BACKGROUND: In China, lung cancer remains the cancer with the highest incidence and mortality rate. Among early-stage lung adenocarcinomas (LUAD), the micropapillary (MPP) component is prevalent and typically exhibits high aggressiveness, significantly correlating with early metastasis, lymphatic infiltration, and reduced five-year survival rates. Therefore, the study is to explore the similarities and differences between MPP and non-micropapillary (non-MPP) components in malignant pulmonary nodules characterized by GGOs in early-stage LUAD, identify unique mutational features of the MPP component and analyze the relationship between the ZNF469 gene, a member of the zinc-finger protein family, and the prognosis of early-stage LUAD, as well as its correlation with immune infiltration. METHODS: A total of 31 malignant pulmonary nodules of LUAD were collected and dissected into paired MPP and non-MPP components using microdissection. Whole-exome sequencing (WES) was performed on the components of early-stage malignant pulmonary nodules. Mutational signatures analysis was conducted using R packages such as maftools, Nonnegative Matrix Factorization (NMF), and Sigminer to unveil the genomic mutational characteristics unique to MPP components in invasive LUAD compared to other tumor tissues. Furthermore, we explored the expression of the ZNF469 gene in LUAD using The Cancer Genome Atlas (TCGA) database to investigate its potential association with the prognosis. We also investigated gene interaction networks and signaling pathways related to ZNF469 in LUAD using the GeneMANIA database and conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Lastly, we analyzed the correlation between ZNF469 gene expression and levels of immune cell infiltration in LUAD using the TIMER and TISIDB databases. RESULTS: MPP components exhibited a higher number of genomic variations, particularly the 13th COSMIC (Catalogue of Somatic Mutations in Cancer) mutational signature characterized by the activity of the cytidine deaminase APOBEC family, which was unique to MPP components compared to non-MPP components in tumor tissues. This suggests the potential involvement of APOBEC in the progression of MPP components in early-stage LUAD. Additionally, MPP samples with high similarity to APOBEC signature displayed a higher tumor mutational burden (TMB), indicating that these patients may be more likely to benefit from immunotherapy. The expression of ZNF469 was significantly upregulated in LUAD compared to normal tissue, and was associated with poor prognosis in LUAD patients (P<0.05). Gene interaction network analysis and GO/KEGG enrichment analysis revealed that COL6A1, COL1A1, COL1A2, TGFB2, MMP2, COL8A2 and C2CD4C interacted with ZNF469 and were mainly involved in encoding collagen proteins and participating in the constitution of extracellular matrix. ZNF469 expression was positively correlated with immune cell infiltration in LUAD (P<0.05). CONCLUSIONS The study has unveiled distinctive mutational signatures in the MPP components of early-stage invasive LUAD in the Asian population. Furthermore, we have identified that the elevated expression of mutated ZNF469 impacts the prognosis and immune infiltration in LUAD, suggesting its potential as a diagnostic and prognostic biomarker in LUAD.
