Machine learning for the prediction of 1-year mortality in patients with sepsis-associated acute kidney injury.

INTRODUCTION: Sepsis-associated acute kidney injury (SA-AKI) is strongly associated with poor prognosis. We aimed to build a machine learning (ML)-based clinical model to predict 1-year mortality in patients with SA-AKI. METHODS: Six ML algorithms were included to perform model fitting. Feature selection was based on the feature importance evaluated by the SHapley Additive exPlanations (SHAP) values. Area under the receiver operating characteristic curve (AUROC) was used to evaluate the discriminatory ability of the prediction model. Calibration curve and Brier score were employed to assess the calibrated ability. Our ML-based prediction models were validated both internally and externally. RESULTS: A total of 12,750 patients with SA-AKI and 55 features were included to build the prediction models. We identified the top 10 predictors including age, ICU stay and GCS score based on the feature importance. Among the six ML algorithms, the CatBoost showed the best prediction performance with an AUROC of 0.813 and Brier score of 0.119. In the external validation set, the predictive value remained favorable (AUROC = 0.784). CONCLUSION: In this study, we developed and validated a ML-based prediction model based on 10 commonly used clinical features which could accurately and early identify the individuals at high-risk of long-term mortality in patients with SA-AKI.

Effectiveness of cardioneuroablation in different subtypes of vasovagal syncope.

BACKGROUND: Cardioneuroablation (CNA) has shown encouraging results in patients with vasovagal syncope (VVS). However, data on different subtypes was scarce. METHODS: This observational study retrospectively enrolled 141 patients [mean age: 40 ± 18 years, 51 males (36.2%)] with the diagnosis of VVS. The characteristics among different types of VVS and the outcomes after CNA were analyzed. RESULTS: After a mean follow-up of 4.3 ± 1.5 years, 41 patients (29.1%) experienced syncope/pre-syncope events after CNA. Syncope/pre-syncope recurrence significantly differed in each subtype (P = 0.04). The cardioinhibitory type of VVS had the lowest recurrence rate after the procedure (n = 6, 16.7%), followed by mixed (n = 26, 30.6%) and vasodepressive (n = 9, 45.0%). Additionally, a significant difference was observed in the analyses of the Kaplan-Meier survival curve (P = 0.02). Syncope/pre-syncope burden was significantly reduced after CNA in the vasodepressive type (P < 0.01). Vasodepressive types with recurrent syncope/pre-syncope after CNA have a lower baseline deceleration capacity (DC) level than those without (7.4 ± 1.0 ms vs. 9.0 ± 1.6 ms, P = 0.01). Patients with DC < 8.4 ms had an 8.1 (HR = 8.1, 95% CI: 2.2-30.0, P = 0.02) times risk of syncope/pre-syncope recurrence after CNA compared to patients with DC ≥ 8.4 ms, and this association still existed after adjusting for age and sex (HR = 8.1, 95% CI: 2.2-30.1, P = 0.02). CONCLUSIONS: Different subtypes exhibit different event-free rates. The vasodepressive type exhibited the lowest event-free rate, but those patients with DC ≥ 8.4 ms might benefit from CNA.

Association between Hematocrit and Acute Kidney Injury in Patients with Acute Myocardial Infarction.

Backgrounds: Hematocrit is found an independent risk factor for acute kidney injury (AKI) in certain patients, but this effect in patients with acute myocardial infarction (AMI) is unclear. We aim to identify the relationship between hematocrit and AKI in patients with AMI. Methods: The patient data for the discovery and validation cohorts were extracted from the electronic Intensive Care Unit database and the Medical Information Mart for Intensive Care III database, respectively, to identify the relationship between hematocrit and AKI. With normal hematocrit as the reference, patients were divided into five groups based on the initial hematocrit value. The primary outcome was AKI during hospitalization. A multivariable logistic regression and a marginal effect analysis were used to evaluate the relationship between hematocrit and AKI. Results: In this study, a total of 9692 patients diagnosed with AMI were included, with 7712 patients in the discovery cohort and 1980 patients in the validation cohort. In the discovery cohort, hematocrit in 30-33%, 27-30% or < 27% were independent risk factors for AKI in the multivariate logistic analysis, with odds ratio (OR) of 1.774 (95% confidence interval [CI]: 1.203-2.617, p = 0.004), 1.834 (95% CI: 1.136-2.961, p = 0.013) and 2.577 (95% CI: 1.510-4.397, p < 0.001), respectively. Additionally, in the validation cohort, low hematocrit levels independently contributed to an increased risk of AKI among patients with AMI. During the analysis of marginal effects, a significant negative linear relationship between hematocrit levels and AKI was observed. Conclusions: Decreased hematocrit was an independent risk factor for AKI in patients with AMI. The relationship between hematocrit and AKI was negative linear.

