In vitro anticancer study of novel curcumin derivatives via targeting PI3K/Akt/p53 signaling pathway.

Four new series of curcumin derivatives bearing NO-donating moiety were synthesized via etherification, nucleophilic substitution, and Knoevenagel condensation etc. The cytotoxicity activity of curcumin derivatives against five human tumor cell lines (A549, Hela, HepG2, MCF-7 and HT-29) and two normal cell lines (LO-2 and HK-2) has been studied. The results showed that compound 6a could inhibit the proliferation of MCF-7 cells remarkably and exhibit low toxicity to normal cells. Also, the underlying mechanism in vitro of compound 6a on MCF-7 was investigated. It has been found that compound 6a induced G2/M arrest and apoptosis of MCF-7 in a dose-dependent manner. Compound 6a-induced the fluorescence changes of ROS in MCF-7 cells confirmed the occurrence of apoptosis. Western Blot suggested that compound 6a decreased the expression of PI3K, as well as increased the expression of p53, cleaved caspase-9 and cleaved caspase-3. Furthermore, molecular docking revealed that compound 6a could bind well at active site of PI3K (3zim) with total score 9.59. Together, compound 6a, a potential PI3K inhibitor, may inhibit the survival of MCF-7 cells via interfering with PI3K/Akt/p53 pathway.

Factors Associated with Extended Hospital Stay and its Impact on Subsequent Short-term Readmission with Tuberculosis Patients.

BACKGROUND: This study aimed to explore the factors associated with extended length of stay (LOSE) for patients with tuberculosis (TB) in China, and construct a nomogram to predict it. In addition, the impact of extended hospital stay on short-term readmission after discharge was assessed. METHODS: A retrospective observational study was conducted at Changsha Central Hospital, from January 2018 to December 2020. Patients (≥18 years who were first admitted to hospital for TB treatment) with non-multidrug-resistant TB were selected using the World Health Organization's International Classification of Diseases, 10th Revision (ICD-10-CM), and the hospital's electronic medical record system. RESULTS: A multivariate logistic regression analysis was used to evaluate the associations between TB and LOSE. The relationship between length of hospital stay and readmission within 31 days after discharge was assessed using a univariate Cox proportional risk model. A total of 14259 patients were included in this study (13629 patients in the development group and 630 in the validation group). The factors associated with extended hospital stays were age, smear positivity, extrapulmonary involvement, surgery, transfer from other medical structures, smoking, chronic liver disease, and drug-induced hepatitis. There was no statistical significance in the 31-day readmission rate of TB between the LOSE and length of stay≤14 days groups (hazards ratio: 0.92, 95% CI: 0.80-1.06, P=0.229). CONCLUSION: LOSE with TB was influenced by several patient-level factors, which were combined to construct a nomograph. The established nomograph can help hospital administrator and clinicians to identify patients with TB requiring extended hospital stays, and more efficiently plan for treatment programs and resource needs.

Unifying community-wide whole-brain imaging datasets enables robust automated neuron identification and reveals determinants of neuron positioning in C. elegans.

We develop a data harmonization approach for C. elegans volumetric microscopy data, still or video, consisting of a standardized format, data pre-processing techniques, and a set of human-in-the-loop machine learning based analysis software tools. We unify a diverse collection of 118 whole-brain neural activity imaging datasets from 5 labs, storing these and accompanying tools in an online repository called WormID (wormid.org). We use this repository to train three existing automated cell identification algorithms to, for the first time, enable accuracy in neural identification that generalizes across labs, approaching human performance in some cases. We mine this repository to identify factors that influence the developmental positioning of neurons. To facilitate communal use of this repository, we created open-source software, code, web-based tools, and tutorials to explore and curate datasets for contribution to the scientific community. This repository provides a growing resource for experimentalists, theorists, and toolmakers to (a) study neuroanatomical organization and neural activity across diverse experimental paradigms, (b) develop and benchmark algorithms for automated neuron detection, segmentation, cell identification, tracking, and activity extraction, and (c) inform models of neurobiological development and function.

