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European Heart Journal Aug 2023The PARAGLIDE-HF trial demonstrated reductions in natriuretic peptides with sacubitril/valsartan compared with valsartan in patients with heart failure (HF) with mildly... (Randomized Controlled Trial)
Randomized Controlled Trial
Sacubitril/valsartan in heart failure with mildly reduced or preserved ejection fraction: a pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF.
AIMS
The PARAGLIDE-HF trial demonstrated reductions in natriuretic peptides with sacubitril/valsartan compared with valsartan in patients with heart failure (HF) with mildly reduced or preserved ejection fraction who had a recent worsening HF event, but was not adequately powered to examine clinical outcomes. PARAGON-HF included a subset of PARAGLIDE-HF-like patients who were recently hospitalized for HF. Participant-level data from PARAGLIDE-HF and PARAGON-HF were pooled to better estimate the efficacy and safety of sacubitril/valsartan in reducing cardiovascular and renal events in HF with mildly reduced or preserved ejection fraction.
METHODS AND RESULTS
Both PARAGLIDE-HF and PARAGON-HF were multicentre, double-blind, randomized, active-controlled trials of sacubitril/valsartan vs. valsartan in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF >40% in PARAGLIDE-HF and ≥45% in PARAGON-HF). In the pre-specified primary analysis, we pooled participants in PARAGLIDE-HF (all of whom were enrolled during or within 30 days of a worsening HF event) with a 'PARAGLIDE-like' subset of PARAGON-HF (those hospitalized for HF within 30 days). We also pooled the entire PARAGLIDE-HF and PARAGON-HF populations for a broader context. The primary endpoint for this analysis was the composite of total worsening HF events (including first and recurrent HF hospitalizations and urgent visits) and cardiovascular death. The secondary endpoint was the pre-specified renal composite endpoint for both studies (≥50% decline in estimated glomerular filtration rate from baseline, end-stage renal disease, or renal death). Compared with valsartan, sacubitril/valsartan significantly reduced total worsening HF events and cardiovascular death in both the primary pooled analysis of participants with recent worsening HF [n = 1088; rate ratio (RR) 0.78; 95% confidence interval (CI) 0.61-0.99; P = 0.042] and in the pooled analysis of all participants (n = 5262; RR 0.86; 95% CI: 0.75-0.98; P = 0.027). In the pooled analysis of all participants, first nominal statistical significance was reached by Day 9 after randomization, and treatment benefits were larger in those with LVEF ≤60% (RR 0.78; 95% CI 0.66-0.91) compared with those with LVEF >60% (RR 1.09; 95% CI 0.86-1.40; Pinteraction = 0.021). Sacubitril/valsartan was also associated with lower rates of the renal composite endpoint in the primary pooled analysis [hazard ratio (HR) 0.67; 95% CI 0.43-1.05; P = 0.080] and the pooled analysis of all participants (HR 0.60; 95% CI 0.44-0.83; P = 0.002).
CONCLUSION
In pooled analyses of PARAGLIDE-HF and PARAGON-HF, sacubitril/valsartan reduced cardiovascular and renal events among patients with HF with mildly reduced or preserved ejection fraction. These data provide support for use of sacubitril/valsartan in patients with HF with mildly reduced or preserved ejection fraction, particularly among those with an LVEF below normal, regardless of care setting.
Topics: Humans; Stroke Volume; Tetrazoles; Ventricular Function, Left; Angiotensin Receptor Antagonists; Valsartan; Heart Failure; Aminobutyrates; Drug Combinations
PubMed: 37210743
DOI: 10.1093/eurheartj/ehad344 -
Journal of Education & Teaching in... Oct 2023This scenario was developed to educate emergency medicine residents on the diagnosis and management of ventricular tachycardia (VT) that is refractory to single dose...
AUDIENCE
This scenario was developed to educate emergency medicine residents on the diagnosis and management of ventricular tachycardia (VT) that is refractory to single dose anti-arrhythmic management.
