Air Pollutants and Mortality Risk in Patients with Aortic Dissection: Evidence from a Clinical Cohort, Single-Cell Sequencing, and Proteomics.

We aimed to evaluate the association between air pollutants and mortality risk in patients with acute aortic dissection (AAD) in a longitudinal cohort and to explore the potential mechanisms of adverse prognosis induced by fine particulate matter (PM2.5). Air pollutants data, including PM2.5, PM10.0, nitrogen dioxide (NO2), carbon monoxide (CO), sulfur dioxide (SO2), and ozone (O3), were collected from official monitoring stations, and multivariable Cox regression models were applied. Single-cell sequencing and proteomics of aortic tissue were conducted to explore the potential mechanisms. In total, 1,267 patients with AAD were included. Exposure to higher concentrations of air pollutants was independently associated with an increased mortality risk. The high-PM2.5 group carried approximately 2 times increased mortality risk. There were linear associations of PM10, NO2, CO, and SO2 exposures with long-term mortality risk. Single-cell sequencing revealed an increase in mast cells in aortic tissue in the high-PM2.5 exposure group. Enrichment analysis of the differentially expressed genes identified the inflammatory response as one of the main pathways, with IL-17 and TNF signaling pathways being among the top pathways. Analysis of proteomics also identified these pathways. This study suggests that exposure to higher PM2.5, PM10, NO2, CO, and SO2 are associated with increased mortality risk in patients with AAD. PM2.5-related activation and degranulation of mast cells may be involved in this process.

Abnormal adiposity indices are associated with an increased risk of diabetes in a non-obese Asian population.

OBJECTIVES: The aim of this study was to evaluate the association between adiposity indices and the risk of incident diabetes and to compare their predictive ability in non-obese healthy individuals. STUDY DESIGN: Population-based cohort study. METHODS: Data were taken from the NAGALA research study, which enrolled Japanese adults aged 18-79 years. Cox regression was used to evaluate the association between adiposity indices (including waist circumference [WC], waist-to-height ratio [WHtR], lipid accumulation product index [LAP], body roundness index [BRI], visceral adiposity index [VAI] and Chinese visceral adiposity index [CVAI]) and diabetes risk. The performance of the indices for predicting diabetes was explored using area under the receiver operating characteristic curve (AUC). A Chinese community-based population was used for validation. RESULTS: A total of 12,940 healthy Japanese individuals with normal body mass index and glycaemic levels were included and were followed up for a median of 6 years. Multivariable Cox models revealed a positive and significant association between all indices and incident diabetes, with the hazard ratios for the highest quartile of the indices ranging from 1.89 to 2.90 (all P-values < 0.01). A non-linear association between WC, BRI and VAI and a linear association between WHtR, LAP and CVAI and diabetes risk were observed. CVAI, VAI and LAP had comparable ability in predicting diabetes, with the highest AUC being 0.733 for CVAI. Data from 10,830 Chinese individuals confirmed these results. CONCLUSIONS: Adiposity indices are associated with incident diabetes in healthy non-obese individuals. Participants in the highest quartile of WC, WHtR, LAP, BRI, VAI and CVAI had an increased risk of developing diabetes.

Visceral fat and its dynamic change are associated with renal damage: Evidence from two cohorts.

BACKGROUND AND AIMS: To evaluate the association of Chinese visceral adiposity index (CVAI) and its dynamic trends with risk of renal damage, and to compare its prediction performance with that of other obesity indices. METHODS AND RESULTS: A community-based population with 23 905 participants from Shantou city was included in the cross-sectional analysis. A total of 9,778 individuals from two separated cohort were included in the longitudinal portion. Five patterns of CVAI change were predefined (low-stable, decreasing, moderate, increasing, and persistent-high). Logistic and Cox regressions were used to evaluate the association between CVAI and renal damage. We explored potential mechanisms using the mediating effect method, and the prediction performance was determined by receiver operating characteristic curve analysis. Results from both cross-sectional and longitudinal data revealed a positive and linear association between CVAI and risk of renal damage. Pooled analysis of the two cohorts showed that per unit increase in Z score of CVAI induced 18% increased risk of renal damage (P = .008). Longitudinal trends of CVAI were also associated with renal damage, and the moderate, increasing, and persistent-high patterns showing a higher risk. Blood pressure and glucose had a mediating effect on renal damage induced by CVAI. Among several obesity indices, CVAI was the optimal for predicting renal damage. CONCLUSION: A higher level of immediate CVAI and longitudinal increasing and persistent-high patterns of CVAI were independently associated with increased risk of renal damage. Monitoring immediate level and long-term trend of CVAI may contribute to the prevention of renal damage.

