The relationship between dysphagia and frailty among Chinese hospitalized older patients: a serial mediation model through self-perceived oral health and self-reported nutritional status.

BACKGROUND: Frailty contributes to adverse outcomes in older adults and places a heavy burden on healthcare resources. Dysphagia is associated with frailty, but the mechanisms by which dysphagia affects frailty in older adults are unclear. This study aimed to investigate a serial mediating effect of self-perceived oral health and self-reported nutritional status in the relationship between dysphagia and frailty among hospitalized older patients in China. METHODS: This cross-sectional study included 1200 patients aged ≥ 65 years in the Department of Geriatrics, Shaanxi Provincial People's Hospital. A structured face-to-face interview was used to survey the following questionnaires: General Information Questionnaire, Tilburg Frailty Indicators (TFI), Eating Assessment Tool-10 (EAT-10), 30mL Water Swallow Test (WST), Geriatric Oral Health Assessment Index (GOHAI), and Short-Form Mini-Nutritional Assessment (MNA-SF). A total of 980 participants with complete data were included in the analysis. Statistical analysis was performed using SPSS 26.0 and Amos 28.0 software. Spearman's correlation analysis was used for correlation analysis of study variables. The results of the multivariate linear regression analysis for frailty were used as covariates in the mediation analysis, and the structural equation model (SEM) was used to analyze the mediating effects among the study variables. RESULTS: Dysphagia, self-perceived oral health, self-reported nutritional status, and frailty were significantly correlated (P<0.001). Dysphagia was found to directly affect frailty (ß = 0.161, 95%CI = 0.089 to 0.235) and through three significant mediation pathways: (1) the path through self-perceived oral health (ß = 0.169, 95%CI = 0.120 to 0.221), accounting for 36.98% of the total effect; (2) the path through self-reported nutritional status (ß = 0.050, 95%CI = 0.023 to 0.082), accounting for 10.94% of the total effect; (3) the path through self-perceived oral health and self-reported nutritional status (ß = 0.077, 95%CI = 0.058 to 0.102), accounting for 16.85% of the total effect. The total mediation effect was 64.77%. CONCLUSIONS: This study indicated that dysphagia was significantly associated with frailty. Self-perceived oral health and self-reported nutritional status were serial mediators of this relationship. Improving the oral health and nutritional status of hospitalized older patients may prevent or delay the frailty caused by dysphagia.

Machine learning-enhanced echocardiography for screening coronary artery disease.

BACKGROUND: Since myocardial work (MW) and left atrial strain are valuable for screening coronary artery disease (CAD), this study aimed to develop a novel CAD screening approach based on machine learning-enhanced echocardiography. METHODS: This prospective study used data from patients undergoing coronary angiography, in which the novel echocardiography features were extracted by a machine learning algorithm. A total of 818 patients were enrolled and randomly divided into training (80%) and testing (20%) groups. An additional 115 patients were also enrolled in the validation group. RESULTS: The superior diagnosis model of CAD was optimized using 59 echocardiographic features in a gradient-boosting classifier. This model showed that the value of the receiver operating characteristic area under the curve (AUC) was 0.852 in the test group and 0.834 in the validation group, with high sensitivity (0.952) and low specificity (0.691), suggesting that this model is very sensitive for detecting CAD, but its low specificity may increase the high false-positive rate. We also determined that the false-positive cases were more susceptible to suffering cardiac events than the true-negative cases. CONCLUSIONS: Machine learning-enhanced echocardiography can improve CAD detection based on the MW and left atrial strain features. Our developed model is valuable for estimating the pre-test probability of CAD and screening CAD patients in clinical practice. TRIAL REGISTRATION: Registered as NCT03905200 at ClinicalTrials.gov. Registered on 5 April 2019.

The value of myocardial work in assessment of ventricular function in patients with non-obstructive hypertrophic cardiomyopathy.

