Microneedle electrochemical sensor based on disposable stainless-steel wire for real-time analysis of indole-3-acetic acid and salicylic acid in tomato leaves infected by Pst DC3000 in situ.

BACKGROUND: Indole-3-acetic acid (IAA) and salicylic acid (SA), pivotal regulators in plant growth, are integral to a variety of plant physiological activities. The ongoing and simultaneous monitoring of these hormones in vivo enhances our comprehension of their interactive and regulatory roles. Traditional detection methods, such as liquid chromatography-mass spectrometry, cannot obtain precise and immediate information on IAA and SA due to the complexity of sample processing. In contrast, the electrochemical detection method offers high sensitivity, rapid response times, and compactness, making it well-suited for in vivo or real-time detection applications. RESULTS: A microneedle electrochemical sensor system crafted from disposable stainless steel (SS) wire was specifically designed for the real-time assessment of IAA and SA in plant in situ. This sensor system included a SS wire (100 µm diameter) coated with carbon cement and multi-walled carbon nanotubes, a plain platinum wire (100 µm diameter), and an Ag/AgCl wire (100 µm diameter). Differential pulse voltammetry and amperometry were adopted for detecting SA and IAA within the range of 0.1-20 µM, respectively. This sensor was applied to track IAA and SA fluctuations in tomato leaves during PstDC3000 infection, offering continuous data. Observations indicated an uptick in SA levels following infection, while IAA production was suppressed. The newly developed disposable SS wire-based microneedle electrochemical sensor system is economical, suitable for mass production, and inflicts minimal damage during the monitoring of SA and IAA in plant tissues. SIGNIFICANCE: This disposable microneedle electrochemical sensor facilitates in vivo detection of IAA and SA in smaller plant tissues and allows for long-time monitoring of their concentrations, which not only propels research into the regulatory and interaction mechanisms of IAA and SA but also furnishes essential tools for advancing precision agriculture.

Downlink Transmissions of UAV-RIS-Assisted Cell-Free Massive MIMO Systems: Location and Trajectory Optimization.

In this paper, we investigate a cell-free massive multiple-input multiple-output (CF-mMIMO) system with a reconfigurable intelligent surface (RIS) carried by an unmanned aerial vehicle (UAV), called the UAV-RIS. Compared with the RIS located on the ground, the UAV-RIS has a wider coverage that can reflect all signals from access points (APs) and user equipment (UE). By correlating the UAV location with the Rician K-factor, we derive a closed-form approximation of the UE achievable downlink rate. Based on this, we obtain the optimal UAV location and RIS phase shift that can maximize the UE sum rate through an alternating optimization method. Simulation results have verified the accuracy of the derived approximation and shown that the UE sum rate can be significantly improved with the obtained optimal UAV location and RIS phase shift. Moreover, we find that with a uniform UE distribution, the UAV-RIS should fly to the center of the system, while with an uneven UE distribution, the UAV-RIS should fly above the area where UEs are gathered. In addition, we also design the best trajectory for the UAV-RIS to fly from its initial location to the optimal destination while maintaining the maximum UE sum rate per time slot during the flight.

A novel radiomics-based technique for identifying vulnerable coronary plaques: a follow-up study.

BACKGROUND: Previous reports have suggested that coronary computed tomography angiography (CCTA)-based radiomics analysis is a potentially helpful tool for assessing vulnerable plaques. We aimed to investigate whether coronary radiomic analysis of CCTA images could identify vulnerable plaques in patients with stable angina pectoris. METHODS: This retrospective study included patients initially diagnosed with stable angina pectoris. Patients were randomly divided into either the training or test dataset at an 8 : 2 ratio. Radiomics features were extracted from CCTA images. Radiomics models for predicting vulnerable plaques were developed using the support vector machine (SVM) algorithm. The model performance was assessed using the area under the curve (AUC); the accuracy, sensitivity, and specificity were calculated to compare the diagnostic performance using the two cohorts. RESULTS: A total of 158 patients were included in the analysis. The SVM radiomics model performed well in predicting vulnerable plaques, with AUC values of 0.977 and 0.875 for the training and test cohorts, respectively. With optimal cutoff values, the radiomics model showed accuracies of 0.91 and 0.882 in the training and test cohorts, respectively. CONCLUSION: Although further larger population studies are necessary, this novel CCTA radiomics model may identify vulnerable plaques in patients with stable angina pectoris.

Predicting colorectal cancer risk: a novel approach using anemia and blood test markers.