Helix B Surface Peptide Protects Cardiomyocytes From Hypoxia/Reoxygenation-induced Autophagy Through the PI3K/Akt Pathway.

BACKGROUND: Helix B surface peptide (HBSP) is a newly discovered tissue-protective erythropoietin derivative that provides benefits after myocardial ischemia/reperfusion. This study explores the cardioprotective effects of HBSP in myocardial cells in response to hypoxia/reoxygenation injury and its potential mechanism. METHODS: In this study, rat ventricular (H9c2) cell cultures were established and pretreated with HBSP. H9c2 cardiomyocytes were randomly assigned to the control, H/R, H/R + LY294002 (a PI3K inhibitor), HBSP + H/R, and HBSP + H/R + LY294002 groups. The pretreated cardiomyocytes underwent H/R, and the cardiomyocytes were monitored for viability through a CCK-8 assay, whereas flow cytometry was used to test cell apoptosis. Orgotein Superoxide Dismutase (SOD) and lactate dehydrogenase (LDH) expression were monitored by SOD and LDH kits, respectively. The expression of LC3 autophagosomes was determined by immunocytochemistry. The expression of LC3II/LC3I, p-Mammalian Target of Rapamycin (mTOR) mTOR, mTOR, Beclin 1, p-PI3K, PI3K p-Akt, and Akt was determined by Western blotting. RESULTS: HBSP increased cell viability and reduced SOD and LDH production, and it also reduced H/R-induced cell apoptosis. Moreover, the expression of the autophagy-related proteins (LC3II/LC3I) was inhibited by HBSP, whereas the expression of p-PI3K, p-Akt, and p-mTOR was enhanced. However, the PI3K inhibitor (LY294002) notably abolished these effects in H9c2 cells. CONCLUSIONS: HBSP inhibits excessive autophagy and apoptosis induced by H/R by activating the PI3K/Akt pathway. HBSP may potentially be a therapeutic intervention for myocardial ischemia/reperfusion injury.

Non-O blood group is associated with lower risk of in-hospital mortality in non-surgically managed patients with type A aortic dissection.

BACKGROUND: The association between different ABO blood groups and mortality of aortic dissection (AD) remains controversial. This study aimed to examine whether different ABO blood groups affect the prognosis of AD. METHODS: Demographic and clinical data were collected from 877 patients diagnosed with AD from 2015 to 2019 in the First Affiliated Hospital of Shantou University Medical College. The association between in-hospital mortality of AD patients and ABO blood group was analyzed using Cox proportional hazards regression models. RESULTS: This retrograde cohort study demonstrated that for 877 patients, male gender, non-O blood group, Stanford type B AD (TBAD), higher presenting systolic and diastolic blood pressure, and being a recipient of aortic arch replacement surgery (surgery) or endovascular stent-graft implantation (stent-graft) were associated with decreased in-hospital mortality of AD. In Cox proportional hazards models, non-O blood group was associated with lower risk of early mortality regardless of adjustment (HR = 0.668, 95% confidence interval [CI] 0.473-0.944 before adjustment, HR = 0.662, 95% CI 0.468-0.935 after adjustment for age and sex, and HR = 0.641, 95% CI 0.453-0.906 after adjustment for AD types, SBP and surgery). Further analyses revealed that for patients diagnosed with type A AD (TAAD), non-O blood group renders a significant 34.3% decrease in the risk of in-hospital mortality compared with blood group O. Specifically, this difference in mortality risk was found among TAAD patients who did not undergo surgery (HR = 0.579, 95% CI 0.377-0.889), rather than those who did. There was no significant difference in early mortality for patients with TBAD, whether or not stent-grafts were implanted. CONCLUSIONS: Non-O blood type decreases the risk of in-hospital mortality, especially for TAAD, in AD patients without surgical intervention. More attention must be paid to blood type O TAAD patients without surgical interventions, and early surgical intervention may be an effective means to decrease in-hospital mortality of TAAD.

Coronary-Heart-Disease-Associated Genetic Variant at the COL4A1/COL4A2 Locus Affects COL4A1/COL4A2 Expression, Vascular Cell Survival, Atherosclerotic Plaque Stability and Risk of Myocardial Infarction.