Humans ; Lung Neoplasms/genetics* ; Adenocarcinoma of Lung/genetics* ; China ; Prognosis ; Transcription Factors

Objective:To report the results of national surveillance on the distribution and antimicrobial resistance profile of clinical Gram-negative bacteria isolates from bloodstream infections in China in 2022.Methods:The clinical isolates of Gram-negative bacteria from blood cultures in member hospitals of national bloodstream infection Bacterial Resistant Investigation Collaborative System（BRICS）were collected during January 2022 to December 2022. Antibiotic susceptibility tests were conducted by agar dilution or broth dilution methods recommended by Clinical and Laboratory Standards Institute（CLSI）. WHONET 5.6 and SPSS 25.0 software were used to analyze the data.Results:During the study period，9 035 strains of Gram-negative bacteria were collected from 51 hospitals，of which 7 895（87.4%）were Enterobacteriaceae and 1 140（12.6%）were non-fermenting bacteria. The top 5 bacterial species were Escherichia coli（ n=4 510，49.9%）， Klebsiella pneumoniae（ n=2 340，25.9%）， Pseudomonas aeruginosa（ n=534，5.9%）， Acinetobacter baumannii complex（ n=405，4.5%）and Enterobacter cloacae（ n=327，3.6%）. The ESBLs-producing rates in Escherichia coli， Klebsiella pneumoniae and Proteus spp. were 47.1%（2 095/4 452），21.0%（427/2 033）and 41.1%（58/141），respectively. The prevalence of carbapenem-resistant Escherichia coli（CREC）and carbapenem-resistant Klebsiella pneumoniae（CRKP）were 1.3%（58/4 510）and 13.1%（307/2 340）；62.1%（36/58）and 9.8%（30/307）of CREC and CRKP were resistant to ceftazidime/avibactam combination，respectively. The prevalence of carbapenem-resistant Acinetobacter baumannii（CRAB）complex was 59.5%（241/405），while less than 5% of Acinetobacter baumannii complex was resistant to tigecycline and polymyxin B. The prevalence of carbapenem-resistant Pseudomonas aeruginosa（CRPA）was 18.4%（98/534）. There were differences in the composition ratio of Gram-negative bacteria in bloodstream infections and the prevalence of main Gram-negative bacteria resistance among different regions，with statistically significant differences in the prevalence of CRKP and CRPA（ χ2=20.489 and 20.252， P<0.001）. The prevalence of CREC，CRKP，CRPA，CRAB，ESBLs-producing Escherichia coli and Klebsiella pneumoniae were higher in provinicial hospitals than those in municipal hospitals（ χ2=11.953，81.183，10.404，5.915，12.415 and 6.459， P<0.01 or <0.05），while the prevalence of CRPA was higher in economically developed regions（per capita GDP ≥ 92 059 Yuan）than that in economically less-developed regions（per capita GDP <92 059 Yuan）（ χ2=6.240， P=0.012）. Conclusions:The proportion of Gram-negative bacteria in bloodstream infections shows an increasing trend，and Escherichia coli is ranked in the top，while the trend of CRKP decreases continuously with time. Decreasing trends are noted in ESBLs-producing Escherichia coli and Klebsiella pneumoniae. Low prevalence of carbapenem resistance in Escherichia coli and high prevalence in CRAB complex have been observed. The composition ratio and antibacterial spectrum of bloodstream infections in different regions of China are slightly different，and the proportion of main drug resistant bacteria in provincial hospitals is higher than those in municipal hospitals.

Objective:To report the results of national surveillance on the distribution and antimicrobial resistance profile of clinical Gram-positive bacteria isolates from bloodstream infections in China in 2022.Methods:The clinical isolates of Gram-positive bacteria from blood cultures in member hospitals of National Bloodstream Infection Bacterial Resistant Investigation Collaborative System（BRICS）were collected during January 2022 to December 2022. Antibiotic susceptibility tests were conducted by agar dilution or broth dilution methods recommended by Clinical and Laboratory Standards Institute（CLSI）. WHONET 5.6 and SPSS 25.0 software were used to analyze the data.Results:A total of 3 163 strains of Gram-positive pathogens were collected from 51 member units，and the top five bacteria were Staphylococcus aureus（ n=1 147，36.3%），coagulase-negative Staphylococci（ n=928，29.3%）， Enterococcus faecalis（ n=369，11.7%）， Enterococcus faecium（ n=296，9.4%）and alpha-hemolyticus Streptococci（ n=192，6.1%）. The detection rates of methicillin-resistant Staphylococcus aureus（MRSA）and methicillin-resistant coagulase-negative Staphylococci（MRCNS）were 26.4%（303/1 147）and 66.7%（619/928），respectively. No glycopeptide and daptomycin-resistant Staphylococci were detected. The sensitivity rates of Staphylococcus aureus to cefpirome，rifampin，compound sulfamethoxazole，linezolid，minocycline and tigecycline were all >95.0%. Enterococcus faecium was more prevalent than Enterococcus faecalis. The resistance rates of Enterococcus faecium to vancomycin and teicoplanin were both 0.5%（2/369），and no vancomycin-resistant Enterococcus faecium was detected. The detection rate of MRSA in southern China was significantly lower than that in other regions（ χ2=14.578， P=0.002），while the detection rate of MRCNS in northern China was significantly higher than that in other regions（ χ2=15.195， P=0.002）. The detection rates of MRSA and MRCNS in provincial hospitals were higher than those in municipal hospitals（ χ2=13.519 and 12.136， P<0.001）. The detection rates of MRSA and MRCNS in economically more advanced regions（per capita GDP≥92 059 Yuan in 2022）were higher than those in economically less advanced regions（per capita GDP<92 059 Yuan）（ χ2=9.969 and 7.606， P=0.002和0.006）. Conclusions:Among the Gram-positive pathogens causing bloodstream infections in China， Staphylococci is the most common while the MRSA incidence decreases continuously with time；the detection rate of Enterococcus faecium exceeds that of Enterococcus faecalis. The overall prevalence of vancomycin-resistant Enterococci is still at a low level. The composition ratio of Gram-positive pathogens and resistant profiles varies slightly across regions of China，with the prevalence of MRSA and MRCNS being more pronounced in provincial hospitals and areas with a per capita GDP≥92 059 yuan.