BACKGROUND: To evaluate myocardial work using speckle tracking echocardiography in patients with non-obstructive hypertrophic cardiomyopathy (HCM). METHODS: Fifty patients with HCM and 50 normal controls were included. Left ventricular ejection fraction (LVEF) was quantified using the bi-plane Simpson's method. Myocardial work parameters, which included global work index (GWI), global constructive work (GCW), global waste work (GWW), and global work efficiency (GWE), were derived from the 2D strain-pressure loop. RESULTS: The patient group was older (49.19 ± 14.69 vs. 37.16 ± 7.49 years old) and had a higher body mass index (24.93 ± 3.67 vs. 23.26 ± 3.32 kg/m2) and systolic blood pressure (121.81 ± 16.50 vs. 115.30 ± 11.01 mmHg) (P < 0.05). The mean LVEF in patients was 51%, with 54% of patients had LVEF ≤ 50%. Compared to controls, GWI (946.42 ± 360.64 vs. 1639.72 ± 204.56 mmHg%), GCW (1176.94 ± 373.23 vs. 1960.16 ± 255.72 mmHg%), and GWE (83.96 ± 7.68 vs. 95.26 ± 1.98%) were significantly decreased, while GWW (158.17 ± 82.47 vs. 79.12 ± 40.26 mmHg%) was significantly increased (P < 0.05) in the patient group. In patients, GWE showed a trend of positive correlation with LVEF (r = 0.276, P = 0.06), while GWW had a trend of negative correlation with LVEF (r = - 0.241, P = 0.09). No correlation between myocardial work and LV diastolic function or QRS duration was observed. Maximal wall thickness significantly correlated with all the myocardial work parameters. CONCLUSIONS: Assessing myocardial work adds useful information of LV function in patients with non-obstructive HCM.

Two-Dimensional Speckle Tracking Echocardiography Identifies Coronary Artery Disease in 690 Patients: A Retrospective Study from a Single Center.

BACKGROUND Two-dimensional speckle tracking echocardiography (2D-STE) is a novel and non-invasive technique for the diagnosis of coronary artery disease (CAD). This retrospective study from a single center aimed to identify myocardial ischemia using 2D-STE in CAD patients identified by angiography. MATERIAL AND METHODS From March 1 to November 30, 2019, 690 patients in Beijing Hospital were enrolled. After angiography, 346 patients were diagnosed with CAD. Reduction in vessel diameter of ≥50% by stenosis in at least 1 major coronary artery or its main branch was considered CAD. Analysis of 2D-STE was performed using EchoPAC version 201. RESULTS The global strain was significantly impaired in CAD patients (P<0.01). Global longitudinal peak strain (GLPS) was analyzed in layers. For GLPS of the epicardium, the odds ratio (OR) was 1.297 (1.217-1.382; P=0.002), the area under the curve (AUC) was 0.727, and the cut-off value was -16.95; sensitivity and specificity were 73.7% and 63.0%, respectively. For GLPS of the middle layer, the OR was 1.260 (1.192-1.333; P<0.001), the AUC was 0.732, and the cut-off value was -20.95; sensitivity and specificity were 82.4% and 56.2%, respectively. For GLPS of the endocardium, the OR was 1.193 (1.137-1.251; P<0.001), the AUC was 0.708, and the cut-off value was -22.95; sensitivity and specificity were 82.9% and 52.9%, respectively. CONCLUSIONS The findings from this study support the clinical application of 2D-STE in patient populations with suspected myocardial ischemia due to CAD. Therefore, 2D-STE combined with ECG monitoring may have a future role for early screening of CAD patients.

Manifestation of cardiac injury in hospitalised patients with COVID-19.

