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1.
J Affect Disord ; 358: 211-221, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38705530

ABSTRACT

BACKGROUND: Neuroinflammation is involved in the advancement of depression. Du-moxibustion can treat depression. Here, we explored whether Du-moxibustion could alleviate neuroglia-associated neuro-inflammatory process in chronic unpredictable mild stress (CUMS) mice. METHODS: C57BL/6J mice were distributed into five groups. Except for the CON group, other four groups underwent CUMS for four consecutive weeks, and Du-moxibustion was given simultaneously after modeling. Behavioral tests were then carried out. Additionally, Western blot was conducted to measure the relative expression levels of high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB). Immunofluorescence was employed to evaluate the positive cells of ionized calcium binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP). Furthermore, interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) were analyzed using an ELISA assay. RESULTS: We found that CUMS induced depression-like behaviors, such as reduced sucrose preference ratio, decreased locomotor and exploratory activity, decreased the time in open arms and prolonged immobility. Furthermore, versus the CON group, the expression of HMGB1, TLR4, MyD88, NF-κB, positive cells of Iba-1, IL-1ß and TNF-α were increased but positive cells of GFAP were decreased in CUMS group. However, the detrimental effects were ameliorated by treatment with CUMS+FLU and CUMS+DM. LIMITATIONS: A shortage of this study is that only CUMS model of depression were used, while other depression model were not included. CONCLUSIONS: Du-moxibustion alleviates depression-like behaviors in CUMS mice mainly by reducing neuroinflammation, which offers novel insights into the potential treatment of depression.

2.
J Transl Med ; 22(1): 437, 2024 May 08.
Article in English | MEDLINE | ID: mdl-38720345

ABSTRACT

BACKGROUND: Biological-derived hydroxyapatite is widely used as a bone substitute for addressing bone defects, but its limited osteoconductive properties necessitate further improvement. The osteo-immunomodulatory properties hold crucial promise in maintaining bone homeostasis, and precise modulation of macrophage polarization is essential in this process. Metabolism serves as a guiding force for immunity, and fluoride modification represents a promising strategy for modulating the osteoimmunological environment by regulating immunometabolism. In this context, we synthesized fluorinated porcine hydroxyapatite (FPHA), and has demonstrated its enhanced biological properties and osteogenic capacity. However, it remains unknown whether and how FPHA affects the immune microenvironment of the bone defects. METHODS: FPHA was synthesized and its composition and structural properties were confirmed. Macrophages were cultured with FPHA extract to investigate the effects of FPHA on their polarization and the related osteo-immune microenvironment. Furthermore, total RNA of these macrophages was extracted, and RNA-seq analysis was performed to explore the underlying mechanisms associated with the observed changes in macrophages. The metabolic states were evaluated with a Seahorse analyzer. Additionally, immunohistochemical staining was performed to evaluate the macrophages response after implantation of the novel bone substitutes in critical size calvarial defects in SD rats. RESULTS: The incorporation of fluoride ions in FPHA was validated. FPHA promoted macrophage proliferation and enhanced the expression of M2 markers while suppressing the expression of M1 markers. Additionally, FPHA inhibited the expression of inflammatory factors and upregulated the expression of osteogenic factors, thereby enhancing the osteogenic differentiation capacity of the rBMSCs. RNA-seq analysis suggested that the polarization-regulating function of FPHA may be related to changes in cellular metabolism. Further experiments confirmed that FPHA enhanced mitochondrial function and promoted the metabolic shift of macrophages from glycolysis to oxidative phosphorylation. Moreover, in vivo experiments validated the above results in the calvarial defect model in SD rats. CONCLUSION: In summary, our study reveals that FPHA induces a metabolic shift in macrophages from glycolysis to oxidative phosphorylation. This shift leads to an increased tendency toward M2 polarization in macrophages, consequently creating a favorable osteo-immune microenvironment. These findings provide valuable insights into the impact of incorporating an appropriate concentration of fluoride on immunometabolism and macrophage mitochondrial function, which have important implications for the development of fluoride-modified immunometabolism-based bone regenerative biomaterials and the clinical application of FPHA or other fluoride-containing materials.


