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.

Chloropicrin is a commonly used pesticide in agricultural production. The clinical manifestations of oral poisoning patients are complex, and the lesions involve multiple organs. At present, the specific pathogenic mechanism of such poisoning is not clear, and the treatment experience is insufficient, so there are certain difficulties in clinical diagnosis, treatment and treatment. In this paper, the data of a patient with oral chloropicrin poisoning treated in Yidu Central Hospital of Weifang City in April 2023 were summarized. The patient was admitted to our hospital for treatment in time, and his condition improved after Hemopurification, methylene blue reduction, organ support, infection prevention as well as other symptomatic support. Oral chlorophenol can cause lung damage, skin and mucous membrane damage, and may have certain effects on the nervous system and kidney. Early intervention, especially blood purification, is effective.

Objective To establish a rapid detection and identification method for the chemical components of Longshengzhi capsules based on UPLC-Q-TOF/MS.Method UPLC-Q/TOF-MS technology was used to analyze and identify the chemical components of Longshengzhi capsules.The chromatographic column was a Waters Acquity UPLC BEH C18 column(100mm×2.1mm,1.7 μm),and the mobile phase A was 0.1%formic acid water.The mobile phase B was a methanol acetonitrile(1∶1)solution containing 0.1%formic acid(B).The flow rate is 0.3mL/min,the column temperature is 40℃,and the injection volume is 2 μL.The ion source adopts the electric spray ion source.The data is collected in the positive and negative ion modes,and the collection range is m/z 50～1200.The identification and matching are carried out through UNIFI software combined with manual verification of chemical components.Result 87 chemical components were preliminarily and rapidly identified.Conclusion The established method can systematically and rapidly analyze the chemical components in Longsheng leeches,providing a basis for the study of medicinal substances and having important significance for the quality control of Longsheng leeches.

Chloropicrin is a commonly used pesticide in agricultural production. The clinical manifestations of oral poisoning patients are complex, and the lesions involve multiple organs. At present, the specific pathogenic mechanism of such poisoning is not clear, and the treatment experience is insufficient, so there are certain difficulties in clinical diagnosis, treatment and treatment. In this paper, the data of a patient with oral chloropicrin poisoning treated in Yidu Central Hospital of Weifang City in April 2023 were summarized. The patient was admitted to our hospital for treatment in time, and his condition improved after Hemopurification, methylene blue reduction, organ support, infection prevention as well as other symptomatic support. Oral chlorophenol can cause lung damage, skin and mucous membrane damage, and may have certain effects on the nervous system and kidney. Early intervention, especially blood purification, is effective.

Specnuezhenide(SNZ)is among the main components of Fructus Ligustri Lucidi,which has anti-inflammation,anti-oxidation,and anti-tumor effect.The low bioavailability makes it difficult to explain the mechanism of pharmacological effect of SNZ.In this study,the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were explored.SNZ can be rapidly metabolized by the gut microbiome,and two intestinal bacterial metabolites of SNZ,salidroside and tyrosol,were discovered.In addition,carboxylesterase may be the main intestinal bacterial enzyme that mediates its metabolism.At the same time,no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate,indicating that the gut microbiota is the main part involved in the metabolism of SNZ.In addition,pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut microbiota.Interestingly,tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ,which indicated that SNZ exhibited potential to inhibit tumor growth,and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor tissues.At the same time,SNZ modulated the structure of gut microbiota and fungal group,which may be the mechanism governing the antitumoral activity of SNZ.Furthermore,SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in vivo.In the future,targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs.

At present, clinical interventions for chronic kidney disease are very limited, and most patients rely on dialysis to sustain their lives for a long time. However, studies on the gut-kidney axis have shown that the gut microbiota is a potentially effective target for correcting or controlling chronic kidney disease. This study showed that berberine, a natural drug with low oral availability, significantly ameliorated chronic kidney disease by altering the composition of the gut microbiota and inhibiting the production of gut-derived uremic toxins, including p-cresol. Furthermore, berberine reduced the content of p-cresol sulfate in plasma mainly by lowering the abundance of g_Clostridium_sensu_stricto_1 and inhibiting the tyrosine-p-cresol pathway of the intestinal flora. Meanwhile, berberine increased the butyric acid producing bacteria and the butyric acid content in feces, while decreased the renal toxic trimethylamine N-oxide. These findings suggest that berberine may be a therapeutic drug with significant potential to ameliorate chronic kidney disease through the gut-kidney axis.

Objective:To investigate the main factors that influence ALT abnormalities in workers exposed to benzene.Methods:In June 2022, data of 613 enterprises with benzene hazards and 585 enterprises with non-benzene hazards in Tianjin in 2021 were collected, and occupational health examination data of 13018 workers with benzene exposure and 13018 workers with non-benzene exposure were collected, and the region, enterprise type, industry classification and enterprise scale of the employer were analyzed. And occupational health examination data of workers with benzene exposure and non-benzene exposure. The effects of personal general situation, occupational history, enterprise information and benzene exposure on alanine aminotransferase were evaluated by additive interaction.Results:Compared with the group of non-benzene-exposed workers, the personal general conditions, occupational history, company information were higher in the benzene-exposed workers, and the differences were statistically significant ( P<0.05). The quantitative analysis of additive interaction found that gender ( RERI=2.632, 95% CI: 1.966-3.297; AP=0.383, 95% CI: 0.311-0.456; S=1.813, 95% CI: 1.530-2.149), age ( RERI=1.142, 95% CI: 0.928-1.356; AP=0.462, 95% CI: 0.371-0.552; S=4.461, 95% CI: 1.800-11.053), length of service ( RERI=-1.199, 95% CI: -1.653--0.745; AP=-0.456, 95% CI: -0.640--0.271; S=0.576, 95% CI: 0.479-0.693), region ( RERI=0.421, 95% CI: 0.148-0.694; AP=0.161, 95% CI: 0.053-0.268; S=1.350, 95% CI: 1.057-1.726), industry classification ( RERI=0.627, 95% CI: 0.345-0.910; AP=0.232, 95% CI: 0.132-0.332; S=1.584, 95% CI: 1.233-2.035) and benzene exposure had a statistically significant additive interaction with abnormal serum ALT. Conclusion:Emphasis should be placed on male workers under the age of 40 in the petrochemical industry, oil storage and transportation, and power production, so as to protect the health of workers more specifically and reduce the risk of disability due to disease.

