OBJECTIVE To evaluate the cost-effectiveness of cefiderocol versus best available therapy （BAT） or standard-of- care （SOC） for the treatment of confirmed or suspected carbapenem-resistant Gram-negative bacterial （CRGNB） serious infections from the perspective of the Chinese healthcare system， and to explore its reasonable pricing. METHODS A decision tree model was constructed based on data from two phase Ⅲ clinical trials （CREDIBLE-CR and GAME CHANGER） to simulate the cost- effectiveness of cefiderocol in two scenarios： salvage therapy for confirmed CRGNB infection （scenario 1） and empirical therapy for suspected CRGNB infection （scenario 2）. The primary outcome measure was the incremental cost-effectiveness ratio （ICER）. The willingness-to-pay （WTP） was set at 1 to 3 times China’s per capita GDP in 2024. To verify the robustness of the results， one- way and probabilistic sensitivity analyses were conducted， and based on these， a reasonable price range for cefiderocol in the Chinese market was explored. RESULTS The results for scenario 1 showed that the clinical cure rate in the cefiderocol group was higher than that in the BAT group （47.50% vs. 34.21%）， but its ICER was 415 065.03 yuan per cured case， exceeding three times China’s GDP per capita. Scenario 2 revealed that the ICER for cefiderocol relative to SOC was as high as 1 362 446.16 yuan per cured case， far exceeding the WTP. Sensitivity analysis indicated that the treatment duration and price of cefiderocol were key factors affecting its cost-effectiveness. In the two scenarios described above， the unit price of cefiderocol must fall below 683.47 and 242.00 yuan/g， respectively， to be considered cost-effective. CONCLUSIONS Based on the current market price， cefiderocol lacks sufficient cost-effectiveness for treating confirmed or suspected CRGNB serious infections within China’s healthcare system. To improve its accessibility， price negotiations or a tiered medical insurance payment strategy are required.

Objective To investigate whether Yiqicongming Decoction(YCD)can alleviate dry eye syndrome in rats.Methods Thirty-six male SD rats at 6 weeks of age were divided into blank group,model group,positive group,YCD high-dose group,YCD medium-dose group,and YCD low-dose group,with six rats in each group.The rats underwent iris,tear secretion volume,and corneal epithelial damage scoring assessments.Conjunctival tissue was stained with PAS,and the activity of superoxide dismutase(SOD)and the content of malondialdehyde(MDA)were detected using the en-zyme-linked immunosorbent assay(ELISA).The level of reactive oxygen species(ROS)was measured by flow cytometry.Western blot was used to detect the protein expression of nuclear factor erythroid 2-related factor 2(Nrf2)and hymeoxyge-nase-1(HO-1)in corneal tissues.Results Compared with the blank group,the number of goblet cells in the conjuncti-va,corneal epithelial injury score,MDA content and ROS level in the model group were significantly increased at all time points(all P＜0.05).The tear secretion volume of rats decreased on days 3,7,and 14,and the number of conjunctival goblet cells and SOD activity also decreased(all P＜0.05).Compared with the model group,the conjunctival score,corne-al epithelial injury score,MDA content,and ROS level in the positive control group and high-,medium-,and low-dose YCD groups were significantly reduced(all P＜0.05),while SOD activity and protein expression levels of Nrf2 and HO-1 in rats on day 14 were significantly increased(all P＜0.05).Compared with the high-dose YCD group,the conjunctival score,corneal epithelial injury score,and ROS level in the low-and medium-dose YCD groups were significantly increased(all P＜0.05),while SOD activity and protein expression levels of Nrf2 and HO-1 on day 14 were significantly decreased(all P＜0.05).On day 14,the tear secretion volume and the number of goblet cells in the conjunctiva of rats administered a low dose of Yiqi Congming Decoction both decreased(all P＜0.05).Compared with the medium-dose YCD group,the conjunc-tival score,corneal epithelial injury score and ROS level in the low-dose YCD group were significantly increased(all P＜0.05),while the tear secretion volume and protein expression levels of Nrf2 and HO-1 on day 14 were significantly de-creased(all P＜0.05).Conclusion YCD can increase tear secretion,alleviate iris and corneal epithelial damage,acti-vate Nrf2/HO-1 pathway,regulate oxidative stress,and alleviate dry eye syndrome.