Subject(s)
Durapatite , Glycolysis , Macrophages , Oxidative Phosphorylation , Rats, Sprague-Dawley , Animals , Durapatite/chemistry , Macrophages/metabolism , Macrophages/drug effects , Oxidative Phosphorylation/drug effects , Glycolysis/drug effects , Rats , Swine , Cell Proliferation/drug effects , Male , Osteogenesis/drug effects , Skull/pathology , Skull/drug effects , Mice , Cellular Microenvironment/drug effects , RAW 264.7 Cells , Bone and Bones/metabolism , Bone and Bones/drug effects
3.
J Psychiatr Res ; 175: 218-226, 2024 May 11.
Article in English | MEDLINE | ID: mdl-38744161

ABSTRACT

BACKGROUND: Ketamine, electroconvulsive therapy (ECT), and their combination are effective for treating severe depression, but few large-scale studies have compared these. METHODS: We searched databases for randomized controlled trials (RCTs) using ketamine, ECT, ketamine + ECT, or placebo for severe depression. Standardized measures were efficacy outcomes. Risk of bias was assessed. Stata and ADDIS were used for network meta-analysis (NMA) comparing efficacy and adverse reactions post-treatment. This study was registered on PROSPERO (CRD42023476740). RESULTS: 17 RCTs with 1370 patients were included. NMA showed ECT and ketamine improved Hamilton Depression Rating Scale (HDRS) versus placebo; other comparisons not significant. Rank probabilities showed highest probability for ECT, followed by ketamine + ECT, ketamine, placebo. No differences in Montgomery-Asberg Depression Rating Scale (MADRS); highest rank probability again for ECT, followed by ketamine + ECT, ketamine, placebo. CONCLUSIONS: Analysis suggests ECT superior to ketamine and their combination for improving depressive severity, but individualized treatment selection warranted. Higher adverse reactions with ketamine + ECT need further study for optimized combined use.

4.
J Affect Disord ; 358: 61-69, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38705524

ABSTRACT

BACKGROUND: Depression, a prevalent mental disorder, has shown an increasing trend in recent years, imposing a significant burden on health and society. Adequate sleep has been proven to reduce the incidence of depression. This study seeks to explore how Weekend Catch-up Sleep (WCS) is connected with the prevalence of depression in the American population. METHODS: The National Health and Nutrition Examination Survey (NHANES) provides representative data for the U.S. POPULATION: We utilized data from the 2017-2018 and 2019-2020 cycles. Depression was operationally defined as a PHQ-9 score exceeding 10. WCS duration was categorized into five groups: no change in sleep duration (=0 h), decreased sleep duration (<0), short catch-up sleep duration (>0 h, ≤1 h), moderate catch-up sleep duration (>1 h, <2 h), and long catch-up sleep duration (≥2 h). RESULTS: Among the 8039 individuals, the distribution of WCS duration was as follows: no change (WCS = 0 h) in 2999 individuals (37.3 %), decreased sleep (WCS < 0 h) in 1199 individuals (14.9 %), short catch-up sleep (0 h < WCS ≤ 1 h) in 1602 individuals (19.9 %), moderate catch-up sleep (1 h < WCS < 2 h) in 479 individuals (6.0 %), and long catch-up sleep (WCS ≥ 2 h) in 1760 individuals (21.9 %). Acting by adjustment for all covariates in a multiple regression analysis, we discovered that persons with 1 to 2 h of weekend catch-up sleep had a substantially low prevalence of depression concerning those with WCS = 0 (OR 0.22, 95 % CI 0.08-0.59, P = 0.007). CONCLUSION: The prevalence of depression in individuals engaging in weekend catch-up sleep for 1 to 2 h is lower than those who do not catch up on weekends. This discovery on the treatment and prevention of depression provides a new perspective. However, further prospective research and clinical trials are needed for a comprehensive investigation.

