Objective:To detect adverse reaction risk signals of triazole antifungal agents and provide evidences for their safe use in clinic.Methods:Adverse reaction/event reports with fluconazole, itraconazole, voriconazole, posaconazole, or isavuconazonium as the primary suspect drug were collected from the data in National Adverse Drug Reaction Monitoring System of China reported by Shandong Province from January 2004 to June 2024 and the US Food and Drug Administration Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the second quarter of 2023. Adverse reaction/event terms were standardized using the preferred term (PT) and system organ class in Medical Dictionary for Regulatory Activities 24.0. Risk signals were detected using the reporting odds ratio (ROR) method and the Bayesian confidence propagation neural network (BCPNN) algorithm. A PT was defined as an adverse reaction risk signal if the number of reports was ≥3, the lower limit of the 95% confidence interval ( CI) for ROR was >2, and the lower limit of the 95% CI for the information component ( IC) was >0. Descriptive statistical analysis was performed. Results:A total of 3 988 reports with the above 5 antifungal drugs as the primary suspect drug were collected from data in National Adverse Drug Reaction Monitoring System of China reported by Shandong Province, 822 (20.6%) of which were serious cases. Voriconazole, fluconazole, itraconazole, posaconazole, and isavuconazonium was the primary suspect drug in 1 852, 1 395, 703, 27, and 11 cases among the 3 988 reports, and in 591 (31.9%), 149 (10.7%), 59 (8.4%), 18 (66.7%), and 5 (5/11) serious cases among the 822 serious case reports, respectively. A total of 20 066 reports with the above 5 drugs as the primary suspect drug were collected in FAERS database, 9 635 (48.0%) of which were serious cases. Voriconazole, fluconazole, itraconazole, posaconazole, and isavuconazonium was the primary suspect drug in 7 758, 6 180, 2 869, 1 796, and 1 463 cases among the 20 066 reports, and in 4 295 (55.4%), 2 806 (45.4%), 1 191 (41.5%), 828 (46.1%), and 515 (35.2%) serious cases among the 9 635 serious case reports, respectively. Based on the data reported by Shandong Province and in FAERS database, 18 and 207 risk signals of adverse reaction not mentioned in the labels were identified, respectively, and 5 of them were identified in both databases, including fluconazole-induced renal impairment and voriconazole-induced oliguria, delirium, psychiatric disorders, and rhabdomyolysis. In the data reported by Shandong Province and in FAERS database, 13 and 189 reports of muscle-related disorders (rhabdomyolysis, myopathy, and myositis) were identified respectively, involving voriconazole (in 8 and 62 cases), itraconazole (in 4 and 74 cases), and fluconazole (in 1 and 53 cases).Conclusions:Renal impairment induced by fluconazole and oliguria, delirium, psychiatric disorders, and rhabdomyolysis induced by voriconazole are risk signals of adverse reaction not mentioned in the labels for triazole antifungal agents. Voriconazole, itraconazole, and fluconazole may also cause muscle-related disorders, warranting vigilance in clinical practice.

