Association of point-of-care testing for sST2 with clinical outcomes in patients hospitalized with heart failure.

AIMS: This study aimed to investigate the association of soluble suppression of tumorigenicity-2 (sST2) measured by point-of-care testing assay with clinical outcomes in patients hospitalized with heart failure after adjusting for other predictors including N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT). METHODS: A total of 1726 consecutive patients hospitalized with heart failure from July 2015 to December 2021 were enrolled. Baseline serum sST2 concentrations were measured by immunofluorescence assay. Primary endpoint event was the composite of all-cause death, heart transplantation, or left ventricular assist device. RESULTS: During the median follow-up duration of 682 days, 434 patients (25.1%) suffered from primary endpoint events. Baseline sST2 remained an independent predictor of the primary endpoint event in patients hospitalized with heart failure after adjusting for other predictors including NT-proBNP and hs-cTnT [per log (unit) increase, adjusted hazard ratio (HR) (95% confidence interval) (CI): 1.20 (1.09, 1.32), P < 0.001]. And baseline sST2 had a better prognostic value for patients with chronic decompensated heart failure [per log (unit) increase, adjusted HR (95% CI): 1.19 (1.07, 1.31)] than for those with acute new onset heart failure [per log (unit) increase, adjusted HR (95% CI): 1.28 (0.94, 1.75), P value for interaction <0.001], as well as a better prognostic value for patients with New York Heart Association (NYHA) functional class I-II [per log (unit) increase, adjusted HR (95% CI): 1.67 (1.11, 2.52)] than for those with NYHA functional class III-IV [per log (unit) increase, adjusted HR (95% CI): 1.18 (1.07, 1.31), P value for interaction <0.001]. Baseline sST2 was also a good predictor of the primary endpoint event in patients hospitalized with heart failure at 1 month, 3 months, 1 year and 2 years (area under the curve: 0.789, 0.775, 0.736 and 0.733, respectively), and the best cut-off values were 27.2 ng/ml, 27.1 ng/ml, 27.1 ng/ml and 25.1 ng/ml, respectively. Furthermore, baseline sST2 could provide additional prognostic value when added to baseline NT-proBNP and hs-cTnT (all P values <0.05). According to the category of elevated biomarkers (including NT-proBNP, hs-cTnT, and sST2), patients with three elevated biomarkers had a higher risk of the primary endpoint event compared with those with one or two elevated biomarkers (all P values <0.05). CONCLUSIONS: Baseline sST2 remained an independent predictor of adverse events after adjusting for other predictors including NT-proBNP and hs-cTnT, particularly in patients with chronic decompensated heart failure and NYHA functional class I-II. And in the basis of baseline NT-proBNP and hs-cTnT, adding baseline sST2 could provide additional prognostic value for patients hospitalized with heart failure.

Current Status and Challenges in Anti-Hepatitis B Virus Agents Based on Inactivation/Inhibition or Elimination of Hepatitis B Virus Covalently Closed Circular DNA.

