OBJECTIVE To evaluate the cost-utility of enfortumab vedotin combined with pembrolizumab （PemEV） versus gemcitabine combined with cisplatin or carboplatin （GP） in the first-line treatment of advanced urothelial carcinoma （aUC）. METHODS From the perspective of China’s health system， a dynamic Markov model was established based on the pan-Asian subgroup data from the EV-302 trial. The study timeframe was set at 20 years， with a cycle length of 21 days and a discount rate of 5%. Using total direct medical costs and quality-adjusted life years （QALYs） as outcome measures， the incremental cost- effectiveness ratio （ICER） of the PemEV regimen compared to the GP regimen was calculated. The robustness of the model was validated through sensitivity analysis and scenario analysis， and the price thresholds for enfortumab vedotin and pembrolizumab were estimated under conditions where the PemEV regimen was more cost-effective compared to the GP regimen. RESULTS Cost- utility analysis indicated that compared to the GP regimen， PemEV regimen could generate an additional 2.602 QALYs in aUC patients， but the treatment cost increased by 3 339 703.56 yuan， with an ICER of 1 283 554.39 yuan/QALY. This figure significantly exceeded the willingness-to-pay （WTP） threshold （3 times China’s gross domestic product per capita in 2024， 287 247 yuan/QALY）. The rate parameter of the exponential distribution fitted to the overall survival curve in the PemEV regimen had the greatest impact on ICER， according to the one-way sensitivity analysis. Probabilistic sensitivity analysis suggested that the PemEV regimen had no chance of being more cost-effective than the GP regimen at the current WTP threshold. Scenario analysis revealed that the PemEV regimen consistently lacked cost-utility advantage over the GP regimen， regardless of whether the study model was changed to a partitioned survival model， the study timeframe was set to 5， 10 or 20 years， or the prices of enfortumab vedotin and/or pembrolizumab were reduced by 60%. The prices of enfortumab vedotin and pembrolizumab should be simultaneously reduced by 78.65% （55.71 yuan/mg and 38.26 yuan/mg， respectively） when the PemEV regimen had a cost-utility advantage over the GP regimen. CONCLUSIONS From the perspective of China’s healthcare system， PemEV regimen does not demonstrate a cost-utility advantage over GP regimen in the first-line treatment of aUC.

Aim To investigate the effect and role of neuronal restriction silencing factor(REST/NRSF)in epilepsy disorder.Methods Immunohistochemistry,immunofluorescence,Western blot and qPCR tech-niques were used to detect REST/NRSF expression levels in hippocampal tissues of mice induced by kainic acid and human brain tissue.Viral injections,EEG re-cordings and behavioral methods were used to test the effects on epileptic mice after knockdown and overex-pression of REST/NRSF in the hippocampal CA1 re-gion,respectively.Results The positive rate of REST/NRSF in the lesions of epileptic patients was significantly higher compared with that in the control group.The levels of REST/NRSF protein and mRNA in the CA1 region of the hippocampus of mice in the KA model group were significantly higher.Kv7.2 and Kv7.3 potassium channel mRNA expression levels were significantly down-regulated.Significant up-regu-lation of REST/NRSF expression levels was observed in mouse hippocampus after NMDA injection.Knock-down of REST/NRSF in the CA1 region of hippocam-pus significantly elevated the expression levels of Kv7.2 and Kv7.3 potassium channel mRNAs.The fre-quency of EEG spiking and sharp-wave issuance and epileptic seizure grade were significantly lower.Over-expression of REST/NRSF in the CA1 region of hippo-campus significantly reduced the mRNA expression lev-els of Kv7.2 and Kv7.3 potassium channels.The fre-quency of EEG spiking and sharp-wave issuance was significantly higher and epileptic symptoms were exac-erbated.Conclusion REST/NRSF in mouse hipp-ocampal brain regions is involved in epileptic disease development through transcriptional regulation of Kv7.2 and Kv7.3 potassium channels.

