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.

BACKGROUND: Perioperative treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancelation of surgery, additional illness, and even death, and have therefore attracted much attention. The purpose of the clinical recommendations is to form a diagnosis and treatment plan suitable for the current domestic medical situation for the immune-related adverse event (irAE). METHODS: This recommendation is composed of experts in thoracic surgery, oncologists, thoracic medicine and irAE related departments (gastroenterology, respirology, cardiology, infectious medicine, hematology, endocrinology, rheumatology, neurology, dermatology, emergency section) to jointly complete the formulation. Experts make full reference to the irAE guidelines, large-scale clinical research data published by thoracic surgery, and the clinical experience of domestic doctors and publicly published cases, and repeated discussions in multiple disciplines to form this recommendation for perioperative irAE. RESULTS: This clinical recommendation covers the whole process of prevention, evaluation, examination, treatment and monitoring related to irAE, so as to guide the clinical work comprehensively and effectively. CONCLUSIONS Perioperative irAE management is an important part of immune perioperative treatment of lung cancer. With the continuous development of immune perioperative treatment, more research is needed in the future to optimize the diagnosis and treatment of perioperative irAE.

Objective: To investigate the effects of different expression of monoacylglycerol lipase (MAGL) in tumor-associated macrophages (TAMs) with the proliferation of MHCC97H human liver cancer cells in vivo and its mechanism. Methods: Human peripheral blood-derived monocyte was induced to differentiate into M2-type TAMs and was identified by flow cytometry. The co-culture model of TAMs and MHCC97H human liver cancer cells was established, and the expression of MAGL in TAMs cells was detected by qRT-PCR. The expression of MAGL in TAMs cells was detected by plasmid transfection. ELISA and qRT-PCR was used to detect the mRNA expression levels and secretion levels of inflammatory factors in TAMs cells. The subcutaneous tumor model of MHCC97H mice was constructed to observe the effect of different expression of MAGL in TAMs cells with the proliferation of MHCC97H human liver cancer cells in vivo. F-test was used for the measurement of homogeneity of variance between two independent samples. A t-test was used for homogeneity of variance, and the corrected t-test was used for non-homogeneity of variance. Results: Human peripheral blood-derived monocytes were successfully induced to differentiate into M2-type TAMs. An in vitro co-culture model was established. qRT-PCR showed that MHCC97H human liver cancer cells significantly down-regulated the expressional level of MAGL in TAMs cells. The constructed subcutaneous tumor model of mice demonstrated that up-regulation up-regulation of MAGL expression in M2-type TAMs inhibited the proliferation of MHCC97H human liver cancer cells in vivo. Furthermore, the mechanistic study illustrated that the high expression of MAGL promoted the transcription and secretion of inflammatory factors such as interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha in M2-type TAMs cells. Conclusion The overexpression of MAGL inhibits the proliferation of MHCC97H hepatocellular carcinoma cells in vivo, and its mechanism may be associated to the release of inflammatory factors that from TAMs cells.

Objective To investigate the fluoride content in drinking water as well as the current status of endemic fluorosis in 5 counties of Shandong Province,in order to provide a scientific basis for making prevention and control strategies.Methods According to the survey data of fluoride content in drinking water in Shandong Province between 2005 to 2007,an epidemiological investigation was carried out in Mudan,Jiaxiang,Wucheng,Pingdu and Boxing Counties from September to November 2013.The fluoride content in drinking water and urine and dental fluorosis of children aged 8 to 12 were investigated in 3-4 major survey villages selected in the five counties.The fluoride content in drinking water was detected by fluoride ion selective electrode method,and dental fluorosis was diagnosed by Deans method.Results Fifty-eight drinking water samples were investigated in 16 villages of the five counties.Water fluorine content in Wucheng,Mudan,Pingdu,Boxing and Jiaxiang counties was 4.14,3.84,1.83,1.33 and 0.43 mg/L,respectively.There were 4 counties' fluorine content exceeding the national standard (1.20 mg/L) except Jiaxiang County.The exceeding rate was 100％ in Wucheng and Mudan counties.Urine fluorine content of 320 children aged 8 to 12 in Wucheng,Mudan,Boxing,Pingdu and Jiaxiang counties was 4.51,4.62,1.82,1.30,1.01 mg/L respectively;the total detection rate of dental fluorosis of 574 children was 61.85％ (355/574),the rate of dental damage was 12.89％ (74/574),and dental fluorosis index was 1.27;the detection rate of dental fluorosis in Wucheng,Mudan,Boxing,Pingdu and Jiaxiang Counties was 90.18％ (101/112),97.73％ (86/88),62.22％ (84/135),54.90％ (28/51) and 29.79％ (56/188),respectively.Conclusions The exceeding rate of water fluorine content is very high in 5 counties of severe endenic fluorosis areas in Shandong Province.The urinary fluorine level of the population is still high and the prevalence of dental fluorosis of children is high.Endemic fluorosis in Shandong Province has not yet been effectively controlled,control situation is still grim.