There has been over half a century since the discovery of hepatitis B virus (HBV) to now, but approximately 300 million patients with chronic hepatitis B (CHB) still live in the world, resulting in about one million deaths every year. Although currently approved antivirals (e.g., nucleoside analogues) are effective at reducing HBV replication, they have almost no impact on the existing HBV covalently closed circular DNA (cccDNA) reservoir. HBV cccDNA is a critical obstacle to the complete elimination of the virus via antiviral therapy. The true cure of HBV infection requires the eradication of viral cccDNA from HBV-infected cells; thus, the development of new agents directly or indirectly targeting HBV cccDNA is urgently needed due to the limitations of current available drugs against HBV infection. In this regard, it is the major focus of current anti-HBV research worldwide via different mechanisms to either inactivate/inhibit (functional cure) or eliminate (complete cure) HBV cccDNA. Therefore, this review discussed and summarized recent advances and challenges in efforts to inactivate/silence or eliminate viral cccDNA using anti-HBV agents from different sources, such as small molecules (including epigenetic drugs) and polypeptides/proteins, and siRNA or gene-editing approaches targeting/attenuating HBV cccDNA via different mechanisms, as well as future directions that may be considered in efforts to truly cure chronic HBV infection. In conclusion, no breakthrough has been made yet in attenuating HBV cccDNA, although a number of candidates have advanced into the phase of clinical trials. Furthermore, the overwhelming majority of the candidates function to indirectly target HBV cccDNA. No outstanding candidate directly targets HBV cccDNA. Relatively speaking, CCC_R08 and nitazoxanide may be some of the most promising agents to clear HBV infection in small molecule compounds. Additionally, CRISPR-Cas9 systems can directly target HBV cccDNA for decay and demonstrate significant anti-HBV activity. Consequently, gene-editing approaches targeting HBV cccDNA may be one of the most promising means to achieve the core goal of anti-HBV therapeutic strategies. In short, more basic studies on HBV infection need to be carried out to overcome these challenges.

Clinical characteristics and outcomes of patients hospitalized with heart failure with preserved ejection fraction and low NT-proBNP levels.

The aim of this study was to investigate the clinical characteristics and prognosis of patients hospitalized with heart failure with preserved ejection fraction (HFpEF) and low N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Seven hundred ninety consecutive patients hospitalized with HFpEF from 2006 to 2017 were enrolled. Clinical characteristics and outcomes were compared between low NT-proBNP group (<300 ng/L) and elevated NT-proBNP group (≥300 ng/L). 108 HFpEF patients (13.7%) presented with low NT-proBNP levels. Age, body mass index, atrial fibrillation, New York Heart Association functional class, and albumin were independent predictors of low NT-proBNP levels in HFpEF patients. During the median follow-up duration of 1103 days, 11 patients (10.2%) in low NT-proBNP group suffered from primary endpoint event. Elevated NT-proBNP group had a higher risk of all-cause death or heart transplantation than low NT-proBNP group (adjusted HR [95%CI]: 2.36 [1.24,4.49], P = .009). Stratified analyses showed that the association between NT-proBNP (elevated NT-proBNP group vs low NT-proBNP group) and risk of all-cause death or heart transplantation was stronger in non-atrial fibrillation patients than in atrial fibrillation patients (P value for interaction = .025). Furthermore, the associations between NT-proBNP and risk of all-cause death or heart transplantation were stronger in younger and male patients than in older and female patients. However, both subgroups only reached borderline significant (P values for interaction = .062 and .084, respectively). Our findings suggest that low NT-proBNP levels were common in patients hospitalized with HFpEF. Patients with HFpEF and low NT-proBNP levels had a better prognosis than those with elevated NT-proBNP levels, particularly in younger, male, and non-atrial fibrillation patients.

sST2 and Big ET-1 as Alternatives of Multi-Biomarkers Strategies for Prognosis Evaluation in Patients Hospitalized with Heart Failure.

