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.

Purpose This study aims to investigate the clinicopathological features of diffuse pulmonary menin-gotheliomatosis(DPM).Methods The clinical data of 10 patients with DPM undergoing video-assisted thoracic sur-gery(VATS)were collected,and their clinical and pathological characteristics were analyzed using immunohistochem-istry.Results The detection rate of DPM was 1.19‰,with 90％of the patients being female.DPM predominantly occurred in the age range of 40-60 years,with an average age at diagnosis of 50.7 years.Most patients had no smok-ing history.Pathological diagnosis combined with imaging findings was the main method for diagnosing DPM.80％of the patients were prone to concurrent early-stage invasive pulmonary adenocarcinoma.Laboratory indicators,including pulmonary function,were generally normal.Chest CT showed diffuse multiple ground-glass opacity or cystic nodules in both lungs,with the number of nodules in both lungs ranging from dozens to hundreds,and the maximum diameter of the nodules was 2-6 mm.The median volume and CT value of the pulmonary nodules were 35.32 mm3 and-566 HU,respectively.Pathological features mainly included multiple meningothelial-like nodules observed under the micro-scope.Immunophenotypically,CD56,EMA,PR,and vimentin were often positive.Conclusion DPM is a rare lung disease with no obvious clinical symptoms,and is more common in middle-aged and elderly women.Diffuse multiple nodules in both lungs are its main imaging features.Most DPM patients are complicated with lung adenocarcinoma,and regular follow-up is recommended.

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.

Purpose This study aims to investigate the clinicopathological features of diffuse pulmonary menin-gotheliomatosis(DPM).Methods The clinical data of 10 patients with DPM undergoing video-assisted thoracic sur-gery(VATS)were collected,and their clinical and pathological characteristics were analyzed using immunohistochem-istry.Results The detection rate of DPM was 1.19‰,with 90％of the patients being female.DPM predominantly occurred in the age range of 40-60 years,with an average age at diagnosis of 50.7 years.Most patients had no smok-ing history.Pathological diagnosis combined with imaging findings was the main method for diagnosing DPM.80％of the patients were prone to concurrent early-stage invasive pulmonary adenocarcinoma.Laboratory indicators,including pulmonary function,were generally normal.Chest CT showed diffuse multiple ground-glass opacity or cystic nodules in both lungs,with the number of nodules in both lungs ranging from dozens to hundreds,and the maximum diameter of the nodules was 2-6 mm.The median volume and CT value of the pulmonary nodules were 35.32 mm3 and-566 HU,respectively.Pathological features mainly included multiple meningothelial-like nodules observed under the micro-scope.Immunophenotypically,CD56,EMA,PR,and vimentin were often positive.Conclusion DPM is a rare lung disease with no obvious clinical symptoms,and is more common in middle-aged and elderly women.Diffuse multiple nodules in both lungs are its main imaging features.Most DPM patients are complicated with lung adenocarcinoma,and regular follow-up is recommended.

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.

