BACKGROUND: Based on the China-VHD database, this study sought to develop and validate a Valvular Heart Disease- specific Age-adjusted Comorbidity Index (VHD-ACI) for predicting mortality risk in patients with VHD. METHODS & RESULTS: The China-VHD study was a nationwide, multi-centre multi-centre cohort study enrolling 13,917 patients with moderate or severe VHD across 46 medical centres in China between April-June 2018. After excluding cases with missing key variables, 11,459 patients were retained for final analysis. The primary endpoint was 2-year all-cause mortality, with 941 deaths (10.0%) observed during follow-up. The VHD-ACI was derived after identifying 13 independent mortality predictors: cardiomyopathy, myocardial infarction, chronic obstructive pulmonary disease, pulmonary artery hypertension, low body weight, anaemia, hypoalbuminaemia, renal insufficiency, moderate/severe hepatic dysfunction, heart failure, cancer, NYHA functional class and age. The index exhibited good discrimination (AUC, 0.79) and calibration (Brier score, 0.062) in the total cohort, outperforming both EuroSCORE II and ACCI (P < 0.001 for comparison). Internal validation through 100 bootstrap iterations yielded a C statistic of 0.694 (95% CI: 0.665-0.723) for 2-year mortality prediction. VHD-ACI scores, as a continuous variable (VHD-ACI score: adjusted HR (95% CI): 1.263 (1.245-1.282), P < 0.001) or categorized using thresholds determined by the Yoden index (VHD-ACI ≥ 9 vs. < 9, adjusted HR (95% CI): 6.216 (5.378-7.184), P < 0.001), were independently associated with mortality. The prognostic performance remained consistent across all VHD subtypes (aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, tricuspid valve disease, mixed aortic/mitral valve disease and multiple VHD), and clinical subgroups stratified by therapeutic strategy, LVEF status (preserved vs. reduced), disease severity and etiology. CONCLUSION The VHD-ACI is a simple 13-comorbidity algorithm for the prediction of mortality in VHD patients and providing a simple and rapid tool for risk stratification.

Cytotoxicity, usually represented by cell viability, is a crucial parameter for evaluating drug safety in vitro. Accurate prediction of cell viability/cytotoxicity could accelerate drug development in the early stage. In this study, by integrating cellular transcriptome and cell viability data using four machine learning algorithms (support vector machine (SVM), random forest (RF), extreme gradient boosting (XGBoost), and light gradient boosting machine (LightGBM)) and two ensemble algorithms (voting and stacking), highly accurate prediction models of 50% and 80% cell viability were developed with area under the receiver operating characteristic curve (AUROC) of 0.90 and 0.84, respectively; these models also showed good performance when utilized for diverse cell lines. Concerning the characterization of the employed Feature Genes, the models were interpreted, and the mechanisms of bioactive compounds with a narrow therapeutic index (NTI) can also be analyzed. In summary, the models established in this research exhibit superior capacity to those of previous studies; these models enable accurate high-safety substance screening via cytotoxicity prediction across cell lines. Moreover, for the first time, Cytotoxicity Signature (CTS) genes were identified, which could provide additional clues for further study of mechanisms of action (MOA), especially for NTI compounds.

Although a single nucleotide polymorphism for N-acetyltransferase 10 (NAT10) has been identified in patients with early-onset stroke, the role of NAT10 in ischemic injury and the related underlying mechanisms remains elusive. Here, we provide evidence that NAT10, the only known RNA N4-acetylcytidine (ac4C) modification "writer", is increased in the damaged cortex of patients with acute ischemic stroke and the peri-infarct cortex of mice subjected to photothrombotic (PT) stroke. Pharmacological inhibition of NAT10 with remodelin on Days 3-7 post-stroke or astrocytic depletion of NAT10 via targeted virus attenuates ischemia-induced infarction and improves functional recovery in PT mice. Mechanistically, NAT10 enhances ac4C acetylation of the inflammatory cytokine tissue inhibitor of metalloproteinase 1 (Timp1) mRNA transcript, which increases TIMP1 expression and results in the accumulation of microtubule-associated protein 1 light chain 3 (LC3) and progression of astrocyte autophagy. These findings demonstrate that NAT10 regulates astrocyte autophagy by targeting Timp1 ac4C after stroke. This study highlights the critical role of ac4C in the regulation of astrocyte autophagy and proposes a promising strategy to improve post-stroke outcomes via NAT10 inhibition.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint damage, accompanied by the accumulation of plasma cells, which contributes to its pathogenesis. Understanding the genetic alterations occurring during plasma cell differentiation in RA can deepen our comprehension of its pathogenesis and guide the development of targeted therapeutic interventions. Here, our study elucidates the intricate molecular mechanisms underlying plasma cell differentiation by demonstrating that PRDX1 interacts with DOK3 and modulates its degradation by the autophagy-lysosome pathway. This interaction results in the inhibition of plasma cell differentiation, thereby alleviating the progression of collagen-induced arthritis. Additionally, our investigation identifies Salvianolic acid B (SAB) as a potent small molecular glue-like compound that enhances the interaction between PRDX1 and DOK3, consequently impeding the progression of collagen-induced arthritis by inhibiting plasma cell differentiation. Collectively, these findings underscore the therapeutic potential of developing chemical stabilizers for the PRDX1-DOK3 complex in suppressing plasma cell differentiation for RA treatment and establish a theoretical basis for targeting PRDX1-protein interactions as specific therapeutic targets in various diseases.