Sex Differences in the Epidemiology, Risk Factors, and Prognosis of Malignant Ventricular Arrhythmias in Sepsis Patients.

Background: Women are frequently underrepresented in clinical trials and databases focusing on ventricular arrhythmias (VAs). However, understanding sex-based differences in risk factors and the prognosis of VAs is essential for tailoring personalized prevention and treatment strategies. This study aimed to investigate sex differences in the epidemiology, risk factors, and prognosis of VAs in patients with sepsis. Methods: We conducted a comprehensive analysis of 27,139 sepsis patients (mean [SD] age, 66.6 [16.2] years; 15,626 [57.6%] male), among whom 1136 (4.2%) developed VAs during their hospitalization. We evaluated VAs incidence and potential risk elements in both male and female patients, along with in-hospital mortality. Results: Men had a significantly higher likelihood of developing VAs compared to women (odds ratio [OR]: 1.70, 95% confidence interval [CI]: 1.50-1.94, p < 0.001). In the case of non-ischemic cardiomyopathy (NICM), the association with VAs was stronger in men than in women (relative risk ratio [RRR] = 1.63, 95% CI: 1.10-2.40, interaction p = 0.014). Furthermore, we observed significant sex-specific interactions in the relationship between incident VAs, congestive heart failure (CHF) (RRR = 1.35, 95% CI: 1.03-1.76, interaction p = 0.031), and pneumonia (RRR = 1.33, 95% CI: 1.02-1.74, interaction p = 0.036) when considering the adjusted model. The presence of VAs was associated with a nearly twofold increase in the risk of in-hospital mortality, a result that was observed in both sexes. Conclusions: In sepsis patients, the emergence of VAs independently escalates the risk of in-hospital mortality, with a notable correlation between male sex and an increased VAs risk. The impacts of CHF, NICM and pneumonia on incident VAs were significantly influenced by sex.

Electrocardiographic tracking of left ventricular hypertrophy in hypertension: incidence and prognostic outcomes from the SPRINT trial.

BACKGROUND: This study explores the impact of intensive blood pressure (BP) control on left ventricular hypertrophy (LVH) incidence and evaluates the prognostic implications of LVH status (pre-existing/new-onset/persistent/regression) using Systolic Blood Pressure Intervention Trial (SPRINT) Electrocardiogram Data. METHODS: Poisson regression was used to assess new-onset LVH and LVH regression rates. Multivariable-adjusted Cox proportional hazard models determined the risk of adverse cardiovascular events (ACE), a composite of myocardial infarction (MI), non-MI acute coronary syndrome, stroke, heart failure, or cardiovascular death, alongside safety adverse events. RESULTS: In 8,016 participants, intensive BP control significantly reduced new-onset LVH (8.27 vs. 14.79 per 1000-person years; adjusted p<0.001) and increased LVH regression (14.89 vs. 11.89 per 1000-person years; adjusted p<0.001). Elevated ACE risk was notable in participants with pre-existing LVH [adjusted HR: 1.94 (95% CI: 1.25-2.99); p = 0.003], new-onset LVH [adjusted 1.74 (95% CI: 1.16-2.60); p = 0.007], and persistent LVH[adjusted HR: 1.96 (95% CI: 1.11-3.46); p = 0.020], compared to those without LVH. Intriguingly, LVH regression attenuated this risk increment [adjusted HR: 1.57 (95% CI: 0.98-2.53); p = 0.062]. Achieving a BP target of < 120/80 mmHg nullified the increased ACE risk in those with pre-existing LVH. CONCLUSIONS: Intensive BP control is instrumental in both reducing the emergence of LVH and fostering its regression. Pre-existing, new-onset LVH and persistent LV remain a predictor of adverse cardiovascular prognosis, whereas LVH regression and achieving on-treatment BP < 120/80 mmHg in pre-existing LVH individuals may further mitigate residual cardiovascular risk. CLINICAL TRIAL REGISTRATION: URL: ClinicalTrials.gov Unique Identifier: NCT01206062.

