NCube/papyrus huggingface dataset:
Évaluation de la sécurité des héparines de bas poids moléculaire en hémodialyse au Québec : une étude de cohorte rétrospective

The proportion of patients with end-stage renal disease and patients receiving hemodialysis treatments chronically is constantly increasing worldwide. The hemodialysis procedure requires an appropriate anticoagulation to avoid blood clots in the extracorporeal circuit. Unfractionated heparin (UFH) is the most commonly used anticoagulant for this indication in Canada. However, low-molecular-weight heparin (LMWH) has recently been introduced as an alternative to UFH. The use of LMWH is more convenient than UFH since it requires fewer injections and monitoring, allowing time to dialysis nurses to perform other care. Among patients without chronic kidney disease (CKD), safety of LMWH was extensively evaluated and LMWH is now a first-choice agent in various clinical settings. While LMWH is now used by an increasing number of hemodialysis units, concerns remain due to drug accumulation and increase risk of bleeding reported with LMWH use among CKD patients. Only a few small studies evaluated safety of LMWH in the hemodialysis setting, and their conclusions remain controversial. The overall aim of this study is to evaluate the comparative safety of LMWH when used for hemodialysis anticoagulation. We first conducted a systematic review and meta-analysis in order to evaluate the safety of LMWH in chronic hemodialysis compared to UFH. We then conducted an observational retrospective multicentre study among a cohort of all incident and prevalent chronic hemodialysis patients in Québec between 2007 and 2013 which specific aims are to compare between LMWH and UFH the risk of major and minor bleeding; to evaluate the risk of osteoporotic fractures; and to evaluate the risk of infection. The data was extracted from existing databases (RAMQ-Régie de l’assurance maladie du Québec, Med-Echo-Maintenance et exploitation des données pour l’étude de la clientèle hospitalière. The information on exposure to heparin type was collected from 21 hemodialysis units in Québec. We estimated the risk for each outcome of interest using a COX proportional model or a time-dependent COX proportional model where appropriate, adjusting for multiple covariates. Compared to UFH, LMWH showed no risk difference for bleeding and osteoporotic fracture. A decreased risk of infection was observed for patients receiving LMWH compared to UFH in chronic hemodialysis.

Keyphrases: Infection, Low-molecular-weight heparin, Unfractionated heparin, Bleeding, Osteoporotic fracture, Infection, Hemodialysis, Cohort study, Pharmacoepidemiology
Stimulateur cardiaque biologique : effets de la répartition spatiale des cardiomyocytes avec activité spontanée et de l'étirement uniaxial

Bradycardia refers to pathologically slow heart rhythm. Implantation of an electronic pacemaker (EP) is a standard treatment. Despite reducing morbidity and mortality in appropriate patients, EPs display many shortcomings, notably limited lifespan of the battery, inflammation and tissue remodeling. Biological pacemakers (BPs) may be a therapeutic alternative to EPs. They are created in vivo via ionic channels manipulation, stem cells injection or somatic reprogramming. Those methods usually ignore the random spatial disposition of spontaneous cardiomyocytes and mechano-electric coupling. This thesis aims to investigate the effects of those two phenomena on the spontaneous activity of the BP. Our first project, a theoretical study, demonstrated that random spatial disposition of spontaneous cardiomyocytes, a priori unknown, may induce non negligible intrinsic variability in the BP's spontaneous activity. Intrinsic variability, defined as performance disparities experimentally observed among BPs created under the same protocol, may compromise success rate of implantations to the patient. Our second project, another theoretical study, demonstrated that automaticity strength (the autonomous cardiomyocyte’s ability to drive its quiescent neighbors) and linear structural anisotropy may modulate but not eliminate intrinsic variability. Our last project, an experimental study, characterized effects of uniaxial stretch in BP monolayer cultures, and revealed both temporal and spatial stabilizing roles of that type of mechanical stimulus. Together, those studies stress that random spatial disposition of spontaneous cardiomyocytes and cardiac mechano-electric coupling are important phenomena that most be taken into account before BP's implantation to the patient.

