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 evaluate the association between preoperative serum β 2-microglobulin (β 2MG) concentrations and postoperative delirium (POD) in elderly patients. Methods:The study selected patients who underwent knee or hip arthroplasty under spinal-epidural anesthesia on an elective basis at Qingdao Municipal Hospital from May 2021 to November 2022. The patients were divided into a POD group and a non-POD group based on the occurrence of POD. The study was conducted as part of the Perioperative Neurocognitive Impairment and Biomarkers Lifestyle Cohort, which was a nested case-control study. The study collected baseline data from two groups of patients and analyzed the differences between them. Logistic regression was used to identify the risk factors for POD. The stability of the regression model was tested using sensitivity analysis. The mediation model was used to examine whether cerebrospinal fluid (CSF) biomarkers mediated the relationship between β 2MG and POD. The receiver operating characteristic curve was drawn and the area under the curve was calculated to evaluate the accuracy of preoperative β 2MG concentrations and CSF biomarker concentration in predicting POD. Results:There were 57 cases in POD group and 449 cases in non-POD group. The results of logistic regression analysis showed that the increased β 2MG and CSF total tau protein (t-tau) concentrations were risk factors for POD, and the increased CSF β-amyloid 42 concentration was a protective factor for POD after adjustment for multiple confounders such as age, gender, education, Mini-Mental State Examination, history of hypertension and infusion volume ( P<0.05). The results of mediation analysis showed that the serum β 2MG′s effect on POD was partly mediated by t-tau (18.1%). The results of the receiver operating characteristic curve showed that the area under the curve of the β 2MG concentration combined with the CSF biomarker concentration was 0.742. Conclusions:Elevated preoperative serum β 2MG concentration is a risk factor for POD in elderly patients, and the relationship may be partly mediated by CSF t-tau.

Objective:To observe the clinical efficacy and safety of Tongren Niuhuang Qingxin Pills combined with telmisartan tablets in the treatment of hypertensive vertigo syndrome of phlegm-heat disturbance.Methods:Randomized controlled trial was conducted. Totally 80 patients with hypertension vertigo and phlegm-heat disturbance syndrome were selected from March 2021 to August 2022 at Beijing Tongrentang Hospital of Traditional Chinese Medicine as the observation objects. They were randomly divided into two groups using a random number table method, with 40 cases in each group. The control group received oral telmisartan tablets, while the experimental group received Tongren Niuhuang Qingxin Pills in addition to the control group. Both groups were treated for 28 days and followed up for 1 month. The patients' room blood pressure before and after treatment was measured, and TCM syndrome scores were evaluated. The dizziness assessment rating scale (DARS) was used to evaluate the severity of dizziness, adverse reactions during treatment were recorded, drug safety was observed, and clinical efficacy was evaluated.Results:The total effective rate of the experimental group was 85.0% (34/40), and that of the control group was 7.5% (3/40), with statistical significance between the two groups ( χ2=48.32, P<0.001). Compared with before treatment, the experimental group had SBP [(136.63 ± 6.01) mmHg vs. (159.30 ± 9.01) mmHg, t=-21.00] and DBP [(84.48 ± 4.36) mmHg vs. (95.30 ± 3.75) mmHg, t=-13.80] after treatment; after treatment, SBP [(137.34 ± 6.39) mmHg vs. (158.00 ± 10.06) mmHg, t=-5.28] and DBP [(86.08 ± 4.43) mmHg vs. (95.18 ± 6.61) mmHg, t=-8.09] decreased in the control group ( P<0.01), but there was no statistical significance between the two groups after treatment ( P>0.05). After treatment, the TCM syndrome scores in the experimental group (8.68 ± 3.39 vs. 15.12 ± 3.03, Z=-6.61) were lower than those in the control group ( P<0.001), and DARS score [(8.53 ± 3.93) vs. (12.20 ± 3.95), Z=-3.63] was lower than that in the control group ( P<0.001). After treatment, the therapeutic effect index of TCM syndromes in the experimental group improved compared to before treatment in the same group. The therapeutic effect index of each symptom, from high to low, was as follows: rotation of oneself or visual objects>numbness of limbs>dry stool>dizziness and dizziness>liking cold drinks>bitter and dry mouth>red urine>red tongue, yellow coating, and greasy tongue>vomiting sticky and turbid phlegm>tinnitus>smooth pulse. There were no significant adverse reactions during the treatment of the two groups. Conclusion:Tongren Niuhuang Qingxin Pills combined with telmisartan can reduce the blood pressure of patients with hypertensive vertigo syndrome of phlegm-heat disturbance, improve the vertigo symptoms and TCM syndromes of patients, and the efficacy evaluation is superior to that of telmisartan alone.