Efficacy of catheter ablation for ventricular tachycardia in ischemic cardiomyopathy patients without an ICD implantation.

BACKGROUND: The implantable cardioverter-defibrillator (ICD) prevents sudden cardiac death in patients with ischemic cardiomyopathy (ICM). Catheter ablation has been shown to effectively reduce ventricular tachycardia (VT) recurrence, yet its efficacy in patients without an ICD implantation remains uncertain. OBJECTIVE: We aimed to investigate the outcomes of ablation for VT in patients with ICM without a backup ICD. METHODS: Patients with ICM who received ablation for VT without an ICD implantation were included in this study. Ablation was guided by either activation mapping or substrate mapping. Endocardial ablation was the primary strategy; epicardial access was considered when endocardial ablation failed. The primary end point was VT recurrence during follow-up; secondary end points included cardiovascular rehospitalization, all-cause mortality, and a composite of these events. RESULTS: A total of 114 patients were included, with the mean age of 58.2 ± 11.1 years, 102 of whom (89.5%) were male. Twelve patients (10.5%) underwent endo-epicardial ablation, whereas the rest received endocardial ablation. With a median follow-up of 53.8 months (24.8-84.2 months), VT recurred in 45 patients (39.5%), and 6 patients (5.3%) died, including 2 sudden cardiac deaths. The recurrence rate of VT was significantly lower in patients undergoing endo-epicardial ablation than in those with endocardial ablation only (8.3% vs 43.1%; log-rank P = .032). After multivariate adjustment, epicardial ablation remained associated with a reduced risk of VT recurrence (hazard ratio, 0.14; 95% confidential interval, 0.02-0.98; P = .048). CONCLUSION: Patients with ICM undergoing VT ablation without a backup ICD experienced a notably low rate of arrhythmic death. Most recurrences proved nonlethal.

Association of stress hyperglycemia ratio and mortality in patients with sepsis: results from 13,199 patients.

BACKGROUND: The stress hyperglycemia ratio (SHR), adjusted for average glycemic status, is suggested for assessing actual blood glucose levels. Its link with adverse outcomes is known in certain populations, yet its impact on sepsis patients' prognosis is unclear. This study explores the association between SHR and mortality in sepsis. METHODS: We included 13,199 sepsis patients in this study and categorized SHR into distinct groups. Additionally, we utilized restricted cubic spline analysis to evaluate the correlation between SHR as a continuous variable and mortality. The primary outcome was 1-year all-cause mortality. Logistic regression and Cox proportional hazards models were employed to assess the associations between the SHR and both in-hospital mortality and 1-year mortality, respectively. RESULTS: Among the study participants, 4,690 (35.5%) patients died during the 1-year follow-up. After adjusting for confounding variables, we identified a U-shaped correlation between SHR and 1-year mortality. Using an SHR of 0.99 as the reference point, the hazard ratio for predicted 1-year mortality increased by 1.17 (95% CI 1.08 to 1.27) per standard deviation above 0.99, whereas each standard deviation increase predicted the hazard ratio of 0.52 (95% CI 0.39 to 0.69) below 0.99. Furthermore, we found that SHR could enhance the predictive performance of conventional severity scores. CONCLUSION: There exists a U shaped association between SHR and mortality in sepsis patients, where both low and high SHR values are associated with an increased risk of poor outcomes.

Associations of 50 modifiable risk factors with atrial fibrillation using Mendelian randomization analysis.

