Comparative effects of sacubitril/valsartan and ACEI/ARB on endothelial function and arterial stiffness in patients with heart failure: a protocol for systematic review and meta-analysis.

INTRODUCTION: Heart failure (HF) is a complex syndrome that affects millions of people worldwide and leads to significant morbidity and mortality. Sacubitril/valsartan, a combination drug consisting of a neprilysin inhibitor and an angiotensin receptor blocker (ARB), has shown a greater improvement in the prognosis of HF than ACE inhibitors (ACEI) or ARB. Recent studies have found that ACEI/ARB or sacubitril/valsartan can increase flow-mediated dilation (FMD) and reduce pulse wave velocity (PWV), which are independent predictors of cardiovascular events and HF prognosis. The purpose of this study is to assess and compare the effect of sacubitril/valsartan and ACEI/ARB on FMD and PWV using meta-analysis and further provide a reference for the role of sacubitril/valsartan in the treatment of HF. METHODS AND ANALYSIS: Clinical randomised controlled trials investigating the effect of sacubitril/valsartan and/or ACEI/ARB on FMD and PWV in patients with HF will be searched in the relevant database, including PubMed, Web of Science, Embase, Cochrane Library and China's National Knowledge Infrastructure up to January 2024. The outcomes of interest are changes in endothelial function assessed by FMD and changes in arterial stiffness assessed by PWV. The risk of bias was evaluated using the revised Cochrane risk of bias tool for randomised trials (RoB2.0). Review Manager V.5.3 software is used for meta-analysis data synthesis, sensitivity analysis, meta-regression analysis, subgroup analysis and risk of bias assessment. The reporting bias of studies will be evaluated using the funnel plot, in which symmetry will be assessed by Begg's and Egger's tests. The evidence quality of the included studies will be evaluated by the Grading of Recommendations Assessment, Development, and Evaluation. ETHICS AND DISSEMINATION: This study only analyses research data from the published literature and therefore does not require ethical approval. We will submit the systematic review to a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42024538148.

Clinical Efficacy and Safety Analysis of Recombinant Human Brain Natriuretic Peptide Combined with Sacubitril/Valsartan in the Sequential Treatment of Senile Patients with Acute Heart Failure.

This study aims to evaluate the comparative efficacy and safety of the combination of recombinant human brain natriuretic peptide (rhBNP) and sacubitril/valsartan in the sequential treatment of senile patients with acute heart failure (AHF).The study objects were a total of 136 senile patients over 60 years old with AHF admitted to the Department of Cardiology of Anji County People's Hospital of Huzhou from August 2022 to August 2023. Using the envelope method, the patients were divided into three groups: the standard treatment group (45 patients who underwent hydragogue, digoxin, valsartan, and beta-blockers), the rhBNP group (46 patients were performed with basic treatment for AHF combined with rhBNP), and the sequential treatment group (45 patients received the basic treatment for AHF combined with rhBNP followed by sacubitril/valsartan). The clinical effects, cardiac function, safety, and prognosis among the three groups were compared.In the sequential treatment group, the duration of clinical symptom remission, the duration of hospitalization, and the improvement rate of New York Heart Association classification at discharge were (2.27 ± 0.76) days, (6.99 ± 1.96) days, and 93.3%, which were better than those in the rhBNP group ([2.58 ± 0.94] days, [7.43 ± 2.78] days, and 78.3%) and the standard treatment group ([2.89 ± 0.71] days, [8.82 ± 2.89] days, and 71.1%); the P value among all groups was lower than 0.05. In terms of cardiac function and myocardial injury, the sequential treatment group was superior to the standard treatment group and rhBNP group. The incidence of adverse reactions in the standard treatment group, the rhBNP group, and the sequential treatment group was 37.8%, 34.8%, and 26.7%, respectively, P = 0.510. In the sequential treatment group, the rate of heart failure readmitted within 6 months after discharge was 28.9% and no death occurred, which was lower than those in the rhBNP (34.8%) and the standard treatment group (35.6%).Sequential treatment with rhBNP and sacubitril/valsartan could significantly improve the clinical symptoms of elderly patients with AHF, enhance cardiac function, and reduce myocardial damage, which could also improve the prognosis.

Glufosinate-ammonium increased nitrogen and phosphorus content in water and shaped microbial community in epiphytic biofilm of Hydrilla verticillata.

