A novel high signal-to-noise ratio fluorescent probe for real-time mitochondrial viscosity detection and imaging in vitro and in vivo.

Mitochondrial viscosity serves as a critical indicator for assessing mitochondrial functionality and offers valuable insights into cellular homeostasis. Continuous, real-time monitoring of mitochondrial viscosity is indispensable for understanding and diagnosing diseases associated with these dynamic changes. In this study, we introduce a novel mitochondrial viscosity-responsive probe named "JL-JC" which is designed by using a molecular strategy, with a classic "D-π-A" molecular structure. Leveraging the distinctive twisted intramolecular charge transfer (TICT) properties of the probe, JL-JC exhibits exceptional sensitivity and a high signal-to-noise ratio, enabling precise detection of viscosity variations within its microenvironment while remaining unaffected by other factors. Upon rapid cellular uptake, JL-JC can efficiently evaluate the mitochondrial viscosity changes under diverse physiological and pathological conditions. Notably, this probe also enables viscosity imaging in zebrafish, offering insights into mitochondrial states in vivo. Our findings present JL-JC as a promising tool and potential diagnostic platform for mitochondria-related diseases.

Coumarin-aurone based fluorescence probes for cysteine sensitive in-situ identification in living cells.

The quantification of cysteine (Cys) levels in the organisms holds paramount significance in biological research and disease diagnosis, which can give the correlation between abnormal Cys levels and diseases. In this study, two fluorescent probes, designated as DEA-OH and DEA-AC, featuring a coumarin-aurone backbone specifically engineered for Cys detection, were meticulously designed and synthesized. The diethylamino coumarin-aurone probe DEA-OH and the acrylate-substituted probe DEA-AC demonstrated remarkable sensitivity in detecting cysteine by means of copper displacement (DEA-OH) and acrylate hydrolysis mechanisms (DEA-AC) with fluorescence detection limits of 7.25 µM and 1.65 µM, respectively. Moreover, the fluorescence peak wavelength of the two probes displayed a linear relationship with solvent polarity in the ET (30) range of 30-65 kcal•mol-1, indicating the potential for monitoring changes in environmental polarity within this ET (30) range. The outstanding attributes exhibited by DEA-AC including superior photostability, remarkable selectivity, and swift response (kinetic rate constant: 0.00747 s-1), coupled with the exceptional anti-interference ability, have significantly broadened its scope of applications, for example detecting alterations in Cys within biological systems.

Plasma metabolomics reveals the shared and distinct metabolic disturbances associated with cardiovascular events in coronary artery disease.

Risk prediction for subsequent cardiovascular events remains an unmet clinical issue in patients with coronary artery disease. We aimed to investigate prognostic metabolic biomarkers by considering both shared and distinct metabolic disturbance associated with the composite and individual cardiovascular events. Here, we conducted an untargeted metabolomics analysis for 333 incident cardiovascular events and 333 matched controls. The cardiovascular events were designated as cardiovascular death, myocardial infarction/stroke and heart failure. A total of 23 shared differential metabolites were associated with the composite of cardiovascular events. The majority were middle and long chain acylcarnitines. Distinct metabolic patterns for individual events were revealed, and glycerophospholipids alteration was specific to heart failure. Notably, the addition of metabolites to clinical markers significantly improved heart failure risk prediction. This study highlights the potential significance of plasma metabolites on tailed risk assessment of cardiovascular events, and strengthens the understanding of the heterogenic mechanisms across different events.

Differential DNA methylation landscape of miRNAs genes in mice liver fibrosis.

