This study investigated the effects and underlying mechanisms of the luteolin-naringenin combination(LN)on liver injury induced by acetaminophen(APAP).Forty-eight Kunming mice were randomly allocated into six groups:a normal control group,an APAP-induced liver injury model group,a positive drug treatment group,and three LN treatment groups with low,medium,and high doses.After the final drug administration,the mice were fasted for 12 hours prior to eu-thanasia for sample collection.Serum transaminase activity,oxidative stress indices,and hematoxy-lin-eosin(HE)staining were assessed to evaluate the effects of LN on APAP-induced hepatic inju-ry.Additionally,Western blot analysis was conducted to examine the expression levels of sphingo-sine kinase 1(SPHK1)and endoplasmic reticulum stress(ERS)-related proteins,thereby elucida-ting the potential mechanisms by which LN mitigates APAP-induced liver injury.The results dem-onstrated that varying concentrations of LN effectively ameliorated serum aminotransferase activi-ty and oxidative stress levels induced by APAP in a dose-dependent manner.Histopathological ex-amination via HE staining revealed significant improvement in APAP-induced liver tissue injury following treatment with different concentrations of LN.Furthermore,Western blot analysis indi-cated that the protein expressions of SPHK1,CHOP,p-IRE1α,ATF6,p-PERK,p-eIF2α,and ATF4 were markedly reduced after administration of various concentrations of LN.The results demonstrate that LN exhibits a significant protective effect against APAP-induced liver injury by inhibiting the SPHK1-mediated aberrant expression of ERS-related molecules.This study high-lights the importance of targeting SPHK1 in the treatment of APAP liver injury and provides a no-vel therapeutic approach through the multi-target and multi-pathway combination of monomers.

This study investigated the effects and underlying mechanisms of the luteolin-naringenin combination(LN)on liver injury induced by acetaminophen(APAP).Forty-eight Kunming mice were randomly allocated into six groups:a normal control group,an APAP-induced liver injury model group,a positive drug treatment group,and three LN treatment groups with low,medium,and high doses.After the final drug administration,the mice were fasted for 12 hours prior to eu-thanasia for sample collection.Serum transaminase activity,oxidative stress indices,and hematoxy-lin-eosin(HE)staining were assessed to evaluate the effects of LN on APAP-induced hepatic inju-ry.Additionally,Western blot analysis was conducted to examine the expression levels of sphingo-sine kinase 1(SPHK1)and endoplasmic reticulum stress(ERS)-related proteins,thereby elucida-ting the potential mechanisms by which LN mitigates APAP-induced liver injury.The results dem-onstrated that varying concentrations of LN effectively ameliorated serum aminotransferase activi-ty and oxidative stress levels induced by APAP in a dose-dependent manner.Histopathological ex-amination via HE staining revealed significant improvement in APAP-induced liver tissue injury following treatment with different concentrations of LN.Furthermore,Western blot analysis indi-cated that the protein expressions of SPHK1,CHOP,p-IRE1α,ATF6,p-PERK,p-eIF2α,and ATF4 were markedly reduced after administration of various concentrations of LN.The results demonstrate that LN exhibits a significant protective effect against APAP-induced liver injury by inhibiting the SPHK1-mediated aberrant expression of ERS-related molecules.This study high-lights the importance of targeting SPHK1 in the treatment of APAP liver injury and provides a no-vel therapeutic approach through the multi-target and multi-pathway combination of monomers.