6.
Heliyon ; 10(6): e27437, 2024 Mar 30.
Article in English | MEDLINE | ID: mdl-38501016

ABSTRACT

As the second most common neurodegenerative disease globally, Parkinson's disease (PD) affects millions of people worldwide. In recent years, the scientific publications related to PD biomarker research have exploded, reflecting the growing interest in unraveling the complex pathophysiology of PD. In this study, we aim to use various bibliometric tools to identify key scientific concepts, detect emerging trends, and analyze the global trends and development of PD biomarker research.The research encompasses various stages of biomarker development, including exploration, identification, and multi-modal research. MOVEMENT DISORDERS emerged as the leading journal in terms of publications and citations. Key authors such as Mollenhauer and Salem were identified, while the University of Pennsylvania and USA stood out in collaboration and research output. NEUROSCIENCES emerged as the most important research direction. Key biomarker categories include α-synuclein-related markers, neurotransmitter-related markers, inflammation and immune system-related markers, oxidative stress and mitochondrial function-related markers, and brain imaging-related markers. Furthermore, future trends in PD biomarker research focus on exosomes and plasma biomarkers, miRNA, cerebrospinal fluid biomarkers, machine learning applications, and animal models of PD. These trends contribute to early diagnosis, disease progression monitoring, and understanding the pathological mechanisms of PD.

7.
Antimicrob Agents Chemother ; 68(4): e0167823, 2024 Apr 03.
Article in English | MEDLINE | ID: mdl-38477539

ABSTRACT

Horizontal gene transfer has been demonstrated to be an important driver for the emergency of multidrug-resistant pathogens. Recently, a transferable gene cluster tmexCD1-toprJ1 of the resistance-nodulation-division (RND) superfamily was identified in the plasmids of animal-derived Klebsiella pneumoniae strains, with a higher efflux capacity for various drugs than the Escherichia coli AcrAB-TolC homolog system. In this study, we focused on the differences in the inner membrane pump of these two systems and identified some key residues that contribute to the robust efflux activity of the TMexCD1 system. With the aid of homologous modeling and molecular docking, eight residues from the proximal binding pocket (PBP) and nine from the distal binding pocket (DBP) were selected and subjected to site-directed mutagenesis. Several of them, such as S134, I139, D181, and A290, were shown to be important for substrate binding in the DBP region, and all residues in PBP and DBP showed certain substrate preferences. Apart from the conservative switch loop (L613-623TMexD1) previously identified in the E. coli AcrB (EcAcrB), a relatively unconservative loop (L665-675TMexD1) at the bottom of PBP was proposed as a critical element for the robust activity of TMexD1, due to variations at sites E669, G670, N673, and S674 compared to EcAcrAB, and the significantly altered efflux activity due to their mutations. The conservation and flexibility of these key factors can contribute to the evolution of the RND efflux pumps and thus serve as potential targets for developing inhibitors to block the widespread of the TMexCD1 system.


Subject(s)
Escherichia coli Proteins , Escherichia coli , Animals , Escherichia coli/genetics , Escherichia coli/metabolism , Escherichia coli Proteins/metabolism , Anti-Bacterial Agents/chemistry , Molecular Docking Simulation , Drug Resistance, Multiple, Bacterial/genetics , Multidrug Resistance-Associated Proteins/genetics , Microbial Sensitivity Tests
8.
BMC Psychiatry ; 24(1): 110, 2024 Feb 08.
Article in English | MEDLINE | ID: mdl-38326834

ABSTRACT

BACKGROUND: Studies examining whether diet sugar intake increases the risk of depression have produced inconsistent results. Therefore, we investigated this relationship, using the US' National Health and Nutrition Examination Survey (NHANES) database. METHODS: This cross-sectional study included 18,439 adults (aged ≥ 20 years) from NHANES (2011-2018). Depressive symptoms were assessed using the nine-item version of the Patient Health Questionnaire (PHQ-9). Covariates, including age, sex, race/ethnicity, poverty-income ratio, education, marital status, hypertension, diabetes mellitus, cardiovascular disease, alcohol intake, smoking status, physical activity, and dietary energy intake, were adjusted in multivariate logistic regression models. Subgroup and threshold saturation effect analyses were performed. RESULTS: After adjusting for potential confounders, we found that a 100 g/day increase in dietary sugar intake correlated with a 28% higher prevalence of depression (odds ratio = 1.28, 95% confidence interval = 1.17-1.40, P < 0.001). CONCLUSION: Dietary sugar intake is positively associated with depression in US adults.


