ObjectiveTo explore the molecular mechanism of Sanhuang Xiexintang （SHXXT） in protecting stress gastric ulcer （SGU） in rats through network pharmacology， molecular docking， and animal experiments. MethodThe active ingredients and corresponding targets in SHXXT were collected and screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， Traditional Chinese Medicine Information Database （TCMID）， Bioinformation Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine （BATMAN-TCM）， and Swiss Target Prediction database. SGU-related targets were screened from the Online Mendelian Inheritance in Man （OMIM）， Therapeutic Target Database （TTD）， GeneCards database， and PharmGKB database. Herbal-ingredient-target （H-C-T） network was constructed by using Cytoscape 3.9.1 software. Protein-protein interaction （PPI） of drug and disease intersection targets was analyzed by using the Protein Interaction Platform （STRING） database. Gene ontology （GO） enrichment analysis and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway analysis were conducted through the Database for Annotation Visualization and Integrated Discovery （DAVID）. The active ingredients and key targets were validated using AutodockVina 1.2.2 molecular docking software， and the experimental results were further validated through animal experiments. ResultThe 55 active ingredients were screened， and 255 potential target genes for SHXXT treatment of SGU were predicted. The PPI analysis showed that protein kinase B （Akt）， phosphatase and tensin homolog deleted on chromosome ten （PTEN）， tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， and cyclooxygenase-2 （COX-2） are the core targets of SHXXT for protecting SGU. GO and KEGG analyses showed that SHXXT may affect the development of SGU by regulating various biological processes such as the phosphoinositide 3-kinase （PI3K）/Akt signaling pathway and inflammatory processes. The molecular docking results showed that both the active ingredients and key targets had good binding ability. Animal experiments showed that compared with the blank group， the ulcer index （UI） of the model group was significantly increased （P<0.01）， and the serum levels of TNF-α and IL-1β significantly increased （P<0.01）. The phosphorylation level of PTEN in gastric mucosal tissue was significantly down-regulated （P<0.05）. The phosphorylation levels of PI3K， Akt， and nuclear factor kappa-B （NF-κB） were significantly up-regulated （P<0.05）. Compared with the model group， the UI of the treatment group was significantly reduced （P<0.01）， and the serum levels of TNF-α and IL-1β were significantly reduced （P<0.01）. The phosphorylation level of PTEN in gastric mucosal tissue was significantly up-regulated （P<0.01）， and the phosphorylation levels of PI3K， Akt， and NF-κB were significantly downregulated （P<0.01）. ConclusionThe application of network pharmacology prediction， molecular docking simulation， and animal experimental validation confirms that SHXXT regulates the PI3K/Akt/NF-κB signaling pathway to regulate the inflammatory response of rats and thus protects the gastric mucosa of SGU rats.

