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Purpose: This article aimed at investigating the neural underpinnings of music-to-language transfer effects at the pre-attentive level of processing. Method: We conducted a longitudinal experiment with a test–training–retest procedure. Nonmusician adults were trained either on frequency (experimental group) or on intensity (control group) of harmonic tones using methods from psychophysics. Pre- and posttraining, we recorded brain electrical activity and we analyzed the mismatch negativity (MMN) and the P3a component both to harmonic complex sounds and to syllables varying in frequency. Results: Frequency training influenced the pre-attentive perception of pitch for large harmonic deviant sounds but not for syllables. Conclusion: Results are discussed in terms of near and far transfer effects from psychoacoustic training to pre-attentive pitch processing and as possibly showing some limits to transfer effects.

A previous study have shown that musical background during training improve handwriting speed and fluency in a child with difficulties (Veron-Delor et al., 2017). However, it is still necessary to explain this effect. One hypothesis is that handwriting movement synchronizes with the music rhythm. This should lead to a stabilization of the movement, as it has been reported in other motor activities (e.g. Dalla Bella et al., 2018). To address this issue, we propose here to record handwriting kinematics in children under different background conditions. Specifically, three main questions will be addressed. First, we will investigate if rhythm could explain the benefits of musical background reported in previous studies. To this aim, melodic and rhythmic+melodic background will be compared to a silent condition. Second, we will test the influence of tempo on handwriting to confirm the synchronization of handwriting to auditory stimuli. Third, different variables may modulate the benefits of rhythmic background. Specifically, we will investigate the role of handwriting automation by testing this effect in two age groups. In addition, spontaneous tempo and handwriting deficits will be assessed to correlate these variables to rhythmic background benefits.

Interest in applications for the simultaneous acquisition of data from different devices is growing. In neuroscience for example, co-registration complements and overcomes some of the shortcomings of individual methods. However, precise synchronization of the different data streams involved is required before joint data analysis. Our article presents and evaluates a synchronization method which maximizes the alignment of information across time. Synchronization through common triggers is widely used in all existing methods, because it is very simple and effective. However, this solution has been found to fail in certain practical situations, namely for the spurious detection of triggers and/or when the timestamps of triggers sampled by each acquisition device are not jointly distributed linearly for the entire duration of an experiment. We propose two additional mechanisms, the "Longest Common Subsequence" algorithm and a piecewise linear regression, in order to overcome the limitations of the classical method of synchronizing common triggers. The proposed synchronization method was evaluated using both real and artificial data. Co-registrations of electroencephalographic signals (EEG) and eye movements were used for real data. We compared the effectiveness of our method to another open source method implemented using EYE-EEG toolbox. Overall, we show that our method, implemented in C++ as a DOS application, is very fast, robust and fully automatic.

In this article, through the close analysis of the Brazilian feature film Xingu. I discuss potential contributions of Indigenous peoples’ epistemologies to debates about environmental crises. The t...

International audience; The present study investigated whether children with developmental dyslexia showed specific deficits in the perception of three phonetic features (voicing, place, and manner of articulation) in optimal (silence) and degraded listening conditions (envelope-coded speech versus noise), using both standard behavioral and electrophysiological measures. Performance of children with dyslexia was compared to that of younger typically developing children who were matched in terms of reading age. Results showed no significant group differences in response accuracy except for the reception of place-of-articulation in noise. However, dyslexic children responded more slowly than typically developing children across all conditions with larger deficits in noise than in envelope than in silence. At the neural level, dyslexic children exhibited reduced N1 components in silence and the reduction of N1 amplitude was more pronounced for voicing than for the other phonetic features. In the envelope condition, the N1 was localized over the right hemisphere and it was larger for typically developing readers than for dyslexic children. Finally, in stationary noise, the N1 to place of articulation was clearly delayed in children with dyslexia, which suggests a temporal de-organization in the most adverse listening conditions.The results clearly show abnormal neural processing to speech sounds in all conditions. They are discussed in the context of recent theories on perceptual noise exclusion, neural noise and temporal sampling.

Previous results showed a positive influence of music training on linguistic abilities at both attentive and preattentive levels. Here, we investigate whether six months of active music training is more efficient than painting training to improve the preattentive processing of phonological parameters based on durations that are often impaired in children with developmental dyslexia (DD). Results were also compared to a control group of Typically Developing (TD) children matched on reading age. We used a Test&ndash, Training&ndash, Retest procedure and analysed the Mismatch Negativity (MMN) and the N1 and N250 components of the Event-Related Potentials to syllables that differed in Voice Onset Time (VOT), vowel duration, and vowel frequency. Results were clear-cut in showing a normalization of the preattentive processing of VOT in children with DD after music training but not after painting training. They also revealed increased N250 amplitude to duration deviant stimuli in children with DD after music but not painting training, and no training effect on the preattentive processing of frequency. These findings are discussed in view of recent theories of dyslexia pointing to deficits in processing the temporal structure of speech. They clearly encourage the use of active music training for the rehabilitation of children with language impairments.