Keyphrases: Cardiac automaticity, Bradycardia, Electronic pacemaker, Biological pacemaker, Spontaneous cardiomyocyte, Spatial disposition, Automaticity strength, Anisotropy, Cardiac modeling, Uniaxial stretch
Rôle des ARFs dans la migration et la régulation phénotypique des cellules du muscle lisse vasculaire

Atherosclerosis is a disorder of the vascular wall, characterized by an uncontrolled migration and proliferation of vascular smooth muscle cells (VSMC). In this disease, these cells switch from a normal « contractile » to deregulated « synthetic » phénotype. This disease can cause grave complications and the current available therapies can still be improved.  In these studies, we are going to examine the role of ADP ribosylation factors (ARF) in migration and phenotypic regulation of vascular smooth muscle cells. ARFs are molecular switches which are implicated in many biological processes such as membrane lipid remodeling and vesicular trafic control. More and more roles have been found for these, and we emit the hypothesis that ARFs are implicated in VSMC migration and proliferation. First, we have studied the role of ARF6 in VSMC migration stimulated by Angiotensin II. The latter is a hypertensive hormone which also has mitotic effects on smooth muscle. ARF6 is activated by Ang II through the beta-arrestin pathway, and these two proteins control Ang II-stimulated cell migration by coordinating the internalisation of the Ang II receptor.  Secondly, we have studied the role of ARFs in VSMC phenotypic regulation. We observed that ARF1 inhibition reduces the expression of smooth muscle markers SM22α et αSMA through the Akt pathway. ARF1 regulates this signaling pathway by controlling focal adhesion complex assembly.   In sum, we demonstrated the importance of ARFs in VSMC biology. The elucidations of the mechanism of AT1 endocytosis controlling cell migration, and also of the role of ARF1 in phenotypical regulation, are both original contributions which would assist in the elaboration of new therapeutic strategies.

Keyphrases: ARF6, ARF1, Clathrine, Akt, Vascular smooth muscle, Atherosclerosis, Angiotensin II, Beta-arrestin, Clathrin
Role of the CBL Family of E3-Ubiquitin Ligases in the Humoral Immune Response

Production of high affinity antibodies is a hallmark of the humoral immune response and occurs in the germinal center (GC). It depends on a stage-wise developmental process that includes B cell activation, antigen processing and presentation to T follicular helper (Tfh) cells, proliferation and somatic hypermutation in GC, selection and eventual differentiation into antibody-secreting plasma cells (PC) or memory B cells. Previous studies have shown that B cell development and activation in GC are controlled by different molecular mechanisms, such as protein phosphorylation, transcription, microRNA, and epigenetic modification. My thesis tries to extend these studies by exploring the potential role of protein ubiquitination in the GC reaction. We have found that both CBL and CBLB are highly upregulated in GC B cells as compared to naïve B cells and, within the GC B cells, light zone (LZ) GC B cells expressed higher level of CBLs compare to dark zone (DZ) cells. To understand the function of CBLs in the GC reaction, we have examined GC B cell development and differentiation in the mutant mice in which CBLs are either conditionally ablated before GC initiation (in CBLdKO-Mb1 mice) or during GC progression (in CBLdKO-Cg mice). Our findings reveal that CBLs play critical roles in both GC entry and exit checkpoints. At the entry checkpoint of the GC reaction, CBLs are required for naïve B cell antigen uptake, processing, and presentation to Tfh cells. They regulate this process by promoting B cell antigen receptor (BCR) internalization and sorting to lysosome for degradation via ubiquitination Ig, a component of the BCR complex. However, after entering the GC stage, CBLs control selection for high affinity antibodies but not the production of total antibodies, because in the absence of CBLs GC B cells can still develop relatively normally but fail to selectively expand high affinity BCR producing clones as compared to control B cells. Our further analyses reveal that CBLs control this step of GC B cell development by promoting ubiquitination of IRF4, a transcription factor that is upregulated in the later stage GC B cells with high affinity BCR. Together, our studies provide clear evidence that CBL-mediated ubiquitination is an important and novel regulatory mode in B cells that controls different stages of GC reaction and antibody responses. Modulation of the CBL pathway can be a potentially useful approach not only to interfere humoral immunity for the treatment and prevention of human diseases, but also enhance vaccination in the future.

Keyphrases: T-dependent immune response, Germinal centre, B cell, Tfh cell, Antigen presentation, E3 ubiquitin ligase, CBL, CBLB, Antibody affinity maturation, IRF4
Virus de l’hépatite C chez la femme enceinte et l’enfant : diversité, réponse neutralisante et transmission verticale

