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.

UNASSIGNED: To investigate the effects and mechanisms of LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNI), on epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells and on macrophage M2 polarization.
UNASSIGNED: We examined the effects of LCZ696 in a 4.25% high glucose peritoneal dialysis fluid (PDF)-induced peritoneal fibrosis (PF) mouse model, and explored the mechanisms of LCZ696 on human peritoneal mesothelial cells (HPMCs) stimulated by TGF-β1 (5 ng/mL) and on Raw264.7 cells stimulated by IL-4 (10 ng/mL). To further elucidate the mechanism, we treated HPMCs with the conditioned medium of Raw264.7 cells.
UNASSIGNED: LCZ696 effectively improved PF and inhibited the process of EMT in PDF mice. In vitro, LCZ696 also significantly alleviated the EMT of TGF-β1 induced HPMCs, although there was no statistically significant difference when compared to the Valsartan treatment group. Moreover, LCZ696 ameliorates the increased expression of Snail and Slug, two nuclear transcription factors that drive the EMT. Mechanistically, TGF-β1 increased the expression of TGFβRI, p-Smad3, p-PDGFRβ and p-EGFR, while treatment with LCZ696 abrogated the activation of TGF-β/Smad3, PDGFRβ and EGFR signaling pathways. Additionally, exposure of Raw264.7 to IL-4 results in increasing expression of Arginase-1, CD163 and p-STAT6. Treatment with LCZ696 inhibited IL-4-elicited M2 macrophage polarization by inactivating the STAT6 signaling pathway. Furthermore, we observed that LCZ696 inhibits EMT by blocking TGF-β1 secretion from M2 macrophages.
UNASSIGNED: Our study demonstrated that LCZ696 improves PF and ameliorates TGF-β1-induced EMT of HPMCs by blocking TGF-β/Smad3, PDGFRβ and EGFR pathways. Meanwhile, LCZ696 also inhibits M2 macrophage polarization by regulating STAT6 pathway.

UNASSIGNED: Randomized clinical trials have shown that sacubitril-valsartan reduces the risks of mortality and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF), but patients with kidney failure requiring dialysis were excluded.
UNASSIGNED: To investigate the comparative effectiveness of sacubitril-valsartan vs angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs or ARBs) in patients with HFrEF requiring hemodialysis.
UNASSIGNED: This retrospective, 1:1 propensity score-matched comparative effectiveness study included patients who were 18 years or older with HFrEF, enrolled in Medicare Parts A, B, and D, and survived at least 90 days receiving in-center hemodialysis from July 8, 2015, to December 31, 2020. Patients were excluded for less than 180 days of continuous Medicare Parts A, B, and D primary payer coverage or prior dispensing of sacubitril-valsartan. Data analysis was conducted from September 23, 2023, to June 25, 2024.
UNASSIGNED: New use of sacubitril-valsartan vs new or continued use of ACEIs or ARBs.
UNASSIGNED: The associations between initiation of sacubitril-valsartan therapy and all-cause mortality, cardiovascular mortality, all-cause hospitalization, and HF hospitalization were assessed using Cox proportional hazards regression models in a propensity score-matched sample.
UNASSIGNED: Participants included 1:1 matched pairs of 1434 sacubitril-valsartan users and 1434 ACEI or ARB users (mean [SD] age, 64 [13] years). Of the 2868 matched participants, 996 (65%) were male; 987 (34%) were Black or African American and 1677 (58%) were White; and median dialysis vintage was 3.8 (IQR, 1.8-6.3) years. The median follow-up was 0.9 (IQR, 0.4-1.7) years. Sacubitril-valsartan (vs ACEI or ARB) therapy was associated with a reduction in all-cause mortality (hazard ratio [HR], 0.82 [95% CI, 0.73-0.92]) and all-cause hospitalization (HR, 0.86 [95% CI, 0.79-0.93]) but not cardiovascular mortality (HR, 1.01 [95% CI, 0.86-1.19]) or HF hospitalization (HR, 0.91 [95% CI, 0.82-1.02]). There was a decrease in hyperkalemia (HR, 0.71 [95% CI, 0.62-0.81]) and no difference in hypotension (HR, 0.99 [95% CI, 0.83-1.19]). Only 195 participants (14%) ever received the maximum combination dose of sacubitril (97 mg twice daily) and valsartan (103 mg twice daily).
UNASSIGNED: In this comparative effectiveness study of patients with HFrEF requiring hemodialysis, sacubitril-valsartan therapy was associated with beneficial effects in all-cause mortality and all-cause hospitalization.