Contemporary spectrum, characteristics, and outcomes of adult patients with rheumatic valvular disease in China: Insights from the China-VHD study.

Background: Rheumatic valvular disease (RVD) represents a significant health concern in developing countries, yet a scarcity of detailed data exists. This study conducts a comprehensive examination of RVD patients in China, exploring aspects of the disease's spectrum, characteristics, investigation, management, and outcomes. Methods: The China Valvular Heart Disease (China-VHD) study, a nationwide, multicenter, prospective observational study, enrolled 13,917 adults with moderate-to-severe valvular heart disease from April to June 2018. Among these, 2402 patients with native RVD (19.7% of native VHD patients) were analyzed. Results: Among the RVD patients, the median age was 57 years (interquartile range 50-65), with 82.5% falling within the 40-70 age range; females were notably predominant (63.9%). Rheumatic etiology prevailed, particularly in southern regions (48.8%). Multivalvular involvement was observed in 47.4% of RVD cases, and atrial fibrillation emerged as the most common comorbidity (43.2%). Severe RVD affected 64.2% of patients. Valvular interventions were undertaken by 66.9% of RVD patients, predominantly involving surgical valve replacement (90.8%). Adverse events, encompassing all-cause mortality and heart failure hospitalization, occurred in 7.3% of patients during the 2-year follow-up. Multivariable analysis identified factors such as age, geographical region, low body mass index, renal insufficiency, left atrial diameter, and left ventricular ejection fraction <50% (all P < 0.05) associated with adverse events, with valvular intervention emerging as a protective factor (HR: 0.201; 95%CI: 0.139 to 0.291; p < 0.001). Conclusions: This study delivers a comprehensive evaluation of RVD patients in China, shedding light on the spectrum, characteristics, investigation, management, and outcomes of this prevalent condition.

Prevalence and impact of diabetes in patients with valvular heart disease.

This study aimed to investigate the prevalence of diabetes in valvular heart disease (VHD), as well as the relationship of diabetes with severity of valvular lesions and clinical outcome. A total of 11,862 patients with significant (≥moderate) VHD from the China Valvular Heart Disease study were included in the analysis. The primary outcome was the composite of all-cause death, hospitalization for heart failure, and myocardial infarction during two-year follow-up. The prevalence of diabetes was 14.5% (1,721/11,862) in VHD. After adjusting for patients' demographics, diabetes was associated with a significantly lower risk of severe valvular lesion in aortic regurgitation and mitral regurgitation (MR). In multivariable analysis, diabetes was identified as an independent predictor of two-year outcome in patients with MR (hazard ratio: 1.345, 95% confidence interval: 1.069-1.692, p = 0.011). More efforts should be made to enhance our understanding and improve outcomes of concomitant VHD and diabetes.

Automated cell annotation in multi-cell images using an improved CRF_ID algorithm.

Cell identification is an important yet difficult process in data analysis of biological images. Previously, we developed an automated cell identification method called CRF_ID and demonstrated its high performance in C. elegans whole-brain images (Chaudhary et al, 2021). However, because the method was optimized for whole-brain imaging, comparable performance could not be guaranteed for application in commonly used C. elegans multi-cell images that display a subpopulation of cells. Here, we present an advance CRF_ID 2.0 that expands the generalizability of the method to multi-cell imaging beyond whole-brain imaging. To illustrate the application of the advance, we show the characterization of CRF_ID 2.0 in multi-cell imaging and cell-specific gene expression analysis in C. elegans. This work demonstrates that high accuracy automated cell annotation in multi-cell imaging can expedite cell identification and reduce its subjectivity in C. elegans and potentially other biological images of various origins.

Meta-Analysis Global Group in Chronic Heart Failure score for the prediction of mortality in valvular heart disease.