Background and objectives: Colorectal cancer remains an important public health problem in the context of the COVID-19 (Corona virus disease 2019) pandemic. The decline in detection rates and delayed diagnosis of the disease necessitate the exploration of novel approaches to identify individuals with a heightened risk of developing colorectal cancer. The study aids clinicians in the rational allocation and utilization of healthcare resources, thereby benefiting patients, physicians, and the healthcare system. Methods: The present study retrospectively analyzed the clinical data of colorectal cancer cases diagnosed at the Affiliated Hospital of Guilin Medical University from September 2022 to September 2023, along with a control group. The study employed univariate and multivariate logistic regression as well as LASSO (Least absolute shrinkage and selection operator) regression to screen for predictors of colorectal cancer risk. The optimal predictors were selected based on the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. These predictors were then utilized in constructing a Nomogram Model for predicting colorectal cancer risk. The accuracy of the risk prediction Nomogram Model was assessed through calibration curves, ROC curves, and decision curve analysis (DCA) curves. Results: Clinical data of 719 patients (302 in the case group and 417 in the control group) were included in this study. Based on univariate logistic regression analysis, there is a correlation between Body Mass Index (BMI), red blood cell count (RBC), anemia, Mean Corpuscular Volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count (PLT), Red Cell Distribution Width-Standard Deviation (RDW-SD), and the incidence of colorectal cancer. Based on the findings of multivariate logistic regression analysis, the variables of BMI and RBC exhibit a decrease, while anemia and PLT demonstrate an increase, all of which are identified as risk factors for the occurrence of colorectal cancer. LASSO regression selected BMI, RBC, anemia, and PLT as prediction factors. LASSO regression and multivariate logistic regression analysis yielded the same results. A nomogram was constructed based on the 4 prediction factors identified by LASSO regression analysis to predict the risk of colorectal cancer. The AUC of the nomogram was 0.751 (95% CI, OR: 0.708-0.793). The calibration curves in the validation and training sets showed good performance, indicating that the constructed nomogram model has good predictive ability. Additionally, the DCA demonstrated that the nomogram model has diagnostic accuracy. Conclusion: The Nomogram Model offers precise prognostications regarding the likelihood of Colorectal Cancer in patients, thereby helping healthcare professionals in their decision-making processes and promoting the rational categorization of patients as well as the allocation of medical resources.

REXO2 up-regulation is positively correlated with poor prognosis and tumor immune infiltration in hepatocellular carcinoma.

BACKGROUND: As a homologous counterpart to the prokaryotic oligonuclease found in the cellular cytoplasm and mitochondrion, REXO2 assumes a pivotal role in the maintenance of mitochondrial homeostasis. Nevertheless, the precise functions and mechanisms by which REXO2 operates within the context of hepatocellular carcinoma (HCC) have hitherto remained unexamined. METHODS: The expression levels of REXO2 in HCC tissues were evaluated through the utilization of the immunohistochemical (IHC) method, and subsequently, the association between REXO2 expression and the clinicopathological characteristics of HCC patients was scrutinized employing the χ2 test. A battery of experimental assays, encompassing CCK8 viability assessment, cell colony formation, wound healing, and transwell assays, were conducted with the aim of elucidating the biological role of REXO2 within HCC cells. Complementary bioinformatics analyses were undertaken to discern potential correlations between REXO2 and immune infiltration in tumor tissues. RESULTS: Our IHC findings have unveiled a notable up-regulation of REXO2 within HCC tissues, and this heightened expression bears the status of an independent prognostic factor, portending an adverse outcome for HCC patients (P < 0.05). Upon the attenuation of REXO2 expression, a discernible reduction in the rates of proliferation, invasion and migration of HCC cells ensued (P < 0.05). Furthermore, transcriptome sequencing analysis has provided insights into the putative influence of REXO2 on the development of HCC through the modulation of TNF and NF-κB signaling pathways. Additionally, our bioinformatics analyses have demonstrated a positive correlation between REXO2 and tumor immune cell infiltration, as well as immune checkpoint CTLA-4. CONCLUSIONS: In summation, our results posit an association between the up-regulation of REXO2 and adverse prognostic outcomes, alongside the involvement of immune-related signaling pathways and tumor immune infiltration within the realm of HCC.

Migrasomes and tetraspanins in hepatocellular carcinoma: current status and future prospects.

In recent years, many studies have attempted to clarify the formation, structure and biological function of migrasomes, which are defined as specialized organelles formed by the tips and intersections of Retraction Fibrils during cell migration. It has confirmed that migrasomes were involved in various critical biological processes and diseases, and has became a new research hotspot. In this paper, we reviewed the formation and biological functions of migrasomes, explored the relationship between migrasomes, tetraspanins and hepatocellular carcinoma and discussed the potential applications of migrasomes in hepatocellular carcinoma.