Schizophrenia (SZ) stands as a severe psychiatric disorder. This study applied diffusion tensor imaging (DTI) data in conjunction with graph neural networks to distinguish SZ patients from normal controls (NCs) and showcases the superior performance of a graph neural network integrating combined fractional anisotropy and fiber number brain network features, achieving an accuracy of 73.79% in distinguishing SZ patients from NCs. Beyond mere discrimination, our study delved deeper into the advantages of utilizing white matter brain network features for identifying SZ patients through interpretable model analysis and gene expression analysis. These analyses uncovered intricate interrelationships between brain imaging markers and genetic biomarkers, providing novel insights into the neuropathological basis of SZ. In summary, our findings underscore the potential of graph neural networks applied to multimodal DTI data for enhancing SZ detection through an integrated analysis of neuroimaging and genetic features.
Humans ; Schizophrenia/pathology* ; Diffusion Tensor Imaging/methods* ; Male ; Female ; Adult ; Brain/metabolism* ; Young Adult ; Middle Aged ; White Matter/pathology* ; Gene Expression ; Nerve Net/diagnostic imaging* ; Graph Neural Networks

OBJECTIVES: This study aims to evaluate the short- to medium-term clinical efficacy of demineralized dentin matrix (DDM) particles applied during the immediate implantation of alveolar bone defects in the posterior region. METHODS: A total of 76 patients with 110 simple taper retentive implants were included in the conducted study and divided into Groups A and B in accordance with the bone grafting materials. Cone beam computed tomography and panoramic radiographs were taken immediately after implant surgery, immediate crown repair, and final follow-up time. The average follow-up time for Groups A and B was recorded. The primary observed clinical indicators were overall survival rate of the implant, bone resorption of the mesial and distal margins of the implant, buccal bone width resorption at the platform level and 1 mm below the platform, and bone height of the implant. Implant complication was a secondary observed clinical indicator. RESULTS: During the 1-to-5-year follow-up observation period, the mean follow-up of Group A was 38.2 months while that of Group B was 39.9 months. In Group A, two implants failed, one of which fractured, and implant overall survival rate was 96.4%. Four implants failed in Group B due to peri-implantitis, and implant overall survival rate was 92.6%. No statistically significant difference in implant overall survival rate was found between the two groups (P>0.05). In Group A, the average bone resorption in the mesial and distal margins of the implants was (1.011±2.047) mm and (0.841±2.183) mm, respectively. In Group B, the average bone resorption of the mesial and distal margins of the implants was (1.546±1.778) mm and (1.431±1.909) mm, respectively. No statistically significant difference was noted between the two groups (P>0.05). In Group A, buccal bone width resorption at the platform level and 1 mm below the platform of the implant was (0.782±2.084) mm and (0.681±2.307) mm, respectively. In Group B, buccal bone width resorption at the platform level and 1 mm below the platform of implant was (1.071±1.474) mm and (0.949±1.909) mm, respectively. No statistically significant difference was found between the two groups (P>0.05). In Group A, the buccal bone height of resorption of the implant was (1.044±2.214) mm. In Group B, the buccal bone height of resorption of the implant was (1.075±1.456) mm. No statistically significant difference in bone height was observed between the two groups (P>0.05). CONCLUSIONS During the 1-to-5-year follow-up observation period, DDM particles can effectively increase the height and width of alveolar bone, and they can achieve the same effect of maintaining alveolar bone contour and bone augmentation compared with deproteinized inorganic calf bone. DDM particles can be used as a potential new bone grafting material for the treatment of bone defects in clinical practice.
Humans ; Follow-Up Studies ; Dentin ; Cone-Beam Computed Tomography ; Dental Implants ; Male ; Female ; Adult ; Alveolar Bone Loss/surgery* ; Middle Aged ; Bone Transplantation ; Radiography, Panoramic ; Dental Implantation, Endosseous/methods* ; Immediate Dental Implant Loading