Objective To determine the effect of selexipag, an oral, selective IP prostacyclin receptor agonist, on the frequency of attacks of Raynaud's phenomenon (RP) in patients with systemic sclerosis (SSc). Methods Patients with SSc-related RP were randomized 1:1 to placebo (n = 38) or selexipag (n = 36) in individualized doses (maximum of 1,600 μg twice daily) during a 3-week titration period. The primary end point was the weekly average number of RP attacks during the study maintenance period, analyzed using a Bayesian approach with a negative binomial model adjusted for baseline number of RP attacks. Other outcome measures included Raynaud's Condition Score (RCS), RP attack duration, and treatment-emergent adverse events (AEs). Results Baseline characteristics were comparable between treatment groups. For 83.3% of patients, the individualized maintenance dosage of selexipag was ≤800 μg twice daily. No significant difference was observed between placebo and selexipag in weekly average number of electronic diary (eDiary)–recorded RP attacks during the maintenance period (14.2 attacks during the maintenance period and 21.5 attacks during the baseline week in the placebo group [n = 32] versus 18.0 attacks during the maintenance period and 22.4 attacks during the baseline week in the selexipag group [n = 27]; adjusted mean treatment difference of 3.4 in favor of placebo). No significant treatment effect was observed on RCS or RP attack duration. In the double-blind period, 86.8% of placebo-treated patients and 100% of selexipag-treated patients reported ≥1 AE; 55.3% and 91.7%, respectively, reported ≥1 prostacyclin-associated AE. Conclusion Treatment with selexipag did not reduce the number of RP attacks compared with placebo. The safety profile of selexipag was similar to that previously reported. This study provides important information about the feasibility of eDiary reporting of RP attacks in clinical trials.

Background The most common outcome currently assessed in acute heart failure trials (AHF) is dyspnea improvement. Worsening hear failure (WHF) is a new outcome measure that incorporates failure to improve or recurrent symptoms of AHF requiring rescue intravenous therapy, mechanical circulatory or ventilatory support, or readmission because of AHF, occurring within 30 days of AHF admission. Methods and Results Retrospective data analysis of 120 patients with AHF requiring hemodynamic monitoring who enrolled in the placebo arm of 2 prospective randomized studies. The incidence of WHF was 42% at 30 days from enrollment. Most WHF events occurred in-hospital during the first 7 days after admission (early WHF). Thirty-day readmission from AHF was an infrequent event in the present cohort (5.0%). The strongest hemodynamic predictors of WHF were cardiac power at baseline and its change during the initial 6 hours of monitoring. Other hemodynamic parameters associated with WHF events were blood pressure and its increase, cardiac output, and pulmonary wedge pressure change during the initial 6 hours of monitoring. WHF was found to be a strong predictor of 6-month mortality. Conclusions WHF is a common morbid event clustered mostly during the first week of AHF admission and is associated with higher 6-month mortality. The hemodynamic measurements associated with WHF are similar to those predicting adverse outcome in AHF and cardiogenic shock (low cardiac power, higher pulmonary capillary wedge pressure, and vascular resistance), emphasizing the notion that early WHF should become an important AHF-specific outcome measure.

International audience; Dans la lignée des travaux de Pierre Schaeffer, le laboratoire Musique et Informatique de Marseille (MIM) a mis en évidence des figures temporelles sonores dénommées Unités Sémiotiques Temporelles (UST) qui correspondent à des segments musicaux qui possèdent, per se, une signification temporelle en raison de leur organisation morphologique et dynamique (Delalande, 1996). Dans cet article, nous rapportons la description des UST et les résultats de deux expériences, menées auprès de musiciens et de non musiciens en utilisant une tâche de catégorisation libre, pour évaluer la pertinence des UST, comme unités cognitives de l'écoute du flux sonore. Les résultats montrent que les segments musicaux relevant d'une même UST sont regroupés de façon significative et qu'il n'y a pas de différences entre musiciens et non musiciens dans l'appréhension des UST. Ces résultats sont discutés au regard de la formalisation des UST.

In the Phase III GRIPHON study in which 1156 patients (pts) with PAH were randomised 1:1 to selexipag or placebo (PBO), selexipag significantly reduced the risk of morbidity/mortality (M/M) events up to end of treatment by 40% (hazard ratio [HR] 0.60; 99% CI: 0.46, 0.78; log-rank p

International audience; Over the last decades, the analysis of eye movements has proven very useful to investigate the cognitive processes underlying reading. However, from a developmental perspective, this technique has yet hardly been used to better understand the children’s acquisition of reading. This chapter aims at presenting a review of the studies comparing the eye-movement patterns observed in children with those observed in adult readers. Firstly, it presents the differences and similarities in eye-movement patterns between those two groups, and then it proposes different attempts at explaining these differences in terms of oculomotor, visual and linguistic constraints.