BACKGROUND: COVID-19 has been sweeping the world since it emerged in late December 2019. However, little is known about cardiac injury in hospitalised COVID-19 patients. This study is to investigate the incidence and characteristics of myocardial injury in COVID-19 patients admitted in hospital. METHODS: Fifty-four COVID-19 patients were enrolled in one ward in Tongji Hospital, Wuhan, China, and 5 were excluded caused by missing cardiac troponin I levels. Forty-nine participants were included in the final analysis. The clinical manifestations of hospitalised patients were analysed. Patients were divided into two groups, cardiac injury group and non-cardiac injury group, based on whether cardiac troponin I was elevated. Epidemic characteristics and laboratory test results were analysed in these two group. RESULTS: The average age of patients in the cardiac injury group was older (68.0 years old) than that in the non-cardiac injury group (61.5 years old). The percentages of patients with diabetes and critically severe pneumonia in the cardiac injury group were 38.5% and 38.5% respectively. Lymphocytes were decreased in 53.1% of all enrolled patients, but this decrease was more prominent (76.9%) in the cardiac injury group than the non-cardiac injury group (44.4%). Patients in the cardiac injury group also had lower platelet counts. CONCLUSIONS: COVID-19 can cause cardiac injury in many patients. It is more common in older patients and patients with diabetes and is associated with a significant decrease in lymphocytes.

Ensemble machine learning approach for screening of coronary heart disease based on echocardiography and risk factors.

BACKGROUND: Extensive clinical evidence suggests that a preventive screening of coronary heart disease (CHD) at an earlier stage can greatly reduce the mortality rate. We use 64 two-dimensional speckle tracking echocardiography (2D-STE) features and seven clinical features to predict whether one has CHD. METHODS: We develop a machine learning approach that integrates a number of popular classification methods together by model stacking, and generalize the traditional stacking method to a two-step stacking method to improve the diagnostic performance. RESULTS: By borrowing strengths from multiple classification models through the proposed method, we improve the CHD classification accuracy from around 70-87.7% on the testing set. The sensitivity of the proposed method is 0.903 and the specificity is 0.843, with an AUC of 0.904, which is significantly higher than those of the individual classification models. CONCLUSION: Our work lays a foundation for the deployment of speckle tracking echocardiography-based screening tools for coronary heart disease.

Prevention of non-response to cardiac resynchronization therapy: points to remember.

Cardiac resynchronization therapy (CRT) is an important and effective therapy for end-stage heart failure. Non-response to CRT is one of the main obstacles to its application in clinical practice. There is no uniform consensus or definition of CRT "response." Clinical symptoms, ventricular remodeling indices, and cardiovascular events have been reported to be associated with non-responders. To prevent non-response to CRT, three aspects should be thoroughly considered: preoperative patient selection, electrode implantation, and postoperative management. Preoperative selection of appropriate patients for CRT treatment is an important step in preventing non-response. Currently, the CRT inclusion criteria are mainly based on the morphology of QRS waves in deciding ventricular dyssynchrony. Echocardiography and cardiac magnetic resonance are being explored to predict nonresponse to CRT. The location of left ventricular electrode implantation is a current hot spot of research; it is important to identify the location of the latest exciting ventricular segment and avoid scars. Cardiac magnetic resonance and ultrasonic spot tracking are being progressively developed in this field. Some new techniques such as His Bundle pacing, endocardial electrodes, and novel sensors are also being investigated. Postoperative management of patients is another essential step towards preventing non-response; it mainly focuses on the treatment of the disease itself and CRT program control optimization. CRT treatment is just one part of the overall treatment of heart failure, and multidisciplinary efforts are needed to improve the overall outcome.

Klotho Improves Cardiac Function by Suppressing Reactive Oxygen Species (ROS) Mediated Apoptosis by Modulating Mapks/Nrf2 Signaling in Doxorubicin-Induced Cardiotoxicity.