BACKGROUND: Patients with chronic liver disease were found nearly all to have liver fibrosis, which is characterized by excess accumulation of extracellular matrix (ECM) proteins. While ECM accumulation can prevent liver infection and injury, it can destroy normal liver function and architecture. miRNA's own regulation was involved in DNA methylation change. The purpose of this study is to detect DNA methylation landscape of miRNAs genes in mice liver fibrosis tissues. METHODS: Male mice (10-12 weeks) were injected CCl4 from abdominal cavity to induced liver fibrosis. 850 K BeadChips were used to examine DNA methylation change in whole genome. The methylation change of 16 CpG dinucleotides located in promoter regions of 4 miRNA genes were detected by bisulfite sequencing polymerase chain reaction (BSP) to verify chip data accuracy, and these 4 miRNA genes' expressions were detected by RT-qPCR methods. RESULTS: There are 769 differential methylation sites (DMS) in total between fibrotic liver tissue and normal mice liver tissue, which were related with 148 different miRNA genes. Chips array data were confirmed by bisulfite sequencing polymerase chain reaction (R = 0.953; P < 0.01). GO analysis of the target genes of 2 miRNA revealed that protein binding, cytoplasm and chromatin binding activity were commonly enriched; KEGG pathway enrichment analysis displayed that TGF-beta signaling pathway was commonly enriched. CONCLUSION: The DNA of 148 miRNA genes was found to have methylation change in liver fibrosis tissue. These discoveries in miRNA genes are beneficial to future miRNA function research in liver fibrosis.

Neutrophil ALDH2 is a new therapeutic target for the effective treatment of sepsis-induced ARDS.

Acetaldehyde dehydrogenase 2 (ALDH2) mutations are commonly found in a subgroup of the Asian population. However, the role of ALDH2 in septic acute respiratory distress syndrome (ARDS) remains unknown. Here, we showed that human subjects carrying the ALDH2rs671 mutation were highly susceptible to developing septic ARDS. Intriguingly, ALDH2rs671-ARDS patients showed higher levels of blood cell-free DNA (cfDNA) and myeloperoxidase (MPO)-DNA than ALDH2WT-ARDS patients. To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS, we utilized Aldh2 gene knockout mice and Aldh2rs671 gene knock-in mice. In clinically relevant mouse sepsis models, Aldh2-/- mice and Aldh2rs671 mice exhibited pulmonary and circulating NETosis, a specific process that releases neutrophil extracellular traps (NETs) from neutrophils. Furthermore, we discovered that NETosis strongly promoted endothelial destruction, accelerated vascular leakage, and exacerbated septic ARDS. At the molecular level, ALDH2 increased K48-linked polyubiquitination and degradation of peptidylarginine deiminase 4 (PAD4) to inhibit NETosis, which was achieved by promoting PAD4 binding to the E3 ubiquitin ligase CHIP. Pharmacological administration of the ALDH2-specific activator Alda-1 substantially alleviated septic ARDS by inhibiting NETosis. Together, our data reveal a novel ALDH2-based protective mechanism against septic ARDS, and the activation of ALDH2 may be an effective treatment strategy for sepsis.

Carbonylation of Runx2 at K176 by 4-Hydroxynonenal Accelerates Vascular Calcification.

BACKGROUND: Vascular calcification, which is characterized by calcium deposition in arterial walls and the osteochondrogenic differentiation of vascular smooth muscle cells, is an actively regulated process that involves complex mechanisms. Vascular calcification is associated with increased cardiovascular adverse events. The role of 4-hydroxynonenal (4-HNE), which is the most abundant stable product of lipid peroxidation, in vascular calcification has been poorly investigated. METHODS: Serum was collected from patients with chronic kidney disease and controls, and the levels of 4-HNE and 8-iso-prostaglandin F2α were measured. Sections of coronary atherosclerotic plaques from donors were immunostained to analyze calcium deposition and 4-HNE. A total of 658 patients with coronary artery disease who received coronary computed tomography angiography were recruited to analyze the relationship between coronary calcification and the rs671 mutation in aldehyde dehydrogenase 2 (ALDH2). ALDH2 knockout (ALDH2-/-) mice, smooth muscle cell-specific ALDH2 knockout mice, ALDH2 transgenic mice, and their controls were used to establish vascular calcification models. Primary mouse aortic smooth muscle cells and human aortic smooth muscle cells were exposed to medium containing ß-glycerophosphate and CaCl2 to investigate cell calcification and the underlying molecular mechanisms. RESULTS: Elevated 4-HNE levels were observed in the serum of patients with chronic kidney disease and model mice and were detected in calcified artery sections by immunostaining. ALDH2 knockout or smooth muscle cell-specific ALDH2 knockout accelerated the development of vascular calcification in model mice, whereas overexpression or activation prevented mouse vascular calcification and the osteochondrogenic differentiation of vascular smooth muscle cells. In patients with coronary artery disease, patients with ALDH2 rs671 gene mutation developed more severe coronary calcification. 4-HNE promoted calcification of both mouse aortic smooth muscle cells and human aortic smooth muscle cells and their osteochondrogenic differentiation in vitro. 4-HNE increased the level of Runx2 (runt-related transcription factor-2), and the effect of 4-HNE on promoting vascular smooth muscle cell calcification was ablated when Runx2 was knocked down. Mutation of Runx2 at lysine 176 reduced its carbonylation and eliminated the 4-HNE-induced upregulation of Runx2. CONCLUSIONS: Our results suggest that 4-HNE increases Runx2 stabilization by directly carbonylating its K176 site and promotes vascular calcification. ALDH2 might be a potential target for the treatment of vascular calcification.