Migrasomes are specialized parts of the cell that are responsible for transporting proteins and molecules to their designated cellular locations. In this review, we have attempted to understand their formation, structure and biological function. We have also discussed the potential applications of migrasomes in liver cancer. Our study concluded that more research is required for a better understanding of migrasomes and their contents in liver cancer.

The m6A methylation enzyme METTL14 regulates myocardial ischemia/reperfusion injury through the Akt/mTOR signaling pathway.

Herein, we investigated the role of the m6A methylation enzyme METTL14 in regulating myocardial ischemia/reperfusion injury (IR/I) through the Akt/mTOR signaling pathway and related biological mechanisms. Enzyme-linked immunosorbent assay (ELISA) and fluorescence quantitative polymerase chain reaction (qPCR) were performed to detect the m6A mRNA and METTL3, METTL14, WTAP, and KIAA1429 levels in a mouse myocardial IR/I model. An oxygen-glucose deprivation/reperfusion (OGD/R) model was constructed by transfecting neonatal rat cardiomyocytes (NRCM) with METTL14-knockdown lentivirus. METTL14, Bax, and cleaved-caspase3 mRNA expression levels were detected using fluorescence qPCR. Apoptosis was detected using TUNEL staining. After the IR/I surgery following the adeno-associated virus injection, the METTL14 mRNA and apoptosis-related BAX/BCL2 protein expression was detected using fluorescence qPCR and western blotting, respectively. Degree of cell necrosis was detected using an LDH assay. The oxidative stress response of the myocardial tissue was detected, and IL-6 and IL-1ß serum levels were detected using ELISAs. The mice injected with METTL14-knockdown AAV9 adeno-associated virus underwent IR/I surgery after the injection of an Akt/mTOR pathway inhibitor (MK2206) into the myocardial layer. Elevated mRNA m6A modification and m6A methyltransferase METTL14 levels were observed in the IR/I-injured mouse heart tissues. METTL14 knockdown significantly inhibited the OGD/R- and IR/I-induced apoptosis and necrosis in cardiac myocytes, inhibited IR/I-induced oxidative stress and inflammatory factor secretion, and activated the Akt/ mTOR pathway in vitro and in vivo. Akt/mTOR pathway inhibition significantly attenuated the alleviating effect of METTL14 knockdown on myocardial IR/I injury-induced apoptosis. Knocking down m6A methylase METTL14 inhibits IR/I-induced myocardial apoptosis and necrosis, inhibits myocardial oxidative stress and secretion of inflammatory cytokines, and activates the Akt/mTOR signaling pathway. Hence, METTL14 regulated myocardial apoptosis and necrosis in mice with IR/I through the Akt/mTOR signaling pathway.

Application of TVD-Net for sagittal alignment and instability measurements in cervical spine radiographs.

BACKGROUND: Cervical spinal malalignment and instability are frequently occurring pathological conditions involving neck pain, radiculopathy, and myelopathy, often requiring surgical intervention. Accurate assessment of cervical alignment and instability are essential in surgical planning and evaluating postoperative outcomes. PURPOSE: To automatically measure the sagittal alignment and instability of the cervical spine, we develop a novel deep-learning model by detecting landmarks on cervical radiographs. METHODS: We introduce the transformer-embedded residual network (ResNet) as the network's core to automatically identify vertebral landmarks on digital and film-transformed cervical radiographs, and simultaneously measure the segmental Cobb angle and horizontal displacement. A Transformer Module was embedded into the latent space to extract the relationship between different vertebrae. Then a Rotating Attention Module was integrated between the encoder-decoder pairs to highlight the key points and maintain more details. Finally, a Vector Loss Module was proposed to restrain the orientation of the adjacent vertebra to reduce misdetection. All images were obtained from local hospital. Digital images were split into training, validation, and test subsets (896, 225, and 353 images, respectively). Likewise, film-transformed images were split into 404, 115, and 150 images, respectively. The results of the model were compared with manual measurements. RESULTS: Our deep learning algorithm achieved mean absolute difference (MAD) at a level of 2.20° and 2.33°, symmetric mean absolute error(SMAPE)at 16.63% and 19.35%, respectively, when measuring Cobb angle on digital images and films. On evaluating cervical instability, the diagnostic accuracy, sensitivity, specificity, precision, and F1-score evaluation metrics were calculated. The corresponding values were 89.80%, 86.49%, 90.68%, 71.11%, and 78.05% on digital images, and 90.00%, 83.78%, 91.15%, 75.61%, and 79.49% on film-transformed images, which were comparable to experienced surgeons. Visualization results demonstrated robust effectiveness in subjects with severe osteophytes or artifacts. CONCLUSION: This study presents a novel and efficient deep-learning model to assist landmarks identification and angulation and displacement calculation on lateral cervical spine radiographs, and demonstrates excellent accuracy in measuring cervical alignment and sound sensitivity and specificity in cervical instability diagnosis. It should be helpful for future research and clinical applications.