BACKGROUND Anthracyclines-induced cardiotoxicity has become one of the major restrictions of their clinical applications. Klotho showed cardioprotective effects. This study aimed to investigate the effects and possible mechanisms of klotho on doxorubicin (DOX)-induced cardiotoxicity. MATERIAL AND METHODS Rats and isolated myocytes were exposed to DOX and treated with exogenous klotho. Specific inhibitors and siRNAs silencing MAPKs were also used to treat the animals and/or myocytes. An invasive hemodynamic method was used to determine cardiac functions. Intracellular ROS generation was evaluated by DHE staining. Western blotting was used to determine the phosphorylation levels of JNK, ERK, and p38 MAPKs in plasma extracts and Nrf2 in nuclear extracts. Nuclear translocation of Nrf2 in myocytes was evaluated by immunohistochemistry. Cell apoptosis was evaluated by TUNEL assay and flow cytometry. RESULTS Klotho treatment improved DOX-induced cardiac dysfunction in rats. The DOX-induced ROS accumulation and cardiac apoptosis were attenuated by klotho. Impaired phosphorylations of MAPKs, Nrf2 translocation and expression levels of HO1 and Prx1 were also attenuated by klotho treatment. However, the anti-oxidant and anti-apoptotic effects of klotho on DOX-exposed myocardium and myocytes were impaired by both specific inhibitors and siRNAs against MAPKs. Moreover, the recovery effects of klotho on phosphorylations of MAPKs, Nrf2 translocation and expression levels of HO1 and Prx1 were also impaired by specific inhibitors and siRNAs against MAPKs. CONCLUSIONS By recovering the activation of MAPKs signaling, klotho improved cardiac function loss which was triggered by DOX-induced ROS mediated cardiac apoptosis.

Circulating interleukin-1ß promotes endoplasmic reticulum stress-induced myocytes apoptosis in diabetic cardiomyopathy via interleukin-1 receptor-associated kinase-2.

AIM: IL-1ß was considered as an important inflammatory cytokine in diabetic cardiovascular complications. DCM is one of the major manifestations of diabetic cardiovascular complications whose specific mechanisms are still unclear. In this study, we investigated the role of IL-1ß in myocytes apoptosis in DCM. METHODS: In the in vitro study, high- glucose medium and/or IL-1ß were used to incubate the isolated primary myocytes. siRNA was used to knockdown the irak2 gene expression. Apoptosis was evaluated by Hoechst and TUNEL staining. In the in vivo study, DCM in rats was induced by STZ injection and confirmed by cardiac hemodynamic determinations. The IL-1 receptor antagonist, IL-1Ra was also used to treat DCM rats. Myocardial apoptosis was assessed by TUNEL assay. In both in vitro and in vivo studies, expression levels of GRP-78, IRAK-2 and CHOP were analyzed by Western Blotting. ELISA was employed to exam the IL-1ß content in serum and cell supernatants. RESULTS: Myocytes were not identified as the source of IL-1ß secretion under high- glucose incubation. High glucose incubation and/or IL-1ß incubation elevated ER- stress mediated myocytes apoptosis which was attenuated by irak2 silencing. Dramatically increased circulating and myocardial IL-1ß levels were found in DCM rats which stimulated activation of ER stress and lead to elevated myocytes apoptosis. The administration of IL-1Ra, however, attenuated IRAK2/CHOP induced apoptosis without affecting fasting blood glucose concentration. CONCLUSIONS: Elevated circulating IL-1ß contributed to promote ER stress- induced myocytes apoptosis by affecting IRAK-2/CHOP pathway in DCM.

Research hotspots and trends of oral health in older adults from 2013 to 2023: A bibliometric and visual analysis.

Background: Oral health problems seriously affect the quality of life of older adults. It is of great significance to investigate the statuses of oral health in older adults. The study aimed to analyze the current status, hotspots and frontiers of global oral health research in older adults through bibliometrics to provide references and guidance for future research in this field. Methods: Literature on oral health in older adults from 2013 to 2023 was retrieved from the Web of Science Core Collection (WoSCC) database. CiteSpace 6.2.R4 was used for bibliometric and visual analysis, including journal and co-cited journal, country/region, institution, author, co-cited references, and keyword analysis. Results: A total of 1430 publications related to oral health in older adults were included. The number of publications has gradually increased over the past decade. The most widely published and cited journal was Gerodontology. The most prominent contribution came from the United States of America, and the University of London and Hirohiko Hirano were the most prolific institution and author, respectively. The current research hotspots were summarized as oral hygiene interventions, oral health-related quality of life and oral health issues in older adults. Cohort studies of oral health, the relationship between oral health and frailty, and the correlation between oral health and nutritional status may be emerging research trends. Conclusions: This study systematically analyzed the hotspots and frontiers of oral health in older adults and called for increased collaboration among countries, institutions, and authors. In addition, oral hygiene interventions for older adults, oral health-related quality of life, oral health issues, cohort studies of oral health, and the relationship between oral health and frailty or nutritional status may be the focus of future research.