Glufosinate-ammonium (GLAM) can be released into adjacent water bodies with rainfall runoff and return water from farmland irrigation. However, impacts of GLAM on aquatic organisms remain unclear. In this study, changes in water quality, plant physiological parameters and epiphytic microbial community were investigated in wetlands with Hydrilla verticillata exposed to GLAM for 24 days. We found GLAM addition damaged cell and reduced chlorophyll a content in Hydrilla verticillata leaves, and increased ammonium and phosphorus in water (p < 0.001). The α-diversity increased in bacterial community but decreased in eukaryotic community with GLAM exposure. Neutral community models explained 62.3 % and 55.0 % of the variance in bacterial and eukaryotic communities, respectively. Many GLAM micro-biomarkers were obtained, including some clades from Proteobacteria, Bacteroidete, Actinobacteriota, Phragmoplastophyta, Annelida and Arthropoda. Redundancy analysis revealed that GLAM concentration was positively correlated to Flavobacterium, Gomphonema and Closterium but negatively to Methyloglobulus and Methylocystis. Network analysis revealed that 15 mg/L GLAM disturbed the interactions among phytoplankton, protozoa, metazoan and bacteria and reduced the stability of the microbial communities compared to 8 mg/L GLAM. GLAM shaped the nitrogen and phosphorus cycle related bacterial genes. This study highlights that herbicides are non-neglectable factors affecting the efficiency of aquatic ecological restoration in agricultural areas to control agricultural non-point source pollution.

Subgroup disproportionality analysis of dementia-related adverse events with sacubitril/valsartan across geographical regions.

This study aimed to evaluate the association between sacubitril/valsartan and dementia-related adverse events (AEs) in geographical subpopulations using subgroup disproportionality analysis. Cases from the FDA adverse event reporting system involving patients aged 60 or older with sacubitril/valsartan or angiotensin receptor blockers (ARBs) were analyzed. The adjusted reporting odds ratios (RORs) for dementia-related AEs were calculated for each continent. A total of 61,518 AEs associated with sacubitril/valsartan or ARBs were identified. Among these, 1441 were dementia-related AEs. In Asia, Europe, and Africa, the reporting risk of dementia-related AEs associated with sacubitril/valsartan was lower compared to ARBs (adjusted ROR, 0.57 [95% CI 0.31-1.01]; adjusted ROR, 0.89 [95% CI 0.69-1.14]; adjusted ROR, 0.40 [95% CI 0.27-0.61], respectively). In Latin America and Oceania, the reporting risk of dementia-related AEs associated with sacubitril/valsartan was similar to that associated with ARBs (adjusted ROR, 1.04 [95% CI 0.75-1.44]; adjusted ROR, 1.02 [95% CI 0.31-3.37], respectively). On the contrary, in North America, the reporting risk associated with sacubitril/valsartan was higher compared to ARBs (adjusted ROR, 1.29 [95% CI 1.10-1.53]). Although the ROR value did not meet the criteria for signal detection, the significantly greater than 1 ROR observed in North America suggests that caution may be warranted regarding potential dementia-related adverse events associated with sacubitril/valsartan.

Kidney Outcomes Following Angiotensin Receptor-Neprilysin Inhibitor vs Angiotensin-Converting Enzyme Inhibitor/Angiotensin Receptor Blocker Therapy for Thrombotic Microangiopathy.