Objective To explore the cut-off value of three dimensional(3D)vena contracta area(VCA)in diagnosing severe tricuspid regrugitation(TR)under different etiologies and its accuracy and practicality in clinical application.Methods From Mar 2019 to May 2021,ninety-two patients with confirmed TR underwent two dimensional(2D)and 3D transthoracic echocardiography.The correlation and consistency between 3D VCA 3D calculated based on the proximal isokinetic surface area(PISA)effective regurgitant orifice area(EROA)was calculated.Comprehensive 2D multi-parameter method was used as a reference method to calculate the cut-off value of the diagnosis of severe TR.Results A total of 85 patients were ultimately included.3D VCA and 3D PISA EROA had similar and acceptable correlations in both primary TR and secondary TR(primary TR:r=0.831,P<0.01;secondary TR:r=0.806,P<0.01).Bland-Altman analysis showed that 3D VCA overestimated TR compared with 3D PISA EROA(62%overestimated in the total patient population,51%overestimated in primary TR,and 74%overestimated in secondary TR).In secondary TR,the cut-off value of 3D VCA for diagnosing severe TR was 0.45 cm2(sensitivity 89%,specificity 82%);combining clinical symptoms,positive 2D PISA EROA results and 3D VCA results for severe TR,the chi-square value was higher than those only included clinical symptoms or incorporated clinical symptoms and positive 2D PISA EROA results(42.168 vs.26.059 and 16.759,P<0.01).Conclusion 3D VCA would overestimate TR,and had high and incremental diagnostic value for evaluating severe TR in secondary TR.

Hip fracture in the elderly is characterized by high incidence, high disability rate, and high mortality and has been recognized as a public health issue threatening their health. Surgery is the preferred choice for the treatment of elderly patients with hip fracture. However, lower extremity deep venous thrombosis (DVT) has an extremely high incidence rate during the perioperative period, and may significantly increase the risk of patients′ death once it progresses to pulmonary embolism. In response to this issue, the clinical guidelines and expert consensuses all emphasize active application of comprehensive preventive measures, including basic prevention, physical prevention, and pharmacological prevention. In this prevention system, basic prevention is the basis of physical and pharmacological prevention. However,there is a lack of unified and definite recommendations for basic preventive measures in clinical practice. To this end, the Orthopedic Nursing Professional Committee of the Chinese Nursing Association and Nursing Department of the Orthopedic Branch of the China International Exchange and Promotive Association for Medical and Health Care organized relevant nursing experts to formulate Expert consensus on perioperative basic prevention for lower extremity deep venous thrombosis in elderly patients with hip fracture ( version 2024) . A total of 10 recommendations were proposed, aiming to standardize the basic preventive measures for lower extremity DVT in elderly patients with hip fractures during the perioperative period and promote their subsequent rehabilitation.

Objective:To explore the application of COVID-19-specific IgG antibody in identifying epidemic Omicron BA.5 strain infection.Method:Omicron BF.7/BA.5 naturally infected population, healthy population vaccinated with the COVID-19 vaccine, and Omicron BF.7/BA.5 breakthrough cases were enrolled into this study. The serum WT-S-IgG and BA.5-S-IgG were detected by indirect ELISA, and the serum-specific IgG antibody levels of different populations were compared. The application value of the two antibody titers and the ratio of the two antibodies in identifying Omicron BA.5 epidemic strain infection were explored by the ROC curve, aiming to provide technical support for pathogen diagnosis.Results:The antibody titers of WT-S-IgG and BA.5-S-IgG in the breakthrough cases were higher than those in the naturally infected population and the healthy population ( P<0.05). The area under the curve (AUC) of WT-S-IgG and BA.5-S-IgG in identifying epidemic Omicron BA.5 strain infection was 0.947 and 0.961, respectively. The AUC of BA.5-S-IgG and WT-S-IgG antibody titer ratio was 0.873. When the antibody titer ratio was 0.855, the sensitivity and specificity were 80.00% and 90.00%, respectively. According to the interval since the last infection, the AUC of the ratio of BA.5-S-IgG to WT-S-IgG antibody titer to identify the infection of epidemic strains less than 30 days and more than 30 days was 0.887 and 0.863, respectively, and the sensitivity and specificity were both above 80%. Conclusion:Both BA.5-S-IgG and WT-S-IgG, as well as the combination of these two antibodies, are of high value in the identification of epidemic strains.

