Azvudine for the Treatment of COVID-19 in Pre-Existing Cardiovascular Diseases: A Single-Center, Real-World Experience.

COVID-19 can lead to adverse outcomes in patients with pre-existing diseases. Azvudine has been approved for treating COVID-19 in China, but the real-world data is limited. It is aimed to investigate the efficacy of Azvudine in patients with COVID-19 and pre-existing cardiovascular diseases. Patients with confirmed COVID-19 and pre-existing cardiovascular diseases are retrospectively enrolled. The primary outcome is all-cause death during hospitalization. Overall, 351 patients are included, with a median age of 74 years, and 44% are female. 212 (60.6%) patients are severe cases. Azvudine is used in 106 (30.2%) patients and not in 245 (69.8%). 72 patients died during hospitalization. After multivariate adjustment, patients who received Azvudine a lower risk of all-cause death (hazard ratio: 0.431; 95% confidence interval: 0.252-0.738; p = 0.002) than controls. Azvudine therapy is also associated with lower risks of shock and acute kidney injury. For sensitivity analysis in the propensity score-matched cohort (n = 90 for each group), there is also a significant difference in all-cause death between the two groups (hazard ratio: 0.189; 95% confidence interval: 0.071-0.498; p < 0.001). This study indicated that Azvudine therapy is associated with better outcomes in COVID-19 patients with pre-existing cardiovascular diseases.

Piperine protects against pyroptosis in myocardial ischaemia/reperfusion injury by regulating the miR-383/RP105/AKT signalling pathway.

miRNA-mediated pyroptosis play crucial effects in the development of myocardial ischaemia/reperfusion (I/R) injury (MIRI). Piperine (PIP) possesses multiple pharmacological effects especially in I/R condition. This study focuses on whether PIP protects MIRI from pyroptosis via miR-383-dependent pathway. Rat MIRI model was established by 30 minutes of LAD ligation and 4 hours of reperfusion. Myocardial enzymes, histomorphology, structure and function were detected to evaluate MIRI. Recombinant adenoviral vectors for miR-383 overexpression or miR-383 silencing or RP105 knockdown were constructed, respectively. Luciferase reporter analysis was used to confirm RP105 as a target of miR-383. Pyroptosis-related markers were measured by Western blotting assay. The results showed that I/R provoked myocardial injury, as shown by the increases of LDH/CK releases, infarcted areas and apoptosis as well as worsened function and structure. Pyroptosis-related mediators including NLRP3, cleaved caspase-1, cleaved IL-1ß and IL-18 were also reinforced after MIRI. However, PIP treatment greatly ameliorated MIRI in parallel with pyroptotic repression. In mechanistic studies, MIRI-caused elevation of miR-383 and decrease of RP105/PI3K/AKT pathway were reverted by PIP treatment. Luciferase reporter assay confirmed RP105 as a miR-383 target. miR-383 knockdown ameliorated but miR-383 overexpression facilitated pyroptosis and MIRI. Moreover, the anti-pyroptotic effect from miR-383 silencing was verified to be relied on the RP105/PI3K/AKT signalling pathway. Additionally, our present study further indicated the miR-383/RP105/AKT-dependent approach resulting from PIP administration against pyroptosis in MIRI. Therefore, PIP treatment attenuates MIRI and pyroptosis by regulating miR-383/RP105/AKT pathway, and it may provide a therapeutic manner for the treatment of MIRI.

Varying coefficient transformation cure models for failure time data.

This article discusses regression analysis of right-censored failure time data where there may exist a cured subgroup, and also covariate effects may be varying with time, a phenomena that often occurs in many medical studies. To address the problem, we discuss a class of varying coefficient transformation models along with a logistic model for the cured subgroup. For inference, a sieve maximum likelihood approach is developed with the use of spline functions, and the asymptotic properties of the proposed estimators are established. The proposed method can be easily implemented, and the conducted simulation study suggests that the proposed method works well in practical situations. An illustrative example is provided.

Relationship of lipid and lipoprotein ratios with coronary severity in patients with new on-set coronary artery disease complicated with type 2 diabetics.