Sex differences in the management of patients with suspected acute coronary syndrome in China.

Few studies have assessed sex differences in the management of suspected acute coronary syndrome (ACS). We aimed to compare the evaluation, treatment, and outcomes between males and females with suspected ACS in the emergency department. Data were obtained from a prospective registry of acute chest pain involving 21 emergency departments in Shandong Province, China. The primary endpoint was 30-day major adverse cardiac events (MACEs). Overlap propensity score weighting was used to address potential confounding. A total of 8046 patients were analysed (42.8% female). Overlap-weighted analysis showed no significant association of female sex with 30-day MACEs (odds ratio, 0.91; 95% CI 0.75 to 1.11; P = 0.363). Secondary analyses found that women were less likely to be identified as high risk at first presentation (odds ratio, 0.86; 95% CI 0.78 to 0.94; P < 0.001). In the emergency department, women were less likely to undergo antiplatelet therapy (odds ratio, 0.87; 95% CI 0.79 to 0.96; P = 0.004) or coronary angiography (odds ratio, 0.78; 95% CI, 0.69 to 0.88; P < 0.001). Women had a longer length of stay in the emergency department and were less likely to be admitted to a ward at disposition. These sex differences existed only in the non-ST-elevation subgroup and were independent of risk stratification. Women with non-ST-elevation chest pain in China received suboptimal treatment in the emergency department. However, their clinical outcomes were not significantly different from those of men. Further studies are needed to determine the causes and impacts of these sex differences.

Effects of Chest Compression on Ventilation Quality during Cardiopulmonary Resuscitation.

Ventilation is an important part of cardiopulmonary resuscitation (CPR). The advanced airway mode and 30:2 mode are used for intubated and non-intubated patients, respectively. It is debatable that passive produced by 30 compressions can provide adequate tidal volume for 30:2 mode. In addition, the fragmented ventilation caused by continuous compression may result in ineffective ventilation. In the study, one pig was anaesthetized and intubated for 2 CPRs. Continuous chest compressions with ventilation and continuous chest compressions without mechanical ventilation were performed in 2 CPRs, respectively. Three 10-minute data segments including a period of normal ventilation (V segment), a period of only compressions without ventilation (C segment), and a period of compressions with ventilation (C-V segment) were used to analyze peek flow (PF), peek pressure (PP) and tidal volume. All the data was presented as mean ± standard deviation. Chest compression resulted in 14.90% increase in mean PP (2401.40 ± 94.75 Pa vs 2822.06 ± 291.10 Pa, p<0.05), 81.46% increase in average PF (319.58 ± 56.93 ml/s vs 579.92 ± 80.27 ml/s, p<0.05). The mean tidal volumes for C segment, V segment and C-V segment were 189.13 ml, 514.72 ml, and 429.26ml, respectively. Continuous compressions reduced the accumulative tidal volume, but when five compressions were made in one inspiratory phase, there is almost no loss of tidal volume (510.86 ± 47.24 ml vs 514.72 ± 29.25 ml, p<0.05). The study suggested the ventilator without feedback regulation might reduce the peek pressure during CPR and 5 compressions in 2 s inspiratory phase provided higher tidal volume.Clinical Relevance- This study shows that 150 chest compressions per minute provided greater tidal volume than 100 and 120 compressions per minute; continuous chest compressions could also provide a certain amount of oxygen supply.