BACKGROUND: Substantial focus has been placed on atrial fibrillation (AF) treatment and associated stroke prevention rather than preventing AF itself. We employed Mendelian randomization (MR) approach to examine the causal relationships between 50 modifiable risk factors (RFs) and AF. METHODS: Instrumental variables for genetically predicted exposures were derived from corresponding genome-wide association studies (GWASs). Summary-level statistical data for AF were obtained from a GWAS meta-analysis (discovery dataset, N = 1,030,836) and FinnGen (validation dataset, N = 208,594). Univariable and multivariable MR analyses were performed, primarily using inverse variance weighted method with a series of robust sensitivity analyses. RESULTS: Genetic predisposition to insomnia, daytime naps, apnea, smoking initiation, moderate to vigorous physical activity and obesity traits, including body mass index, waist-hip ratio, central and peripheral fat/fat-free mass, exhibited significant associations with an increased risk of AF. Coffee consumption and ApoB had suggestive increased risks. Hypertension (odds ratio (OR) 95% confidence interval (CI): 5.26 (4.42, 6.24)), heart failure (HF) (OR 95% CI, 4.77 (2.43, 9.37)) and coronary artery disease (CAD) (OR 95% CI: 1.20 (1.16, 1.24)) were strongly associated with AF, while college degree, higher education attachment and HDL levels were associated with a decreased AF risk. Reverse MR found a bidirectional relationship between genetically predicted AF and CAD, HF and ischemic stroke. Multivariable analysis further indicated that obesity-related traits, systolic blood pressure and lower HDL levels independently contributed to the development of AF. CONCLUSIONS: This study identified several lifestyles and cardiometabolic factors that might be causally related to AF, underscoring the importance of a holistic approach to AF management and prevention.

Lupeol alleviates autoimmune myocarditis by suppressing macrophage pyroptosis and polarization via PPARα/LACC1/NF-κB signaling pathway.

BACKGROUND: Autoimmune myocarditis, with increasing incidence and limited therapeutic strategies, is in urgent need to explore its underlying mechanisms and effective drugs. Pyroptosis is a programmed cell death that may contribute to the pathogenesis of myocarditis. Nonetheless, no direct evidence validated the role of pyroptosis in autoimmune myocarditis. Lupeol (Lup), a pentacyclic triterpene, possesses various biological activities such as antidiabetic properties. However, the effects of Lup on autoimmune myocarditis and pyroptosis remain unelucidated. PURPOSE: This study aimed to reveal the role of pyroptosis in autoimmune myocarditis and explore the protective effects of Lup, and its engaged mechanisms. METHODS: The experimental autoimmune myocarditis (EAM) mouse model was established by immunization with a fragment of cardiac myosin in Balb/c mice. Lup and MCC950 were administered after EAM induction. The protective effects were assessed by inflammation score, cardiac injury, chronic fibrosis, and cardiac function. Mechanistically, the effects of Lup on the M1 polarization and pyroptosis of macrophages were evaluated. Transcriptome sequencing and molecular docking were subsequently employed, and the underlying mechanisms of Lup were further explored in vitro with small interfering RNA and adenovirus. RESULTS: Administration of Lup and MCC950 alleviated EAM progression. Western blotting and immunofluorescence staining identified macrophages as the primary cells undergoing pyroptosis. Lup inhibited the expression of pyroptosis-associated proteins in macrophages during EAM in a dose-dependent manner. Furthermore, Lup suppressed pyroptosis in both bone marrow-derived macrophages (BMDMs) and THP-1-derived macrophages in vitro. In addition, Lup inhibited the M1 polarization of macrophages both in vivo and in vitro. Mechanistically, the protective effects of Lup were demonstrated via the suppression of the nuclear factor-κΒ (NF-κB) signaling pathway. Transcriptome sequencing and molecular docking revealed the potential involvement of peroxisome proliferator-associated receptor α (PPARα). Subsequently, we demonstrated that Lup activated PPARα to reduce the expression level of LACC1, thereby inhibiting the NF-κB pathway and pyroptosis. CONCLUSION: Our findings indicated the crucial role of macrophage pyroptosis in the pathogenesis of EAM. Lup ameliorated EAM by inhibiting the M1 polarization and pyroptosis of macrophages through the PPARα/LACC1/NF-κB signaling pathway. Thus, our results provided a novel therapeutic target and agent for myocarditis.

[Retracted] Effects of miR­138­5p and miR­204­5p on the migration and proliferation of gastric cancer cells by targeting EGFR.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that the numerous immunohistochemical images shown in Fig. 1D on p. 2626 exhibited a number of overlaps comparing among the data panels, such that data which were intended to show the results from differently performed experiments were likely to have been derived from a smaller number of original sources. A subsequent independent investigation of the data in this paper in the Editorial Office also revealed that certain of the cell migration and invasion assay data shown in Fig. 4A on p. 2629 were strikingly similar to data that had previously appeared in a couple of already published papers written by different authors at different research institutes.  Owing to the fact that the contentious data in Fig. 4 in the above article had already been published prior to its submission to Oncology Reports, in addition to the matter of several panels in Fig. 1D showing overlapping data, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 39: 2624-2634, 2018; DOI: 10.3892/or.2018.6389].