Selexipag, an orally available, selective IP receptor agonist targeting the prostacyclin pathway, is chemically and pharmacologically distinct from prostanoids. The GRIPHON trial evaluated the long-term effect of selexipag on morbidity/mortality (M/M) as well as tolerability and safety in patients

Background: In previous studies (the RITZ project), tezosentan, an intravenous (i.v.)-balanced dual endothelin (ET-A/B) antagonist, in doses of 50 and 100 mg/h, improved the hemodynamics but not the clinical outcome of patients with acute heart failure (AHF). Objective: To evaluate the effect of lower doses of tezosentan in patients with AHF. Subjects and methods: Included were 130 patients hospitalized due to AHF with dyspnea at rest, despite initial treatment, and were in need of hemodynamic monitoring with cardiac index (CI)

OBJECTIVES We sought to determine the effect of tezosentan in patients with acute decompensated heart failure (HF) associated with acute coronary syndrome (ACS). BACKGROUND Tezosentan is a dual endothelin receptor antagonist that has been shown to improve cardiac output, decrease pulmonary capillary wedge pressure, and reduce pulmonary and systemic vascular resistance in initial clinical studies in acute decompensated HF. METHODS The Randomized Intravenous TeZosentan (RITZ)-4 study was a multicenter, randomized, double-blinded, placebo-controlled study of tezosentan in patients with acute decompensated HF associated with ACS. A total of 193 patients were randomized to receive tezosentan (25 mg/h for 1 h, then 50 mg/h for 23 to 47 h) or placebo. Patients with evidence of acute decompensated HF and ACS were eligible to participate. The primary end point was the composite of death, worsening HF, recurrent ischemia, and recurrent or new myocardial infarction within 72 h. RESULTS No significant differences were observed between placebo and 50 mg/h tezosentan in the composite primary end point: 24.2% (95% confidence interval [CI] 16.0% to 34.1%) and 28.9% (95% CI 20.1% to 39.0%), respectively (p = 0.5152). Symptomatic hypotension was more frequent in the treatment group. CONCLUSIONS At the doses studied, tezosentan did not result in a significant improvement in the composite primary clinical end point in the RITZ-4 trial. Tezosentan did not demonstrate pro-ischemic effects in this population. Symptomatic hypotension may have resulted in an increased number of adverse events in the treatment group. Further studies with lower tezosentan doses are warranted.

Objectives The objective of this study was to evaluate the addition of intravenous (IV) tezosentan to standard therapy for patients with pulmonary edema. Background Tezosentan is an IV nonselective endothelin (ET)-1 antagonist that yields favorable hemodynamic effects in patients with acute congestive heart failure (CHF). Methods Pulmonary edema was defined as acute CHF leading to respiratory failure, as evidenced by an oxygen saturation (SO2)

Two experiments were conducted using both behavioral and Event-Related brain Potentials methods to examine conceptual priming effects for realistic auditory scenes and for auditory words. Prime and target sounds were presented in four stimulus combinations: Sound-Sound, Word-Sound, Sound-Word and Word-Word. Within each combination, targets were conceptually related to the prime, unrelated or ambiguous. In Experiment 1, participants were asked to judge whether the primes and targets fit together (explicit task) and in Experiment 2 they had to decide whether the target was typical or ambiguous (implicit task). In both experiments and in the four stimulus combinations, reaction times and/or error rates were longer/higher and the N400 component was larger to ambiguous targets than to conceptually related targets, thereby pointing to a common conceptual system for processing auditory scenes and linguistic stimuli in both explicit and implicit tasks. However, fine-grained analyses also revealed some differences between experiments and conditions in scalp topography and duration of the priming effects possibly reflecting differences in the integration of perceptual and cognitive attributes of linguistic and nonlinguistic sounds. These results have clear implications for the building-up of virtual environments that need to convey meaning without words.

22 pages; International audience; Reading on a web page is known to be not linear and people need to make fast decisions about whether they have to stop or not reading. In such context, reading and decision-making processes are intertwined and this experiment attempts to separate them through electrophysiological patterns provided by the Eye-Fixation-Related Potentials technique (EFRPs). We conducted an experiment in which EFRPs were recorded while participants read blocks of text that were semantically highly related, moderately related and unrelated to a given goal. Participants had to decide as fast as possible whether the text was related or not to the semantic goal given at a prior stage. Decision making (stopping information search) may occur when the paragraph is highly related to the goal (positive decision) or when it is unrelated to the goal (negative decision). EFRPs were analyzed on and around typical eye fixations: either on words belonging to the goal (target), subjected to a high rate of positive decisions, or on low frequency unrelated words (incongruent), subjected to a high rate of negative decisions. In both cases, we found EFRPs specific patterns (amplitude peaking between 51-120ms after fixation onset) spreading out on the next words following the goal word and the second fixation after an incongruent word, in parietal and occipital areas. We interpreted these results as delayed late components (P3b and N400), reflecting the decision to stop information searching. Indeed, we show a clear spill-over effect showing that the effect on word N spread out on word N+1 and N+2.

