Objective To explore the relationship between circadian rhythm genes and the occurrence, development, prognosis, and tumor microenvironment (TME) of lung adenocarcinoma (LUAD). Methods The Cancer Genome Atlas data were used to evaluate the expression, copy number variation, and somatic mutation frequency of circadian gene sets in LUAD. Gene ontology, Kyoto encyclopedia of genes and genomes, and gene set enrichment analysis were used to explore the potential mechanisms by which circadian rhythm genes affected LUAD progression. Cox regression, least absolute shrinkage and selection operator regression, support vector machine recursive feature elimination, and random forest screened circadian genes and established prognostic models, and on this basis constructed nomogram to predict patients’ 1-, 3-, and 5-year survival rates. Kaplan-Meier survival curves, receiver operating characteristic (ROC) curves, and time-dependent ROC curves were drawn to evaluate the predictive ability of the model, and the external dataset of GEO further verified the prognostic value of the prediction model. In addition, we evaluated the association of the prognostic model with immune cells and immune checkpoint genes. Single cell RNA sequencing (scRNA-seq) analysis was used to explore the molecular characteristics between prognostically relevant circadian genes and different immune cell populations in TME. Results Differentially expressed circadian rhythm genes were mainly enriched in biological processes related to cGMP-PKG signaling pathway, lipid and atherosclerosis, and JAK-STAT signaling pathway. Seven circadian rhythm genes: LGR4, CDK1, KLF10, ARNTL2, RORA, NPAS2, PTGDS were screened out, and a RiskScore model was established. According to the median RiskScore, samples were divided into a high-risk group and a low-risk group. Compared with patients in the low-risk group, patients in the high-risk group showed a poorer prognosis (P<0.001). Immunological characterization analysis showed that there were differences in the infiltration of multiple immune cells between the low-risk group and high-risk group. Most immune checkpoint genes had higher expression levels in the high-risk group than those in the low-risk group, and RiskScore was positively correlated with the expression of CD276, TNFSF4, PDCD1LG2, CD274, and TNFRSF9, and negatively correlated with the expression of CD40LG and TNFSF15. The scRNA-seq analysis showed that RORA and KLF10 were mainly expressed in natural killer cells. Conclusion The prognostic model based on seven feature circadian rhythm genes has certain predictive value for predicting survival of LUAD patients. Dysregulated expression of circadian genes may regulate the occurrence, progression as well as prognosis of LUAD through affecting TME, which provides a possible direction for finding potential strategies for treating LUAD from the perspective of mechanism by which circadian disorder affects immune cells.

Background/Aims: Acetyl coenzyme A (acetyl-CoA) is one of the most essential metabolites in cell metabolism but its function and concentration in hepatocellular carcinoma (HCC) remain elusive and controversial. Methods: A comprehensive analysis of acetyl-CoA levels and acetyl-CoA synthetase 2 (ACSS2) expression across a range of samples, including patient specimens from both hepatitis B virus (HBV) positive and HBV negative HCC individuals, HBV-transgenic mouse HCC models, and multiple cell lines. Furthermore, to evaluate the functional significance of ACSS2 in HBV-related HCC, we implemented both genetic and pharmacological inhibition strategies targeting ACSS2. Molecular mechanism and mitophagy assessment were revealed by cleavage under target and tagmentation sequencing, RNA sequencing, bioinformatic analyses, transmission electron microscopy and JC-1 staining. Results: Our study revealed a distinct metabolic signature of HBV-related HCC, marked by elevated acetyl-CoA, which was driven by ACSS2. ACSS2 was upregulated by the carbohydrate response element-binding protein in HBV-related HCC. Furthermore, ACSS2 improved tumor cell proliferation, an effect that was dependent on its enzymatic activity. Mechanistically, ACSS2-induced acetyl-CoA accumulation activated voltage-dependent anion channels 1 transcription through increased H3K27ac occupancy, which subsequently promoted mitophagy and HBV-related HCC tumorigenesis. Notably, targeting ACSS2 by depletion or inhibition with a catalytic inhibitor significantly suppressed tumor growth. Conclusions These findings not only illustrate the interplay between metabolic reprogramming, epigenetic modification, and tumorigenesis in the context of HBV infection, but also highlight ACSS2 as a novel metabolic vulnerability in HBV-related HCC. Therefore, targeting ACSS2 could be a novel strategy against HBV-related HCC.

