NCube/papyrus huggingface dataset:
Une procédure de sélection automatique de la discrétisation optimale de la ligne du temps pour des méthodes longitudinales d’inférence causale

In longitudinal observational studies, subject characteristics are measured and followed over time. Although the underlying evolution of such response variables may be continuous in time, in practice the measurements are observed at discrete time points. In real world data sets such as administrative databases, it is reasonable to assume that the underlying observed exposure processes happen in real time. However, standard causal inference methods for longitudinal data usually assume that the underlying exposures are discrete time processes, and that the observational time points are the only time points when the exposures may change values. A crucial pitfall of this traditional approach lies in the manner to discretize this underlying continuous timeline.   The common approach is to arbitrarily discretize the timeline into several time-points that separate the data into intervals. The problem at hand is then selecting the appropriate discretization that sufficiently captures all of the intricate relationships between the variables in the optic of appropriately controlling the time-dependent confounding bias. On the other hand, the common theme of this problem is that as the number of time-points increases, the dimensionality increases, and the volume of the space increases so rapidly that the available data may become sparse. In particular, standard causal inference methods rely on reasonable data support for the exposure of interest. Without such support, estimators will be ill-defined or extremely variable. Although one might respond to this challenge by creating a coarser discretization, such an approach introduces bias by failing to capture all the time-dependent confounding and leaves open the question of how to choose an optimal degree of coarsening. Hence, an arbitrary number of time-points may result in unpredictable bias or inflated variance.  We propose a novel method that data-adaptively selects an optimal discretization. This will be done through the cross-validation of a loss function based on pooled Longitudinal Targeted Maximum Likelihood Estimation. We conduct a simulation study in which we generate time-dependent confounded data to evaluate the bias-variance trade-off and the performance of the selection procedure. We also apply our selection procedure to a real-world data application of the effect of asthma medication during pregnancy on pregnancy duration.

Keyphrases: Administrative databases, Coarsening, Semi-parametric estimation, Machine learning
Évaluation et caractérisation des enzymes de métabolisme de la superfamille des CYP450 dans l’intestin grêle humain

Oral administration of drugs has proven to be the easiest and safest way to treat patients. However, it is associated with great interindividual variability that could be attributed to genetics, environment, pathologies, etc. Hepatic first-pass metabolism was long considered as a major cause for variability in drug plasma concentrations. It is now recognized that extrahepatic organs, especially the small intestine, can have a significant effect in pre-systemic metabolism for orally administrated drugs. Indeed, those compounds must go through the enterocytes before reaching the blood circulation, exposing them to drug-metabolizing enzymes, such as Cytochromes P450s (CYP450s). CYP450s mediate phase I metabolism reactions and are involved in the metabolism of 75% of clinically used drugs.  Our hypothesis is that regional CYP450 distribution in the small intestine can partly explain the observed interindividual variability in drug plasma levels and drug response for orally administered drugs. Therefore, our objectives are to characterize relative mRNA expression levels and in vitro activities of major CYP450 isoenzymes in human small intestine. Since drug transport can affect xenobiotic absorption in the small intestine, our secondary objective is to assess mRNA expression levels for membrane drug transporters. We showed high interindividual variability in CYP450 mRNA expression and activity along the small intestine, as well as significant activity for CYP3A4, CYP2J2 and CYP2C9.  Our results will lead to better pharmacokinetic models and will improve variability prediction in plasma concentrations for orally administered drugs.

Keyphrases: Cytochromes P450, Human small intestine, Interindividual variability, Metabolism, Pharmacokinetics, Membrane drug transporters
Programme d’amélioration de la qualité de la surveillance de la thérapie anticoagulante orale en fibrillation auriculaire en pharmacie : une étude pilote intégrée au Réseau STAT

About 1%-2% of the general population is affected by atrial fibrillation (AF), with higher prevalence in the older population. For these patients, the risk of stroke is up to five times greater than for those without AF. Guidelines recommend oral anticoagulant agents in a majority of AF patients to prevent thromboembolic events. Close monitoring is needed to achieve adequate anticoagulation while avoiding bleeding complications. However, a practice gap exists between guideline recommendations and real world use of oral anticoagulants in patients with AF. Moreover, very few studies have evaluated the quality of anticoagulant management by community pharmacists.  A first study, involving an experts group, led to the development of a quality indicators (QIs) list to evaluate oral anticoagulant (vitamin K antagonist (VKA) and direct oral anticoagulant (DOAC)) management in AF patients by community pharmacists. A second study assessed the feasibility of implementing a quality improvement program in this field through a practice-based research network (Réseau STAT) and explored the impact of the program on the quality of therapy management and pharmacists’ knowledge. The program included an audit with feedback based on QIs previously developed and specific training activities. The results suggest the program is relevant in community pharmacy. Indeed, although the time in the therapeutic range of international normalized ratios (INRs) for patients on VKAs and adherence to DOACs were initially high, the overall quality of oral anticoagulant management and pharmacists’ knowledge at baseline were low. The feasibility of providing the program through the Réseau STAT was demonstrated. Participation and satisfaction rates were relatively high. Lack of time was the most important reported barrier. Finally, over a six-month period, improvements in the quality of clinical practices and pharmacists’ knowledge were observed.