BACKGROUND:Previous studies found that the proliferative scar-specific long non-coding RNA lncRNA HSFAS is a novel biomarker that can be used in the diagnosis of hypertrophic scar,but how it functions in hypertrophic scar is not clear. OBJECTIVE:To investigate the role and mechanism of lncRNA HSFAS in hypertrophic scar.METHODS:Fresh scar tissue and surrounding normal skin tissue samples from three patients with hypertrophic scar were collected,and tissue immunofluorescence was used to detect the expression of lncRNA HSFAS in frozen sections of two skin tissues. Primary fibroblasts were isolated from proliferative scarred skin tissue and normal skin tissue and cultured by enzyme digestion method. Quantitative real-time PCR was used to detect the mRNA expression of lncRNA HSFAS in cells. The proteins bound to lncRNA HSFAS were detected by RNA pull-down combined mass spectrometry. GO and KEGG were used to analyze the main functions and pathways of lncRNA HSFAS involved in hypertrophic scar progression. The targeted binding of lncRNA HSFAS to proteins was determined by catRAPID and RPISeq website analysis. RESULTS AND CONCLUSION:Compared with normal skin tissue and fibroblasts from normal skin tissue,the expression of lncRNA HSFAS in human hypertrophic scar tissue and primary fibroblasts from hypertrophic scar tissue was significantly increased (P<0.05). There were 510 proteins clearly bound to lncRNA HSFAS by RNA pull-down combined mass spectrometry. The results of GO and KEGG analyses showed that these proteins were mainly involved in RNA splicing and processing,chromosome synthesis and separation,and cell cycle. Among them,the proteins involved in RNA splicing and processing included scaffold attachment factor B2 and DICER1,and the binding fraction with lncRNA HSFAS was higher. The results of bioinformatics analysis showed that lncRNA HSFAS was bound to scaffold attachment factor B2 and DICER1 proteins. To conclude,lncRNA HSFAS may affect gene expression by interacting with scaffold attachment factor B2 and DICER1 proteins to regulate RNA splicing and processing modification,thus promoting the occurrence and development of hypertrophic scar.

Objective:To investigate the characteristics of resting-state mirror homotopic connectivity and the gray matter volume of brain in patients with neuropsychiatric systemic lupus erythematosus (NPSLE).Methods:From June 2020 to March 2023, a total of 35 NPSLE patients (NPSLE group) and 30 non-NPSLE patients (non-NPSLE group) were selected from Taizhou People's Hospital Affiliated to Nanjing Medical University, another 31 healthy volunteers were recruited as the healthy controls(HC group). All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) and mini-mental state examination (MMSE) assessments. The patients in NPSLE and non-NPSLE groups were additionally assessed using the fatigue scale for motor and cognitive functions (FSMC) and the hospital anxiety and depression scale (HADS).The DPABI V7.0 toolkit based on the MATLAB platform was used to preprocess the rs-fMRI data and calculate the voxel-mirrored homotopic connectivity(VMHC) indexes, and the differences in VMHC between groups were evaluated by covariance analysis in SPM12.0 software, and the VMHC values of brain regions with significant differences were extracted for further comparison between the two groups.Partial correlation analysis was performed to investigate the association between VMHC values and clinical parameters in NPSLE patients.The brain regions with significant differences between NPSLE patients and non-NPSLE patients were used as region of interest (ROI), and gray matter volumes within these ROIs were then calculated by VBM8 toolbox.Results:(1)There were statistically significant differences in the VMHC values of bilateral precentral gyrus, bilateral dorsolateral superior frontal gyrus, bilateral medial and paracingulate gyrus, bilateral parahippocampal gyrus, bilateral middle occipital gyrus, bilateral postcentral gyrus, and bilateral superior temporal gyrus among the 3 groups( F=11.246-14.102, all P<0.05). The NPSLE group exhibited significantly lower VMHC values in these regions compared to both the non-NPSLE group and HC group (all P<0.05), but there were no significant differences in these regions between the non-NPSLE group and HC group (all P>0.05).(2) The gray matter volumes of bilateral dorsolateral superior frontal gyrus(right: (0.57±0.11)mm 3, (0.65±0.08)mm 3, t=-3.409, P=0.001; left: (0.53±0.10)mm 3, (0.60±0.07)mm 3, t=-3.082, P=0.003), bilateral precentral gyrus(right: (0.32±0.06)mm 3, (0.35±0.04)mm 3, t=-2.044, P=0.045; left: (0.39±0.06)mm 3, (0.42±0.04)mm 3, t=-2.505, P=0.015), right medial and paracingulate gyrus((0.66±0.08)mm 3, (0.70±0.07)mm 3, t=-2.491, P=0.015) and left superior temporal gyrus((0.57±0.09)mm 3, (0.61±0.06)mm 3, t=- 2.344, P=0.022) in the NPSLE group were smaller than those of non-NPSLE group.(3)Correlation analysis showed that the VMHC value of dorsolateral superior frontal gyrus was positively correlated with IgA level in NPSLE patients ( r=0.353, P=0.047). Conclusion:Patients with NPSLE generally have decreased mirror homotopy functional connectivity in the cerebral hemispheres, accompanied by a decrease in gray matter volume in some brain regions, which can provide a certain neuroimaging basis for the pathogenesis of brain injury.