Objective:To discuss the effect of sialic acid-binding immunoglobulin-like lectin-15(Siglec15)derived from M2 tumor-associated macrophages(M2-TAMs)on promoting the malignant biological behavior of the esophageal squamous cell carcinoma(ESCC)through bioinformatics analysis,and to validate the findings through cell experiment.Methods:The Tumor Immune Estimation Resource(TIMER)online Database was used to analyze the expression differences and immune infiltration of Siglec15 in pan-cancer and adjacent normal tissues.Real-time fluorescence quantitative PCR(RT-qPCR)method was used to detect the expression levels of Siglec15 mRNA in M2-TAMs and ESCC EC109 and KYSE150 cells.Based on the non-contact co-culture of M2-TAMs and ESCC cells,the following groups were set up,such as EC109/KYSE150 group,EC109/KYSE150+si-NC group(transfected with si-NC sequence),and EC109/KYSE150+si-Siglec15 group(transfected with si-Siglec15#1 and si-Siglec15#2 sequences).CCK-8 method was used to detect the proliferation activities of the cells in various groups;wound healing assay was used to detect the wound healing rates of the cells in various groups;Transwell chamber assay was used to detect the numbers of migration and invasion cells in various groups;flow cytometry was used to detect the apoptotic rates of the cells in various groups.Results:The bioinformatics analysis results showed that compared with adjacent normal tissue,the expression levels of Siglec15 mRNA in pan-cancer tissues such as esophageal cancer,colon cancer,and head and neck squamous cell carcinoma tissues were increased(P＜0.05 or P＜0.01),and the expression level of Siglec15 mRNA in esophageal cancer tissue was significantly positively correlated with the infiltration of the macrophages(P＜0.05).Compared with the EC109 cells and KYSE150 cells,the expression level of Siglec15 mRNA in M2-TAMs was significantly increased(P＜0.01).There was no significant difference in the proliferation rate of the cells among EC109/KYSE150 group,EC109/KYSE150+si-NC group,and EC109/KYSE150+si-Siglec15 group(P＞0.05).Compared with EC109/KYSE150 group,after treated for 24 and 48 h,the wound healing rate of the cells in EC109/KYSE150+si-NC group was increased(P＜0.01),the numbers of migration and invasion cells were increased(P＜0.05),and the apoptotic rate was decreased(P＜0.01).Compared with EC109/KYSE150+si-NC group,the wound healing rates of the cells in EC109/KYSE150+si-Siglec15#1 group and EC109/KYSE150+si-Siglec15#2 group were decreased(P＜0.05),the numbers of migration and invasion cells were decreased(P＜0.05),and the apoptotic rates of the cells had no significant difference(P＞0.05).Conclusion:Siglec15 derived from M2-TAMs may be a key factor in promoting the migration and invasion of the ESCC cells.

Objective To study the infection of multidrug-resistant organism(MDRO)in elderly pa-tients with catheter-associated urinary tract infection(CAUTI)and analyze the infection factors.Methods The medi-cal records of 175 elderly patients with CAUTI admitted to Jiangsu Province Hospital from January 2021 to July 2022 were selected,the distribution of MDRO infection in elderly patients with CAUTI was analyzed,and the influencing factors of MDRO infection were analyzed.The predictive value of independent risk factors for rele-vant nosocomial infections was analyzed by receiver operating characteristics(ROC)curves.Results Among the 175 elderly patients with CAUTI,87 cases(49.71％)developed MDRO infection and were included in the MDRO infection group),and 88 cases(50.29％)had no MDRO infection and were included in the non-MDRO infection group.A total of 432 MDRO pathogens were detected in the MDRO infection group,inclu-ding 415 strains of Gram-negative bacteria,accounting for 96.06％,186 strains of carbapenem-resistant Acine-tobacter baumannii(43.06％),147 strains of carbapenem-resistant Klebsiella pneumoniae(34.03％),79 strains of carbapenem-resistant Pseudomonas aeruginosa(18.29％)and 3 strains of carbapenem-resistant Escherichia coli(0.69％).There were 17 strains of Gram-positive bacteria(3.94％),all of which were methi-cillin-resistant Staphylococcus aureus.Multivariate analysis showed that the use of carbapenems,tigecycline,polymyxin,and days of central venous intubation were considered as independent risk factors.The area under the curve of MDRO infection was 0.883.Conclusion For elderly patients with CAUTI,it is necessary to take strict antimicrobial management measures,master the indications of antimicrobial application,shorten the hos-pitalization time of patients and reduce the incidence of MDRO infection.

Objective To evaluate the effect of manual massage on complications after endoscopic foam sclerotherapy injection for the treatment of internal hemorrhoids.Methods Consecutive 113 patients with grade Ⅰinternal hemorrhoids were prospectively enrolled and completed endoscopic foam sclerotherapy.The patients were randomly divided into a massage group(n=65)and a control group(n=68).Massage group performed manual perianal massage,Visual analogue scale(VAS)was used to evaluate perianal pain.The postoperative bleeding,short-term and long-term efficacy were also compared.Results The median VAS of 24 h postoperation was 1.0(0.0,3.0)in massage group,which was significantly lower than 2.0(1.0,4.0)in control group,the difference was statistically significant(P=0.014).The no bleeding rate of one week postoperation was 84.6％in massage group,which was significantly higher than 64.7％in control group,the difference was statistically significant(P=0.009).After 12 weeks,6 months and 12 months of follow-up,there were no significant differences in cure rate and remission rate between the two groups(P＞0.05).Conclusion Manual massage after endoscopic sclerosing agent injection is beneficial to relieve postoperative pain of grade Ⅰ internal hemorrhoids and reduce bleeding.