Background Raynaud9s phenomenon (RP) occurs in >95% of patients (pts) with systemic sclerosis (SSc) and contributes to digital ischaemia that may lead to digital ulcers (DUs) and gangrene.1,2 Empirical treatment of SSc-associated RP includes oral vasodilators, particularly calcium channel blockers and intermittent intravenous prostacyclin analogues.3,4 However, there is a need to identify oral therapies that are more efficacious than those currently available. Objectives To determine the activity of selexipag, an oral, selective, prostacyclin receptor agonist, on RP attack frequency in pts with SSc. Methods The study comprised a placebo single-blind run-in phase of 2–4-weeks followed by an 8-week double-blind treatment phase. Pts (≥18 years) with definite SSc and ≥7 RP attacks on ≥5 days in the week before randomisation were assigned 1:1 to selexipag or placebo. Study drug was titrated to an individual highest tolerated dose (200–1600 μg BID). The primary efficacy endpoint was the number of RP attacks per week in the maintenance phase (5 weeks) as determined from the pt9s daily entries in the eDiary, and was analysed using a negative binomial model adjusted for the baseline number of RP attacks. Other outcomes included Raynaud Condition Score (RCS),5 RP attack duration, new DU frequency, and treatment-emergent adverse events (AEs). Results Baseline (BL) characteristics were comparable between the groups (selexipag n=36, placebo n=38). No significant difference in effect was demonstrated for selexipag vs placebo (observed average number of RP attacks per week during the maintenance phase: 18.0 [vs 22.4 at BL, selexipag, n=27], 14.2 [vs 21.5 at BL, placebo, n=32]), adjusted mean treatment difference 3.43 in favour of placebo. During the maintenance phase, 63.0% (selexipag) and 81.3% (placebo) of pts had an improvement in the average number of RP attacks per week vs BL. No significant treatment effect was observed on RCS, RP attack duration and new DU frequency. At least one AE occurred in 100% (selexipag) and 86.8% (placebo) of pts; ≥1 prostacyclin-associated AE occurred in 91.7% (selexipag) and 55.3% (placebo) of pts. AEs were mostly reported as mild (16.7% selexipag pts, 34.2% placebo pts) or moderate (61.1% selexipag pts, 44.7% placebo pts) in intensity. Conclusions The primary efficacy endpoint was not met (no reduction in number of RP attacks per week for selexipag vs placebo). The robust study design may nevertheless provide a template for future studies in RP. The marked reduction in attack frequency on placebo may underlie failure to show additional potential benefit with selexipag, which should be considered when designing future studies in RP. The safety profile of selexipag was similar to previous studies,6 with no new safety signals identified. References Hettema et al. Ann Rheum Dis 2007;66:1398–9 Sunderkotter & Riemekasten. Rheumatology 2006;45:iii33–5 Belch et al. Lancet 1983; 54:313–5 Kowal Bielecka et al. Ann Rheum Dis 2009;68:620–8 Merkel et al. Arthritis Rheum 2002;46:2410–20 Sitbon et al. NEJM 2015;373:2522–33 Acknowledgement The study was sponsored by Actelion Pharmaceuticals Ltd. Medical writing support was provided by Lynda McEvoy PhD, of ApotheCom Ltd, sponsored by Actelion. Disclosure of Interest C. P. Denton Grant/research support from: Actelion Pharmaceuticals Ltd, CSL Behring, Novartis, Consultant for: Actelion Pharmaceuticals Ltd, GlaxoSmithKline, Bayer, Inventiva, Takeda, Speakers bureau: Actelion Pharmaceuticals Ltd, GlaxoSmithKline, Bayer, Inventiva, Takeda, Έ. Hachulla Grant/research support from: Actelion Pharmaceuticals Ltd, GlaxoSmithKline, Consultant for: Actelion Pharmaceuticals Ltd, GlaxoSmithKline, Bayer, Pfizer, Speakers bureau: Actelion Pharmaceuticals Ltd, GlaxoSmithKline, Bayer, Pfizer, G. Riemekasten Consultant for: Bayer, Paid instructor for: Schering, Bayer, A. Schwarting Grant/research support from: Actelion Pharmaceuticals Ltd, Consultant for: GlaxoSmithKline, Speakers bureau: GlaxoSmithKline, J.-M. Frenoux Employee of: Actelion Pharmaceuticals Ltd, A. Frey Employee of: Actelion Pharmaceuticals Ltd, F.-O. Le Brun Employee of: Actelion Pharmaceuticals Ltd, A. Herrick Grant/research support from: Actelion Pharmaceuticals Ltd, Consultant for: Actelion Pharmaceuticals Ltd, Apricus, Speakers bureau: Actelion Pharmaceuticals Ltd

We report here results of a randomized, double-blind, placebo-controlled study ( http://www.ClinicalTrials.gov , NCT00558311) that investigated the effect of clazosentan (5 mg/h, n = 768) or placebo (n = 389) administered for up to 14 days in patients with aneurysmal subarachnoid hemorrhage (SAH) repaired by surgical clipping. The primary endpoint was a composite of all-cause mortality, new cerebral infarction or delayed ischemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was the Glasgow Outcome Scale Extended (GOSE), which was dichotomized. Twenty-one percent of clazosentan- compared to 25% of placebo-treated patients met the primary endpoint (relative risk reduction [RRR] [95% CI]: 17% [-4% to 33%]; p = 0.10). Poor outcome (GOSE score ≤ 4) occurred in 29% of clazosentan- and 25% of placebo-treated patients (RRR: -18% [-45% to 4%]; p = 0.10). In prespecified subgroups, mortality/vasospasm-related morbidity was reduced in clazosentan-treated patients by 33% (8-51%) in poor WFNS (World Federation of Neurological Surgeons) grade (≥III) and 25% (5-41%) in patients with diffuse, thick SAH. Lung complications, anemia and hypotension occurred more frequently with clazosentan. Mortality (week 12) was 6% in both groups. The results showed that clazosentan nonsignificantly decreased mortality/vasospasm-related morbidity and nonsignificantly increased poor functional outcome in patients with aneurysmal SAH undergoing surgical clipping.