BACKGROUND: β-Aminobutyric acid (BABA) has been successfully used to prime stress resistance in numerous plant species; however, its effectiveness in forest trees has been poorly explored thus far. This study aimed to investigate the influence of BABA on morphological, physiological, and epigenetic parameters in field elms under various growth conditions. Epigenetic changes were assessed in both DNA and RNA through the use of reversed-phase ultra-performance liquid chromatography (UPLC) coupled with sensitive mass spectrometry.
RESULTS: The presented results confirm the influence of BABA on the development, physiology, and stress tolerance in field elms. However, the most important findings are related to the broad epigenetic changes promoted by this amino acid, which involve both DNA and RNA. Our findings confirm, for the first time, that BABA influences not only well-known epigenetic markers in plants, such as 5-methylcytosine, but also several other non-canonical nucleobases, such as 5-hydroxymethyluracil, 5-formylcytosine, 5-hydroxymethylcytosine, N6-methyladenine, uracil (in DNA) and thymine (in RNA). The significant effect on the levels of N6-methyladenine, the main bacterial epigenetic marker, is particularly noteworthy. In this case, the question arises as to whether this effect is due to epigenetic changes in the microbiome, the plant genome, or both.
CONCLUSIONS: The plant phenotype is the result of complex interactions between the plant\'s DNA, the microbiome, and the environment. We propose that different types of epigenetic changes in the plant and microbiome may play important roles in the largely unknown memory process that enables plants to adapt faster to changing environmental conditions.

Since 2014, sacubitril/valsartan (Entresto®) is widely prescribed for heart failure. Despite neprilysin inhibition\'s benefits in heart failure, concerns about potential amyloid-beta (Aβ) accumulation and Alzheimer\'s disease (AD) risk have persisted. This narrative review, a decade post-approval, evaluates the risk of amyloid pathology and neurocognitive disorders in long-term sacubitril/valsartan use. Clinical trials, real-world studies, and pharmacovigilance data do not indicate an increased risk of cognitive decline. In patients treated with sacubitril/valsartan blood-based amyloid biomarkers show perturbations, while neuroimaging biomarkers reveal no significant increase in amyloid load. Despite a theoretical risk of amyloid accumulation and AD under treatment with sacubitril/valsartan, current clinical data appears reassuring, and there is no signal indicating an increased risk of cognitive decline, but a perturbation of amyloid blood-based biomarkers, which implies great caution when interpreting biomarkers in this context.

Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) that has been shown in multiple clinical trials to have clinical benefits and is recommended by major clinical management guidelines as a first-line treatment for heart failure with reduced ejection fraction (HFrEF). The most significant benefit that was observed in clinical trials is its effect in reducing hospital readmissions. However, little evidence supports its effectiveness in practice, especially in Saudi Arabia. A multicenter retrospective cohort study was conducted using the patient medical records at 2 tertiary hospitals in Saudi Arabia. Eligible patients were adults (≥18 years old) with a confirmed diagnosis of HFrEF who were discharged on either sacubitril/valsartan or angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) in addition to the other recommended therapy for HFrEF. The primary endpoint was the all-cause 30-day readmission rate. The secondary endpoints included all-cause readmissions at 60-day, 90-day, and 12 months. Additionally, 30-day, 60-day, and 90-day readmissions due to HF were evaluated. A total of 398 patients were included in our analysis; 199 (50.0%) received sacubitril/valsartan (group 1), and 199 (50.0%) received ACEI/ARB (group 2). Our results showed that all-cause 30-day readmissions in group 1 were significantly lower than in group 2 (7% vs 25.0%, RR 0.28, 95% Cl 0.16-0.49; P < .001). Additionally, the secondary outcomes showed significantly fewer 60-day, 90-day, and 12-month all-cause readmissions were identified in group 1 compared to group 2 (11% vs 30.7%, RR 0.36, 95% CI 0.23-0.56; P < .001), (11.6%. vs 32.6%, RR 0.35, 95% CI 0.23-0.55; P < .001) and (23.6% vs 51.2%, RR 0.46, 95% CI 0.35-0.62; P < .001), respectively. Furthermore, HF readmissions at 30-day, 60-day, and 90-day in group 1 were significantly lower than in group 2 (P < .05). Sacubitril/valsartan for the treatment of HFrEF is associated with a significantly lower rate of all-cause readmission as well as HF readmissions compared to ACEI/ARB. These benefits extend up to 12 months post-discharge.