Genome-wide association studies have revealed an association between coronary heart disease (CHD) and genetic variation on chromosome 13q34, with the lead single nucleotide polymorphism rs4773144 residing in the COL4A2 gene in this genomic region. We investigated the functional effects of this genetic variant. Analyses of primary cultures of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) from different individuals showed a difference between rs4773144 genotypes in COL4A2 and COL4A1 expression levels, being lowest in the G/G genotype, intermediate in A/G and highest in A/A. Chromatin immunoprecipitation followed by allelic imbalance assays of primary cultures of SMCs and ECs that were of the A/G genotype revealed that the G allele had lower transcriptional activity than the A allele. Electrophoretic mobility shift assays and luciferase reporter gene assays showed that a short DNA sequence encompassing the rs4773144 site interacted with a nuclear protein, with lower efficiency for the G allele, and that the G allele sequence had lower activity in driving reporter gene expression. Analyses of cultured SMCs from different individuals demonstrated that cells of the G/G genotype had higher apoptosis rates. Immunohistochemical and histological examinations of ex vivo atherosclerotic coronary arteries from different individuals disclosed that atherosclerotic plaques with the G/G genotype had lower collagen IV abundance and thinner fibrous cap, a hallmark of unstable, rupture-prone plaques. A study of a cohort of patients with angiographically documented coronary artery disease showed that patients of the G/G genotype had higher rates of myocardial infarction, a phenotype often caused by plaque rupture. These results indicate that the CHD-related genetic variant at the COL4A2 locus affects COL4A2/COL4A1 expression, SMC survival, and atherosclerotic plaque stability, providing a mechanistic explanation for the association between the genetic variant and CHD risk.

Integrative analysis of competing endogenous RNA networks reveals the functional lncRNAs in heart failure.

Heart failure has become one of the top causes of death worldwide. It is increasing evidence that lncRNAs play important roles in the pathology processes of multiple cardiovascular diseases. Additionally, lncRNAs can function as ceRNAs by sponging miRNAs to affect the expression level of mRNAs, implicating in numerous biological processes. However, the functional roles and regulatory mechanisms of lncRNAs in heart failure are still unclear. In our study, we constructed a heart failure-related lncRNA-mRNA network by integrating probe re-annotation pipeline and miRNA-target interactions. Firstly, some lncRNAs that had the central topological features were found in the heart failure-related lncRNA-mRNA network. Then, the lncRNA-associated functional modules were identified from the network, using bidirectional hierarchical clustering. Some lncRNAs that involved in modules were demonstrated to be enriched in many heart failure-related pathways. To investigate the role of lncRNA-associated ceRNA crosstalks in certain disease or physiological status, we further identified the lncRNA-associated dysregulated ceRNA interactions. And we also performed a random walk algorithm to identify more heart failure-related lncRNAs. All these lncRNAs were verified to show a strong diagnosis power for heart failure. These results will help us to understand the mechanism of lncRNAs in heart failure and provide novel lncRNAs as candidate diagnostic biomarkers or potential therapeutic targets.

Histone acetylation regulates orphan nuclear receptor NR4A1 expression in hypercholesterolaemia.

Hypercholesterolaemia and inflammation are correlated with atherogenesis. Orphan nuclear receptor NR4A1, as a key regulator of inflammation, is closely associated with lipid levels in vivo. However, the mechanism by which lipids regulate NR4A1 expression remains unknown. We aimed to elucidate the underlying mechanism of NR4A1 expression in monocytes during hypercholesterolaemia, and reveal the potential role of NR4A1 in hypercholesterolaemia-induced circulating inflammation. Circulating leucocytes were collected from blood samples of 139 patients with hypercholesterolaemia and 139 sex- and age-matched healthy subjects. We found that there was a low-grade inflammatory state and higher expression of NR4A1 in patients. Both total cholesterol and low-density lipoprotein cholesterol levels in plasma were positively correlated with NR4A1 mRNA level. ChIP revealed that acetylation of histone H3 was enriched in the NR4A1 promoter region in patients. Human mononuclear cell lines THP-1 and U937 were treated with cholesterol. Supporting our clinical observations, cholesterol enhanced p300 acetyltransferase and decreased HDAC7 (histone deacetylase 7) recruitment to the NR4A1 promoter region, resulting in histone H3 hyperacetylation and further contributing to NR4A1 up-regulation in monocytes. Moreover, cytosporone B, an NR4A1 agonist, completely reversed cholesterol-induced IL-6 (interleukin 6) and MCP-1 (monocyte chemoattractant protein 1) expression to below basal levels, and knockdown of NR4A1 expression by siRNA not only mimicked, but also exaggerated the effects of cholesterol on inflammatory biomarker up-regulation. Thus we conclude that histone acetylation contributes to the regulation of NR4A1 expression in hypercholesterolaemia, and that NR4A1 expression reduces hypercholesterolaemia-induced inflammation.