We report here results of a randomized, double-blind, placebo-controlled study (http://www.ClinicalTrials.gov, NCT00558311) that investigated the effect of clazosentan (5 mg/h, n = 768) or placebo (n = 389) administered for up to 14 days in patients with aneurysmal subarachnoid hemorrhage (SAH) repaired by surgical clipping. The primary endpoint was a composite of all-cause mortality, new cerebral infarction or delayed ischemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was the Glasgow Outcome Scale Extended (GOSE), which was dichotomized. Twenty-one percent of clazosentan- compared to 25% of placebo-treated patients met the primary endpoint (relative risk reduction [RRR] [95% CI]: 17% [−4% to 33%]; p = 0.10). Poor outcome (GOSE score ≤ 4) occurred in 29% of clazosentan- and 25% of placebo-treated patients (RRR: −18% [−45% to 4%]; p = 0.10). In prespecified subgroups, mortality/vasospasm-related morbidity was reduced in clazosentan-treated patients by 33% (8–51%) in poor WFNS (World Federation of Neurological Surgeons) grade (≥III) and 25% (5–41%) in patients with diffuse, thick SAH. Lung complications, anemia and hypotension occurred more frequently with clazosentan. Mortality (week 12) was 6% in both groups. The results showed that clazosentan nonsignificantly decreased mortality/vasospasm-related morbidity and nonsignificantly increased poor functional outcome in patients with aneurysmal SAH undergoing surgical clipping.

Background and Purpose— Clazosentan, an endothelin receptor antagonist, has been shown to reduce vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). CONSCIOUS-3 assessed whether clazosentan reduced vasospasm-related morbidity and all-cause mortality postaSAH secured by endovascular coiling. Methods— This double-blind, placebo-controlled, phase III trial randomized patients with aSAH secured by endovascular coiling to ≤14 days intravenous clazosentan (5 or 15 mg/h) or placebo. The primary composite end point (all-cause mortality; vasospasm-related new cerebral infarcts or delayed ischemic neurological deficits; rescue therapy for vasospasm) was evaluated 6 weeks postaSAH. The main secondary end point was dichotomized extended Glasgow Outcome Scale (week 12). Results— CONSCIOUS-3 was halted prematurely following completion of CONSCIOUS-2; 577/1500 of planned patients (38%) were enrolled and 571 were treated (placebo, n=189; clazosentan 5 mg/h, n=194; clazosentan 15 mg/h, n=188). The primary end point occurred in 50/189 of placebo-treated patients (27%), compared with 47/194 patients (24%) treated with clazosentan 5 mg/h (odds ratio [OR], 0.786; 95% CI, 0.479–1.289; P= 0.340), and 28/188 patients (15%) treated with clazosentan 15 mg/h (OR, 0.474; 95% CI, 0.275–0.818; P= 0.007). Poor outcome (extended Glasgow Outcome Scale score ≤4) occurred in 24% of patients with placebo, 25% of patients with clazosentan 5 mg/h (OR, 0.918; 95% CI, 0.546–1.544; P= 0.748), and 28% of patients with clazosentan 15 mg/h (OR, 1.337; 95% CI, 0.802–2.227; P= 0.266). Pulmonary complications, anemia, and hypotension were more common in patients who received clazosentan than in those who received placebo. At week 12, mortality was 6%, 4%, and 6% with placebo, clazosentan 5 mg/h, and clazosentan 15 mg/h, respectively. Conclusions— Clazosentan 15 mg/h significantly reduced postaSAH vasospasm-related morbidity/all-cause mortality; however, neither dose improved outcome (extended Glasgow Outcome Scale). Clinical Trial Registration— URL: http://clinicaltrials.gov . Unique identifier: NCT00940095.

Introduction: In CONSCIOUS-1, clazosentan, an endothelin receptor antagonist, significantly and dose-dependently reduced angiographic vasospasm (VSP) after aneurysmal subarachnoid hemorrhage (aSAH). CONSCIOUS-3 aimed to assess whether clazosentan improves VSP-related morbidity/all cause mortality after aSAH. Methods: This was a randomized, double-blind, placebo-controlled trial. Patients included in the study were 18-75 years old with SAH due to ruptured saccular aneurysm secured by endovascular coiling, any thick clot and WFNS grades I-IV prior to coiling procedure. Patients were randomized 1:1:1 to intravenous clazosentan (5 or 15 mg/h) or placebo for ≤2 weeks. The primary composite endpoint (all-cause mortality; VSP-related new cerebral infarcts; delayed ischemic neurological deficit [DIND] due to VSP; rescue therapy in the presence of confirmed angiographic VSP) was evaluated 6 weeks post-aSAH and assessed centrally by a blinded critical events committee, with significance determined using logistic regression adjusted for WFNS. The main secondary endpoint was the extended Glasgow Outcome Scale (GOSE; dichotomized) at week 12. Results: CONSCIOUS-3 was halted prematurely following nonsignificant results from the parallel CONSCIOUS-2 clipping study. There were 571 treated patients (placebo n=189, clazosentan 5 mg/h n=194, clazosentan 15 mg/h n=188). The primary endpoint occurred in 27% of the placebo group compared with 24% and 15% in the 5 and 15 mg/h clazosentan groups, respectively; significant improvement was seen with 15 mg/h clazosentan (odds ratio [OR] 0.474, 95% CI 28-82%; p=0.007) but not 5 mg/h (OR 0.786, 95% CI 48-129%; p=0.340). DIND decreased with increasing clazosentan dose (placebo 21%; clazosentan 5 mg/h 18%; clazosentan 15 mg/h 10%). VSP-related new cerebral infarct occurred in 13%, 16% and 7% in the placebo, clazosentan 5 and 15 mg/h groups, respectively. A 3-fold greater use of rescue therapy was seen in patients receiving placebo (21%) compared with 15 mg/h clazosentan (7%). Poor functional outcome (GOSE score ≤4) occurred in 24% of patients in the placebo group compared with 25% (OR 0.918, 95% CI 55-154%; p=0.748) and 28% (OR 1.337, 95% CI 80-223%; p=0.266) in the clazosentan 5 and 15 mg/h groups, respectively. At week 12, mortality rates were 6%, 4% and 6% with placebo, clazosentan 5 and 15 mg/h, respectively. Treatment-emergent adverse events of specific interest were lung complications (21%, 36%, 37%), anemia (10%, 13%, 13%) and hypotension (7%, 11%, 16%) in the placebo, clazosentan 5 and 15 mg/h groups, respectively. Conclusions: Clazosentan (15 mg/h) significantly reduced mortality/VSP-related morbidity; however, no significant effect on GOSE occurred, possibly due to greater use of rescue therapy with placebo. Pulmonary complications, anemia and hypotension were more common in patients receiving clazosentan.

