Objective To develop a risk assessment scale for immune checkpoint inhibitor (ICI)-associated myocarditis based on multidisciplinary collaboration, and to evaluate its diagnostic performance. Methods Based on multidisciplinary cooperation, integrating clinical experience from oncology and cardiology, literature data, and patient conditions, a risk assessment scale for ICI-associated myocarditis was developed. A total of 101 patients with malignancies who received immunotherapy at Zhongshan Hospital, Fudan University, from October 2020 to October 2024 were included as the validation cohort. Patients were stratified into low-risk (0-1 point), medium-risk (2-4 points), and high-risk (≥5 points) groups based on their scale scores. The association between pretictive risk stratifications and actual assessment results was assessed using the Cox proportional hazards regression model. The predictive value of the scale for ICI-associated myocarditis was evaluated using receiver operating characteristic (ROC) curve. Agreement between the scale scores and actual assessment results was assessed using Cohen’s Kappa coefficient. Results Based on the scale pretictive results, 28(27.7%), 8(7.9%), 65(64.4%) patients were at low risk, medium risk, and high risk for ICI-related myocarditis, respectively; however, 46(45.5%), 8(7.9%), 47(46.5%) were at low risk, medium risk, and high risk actually. Kaplan-Meier survival analysis showed that the cumulative incidence of ICI-related myocarditis in the high-risk group was significantly higher than that in the medium- and low-risk groups (P＜0.05). In the multivariable-adjusted Cox proportional hazards model, the ICI-related myocarditis risk in high-risk group was about 4 times that in the low-risk group. ROC curve analysis demonstrated that the average area under the curve (AUC) for predicting ICI-related myocarditis was 0.81, with an accuracy of 0.74. The Cohen’s Kappa coefficient was 0.55, indicating moderate agreement. In the actual high-risk group, no patient was predicted to be at low risk; in the actual low-risk group, 16 patients were predicted to be at high risk. Conclusions This risk assessment scale for ICI-associated myocarditis shows high predictive performance. It provides oncologists with a simple yet effective multidisciplinary diagnostic reference tool, potentially enhancing early identification of ICI-associated myocarditis.

OBJECTIVE: Coptis chinensis (Huanglian in Chinese, HL) is commonly utilized in clinical settings to counteract dyslipidemia in patients with hot syndrome. Its lipid-reducing efficacy has been consistently demonstrated in high-fat diet (HFD)-induced hyperlipidemic animal models. However, whether HL's efficacy differs in HFD-fed animals with hot or cold syndromes remains unclear. This study aims to discern the variations in the anti-hyperlipidemic effects of HL in HFD-fed mice with hot or cold syndromes. METHODS: HFD-induced C57BL/6 mice were subjected to cold or hot syndrome via two weeks of ice water (0 °C) and levothyroxine sodium (240 µg/kg) treatment, respectively. Then, an aqueous extract of HL was administered to the mice via oral gavage over the following four-week period. Lipid levels in the serum and liver were gauged to determine the lipid-reducing effects of HL. Furthermore, gut microbiota composition was elucidated using full-length 16S rRNA gene sequencing. RESULTS: HL notably reduced lipid levels in HFD-induced hyperlipidemic mice. Its efficacy was amplified in hyperlipidemic mice with a hot syndrome but was markedly reduced in those with a cold syndrome. HL treatment led to a decline in alpha-diversity (characterized by ACE, Chao1, Shannon and Simpson index) of the gut microbiota in both sets of mice but affected specific microbial populations based on the syndrome. Specifically, while HL led to a notable increase in Eubacterium, Robinsoniella, and Lachnoclostridium genera, along with the enhancement of Clostridium innocuum and Bacteroides thetaiotaomicron species across all conditions, it syndrome-dependently stimulated Romboutsia ilealis and Parabaceroides_sp_HGS0025 species in mice with hot syndrome. CONCLUSION HL shows stronger lipid-lowering effect on hyperlipidemic mice with hot syndrome, which is in accordance with its traditional usage in clinic. The therapeutic outcomes of HL are intrinsically tied, at least in part, to its modulatory effects on the gut microbiota, offering fresh insights into the foundational principles of traditional Chinese medicine.