U-shaped association between stress hyperglycemia ratio and risk of all-cause mortality in cardiac ICU.

BACKGROUND: Stress hyperglycemia has been associated with poor prognosis in patients admitted to the cardiac intensive care unit (ICU). Recently, the stress hyperglycemia ratio (SHR) has been proposed to reflect true acute hyperglycemic. This study aimed to investigate the relationship between SHR and prognosis of patients in the cardiac ICU. METHODS: A retrospective analysis was conducted on a cohort of 5,564 patients admitted to the cardiac ICU. The participants were divided into seven groups based on their SHR levels. SHR was calculated as admission blood glucose/[(28.7 × HbA1c %) - 46.7]. The primary outcomes of this study were 28-day all-cause mortality. RESULTS: During the follow-up period, 349 (6.3%) patients succumbed within 28 days. A U-shaped correlation between SHR and mortality persisted, even after adjusting for other confounding variables, with a discernible inflection point at 0.95. When SHR surpassed 0.95, each standard deviation (SD) increase corresponded to a 1.41-fold elevation in the risk of mortality (odds ratio [OR]: 1.41, 95% CI: 1.25 to 1.59). In contrast, when SHR fell below 0.95, each SD increment correlated with a significantly reduced risk of mortality (OR: 0.56, 95% CI: 0.34 to 0.91). CONCLUSION: There was a U-shaped association between SHR and short -term mortality in patients in the cardiac ICU. The inflection point of SHR for poor prognosis was identified at an SHR value of 0.95.

Development and Validation of Machine Learning-Based Models to Predict In-Hospital Mortality in Life-Threatening Ventricular Arrhythmias: Retrospective Cohort Study.

BACKGROUND: Life-threatening ventricular arrhythmias (LTVAs) are main causes of sudden cardiac arrest and are highly associated with an increased risk of mortality. A prediction model that enables early identification of the high-risk individuals is still lacking. OBJECTIVE: We aimed to build machine learning (ML)-based models to predict in-hospital mortality in patients with LTVA. METHODS: A total of 3140 patients with LTVA were randomly divided into training (n=2512, 80%) and internal validation (n=628, 20%) sets. Moreover, data of 2851 patients from another database were collected as the external validation set. The primary output was the probability of in-hospital mortality. The discriminatory ability was evaluated by the area under the receiver operating characteristic curve (AUC). The prediction performances of 5 ML algorithms were compared with 2 conventional scoring systems, namely, the simplified acute physiology score (SAPS-II) and the logistic organ dysfunction system (LODS). RESULTS: The prediction performance of the 5 ML algorithms significantly outperformed the traditional models in predicting in-hospital mortality. CatBoost showed the highest AUC of 90.5% (95% CI 87.5%-93.5%), followed by LightGBM with an AUC of 90.1% (95% CI 86.8%-93.4%). Conversely, the predictive values of SAPS-II and LODS were unsatisfactory, with AUCs of 78.0% (95% CI 71.7%-84.3%) and 74.9% (95% CI 67.2%-82.6%), respectively. The superiority of ML-based models was also shown in the external validation set. CONCLUSIONS: ML-based models could improve the predictive values of in-hospital mortality prediction for patients with LTVA compared with traditional scoring systems.

Comprehensive Comparison of MOCVD- and LPCVD-SiNx Surface Passivation for AlGaN/GaN HEMTs for 5G RF Applications.