BACKGROUND: Diabetes mellitus (DM) is associated with coronary artery disease (CAD) progression. Although previous studies have demonstrated the association of lipid and lipoprotein ratios with CAD, no data are currently available concerning the relationship between lipid and lipoprotein ratios and the severity of new on-set CAD in diabetics. Therefore, the aim of the present study was to investigate the usefulness of lipid and lipoprotein ratios in predicting the severity of CAD in patients with type 2 DM (T2DM). METHODS: A total of 380 consecutive T2DM patients with new on-set CAD were enrolled in the present study. Then, they were classified into the three groups according to Gensini score (GS) tertiles. The relationship between lipid and lipoprotein ratios currently used and the GS was investigated. RESULTS: Positive correlations of natural log-transformed GS (lnGS) with apolipoprotein B to apoA-I ratio (apoB/apoA-I), non-high-density lipoprotein cholesterol to apoA-I ratio (non-HDL-C/apoA-I), and low-density lipoprotein cholesterol to apoA-I ratio (LDL-C/apoA-I) were found (r = 0.18, 0.13, 0.12, respectively, all P < 0.05). Multivariate logistic analysis indicated apoB/apoA-I as the strongest predictor for high GS (OR = 5.67, 95% CI: 1.45-23.92, P = 0.003). Area under receivers operating characteristic curve of apoB/apoA-I was 0.63 (95% CI: 0.60-0.66, P = 0.001) for predicting high GS. The optimal cutoff value of apoB/apoA-I to predict high GS was 0.72 with the sensitivity of 61.2% and the specificity of 62.1%. CONCLUSIONS: Lipid and lipoprotein ratios might be useful for predicting the severity of new on-set CAD in T2DM patients, and the apoB/apoA-I appeared as the most significant predictor in this population.

Targeting hepatic TRAF1-ASK1 signaling to improve inflammation, insulin resistance, and hepatic steatosis.

BACKGROUND & AIMS: Tumor necrosis factor receptor-associated factor 1 (TRAF1) is an important adapter protein that is largely implicated in molecular events regulating immunity/inflammation and cell death. Although inflammation is closely related to and forms a vicious circle with insulin dysfunction and hepatic lipid accumulation, the role of TRAF1 in hepatic steatosis and the related metabolic disorders remains unclear. METHODS: The participation of TRAF1 in the initiation and progression of hepatic steatosis was evaluated in high fat diet (HFD)-induced and genetic obesity. Mice with global TRAF1 knockout or liver-specific TRAF1 overexpression were employed to investigate the role of TRAF1 in insulin resistance, inflammation, and hepatic steatosis based on various phenotypic examinations. Molecular mechanisms underlying TRAF1-regulated hepatic steatosis were further explored in vivo and in vitro. RESULTS: TRAF1 expression was significantly upregulated in the livers of NAFLD patients and obese mice and in palmitate-treated hepatocytes. In response to HFD administration or in ob/ob mice, TRAF1 deficiency was hepatoprotective, whereas the overexpression of TRAF1 in hepatocytes contributed to the pathological development of insulin resistance, inflammatory response and hepatic steatosis. Mechanistically, hepatocyte TRAF1 promotes hepatic steatosis through enhancing the activation of ASK1-mediated P38/JNK cascades, as evidenced by the fact that ASK1 inhibition abolished the exacerbated effect of TRAF1 on insulin dysfunction, inflammation, and hepatic lipid accumulation. CONCLUSIONS: TRAF1 functions as a positive regulator of insulin resistance, inflammation, and hepatic steatosis dependent on the activation of ASK1-P38/JNK axis.

Role of lipoprotein(a) in predicting the severity of new on-set coronary artery disease in type 2 diabetics: A Gensini score evaluation.

The objective of the study was to investigate the usefulness of serum lipoprotein(a) level in predicting the severity of new on-set coronary artery disease in type 2 diabetics. A total of 1254 new on-set, consecutive coronary artery disease patients were classified into two groups: diabetes group (n = 380) and non-diabetes group (n = 874). The relationship between serum lipoprotein(a) levels and the severity of coronary artery disease assessed by Gensini score was analysed. Data showed that the diabetes group had higher serum triglyceride and high sensitivity C-reactive protein levels but lower high-density lipoprotein cholesterol levels (all p < 0.05). The multivariate logistic regression analysis suggested that lipoprotein(a) was an independent predictor for high Gensini score (odds ratio = 1.82, 95% confidence interval: 1.10-3.12, p = 0.029) after adjusting for traditional cardiovascular risk factors. Additionally, lipoprotein(a) levels were positively correlated with Gensini score (rho = 0.15, p = 0.014) and significantly elevated according to the tertiles of Gensini score (p = 0.008) in diabetics. However, no such results were observed in non-diabetics. Our data indicate that lipoprotein(a) is an independent predictor for the severity of new on-set coronary artery disease patients accompanied by type 2 diabetes, suggesting that these patients may benefit from lipoprotein(a) management in clinical assessment.