Objective:To explore the application of COVID-19-specific IgG antibody in identifying epidemic Omicron BA.5 strain infection.Method:Omicron BF.7/BA.5 naturally infected population, healthy population vaccinated with the COVID-19 vaccine, and Omicron BF.7/BA.5 breakthrough cases were enrolled into this study. The serum WT-S-IgG and BA.5-S-IgG were detected by indirect ELISA, and the serum-specific IgG antibody levels of different populations were compared. The application value of the two antibody titers and the ratio of the two antibodies in identifying Omicron BA.5 epidemic strain infection were explored by the ROC curve, aiming to provide technical support for pathogen diagnosis.Results:The antibody titers of WT-S-IgG and BA.5-S-IgG in the breakthrough cases were higher than those in the naturally infected population and the healthy population ( P<0.05). The area under the curve (AUC) of WT-S-IgG and BA.5-S-IgG in identifying epidemic Omicron BA.5 strain infection was 0.947 and 0.961, respectively. The AUC of BA.5-S-IgG and WT-S-IgG antibody titer ratio was 0.873. When the antibody titer ratio was 0.855, the sensitivity and specificity were 80.00% and 90.00%, respectively. According to the interval since the last infection, the AUC of the ratio of BA.5-S-IgG to WT-S-IgG antibody titer to identify the infection of epidemic strains less than 30 days and more than 30 days was 0.887 and 0.863, respectively, and the sensitivity and specificity were both above 80%. Conclusion:Both BA.5-S-IgG and WT-S-IgG, as well as the combination of these two antibodies, are of high value in the identification of epidemic strains.

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 investigate the clinical features and therapeutic efficacy of patients with hereditary leiomyomatosis and renal cell carcinoma(RCC) syndrome-associated RCC (HLRCC-RCC) in China.Methods:The clinical data of 119 HLRCC-RCC patients with fumarate hydratase (FH) germline mutation confirmed by genetic diagnosis from 15 medical centers nationwide from January 2008 to December 2021 were retrospectively analyzed. Among them, 73 were male and 46 were female. The median age was 38(13, 74) years. The median tumor diameter was 6.5 (1.0, 20.5) cm. There were 38 cases (31.9%) in stage Ⅰ-Ⅱand 81 cases (68.1%) in stage Ⅲ-Ⅳ. In this group, only 11 of 119 HLRCC-RCC patients presented with skin smooth muscle tumors, and 44 of 46 female HLRCC-RCC patients had a history of uterine fibroids. The pathological characteristics, treatment methods, prognosis and survival of the patients were summarized.Results:A total of 86 patients underwent surgical treatment, including 70 cases of radical nephrectomy, 5 cases of partial nephrectomy, and 11 cases of reductive nephrectomy. The other 33 patients with newly diagnosed metastasis underwent renal puncture biopsy. The results of genetic testing showed that 94 patients had FH gene point mutation, 18 had FH gene insertion/deletion mutation, 4 had FH gene splicing mutation, 2 had FH gene large fragment deletion and 1 had FH gene copy number mutation. Immunohistochemical staining showed strong 2-succinocysteine (2-SC) positive and FH negative in 113 patients. A total of 102 patients received systematic treatment, including 44 newly diagnosed patients with metastasis and 58 patients with postoperative metastasis. Among them, 33 patients were treated with tyrosine kinase inhibitor (TKI) combined with immune checkpoint inhibitor (ICI), 8 patients were treated with bevacizumab combined with erlotinib, and 61 patients were treated with TKI monotherapy. Survival analysis showed that the median progression-free survival (PFS) of TKI combined with ICI was 18 (5, 38) months, and the median overall survival (OS) was not reached. The median PFS and OS were 12 (5, 14) months and 30 (10, 32) months in the bevacizumab combined with erlotinib treatment group, respectively. The median PFS and OS were 10 (3, 64) months and 44 (10, 74) months in the TKI monotherapy group, respectively. PFS ( P=0.009) and OS ( P=0.006) in TKI combined with ICI group were better than those in bevacizumab combined with erlotinib group. The median PFS ( P=0.003) and median OS ( P=0.028) in TKI combined with ICI group were better than those in TKI monotherapy group. Conclusions:HLRCC-RCC is rare but has a high degree of malignancy, poor prognosis and familial genetic characteristics. Immunohistochemical staining with strong positive 2-SC and negative FH can provide an important basis for clinical diagnosis. Genetic detection of FH gene germ line mutation can confirm the diagnosis. The preliminary study results confirmed that TKI combined with ICI had a good clinical effect, but it needs to be confirmed by the results of a large sample multi-center randomized controlled clinical study.