Corrigendum: Regional myocardial work measured by echocardiography for the detection of myocardial ischemic segments: a comparative study with invasive fractional flow reserve.

[This corrects the article DOI: 10.3389/fcvm.2022.813710.].

A machine learning prediction model for cancer risk in patients with type 2 diabetes based on clinical tests.

BACKGROUND: The incidence of type 2 diabetes is rapidly increasing worldwide. Studies have shown that it is also associated with cancer-related morbidities. Early detection of cancer in patients with type 2 diabetes is crucial. OBJECTIVE: This study aimed to construct a model to predict cancer risk in patients with type 2 diabetes. METHODS: This study collected clinical data from a total of 5198 patients. A cancer risk prediction model was established by analyzing 261 items from routine laboratory tests. We screened 107 risk factors from 261 clinical tests based on the importance of the characteristic variables, significance of differences between groups (P< 0.05), and minimum description length algorithm. RESULTS: Compared with 16 machine learning classifiers, five classifiers based on the decision tree algorithm (CatBoost, light gradient boosting, random forest, XGBoost, and gradient boosting) had an area under the receiver operating characteristic curve (AUC) of > 0.80. The AUC for CatBoost was 0.852 (sensitivity: 79.6%; specificity: 83.2%). CONCLUSION: The constructed model can predict the risk of cancer in patients with type 2 diabetes based on tumor biomarkers and routine tests using machine learning algorithms. This is helpful for early cancer risk screening and prevention to improve patient outcomes.

The genetic correlation and causal association between key factors that influence vascular calcification and cardiovascular disease incidence.

Background: Serum calcium (Ca), vitamin D (VD), and vitamin K (VK) levels are key determinants of vascular calcification, which itself impacts cardiovascular disease (CVD) risk. The specific relationships between the levels of these different compounds and particular forms of CVD, however, remain to be fully defined. Objective: This study was designed to explore the associations between these serum levels and CVDs with the goal of identifying natural interventions capable of controlling vascular calcification and thereby protecting against CVD pathogenesis, extending the healthy lifespan of at-risk individuals. Methods: Linkage disequilibrium score (LDSC) regression and a two-sample Mendelian randomization (MR) framework were leveraged to systematically examine the causal interplay between these serum levels and nine forms of CVD, as well as longevity through the use of large publically accessible Genome-Wide Association Studies (GWAS) datasets. The optimal concentrations of serum Ca and VD to lower CVD risk were examined through a restrictive cubic spline (RCS) approach. Results: After Bonferroni correction, the positive genetic correlations were observed between serum Ca levels and myocardial infarction (MI) (p = 1.356E-04), as well as coronary artery disease (CAD) (p = 3.601E-04). Negative genetic correlations were detected between levels of VD and CAD (p = 0.035), while elevated VK1 concentrations were causally associated with heart failure (HF) [odds ratios (OR) per 1-standard deviation (SD) increase: 1.044], large artery stroke (LAS) (OR per 1-SD increase: 1.172), and all stroke (AS) (OR per 1-SD increase: 1.041). Higher serum Ca concentrations (OR per 1-SD increase: 0.865) and VD levels (OR per 1-SD increase: 0.777) were causally associated with reduced odds of longevity. These findings remained consistent in sensitivity analyses, and serum Ca and VD concentrations of 2.376 mmol/L and 46.8 nmol/L, respectively, were associated with a lower CVD risk (p < 0.001). Conclusion: Our findings support a genetic correlation between serum Ca and VD and CVD risk, and a causal relationship between VK1 levels and CVD risk. The optimal serum Ca (2.376 mmol/L) and VD levels (46.8 nmol/L) can reduce cardiovascular risk.

Selenium Supplementation Improved Cardiac Functions by Suppressing DNMT2-Mediated GPX1 Promoter DNA Methylation in AGE-Induced Heart Failure.