Co-registration of OPM-MCG signals with CT using optical scanning.

Magnetocardiography (MCG) can be used to noninvasively measure the electrophysiological activity of myocardial cells. The high spatial resolution of magnetic source localization can precisely determine the location of cardiomyopathy, which is of great significance for the diagnosis and treatment of cardiovascular disease. To perform magnetic source localization, MCG data must be co-registered with anatomical images. We propose a co-registration method that can be applied to OPM-MCG systems. In this method, the sensor array and the trunk of the subject are scanned using structured light-scanning technology, and the scan results are registered with the reconstructed structure using computed tomography (CT). This can increase the number of effective cloud points acquired and reduce the interference from respiratory motion. The scanning bed of the OPM-MCG system was modified to be consistent with the CT device, ensuring that the state of the body remains consistent between the cardiac magnetometry measurements and CT scans.

Magnetocardiography-based coronary artery disease severity assessment and localization using spatiotemporal features.

Objective.This study aimed to develop an automatic and accurate method for severity assessment and localization of coronary artery disease (CAD) based on an optically pumped magnetometer magnetocardiography (MCG) system.Approach.We proposed spatiotemporal features based on the MCG one-dimensional signals, including amplitude, correlation, local binary pattern, and shape features. To estimate the severity of CAD, we classified the stenosis as absence or mild, moderate, or severe cases and extracted a subset of features suitable for assessment. To localize CAD, we classified CAD groups according to the location of the stenosis, including the left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA), and separately extracted a subset of features suitable for determining the three CAD locations.Main results.For CAD severity assessment, a support vector machine (SVM) achieved the best result, with an accuracy of 75.1%, precision of 73.9%, sensitivity of 67.0%, specificity of 88.8%, F1-score of 69.8%, and area under the curve of 0.876. The highest accuracy and corresponding model for determining locations LAD, LCX, and RCA were 94.3% for the SVM, 84.4% for a discriminant analysis model, and 84.9% for the discriminant analysis model.Significance. The developed method enables the implementation of an automated system for severity assessment and localization of CAD. The amplitude and correlation features were key factors for severity assessment and localization. The proposed machine learning method can provide clinicians with an automatic and accurate diagnostic tool for interpreting MCG data related to CAD, possibly promoting clinical acceptance.

Early Progression of Abdominal Aortic Aneurysm is Decelerated by Improved Endothelial Barrier Function via ALDH2-LIN28B-ELK3 Signaling.

The involvement of endothelial barrier function in abdominal aortic aneurysm (AAA) and its upstream regulators remains unknown. Single-cell RNA sequencing shows that disrupted endothelial focal junction is an early (3 days) and persistent (28 days) event during Angiotensin II (Ang II)-induced AAA progression. Consistently, mRNA sequencing on human aortic dissection tissues confirmed downregulated expression of endothelial barrier-related genes. Aldehyde dehydrogenase 2 (ALDH2), a negative regulator of AAA, is found to be upregulated in the intimal media of AAA samples, leading to testing its role in early-stage AAA. ALDH2 knockdown/knockout specifically in endothelial cells (ECs) significantly increases expression of EC barrier markers related to focal adhesion and tight junction, restores endothelial barrier integrity, and suppresses early aortic dilation of AAA (7 and 14 days post-Ang II). Mechanically, ELK3 acts as an ALDH2 downstream regulator for endothelial barrier function preservation. At the molecular level, ALDH2 directly binds to LIN28B, a regulator of ELK3 mRNA stability, hindering LIN28B binding to ELK3 mRNA, thereby depressing ELK3 expression and impairing endothelial barrier function. Therefore, preserving vascular endothelial barrier integrity via ALDH2-specific knockdown in ECs holds therapeutic potential in the early management of AAAs.

Electrical-mechanical dynamical coupling between electrocardiographic and photoplethysmographic signals during cardiopulmonary resuscitation.