AIM:To investigate the antitumor activity and targets of baicalein(Bai)in pancreatic cancer using network pharmacology combined with in vitro and in vivo experiments.METHODS:The targets of Bai and pancreatic can-cer were analyzed via multi-data screening.A protein-protein interaction network was constructed using STRING,and core targets were identified via Cytoscape.Functional enrichment was analyzed by Gene Ontology(GO)and Kyoto Ency-clopedia of Genes and Genomes(KEGG).Antitumor effects of Bai were assessed in pancreatic cancer cells Aspc-1 and Bxpc-3 using MTT and colony formation assays for proliferation,flow cytometry for apoptosis and cell cycle analysis,and Transwell assays for migration and invasion.A xenograft tumor model was established to evaluate tumor proliferation,im-munohistochemistry was performed to detect the protein expression of AKT in tumor tissues,and Western blot was used to analyze the expression levels of AKT,β-catenin,N-cadherin and Slug.RESULTS:A total of 108 overlapping targets were identified between Bai and pancreatic cancer.Among these,7 core targets were recognized,including proto-onco-gene tyrosine-protein kinase Src,heat shock protein 90 alpha family class A member 1(HSP90AA1),estrogen receptor 1(ESR1),tumor protein p53(TP53),epidermal growth factor receptor(EGFR),AKT1,and mitogen-activated protein ki-nase 3(MAPK3).The GO analysis revealed significant enrichment in oxidative stress response,protein phosphorylation,and serine/threonine kinase activity.The KEGG analysis primarily enriched the PI3K/AKT,MAPK and Ras signaling pathways.The MTT and colony formation assays showed that Bai inhibited the viability of Aspc-1 and Bxpc-3 cells in a dose-dependent manner(72 h IC50 values were 73.6 μmol/L and 83.4 μmol/L,respectively)and reduced cell colony for-mation(P<0.05 or P<0.01).Flow cytometry confirmed that Bai induced apoptosis of Aspc-1 and Bxpc-3 cells(P<0.01)and blocked the cell cycle at the G0/G1 phase(P<0.05 or P<0.01).Transwell experiments indicated that Bai inhibited the migration and invasion of Aspc-1 and Bxpc-3 cells(P<0.05 or P<0.01).In vivo,Bai significantly inhibited the growth of Aspc-1 cell xenograft tumors(P<0.01).Immunohistochemistry revealed a significant reduction in AKT expression in tu-mor tissues(P<0.01),and Western blot showed decreased expression of AKT,β-catenin,N-cadherin and Slug in both Aspc-1 and Bxpc-3 cells(P<0.01).CONCLUSION:Baicalein inhibits pancreatic cancer cell proliferation,migration,and invasion,potentially through down-regulation of AKT,β-catenin,N-cadherin,and Slug expression.

Objective:To investigate the differences in electrophysiological brain development of neonates in Tibet and Beijing.Methods:This prospective cohort study included neonates with gestational ages of 28 to 40 weeks and 6 days, without asphyxia, hypoxia, or brain injury, who were born between January 2022 and June 2024 at the Tibet Autonomous Region People's Hospital and Peking University First Hospital. The first electroencephalographic (EEG) monitoring was completed within 48 hours to 7 days after birth, which included a 4-channel amplitude-integrated EEG (aEEG) and a 12-channel continuous EEG (cEEG). Two electrophysiology experts scored the EEG results according to a rating scale, and the intraclass correlation coefficient (ICC) was used to explore the consistency between different evaluators. Preterm infants with gestational ages of 32 to 36 weeks and 6 days and post-menstrual age (PMA) less than full-term at the first EEG monitoring were re-examined with aEEG and cEEG at PMA of 37 to 40 weeks and 6 days. Infants were grouped based on PMA at the first EEG monitoring. Spearman rank correlation was used to analyze the correlations between total aEEG+cEEG scores, individual aEEG and cEEG scores, and PMA, gestational age, birth weight, and head circumference at the first EEG monitoring. Mann-Whitney U test, Kruskal-Wallis H test, and Bonferroni correction were used to compare the differences in total aEEG+cEEG scores, individual aEEG and cEEG scores between Tibet and Beijing, among adjacent PMA groups, and for premature infants at full-term PMA. Results:(1) A total of 341 neonates were included in this study, including 154 cases from Tibet (nine cases in the PMA of 28-29 weeks and 6 days group, 13 cases in the PMA of 30-31 weeks and 6 days group, 28 cases in the PMA of 32-33 weeks and 6 days group, 38 cases in the PMA of 34-36 weeks and 6 days group, and 66 cases in the PMA of 37-40 weeks and 6 days group) and 187 cases from Beijing (10 cases in the PMA of 28-29 weeks and 6 days group, 10 cases in the PMA of 30-31 weeks and 6 days group, 16 cases in the PMA of 32-33 weeks and 6 days group, 91 cases in the PMA of 34-36 weeks and 6 days group, and 60 cases in the PMA of 37-40 weeks and 6 days group). (2) Inter-rater consistency:the consistency of PMA inferred based on the total aEEC+CEEC score and actual PMA was high in two raters ( ICCrater one=0.96, ICCrater two=0.94, both P<0.01). (3) The correlation between total aEEG+cEEG score and PMA ( r=0.80) was stronger than that between the aEEG alone or cEEG scores and PMA ( r were 0.79 and 0.66, respectively). The total aEEG+cEEG score also correlated with gestational age at birth ( r=0.74), birth weight ( r=0.69), and head circumference at first EEG monitoring ( r=0.69) (all P<0.01). (4) Regardless of whether in Tibet or Beijing, the total aEEG+cEEG score increased sequentially in the PMA of 30- 31 weeks and 6 days, 32-33 weeks and 6 days, 34-36 weeks and 6 days, and 37-40 weeks and 6 days groups; the cEEG score increased sequentially in the PMA of 32-33 weeks and 6 days group, 34-36 weeks and 6 days group, and 37-40 weeks and 6 days groups; the aEEG score in the PMA 32- 33 weeks and 6 days group was higher than that in the 30-31 weeks and 6 days group, and the score in the PMA 37-40 weeks and 6 days group was higher than that in the 34-36 weeks and 6 days group (Bonferroni correction, all P<0.05). (5) At PMA of 34-36 weeks and 6 days, the total aEEG+cEEG score [25 points (22-26 points) vs. 26 points (24-28 points), Z=－2.62, P=0.009] and cEEG score [12 points (12-14 points) vs. 15 points (13-16 points), Z=－4.77, P<0.001] of newborns in Tibet were lower than those in Beijing, while the aEEG score was higher than those in Beijing [12 points (10-13 points) vs. 11 points (10-12 points), Z=2.17, P=0.030]; at PMA of 37-40 weeks and 6 days, the cEEG score of newborns in Tibet was lower than those in Beijing [16 points (15-17 points) vs. 17 points (15-18 points), Z=－2.27, P=0.023]. (6) The total aEEG+cEEG score of preterm infants born at 32 to 33 weeks and 6 days in Tibet was lower at PMA full-term compared to those in Beijing [27 points (26-28 points) vs. 29 points (28 -30 points), Z=－2.94], and also lower compared to the total aEEG+cEEG score of full-term gestational age newborns in Tibet during their first EEG monitoring [29 points (27-30 points)] (both P<0.05). Conclusions:In the high-altitude hypobaric hypoxic environment, the electroencephalographic development of newborns, especially premature infants, maybe lag behind of plain areas. The combined use of aEEG+cEEG may provide a better evaluation of neonatal brain development than using cEEG or aEEG alone.