OBJECTIVES: This study aimed to investigate the association between temporomandibular disorder (TMD) and insomnia using a two-sample Mendelian randomization (MR) approach. METHODS: Bidirectional MR analyses of two samples, TMD (n=377 277) and insomnia (n=375 359), were performed using genome-wide association study statistics published in the FinnGen database. Instrumental variables were first screened, and then inverse variance weighting (IVW) and MR-Egger were used as the main-effect assessment methods. Weighted median, weighted mode, and simple mode served as supplementary methods. We used IVW and MR-Egger to test for heterogeneity, as well as MR-Egger intercepts to assess the single nucleotide polymorphism (SNP) potential level of multiplicity effects. Sensitivity analyses were conducted based on leave-one-out to identify potentially influential SNPs. All analyses were conducted by using the two-sample MR R package and were considered statistically significant when P<0.05. RESULTS: MR analysis showed the presence of TMD on insomnia (OR=1.089, 95%CI: 1.017-1.166, P=0.014). Meanwhile, no effect of insomnia on TMD (OR=0.996, 95%CI: 0.964-1.029, P=0.816) was found. The sensitivity-analysis showed that no heterogeneity existed (P>0.05), and the presence of horizontal pleiotropy was not detected (P>0.05). Leave-one-out sensitivity analysis showed no single SNP, which may affect the causal relation. All findings indicated that the causal relationship between TMD and insomnia was not significantly affected by any individual SNP and that IV did not bias the results. CONCLUSIONS Results of MR analyses showed that TMD is a risk factor for insomnia, whereas insomnia is not a risk factor for TMD.
Humans ; Sleep Initiation and Maintenance Disorders/genetics* ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; Temporomandibular Joint Disorders/complications* ; Genome-Wide Association Study

The mild-natured and bitter-flavored traditional Chinese medicines (MB-TCMs) are an important class of TCMs that have been widely used in clinical practice and recognized as safe long-term treatments for chronic diseases. However, as an important class of TCMs, the panorama of pharmacological effects and the mechanisms of MB-TCMs have not been systemically reviewed. Compelling studies have shown that gut microbiota can mediate the therapeutic activity of TCMs and help to elucidate the core principles of TCM medicinal theory. In this systematic review, we found that MB-TCMs commonly participated in the modulation of metabolic syndrome, intestinal inflammation, nervous system disease and cardiovascular system disease in association with promoting the growth of beneficial bacteria Bacteroides, Akkermansia, Lactobacillus, Bifidobacterium, Roseburia as well as inhibiting the proliferation of harmful bacteria Helicobacter, Enterococcus, Desulfovibrio and Escherichia-Shigella. These alterations, correspondingly, enhance the generation of protective metabolites, mainly including short-chain fatty acids (SCFAs), bile acid (BAs), 5-hydroxytryptamine (5-HT), indole and gamma-aminobutyric acid (GABA), and inhibit the generation of harmful metabolites, such as proinflammatory factors trimethylamine oxide (TAMO) and lipopolysaccharide (LPS), to further exert multiplicative effects for the maintenance of human health through several different signaling pathways. Altogether, this present review has attempted to comprehensively summarize the relationship between MB-TCMs and gut microbiota by establishing the TCMs-gut microbiota-metabolite-signaling pathway-diseases axis, which may provide new insight into the study of TCM medicinal theories and their clinical applications.

Objective To investigate the effect of autophagy activation on cell proliferation in human umbilical vein endothelial cells(HUVECs).Methods HUVECs were treated with rapamycin(Rapa).Western blot assay was performed to examine the expression of protein of microtubule associated protein 1 light chain 3(LC3),Beclin 1 and unc-51-like kinase 1(ULK1).Autophagosomes were detected by transmission electron microscopy(TEM),and autophagy fluorescence was detected by monodansylcadaverine staining(MDC)assay.The effect of autophagy activation on cell proliferation was assessed by CCK-8 assay and EdU assay.Vascular formation experiments were used to detect vasculogenic ability.Results After Rapa treatment,LC3,Beclin1 and ULK1 expressions were en-hanced,while the green autophagy fluorescence expression in the experimental group was stronger than that in the control group,and autophagosomes were visible by TEM;CCK-8 and EdU results showed that compared with the control group,the cell proliferation ability was weakened and tubes formation ability was reduced after the activation of autophagy in experimental cells.Conclusion Rapa upregulates autophagy activity in HUVECs to inhibit cell proliferation under certain time.