AIMS: Valvular heart disease (VHD) is one of the leading causes of heart failure. Clinically significant VHD can induce different patterns of cardiac remodelling, and risk stratification is challenging in patients with various degrees of cardiac dysfunction. The study aimed to investigate the prognostic implications of Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score in patients with VHD. METHODS AND RESULTS: This study used data from the China Valvular Heart Disease (China-VHD) registry, which was a multicentre, prospective, observational cohort study for patients with significant (at least moderate) VHD. In total, 10 446 patients with moderate or greater VHD from the China-VHD study were included in the present analysis. The primary outcome of interest was all-cause mortality within 2 years. Among 10 446 patients with VHD, the mean age was 61.98 ± 13.47 years, and 5819 (55.7%) were male. During 2 years of follow-up, 895 (8.6%) patients died. The MAGGIC score was monotonically and independently associated with mortality in both total cohort [adjusted hazard ratio: 1.095, 95% confidence interval (CI): 1.084-1.107, P < 0.001] and most types of VHD (aortic regurgitation, mitral stenosis, mitral regurgitation, tricuspid regurgitation, mixed aortic stenosis and aortic regurgitation, and multiple VHD). The score was also an independent prognostic factor in patients with or without symptoms or preserved left ventricular ejection fraction (LVEF) and exhibited both satisfactory discrimination and calibration properties in predicting mortality. The prognostic value of MAGGIC score was robust in most quartiles of N-terminal pro-brain natriuretic peptide level, with no significant interaction observed (Pinteraction  = 0.498). Compared with the EuroSCORE II, the MAGGIC score achieved significantly better predictive performance in overall population [C index: 0.769 vs. 0.727; net reclassification improvement index (95% CI): 0.354 (0.313-0.396), P < 0.001; integrated discrimination improvement index (95% CI): 0.069 (0.052-0.085), P < 0.001] and in subgroups of patients divided by therapeutic strategy, LVEF, symptomatic status, stage of VHD, and aetiology of VHD. CONCLUSIONS: The MAGGIC score is a reliable prognostic factor across the range of cardiac dysfunction in VHD and may assist in risk stratification and guide clinical decision-making.

Development and validation of a score predicting mortality for older patients with mitral regurgitation.

OBJECTIVE: To develop and validate a user-friendly risk score for older mitral regurgitation (MR) patients, referred to as the Elder-MR score. METHODS: The China Senile Valvular Heart Disease (China-DVD) Cohort Study functioned as the development cohort, while the China Valvular Heart Disease (China-VHD) Study was employed for external validation. We included patients aged 60 years and above receiving medical treatment for moderate or severe MR (2274 patients in the development cohort and 1929 patients in the validation cohort). Candidate predictors were chosen using Cox's proportional hazards model and stepwise selection with Akaike's information criterion. RESULTS: Eight predictors were identified: age ≥ 75 years, body mass index < 20 kg/m2, NYHA class III/IV, secondary MR, anemia, estimated glomerular filtration rate < 60 mL/min per 1.73 m2, albumin < 35 g/L, and left ventricular ejection fraction < 60%. The model displayed satisfactory performance in predicting one-year mortality in both the development cohort (C-statistic = 0.73, 95% CI: 0.69-0.77, Brier score = 0.06) and the validation cohort (C-statistic = 0.73, 95% CI: 0.68-0.78, Brier score = 0.06). The Elder-MR score ranges from 0 to 15 points. At a one-year follow-up, each point increase in the Elder-MR score represents a 1.27-fold risk of death (HR = 1.27, 95% CI: 1.21-1.34, P < 0.001) in the development cohort and a 1.24-fold risk of death (HR = 1.24, 95% CI: 1.17-1.30, P < 0.001) in the validation cohort. Compared to EuroSCORE II, the Elder-MR score demonstrated superior predictive accuracy for one-year mortality in the validation cohort (C-statistic = 0.71 vs. 0.70, net reclassification improvement = 0.320, P < 0.01; integrated discrimination improvement = 0.029, P < 0.01). CONCLUSIONS: The Elder-MR score may serve as an effective risk stratification tool to assist clinical decision-making in older MR patients.