Keyphrases: Anticoagulation, Atrial fibrillation, Community pharmacy, Therapy management, Quality indicator, Quality improvement, Practice-based research network
Étude de la perméabilité intestinale des médicaments par la reconstitution du transporteur BCRP/ABCG2 dans des protéoliposomes

Intestinal membrane transporters play a critical role in the pharmacokinetics of orally administered drugs. Membrane permeability of cells regulate the absorption of drugs by modulating their distribution in the body. In vitro models like the Caco-2 cell-based assay and the non-cellular PAMPA assay are used to predict the bioavailability of drugs. However, the Caco-2 assay is limited by its reproducibility and heterogeneity of the culture conditions while the PAMPA assay is only used to observe passive permeability. Thus, no model allows the study of isolated and specific membrane transporters. We propose to study membrane permeability with a new approach using a non-cellular lipid bilayer constituted of recombinant transporter. In this study, the isoform 1 of the human BCRP/ABCG2, which is known to limit the intestinal absorption of drug substrates, was expressed in the yeast Pichia pastoris and purified by affinity chromatography. The isoform 1 of BCRP cDNA was modified by PCR and cloned into the expression vector pJ902-15. The resulting construct contain the coding region of BCRP with a 10 histidines tag under the control of the AOX1 promoter. P. pastoris transformation was carried by electroporation with the linearized vector pJ902-ABCG2i-His10. The clone with the highest BCRP expression was determined immunoblotting using mAb BXP-21. This clone was inoculated in 1 L of MGY media and induced in the MM media containing methanol. The cells were lysed using a Freezer/Mill and the microsomes were solubilized and purified on an ÄKTA-FPLC system using a HisTrap HP column.  We have established a P. pastoris expression system for the production of the recombinant transporter BCRP. Immunoblotting of whole cell lysates shows that the recombinant BCRP has an apparent weight of 65 kDa. From a 1 L yeast culture, approximately 125 mg of BCRP was partially purified. To confirm that BCRP-His10 is functional, further studies are necessary by measuring the ATPase activity in presence of prazosin. The proteoliposomes of the recombinant BCRP will serve as a proof-of-concept for the generation of a library of recombinant transporter proteins incorporated into liposomes. This model will facilitate the assessment and understanding of the bioavailability of drug candidates.

Keyphrases: BCRP, ABCG2, Pichia pastoris, Drug bioavailability, Intestinal permeability, Proteoliposomes
Impact de l’âge et de l’effet stéréoscopique sur une tâche de poursuite d’objets multiples

3D vision develops during childhood and tends to diminish after 65 years old. It is relatively unknown how stereopsis helps in a more complex environment, such as walking in a crowd where objects in movement can occlude each other. One task that reflects this dynamic environment is a multiple object tracking task (MOT). For this research, the portable version of NeuroTrackerTM showing a MOT task with and without stereoscopic effect has been used, to evaluate the impact of stereopsis on performances depending on the age. Three groups of 20 subjects (7-12 years old, 18-40 years old and 65 years and older) completed the task in both conditions. The adult group obtained the higher scores (mean of both conditions), followed by the children and the older adult group. Also, the score difference between both conditions was similar for the adults and the children, and was non significant for the elderlies. It demonstrates that stereopsis helps adults and children 7-12 years old to accomplish this kind of task. The NeuroTrackerTM, by evaluating how stereopsis is used in a complex scene, could be useful in various domains. The portability of the NeuroTrackerTM could also facilitate its clinical application with different populations.

Keyphrases: MOT, Vision sciences, Stereoscopic vision, Aging, Children
Brasília – Sinfonia da Alvorada d’Antonio Carlos Jobim : enjeux esthétique et idéologique d’une commande de l’état brésilien