Objective:To compare the therapeutic effects of 0.05% cyclosporine and 0.1% fluorometholone eye drops in patients with moderate and severe dry eye.Methods:A randomized controlled study was conducted.Fifty-two patients (52 eyes) with moderate to severe dry eye in Tianjin Medical University Eye Hospital from August 2021 to December 2022 were enrolled and randomly divided into 0.05% cyclosporine group and 0.1% fluorometholone group by random number table method, with 26 cases (26 eyes) in each group.Patients received 0.05% cyclosporine eye drops (2 times/day) and 0.1% fluorometholone eye drops (2 times/day) combined with calf blood deproteinized extract eye drops (4 times/day) according to the grouping.Before and 1, 3 and 6 months after treatment, clinical symptoms and signs were observed and Ocular Surface Disease Index (OSDI) score, corneal fluorescein staining (CFS) score, Schirmer Ⅰ test (SⅠT), non-invasive first tear film break-up time (NIBUTf), and conjunctival goblet cell (CGC) density were recorded.Before treatment and after 6 months of treatment, changes in corneal nerves and dendritic cells (DC) were observed by in vivo confocal microscopy (IVCM).This study adhered to the Declaration of Helsinki and was approved by the Medical Ethics Committee of Eye Hospital of Tianjin Medical University (No.2021KY-17).Written informed consent was obtained from each subject. Results:Compared with the 0.1% fluorometholone group, CFS score decreased after 1 month of treatment, but SⅠT, NIBUTf and CFS score increased after 3 months of treatment, and OSDI score, SⅠT and CFS score decreased after 6 months of treatment in the 0.05% cyclosporine group, showing statistically significant differences (all at P<0.05).Compared with baseline, in the 0.05% cyclosporine group, NIBUTf increased and CFS score decreased after 1 month of treatment, OSDI score and CFS score decreased, SⅠT and NIBUTf increased after 3 and 6 months of treatment, showing statistically significant differences (all at P<0.05).In the 0.1% fluorometholone group, CFS score decreased after 3 months of treatment, OSDI score and CFS score decreased, SⅠT increased after 6 months of treatment compared to baseline, showing statistically significant differences (all at P<0.05).OSDI score and CFS score decreased, SⅠT increased after 6 months of treatment compared to 3 months of treatment in the 0.05% cyclosporine group, and the differences were statistically significant (all at P<0.05).Baseline and CGC densities after 1, 3 and 6 months of treatment were (147.66±17.29), (195.44±15.46), (210.36±19.15) and (282.09±22.63)cells/mm 2 in the 0.05% cyclosporine group and (138.09±17.29), (95.67±15.46), (117.77±19.15) and (109.13±22.63)cells/mm 2 in the 0.1% fluorometholone group, respectively, with a statistically significant overall difference ( Fgroup=11.724, P<0.001; Ftime=4.837, P=0.005).Compared with the 0.1% fluorometholone group, CGC density in the 0.05% cyclosporine group increased after 1, 3 and 6 months of treatment, with statistically significant differences (all at P<0.05).Compared with baseline, the CGC density increased in the 0.05% cyclosporine group after 1, 3 and 6 months of treatment, and the differences were statistically significant (all at P<0.05).Compared with the 0.1% fluorometholone group, the corneal nerve fiber density in the 0.05% cyclosporine group increased after 6 months of treatment, and corneal DC density, area and dendrite number decreased, showing statistically significant differences (all at P<0.05). Conclusions:Cyclosporine 0.05% eye drops combined with calf blood deproteinized extract eye drops can improve symptoms and signs in patients with moderate to severe dry eye, and the long-term effect is better than that of 0.1% fluorometholone plus calf blood deproteinized extract eye drops.

