Abstract
Aims
The Valve Academic Research Consortium (VARC), founded in 2010, was intended to (i) identify appropriate clinical endpoints and (ii) standardize definitions of these endpoints for ...transcatheter and surgical aortic valve clinical trials. Rapid evolution of the field, including the emergence of new complications, expanding clinical indications, and novel therapy strategies have mandated further refinement and expansion of these definitions to ensure clinical relevance. This document provides an update of the most appropriate clinical endpoint definitions to be used in the conduct of transcatheter and surgical aortic valve clinical research.
Methods and results
Several years after the publication of the VARC-2 manuscript, an in-person meeting was held involving over 50 independent clinical experts representing several professional societies, academic research organizations, the US Food and Drug Administration (FDA), and industry representatives to (i) evaluate utilization of VARC endpoint definitions in clinical research, (ii) discuss the scope of this focused update, and (iii) review and revise specific clinical endpoint definitions. A writing committee of independent experts was convened and subsequently met to further address outstanding issues. There were ongoing discussions with FDA and many experts to develop a new classification schema for bioprosthetic valve dysfunction and failure. Overall, this multi-disciplinary process has resulted in important recommendations for data reporting, clinical research methods, and updated endpoint definitions. New definitions or modifications of existing definitions are being proposed for repeat hospitalizations, access site-related complications, bleeding events, conduction disturbances, cardiac structural complications, and bioprosthetic valve dysfunction and failure (including valve leaflet thickening and thrombosis). A more granular 5-class grading scheme for paravalvular regurgitation (PVR) is being proposed to help refine the assessment of PVR. Finally, more specific recommendations on quality-of-life assessments have been included, which have been targeted to specific clinical study designs.
Conclusions
Acknowledging the dynamic and evolving nature of less-invasive aortic valve therapies, further refinements of clinical research processes are required. The adoption of these updated and newly proposed VARC-3 endpoints and definitions will ensure homogenous event reporting, accurate adjudication, and appropriate comparisons of clinical research studies involving devices and new therapeutic strategies.
Graphical Abstract
The Valve Academic Research Consortium (VARC), founded in 2010, was intended to (i) identify appropriate clinical endpoints and (ii) standardize definitions of these endpoints for transcatheter and ...surgical aortic valve clinical trials. Rapid evolution of the field, including the emergence of new complications, expanding clinical indications, and novel therapy strategies have mandated further refinement and expansion of these definitions to ensure clinical relevance. This document provides an update of the most appropriate clinical endpoint definitions to be used in the conduct of transcatheter and surgical aortic valve clinical research.
Several years after the publication of the VARC-2 manuscript, an in-person meeting was held involving over 50 independent clinical experts representing several professional societies, academic research organizations, the US Food and Drug Administration (FDA), and industry representatives to (i) evaluate utilization of VARC endpoint definitions in clinical research, (ii) discuss the scope of this focused update, and (iii) review and revise specific clinical endpoint definitions. A writing committee of independent experts was convened and subsequently met to further address outstanding issues. There were ongoing discussions with FDA and many experts to develop a new classification schema for bioprosthetic valve dysfunction and failure. Overall, this multi-disciplinary process has resulted in important recommendations for data reporting, clinical research methods, and updated endpoint definitions. New definitions or modifications of existing definitions are being proposed for repeat hospitalizations, access site-related complications, bleeding events, conduction disturbances, cardiac structural complications, and bioprosthetic valve dysfunction and failure (including valve leaflet thickening and thrombosis). A more granular 5-class grading scheme for paravalvular regurgitation (PVR) is being proposed to help refine the assessment of PVR. Finally, more specific recommendations on quality-of-life assessments have been included, which have been targeted to specific clinical study designs.
Acknowledging the dynamic and evolving nature of less-invasive aortic valve therapies, further refinements of clinical research processes are required. The adoption of these updated and newly proposed VARC-3 endpoints and definitions will ensure homogenous event reporting, accurate adjudication, and appropriate comparisons of clinical research studies involving devices and new therapeutic strategies.