Subject(s)
Depression , Diet , Humans , Adult , Nutrition Surveys , Cross-Sectional Studies , Depression/epidemiology , Depression/etiology , Dietary Sugars/adverse effects
12.
J Affect Disord ; 347: 299-305, 2024 02 15.
Article in English | MEDLINE | ID: mdl-38000467

ABSTRACT

OBJECTIVE: The weight-adjusted-waist index (WWI) serves as an innovative obesity measure, seemingly surpassing body mass index (BMI) and waist circumference (WC) in evaluating lean and fat mass. This study aimed to explore the relationship between WWI and depression in United States (US) adults. METHODS: This population-based study investigated adults with comprehensive WWI and PHQ-9 (9-item Patient Health Questionnaire) data from the National Health and Nutrition Examination Survey (NHANES) 2005-2018. WWI was computed by dividing WC by the square root of body weight. Weighted multivariate logistic regression and smoothed curve fitting were employed to examine linear and non-linear associations. Additionally, subgroup analyses and interaction tests were conducted. RESULTS: A total of 34,528 participants were enrolled with a prevalence of depression of 7.61 %. WWI was positively related to depression with the full adjustment [odds ratio (OR) = 1.21, 95 % confidence interval (95 % CI): 1.13-1.29]. After converting WWI to a categorical variable by quartiles (Q1-Q4), compared to Q1 the highest WWI quartile was linked to an obviously increased likelihood of depression (OR = 1.51, 95 % CI: 1.29-1.76). Subgroup analysis revealed the stability of the independent positive relationship between WWI and depression (all P for trend >0.05). CONCLUSION: WWI levels were positively related to an increased likelihood of depression in US adults. Our findings indicated that WWI may serve as a simple anthropometric index to predict depression.


Subject(s)
Obesity , Adult , Humans , United States/epidemiology , Nutrition Surveys , Obesity/epidemiology , Body Mass Index , Waist Circumference , Anthropometry
13.
Medicine (Baltimore) ; 102(50): e36721, 2023 Dec 15.
Article in English | MEDLINE | ID: mdl-38115242

ABSTRACT

The sacroiliac joint is an important part of human life behavior and daily activities. With the increase in people's lives and work pressure and the change of travel mode, the incidence rate of sacroiliac joint subluxation is getting higher and higher. The purpose of this study is to explore the relationship between medical choice, health behavior, and health status of patients with sacroiliac joint subluxation and put forward feasible suggestions for promoting the treatment and rehabilitation of patients. The EuroQoL 5 Dimensions 5 Levels health index survey scale was selected to investigate the health status of patients with sacroiliac joint subluxation. T test and analysis of variance were used for univariate analysis of medical choice and health behavior of patients with sacroiliac subluxation, and ordinary least squares was used for multivariate analysis. The elderly patients with subluxation of sacroiliac joint are in poor health. The health status of patients who chose to seek medical treatment for disease diagnosis and prescription was significantly worse. Patients with subluxation of sacroiliac joint with regular defecation have better health status. Patients who travel by bike or bus have worse health. The health status of those who sit still for more than 1 hour a day is significantly better. The health status of patients with sacroiliac subluxation is closely related to their choice of medical treatment and health behavior. It is suggested that rehabilitation therapy such as acupuncture and manipulation should be selected for intervention. Good health behaviors such as abstinence and regular defecation should be shaped. More attention should be paid to the health status of women at risk.


Subject(s)
Acupuncture Therapy , Joint Dislocations , Humans , Female , Aged , Sacroiliac Joint , Health Status , Joint Dislocations/therapy , Health Behavior
14.
Stem Cell Res ; 73: 103244, 2023 12.
Article in English | MEDLINE | ID: mdl-37995436

ABSTRACT

Nicolaides-Baraitser syndrome (NCBRS) is characterized by severe mental retardation, early-onset seizures, short stature, dysmorphic facial features, and sparse hair. Heterozygous mutations in the SMARCA2 gene are the most common cause of NCBRS. Here, we generated an induced pluripotent stem cell line SDQLCHi056-A from a five-year-old girl with NCBRS caused by heterozygous mutation (c.3592 G > A, p.V1198M) in the SMARCA2 gene (OMIM#601358). The established iPSC line was validated by pluripotency markers, original gene mutation and demonstrated trilineage differentiation potential in vitro.