The means of survival of genomic dsRNA of reoviruses from dsRNA-triggered and Dicer-initiated RNAi pathway remains to be defined.The present study aimed to investigate the effect of Grass carp reovirus (GCRV) replication on the RNAi pathway of grass carp kidney cells (CIK).The dsRNA-triggered RNAi pathway was demonstrated unimpaired in CIK cells through RNAi assay.GCRV-specific siRNA was generated in CIK cells transfected with purified GCRV genomic dsRNA in Northern blot analysis; while in GCRV-infected CIK cells,no GCRV-specific siRNA could be detected.Infection and transfection experiments further indicated that replication of GCRV correlated with the increased transcription level of the Dicer gene and functional inhibition of in vitro synthesized egfp-siRNA in silencing the EGFP reporter gene.These data demonstrated that although only the genomic dsRNA of GCRV was sensitive to the cellular RNAi pathway,unidentified RNAi suppressor protein(s) might contribute to the survival of the viral genome and efficient viral replication.

BACKGROUND: Traditional scaphotrapeziotrapezoid limited intercarpal arthrodesis contains Kirschner wire, U-shaped nail, AO/ASIF steel plate and so on. Long-term plaster external fixation was needed following surgery. USA-designed arthrodesis apparatus is mainly suitable for European and people from USA, but not fit for Asian.OBJECTIVE: To simulate scaphotrapeziotrapezoid limited intercarpal arthrodesis, and to test the stability of the novel arthrodesis apparatus developed by the group according to anatomic form of dorsal joint fovea of Chinese scaphotrapeziotrapezoid.DESIGN, TIME AND SETTING: The observational study was performed at the Laboratory of Biomechanics of the Department of Orthopaedics, Nantong University from April 2006 to March 2007.MATERIALS: A total of 40 fresh forearm samples of corpses that were not subjected to antiseptic treatment were used for this study. Radiograph verified that these samples did not develop wrist joint affection or abnormal alinement.METHODS: The cadaver models were imitated limited intercarpal instability before scaphotrapeziotrapezoid arthrodesis used circular plate. Then, simulated flexion 50°, extenion 35°, ulnar deviation 30°, radial deviation 10° ultimate activities (50000).CT scan and 3-D reconstruction should be taken before and after motion.MAIN OUTCOME MEASURES: The index of the radial-scapho angle (RSA), radial-scapho distance (RSD), scapho length(SL), trapezium-trapezoid inclination (TTI), trapezium-trapezoid width (TTW) were measured.RESULTS: Prior to motion RSA, RSD, SL, TTW and TTI were (38.725±2.230) °, (18.988±1.216) mm, (1.686±0.191) cm,(27.360±1.571) mm and (114.975±2.293) °. Following motion RSA, RSD, SL, TTW and TTI were (38.800±2.388) °,(19.215±1.443) mm, (1.683±0.209) cm, (27.718±1.910) mm, (115.300±3.023) °. No significant difference in above-described indexes was determined before and after motion (P > 0.05).CONCLUSION: The novel STT limited intercarpal arthrodesis apparatus shows confidential stability. Thus, wrist joint can do exercises in an early stage at the range of 35 dorsal extension, 50 palmar flexion, 10 radial deviation and 30 ulnar deviation.