Objective: To conduct a scoping review on the types, construction methods and predictive performance of health literacy prediction models based on machine learning methods, so as to provide the reference for the improvement and application of such models. Methods: Publications on health literacy prediction models conducted using machine learning methods were retrieved from CNKI, Wanfang Data, VIP, PubMed and Web of Science from inception to May 1, 2024. The quality of literature was assessed using the Prediction Model Risk of Bias ASsessment Tool. Basic characteristics, modeling methods, data sources, missing value handling, predictors and predictive performance were reviewed. Results: A total of 524 publications were retrieved, and 22 publications between 2007 and 2024 were finally enrolled. Totally 48 health literacy prediction models were involved, and 25 had a high risk of bias (52.08%), with major issues focusing on missing value handling, predictor selection and model evaluation methods. Modeling methods included regression models, tree-based machine learning methods, support vector machines and neural network models. Predictors primarily encompassed factors at four aspects: individual, interpersonal, organizational and society/policy aspects, with age, educational level, economic status, health status and internet use appearing frequently. Internal validation was conducted in 14 publications, and external validation was conducted in 4 publications. Forty-two models reported the areas under the receiver operating characteristic curve, which ranged from 0.52 to 0.983, indicating good discrimination. Conclusion Health literacy prediction models based on machine learning methods perform well, but have deficiencies in risk of bias, data processing and validation.

Objective To explore the changes in neural activity in patients with type 2 diabetes mellitus(T2DM)and their corre-lation with executive function,and to analyze the neural mechanisms underlying the decline in executive function in T2DM patients.Methods Thirty-one T2DM patients(T2DM group)and thirty-two healthy controls(HC)(HC group)matched for body mass index(BMI)underwent resting-state functional magnetic resonance imaging(rs-fMRI)scans and N-back task tests were included.Differ-ences in the amplitude of low-frequency fluctuation(ALFF),regional homogeneity(ReHo),and seed-based functional connectivity(FC)between the two groups were compared,and partial correlation analyses were performed between the difference results and N-back task performance.Results The T2DM group showed prolonged reaction time(RT)in the 1-back and 2-back tasks.T2DM patients exhibited increased ALFF in the bilateral caudate nucleus,left medial superior frontal gyrus,and right postcentral gyrus,as well as elevated ReHo in the right putamen.FC analysis revealed significant alterations in FC between the caudate nucleus,putamen,and multiple brain regions in T2DM patients,with some of these FC changes significantly correlated with RT and accuracy(ACC)in the N-back task.Conclusion The decline in executive function in T2DM patients may be associated with abnormal neural activity in brain regions such as the striatum,salience network,and frontoparietal control network.FC further decreases under increased cognitive load.These findings provide evidence for the study of the neural mechanisms of executive function impairment in T2DM patients.

Implementing the reform of outpatient mutual-aid is a crucial measure to improve China's medical security system.Based on the policy diffusion theory,we took 228 prefecture-level cities across the country as the research objects and used the event history method to analyze the diffusion mode and influencing factors of the general outpatient pooling policy for employees'basic medical insurance,and divided into three types:the type of reducing the stock of Medical Savings Accounts(MSA),the welfare increment type I and type II for separate analysis.We found that the diffusion of the general outpatient pooling policy presented an"S"-shaped curve over time,and was mainly horizontally diffused in space,with a neighboring effect and a regional demonstration effect.The type of reducing the stock of MSA policy diffuses horizontally;the welfare increment type I is mainly horizontal diffusion,supplemented by vertical diffusion;the welfare increment type II is not affected by the pressure from higher-level governments,and mainly adopts the horizontal diffusion mode.In terms of the influencing factors of policy diffusion,the diffusion of the general outpatient pooling policy was affected by multiple factors such as policy issues,legitimacy,and government capacity.The diffusion of the type of reducing the stock of MSA policy was not affected by the pressure from higher-level governments,but was influenced by policy issues and government capacity.The diffusion of the welfare increment type I policy was most affected by policy issues,and the welfare increment type II was most affected by government capacity.