BACKGROUND AND OBJECTIVE: Cardiac arrest (CA) remains a significant cause of death and disability. High-quality cardiopulmonary resuscitation (CPR) can improve the survival rate of CA. A challenging issue is to find physiological indicators for screening and evaluating the cardiovascular function associated with CPR. This study aimed to investigate the electrical-mechanical dynamic coupling between electrocardiographic (ECG) and photoplethysmographic (PPG) signals for indicating cardiovascular function in the progress of CPR. METHOD: The ECG and PPG signals were simultaneously collected from a porcine CA model (n = 10) induced by ventricular fibrillation, and were further divided into four periods: Baseline, CA, CPR, and recovery of spontaneous circulation (ROSC). Recurrence quantitative analysis (RQA) was applied to examine the nonlinear dynamics of the ECG and PPG signals individually, and cross recurrence quantitative analysis (CRQA) was used to examine the ECG-PPG dynamical coupling. RESULTS: The CA influenced the dynamic patterns of electrical and mechanical activities and the electrical-mechanical coupling, which can be observed from the reduced entropy (ENTR) (p < 0.01), reduced determinism (DET) (p < 0.01) and reduced trapping time (TT) (p < 0.01) at CA compared to Baseline. The recurrence rate (RR), ENTR, DET, and TT at CPR were significantly lower than the parameters at ROSC but higher than those at CA. CONCLUSIONS: The electrical-mechanical dynamical coupling was sensitive to CPR and able to reflect the changes in cardiac function in the process of CPR.

GDF-15 at admission predicts cardiovascular death, heart failure, and bleeding outcomes in patients with CAD.

AIMS: We aimed to investigate the independent associations between growth differentiation factor 15 (GDF-15) level at admission and cardiovascular (CV) death, thrombotic events, heart failure (HF), and bleeding outcomes in patients with coronary artery disease (CAD). METHODS AND RESULTS: We measured the plasma concentrations of GDF-15 centrally in patients from the BIomarker-based Prognostic Assessment for patients with Stable angina and acute coronary Syndrome (BIPass) registry, which consecutively enrolled patients with CAD from November 2017 to September 2019 at five tertiary hospitals in China. The outcomes included CV death, thrombotic events [myocardial infarction (MI) and ischaemic stroke], HF events [acute HF during hospitalization and hospitalization for HF post-discharge (A/H HF) and cardiogenic shock], and bleeding outcomes [non-coronary artery bypass grafting-related major bleeding and clinically significant bleeding (CSB)] during the 12 month follow-up period after hospitalization. Among 6322 patients with CAD {65.4% male, median age 63.7 [inter-quartile range (IQR)] 56.0-70.1 years}, the median concentration of plasma GDF-15 at admission was 1091 (IQR 790.5-1635.0) ng/L. Higher concentrations of GDF-15 were associated with an increased risk of CV death [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.35-2.88, P < 0.001], A/H HF (HR 2.69, 95% CI 1.92-3.77, P < 0.001), cardiogenic shock (HR 1.46, 95% CI 1.04-2.05, P = 0.029), and CSB (HR 1.48, 95% CI 1.22-1.79, P < 0.001), but not for MI or stroke, after adjusting for clinical risk factors and prognostic biomarkers. Adding GDF-15 to the model with risk factors and biomarkers improved the net reclassification for CV death, A/H HF, cardiogenic shock, and CSB. CONCLUSIONS: In patients with CAD, admission levels of GDF-15 were associated with an increased 1 year risk of CV death, HF, and bleeding outcomes, but not with thrombotic events. GDF-15 may be a prognostic biomarker for CV death, HF, and bleeding outcomes and could be used to refine the risk assessment of these specific clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04044066.

Deubiquitinase OTUD5 as a Novel Protector against 4-HNE-Triggered Ferroptosis in Myocardial Ischemia/Reperfusion Injury.