Homocysteine upregulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo.

RATIONALE: Hyperhomocysteinemia is a risk factor of atherogenesis. Soluble epoxide hydrolase (sEH) is a major enzyme that hydrolyzes epoxyeicosatrienoic acids and attenuates their cardiovascular protective effects. Whether homocysteine (Hcy) regulates sEH and the underlying mechanism remains elusive. OBJECTIVE: To elucidate the mechanism by which Hcy regulates sEH expression and endothelial activation in vitro and in vivo. METHODS AND RESULTS: Hcy treatment in cultured human endothelial cells dose-dependently and time-dependently upregulated sEH mRNA and protein. Hcy increased the expression of adhesion molecules, which was markedly reversed by inhibiting sEH activity. Hcy-induced sEH upregulation is associated with activation of activating transcription factor-6 (ATF6). Bioinformatics analysis revealed a putative ATF6-binding motif in the promoter region of the sEH gene, which was found at a methylation site. Site-directed mutagenesis and chromatin immunoprecipitation assays demonstrated that Hcy treatment or ATF6 overexpression promoted ATF6 binding to the promoter of sEH and increased its activity. Results of methylation-specific polymerase chain reaction revealed that the ATF6 binding site on the sEH promoter was partially methylated and was demethylated with Hcy. SiRNA knockdown of ATF6α or SP1 blocked and ATF6 overexpression and DNA methyltransferase inhibitor mimicked the effect of homocysteine on sEH upregulation. In vivo, immunofluorescence assay revealed elevated expression of sEH and adhesion molecules in the aortic intima of mice with mild hyperhomocysteinemia, which was attenuated by sEH deletion or inhibition. CONCLUSION: ATF6 activation and DNA demethylation may coordinately contribute to Hcy-induced sEH expression and endothelial activation. Inhibition of sEH may be a therapeutic approach for treating Hcy-induced cardiovascular diseases.

Preeclampsia/eclampsia impacts the structure and function of neonatal hearts probably by reducing myocardial compaction.

PURPOSE: Preeclampsia/Eclampsia (PE/E) poses significant risks to neonatal cardiac health. Traditional echocardiographic methods have limitations in detailing these impacts. This study hypothesized that echocardiographic radiomics could provide a more comprehensive assessment of the cardiac changes in neonates affected by PE/E. METHOD: In a comprehensive analysis, 2594 neonates underwent echocardiographic screening. From these, 556 were selected for detailed radiomics analysis, focusing on cardiac shape, movement, and texture features. A multiblock sparse partial least squares (sPLS) model integrated these features to assess their association with PE/E. RESULTS: Newborns from PE/E-affected pregnancies displayed lower left ventricular ejection fractions compared to the control group (61.1 % vs. 66.2 %). Our radiomics approach extracted 15,494 features per neonate, with the sPLS model identifying 17 features significantly correlated with PE/E. Among these, texture features representing myocardial non-compaction were most strongly correlated with PE/E (correlation coefficient r = 0.63). Detailed visualization of these texture features suggested that PE/E might lead to more pronounced myocardial non-compaction, characterized by a thicker non-compaction layer and increased cardiac trabeculation. CONCLUSIONS: Our findings demonstrate the potential of echocardiographic radiomics as a tool for assessing the impact of PE/E on neonatal cardiac function. The correlation between PE/E and myocardial non-compaction underlines the need for enhanced cardiac monitoring in neonates born to PE/E-affected mothers. This study contributes to a better understanding of PE/E's cardiac implications, potentially guiding future clinical practices.

Effect of sacubitril/valsartan on sinus rhythm maintenance after catheter ablation in patients with persistent atrial fibrillation without reduced ejection fraction heart failure: a study protocol for a multi-center, open-label, randomized, controlled, superiority clinical trial.