Importance: Thrombotic microangiopathy (TMA) on kidney biopsy is a pattern of endothelial injury commonly seen in malignant hypertension (mHTN), but treatment strategies are not well established. Objective: To evaluate the kidney outcomes of angiotensin receptor-neprilysin inhibitor (ARNI), specifically sacubitril/valsartan, vs angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy for patients with mHTN-associated TMA. Design, Setting, and Participants: This single-center cohort study enrolled consecutive patients in China diagnosed with mHTN-associated TMA through kidney biopsy from January 2008 to June 2023. Follow-up was conducted until the conclusion of the study period. Data were analyzed in September 2023. Exposures: Treatment with sacubitril/valsartan or ACEI/ARBs during hospitalization and after discharge. Main Outcomes and Measures: The primary outcome was a composite of kidney recovery: a 50% decrease in serum creatinine level, decrease in serum creatinine levels to the reference range, or kidney survival free from dialysis for more than 1 month. The secondary and tertiary outcomes were a 15% increase in the estimated glomerular filtration rate (eGFR) relative to baseline and kidney survival free from dialysis, respectively. Propensity score matching (PSM) and Cox proportional hazards regression analysis were used to evaluate the association between sacubitril/valsartan and ACEI/ARB therapy with kidney recovery outcomes. Results: Among the 217 patients (mean [SD] age, 35.9 [8.8] years; 188 men [86.6%]) included in the study, 66 (30.4%) received sacubitril/valsartan and 151 (69.6%) received ACEI/ARBs at baseline. Sacubitril/valsartan treatment was associated with shorter time to the primary outcome compared with ACEI/ARB treatment (20 of 63 [31.7%] vs 38 of 117 [32.5%]; adjusted hazard ratio [aHR], 1.85; 95% CI, 1.05-3.23). Sacubitril/valsartan treatment was independently associated with shorter time to a 15% increase in eGFR (15 of 46 [32.6%] vs 46 of 83 [55.4%]; aHR, 2.13; 95% CI, 1.09-4.17) and kidney survival free from dialysis (11 of 23 [47.8%] vs 16 of 57 [28.1%]; aHR, 2.63; 95% CI, 1.15-5.88) compared with ACEI/ARB treatment. These differences remained significant in the PSM comparison. Conclusions and Relevance: In this cohort study, sacubitril/valsartan treatment was associated with a potential kidney function benefit in patients with mHTN-associated TMA compared with ACEI/ARB treatment. The findings suggested that sacubitril/valsartan could be a superior therapeutic approach for managing this serious condition in terms of kidney recovery.

Metabolic resistance mechanism to glufosinate in Eleusine indica.

Eleusine indica is one of the most troublesome weeds in farmland worldwide, especially in Citrus Orchard of China. Glufosinate, as an efficient non-selective broad-spectrum herbicide, has been widely utilized for the control of E. indica in Citrus Orchard. The E. indica resistant population (R) was collected from a Citrus Orchard in Yichang City in Hubei province, China. Bioassay experiments showed that the R plants exhibited 3-fold resistance to glufosinate compared with the E. indica susceptible population (S). No known glutamine synthetase (GS) gene mutation associated with glufosinate resistance was found in R plants. And there was also no significant difference in GS activity between R and S plants. Those results indicated that the resistance to glufosinate in R did not involve target-site resistance. However, glutathione S-transferase (GST) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) plus glufosinate gave a better control of R plants compared with glufosinate treatment alone. Moreover, both before and after glufosinate treatment, the GST activity in R plants was significantly higher than that in S plants. By RNA-seq, the expression of GSTU6 and GST4 up-regulated in R plants relative to S plants with or without glufosinate treatment. They were also significantly up-regulated expression in E. indica field resistant populations compared with S population. In summary, the study elucidated that R plants developed metabolic resistance to glufosinate involving GST. And GSTU6 and GST4 genes may play an important role in this glufosinate metabolic resistance. The research results provide a theoretical basis for a deeper understanding of resistance mechanism to glufosinate in E. indica.

Master Regulatory Transcription Factors in ß-Aminobutyric Acid-Induced Resistance (BABA-IR): A Perspective on Phytohormone Biosynthesis and Signaling in Arabidopsis thaliana and Hordeum vulgare.

The endogenous stress metabolite ß-aminobutyric acid (BABA) primes plants for enhanced resistance against abiotic and biotic stress by activating a complex phytohormone signaling network that includes abscisic acid (ABA), jasmonic acid (JA), salicylic acid (SA), and ethylene (ET). In this study, through stringent filtering, we identify 14 master regulatory transcription factors (TFs) from the DOF, AHL, and ERF families that potentially regulate the biosynthesis and signaling of these phytohormones. Transcriptional analysis of BABA-treated Arabidopsis thaliana and Hordeum vulgare suggests that DOF family TFs play a crucial role in stress response regulation in both species. BABA treatment in A. thaliana upregulates the TFs MNB1A and PBF and enhances the expression of the genes ICS1, EDS5, and WIN3 in the SA biosynthesis pathway, potentially boosting NPR1 and PR1 in the SA signaling pathway. Conversely, in H. vulgare, the BABA-induced upregulation of TF DOF5.8 may negatively regulate SA biosynthesis by downregulating ICS1, EDS5, and PR1. Additionally, in A. thaliana, BABA triggers the expression of TF PBF, which may result in the decreased expression of MYC2, a key gene in JA signaling. In contrast, H. vulgare exhibits increased expression of ERF2 TF, which could positively regulate the JA biosynthesis genes LOX and Tify9, along with the COI1 and JAZ genes involved in the JA signaling pathway. These findings offer new perspectives on the transcriptional regulation of phytohormones during plant priming.