Objective To monitor the susceptibility of clinical isolates to antimicrobial agents in tertiary hospitals in major regions of China in 2022.Methods Clinical isolates from 58 hospitals in China were tested for antimicrobial susceptibility using a unified protocol based on disc diffusion method or automated testing systems.Results were interpreted using the 2022 Clinical &Laboratory Standards Institute(CLSI)breakpoints.Results A total of 318 013 clinical isolates were collected from January 1,2022 to December 31,2022,of which 29.5％were gram-positive and 70.5％were gram-negative.The prevalence of methicillin-resistant strains in Staphylococcus aureus,Staphylococcus epidermidis and other coagulase-negative Staphylococcus species(excluding Staphylococcus pseudintermedius and Staphylococcus schleiferi)was 28.3％,76.7％and 77.9％,respectively.Overall,94.0％of MRSA strains were susceptible to trimethoprim-sulfamethoxazole and 90.8％of MRSE strains were susceptible to rifampicin.No vancomycin-resistant strains were found.Enterococcus faecalis showed significantly lower resistance rates to most antimicrobial agents tested than Enterococcus faecium.A few vancomycin-resistant strains were identified in both E.faecalis and E.faecium.The prevalence of penicillin-susceptible Streptococcus pneumoniae was 94.2％in the isolates from children and 95.7％in the isolates from adults.The resistance rate to carbapenems was lower than 13.1％in most Enterobacterales species except for Klebsiella,21.7％-23.1％of which were resistant to carbapenems.Most Enterobacterales isolates were highly susceptible to tigecycline,colistin and polymyxin B,with resistance rates ranging from 0.1％to 13.3％.The prevalence of meropenem-resistant strains decreased from 23.5％in 2019 to 18.0％in 2022 in Pseudomonas aeruginosa,and decreased from 79.0％in 2019 to 72.5％in 2022 in Acinetobacter baumannii.Conclusions The resistance of clinical isolates to the commonly used antimicrobial agents is still increasing in tertiary hospitals.However,the prevalence of important carbapenem-resistant organisms such as carbapenem-resistant K.pneumoniae,P.aeruginosa,and A.baumannii showed a downward trend in recent years.This finding suggests that the strategy of combining antimicrobial resistance surveillance with multidisciplinary concerted action works well in curbing the spread of resistant bacteria.

Enteropathogenic Escherichia coli(EPEC),a zoonotic foodborne pathogen,can induce severe and prolonged di-arrhea,thus substantially affecting global public health safety.To understand the pathogenicity of EPEC and its potential risk to human health,this study investigated the antimicrobial resistance and genome-wide characteristics of EPEC originating from ducks.After identification of EPEC with the plate method and PCR,antimicrobial susceptibility of the isolates was examined with the microbroth dilution method.In addition,analyses of serotype,sequence type(ST),and plasmid incompatibility groups were conducted with whole-genome sequencing(WGS)and bioinformatic methods.Ten EPEC isolates were identified,including serotypes O71∶H40 and O3∶H21.All EPEC strains exhibited multiple drug resistance.The highest proportion of resistance(100％)was observed to ciprofloxacin,streptomycin,tetracycline,and polymyxin B.In contrast,the isolates showed susceptibility to cefoxitin,amikacin,and imipenem.Furthermore,all strains carried the tetracycline resistance gene tet(A)and extended-spectrum β-lactamase(ESBL)resistance genes,including blaOXA-10,blaTEM-1A,and blaTEM-1B.Various virulence genes,associated primarily with the secretory system,were de-tected in the isolates.However,no bf p genes or per ARC genes were identified,thus indicating that the EPEC isolates were atypical EPEC(aEPEC).The results demonstrated the presence of multiple antimicrobial resistance,multiple resistance and viru-lence genes,and various plasmid incompatibility groups,thus in-dicating potential pathogenicity to humans.Strengthened monitoring of duck-derived EPEC is crucial to effectively control the spread of the pathogen and safeguard public health.