Objective:To investigate levels of endothelin-1(ET-1)and Apclin in patients with hypertrophic car-diomyopathy(HCM)and diagnostic value of their combination with ECG for HCM,and their association with prognosis.Methods:A total of 150 HCM patients admitted in the Second Affiliated Hospital of Xi'an Medical Uni-versity between June 2020 and June 2022 were selected as observation group.According to death during follow-up,the observation group was divided into survival group(n=64)and death group(n=86),and another 100 healthy volunteers who underwent physical examination in our hospital simultaneously were selected as control group.ET-1,Apelin and ECG indexes were compared between above-mentioned groups.Diagnostic value of ET-1,Apelin and ECG combined detection for HCM was analyzed by receiver operating characteristic(ROC)curve.Multivariate Logistic regression was used to analyze influencing factors of death within 6-month follow-up in HCM patients,and nomogram model was established.Results:Compared with participants in control group,those in the observa-tion group had significant higher ET-1[(0.64±0.15)pmol/L vs.(0.39±0.07)pmol/L],QRS wave group(∑QRS)[(23.60±3.96)mm vs.(14.02±1.78)mm],Cornell voltage index(SV3+RaVL)[(2.12±0.40)mV vs.(1.05±0.20)mV]and S-wave on V1 lead+R-wave on V5 lead(SV1+RV5)[(3.88±0.73)mV vs.(2.24±0.34)mV],and significant lower Apelin[(1.10±0.25)pg/ml vs.(1.58±0.17)pg/ml]level(P＜0.001 all).ROC curve indicated that the area under the curve(AUC)of combined detection of above five indexes diagno-sing HCM was 0.933(95％CI 0.895～0.961),significantly higher than any single detection(Z=3.681～6.428,P＜0.001 all),the H-L goodness of fit test showed P=0.056,suggesting that the model was well accepted,and DCA showed that ET-1 and Apelin combined ECG detection model had good clinical application value in HCM.Multivariate Logistic regression indicated that ET-1,∑QRS,SV3+RaV and SV1+RV5 were independent risk factors for death within 6-month in HCM patients(OR=2.617～3.600,P＜0.001 all),and Apelin was its inde-pendent protective factor(OR=0.271,P＜0.001).The nomogram model of HCM patients dying within 6 months was 4.627+0.452 × ET-1+0.536 × Apelin+0.575 × ∑QRS+0.541 × SV3+RaVL+0.352 × SV1+RV5.Conclusion:Serum ET-1 and Apelin levels significantly change in HCM patients,and the combination of ECG detection and both indexes have good performance diagnosing HCM and are independent influential factors for the death of HCM patients within 6 months.

Rheumatoid arthritis(RA)is a systemic inflammatory disease characterized by erosive arthritis that can eventually lead to joint deformity and loss of function,which is unknown.Autophagy is a self-degradation process in which cells reuse internal proteins and organelles allowing organisms to withstand adverse situations such as starvation and infection,and eventually allowing cells to survive.In recent years,many studies have discovered that autophagy plays a role in the pathogenesis of RA,including the production of pannus,synovitis,bone degradation,and other critical pathological connections that influence RA progression and prog-nosis.This article examines the function of autophagy in the pathogenesis of RA,with the goal of generating new ideas for future RA treatment and drug development.