Add-on multidrug treatment based on quadruple therapy successfully treated worsening heart failure caused by anthracycline-induced cardiomyopathy in a survivor of cancer as a young adult: a case report.

BACKGROUND: The overall mortality and morbidity benefit in patients with heart failure with a reduced ejection fraction is greatest with a treatment combination of sacubitril/valsartan, beta-blockers, mineralocorticoid-receptor antagonists, and sodium-glucose transporter-2 inhibitors, termed the "fantastic four" or "quadruple therapy." The addition of vericiguat (an oral soluble guanylate cyclase stimulator) is believed to aid in managing worsening heart failure after quadruple therapy. Among childhood and young adult cancer survivors, cardiovascular complications that develop more than 10 years after anthracycline-based chemotherapy have a poor prognosis. Therefore, this study reports the efficacy of multidrug regimen based on quadruple therapy for worsening heart failure in cancer survivors with anthracycline-induced cardiomyopathy. CASE PRESENTATION: A survivor of cancer as a young adult who received high-dose anthracycline chemotherapy presented with acute decompensated heart failure 20 years post-chemotherapy and worsening heart failure 1.5 years after discharge. The patient showed signs of improvement after a step-wise introduction of carvedilol, empagliflozin, sacubitril/valsartan, ivabradine, and spironolactone for worsening heart failure. Vericiguat was accelerated owing to the risk of more severe cardiovascular events associated with ongoing aortic stenosis and the poor prognosis of anthracycline-induced cardiomyopathy. Heart failure symptoms continued to improve, with significant cardiac reverse remodeling, and the patient successfully underwent aortic valve replacement for severe aortic stenosis. CONCLUSIONS: Our case highlighted that multidrug treatment with add-on vericiguat and ivabradine based on quadruple therapy can potentially treat worsening heart failure in young adult cancer survivors with severe anthracycline-induced cardiomyopathy.

Risk of dyslipidaemia in people living with HIV who are taking tenofovir alafenamide: a systematic review and meta-analysis.

INTRODUCTION: Among many antiretroviral drugs, tenofovir alafenamide is used extensively in combination regimens of tenofovir/emtricitabine or tenofovir/emtricitabine/bictegravir. However, concerns have arisen about the potential of tenofovir alafenamide to exacerbate hyperlipidaemia. This meta-analysis evaluates the relationship between tenofovir alafenamide use and lipid-profile alterations in people living with HIV. METHODS: We searched PubMed, Ovid MEDLINE, EMBASE and the Cochrane Library to identify studies on changes in cholesterol levels (e.g. total cholesterol, low-density and high-density lipoprotein cholesterol, and triglycerides) in people living with HIV who received treatment with a regimen containing tenofovir alafenamide (data collected 31 March 2023, review completed 30 July 2023). Potential risk factors for worsening lipid profile during treatment with tenofovir alafenamide were also evaluated. RESULTS: Sixty-five studies involving 39,713 people living with HIV were selected. Significant increases in total cholesterol, low-density and high-density lipoprotein cholesterol, and triglycerides were observed after treatment with tenofovir alafenamide. Specifically, low-density lipoprotein cholesterol (+12.31 mg/dl) and total cholesterol (+18.86 mg/dl) increased markedly from the third month of tenofovir alafenamide use, with significant elevations observed across all time points up to 36 months. Comparatively, tenofovir alafenamide regimens resulted in higher lipid levels than tenofovir disoproxil fumarate regimens at 12 months of use. Notably, discontinuation of the tenofovir alafenamide regimen led to significant decreases in low-density lipoprotein cholesterol (-9.31 mg/dl) and total cholesterol (-8.91 mg/dl). Additionally, tenofovir alafenamide use was associated with increased bodyweight (+1.38 kg; 95% confidence interval: 0.92-1.84), which became more pronounced over time. Meta-regression analysis identified young age, male sex and low body mass index as risk factors for worsening cholesterol levels in individuals treated with tenofovir alafenamide. CONCLUSIONS: Tenofovir alafenamide use in people living with HIV is associated with significant alterations in lipid profile.