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.

Meniere's disease represents an idiopathic inner ear disorder characterized by endolymphatic hy-drops.Currently,the research methods for identifying genes associated with this disease mainly involve first-genera-tion sequencing and second-generation sequencing.This article reviews research on the genetic study of Meniere's disease,mainly summarizing the candidate genes with repeated pedigree validation in familial Meniere's disease,as well as those frequently reported in sporadic Meniere's disease.

[Purpose]To analyze the trends in incidence,mortality and potential life loss of esophageal cancer in Linzhou City of Henan Province from 2010 to 2019.[Methods]The data of esophageal cancer incidence and mortality from 2010 to 2019 were collected from Linzhou cancer registries.The crude incidence and mortality rates,age-standardized rates(ASR)by sex and age group,the potential years of life lost(PYLL),average potential years of life lost(APYLL),and potential years of life lost rate(PYLLR)were calculated.The average annual percentage change(AAPC)from 2010 to 2019 were analyzed with Joinpoint software.[Results]From 2010 to 2019,there were a total of 8 447 newly diagnosed cases and 6 475 deaths of esophageal cancer in Linzhou.The ASR incidence and ASR mortality of esophageal cancer in the total population,males,females all showed significant downward trends,with AAPCs of-3.97％,-4.35％,-3.29％and-3.78％,-2.68％,-4.95％,respectively(all P＜0.05).The crude incidence and mortality rates in all age groups also showed significant downward trends.The AAPCs of incidence rate for the age groups of 0～49,50～59,60～69,and ≥70 years old were-9.92％,-8.27％,-1.41％,and-3.86％,respectively(all P＜0.05),and the AAPCs of mortality rate were-950％,-12.36％,-2.61％,and-2.98％,respectively(all P＜0.05).From 2010 to 2019,the total PYLL caused by esophageal cancer was 60 880 person years,APYLL was 13.73 person years,and PYLLR was 5.77‰.The PYLL,APYLL,and the PYLLR of the total population and those stratified by sex all showed a decreasing trend(all P＜0.05).[Con-clusion]From 2010 to 2019,the incidence,mortality and potential life loss of esophageal cancer in Linzhou City all decreased,and the long-term effect and screening programs is significant.How-ever,the risk of esophageal cancer among men and the elderly is still relatively high,indicating that more targeted prevention and control strategies should be developed.

[Purpose]To analyze the trends of incidence and mortality of malignant tumors in Linzhou City of Henan Province from 2010 to 2019.[Methods]The incidence and mortality data of malignant tumors of Linzhou cancer registration areas from 2010 to 2019 were collected and evaluated for data quality.The crude incidence/mortality rates and age-standardized incidence/mortality rates by Chinese standard population(ASIRC/ASMRC)were calculated by sex,age and can-cer type.Joinpoint software was used to calculate the average annual percentage change(AAPC)to analyze the trends from 2010 to 2019.[Results]From 2010 to 2019,the crude incidence of malig-nant tumors in Linzhou City showed an upward trend,with an AAPC of 2.09％(95％CI:0.58％～3.63％),while the ASIRC tended to be stable.The incidence of malignant tumors showed a signifi-cant upward trend in the 15～29 and 60～69 age groups,and a significant downward trend in the 70～79 age group.From 2010 to 2019,the ASIRC of esophageal cancer and stomach cancer in both men and women showed a significant downward trend,while that of lung cancer and prostate cancer increased in men,and the incidences of thyroid cancer,uterus cancer,cervical cancer,lung cancer and breast cancer increased significantly in women.From 2010 to 2019,the crude mortality of malignant tumors in Linzhou showed a significant upward trend,with an AAPC of 1.18％(95％CI:0.88％～1.48％),while ASMRC showed a significant downward trend,with an AAPC of-1.63％(95％CI:-1.86％～-1.40％).The mortality increased in the group aged 80 and above,while the other age groups remained in a downward or stable state.From 2010 to 2019,the ASMRC of stomach cancer and esophageal cancer in both men and women showed a down-ward trend,while those of prostate cancer,and malignant tumors of the lip,oral cavity and pha-ryngeal in men increased,and that of ovarian cancer in women increased significantly.[Conclu-sion]The disease burden of malignant tumors in Linzhou City is still heavy.The incidence of common cancer types such as thyroid cancer,prostate cancer and lung cancer shows a significant-ly increasing trends from 2010 to 2019.