Plasma big endothelin-1 level and the severity of new-onset stable coronary artery disease.

AIM: To investigate the usefulness of the plasma big endothelin-1 (big ET-1) level in predicting the severity of new-onset stable angiography-proven coronary artery disease (CAD). METHODS: A total of 963 consecutive stable CAD patients with more than 50% stenosis in at least one main vessel were enrolled. The patients were classified into the three groups according to the tertile of the Gensini score (GS, low GS ＜20, n=300; intermediate GS 20-40, n=356 and high GS ＞40, n=307), and the relationship between the big ET-1 level and GS was evaluated. RESULTS: The plasma levels of big ET-1 increased significantly in association with increases in the GS tertile (p=0.007). A multivariate analysis suggested that the plasma big ET-1 level was an independent predictor for a high GS (OR=2.26, 95%CI: 1.23-4.15, p=0.009), and there was a positive correlation between the big ET-1 level and the GS (r=0.20, p=0.000). The area under the receiver operating characteristic curve (AUC) for the big ET-1 level in predicting a high GS was 0.64 (95% CI 0.60-0.68, p=0.000), and the optimal cutoff value for the plasma big ET-1 level for predicting a high GS was 0.34 fmol/mL, with a sensitivity of 62.6% and specificity of 60.3%. In the high-big ET-1 level group (≥0.34 fmol/mL), there were significantly increased rates of three-vessel disease (43.6% vs. 35.4%, p=0.017) and a high GS [31 (17-54) vs. 24 (16-44), p=0.001] compared with that observed in the low-big ET-1 level group. CONCLUSIONS: The present findings indicate that the plasma big ET-1 level is a useful predictor of the severity of new-onset stable CAD associated with significant stenosis.

The impact of inhalation injury in patients with small and moderate burns.

BACKGROUND: Inhalation injury is an independent risk factor of mortality in burn patients. The burn index (BI), which includes burn depth and size, also plays a role in predicting mortality. We aimed to establish a relationship between survival rate, inhalation injury, and BI. METHODS: From 1997 to 2010, 21,791 burn patients from 44 hospitals were retrospectively reviewed. Kaplan-Meier and log-rank assessments were used for survival curve analysis. Chi-square, Fishers-exact test and odds ratio evaluations were used to assess the relationship between mortality rate, inhalation injury, BI. Two population proportion Z test was used to analyze the causes of death and morbidity. The significance level was set at 0.01. RESULTS: The overall mortality rate was 2.1%. Inhalation injuries were found in 7.9% of the patients. The mortality rate of inhalation and non-inhalation injury group was 17.9% and 0.7%, respectively. The survival rate of the inhalation injury group was significantly lower than that of the non-inhalation injury group at BI 0-50. The patients with both inhalation injury and BI less than 50 had significant higher rate to die of pneumonia, respiratory failure, sepsis and wound infection. There was no significant difference when BI was larger than 50. CONCLUSIONS: Inhalation injuries significantly reduced the survival rate, especially when the BI was less than 50. The possibility of pulmonary dysfunction and complications arising from inhalation injury should be considered even in patients who have small cutaneous burns associated with inhalation injuries.

Usefulness of the neutrophil-to-lymphocyte ratio in predicting the severity of coronary artery disease: a Gensini score assessment.