Introduction: A high recurrence rate of atrial fibrillation was monitored after catheter ablation for persistent atrial fibrillation. Sacubitril/valsartan can improve outcomes for patients with heart failure and ventricular tachycardia, but few studies examined whether it can reduce recurrence or improve cardiovascular outcomes in patients with persistent atrial fibrillation after catheter ablation. In this study, we will assess the effect of sacubitril/valsartan on sinus rhythm maintenance and incidence of major adverse cardiovascular events (MACE) in patients with persistent atrial fibrillation after catheter ablation through a randomized controlled trial (RCT). Methods: This is a multi-center, randomized, controlled, open-label, superiority clinical trial involving 462 patients without reduced ejection fraction heart failure after catheter ablation of persistent atrial fibrillation. Patients will be randomized to (1) receive the standard treatment strategy plus sacubitril/valsartan titration, or (2) receive the standard treatment strategy without taking sacubitril/valsartan. The primary outcome will be sinus rhythm maintenance rate over 12 months, monitored by random electrocardiogram and 24-h Holter electrocardiogram. Discussion: This study is designed to evaluate the effect of sacubitril/valsartan on sinus rhythm maintenance and incidence of major adverse cardiovascular events (MACE) in patients with persistent atrial fibrillation after catheter ablation. The results will evaluate sacubitril/valsartan as a novel treatment for improving prognosis and a complement to conventional drug therapy. Trial Registration: Registered with Chinese Clinical Trials Registry on 27 August 2022, identifier: ChiCTR2200062995.

Effectiveness of a standardized quality control management procedure for COVID-19 RT-PCR testing: a large-scale diagnostic accuracy study in China.

BACKGROUND: The study aimed to construct a standardized quality control management procedure (QCMP) and access its accuracy in the quality control of COVID-19 reverse transcriptase-polymerase chain reaction (RT-PCR). METHODS: Considering the initial RT-PCR results without applying QCMP as the gold standard, a large-scale diagnostic accuracy study including 4,385,925 participants at three COVID-19 RT-PCR testing sites in China, Foshan (as a pilot test), Guangzhou and Shenyang (as validation sites), was conducted from May 21, 2021, to December 15, 2022. RESULTS: In the pilot test, the RT-PCR with QCMP had a high accuracy of 99.18% with 100% specificity, 100% positive predictive value (PPV), and 99.17% negative predictive value (NPV). The rate of retesting was reduced from 1.98% to 1.16%. Its accuracy was then consistently validated in Guangzhou and Shenyang. CONCLUSIONS: The RT-PCR with QCMP showed excellent accuracy in identifying true negative COVID-19 and relieved the labor and time spent on retesting.

Machine-learning predictive model of pregnancy-induced hypertension in the first trimester.

In the first trimester of pregnancy, accurately predicting the occurrence of pregnancy-induced hypertension (PIH) is important for both identifying high-risk women and adopting early intervention. In this study, we used four machine-learning models (LASSO logistic regression, random forest, backpropagation neural network, and support vector machines) to predict the occurrence of PIH in a prospective cohort. Candidate features for predicting the occurrence of middle and late PIH were acquired using a LASSO algorithm. The performance of predictive models was assessed using receiver operating characteristic analysis. Finally, a nomogram was established with the model scores, age, and nulliparity. Calibration, clinical usefulness, and internal validation were used to assess the performance of the nomogram. In the training set (2258 pregnant women), eleven candidate factors in the first trimester were significantly associated with the occurrence of PIH (P < 0.001 in the training set). Four models showed AUCs from 0.780 to 0.816 in the training set. For the validation set (939 pregnant women), AUCs varied from 0.516 to 0.795. The nomogram showed good discrimination, with an AUC of 0.847 (95% CI: 0.805-0.889) in the training set and 0.753 (95% CI: 0.653-0.853) in the validation set. Decision curve analysis suggested that the model was clinically useful. The model developed using LASSO logistic regression achieved the best performance in predicting the occurrence of PIH. The derived nomogram, which incorporates the model score and maternal risk factors, can be used to predict PIH in clinical practice. We develop a model with good performance for clinical prediction of PIH in the first trimester.

The association of coagulation indicators with in-hospital acute kidney injury and malignant events of patients with acute aortic dissection: a retrospective cohort study.

