Showing papers by "Laval University published in 2019"

Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in Low-Risk Patients

Abstract: Background Among patients with aortic stenosis who are at intermediate or high risk for death with surgery, major outcomes are similar with transcatheter aortic-valve replacement (TAVR) an...

Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma

Abstract: Background The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear. Methods In an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis. Results After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P Conclusions Among patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.).

Benefits and limitations of genome-wide association studies.

Abstract: Genome-wide association studies (GWAS) involve testing genetic variants across the genomes of many individuals to identify genotype–phenotype associations. GWAS have revolutionized the field of complex disease genetics over the past decade, providing numerous compelling associations for human complex traits and diseases. Despite clear successes in identifying novel disease susceptibility genes and biological pathways and in translating these findings into clinical care, GWAS have not been without controversy. Prominent criticisms include concerns that GWAS will eventually implicate the entire genome in disease predisposition and that most association signals reflect variants and genes with no direct biological relevance to disease. In this Review, we comprehensively assess the benefits and limitations of GWAS in human populations and discuss the relevance of performing more GWAS. Despite the success of human genome-wide association studies (GWAS) in associating genetic variants and complex diseases or traits, criticisms of the usefulness of this study design remain. This Review assesses the pros and cons of GWAS, with a focus on the cardiometabolic field.

Permafrost is warming at a global scale

Abstract: Permafrost warming has the potential to amplify global climate change, because when frozen sediments thaw it unlocks soil organic carbon. Yet to date, no globally consistent assessment of permafrost temperature change has been compiled. Here we use a global data set of permafrost temperature time series from the Global Terrestrial Network for Permafrost to evaluate temperature change across permafrost regions for the period since the International Polar Year (2007–2009). During the reference decade between 2007 and 2016, ground temperature near the depth of zero annual amplitude in the continuous permafrost zone increased by 0.39 ± 0.15 °C. Over the same period, discontinuous permafrost warmed by 0.20 ± 0.10 °C. Permafrost in mountains warmed by 0.19 ± 0.05 °C and in Antarctica by 0.37 ± 0.10 °C. Globally, permafrost temperature increased by 0.29 ± 0.12 °C. The observed trend follows the Arctic amplification of air temperature increase in the Northern Hemisphere. In the discontinuous zone, however, ground warming occurred due to increased snow thickness while air temperature remained statistically unchanged.

Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives.

Abstract: Clinical and translational research has played a major role in advancing our understanding of pulmonary hypertension (PH), including pulmonary arterial hypertension and other forms of PH with severe vascular remodelling (e.g. chronic thromboembolic PH and pulmonary veno-occlusive disease). However, PH remains an incurable condition with a high mortality rate, underscoring the need for a better transfer of novel scientific knowledge into healthcare interventions. Herein, we review recent findings in pathology (with the questioning of the strict morphological categorisation of various forms of PH into pre- or post-capillary involvement of pulmonary vessels) and cellular mechanisms contributing to the onset and progression of pulmonary vascular remodelling associated with various forms of PH. We also discuss ways to improve management and to support and optimise drug development in this research field.

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Abstract: Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

Deep Learning for Electromyographic Hand Gesture Signal Classification Using Transfer Learning

Abstract: In recent years, deep learning algorithms have become increasingly more prominent for their unparalleled ability to automatically learn discriminant features from large amounts of data. However, within the field of electromyography-based gesture recognition, deep learning algorithms are seldom employed as they require an unreasonable amount of effort from a single person, to generate tens of thousands of examples. This paper’s hypothesis is that general, informative features can be learned from the large amounts of data generated by aggregating the signals of multiple users, thus reducing the recording burden while enhancing gesture recognition. Consequently, this paper proposes applying transfer learning on aggregated data from multiple users while leveraging the capacity of deep learning algorithms to learn discriminant features from large datasets. Two datasets comprised 19 and 17 able-bodied participants, respectively (the first one is employed for pre-training), were recorded for this work, using the Myo armband. A third Myo armband dataset was taken from the NinaPro database and is comprised ten able-bodied participants. Three different deep learning networks employing three different modalities as input (raw EMG, spectrograms, and continuous wavelet transform (CWT)) are tested on the second and third dataset. The proposed transfer learning scheme is shown to systematically and significantly enhance the performance for all three networks on the two datasets, achieving an offline accuracy of 98.31% for 7 gestures over 17 participants for the CWT-based ConvNet and 68.98% for 18 gestures over 10 participants for the raw EMG-based ConvNet. Finally, a use-case study employing eight able-bodied participants suggests that real-time feedback allows users to adapt their muscle activation strategy which reduces the degradation in accuracy normally experienced over time.

