Objective: To examine the mediating effect of frailty on social isolation and cognitive function among the elderly. Methods: Demographic information, smoking, alcohol consumption and cognitive function of the elderly at ages of 60 years and older were collected from the China Health and Retirement Longitudinal Study 2020. Social isolation and frailty were evaluated using social isolation index and frailty index, respectively. The mediating effect of frailty on social isolation and cognitive function was analyzed using the Process program, and the significance of the mediating role was tested using the Bootstrap test. Results: A total of 2 822 individuals were enrolled, including 1 483 males (52.55%) and 1 339 females (47.45%). There were 2 497 (88.48%) and 325 (11.52%) individuals at ages of 60-<75 years and ≥75 years, respectively. The median cognitive function score was 14 (interquartile range, 16) points. There were 432 cases with social isolation (15.31%), with a median social isolation index of 10 (interquartile range, 5) points. The median frailty index was 0.11 (interquartile range, 0.15). There were 1 111 individuals without frailty, accounting for 39.37%; 1 214 individuals with pre-frailty, accounting for 43.02%; and 497 individuals with frailty, accounting for 17.61%. Mediating effect analysis showed that social isolation affected cognitive function directly and negatively with the effect value of -0.773 (95%CI: -0.899 to -0.647), and also affected cognitive function by frailty indirectly and negatively with the effect value of -0.147 (95%CI: -0.188 to -0.110), with the mediating effect contributed 15.98% of the total effect. Conclusion Frailty can directly or indirectly affect cognitive function among elderly through social isolation.

Metabolomics covers a wide range of applications in life sciences, biomedicine, and phytology. Data acquisition (to achieve high coverage and efficiency) and analysis (to pursue good classification) are two key segments involved in metabolomics workflows. Various chemometric approaches utilizing either pattern recognition or machine learning have been employed to separate different groups. However, insufficient feature extraction, inappropriate feature selection, overfitting, or underfitting lead to an insufficient capacity to discriminate plants that are often easily confused. Using two ginseng varieties, namely Panax japonicus (PJ) and Panax japonicus var. major (PJvm), containing the similar ginsenosides, we integrated pseudo-targeted metabolomics and deep neural network (DNN) modeling to achieve accurate species differentiation. A pseudo-targeted metabolomics approach was optimized through data acquisition mode, ion pairs generation, comparison between multiple reaction monitoring (MRM) and scheduled MRM (sMRM), and chromatographic elution gradient. In total, 1980 ion pairs were monitored within 23 min, allowing for the most comprehensive ginseng metabolome analysis. The established DNN model demonstrated excellent classification performance (in terms of accuracy, precision, recall, F1 score, area under the curve, and receiver operating characteristic (ROC)) using the entire metabolome data and feature-selection dataset, exhibiting superior advantages over random forest (RF), support vector machine (SVM), extreme gradient boosting (XGBoost), and multilayer perceptron (MLP). Moreover, DNNs were advantageous for automated feature learning, nonlinear modeling, adaptability, and generalization. This study confirmed practicality of the established strategy for efficient metabolomics data analysis and reliable classification performance even when using small-volume samples. This established approach holds promise for plant metabolomics and is not limited to ginseng.

