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Background: The integration of chemotherapy and immunotherapy as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC) has been adopted in clinical practice, yet the response to immune checkpoint inhibitors (ICIs) is variable, benefiting only a fraction of patients. The current absence of reliable biomarkers for predicting treatment response and prognosis represents a significant gap in knowledge, hindering the optimization of patient stratification and treatment planning. This retrospective cohort study aims to assess the potential predictive and prognostic significance of clinicopathological baseline features in ES-SCLC patients. Methods: Our study retrospectively analyzed the data of consecutive patients with ES-SCLC treated with first-line etoposide plus platinum chemotherapy ± immunotherapy at The Affiliated Lihuili Hospital of Ningbo University from April 2017 to April 2023. Data on clinical information, serum laboratory indicators, pathological immunohistochemical markers, and progression-free survival (PFS) times were collected. Univariate and multivariate Cox regression analyses were employed to determine whether these indicators could serve as independent prognostic factors for PFS. Further, potential predictive markers for treatment efficacy were identified using a Cox regression model that incorporated an interaction term between treatment modality and the indicator. Results: A total of 121 patients with ES-SCLC were enrolled in the study, of whom 62 received chemotherapy alone, and 59 received chemotherapy in combination with immunotherapy. Compared to chemotherapy alone, the addition of immunotherapy to first-line chemotherapy significantly extended the PFS time [P<0.001; hazard ratio (HR) =0.42; 95% confidence interval (CI): 0.28, 0.64] of the ES-SCLC patients. The multivariate analysis revealed that an immunochemotherapy regimen (P<0.001, HR =0.40; 95% CI: 0.24, 0.68), a low-density lipoprotein (LDL) level of >1.8 mmol/L (P=0.02; HR =0.41; 95% CI: 0.20, 0.85) were independent prognostic factors of favorable PFS in the first-line treatment of all ES-SCLC, while a lactate dehydrogenase (LDH) level of >273 U/L (P=0.04; HR =1.78; 95% CI: 1.03, 3.07), a neuron-specific enolase (NSE) concentration of >102.6 ng/mL (P=0.009; HR =6.49; 95% CI: 1.60, 26.32), an apolipoprotein A1 (ApoA1) concentration of >0.9 g/L (P<0.001; HR =4.15; 95% CI: 1.98, 8.71), and an apolipoprotein B (ApoB) concentration of >0.8 g/L (P=0.002; HR =2.24; 95% CI: 1.34, 3.75) were independent prognostic factors of poorer PFS. Further, the interaction effect analysis demonstrated that an LDL level of >1.8 mmol/L and the absence of bone metastasis were potential predictors of an improved response to ICI therapy compared to chemotherapy alone. Conclusions: This study showed the survival benefit of receiving a chemoimmunotherapy regimen as the first-line treatment in a real-world scenario. It also suggests the prognostic significance of pre-treatment LDL, LDH, NSE, ApoA1, and ApoB with optimal cut-off values in the first-line treatment of all ES-SCLC, and the potential utility of baseline LDL level or the presence of bone metastasis in guiding first-line treatment strategies.

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Peri-operative neurocognitive disorders (PNDs) include postoperative delirium (POD) and postoperative cognitive dysfunction (POCD). Children and the elderly are the two populations most vulnerable to the development of POD and POCD, which results in both high morbidity and mortality. There are many factors, including neuroinflammation and oxidative stress, that are associated with POD and POCD. General anesthesia is a major risk factor of PNDs. However, the molecular mechanisms of PNDs are poorly understood. Dexmedetomidine (DEX) is a useful sedative agent with analgesic properties, which significantly improves POCD in elderly patients. In this review, the current understanding of anesthesia in PNDs and the protective effects of DEX are summarized, and the underlying mechanisms are further discussed.

