OBJECTIVE To assess the bleeding risk signals associated with the concomitant use of direct oral anticoagulants （DOACs） and triazole antifungals， and to provide pharmacovigilance evidence for the safety evaluation and monitoring of combined clinical use. METHODS Adverse event reports involving the concomitant use of DOACs and triazole antifungals were extracted from the US FDA Adverse Event Reporting System （FAERS） from the first quarter of 2004 to the third quarter of 2025. Nine bleeding-related preferred terms （PTs） were selected. The Ω shrinkage measure， additive model， multiplicative model， and combined risk ratio method were employed to detect drug-drug interaction signals. The strength of positive signals was further analyzed based on the Ω shrinkage measure. RESULTS A total of 790 adverse event reports involving the concomitant use of DOACs and triazole antifungals were included， among which 229 reports involved nine bleeding-related PTs. A total of 13 signals were consistently identified as posit ive by all four methods. These signals involved six drug combinations： apixaban-fluconazole， apixaban-posaconazole， rivaroxaban-itraconazole， dabigatran etexilate-fluconazole， apixaban-voriconazole， and dabigatran etexilate-itraconazole. The Ω shrinkage measure showed that the apixaban-posaconazole combination exhibited stronger signals for bleeding （ Ω ＝2.73， Ω 025 ＝2.05） and hemoptysis （ Ω ＝2.17， Ω 025 ＝0.83）； the apixaban-fluconazole combination exhibited stronger signals for hematoma （ Ω ＝2.30， Ω 025 ＝1.47） and hematuria （ Ω ＝1.71， Ω 025 ＝0.74）； the rivaroxaban-itraconazole combination exhibited stronger signals for epistaxis （ Ω ＝2.01， Ω 025 ＝0.90） and hematoma （ Ω ＝1.93， Ω 025 ＝0.42）； no positive Ω signals were observed for intracranial hemorrhage or upper gastrointestinal hemorrhage. CONCLUSION S This study suggests that the concomitant use of DOACs and triazole antifungals may increase the risk of bleeding-related events， with differences in signal strength and signal distribution across various drug combinations. In clinical practice， particular attention should be paid to the concomitant use of apixaban or rivaroxaban with strong cytochrome P450 3A4 or P-glycoprotein inhibitors such as posaconazole and itraconazole. For other DOAC-triazole antifungal combinations， close monitoring for bleeding-related manifestations and timely adjustment of anticoagulation or antifungal regimens are also warranted.

[摘 要] 目的：探讨复发/转移性鼻咽癌（NPC）接受含PD-1单抗免疫治疗的临床特征和预后影响因素。方法：回顾性分析2019年3月至2024年7月期间南部战区总医院确诊的95例NPC患者的临床资料和外周血生化及免疫学指标。预后分析采用Kaplan-Meier曲线，组间比较使用Log-rank检验，采用Cox比例风险模型进行单因素和多因素分析。结果：95例患者中男性81例，女性14例，中位年龄49.72岁（16~74岁），Ⅳ期91例（95.79%），所有患者均采用免疫治疗，联合或不联合化疗方案治疗，中位无进展生存期（mPFS）为10.5个月，客观缓解率（ORR）70.53%，疾病控制率（DCR）89.47%，接受含铂治疗方案患者PFS相对更长，且差异有统计学意义。紫杉醇 + 顺铂 + 氟尿嘧啶（TPF）对比吉西他滨 + 顺铂（GP）和紫杉醇 + 顺铂（TP）显示出更长的PFS，但差异无统计学意义。不同PD-1单抗治疗组间的PFS未显示出有统计学意义的差异。单因素及多因素Cox回归分析结果显示，肿瘤复发状态、初始血浆EBV感染状态、治疗周期数、基线外周血SII是复发/转移性NPC患者接受PD-1抑制剂治疗疗效预测的独立相关因素（均P < 0.05），并且非复发患者、初始血浆EBV DNA阳性、接受 ≥ 4治疗周期、基线外周血SII < 772.81的患者接受PD-1抑制剂治疗预后相对更好。结论：在接受PD-1抑制剂治疗的复发/转移性NPC患者中，非复发患者、初始血浆EBV DNA阳性、≥ 4治疗周期且外周血SII < 772.81者PFS相对更长，可早期识别免疫治疗效果不佳患者并精准干预。