AIM: The usefulness of the white blood cell (WBC) count and neutrophil-to-lymphocyte ratio (NLR) in predicting the severity of stable coronary artery disease (CAD) has not been sufficiently evaluated, particularly based on strict coronary assessments. The aim of the present study was to investigate the WBC count and NLR in predicting the severity of angiographically proven CAD. METHODS: A total of 2,976 CAD patients and 571 non-CAD patients were consecutively enrolled, and the CAD patients were classified into the three groups according to the tertile of the Gensini score (GS, low GS<18, n=989; intermediate GS 18-41, n=995 and high GS>41, n=992). The efficacy of the WBC count and NLR in predicting the risk and severity of CAD as well as the correlations between these markers and the GS were analyzed. A receiver operating characteristic (ROC) curve analysis was also performed. RESULTS: The NLR was found to be an independent predictor of both the presence of CAD (OR=1.18, 95%CI: 1.09-1.27, p=0.009) and a high GS (OR=1.10, 95%CI: 1.01-1.16, p=0.032). In addition, there were mild positive correlations between the GS and the NLR, WBC and proportions of neutrophils and monocytes. In the ROC curves analysis, the NLR was found to have the largest area under the curve (AUC=0.63, 95%CI: 0.59-0.67, p=0.000), with an optimal cut-off value of 2.04 (sensitivity: 62.1%, specificity: 54.8%) for predicting a high GS. CONCLUSIONS: The NLR is a valuable independent predictor of the severity of CAD assessed according to the GS. In particular, an NLR of >2.04 indicates a higher risk of CAD and greater severity of CAD lesions.

Difference of dilation resistance to coronary stenting between fibrous plaques and lipid-rich plaques.

BACKGROUND: Dilation resistance to stenting in non-calcified coronary plaques was compared in patients with percutaneous coronary intervention (PCI) in order to confirm the clinical usefulness of multislice computed tomography in examining coronary plaque type and to provide information pertaining to the effects of plaque type on dilatation resistance. METHODS: A retrospective analysis of 64-slice computed tomography coronary imaging data collected in the month prior to coronary stenting in 93 patients (65 male and 28 female, mean age of (57.22±7.22) years) was conducted. Non-calcified coronary plaques were divided into lipid-rich (lipid content >25% of plaque volume) and fibrous plaques according to the Hammer-Hansen S method: where lipids, fiber, and intraluminal components were indicated by contrast using Hu values of -100-49, 50-129, and >130, respectively. Clinical features, pre-dilatation balloon specifications and filling pressure, and stent size and release pressure were compared. RESULTS: High-sensitivity C-reactive protein levels were higher in the lipid-rich plaque group. In patients with typical symptoms, unstable angina was more commonly observed in the lipid-rich plaque group. No significant differences in low density lipoprotein, pre-dilatation balloon specifications, pre-dilatation pressure, or stent specifications were observed. Stent release pressure in the lipid-rich plaque group ((1130.16±202.04) kPa), was significantly lower than that observed in the fibrous plaque group ((1240.61±193.29) kPa, P = 0.009). CONCLUSION: Softer, lipid-rich plaques exhibit lower dilation resistance during stenting in PCI patients.

[Association between various rs501120 genotypes and progress of unstable coronary atherosclerotic plaque in diabetes mellitus complicated with acute coronary syndrome].

OBJECTIVE: To assess the association between single nucleotide polymorphism rs501120 and progress of unstable coronary atherosclerotic plaque in diabetes mellitus complicated with acute coronary syndrome (ACS). METHODS: Nine hundred and two patients with diabetes complicated with acute coronary syndrome were enrolled. The genotype of rs501120 was determined with TaqMan-MGB probes. Two hundred and five cases of TT genotype, 205 age-and sex-frequency-matched cases of TC genotype and 205 age- and sex-frequency-matched cases of CC genotype were chosen and followed up for 3 years. Clinical data and re-occurrences of ACS were recorded. RESULTS: Patients with TT genotype had a significantly higher incidence of recurrence of ACS than those with CC genotype (TT vs. CC: OR 1.7, 95%CI 1.1-2.7, P= 0.02). And the significance has remained even after adjusting for conventional risk factors by logistic regression (OR 1.6, 95% CI1.05-3.6, P= 0.03). Patients with TT genotype had a significantly higher incidence of myocardial infarction than those with CC genotype(TT vs. CC: OR 1.9, 95% CI 1.2-3.2, P= 0.007). CONCLUSION: Our results has suggested an association between the rs501120 polymorphism and progress of unstable coronary atherosclerotic plaque.

Semiparametric transformation models for current status data with informative censoring.