Despite the development of advanced technologies for interventional coronary reperfusion after myocardial infarction, a substantial number of patients experience high mortality due to myocardial ischemia-reperfusion (MI/R) injury. An in-depth understanding of the mechanisms underlying MI/R injury can provide crucial strategies for mitigating myocardial damage and improving patient survival. Here, it is discovered that the 4-hydroxy-2-nonenal (4-HNE) accumulates during MI/R, accompanied by high rates of myocardial ferroptosis. The loss-of-function of aldehyde dehydrogenase 2 (ALDH2), which dissipates 4-HNE, aggravates myocardial ferroptosis, whereas the activation of ALDH2 mitigates ferroptosis. Mechanistically, 4-HNE targets glutathione peroxidase 4 (GPX4) for K48-linked polyubiquitin-related degradation, which 4-HNE-GPX4 axis commits to myocyte ferroptosis and forms a positive feedback circuit. 4-HNE blocks the interaction between GPX4 and ovarian tumor (OTU) deubiquitinase 5 (OTUD5) by directly carbonylating their cysteine residues at C93 of GPX4 and C247 of OTUD5, identifying OTUD5 as the novel deubiquitinase for GPX4. Consequently, the elevation of OTUD5 deubiquitinates and stabilizes GPX4 to reverse 4-HNE-induced ferroptosis and alleviate MI/R injury. The data unravel the mechanism of 4-HNE in GPX4-dependent ferroptosis and identify OTUD5 as a novel therapeutic target for the treatment of MI/R injury.

ALDH2 attenuates myocardial pyroptosis through breaking down Mitochondrion-NLRP3 inflammasome pathway in septic shock.

Cell survival or death is critical for cardiac function. Myocardial pyroptosis, as a newly recognized programmed cell death, remains poorly understood in sepsis. In this study, we evaluated the effect of aldehyde dehydrogenase (ALDH2) on myocardial pyroptosis and revealed the underlying mechanisms in sepsis. We established a septic shock mice model by intraperitoneal injection of Lipopolysaccharide (LPS, 15 mg/kg) 12 h before sacrifice. It was found that aldehyde dehydrogenase significantly inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation and Caspase-1/GSDMD-dependent pyroptosis, which remarkably improved survival rate and septic shock-induced cardiac dysfunction, relative to the control group. While aldehyde dehydrogenase knockout or knockdown significantly aggravated these phenomena. Intriguingly, we found that aldehyde dehydrogenase inhibited LPS-induced deacetylation of Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex α subunit (HADHA) by suppressing the translocation of Histone deacetylase 3 (HDAC3) from nuclei to mitochondria. Acetylated HADHA is essential for mitochondrial fatty acid ß-oxidation, and its interruption can result in accumulation of toxic lipids, induce mROS and cause mtDNA and ox-mtDNA release. Our results confirmed the role of Histone deacetylase 3 and HADHA in NOD-like receptor protein 3 inflammasome activation. Hdac3 knockdown remarkedly suppressed NOD-like receptor protein 3 inflammasome and pyroptosis, but Hadha knockdown eliminated the effect. aldehyde dehydrogenase inhibited the translocation of Histone deacetylase 3, protected ac-HADHA from deacetylation, and significantly reduced the accumulation of toxic aldehyde, and inhibited mROS and ox-mtDNA, thereby avoided NOD-like receptor protein 3 inflammasome activation and pyroptosis. This study provided a novel mechanism of myocardial pyroptosis through mitochondrial Histone deacetylase 3/HADHA- NOD-like receptor protein 3 inflammasome pathway and demonstrated a significant role of aldehyde dehydrogenase as a therapeutic target for myocardial pyroptosis in sepsis.

The role of aldehyde dehydrogenase 2 in cardiovascular disease.

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in the detoxification of alcohol-derived acetaldehyde and endogenous aldehydes. The inactivating ALDH2 rs671 polymorphism, present in up to 8% of the global population and in up to 50% of the East Asian population, is associated with increased risk of cardiovascular conditions such as coronary artery disease, alcohol-induced cardiac dysfunction, pulmonary arterial hypertension, heart failure and drug-induced cardiotoxicity. Although numerous studies have attributed an accumulation of aldehydes (secondary to alcohol consumption, ischaemia or elevated oxidative stress) to an increased risk of cardiovascular disease (CVD), this accumulation alone does not explain the emerging protective role of ALDH2 rs671 against ageing-related cardiac dysfunction and the development of aortic aneurysm or dissection. ALDH2 can also modulate risk factors associated with atherosclerosis, such as cholesterol biosynthesis and HDL biogenesis in hepatocytes and foam cell formation and efferocytosis in macrophages, via non-enzymatic pathways. In this Review, we summarize the basic biology and the clinical relevance of the enzymatic and non-enzymatic, tissue-specific roles of ALDH2 in CVD, and discuss the future directions in the research and development of therapeutic strategies targeting ALDH2. A thorough understanding of the complex roles of ALDH2 in CVD will improve the diagnosis, management and prognosis of patients with CVD who harbour the ALDH2 rs671 polymorphism.

