Tailored lipid nanoparticles (LNPs)-mediated small interfering RNA (siRNA) nanomedicines show promise in treating liver disease, such as acute liver injury (ALI) and non-alcoholic steatohepatitis (NASH). However, constructing LNPs that address biosafety concerns, ensure efficient delivery, and target specific hepatic subcellular fractions has been challenging. To evade above obstacles, we develop three novel self-degradable "gemini-like" ionizable lipids (SS-MA, SS-DC, SS-MH) by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head. Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release, improving both biosafety and siRNA delivery efficiency. Furthermore, the distance of ester bond and tertiary amino head significantly influences the LNPs' pK _a, thereby affecting endosomal escape, hemolytic efficiency, absorption capacity of ApoE, uptake efficiency of hepatocytes and liver accumulation. We also develop the modified-mannose LNPs (M-LNP) to target liver macrophages specifically. The optimized M-MH_LNP@TNFα exhibits potential in preventing ALI by decreasing tumor necrosis factor α (TNFα) levels in the macrophages, while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-acyltransferase 2 (DGAT2) in the hepatocytes. Our findings provide new insights into developing novel highly effective and low-toxic "gemini-like" ionizable lipids for constructing LNPs, potentially achieving more effective treatment for hepatic diseases.

Background: The function of CD69 expressed on T cells in chronic hepatitis B (CHB) remains unclear. We aimed to elucidate the roles of CD69 on T cells in the disease process and in antiviral therapy for CHB. Methods: We enrolled 335 treatment-naive patients with CHB and 93 patients with CHB on antiviral therapy. CD69, antiviral cytokine production by T cells, T-helper (Th) cells, and inhibitory molecules of T cells were measured using flow cytometry, and clinical-virological characteristics were examined dynamically during antiviral therapy. Results: CD69 expression on CD3+, CD4+, and CD8+ T cells was the lowest in the immune-active phase and was negatively correlated with liver transaminase activity, fibrosis features, inflammatory cytokine production by T cells, and Th-cell frequencies but positively with inhibitory molecules on T cells. CD69 expression on CD3+, CD4+, and CD8+ T cells decreased after 48 weeks of antiviral therapy, and patients with hepatitis B e antigen (HBeAg) seroconversion in week 48 showed lower CD69 expression on T cells at baseline and week 48. The area under the ROC curve of CD69 expression on T cells at baseline for predicting HBeAg seroconversion in week 48 was 0.870, the sensitivity was 0.909, and the specificity was 0.714 (P = 0.002). Conclusions CD69 negatively regulates T-cell immunity during CHB, and its expression decreases with antiviral therapy. CD69 expression predicts HBeAg seroconversion in week 48. CD69 may play an important negative role in regulating T cells and affect the efficacy of antiviral therapy.

The clinical phenotype heterogeneity of epilepsy patients with ADGRV1 gene mutation is significant, ranging from self limiting febrile seizures to developmental epileptic encephalopathy, even causing sudden epileptic death. A case of infantile epileptic spasms syndrome with a novel heterozygous variant of the ADGRV1 gene c.4100C>A (p.Thr1367Lys) was reported in this article. The site of this variant had not been reported yet, and the clinical manifestations of the child mainly included epileptic spasms (first onset at 4 months old), mild growth and development delay, highly irregular video electroencephalogram, and effective treatment with adrenocorticotropic hormone.

The clinical phenotype heterogeneity of epilepsy patients with ADGRV1 gene mutation is significant, ranging from self limiting febrile seizures to developmental epileptic encephalopathy, even causing sudden epileptic death. A case of infantile epileptic spasms syndrome with a novel heterozygous variant of the ADGRV1 gene c.4100C>A (p.Thr1367Lys) was reported in this article. The site of this variant had not been reported yet, and the clinical manifestations of the child mainly included epileptic spasms (first onset at 4 months old), mild growth and development delay, highly irregular video electroencephalogram, and effective treatment with adrenocorticotropic hormone.

Objective:To explore the expression of long non-coding RNA(lncRNA)ZIM2-AS1 in hepatocellular carcinoma(HCC)and its clinical significance as well as diagnostic value using the data obtained from the Cancer Genome Atlas(TCGA).Meth-ods:The transcriptome sequencing(RNA-seq)data and clinical information of 374 HCC tissues and 50 paired paracancerous tissues were gathered from the TCGA database,then the expression trends of ZIM2-AS1 in HCC and its correlation with clinicopathological features,prognosis,immune cell infiltration,as well as diagnostic value was inspected by bioinformatics analysis using relevant R packages.The expression of ZIM2-AS1 in human normal liver cell line and HCC cell lines was examined by qRT-PCR.Results:The ex-pression of ZIM2-AS1 was highly expressed in HCC tissues(P<0.001),and its expression level was significantly correlated with age,gender,N stage,histologic grade and AFP level(P all<0.05).The overall survival(OS)and disease specific survival(DSS)of patients with high ZIM2-AS1 expression were significantly shorter than those of patients with low expression(P<0.05),and ZIM2-AS1 was an in-dependent risk factor affecting OS.Immune cell infiltration analysis showed that ZIM2-AS1 was closely related to the infiltration of Th2 cells,CD56brightNK cells,follicular helper T cells(Tfh),neutrophils and plasmacytoid dendritic cells(pDC)(|Spearman's r|>0.1,P<0.05)in HCC.ROC curve analysis revealed that the expression level of ZIM2-AS1 possesse potential diagnostic value in HCC,N0 stage,histologic grade G1 and G2,OS and DSS(AUC all>0.50).qRT-PCR results showed that the expression level of ZIM2-AS1 in HCC cell lines was significantly higher than that in human normal liver cells(P all<0.05).Conclusion:The elevated expression of lncRNA ZIM2-AS1 is an independent risk factor for poor prognosis of HCC patient and has potential application value as a biomarker for HCC diagnosis,prognosis as well as tumor immune microenvironment assessment.