Stroke is the leading cause of death and disability among adults in China， and its common complications include digestive system abnormalities， cognitive impairment， depression， stroke-associated pneumonia， and hemiplegia. The combination of traditional Chinese and Western medicine has great potential in treating post-stroke complications. Xinglou Chengqitang （XLCQT） is a representative prescription of alleviating the disease in the upper part by treating the lower part. It has definite therapeutic effect and high safety. Clinically， XLCQT is often used to treat stroke and its complications. However， the quantity and quality of clinical trials of XLCQT in treating post-stroke complications need to be improved. Additionally， since the basic research is weak， the material basis and multi-target mechanism for the efficacy of this prescription are unknown. This article reviews XLCQT in terms of the pharmacodynamic basis， medicinal properties， safety evaluation， and progress in clinical research and mechanisms in treating post-stroke complications. This article summarizes 22 key active ingredients of XLCQT in treating acute stroke complicated with syndrome of phlegm heat and fu-organ excess. Among these key active ingredients， resveratrol， kaempferol， luteolin， chrysoeriol， apigenin， （+）-catechin， and adenosine have good pharmacokinetic properties and high bioavailability. The mechanisms of XLCQT in treating post-stroke complications are complex， including inflammatory response， brain-gut axis， hypothalamic-pituitary-adrenal （HPA） axis， intestinal flora， neurotrophic factors， autophagy， oxidative stress， and free radical damage. This review helps to deeply understand the pharmacodynamic basis and mechanisms of XLCQT in treating post-stroke complications and provides a theoretical basis for the clinical application of XLCQT against post-stroke complications and the development of drugs.

Objective: To investigate the urban and rural differences in adverse outcomes of pulmonary tuberculosis (PTB) in patients with pulmonary tuberculosis-diabetes mellitus comorbidity (PTB-DM), so as to provide insights into improving the prevention and treatment measures for PTB-DM. Methods: Patients with PTB-DM who were admitted and discharged from 14 designated tuberculosis hospitals in Hangzhou City from 2018 to 2022 were selected. Basic information, and history of diagnosis and treatment were collected through hospital information systems. The adverse outcomes of PTB were defined as endpoints, and the proportions of adverse outcomes of PTB in urban and rural patients with PTB-DM were analyzed. Factors affecting the adverse outcomes of PTB were identified using a multivariable Cox proportional hazards regression model. Results: A total of 823 patients with PTB-DM were enrolled, including 354 (43.01%) urban and 469 (56.99%) rural patients. There were 112 (13.61%) patients with adverse outcomes of PTB. The proportions of adverse outcomes of PTB in urban and rural patients were 14.41% and 13.01%, respectively, with no statistically significant difference (P>0.05). Multivariable Cox proportional hazards regression analysis identified first diagnosed in county-level hospitals or above (HR=2.107, 95%CI: 1.181-3.758) and drug resistance (HR=3.303, 95%CI: 1.653-6.600) as the risk factors for adverse outcomes of PTB in urban patients with PTB-DM, while the treatment/observed management throughout the process (HR=0.470, 95%CI: 0.274-0.803) and fixed-dose combinations throughout the process (HR=0.331, 95%CI: 0.151-0.729) as the protective factors for adverse outcomes in rural patients with PTB-DM. Conclusions There are differences in influencing factors for adverse outcomes of PTB in urban and rural patients with PTB-DM. The adverse outcomes of PTB are associated with first diagnosed hospitals and drug resistance in urban patients, and are associated with the treatment/observed management and fixed-dose combinations throughout the process in rural patients.