Objective To investigate the associations of reproductive health indicators with lung function and chronic obstructive pulmonary disease(COPD)among women aged 40 years and above.Methods From Jul to Sep,2021,female subjects aged 40 years and above were randomly selected from the Shanghai Suburban Adult Cohort and Biobank for COPD screening.A questionnaire was used to obtain information on demographic characteristics and reproductive health indicators.Linear regression was used to analyze the effects of reproductive health indicators on forced vital capacity(FVC)and forced expiratory volume in the first second(FEV1).Logistic regression was also used to analyze the effects of reproductive health factors on FVC as a percentage of the predicted value(FVC%Pred)and FEV1%Pred as well as on COPD.Results A total of 1876 women aged 40 years and above were enrolled with mean age of(62.1±8.2)years old,among them,78.1%were menopausal,and 40.9%had been pregnant≥3 times.Multivariate analysis showed that FVC and FEV1 decreased in postmenopausal women,but menopause was not associated with a decrease in their percentage of predicted values.Pregnancies≥3 times was a risk factor for COPD(for 3 times,OR=4.92,95%CI:1.48-19.95,P<0.05;for≥4 times,OR=9.06,95%CI:2.32-41.57,P<0.01),while pregnancies of 2 times did not increase the risk of COPD.Conclusion In women aged 40 years and above,menopause is associated with poorer FVC and FEV1,and excessive pregnancy(≥3 times)is a risk factor for COPD.

This study aims to improve the solubility and bioavailability of daidzein by preparing the β-cyclodextrin-daidzein/PEG_(20000)/Carbomer_(940) nanocrystals. Specifically, the nanocrystals were prepared with daidzein as a model drug, PEG_(20000), Carbomer_(940), and NaOH as a plasticizer, a gelling agent, and a crosslinking agent, respectively. A two-step method was employed to prepare the β-cyclodextrin-daidzein/PEG_(20000)/Carbomer_(940) nanocystals. First, the insoluble drug daidzein was embedded in β-cyclodextrin to form inclusion complexes, which were then encapsulated in the PEG_(20000)/Carbomer_(940) nanocrystals. The optimal mass fraction of NaOH was determined as 0.8% by the drug release rate, redispersability, SEM morphology, encapsulation rate, and drug loading. The inclusion status of daidzein nanocrystals was determined by Fourier transform infrared spectroscopy(FTIR), thermogravimetric analysis(TGA), and X-ray diffraction(XRD) analysis to verify the feasibility of the preparation. The prepared nanocrystals showed the average Zeta potential of(-30.77±0.15)mV and(-37.47±0.64)mV and the particle sizes of(333.60±3.81)nm and(544.60±7.66)nm before and after daidzein loading, respectively. The irregular distribution of nanocrystals before and after daidzein loading was observed under SEM. The redispersability experiment showed high dispersion efficiency of the nanocrystals. The in vitro dissolution rate of nanocrystals in intestinal fluid was significantly faster than that of daidzein, and followed the first-order drug release kinetic model. XRD, FTIR, and TGA were employed to determine the polycrystalline properties, drug loading, and thermal stability of the nanocrystals before and after drug loading. The nanocrystals loaded with daidzein demonstrated obvious antibacterial effect. The nanocrystals had more significant inhibitory effects on Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa than daidzein because of the improved solubility of daidzein. The prepared nanocrystals can significantly increase the dissolution rate and oral bioavailability of the insoluble drug daidzein.
Sodium Hydroxide ; Acrylic Resins ; Escherichia coli ; Nanoparticles