Objective To examine the association between sleep and depressive symptoms among community-dwelling older adults and whether loneliness mediates this association.Methods Using a multistage sampling approach,we enrolled participants aged 60 years or older from two communities in Chengdu,China.A questionnaire was used to collect basic information,including age,sex,etc.,from the participants.In addition,loneliness,depressive symptoms,and sleep quality were assessed using a short-form University of California Los Angeles Loneliness Scale(ULS-8),the 10-item version of Center of Epidemiologic Studies Depression Scale(CESD-10),and the Pittsburgh Sleep Quality Index(PSQI),respectively.The Spearman rank correlation coefficient was employed to assess the correlations among social sleep,loneliness,and depression symptoms.Generalized structural equation modeling was used to assess the mediating effect of loneliness between sleep and depressive symptoms.Results Of the 1377 participants,32.03％(441)experienced loneliness and 30.57％(421)had depressive symptoms,with the median and interquartile range of their sleep quality being 6(3,9).Correlation analysis revealed statistically significant associations between sleep quality,loneliness,and depressive symptoms(P＜0.001).Generalized structural equation modeling analysis revealed that loneliness had a partial mediation effect on the association between sleep quality and depressive symptoms(b=0.075;95％CI,0.025-0.125;P＜0.05),accounting for 44.38％of the total effect(95％CI,0.258-0.630;P＜0.001).Conclusion Poor sleep quality is associated with a higher risk of depressive symptoms in community-dwelling older adults,with loneliness mediating the association.Further research on improving the sleep quality to mitigate depressive symptoms in older adults is warranted.Special attention should be given to older adults experiencing both poor sleep and loneliness.

Objective:To investigate the efficacy of fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet count ratio (APRI), liver stiffness value (LSM), and Agile 3+ score and their combined model in predicting advanced-stage liver fibrosis in patients with chronic hepatitis B (CHB) combined with metabolic-associated fatty liver disease (MAFLD).Methods:A multicenter retrospective cohort study was conducted on the BMOVE population.Nine hundred twenty CHB cases combined with MAFLD who underwent liver biopsy at seven medical centers in China from April 2006 to December 2023 were included. The patients were divided into advanced-stage liver fibrosis (159 cases) and non-advanced-stage liver fibrosis (761 cases) according to the Scheuer's scoring system.The area under the receiver operating characteristic curve (AUROC), decision curve, and calibration curve analysis were used to evaluate the efficacy of the firbrosis-4 index (FIB-4) score, NFS score, APRI index, LSM, and Agile 3+ score and their combined model in predicting advanced-stage fibrosis. The liver fibrosis grade of all patients was diagnosed by liver biopsy. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each scoring model and combined model, as well as the proportion of correctly classified patients, were calculated based on different cutoff values.Results:AUROC analysis showed that Agile 3+ (0.814, 95% CI: 0.787-0.838) and LSM (0.805, 95% CI: 0.778-0.829) had similar accuracy and were superior to FIB-4 (0.721, 95% CI: 0.691-0.749), NFS (0.687, 95% CI: 0.656-0.716) and APRI ( 0.689, 95% CI: 0.658-0.718); however, HBV DNA level and HBV e antigen status had no effect on this outcome. Decision curve analysis showed that interventions based on LSM and Agile 3+ had provided higher net benefits compared with serological scores. Calibration curves showed that Agile 3+ had better predicitive accuracy than all other models. Agile 3+ had the highest PPV (0.54), minimal uncertainty interval (11.6%), and the highest proportion of correctly classified patients (76%); followed by LSM (PPV: 0.43, uncertainty interval: 15.5%, correct classification rate: 66%), and FIB-4 (PPV: 0.42, uncertainty interval: 26.1%, correct classification rate: 62.6%) in terms of identifying advanced-stage liver fibrosis. Combined model analysis demonstrated that FIB-4 combined with Agile 3+ had improved the correct classification rate and reduced the proportion of missed patients compared with FIB-4 combined with LSM. Conclusion:The Agile 3+ score is superior than LSM, FIB-4, NFS, and APRI index at identifying advanced-stage fibrosis in patients with CHB combined with MAFLD. This study supports the use of FIB-4 index combined with Agile 3+ for risk stratification in patients with CHB combined with MAFLD.