Passivation is commonly used to suppress current collapse in AlGaN/GaN HEMTs. However, the conventional PECV-fabricated SiNx passivation layer is incompatible with the latest process, like the "passivation-prior-to-ohmic" method. Research attention has therefore turned to high-temperature passivation schemes. In this paper, we systematically investigated the differences between the SiNx/GaN interface of two high-temperature passivation schemes, MOCVD-SiNx and LPCVD-SiNx, and investigated their effects on the ohmic contact mechanism. By characterizing the device interface using TEM, we reveal that during the process of MOCVD-SiNx, etching damage and Si diffuses into the semiconductor to form a leakage path and reduce the breakdown voltage of the AlGaN/GaN HEMTs. Moreover, N enrichment at the edge of the ohmic region of the LPCVD-SiNx device indicates that the device is more favorable for TiN formation, thus reducing the ohmic contact resistance, which is beneficial to improving the PAE of the device. Through the CW load-pull test with drain voltage VDS = 20V, LPCVD-SiNx devices obtain a high PAE of 66.35%, which is about 6% higher than MOCVD-SiNx devices. This excellent result indicates that the prospect of LPCVD-SiNx passivation devices used in 5G small terminals will be attractive.

Outcomes of catheter ablation in high-risk patients with Brugada syndrome refusing an implantable cardioverter defibrillator implantation.

AIMS: The aim of this study was to investigate the outcomes of catheter ablation (CA) in preventing arrhythmic events among patients with symptomatic Brugada syndrome (BrS) who declined implantable cardioverter defibrillator (ICD) implantation. METHODS AND RESULTS: A total of 40 patients with symptomatic BrS were included in the study, of which 18 refused ICD implantation and underwent CA, while 22 patients received ICD implantation. The study employed substrate modification (including endocardial and epicardial approaches) and ventricular fibrillation (VF)-triggering pre-mature ventricular contraction (PVC) ablation strategies. The primary outcomes were a composite endpoint consisting of episodes of VF and sudden cardiac death during the follow-up period. The study population had a mean age of 43.8 ± 9.6 years, with 36 (90.0%) of them being male. All patients exhibited the typical Type 1 BrS electrocardiogram pattern, and 16 (40.0%) were carriers of an SCN5A mutation. The Shanghai risk scores were comparable between the CA and the ICD groups (7.05 ± 0.80 vs. 6.71 ± 0.86, P = 0.351). Ventricular fibrillation-triggering PVCs were ablated in 3 patients (16.7%), while VF substrates were ablated in 15 patients (83.3%). Epicardial ablation was performed in 12 patients (66.7%). During a median follow-up of 46.2 (17.5-73.7) months, the primary outcomes occurred more frequently in the ICD group than in the CA group (5.6 vs. 54.5%, Log-rank P = 0.012). CONCLUSION: Catheter ablation is an effective alternative therapy for improving arrhythmic outcomes in patients with symptomatic BrS who decline ICD implantation. Our findings support the consideration of CA as an alternative treatment option in this population.

Prognostic significance of the stress hyperglycemia ratio in critically ill patients.

BACKGROUND: The stress hyperglycemia ratio (SHR) has demonstrated a noteworthy association with unfavorable cardiovascular clinical outcomes and heightened in-hospital mortality. Nonetheless, this relationship in critically ill patients remains uncertain. This study aims to elucidate the correlation between SHR and patient prognosis within the critical care setting. METHODS: A total of 8978 patients admitted in intensive care unit (ICU) were included in this study. We categorized SHR into uniform groups and assessed its relationship with mortality using logistic or Cox regression analysis. Additionally, we employed the restricted cubic spline (RCS) analysis method to further evaluate the correlation between SHR as a continuous variable and mortality. The outcomes of interest in this study were in-hospital and 1-year all-cause mortality. RESULTS: In this investigation, a total of 825 (9.2%) patients experienced in-hospital mortality, while 3,130 (34.9%) individuals died within the 1-year follow-up period. After adjusting for confounding variables, we identified a U-shaped correlation between SHR and both in-hospital and 1-year mortality. Specifically, within the SHR range of 0.75-0.99, the incidence of adverse events was minimized. For each 0.25 increase in the SHR level within this range, the risk of in-hospital mortality rose by 1.34-fold (odds ratio [OR]: 1.34, 95% CI: 1.25-1.44), while a 0.25 decrease in SHR within 0.75-0.99 range increased risk by 1.38-fold (OR: 1.38, 95% CI: 1.10-1.75). CONCLUSION: There was a U-shaped association between SHR and short- and long-term mortality in critical ill patients, and the inflection point of SHR for poor prognosis was identified at an SHR value of 0.96.

The Molecular and Function Characterization of Porcine MID2.