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BACKGROUND: This work elucidated the effect of honokiol (HKL) on hippocampal neuronal mitochondrial function in Alzheimer's disease (AD). METHODS: APP/PS1 mice were used as AD mice models and exposed to HKL and 3-TYP. Morris water maze experiment was performed to appraise cognitive performance of mice. Hippocampal Aß+ plaque deposition and neuronal survival was evaluated by immunohistochemistry and Nissl staining. Hippocampal neurons were dissociated from C57BL/6 mouse embryos. Hippocampal neuronal AD model was constructed by Aß oligomers induction and treated with HKL, CsA and 3-TYP. Neuronal viability and apoptosis were detected by cell counting kit-8 assay and TUNEL staining. mRFP-eGFP-LC3 assay, MitoSOX Red, dichlorodihydrofluorescein diacetate, and JC-1 staining were performed to monitor neuronal autophagosomes, mitochondrial reactive oxygen species (ROS), neuronal ROS, and mitochondrial membrane potential. Autophagy-related proteins were detected by Western blot. RESULTS: In AD mice, HKL improved cognitive function, relieved hippocampal Aß1-42 plaque deposition, promoted hippocampal neuron survival, and activated hippocampal SIRT3 expression and mitochondrial autophagy. These effects of HKL on AD mice were abolished by 3-TYP treatment. In hippocampal neuronal AD model, HKL increased neuronal activity, attenuated neuronal apoptosis and Aß aggregation, activated SIRT3 and mitochondrial autophagy, reduced mitochondrial and neuronal ROS, and elevated mitochondrial membrane potential. CsA treatment and 3-TYP treatment abrogated the protection of HKL on hippocampal neuronal AD model. The promotion of mitochondrial autophagy by HKL in hippocampal neuronal AD model was counteracted by 3-TYP. CONCLUSIONS: HKL activates SIRT3-mediated mitochondrial autophagy to mitigate hippocampal neuronal damage in AD. HKL may be effective in treating AD.

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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Autofagia , Compuestos de Bifenilo , Hipocampo , Lignanos , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias , Neuronas , Sirtuina 3 , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/metabolismo , Sirtuina 3/metabolismo , Ratones , Neuronas/efectos de los fármacos , Neuronas/patología , Neuronas/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Compuestos de Bifenilo/farmacología , Autofagia/efectos de los fármacos , Lignanos/farmacología , Péptidos beta-Amiloides/toxicidad , Fragmentos de Péptidos/toxicidad , Masculino , Fármacos Neuroprotectores/farmacología , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismo , Compuestos Alílicos , Fenoles

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Telomere length, a biomarker of human aging, is related to adverse health outcomes. Growing evidence indicates that oxidative stress and inflammation contributes to telomere shortening, whereas social support may protect from telomere shortening. Despite sex differences in telomere length and social support, little is known about whether there are sex differences in the relationship between oxidative stress/inflammation and telomere length, and sex-specific moderating roles of social support in older adults. Using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002, this study assessed whether the associations between oxidative stress/inflammation and telomere length vary with sex and explored social support as a moderator in these associations among 2289 older adults. Oxidative stress was measured based on serum Gamma-glutamyl transferase (GGT), and inflammation was measured based on C-reactive protein (CRP). After adjusting for the covariates, GGT was significantly associated with telomere length in females only (ß = - 0.037, 95% CI = - 0.070, - 0.005), while CRP was associated with telomere length in males only (ß = - 0.019, 95% CI = - 0.035, - 0.002). Moreover, high social support mitigated the negative association between GGT and telomere length, which was more evident in females. Furthermore, social support moderated the association between CRP and telomere length in males aged 70 and above. Our findings indicated that biological mechanisms related to telomere length may vary with sex, while social support plays a sex-specific moderating role.

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BACKGROUND: The bidirectional relationship between cognitive function and depressive symptoms has been extensively reported. However, the potential mechanisms are still not clear. We aim to longitudinally investigate whether physical activity mediates the bidirectional relationships between cognitive function and specific dimensions of depressive symptoms. METHODS: Data from 6,787 individuals aged ≥50 of 2014/15 (T1), 2016/17 (T2), and 2018/19 (T3) waves of the English Longitudinal Study of Ageing (ELSA). Cognitive function was assessed by domains of memory, orientation in time, and executive function. Physical activity was measured with the intensity and frequency of participation. Specific dimensions of depressive symptoms were assessed by the 8-item Center for Epidemiologic Studies Depression Scale, distinguishing between cognitive-affective and somatic symptoms. Cross-lagged panel models were used to investigate the mediating role of physical activity in the bidirectional relationships between cognitive function and two dimensions of depressive symptoms. RESULTS: Poorer cognitive function was indirectly associated with worse cognitive-affective symptoms (indirect effect = -0.002, 95%CI: -0.004, -0.001) through lower physical activity levels. Poorer cognitive function was also indirectly associated with worse somatic symptoms (indirect effect = -0.003, 95%CI: -0.006, -0.002) through lower physical activity levels, and the reverse mediation was observed as well (indirect effect = -0.002, 95%CI: -0.004, -0.001). LIMITATIONS: There is no distinction between potential within-person and between-person effects. CONCLUSIONS: Collaborative interventions of physical activity are beneficial in protecting cognitive function and mental health in older adults.