Low-dose celecoxib-loaded PCL fibers reverse intervertebral disc degeneration by up-regulating CHSY3 expression.

Intervertebral disc degeneration (IDD) has been identified as one of the predominant factors leading to persistent low back pain and disability in middle-aged and elderly people. Dysregulation of Prostaglandin E2 (PGE2) can cause IDD, while low-dose celecoxib can maintain PGE2 at the physiological level and activate the skeletal interoception. Here, as nano fibers have been extensively used in the treatment of IDD, novel polycaprolactone (PCL) nano fibers loaded with low-dose celecoxib were fabricated for IDD treatment. In vitro studies demonstrated that the nano fibers had the ability of releasing low-dose celecoxib slowly and sustainably and maintain PGE2. Meanwhile, in a puncture-induced rabbit IDD model, the nano fibers reversed IDD. Furthermore, low-dose celecoxib released from the nano fibers was firstly proved to promote CHSY3 expression. In a lumbar spine instability-induced mouse IDD model, low-dose celecoxib inhibited IDD in CHSY3wt mice rather than CHSY3-/- mice. This model indicated that CHSY3 was indispensable for low-dose celecoxib to alleviate IDD. In conclusion, this study developed a novel low-dose celecoxib-loaded PCL nano fibers to reverse IDD by maintaining PGE2 at the physiological level and promoting CHSY3 expression.

Irisin reduces bone fracture by facilitating osteogenesis and antagonizing TGF-ß/Smad signaling in a growing mouse model of osteogenesis imperfecta.

Objective: Osteogenesis imperfecta (OI) is a congenital disorder characterized by muscle defect and skeletal fragility, and no cure is yet available. Crosstalk between bone and muscle has become a new coming focus of therapeutic strategy in OI. Irisin, a secreted myokine, was found to be involved in regulating bone metabolism, and may be beneficial for the treatment of OI. However, its effects in OI have yet to be determined. This study sought to determine whether Irisin therapy is capable of reducing fracture risk in OI and to investigate the potential mechanisms of action. Methods: Fibronectin type III domain containing 5 (FNDC5)/Irisin expression was assessed by enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining. In vivo, X-ray was used for fracture counting and micro-CT, dynamic histomorphometry analysis, immunohistochemistry, histomorphometry, and biomechanical test were used to evaluate the effects of Irisin on fracture frequency and bone quality in OI mouse model, oim/oim mouse. In vitro, osteogenesis-related gene expressions were determined by quantitative real-time PCR (qRT-PCR), western blot, and osteoblastogenesis assay were assessed by alkaline phosphatase (ALP) staining and alizarin red S (ARS) staining. Mechanistically, cell immunofluorescence staining, co-immunoprecipitation (co-IP) (Co-IP), molecular docking, western blot, luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay were used for elucidating the mechanisms of how Irisin antagonized transforming growth factor-ß (TGF-ß)/Smad signaling in oim/oim osteoblasts and further attenuated the inhibitory effect of TGF-ß1 on osteogenic differentiation. Results: Musculoskeletal system-related FNDC5/Irisin was decreased in the serum, muscle, and bone in oim/oim mice. Irisin administration reduced bone fracture and attenuated bone abnormalities by improving bone mass and strength and facilitating the expression of osteogenic differentiation markers. In vivo study and in vitro experiments showed that Irisin antagonized TGF-ß/Smad signaling by interfering with TGF-ß1-TGF-ß receptor II (TßRII) binding. In oim/oim osteoblasts, Irisin alleviated TGF-ß1-induced suppression of osteogenic differentiation through both integrin-dependent and integrin-independent mechanisms. Independent of integrin receptors, Irisin affected osteogenesis by activating ERK/p38 signaling and counteracting TGF-ß/Smad2/3 signaling. In particular, Irisin alleviated TGF-ß1-induced inhibition of Runx2 function at the osteocalcin promoter through decreasing Smad2/3 signaling and inducing HADC4/5 degeneration. Conclusions: Collectively, Irisin could effectively reduce bone fracture in oim/oim mice through promoting osteogenesis and counteracting TGF-ß/Smad signaling. Translational potential statement: Findings from this study provided evidence for using Irisin as a potential therapeutic reagent to prevent the progression of OI.