BACKGROUND:In recent years,the incidence of hyperuricemia caused by purine metabolism disorders has been increasing,which can induce inflammatory responses and lead to renal injury. OBJECTIVE:To explore the role and mechanism of solute carrier family 2 member 12(SLC2A12)in hyperuricemia-related renal injury. METHODS:Renal tubular cells(HK2 cells)were divided into five groups:HK2 group,HK2+uric acid group,HK2+uric acid+NC group,HK2+uric acid+siSLC2A12 group,and HK2+uric acid+siSLC2A12+MK-2206 group.HK2 cells were treated with uric acid and transfected with siRNA SLC2A12,followed by MK-2206 treatment to inhibit AKT expression.Cell proliferation was detected by CCK-8 assay.Apoptosis was detected by TUNEL assay.qRT-PCR and western blot assay were used to detect fibrogenic factors as well as activation of the AKT/FOXO3a pathway.The concentrations of inflammatory cytokines were measured by enzyme-linked immunosorbent assay. RESULTS AND CONCLUSION:(1)Uric acid treatment inhibited cell proliferation and promoted cell apoptosis in the HK2+uric acid group compared with the HK2 group.The proliferative ability of cells in the HK2+uric acid+siSLC2A12 group was further decreased and apoptotic cells were further increased compared with the HK2 group.Compared with the HK2+uric acid+siSLC2A12 group,the HK2+uric acid+siSLC2A12+MK-2206 group showed an increase in cell proliferation and a decrease in apoptotic cells.(2)Compared with the HK2 group,the connective tissue growth factor(CTGF),α-smooth muscle actin(α-SMA)and transforming growth factor beta(TGF-β)expressions increased in the HK2+uric acid group;CTGF,α-SMA and TGF-β expression further increased in the HK2+uric acid+siSLC2A12 group.Compared with the HK2+uric acid+siSLC2A12 group,the CTGF,α-SMA and TGF-β expressions decreased.(3)Compared with the HK2 group,the expression of p-AKT,FOXO3a,and p-FOXO3a elevated in the HK2+uric acid group;the expression of p-AKT further increased,while the expression of FOXO3a and p-FOXO3a decreased in the HK2+uric acid+siSLC2A12 group.Compared with the HK2+uric acid+siSLC2A12 group,p-AKT expression decreased;FOXO3a and p-FOXO3a expression increased in the HK2+uric acid+siSLC2A12+MK-2206 group.(4)Compared with the HK2 group,interleukin-6,interleukin-1 β,and tumor necrosis factor α levels increased in the HK2+uric acid group;interleukin-6,interleukin-1 β,and tumor necrosis factor α levels further increased in the HK2+uric acid+siSLC2A12 group.Compared with the HK2+uric acid+siSLC2A12 group,interleukin-6,interleukin-1 β,and tumor necrosis factor α levels diminished in the HK2+uric acid+siSLC2A12+MK-2206 group.(5)These findings indicate that SLC2A12 may protect against hyperuricemia-induced renal injury by counteracting uric acid-induced tubular fibrosis and inflammation through activation of the FOXO3a pathway.

Purpose: This study aims to evaluate the efficacy and safety of a new combination treatment of vinorelbine and pyrotinib in human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) and provide higher level evidence for clinical practice. Materials and Methods: This was a prospective, single-arm, phase 2 trial conducted at three institutions in China. Patients with HER2-positive MBC, who had previously been treated with trastuzumab plus a taxane or trastuzumab plus pertuzumab combined with a chemotherapeutic agent, were enrolled between March 2020 and December 2021. All patients received pyrotinib 400 mg orally once daily plus vinorelbine 25 mg/m2 intravenously or 60-80 mg/m2 orally on day 1 and day 8 of 21-day cycle. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival, and safety. Results: A total of 39 patients were enrolled. All patients had been pretreated with trastuzumab and 23.1% (n=9) of them had accepted trastuzumab plus pertuzumab. The median follow-up time was 16.3 months (95% confidence interval [CI], 5.3 to 27.2), and the median PFS was 6.4 months (95% CI, 4.0 to 8.8). The ORR was 43.6% (95% CI, 27.8% to 60.4%) and the DCR was 84.6% (95% CI, 69.5% to 94.1%). The median PFS of patients with versus without prior pertuzumab treatment was 4.6 and 8.3 months (p=0.017). The most common grade 3/4 adverse events were diarrhea (28.2%), neutrophil count decreased (15.4%), white blood cell count decreased (7.7%), vomiting (5.1%), and anemia (2.6%). Conclusion Pyrotinib plus vinorelbine showed promising efficacy and tolerable toxicity as second-line treatment in patients with HER2-positive MBC.