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Cognición , Depresión , Ejercicio Físico , Humanos , Femenino , Estudios Longitudinales , Masculino , Ejercicio Físico/psicología , Depresión/psicología , Anciano , Persona de Mediana Edad , Cognición/fisiología , Disfunción Cognitiva/fisiopatología , Función Ejecutiva/fisiología , Envejecimiento/psicología , Envejecimiento/fisiología , Anciano de 80 o más Años

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OBJECTIVES: Central obesity poses significant health risks because it increases susceptibility to multiple chronic diseases. Epigenetic features such as DNA methylation may be associated with specific obesity traits, which could help us understand how genetic and environmental factors interact to influence the development of obesity. This study aims to identify DNA methylation sites associated with the waist circumference (WC) in Northern Han Chinese population, and to elucidate potential causal relationships. METHODS: A total of 59 pairs of WC discordant monozygotic twins (ΔWC >0) were selected from the Qingdao Twin Registry in China. Generalized estimated equation model was employed to estimate the methylation levels of CpG sites on WC. Causal relationships between methylation and WC were assessed through the examination of family confounding factors using FAmiliaL CONfounding (ICE FALCON). Additionally, the findings of the epigenome-wide analysis were corroborated in the validation stage. RESULTS: We identified 26 CpG sites with differential methylation reached false discovery rate (FDR) < 0.05 and 22 differentially methylated regions (slk-corrected p < 0.05) strongly linked to WC. These findings provided annotations for 26 genes, with notable emphasis on MMP17, ITGA11, COL23A1, TFPI, A2ML1-AS1, MRGPRE, C2orf82, and NINJ2. ICE FALCON analysis indicated the DNA methylation of ITGA11 and TFPI had a causal effect on WC and vice versa (p < 0.05). Subsequent validation analysis successfully replicated 10 (p < 0.05) out of the 26 identified sites. CONCLUSIONS: Our research has ascertained an association between specific epigenetic variations and WC in the Northern Han Chinese population. These DNA methylation features can offer fresh insights into the epigenetic regulation of obesity and WC as well as hints to plausible biological mechanisms.

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Metilación de ADN , Epigenoma , Gemelos Monocigóticos , Circunferencia de la Cintura , Humanos , Gemelos Monocigóticos/genética , Circunferencia de la Cintura/genética , Masculino , Femenino , China/epidemiología , Epigenoma/genética , Metilación de ADN/genética , Persona de Mediana Edad , Estudio de Asociación del Genoma Completo , Adulto , Epigénesis Genética , Pueblo Asiatico/genética , Obesidad Abdominal/genética , Pueblos del Este de Asia

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BACKGROUND: The loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) is a major pathological hallmark of Parkinson's disease (PD). Orexin B (OXB) has been reported to promote the growth of DA neurons. However, the roles of OXB in the degeneration of DA neurons still remained not fully clear. METHODS: An in vivo PD model was constructed by administrating 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Pole test was performed to investigate the motor function of mice and the number of DA neurons was detected by immunofluorescence (IF). A PD cell model was established by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+). OXB was added to the culture medium 2 h after MPP + treatment. Microscopic analysis was carried out to investigate the function of OXB in the cell model of PD 24 h after MPP + challenge. RNA-Seq analysis of the PD cell model was performed to explore the possible mechanisms. Western blot was used to detect the phosphorylation levels of extracellular signal-regulated kinase (ERK). RESULTS: OXB significantly decreased the DA neurons death caused by MPTP, alleviated MPP+-induced neurotoxicity in SH-SY5Y cells, and robustly enhanced the weight and motor ability of PD mice. Besides, RNA-Seq analysis demonstrated that the mitogen-activated protein kinase (MAPK) pathway was involved in the pathology of PD. Furthermore, MPP + led to increased levels of phosphorylation of ERK (p-ERK), OXB treatment significantly decreased the levels of p-ERK in MPP+-treated SH-SY5Y cells. CONCLUSIONS: This study demonstrated that OXB exerts a neuroprotective role associated with reduced ERK phosphorylation in the PD model. This suggests that OXB may have therapeutic potential for treatment of PD.