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Sonochemically mediated dehydrogenation of in situ generated complex metal hydrides is a promising methodology for the synthesis of mixed-metal powders for fuel applications that can be tailored ...toward greater energy content and other desirable characteristics. Here, we report a significant improvement in the synthesis of Ti–Al–B reactive metal powders by the elimination of parasitic impurities from the synthesis, focusing on the effects of synthetic and processing parameters on the final fuel composition, morphology, energy content, and reactivity. Reactions to produce fuel samples were carried out using both the previously reported addition of ethereal solutions of LiAlH4 and LiBH4 to a solution of TiCl4 and, importantly, the reverse, where a homogeneous solution of TiCl4 in diethyl ether was added to a homogeneous solution of LiAlH4 and LiBH4. The product powders were characterized via TGA/DSC, XPS, ICP-OES of the digestate, and oxygen bomb calorimetry of polymer-encased metal powder–fuel composites. In order to accurately measure the energy content of these materials, HTPB was used as a protective matrix for powders combusted using bomb calorimetry. The powders produced by the two methods had similar elemental compositions; however, the materials produced by “reverse addition” exhibited surprisingly different morphology and fuel properties compared to the “traditional” counterparts. The improvements in synthetic methodology lead to significant improvements in the fuel energy content, remarkable particle size monodispersity in the submicron size regime, and excellent reproducibility of the energy release observed for powder fuel-HTPB composites.
Domestic animals are excellent models for genetic studies of phenotypic evolution. They have evolved genetic adaptations to a new environment, the farm, and have been subjected to strong human-driven ...selection leading to remarkable phenotypic changes in morphology, physiology and behaviour. Identifying the genetic changes underlying these developments provides new insight into general mechanisms by which genetic variation shapes phenotypic diversity. Here we describe the use of massively parallel sequencing to identify selective sweeps of favourable alleles and candidate mutations that have had a prominent role in the domestication of chickens (Gallus gallus domesticus) and their subsequent specialization into broiler (meat-producing) and layer (egg-producing) chickens. We have generated 44.5-fold coverage of the chicken genome using pools of genomic DNA representing eight different populations of domestic chickens as well as red jungle fowl (Gallus gallus), the major wild ancestor. We report more than 7,000,000 single nucleotide polymorphisms, almost 1,300 deletions and a number of putative selective sweeps. One of the most striking selective sweeps found in all domestic chickens occurred at the locus for thyroid stimulating hormone receptor (TSHR), which has a pivotal role in metabolic regulation and photoperiod control of reproduction in vertebrates. Several of the selective sweeps detected in broilers overlapped genes associated with growth, appetite and metabolic regulation. We found little evidence that selection for loss-of-function mutations had a prominent role in chicken domestication, but we detected two deletions in coding sequences that we suggest are functionally important. This study has direct application to animal breeding and enhances the importance of the domestic chicken as a model organism for biomedical research.
The ability to rewrite large stretches of genomic DNA enables the creation of new organisms with customized functions. However, few methods currently exist for accumulating such widespread genomic ...changes in a single organism. In this study, we demonstrate a rapid approach for rewriting bacterial genomes with modified synthetic DNA. We recode 200 kb of the Salmonella typhimurium LT2 genome through a process we term SIRCAS (stepwise integration of rolling circle amplified segments), towards constructing an attenuated and genetically isolated bacterial chassis. The SIRCAS process involves direct iterative recombineering of 10-25 kb synthetic DNA constructs which are assembled in yeast and amplified by rolling circle amplification. Using SIRCAS, we create a Salmonella with 1557 synonymous leucine codon replacements across 176 genes, the largest number of cumulative recoding changes in a single bacterial strain to date. We demonstrate reproducibility over sixteen two-day cycles of integration and parallelization for hierarchical construction of a synthetic genome by conjugation. The resulting recoded strain grows at a similar rate to the wild-type strain and does not exhibit any major growth defects. This work is the first instance of synthetic bacterial recoding beyond the Escherichia coli genome, and reveals that Salmonella is remarkably amenable to genome-scale modification.