Total Cholesterol Levels and Risk of Mortality or Heart Failure Rehospitalization in Patients With Valvular Heart Disease.

Low total cholesterol (TC) levels have been found to significantly increase mortality risk in patients experiencing heart failure. However, it is unclear whether the same relation applies specifically to patients with valvular heart disease (VHD). This study included patients with significant VHD from the China Valvular Heart Disease Study. Patients with atherosclerotic cardiovascular disease were excluded. The primary end point of this study was a combined indicator of either all-cause mortality or rehospitalization because of heart failure (HF). The association between TC and the primary outcome was evaluated using Cox proportional hazard models. The cut-off value of TC for predicting mortality or rehospitalization was determined by the maximally selected rank test. The study population comprised 6,235 patients with VHD. Over a 2-year follow-up period, there were 393 deaths and 265 HF rehospitalizations. The adjusted hazard models showed that for every 1 mmol/L decrease in TC, there was a 1.19-fold increased risk of death or HF rehospitalization (adjusted hazard ratio 1.19, 95% confidence interval 1.09 to 1.30, p <0.001). The optimal cut-off value of TC was 3.53 mmol/L; patients at or below this level had significantly higher mortality and HF rehospitalization rates. After adjustment for confounding factors, low TC levels (≤3.53 mmol/L) remained a significant risk factor for patients with aortic regurgitation, mitral regurgitation, and tricuspid regurgitation. Decreased TC levels are associated with an increased risk of death or HF rehospitalization among patients with VHD.

Assessment of cardio-renal-hepatic function in patients with valvular heart disease: a multi-biomarker approach-the cardio-renal-hepatic score.

BACKGROUND: Valvular heart disease (VHD) can cause damage to extra-cardiac organs, and lead to multi-organ dysfunction. However, little is known about the cardio-renal-hepatic co-dysfunction, as well as its prognostic implications in patients with VHD. The study sought to develop a multi-biomarker index to assess heart, kidney, and liver function in an integrative fashion, and investigate the prognostic role of cardio-renal-hepatic function in VHD. METHODS: Using a large, contemporary, prospective cohort of 6004 patients with VHD, the study developed a multi-biomarker score for predicting all-cause mortality based on biomarkers reflecting heart, kidney, and liver function (N-terminal pro-B-type natriuretic peptide [NT-proBNP], creatinine, and albumin). The score was externally validated in another contemporary, prospective cohort of 3156 patients with VHD. RESULTS: During a median follow up of 731 (704-748) days, 594 (9.9%) deaths occurred. Increasing levels of NT-proBNP, creatinine, and albumin were independently and monotonically associated with mortality, and a weighted multi-biomarker index, named the cardio-renal-hepatic (CRH) score, was developed based on Cox regression coefficients of these biomarkers. The CRH score was a strong and independent predictor of mortality, with 1-point increase carrying over two times of mortality risk (overall adjusted hazard ratio [95% confidence interval]: 2.095 [1.891-2.320], P < 0.001). The score provided complementary prognostic information beyond conventional risk factors (C index: 0.78 vs 0.81; overall net reclassification improvement index [95% confidence interval]: 0.255 [0.204-0.299]; likelihood ratio test P < 0.001), and was identified as the most important predictor of mortality by the proportion of explainable log-likelihood ratio χ2 statistics, the best subset analysis, as well as the random survival forest analysis in most types of VHD. The predictive performance of the score was also demonstrated in patients under conservative treatment, with normal left ventricular systolic function, or with primary VHD. It achieved satisfactory discrimination (C index: 0.78 and 0.72) and calibration in both derivation and validation cohorts. CONCLUSIONS: A multi-biomarker index was developed to assess cardio-renal-hepatic function in patients with VHD. The cardio-renal-hepatic co-dysfunction is a powerful predictor of mortality and should be considered in clinical management decisions.