Objective:To investigate the value of T helper 17 cells（Th17）/regulatory T cells（Treg）imbalance in the evaluation of intravenous immunoglobulin（IVIG）resistance in children with Kawasaki disease and Kobayashi score≤4.Methods:A total of 78 children with Kawasaki disease and Kobayashi score ≤ 4 admitted to Hunan Children's Hospital from January 2020 to December 2023 were prospectively selected as the study subjects，all of whom received IVIG treatment.In the acute phase，the proportion of Th17 cells and Treg cells was detected.Children were divided into IVIG sensitive group and IVIG resistance group based on their responsiveness to IVIG treatment.Baseline data of children with different IVIG treatment responsiveness，acute Th17 cell inflammatory factors [interleukin（IL）-17，IL-21，tumor necrosis factor-α（TNF-α）]，Treg cell inflammatory factors [IL-10，IL-35，transforming growth factor-β（TGF-β）] levels，and Th17/Treg values were compared.The correlation between Th17/Treg values and IVIG resistance in children with Kawasaki disease was analyzed using a restricted cubic spline model（RCS）.According to the threshold of correlation between Th17/Treg values obtained from RCS analysis and drug resistance in children，Th17/Treg was grouped，with a focus on analyzing the predictive value and clinical benefits of Th17/Treg values for IVIG resistance in children with Kawasaki disease.Results:Among the 78 children with Kawasaki disease，16 were resistant to IVIG treatment，accounting for 20.51%.The levels of C-reactive protein（CRP）,IL-17,and Th17/Treg in the acute phase of children in the IVIG resistance group were higher than those in the IVIG sensitive group，while the levels of IL-10 were lower than those in the IVIG sensitive group（ P<0.05）.RCS analysis showed that there was a non-linear dose-response relationship between IVIG resistance and acute Th17/Treg values in children with Kawasaki disease（ P<0.05）.When the acute Th17/Treg value was greater than 1.05，the risk of IVIG resistance in children with Kawasaki disease increased with the increase in indicator levels.The levels of CRP and IL-17 in the acute phase of children with Th17/Treg>1.05 were higher than those in the Th17/Treg < 1.05 group，while IL-10 levels were lower than those in the Th17/Treg<1.05 group.The proportion of children resistant to IVIG treatment was higher than that in the Th17/Treg<1.05 group（ P<0.05）.Multivariate Logistic regression analysis showed that CRP，IL-17，IL-10，and Th17/Treg were the influencing factors of IVIG resistance in children with Kawasaki disease（ P<0.05）.It was found through a nomogram that the C-index of the acute phase Th17/Treg values and their secretion of inflammatory factors in children with Kawasaki disease and Kobayashi score ≤ 4，as well as other major indicators，predicted the risk of IVIG resistance.The C-index was 0.975（95% CI 0.944-1.000），indicating good discrimination.When drawing the decision curve，it was found that compared to using each indicator separately，the Th17/Treg value and its secreted inflammatory factors in the acute phase assisted other major indicators in drawing the decision curve with a higher net benefit rate，with a maximum net benefit rate of 0.205. Conclusion:IVIG resistance in children with Kawasaki disease and Kobayashi score≤4 is related to Th17/Treg imbalance.When the Th17/Treg value in the acute phase of the disease is greater than 1.05，the risk of IVIG resistance is higher.The inflammatory factors IL-17 and IL-10 secreted by the two can assist other known indicators related to IVIG resistance in Kawasaki disease patients，improving the accuracy of predicting resistance risk.

Objective To investigate the expression changes of serum circRNA membrane bound O-acyltransferase 2(circRNA MBOAT2)and circRNA recombinant actinin 4(circRNA ACTN4)in patients with cholangiocarcinoma and their relationship with prognosis.Methods 96 patients with cholangiocarcinoma treated at the First Hospital of Handan City from January 2020 to January 2022 in Department of Hepatobiliary Surgery were regarded as as the cholangiocarcinoma group.Additionally,85 patients with intraductal stones and 90 healthy volunteers were collected as the stone group and control group,respectively.Quantitative real-time reverse transcription PCR(qRT-PCR)was applied to detect the expression levels of circRNA MBOAT2 and circRNA ACTN4.χ2 test was applied to analyze the relationship between circRNA MBOAT2 and circRNA ACTN4 and clinical pathological features.Pearson was applied to analyze the correlation between circRNA MBOAT2 and circRNA ACTN4 in patients with cholangiocarcinoma.ROC was applied to analyze the diagnostic value of circRNA MBOAT2 and circRNA ACTN4 in the occurrence of cholangiocarcinoma.COX was applied to analyze the influencing factors of poor prognosis in patients with cholangiocarcinoma.Kaplan-Meier method was applied for survival analysis.Results circRNA MBOAT2(1.24±0.38)and circRNA ACTN4(1.27±0.42)in cholangiocarcinoma group were higher than those in stone group(1.02±0.31,1.05±0.34)and control group(0.83±0.24,0.78±0.21),and the stone group was higher than that in control group,with statistically significance(t=5.016～14.025,all P<0.05).There was a positive correlation between circRNA MBOAT2 and circRNA ACTN4 in patients with cholangiocarcinoma group(r=0.428,P<0.05).Combined diagnosis of MBOAT2 and ACTN4 was better than single diagnosis of cholangiocarcinoma(Z=4.063,4.004,all P<0.05);circRNA MBOAT2 and circRNA ACTN4 were correlated with clinical staging and lymph node status(t=5.091～5.984,all P<0.05).Positive lymph node status and elevated levels of circRNA MBOAT2 and circRNA ACTN4 were independent risk factors for mortality(HR=1.527,1.582,1.727,all P<0.05).The cumulative survival rate of patients with high expression of circRNA MBOAT2(23.40%vs 46.94%)and circRNA ACTN4(24.00%vs 47.83%)was lower than that of patients with low expression(χ2=5.809,5.946,all P<0.05).Conclusion The serum levels of circRNA MBOAT2 and circRNA ACTN4 increase with the progression of the disease,and the combination of the two has certain value in diagnosing the occurrence of cholangiocarcinoma.