Objective:To explore the safety and efficacy of Propafenone in terminating paroxysmal supraventricular tachycardia (PSVT) in children and analyze the factors influencing the effectiveness.Methods:A retrospective study was conducted on 169 PSVT children treated with Propafenone in the Department of Pediatric Cardiology, Heart Center, the First Hospital of Tsinghua University from September 2014 to October 2021.There were 118 boys and 51 girls with an average age of (2.84±2.91) years (age range: 14 days-13 years). According to age, they were divided into ≤ 1-year-old group, >1-3-year-old group, >3-7-year-old group, and >7-year-old group.Mea-surement data were compared between groups using t-test and Mann- Whitney U test.Counting data were analyzed by χ2 test. Results:Among the 169 children with PSVT, 65 cases (38.5%) were below 1 year old, 47 cases (27.8%) were >1-3 years old, 40 cases (23.7%) were >3-7 years old, 17 cases (10.1%) were above 7 years old.About 24 cases (14.2%) were combined with congenital heart disease.A total of 153 cases (90.5%) had nonspecific symptoms at the first visit.A total of 4.1% (7/169 cases) were complicated with tachycardia-induced cardiomyopathy, and their left ventricular ejection fraction increased from (44.0±4.0)% to (53.7±6.9)% after successful control of PSVT ( t=-4.700, P=0.003). The complete termination of PSVT by intravenous Propafenone was achieved in 125 of 169 cases (74.0%, 125/169 cases). The complete termination rate after multiple times of administration (74.0%) was significantly higher than that after the first intravenous injection (53.3%, 90/169 cases) ( χ2=15.657, P<0.001). There was a significant difference regarding the complete termination rate between children ≤1 year old (60.0%, 39/65 cases) and those >1 year old (82.7%, 86/104 cases) ( χ2=10.696, P=0.001). For children ≤1 year old, 1.5 mg/kg Propafenone (51.1%, 23/45 cases) showed better efficacy for PSVT termination than 1.0 mg/kg Propafenone (20.0%, 4/20 cases) ( χ2=5.519, P=0.019). For children >1 year old, there was no significant diffe-rence between 1.5 mg/kg and 1.0 mg/kg Propafenone groups (57.9% vs.62.1%) ( χ2=0.180, P=0.671). The adverse reaction rate of intravenous Propafenone was 9.5% (16/169 cases). One case presented with severe hypotension, which occurred in a child with right cardiac insufficiency with tricuspid valve depression; 15 cases showed abnormal cardiac conduction and recovered spontaneously in a short time.There was no deterioration of cardiac function in children with mildly to moderately reduced cardiac function. Conclusions:It is relatively safe and effective to terminate PSVT in children with intravenous Propafenone.The complete termination rate is 74.0%, which is related to age, dose and times of administration.Despite of low incidence of side effects, Propafenone should not be used to treat PSVT with cardiac function which is significantly impaired or unclear secondary to persistent tachycardia.Special attention should be paid to cardiac function deterioration in these patients.

Objective:To investigate the effect of lipopolysaccharide (LPS) on primary neonatal rat cardiomyocytes (CMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs).Methods:The hiPS-CMs and primary neonatal rat CMs were treated with different concentrations of LPS for 24 to 48 h. Then the cellular viability was analyzed by the xCELLigence RTCA Cardio system. The measurement of NPPB gene was studied by qRT-PCR and the gene expression analysis was performed by the qPCR array, in order to evaluate the cardiac inflammation effect induced by LPS.Results:The LPS exposure led to dysfunction in the primary neonatal rat CMs, which shown as an increase in beating rate and a decrease in contraction amplitude ( P<0.01), accompanied by an increased NPPB mRNA level ( P<0.01). There was no significant alteration in beating rate and the contraction amplitude in the corresponding concentration of the primary neonatal rat CMs ( P>0.05), as well as the NPPB mRNA level ( P>0.05). However, the expression of NPPB mRNA in hiPS-CMs was significantly different at a higher concentration of LPS (5 μg/mL~40 μg/mL) ( P<0.01), but the beating rate and the contraction amplitude showed no significant change, even the concentration of LPS up to 40 μg/mL ( P>0.05). Finally, the genes of C3, Gpnmb, Atf3, Il6r and Ly96 upregulated to 1.5 folds in the primary neonatal rat CMs. In comparison with primary neonatal rat CMs, the AK4, TOLLIP, SPP1, FABP1, IL6R, LY96 and C3 were over expression to 1.5 folds in the hiPS-CMs. Conclusions:In comparison with primary neonatal rat CMs, hiPS-CMs are markedly less injured by LPS and show a different pattern of inflammation gene expression.