Objective: To identify biomarkers with independent prognostic value and investigate the prognostic value of multiple biomarkers in combination in patients hospitalized with heart failure. Methods: A total of 884 consecutive patients hospitalized with heart failure from 2015 to 2017 were enrolled. Twelve biomarkers were measured on admission, and the relationships between biomarkers and outcomes were assessed. Results: During the median follow-up of 913 days, 291 patients (32.9%) suffered from primary endpoint events. Soluble suppression of tumorigenicity-2 (sST2) (per log [unit] increase, adjusted HR [95% CI]: 1.39 [1.13,1.72], P = 0.002) and big endothelin-1 (big ET-1) (per log [unit] increase, adjusted HR [95% CI]: 1.56 [1.23,1.97], P < 0.001) remained independent predictors of primary endpoint event after adjusting for other predictors including N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT). Both sST2 (C-statistic: 0.810 vs 0.801, P = 0.005, and 0.832 vs 0.826, P = 0.024, respectively) and big ET-1 (C-statistic: 0.829 vs 0.801, P = 0.001, and 0.843 vs 0.826, P < 0.001, respectively) significantly improved the predictive value for primary endpoint event at 1 year and 3 years. However, only big ET-1 (C-statistic: 0.852 vs 0.846, P = 0.014) significantly improved the predictive value at 3 months when added to clinical predictors and known biomarkers. According to the number of elevated biomarkers (including NT-proBNP, hs-cTnT, sST2, and big ET-1), patients with three or more elevated biomarkers had a higher risk of primary endpoint event compared to those with two elevated biomarkers (P = 0.001), as well as in patients with two elevated biomarkers compared to those with one elevated biomarker (P = 0.004). However, the risk of primary endpoint event was comparable between patients with one elevated biomarker and those with no elevated biomarker (P = 0.582). Conclusion: Multiple biomarkers in combination could provide a better prognostic value than a single biomarker. sST2 and big ET-1 could act as alternatives of multi-biomarkers strategies for prognosis evaluation beyond NT-proBNP and hs-cTnT in patients hospitalized with heart failure.

Estimated plasma volume status adds prognostic value to hemodynamic parameters in advanced heart failure.

BACKGROUND: Estimated plasma volume status (ePVS) is a marker of intravascular congestion and has prognostic value in patients with heart failure (HF). The elevation of intracardiac filling pressures is defined as hemodynamic congestion and is also associated with poor prognosis. However, the relationship between intravascular congestion and hemodynamic congestion remains unclear. This study sought to explore the correlation between ePVS and hemodynamic parameters and determine the association between ePVS and clinical outcomes in patients with advanced HF. METHODS: Patients with advanced HF underwent right heart catheterization (RHC) for hemodynamic profiles. The sum of right atrial pressure (RAP) and pulmonary arterial wedge pressure (PAWP) > 30 mmHg was considered to present with hemodynamic congestion. Blood tests were conducted within 24 h of RHC. We calculated ePVS using the Strauss-derived Duarte formula. The primary outcome was all-cause mortality. RESULTS: A total of 195 patients were divided into two groups based on the cut-off value of ePVS (4.08 dL/g) calculated from receiver operating characteristic analysis. Patients with ePVS > 4.08 dL/g were more likely to present with wet rales (21.2% vs. 9.9%, P = 0.032) and had a higher risk of death (HR 4.748, 95% CI 2.385-9.453), regardless of whether RAP + PAWP was normal or elevated (all P < 0.05). Hemodynamic parameters and ePVS were not correlated (all P > 0.05). High ePVS significantly improved the predictive value beyond the clinical plus hemodynamic prognostic model (area under the curve of 0.844, Delong test, P = 0.024). CONCLUSION: ePVS could additionally add prognostic value to hemodynamic parameters in advanced heart failure, although not correlated with hemodynamic parameters.

Improved Prognostic Performance of Right Atrial Pressure-Corrected Cardiac Power Output in Pulmonary Hypertension and Heart Failure with Preserved Ejection Fraction.

Cardiac power output (CPO) is a powerful predictor of adverse outcomes in heart failure (HF). However, the original formula of CPO included the difference between mean arterial pressure and right atrial pressure (RAP). The prognostic performance of RAP-corrected CPO (CPORAP) remains unknown in heart failure with preserved ejection fraction (HFpEF). We studied 101 HF patients with a left ventricular ejection fraction > 40% who had pulmonary hypertension due to left heart disease. CPORAP was significantly more discriminating than CPO in predicting outcomes (Delong test, P = 0.004). Twenty-five (24.8%) patients presented with dis-concordantly high CPORAP and low CPO when stratified by the identified CPORAP threshold of 0.547 W and the accepted CPO threshold of 0.803 W. These patients had the lowest RAP, and their cumulative incidence was comparable with those with concordantly high CPO and CPORAP (P = 0.313). CPORAP might identify patients with right ventricular involvement, thereby providing better prognostic performance than CPO in HFpEF.