Dysfunction of Caveolae-Mediated Endocytic TßRI Degradation Results in Hypersensitivity of TGF-ß/Smad Signaling in Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a genetic disorder caused by mutations of type I collagen-related genes, and excessive transforming growth factor-beta (TGF-ß) signaling is a common mechanism. TGF-ß/Smad signaling has inhibitory effects on osteoblast differentiation and maturation and is mainly transduced and regulated by the internalization of a tetrameric receptor complex comprising types I and II TGF-ß receptors (TßRI and TßRII). During internalization, clathrin-mediated endocytosis enhances TGF-ß/Smad signaling via Smad2/3 phosphorylation and receptors recycling, while caveolae-mediated endocytosis turns off TGF-ß/Smad signaling by promoting receptor ubiquitination and degradation. In this study, using an animal model of OI (Colla2oim , osteogenesis imperfecta murine [oim]/oim mouse), we found that osteoblastic cells of oim/oim mice were more sensitive to the inhibitory effects of TGF-ß on osteoblast differentiation and maturation and had much higher cell membrane protein levels of TGF-ß receptors than those of wild-type (wt)/wt mice. Further results showed that clathrin-mediated endocytosis of TßRI was enhanced, whereas caveolae-mediated TßRI endocytic degradation was reduced in oim/oim mice, combined with reduced caveolin-1 (Cav-1) phosphorylation. In addition, type I collagen downregulated TßRI via focal adhesion kinase (FAK) and Src activation-dependent Cav-1 phosphorylation. To further examine this mechanism, 4-week-old oim/oim and wt/wt mice were treated with either TßRI kinase inhibitor (SD-208) or vehicle for 8 weeks. SD-208 treatment significantly reduced the fracture incidence in oim/oim mice. Micro-computed tomography and biomechanical testing showed that femoral bone mass and strength were significantly improved with SD-208 treatment in both genotypes. Additionally, SD-208 significantly promoted osteoblast differentiation and bone formation and inhibited bone resorption. In conclusion, dysfunction of caveolae-mediated endocytic TßRI degradation is a possible mechanism for the enhanced TGF-ß/Smad signaling in OI. Targeting this mechanism using a TßRI kinase inhibitor effectively reduced fractures and improved bone mass and strength in OI model and, thus, may offer a new strategy for the treatment of OI. © 2022 American Society for Bone and Mineral Research (ASBMR).

hsa-miR-9-5p-Mediated TSPAN9 Downregulation Is Positively Related to Both Poor Hepatocellular Carcinoma Prognosis and the Tumor Immune Infiltration.

Tetraspanins (TSPANs) play crucial roles in cell adhesion, migration, and metastasis of human cancer. However, there is no study in revealing the aspects of TSPAN9 traits and its functions in hepatocellular carcinoma (HCC) prognosis. Our study is the first to portray the TSPAN9 expression in HCC tissues with immunohistochemistry (IHC) analysis. Subsequently, a series of bioinformatics analyses such as expression estimation, survival assessment, and correlation analysis were implemented to dig out the possible upstream noncoding RNAs (ncRNAs) for TSPAN9 in HCC. In this way, the relevance within TSPAN9 and tumor immunity was then explored. We found that the TSPAN9 was downregulated in HCC tissues and had a correlation with HCC prognosis. Furthermore, we identified that the AL139383.1-hsa-miR-9-5p axis was the upstream ncRNA-related pathway most associated with TSPAN9 in HCC. Besides that, expression of TSPAN9 held a significantly negative correlation with tumor immunocyte infiltration as well as immune checkpoint CTLA4. TSPAN9-related immunomodulators were mainly enriched in T cell activation, leukocyte cell-cell adhesion, regulation of T cell activation, and regulation of leukocyte cell-cell adhesion signaling pathway. In conclusion, our results indicated that hsa-miR-9-5p-mediated downregulation of TSPAN9 was associated with poor HCC prognosis, immune-related signaling pathway, and tumor immune infiltration.

Combined use of low T3 syndrome and NT-proBNP as predictors for death in patients with acute decompensated heart failure.