Objective:To analyze the sepsis related long non-coding RNA (lncRNA) and mRNA expression profiles based on Gene Expression Omnibus (GEO) datasets and bioinformatic analysis, and to analyze the sepsis-associated competing endogenous RNA (ceRNA) network based on microRNA (miRNA) database.Methods:The sepsis-related lncRNA dataset was downloaded from the GEO database, and the differential expression analysis was conducted by Bioconductor on the sepsis dataset to obtain differentially expressed lncRNA (DElncRNA) and differentially expressed mRNA (DEmRNA), and cluster heat map was drawn. miRNA combined with DElncRNA were predicted by miRcode. mRNA targeted by miRNA was simultaneously met by three databases: TargetScan, miRDB, and mirTarBase. The interaction relationship of lncRNA-miRNA-mRNA was obtained. The regulatory network visualization software CytoScape was used to draw ceRNA networks. DEmRNA in the ceRNA networks were imported into the Search Tool for the Retrieval of Interacting Genes Database (STRING) online database to draw the protein-protein interaction (PPI) map. The gene ontology (GO) function annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEmRNA were performed.Results:Dataset GSE89376 and GSE145227 were found from GEO database. Difference analysis showed there were 14 DElncRNA and 359 DEmRNA in the elderly group of GSE89376; 8 DElncRNA and 153 DEmRNA in the adult group of GSE89376; 1 232 DElncRNA and 1 224 DEmRNA in the children group of GSE145227. Clustering heatmap showed that there were significant differences in the expression of lncRNA and mRNA between the sepsis group and the control group. The ceRNA networks were constructed with miRNA. Several DElncRNA and multiple DEmRNA participated in the ceRNA network of sepsis. The PPI diagram demonstrated that several genes encoding proteins interacted with each other and form a multi-node interaction network with multiple genes encoding proteins. Functional annotation and enrichment analysis demonstrated that there might be a crosstalk mechanism on functionally related genes such as nuclear receptor activity, ligand-activated transcription factor activity, and steroid hormone receptor activity, and played a role in the occurrence and development of diseases through forkhead box transcription factor O (FoxO) signaling pathway, Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway, p53 signaling pathway, and phosphateidylinositol 3-kinase (PI3K)/Akt signaling pathway.Conclusion:Through sepsis-related lncRNA-miRNA-mRNA ceRNA network and combining with KEGG pathway analysis, there were several lncRNA and mRNA participating in the ceRNA network related sepsis, which played an important role in several signal pathways.

Objective:To explore the safety and efficacy of adenosine triphosphate (ATP) in terminating paro-xysmal supraventricular tachycardia (PSVT) in children and the correlation between its efficacy, age and dose.Methods:A retrospective analysis was performed on the clinical data, efficacy and adverse effects of intravenous ATP in 120 children who had received ATP emergency cardioversion among 1 488 children with PSVT hospitalized in the Department of Pediatric Cardiology, Heart Center, First Hospital of Tsinghua University from September 2014 to November 2019.There were 80 boys and 40 girls with the age of (3.50±3.66) years (25 d-15 years). As for the group comparison, the measurement data was subject to the independent samples t test and Mann- Whitney U test; the enumeration data was subject to χ2 test. Results:Among the 120 children with PSVT, there were 42 cases (35.0%) <1 year old, and 24 cases(20.0%) combined with congenital heart disease.There were 8.3% of them (10/120 cases) suffering from tachycardiomyopathy (TCM) secondary to PSVT, whose LVEF increased from (32.70±11.69)% to (40.50±11.63)% after successful control of PSVT ( t=-3.647, P=0.005). The complete termination of PSVT by intravenous ATP was achieved in 53 of 120 cases (44.2%). ATP was given at 0.3 mg/kg, 0.2 mg/kg and 0.1 mg/kg in dose, and the significant effective rate was 56.5%(13/23 cases), 36.4%(32/88 cases) and 0, respectively, which showed that there was a significant difference in the therapeutic effect between different dose groups ( χ2=10.058, P=0.007). There was a significant difference regarding the complete termination rate between children <1 year old and those ≥1 year old [31.0%(13/42 cases) vs.51.3%(40/78 cases), χ2=4.575, P=0.032]. For refractory PSVT, the intravenous ATP was performed based on the absence of cardioversion with continuous pumping of other antiarrhythmic drugs, which achieved a significantly complete termination rate of 55.6% (10/18 cases). The rate of ATP adverse reactions was 2.5%(3/120 cases), presented with sinus arrest in children >1 year old with the dose of 0.2-0.3 mg/kg. Conclusions:It was relatively safe and effective to terminate PSVT in children with ATP, which was related to dose and age.For refractory PSVT, ATP can be intravenously pushed on the basis of continuous pumping of other antiarrhythmic drugs, which can achieve a higher complete termination rate.