Objective To compare the efficacy of Qwen2.5(model A)and GPT-4o model(model B)for converting free-text reports of thyroid ultrasound into structured reports.Methods Preoperative thyroid ultrasound data of 100 patients who then underwent thyroidectomy(236 thyroid nodules)were retrospectively collected.Free-text reports were written by an attending ultrasound physician in accordance with guidelines of American College of Radiology thyroid imaging reporting and data system(ACR TI-RADS)and input into both model A and B for 3 times to generate structured thyroid ultrasound reports.The quality of these structured reports output by 2 models were compared,including structured writing,ACR TI-RADS categories and management recommendations,while the consistency of 3 times structured reports output by the models were analyzed.Results Among 300 structured reports output by models,the total satisfaction rate of structured writing was 94.00％(282/300)for model A and 94.67％(284/300)for model B,and no significant difference was found(x2=0.045,P=0.832).Among 236 thyroid nodules,there were 36,47,33,39 and 81 in ACR TI-RADS categories 1,2,3,4 and 5,respectively.The total accuracy model A and B for 3 times categories of thyroid nodules was 88.28％(625/708)and 89.27％(632/708),respectively,with no significant difference(x2=0.582,P=0.505).Moderate consistencies of results of 3 times structured writing(ICC=0.531,0.673)and nodules categories(ICC=0.714,0.747)were noticed between 2 models.The coincidence rate of model A and B for providing management recommendations for thyroid nodules was 74.86％(530/708)and 67.51％(478/708),respectively,the former was higher than the latter(x2=4.567,P=0.033),and the consistencies of 3 times management recommendations provided by 2 models were both good(ICC=0.836,0.769).Conclusion The efficacy of structured writing and ACR TI-RADS categories of Qwen2.5 and GPT-4o models for converting thyroid ultrasound free-text reports into structured reports was comparable,while the former was more effective for providing management recommendations.

Aim To investigate the neuroprotective effect of Takeda G protein-coupled receptor-5(TGR5)activated by INT-777 on hypoxic-ischemic encephalop-athy(HIE)in neonatal rats.Methods Seven-day-old SD rats were randomly divided into the sham opera-tion group(Sham,S),model group(HIE,G),INT-777 low-dose(L),medium-dose(M),and high-dose(H)groups.The modified Rice-Vanucci method was used to construct the HIE model and Intranasal admin-istration 1 h after modeling.Short-term neurobehavioral tests were performed 48 h after modeling to evaluate the neurological function of neonatal rats,TTC staining was used to determine the volume of cerebral infarction,dry and wet specific gravity was used to determine the brain water content,ferrous ion kit was used to deter-mine the brain ferrous ion content,HE staining was used to observe the pathological damage of brain tis-sue,Nissl staining was used to observe the loss of Nissl substance,Transmission electron microscopy(TEM)was used to observe the mitochondrial morphological changes of cortical neurons,and Western blot was em-ployed to detect the expression of ferroptosis-related proteins TFR1 and GPX4.Results Compared with group S,group G had increased short-term neurobehav-ioral test consumption time,higher scores,increased cerebral infarct volume,brain water content,and brain ferrous iron content,significant brain tissue damage on the affected side,severe loss of Nissl substance,smaller neuronal mitochondria,decreased mitochondrial cris-tae,and increased expression of TFR1 and reduced ex-pression of GPX4.Compared with group G,the INT-777 administration group had a shorter consumption time for short-term neurobehavioral tests,lower scores,the cerebral infarction volume,brain water content,and brain ferrous ion content decreased,the brain tissue damage on the affected side was reduced,and there was insignificant loss of Nissl substance,larger neuronal mi-tochondrial volume,increased mitochondrial cristae,re-duced expression of TFR1,and increased expression of GPX4.Conclusions INT-777 agonist TGR5 has a protective effect against hypoxic-ischemic encephalopa-thy in neonatal rats,and its mechanism of action may be related to the inhibition of neuronal ferroptosis.

Aim To investigate the neuroprotective effect of Takeda G protein-coupled receptor-5(TGR5)activated by INT-777 on hypoxic-ischemic encephalop-athy(HIE)in neonatal rats.Methods Seven-day-old SD rats were randomly divided into the sham opera-tion group(Sham,S),model group(HIE,G),INT-777 low-dose(L),medium-dose(M),and high-dose(H)groups.The modified Rice-Vanucci method was used to construct the HIE model and Intranasal admin-istration 1 h after modeling.Short-term neurobehavioral tests were performed 48 h after modeling to evaluate the neurological function of neonatal rats,TTC staining was used to determine the volume of cerebral infarction,dry and wet specific gravity was used to determine the brain water content,ferrous ion kit was used to deter-mine the brain ferrous ion content,HE staining was used to observe the pathological damage of brain tis-sue,Nissl staining was used to observe the loss of Nissl substance,Transmission electron microscopy(TEM)was used to observe the mitochondrial morphological changes of cortical neurons,and Western blot was em-ployed to detect the expression of ferroptosis-related proteins TFR1 and GPX4.Results Compared with group S,group G had increased short-term neurobehav-ioral test consumption time,higher scores,increased cerebral infarct volume,brain water content,and brain ferrous iron content,significant brain tissue damage on the affected side,severe loss of Nissl substance,smaller neuronal mitochondria,decreased mitochondrial cris-tae,and increased expression of TFR1 and reduced ex-pression of GPX4.Compared with group G,the INT-777 administration group had a shorter consumption time for short-term neurobehavioral tests,lower scores,the cerebral infarction volume,brain water content,and brain ferrous ion content decreased,the brain tissue damage on the affected side was reduced,and there was insignificant loss of Nissl substance,larger neuronal mi-tochondrial volume,increased mitochondrial cristae,re-duced expression of TFR1,and increased expression of GPX4.Conclusions INT-777 agonist TGR5 has a protective effect against hypoxic-ischemic encephalopa-thy in neonatal rats,and its mechanism of action may be related to the inhibition of neuronal ferroptosis.