BACKGROUND: In patients with established HF, low triiodothyronine syndrome (LT3S) is commonly present, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a useful marker for predicting death. This study was aimed to evaluate the prognostic value of LT3S in combination with NT-proBNP for risk of death in patients with heart failure (HF). METHODS: A total of 594 euthyroid patients hospitalized with acute decompensated HF were enrolled by design. Of these patients, 27 patients died during hospitalization and 100 deaths were identified in patients discharged alive during one year follow-up. Patients were divided into 2 groups on the base of the reference ranges of free T3 (FT3) levels: LT3S group (FT3 < 2.3pg/mL, n = 168) and non-LT3S group (FT3 ≥ 2.3pg/mL, n = 426). RESULTS: In multivariable Cox regression, LT3S was significantly associated with 1 year all-cause mortality (adjusted hazard ratio, 1.85; 95 % confidence interval [CI], 1.21 to 2.82; P = 0.005), but not significant for in-hospital mortality (adjusted hazard ratio, 1.58; 95 % CI, 1.58 to 2.82; P = 0.290) after adjustment for clinical variables and NT-proBNP. Addition of LT3S and NT-proBNP to the prediction model with clinical variables significantly improved the C statistic for predicting 1 year all-cause mortality. CONCLUSIONS: In patients with acute decompensated HF, the combination of LT3S and NT-proBNP improved prediction for 1 year all-cause mortality beyond established risk factors, but was not strong enough for in-hospital mortality.

Does higher SBP at discharge explain better outcomes in non-heart failure with reduced ejection fraction patients? Insights from Fuwai Hospital.

OBJECTIVE: We hypothesized that discharge SBP had different associations with outcomes in non-HFrEF (left ventricular ejection fraction ≥40%) patients with or without high blood pressure (HBP) at admission. METHODS: Non-HFrEF patients hospitalized for decompensated heart failure were consecutively recruited and were categorized into HBP (admission SBP ≥130 mmHg) group and non-HBP group. The primary outcome was a composite of cardiovascular death and heart transplantation. Multivariate Cox and penalized spline analyses were used to assess the relationships between discharge SBP and outcomes. RESULTS: Nine hundred and sixty-four non-HFrEF patients were enrolled with a median follow-up of 71.8 months. Three hundred and sixty-five (37.9%) patients had HBP. In multivariate Cox analyses, non-HBP patients with higher discharge SBP were associated with a better outcome (per 10 mmHg increased, hazard ratio = 0.788, P = 0.001). However, an opposite relationship between discharge SBP and the primary outcome was observed in HBP group (per 10 mmHg increased, hazard ratio = 1.312, P = 0.002). Results of penalized spline regression models showed that there was a U-shaped association between discharge SBP and outcomes in the total cohort. Compared with 120 mmHg, the risk of the primary outcome increased when discharge SBP was below 99 mmHg in non-HBP group; in HBP group, a worse outcome was observed when discharged SBP was above 145 mmHg. CONCLUSION: Non-HFrEF had a U-shaped association between discharge SBP and adverse events. Such an association was modified by admission HBP. Higher discharge SBP correlated with a worse outcome in non-HFrEF patients with admission HBP, as opposed to patients admitted without HBP.

Cost-effectiveness of adding dapagliflozin to standard treatment for heart failure with reduced ejection fraction patients in China.

AIMS: This study was to determine the cost-effectiveness of dapagliflozin in heart failure with reduced ejection fraction (HFrEF) patients in China from a perspective of health care payers. METHODS AND RESULTS: We built a Markov model to perform a cost-effectiveness analysis comparing standard treatment + dapagliflozin (10 mg, q.d.) with standard treatment for HFrEF. The base case in our simulation was a 65-year-old HFrEF patient and was modelled over 15 years. Inputs of the model were derived from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial and other relevant data from China. Costs, quality-adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER) were estimated for adding dapagliflozin relative to standard treatment. Costs and QALY were discounted at a 4.2% rate annually. All costs are presented in 2017 US dollars. Dapagliflozin would be considered very cost-effective if the ICER was lower than a willingness-to-pay (WTP) threshold of $8573.4. Uncertainty was assessed in our model using one-way, two-way, and probabilistic sensitivity analysis (PSA). In our base case, compared with standard treatment, adding dapagliflozin was more expensive ($5829.4 vs. $4377.1) but more effective (4.82 vs. 4.44 QALYs). The respondent ICER was $3827.6 per QALY gained at 15-year follow-up. When the simulated horizon was longer than 3.5 years, the respondent ICER became lower than the WTP threshold. The inputs with the largest impact on ICER were the cost of dapagliflozin, the cardiovascular mortality in both groups, and the cost of hospitalization for heart failure. Most results of sensitivity analysis were robust. PSA showed a similar result as the base case (ICER = $4412.5 per QALY gained). In Monte Carlo simulation, at a WTP threshold of $8573.4 per QALY, dapagliflozin was considered very cost-effective in 53.10% of the simulations. CONCLUSIONS: Dapagliflozin was a very cost-effective treatment option for HFrEF patients in China according to the result of our model. Our findings will help doctors and health care payers to make decisions in clinical practice. Future real-world studies of cost-effectiveness of dapagliflozin based on Chinese population were also needed.