P-glycoprotein(P-gp)is a transmembrane protein widely involved in the absorption,distribution,metabolism,excretion,and toxicity(ADMET)of drugs within the human body.Accurate prediction of P-gp inhibitors and substrates is crucial for drug discovery and toxicological assessment.However,existing models rely on limited molecular information,leading to suboptimal model performance for predicting P-gp inhibitors and substrates.To overcome this challenge,we compiled an extensive dataset from public databases and literature,consisting of 5,943 P-gp inhibitors and 4,018 substrates,notable for their high quantity,quality,and structural uniqueness.In addition,we curated two external test sets to validate the model's generalization capability.Subsequently,we developed a multimodal graph contrastive learning(GCL)model for the prediction of P-gp inhibitors and substrates(MC-PGP).This framework integrates three types of features from Simplified Molecular Input Line Entry System(SMILES)sequences,molecular fingerprints,and molecular graphs using an attention-based fusion strategy to generate a unified mo-lecular representation.Furthermore,we employed a GCL approach to enhance structural representations by aligning local and global structures.Extensive experimental results highlight the superior perfor-mance of MC-PGP,which achieves improvements in the area under the curve of receiver operating characteristic(AUC-ROC)of 9.82％and 10.62％on the external P-gp inhibitor and external P-gp substrate datasets,respectively,compared with 12 state-of-the-art methods.Furthermore,the interpretability analysis of all three molecular feature types offers comprehensive and complementary insights,demonstrating that MC-PGP effectively identifies key functional groups involved in P-gp interactions.These chemically intuitive insights provide valuable guidance for the design and optimization of drug candidates.

Objective To investigate whether Yiqicongming Decoction(YCD)can alleviate dry eye syndrome in rats.Methods Thirty-six male SD rats at 6 weeks of age were divided into blank group,model group,positive group,YCD high-dose group,YCD medium-dose group,and YCD low-dose group,with six rats in each group.The rats underwent iris,tear secretion volume,and corneal epithelial damage scoring assessments.Conjunctival tissue was stained with PAS,and the activity of superoxide dismutase(SOD)and the content of malondialdehyde(MDA)were detected using the en-zyme-linked immunosorbent assay(ELISA).The level of reactive oxygen species(ROS)was measured by flow cytometry.Western blot was used to detect the protein expression of nuclear factor erythroid 2-related factor 2(Nrf2)and hymeoxyge-nase-1(HO-1)in corneal tissues.Results Compared with the blank group,the number of goblet cells in the conjuncti-va,corneal epithelial injury score,MDA content and ROS level in the model group were significantly increased at all time points(all P＜0.05).The tear secretion volume of rats decreased on days 3,7,and 14,and the number of conjunctival goblet cells and SOD activity also decreased(all P＜0.05).Compared with the model group,the conjunctival score,corne-al epithelial injury score,MDA content,and ROS level in the positive control group and high-,medium-,and low-dose YCD groups were significantly reduced(all P＜0.05),while SOD activity and protein expression levels of Nrf2 and HO-1 in rats on day 14 were significantly increased(all P＜0.05).Compared with the high-dose YCD group,the conjunctival score,corneal epithelial injury score,and ROS level in the low-and medium-dose YCD groups were significantly increased(all P＜0.05),while SOD activity and protein expression levels of Nrf2 and HO-1 on day 14 were significantly decreased(all P＜0.05).On day 14,the tear secretion volume and the number of goblet cells in the conjunctiva of rats administered a low dose of Yiqi Congming Decoction both decreased(all P＜0.05).Compared with the medium-dose YCD group,the conjunc-tival score,corneal epithelial injury score and ROS level in the low-dose YCD group were significantly increased(all P＜0.05),while the tear secretion volume and protein expression levels of Nrf2 and HO-1 on day 14 were significantly de-creased(all P＜0.05).Conclusion YCD can increase tear secretion,alleviate iris and corneal epithelial damage,acti-vate Nrf2/HO-1 pathway,regulate oxidative stress,and alleviate dry eye syndrome.