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1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Neuronas Dopaminérgicas , Quinasas MAP Reguladas por Señal Extracelular , Orexinas , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Animales , Ratones , Fosforilación/efectos de los fármacos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Orexinas/metabolismo , Orexinas/farmacología , Humanos , Masculino , Línea Celular Tumoral , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Ratones Endogámicos C57BL , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , 1-Metil-4-fenilpiridinio/toxicidad , Sistema de Señalización de MAP Quinasas/efectos de los fármacos

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Background: Maternal education is one of key factors affecting nurturing environment which significantly impacts children's height levels throughout their developmental stages. However, the influence of maternal education on children's height is less studied. This study aims to investigate the dynamic influence of maternal education on children's height among Chinese children aged 0-18 years. Methods: Children undergoing health examinations from January 2021 to September 2023 were included in this study. Clinical information including height, weight, maternal pregnancy history, blood specimens for bone metabolism-related indicators and maternal education level was collected. Children's height was categorized into 14 groups based on age and gender percentiles, following WHO 2006 growth standards. One-way analysis of variance (ANOVA), linear regression, chi-square test and Fisher's exact test were applied for data analysis. Results: A total of 6269 samples were collected, including 3654 males and 2615 females, with an average age of 8.38 (3.97) for males and 7.89 (3.55) for females. Significant correlations between maternal education level, birth weight, birth order, weight percentile, vitamin D, serum phosphorus, alkaline phosphatase levels, and children's height were identified. Birth weight's influence on height varied across age groups. Compared with normal birth weight children, low birth weight children exhibited catch-up growth within the first 6 years and a subsequent gradual widening of the height gap from 6 to 18 years old. Remarkably, the impact of maternal education on height became more pronounced among children above 3-6 years old, which can mitigate the effect of low birth weight on height. Conclusion: We found that weight percentile, birth weight, birth order, bone marker levels, and maternal education level have significant effect on height. Maternal education attenuates the impact of low birth weight on height. The findings indicated that maternal education plays a consistent and critical role in promoting robust and healthy growth.

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Diphthamide is a modified histidine residue unique for eukaryotic translation elongation factor 2 (eEF2), a key ribosomal protein. Loss of this evolutionarily conserved modification causes developmental defects through unknown mechanisms. In a patient with compound heterozygous mutations in Diphthamide Biosynthesis 1 (DPH1) and impaired eEF2 diphthamide modification, we observe multiple defects in neural crest (NC)-derived tissues. Knockin mice harboring the patient's mutations and Xenopus embryos with Dph1 depleted also display NC defects, which can be attributed to reduced proliferation in the neuroepithelium. DPH1 depletion facilitates dissociation of eEF2 from ribosomes and association with p53 to promote transcription of the cell cycle inhibitor p21, resulting in inhibited proliferation. Knockout of one p21 allele rescues the NC phenotypes in the knockin mice carrying the patient's mutations. These findings uncover an unexpected role for eEF2 as a transcriptional coactivator for p53 to induce p21 expression and NC defects, which is regulated by diphthamide modification.

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Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Histidina , Histidina/análogos & derivados , Antígenos de Histocompatibilidad Menor , Cresta Neural , Factor 2 de Elongación Peptídica , Proteína p53 Supresora de Tumor , Proteínas Supresoras de Tumor , Animales , Cresta Neural/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Humanos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Ratones , Factor 2 de Elongación Peptídica/metabolismo , Factor 2 de Elongación Peptídica/genética , Histidina/metabolismo , Ribosomas/metabolismo , Mutación , Proliferación Celular , Xenopus laevis , Femenino , Técnicas de Sustitución del Gen , Xenopus , Masculino , Ratones Noqueados

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Mutations in the Contactin-associated protein-like 2 (CNTNAP2) gene are associated with autism spectrum disorder (ASD), and ectodomain shedding of the CNTNAP2 protein plays a role in its function. However, key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown, and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain elusive. In this report we showed that CNTNAP2 undergoes sequential cleavages by furin, ADAM10/17-dependent α-secretase and presenilin-dependent γ-secretase. We identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue I79 and L96, and the main α-cleavage product C79 by ADAM10 is required for the subsequent γ-secretase cleavage to generate CNTNAP2 intracellular domain (CICD). ASD-associated CNTNAP2 mutations impair the α-cleavage to generate C79, and the inhibition leads to ASD-like repetitive and social behavior abnormalities in the Cntnap2-I1254T knock-in mice. Finally, exogenous expression of C79 improves autism-like phenotypes in the Cntnap2-I1254T knock-in and Cntnap2-/- knockout mice. This data demonstrates that the α-secretase is essential for CNTNAP2 processing and its function. Our study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis, and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment.