Summary Background Clazosentan, an endothelin receptor antagonist, significantly and dose-dependently reduced angiographic vasospasm after aneurysmal subarachnoid haemorrhage (aSAH). We investigated whether clazosentan reduced vasospasm-related morbidity and all-cause mortality. Methods In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with aSAH secured by surgical clipping to clazosentan (5 mg/h, n=768) or placebo (n=389) for up to 14 days (27 countries, 102 sites, inpatient and outpatient settings) using an interactive web response system. The primary composite endpoint (week 6) included all-cause mortality, vasospasm-related new cerebral infarcts, delayed ischaemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was dichotomised extended Glasgow outcome scale (GOSE; week 12). This trial is registered with ClinicalTrials.gov, number NCT00558311. Findings In the all-treated dataset, the primary endpoint was met in 161 (21%) of 764 clazosentan-treated patients and 97 (25%) of 383 placebo-treated patients (relative risk reduction 17%, 95% CI −4 to 33; p=0·10). Poor functional outcome (GOSE score ≤4) occurred in 224 (29%) clazosentan-treated patients and 95 (25%) placebo-treated patients (−18%, −45 to 4; p=0·10). Lung complications, anaemia, and hypotension were more common with clazosentan. Mortality (week 12) was 6% in both groups. Interpretation Clazosentan at 5 mg/h had no significant effect on mortality and vasospasm-related morbidity or functional outcome. Further investigation of patients undergoing endovascular coiling of ruptured aneurysms is needed to fully understand the potential usefulness of clazosentan in patients with aSAH. Funding Actelion Pharmaceuticals.

Objectives: Recent heart failure studies have suggested that inflammatory and immune system activation are associated with increased levels of cytokines, chemokines and inflammatory proteins during acutely decompensated heart failure. The objectives of this substudy were to evaluate the role of neurohormonal and inflammatory activation in the pathogenesis and outcome of acute heart failure (AHF) and the correlation between biomarker levels and clinical outcomes. Methods: Serum levels of B-type natriuretic peptide-32 (BNP-32), endothelin-1 (ET-1), norepinephrine, troponins I and T, C-reactive protein (CRP), von Willebrand factor, plasminogen activator inhibitor-1, interleukin-6 (IL-6) and tissue plasminogen activator (TPA) were measured at baseline, 24 and 48 h and 7 and 30 days in 112 patients with AHF recruited to the Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Study neurohormonal substudy. Results: On univariable analysis, CRP, BNP and ET-1 were predictive of worsening heart failure by day 30; when considered together, only CRP and BNP were significantly associated with this outcome. On adjustment for age, baseline blood pressure, serum sodium and serum creatinine, only age and BNP remained significant. CRP, IL-6 and TPA levels were significantly correlated with 180-day mortality on univariable analysis. Conclusion: Circulating markers of inflammation may be useful in gauging prognosis in patients with AHF.

