Dynamics of conduction blocks in a model of paced cardiac tissue

We study numerically the dynamics of conduction blocks using a detailed electrophysiological model. We find that this dynamics depends critically on the size of the paced region. Small pacing regions lead to stationary conduction blocks while larger pacing regions can lead to conduction blocks that travel periodically towards the pacing region. We show that this size-dependence dynamics can lead to a novel arrhythmogenic mechanism. Furthermore, we show that the essential phenomena can be captured in a much simpler coupled-map model.Comment: 8 pages 6 figure

Emotional processing in Parkinson's disease and anxiety: an EEG study of visual affective word processing

A general problem in the design of an EEG-BCI system is the poor quality and low robustness of the extracted features, affecting overall performance. However, BCI systems that are applicable in real-time and outside clinical settings require high performance. Therefore, we have to improve the current methods for feature extraction. In this work, we investigated EEG source reconstruction techniques to enhance the extracted features based on a linearly constrained minimum variance (LCMV) beamformer. Beamformers allow for easy incorporation of anatomical data and are applicable in real-time. A 32-channel EEG-BCI system was designed for a two-class motor imagery (MI) paradigm. We optimized a synchronous system for two untrained subjects and investigated two aspects. First, we investigated the effect of using beamformers calculated on the basis of three different head models: a template 3-layered boundary element method (BEM) head model, a 3-layered personalized BEM head model and a personalized 5-layered finite difference method (FDM) head model including white and gray matter, CSF, scalp and skull tissue. Second, we investigated the influence of how the regions of interest, areas of expected MI activity, were constructed. On the one hand, they were chosen around electrodes C3 and C4, as hand MI activity theoretically is expected here. On the other hand, they were constructed based on the actual activated regions identified by an fMRI scan. Subsequently, an asynchronous system was derived for one of the subjects and an optimal balance between speed and accuracy was found. Lastly, a real-time application was made. These systems were evaluated by their accuracy, defined as the percentage of correct left and right classifications. From the real-time application, the information transfer rate (ITR) was also determined. An accuracy of 86.60 ± 4.40% was achieved for subject 1 and 78.71 ± 0.73% for subject 2. This gives an average accuracy of 82.66 ± 2.57%. We found that the use of a personalized FDM model improved the accuracy of the system, on average 24.22% with respect to the template BEM model and on average 5.15% with respect to the personalized BEM model. Including fMRI spatial priors did not improve accuracy. Personal fine- tuning largely resolved the robustness problems arising due to the differences in head geometry and neurophysiology between subjects. A real-time average accuracy of 64.26% was reached and the maximum ITR was 6.71 bits/min. We conclude that beamformers calculated with a personalized FDM model have great potential to ameliorate feature extraction and, as a consequence, to improve the performance of real-time BCI systems

Long-term safety and efficacy of tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study

Background: Tezacaftor-ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8-24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor-ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor-ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods: Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor-ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and 'tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor-ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov (NCT02565914). Findings: Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor-ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor-ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor-ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation: Tezacaftor-ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor-ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor-ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding: Vertex Pharmaceuticals Incorporated