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.

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that severely affects the health of the elderly, marked by its incurability, high prevalence, and extended latency period. The current approach to AD prevention and treatment emphasizes early detection and intervention, particularly during the pre-AD stage of mild cognitive impairment (MCI), which provides an optimal “window of opportunity” for intervention. Clinical detection methods for MCI, such as cerebrospinal fluid monitoring, genetic testing, and imaging diagnostics, are invasive and costly, limiting their broad clinical application. Speech, as a vital cognitive output, offers a new perspective and tool for computer-assisted analysis and screening of cognitive decline. This is because elderly individuals with cognitive decline exhibit distinct characteristics in semantic and audio information, such as reduced lexical richness, decreased speech coherence and conciseness, and declines in speech rate, voice rhythm, and hesitation rates. The objective presence of these semantic and audio characteristics lays the groundwork for computer-based screening of cognitive decline. Speech information is primarily sourced from databases or collected through tasks involving spontaneous speech, semantic fluency, and reading, followed by analysis using computer models. Spontaneous language tasks include dialogues/interviews, event descriptions, narrative recall, and picture descriptions. Semantic fluency tasks assess controlled retrieval of vocabulary items, requiring participants to extract information at the word level during lexical search. Reading tasks involve participants reading a passage aloud. Summarizing past research, the speech characteristics of the elderly can be divided into two major categories: semantic information and audio information. Semantic information focuses on the meaning of speech across different tasks, highlighting differences in vocabulary and text content in cognitive impairment. Overall, discourse pragmatic disorders in AD can be studied along three dimensions: cohesion, coherence, and conciseness. Cohesion mainly examines the use of vocabulary by participants, with a reduction in the use of nouns, pronouns, verbs, and adjectives in AD patients. Coherence assesses the ability of participants to maintain topics, with a decrease in the number of subordinate clauses in AD patients. Conciseness evaluates the information density of participants, with AD patients producing shorter texts with less information compared to normal elderly individuals. Audio information focuses on acoustic features that are difficult for the human ear to detect. There is a significant degradation in temporal parameters in the later stages of cognitive impairment; AD patients require more time to read the same paragraph, have longer vocalization times, and produce more pauses or silent parts in their spontaneous speech signals compared to normal individuals. Researchers have extracted audio and speech features, developing independent systems for each set of features, achieving an accuracy rate of 82% for both, which increases to 86% when both types of features are combined, demonstrating the advantage of integrating audio and speech information. Currently, deep learning and machine learning are the main methods used for information analysis. The overall diagnostic accuracy rate for AD exceeds 80%, and the diagnostic accuracy rate for MCI also exceeds 80%, indicating significant potential. Deep learning techniques require substantial data support, necessitating future expansion of database scale and continuous algorithm upgrades to transition from laboratory research to practical product implementation.

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.

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.

[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 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.

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.