Subject(s)
Induced Pluripotent Stem Cells , Intellectual Disability , Female , Humans , Child, Preschool , Intellectual Disability/genetics , Induced Pluripotent Stem Cells/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Mutation/genetics
15.
BMC Psychiatry ; 23(1): 845, 2023 11 16.
Article in English | MEDLINE | ID: mdl-37974120

ABSTRACT

BACKGROUND: As the most abundant fatty acid in plasma, oleic acid has been found to be associated with multiple neurological diseases; however, results from studies of the relationship between oleic acid and depression are inconsistent. METHODS: This cross-sectional study analyzed 4,459 adults from the National Health and Nutrition Examination Survey 2011-2014. The following covariates were adjusted in multivariable logistic regression models: age, sex, race/ethnicity, education level, marital status, body mass index, physical activity, smoking status, alcohol status, metabolic syndrome, omega-3 polyunsaturated fatty acids, and total cholesterol. RESULTS: Serum oleic acid levels were positively associated with depression. After adjusting for all covariates, for every 1 mmol/L increase in oleic acid levels, the prevalence of depression increased by 40% (unadjusted OR: 1.35, 95%CI: 1.16-1.57; adjusted OR: 1.40, 95% CI: 1.03-1.90). CONCLUSIONS: Our study suggests that oleic acid may play a role in depression. Further research is needed to investigate the potential benefits of changing oleic acid levels for the treatment and prevention of depression.


Subject(s)
Depression , Fatty Acids, Omega-3 , Adult , Humans , United States/epidemiology , Depression/epidemiology , Oleic Acid , Cross-Sectional Studies , Nutrition Surveys
16.
J Vis Exp ; (200)2023 Oct 27.
Article in English | MEDLINE | ID: mdl-37955365

ABSTRACT

Ankylosing spondylitis (AS) is a progressively worsening and disabling form of arthritis that primarily affects the axial skeleton. This disease mainly involves the spine and the sacroiliac joint. Fusion of the spine and the sacroiliac joint may occur in the later stage of the disease, resulting in spinal stiffness and kyphosis, as well as difficulty in walking, which seriously affects the quality of work and daily living activities and imposes a heavy burden on the patient, the family, and society. Increasing attention has been paid to non-pharmacotherapy as an alternative therapy for AS. Moxibustion is an ancient therapeutic technique used in Traditional Chinese Medicine (TCM). Du-moxibustion therapy, a unique and innovative external treatment developed on the basis of ordinary moxibustion, has a definite therapeutic effect on AS. Du-moxibustion skillfully combines the compatible techniques of TCM to integrate meridians, acupoints, Chinese herbal medicine, and moxibustion. This paper describes the operation procedures and precautions to be taken during Du-moxibustion in experimental mice in detail to provide an experimental basis for the study of the mechanism of Du-moxibustion in the treatment of AS.


Subject(s)
Acupuncture Therapy , Meridians , Moxibustion , Spondylitis, Ankylosing , Humans , Animals , Mice , Moxibustion/methods , Spondylitis, Ankylosing/therapy , Medicine, Chinese Traditional
17.
Heliyon ; 9(10): e20566, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37822624