Objective:To develop a convolutional neural network model of whole slide imaging of cerebrospinal fluid cells for rapid and accurate identification and classification of tumor cells in cerebrospinal fluid.Methods:A total of 8 692 cerebrospinal fluid cytology smears from Huashan Hospital Affiliated to Fudan University from January 2nd, 2019, to December 27th, 2024. As randomly assigned, the training set included 4 941 benign and 1 745 malignant samples, while the validation set comprised of 1 368 benign and 638 malignant samples. Whole-slide digital images were acquired using a cytopathology scanner, cells (clusters) were annotated for classification, and a deep learning model was constructed via tiled image patches for cell detection and classification. Model performance was evaluated using accuracy, sensitivity, specificity, and other indicators. The classification efficiency of manual microscopy was compared.Results:The model achieved a mean precision of 96.75% for cerebrospinal fluid cell classification. For malignant tumor cells, the classification accuracy was 96.61% (mAP=98.36%, AUC=0.97). Subtype classification accuracies for epithelial/epithelioid tumors and small round cell tumors were 97.13% (AUC=0.98) and 95.58% (AUC=0.93), respectively. Compared with manual microscopy, which took (9.70±0.82) minutes for classifying 200 cells, (18.27±1.21) minutes for 500 cells, and often exceeded 60 minutes or infeasible for full slides, the AI model took (3.46±0.49) seconds for 200 cells, (6.76±0.82) seconds for 500 cells, and a median of 48.57 seconds for full slides ( P<0.001), representing an efficiency improvement of approximately 161-170 times, significantly enhancing diagnostic efficiency. Conclusion:This fully automated hierarchical deep learning model enables efficient and accurate tumor cell identification and classification in CSF, providing an effective auxiliary tool for the rapid diagnosis of meningeal carcinomatosis.

[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.