Cantharidin analogue alleviates dextran sulfate sodium-induced colitis in mice by inhibiting the activation of NF-κB signaling.

Ulcerative colitis is a chronic inflammatory disease with a remitting-relapsing clinical course, it has evolved into a global burden given its high incidence worldwide. Cantharidin (CTD) derivatives are a class of compounds whose structures characterized with a 7-oxabicyclo [2.2.1]heptane core. Though potent cytotoxicity CTD and its derivatives showed, their clinical usage as anti-cancer drugs was limited by the toxicity in organs. In order to find new CTD analogues with good activity and lower toxicity, 21 CTD analogues with or without alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core were synthesized, some compounds showed better in vitro anti-inflammatory activity compared to CTD and norcantharidin (NCTD). Based on the structure-activity relationship results of in vitro experiment, analogue 3i was chosen for further study. Results from the acute toxicity in mice showed that 3i was hypotoxic with the single-dose MTD (maximum tolerated dose) for oral administration is over 1852 mg/kg, at least 35-fold lower than that of NCTD. Mechanism study indicated that 3i could potently inhibit TNF-α induced activation of NF-κB signaling by down-regulation the expression levels of phosphor- IKK, IκBα, and NF-κB p65, and alleviated dextran sulfate sodium-induced colitis in mice. This study indicated that CTD analogues with alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core is a kind of new compounds with good anti-inflammatory activity and lower toxicity in vivo, and might be used as therapeutic agents for inflammatory diseases.

Incorporating inflammatory biomarkers into a prognostic risk score in patients with non-ischemic heart failure: a machine learning approach.

Objectives: Inflammation is involved in the mechanisms of non-ischemic heart failure (NIHF). We aimed to investigate the prognostic value of 21 inflammatory biomarkers and construct a biomarker risk score to improve risk prediction for patients with NIHF. Methods: Patients diagnosed with NIHF without infection during hospitalization were included. The primary outcome was defined as all-cause mortality and heart transplantations. We used elastic net Cox regression with cross-validation to select inflammatory biomarkers and construct the best biomarker risk score model. Discrimination, calibration, and reclassification were evaluated to assess the predictive value of the biomarker risk score. Results: Of 1,250 patients included (median age, 53 years, 31.9% women), 436 patients (34.9%) experienced the primary outcome during a median of 2.8 years of follow-up. The final biomarker risk score included high-sensitivity C-reactive protein-to-albumin ratio (CAR) and red blood cell distribution width-standard deviation (RDW-SD), both of which were 100% selected in 1,000 times cross-validation folds. Incorporating the biomarker risk score into the best basic model improved the discrimination (ΔC-index = 0.012, 95% CI 0.003-0.018) and reclassification (IDI, 2.3%, 95% CI 0.7%-4.9%; NRI, 17.3% 95% CI 6.4%-32.3%) in risk identification. In the cross-validation sets, the mean time-dependent AUC ranged from 0.670 to 0.724 for the biomarker risk score and 0.705 to 0.804 for the basic model with a biomarker risk score, from 1 to 8 years. In multivariable Cox regression, the biomarker risk score was independently associated with the outcome in patients with NIHF (HR 1.76, 95% CI 1.49-2.08, p < 0.001, per 1 score increase). Conclusions: An inflammatory biomarker-derived risk score significantly improved prognosis prediction and risk stratification, providing potential individualized therapeutic targets for NIHF patients.

Photocatalytic synthesis of alkynylsulfones and alkenylsulfones using sulfonylhydrazides and alkynes.

An efficient and energy saving photocatalytic coupling reaction of benzenesulfonyl hydrazide with bromoacetylene has been reported. A series of alkynylsulfones were obtained in up to 98% yield. In addition, changing the base from KHCO3 to KOAc can give the alkenylsulfone product. In addition, we tested the biological activity of some alkynylsulfone compounds and found that they exhibited excellent in vitro antioxidant activity by activating the Nrf2/ARE pathway, up to 8 fold.

