The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI)clinical endpoints to make ...them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection.
A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous.
Two in-person meetings (held in September 2011 in Washington, DC, USA, and in February 2012 in Rotterdam, the Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and non-interventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC-2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints.
This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavours of applying definitions to other transcatheter valve therapies (for example, mitral valve repair).
A previous analysis in this trial showed that among patients with severe, symptomatic aortic stenosis who were at low surgical risk, the rate of the composite end point of death, stroke, or ...rehospitalization at 1 year was significantly lower with transcatheter aortic-valve replacement (TAVR) than with surgical aortic-valve replacement. Longer-term outcomes are unknown.
We randomly assigned patients with severe, symptomatic aortic stenosis and low surgical risk to undergo either TAVR or surgery. The first primary end point was a composite of death, stroke, or rehospitalization related to the valve, the procedure, or heart failure. The second primary end point was a hierarchical composite that included death, disabling stroke, nondisabling stroke, and the number of rehospitalization days, analyzed with the use of a win ratio analysis. Clinical, echocardiographic, and health-status outcomes were assessed through 5 years.
A total of 1000 patients underwent randomization: 503 patients were assigned to undergo TAVR, and 497 to undergo surgery. A component of the first primary end point occurred in 111 of 496 patients in the TAVR group and in 117 of 454 patients in the surgery group (Kaplan-Meier estimates, 22.8% in the TAVR group and 27.2% in the surgery group; difference, -4.3 percentage points; 95% confidence interval CI, -9.9 to 1.3; P = 0.07). The win ratio for the second primary end point was 1.17 (95% CI, 0.90 to 1.51; P = 0.25). The Kaplan-Meier estimates for the components of the first primary end point were as follows: death, 10.0% in the TAVR group and 8.2% in the surgery group; stroke, 5.8% and 6.4%, respectively; and rehospitalization, 13.7% and 17.4%. The hemodynamic performance of the valve, assessed according to the mean (±SD) valve gradient, was 12.8±6.5 mm Hg in the TAVR group and 11.7±5.6 mm Hg in the surgery group. Bioprosthetic-valve failure occurred in 3.3% of the patients in the TAVR group and in 3.8% of those in the surgery group.
Among low-risk patients with severe, symptomatic aortic stenosis who underwent TAVR or surgery, there was no significant between-group difference in the two primary composite outcomes. (Funded by Edwards Lifesciences; PARTNER 3 ClinicalTrials.gov number, NCT02675114.).
Numerous spacecraft observations reveal that many heliospheric shocks are significantly affected by the presence of energetic particles such as solar energetic particles, pickup ions (PUIs), and ...anomalous cosmic rays. Examples include recent observations by the New Horizon spacecraft that show that the PUI pressure is larger than the thermal solar wind pressure in the solar wind. Voyager 2 observations of the heliospheric termination shock (HTS) show that it is completely mediated by suprathermal PUIs, and that the dissipation process at the HTS is not due to the thermal solar wind protons but to PUIs. We introduce a plasma model to study the structure of collisionless oblique magnetized shocks mediated by suprathermal energetic particles. We show that the incorporation of both collisionless heat flux and viscosity associated with energetic particles can completely determine the structure of collisionless oblique shocks for all angles except θ = 54 7. The limitation at this angle is technical and comes in part from the assumed simplified form of the viscosity coefficient. In modeling the HTS, we show that PUIs are heated much more than the thermal gas through the HTS transition, and thus the HTS is mediated by PUIs. We study different values of the HTS obliquity and find that a parallel HTS heats PUIs more compared to the background thermal gas than it does at a perpendicular HTS.
The use of transcatheter aortic-valve replacement has been shown to reduce mortality among high-risk patients with aortic stenosis who are not candidates for surgical replacement. However, the two ...procedures have not been compared in a randomized trial involving high-risk patients who are still candidates for surgical replacement.
At 25 centers, we randomly assigned 699 high-risk patients with severe aortic stenosis to undergo either transcatheter aortic-valve replacement with a balloon-expandable bovine pericardial valve (either a transfemoral or a transapical approach) or surgical replacement. The primary end point was death from any cause at 1 year. The primary hypothesis was that transcatheter replacement is not inferior to surgical replacement.