Brain cell type-specific enhancer-promoter interactome maps and disease-risk association.

Abstract: Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer's disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type-specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.

The controversies of silicon's role in plant biology.

Abstract: Contents Summary 67 I. Introduction 68 II. Silicon transport in plants: to absorb or not to absorb 69 III. The role of silicon in plants: not just a matter of semantics 71 IV. Silicon and biotic stress: beyond mechanical barriers and defense priming 76 V. Silicon and abiotic stress: a proliferation of proposed mechanisms 78 VI. The apoplastic obstruction hypothesis: a working model 79 VII. Perspectives and conclusions 80 Acknowledgements 81 References 81 SUMMARY: Silicon (Si) is not classified as an essential plant nutrient, and yet numerous reports have shown its beneficial effects in a variety of species and environmental circumstances. This has created much confusion in the scientific community with respect to its biological roles. Here, we link molecular and phenotypic data to better classify Si transport, and critically summarize the current state of understanding of the roles of Si in higher plants. We argue that much of the empirical evidence, in particular that derived from recent functional genomics, is at odds with many of the mechanistic assertions surrounding Si's role. In essence, these data do not support reports that Si affects a wide range of molecular-genetic, biochemical and physiological processes. A major reinterpretation of Si's role is therefore needed, which is critical to guide future studies and inform agricultural practice. We propose a working model, which we term the 'apoplastic obstruction hypothesis', which attempts to unify the various observations on Si's beneficial influences on plant growth and yield. This model argues for a fundamental role of Si as an extracellular prophylactic agent against biotic and abiotic stresses (as opposed to an active cellular agent), with important cascading effects on plant form and function.

Pulmonary hypertension in chronic lung disease and hypoxia.

Abstract: Pulmonary hypertension (PH) frequently complicates the course of patients with various forms of chronic lung disease (CLD). CLD-associated PH (CLD-PH) is invariably associated with reduced functional ability, impaired quality of life, greater oxygen requirements and an increased risk of mortality. The aetiology of CLD-PH is complex and multifactorial, with differences in the pathogenic sequelae between the diverse forms of CLD. Haemodynamic evaluation of PH severity should be contextualised within the extent of the underlying lung disease, which is best gauged through a combination of physiological and imaging assessment. Who, when, if and how to screen for PH will be addressed in this article, as will the current state of knowledge with regard to the role of treatment with pulmonary vasoactive agents. Although such therapy cannot be endorsed given the current state of findings, future studies in this area are strongly encouraged.

Coming together to define membrane contact sites.

Abstract: Close proximities between organelles have been described for decades. However, only recently a specific field dealing with organelle communication at membrane contact sites has gained wide acceptance, attracting scientists from multiple areas of cell biology. The diversity of approaches warrants a unified vocabulary for the field. Such definitions would facilitate laying the foundations of this field, streamlining communication and resolving semantic controversies. This opinion, written by a panel of experts in the field, aims to provide this burgeoning area with guidelines for the experimental definition and analysis of contact sites. It also includes suggestions on how to operationally and tractably measure and analyze them with the hope of ultimately facilitating knowledge production and dissemination within and outside the field of contact-site research.