Objective To evaluate the factors affecting urinary stone detection rate using virtual unenhanced(VUE)images obtained from triphasic dual-energy CT urography(DECTU)based on Logistic regression analysis.Methods For this study,150 patients who had suspected urinary stone and underwent triphasic DECTU were included.The true unenhanced(TUE)images were reconstructed as 120 kVp-like images,and VUE images at the portal venous phase[VUE(VP)]and excretory phase[VUE(EP)]were obtained using iodine removal technique from portal venous and excretory phase DECTU images,respectively.Two readers independently evaluated the above three types of images,and recorded the number of urinary stones,their anatomical locations,and whether there was residual iodine on the VUE images.Stone size and CT number were recorded only on the TUE images.Stone size,CT number,anatomical location,and iodine contrast agent were included in univariate and multivariate Logistic regression analyses to evaluate the factors affecting urinary stone detection rate using VUE images.Thresholds for detecting urinary stones on VUE images were determined using receiver operating characteristics(ROC)analysis.Results We detected 304 stones on TUE images,while the detection rates were 92.4％and 71.4％when using VUE(VP)and VUE(EP)images,respectively.Stone size and CT number were important factors influencing urinary stone detection rate using VUE(VP)and VUE(EP)images(P＜0.01).The area under curve(AUC)of using stone size and CT number for detecting stones using the VUE(VP)images was up to 0.96,and as threshold values,stones with size larger than 3.52 mm and CT number greater than 469 HU were found to have high accuracy.However,the AUC decreased to 0.88 when we combined stone size,CT number and anatomical location using the VUE(EP)images.In addition,different contrast agents did not affect the detection rate of stones on the VUE(EP)images(P=0.57).The stone detection rate in the kidney was significantly lower than those on the VUE(EP)images(P＜0.001).Conclusion VUE(VP)images provide better stone detection.Stone size and CT number have significant impacts on the stone detection rate using VUE images.The lower stone detection rate in the kidney on the VUE(EP)images is related to the residual iodine.

Objective To investigate the value of abdominal aortic combined with routine one-stop triple rule-out computed tomography angiography(TRO-CTA)in the examination of patients with acute chest pain.Methods A total of 1 482 patients with nontraumatic chest pain were included in this retrospective study.Of them 414 patients underwent the conventional TRO-CTA scanning while 1 068 patients underwent TRO-CTA that included the abdominal aorta(TRO-CTAwAA)under the request of clinicians.All scanning parameters were the same,except the scanning range for the third phase in TRO-CTA:conventional TRO-CTA covered only the thoracic aorta,while TRO-CTAwAA extended to the entire aorta.Patient etiology was investigated and the detection rates of major vessel abnormalities(aortic dissection,aneurysm,penetrating ulcer,intramural hematoma,vascular occlusion,and thrombosis)between the two groups was compared using chi square tests.The radiation dose(CTDIvol and DLP)and scanning time between the two groups were compared using analysis of variance(ANOVA).Results The TRO-CTAwAA had significantly higher detection rate of major artery abnormalities than the TRO-CTA group(35.1％vs.4.8％,P＜0.001).In the TRO-CTAwAA group,26.5％of the vascular anomalies were detected in both the thoracic and abdominal aortas,and another 8.6％were seen only in the abdominal aorta.With regard to the radiation dose between the two groups,the total DLP was significantly higher in the TRO-CTAwAA group than in the conventional TRO-CTA group(P＜0.001).The two groups did not significantly differ in scanning time(P=0.410).Conclusion TRO-CTA with scan range including the abdominal aorta significantly improves the detection rate for major vessel abnormalities in patients with chest pain without increasing the examination process.

Objective:To investigate the efficacy and mechanism of canagliflozin (Cana) in the treatment of high glucose-induced human podocyte (HPC) injury.Methods:The HPCs were divided into 5 groups: normal glucose group (NG group), mannitol group (MA group), high glucose group (HG group), Cana low dose (0.3 μmol/L) group and Cana high dose (1.0 μmol/L) group. Western blotting was used to examine the protein expressions of membrane-associated guanylate kinase inverted-2 (MAGI2), podocyte-associated protein nephrin, sodium-glucose transporter 2 (SGLT2), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis- associated speck-like protein containing a CARD (ASC), and cleaved-caspase1 in podocytes. Phalloidin staining of F-actin in podocytes was used to observe cytoskeletal injury. Intracellular reactive oxygen species (ROS) level of HPC was detected by the 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. Levels of interleukin (IL)-18 and IL-1β in culture medium of podocytes were detected by enzyme-linked immunosorbent assay (ELISA).Results:(1) Compared with the NG group, the protein expressions of MAGI2 and nephrin decreased (both P<0.01), the protein expression of SGLT2 increased ( P<0.01), the changes of cell morphology and cytoskeleton remodeling were obvious, intracellular ROS level increased ( P<0.01), while NLRP3, ASC and cleaved-caspase1 protein expressions decreased in the HG group (all P<0.01). The results of ELISA showed that IL-18 and IL-1β concentrations were higher in the HG group (both P<0.05). (2) Compared with the HG group, in the Cana groups, MAGI2 and nephrin expressions up-regulated (both P<0.01), the changes of cell morphology and cytoskeleton remodeling were alleviated. Meanwhile the Cana groups showed decreased SGLT2 expression ( P<0.05), lower ROS level, down- regulated NLRP3, ASC, cleaved-caspase1 expressions (all P<0.01), and decreased concentrations of IL-18 and IL-1β in culture medium of podocytes (both P<0.05). Conclusion:Cana can improve high glucose-induced injury and inflammation in human podocyte, possibly due to the repression of the ROS/NLRP3 signaling pathway.