Objective To explore the value of deep learning(DL)model based on grayscale ultrasound for predicting asymptomatic advanced chronic liver disease(cACLD).Methods Totally 258 patients with asymptomatic compensatory chronic liver diseases were retrospectively included,among them 117 with F3 or F4 stage liver fibrosis were classified into cACLD group,while 141 with F1 or F2 stage liver fibrosis were taken as non-cACLD group.The patients were divided into training set(n=180,including 82 cases of cACLD and 98 cases of non-cACLD)and validation set(n=78,including 35 cases of cACLD and 43 cases of non-cACLD)at the ratio of 7∶3.Univariate and multivariate logistic regression were used to screen independent clinical predictors of cACLD and construct a clinical model.Based on liver grayscale ultrasound,optimal DL features were extracted and screened,and Resnet50 network was adopted as framework,na?ve Bayes classifier was used to construct DL model,and a combined model was constructed based on clinical model and DL model.The efficacy and clinical value of each model for predicting asymptomatic cACLD were evaluated.Results Age,gamma-glutamyl transferase and platelet count were all independent clinical predictors of cACLD,and a clinical model was constructed.Totally 38 optimal DL features were screened to build a DL model.The AUC of combined model in training set and validation set was 0.950 and 0.740,of DL model was 0.944 and 0.737,respectively,being not significantly different(both P＞0.05)but all higher than that of clinical model(0.667 and 0.573,all P＜0.05).Taken 0.59-0.90 as the threshold,the net benefits of combined model in both training and validation sets were higher than that of other models.Conclusion DL model based on grayscale ultrasound could be used to effectively predict asymptomatic cACLD.Combining with clinical characteristics might improve clinical net benefit of this model.

Objective To explore the value of deep learning(DL)model based on grayscale ultrasound for predicting asymptomatic advanced chronic liver disease(cACLD).Methods Totally 258 patients with asymptomatic compensatory chronic liver diseases were retrospectively included,among them 117 with F3 or F4 stage liver fibrosis were classified into cACLD group,while 141 with F1 or F2 stage liver fibrosis were taken as non-cACLD group.The patients were divided into training set(n=180,including 82 cases of cACLD and 98 cases of non-cACLD)and validation set(n=78,including 35 cases of cACLD and 43 cases of non-cACLD)at the ratio of 7∶3.Univariate and multivariate logistic regression were used to screen independent clinical predictors of cACLD and construct a clinical model.Based on liver grayscale ultrasound,optimal DL features were extracted and screened,and Resnet50 network was adopted as framework,na?ve Bayes classifier was used to construct DL model,and a combined model was constructed based on clinical model and DL model.The efficacy and clinical value of each model for predicting asymptomatic cACLD were evaluated.Results Age,gamma-glutamyl transferase and platelet count were all independent clinical predictors of cACLD,and a clinical model was constructed.Totally 38 optimal DL features were screened to build a DL model.The AUC of combined model in training set and validation set was 0.950 and 0.740,of DL model was 0.944 and 0.737,respectively,being not significantly different(both P＞0.05)but all higher than that of clinical model(0.667 and 0.573,all P＜0.05).Taken 0.59-0.90 as the threshold,the net benefits of combined model in both training and validation sets were higher than that of other models.Conclusion DL model based on grayscale ultrasound could be used to effectively predict asymptomatic cACLD.Combining with clinical characteristics might improve clinical net benefit of this model.

Objective:To investigate the efficacy of fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet count ratio (APRI), liver stiffness value (LSM), and Agile 3+ score and their combined model in predicting advanced-stage liver fibrosis in patients with chronic hepatitis B (CHB) combined with metabolic-associated fatty liver disease (MAFLD).Methods:A multicenter retrospective cohort study was conducted on the BMOVE population.Nine hundred twenty CHB cases combined with MAFLD who underwent liver biopsy at seven medical centers in China from April 2006 to December 2023 were included. The patients were divided into advanced-stage liver fibrosis (159 cases) and non-advanced-stage liver fibrosis (761 cases) according to the Scheuer's scoring system.The area under the receiver operating characteristic curve (AUROC), decision curve, and calibration curve analysis were used to evaluate the efficacy of the firbrosis-4 index (FIB-4) score, NFS score, APRI index, LSM, and Agile 3+ score and their combined model in predicting advanced-stage fibrosis. The liver fibrosis grade of all patients was diagnosed by liver biopsy. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each scoring model and combined model, as well as the proportion of correctly classified patients, were calculated based on different cutoff values.Results:AUROC analysis showed that Agile 3+ (0.814, 95% CI: 0.787-0.838) and LSM (0.805, 95% CI: 0.778-0.829) had similar accuracy and were superior to FIB-4 (0.721, 95% CI: 0.691-0.749), NFS (0.687, 95% CI: 0.656-0.716) and APRI ( 0.689, 95% CI: 0.658-0.718); however, HBV DNA level and HBV e antigen status had no effect on this outcome. Decision curve analysis showed that interventions based on LSM and Agile 3+ had provided higher net benefits compared with serological scores. Calibration curves showed that Agile 3+ had better predicitive accuracy than all other models. Agile 3+ had the highest PPV (0.54), minimal uncertainty interval (11.6%), and the highest proportion of correctly classified patients (76%); followed by LSM (PPV: 0.43, uncertainty interval: 15.5%, correct classification rate: 66%), and FIB-4 (PPV: 0.42, uncertainty interval: 26.1%, correct classification rate: 62.6%) in terms of identifying advanced-stage liver fibrosis. Combined model analysis demonstrated that FIB-4 combined with Agile 3+ had improved the correct classification rate and reduced the proportion of missed patients compared with FIB-4 combined with LSM. Conclusion:The Agile 3+ score is superior than LSM, FIB-4, NFS, and APRI index at identifying advanced-stage fibrosis in patients with CHB combined with MAFLD. This study supports the use of FIB-4 index combined with Agile 3+ for risk stratification in patients with CHB combined with MAFLD.