Based on the results of a series of seminal studies very clearly reviewed in the paper, Stefan Koelsch proposes a neurobiological theory of musical meaning [4]. In this theory, the distinction between extraand intra-musical meaning [5] is implemented in the brain of the listener, with the N400 reflecting extra-musical meaning and the N5 associated with the processing of intra-musical meaning. The finding of an N400-like effect (unrelated minus related) in semantic priming experiments when the prime is a musical sound and the target a word (or vice versa) is indeed good evidence that the semantic properties of both elements are combined in an extra-musical conceptual space to determine whether they are semantically related or unrelated. Because the occurrence of words in an experimental design may encourage labeling of the musical sounds (e.g., mental generation of the word “heroic” when listening to an excerpt of Beethoven’s 3rd Symphony), one of the most interesting experimental condition is when two non-linguistic sounds are successively presented as prime and target. Importantly, Aramaki et al. [1], Frey et al. [2] and Grieser-Painter and Koelsch [3] reported an N400-like effect in such a condition of reduced linguistic mediation. However, if an N400 is generated in a purely musical condition (e.g., sound–sound) in which a musical element (be it a note, a chord, the first theme in the sonata form . . .) is driving expectations for another musical element, why should we consider the N400 as reflecting the processing of extra-musical meaning rather than the processing of intra-musical meaning? The possibility that the N400 also reflects intra-musical meaning is supported by the results of Steinbeis and Koelsch [6] showing an interaction between the N400 and the N5. This interaction implies that the processes underlying the N5 and N400 components are not independent and draw, at least partly, on the same pool of neural resources. It is thus possible that the N5 is, in fact, a delayed N400. In other words, the implementation in the brain of the extra-musical vs intra-musical meaning distinction may not be as straightforward as one would like it to

Korrespondenz zu 10.1016/S1474-4422(11)70189-2

Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) is a frequent but unpredictable complication associated with poor outcome. Current vasospasm therapies are suboptimal; new therapies are needed. Clazosentan, an endothelin receptor antagonist, has shown promise in phase 2 studies, and two randomized, double-blind, placebo-controlled phase 3 trials (CONSCIOUS-2 and CONSCIOUS-3) are underway to further investigate its impact on vasospasm-related outcome after aSAH. Here, we describe the design of these studies, which was challenging with respect to defining endpoints and standardizing endpoint interpretation and patient care. Main inclusion criteria are: age 18-75 years; SAH due to ruptured saccular aneurysm secured by surgical clipping (CONSCIOUS-2) or endovascular coiling (CONSCIOUS-3); substantial subarachnoid clot; and World Federation of Neurosurgical Societies grades I-IV prior to aneurysm-securing procedure. In CONSCIOUS-2, patients are randomized 2:1 to clazosentan (5 mg/h) or placebo. In CONSCIOUS-3, patients are randomized 1:1:1 to clazosentan 5, 15 mg/h, or placebo. Treatment is initiated within 56 h of aSAH and continued until 14 days after aSAH. Primary endpoint is a composite of mortality and vasospasm-related morbidity within 6 weeks of aSAH (all-cause mortality, vasospasm-related new cerebral infarction, vasospasm-related delayed ischemic neurological deficit, neurological signs or symptoms in the presence of angiographic vasospasm leading to rescue therapy initiation). Main secondary endpoint is extended Glasgow Outcome Scale at week 12. A critical events committee assesses all data centrally to ensure consistency in interpretation, and patient management guidelines are used to standardize care. Results are expected at the end of 2010 and 2011 for CONSCIOUS-2 and CONSCIOUS-3, respectively.

International audience; The aim of this study was to determine whether conceptual priming occurs between successively presented short musical pieces called Temporal Semantic Units (TSUs). Behavioral and ERP data were recorded while participants, experts and nonexperts in TSUs, were listening to pairs of TSUs and were asked to determine whether the target TSU evoked the same or a different concept than the prime TSU. Target TSUs were either congruous (i.e., they developed the same musical concept as the prime TSUs) or incongruous (i.e., they started as congruous TSUs but shifted midstream into a different concept). Results showed that, whereas P3a components were elicited in both groups by the shifting into incongruous TSUs, thereby reflecting an automatic shift of attention when the changes occurred, P3b components were elicited in experts and N400-like components were found in nonexperts. The functional significance of these results is discussed in regard of previous results with environmental sounds.

Background and Purpose— This randomized, double-blind, placebo-controlled, dose-finding study assessed efficacy and safety of 1, 5, and 15 mg/h intravenous clazosentan, an endothelin receptor antagonist, in preventing vasospasm after aneurysmal subarachnoid hemorrhage. Methods— Patients (n=413) were randomized to placebo or clazosentan beginning within 56 hours and continued up to 14 days after initiation of treatment. The primary end point was moderate or severe angiographic vasospasm based on centrally read, blinded evaluation of digital subtraction angiography at baseline and 7 to 11 days postsubarachnoid hemorrhage. A morbidity/mortality end point, including all-cause mortality, new cerebral infarct from any cause, delayed ischemic neurological deficit due to vasospasm, or use of rescue therapy, was evaluated by local assessment. Clinical outcome was assessed by the extended Glasgow Outcome Scale at 12 weeks. Results— Moderate or severe vasospasm was reduced in a dose-dependent fashion from 66% in the placebo group to 23% in the 15 mg/h clazosentan group (risk reduction, 65%; 95% CI, 47% to 78%; P Conclusions— Clazosentan significantly decreased moderate and severe vasospasm in a dose-dependent manner and showed a trend for reduction in vasospasm-related morbidity/mortality in patients with aneurysmal subarachnoid hemorrhage when centrally assessed. Overall, the adverse effects were manageable and not considered serious.