Prognostic value of modified model for end-stage liver disease scores in patients with significant tricuspid regurgitation.

AIMS: Tricuspid regurgitation (TR) may cause damage to liver and kidney function. The Model for End-Stage Liver Disease excluding international normalized ratio (MELD-XI) and the model with albumin replacing international normalized ratio (MELD-Albumin) scores, which include both liver and kidney function indexes, may predict mortality in patients with TR. The study aimed to analyse the prognostic value of MELD-XI and MELD-Albumin scores in patients with significant TR. METHODS AND RESULTS: A total of 1825 patients with at least moderate pure native TR from the China Valvular Heart Disease study between April and June 2018, were included in this analysis. The primary outcome was all-cause death within 2 years. Of 1825 patients, 165 (9.0%) died during follow-up. Restricted cubic splines revealed that hazard ratio for death increased monotonically with greater modified MELD scores. The MELD-XI and MELD-Albumin scores, as continuous variables or categorized using thresholds determined by maximally selected rank statistics, were independently associated with 2-year mortality (all adjusted P < 0.001). Both scores provided incremental value over prognostic model without hepatorenal indexes {MELD-XI score: net reclassification index [95% confidence interval (95% CI), 0.237 (0.138-0.323)]; MELD-Albumin score: net reclassification index (95% CI), 0.220 (0.122-0.302)}. Results were similar in clinically meaningful subgroups, including but not limited to patients under medical treatment and those with normal left ventricular ejection fraction. Models including modified MELD scores were established for prognostic evaluation of significant TR. CONCLUSION: Both MELD-XI and MELD-Albumin scores provided incremental prognostic information and could play important roles in risk assessment in patients with significant TR.

Netrin-3 Suppresses Diabetic Neuropathic Pain by Gating the Intra-epidermal Sprouting of Sensory Axons.

Diabetic neuropathic pain (DNP) is the most common disabling complication of diabetes. Emerging evidence has linked the pathogenesis of DNP to the aberrant sprouting of sensory axons into the epidermal area; however, the underlying molecular events remain poorly understood. Here we found that an axon guidance molecule, Netrin-3 (Ntn-3), was expressed in the sensory neurons of mouse dorsal root ganglia (DRGs), and downregulation of Ntn-3 expression was highly correlated with the severity of DNP in a diabetic mouse model. Genetic ablation of Ntn-3 increased the intra-epidermal sprouting of sensory axons and worsened the DNP in diabetic mice. In contrast, the elevation of Ntn-3 levels in DRGs significantly inhibited the intra-epidermal axon sprouting and alleviated DNP in diabetic mice. In conclusion, our studies identified Ntn-3 as an important regulator of DNP pathogenesis by gating the aberrant sprouting of sensory axons, indicating that Ntn-3 is a potential druggable target for DNP treatment.

Design of Cross-Platform Information Retrieval System of Library Based on Digital Twins.

In order to improve the library's ability of cross-platform information retrieval and data scheduling and distribution, a library cross-platform information retrieval system based on digital twin technology is designed. Using data warehouse decision support and data source structured query methods, the spectral characteristics of Library cross-platform information resources are extracted. Using the method of Hadoop data parallel loading, the library cross-platform operation data is divided into decision-making data, computing resource pool data, and Hadoop parallel loading data. A library cross-platform information digital twin parallel retrieval and information fusion feature matching model is established, and the retrieval channels are allocated through multiple complex and balanced task scheduling sequences. According to the queue configuration model of Library cross-platform information retrieval, the optimization design of Library cross-platform information retrieval system is realized. The simulation test results show that the designed system has good recall ability of cross-platform information retrieval data, and improves the utilization rate of cross-platform resources and the dynamic scheduling ability of online resources.

Intelligent Optimization Method of Resource Recommendation Service of Mobile Library Based on Digital Twin Technology.