Objective To retrospectively analyze the clinical risk factors and prognosis of perioperative myocardial injury(MINS)in non-cardiac surgery patients admitted to the intensive care unit(ICU).Methods A total of 478 postoperative patients admitted to the Department of Intensive Medicine,Minhang Hospital,Fudan University from Jan 2020 to Dec 2023 were selected.They were divided into MINS group(n=302)and normal group(n=176)based on whether myocardial injury occurred within 7 days after surgery.The differences in clinical characteristics between the two groups were compared,and risk factors for perioperative myocardial injury were identified.Risk factors for mortality in the MINS group were analyzed with 30-day mortality as the clinical endpoint.Results The prevalence of acute physiology and chronic health evaluation Ⅱ(Apache Ⅱ)score,coronary artery disease,and chronic kidney disease were all higher in the MINS group than those in the normal group,with statistically significant differences(P<0.05).The proportion of emergency surgeries,co-infection,and perioperative hypotension were significantly different between the MINS group and the normal group(P<0.05).Multivariate logistic regression analysis revealed that chronic kidney disease,emergency surgery,co-infection,and intraoperative and postoperative hypotension were risk factors for MINS occurrence.Prognostic analysis indicated that perioperative hypotension was a risk factor for 30-day mortality in MINS patients.Conclusion MINS is closely associated with patients'underlying conditions,timing of surgery,and perioperative hypotension status,and especially perioperative hypotension affects the final outcomes.

Aim To explore the mechanism of the syn-ergistic effect of the ferroptosis inducer erastin com-bined with shikonin in promoting ferroptosis in human hypertrophic scar fibroblasts(HSFBs).Methods Hypertrophic scar tissues provided by the General Hos-pital of Ningxia Medical University were collected,and HSFBs were extracted.HSFBs were identified by HE staining and immunofluorescence.The inhibitory rates of Era and SHK on HSFBs at different concentrations were detected by CCK-8 assay,and the IC50 value was calculated.CompuSyn software was used to calculate the co-use index(CI).Control group,Erastin(Era)group,shikonin(SHK)group and Era+SHK group were set up,and the number and morphological chan-ges of cells were observed after 24 hours of interven-tion.The ability of cell migration and invasion was de-tected by scratch test and Transwell test.The changes of malondialdehyde(MDA),total iron ion and reactive oxygen species(ROS)were detected by corresponding biochemical kits.The expressions of collagen I,α-SMA and GOT1,SLC7A11,GPX4 and FTH1 were detected by Western blot.Results The IC50 value of Era and SHK of primary HSFBs was 2.22 μmol·L-1 and 3.94μmol·L-1 respectively,which was used as the single drug concentration for subsequent experiments.The CompuSyn software was employed to calculate the CI value when the two drugs were used in combination,and the concentrations corresponding to CI=0.39597(Era:1.2 μmol·L-1+SHK:1.5 μmol·L-1)were selected as subsequent combination concentrations(Because when CI was equal to 0.395 97,the concen-tration of each drug was lower than the concentration of single drug,and the inhibition rate of combined drug was greater than 50％).Compared with the monother-apy group,the number of HSFBs in the SHK+Era group was significantly reduced,cell membrane showed breakage and vesiculation,cell wrinkling became smal-ler,and cytoplasm was concentrated.The migration and invasion ability of HSFBs in the SHK+Era group were obviously weakened(P＜0.05),and the expres-sion of fibrosis-related proteins collagen Ⅰ and α-SMA was reduced(P＜0.05);the contents of MDA,total i-ron ions,and ROS in HSFBs of the SHK+Era group increased(P＜0.05),and the protein expression lev-els of SLC7A11,GOT1,GPX4,and FTH1 further de-creased(P＜0.05).Conclusions Erastin in combi-nation with shikonin can synergistically inhibit the pro-liferation,migration and fibrosis levels of HSFBs.The mechanism may be that erastin enhances the inhibition of shikotin on GOT1,increases the levels of cellular i-ron ions,ROS,and lipid peroxides,thereby promoting ferroptosis in HSFBs.