Objective: Advanced glycation end products (AGEs) are featured metabolites associated with diabetic cardiomyopathy which is characterized by heart failure caused by myocyte apoptosis. Selenium was proved cardioprotective. This study was aimed at investigating the therapeutic effects and underlying mechanisms of selenium supplementation on AGE-induced heart failure. Methods: Rats and primary myocytes were exposed to AGEs. Selenium supplementation was administrated. Cardiac functions and myocyte apoptosis were evaluated. Oxidative stress was assessed by total antioxidant capacity (TAC), reactive oxygen species (ROS) generation, and GPX activity. Expression levels of DNA methyltransferases (DNMTs) and glutathione peroxidase 1 (GPX1) were evaluated. DNA methylation of the GPX1 promoter was analyzed. Results: AGE exposure elevated intracellular ROS generation, induced myocyte apoptosis, and impaired cardiac functions. AGE exposure increased DNMT1 and DNMT2 expression, leading to the reduction of GPX1 expression and activity in the heart. Selenium supplementation decreased DNMT2 expression, recovered GPX1 expression and activity, and alleviated intracellular ROS generation and myocyte apoptosis, resulting in cardiac function recovery. DNA methylation analysis in primary myocytes indicated that selenium supplementation or DNMT inhibitor AZA treatment reduced DNA methylation of the GPX1 gene promoter. Selenium supplementation and AZA administration showed synergic inhibitory effect on GPX1 gene promoter methylation. Conclusions: Selenium supplementation showed cardioprotective effects on AGE-induced heart failure by suppressing ROS-mediated myocyte apoptosis. Selenium supplementation suppressed ROS generation by increasing GPX1 expression via inhibiting DNMT2-induced GPX1 gene promoter DNA methylation in myocytes exposed to AGEs.

Regional Myocardial Work Measured by Echocardiography for the Detection of Myocardial Ischemic Segments: A Comparative Study With Invasive Fractional Flow Reserve.

Purpose: This study is to assess the diagnostic value of noninvasive regional myocardial work (MW) by echocardiography for detecting the functional status of coronary stenosis using fractional flow reserve (FFR) as a standard criterion. Methods: A total of 84 consecutive patients were included in this study, among which 92 vessels were identified with ≥50% stenosis confirmed by invasive coronary angiography. Patients were investigated by invasive FFR and transthoracic echocardiography. Regional MW indices including myocardial work index (MWI), myocardial constructive work (MCW), myocardial wasted work, and myocardial work efficiency were calculated. Results: MWI and MCW were significantly impaired in the FFR ≤ 0.75 group compared with the FFR > 0.75 group (both p < 0.01). There were significant positive associations between MWI and MCW with FFR. In total group, MWI <1,623.7 mmHg% [sensitivity, 78.4%; specificity, 72.2%; area under the curve value, 0.768 (0.653-0.883)] and MCW <1,962.4 mmHg% [77.0%; 72.2%; 0.767 (0.661-0.872)], and in single-vessel subgroup, MWI <1,412.1 mmHg% [93.5%; 63.6%; 0.808 (0.652-0.965)] and MCW <1,943.3 mmHg% [(84.8%; 72.7%; 0.800 (0.657-0.943)] were optimal to detect left ventricular segments with an FFR ≤ 0.75. MWI and MCW significantly increased after percutaneous coronary intervention in 13 cases. Conclusion: In patients with coronary artery disease, especially those with single-vessel stenosis, the regional MW measured by echocardiography exhibited a good diagnostic value in detecting significant myocardial ischemia compared to the standard FFR approach.

Myocardial Work by Speckle Tracking Echocardiography Accurately Assesses Left Ventricular Function of Coronary Artery Disease Patients.