In order to improve the Resource Recommendation and sharing ability of mobile library, an intelligent optimization model of Mobile Library Resource Recommendation Service Based on digital twin technology is proposed. Build the association rule feature distribution set of mobile library resource recommendation service, carry out text information retrieval in the process of Mobile Library Resource Recommendation and sharing, carry out semantic correlation feature registration according to the retrieval preference of mobile library reading user object, establish the association rule data set of mobile library reading user object preference for mobile library Resource Recommendation and sharing, carry out feature block processing, and analyze the library reader preference. Complete the collaborative filtering recommendation of Mobile Library Resource Recommendation sharing. The simulation results show that the collaborative recommendation under the intelligent optimization mode of mobile library resource recommendation service using this method has high accuracy and good confidence level, which improves the intelligent level of Mobile Library Resource Recommendation and user satisfaction.

Prognostic value of blood pressure and resting heart rate in patients with tricuspid regurgitation.

Background: The prognostic value of blood pressure (BP) and resting heart rate (RHR) in tricuspid regurgitation (TR) patients is unknown. Aims: This study aimed to investigate the associations of BP and RHR with all-cause mortality in patients with TR. Methods: A total of 2,013 patients with moderate or severe TR underwent echocardiography and BP measurement. The associations of routinely measured BP and RHR with 2-year all-cause mortality were analyzed. Results: The cohort had 45.9% male patients and a mean age of 62.5 ± 15.9 years. At the 2-year follow-up, 165 patient deaths had occurred. The risk of death decreased rapidly, negatively correlating with systolic blood pressure (SBP) up to 120 mmHg and diastolic blood pressure (DBP) up to 70 mmHg. For RHR, the risk increased in direct proportion, starting at 80 beats per min. After adjusting for age, sex, body mass index (BMI), diabetes, coronary heart disease, pulmonary hypertension, estimated glomerular filtration rate (eGFR), and NYHA class, SBP [hazard ratio (HR):0.89; 95% CI:0.823-0.957 per 10 mmHg increase; P =0.002], DBP (HR:0.8; 95% CI:0.714-0.908 per 10 mmHg increase; P < 0.001), and RHR (HR: 1.1; 95% CI: 1.022-1.175 per 10 beats per min increase; P = 0.011) were independently associated with all-cause mortality. These associations persisted after further adjustments for echocardiographic indices, medications, serological tests, and etiologies. Conclusion: In this cohort of patients with TR, routinely measured BP and RHR were associated with all-cause mortality independently. However, further large-scale, high-quality studies are required to validate our findings.

Comprehensive Geriatric Assessment and Exercise Capacity in Cardiac Rehabilitation for Patients Referred to Transcatheter Aortic Valve Implantation.

Comprehensive geriatric assessment (CGA)-based cardiac rehabilitation (CR) program is essential for patients before and after transcatheter aortic valve implantation (TAVI). This study aimed to explore the values of CGA and exercise capacity in CR for patients referred to TAVI. A retrospective analysis was conducted in 90 patients referred to TAVI from January to October 2019. CR strategies started before TAVI. The association between clinical characteristics, CGA, and change in six-minute walk distance (Δ6MWD) was analyzed with multivariate regression models. Most of patients had cognitive impairment (50%), malnutrition (61%), and frailty (83%). After the CR, the proportion of cognitive impairment, malnutrition, and frail patients was significantly decreased by 21%, 40%, and 57%, respectively (p = 0.002, p <0.001, p <0.001). The 6MWD at a month after discharge (291.9 ± 98.8 m) was significantly improved than that at discharge after TAVI (218.8 ± 114.3m, p <0.001). The multivariate regression analysis indicated body mass index (BMI; Δ6MWD:12.0, 95% confidence interval [CI] 0.3 to 23.8, p = 0.045), frailty (Δ6MWD: -57.9, 95% CI -81.8 to -34.1, p <0.001) and malnutrition (Δ6MWD: -25.1, 95% CI -47.0 to -3.2, p = 0.026) as the associated predictors of Δ6MWD. In conclusion, functional status in patients referred to TAVI could be improved by CGA-based CR. BMI, frailty, and malnutrition were associated with the efficacy of CR on exercise capacity. CGA can play the important role in the evaluation and making strategies for CR in patients.