Background: Acute kidney injury (AKI) is a prevalent complication of acute aortic dissection (AAD) and is associated with poor outcomes. The onset of AAD may result in endothelial injury due to the formation of the false lumen, which can activate the coagulation pathway and lead to coagulation dysfunction. It serves as a valuable diagnostic and prognostic marker for AAD, but also plays a role in the pathological mechanisms underlying AKI. We aimed to investigate the potential value of coagulation indicators at admission for assessing in-hospital AKI and malignant events after AAD. Methods: We identified patients with AAD admitted to the First Affiliated Hospital of Shantou University Medical College from January 2015 to October 2020 and divided them into two groups according to coagulation function. Univariable and multivariable analyses were used to analyze the association between coagulation indicators and AKI and malignant events in patients with AAD. Chi-squared or Fisher exact test and receiver operating characteristic (ROC) curve analysis was conducted to assess the value of coagulation indicators in predicting in-hospital AKI and malignant events. Results: A total of 487 patients were enrolled in this study, including 309 cases with normal coagulation. After the multivariable adjustment, the incidence of in-hospital AKI in the abnormal coagulation group was significantly higher [model 1: 2.061 (1.214-3.501), P=0.007; model 2: 1.833 (1.058-3.177), P=0.031; model 3: 1.836 (1.048-3.216), P=0.034]. The incidence of malignant events was higher in the abnormal prothrombin time (PT) group [model 1: 4.283 (0.983-18.665), P=0.053; model 2: 7.342 (1.467-36.749), P=0.015; model 3: 6.996 (1.377-35.537), P=0.019]. Chi-squared and Fisher exact test showed that PT and abnormal coagulation score (ACS) were statistically different among the AKI groups and malignant event groups. Under ROC analysis, coagulation indicators were helpful to predict AKI (AUC =0.668; P<0.001). Conclusions: Our study confirmed the presence of coagulation dysfunction is associated with an increased risk of AKI and malignant events. It suggested the severity of coagulation dysfunction is positively correlated with the incidence of in-hospital AKI in AAD patients. These results highlight the importance of considering coagulation dysfunction as a potential mechanism underlying AKI and malignant events after AAD.

Effect of probiotic supplementation on in-hospital mortality in patients with acute myocardial infarction: a study protocol for an open-label, randomized, controlled, superiority clinical trial.

BACKGROUND: Recent studies have demonstrated a correlation between intestinal flora and the severity of myocardial infarction as well as post-myocardial infarction repair. However, few studies have investigated whether probiotics reduce mortality and improve cardiovascular outcomes in patients with acute myocardial infarction. In this study, we will conduct a randomized controlled trial (RCT) to evaluate the effect of probiotics on in-hospital mortality and the incidence of major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI). METHODS: This is an open-label, randomized, controlled, superiority clinical trial involving 2594 adult patients who were diagnosed with acute myocardial infarction. Patients will be randomized to (1) receive bifidobacteria triple viable capsule (Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis) 840 mg, twice a day, plus standard treatment strategy during the hospital stay, for a maximum of 30 days, or (2) receive the standard treatment strategy and will not take the bifidobacterium triple live capsule. The primary outcome was in-hospital all-cause mortality. DISCUSSION: The purpose of this clinical trial is to determine whether probiotics can reduce in-hospital mortality and improve prognosis in patients with AMI, and the results will provide evidence for probiotics as a complementary treatment for AMI. TRIAL REGISTRATION: Chinese Clinical Trials Registry ChiCTR2000038797. Registered on 2 October 2020.

Predicting 1-, 3-, 5-, and 8-year all-cause mortality in a community-dwelling older adult cohort: relevance for predictive, preventive, and personalized medicine.