Objective To analyze the molecular epidemiology of Candida tropicalis(C.tropicalis)isolates from bloodstream infections,and to investigate preliminarily the underlying mechanisms of fluconazole resistance.Methods Clinical C.tropicalis isolates were collected from bloodstream infections at West China Hospital,Sichuan University and other hospitals in Sichuan Province.All the collected isolates were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry,and the antifungal susceptibility test was performed by the broth microdilution method.Multilocus sequence typing(MLST)was conducted using the first generation sequencing technique.Genes associated with drug-resistance were sequenced and the mutation sites were identified.The relative expression levels of genes associated with drug-resistance were analyzed using reverse transcription-quantitative polymerase chain reaction(RT-qPCR).Results A total of 39 C.tropicalis isolates from bloodstream infections were collected.The MLST phylogenetic tree showed that most of the strains clustered in the phylogenetic tree shared identical or similar minimal inhibitory concentrations(MICs).All MLST types were not matched with the isolates in the PubMLST database,representing new diploid sequence types(DSTs).A total of 3 sense mutations,including Ser154Phe,Tyr132Phe,and Tyr257His were identified in ERG11,and were present only in drug-resistant strains.UPC2 contained 4 sense mutations,including Ala251Thr,Gln289Leu,Ser279Glu,and Gln313His,which were also present only in drug-resistant strains.Ser279Glu and Gln313His were previously unreported.There were two sense mutations in ERG3,namely Ser112Gly and Ala48Ser,both being previously unreported,and Ser112Gly was found only in drug-resistant strains.The expression levels of ERG11(14.48 vs 7.109,P=0.003)and UPC2(1.922 vs 0.832,P=0.04)in non-sensitive group(MIC>2 mg/L)were higher than those in sensitive group(MIC≤2 mg/L),and the difference was statistically significant.Conclusion There may be a unique genetic relationship among C.tropicalis isolates from Sichuan province,and the MICs of fluconazole against C.tropicalis are associated with molecular typing.ERG11 mutations were the major mechanism underlying fluconazole resistance in C.tropicalis isolates.The upregulation of ERG11 and UPC2 was associated with fluconazole resistance in C.tropicalis.

Objective To investigate the effects of light-at-night exposure on anxiety and depression behaviors in mice and to explore the underlying neural mechanisms.Methods Six-week-old male C57BL/6J mice were randomly assigned to a control(Ctrl)group and a light-at-night exposure(LAN)group.Mice in the LAN group were exposed to 460 nm blue light for 1 h daily during the zeitgeber time(ZT)13-14 while the Ctrl group mice were maintained under a 12-h light/12-h dark cycle.Behavioral tests were conducted at different time points following LAN exposure to evaluate anxiety and depression behaviors in the mice.Immunofluorescence staining was used to observe the effect of LAN on c-fos expressions in the medial prefrontal cortex(mPFC),basal ateral amygdala(BLA),paraventricular nucleus(PVN)and paraventricular thalamus(PVT).ELISA was performed to measure changes in serum corticosterone,adrenocorticotropic hormone(ACTH)and corticotropin-releasing hormone(CRH)levels.Golgi staining was applied to measurethe dendritic spine density and morphology from mPFC and CA1.Western blotting analysis was conducted to detect expression levels of brain-derived neurotrophic factors(BDNFs),phosphorylated tropomyosin receptor kinase B(p-TrkB)/TrkB,postsynaptic density protein 95(PSD95)and synaptophysin(SYP)in the mPFC.Results Mice exhibited anxiety-like behaviors after 14 days of LAN exposure,with depression-like behaviors emerging after 28 days.LAN exposure of 28 days led to a significant increase in the number of c-fos-positive neurons in the mPFC,BLA,PVN and PVT(P＜0.05),resulted in elevated serum corticosterone levels(P＜0.01)and reduced protein expression levels of BDNF and SYP(P＜0.05).Furthermore,there was a marked decrease in synapse numbers and synaptic density in the mPFC(P＜0.01).Conclusion Prolonged exposure to blue light at night enhances neuronal activity in the mPFC and BLA and suppresses the BDNF/TrkB signaling pathway by activating the hypothalamic-pituitary-adrenal axis(HPA),thus leading to synaptic structural and functional damage and inducing anxiety and depression behaviors in mice.