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Trastorno del Espectro Autista , Trastorno Autístico , Animales , Ratones , Secretasas de la Proteína Precursora del Amiloide/genética , Trastorno del Espectro Autista/genética , Mutación/genética , Ratones Noqueados , Contactinas/genética , Fenotipo , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética

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We optimized the extraction process of Bletilla striata polysaccharides using orthogonal design, Box-Behnken design (BBD), and genetic algorithm-back propagation (GA-BP), then compared and evaluated them to confirm that the combination of BBD and GA-BP neural networks was capable of increasing polysaccharide yields and antioxidant activity. The optimal extraction parameters were as follows: liquid-to-solid ratio of 15 mL/g, extraction power of 450 W, and extraction time of 34 min. Under these conditions, the polysaccharide yield and antioxidant activity were 8.29 ± 0.50 % and 26.20 ± 0.28 (mM FE/mg). Subsequently, the polysaccharide was purified to obtain purified Bletilla striata polysaccharides 1 (pBSP1) with a Mw of 255.172 kDa. Scanning electron microscope (SEM), ultraviolet-visible detector (UV), fourier transform infrared spectrometer (FTIR), high performance liquid chromatography (HPLC), X-ray diffraction (XRD), nuclear magnetic resonance (NMR) and periodate oxidation were used to analyze the structure of pBSP1. The results showed pBSP1 had a smooth surface and a rough interior, with a composition of α-D conformation glucose (18.23 %) and ß-D conformation mannose (53.77 %), and an amorphous crystal structure. According to the results of thermogravimetric and rheological tests, pBSP1 exhibits good thermal stability and viscoelastic behavior. Furthermore, pBSP1 protected lipopolysaccharide (LPS)-induced GES - 1 and Caco2 cells, the results showed pBSP1(400 µg/mL) lowered TEER synthesis in Caco2 cells as well as apoptosis and reactive oxygen species (ROS) production in both cells, indicating that pBSP1 may have an intestine protective effect.

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Antioxidantes , Orchidaceae , Humanos , Antioxidantes/farmacología , Antioxidantes/química , Células CACO-2 , Oxidación-Reducción , Glucosa , Polisacáridos/farmacología , Polisacáridos/química , Orchidaceae/química

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BACKGROUND: A considerable number of individuals infected with COVID-19 experience residual symptoms after the acute phase. However, the correlation between residual symptoms and psychological distress and underlying mechanisms are scarcely studied. We aim to explore the association between residual symptoms of COVID-19 and psychological distress, specifically depression, anxiety, and fear of COVID-19, and examine the role of risk perception and intolerance of uncertainty in the association. METHODS: A cross-sectional survey was conducted by online questionnaire-based approach in mid-January 2023. Self-reported demographic characteristics, COVID-19-related information, and residual symptoms were collected. Depression, anxiety, fear, risk perception and intolerance of uncertainty were evaluated using the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Fear of COVID-19 Scale (FCV-19S), COVID-19 Risk Perception Scale and Intolerance of Uncertainty Scale-12 (IUS-12), respectively. Linear regression analyses were conducted to explore the associations. A moderated mediation model was then constructed to examine the role of risk perception of COVID-19 and intolerance of uncertainty in the association between residual symptoms and psychological distress. RESULTS: 1735 participants effectively completed the survey. 34.9% of the patients experienced residual symptoms after acute phase of COVID-19. Psychological distress was markedly increased by COVID-19 infection, while residual symptoms had a significant impact on psychological distress (Ps < 0.001), including depression (ß = 0.23), anxiety (ß = 0.21), and fear of COVID-19 (ß = 0.14). Risk perception served as a mediator between residual symptoms and all forms of psychological distress, while intolerance of uncertainty moderated the effect of risk perception on depression and anxiety. CONCLUSION: A considerable proportion of patients experience residual symptoms after acute phase of COVID-19, which have a significant impact on psychological distress. Risk perception and intolerance of uncertainty play a moderated-mediation role in the association between residual symptoms and depression/anxiety. It highly suggests that effective treatment for residual symptoms, maintaining appropriate risk perception and improving intolerance of uncertainty are critical strategies to alleviate COVID-19 infection-associated psychological distress.

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COVID-19 , Distrés Psicológico , Humanos , Estudios Transversales , Incertidumbre , Depresión/psicología , Ansiedad/psicología , Percepción