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

ObjectiveAntibiotic resistance genes （ARGs） have received wide attention all over the world. The purpose of this study was to explore the bacterial community structure， the types and levels of antibiotic resistance genes in a water body in east China， and to compare and analyze the characteristics of microbial species distribution and antibiotic resistance gene distribution in various water environments. MethodsA total of 10 households in Haimen City， Jiangsu Province were selected and their surrounding water environment samples were collected. 21 water samples including river water （4）， Mingou water （9） and well water （8） were collected for metagenomics sequencing， assembled with MetaWRAP， annotated with CARD database， and analyzed with R software. ResultsIn various water bodies， the dominant bacteria phyla was Proteobacteria， the dominant bacteria genera were Deuterostomia， Pseudomonas， Flavobacteriales and Streptomycetaceae. The ARGs annotated were mainly composed of quinolones， aminoglycosides， macrolides and beta-lactams antibiotic resistance genes. The top four relative abundance of resistance genes were macB， RanA， evgS and TxR， The average absolute abundance and expression of resistance genes in well water and Mingou water were higher than those in river water. ConclusionMultiple ARGs are detected to varying degrees in well water， river water， and Mingou water bodies， and the expression of resistance genes in well water and Mingou water bodies is higher than that in river water bodies， possibly due to human production and living activities.

Objective:To investigate the clinical value of magnetic resonance imaging (MRI) based integrated deep learning model for predicting the times of linear staplers used in double stapling technique for middle-low rectal cancer resection.Methods:The retrospective cohort study was conducted. The clinicopathological data of 263 patients who underwent low anterior resection (LAR) for middle-low rectal cancer in Ruijin Hospital of Shanghai Jiaotong University School of Medicine from January 2018 to December 2022 were collected as training dataset. There were 183 males and 80 females, aged 63(55,68)years. The clinicopathological data of 128 patients with middle-low rectal cancer were collected as validation dataset, including 83 males and 45 females, with age as 65(57,70)years. The training dataset was used to construct the prediction model, and the validation dataset was used to validate the prediction model. Observation indicators: (1) clinicopathological features of patients in the training dataset; (2) influencing factors for ≥3 times using of linear staplers in the operation; (3) prediction model construction; (4) efficiency evaluation of prediction model; (5) validation of prediction model. Measurement data with skewed distribution were represented as M( Q1, Q3), and Mann-Whitney U test was used for comparison between groups. Count data were expressed as absolute numbers, and comparison between groups was conducted using the chi-square test. Wilcoxon rank sum test was used for non-parametric data analysis. Univariate analysis was conducted using the Logistic regression model, and multivariate analysis was conducted using the Logistic stepwise regression model. The receiver operating characteristic (ROC) curve was draw and the area under the curve (AUC) was calculated. The AUC of the ROC curve >0.75 indicated the prediction model as acceptable. Comparison of AUC was conducted using the Delong test. Results:(1) Clinicopathological features of patients in the training dataset. Of the 263 patients, there were 48 cases with linear staplers used in the operation ≥3 times and 215 cases with linear staplers used in the operation ≤2 times. Cases with preoperative serum carcinoembryonic antigen (CEA) >5 μg/L, cases with anastomotic leakage, cases with tumor diameter ≥5 cm were 20, 12, 13 in the 48 cases with linear staplers used ≥3 times in the operation, versus 56, 26, 21 in the 215 cases with linear staplers used ≤2 times in the operation, showing significant differences in the above indicators between them ( χ2=4.66, 5.29, 10.45, P<0.05). (2) Influencing factors for ≥3 times using of linear staplers in the operation. Results of multivariate analysis showed that preoperative serum CEA >5 μg/L and tumor diameter ≥5 cm were independent risk factors for ≥3 times using of linear staplers in the operation ( odds ratio=2.26, 3.39, 95% confidence interval as 1.15-4.43, 1.50-7.65, P<0.05). (3) Prediction model construction. According to the results of multivariate analysis, the clinical prediction model was established as Logit(P)=-2.018+0.814×preoperative serum CEA (>5 μg/L as 1, ≤5 μg/L as 0)+ 1.222×tumor diameter (≥5 cm as 1, <5 cm as 0). The image data segmented by the Mask region convolutional neural network (MASK R-CNN) was input into the three-dimensional convolutional neural network (C3D), and the image prediction model was constructed by training. The image data segmented by the MASK R-CNN and the clinical independent risk factors were input into the C3D, and the integrated prediction model was constructed by training. (4) Efficiency evaluation of prediction model. The sensitivity, specificity and accuracy of the clinical prediction model was 70.0%, 81.0% and 79.4%, respectively, with the Yoden index as 0.51. The sensitivity, specificity and accuracy of the image prediction model was 50.0%, 98.3% and 91.2%, respectively, with the Yoden index as 0.48. The sensitivity, specificity and accuracy of the integrated prediction model was 70.0%, 98.3% and 94.1%, respectively, with the Yoden index as 0.68. The AUC of clinical prediction model, image prediction model and integrated prediction model was 0.72(95% confidence interval as 0.61-0.83), 0.81(95% confidence interval as 0.71-0.91) and 0.88(95% confidence interval as 0.81-0.95), respectively. There were significant differences in the efficacy between the integrated prediction model and the image prediction model or the clinical prediction model ( Z=2.98, 2.48, P<0.05). (5) Validation of prediction model. The three prediction models were externally validated by validation dataset. The sensitivity, specificity and accuracy of the clinical prediction model was 62.5%, 66.1% and 65.6%, respectively, with the Yoden index as 0.29. The sensitivity, specificity and accuracy of the image prediction model was 58.8%, 95.5% and 92.1%, respectively, with the Yoden index as 0.64. The sensitivity, specificity and accuracy of the integrated prediction model was 68.8%, 97.3% and 93.8%, respectively, with the Yoden index as 0.66. The AUC of clinical prediction model, image prediction model and integrated prediction model was 0.65(95% confidence interval as 0.55-0.75), 0.75(95% confidence interval as 0.66-0.84) and 0.84(95% confidence interval as 0.74-0.93), respec-tively. There was significant differences in the efficacy between the clinical prediction model and the integrated prediction model ( Z=3.24, P<0.05). Conclusion:The MRI-based deep-learning model can help predicting the high-risk population with ≥3 times using of linear staplers in resection of middle-low rectal cancer with double stapling technique.