Objective To explore the characteristics of the cross-sectional area(CSA)of the vagus nerve in a healthy population in Qujing,Yunnan,and its correlation with demographic characteristics.Methods High-resolution nerve ultrasound examinations were conducted on the vagus nerve of 201 healthy volunteers from a hospital in Qujing,Yunnan from September 2022 to March 2023.The CSA was measured through transverse scans of the vagus nerve.The correlation of vagus nerve CSA with age,body mass index(BMI),and gender was assessed.Results The mean CSA of the bilateral VN were 1.9 mm2(right)and 1.3 mm2(left),respectively.The average CSA of the right vagus nerve was significantly greater than that of the left(P<0.001).In the high-age group(>50 years),the average CSA of the right vagus nerve was significantly higher than that of the low-age group(≤50 years)(P=0.0142).However,there was no statistically significant difference in the average CSA of the right vagus nerve between the BMI>24 kg/m2 group and the≤24 kg/m2 group(P=0.0852).The average CSA of the left vagus nerve showed no statistically significant differences across different age groups and BMI groups(P>0.05),but the average CSA of the bilateral vagus nerve in the male group was greater than that in the female group,with a statistically significant difference(P<0.05).Correlation analysis further confirmed a negative correlation between the average CSA of the right vagus nerve and age(r=-0.17,P=0.0139).Multiple linear regression models indicated that age(P=0.007)and gender(P=0.001)were independent influencing factors for the average CSA of the right vagus nerve.Conclusion In the healthy population of Qujing,Yunnan,the CSA of the right vagus nerve is significantly greater than that of the left,and males also exhibit a significantly greater CSA than females.With increasing age,the vagus nerve gradually becomes thinner.

Objective This study aimed to explore the clinical and etiological characteristics of bloodstream infections in diabetic patients with different levels of glycosylated hemoglobin(HbA1c)for improving empirical diagnosis and treatment in clinical practice.Methods A retrospective study was conducted for diabetic patients with bloodstream infections who were admitted to Sichuan Mental Health Center from 2017 to 2023.Patients were assigned to one of the three groups based on HbA1c levels:low level(HbA1c＜7.0％),medium level(7.0％≤HbA1c＜9.0％),high level(HbA1c≥9.0％).The clinical data,pathogen distribution,and antimicrobial resistance were analyzed and compared between groups.Results A total of 426 diabetic patients with bloodstream infection were included.The proportion of community-acquired bloodstream infection,acidosis,and liver abscess in the high level HbA1c group were significantly higher than those in the medium and low level HbA1c groups.Overall,452 strains of nonduplicate pathogenic bacteria were isolated,the most common of which were Escherichia coli(47.1％),Klebsiella pneumoniae(23.0％),and Staphylococcus aureus(5.8％).The pathogens of bloodstream infections varied with different HbA1c levels.The proportion of K.pneumoniae in the high-level HbA1c group(30.7％)was significantly higher than that in the low-level HbA1c group(15.1％)and medium level HbA1c group(16.0％).More than 50％of E.coli isolates were resistant to piperacillin,cefazolin,and ampicillin,while lower than 10％of the isolates were resistant to cefoxitin and minocycline,and lower than 1％of the isolates were resistant to piperacillin-tazobactam,meropenem,imipenem,and amikacin.The E.coli strains isolated from hospital-acquired infections showed slightly higher resistance rates to penicillin,cephalosporins,aminoglycosides,and fluoroquinolones than the strains isolated from community-acquired infections.K.pneumoniae strains showed low resistance rates(＜30％)to the commonly used antibiotics.However,the strains isolated from hospital-acquired infections were significantly more resistant to cephalosporins,carbapenems,and aminoglycosides than the strains isolated from community-acquired infections.Conclusions E.coli,K.pneumoniae and S.aureus were the common pathogens of bloodstream infections in diabetic patients.Poor HbA1c control was associated with K.pneumoniae bloodstream infection,especially those originated from liver abscess.The antibiotic-resistant E.coli and K.pneumoniae strains were prevalent in hospital-acquired bloodstream infections in diabetic patients.Antimicrobial resistance surveillance should be strengthened for this patient population.