BACKGROUND
Electrical storm, defined as three or more episodes of sustained VT, ventricular fibrillation, or appropriate shocks from an implantable cardioverter defibrillator within 24 hours,1 has a mortality rate up to 14% in the first 48 hours.2 Ventricular tachycardia may present in a heterogenous fashion, not only with stable versus unstable clinical presentations, but also with different electrocardiographic morphologies and etiologies.1 Understanding how to rapidly diagnose, treat, and utilize second or third-line treatments is vital in the setting of refractory ventricular tachycardia rather than relying on the success of first-line agents. Appreciation for what medications are readily available in your crash cart and medication dispensing cabinet is critical for timely management for refractory ventricular tachycardia.
EDUCATIONAL OBJECTIVES
At the conclusion of the simulation session, learners will be able to: 1) identify the different etiologies of VT, including structural heart disease, acute ischemia, and acquired or congenital QT syndrome; 2) describe confounding factors of VT, such as electrolyte abnormalities and sympathetic surge; 3) describe how to troubleshoot an unsuccessful synchronized cardioversion, including checking equipment connections, increasing delivered energy, and changing pad placement; 4) compare and contrast treatments of VT based on suspected underlying etiology; 5) describe reasons to activate the cardiac catheterization lab other than occlusive myocardial infarction; and 6) identify appropriate disposition of the patient to the cardiac catheterization lab.
EDUCATIONAL METHODS
This session was conducted using high-fidelity simulation, followed by a debriefing session and lecture on the diagnosis, differential diagnosis, and management of VT. Debriefing methods may be left to the discretion of participants, but the authors have utilized advocacy-inquiry techniques. This scenario may also be run as an oral board case.
RESEARCH METHODS
Our residents are provided a survey at the completion of the debriefing session so they may rate different aspects of the simulation, as well as provide qualitative feedback on the scenario.
RESULTS
The local institution's simulation center's electronic feedback form is based on the Center of Medical Simulation's Debriefing Assessment for Simulation in Healthcare (DASH) Student Version Short Form with the inclusion of required qualitative feedback if an element was scored less than a 6 or 7. Twelve learners completed a feedback form. This session received 6 and 7 scores (consistently effective/very good and extremely effective/outstanding, respectively) other than three isolated 5 scores. The lowest average score was 6.67 for "Before the simulation, the instructor set the stage for an engaging learning experience." The highest average score was 7 for "The instructor helped me see how to improve or how to sustain good performance." The form also includes an area for general feedback about the case at the end. Illustrative examples of feedback include: "Excellent care and debrief." Specific scores are available upon request.
DISCUSSION
This is a cost-effective method for reviewing VT diagnosis and management. The case may be modified for appropriate audiences, such as describing what medications may be readily available in a free-standing emergency department or pre-hospital setting.
TOPICS
Medical simulation, ventricular tachycardia, cardiac emergencies, dysrhythmias, cardiology, emergency medicine.
PubMed: 37969159
DOI: 10.21980/J8KD2R -
Journal of Nanobiotechnology Nov 2023Osteoarthritis (OA) is an age-related disease characterised by the accumulation of senescent chondrocytes, which drives its pathogenesis and progression. Senescent cells...
BACKGROUND
Osteoarthritis (OA) is an age-related disease characterised by the accumulation of senescent chondrocytes, which drives its pathogenesis and progression. Senescent cells exhibit distinct features, including mitochondrial dysfunction and the excessive accumulation and release of reactive oxygen species (ROS), which are highly correlated and lead to a vicious cycle of increasing senescent cells. Stem cell therapy has proven effective in addressing cellular senescence, however, it still has issues such as immune rejection and ethical concerns. Microvesicles (MVs) constitute the primary mechanism through which stem cell therapy exerts its effects, offering a cell-free approach that circumvents these risks and has excellent anti-ageing potential. Nonetheless, MVs have a short in vivo half-life, and their secretion composition varies considerably under diverse conditions. This study aims to address these issues by constructing a ROS-responsive hydrogel loaded with pre-stimulant MVs. Through responding to ROS levels this hydrogel intelligently releases MVs, and enhancing mitochondrial function in chondrocytes to improving cellular senescence.
