OBJECTIVE To evaluate the cost-effectiveness of culmerciclib combined with fulvestrant as second-line treatment for patients with hormone receptor-positive（HR+）/human epidermal growth factor receptor 2-negative （HER2–） locally advanced or metastatic breast cancer， within the context of the Chinese healthcare system. METHODS A partitioned survival model was established based on the CULMATE-1 study， with a simulation time horizon set at 15 years and a cycle length of 28 days. The incremental cost-effectiveness ratio （ICER） of culmerciclib combined with fulvestrant versus fulvestrant monotherapy as second-line treatment for HR+/HER2– breast cancer was calculated. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the model. Meanwhile， scenario analysis of culmerciclib price reduction was conducted； the required price reduction and price to reach the willingness-to-pay （WTP） threshold in this study were calculated. RESULTS The results of the base-case analysis indicated that， compared with the fulvestrant monotherapy regimen， culmerciclib combined with fulvestrant yielded an additional 0.823 quality-adjusted life year （QALY）， with a corresponding ICER of 371 696.26 yuan/QALY， which exceeded the WTP threshold （199 330 yuan/QALY）. The results of the univariate sensitivity analysis indicated that the cost of culmerciclib， the discount rate， the utility values for progression disease and progression free survival status were significant factors influencing the ICER； both the univariate sensitivity analysis and the probabilistic sensitivity analysis validated the robustness of the model results. Scenario analysis indicated that when the price of culmerciclib was reduced by 30%， 55% and 85% respectively， the corresponding ICER values fell below 3， 2， and 1 times China’s per capita GDP in 2025， with the probability of cost-effectiveness being 3.00%， 94.90%， 100%. When the cost of culmerciclib （60 mg） was reduced by 52.6% to 50.96 yuan， the ICER value met the WTP threshold established in this study. CONCLUSIONS When the WTP threshold is set at twice China’s per capita GDP in 2025， second-line treatment with culmerciclib combined with fulvestrant for HR+/HER2– locally advanced or metastatic breast cancer does not exhibit cost-effectiveness advantage over fulvestrant monotherapy. Therefore， a reasonable price reduction is required to alleviate the financial burden on patients.

Background/Aims: Liver transplantation (LT) following total hepatectomy is a life-saving treatment for hepatocellular carcinoma (HCC). The HCC recurrence after LT hinders the effectiveness of the procedure. The objective of this study is to develop a pre-operative risk stratification model based on a liquid biopsy. Methods: We conducted a comprehensive multi-omics study of 260 HCC patients from three centers, including clinical data, low-coverage whole-genome sequencing of cell-free DNA (cfDNA) from plasma, as well as whole-exome, single-nucleus RNA, and spatial transcriptomics from matched tumor and non-tumor tissues. Results: We identified cfDNA-derived copy number alteration (CNA) signatures associated with post-transplant recurrence. By integrating cfDNA-derived CNA profiles with single-cell transcriptomic data, we traced recurrence-associated cfDNA to a distinct subpopulation of malignant cells within the primary tumor. These cells were embedded in a pro-metastatic microenvironment of specialized endothelial subtypes and cancer-associated fibroblasts. Notably, most recurrence-associated lesions were detectable in cfDNA prior to liver transplantation (LT). Building on these insights, we developed the ZJU Criteria based on CNA fragments and tumor markers, a pre-LT risk prediction tool that integrates conventional clinical factors with cfDNA-derived CNA signatures, and validated it using internal and independent external cohorts. Conclusion Our findings suggest that post-transplant recurrence commonly originates from advanced subclones that emerge late during tumor evolution. The ZJU Criteria provides an accurate, non-invasive strategy that significantly improves pre-LT risk stratification and clinical decision-making for patients with HCC.

OBJECTIVE To evaluate the cost-effectiveness of onradivir versus oseltamivir in the treatment of influenza A in adults from the perspective of the Chinese healthcare system. METHODS Based on data from a phase Ⅲ clinical trial （NCT04683406）， a decision tree model was constructed to simulate the efficacy and cost of using onradivir versus oseltamivir in treating adult patients with influenza A， with a cycle length of 5 days and a simulation period of 29 days. The two drug prices correspond to the median listing prices published by Yaozhi Network and the national negotiated prices. Patient characteristics and influenza utility values were derived from the phase Ⅲ clinical trial of onradivir， and medical costs and complication utility values were sourced from published literature. Quality-adjusted life year（QALY） was used as an effect indicator， and the incremental cost-effectiveness ratio（ICER） of onradivir versus oseltamivir was calculated， using China’s per capita disposable income in 2025 （43 377 yuan） as the willingness-to-pay （WTP） threshold to evaluate the cost-effectiveness of the results. One-way and probabilistic analyses were performed to verify the robustness of the results. RESULTS Compared with the oseltamivir regimen， the onradivir regimen yielded an incremental 0.000 67 QALY with direct medical cost savings of 12.41 yuan， thus being a dominant strategy. One-way sensitivity analysis showed that the utility values on day 15 of oseltamivir treatment， the incidence of influenza pneumonia in the oseltamivir group and the costs of the two drugs significantly affected the results. Probabilistic sensitivity analysis indicated that at the pre-specified WTP threshold， onradivir had a 70.6% probability of being cost-effective. CONCLUSIONS At a WTP threshold set at the 2025 per capita disposable income of China， compared with oseltamivir， onradivir can improve the health outcomes of adult patients with influenza A and reduce costs， demonstrating greater cost-effectiveness.