Objective:To evaluate the clinical and prognostic value of prothrombin time(PT)and activated partial thromboplastin time(APTT)in newly diagnosed patients with multiple myeloma(MM).Methods:The clinical data of 116 newly diagnosed MM patients in the Second Hospital and Third Hospital of Shanxi Medical University from October 2014 to March 2022 were analyzed retrospectively,and the patients were divided into two groups:normal PT and APTT group and prolonged PT or APTT group.The differences in sex,age,classification,staging,bleeding events,laboratory indicators[including hemoglobin(Hb),platelet count(PLT),serum calcium,serum albumin(ALB),lactate dehydrogenase(LDH),serum creatinine and β 2-microglobulin],and cytogenetic characteristics between the two groups of patients were compared.The effect of prolonged PT or APTT on survival of patients with MM was analyzed.Results:Compared with patients in normal PT and APTT group,patients in prolonged PT or APTT group were more likely to experience bleeding events(x2=5.087,P=0.024),with lower ALB levels(x2=4.962,P=0.026)and PLT levels(x2=4.309,P=0.038),and higher serum calcium levels(x2=5.056,P=0.025).The positive rates of del17p,del13q and 1q21+in prolonged PT or APTT group were higher than those in normal PT and APTT group,but the difference was not statistically significant(P＞0.05).K-M survival analysis showed that the prolonged PT or APTT group had a shorter median progression-free survival(PFS)(P=0.032)and overall survival(OS)(P=0.032).Multivariate Cox analysis showed that prolonged PT or APTT(HR=2.1 16,95％CI:1.025-4.372,P=0.043)and age ≥65 years(HR=2.403,95％CI:1.195-4.836,P=0.014)were independent risk factor for OS in newly diagnosed MM patients.However,prolonged PT or APTT had no significant effect on PFS of newly diagnosed MM patients(HR=1.162,95％CI:0.666-2.026,P=0.597).Conclusion:Newly diagnosed MM patients with prolonged PT or APTT have worse clinical indicators,shorter PFS and OS.Prolonged PT or APTT is an independent risk factor for OS in MM patients.

Objective To compare the efficacy and safety of vedolizumab(VDZ)and infliximab(IFX)for moderate to severe ulcerative colitis(UC)patients through a multicenter retrospective cohort study.Methods All patients with moderate to severe UC who were naive to biologic agents and treated with IFX or VDZ for at least 14 weeks at 3 hospitals in Southwest China between January 2021 and January 2023 were retrospectively enrolled.The efficacy evaluation indicators,including steroid-free clinical remission rates,clinical remission rates and endoscopic remission rates at weeks 14 and 52 were compared between the 2 groups.The occurrence of adverse events during treatment were recorded.Taking whether mucosal healing could be achieved after 14 and 52 weeks of treatment as the dependent variable,firstly,univariate analysis was performed to analyze the risk factors affecting mucosal healing at weeks 14 and 52,and then multivariate logistic regression analysis was applied to identify the independent risk factors of mucosal healing at the 2 time points.Results A total of 151 patients with moderate to severe UC were included,after propensity score matching(PSM),each group included 57 patients.There were no significant differences in the steroid-free clinical remission rate and clinical remission rate between the 2 groups at weeks 14 and 52(P＞0.05).The endoscopic remission rate at week 14 was significantly higher in the VDZ group than the IFX group[40.4％(23/57)vs 22.8％(13/57),P=0.044],but no such difference was observed at week 52[64.5％(20/31)vs 59.5％(22/37),P=0.669].Multivariate logistic regression analysis showed that left-sided disease(E2)[vs pancolitis(E3)](OR=0.46,95％CI:0.21～0.98,P=0.045)was independent risk factor for mucosal healing at week 14 and a disease duration ≥36 months(OR=0.25,95％CI:0.09～0.66,P=0.005)was independent risk factor for mucosal healing at week 52.No statistical difference was observed in the incidence of adverse events between the 2 groups(1.8％vs 7.0％,P=0.360).Conclusion VDZ and IFX have similar efficacy and safety,and both can be used as first-line options for patients with moderate to severe UC.

