The DARWIN observatory is a proposed next-generation experiment to search for particle dark matter and for the neutrinoless double beta decay of \(^{136}\)Xe. Out of its 50\(\,\)t total natural xenon ...inventory, 40\(\,\)t will be the active target of a time projection chamber which thus contains about 3.6 t of \(^{136}\)Xe. Here, we show that its projected half-life sensitivity is \(2.4\times10^{27}\,\)yr, using a fiducial volume of 5t of natural xenon and 10\(\,\)yr of operation with a background rate of less than 0.2\(~\)events/(t\(\cdot\)yr) in the energy region of interest. This sensitivity is based on a detailed Monte Carlo simulation study of the background and event topologies in the large, homogeneous target. DARWIN will be comparable in its science reach to dedicated double beta decay experiments using xenon enriched in \(^{136}\)Xe.
In listed companies, the Board of directors has ultimate responsibility for information disclosure. The conventional wisdom is that director independence is an essential factor in improving the ...quality of that disclosure. In a sense, this approach subordinates expertise to independence. We argue that effective certification may require firm-specific expertise, in particular for intangible-intensive business models. However, this latter form of expertise is negatively related to independence as it is commonly measured and evaluated. Accordingly, there exists an optimal share of independent directors for each company, related to the level of intangible resources.
Aims Thrombectomy in patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) is associated to better myocardial reperfusion. However, no single ...trial was adequately powered to asses the impact of thrombectomy on long-term clinical outcome and to identify patients at higher benefit. Thus, we sought to assess these issues in a collaborative individual patient-data pooled analysis of randomized studies (study acronym: ATTEMPT, number of registration: NCT00766740). Methods and results Individual data of 2686 patients enrolled in 11 trials entered the pooled analysis. Primary endpoint of the study was all-cause mortality. Major adverse cardiac events (MACE) were considered as the occurrence of all-cause death and/or target lesion/vessel revascularization and/or myocardial infarction (MI). Subgroups analysis was planned according to type of thrombectomy device (manual or non-manual), diabetic status, IIb/IIIa-inhibitor therapy, ischaemic time, infarct-related artery, pre-PCI TIMI flow. Clinical follow-up was available in 2674 (99.6%) patients at a median of 365 days. Kaplan–Meier analysis showed that allocation to thrombectomy was associated with significantly lower all-cause mortality (P = 0.049). Thrombectomy was also associated with significantly reduced MACE (P = 0.011) and death + MI rate during the follow-up (P = 0.015). Subgroups analysis showed that thrombectomy is associated to improved survival in patients treated with IIb/IIIa-inhibitors (P = 0.045) and that the survival benefit is confined to patients treated in manual thrombectomy trials (P = 0.011). Conclusion The present large pooled analysis of randomized trials suggests that thrombectomy (in particular manual thrombectomy) significantly improves the clinical outcome in patients with STEMI undergoing mechanical reperfusion and that its effect may be additional to that of IIb/IIIa-inhibitors.
We sought to compare, through a meta-analytic process, the transradial and transfemoral approaches for coronary procedures in terms of clinical and procedural outcomes.
The radial approach has been ...increasingly used as an alternative to femoral access. Several trials have compared these two approaches, with inconclusive results.
The MEDLINE, CENTRAL, and conference proceedings from major cardiologic associations were searched. Random-effect odds ratios (ORs) for failure of the procedure (crossover to different entry site or impossibility to perform the planned procedure), entry site complications (major hematoma, vascular surgery, or arteriovenous fistula), and major adverse cardiovascular events (MACE), defined as death, myocardial infarction, emergency revascularization, or stroke, were computed.
Twelve randomized trials (n = 3,224) were included in the analysis. The risk of MACE was similar for the radial versus femoral approach (OR 0.92, 95% confidence interval CI 0.57 to 1.48; p = 0.7). Instead, radial access was associated with a significantly lower rate of entry site complications (OR 0.20, 95% CI 0.09 to 0.42; p < 0.0001), even if at the price of a higher rate of procedural failure (OR 3.30, 95% CI 1.63 to 6.71; p < 0.001).
The radial approach for coronary procedures appears as a safe alternative to femoral access. Moreover, radial access virtually eliminates local vascular complications, thanks to a time-sparing hemostasis technique. However, gaining radial access requires higher technical skills, thus yielding an overall lower success rate. Nonetheless, a clear ongoing trend toward equalization of the two procedures, in terms of procedural success, is evident through the years, probably due to technologic progress of materials and increased operator experience.
Adoptive transfer of chimeric antigen receptor (CAR) T lymphocytes is a powerful technology that has revolutionized the way we conceive immunotherapy. The impressive clinical results of complete and ...prolonged response in refractory and relapsed diseases have shifted the landscape of treatment for hematological malignancies, particularly those of lymphoid origin, and opens up new possibilities for the treatment of solid neoplasms. However, the widening use of cell therapy is hampered by the accessibility to viral vectors that are commonly used for T cell transfection. In the era of messenger RNA (mRNA) vaccines and CRISPR/Cas (clustered regularly interspaced short palindromic repeat–CRISPR-associated) precise genome editing, novel and virus-free methods for T cell engineering are emerging as a more versatile, flexible, and sustainable alternative for next-generation CAR T cell manufacturing. Here, we discuss how the use of non-viral vectors can address some of the limitations of the viral methods of gene transfer and allow us to deliver genetic information in a stable, effective and straightforward manner. In particular, we address the main transposon systems such as Sleeping Beauty (SB) and piggyBac (PB), the utilization of mRNA, and innovative approaches of nanotechnology like Lipid-based and Polymer-based DNA nanocarriers and nanovectors. We also describe the most relevant preclinical data that have recently led to the use of non-viral gene therapy in emerging clinical trials, and the related safety and efficacy aspects. We will also provide practical considerations for future trials to enable successful and safe cell therapy with non-viral methods for CAR T cell generation.