Aim To investigate the mechanism of py-roptosis mediated by the NLRP3/caspase-1/GSDMD signaling pathway and the intervention effect of Radix Angelica Sinensis and Radix Astragalus ultrafiltration extract(RAS-RA)in radiation-induced pulmonary fi-brosis.Methods Fifty Wistar rats were randomly di-vided into five groups,with ten rats in each group.Ex-cept for the blank control group,all other groups of rats were anesthetized and received a single dose of 40 Gy X-ray local chest radiation to establish a radiation-in-duced pulmonary fibrosis rat model.After radiation,the rats in the RAS-RA intervention groups were orally administered doses of 0.12,0.24 and 0.48 g·kg-1 once a day for 30 days.The average weight and lung index of the rats were observed after 30 days of contin-uous administration.Hydroxyproline(HYP)content in lung tissue was determined by hydrolysis method.The levels of IL-18 and IL-1 β in serum were detected by ELISA.Lung tissue pathological changes were ob-served by HE and Masson staining.Ultrastructural changes in lung tissue were observed by transmission e-lectron microscopy.The expression levels of NLRP3/caspase-1/GSDMD pyroptosis pathway-related proteins and fibrosis-related proteins in lung tissue were detec-ted by Western blot.Results Compared with the blank group,the HYP content in lung tissue and the levels of IL-18 and IL-1 β in serum significantly in-creased in the model group(P＜0.01).HE and Mas-son staining showed inflammatory cell infiltration and collagen fiber deposition.Transmission electron mi-croscopy revealed increased damaged mitochondria,disordered arrangement,irregular morphology,shallow matrix,outer membrane rupture,mostly fractured and shortened cristae,mild expansion,increased electron density of individual mitochondrial matrix,mild sparse structure of lamellar bodies,partial disorder,unclear organelles,and characteristic changes of pyroptosis.Western blot analysis showed increased expression of caspase-1,GSDMD,NLRP3,CoL-Ⅰ,α-SMA,and CoL-Ⅲ proteins(P＜0.01).Compared with the model group,the RAS-RA intervention group showed signifi-cant improvement in body mass index and lung index of rats,decreased levels of IL-18 and IL-1 β inflammatory factors(P＜0.01),improved mitochondrial structure,reduced degree of fibrosis,and decreased expression of caspase-1,GSDMD,NLRP3,COL-Ⅰ,COL-Ⅲ,and α-SMA proteins in lung tissue(P＜0.01).Conclusion RAS-RA has an inhibitory effect on radiation-in-duced pulmonary fibrosis,and its mechanism may be related to the inhibition of pyroptosis through the regu-lation of the NLRP3/caspase-1/GSDMD signaling pathway.

This study was aimed at investigating the antimicrobial susceptibility and genomic characteristics of multidrug resistant diarrheagenic Escherichia coli isolated from human and food samples in Henan Province from 2017 to 2022.A total of 101 strains of multidrug resistant diarrheagenic E.coli were subjected to antimicrobial susceptibility testing with the broth di-lution method.Whole genome sequencing was performed to analyze the antimicrobial resistance genes,multilocus sequence typ-ing,and plasmid types.The sequencing data were used to construct a phylogenetic tree based on core genome single-nucleotide polymorphisms(cgSNPs).The isolates showed the highest resistance to ampicillin(87.1％),followed by tetracycline(79.2％)and nalidixic acid(64.4％).The resistance rate to cefotaxime was 38.6％.All 101 strains were classified into 60 STs,among which ST10,ST1491,and ST38 were dominant.Moreover,23 distinct plasmid replicons were identified,among which IncFIB was dominant.Diverse antimicrobial resistance genes(including quinolone,aminoglycoside,β-lactamase,and tetracycline)were identified.Insertion sequences(IS26,IS903B,and ISECP 1)were identified in upstream and downstream analysis of the gene context of the extended-spectrum β-lactamase bla CTX-M-14 and bla CTX-M-55 genes.In conclusion,multidrug resistant diarrhea-genic Escherichia coli isolated from clinical and food samples in Henan Province showed high genetic diversity and high antimi-crobial resistance.The dissemination of blaCTX-M carried by the strains was shown to be associated with the insertion sequence(IS).