Background: Population aging is a global public health issue involving increased prevalence of age-related diseases, and concomitant burden on medical resources and the economy. Ninety-two diseases have been identified as age-related, accounting for 51.3% of the global adult disease burden. The economic cost per capita for older people over 60 years is 10 times that of the younger population. From the aspects of predictive, preventive, and personalized medicine (PPPM), developing a risk-prediction model can help identify individuals at high risk for all-cause mortality and provide an opportunity for targeted prevention through personalized intervention at an early stage. However, there is still a lack of predictive models to help community-dwelling older adults do well in healthcare. Objectives: This study aims to develop an accurate 1-, 3-, 5-, and 8-year all-cause mortality risk-prediction model by using clinical multidimensional variables, and investigate risk factors for 1-, 3-, 5-, and 8-year all-cause mortality in community-dwelling older adults to guide primary prevention. Methods: This is a two-center cohort study. Inclusion criteria: (1) community-dwelling adult, (2) resided in the districts of Chaonan or Haojiang for more than 6 months in the past 12 months, and (3) completed a health examination. Exclusion criteria: (1) age less than 60 years, (2) more than 30 incomplete variables, (3) no signed informed consent. The primary outcome of the study was all-cause mortality obtained from face-to-face interviews, telephone interviews, and the medical death database from 2012 to 2021. Finally, we enrolled 5085 community-dwelling adults, 60 years and older, who underwent routine health screening in the Chaonan and Haojiang districts, southern China, from 2012 to 2021. Of them, 3091 participants from Chaonan were recruited as the primary training and internal validation study cohort, while 1994 participants from Haojiang were recruited as the external validation cohort. A total of 95 clinical multidimensional variables, including demographics, lifestyle behaviors, symptoms, medical history, family history, physical examination, laboratory tests, and electrocardiogram (ECG) data were collected to identify candidate risk factors and characteristics. Risk factors were identified using least absolute shrinkage and selection operator (LASSO) models and multivariable Cox proportional hazards regression analysis. A nomogram predictive model for 1-, 3-, 5- and 8-year all-cause mortality was constructed. The accuracy and calibration of the nomogram prediction model were assessed using the concordance index (C-index), integrated Brier score (IBS), receiver operating characteristic (ROC), and calibration curves. The clinical validity of the model was assessed using decision curve analysis (DCA). Results: Nine independent risk factors for 1-, 3-, 5-, and 8-year all-cause mortality were identified, including increased age, male, alcohol status, higher daily liquor consumption, history of cancer, elevated fasting glucose, lower hemoglobin, higher heart rate, and the occurrence of heart block. The acquisition of risk factor criteria is low cost, easily obtained, convenient for clinical application, and provides new insights and targets for the development of personalized prevention and interventions for high-risk individuals. The areas under the curve (AUC) of the nomogram model were 0.767, 0.776, and 0.806, and the C-indexes were 0.765, 0.775, and 0.797, in the training, internal validation, and external validation sets, respectively. The IBS was less than 0.25, which indicates good calibration. Calibration and decision curves showed that the predicted probabilities were in good agreement with the actual probabilities and had good clinical predictive value for PPPM. Conclusion: The personalized risk prediction model can identify individuals at high risk of all-cause mortality, help offer primary care to prevent all-cause mortality, and provide personalized medical treatment for these high-risk individuals from the PPPM perspective. Strict control of daily liquor consumption, lowering fasting glucose, raising hemoglobin, controlling heart rate, and treatment of heart block could be beneficial for improving survival in elderly populations. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00342-4.

Homocysteine activates vascular smooth muscle cells by DNA demethylation of platelet-derived growth factor in endothelial cells.

Hyperhomocysteinemia (HHcy), as an independent risk factor of atherosclerosis, facilitates endothelial dysfunction and activation of vascular smooth muscle cells (VSMCs). However, little is known about the crosstalk between endothelial cells (ECs) and VSMCs under HHcy. We investigated whether homocysteine (Hcy) activates VSMCs by aberrant secretion of mitogen platelet-derived growth factors (PDGFs) from ECs in human and in mice. In this study, we found that increased Hcy level did not affect VSMC activity in 24 hrs until the concentration reached 500 µM. In contrast, Hcy at 100 µM significantly promoted proliferation and migration of VSMCs co-cultured with human ECs. This effect was partially reversed by pretreatment with a PDGF receptor inhibitor. Hcy concentration-dependently upregulated the mRNA level of PDGF-A, -C and -D but not PDGF-B in ECs. Hcy reduced the expression and activity of DNA methyltransferase 1, demethylation of PDGF-A, -C and -D promoters and enhanced the binding activity of transcriptional factor SP-1 to the promoter. Hcy upregulation of PDGF was confirmed in the aortic intima of mice with HHcy. Multivariate regression analysis revealed HHcy was a predictor of increased serum PDGF level in patients. Thus, Hcy upregulates PDGF level via DNA demethylation in ECs, affects cross-talk between ECs and VSMCs and leads to VSMC activation.

NUF2 Drives Clear Cell Renal Cell Carcinoma by Activating HMGA2 Transcription through KDM2A-mediated H3K36me2 Demethylation.