AIM:To establish methods for the isolation,identification,primary culture and evaluation of gas-tric smooth muscle cells(GSMC)from rat and mouse.METHODS:Thirty SD rats and thirty C57BL/6 mice were random-ly assigned into three groups,with 10 rats or mice in each group.Three parallel experiments were conducted to isolate pri-mary GSMC under aseptic conditions.The isolated cells were identified through morphological observation,immunofluo-rescence and Western blot.Flow cytometry was employed to analyze the purity of the cells.Additionally,trypan blue ex-clusion test was utilized to evaluate the viability of the cells after resuscitation.RESULTS:Isolated rat and mouse GSMC exhibited a fusiform or polygonal morphology.Immunofluorescence and Western blot results demonstrated the expression of α-smooth muscle actin(α-SMA).Flow cytometry showed that the positive expression rate of α-SMA was 99.6%in rat GSMC and 97.4%in mouse GSMC.Moreover,the viability rates of rat and mouse GSMC after cryopreservation were found to be greater than 97%.CONCLUSION:A stable and reliable method for the isolation,culture and evaluation of primary GSMC from rat and mouse has been established.

Aim To investigate the therapeutic effects of corylifol A(CYA)on Lewis lung carcinoma(LLC)cachexia mice and its ameliorating effects on myotube atrophy induced by LLC cell-conditioned medium(LLC CM)in vitro,and to explore the mechanisms.Methods The cancer cachexia was induced by subcu-taneous inoculation of LLC cells to C57BL/6J mice.The effects of CYA(10,20 mg·kg-1·d-1,i.p.)on the cachexia symptoms and survival time of cachexia mice were observed.The effects of 2.5 or 5 μmol·L-1 CYA on myotube atrophy of C2C12 induced by LLC CM were observed.The effects of CYA on its pos-sible target the serine/threonine-protein kinase TAO1(TAOK1)and downstream signaling pathways were detected using Western blot.The influence of TAOK1 knockout on the ameliorating effects of CYA on myo-tube atrophy was observed.Results CYA could sig-nificantly prolong the survival time of tumor-bearing mice and ameliorate the muscle atrophy associated with LLC.The effects of CYA on myotube atrophy are relat-ed to its regulation of TAOK1.The effects of CYA could be reduced by knockout of TAOK1.Conclusions CYA improves the survival of LLC cachexia mice and ameliorates the related skeletal muscle atrophy.The mechanism of CYA is related to its inhibition on TAOK1 and downstream signaling pathways.

Aim To investigate the therapeutic effects of corylifol A(CYA)on Lewis lung carcinoma(LLC)cachexia mice and its ameliorating effects on myotube atrophy induced by LLC cell-conditioned medium(LLC CM)in vitro,and to explore the mechanisms.Methods The cancer cachexia was induced by subcu-taneous inoculation of LLC cells to C57BL/6J mice.The effects of CYA(10,20 mg·kg-1·d-1,i.p.)on the cachexia symptoms and survival time of cachexia mice were observed.The effects of 2.5 or 5 μmol·L-1 CYA on myotube atrophy of C2C12 induced by LLC CM were observed.The effects of CYA on its pos-sible target the serine/threonine-protein kinase TAO1(TAOK1)and downstream signaling pathways were detected using Western blot.The influence of TAOK1 knockout on the ameliorating effects of CYA on myo-tube atrophy was observed.Results CYA could sig-nificantly prolong the survival time of tumor-bearing mice and ameliorate the muscle atrophy associated with LLC.The effects of CYA on myotube atrophy are relat-ed to its regulation of TAOK1.The effects of CYA could be reduced by knockout of TAOK1.Conclusions CYA improves the survival of LLC cachexia mice and ameliorates the related skeletal muscle atrophy.The mechanism of CYA is related to its inhibition on TAOK1 and downstream signaling pathways.