Objective: Myocardial work (MW) is a novel non-invasive method that uses speckle tracking echocardiography (STE) to assess left ventricular (LV) function. MW incorporates the global longitudinal strain and afterload conditions. Here we aimed to use MW to assess the LV function of patients with coronary artery disease (CAD) with or without heart failure (HF). Methods: We enrolled a total of 150 individuals (50 each) with CAD and a normal LV ejection fraction (LVEF), CAD with HF, and healthy controls. Patients were divided into the hypertension (HTN) and normal blood pressure (no HTN) subgroups. MW was determined from the pressure-strain loop using STE. The relationships between MW indices and conventional echocardiographic parameters were evaluated, and the MW indices were compared among groups. Results: Univariate and multivariate analyses showed that MW indices were strongly correlated with LVEF. The global work index (GWI) was increased in the CAD with normal LVEF subgroup with HTN vs. controls (1,922.3 ± 393.1 vs. 1,639.7 ± 204.6 mmHg%, p < 0.05) and decreased in CAD patients with HF (no HTN: 940.9 ± 380.6 vs. 1,639.7 ± 204.6 mmHg%, p < 0.05; HTN: 857.3 ± 369.3 vs. 1,639.7 ± 204.6 mmHg%, p < 0.05). Global waste work was increased in all CAD subgroups vs. controls. Global constructive work had the same tendency as GWI in patients with CAD. Global MW efficiency was decreased in all patients with CAD. Conclusion: MW using STE accurately quantifies LV function in patients with CAD. It offers additional information about LV function with respect to disease progression, particularly in CAD patients with a normal LVEF.

The Impact of ABCB1 and CES1 Polymorphisms on Dabigatran Pharmacokinetics in Healthy Chinese Subjects.

Dabigatran is a novel direct oral anticoagulant agent, whose plasma concentration is closely related to bleeding risk. Genetic polymorphisms can affect the level of plasma dabigatran. The purpose of this study was to understand the relationship between dabigatran-related genes and the plasma level of dabigatran in healthy Chinese subjects after taking a single oral dose. This study was performed with a single-center, single-dose, randomized, open-label, and four-period crossover trial design under both fasting and fed conditions. A total of 106 eligible healthy subjects were enrolled in the study and 104 were genotyped. One-way analysis of variance (ANOVA) was used to compare pharmacokinetic parameters among different genotypes and linear regression was applied to explore the multiplicative interaction between variables. In this study, we found that the genotype frequencies of CES1 rs2244613 and CES1 rs8192935 were significantly different between Chinese and Caucasians, but the genotype frequencies of ABCB1 rs1045642 and ABCB1 rs4148738 were similar in both populations. CES1 rs8192935 were associated with the peak concentration of dabigatran. There was no significant gender difference in the exposure level of dabigatran. Furthermore, food significantly delayed the absorption of dabigatran but had little effect on Cmax and AUC0-∞.

Pharmacogenetic-Guided Algorithm to Improve Daily Dose of Warfarin in Elder Han-Chinese Population.

OBJECTIVES: To verify the accuracy of the International Warfarin Pharmacogenetics Consortium (IWPC) algorithm, identify the effects of genetic and clinical factors on warfarin stable dose, and to establish a new warfarin stable dose prediction algorithm for the elderly Han-Chinese population under the guidance of pharmacogenetics. METHODS: According to the inclusion criteria, 544 non-valvular atrial fibrillation patients taking warfarin for anticoagulation treatment were enrolled. Data information of three groups including the whole population, people under 65 years old and over 65 years old were substituted into the IWPC algorithm respectively to verify its accuracy. The basic data and clinical information of 360 elderly people were collected for statistical analysis and the genotypes of VKORC1-G1639A and CYP2C9 were detected by Sanger sequencing. The new algorithm of the elder pharmacogenetics warfarin dosing was obtained by stepwise multiple regression. The determination coefficient (R2), root mean squared error (RMSE), and the proportion of the predicted value within the true value range of ±20%(20%-p) were used to evaluate the accuracy of the IWPC algorithm and the new algorithm. RESULTS: Among the three different age groups, the warfarin stable dose predictive accuracy of IWPC algorithm was the lowest in the elderly patients above 65-year-old. In this study, the important factors influencing the stable dose of warfarin in the elderly Han-Chinese were height, weight, body surface area, serum creatinine level, amiodarone usage, CYP2C9 (*1*2, *1*3), and VKORC1 (GG/GA) genotypes. By means of stepwise multiple regression analysis, we established a new elder warfarin dosing algorithm (R2=0.3714) containing height, creatinine, amiodarone usage, CYP2C9 (*1*2 or *1*3), and VKORC1 (GA or GG) genotypes. The prediction accuracy and clinical availability of the Elderly algorithm was significantly better than that of IWPC algorithm verified by RMSE, R2, and (20%-p) methods. CONCLUSIONS: The IWPC model may not be suitable for the elder Han-Chinese population. Polymorphism of CYP2C9 and VKORC1 obviously affected warfarin stable dose of the elder Han-Chinese. Combination of genetic data with demographic and clinical factors could help to better improve warfarin doses in the elder Han-Chinese population.