Inflammatory breast cancer(IBC)is a rare but highly aggressive subtype of breast cancer characterized by rapid clinical progression and poor prognosis.Although it accounts for only 2%-4%of all breast cancer cases,it is responsible for 8%-10%of breast cancer-related mortality.The etiology of IBC is multifactorial,involving genetic,hormonal,environmental,and socioeconomic factors.Pathologically,IBC is marked by the presence of dermal lymphatic tumor emboli,and molecular subtypes are predominantly HER2-positive and triple-negative,indicating high tumor invasiveness.Diagnosis relies on characteristic clinical manifestations and histopathological confirmation,while imaging techniques such as MRI and PET/CT play important roles in evaluating disease extent and metastasis.Given that IBC is often diagnosed at a locally advanced or metastatic stage,there is currently no specific treatment protocol.Instead,management generally follows the treatment paradigm of non-IBC,emphasizing systemic therapy within a multidisciplinary framework.HER2-positive IBC benefits from chemotherapy combined with dual-targeted anti-HER2 therapy;triple-negative IBC may respond to immune checkpoint inhibitors;and CDK4/6 inhibitors show potential efficacy in hormone receptor-positive subtypes.Despite advancements,the prognosis remains poor,with a high risk of early recurrence and distant metastasis.Prognostic factors include lymph node involvement,molecular subtype,and response to neoadjuvant therapy.As research into the tumor microenvironment and molecular mechanisms deepens,targeted and individualized therapies hold promise for improving outcomes.This review summarizes the epidemiology,pathology,diagnostic criteria,treatment strategies,and prognostic factors of IBC,aiming to inform clinical practice and future research.

Objective To explore the significance of immunotherapy for patients with hepatitis B virus-related acute-on-chronic liver failure(HBV-ACLF)using plasma exchange(PE)followed by double plasma molecular adsorption system(DPMAS),as well as its impact on prognosis.Methods Patients who were admitted to the Third People's Hospital of Kunming from June 2019 to June 2023 and met the early and mid-stage diagnostic criteria for HBV-ACLF were selected as the research subjects,with a total of 120 cases.After admission,the patients were divided into the PE+DPMAS group(PD group,63 cases)and the PE group(57 cases)based on different treatment plans.The changes in liver function,coagulation function,cytokines,and model for end-stage liver disease(MELD)scores after treatment,as well as the clinical improvement rates,were observed in both groups.Results ① After treatment,the levels of serum total bilirubin(TBil)in the PD group were significantly lower than those in the PE group(μmol/L:163.4±53.3 vs.226.1±72.5,P<0.05),and the prothrombin activity(PTA)was significantly increased[(51.5±9.2)%vs.(41.1±7.7)%,P<0.05].②After treatment,the levels of interleukins(IL-2,IL-6,IL-8)and tumor necrosis factor-α(TNF-α)in both groups decreased compared to before treatment at 1,2,and 4 weeks,reaching the lowest levels at 4 weeks,the levels of IL-2,IL-6,IL-8,and TNF-α in the PD group were lower than those in the PE group[IL-2(ng/L):1.83(1.75)vs.2.04(1.85),IL-6(ng/L):11.31(5.07)vs.18.18(9.05),IL-8(ng/L):21.14(8.35)vs.29.09(12.41),TNF-α(ng/L):9.16(5.10)vs.14.12(7.27)].The levels of IL-10 decreased at 1 week and 2 weeks after treatment.In the PD group,IL-10 increased at 4 weeks after treatment.The differences compared to the baseline levels before treatment were statistically significant(P<0.05).At 4 weeks after treatment,the level of IL-10 in the PD group was significantly higher than that in the PE group[ng/L:24.72(11.56)vs.19.03(10.04),P<0.05].③ The clinical improvement rates in the PD group were significantly higher than those in the PE group at 2 weeks and 4 weeks after treatment[2 weeks after treatment:65.08%(41/63)vs.40.35%(23/57);4 weeks after treatment:84.13%(53/63)vs.54.39%(31/57),both P<0.05].④After 4 weeks of treatment,the MELD scores in both groups decreased significantly.Compared with the PE group,the MELD score in the PD group was significantly lower(14.87±3.45 vs.19.68±4.63,P<0.05).Conclusion Compared with PE alone,PE+DPMAS treatment for early and mid-stage ACLF patients can more effectively clear the large amount of inflammatory mediators released in the body,better regulate the balance between pro-inflammatory and anti-inflammatory cytokines in the patient's serum,thereby preventing or delaying the formation of systemic inflammatory response syndrome(SIRS)and multiple organ dysfunction syndrome(MODS).The clinical therapeutic effect is better,with a higher improvement rate,achieving the goal of reducing liver damage,improving patient survival rate,and thus improving prognosis.