Objective:To analyze the clinical features of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), and to evaluate the accuracy of the TEN-specific severity-of-illness score (SCORTEN) in predicting death.Methods:A retrospective analysis was conducted on 104 patients with SJS/TEN at the First Affiliated Hospital of Army Medical University between December 2003 and December 2023. Clinical data, such as sensitizing drugs, clinical manifestations, laboratory tests, SCORTEN scores, and treatment regimens, were collected and retrospectively analyzed. The efficacy of different treatment modalities for TEN was analyzed. The receiver operating characteristic (ROC) curve was used to assess the accuracy of SCORTEN in predicting death in TEN patients.Results:Among the 104 patients, 57 were males and 47 were females, with ages ranging from 12 to 93 years (45.45 ± 19.76 years). There were 52 cases of SJS and 52 cases of TEN (including 1 case of SJS-TEN overlap). The ages of SJS patients (40.42 ± 17.06 years) were significantly lower than those of TEN patients (50.48 ± 21.13 years; t = 2.67, P = 0.009) ; the total hospital stay was 14.47 ± 7.24 days, and the TEN patients had significantly longer hospital stays (16.65 ± 7.82 days) compared with the SJS patients (12.29 ± 5.92 days; t = 3.21, P = 0.002). Definite sensitizing drugs were identified in 82 patients; combined drugs were the most common sensitizing cause (26 cases, 25.00%), and 20 patients reported combination treatment with antibiotics; 56 patients (53.85%) were treated with single drugs, and the common sensitizing drugs included carbamazepine (16 cases, 15.38%), nonsteroidal anti-inflammatory drugs (13 cases, 12.50%), and allopurinol (9 cases, 8.65%). Laboratory test results showed that the proportions of patients with decreased lymphocyte counts, elevated alanine aminotransferase and/or aspartate aminotransferase levels, decreased albumin levels, and with increased creatinine levels were significantly higher in the TEN patients than in the SJS patients (all P < 0.05), while the proportion of patients with increased monocyte counts was significantly lower in the TEN patients than in the SJS patients ( P = 0.006). Among the 52 TEN patients, 33 had SCORTEN scores < 3 points and 19 had scores ≥ 3 points, with 12.32 expected deaths and 4 actual deaths; the ROC curve analysis indicated that the area under the curve for SCORTEN in predicting death in TEN patients was 0.784 (95% CI: 0.558 - 1.00). Of the 104 patients, 57 (54.81%) received a monotherapy regimen (glucocorticoids only), and 47 (45.19%) received combination therapies, including glucocorticoids combined with intravenous immunoglobulin (IVIG) in 42 cases. Among the TEN patients, 30 started combination therapy with IVIG within 7 days after glucocorticoid treatment (early combination therapy group), and 7 patients started IVIG after 7 days of glucocorticoid treatment (late combination therapy group). The early combination therapy group showed a shorter time to lesion stabilization (10.82 ± 3.35 days) compared with the late combination therapy group (15.50 ± 4.04 days; LSD- t = 2.87, P = 0.006) . Conclusions:The main sensitizing cause in SJS/TEN patients was the combination of antibiotics. Early combination of glucocorticoids and IVIG could shorten the disease course in TEN patients to some extent. SCORTEN still holds a certain clinical value in predicting the prognosis of TEN patients.