RESULT
We employed Interferon-gamma (IFN-γ) as a stem cell-specific stimulus to generate IFN-γ-microvesicles (iMVs) with enhanced anti-ageing effects. Simultaneously, we developed a ROS-responsive carrier utilising 3-aminophenylboronic acid (APBA)-modified silk fibroin (SF) and polyvinyl alcohol (PVA). This carrier served to protect MVs, prolong longevity, and facilitate intelligent release. In vitro experiments demonstrated that the Hydrogel@iMVs effectively mitigated cell senescence, improved mitochondrial function, and enhanced cellular antioxidant capacity. In vivo experiments further substantiated the anti-ageing capabilities of the Hydrogel@iMVs.
CONCLUSION
The effect of MVs can be significantly enhanced by appropriate pre-stimulation and constructing a suitable carrier. Therefore, we have developed a ROS-responsive hydrogel containing IFN-γ pre-stimulated iMVs to target the characteristics of ageing chondrocytes in OA for therapeutic purposes. Overall, this novel approach effectively improving mitochondrial dysfunction by regulating the balance between mitochondrial fission and fusion, and the accumulation of reactive oxygen species was reduced, finally, alleviates cellular senescence, offering a promising therapeutic strategy for OA.
Topics: Humans; Reactive Oxygen Species; Hydrogels; Cellular Senescence; Osteoarthritis; Mitochondria
PubMed: 37968657
DOI: 10.1186/s12951-023-02211-8 -
Frontiers in Pharmacology 2023The human immunodeficiency virus (HIV) persists in latently infected CD4T cells and integrates with the host genome until cell death. Acquired immunodeficiency syndrome... (Review)
Review
The human immunodeficiency virus (HIV) persists in latently infected CD4T cells and integrates with the host genome until cell death. Acquired immunodeficiency syndrome (AIDS) is associated with HIV-1. Possibly, treating HIV/AIDS is an essential but challenging clinical goal. This review provides a detailed account of the types and mechanisms of monotherapy and combination therapy against HIV-1 and describes nanoparticle and hydrogel delivery systems. In particular, the recently developed capsid inhibitor (Lenacapavir) and the Ainuovirine/tenofovir disoproxil fumarate/lamivudine combination (ACC008) are described. It is interestingly to note that the lack of the multipass transmembrane proteins serine incorporator 3 (SERINC3) and the multipass transmembrane proteins serine incorporator 5 (SERINC5) may be one of the reasons for the enhanced infectivity of HIV-1. This discovery of SERINC3 and SERINC5 provides new ideas for HIV-1 medication development. Therefore, we believe that in treating AIDS, antiviral medications should be rationally selected for pre-exposure and post-exposure prophylaxis to avoid the emergence of drug resistance. Attention should be paid to the research and development of new drugs to predict HIV mutations as accurately as possible and to develop immune antibodies to provide multiple guarantees for the cure of AIDS.
PubMed: 37954841
DOI: 10.3389/fphar.2023.1294966 -
Nature Communications Apr 2024Between 30% and 70% of patients with breast cancer have pre-existing chronic conditions, and more than half are on long-term non-cancer medication at the time of...
Between 30% and 70% of patients with breast cancer have pre-existing chronic conditions, and more than half are on long-term non-cancer medication at the time of diagnosis. Preliminary epidemiological evidence suggests that some non-cancer medications may affect breast cancer risk, recurrence, and survival. In this nationwide cohort study, we assessed the association between medication use at breast cancer diagnosis and survival. We included 235,368 French women with newly diagnosed non-metastatic breast cancer. In analyzes of 288 medications, we identified eight medications positively associated with either overall survival or disease-free survival: rabeprazole, alverine, atenolol, simvastatin, rosuvastatin, estriol (vaginal or transmucosal), nomegestrol, and hypromellose; and eight medications negatively associated with overall survival or disease-free survival: ferrous fumarate, prednisolone, carbimazole, pristinamycin, oxazepam, alprazolam, hydroxyzine, and mianserin. Full results are available online from an interactive platform ( https://adrenaline.curie.fr ). This resource provides hypotheses for drugs that may naturally influence breast cancer evolution.
Topics: Humans; Female; Breast Neoplasms; Cohort Studies; Comorbidity; Simvastatin
PubMed: 38580683
DOI: 10.1038/s41467-024-47002-3