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BACKGROUND: Increasing evidence shows that social isolation and depression are likely to interact with each other, yet the direction and causality of the association are not clear. This study aims to examine the possible reciprocity in the relationship between social isolation and depression. METHODS: This study fitted a cross-lagged panel model (CLPM) by using data from the English Longitudinal Study of Aging (ELSA, 2014-2019, n = 6787) to examine the temporal relationship between social isolation and depressive symptoms in older adults. We then conducted two-sample bidirectional Mendelian randomization (MR) analyses by using independent genetic variants associated with multiple social isolation phenotypes (n = 448,858-487,647) and with depression (n = 215,644-2,113,907) as genetic instruments from genome-wide association studies to assess the causality between social isolation and onset of depression. RESULTS: The CLPM in the ELSA cohort showed a significant and positive lagged effect of social isolation on depressive symptoms (ß = 0.037, P < .001). The reverse cross-lagged path from depressive symptoms to social isolation was also statistically significant (ß = 0.039, P < .001). In two-sample bidirectional MR, the genetically predicted loneliness and social isolation combined phenotype (LNL-ISO) was positively associated with occurrence of depression (OR = 1.88, 95 % CI: 1.41-2.50, P < .001), vice versa (OR = 1.16, 95 % CI:1.13-1.20, P < .001). LIMITATIONS: The self-report nature of the assessments and missing data are study limitations. CONCLUSIONS: These findings suggest a bidirectional relationship between social isolation and depression. It is important to develop interventions that highlight the reciprocal consequences of improving either mental health or social connection in older adults.

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Depresión , Análisis de la Aleatorización Mendeliana , Humanos , Anciano , Depresión/epidemiología , Depresión/genética , Depresión/psicología , Estudios Longitudinales , Estudio de Asociación del Genoma Completo , Aislamiento Social/psicología

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Constructing synthetic microbial consortia is a challenging task but holds enormous potential for various applications. Our previous droplet-based microfluidic approach allowed for the isolation of bacteria that could utilize metabolites from an engineered bacterium BsS-RS06551 with anti-obesity potential, facilitating the construction of synthetic microbial consortia. Here, we identified a strain of Bifidobacterium pseudocatenulatum JJ3 that interacted with BsS-RS06551, and in vitro coculture showed that BsS-RS06551 was likely to interact with JJ3 through five dipeptides. Pathway analysis revealed that the vitamin B6 metabolism pathway was enriched in the coculture of BsS-RS06551 and JJ3 compared with the individual culture of BsS-RS06551. Additionally, we confirmed that the administration of JJ3 significantly alleviated obesity and related disorders in mice fed a high-fat diet. Notably, continuous ingestion of the synthetic microbial consortium comprising BsS-RS06551 and JJ3 not only exhibited a more pronounced impact on alleviating obesity compared to the individual administration of BsS-RS06551 or JJ3 but also enriched the population of Bifidobacterium longum and perturbed the vitamin B6 metabolism pathway in the gut. Synthetic microbial consortia represent a promising frontier for synthetic biology, and our strategy provides guidance for constructing and applying such consortia.

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Bifidobacterium longum , Microbioma Gastrointestinal , Animales , Ratones , Consorcios Microbianos , Obesidad/prevención & control , Vitamina B 6

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BACKGROUND: Depression and anxiety have been found prevalent during all phases of the COVID-19 pandemic. In late December 2022, almost all COVID-19 control measures were lifted in China, leading to a surge in COVID-19 infections. The public's perceived risk and fear of COVID-19 would be increased. This study aims to examine the prevalence of depression and anxiety in the Chinese general population and explores the mediating role of fear of COVID-19 between COVID-19 perceived risk and depression/anxiety and the moderating role of resilience between fear of COVID-19 and depression/anxiety. METHODS: A cross-sectional online survey was conducted in Wenzhou, China, immediately following almost all COVID-19 control measures lifted. The 9-item Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), the COVID-19 Risk Perception Scale, the Fear of COVID-19 Scale, and the Connor-Davidson Resilience Scale (CD-RISC) were used to evaluate depression, anxiety, COVID-19 perceived risk, fear of COVID-19, and resilience, respectively. Structural Equation Modeling (SEM) with Maximum Likelihood (ML) estimator and adjusted for significant background factors was performed to test the moderated mediation. Data obtained from 935 participants were analyzed. RESULTS: The prevalence of moderate to severe depression and anxiety was 23.7% and 9.5%, respectively. The present study revealed positive associations among COVID-19 perceived risk, fear of COVID-19 and depression/anxiety, and negative associations between resilience and fear of COVID-19/depression/anxiety. Fear of COVID-19 partially mediated the association between COVID-19 perceived risk and depression/anxiety. Furthermore, resilience significantly moderated the association between fear of COVID-19 and depression/anxiety. Two moderated mediation models were constructed. CONCLUSION: Depression and anxiety were prevalent among Chinese adults during the final phase of the pandemic in China. The significant mediation role of fear of COVID-19 implies that reducing fear of COVID-19 may effectively alleviate depression and anxiety symptoms. Moreover, enhancing public resilience during an epidemic crisis is crucial for promoting mental health.