Electroencephalography Signal Processing: A Comprehensive Review and Analysis of Methods and Techniques.

The electroencephalography (EEG) signal is a noninvasive and complex signal that has numerous applications in biomedical fields, including sleep and the brain-computer interface. Given its complexity, researchers have proposed several advanced preprocessing and feature extraction methods to analyze EEG signals. In this study, we analyze a comprehensive review of numerous articles related to EEG signal processing. We searched the major scientific and engineering databases and summarized the results of our findings. Our survey encompassed the entire process of EEG signal processing, from acquisition and pretreatment (denoising) to feature extraction, classification, and application. We present a detailed discussion and comparison of various methods and techniques used for EEG signal processing. Additionally, we identify the current limitations of these techniques and analyze their future development trends. We conclude by offering some suggestions for future research in the field of EEG signal processing.

Recent Advances on PKM2 Inhibitors and Activators in Cancer Applications.

Metabolic reprogramming of cells, from the normal mode of glucose metabolism named glycolysis, is a pivotal characteristic of impending cancerous cells. Pyruvate kinase M2 (PKM2), an important enzyme that catalyzes the final rate-limiting stage during glycolysis, is highly expressed in numerous types of tumors and aids in development of favorable conditions for the survival of tumor cells. Increasing evidence has suggested that PKM2 is one of promising targets for innovative drug discovery, especially for the developments of antitumor therapeutics. Herein, we systematically summarize the recent advancement on PKM2 modulators including inhibitors and activators in cancer applications. We also discussed the classifications of pyruvate kinases in mammals and the biological functions of PKM2 in this review. We do hope that this review would provide a comprehensive understanding of the current research on PKM2 modulators, which may benefit the development of more potent PKM2-related drug candidates to treat PKM2-associated diseases including cancers in future.

Afterload-related cardiac performance is a powerful hemodynamic predictor of mortality in patients with chronic heart failure.

Background: Afterload-related cardiac performance (ACP), a diagnostic parameter for septic cardiomyopathy, integrates both cardiac performance and vascular effects and could predict prognosis in septic shock. Objectives: We hypothesized that ACP would also correlate with clinical outcomes in patients with chronic heart failure (HF). Design: A retrospective study. Methods: We retrospectively studied consecutive patients with chronic HF who underwent right heart catheterization and established an expected cardiac output-systemic vascular resistance (CO-SVR) curve model in chronic HF for the first time. ACP was calculated as COmeasured/COpredicted × 100%. ACP > 80%, 60% < ACP ⩽ 80%, and ACP ⩽ 60% represented less impaired, mildly impaired, and severely impaired cardiovascular function, respectively. The primary outcome was all-cause mortality, and the secondary outcome was event-free survival. Results: A total of 965 individual measurements from 290 eligible patients were used to establish the expected CO-SVR curve model (COpredicted = 53.468 × SVR -0.799). Patients with ACP ⩽ 60% had higher serum NT-proBNP levels (P < 0.001), lower left ventricular ejection fraction (P = 0.001), and required dopamine more frequently (P < 0.001). Complete follow-up data were available in 263 of 290 patients (90.7%). After multivariate adjustment, ACP remained associated with both primary outcome (hazard ratio (HR) 0.956, 95% confidence interval (CI) 0.927-0.987) and secondary outcome (HR 0.977, 95% CI 0.963-0.992). Patients with ACP ⩽ 60% had the worst prognosis (all P < 0.001). ACP was significantly more discriminating (area under the curve of 0.770) than other conventional hemodynamic parameters in predicting mortality (Delong test, all P < 0.05). Conclusion: ACP is a powerful independent hemodynamic predictor of mortality in patients with chronic HF. ACP and the novel CO-SVR two-dimensional graph could be useful in assessing cardiovascular function and making clinical decisions. Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02664818.