Pretreatment of Huoxue Jiedu Formula Ameliorates Myocardial Ischaemia/Reperfusion Injury by Decreasing Autophagy via Activation of the PI3K/AKT/mTOR Pathway.

Background: Myocardial ischaemia/reperfusion (I/R) results in myocardial injury via excessive autophagy. Huoxue Jiedu Formula (HJF) has been widely applied in China for the treatment of ischaemic heart disease. However, the mechanisms of HJF are still poorly understood. Thus, the present experiment was designed to observe the effects of HJF on myocardial I/R injury and explore the possible mechanism. Methods: Myocardial injury in rats subjected to myocardial I/R was reflected by nitrotetrazolium blue chloride staining, thioflavin S staining, serum creatine kinase-MB (CK-MB) and cardiac troponin T (cTnT). Autophagy was determined by electron microscopy, laser confocal microscopy, Q-PCR and western blot. The possible pathway was predicted by network pharmacology and validated in vivo and in vitro. Results: Pretreatment of HJF decreased the no-reflow area, infarcted area, serum CK-MB levels and serum cTnT levels in I/R rat model. In addition, pretreatment of HJF decreased autophagy in heart tissues (decrease in Beclin-1 and LC3-II, and increase in Bcl-2, p62 and ratio of LC3-I/LC3-II). In the vivo study, pretreatment of HJF significantly decreased hypoxia/reoxygenation (H/R)-induced autophagy in H9C2 cells. Network pharmacology was applied to predict the possible mechanism by which HJF affects cardiac autophagy, and the PI3K/AKT/mTOR signalling pathway was the most significantly enriched pathway. And experimental studies demonstrated that pretreatment of HJF increased the phosphorylation of AKT and mTOR, and the effects of HJF on autophagy would be offset by PI3K inhibitor LY294002. Conclusion: Pretreatment of HJF ameliorates myocardial I/R injury by decreasing autophagy through activating PI3K/AKT/mTOR pathway.

Effectiveness and safety of Yufeng Ningxin for the treatment of essential hypertension: A protocol for systematic review and meta-analysis.

BACKGROUND: Essential hypertension is the primary cause of death and disability and it has become a major public health problem globally. Yufeng Ningxin (YFNX) is a commonly used Chinese patent medicine in treating essential hypertension. The objective of this protocol is to evaluate the effectiveness and safety of YFNX for the treatment of essential hypertension. METHODS: Randomized controlled trials (RCTs) in relation to the effectiveness and safety of YFNX in the treatment of essential hypertension will be systematically searched and collected from the following databases: PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang Database, Chinese Biomedical Literature Database, and Chinese Scientific Journal Database from the database inception to January 1, 2021. The data screening and extraction will be carried out by 2 different reviewers. The quality of randomized controlled trials will be assessed based on the version 2 of the risk-of-bias tool for randomized trials (RoB 2) in the Cochrane Handbook. The reduction of systolic blood pressure (SBP) and diastolic blood pressure (DBP) will be served as the primary outcome. The secondary outcomes will include average SBP and average DBP during the day and the night measured by 24 hours ambulatory blood pressure monitoring, the clinical effectiveness rate, scores of traditional Chinese medicine syndrome, clinical symptoms, the quality of life and adverse events. Statistical analysis will be conducted with Review Manager 5.3 and STATA 14.0 software. CONCLUSION: This systematic review will provide strong evidence to assess the effectiveness and safety of YFNX in the treatment of essential hypertension. TRIAL REGISTRATION NUMBER: INPLASY202110059.

Prognostic Impact of Left Ventricular Ejection Fraction in Patients With Moderate Aortic Regurgitation: Potential Implications for Treatment Decision-Making.