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COVID-19 , Pruebas Psicológicas , Resiliencia Psicológica , Adulto , Humanos , Estudios Transversales , Salud Mental , Pandemias , COVID-19/epidemiología , Miedo

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BACKGROUND: Both genetic and epigenetic variations of GLP1R influence the development and progression of obesity. However, the underlying mechanism remains elusive. This study aims to explore the mediation roles of obesity-related methylation sites in GLP1R gene variants-obesity association. METHODS: A total of 300 Chinese adult participants were included in this study and classified into two groups: 180 metabolically healthy obesity (MHO) cases and 120 metabolically healthy normal-weight (MHNW) controls. Questionnaire investigation, physical measurement and laboratory examination were assessed in all participants. 18 single nucleotide polymorphisms (SNPs) and 31 CpG sites were selected for genotype and methylation assays. Causal inference test (CIT) was performed to evaluate the associations between GLP1R genetic variation, DNA methylation and MHO. RESULTS: The study found that rs4714211 polymorphism of GLP1R gene was significantly associated with MHO. Additionally, methylation sites in the intronic region of GLP1R (GLP1R-68-CpG 7.8.9; GLP1R-68-CpG 12.13; GLP1R-68-CpG 17; GLP1R-68-CpG 21) were associated with MHO, and two of these methylation sites (GLP1R-68-CpG 7.8.9; GLP1R-68-CpG 17) partially mediated the association between genotypes and MHO. CONCLUSIONS: Not only the gene polymorphism, but also the DNA methylation of GLP1R was associated with MHO. Epigenetic changes in the methylome may in part explain the relationship between genetic variants and MHO.

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Epigénesis Genética , Receptor del Péptido 1 Similar al Glucagón , Obesidad Metabólica Benigna , Adulto , Humanos , Causalidad , Obesidad Metabólica Benigna/diagnóstico , Factores de Riesgo , Receptor del Péptido 1 Similar al Glucagón/genética

RESUMEN

OBJECTIVES: Sleep is associated with physical activity (PA), yet the nature and directions of this association are less understood. This study aimed to disentangle the long-term temporal sequences between sleep duration/disturbance and PA in older adults, distinguishing between- and within-person effects. DESIGN: Longitudinal panel study. SETTING AND PARTICIPANTS: We conducted a longitudinal study using 3 waves of data collected in 2008/09 (T1), 2012/13 (T2), and 2016/17(T3) from adults aged ≥50 years in the English Longitudinal Study of Ageing (N = 10,749 individuals). MEASURES: Sleep duration, sleep disturbance, and PA were assessed by self-reported questionnaires. We used cross-lagged panel models (CLPMs) to examine between-person effects and random intercept cross-lagged panel models (RI-CLPMs) to examine within-person effects. RESULTS: Our analyses revealed a reciprocal relationship between abnormal sleep duration and low PA levels at between-person level (abnormal sleep duration to PA: ßT1-T2 = -0.053, ßT2-T3 = -0.058, all P < .001; PA to abnormal sleep duration: ßT1-T2 = -0.040, ßT2-T3 = -0.045, all P < .05), with abnormal sleep duration being the driving force in the dynamic association. In addition, there was a unidirectional effect of more severe sleep disturbance on lower levels of PA at both between- and within-person levels (between-person level: ßT1-T2 = -0.032, ßT2-T3 = -0.028, all P < .001; within-person level: ßT1-T2 and T2-T3 = -0.031, all P = .011). CONCLUSIONS AND IMPLICATIONS: This study adds novel insights into the temporal directionality of sleep and PA among community-dwelling older adults and highlights poor sleep as a potential risk factor for PA. Intervention strategies should aim to improve sleep to promote PA levels and successful aging.

Asunto(s)

Ejercicio Físico , Duración del Sueño , Humanos , Anciano , Estudios Longitudinales , Envejecimiento , Sueño

