Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium

To propose standardized consensus definitions for important clinical endpoints in transcatheter aortic valve implantation (TAVI), investigations in an effort to improve the quality of clinical research and to enable meaningful comparisons between clinical trials. To make these consensus definitions accessible to all stakeholders in TAVI clinical research through a peer reviewed publication, on behalf of the public health.

Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the valve academic research consortium

To propose standardized consensus definitions for important clinical endpoints in transcatheter aortic valve implantation (TAVI), investigations in an effort to improve the quality of clinical research and to enable meaningful comparisons between clinical trials. To make these consensus definitions accessible to all stakeholders in TAVI clinical research through a peer reviewed publication, on behalf of the public health.

Evidence for impaired sound intensity processing in schizophrenia

Patients with schizophrenia are impaired in many aspects of auditory processing, but indirect evidence suggests that intensity perception is intact. However, because the extraction of meaning from dynamic intensity relies on structures that appear to be altered in schizophrenia, we hypothesized that the perception of auditory looming is impaired as well. Twenty inpatients with schizophrenia and 20 control participants, matched for age, gender, and education, gave intensity ratings of rising (looming) and falling intensity sounds with different mean intensities. Intensity change was overestimated in looming as compared with receding sounds in both groups. However, healthy individuals showed a stronger effect at higher mean intensity, in keeping with previous findings, while patients with schizophrenia lacked this modulation. We discuss how this might support the notion of a more general deficit in extracting emotional meaning from different sensory cues, including intensity and pitch.

Pathology of transcatheter valve therapy

This study sought to report on the pathology of transcatheter aortic valves explanted at early and late time points after transcatheter aortic valve implantation.

Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document

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.

Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document (VARC-2)

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.

Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document

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.

Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document

The aim of the current Valvular 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 understanding of patient risk stratification and case selection.

Enhancing BOLD response in the auditory system by neurophysiologically tuned fMRI sequence

Auditory neuroscience has not tapped fMRI's full potential because of acoustic scanner noise emitted by the gradient switches of conventional echoplanar fMRI sequences. The scanner noise is pulsed, and auditory cortex is particularly sensitive to pulsed sounds. Current fMRI approaches to avoid stimulus-noise interactions are temporally inefficient. Since the sustained BOLD response to pulsed sounds decreases with repetition rate and becomes minimal with unpulsed sounds, we developed an fMRI sequence emitting continuous rather than pulsed gradient sound by implementing a novel quasi-continuous gradient switch pattern. Compared to conventional fMRI, continuous-sound fMRI reduced auditory cortex BOLD baseline and increased BOLD amplitude with graded sound stimuli, short sound events, and sounds as complex as orchestra music with preserved temporal resolution. Response in subcortical auditory nuclei was enhanced, but not the response to light in visual cortex. Finally, tonotopic mapping using continuous-sound fMRI demonstrates that enhanced functional signal-to-noise in BOLD response translates into improved spatial separability of specific sound representations.

Rising sound intensity: an intrinsic warning cue activating the amygdala

Human subjects overestimate the change of rising intensity sounds compared with falling intensity sounds. Rising sound intensity has therefore been proposed to be an intrinsic warning cue. In order to test this hypothesis, we presented rising, falling, and constant intensity sounds to healthy humans and gathered psychophysiological and behavioral responses. Brain activity was measured using event-related functional magnetic resonance imaging. We found that rising compared with falling sound intensity facilitates autonomic orienting reflex and phasic alertness to auditory targets. Rising intensity sounds produced neural activity in the amygdala, which was accompanied by activity in intraparietal sulcus, superior temporal sulcus, and temporal plane. Our results indicate that rising sound intensity is an elementary warning cue eliciting adaptive responses by recruiting attentional and physiological resources. Regions involved in cross-modal integration were activated by rising sound intensity, while the right-hemisphere phasic alertness network could not be supported by this study.

Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document

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).

Synchronization and desynchronization in epilepsy: controversies and hypotheses

Epilepsy has been historically seen as a functional brain disorder associated with excessive synchronization of large neuronal populations leading to a hypersynchronous state. Recent evidence showed that epileptiform phenomena, particularly seizures, result from complex interactions between neuronal networks characterized by heterogeneity of neuronal firing and dynamical evolution of synchronization. Desynchronization is often observed preceding seizures or during their early stages; in contrast, high levels of synchronization observed towards the end of seizures may facilitate termination. In this review we discuss cellular and network mechanisms responsible for such complex changes in synchronization. Recent work has identified cell-type-specific inhibitory and excitatory interactions, the dichotomy between neuronal firing and the non-local measurement of local field potentials distant to that firing, and the reflection of the neuronal dark matter problem in non-firing neurons active in seizures. These recent advances have challenged long-established views and are leading to a more rigorous and realistic understanding of the pathophysiology of epilepsy.

Transcatheter Aortic Valve Replacement in Bicuspid Aortic Valve Disease.

BACKGROUND Limited information exists describing the results of transcatheter aortic valve (TAV) replacement in patients with bicuspid aortic valve (BAV) disease (TAV-in-BAV). OBJECTIVES This study sought to evaluate clinical outcomes of a large cohort of patients undergoing TAV-in-BAV. METHODS We retrospectively collected baseline characteristics, procedural data, and clinical follow-up findings from 12 centers in Europe and Canada that had performed TAV-in-BAV. RESULTS A total of 139 patients underwent TAV-in-BAV with the balloon-expandable transcatheter heart valve (THV) (n = 48) or self-expandable THV (n = 91) systems. Patient mean age and Society of Thoracic Surgeons predicted risk of mortality scores were 78.0 ± 8.9 years and 4.9 ± 3.4%, respectively. BAV stenosis occurred in 65.5%, regurgitation in 0.7%, and mixed disease in 33.8% of patients. Incidence of type 0 BAV was 26.7%; type 1 BAV was 68.3%; and type 2 BAV was 5.0%. Multislice computed tomography (MSCT)-based TAV sizing was used in 63.5% of patients (77.1% balloon-expandable THV vs. 56.0% self-expandable THV, p = 0.02). Procedural mortality was 3.6%, with TAV embolization in 2.2% and conversion to surgery in 2.2%. The mean aortic gradient decreased from 48.7 ± 16.5 mm Hg to 11.4 ± 9.9 mm Hg (p < 0.0001). Post-implantation aortic regurgitation (AR) grade ≥2 occurred in 28.4% (19.6% balloon-expandable THV vs. 32.2% self-expandable THV, p = 0.11) but was prevalent in only 17.4% when MSCT-based TAV sizing was performed (16.7% balloon-expandable THV vs. 17.6% self-expandable THV, p = 0.99). MSCT sizing was associated with reduced AR on multivariate analysis (odds ratio [OR]: 0.19, 95% confidence intervals [CI]: 0.08 to 0.45; p < 0.0001). Thirty-day device safety, success, and efficacy were noted in 79.1%, 89.9%, and 84.9% of patients, respectively. One-year mortality was 17.5%. Major vascular complications were associated with increased 1-year mortality (OR: 5.66, 95% CI: 1.21 to 26.43; p = 0.03). CONCLUSIONS TAV-in-BAV is feasible with encouraging short- and intermediate-term clinical outcomes. Importantly, a high incidence of post-implantation AR is observed, which appears to be mitigated by MSCT-based TAV sizing. Given the suboptimal echocardiographic results, further study is required to evaluate long-term efficacy.