Based on network pharmacology and in vitro assays,we conducted a collaborative investi-gation into the protective effects of ginsenosides Rg1 and Re on LPS-induced damage of porcine je-junal epithelial cells IPEC-J2.Network pharmacology was used to obtain and screen the intersec-ting targets of Rg1 and Re to alleviate intestinal barrier damage,and molecular docking technique was used to verify the predicted results of network pharmacology.The experiment included the Control group,LPS group,Rg1 group,and Re group.The effects of different concentrations of Rg1 and Re on cell survival rate,apoptosis rate,TEER value,FD4 permeability,and inflammatory fac-tors of IPEC-J2 were observed,and the effects of different concentrations of Rg1 and Re on the mRNA expression levels of apoptosis-related genes were also detected by fluorescence quantitative PCR.The results of network pharmacology showed that the prevention of intestinal barrier damage by Rg1,Re mainly involved the processes of PI3K-Akt and MAPK signaling pathways.The molec-ular docking results showed that the binding energy of Rg1 to all intersecting targets was less than 0,while that of ginsenoside Re to SRC targets only was less than 0.In vitro experiments showed that pretreatment with different concentrations of Rg1 and Re increased the survival rate and TEER value of LPS-treated IPEC-J2 to varying degrees,and reduced the apoptosis,the decrease of FD4 permeability,and the secretion of inflammatory factor TNF-α,suggesting that Re and Rg1 prevented the intestinal barrier from damage.It was shown that Re and Rg1 could effectively re-duce the effects of LPS treatment on IPEC-J2 cells.Rg1 significantly upregulated the mRNA ex-pression levels of MAPK8,MAPK10,HRAS,and significantly down-regulated the mRNA expres-sion levels of MAP2K1,PIK3CG,IL-2 and SRC;and Re significantly upregulated the mRNA ex-pression levels of MAPK8,MAPK10,HRAS,and PIK3R1,BCL2 gene mRNA expression levels.These results suggest that ginsenosides Rg1,Re and ginsenoside products containing Rg1 and Re deserve further investigation in preventing intestinal barrier damage in piglets.

Objective:To compare the short-term effect and adverse reaction of venetoclax(VEN)combined with azacitidine(AZA)versus"7+3"regimen in newly diagnosed elder patients with acute myeloid leukemia(AML).Methods:From January 2021 to January 2022,the clinical data of seventy-nine newly diagnosed elder patients with AML at the Second Hospital of Shanxi Medical University and the Shanxi Bethune Hospital were retrospectively analyzed,including VEN+AZA group(41 cases)and"7+3"group(38 cases).The propensity score matching(PSM)method was used to balance confounding factors,then response,overall survival(OS),progression-free survival(PFS)and adverse reactions between the two groups were compared.Results:The ORR of VEN+AZA group and"7+3"group was 68％and 84％,respectively,and the CRc was 64％and 72％,respectively,the differents were not statistically significant(P＞0.05).In the VEN+AZA group,there were 5 non-remission(NR)patients,4 with chromosome 7 abnormality(7q-/-7),and 1 with ETV6 gene mutation.Median followed-up time between the two groups was 8 months and 12 months,respectively,and the 6-months OS was 84％vs 92％(P=0.389),while 6-months PFS was 84％vs 92％(P=0.258).The main hematological adverse reactions in two groups were stage Ⅲ-Ⅳmyelosuppression,and the incidence rate was not statistically different(P＞0.05).The median time of neutrophil recovery in two groups was 27(11-70)d,25(14-61)d(P=0.161),and platelet recovery was 27(11-75)d,25(16-50)d(P=0.270),respectively.The infection rate of VEN+AZA group was lower than that of"7+3"group(56％vs 88％,P=0.012).The rate of lung infections of two groups was 36％and 64％,respectively,the difference was statistically significant(P=0.048).Conclusion:The short-term effect of VEN+AZA group and"7+3"regimens in eldrly AML patients are similar,but the VEN+AZA regimen had a lower incidence of infection.The presence of chromosome 7 abnormality(7q-/-7)may be a poor prognostic factor for elderly AML patients treated with VEN+AZA.