The rates of death from any cause were 3.4% in the transcatheter group and 6.5% in the surgical group at 30 days (P=0.07) and 24.2% and 26.8%, respectively, at 1 year (P=0.44), a reduction of 2.6 percentage points in the transcatheter group (upper limit of the 95% confidence interval, 3.0 percentage points; predefined margin, 7.5 percentage points; P=0.001 for noninferiority). The rates of major stroke were 3.8% in the transcatheter group and 2.1% in the surgical group at 30 days (P=0.20) and 5.1% and 2.4%, respectively, at 1 year (P=0.07). At 30 days, major vascular complications were significantly more frequent with transcatheter replacement (11.0% vs. 3.2%, P<0.001); adverse events that were more frequent after surgical replacement included major bleeding (9.3% vs. 19.5%, P<0.001) and new-onset atrial fibrillation (8.6% vs. 16.0%, P=0.006). More patients undergoing transcatheter replacement had an improvement in symptoms at 30 days, but by 1 year, there was not a significant between-group difference.
In high-risk patients with severe aortic stenosis, transcatheter and surgical procedures for aortic-valve replacement were associated with similar rates of survival at 1 year, although there were important differences in periprocedural risks. (Funded by Edwards Lifesciences; Clinical Trials.gov number, NCT00530894.).
Objectives The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI) clinical ...endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection. Background A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous. Methods and Results Two in-person meetings (held in September 2011 in Washington, DC, and in February 2012 in Rotterdam, The Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and noninterventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC-2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints. Conclusions This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavors of applying definitions to other transcatheter valve therapies (for example, mitral valve repair).
OBJECTIVES
The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI) clinical ...endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection.
BACKGROUND
A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous.
METHODS AND RESULTS
Two in-person meetings (held in September 2011 in Washington, DC, USA, and in February 2012 in Rotterdam, Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and non-interventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC-2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints.
CONCLUSIONS
This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavours of applying definitions to other transcatheter valve therapies (for example, mitral valve repair).
Abstract
A steady-state, semi-analytical model of energetic particle acceleration in radio-jet shear flows due to cosmic-ray viscosity obtained by Webb et al. is generalized to take into account more ...general cosmic-ray boundary spectra. This involves solving a mixed Dirichlet–Von Neumann boundary value problem at the edge of the jet. The energetic particle distribution function
f
0
(
r
,
p
) at cylindrical radius
r
from the jet axis (assumed to lie along the
z
-axis) is given by convolving the particle momentum spectrum
f
0
(
∞
,
p
′
)
with the Green’s function
G
(
r
,
p
;
p
′
)
, which describes the monoenergetic spectrum solution in which
f
0
→
δ
(
p
−
p
′
)
as
r
→ ∞ . Previous work by Webb et al. studied only the Green’s function solution for
G
(
r
,
p
;
p
′
)
. In this paper, we explore for the first time, solutions for more general and realistic forms for
f
0
(
∞
,
p
′
)
. The flow velocity
u
=
u
(
r
)
e
z
is along the axis of the jet (the
z
-axis).
u
is independent of
z
, and
u
(
r
) is a monotonic decreasing function of
r
. The scattering time
τ
(
r
,
p
)
=
τ
0
(
p
/
p
0
)
α
in the shear flow region 0 <
r
<
r
2
, and
τ
(
r
,
p
)
=
τ
0
(
p
/
p
0
)
α
(
r
/
r
2
)
s
, where
s
> 0 in the region
r
>
r
2
is outside the jet. Other original aspects of the analysis are (i) the use of cosmic ray flow lines in (
r
,
p
) space to clarify the particle spatial transport and momentum changes and (ii) the determination of the probability distribution
ψ
p
(
r
,
p
;
p
′
)
that particles observed at (
r
,
p
) originated from
r
→ ∞ with momentum
p
′
. The acceleration of ultrahigh-energy cosmic rays in active galactic nuclei jet sources is discussed. Leaky box models for electron acceleration are described.