Background Several randomized trials have compared the patency of coronary artery bypass conduits. All of the published studies, however, have performed pairwise comparisons and a comprehensive ...evaluation of the patency rates of all conduits has yet to be published. We set out to investigate the angiographic patency rates of all conduits used in coronary bypass surgery by performing a network meta-analysis of the current available randomized evidence. Methods and Results A systematic literature search was conducted for randomized controlled trials comparing the angiographic patency rate of the conventionally harvested saphenous vein, the no-touch saphenous vein, the radial artery (RA), the right internal thoracic artery, or the gastroepiploic artery. The primary outcome was graft occlusion. A total of 4160 studies were retrieved of which 14 were included with 3651 grafts analyzed. The weighted mean angiographic follow-up was 5.1 years. Compared with the conventionally harvested saphenous vein, both the RA (incidence rate ratio IRR 0.54; 95% CI, 0.35-0.82) and the no-touch saphenous vein (IRR 0.55; 95% CI, 0.39-0.78) were associated with lower graft occlusion. The RA ranked as the best conduit (rank score for RA 0.87 versus 0.85 for no-touch saphenous vein, 0.23 for right internal thoracic artery, 0.29 for gastroepiploic artery, and 0.25 for the conventionally harvested saphenous vein). Conclusions Compared with the conventionally harvested saphenous vein, only the RA and no-touch saphenous vein grafts are associated with significantly lower graft occlusion rates. The RA ranks as the best conduit. Registration URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42020164492.
Graphical Abstract
Graphical abstract
Key concurrences and divergences of ESC/EACTS and ACC/AHA Guidelines. ACC/AHA, American College of Cardiology/American Heart Association; AS, aortic stenosis; ...AVR, aortic valve replacement; ESC/EACTS, European Society of Cardiology/European Association for Cardio-Thoracic Surgery; LVEF, left ventricular ejection fraction; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation.
Abstract
Aortic stenosis (AS) is a serious and complex condition, for which optimal management continues to evolve rapidly. An understanding of current clinical practice guidelines is critical to effective patient care and shared decision-making. This state of the art review of the 2021 European Society of Cardiology/European Association for Cardio-Thoracic Surgery Guidelines and 2020 American College of Cardiology/American Heart Association Guidelines compares their recommendations for AS based on the evidence to date. The European and American guidelines were generally congruent with the exception of three key distinctions. First, the European guidelines recommend intervening at a left ventricular ejection fraction of 55%, compared with 60% over serial imaging by the American guidelines for asymptomatic patients. Second, the European guidelines recommend a threshold of ≥65 years for surgical bioprosthesis, whereas the American guidelines employ multiple age categories, providing latitude for patient factors and preferences. Third, the guidelines endorse different age cut-offs for transcatheter vs. surgical aortic valve replacement, despite limited evidence. This review also discusses trends indicating a decreasing proportion of mechanical valve replacements. Finally, the review identifies gaps in the literature for areas including transcatheter aortic valve implantation in asymptomatic patients, the appropriateness of Ross procedures, concomitant coronary revascularization with aortic valve replacement, and bicuspid AS. To summarize, this state of the art review compares the latest European and American guidelines on the management of AS to highlight three areas of divergence: timing of intervention, valve selection, and surgical vs. transcatheter aortic valve replacement criteria.
Audio Abstract
10.1093/eurheartj/ehac803audio1
Audio Abstract
ehac803media1
6318549093112
SMN1, the causative gene for spinal muscular atrophy (SMA), plays a housekeeping role in the biogenesis of small nuclear RNA ribonucleoproteins. SMN is also present in granular foci along axonal ...projections of motoneurons, which are the predominant cell type affected in the pathology. These so-called RNA granules mediate the transport of specific mRNAs along neurites and regulate mRNA localization, stability, as well as local translation. Recent work has provided evidence suggesting that SMN may participate in the assembly of RNA granules, but beyond that, the precise nature of its role within these structures remains unclear. Here, we demonstrate that SMN associates with polyribosomes and can repress translation in an in vitro translation system. We further identify the arginine methyltransferase CARM1 as an mRNA that is regulated at the translational level by SMN and find that CARM1 is abnormally up-regulated in spinal cord tissue from SMA mice and in severe type I SMA patient cells. We have previously characterized a novel regulatory pathway in motoneurons involving the SMN-interacting RNA-binding protein HuD and CARM1. Thus, our results suggest the existence of a potential negative feedback loop in this pathway. Importantly, an SMA-causing mutation in the Tudor domain of SMN completely abolished translational repression, a strong indication for the functional significance of this novel SMN activity in the pathology.
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