Combined use of right ventricular coupling and pulmonary arterial elastance as a comprehensive stratification approach for right ventricular function.

Right ventricular (RV)-pulmonary arterial uncoupling is the consequence of increased afterload and/or decreased RV contractility. However, the combination of arterial elastance (Ea) and end-systolic elastance (Ees)/Ea ratio to assess RV function is unclear. We hypothesized that the combination of both could comprehensively assess RV function and refine risk stratification. The median Ees/Ea ratio (0.80) and Ea (0.59 mmHg/mL) were used to classify 124 patients with advanced heart failure into four groups. RV systolic pressure differential was defined as end-systolic pressure (ESP) minus beginning-systolic pressure (BSP). Patients among different subsets showed dissimilar New York Heart Association functional class (V = 0.303, p = 0.010), distinct tricuspid annular plane systolic excursion/ pulmonary artery systolic pressure (mm/mmHg; 0.65 vs. 0.44 vs. 0.32 vs. 0.26, p < 0.001), and diverse prevalence of pulmonary hypertension (33.3% vs. 35% vs. 90% vs. 97.6%, p < 0.001). By multivariate analysis, Ees/Ea ratio (hazard ratio [HR] 0.225, p = 0.004) and Ea (HR 2.194, p = 0.003) were independently associated with event-free survival. Patients with Ees/Ea ratio greater than or equal to 0.80 and Ea less than 0.59 mmHg/mL had better outcomes (p < 0.05). In patients with Ees/Ea ratio greater than or equal to 0.80, those with Ea greater than or equal to 0.59 mmHg/mL had a higher adverse outcome risk (p < 0.05). Ees/Ea ratio less than or equal to 0.80 was associated with adverse outcomes, even when Ea was less than 0.59 mmHg/mL (p < 0.05). Approximately 86% of patients with ESP-BSP greater than 5 mmHg had an Ees/Ea ratio less than or equal to 0.80 and/or an Ea greater than or equal to 0.59 mmHg/mL (V = 0.336, p = 0.001). Combined use of Ees/Ea ratio and Ea could be a comprehensive approach to assessing RV function and predicting outcomes. An exploratory analysis demonstrated that Ees/Ea ratio and Ea might be roughly estimated based on RV systolic pressure differential.

Switching the chemoselectivity of perakine reductase for selective reduction of α,ß-unsaturated ketones by Arg127 mutation.

The chemoselectivity of perakine reductase (PR) was engineered through rational design. We identified Arg127 as a control site of chemoselectivity. Mutation of Arg127 switched the chemoselectivity of PR between CO and CC or led to non-selectivity towards α,ß-unsaturated ketones, leading to the production of allylic alcohols, saturated ketones, or a mixture of both. This study provides an example for developing novel reductases for α,ß-unsaturated ketones.

[Prediction of PAHs Content in Soil Around Gas Stations in Beijing Based on BP Neural Network].

With the rapid development of urbanization in China, the number of gas stations in cities is increasing. The composition of oil products in gas stations is complex and diverse, and a series of pollutants will be generated in the process of oil diffusion. Polycyclic aromatic hydrocarbons (PAHs) produced by gas stations can pollute the nearby soil and affect human health. In this study, soil samples (0-20 cm) near 117 gas stations in Beijing were collected, and the contents of seven PAHs were analyzed. Based on the BP neural network model, the contents of PAHs in soil of Beijing gas stations in 2025 and 2030 were predicted. The results showed that the total concentrations of the seven PAHs were 0.01-3.53 mg·kg-1. The concentrations of PAHs were lower than the soil environmental quality risk control standard for soil contamination of development land (Trial) GB 36600-2018. At the same time, the toxic equivalent concentrations (TEQ) of the above seven PAHs were lower than the standard value (1 mg·kg-1) of the World Health Organization (WHO), which they indicate a lower risk to human health. The prediction results showed that the rapid development of urbanization had a positive correlation with the increase in soil PAHs content. By 2030, the content of PAHs in Beijing gas station soil will continue to grow. The predicted concentrations of PAHs in the soil of Beijing gas stations in 2025 and 2030 were 0.085-4.077 mg·kg-1and 0.132-4.412 mg·kg-1, respectively. The contents of seven PAHs were lower than the soil pollution risk screening value of GB 36600-2018; however, the concentration of PAHs increased over time.The contents of PAHs in Chaoyang, Fengtai, and Haidian were relatively higher, which requires further attention.