Antonio Carlos Jobim (1927-1994), a musician best known for his bossa novas (including the hits "Garota de Ipanema" and "Desafinado") and his Orfeo da Conceição (1956), is also the author of musical compositions written in the Western avant-garde tradition. His sole symphony, Brasília — Sinfonia da Alvorada (1958-1961), is rooted in rich musical and ideological terrain. In fact, the piece was commisioned by the Brazilian president Juscelino Kubitschek (1902-1976) for the inauguration ceremony of Brasilia as the new federal capital, in place of Rio de Janeiro. Juscelino Kubitschek's democratically elected government (1956-1961) was caracterized by a wave of prosperity and rapid modernization. It is situated between two dictatorships that marked Brazil's history: that of Getúlio Vargas (1930-1945) and the coup carried out by the military (1964-1985). In this thesis, I will retrace the circumstances leading to the commisioning of the piece, lay out the government's expectations and speculate on the reasons leading to their chosing Jobim over other Brazilian composers (particularly Heitor Villa-Lobos). I will describe the genesis of Jobim's piece and that of the libretto by Vinicius de Moraes, as well as their efforts to infuse it with the spirit of modernization present in the 1950s and 60s brazilian society. The piece itself did not end up being played at the inauguration of the capital in 1961, and was only performed in Brasilia for the first time in 1986.  This study is based on secondary literature and a variety of sources, such as the orchestral score and piano reduction of the piece, newspaper articles surrounding its composition and reception, and three separate recordings (the first of which being the long-playing record produced within Jobim's lifetime, in 1961.) A musical analysis of the score will highlight its use of Brazilian Folklore, bird songs and paraphrases of modernist pieces by famous Western composers, such as Igor Stravinsky (Rite of Spring) and Heitor Villa-Lobos (Choro n° 10 et Bachianas Brasileiras n° 5).

Keyphrases: Antonio Carlos Jobim, Sinfonia da Alvorada, Vinicius de Moraes, Brasília, Bossa Nova, Brazil, Modernism
Discovering and analyzing my compositional language : developing a personal style without severing ties to classical music

This paper presents an analysis and discussion of five compositions I wrote during my master’s studies. The works are for solo piano, voice and piano, trombone and piano, string quartet, and wind quintet.  The objective of this project was to develop my musical language and to observe the different influences that characterize it. To achieve this, some of the pieces were restricted using specific modes or techniques, while others remained freely composed. I observe many influences from my formation as a pianist, particularly those of Scriabin, Shostakovich, and Prokofiev. Additionally, I discuss the influence that Jewish music has had on me and how I use elements of it in my music.

Keyphrases: Composition, Klezmer, Analysis, Jewish music, Modes of limited transposition
Innovations médiatiques et avant-garde musicale : une sociomusicologie des «musiques émergentes» à l’ère du web 2.0

Through the study of Montreal’s early 2010s "post-rap" scene, our goal is to observe how the artists of this scene built a musical genre that stands out, within its audience, from all other hip hop production in Quebec. We proceed to this exercice with the use of taste and cultural practices ranking schemes developed by French and American sociology. We interviewed several stakeholders of the Quebec alternative media world and a band associated with the label "post-rap" to understand how the mediation of this music could create a social distinction between this scene and the rest of the production of other hip hop music. “Post-rap’s” mediation and dissemination of musical schemes, which involve specific uses of digital marketing and technologies, associate it with the world of "emerging music", whose consumption is theoretically linked to the habits of a student or educated population, thus to average or higher social classes. We observe that “emerging musics” aren’t filed under any specific genre but rather the belonging to an autonomous professional network standing in the margins of the Quebec music industry. As a scene, “post-rap” does belong to the “emerging music” network but shares stylistic traits with hip hop music. Since “post-rap” music manifests itself as a musically similar but socially different phenomenon than Quebec’s hip hop, we query the ways genres are classified within sociological studies of cultural and musical tastes.

Keyphrases: Rap, Sociomusicology, Pop music, Indie music, Cultural capital
Arcade Fire et le paradoxe de l’indie : de la scène montréalaise à la reconnaissance internationale

Almost fifteen years after the mainstream breakthrough of Nirvana’s grunge, the group Arcade Fire, originating from the early 2000s indie scene in Montreal, has earned important international recognition. In fact, despite the close association of their early career and their first album, Funeral, with the independent music scene, Arcade Fire has gone on to meet with great commercial, public and critical success. Why, therefore, is this group, who has changed their scene and their scale of production, diffusion and distribution, still linked with the term “indie”? Supported by a bibliography in popular music studies and sociomusicology, this master’s thesis explores this question firstly through a historical study of the term indie and of Montreal’s indie scene, followed by an analysis of Arcade Fire’s career, in order to understand this term’s continued relevance in writing about the group. This work shows that while the Arcade Fire’s career is now less indie in their manner of producing, distributing and diffusing their music, the label still serves as a way of referring to the group, since it is linked to the human values of identity and authenticity. In fact, the construction of an indie identity and an aura of authenticity around the group functions as a strategy to add value and legitimate its career to date.