Midline2 (MID2/TRIM1) is a member of the tripartite motif-containing (TRIM) family, which is involved in a wide range of cellular processes. However, fundamental studies on porcine MID2 (pMID2) are still lacking. In this study, we identified and characterized the full length MID2 gene of pig (Sus scrofa). The sequence alignment analysis results showed that pMID2 had an N-terminal RING zinc-finger domain, BBC domain, and C-terminal COS box, FN3 motif, and PRY-SPRY domain that were conserved and similar to those of other vertebrates. Furthermore, pMID2 had the highest expression levels in porcine lung and spleen. Serial deletion and site-directed mutagenesis showed that the putative nuclear factor-κB (NF-κB) binding site may be an essential transcription factor for regulating the transcription expression of pMID2. Furthermore, the immunofluorescence assay indicated that pMID2 presented in the cell membrane and cytoplasm. To further study the functions of pMID2, we identified and determined its potential ability to perceive poly (I:C) and IFN-α stimulation. Stimulation experiments showed pMID2 enhanced poly (I:C)-/IFN-α-induced JAK-STAT signaling pathway, indicating that pMID2 might participate in the immune responses. In conclusion, we systematically and comprehensively analyzed the characterizations and functions of pMID2, which provide valuable information to explore the pMID2 functions in innate immunity. Our findings not only enrich the current knowledge of MID2 in IFN signaling regulation but also offer the basis for future research of pig MID2 gene.

Prognostic value of high-sensitivity C-reactive protein in patients undergoing percutaneous coronary intervention with different glycemic metabolism status.

BACKGROUND: High-sensitivity C-reaction protein (hsCRP), a biomarker of residual inflammatory risk, has been demonstrated with poor cardiovascular outcomes. We aimed to investigate the prognostic value of hsCRP in patients undergoing percutaneous coronary intervention (PCI) with or without diabetes mellitus (DM). METHODS: In this large-scale, prospective cohort study, we enrolled 8050 consecutive patients who underwent PCI for coronary artery stenosis. All subjects were stratified as high hsCRP (> 3 mg/L) and low hsCRP (≤ 3 mg/L) and were divided into four groups (hsCRP-L/non-DM, hsCRP-H/non-DM, hsCRP-L/DM, hsCRP-H/DM). The primary endpoint of the study was major adverse cardiovascular events (MACEs), including all-cause mortality, myocardial infarction, stroke, and unplanned vessel revascularization, evaluated at a 3 year follow-up. RESULTS: After 35.7 months (interquartile range: 33.2 to 36.0 months) of median follow-up time, 674 patients suffered from MACEs. We found elevated hsCRP was highly associated with an increased risk of MACEs in both diabetic (hazard ratio [HR] = 1.68, 95% confidence interval CI 1.29-2.19, P < 0.001) and non-diabetic patients (HR = 1.31, 95% CI: 1.05-1.62, P = 0.007) after adjustment for other confounding factors. Kaplan-Meier survival analysis showed the highest incidence of MACEs in hsCRP-H/DM (P < 0.001). In addition, the results of the restricted cubic spline analysis suggested a positive linear relationship between hsCRP and MACEs. CONCLUSION: Elevated hsCRP is an independent risk factors of MACEs in patients undergoing PCI irrespective of glycemic metabolism status.

The causal associations of non-alcoholic fatty liver disease with blood pressure and the mediating effects of cardiometabolic risk factors: A Mendelian randomization study.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is prevalent in hypertensive people, but the causal effect remains unclear. We employed Mendelian randomization (MR) approach to assess the causality between NAFLD and different blood pressure (BP) parameters. METHOD AND RESULTS: Instrumental variables for genetically predicted NAFLD, including chronically elevated serum alanine aminotransferase levels (cALT) and imaging and biopsy-confirmed NAFLD, were obtained from a genome-wide association study (N = 164,197). Multiple MR methods were implemented, including Inverse variance weighted, MR-Egger, Maximum likelihood, Weighted median, Simple median, Penalised weighted median, MR-RAPS, and cML-MA. Outliers were detected using MR-PRESSO, and pleiotropy was assessed using MR-Egger intercept and Phenoscanner. Heterogeneity was quantified using Cochran's Q and Rucker's Q' tests. Potential shared risk factors were analyzed to reveal the mediating effect. A higher genetic predisposition to cALT was causally associated with an increased risk of elevated BP levels, resulting in 0.65 mmHg (95% CI, 0.42-0.87), 0.38 mmHg (95% CI, 0.25-0.50) and 0.33 mmHg (95% CI, 0.22-0.44) higher for systolic BP, diastolic BP and pulse pressure, respectively. When more stringent criteria were used, imaging and biopsy-confirmed NAFLD showed a 1.12 mmHg (95% CI, 0.94-1.30) increase in SBP and a 0.55 mmHg (95% CI, 0.39-0.70) increase in DBP. Risk factor and mediation analyses suggested type 2 diabetes and fasting insulin levels might mediate the causal relationship between NAFLD and BP. CONCLUSION: The two-sample MR analyses showed robust causal effects of genetically predicted NAFLD on 3 different BP indices. The shared genetic profile between NAFLD and BP may suggest important therapeutic targets and early interventions for cardiometabolic risk factors.