Thymoquinone Protects against Hyperlipidemia-Induced Cardiac Damage in Low-Density Lipoprotein Receptor-Deficient (LDL-R-/-) Mice via Its Anti-inflammatory and Antipyroptotic Effects.

Hyperlipidemia is a risk factor for cardiac damage and cardiovascular disease. Increasing evidence has shown that dyslipidemia-related cardiac damage is associated with lipid accumulation, oxidative stress, and inflammation. Thymoquinone (TQ) is the major constituent of Nigella sativa, commonly known as black seed or black cumin, and is globally used in folk (herbal) medicine for treating and preventing a number of diseases and conditions. Several studies have shown that TQ can protect against cardiac damage. This study is aimed at investigating the possible protective effects of TQ on hyperlipidemia-induced cardiac damage in low-density lipoprotein receptor-deficient (LDL-R-/-) mice. Eight-week-old male LDL-R-/- mice were randomly divided into normal diet (ND), high-fat diet (HFD), and HFD and TQ (HFD+TQ) groups and were fed the different diets for eight weeks. Blood samples were obtained from the inferior vena cava in serum tubes and stored at -80°C until use. Some cardiac tissues were fixed in 10% formalin and then embedded in paraffin for histological evaluation. The remainder of the cardiac tissues was snap-frozen in liquid nitrogen for mRNA preparation or immunoblotting. The levels of metabolism-related factors, such as total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), and high-sensitivity C-reactive protein (hs-CRP), were decreased in the HFD+TQ group compared with those in the HFD group. Periodic acid-Schiff staining demonstrated that lipid deposition was lower in the HFD+TQ group than in the HFD group. The expression of pyroptosis indicators (NOD-like receptor 3 (NLRP3), interleukin- (IL-) 1ß, IL-18, and caspase-1), proinflammatory factors (IL-6 and tumor necrosis factor alpha (TNF-α)), and macrophage markers (cluster of differentiation (CD) 68) was significantly downregulated in the HFD+TQ group compared with that in the HFD group. Our results indicate that TQ may serve as a potential therapeutic agent for hyperlipidemia-induced cardiac damage.

A study of genes involved in adipocyte differentiation.

OBJECTIVE: With the use of the microarray technique, genes expressed in the late phase of adipocyte differentiation were investigated. These genes play an important role in stimulating adipocyte growth and lipid droplet formation. Therefore, they contribute a great deal to the onset of obesity. METHODS: With the use of SW872 adipocytes and the microarray technique, genes related to adipocyte differentiation were tested and compared with undifferentiated preadipocytes 14 days after induction. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used for confirmation. RESULTS: More than 21,329 transcriptors were expressed and determined, of which 1326 increased and 687 decreased undifferentiated adipocytes. Among them, 21 were highly expressed by more than 10-fold. With RT-PCR, 12 were confirmed, including apelin, CIDEC, PID1, LYRM1, ADD1, PPARγ2, ANGPTL4, ADIPOQ, ACOX1, FIP1L1, MAP3K2 and PEX14. Furthermore, genes involved in lipid metabolism, signal transduction, DNA replication, redox status and transcription factors were determined as well. Novel genes involved in adipogenesis (e.g., apelin) were detected. CONCLUSION: A variety of genes were discovered and validated with RT-PCR at the late phase of adipocyte differentiation. This may help us better understand the onset of obesity and the potential role of adipocytes in other organs.