Background: Triglyceride glucose (TyG) and TyG-body mass index (TyG-BMI) are reliable surrogate indices of insulin resistance and used for risk stratification and outcome prediction in patients with atherosclerotic cardiovascular disease (ASCVD). Here, we inserted estimated average glucose (eAG) into the TyG (TyAG) and TyG-BMI (TyAG-BMI) as derived parameters and explored their clinical significance in cardiovascular risk prediction. Methods: This was a population-based cohort study of 9,944 Chinese patients with ASCVD. The baseline admission fasting glucose and A1C-derived eAG values were recorded. Cardiovascular events (CVEs) that occurred during an average of 38.5 months of follow-up were recorded. We stratified the patients into four groups by quartiles of the parameters. Baseline data and outcomes were analyzed. Results: Distribution of the TyAG and TyAG-BMI indices shifted slightly toward higher values (the right side) compared with TyG and TyG-BMI, respectively. The baseline levels of cardiovascular risk factors and coronary severity increased with quartile of TyG, TyAG, TyG-BMI, and TyAG-BMI (all P<0.001). The multivariate-adjusted hazard ratios for CVEs when the highest and lowest quartiles were compared from low to high were 1.02 (95% confidence interval [CI], 0.77 to 1.36; TyG), 1.29 (95% CI, 0.97 to 1.73; TyAG), 1.59 (95% CI, 1.01 to 2.58; TyG-BMI), and 1.91 (95% CI, 1.16 to 3.15; TyAG-BMI). The latter two showed statistical significance. Conclusion This study suggests that TyAG and TyAG-BMI exhibit more information than TyG and TyG-BMI in disease progression among patients with ASCVD. The TyAG-BMI index provided better predictive performance for CVEs than other parameters.

Background: Triglyceride glucose (TyG) and TyG-body mass index (TyG-BMI) are reliable surrogate indices of insulin resistance and used for risk stratification and outcome prediction in patients with atherosclerotic cardiovascular disease (ASCVD). Here, we inserted estimated average glucose (eAG) into the TyG (TyAG) and TyG-BMI (TyAG-BMI) as derived parameters and explored their clinical significance in cardiovascular risk prediction. Methods: This was a population-based cohort study of 9,944 Chinese patients with ASCVD. The baseline admission fasting glucose and A1C-derived eAG values were recorded. Cardiovascular events (CVEs) that occurred during an average of 38.5 months of follow-up were recorded. We stratified the patients into four groups by quartiles of the parameters. Baseline data and outcomes were analyzed. Results: Distribution of the TyAG and TyAG-BMI indices shifted slightly toward higher values (the right side) compared with TyG and TyG-BMI, respectively. The baseline levels of cardiovascular risk factors and coronary severity increased with quartile of TyG, TyAG, TyG-BMI, and TyAG-BMI (all P<0.001). The multivariate-adjusted hazard ratios for CVEs when the highest and lowest quartiles were compared from low to high were 1.02 (95% confidence interval [CI], 0.77 to 1.36; TyG), 1.29 (95% CI, 0.97 to 1.73; TyAG), 1.59 (95% CI, 1.01 to 2.58; TyG-BMI), and 1.91 (95% CI, 1.16 to 3.15; TyAG-BMI). The latter two showed statistical significance. Conclusion This study suggests that TyAG and TyAG-BMI exhibit more information than TyG and TyG-BMI in disease progression among patients with ASCVD. The TyAG-BMI index provided better predictive performance for CVEs than other parameters.