Objective:To investigate the main factors that influence ALT abnormalities in workers exposed to benzene.Methods:In June 2022, data of 613 enterprises with benzene hazards and 585 enterprises with non-benzene hazards in Tianjin in 2021 were collected, and occupational health examination data of 13018 workers with benzene exposure and 13018 workers with non-benzene exposure were collected, and the region, enterprise type, industry classification and enterprise scale of the employer were analyzed. And occupational health examination data of workers with benzene exposure and non-benzene exposure. The effects of personal general situation, occupational history, enterprise information and benzene exposure on alanine aminotransferase were evaluated by additive interaction.Results:Compared with the group of non-benzene-exposed workers, the personal general conditions, occupational history, company information were higher in the benzene-exposed workers, and the differences were statistically significant ( P<0.05). The quantitative analysis of additive interaction found that gender ( RERI=2.632, 95% CI: 1.966-3.297; AP=0.383, 95% CI: 0.311-0.456; S=1.813, 95% CI: 1.530-2.149), age ( RERI=1.142, 95% CI: 0.928-1.356; AP=0.462, 95% CI: 0.371-0.552; S=4.461, 95% CI: 1.800-11.053), length of service ( RERI=-1.199, 95% CI: -1.653--0.745; AP=-0.456, 95% CI: -0.640--0.271; S=0.576, 95% CI: 0.479-0.693), region ( RERI=0.421, 95% CI: 0.148-0.694; AP=0.161, 95% CI: 0.053-0.268; S=1.350, 95% CI: 1.057-1.726), industry classification ( RERI=0.627, 95% CI: 0.345-0.910; AP=0.232, 95% CI: 0.132-0.332; S=1.584, 95% CI: 1.233-2.035) and benzene exposure had a statistically significant additive interaction with abnormal serum ALT. Conclusion:Emphasis should be placed on male workers under the age of 40 in the petrochemical industry, oil storage and transportation, and power production, so as to protect the health of workers more specifically and reduce the risk of disability due to disease.

O ⁶-carboxymethyl guanine(O ⁶-CMG) is a highly mutagenic alkylation product of DNA that causes gastrointestinal cancer in organisms. Existing studies used mutant Mycobacterium smegmatis porin A (MspA) nanopore assisted by Phi29 DNA polymerase to localize it. Recently, machine learning technology has been widely used in the analysis of nanopore sequencing data. But the machine learning always need a large number of data labels that have brought extra work burden to researchers, which greatly affects its practicability. Accordingly, this paper proposes a nano-Unsupervised-Deep-Learning method (nano-UDL) based on an unsupervised clustering algorithm to identify methylation events in nanopore data automatically. Specially, nano-UDL first uses the deep AutoEncoder to extract features from the nanopore dataset and then applies the MeanShift clustering algorithm to classify data. Besides, nano-UDL can extract the optimal features for clustering by joint optimizing the clustering loss and reconstruction loss. Experimental results demonstrate that nano-UDL has relatively accurate recognition accuracy on the O ⁶-CMG dataset and can accurately identify all sequence segments containing O ⁶-CMG. In order to further verify the robustness of nano-UDL, hyperparameter sensitivity verification and ablation experiments were carried out in this paper. Using machine learning to analyze nanopore data can effectively reduce the additional cost of manual data analysis, which is significant for many biological studies, including genome sequencing.
Deep Learning ; Guanine ; Nanopore Sequencing ; Nanopores ; Porins/genetics*

Marine fungi are important members of the marine microbiome, which have been paid growing attention by scientists in recent years. The secondary metabolites of marine fungi have been reported to contain rich and diverse compounds with novel structures (Chen et al., 2019). Aspergillus terreus, the higher level marine fungus of the Aspergillus genus (family of Trichocomaceae, order of Eurotiales, class of Eurotiomycetes, phylum of Ascomycota), is widely distributed in both sea and land. In our previous study, the coral-derived A. terreus strain C23-3 exhibited potential in producing other biologically active (with antioxidant, acetylcholinesterase inhibition, and anti-inflammatory activity) compounds like arylbutyrolactones, territrems, and isoflavones, and high sensitivity to the chemical regulation of secondary metabolism (Yang et al., 2019, 2020; Nie et al., 2020; Ma et al., 2021). Moreover, we have isolated two different benzaldehydes, including a benzaldehyde with a novel structure, from A. terreus C23-3 which was derived from Pectinia paeonia of Xuwen, Zhanjiang City, Guangdong Province, China.
Acetylcholinesterase/metabolism* ; Animals ; Anthozoa/microbiology* ; Anti-Inflammatory Agents/pharmacology* ; Aspergillus/chemistry* ; Benzaldehydes/pharmacology* ; Mice ; RAW 264.7 Cells ; Signal Transduction