Causal effects between atrial fibrillation and heart failure: evidence from a bidirectional Mendelian randomization study.

BACKGROUND: Observational studies have suggested a close association between atrial fibrillation (AF) and heart failure (HF), yet the causal effect remains uncertain. In this study, we employed a bidirectional Mendelian randomization analysis to investigate the causal effect of one disease on the other. METHODS: Genetic instrumental variables were obtained from large-scale summary-level genome-wide association studies of AF (n = 1,030,836) and HF(n = 1,665,481), respectively. Two-sample Mendelian randomization was conducted to establish causal inferences. Inverse-variance weighted (IVW) was the primary estimate, while additional analyses including MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), MR-Egger, and Weighted median were performed to validate robustness and identify pleiotropy. RESULTS: After accounting for confounding variables, MR analysis suggested a potential causal relationship between AF and HF. An augmented genetic predisposition to atrial fibrillation was associated with an elevated risk of heart failure (odds ratio (OR) = 1.18, 95% confidence interval (CI):1.14-1.22). Likewise, genetically determined heart failure also increased the risk of heart failure (OR = 1.44, 95%CI:1.23-1.68). The robustness of the findings was corroborated through MR sensitivity analyses, and the causal estimates remained consistent when the instrument P-value threshold was tightened. CONCLUSIONS: Our bidirectional Mendelian randomization study supports a reciprocal causal relationship between AF and HF. The shared genetic profile of these conditions may provide crucial insights into potential therapeutic targets for the prevention and progression of both disorders. These findings underscore the necessity for further investigation into the underlying molecular mechanisms linking AF and HF, as well as the potential for personalized treatment strategies grounded in genetic profiling.

The Host E3-Ubiquitin Ligase TRIM28 Impedes Viral Protein GP4 Ubiquitination and Promotes PRRSV Replication.

Porcine reproductive and respiratory syndrome (PRRS), caused by the PRRS virus (PRRSV), is a highly pathogenic porcine virus that brings tremendous economic losses to the global swine industry. PRRSVs have evolved multiple elegant strategies to manipulate the host proteins and circumvent against the antiviral responses to establish infection. Therefore, the identification of virus-host interactions is critical for understanding the pathogenesis of PRRSVs. Tripartite motif protein 28 (TRIM28) is a transcriptional co-repressor involved in the regulation of viral and cellular transcriptional programs; however, its precise role in regulating PRRSV infection remains unknown. In this study, we found that the mRNA and protein levels of TRIM28 were up-regulated in PRRSV-infected porcine alveolar macrophages (PAMs) and MARC-145 cells. Ectopic TRIM28 expression dramatically increased viral yields, whereas the siRNA-mediated knockdown of TRIM28 significantly inhibited PRRSV replication. Furthermore, we used a co-immunoprecipitation (co-IP) assay to demonstrate that TRIM28 interacted with envelope glycoprotein 4 (GP4) among PRRSV viral proteins. Intriguingly, TRIM28 inhibited the degradation of PRRSV GP4 by impeding its ubiquitination. Taken together, our work provides evidence that the host E3-ubiquitin ligase TRIM28 suppresses GP4 ubiquitination and is important for efficient virus replication. Therefore, our study identifies a new host factor, TRIM28, as a potential target in the development of anti-viral drugs against PRRSV.