ABSTRACT

Background: Monkeypox (MPX) has made recurrence after decades as a neglected zoonotic disease. More nations have reported endemic monkeypox in the past decade than in the previous forty. The World Health Organization has warned that the world may face another significant challenge after dealing with COVID-19, a pandemic, and the Monkeypox outbreak. Early appraisal of monkeypox research and development allows researchers to anticipate solutions for large outbreaks. We conducted a bibliometric analysis of this study's top 100 cited papers to identify regional research patterns. Methods: Our method was to search the SCI-Expanded database on Web of Science (WOS) for the top 100 papers that were cited in MPX on this database. We examined relevant literature from different years, journals, countries/regions, institutions, authors, and keywords.In order to create knowledge maps, we used the programs VOSviewer, Citespace, Scimago Graphica and the bibliometric online analysis platform. After compiling the relevant literature in Excel, we could estimate the field's focus and trends. Results: A total of 47 journals from 36 countries and regions published the top 100 cited papers between 1999 and 2023. The majority of articles were published in EMERGING INFECTIOUS DISEASES, while the highest average number of citations per paper were found in the NEW ENGLAND JOURNAL OF MEDICINE. The UNITED STATES contributed the most publications, followed by ENGLAND and SWITZERLAND. As far as the total number of publications goes, the Centers for Disease Control & Prevention in the USA, the National Institute of Health in the USA, and the World Health Organization each contributed the most papers. The major categories are immunology, virology and infectious diseases. The top five keywords were infection, Congo, virus, smallpox, and transmission. The cluster analysis suggests MPX research will focus on safe and effective vaccines and epidemic prevention. Conclusion: By using bibliometric analysis, MPX researchers can quickly and visually identify their research focus and boundaries. Although studies suggest that antiviral medicine is the best treatment, creating an effective vaccine might lessen and avoid MPX pandemics in the long term. Our findings imply that safe and effective vaccines may be the focus and trends for future MPX research. International coordination for case monitoring and identification is essential to understand monkeypox disease's ever-changing epidemiology.

18.
BMJ Open ; 13(10): e074001, 2023 10 29.
Article in English | MEDLINE | ID: mdl-37899167

ABSTRACT

OBJECTIVE: The pathogenesis of depression is related to immune inflammatory response. Atherogenic coefficient (AC) is an important indicator of lipid abnormalities, which can lead to immune inflammatory responses. However, no study has investigated the relationship between AC and depression in adult Americans. Therefore, we investigated this relationship. DESIGN: This study used a cross-sectional design. SETTING: The National Health and Nutrition Examination Survey (2005-2018) data were used for this study. PARTICIPANTS: A total of 32 502 participants aged 20 years or older who had complete information for AC and depression were included in this study. PRIMARY AND SECONDARY OUTCOME MEASURES: Depressive symptoms were assessed using the nine-item version of the Patient Health Questionnaire (PHQ-9), with a cut-off point of 9/10 indicating likely depression cases. Weighted logistic regression analyses and the smooth curve fittings were performed to explore the association between AC and depression. RESULTS: After adjusting for potential confounders, a single unit increase in AC was associated with a 3% increase in the prevalence of depression (HR=1.03, 95% CI=1.00 to 1.06, p=0.039). The relationship between AC and depression was more obvious in females. CONCLUSIONS: The AC is positively associated with depression.


Subject(s)
Atherosclerosis , Depression , Female , Adult , Humans , United States/epidemiology , Depression/epidemiology , Nutrition Surveys , Cross-Sectional Studies , Patient Health Questionnaire , Prevalence , Atherosclerosis/epidemiology
20.
BMC Psychiatry ; 23(1): 671, 2023 09 15.
Article in English | MEDLINE | ID: mdl-37715146

ABSTRACT

BACKGROUND: Despite the close relationship between sleep-wake cycles and depression symptoms, the relationship between sleep midpoint and depression symptoms in adults remains understudied. METHODS: In this cross-sectional study, 18280 adults aged ≥ 18 years from the National Health and Nutrition Examination Survey (NHANES) 2015-2020 were analyzed. Covariates included age, sex, race/ethnicity, education level, marital status, family income, body mass index, smoking status, drinking status, physical activity, comorbid condition, sleep duration, and sleep disturbance were adjusted in multivariate regression models. RESULTS: Weighted restricted cubic spline based on the complex sampling design of NHANES showed that in participants with a sleep midpoint from 2:18 AM to 6:30 AM, the prevalence of depression symptoms increased by 0.2 times (adjusted odds ratio [OR] = 1.20, 95% confidence interval [CI]: 1.08-1.33) per 1-h increment in sleep midpoint compared to the reference point of 2:18 AM. For participants with a sleep midpoint after 6:30 AM and before 2:18 AM the next day, the relationship between sleep midpoint and depression symptoms was not significant after adjusting for all covariates (adjusted OR = 1.01, 95% CI: 0.99-1.03). CONCLUSIONS: The findings indicate a significant nonlinear association between sleep midpoint and depression symptoms in a nationally representative sample of adults.


Subject(s)
Depression , Sleep , Humans , Adult , Cross-Sectional Studies , Depression/epidemiology , Nutrition Surveys , Sleep Duration
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