Objective:To identify the risk factors for cardiac events like recurrent syncope and fatal events in children with long QT syndrome (LQTS).Methods:A retrospective review involving 69 children with LQTS with the age of (7.6±4.2) years (43 male patients, 26 female patients) admitted in the Heart Center, Division of Pediatric Cardiology, First Hospital of Tsinghua University from August 2013 to March 2019 was conducted.Medical history, surface electrocardiogram, Doppler echocardiography and screening results of pathogenic genes of each patient were analyzed.Patients were divided into cardiac event group (32 cases) and non-cardiac event group (37 cases) according to the presence or absence of cardiac events like syncope or sudden death.Differences between 2 groups were compared using the independent sample Student′s t test and Chi- square test. Results:There were 32 cases among 69 children (46.4%) had recurrent syncope, involving 2 deaths, 14 cases among 69 children (20.3%) had a positive family history and 8 cases among 69 children (11.6%) had family history of sudden death.There were 52 cases among 69 children (75.4%) had arrhythmias.Among them, 32 patients (46.4%) with ventricular arrhythmia, including 11 cases (15.9%) with torsades de pointes (TdP). Ten LQTS-associated pathogenic or pathogenic pathologic mutations were found in 53 cases among 69 children (76.8%). Children with cardiac events had a younger mean age of onset [(4.7±4.1) years vs.(7.4±3.7) years, t=-2.856, P=0.006], a longer mean corrected QT (QTc) [(529±66) ms vs.(478±52) ms, t=3.537, P=0.001] and a higher incidence of TdP (34.4% vs.0%, P<0.001) compared with those who did not have cardiac events.Pathogenic mutations of KCNQ1 and KCNH2 were more frequent in children with cardiac events (62.5% vs.18.9%, χ2=14.178, P=0.001). Conclusions:Children with LQTS are prone to cardiac events.Children with a younger onset age, a longer QTc duration, malignant ventricular tachycardia and mutations of the KCNQ1 and KCNH2 genes are more frequently complicated by cardiac events.

Objective:To investigate clinical electrophysiological characteristics of idiopathic ventricular arrhythmias (VAs) and outcomes of radiofrequency catheter ablation (RFCA) in pediatric patients.Methods:A total of 328 consecutive pediatric patients with VAs and treated with RFCA in the First Hospital of Tsinghua University from January 2014 to December 2019 were recruited, involving 205 males and 123 females with the mean age of (7.8±3.9) years and the mean body weight of (32.8±17.7) kg.Their clinical electrophysiological characteristics, RFCA outcomes of different origins of VAs and complications were analyzed.Results:Among the 328 patients with the mean onset age of (5.4±4.1) years, 57.6% had frequent premature ventricular complex (PVC), 28.7% had paroxysmal ventricular tachycardia (VT) and 13.7% had incessant VT.A total of 38/328 cases (11.6%) VAs children were complicated with tachycardia-induced cardiomyopathy.Except for 13 cases of non-induced VAs, among 315 cases there were 152/328 cases (46.4%) originated from the ventricular outflow tract (including 46.1% of the origination of the right ventricular outflow tract septum, 27.6% of the origination of the left coronary cusp, 18.4% of the origination of the right coronary cusp, and 7.9% of the origination of the right ventricular outflow tract free wall), 55/328 cases (16.5%) originated from the tricuspid valve, 54/328 cases (17.4%) originated from the left posterior fascicle, 39/328 cases (11.9%) originated from the left posterior papillary muscle, 5/328 cases (1.5%) originated from multi-origin VAs, 3/328 cases (0.9%) originated from the left anterior fascicle, and 7/328 cases (2.1%) originated from other origins.Among 307/328 cases (93.6%) VAs patients receiving RFCA, 271/307 cases (88.3%) were instantly successful, 14/307 cases (4.6%) were effectively treated and 22/307 cases (7.2%) were invalid.During the follow-up time of 3 to 36 months, there were 42/271 cases (15.5%) recurrent cases.The mean radiation time and dose were (3.2±5.8) min, and (1.4±2.6) mGy, respectively.The mean dose-area product (DAP) was (384.2±42.6) mGy·cm 2.A total of 4/328 cases (1.2%) reported perioperative vascular complication.In 20 infant patients younger than 3 years, only 1 case was not induced during procedure of RFCA, and the remaining 19 cases were performed with RFCA, including 18/19 cases (94.7%) with an instant success and 4/18 (22.2%) recurrent cases during follow-up.There were 1/20 case (5.0%) had perioperative vascular complication caused by vascular puncture.No serious complications, such as myocardial perforation, cardiac tamponade and atrioventricular block were reported. Conclusions:The right ventricular outflow tract septum is the most common origin of the idiopathic VAs in pediatric patients.VAs originated from the ventricular outflow tract and tricuspid valve usually have an acceptable outcome following ablation.The recurrent rate is high following ablation in VAs cases originated from the left ventricular fascicle and posterior papillary muscle.RFCA is safe and effective for drug resistant or intolerant VAs in infants, but the surgical indications should be strictly mastered and operated by experienced pediatric electrophysiologists.The radiation dose of RFCA can be limited in a safe range under the guidance of the 3-dimensional mapping system.