Objective:To juxtapose laparoscopic cholecystectomy combined with common bile duct exploration and stone extraction (LC+ LCBDE) against endoscopic retrograde cholangiopancreatography/sphincterotomy with laparoscopic cholecystectomy (LC+ ERCP/EST) in the therapeutic context of acute biliary pancreatitis.Methods:The clinical data of patients with acute biliary pancreatitis in Department of Hepatobiliary Surgery, Datong Third People's Hospital from January 2017 to January 2021 were retrospectively analyzed. A total of 44 patients were inrolled, including 23 males and 21 females, with the age of (60.6±11.7) years. Based on different treatment approaches, the patients were divided into the LC+ LCBDE group ( n=33) and the LC+ ERCP group ( n=11, LC+ ERCP/EST). Total bilirubin, direct bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood amylase, operation time, postoperative hospitalization stays, total hospitalization cost, postoperative anal exhaust time, and postoperative complications (bile leakage, fever, bleeding) were compared between the two groups. Results:There were no significant differences in preoperative total bilirubin, direct bilirubin, ALT, AST, and blood amylase between LC+ ERCP group and LC+ LCBDE groups (all P>0.05). In LC+ LCBDE group, operation time was 110.0 (96.3, 147.5) min, postoperative hospitalization time was 9.0 (7.5, 11.0) d, postoperative exhaust time was 2.0 (1.0, 2.0) d, and in LC+ LCBDE group, operation time was 60.0 (32.0, 65.0) min, postoperative hospitalization time was 7.0 (4.0, 8.0) d, postoperative exhaust time was 1.0 (1.0, 1.0) d. Comparisons with LC+ LCBDE group, LC+ ERCP group had shorter postoperative hospitalization stay and earlier postoperative exhaust time, the total hospitalization cost of LC+ LCBDE group was 23 829.3 (21 779.6, 27 221.9) yuan, which was higher than 36 894.8 (31 963.5, 41 172.2) yuan in LC+ ERCP group, and the differences were statistically significant (all P<0.05). Comparison of postoperative total bilirubin, direct bilirubin, ALT and AST between LC+ ERCP group and LC+ LCBDE group, with no significant difference(all P>0.05). No postoperative complications such as bile leakage, residual stones, fever and bleeding occurred in both groups. Conclusion:Compared with LC+ ERCP/EST, LC+ LCBDE in the treatment of acute biliary pancreatitis, although the operation time and hospital stay are longer, but the total hospitalization cost is less, there is no need for multiple operations, and it can be used as the first choice for acute biliary pancreatitis.

Objective:To evaluate the effect of patent foramen ovale on the development of post-operative stroke in the patients undergoing non-cardiac surgery using a meta-analysis approach.Methods:A comprehensive search was conducted across multiple databases including PubMed, Embase, Web of Science, CINAHL, Cochrane Library, China Biomedical Literature Database, Wanfang Data Knowledge Service Platform, and China Journal Full Text Database.The inclusion criteria encompassed studies assessing the correlation between patent foramen ovale and post-operative stroke.The primary outcome measure focused on the incidence of post-operative stroke, and secondary outcome measures comprised mortality, myocardial infarction rate, and readmission rate within 30 days after surgery. The quality of literature meeting the inclusion criteria was evaluated and data were extracted, and then meta-analysis was conducted using RevMan 5.4 software.Results:Eight retrospective cohort studies involving 21 142 237 patients were included.The results of meta-analysis showed that patent foramen ovale was associated with post-operative stroke and readmission within 30 days after surgery.There were no significant differences in all-cause mortality and myocardial infarction rates between patent foramen ovale group and mon-patent foramen ovale group ( P>0.05). Conclusions:Patent foramen ovale can increase the risk of post-operative stroke in the patients undergoing non-cardiac surgery.

Purpose To construct the model of differentiating primary central nervous system lymphoma(PCNSL)and atypical glioblastoma(GBM)by combining multi-parameter MRI radiomics and six machine learning algorithms,thus to compare the diagnostic efficacy of different machine learning algorithms.Materials and Methods The clinical and imaging data of 77(125 lesions)PCNSL and 90 atypical GBM(108 lesions)from PLA General Hospital and public databases were retrospectively analyzed from January 2013 to December 2023,and all patients were randomly divided into a training set(163 cases)and a validation set(70 cases)according to 7∶3.T1WI,T2WI and T1-weighted contrast-enhanced sequences were selected for tumor segmentation,and 1 132 radiomics features were extracted from each region of interest.The intraclass correlation coefficient(ICC)was used for the consistency test,and image features with ICC≥0.85 were selected.ICC and recursive feature elimination were used to select the best radiomics features.Six classifiers were used to train and verify three single sequence feature sets,three double-sequence sets and one multi-sequence set.The receiver operating characteristic curve was used to evaluate the diagnostic efficacy of the model.Results The combination model of the support vector machine of radial basis function classifier and multi-sequence feature set were the best model for differentiating PCNSL and atypical GBM.The area under the curve of the training set and the validation set were 0.969 and 0.913,respectively;and the accuracy were both 0.886.Conclusion Noninvasive extraction of multiparametric MRI features combined with machine learning algorithms can effectively differentiate PCNSL and atypical GBM,which provides support for the development of individualized treatment plans for patients.