Big Endothelin-1 as a Predictor of Reverse Remodeling and Prognosis in Dilated Cardiomyopathy.

This study aimed to investigate the predictive value of Big endothelin-1(ET-1) for left ventricular reverse remodeling (LVRR) and prognosis in patients with dilated cardiomyopathy (DCM). Patients with DCM and a left ventricular ejection fraction (LVEF) ≤ 50% from 2008 to 2017 were included. LVRR was defined as the LVEF increased by at least 10% or follow-up LVEF increased to at least 50% with a minimum improvement of 5%; meanwhile, the index of left ventricular end-diastolic diameter (LVEDDi) decreased by at least 10% or LVEDDi decreased to ≤33 mm/m2. The composite outcome for prognostic analysis consisted of death and heart transplantations. Of the 375 patients included (median age 47 years, 21.1% female), 135 patients (36%) had LVRR after a median of 14 months of treatment. An independent association was found between Big ET-1 at baseline and LVRR in the multivariate model (OR 0.70, 95% CI 0.55-0.89, p = 0.003, per log increase). Big ET-1, body mass index, systolic blood pressure, diagnosis of type 2 diabetes mellitus (T2DM) and treatment with ACEI/ARB were significant predictors for LVRR after stepwise selection. Adding Big ET-1 to the model improved the discrimination (∆AUC = 0.037, p = 0.042 and reclassification (IDI, 3.29%; p = 0.002; NRI, 35%; p = 0.002) for identifying patients with LVRR. During a median follow-up of 39 (27-68) months, Big ET-1 was also independently associated with the composite outcome of death and heart transplantations (HR 1.45, 95% CI 1.13-1.85, p = 0.003, per log increase). In conclusion, Big ET-1 was an independent predictor for LVRR and had prognostic implications, which might help to improve the risk stratification of patients with DCM.

Availability, Functionality, and Safety as well as Quality Control of Hepatocytes as Seeding Cells in Liver Regenerative Medicine: State of the Art and Challenges.

Hepatic disease is one of the most common causes of death worldwide and has become a global health problem. Liver transplantation is the only effective treatment strategy for patients with hepatic function failure, but the insufficient number of donated healthy livers is the main obstacle limiting this process. To alleviate the demand for donor's livers, alternative approaches are being actively explored using liver tissue engineering principles. Liver tissue engineering consists of three elements, including seeding cells, extracellular matrix, and bioreactors. Among them, seeding cell is the most key factor. In this regard, hepatocyte-based tissue engineering can overcome the above shortages for tissue repair and regeneration in hepatic disorders. Primary human hepatocytes in liver regenerative medicine are the most preferred seeding cells, although limited access to a sufficient number of functional hepatocytes are a major issue due to the difficulties in long-term function maintenance of hepatocyte as well as the lack of availability of healthy donors. Hepatocyte-like cells (HLCs), derived from various stem cells, including non-liver-derived stem cells and liver-derived stem cells, as well as trans-differentiation of other cell types, may provide adequate cell sources and could replace primary human hepatocytes as seeding cells. However, it is still a great difficulty that HLCs generated by stem cell differentiation meet the quality required for clinical therapy. Furthermore, none of the standardized protocols to generate high-quality HLCs is available. Whether primary hepatocytes or HLCs are from various sources, preventing the functional deterioration of hepatocytes or generating fully functional hepatocytes is also a big challenge, respectively. In addition, the adoptions of three-dimensional co-culture systems and some small-molecule compounds contribute to maintaining the hepatic functionality of primary hepatocytes and enhancing the liver-specific functions of HLCs. In short, hepatocyte-based liver regenerative medicine is an attractive alternative strategy for liver diseases, notwithstanding some challenges still exist from bench to bedside. This review summarizes the current status, issues, and challenges in availability, functionality, and safety, as well as quality control of seeding hepatocytes with regard to liver tissue engineering in regenerative medicine for the treatment of liver disorders.