Objective To explore the potential mechanism of Gegen qinlian decoction(GGQLD)containing serum in ameliorating nonalcoholic fatty liver disease(NAFLD)in human hepatocellular carcinoma HepG2 cells based on transcriptomics.Methods An in vitro model of NAFLD was constructed by free fatty acid(FFA)-induced fat accumulation in HepG2 cells,and cells were treated with different proportions of GGQLD and pioglitazone-containing serum.The lipid deposition in each group was detected by oil red O staining,and the lipid content in each group was evaluated by triglyceride level.Transcriptome technology was used to detect the differentially expressed genes between the intervention groups,and GO annotation analysis,KEGG enrichment analysis and protein interaction(PPI)network analysis were performed to verify the differentially expressed genes by RT-PCR.Results Compared with normal control group,the number of red lipid droplets in the model control group increased,and the triglyceride content increased significantly(P＜0.01).Compared with model control group,the content of red lipid droplets in the GGQLD medium dose group showed a decreasing trend,and the intracellular triglyceride content decreased significantly(P＜0.05).A total of 608 differentially expressed genes were identified by transcriptome analysis,of which 163 differentially expressed genes were up-regulated and 445 differentially expressed genes were down-regulated.GO enrichment analysis showed that the differentially expressed genes were mainly involved in the regulation of MAP kinase phosphatase activity.KEGG analysis showed that the differentially expressed genes were mainly involved in MAPK signaling pathway.RT-PCR results showed that GGQLD up-regulated the expression level of MAP2K6 mRNA and down-regulated the expression levels of FOSL1,CTSL,DUSP5,DUSP1,JUN,HSPA6,IL1A,IL11 and RELB mRNA,which may be mainly involved in MAPK signaling pathway.Conclusion GGQLD has the effect of improving NAFLD,which may be related to MAPK signaling pathway.

Objective To observe the value of MR vessel wall imaging(VMI)for predicting instability status of intracranial aneurysm(IA).Methods MR angiography(MRA)and vascular wall imaging(VWI)data of 506 patients with single IA were retrospectively analyzed.Asymptomatic IA was included in stable status group(n=349),while those with enlargement during follow-up or threatened rupture symptoms were taken as instable status group(n=157).The patients were divided into training set(n=354)and validation set(n=152)at a ratio of 7:3.The least absolute shrinkage and selection operator(LASSO)and multivariate logistic regression were performed to screen risk factors associated with IA instability based on clinical data,MRA and VWI manifestations.Then model 1 was constructed based the above indexes,while model 2 was established based only on MRA manifestations of IA.The receiver operating characteristic curve was plotted,and the area under the curve(AUC)was calculated to evaluate the efficacy of each model for predicting IA instability.Results LASSO and multivariate logistic regression showed that female patient,age＜50 years with history of cerebral infarction and IA wall enhancement on MRA were all independent predictors of IA instability status.The AUC of model 1 for predicting instability status of IA was 0.733 and 0.742 in training set and validation set,respectively,both higher than that of model 2(0.593 and 0.609,both P＜0.05).Conclusion MR VWI was helpful for predicting IA instability status.