ERS statement on respiratory muscle testing at rest and during exercise

Abstract: Assessing respiratory mechanics and muscle function is critical for both clinical practice and research purposes. Several methodological developments over the past two decades have enhanced our understanding of respiratory muscle function and responses to interventions across the spectrum of health and disease. They are especially useful in diagnosing, phenotyping and assessing treatment efficacy in patients with respiratory symptoms and neuromuscular diseases. Considerable research has been undertaken over the past 17 years, since the publication of the previous American Thoracic Society (ATS)/European Respiratory Society (ERS) statement on respiratory muscle testing in 2002. Key advances have been made in the field of mechanics of breathing, respiratory muscle neurophysiology (electromyography, electroencephalography and transcranial magnetic stimulation) and on respiratory muscle imaging (ultrasound, optoelectronic plethysmography and structured light plethysmography). Accordingly, this ERS task force reviewed the field of respiratory muscle testing in health and disease, with particular reference to data obtained since the previous ATS/ERS statement. It summarises the most recent scientific and methodological developments regarding respiratory mechanics and respiratory muscle assessment by addressing the validity, precision, reproducibility, prognostic value and responsiveness to interventions of various methods. A particular emphasis is placed on assessment during exercise, which is a useful condition to stress the respiratory system.

Cryoballoon or Radiofrequency Ablation for Atrial Fibrillation Assessed by Continuous Monitoring: A Randomized Clinical Trial.

Abstract: Background: Advanced generation ablation technologies have been developed to achieve more effective pulmonary vein isolation (PVI) and minimize arrhythmia recurrence after atrial fibrillation (AF) ...

Microglial subtypes: diversity within the microglial community.

Abstract: Microglia are brain‐resident macrophages forming the first active immune barrier in the central nervous system. They fulfill multiple functions across development and adulthood and under disease conditions. Current understanding revolves around microglia acquiring distinct phenotypes upon exposure to extrinsic cues in their environment. However, emerging evidence suggests that microglia display differences in their functions that are not exclusively driven by their milieu, rather by the unique properties these cells possess. This microglial intrinsic heterogeneity has been largely overlooked, favoring the prevailing view that microglia are a single‐cell type endowed with spectacular plasticity, allowing them to acquire multiple phenotypes and thereby fulfill their numerous functions in health and disease. Here, we review the evidence that microglia might form a community of cells in which each member (or “subtype”) displays intrinsic properties and performs unique functions. Distinctive features and functional implications of several microglial subtypes are considered, across contexts of health and disease. Finally, we suggest that microglial subtype categorization shall be based on function and we propose ways for studying them. Hence, we advocate that plasticity (reaction states) and diversity (subtypes) should both be considered when studying the multitasking microglia.

Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury.

Abstract: The role of microglia in spinal cord injury (SCI) remains poorly understood and is often confused with the response of macrophages. Here, we use specific transgenic mouse lines and depleting agents to understand the response of microglia after SCI. We find that microglia are highly dynamic and proliferate extensively during the first two weeks, accumulating around the lesion. There, activated microglia position themselves at the interface between infiltrating leukocytes and astrocytes, which proliferate and form a scar in response to microglia-derived factors, such as IGF-1. Depletion of microglia after SCI causes disruption of glial scar formation, enhances parenchymal immune infiltrates, reduces neuronal and oligodendrocyte survival, and impairs locomotor recovery. Conversely, increased microglial proliferation, induced by local M-CSF delivery, reduces lesion size and enhances functional recovery. Altogether, our results identify microglia as a key cellular component of the scar that develops after SCI to protect neural tissue.

New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries

Abstract: Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

Fused Benzothiadiazole: A Building Block for n-Type Organic Acceptor to Achieve High-Performance Organic Solar Cells

Abstract: Narrow bandgap n-type organic semiconductors (n-OS) have attracted great attention in recent years as acceptors in organic solar cells (OSCs), due to their easily tuned absorption and electronic energy levels in comparison with fullerene acceptors. Herein, a new n-OS acceptor, Y5, with an electron-deficient-core-based fused structure is designed and synthesized, which exhibits a strong absorption in the 600-900 nm region with an extinction coefficient of 1.24 × 105 cm-1 , and an electron mobility of 2.11 × 10-4 cm2 V-1 s-1 . By blending Y5 with three types of common medium-bandgap polymers (J61, PBDB-T, and TTFQx-T1) as donors, all devices exhibit high short-circuit current densities over 20 mA cm-2 . As a result, the power conversion efficiency of the Y5-based OSCs with J61, TTFQx-T1, and PBDB-T reaches 11.0%, 13.1%, and 14.1%, respectively. This indicates that Y5 is a universal and highly efficient n-OS acceptor for applications in organic solar cells.