Purpose Based on the WHO(5th edition)classification of cervical adenocarcinoma and Silva infiltra-tion pattern classification,this study explores the value of etiological classification and Silva classification in the clinical treatment and prognosis prediction of cervical adenocarcinoma.Methods The clinical and pathological features of 112 cases of cervical invasive adenocarcinoma were reviewed.Through HE morphological classification,immunohistochemi-cal detection,and Silva classification of infiltration pattern,the related factors and prognosis of patients were statistical-ly analyzed.Results The median age of 112 patients was 46.5 years(30-80 years),with a maximum tumor diame-ter of 0.35-9.0 cm and an average diameter of 3.2 cm.Most patients showed vaginal bleeding after sexual inter-course.89 cases were HPV-associated adenocarcinoma(HPVAs),18 cases were non HPV-associated adenocarcinoma(NHPVAs).There were 5 cases of other types of adenocarcinomas of the uterine cervix,including 4 cases of endome-trial adenocarcinoma and 1 case of serous adenocarcinoma.There were 5 cases(4.5％)of Silva A pattern,30 cases(26.8％)of Silva B pattern,and 77 cases(68.7％)of Silva C pattern.112 cases were followed up for a median time of 34 months(15-78 months),with 16 deaths and 20 metastases.The progression-free survival(PFS)(P＜0.001)and overall survival(OS)(P=0.001)in the NHPVA group were significantly lower than those in the HPVA group.All cases with Silva A and Silva B pattern had a favorable prognosis and survived without tumor.Of the cases with Silva C pattern,16 died after recurrence.The PFS and OS of patients with Silva C type were lower than those of Silva A type and B type(P＜0.05).Conclusion The fifth edition of WHO classification of cervical adenocarcinoma revealed the correlation between etiology and morphology.Silva classification is of great significance for accurately predicting progno-sis and guiding treatment.

OBJECTIVE To investigate the deglycosylation metabolism of dioscin in vivo and the changes of its anti-tumor activi-ty of its deglycosylated metabolites.METHODS An LC-MS/MS analysis method for simultaneous determination of dioscin and its deglycosylation metabolites was established to study the cumulative excretion amount of dioscin and its deglycosylated metabolites in rat feces after oral administration.To mimic its deglycosylation metabolism,HPLC method was applied to investigate the time-dependent changes in the prototype components and metabolites of dioscin after incubation in artificial gastric juice.Solid-phase extraction tech-nology was employed to isolate the product of dioscin following hydrolysis by artificial gastric juice.The cytotoxic effects of this product on human colon cancer cells HCT-116 were assessed using the CCK-8 assay across different hydrolysis time periods.Concurrently,the enzymatic activities of caspase-3 and caspase-9,along with the expression levels of cytochrome C,were measured to elucidate the impact of dioscin post-hydrolysis on the cytotoxicity against HCT-116 cells.RESULTS Dioscin and its series of deglycosylated me-tabolites were detected in rat feces,revealing no significant differences in the cumulative excretion amounts of Polyphyllin Ⅴ and Pro-genin Ⅱ.Dioscin was shown to generate a range of deglycosylated metabolites in artificial gastric juice.Furthermore,dioscin and its deglycosylated metabolites inhibited the proliferation of HCT-116 cells,induced morphological changes,and increased the enzymatic activities of caspase-3 and caspase-9,as well as cytochrome C expression.However,it was observed that the antitumor activity of the deglycosylated metabolites diminished with prolonged hydrolysis time.CONCLUSION The deglycosylation metabolism of dioscin sig-nificantly attenuates its inhibitory effect on the proliferation of HCT-116 cells.Suppressing the acid-mediated or gut microbiota-medi-ated deglycosylation metabolism may be a promising strategy to preserve its antitumor activity.