Objectives:To investigate the efficacy and safety of anlotinib combined with niraparib in treating patients with platinum-resistant ovarian cancer.Methods:Thirty-five patients with pathological confirmed platinum-resistant ovarian cancer who experienced progression after receiving at least two lines of standard treatment were eligible. All of them were treated with anlotinib combined with niraparib between September 2019 and October 2021. The primary endpoint was progression-free survival (PFS). The second endpoints included overall survival, objective response rate (ORR), disease control rate (DCR) and safety. Survival analysis was performed using the Kaplan-Meier method and Log-rank test, and influence factor analysis was performed using Cox proportional risk regression models.Results:The best overall response showed that partial response was observed in 14 patients, stable disease was noted within 13 patients, and progressive disease was found in 8 patients. Therefore, the ORR and DCR of these 35 patients were 40.0% (95% CI:22.9%-57.1%) and 77.1% (95% CI:62.9%-91.4%), respectively. The median follow-up duration was 18.9 months (6.9-32.2). The median PFS was 6.5 months (95% CI:5.35-7.66). Multivariate Cox regression analysis for PFS indicated that age, Eastern Cooperative Oncology Group performance status (ECOG PS) score, International Federation of Gynecology and Obstetrics (FIGO) stage, and BRCA mutation status were independent factors influencing PFS ( P＜0.05). Additionally, the PFS in patients with BRCA mutation who have never received PARP inhibitor treatment was significantly longer than that in patients without BRCA mutation who have been exposed to prior PARPi treatment (15.0 vs 6.0 month, P=0.029). The most common treatment-related adverse reactions were fatigue (85.7%), hematologic toxic (85.7%) and hypertension (74.3%). There were no treatment-related deaths. Conclusion:Anlotinib combined with niraparib shows a promising efficacy and tolerable safety in platinum-resistant ROC patients.

Objectives:To investigate the efficacy and safety of anlotinib combined with niraparib in treating patients with platinum-resistant ovarian cancer.Methods:Thirty-five patients with pathological confirmed platinum-resistant ovarian cancer who experienced progression after receiving at least two lines of standard treatment were eligible. All of them were treated with anlotinib combined with niraparib between September 2019 and October 2021. The primary endpoint was progression-free survival (PFS). The second endpoints included overall survival, objective response rate (ORR), disease control rate (DCR) and safety. Survival analysis was performed using the Kaplan-Meier method and Log-rank test, and influence factor analysis was performed using Cox proportional risk regression models.Results:The best overall response showed that partial response was observed in 14 patients, stable disease was noted within 13 patients, and progressive disease was found in 8 patients. Therefore, the ORR and DCR of these 35 patients were 40.0% (95% CI:22.9%-57.1%) and 77.1% (95% CI:62.9%-91.4%), respectively. The median follow-up duration was 18.9 months (6.9-32.2). The median PFS was 6.5 months (95% CI:5.35-7.66). Multivariate Cox regression analysis for PFS indicated that age, Eastern Cooperative Oncology Group performance status (ECOG PS) score, International Federation of Gynecology and Obstetrics (FIGO) stage, and BRCA mutation status were independent factors influencing PFS ( P＜0.05). Additionally, the PFS in patients with BRCA mutation who have never received PARP inhibitor treatment was significantly longer than that in patients without BRCA mutation who have been exposed to prior PARPi treatment (15.0 vs 6.0 month, P=0.029). The most common treatment-related adverse reactions were fatigue (85.7%), hematologic toxic (85.7%) and hypertension (74.3%). There were no treatment-related deaths. Conclusion:Anlotinib combined with niraparib shows a promising efficacy and tolerable safety in platinum-resistant ROC patients.