Abstract
The initiation mechanism of Earth’s plate tectonic cooling system remains uncertain. A growing consensus suggests that multi-plate tectonics was preceded by cooling through a single-plate ...lithosphere, but models for how this lithosphere was first broken into plates have not converged on a mechanism or a typical early plate scale. A commonality among prior efforts is the use of continuum mechanics approximations to evaluate this solid mechanics problem. Here we use 3D spherical shell models to demonstrate a self-organized fracture mechanism analogous to thermal expansion-driven lithospheric uplift, in which globe-spanning rifting occurs as a consequence of horizontal extension. Resultant fracture spacing is a function of lithospheric thickness and rheology, wherein geometrically-regular, polygonal-shaped tessellation is an energetically favored solution because it minimizes total crack length. Therefore, warming of the early lithosphere itself—as anticipated by previous studies—should lead to failure, propagating fractures, and the conditions necessary for the onset of multi-plate tectonics.
Transcatheter aortic-valve replacement (TAVR) is the recommended therapy for patients with severe aortic stenosis who are not suitable candidates for surgery. The outcomes beyond 1 year in such ...patients are not known.
We randomly assigned patients to transfemoral TAVR or to standard therapy (which often included balloon aortic valvuloplasty). Data on 2-year outcomes were analyzed.
A total of 358 patients underwent randomization at 21 centers. The rates of death at 2 years were 43.3% in the TAVR group and 68.0% in the standard-therapy group (P<0.001), and the corresponding rates of cardiac death were 31.0% and 62.4% (P<0.001). The survival advantage associated with TAVR that was seen at 1 year remained significant among patients who survived beyond the first year (hazard ratio, 0.58; 95% confidence interval CI, 0.36 to 0.92; P=0.02 with the use of the log-rank test). The rate of stroke was higher after TAVR than with standard therapy (13.8% vs. 5.5%, P=0.01), owing, in the first 30 days, to the occurrence of more ischemic events in the TAVR group (6.7% vs. 1.7%, P=0.02) and, beyond 30 days, to the occurrence of more hemorrhagic strokes in the TAVR group (2.2% vs. 0.6%, P=0.16). At 2 years, the rate of rehospitalization was 35.0% in the TAVR group and 72.5% in the standard-therapy group (P<0.001). TAVR, as compared with standard therapy, was also associated with improved functional status (P<0.001). The data suggest that the mortality benefit after TAVR may be limited to patients who do not have extensive coexisting conditions. Echocardiographic analysis showed a sustained increase in aortic-valve area and a decrease in aortic-valve gradient, with no worsening of paravalvular aortic regurgitation.
Among appropriately selected patients with severe aortic stenosis who were not suitable candidates for surgery, TAVR reduced the rates of death and hospitalization, with a decrease in symptoms and an improvement in valve hemodynamics that were sustained at 2 years of follow-up. The presence of extensive coexisting conditions may attenuate the survival benefit of TAVR. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.).
Incorporation of kinetic effects such as Landau damping into a fluid framework was pioneered by Hammett and Perkins, by obtaining closures of the fluid hierarchy, where the gyrotropic heat flux ...fluctuations or the deviation of the fourth-order gyrotropic fluid moment are expressed through lower-order fluid moments. To obtain a closure of a fluid model expanded around a bi-Maxwellian distribution function, the usual plasma dispersion function Z(ζ) that appears in kinetic theory or the associated plasma response function R(ζ)=1+ζZ(ζ) has to be approximated with a suitable Padé approximant in such a way that the closure is valid for all ζ values. Such closures are rare, and the original closures of Hammett and Perkins are often employed. Here we present a complete mapping of all plausible Landau fluid closures that can be constructed at the level of fourth-order moments in the gyrotropic limit and we identify the most precise closures. Furthermore, by considering 1D closures at higher-order moments, we show that it is possible to reproduce linear Landau damping in the fluid framework to any desired precision, thus showing convergence of the fluid and collisionless kinetic descriptions.
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