Aim To clarify the mechanism by which Qishen Yixin Granules improved microcirculation vas-cular endothelial dysfunction(VED)in mice,through activating the Nrf2/HO-1 signaling pathway to regulate oxidative stress.Methods C57 mice were randomly divided into six groups:blank group,model group,pos-itive drug group,and low-,medium-,and high-dose groups of Qishen Yixin Granules.The VED model was established by long-term infusion of Ang Ⅱ combined with a high-fat diet.Each treatment group received the corresponding drug intervention.After four weeks of drug intervention,cardiac function was assessed by echocardiography.Carstairs staining was used to ob-serve the formation of microthrombi in myocardial tis-sue.The micro vascular ischemia was evaluated by Hei-denhain staining.The ultrastructure of endothelial cells was observed by electron microscopy.The levels of EMPs,ROS,NO,ET-1,TF,TM,VWF,and TXA2 in serum were measured by ELISA.The expression levels of MDA,SOD,and GSH-Px in mouse heart tissue were determined by chemical methods.Cardiac microvascu-lar density and the expression of Nrf2,Keap1,and HO-1 proteins were detected by Immunohistochemical stai-ning.The protein expressions of Keap1,cytoplasmic Nrf2,nuclear Nrf2,and HO-1 in myocardial tissue were detected by Western blot.Results Qishen Yixin Granules could effectively improve the cardiac function of mice,alleviate the damage of endothelial cells and endothelial function.They could up-regulate serum NO levels and the activities of antioxidant enzymes SOD and GSH-Px,while down-regulating the expression of ROS and vascular inflammatory injury factors such as ET-1,VWF,TXA2,TF,TM,and EMPs.Qishen Yixin Granules also increased the positive counts of CD34,Nrf2,and HO-1,as well as microvessel density.Fur-thermore,they inhibited the expression of MDA,Keap1,and cytoplasmic Nrf2 protein in myocardial tis-sue,while increasing the expression of nuclear proteins HO-1 and Nrf2.Conclusions Qishen Yixin Granules may inhibit oxidative stress and inflammatory response by regulating the Nrf2/HO-1 signaling pathway,thereby improving vascular endothelial damage and cardiac function in VED mice.

Objective To examine the changing prevalence and antimicrobial resistance profiles of Burkholderia cepacia in 52 hospitals across China from 2015 to 2021.Methods A total of 9 261 strains of B.cepacia were collected from 52 hospitals between January 1,2015 and December 31,2021.Antimicrobial susceptibility of the strains was tested using Kirby-Bauer method or automated antimicrobial susceptibility testing systems according to a unified protocol.The results were interpreted according to the breakpoints released in the Clinical & Laboratory Standards Institute(CLSI)guidelines(2023 edition).Results A total of 9 261 strains of B.cepacia were isolated from all age groups,especially elderly patients.The proportion was 11.1％(1 032 strains)in children,significantly lower than the proportion in adults.About half(46.5％,4 310/9 261)of the strains were isolated from patients at least 60 years old and 42.3％(3 919/9 261)of the strains were isolated from young adults.Most isolates(71.1％)were isolated from sputum and respiratory secretions,followed by urine(10.7％)and blood samples(8.1％).B.cepacia isolates were highly susceptible to the five antimicrobial agents recommended in the CLSI M100 document(33rd edition,2023).B.cepacia isolates showed relatively higher resistance rates to meropenem and levofloxacin.However,the resistance rates to ceftazidime,trimethoprim-sulfamethoxazole,and minocycline remained below 8.1％.The percentage of B.cepacia strains resistant to levofloxacin was the highest compared to other antibiotics in any of the three age groups(from 12.4％in the patients＜18 years old to 20.6％in the patients aged 60 years or older).Conclusions B.cepacia is one of the clinically important non-fermenting gram-negative bacteria.Accurate and timely reporting of antimicrobial susceptibility test results and ongoing antimicrobial resistance surveillance are helpful for rational prescription of antimicrobial agents and proper prevention and control of nosocomial infections.

Objective To investigate alterations in plasma complement levels and white matter imaging characteristics,along with their relationship in patients with first-episode schizophrenia(SCZ).Methods Thirty-eight patients with first-episode schizophrenia and 42 healthy controls were enrolled.Whole-brain diffusion tensor imaging(DTI)was performed using a Philips 3.0 T MRI scanner.Tract-based spatial statistics(TBSS)combined with the Johns Hopkins University(JHU)white matter labels atlas was used to extract and compare white matter characteristics between the two groups.Plasma levels of complement components(C1q,C3,C4,factor B,factor H,and factor P)were measured using the MILLIPLEX? human complement assay kit via multiplex analysis.Spearman correlation analysis was conducted to examine the association between plasma complement levels and white matter features.Results The radial diffusivity(RD)of the left fornix/stria terminalis was significantly higher in the patient group compared to the control group[(0.62±0.04)×10-3mm2/s vs.(0.60±0.03)×10-3mm2/s,PFDR=0.048)].Factor H[677.71(551.58,846.21)ng/mL vs.582.76(513.93,729.71)ng/mL,P=0.041]and factor P[71.36(57.30,95.99)ng/mL vs.60.08(46.67,80.03)ng/mL,P=0.011]were both significantly elevated compared to the control group.Moreover,RD values in the left fornix/stria terminalis were negatively correlated with plasma C3 levels in the patient group(r=-0.362,P=0.025).Conclusion Patients with first-episode schizophrenia exhibit white matter microstructural abnormalities in left fornix/stria terminalis,which are significantly associated with plasma complement levels.