Different prognostic association of systolic blood pressure at different time points with postdischarge events in patients hospitalized for decompensated heart failure.

BACKGROUND: The association of systolic blood pressure (SBP) with mortality in heart failure (HF) patients is paradoxical, and the time points of baseline SBP are also different across prior studies. We hypothesized that the levels of SBP at admission and at discharge had different associations with postdischarge events. METHODS: The study population included patients hospitalized for decompensated HF in the Heart Failure Center of Fuwai Hospital from January 1, 2009 to December 31, 2014. The primary outcome was a composite of cardiovascular (CV) death and heart transplantation. Multivariate Cox proportional-hazards and restricted cubic spline analyses were used to assess the relationships between SBP at different time points and outcomes. RESULTS: In total, 2005 patients were included with a median follow-up of 48.4 months. The median age was 59 years, and 69.9% were male. Multivariate Cox analyses showed that compared with SBP < 105 mmHg, higher SBP at admission was associated with better long-term primary outcome (105-119 mmHg, HR = 0.764, P = 0.005; 120-134 mmHg, HR = 0.658, P < 0.001; ≥ 135 mmHg, HR = 0.657, P = 0.001). Patients whose discharge SBP was higher than 135 mmHg had a similar primary outcome as those with SBP < 105 mmHg (HR = 0.969, P = 0.867), and the results remained unchanged even after adjusting for admission SBP (HR = 1.235, P = 0.291). The results of restricted cubic spline analysis indicated similar associations. CONCLUSIONS: Lower but not higher SBP at admission is associated with more CV deaths/heart transplantations (a reverse J-shaped curve). In contrast, there is a U-shaped association between discharge SBP and CV mortality/heart transplantation.

Mitochondrial miR-762 regulates apoptosis and myocardial infarction by impairing ND2.

Mitochondrial dysfunction plays a major role in the pathogenesis of cardiovascular diseases. MicroRNAs (miRNAs) are small RNAs that act as negative regulators of gene expression, but how miRNAs affect mitochondrial function in the heart is unclear. Using a miRNA microarray assay, we found that miR-762 predominantly translocated in the mitochondria and was significantly upregulated upon anoxia/reoxygenation (A/R) treatment. Knockdown of endogenous miR-762 significantly attenuated the decrease in intracellular ATP levels, the increase in ROS levels, the decrease in mitochondrial complex I enzyme activity and the increase in apoptotic cell death in cardiomyocytes, which was induced by A/R treatment. In addition, knockdown of miR-762 ameliorated myocardial ischemia/reperfusion (I/R) injury in mice. Mechanistically, we showed that enforced expression of miR-762 dramatically decreased the protein levels of endogenous NADH dehydrogenase subunit 2 (ND2) but had no effect on the transcript levels of ND2. The luciferase reporter assay showed that miR-762 bound to the coding sequence of ND2. In addition, knockdown of endogenous ND2 significantly decreased intracellular ATP levels, increased ROS levels, reduced mitochondrial complex I enzyme activity and increased apoptotic cell death in cardiomyocytes, which was induced by A/R treatment. Furthermore, we found that the inhibitory effect of miR-762 downregulation was attenuated by ND2 knockdown. Thus, our findings suggest that miR-762 participates in the regulation of mitochondrial function and cardiomyocyte apoptosis by ND2, a core assembly subunit of mitochondrial complex I. Our results revealed that mitochondrial miR-762, as a new player in mitochondrial dysfunction, may provide a new therapeutic target for myocardial infarction.

Combining the use of amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide in the prognosis of hospitalized heart failure patients.