Objective:To explore the clinical features and prognosis of patients with primary central nervous system lymphoma(PCNSL).Methods:A retrospective analysis was performed on the relationship between clinical features,treatment regimen and prognosis in 46 newly diagnosed patients with primary central nervous system lymphoma who were diagnosed and treated in The Second Hospital of Lanzhou University from January 2015 to September 2022.Fisher's exact probability method was used to analyze the differences in clinical data of different subgroups.Kaplan-Meier survival curve was used to analyze the overall survival rate and progression-free survival rate of patients with different treatments,and the factors influencing survival were analyzed.Results:Among 46 patients with PCNSL,which pathological type were diffuse large B-cell lymphoma(DLBCL).There were 26(56.5％)cases of male and 20(43.5％)of female,with a median age of 54(17-71)years.In Hans subtypes,14 cases(30.4％)of GCB subtype,32 cases(69.6％)of non-GCB subtype.32 cases(69.6％)of Ki-67 ≥80％.Among 36 patients who completed at least 2 cycles of treatment with follow-up data,the efficacy evaluation was as follows:overall response rate(ORR)was 63.9％,complete response(CR)rate was 47.2％,17 cases of CR,6 cases of PR.The 1-year progression-free survival rate and 1-year overall survival rate was 73.6％and 84.9％,respectively.The 2-year progression-free survival rate and 2-year overall survival rate was 52.2％and 68.9％,respectively.The ORR and CR rate of 17 patients treated with RMT regimen was 76.5％and 52.9％(9 cases CR and 4 cases PR),respectively.Univariate analysis of 3 groups of patients treated with RMT regimen,RM-BTKi regimen,and RM-TT regimen as first-line treament showed that deep brain infiltration was associated with adverse PFS(P=0.032),and treatment regimen was associated with adverse OS in PCNSL patients(P=0.025).Conclusion:Different treatment modalities were independent prognosis predictors for OS,the deep brain infiltration of PCNSL is a poor predictive factor for PFS.Patients with relapse/refractory(R/R)PCNSL have a longer overall survival time because to the novel medication BTKi.They have strong toleration and therapeutic potential as a first-line therapy for high-risk patients.

Objective:To investigate the effects of down-regulation of p21 activated kinase 1(PAK1)on the proliferation,differentiation,and apoptosis of myeloproliferative neoplasm(MPN)cells(6133/MPL)with thrombopoietin receptor MPL mutation at codon 515(MPLW515L)and survival of 6133/MPL mice.Methods:Interference with the protein level of PAK1 in 6133/MPL cells was assessed using lentivirus-mediated shRNA transfection technology.CCK-8 assay was used to detect the effect of down-regulation of PAK1 on the proliferation viability of 6133/MPL cells,and colony-forming ability was measured by cell counting.Flow cytometry was used to detect the PAK1 kinase activity on the ability of polyploid DNA formation and cell apoptosis in 6133/MPL cells.The expression of cyclin D1,cyclin D3 and apoptosis-related protein Bax was detected by Western blot.The infiltration of tumor cells in spleen and bone marrow of 6133/MPL mice were detected by HE staining.Results:Down-regulation of PAK1 inhibited the proliferation and reduced the ability of cell colony formation of 6133/MPL cells.After knocking down PAK1,the content of polyploid DNA in 6133/MPL cells increased from 31.8 to 57.5％and 48.0％,and the proportion of apoptosis increased approximately to 10.8％.Down-regulation of PAK1 led to a reduction of infiltration of tumor cells in liver and bone marrow of 6133/MPL mice,thereby prolonging survival time.Conclusion:Down-regulation of PAK1 can significantly inhibit the growth of 6133/MPL cells,promote the formation of polyploid DNA,induce 6133/MPL cell apoptosis,and prolong the survival time of 6133/MPL mice.