RESUMEN

BACKGROUND AND AIMS: The relationship between seafood consumption and cardiovascular disease (CVD) is controversial, and studies have not considered competing risk events. Our study examined the association between a full range of seafood consumption and CVD incidence and mortality based on the Qingdao Diabetes Prevention Program. METHODS AND RESULTS: We followed up 5285 participants without CVD at baseline until December 31, 2021. CVD cases and deaths were identified through record linkage with the Qingdao CVD Surveillance System and the Qingdao Death Surveillance System, respectively. Information on seafood consumption was obtained using a food frequency questionnaire. We used the Cox proportional hazard model and the competing risk model to evaluate the association between all types of seafood consumption and CVD incidence and mortality. During a median follow-up of 11.4 years, 122 CVD cases and 75 deaths occurred. After adjustment for potential confounders, compared with nonconsumers, seafood consumption of 300-500 and > 500 g/week was associated with a lower risk of CVD incidence [hazards ratio and 95 % confidence interval (CI): 0.54 (0.29-0.99) and 0.49 (0.26-0.91), respectively]. However, seafood consumption of >500 g/week had a significantly lower risk of CVD mortality [subdistribution hazard ratio and 95 % CI: 0.40 (0.17-0.95)], but it was insignificant in other groups. CONCLUSION: Seafood consumption of 300-500 g/week and >500 g/week was associated with a lower CVD incidence and mortality. Our findings provide evidence of the recommendations of the 2022 Dietary Guidelines for Chinese residents and may guide the promotion of strategies for CVD prevention.

Asunto(s)

Enfermedades Cardiovasculares , Alimentos Marinos , Adulto , Humanos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , China/epidemiología , Pueblos del Este de Asia , Dieta

RESUMEN

Iron overload has been associated with an increased risk of COVID-19 severity and mortality in observational studies, but it remains unclear whether these associations represent causal effects. We performed a two-sample Mendelian randomization (MR) to determine associations between genetic liability to iron overload and the risk of COVID-19 severity and mortality. From genome-wide association studies of European ancestry, single-nucleotide polymorphisms associated with liver iron (n = 32,858) and ferritin (n = 23,986) were selected as exposure instruments, and summary statistics of the hospitalization (n = 16,551) and mortality (n = 15,815) of COVID-19 were utilized as the outcome. We used the inverse-variance weighted (IVW) method as the primary analysis to estimate causal effects, and other alternative approaches as well as comprehensive sensitivity analysis were conducted for estimating the robustness of identified associations. Genetically predicted high liver iron levels were associated with an increased risk of COVID-19 mortality based on the results of IVW analysis (OR = 1.38, 95% CI: 1.05-1.82, P = 0.02). Likewise, sensitivity analyses showed consistent and robust results in general (all P > 0.05). A higher risk of COVID-19 hospitalization trend was also observed in patients with high liver iron levels without statistical significance. This study suggests that COVID-19 mortality might be partially driven by the iron accumulation in the liver, supporting the classification of iron overload as one of the independent death risk factors. Therefore, avoiding iron overload and maintaining normal iron levels may be a powerful measure to reduce COVID-19 mortality.

RESUMEN

BACKGROUND: Adolescents experience relatively more stress than other populations as they are facing rapid physical changes and adapting to complex social environments. However, access for this population to professional service providers is limited. Therefore, there is an increasing need for access to mental health services and new mental health care resources tailored to adolescents. OBJECTIVE: The aim of this study was to evaluate the functionality and effectiveness of a school digital mental health clinic (DMHC) created by a Chinese psychiatric hospital and provided to secondary school students for a trial. METHODS: The trial period of the DMHC was from January to July 2021 at three secondary schools in Taizhou City, China. Under a collaborative agreement between the local educational bureau and provider, use of the DMHC was free to all students, teachers, and staff of the schools. The functionality of the DMHC was compared with existing digital health interventions introduced in the literature and its effectiveness was quantitatively analyzed in terms of the volume of received counseling calls, number of calls per 100 students, length and time of calls, and reasons for the calls. The mini course video views were analyzed by topics and viewing time. RESULTS: The design functions of the DMHC are well aligned with required factors defined in the literature. The first advantage of this DMHC is its high accessibility to students in the three schools. All functions of the DMHC are free to use by students, thereby eliminating the economic barriers to seeking and receiving care. Students can receive virtual counseling during or after regular working hours. Acceptability of the DHMC was further ensured by the full support from a national top-tier mental health facility. Any audio or video call from a student user would connect them to a live, qualified professional (ie, a psychiatrist or psychologist). Options are provided to view and listen to resources for stress relief or tips to help address mental health needs. The major reasons for the counseling calls included difficulties in learning, interpersonal relationships, and emotional distress. The three topics with the highest level of interest for the mini course videos were emotional assistance, personal growth, and family member relationships. The DMHC served as an effective tool for crisis prevention and intervention during nonworking hours as most of the live calls and mini video viewing occurred after school or over the weekend. Furthermore, the DMHC helped three students at high risk for suicide and self-injury through live-call intervention. CONCLUSIONS: The DMHC is an effective complementary solution to improve access to professional mental health care facilities, especially during nonworking hours, thereby helping adolescents meet their mental health needs. Extension of the DMHC into more schools and other settings is recommended.