Objective To analyze the clinical characteristics of cancer related anemia(CRA)in older cancer patients undergoing multi-line anti-tumor treatment.Methods A cross-sectional study was conducted,including patients with CRA who were≥65 years old and had received or were currently undergoing multi-line treatment at 9 hospitals in Beijing from June 1,2018 to September 30,2023.Data on gender,age,past history,family history,tumor type,metastasis site,clinical symptoms,blood routine,specialized examination for anemia,anti-tumor and anemia correction treatment were collected.The basic characteristics of the included patients,clinical symptoms,the status of blood cell reduction,treatment conditions,and the distribution of traditional Chinese medicine(TCM)syndrome characteristics were analyzed.Results A total of 602 patients were included.The tumor types included lung cancer,colorectal cancer,gastric cancer,esophageal cancer,breast cancer,gynecological tumors,lymphoma.The overall median hemoglobin(HGB)level was 99.00(88.00,107.00)g/L.The HGB levels of patients with different tumor types showed significant differences(P<0.001).The HGB levels of patients with gynecological tumors were significantly lower than those of patients with colorectal cancer,lung cancer and esophageal cancer(P<0.05).The most common clinical symptoms were fatigue,loss of appetite,irregular bowel movements and pain.In terms of anti-tumor treatment,405 patients were receiving multi-line anti-tumor treatment(including combined chemotherapy,combined radiotherapy,combined targeted therapy,and combined immunotherapy),197 patients were receiving symptomatic supportive treatment after multi-line anti-tumor treatment.In terms of anemia correction treatment,183 patients received erythropoietin,folic acid,iron,vitamin B12,or blood transfusion,while 293 patients received TCM for correcting anemia(including Chinese patent medicines,Chinese herbal decoctions,combinations of Chinese patent medicines and Chinese herbal decoctions).Specialized tests for anemia,such as serum iron,total iron binding capacity,transferrin saturation,transferrin,erythropoietin et al,have a detection rate of only 3.65%～27.91%.In terms of the characteristics of TCM syndromes,the main TCM syndrome types of the patients were as follows:syndrome of spleen-stomach weakness,syndrome of qi and blood deficiency,syndrome of heart-spleen deficiency,syndrome of spleen-kidney yang deficiency,syndrome of liver and kidney yin deficiency.Some patients also have the accompanying symptoms of internal binding of static blood and poison,phlegm dampness retention.Further comparison revealed that the HGB level of older patients with CRA who had syndrome of spleen-stomach weakness was significantly lower than patients with other symptom types(P<0.001).The HGB level of patients with syndrome of qi and blood deficiency was significantly lower than patients with syndrome of spleen-kidney yang deficiency(P<0.01)and syndrome of liver and kidney yin deficiency(P<0.001).Patients with symptoms of internal binding of static blood and poison,or symptoms of phlegm dampness retention had significantly lower HGB levels compared to those without accompanying symptoms(P<0.01).Conclusion The rate of specialized blood test for anemia in older patients with CRA was relatively low.The most common TCM syndrome types were syndrome of spleen-stomach weakness and syndrome of qi and blood deficiency.The overall treatment rate was also low.The screening,specialized diagnosis and monitoring of older patients with CRA need to be given more attention,and treatment methods such as TCM,Western medicine,and integrated TCM-Western medicine should be selected based on the patient's condition.

Objective:To investigate the anticipatory grief and to explore its correlates among family caregiv-ers of patients with advanced gastrointestinal cancer.Methods:A total of 283 family caregivers of patients with ad-vanced digestive cancer in the gastroenterology ward of a hospital were assessed using the Perceptive Social Support Scale(PSSS),Simplified Coping Style Questionnaire(SCSQ),Mishel Illness Uncertainty Scale for Family Member(MULS-FM)and Anticipatory Grief Scale(AGS).Results:The median AGS score was 91.00(80.00,98.00).Multiple linear regression analysis revealed that the AGS scores were negatively correlated with PSSS scores(β=-0.21),positive coping scores(β=-0.43),education level(β=-4.99)and age(β=-4.23),but positively correlated with MULS-FM scores(β=0.24).Conclusion:Family caregivers exhibited moderate-to-high anticipato-ry grief,which significantly influenced by age,perceived social support,positive coping style,illness uncertainty and education level.