Objective:To explore the effect of TP53 mutation variant allele frequency(VAF)on the prognosis of diffuse large B-cell lymphoma(DLBCL)patients.Methods:This study included 155 patients with DLBCL who were first diagnosed in the People's Hospital of Xinjiang Uygur Autonomous Region from March 2009 to March 2022. Complete clinical data and paraffin-embedded tumor tissue samples were obtained,and DNA was extracted from tumor tissues.The gene mutation profile of DLBCL patients was detected and analyzed by second-generation sequencing technology.Kaplan-Meier method was used to analyze the mutation status of TP53 gene and the relationship between mutation VAF and OS.Cox regression univariate and multivariate analysis was use to analyze the independent factors affecting OS.A nornogram model for predicting 1,3,and 5 years OS in DLBCL patients were established to evaluated the performance of the model based on C-index and calibration curves.Results:The average value of TP53 mutation VAF in male DLBCL patients was significantly higher than that in female patients (P<0.05 ).Patients with TP53 mutantion had shorter OS than those with wild-type patients (P=0.030).The optimal VAF threshold for TP53 mutation based on OS stratification was 33.61％(P<0.001),and patients with TP53 mutation VAF≥34％had shorter OS than those with TP53 mutation VAF<34％and wild-type patients (P<0.001).Multivariate Cox analysis showed that TP53 mutation VAF≥34％ was an independent poor predictor of OS (HR=4.05,P<0.001),and IPI score ≥3 was an independent predictor of OS poor (HR=2.27,P=0.008).In combination with factors with independent prognostic significance obtained from multi-factor analysis,we constructed a nomogram model for predicting 1-year,3-year,5-year OS in DLBCL patients.The results showed that the C index of TP53-mutated VAF combined with IPI model was 0.743,which predicted the value of 1-year,3-year,and 5-year OS in DLBCL patients.Calibration curves show that the model has good agreement between predicted and actual survival of DLBCL patients at 1-year,3-year,and 5-year. Conclusion:TP53 mutant VAF has prognostic value in DLBCL patients,and TP53 mutant VAF≥34％ is an independent risk factor for OS in DLBCL patients.The prognosis model of TP53 mutation VAF combined with IPI nomogram constructed in this study has good predictive performance for DLBCL patients.

Objective:To comprehensively understand the basic situation of critical care medicine in Xinjiang Production and Construction Corps in order to promote the standardization, specialization, and systematization of quality control in critical care medicine.Methods:A survey was conducted from January 1, 2019, to December 31, 2021, using a questionnaire to investigate the human resources and basic allocation of comprehensive intensive care medicine departments in Xinjiang Production and Construction Corps division level hospitals and surrounding second-class hospitals. The survey content includes: basic situation of medical units, intensive care unit (ICU) basic information, ICU personnel situation, ICU equipment configuration situation, ICU performance situation, etc. The survey questionnaire was distributed in March 2022, with dedicated ICU attending physicians or above designated by each ICU as the contact person for the survey.Results:Sixteen questionnaires were distributed and returned, all of which were included from 16 comprehensive intensive care medicine departments in the Corps and surrounding areas, including 5 second class first class hospitals and 11 third class first class hospitals. There were 196 beds in 16 ICU units, and the ICU bed ratio (1.99% overall, 1.77% in third class first class hospitals) was lower than the 2%-8% stipulated in the Guidelines for the Construction and Management of Critical Care Medicine (Trial) issued by the National Health Commission. Only ICU beds in second class first class hospitals accounted for 2.65%, meeting this standard. The comprehensive ICU doctor-bed ratio in 16 hospitals was 0.55∶1, third class first class hospitals was 0.60∶1, and second class first class hospitals was 0.44∶1, compared with 0.8∶1 stipulated in the ministerial guidelines, there was a certain gap. Among the 108 doctors in 16 ICUs, only four have a master's degree or above. Associate senior and above professional and technical titles accounted for 27.78%, less than one third. Among the 334 nursing staff, there were no personnel with a master's degree or above, and only 10 personnel with associate senior or above professional and technical titles. From 2019 to 2021, there was 1 new master's degree personnel, 2 new senior professional and technical personnel, and 12 deputy senior professional and technical personnel. It indicating that the proportion of highly educated and experienced physicians and nurses were lower, team building lags behind, talent introduction were lower, and highly educated talents were scarce. The statistical analysis results of the absolute growth of core technology showed that the growth of core technology was slow, the progressiveness was insufficient, and the professional technical ability was insufficient. Conclusions:The construction of critical care majors and talent echelons in the Xinjiang Production and Construction Corps region is lagging behind, the overall professional level of the discipline is not high, and there is a lack of specialized personnel. Further improvement is needed in talent cultivation, technical development and training, medical quality management, and other aspects to ensure medical quality and safety.