The poor sensitivity of clear cell renal cell carcinoma (ccRCC) to conventional chemotherapy and radiotherapy makes its treatment challenging. The Ndc80 kinetochore complex component (NUF2) is involved in the development and progression of several cancers. However, its role in ccRCC remains unclear. In this study, we investigated the biological functions and underlying mechanism of NUF2 in ccRCC. We found that NUF2 expression was increased in ccRCC and associated with poor prognosis. Altering NUF2 level affected cell proliferation, migration, and invasion. Moreover, NUF2 acted as a potential oncogene to promote the progression of ccRCC through epigenetic activation of high-mobility group AT-hook 2 (HMGA2) transcription by suppressing lysine demethylase 2A expression and affecting its occupancy on the HMGA2 promoter region to regulate histone H3 lysine 36 di-methylation modification. In addition, Kaplan-Meier and multivariate analysis revealed that patients whose NUF2 and HMGA2 were both elevated showed the shortest survival; and the number of upregulated markers acted as an independent predictor to evaluate survival probability. Thus, our results demonstrate that NUF2 promotes ccRCC progression, at least partly by epigenetically regulating HMGA2 transcription, and that the NUF2-HMGA2 axis could be an ideal therapeutic target and a promising prognostic indicator for ccRCC.

Association of uterine fibroids with increased blood pressure: a cross-sectional study and meta-analysis.

Uterine fibroids (UFs) are the most common benign gynecological tumor and greatly affect reproductive health in women of reproductive age. Some studies have indicated an association between UFs and several cardiovascular disease (CVD) risk factors. To determine whether UFs are associated with increased blood pressure, we performed a cross-sectional study and meta-analysis. In the cross-sectional study, 8401 participants who underwent a physical examination at the First Affiliated Hospital of Shantou University Medical College from June 2011 to June 2013 were divided into a uterine fibroid group (1617 cases) and a control group (6784 cases) to assess the relationship between UFs and blood pressure. Then, we conducted a systematic review to confirm the results. The cross-sectional study showed that UFs were associated with an increased rate of elevated blood pressure [OR = 1.35, 95% confidence interval (CI): 1.016-1.792]. The meta-analysis revealed a significant association between UFs and the prevalence of hypertension [pooled OR = 1.44, 95% CI: 1.17-1.75, P = 0.0004; I2 = 68%]. Thus, UFs may be associated with the prevalence of hypertension. Women with uterine fibroids should be closely monitored for hypertension.

Myocardial strain analysis of echocardiography based on deep learning.

Background: Strain analysis provides more thorough spatiotemporal signatures for myocardial contraction, which is helpful for early detection of cardiac insufficiency. The use of deep learning (DL) to automatically measure myocardial strain from echocardiogram videos has garnered recent attention. However, the development of key techniques including segmentation and motion estimation remains a challenge. In this work, we developed a novel DL-based framework for myocardial segmentation and motion estimation to generate strain measures from echocardiogram videos. Methods: Three-dimensional (3D) Convolutional Neural Network (CNN) was developed for myocardial segmentation and optical flow network for motion estimation. The segmentation network was used to define the region of interest (ROI), and the optical flow network was used to estimate the pixel motion in the ROI. We performed a model architecture search to identify the optimal base architecture for motion estimation. The final workflow design and associated hyperparameters are the result of a careful implementation. In addition, we compared the DL model with a traditional speck tracking algorithm on an independent, external clinical data. Each video was double-blind measured by an ultrasound expert and a DL expert using speck tracking echocardiography (STE) and DL method, respectively. Results: The DL method successfully performed automatic segmentation, motion estimation, and global longitudinal strain (GLS) measurements in all examinations. The 3D segmentation has better spatio-temporal smoothness, average dice correlation reaches 0.82, and the effect of target frame is better than that of previous 2D networks. The best motion estimation network achieved an average end-point error of 0.05 ± 0.03 mm per frame, better than previously reported state-of-the-art. The DL method showed no significant difference relative to the traditional method in GLS measurement, Spearman correlation of 0.90 (p < 0.001) and mean bias -1.2 ± 1.5%. Conclusion: In conclusion, our method exhibits better segmentation and motion estimation performance and demonstrates the feasibility of DL method for automatic strain analysis. The DL approach helps reduce time consumption and human effort, which holds great promise for translational research and precision medicine efforts.