Background Endothelin 1 is a potent endogenous vasoconstrictor neurohormone, and endothelin 1 plasma concentrations predict adverse outcomes in patients with acute. heart failure (AHF). Tezosentan; an intravenous endothelin receptor antagonist, improved hemodynamics in patients with AHF; however, its effects on morbidity and mortality have not been evaluated.Methods The VERITAS program consists of 2 identical, double-blind, randomized, placebo-controlled, concurrently conducted trials (VERITAS-1 and VERITAS-2), performed in 150 centers in Europe, Israel, Australia, and North America: The program is designed to enroll at least 1760 patients hospitalized with dyspnea at rest because of AHF requiring intravenous therapy. In addition to conventional therapy, patients are randomized to receive tezosentan (5 mg/h for 30 minutes, then 1 mg/h for 24-72 hours) or matching placebo. The 2 prespecified primary end points are the incidence of death or worsening heart failure at 7 days in the combined studies and the change from baseline in dyspnea over the first 24 hours of treatment; measured using a visual analog scale in VERITAS-1 and VERITA52, individually.Results Enrollment started in April 2003, and the program was discontinued in November 2005 because of the low probability,of achieving a significant treatment effect.Conclusions No currently available agents have been shown in a prospective, randomized, clinical trial to improve outcomes in patients with AHF. Thus, the VERITAS program will provide valuable insights into the effect of tezosentan on clinical outcomes in patients with AHF, as well as hemodynamics and clinical symptoms.

Background Although echocardiographic ejection fraction (EF) is frequently used for the estimation of left ventricular contractility in patients with acute heart failure, its exact role and correlations with clinical, hemodynamic, and neurohormonal variables of cardiac contractility is not known. Methods Patients (343) with acute heart failure, enrolled into two prospective placebo-controlled hemodynamic studies of tezosentan, and in whom EF was available at baseline, were included. Outcome was evaluated in a subset of 94 patients who were enrolled in the placebo arms of the studies. Results Higher echocardiographic EF was correlated with older age, increased incidence of hypertension and atrial fibrillation, and female gender. We observed weak correlation between EF and cardiac output or cardiac power and no correlation with wedge pressure, and the change in hemodynamic variables over time. Higher EF was correlated with more baseline leukocytosis and higher plasma levels of endothelin-1 and blood urea nitrogen, while lower EF was related to higher baseline B-type natriuretic peptide (BNP). We observed no overall correlations between EF and outcome. Conclusions In patients with acute heart failure, echocardiographic EF is weakly correlated with hemodynamic measures of left ventricular contractility and outcome; hence, it should be interpreted cautiously when evaluating patients admitted due to acute heart failure.

We sought to investigate the efficacy and safety of tezosentan, a dual endothelin receptor antagonist, in patients hospitalized for acute heart failure (HF).Tezosentan has been previously shown to improve hemodynamics in patients with stable chronic HF.In a double-blind fashion, 292 patients (cardiac indexor =2.5 l/min per m(2) and pulmonary capillary wedge pressure (PCWP)or =15 mm Hg) who were admitted to the hospital and in need of intravenous treatment for acute HF and central hemodynamic monitoring were randomized to 24-h intravenous treatment with tezosentan (50 or 100 mg/h) or placebo. Central hemodynamic variables, the dyspnea score, and safety variables were measured.After 6 h of treatment, significantly greater increases in the cardiac index and decreases in PCWP were observed with both tezosentan dosages than with placebo (mean treatment effects at 0.38 and 0.37 l/min per m(2) with 50 and 100 mg/h and -3.9 mm Hg for each dose, respectively; p0.0001). This effect was maintained during the remaining infusion and foror =6 h after treatment cessation. A tendency for an improved dyspnea score and a decreased risk of clinical worsening was observed after 24 h of treatment with each tezosentan dose. Adverse events, more frequent with tezosentan than with placebo (headache, asymptomatic hypotension, early worsening of renal function, nausea, vomiting), were dose-related.Intravenous tezosentan rapidly and effectively improved hemodynamics in these patients. The similar beneficial effects of the two dosages and the increased dose-related adverse events with the higher dosage suggest that the optimal dosing regimen is50 mg/h.

We sought to determine the effect of tezosentan in patients with acute decompensated heart failure (HF) associated with acute coronary syndrome (ACS).Tezosentan is a dual endothelin receptor antagonist that has been shown to improve cardiac output, decrease pulmonary capillary wedge pressure, and reduce pulmonary and systemic vascular resistance in initial clinical studies in acute decompensated HF.The Randomized Intravenous TeZosentan (RITZ)-4 study was a multicenter, randomized, double-blinded, placebo-controlled study of tezosentan in patients with acute decompensated HF associated with ACS. A total of 193 patients were randomized to receive tezosentan (25 mg/h for 1 h, then 50 mg/h for 23 to 47 h) or placebo. Patients with evidence of acute decompensated HF and ACS were eligible to participate. The primary end point was the composite of death, worsening HF, recurrent ischemia, and recurrent or new myocardial infarction within 72 h.No significant differences were observed between placebo and 50 mg/h tezosentan in the composite primary end point: 24.2% (95% confidence interval [CI] 16.0% to 34.1%) and 28.9% (95% CI 20.1% to 39.0%), respectively (p = 0.5152). Symptomatic hypotension was more frequent in the treatment group.At the doses studied, tezosentan did not result in a significant improvement in the composite primary clinical end point in the RITZ-4 trial. Tezosentan did not demonstrate pro-ischemic effects in this population. Symptomatic hypotension may have resulted in an increased number of adverse events in the treatment group. Further studies with lower tezosentan doses are warranted.