Objective To explore the risk factors for intracranial infection in patients after neurosurgery,con-struct and validate a Nomogram prediction model.Methods Data of 978 patients who underwent neurosurgery in a hospital in Nanjing from January 1,2019 to December 31,2022 were retrospectively analyzed.Independent risk fac-tors were screened through logistic univariate and multivariate analyses.Modeling variables were screened through Lasso regression.A Nomogram model was constructed and internally validated by logistic regression.Effectiveness of the model was evaluated with receiver operating characteristic(ROC)curve,calibration curve and decision curve.Results Among 978 patients underwent neurosurgery,293 had postoperative intracranial infection,with an inci-dence of healthcare-associated infection of 29.96％.There was no significant difference in age,gender,proportion of coronary heart disease,cerebral infarction,diabetes and hypertension between the infected group and the non-in-fected group(all P＞0.05).Multivariate logistic analysis showed that postoperative intracranial hypertension,fe-ver,increased neutrophil percentage in blood routine examination,turbid cerebrospinal fluid,positive Pan's test,decreased glucose concentration,abnormal ratio of cerebrospinal fluid/serum glucose,positive microbial culture,absence of indwelling external ventricular drainage tubes,presence of indwelling lumbar cistern drainage tubes,use of immunosuppressive agents,and long duration of surgery were independent risk factors for postoperative intracra-nial infection in patients who underwent neurosurgery(all P＜0.05).Fifteen variables were screened out through Lasso regression.Fourteen variables were finally included for modeling after collinear screening,missing data impu-tation(random forest method)and checking pairwise interaction items.A Nomogram prediction model was con-structed,with the area under ROC curve,sensitivity,specificity,and accuracy of 0.885,0.578,0.896,and 0.704,respectively.Internal validation of the model was conducted.The modeling and validation groups presented similar effects.The calibration curve and decision curve also indicated that the model had good predictive efficacy.Conclusion The constructed Nomogram prediction model for postoperative intracranial infection after neurosurgery is scientific,and the prediction indicators are easy to obtain.The model presents with high stability,reliability,and application value,thus can provide reference for the assessment of postoperative intracranial infection after neuro-surgery.