Current status data arise due to only one feasible examination such that the failure time of interest occurs before or after the examination time. If the examination time is intrinsically related to the failure time of interest, the examination time is referred to as an informative censoring time. Such data may occur in many fields, for example, epidemiological surveys and animal carcinogenicity experiments. To avoid severely misleading inferences resulted from ignoring informative censoring, we propose a class of semiparametric transformation models with log-normal frailty for current status data with informative censoring. A shared frailty is used to account for the correlation between the failure time and censoring time. The expectation-maximization (EM) algorithm combining a sieve method for approximating an infinite-dimensional parameter is employed to estimate all parameters. To investigate finite sample properties of the proposed method, simulation studies are conducted, and a data set from a rodent tumorigenicity experiment is analyzed for illustrative purposes.

A frailty model approach for regression analysis of multivariate current status data.

This paper discusses regression analysis of multivariate current status failure time data (The Statistical Analysis of Interval-censoring Failure Time Data. Springer: New York, 2006), which occur quite often in, for example, tumorigenicity experiments and epidemiologic investigations of the natural history of a disease. For the problem, several marginal approaches have been proposed that model each failure time of interest individually (Biometrics 2000; 56:940-943; Statist. Med. 2002; 21:3715-3726). In this paper, we present a full likelihood approach based on the proportional hazards frailty model. For estimation, an Expectation Maximization (EM) algorithm is developed and simulation studies suggest that the presented approach performs well for practical situations. The approach is applied to a set of bivariate current status data arising from a tumorigenicity experiment.

Regression analysis of multivariate interval-censored failure time data with application to tumorigenicity experiments.

This paper discusses multivariate interval-censored failure time data that occur when there exist several correlated survival times of interest and only interval-censored data are available for each survival time. Such data occur in many fields. One is tumorigenicity experiments, which usually concern different types of tumors, tumors occurring in different locations of animals, or together. For regression analysis of such data, we develop a marginal inference approach using the additive hazards model and apply it to a set of bivariate interval-censored data arising from a tumorigenicity experiment. Simulation studies are conducted for the evaluation of the presented approach and suggest that the approach performs well for practical situations.

The proportional odds model for multivariate interval-censored failure time data.

The proportional odds model is one of the most commonly used regression models in failure time data analysis and has been discussed by many authors (Appl. Stat. 1983; 32:165-171; J. Am. Stat. Assoc. 1999; 94:125-136; J. Am. Stat. Assoc. 1997; 92:960-967; Biometrics 2000; 56:511-518; J. Am. Stat. Assoc. 2001; 96:1446-1457). It specifies that covariates have multiplicative effects on the odds function and is often used when, for example, the covariate effect diminishes over time. Most of the existing methods for the model are for univariate failure time data. In this paper, we discuss how to fit the proportional odds model to multivariate interval-censored failure time data. For inference, the maximum likelihood approach is developed and evaluated by simulation studies, which suggest that the method works well for practical situations. The method is applied to a set of bivariate interval-censored data arising from an AIDS clinical trial.

[Cardioprotective effects of atorvastatin preconditioning via iNOS upregulation in a rabbit ischemia/reperfusion model].

OBJECTIVE: To observe the preconditioning cardioprotection of atorvastatin (ATV) in rabbits underwent 40 min ischemia and 240 min reperfusion and to explore related mechanisms. METHODS: The rabbits were randomized divided into Control group, ATV group (10 mg.kg(-1).d(-1) for 3 days before ischemia), ATV plus iNOS inhibitor S-methylisothiourea sulfate group (ATV + SMT group), SMT group, ATV plus mito K(ATP) channel blocker 5-hydroxydecanoate group (ATV + 5-HD group) and 5-HD group (n = 16 each group). The infarction size, CK-MB, LDH-1, nitric oxide synthase and mitochondrial ATP synthesization capacity ([ATP] m) were determined at the end of reperfusion. RESULTS: Infarction size, CK-MB, LDH-1 were decreased by 26.3%, 31.4%, 19.1% and iNOS, [ATP] m increased by 102.6%, 46.8% post ATV compared to control group (all P < 0.05) and these effects could be blocked by cotreatment with SMT and 5-HD except the iNOS was not affected by 5-HD. CONCLUSION: The atorvastatin preconditioning exerted cardioprotection by upregulating iNOS and activating mito K(ATP).