Paclitaxel drug-coated balloons (DCBs) have been shown to improve patency and lower revascularization rates compared with plain old balloon angioplasty. DCBs continue to evolve by improving ...balloon-coating techniques that minimize the quantity of particles washed off into the bloodstream while maximizing drug retention and vascular-healing profile. Against this backdrop, it is clear that the future of antiproliferatives for the superficial femoral artery will focus on enhancements in device coating materials that will improve the efficiency of drug delivery. The Ranger DCB system recently gained US FDA approval for use. This review discusses the background of DCBs and how the Ranger DCB builds on these previous platforms based on experimental and clinical data.
Abstract Objectives Using intravascular ultrasound (IVUS), the authors compared outcomes by observed wire position (intraplaque vs. subintimal) achieved during successful chronic total occlusion ...(CTO) lesion treatment. Background Recent successes in CTO percutaneous coronary intervention (PCI) have used both intraluminal and subintimal wire tracking to improve procedural success. IVUS may be used to determine the course of wire tracking after crossing a CTO. Methods From March 2014 to March 2016, data were collected into a single-center database from 219 patients undergoing CTO PCI with concomitant IVUS imaging. IVUS-visualized wire tracking patterns were then retrospectively examined. Clinical outcomes with a composite in-hospital cardiovascular endpoint of all-cause death, periprocedural myocardial infarction, and in-hospital target lesion revascularization were analyzed along with IVUS-detected vascular injury. Results Of the 524 lesions assessed, 219 patients with successfully recanalized CTO lesions had adequate IVUS imaging and were included. Subintimal tracking was detected in 52.1% of overall cases (86.7% dissection re-entry, 27.9% wire escalation). Minimal stent area of the CTO segment and prevalence of significant edge dissection were similar in the 2 groups. In the subintimal tracking group, there was a higher rate of the composite endpoint, mostly driven by periprocedural myocardial infarction. Subintimal tracking was associated with significantly greater IVUS-detected vascular injury, angiographic dye staining/extravasation, and branch occlusion. Conclusions IVUS-detected subintimal tracking is observed in approximately one-half of all successful CTO PCI cases and is associated with an expected higher, yet acceptable, event rate with no difference in minimal stent area or edge dissection among patients undergoing contemporary hybrid CTO PCI.
Abstract
Aims
B-type natriuretic peptide (BNP) is a cardiac neurohormone that is secreted in response to ventricular volume expansion and pressure overload. There are conflicting data regarding the ...association between BNP levels and outcomes after transcatheter aortic valve replacement (TAVR). We therefore sought to assess the association between baseline BNP and adverse outcomes in patients with symptomatic, severe aortic stenosis (AS), and left ventricular ejection fraction (LVEF) ≥50%, undergoing TAVR in the PARTNER 2 Trial and Registry.
Methods and results
A total of 1782 patients were included in the analysis, and BNP was evaluated both as a continuous log-transformed value and by a priori categories: low (<50 pg/mL), normal (≥50 and <100 pg/mL), moderately elevated (≥100 and <400 pg/mL), or markedly elevated (≥400 pg/mL). Clinical outcomes from discharge to 2 years were compared between patients according to their baseline BNP level, using Kaplan–Meier event rates and multivariable Cox proportional hazards regression models. After adjustment, spline curves revealed a non-linear association between log-transformed BNP and all-cause and cardiovascular mortality in which both the lowest and highest values were associated with increased mortality. Two-year all-cause mortality rates for those with low (n = 86), normal (n = 202), moderately elevated (n = 885), and markedly elevated (n = 609) baseline BNP were 20.0%, 9.8%, 17.7%, and 26.1%, respectively. In adjusted models, compared to a normal baseline BNP, low adjusted hazard ratio (HR) 2.6, 95% confidence interval (CI) 1.3–5.0, P-value 0.005, moderately elevated (adjusted HR 1.6, 95% CI 1.0–2.6, P-value 0.06), and markedly elevated (adjusted HR 2.1, 95% CI 1.3–3.5, P-value 0.003) BNP were associated with increased all-cause mortality, driven by cardiovascular mortality.
Conclusions
In a large cohort of patients with severe symptomatic AS and preserved LVEF undergoing TAVR, all-cause and cardiovascular mortality rates at 2 years were higher in patients with low and markedly elevated BNP levels.
Clinical Trial Registration
https://clinicaltrials.gov/ unique identifier #NCT01314313, #NCT02184442, #NCT03222128, and #NCT03222141.
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