SUPER Score Contributes to Warning and Management in Early-Stage COVID-19.

Background: Some COVID-19 patients deteriorate to severe cases with relatively higher case-fatality rates, which increases the medical burden. This necessitates identification of patients at risk of severe disease. Early assessment plays a crucial role in identifying patients at risk of severe disease. This study is to assess the effectiveness of SUPER score as a predictor of severe COVID-19 cases. Methods: We consecutively enrolled COVID-19 patients admitted to a comprehensive medical center in Wuhan, China, and recorded clinical characteristics and laboratory indexes. The SUPER score was calculated using parameters including oxygen saturation, urine volume, pulse, emotional state, and respiratory rate. In addition, the area under the receiver operating characteristic curve (AUC), specificity, and sensitivity of the SUPER score for the diagnosis of severe COVID-19 were calculated and compared with the National Early Warning Score 2 (NEWS2). Results: The SUPER score at admission, with a threshold of 4, exhibited good predictive performance for early identification of severe COVID-19 cases, yielding an AUC of 0.985 (95% confidence interval [CI] 0.897-1.000), sensitivity of 1.00 (95% CI 0.715-1.000), and specificity of 0.92 (95% CI 0.775-0.982), similar to NEWS2 (AUC 0.984; 95% CI 0.895-1.000, sensitivity 0.91; 95% CI 0.587-0.998, specificity 0.97; 95% CI 0.858-0.999). Compared with patients with a SUPER score<4, patients in the high-risk group exhibited lower lymphocyte counts, interleukin-2, interleukin-4 and higher fibrinogen, C-reactive protein, aspartate aminotransferase, and lactate dehydrogenase levels. Conclusions: In conclusion, the SUPER score demonstrated equivalent accuracy to the NEWS2 score in predicting severe COVID-19. Its application in prognostic assessment therefore offers an effective early warning system for critical management and facilitating efficient allocation of health resources.

LincRNA-p21 Upregulates Nuclear Orphan Receptor Nr4a2 and Aggravates Myocardial Ischemia/Reperfusion Injury via Targeting MiR-466i-5p.

Myocardial ischemia/reperfusion (I/R) injury can bring about more cardiomyocyte death and aggravate cardiac dysfunction, but its pathogenesis remains unclear. This study aimed to investigate the role of long intergenic noncoding RNA-p21 (LincRNA-p21) in myocardial I/R injury and its underlying mechanism. Mice were subjected to myocardial I/R injury by ligation and release of the left anterior descending artery, and HL-1 cardiomyocytes were treated with hydrogen peroxide. Infarct area, cardiac function, and cardiomyocyte apoptosis were determined. Consequently, LincRNA-p21 was found to significantly be elevated both in the reperfused hearts and H2O2-treated cardiomyocytes. Moreover, genetic inhibition of LincRNA-p21 brought about reduced infarct area and improved cardiac function in mice subjected to myocardial I/R injury. LincRNA-p21 knockdown was also demonstrated to inhibit cardiomyocyte apoptosis both in vivo and in vitro. Notably, LincRNA-p21 silencing increased the expression of microRNA-466i-5p (miR-466i-5p) and suppressed the expression of nuclear receptor subfamily 4 group A member 2 (Nr4a2). Mechanically, LincRNA-p21 downregulated and directly interacted with miR-466i-5p, while application of miR-466i-5p inhibitor promoted cardiomyocyte apoptosis that was improved by LincRNA-p21 inhibition. Furthermore, Nr4a2 upregulation caused by LincRNA-p21 overexpression was partially reversed by miR-466i-5p mimics. Thus, LincRNA-p21 positively regulated the expression of Nr4a2, through sponging miR-466i-5p, promoting cardiomyocyte apoptosis in myocardial I/R injury. The current study revealed a novel LincRNA-p21/miR-466i-5p/Nr4a2 pathway for myocardial I/R injury, indicating that LincRNA-p21 may serve as a potential target for future therapy.