BACKGROUND: The prognostic impact and optimal treatment of left ventricular systolic dysfunction in patients with moderate aortic regurgitation (AR) remain unknown. We aimed to assess the prognostic value of left ventricular ejection fraction (LVEF) in patients with moderate AR and explore the potential benefits of aortic valve intervention (AVI). METHODS: In total, 1,211 consecutive patients with moderate AR (jet width, 25-64% of LV outflow tract; vena contracta, 0.3-0.6 cm; regurgitant volume, 30-59 mL/beat; regurgitant fraction, 30-49%; effective regurgitation orifice, 0.10-0.29 cm2) prospectively registered between April and June 2018 at 46 academic hospitals were included. The primary outcome was a composite of death or hospitalization for heart failure (HHF). The optimal LVEF threshold for predicting the primary outcome was determined through the penalized spline shape and maximally selected rank statistics. RESULTS: During the 2-year follow-up, 125 deaths or HHF occurred. In the penalized splines, the relative hazard of death or HHF monotonically increased with decreasing LVEF. In the multivariate analysis, LVEF ≤55% was identified as the best threshold for independently predicting death or HHF under medical treatment (adjusted hazard ratio [HR]: 2.18; 95% confidence interval [CI] 1.38-3.42; P = 0.001), with substantial incremental values (integrated discrimination improvement index = 0.018, P = 0.030; net reclassification improvement index = 0.225, P = 0.006; likelihood ratio test P < 0.001). Among patients with LVEF 35-55%, AVI within 6 months of diagnosis was associated with a reduced risk of death or HHF compared with medical treatment alone (adjusted HR: 0.15; 95% CI: 0.04-0.50; P = 0.002), whereas this benefit was markedly attenuated when LVEF was ≤35% (adjusted HR: 0.65; 95% CI: 0.21-1.97; P = 0.441, P-interaction = 0.010) or >55% (adjusted HR: 0.40; 95% CI: 0.14-1.15; P = 0.089, P-interaction = 0.723). CONCLUSIONS: LVEF is an independent and incremental prognostic factor in patients with moderate AR, with LVEF ≤55% being a robust marker of poor prognosis. Patients with LVEF 35-55% may benefit from early surgical correction of moderate AR. Further studies are warranted to validate our findings in a randomized setting. REGISTRATION: China Valvular Heart Disease Study (China-VHD study, NCT03484806); clinicaltrials.gov/ct2/show/NCT03484806.

Prediction of the Network Pharmacology-Based Mechanism for Attenuation of Atherosclerosis in Apolipoprotein E Knockout Mice by Panax notoginseng Saponins.

This study investigated whether Panax notoginseng saponins (PNS) reduced atherosclerotic lesion formation in apolipoprotein E knockout (ApoE-KO) mice and illustrated the potential mechanism for a network pharmacology approach. Pharmacodynamics studies on ApoE-KO mice with atherosclerosis (AS) showed that PNS generated an obvious anti-AS action. Then, we explored the possible mechanisms underlying its anti-AS effect using the network pharmacology approach. The main chemical components and their targets of PNS were collected from TCMSP public database and SymMap. The STRING v11.0 was used to establish the protein-protein interactions of PNS. Furthermore, the Gene Ontology (GO) function and KEGG pathways were analyzed using STRING to investigate the possible mechanisms involved in the anti-AS effect of PNS. The predicted results showed that 27 potential targets regulated by DSLHG were related to AS, including ACTA2, AKT1, BCL2, and BDNF. Mechanistically, the anti-AS effect of PNS was exerted by interfering with multiple signaling pathways, such as AGE-RAGE signaling pathway, fluid shear stress and atherosclerosis, and TNF signaling pathway. Network analysis showed that PNS could generate the anti-AS action by affecting multiple targets and multiple pathways and provides a novel basis to clarify the mechanisms of anti-AS of PNS.