Objective:To analyse the effect of ultrasound-guided percutaneous liver biopsy and the coaxial biopsy needle tract radiofrequency ablation on patients diagnosed with hepatocellular carcinoma who are considered to be at risk of bleeding.Methods:The data of 117 patients with hepatocellular carcinoma who underwent coaxial biopsy needle tract radiofrequency ablation after ultrasound-guided percutaneous liver biopsy in Peking University First Hospital from March 2019 to April 2023 were retrospectively analysed. There were 95 males and 22 females, with the age of (62.0±11.8) years. A comprehensive analysis was conducted on the following variables: the pre-puncture platelet count, the international standardised ratio, anticoagulation therapy, the haemoglobin (Hb) level, the success rate of the liver puncture, the qualified rate of liver puncture specimens, the number of puncture samples, the length of hospital stay, the Hb level after puncture, bleeding within 10 days post-operation, and complications after ablation, including biliary fistula, hemothorax and organ perforation.Results:Among the 117 patients, 60 cases (51.3%) had an international normalized ratio >1.1, 40 cases (34.2%) had thrombocytopenia, that is, <150×10 9/L, and 17 cases (14.5%) received continuous anticoagulation therapy before the operation. It is evident that all 117 patients successfully completed the ultrasound-guided percutaneous liver biopsy, and that all liver biopsy specimens were qualified. The absence of biliary fistula, hemothorax, organ perforation or death in the patients post-ablation was noted. According to the adverse event evaluation criteria, version 5.0, 113 cases (96.6%) were classified as grade 1 and 4 cases (3.4%) were classified as grade 3. The Hb concentration of patients with minor bleeding (grade 1) prior to puncture was (119.7±22.2) g/L, which was significantly higher than the Hb concentration of patients with severe bleeding (grade 3), (76.0±10.4) g/L ( t=3.92, P=0.010). A meticulous examination of the data revealed that there were no statistically significant differences between the two groups with regard to pre-puncture platelet count, pre-puncture international standardised ratio, pre-puncture proportion of receiving anticoagulant drugs, length of hospital stay and number of puncture samples (all P>0.05). Conclusion:For patients with hepatocellular carcinoma who are at risk of bleeding, ultrasound-guided percutaneous liver biopsy followed by coaxial biopsy needle tract radiofrequency ablation can obtain satisfactory liver tissue samples and is relatively safe. There were differences in hemoglobin levels before puncture among patients with different bleeding after puncture.

Objective To investigate the sequencing results of the SLC26A4 gene in 34 nuclear families and the genetic diagnosis on the offspring in the nuclear families who have been screened for SLC26A4 gene single-allele mutation in the deafness genetic screening,to provide a basis for genetic consulting.Methods A retrospective anal-ysis was performed on the results of SLC26A4 gene testing in 34 nuclear families,in which the offspring with SLC26A4 gene single-allele mutation in deafness genetic screening of each nuclear family.The offspring of 34 nucle-ar families with the second mutation site detected by sequencing,their audiological results were included in the anal-ysis;and if they suffered from hearing loss,the results of temporal bone CT or inner ear MRI were also included in the analysis.Results The sequencing results of 34 nuclear families showed that there were 23 offsprings(67.65％,23/34)with SLC26A4 gene single-allele mutation,and one parent was SLC26A4 gene single-allele mutation.There were 11 offsprings(32.35％,11/34)with second site,among which 7 offsprings(63.64％,7/11)with SLC26A4 gene complex heterozygous mutations,and their parents were SLC26A4 gene single-allele mutations.Among the 7 offsprings with SLC26A4 gene complex heterozygous mutation,3 cases were with hearing loss,all of which were diagnosed as large vestibular aqueduct syndrome,and the other 4 cases were normal.While 4 offsprings(36.36％,4/11)with SLC26A4 gene double heterozygous mutation(cis mutation),and one parent was SLC26A4 gene double heterozygous mutation.The hearing 4 offsprings with SLC26A4 gene double heterozygous mutations were normal.Among the 34 nuclear families,3 pairs of parents were SLC26A4 gene single-allele mutation,and both mutation sites were pathogenic,risk of reproducing children with hereditary hearing loss was 25％.Conclusion The detec-tion sites of deafness gene chip are limited.Using gene sequencing technology to sequence the nuclear family can fur-ther clarify the gene mutation type in offspring and provide guidance for parents to reproduce.