Biomarker-based risk model to predict cardiovascular events in patients with acute coronary syndromes - Results from BIPass registry.

Background: Risk models integrating new biomarkers to predict cardiovascular events in acute coronary syndromes (ACS) are lacking. Therefore, we evaluated the prognostic value of biomarkers in addition to clinical predictors and developed a biomarker-based risk model for major adverse cardiovascular events (MACE) within 12 months after hospital admission with ACS. Methods: Patients (n = 4407) consecutively enrolled from November, 2017 to October, 2019 in three hospitals of a prospective Chinese registry (BIomarker-based Prognostic Assessment for Patients with Stable Angina and Acute Coronary Syndromes, BIPass) were designated as the risk model development cohort. Validation was performed in 1409 patients enrolled in two independent hospitals. Cox proportional hazards regression analysis was used to generate a risk prediction model and evaluate the incremental prognostic value of each biomarker. Findings: Over 12 months, 196 patients experienced MACE (5.1%/year). Among twelve candidate biomarkers, N-terminal pro-B-type natriuretic peptide (NT-proBNP) measured at baseline showed the most prognostic capability independent of clinical predictors. The developed BIPass risk model included age, hypertension, previous myocardial infarction, stroke, Killip class, heart rate, and NT-proBNP. It displayed improved discrimination (C-statistic 0.79, 95% CI 0.73-0.85), calibration (GOF = 9.82, p = 0.28) and clinical decision curve in the validation cohort, outperforming the GRACE and TIMI risk scores. Cumulative rates for MACE demonstrated good separation in the BIPass predicted low, intermediate, and high-risk groups. Interpretation: The BIPass risk model, integrating clinical variables and NT-proBNP, is useful for predicting 12-month MACE in ACS. It effectively identifies a gradient risk of cardiovascular events to aid personalized care. Funding: National Key R&D Program of China (2017YFC0908700, 2020YFC0846600), National S&T Fundamental Resources Investigation Project (2018FY100600, 2018FY100602), Taishan Pandeng Scholar Program of Shandong Province (tspd20181220), Taishan Young Scholar Program of Shandong Province (tsqn20161065, tsqn201812129), Youth Top-Talent Project of National Ten Thousand Talents Plan and Qilu Young Scholar Program.

Global magnitude of encephalitis burden and its evolving pattern over the past 30 years.

OBJECTIVE: We aimed to estimate the spatiotemporal patterns of the encephalitis burden along with its attributable risk factors at the national, regional, and global levels, which may be helpful in guiding targeted prevention and treatment programs. METHODS: Based on available data sources, the incidence, mortality, and disability-adjusted life years (DALYs) of encephalitis in 204 countries and regions from 1990 to 2019 were reconstructed by the Global Burden of Disease Study 2019 using the Cause of Death Ensemble model, spatiotemporal Gaussian process regression, and DisMod-MR 2.1. We conducted a systematic analysis on the epidemiological characteristics of encephalitis in detail by gender, region, and age over the past three decades. RESULTS: Globally, 1,444,720 incident cases, 89,900 deaths, and 4.80 million DALYs related to encephalitis were estimated in 2019. The age-standardized incidence rate and age-standardized mortality rate (ASMR) decreased from 23.17 and 2.18 to 19.33 and 1.19 per 100,000 person-years over the past 30 years, respectively. However, beginning in 2011-2013, the burden of encephalitis has shown an inflection point, with a further decline of the ASRs ceasing. Lower socio-demographic index (SDI) regions in South Asia, Western and Eastern Sub-Saharan Africa had the highest burden of encephalitis in 2019. During the past three decades, most countries of South Asia achieved significant control of the burden. In contrast, developed countries with a higher SDI have shown a notable increase in ASMR and age-standardized DALYs rate. Children and older adults have always been high-risk groups for encephalitis. CONCLUSION: Although the global burden of encephalitis has decreased in the past 30 years, a further decline stopped from 2011 to 2013. The diverse burden in different regions calls for differentiated management, and the persistent high burden in some low-SDI regions and the increased burden in developed countries with higher SDIs deserve more attention.