OBJECTIVES: To explore the related risk factors of early failure of simple taper retentive implants, and to provide theoretical guidance for clinical work. METHODS: Collect cases of patients who visited the Department of Stomatology of the Fourth Affiliated Hospital of Nanchang University from January 2021 to June 2024, received simple taper retentive implants, and had complete medical records. Taking the implants as the unit, analyze the influence of patient-related factors (gender, age, smoking history, hypertension history, diabetes history), implant-related factors (implant length, implant diameter, implant surface treatment), and surgical-related factors (implant site, implant timing, simultaneous maxillary sinus floor elevation, simultaneous bone augmentation) on the early failure of implants. Univariate analysis and multivariate analysis were adopted to explore the potential risk factors for early failure of simple taper retentive implants. RESULTS: A total of 3,533 simple taper retentive from 1,681 patients were included during the study period. Among them, 53 implants from 49 patients experienced early failure, with an early failure rate of 2.9% at the patient le-vel and 1.5% at the implant level. Multivariate analysis revealed that smoking (OR=2.148, P=0.021), the anterior mandibular region (OR=3.669, P=0.006), and the posterior maxillary region (OR=2.191, P=0.033) were risk factors for early failure of simple taper retentive implants. In the univariate analysis, simultaneous maxillary sinus floor elevation had a higher risk of early failure, but this effects was no longer significant in the multivariate analysis (P>0.05). CONCLUSIONS Smoking, the anterior mandibular region, and the posterior maxillary region are risk factors for the early failure of simple taper retentive implants, and could be comprehensively considered in the preoperative treatment plan.
Humans ; Risk Factors ; Male ; Female ; Middle Aged ; Dental Implants ; Adult ; Smoking/adverse effects* ; Dental Restoration Failure ; Aged

Objective To explore the effect and underlying molecular mechanism of miR-101 on ventricular remod-eling in rats after acute myocardial infarction(AMI).Methods The AMI rat model was established using the left anterior descending coronary artery ligation method.The AMI rats were randomly divided into AMI group,agomir-NC group,miR-101 agomir group and coumermycin A1 group,another 12 rats were selected as sham group with 12 in each.The targeting relationship between miR-101 and JAK2 was analyzed by Target Scan 8.0 database and double luciferase reporter gene assay.The expression of miR-101 in rat myocardium was detected by RT-qPCR.LVESD,LVEDD,LVEF and LVFS were measured by ultrasonography.The level of IL-1β,IL-6 and TNF-α in rats serum was determined by ELISA.The myocardial tissue lesion and fibrosis were detected by HE staining and Mas-son staining.The expression of collagenⅠand TGF-β in rat myocardial tissue was detected by immunohistochemical staining.The expression of E-cadherin,N-cadherin,Vimentin,p-JAK2,JAK2,p-STAT3 and STAT3 proteins was detected by Western blot.Results Compared with AMI group and agomir-NC group,the myocardial tissue lesions and fibrotic area in miR-101 agomir group were significantly decreased(P＜0.05),the level of LVESD,LVEDD,L-1β,IL-6,TNF-α,collagenⅠ,TGF-β,N-cadherin,vimentin,p-JAK2 and p-STAT3 decreased(P＜0.05).The levels of miR-101,LVEF,LVFS and E-cadherin were increased(P＜0.05).Compared with miR-101 agomir group,the myocardial tissue lesions and fibrotic area in coumermycin A1 group significantly increased(P＜0.05),the level of LVESD,LVEDD,L-1β,IL-6,TNF-α,collagenⅠ,TGF-β,N-cadherin,vimentin,p-JAK2 and p-STAT3 was increased(P＜0.05).The level of miR-101,LVEF,LVFS and E-cadherin was decreased(P＜0.05).Conclusions miR-101 inhibits myocardial inflammatory lesions,myocardial fibrosis and epithelial-mesenchymal fransition(EMT)process after AMI with a mechanism targeting at JAK2/STAT3 signaling pathway,thus alleviates ventricular remodeling in rats after AMI.

Objective To analyze the relationship between the visceral adiposity index(VAI)and nocturia in the US adult population.Methods A cross-sectional study was performed.Data from subjects aged≥20 years in the National Health and Nutrition Examination Survey(NHANES)database from 2007 to 2020 were collected,including waist circumference,triglyceride,body mass index(BMI),high-density lipoprotein,age,gender,race,poverty income ratio,education level,marital status,smoking,alcohol consumption,sleep disorders,depression,occupation,hypertension,diabetes,congestive heart failure,cancer,and nocturnal urination frequency.Weighted analysis,multivariate logistic regression,generalized additive model(GAM),and curve fitting were employed to evaluate the association between VAI and nocturia,adjusting for age,gender,race,poverty income ratio,education level,marital status,smoking,alcohol consumption,sleep disorders,depression,occupation,hypertension,diabetes,congestive heart failure,and cancer.Subgroup analyses were conducted based on age,gender,race,hypertension and diabetes to further evaluate the relationship between VAI and the risk of nocturia.Results A total of 29,196 American adults were included.All subjects were divided into 4 groups based on VAI quartiles:Q1 group(0.32≤VAI<1.01),Q2 group(1.01≤VAI<1.70),Q3 group(1.70≤VAI<2.95),and Q4 group(2.95≤VAI<13.59),with nocturia prevalence rates of 28.5%,31.4%,33.3%,and 34.9%,respectively.In subgroup analyses,the risk of nocturia significantly increased with higher VAI in the 20-40 age group,females and other Hispanics(OR=1.04,95%CI 1.01-1.08,P=0.006;OR=1.02,95%CI 1.00-1.04,P=0.035;OR=1.05,95%CI 1.01-1.09,P=0.026).GAM analysis results showed a nonlinear relationship between VAI and nocturia.Conclusion VAI is positively associated with the risk of nocturia,and may be an effective indicator for predicting the risk of nocturia occurrence.