged and older adults. METHODS: This community-based study was based on the Sleep Heart Health Study cohort and included 4710 participants (45.9% men, aged 63.3 ± 11.0 years). Lifestyle and epidemiological information were obtained from baseline records. Self-reported sleep measures provided information on bedtime and wake-up time of weekdays and weekends. Individuals were divided into three categories according to bedtime (≤22:00, 22:01-23:00, and >23:00). Odds ratios (OR) and 95% confidence intervals (CIs) of AP for bedtimes were estimated with multivariate logistic regression analysis. RESULTS: The prevalence of AP was 44.2% and the distribution of weekday bedtimes ≤22:00, 22:01-23:00, and >23:00 were 36.6%, 47.5% and 46.0%, respectively. After adjusting for potential confounders, weekday bedtimes >23:00 (OR 1.34; 95% CI 1.13-1.60; P = 0.001) and 22:01-23:00 (OR 1.54; 95% CI 1.29-1.82; P < 0.001) were significantly associated with an increased risk of AP compared with the reference group (≤22:00). In addition, weekend bedtimes >23:00 (OR 1.44; 95% CI 1.20-1.73; P < 0.001) and 22:01-23:00 (OR 1.70; 95% CI 1.40-2.05; P < 0.001) increased the risk of AP. CONCLUSIONS: Later bedtimes on both weekdays and weekends were significantly associated with an increased prevalence of AP. Early bedtimes may help people decrease the risk of AP.

Genetically Determined Levels of Serum Metabolites and Risk of Neuroticism: A Mendelian Randomization Study.

BACKGROUND: Neuroticism is a strong predictor for a variety of social and behavioral outcomes, but the etiology is still unknown. Our study aims to provide a comprehensive investigation of causal effects of serum metabolome phenotypes on risk of neuroticism using Mendelian randomization (MR) approaches. METHODS: Genetic associations with 486 metabolic traits were utilized as exposures, and data from a large genome-wide association study of neuroticism were selected as outcome. For MR analysis, we used the standard inverse-variance weighted (IVW) method for primary MR analysis and 3 additional MR methods (MR-Egger, weighted median, and MR pleiotropy residual sum and outlier) for sensitivity analyses. RESULTS: Our study identified 31 metabolites that might have causal effects on neuroticism. Of the 31 metabolites, uric acid and paraxanthine showed robustly significant association with neuroticism in all MR methods. Using single nucleotide polymorphisms as instrumental variables, a 1-SD increase in uric acid was associated with approximately 30% lower risk of neuroticism (OR: 0.77; 95% CI: 0.62-0.95; PIVW = 0.0145), whereas a 1-SD increase in paraxanthine was associated with a 7% higher risk of neuroticism (OR: 1.07; 95% CI: 1.01-1.12; PIVW = .0145). DISCUSSION: Our study suggested an increased level of uric acid was associated with lower risk of neuroticism, whereas paraxanthine showed the contrary effect. Our study provided novel insight by combining metabolomics with genomics to help understand the pathogenesis of neuroticism.

Alterations of the Human Gut Microbiome in Chronic Kidney Disease.

Gut microbiota make up the largest microecosystem in the human body and are closely related to chronic metabolic diseases. Herein, 520 fecal samples are collected from different regions of China, the gut microbiome in chronic kidney disease (CKD) is characterized, and CKD classifiers based on microbial markers are constructed. Compared with healthy controls (HC, n = 210), gut microbial diversity is significantly decreased in CKD (n = 110), and the microbial community is remarkably distinguished from HC. Genera Klebsiella and Enterobacteriaceae are enriched, while Blautia and Roseburia are reduced in CKD. Fifty predicted microbial functions including tryptophan and phenylalanine metabolisms increase, while 36 functions including arginine and proline metabolisms decrease in CKD. Notably, five optimal microbial markers are identified using the random forest model. The area under the curve (AUC) reaches 0.9887 in the discovery cohort and 0.9512 in the validation cohort (49 CKD vs 63 HC). Importantly, the AUC reaches 0.8986 in the extra diagnosis cohort from Hangzhou. Moreover, Thalassospira and Akkermansia are increased with CKD progression. Thirteen operational taxonomy units are correlated with six clinical indicators of CKD. In conclusion, this study comprehensively characterizes gut microbiome in non-dialysis CKD and demonstrates the potential of microbial markers as non-invasive diagnostic tools for CKD in different regions of China.

Evaluation of stability of deep venous thrombosis of the lower extremities using Doppler ultrasound.

OBJECTIVE: This study aimed to assess using Doppler ultrasound for analyzing stability of deep venous thrombosis (DVT) of the lower extremities. METHODS: Patients with DVT of the lower extremities who were treated from August 2017 to December 2019 were selected. The patients were divided into stable and unstable groups according to whether thrombus was collected in a filter. Related ultrasound and blood test results were analyzed and compared. RESULTS: A total of 126 patients with DVT of the lower extremities were included, of whom 74 were in the stable group and 52 were in the unstable group. There were significant differences in the prothrombin time (PT), and lipoprotein alpha, D-dimer, and triglyceride levels between the groups. D-dimer levels >2800 ug/L, smoking, history of venous thrombosis, PT >13.15 s, and body mass index >24.45 kg/m2 were independent risk factors for stability of DVT of the lower extremities. The area under the curve with combined detection of DVT was significantly higher than that for body mass index, PT, and D-dimer alone. CONCLUSION: Doppler ultrasound may be reliable for analyzing the stability of DVT of the lower extremities. Related strategies targeting risk factors are required for reducing DVT of the lower extremities.