Comparison and application of SOFM, fuzzy c-means and k-means clustering algorithms for natural soil environment regionalization in China.

Soil attributes and their environmental drivers exhibit different patterns in different geographical directions, along with distinct regional characteristics, which may have important effects on substance migration and transformation such as organic matter and soil elements or the environmental impacts of pollutants. Therefore, regional soil characteristics should be considered in the process of regionalization for environmental management. However, no comprehensive evaluation or systematic classification of the natural soil environment has been established for China. Here, we established an index system for natural soil environmental regionalization (NSER) by combining literature data obtained based on bibliometrics with the analytic hierarchy process (AHP). Based on the index system, we collected spatial distribution data for 14 indexes at the national scale. In addition, three clustering algorithms-self-organizing feature mapping (SOFM), fuzzy c-means (FCM) and k-means (KM)-were used to classify and define the natural soil environment. We imported four cluster validity indexes (CVI) to evaluate different models: Davies-Bouldin index (DB), Silhouette index (Sil) and Calinski-Harabasz index (CH) for FCM and KM, clustering quality index (CQI) for SOFM. Analysis and comparison of the results showed that when the number of clusters was 13, the FCM clustering algorithm achieved the optimal clustering results (DB = 1.16, Sil = 0.78, CH = 6.77 × 106), allowing the natural soil environment of China to be divided into 12 regions with distinct characteristics. Our study provides a set of comprehensive scientific research methods for regionalization research based on spatial data, it has important reference value for improving soil environmental management based on local conditions in China.

Cyclocarboamination of Alkynes with N-Aminopyridiniums by Photoredox Catalysis.

A visible-light photoredox-catalyzed reaction to access structurally diverse pyridoimidazoles has been developed. This transformation features intermolecular carboamination of N-sulfonylaminopyridiniums with a broad scope of alkynes.

Human health risk-based soil environmental criteria (SEC) for park soil in Beijing, China.

Urban parks are important places that allow urban residents to experience nature but are also associated with the risk of exposure to contaminated soil. Therefore, it is necessary to establish appropriate soil environment criteria (SEC) to manage park soil quality. Studies on the demographic characteristics and behavioral patterns of urban park visitors are helpful for the selection of sensitive receptors and the determination of parameters in the establishment of SEC. This study explored the park visitors' demographic characteristics and behavioral patterns, and applied the results to derive SEC. Eighty-six parks in Beijing were selected, and mobile phone data were obtained to analysis the demographic characteristics and residence time of the visitors. Kruskal-Wallis test, kernel density estimation and random forest model were used for data analysis. The CLEA model was used to derive SEC. The results showed that the demographic characteristics and behavioral patterns of visitors in different types of parks were quite different. Parks were mostly used by males and visitors aged 31-45. Most visitors stayed in the park for 1-2 h, and the distance from a given visitor's home to the park was the most important factor affecting stay time. Then, several parameters such as the parameters related to the receptors and occupation period were optimized, and the SEC of sensitive parks and non-sensitive parks were derived. Exposure frequency may be the main reason for the difference of SEC between the two types of parks. The SECs of sensitive parks were higher than the soil screening values (SSVs) for class 1 land in GB36600-2018, indicating that the current SSVs for some parks may be too conservative. This study provides a reference for the formulation and revision of soil environmental standards for park land, and suggests strengthening research on human behavioral patterns.