OBJECTIVE: To investigate whether the combination of measuring amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP) could provide additional prognostic value in hospitalized heart failure patients. METHODS: We measured both BNP and NT-proBNP simultaneously at baseline in 1464 hospitalized heart failure patients who were admitted to our heart failure center. All patients were followed-up with the median follow-up period of 533 days. The primary endpoint is a composite of all-cause death (non-transplantation patients) or heart transplantation. RESULTS: The median molar ratio of NT-proBNP/BNP was 2.37, but the range of the molar ratio varied from 1.57 to 3.75 (lower quartile to higher quartile). Using the cut-off value of 1790 pg/mL for NT-proBNP and 495 pg/mL for BNP from the ROC curve analysis, univariate Cox proportional regression analysis showed that the low/high group (NT-proBNP < 1790 pg/mL and BNP ≥ 495 pg/mL), high/low group (NT-proBNP ≥ 1790 pg/mL and BNP < 495 pg/mL) and high/high group (NT-proBNP ≥ 1790 pg/mL and BNP ≥ 495 pg/mL) had significant higher risk of all-cause death or heart transplantation [HR (hazard ratio): 2.87, 95% CI (confidence interval): 1.69-4.89, p < .001; HR: 2.68, 95% CI: 1.91-3.76, p < .001; HR:5.07, 95% CI: 3.85-6.67, p < .001] than low/low group (NT-proBNP < 1790 pg/mL and BNP < 495 pg/mL). In turn, the high/high group had higher risk of all-cause death or heart transplantation than low/high (HR: 1.70, 95% CI: 1.04-2.80, p = .035) and high/low groups (HR: 1.88, 95% CI: 1.42-2.49, p < .001). The low/high and high/low groups had a similar risk of all-cause death or heart transplantation. Further multivariable Cox regression analysis also showed that both BNP and NT-proBNP above the cut-off values independently predicted the worst prognosis, while either one of the two biomarkers above the cut-off value indicated the moderate poor prognosis and both below the cut-off values indicated the best prognosis (p for trend< 0.001). CONCLUSION: The plasma levels of NT-proBNP and BNP do not always increase proportionally in heart failure patients. The combination of testing NT-proBNP and BNP may add prognostic value to predict adverse events in hospitalized heart failure patients.

The circular RNA ACR attenuates myocardial ischemia/reperfusion injury by suppressing autophagy via modulation of the Pink1/ FAM65B pathway.

Dysregulated autophagy is associated with many pathological disorders such as cardiovascular diseases. Emerging evidence has suggested that circular RNAs (circRNAs) have important roles in some biological processes. However, it remains unclear whether circRNAs participate in the regulation of autophagy. Here we report that a circRNA, termed autophagy-related circular RNA (ACR), represses autophagy and myocardial infarction by targeting Pink1-mediated phosphorylation of FAM65B. ACR attenuates autophagy and cell death in cardiomyocytes. Moreover, ACR protects the heart from ischemia/reperfusion (I/R) injury and reduces myocardial infarct sizes. We identify Pink1 as an ACR target to mediate the function of ACR in cardiomyocyte autophagy. ACR activates Pink1 expression through directly binding to Dnmt3B and blocking Dnmt3B-mediated DNA methylation of Pink1 promoter. Pink1 suppresses autophagy and Pink1 transgenic mice show reduced myocardial infarction sizes. Further, we find that FAM65B is a downstream target of Pink1 and Pink1 phosphorylates FAM65B at serine 46. Phosphorylated FAM65B inhibits autophagy and cell death in the heart. Our findings reveal a novel role for the circRNA in regulating autophagy and ACR-Pink1-FAM65B axis as a regulator of autophagy in the heart will be potential therapeutic targets in treatment of cardiovascular diseases.

Can Torsemide and Combination of Loop Diuretics Improve Mortality in Patients with Chronic Heart Failure After Discharge?

The aim of this study was to investigate the effect on mortality of torsemide and a combination of loop diuretics (furosemide + torsemide) in contemporary practice in patients with chronic heart failure (HF).We investigated patients with HF in the Heart Failure Center of Fuwai Hospital from 2009 to 2013 who were discharged on furosemide, torsemide, or a combination of the 2 drugs. Using inverse probability weighting (IPW) to account for nonrandom selection of diuretic strategies, we assessed the association between different diuretic strategies and mortality.Among 956 patients, 19.7% (n = 188) received furosemide, 36.6% (n = 350) torsemide, and 43.7% (n = 418) the combination therapy. The torsemide-treated and combination-treated patients had worse heart function and higher furosemide equivalent. Univariable Cox proportional hazards models showed that the combination group had worse outcomes (all-cause HR = 2.044, P = 0.008; CV HR = 1.988, P = 0.011), while torsemide was associated with an outcome (all-cause HR = 1.640, P = 0.078; CV HR = 1.509, P = 0.147) similar to that of furosemide. After IPW, torsemide was associated with a nominally lower mortality compared with furosemide (all-cause HR = 0.738, P = 0.222; CV HR = 0.667, P = 0.110), and the association between the combination treatment and increased mortality was no longer statistically significant (all-cause HR = 1.207, P = 0.470;CV HR = 1.174, P = 0.540).We found that torsemide and the combination strategy had similar outcomes when compared with furosemide. However, considering the lack of diuretic randomized clinical trials (RCTs) conducted with the aim of exploring the effect on mortality of different diuretic treatments, prospective trials are needed to investigate the effect of different diuretic strategies in chronic HF.