Objective:To investigate the correlation between RYR1 gene and the development of gastric cancer,as well as the mechanism of RYR1 in promoting the progression of gastric cancer.Methods:We analyzed gastric cancer data from TCGA and conducted high-throughput targeted sequencing and transcriptome sequencing on 81 gastric cancer tissue samples at Tianjin Medical University Cancer Institute&Hos-pital(TJMUCH)from December 2010 to December 2012.We collected clinicopathological data,compared the correlation between RYR1 mutations and expression levels,and analyzed the impact of RYR1 on the prognosis of patients with gastric cancer.Additionally,we explored the underlying molecular mechanism to study its role in promoting the development of gastric cancer by generating stable cell lines overex-pressing RYR1.Results:In TCGA gastric cancer patients,the mutation rate of RYR1 in Asian population was higher than that in others popula-tion(12.68%vs.8.13%).In gastric cancer patients from TJMUCH,RYR1 mutations ranked ninth in frequency,with a mutation rate of 33.33%.Mutations in RYR1 were negatively correlated with RYR1 expression(P=0.006 9,P<0.000 1).Patients with high RYR1 expression had significantly worse overall survival than those with low RYR1 expression(P=0.009 0,P=0.042 0).Overexpression of RYR1 promoted prolifera-tion,migration,invasion and reduced apoptosis of gastric cancer cell lines.Moreover,RYR1 overexpression was associated with decreased sensitivity to chemotherapeutic drugs in gastric cancer cells.Inhibiting RYR1-mediated calcium over-release could suppress malignant beha-viors and reverse chemoresistance.Conclusions:RYR1 had a high mutation rate in Asian gastric cancer patients and a significantly negative correlation with RYR1 mRNA levels.High RYR1 expression serves as a novel prognostic predictive marker for gastric cancer.RYR1 overex-pression promoted malignant progression of gastric cancer and chemoresistance by increasing the release of calcium ions from the endo-plasmic reticulum.Thus,RYR1 inhibition can reduce the proliferation,migration,and invasion of gastric cancer cells and reverse chemores-istance,which highlights potential combination therapies for gastric cancer.

Objective:To explore the value of myocardial work difference between left ventricular lateral wall and septum at baseline in the prediction of cardiac resynchronization therapy (CRT) response and compare their predictive performance with conventional echocardiographic parameters.Methods:One hundred and six heart failure patients who were retrospectively recruited from January 2021 to January 2023, underwent speckle tracking echocardiography before CRT and at 6-month follow-up.Global work index (GWI), global constructive work (GCW), global wasted work (GWW), global work efficiency (GWE), as well as segmental myocardial work index (MWI), constructive work (CW), wasted work (WW) and myocardial work efficiency (MWE), were acquired from non-invasive left ventricular pressure-strain loops before CRT. The differences of all myocardial work indices between left ventricular lateral wall and septum (L-S) at the mid-ventricular level, namely, L-S MWI, L-S CW, L-S WW and L-S MWE were calculated. Response to CRT was defined as left ventricular end-systolic volume reduction ≥15% at 6-month follow-up.Results:CRT response was present in seventy-eight (74%, 78/105) patients. ①At baseline, responders exhibited significantly higher GWI and GCW than non-responders (both P<0.05). ②Besides, L-S MWI, L-S CW, L-S WW and L-S MWE were significant higher in CRT responders than in non-responders at baseline (all P<0.01). ③In multivariate regression analysis, baseline LV end-diastolic volume (LVEDV) ( OR=0.993, 95% CI=0.987-0.999, P=0.020), interventricular mechanical delay (IVMD) ( OR=1.025, 95% CI=1.001-1.050, P=0.040) and L-S MWI ( OR=1.002, 95% CI=1.001-1.003, P=0.001) were identified as independent predictors of CRT response. ④ROC analysis demonstrated that L-S MWI (AUC=0.830, P<0.001) was the most powerful predictor of CRT response and was superior to LVEDV (AUC=0.718, P<0.01) and IVMD (AUC=0.704, P=0.001). ⑤L-S MWI >884 mmHg% was recommended to predict CRT response with the optimal sensitivity of 76% and specificity of 86%. Conclusions:The noninvasive evaluation of myocardial work heterogeneity between left ventricular lateral wall and septum is more valuable than conventional parameters in predicting CRT response and guiding patient selection before CRT, which helps to further improve CRT response rate.