Objective To observe the value of 68Ga-DOTA-NOC PET/CT for diagnosing pheochromocytoma(PCC)and paraganglioma(PGL).Methods Thirty-eight patients with suspected or confirmed PCC/PGL who underwent 68 Ga-DOTA-NOC PET/CT were retrospectively enrolled,among them 20 cases underwent 131I-metaiodobenzylguanidine(MIBG)SPECT/CT during the same period.The value of 68Ga-DOTA-NOC PET/CT for diagnosing PCC/PGL at individual and lesion levels were analyzed and compared to the results of 131I-MIBG SPECT/CT.Results Among 38 cases,there were 20 cases of PCC,14 cases of PGL,1 case of adrenocortical carcinoma and 3 cases of benign adrenal hyperplasia.The sensitivity,specificity,positive predictive value,negative predictive value and accuracy of 68 Ga-DOTA-NOC PET/CT for diagnosing PCC/PGL in all 38 cases was 87.88％(29/33),60.00％(3/5),93.55％(29/31),42.86％(3/7)and 84.21％(32/38),respectively.Totally 188 lesions were detected in 34 cases,with detection rate of 89.95％(188/209).For 20 patients who underwent both 2 kinds examinations,the detection rate of bone,lymph node,liver,lung metastases and the overall lesions of 68Ga-DOTA-NOC PET/CT were all higher than those of 131I-MIBG SPECT/CT(all P＜0.05).No significant difference of diagnostic accuracy of PCC/PGL was found between 68 Ga-DOTA-NOC PET/CT and 131I-MIBG SPECT/CT(P＞0.05).Conclusion The value of 68 Ga-DOTA-NOC PET/CT for diagnosing PCC/PGL was comparable to that of 131I-MIBG SPECT/CT,but the former showed higher detection rate of metastases,hence being helpful to staging and risk stratification of PCC/PGL.

This study aims to comprehensively evaluate the analytical performance and clinical application value of an acridinium ester-based chemiluminescence assay for detecting heparin-binding protein (HBP), providing more accurate laboratory evidence for the early diagnosis of infections and sepsis. The analytical performance of the HBP detection kit based on acridinium ester chemiluminescence was verified in Hangzhou Hospital of Traditional Chinese Medicine in January 2024 to June 2024, including limit of blank (LoB), accuracy, precision, linear range, anti-interference ability, and clinical diagnostic concordance. The potential of this assay in early diagnosis and treatment monitoring of sepsis was assessed. HBP levels were measured in 97 patients with sepsis and 160 healthy controls, and intergroup differences were analyzed using the Mann-Whitney U test. The results showed that the LoB of the HBP detection kit based on acridinium ester chemiluminescence was 0.10 RLU, and low-concentration sample testing showed good discrimination. In the accuracy evaluation, the regression equation between the test reagent and the comparator was y=1.015 2 x-2.850 8 (R2=0.995 1). For precision, the CV in intra-assay was ≤3.51%, and the CV in inter-assay was ≤4.18%. Within the linear range of 0.42-493.46 ng/ml, the regression equation was y=0.996 9 x+3.066 0 (R2=0.999 1). In interference experiments, the relative deviation was <3%. Clinically, the median HBP concentration in the sepsis group (median: 121.1 ng/ml) was significantly higher than in the control group (median: 6.3 ng/ml, P<0.000 1), with a diagnostic sensitivity of 98.97% and specificity of 96.25%. Age stratification had no effect on HBP levels ( U=448 ,P=0.780 0). In conclusion,the acridinium ester-based chemiluminescence assay requires only about 10 minutes to complete the detection and deliver results, demonstrating acceptable sensitivity, precision, and anti-interference capability. Its wide linear range and rapid detection meet emergency testing needs. Clinical validation confirms HBP′s extremely high sensitivity and specificity for sepsis diagnosis, supporting its role as a key marker for early diagnosis, treatment monitoring, and prognosis assessment.