BACKGROUND Heart failure and end-stage renal disease often coexist, and management of heart failure can be challenging in patients during hemodialysis. Sacubitril-valsartan (SV) is the first drug to receive regulatory approval for use in patients with chronic heart failure with reduced ejection fraction (HFrEF) and New York Heart Association (NYHA) classification II, III, or IV. This study aimed to evaluate the efficacy and safety of SV for use in chronic heart failure patients on maintenance hemodialysis (MHD). MATERIAL AND METHODS From September 2021 to October 2022, 28 patients on MHD with chronic heart failure at the hemodialysis center of Shaanxi Second Provincial People\'s Hospital were regularly followed. During the 12-week follow-up period, all patients were administered SV at doses of 100-400 mg per day. Biochemical indicators, echocardiographic parameters, life quality scores, and adverse events were evaluated. RESULTS We enrolled 28 patients. Compared with the baseline levels, NYHA class III in these patients treated with SV was significantly decreased from 60.71% to 32.14% (P<0.05), left ventricular ejection fraction (LVEF) was significantly improved from 44.29±8.92% to 53.32±7.88% (P<0.001), the Physical Component Summary (PCS) score was significantly improved from 40.0±6.41 to 56.20±9.86 (P<0.001), and the Mental Component Summary (MCS) score was significantly improved from 39.99±6.14 to 52.59±11.0 (P<0.001). CONCLUSIONS We demonstrated that SV improved NYHA classification and LVEF values of patients on MHD with chronic heart failure and also improved their quality of life.

BACKGROUND: Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined.
RESULTS: We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity-Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (β-2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein-outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity cardiac troponin.
CONCLUSIONS: Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON-HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum.
BACKGROUND: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

An angiotensin receptor/neprilysin inhibitor (ARNI), a heart failure treatment, is a combination drug made up of sacubitril, a neprilysin inhibitor, and valsartan, a vascular receptor blocker. No human or veterinary studies regarding the effect of ARNI on renal haemodynamics in the absence of cardiac or renal issues exist. Therefore, we investigated the effect of ARNI on renal haemodynamics in five healthy dogs. ARNI was administered to all five dogs at an oral dose of 20 mg/kg twice daily for 4 weeks. Renal haemodynamics were assessed on the day before ARNI administration (BL), on Day 7, and on Day 28. The glomerular filtration rate (GFR) significantly increased on Day 28 compared to BL and Day 7, whereas renal plasma flow increased on Day 7 and Day 28 compared to BL. Systolic blood pressure significantly decreased between BL and Day 28. Plasma atrial natriuretic peptide (ANP) concentrations increased on Day 7 compared to BL. Additionally, ANP concentrations increased on Day 28 in three of the five dogs. Different ANP concentrations were observed in the remaining two dogs. Both urine output volume and heart rate remained relatively stable and did not exhibit significant change. In conclusion, ARNI may enhance renal haemodynamics in healthy dogs. ARNI could be a valuable drug for treating both heart and kidney disease in dogs.

Glufosinate-ammonium (GLA), an organophosphate herbicide, is released at high concentrations in the environment, leading to concerns over its potential genotoxic effects. However, few articles are available in the literature reporting the possible cellular and nuclear effects of this compound. We assessed, by in vitro and in vivo micronucleus assays, the genotoxicity of GLA on cultured human lymphocytes and Lymnaea stagnalis hemocytes at six concentrations: 0.010 (the established acceptable daily intake value), 0.020, 0.050, 0.100, 0.200, and 0.500 µg/mL. In human lymphocytes, our results reveal a significant and concentration-dependent increase in micronuclei frequency at concentrations from 0.100 to 0.500 μg/mL, while in L. stagnalis hemocytes, significant differences were found at 0.200 and 0.500 μg/mL. A significant reduction in the proliferation index was observed at all tested concentrations, with the only exception of 0.010 μg/mL, indicating that the exposure to GLA could lead to increased cytotoxic effects. In L. stagnalis, a significant reduction in laid eggs and body growth was also observed at all concentrations. In conclusion, we provided evidence of the genomic and cellular damage induced by GLA on both cultured human lymphocytes and a model organism\'s hemocytes; in addition, we also demonstrated its effects on cell proliferation and reproductive health in L. stagnalis.