Objective:To analyze the effects of entecavir on tear secretion and tear film function in patients with hepatitis B virus (HBV) infection.Methods:A retrospective analysis was conducted on the clinical data of 24 patients with HBV infection who received treatment with entecavir at the Department of Ophthalmology, Affiliated Hospital of Shaoxing University from April to October 2022. The relevant examination results of dry eye in these patients were analyzed before medication and at 1 and 3 months after medication.Results:Before medication, 13 cases (54.17%) had dry eye, and 3 months after medication, 17 cases (70.83%) had dry eye. At 1 and 3 months after treatment with entecavir, the Ocular Surface Disease Index values of the patients were (13.83 ± 7.11) points and (15.29 ± 6.94) points, respectively. There was no significant difference in Ocular Surface Disease Index value between before and after treatment ( t = -0.24, -1.24, both P>0.05). At 1 and 3 months after treatment, the Schirmer I test results were (8.74 ± 2.40) mm and (8.21 ± 2.40) mm, respectively. The Schirmer I test results at 3 months after treatment were significantly lower than those before treatment ( t = 2.12, P<0.05). At 3 months after treatment, the tear film break-up time was reduced to (7.63 ± 1.97) seconds, which was significantly shorter than the value recorded before treatment ( t = 2.12, P<0.05). At 3 months after treatment, the height of the tear meniscus was (0.21 ± 0.06) mm, which was significantly different from that measured before treatment ( t = 2.26, P<0.05).At 3 months after treatment, the red eye index increased compared with the value recorded before treatment, but the difference was not statistically significant ( t = -0.35, -0.94, both P>0.05). Conclusions:Patients with HBV infection are prone to developing dry eye syndrome. After treatment with entecavir, there may be a reduction in tear secretion and a decline in tear film function, which should be a concern for clinicians.

Aim To explore the protective effects and underlying molecular mechanisms of periplogenin(Ppg)in preventing acetaminophen(APAP)-induced drug-induced liver injury(DILI).Methods An APAP-induced liver injury model was established in vi-vo and in vitro.Liver/spleen indices were recorded,and serum aspartate aminotransferase(AST)and ala-nine aminotransferase(ALT)levels were measured.The pathological changes in liver tissue were observed using hematoxylin-eosin(HE)staining.The influence of Ppg on inflammatory cytokines(IL-6,TNF-α,IL-1 β)and key proteins within the associated signaling pathways was examined using enzyme-linked immu-nosorbent assay(ELISA),quantitative polymerase chain reaction(qPCR),and Western blot.Additional-ly,glutathione(GSH),malondialdehyde(MDA),and superoxide dismutase(SOD)activity levels were meas-ured.The expression of markers related to the NF-κB signaling pathway was assessed using qPCR,Western blot,and immunofluorescence.Results In vivo exper-iments showed that Ppg improved the liver and spleen index of mice with drug-induced liver injury,and the levels of AST and ALT in the serum decreased signifi-cantly,reducing the pathological damage of liver tis-sue.In vitro experiments showed that Ppg significantly inhibited the expression of IL-6,TNF-α and IL-1 β,and decreased the levels of GSH and MDA and in-creased SOD activity in AML-12 cells.Additionally,the inhibition of the NF-κB signaling pathway using pyrrolidinedithiocarbamate ammonium(PDTC),an NF-κB signaling pathway inhibitor reduced inflammato-ry cytokine expression and significantly decreased p65 nuclear translocation,showing results comparable to those observed in the high-dose Ppg group.Conclu-sions Ppg alleviates APAP-induced liver injury,po-tentially by inhibiting the NF-κB signaling pathway in hepatocytes,thereby reducing the inflammatory re-sponse and protecting liver from APAP-induced dam-age.