AIM To investigate the effects of Yunpi Tongchang Formula on intestinal mucosal barrier damage in rats with opioid-induced constipation(OIC)of Spleen-Kidney Yang Deficiency Syndrome.METHODS In contrast to the 10 rats of the blank group,the 50 rats of the modeling group were induced into models of OIC of Spleen-Kidney Yang Deficiency Pattern by 7 days consecutive administration of both subcutaneous loperamide injection and alternating gavage of activated carbon ice water and vinegar.Following successful modeling,rats were randomly allocated into the model group,the mosapride citrate tablet group(1.35 mg/kg),and the high-dose,medium-dose,and low-dose Yunpi Tongchang Formula groups(15.12,7.56,3.78 g/kg),with 8 mice in each group.Upon the completion of the 14 days treatment,the rats had their TCM Syndrome scores assessed;their fecal water content,initial black stool excretion time,and small intestine propulsion rate measured;their colon tissue morphology observed by HE staining;their serum levels of IL-6,TNF-α,and IL-1β detected by ELISA;their expressions of occludin and zonula occludens-1(ZO-1)in colon tissues detected by immunohistochemistry;their mRNA expressions of MyD88,TLR4 and NF-κB p65 in the colon tissues detected by RT-qPCR;and their protein expressions of MyD88,TLR4 and NF-κB p65 in the colon tissues detected by Western blot.RESULTS Compared to the blank group,the model group had higher TCM Syndrome scores(P＜0.01);lower fecal water content and small intestine propulsion rate(P＜0.05,P＜0.01);longer initial black stool excretion time(P＜0.01);more mucosal edema in colon tissue,obvious inflammatory infiltration,and glandular disorder;increased serum levels of IL-6,TNF-α and IL-1 β(P＜0.05);decreased colon expressions of ZO-1 and occludin(P＜0.01);and increased mRNA and protein expressions of TLR4,MyD88 and NF-κB p65(P＜0.01).Compared to the model group,both the medium-dose Yunpi Tongchang Formula group and the mosapride citrate tablet group demonstrated effectively reduced TCM syndrome scores(P＜0.01);increased fecal water content and small intestine propulsion rate(P＜0.05,P＜0.01);and shorter initial black stool excretion time(P＜0.01);improved colon mucosal edema and inflammatory infiltration;decreased serum levels of IL-6,TNF-α and IL-1β(P＜0.01);upregulated protein expressions of ZO-1 and occludin(P＜0.01);and downregulated mRNA and protein expressions of TLR4,MyD88 and NF-κB p65(P＜0.05,P＜0.01).CONCLUSION Yunpi Tongchang Formula significantly ameliorates constipation symptoms in OIC rat models of Spleen-Kidney Yang Deficiency Syndrome because of its efficacy in attenuating intestinal inflammation and preserving the integrity of intestinal epithelial barrier structure,with its mechanistic action in downregulating TLR4/MyD88/NF-κB signaling pathway activation.