Keyphrases: Arcade Fire, Indie, Indie scene, Commercial, public and critical success, Identity, Authenticity
Anatomical Correlates of Working Memory Deficits in Schizophrenia

Working memory, which is the limited capacity to temporarily maintain and manipulate information, is a core cognitive deficit in schizophrenia. This impairment has a strong impact on the daily lives of patients. A previous study of our laboratory observed that working memory deficits are not homogeneous and that some processes are more disturbed than others (Grot, Potvin et al., 2014). This was supported by a subsequent study, which showed that the voluntary association of distinct information into a coherent whole (i.e. an object and its spatial position) was specifically impaired in patients with schizophrenia (Grot, Légaré et al., 2017). This specific deficit, which is referred to as active binding, is underpinned by a hypoactivation of the left prefrontal and parietal cortex in patients (Grot, Légaré et al., 2017). These two regions are related to attentional processes, manipulation, and encoding strategies, which confer the skills and flexibility required for working memory (Kane and Engle 2002, Baddeley 2003). Interestingly, numerous studies report a cortical thickness reduction in these regions, as well as an alteration of the white fibres interconnecting them in patients with schizophrenia (Goldman, Pezawas et al., 2009). Accordingly, our study showed that anatomical modifications of this network could underpin the specific active binding deficit observed in schizophrenia patients. More specifically, a reduced leftward lateralization of the prefrontal-parietal network could contribute to this specific working memory deficit in patients.

Keyphrases: Schizophrenia, Working Memory, Diffusion Imaging, Cortical Thickness
Rôle de la Galectin-3 extra cellulaire dans la migration des cellules B à travers les barrières du système nerveux central dans le contexte de la sclérose en plaques

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), hallmarks of the disease are an important infiltration of immune cells and demyelinating lesions in the CNS of patients. A key event in the disease is CNS barriers’ loss of integrity that allows the migration of immune cells, including B cells, from the blood to the CNS. Migration is regulated by many parameters, among which, the expression of molecules enabling adhesion to the endothelial cells of the CNS barriers. Proteomic data from our lab identified galectin-3, a pro-inflammatory protein, as potentially involved in B cells’ migration toward the CNS. Moreover, galectin-3 could add to B cells pathogenicity. Our results show that healthy donors’ whole blood B cells as well as effector B cells in vitro express galectin-3 on their surface. Moreover, effector B cells are able to secrete galectin-3. In vitro assay revealed that galectin-3+ effector B cells express more pro-inflammatory cytokines than galectin-3- effector B cells. However, a temporary decrease of IL-6 and IFN-γ expression is induced when effector B cells are treated with galectin-3. Furthermore, exogenous galectin-3 can bind to B cells’ surface but it doesn’t influence their migration through in vitro models of the SNC barriers. In addition, we could detect galectin-3 in MS patients’ cerebrospinal fluid (CSF) and serum, the latter showed increased concentration compared to healthy donors’. Moreover, we evidence that MS patients’ B cells express more galectin-3 on the cell surface than healthy donors’. In conclusion, our results don’t support the initial hypothesis that galectin-3 enables B cells’ migration through CNS barriers and galectin-3’s influence on B cells pathogenicity in vitro seems to depend on its concentration. But galectin-3’s increased expression in MS patients suggests that it could be implicated in the disease.

Keyphrases: migration, galectin-3, multiple sclerosis, central nervous system, central nervous system barriers, B cells
Caractérisation moléculaire et fonctionnelle d'un nouvel allèle du gène de la polarité cellulaire planaire (PCP) Vangl2

Neural tube defects (NTDs) including spina bifida, craniorachischisis as well as anencephaly are the most common group of congenital malformations of the central nervous system (CNS). Folic acid recommendations for pregnant women as well as fortification of several foods with folic acid have significantly reduced the incidence of NTDs. Still at least 1 to 2 newborns per 1000 births have NTDs. Several studies have searched for possible genetic factors that could predispose for NTDs. Planar cell polarity (PCP) genes are known to be implicated in important developmental processes, like cell migration and convergent extension. The Looptail (Lp) mutant mouse was the first mutant to link a PCP core member, called Vangl2, to the pathogenesis of NTDs in mammals. In this report, we have studied a novel Vangl2 mouse mutant induced by Ethyl-Nitrosourea (ENU). This mouse called Curly Bob harbors a missense mutation in Vangl2 and causes a change of the amino acid residue I268 in Vangl2 protein. This autosomal mutation segregates in a semi-dominant fashion with heterozygous mice displaying a looped tail appearance, bobbing head and a circling behavior. We also noticed that a small portion of affected females have an imperforate vagina. Homozygote mutant embryos suffer from a severe form of NTD called craniorachischisis and do not survive after birth. They also display severe PCP defects in the inner hair cells of the cochlea and posterior cristae. This mutant genetically interacts with the Lp allele (Vangl2S464N) in neural tube development and inner ear hair cell polarity. The Vangl2I268N protein variant is expressed at very low levels in affected neural tissues of mutant homozygous embryos. This mutant protein no longer physically interacts with another PCP core protein DVL3.

Keyphrases: Vangl2, Neural tube defects, Planar cell polarity, Inner ear hair cells