Objective:To explore the safety and efficacy of intraosseous regional administration (IORA) of vancomycin for preventing infection in primary total knee arthroplasty (TKA).Methods:A total of 124 patients with knee osteoarthritis undergoing TKA between February 2024 and May 2024 at nine hospitals were enrolled. Preoperative infection prophylaxis involved either IORA (0.5 g vancomycin administered via intraosseous regional infusion before incision) or intravenous infusion (1 g vancomycin via peripheral vein). The IORA group included 15 males and 47 females with a median age of 66.5 years (range, 60.0-70.0 years), while the intravenous group included 14 males and 48 females with a median age of 66.0 years (range, 61.8-70.3 years) years. Intraoperative samples were collected including fat and synovium tissues after incision, before prosthesis placement, and after tourniquet release; distal femoral cancellous bone during femoral osteotomy; proximal tibial cancellous bone during tibial osteotomy; proximal intercondylar cancellous bone before prosthesis placement; and peripheral blood from non-infused arms at surgery initiation and after tourniquet release. Vancomycin concentrations were measured using liquid chromatography-tandem mass spectrometry. Vital sign changes were recorded from admission to 5~10 minutes post-IORA (IORA group) or post-incision (intravenous group). Follow-ups were conducted on postoperative day 1 and 3, and at 1 and 3 months, to document complications including IORA-related adverse events, periprosthetic joint infections, surgical site infections, red man syndrome, acute kidney injury, deep vein thrombosis and so on.Results:Vancomycin concentrations in bone, fat, and synovial tissue samples were significantly higher in the IORA group than in the intravenous group ( P<0.05), while vancomycin concentrations in blood samples were significantly lower in the IORA group than in the intravenous group ( P<0.05). Only 7.3%(41/558) of tissue samples in the IORA group had vancomycin concentrations below 2.0 μg/g (the minimum inhibitory concentration of vancomycin against coagulase-negative staphylococcus), compared to 59.3%(331/558) in the intravenous group (χ 2=11.285, P<0.001). In the intravenous group, 16.9%(21/124) of blood samples had vancomycin concentrations exceeding 15.0 mg/L (the threshold associated with a significantly increased risk of nephrotoxicity), while all concentrations in the IORA group were below this threshold, the difference was statistically significant (χ 2=22.943, P<0.001). There were no statistically significant difference ( P>0.05) in vital signs changes before and after vancomycin administration between the two groups. Two patients in the intravenous group experienced incision exudate, while no other related complications occurred in either group. Conclusions:Compared to the traditional intravenous infusion of 1 g vancomycin, intraosseous injection of a low dose (0.5 g) of vancomycin achieves higher local tissue concentrations in the knee joint with a lower incidence of adverse reactions and is safe for infection prophylaxis. Despite guidelines not recommending the routine use of vancomycin for preventing infection after primary TKA, intraosseous injection of 0.5 g vancomycin may be considered intraoperatively for primary TKA in the following scenarios: patients in medical institutions with a high prevalence of methicillin-resistant staphylococcus aureus (MRSA) infections, patients with potential preoperative MRSA colonization, or patients with cephalosporin allergy.

In order to delve into the molecular mechanism underlying the increased pathogenicity of the recombinant Muscovy duck parvovirus(rMDPV)towards Muscovy ducklings,two sub-genom-ic fragments of the rMDPV strain ZW were cloned into the plasmid pBluescript Ⅱ(SK)to gener-ate the recombinant plasmid pZW.A single nucleotide mutation was engineered in the VP3 gene of pZW to discriminate from the parental strain ZW.pZW plasmid-lipid complex was transfected into the chorioallantoic membrane of 11-day-old embryonated Muscovy duck embryos,resulting in res-cue of infectious virus,rZW,carrying the genetic marker.The rescued virus was passaged in 12-day-old embryonated Muscovy duck embryos and exhibited the similar medium embryo lethal dose(ELD50)value and growth curve compared to the parental strain ZW.Both rZW and strain ZW led to 100％mortality in the infection tests performed with 3-day-old Muscovy duckling.Postmortem necropsy revealed a characteristic intestine embolism formed in the rZW-infected ducklings.Taken together,the generation of the infectious clone pZW lays a solid foundation for deciphering the pathogenesis of rMDPV.

Traditional Chinese Medicine (TCM), as a treasure of the Chinese nation, plays a significant role in maintaining public health. In 2019, the Central Committee of the Communist Party of China and the State Council proposed for the first time the establishment of a TCM registration and evaluation evidence system that integrates TCM theory, "personal experience" and clinical trials (referred to as the "Three-in-One" System) to promote the inheritance and innovation of TCM. Subsequently, the National Medical Products Administration issued several guiding principles to advance the improvement and implementation of this system. Owing to the complexity of its implementation, there are still differing understandings within the TCM industry regarding the positioning of the "Three-in-One" Registration and Evaluation Evidence System, as well as the connotation and value orientation of the "personal experience." To address this, Academician WANG Qi, President of the TCM Association, China International Exchange and Promotion Association for Medical and Healthcare and TCM master, led a group of academicians, TCM masters, TCM pharmacology experts and clinical TCM experts to convene a "Seminar on Promoting the Implementation of the ′Three-in-One′ Registration and Evaluation Evidence System for Chinese Medicinals." Through extensive discussions, an expert consensus was formed, clarifying the different roles of the TCM theory, "personal experience" and clinical trials within the system. It was further emphasized that the "personal experience" is the core of this system, and its data should be derived from clinical practice scenarios. In the future, the improvement of this system will require collaborative efforts across multiple fields to promote the high-quality development of the Chinese medicinal industry.