Hepatitis C virus can be transmitted from mother to child during pregnancy and childbirth. At present, there is no effective means to prevent vertical transmission (VT) which occurs in approximately 5 to 10% of cases. HCV is highly diversified and is found as quasispecies, a swarm of closely related yet genetically distinct variants whose composition is influenced by the host immune response. Pregnancy is associated with immune modulations allowing the establishment of maternal tolerance to the fetus, bearing 50% paternal antigens. In addition, we have shown that HCV was subjected to selective pressure targeting the viral envelope during pregnancy and suggesting the involvement of the neutralizing response. To better understand the effect of the maternal humoral response on HCV evolution during pregnancy, and the nature of the quasispecies fraction that is vertically transmitted, we characterized HCV quasispecies composition by ultradeep sequencing in a group of 42 pregnant women infected with HCV alone (n=19) or coinfected with HCV and HIV-1 (n=23), et in 5 mother-child pairs for whom HCV VT occurred. Using molecular clock analysis we also estimated the moment of VT during pregnancy. Overall, a high quasispecies diversity was associated with an effective neutralizing activity. This was also associated with reduced risks of VT in women infected with HCV alone but not in coinfected patients. The fraction of the quasispecies shared between mother and child was also 10 times more important in the cases where the mother was coinfected. Finally, estimations of the moment of VT strongly suggest the incidence of early in utero transmission. Alltogether our results showed that HCV evolution during pregnancy is driven by the maternal neutralizing response, which in turn is important in limiting viral transmission to the child in pregnant women infected with HCV only. This points to a specific mode of VT, potentially related to the ability of HCV to attach to certain vehicles, allowing the transport of specific variants across the placenta. In coinfected women, the absence of association between neutralizing activity and HCV VT, and the transmission of multiple variants from the mother to the child suggest a non specific route of VT, presumably associated with weakened placental barrier or altered fetal immunity that could have restricted the infection. Our findings allow for a better understanding of the mechanisms involved in HCV VT and could inform future strategies in the management of HCV-infected pregnant women.

Keyphrases: HCV, Quasispecies, Pregnancy, Vertical transmission, Transmission bottleneck, Neutralizing response, HIV-1, Ultradeep sequencing, Risk factors
Caractérisation du rôle du facteur ElyC dans la biogenèse de l’enveloppe chez l’organisme modèle Escherichia coli

Peptidoglycan (PG) is the main structural component of bacterial envelope and it protects bacterial cells against osmotic pressure. Defects in PG cause bacterial cell lysis. Therefore, the pathway for PG synthesis is one of the best sources of antibacterial targets. However, the molecular assembly of PG and the regulatory pathways for the maintenance of this critical envelope layer are still not well understood. To broaden our understanding of these processes, we aimed to study the newly discovered Escherichia coli factor ElyC that is needed for maintaining PG integrity at 21°C. The ΔelyC mutant presents a PG biosynthesis arrest followed by bacterial cell lysis at the end of the logarithmic phase of growth at 21°C.         First, we identified the periplasmic proteins, DsbG and Spy, as multi-copy suppressors of the ΔelyC lysis phenotype at 21°C. We showed that these suppressors act by a chaperone activity to restore protein folding defect in the envelope compartment of the mutant which fully correct the PG synthesis defect at 21°C. These results suggest that the PG biosynthesis is blocked due to a protein folding defect in the envelope.          Secondly, we evaluated the requirement of ElyC for cell growth and PG synthesis at 37°C. We showed that ElyC is also important for PG biosynthesis at 37°C. In fact, the compositional analysis of PG revealed a decrease in the amount of this compound either at 21 or 37°C. Nevertheless, this decrease was greater at 21°C, which might explain the lysis of the mutant at this temperature. These results demonstrate that the rate of PG biosynthesis decreases in the absence of ElyC factor and this decrease becomes more severe at low temperature. This suggested that ElyC plays an important role in a cold sensitive process.        Finally, we analysed the transcriptomic response in ElyC defective cells at both temperatures. The response was proportional to the degree of PG damages. The number of differentially expressed genes in the ΔelyC compared to wild-type strain was higher at 21°C than at 37°C. Furthermore, several envelope stress response systems were activated at 21°C, leading to the induction of several genes involved in mechanisms such as envelope stress resistance and damage repair. However, the envelope stress response was moderate at 37°C. The analysis of downregulated genes in the ΔelyC mutant showed that several of these genes are involved in mechanisms taking place in the inner membrane, which suggested a defect at the level of this compartment.         In conclusion, this work demonstrated that ElyC is an important factor for PG biosynthesis at all tested temperatures. ElyC might be a direct or indirect regulator of PG biosynthesis mechanism.

Keyphrases: Escherichia coli, ElyC, 21°C, 37°C, Cold sensitive, Chaperonnes, Peptidoglycan, Chaperones
Évaluation du travail respiratoire dans l’insuffisance respiratoire aiguë de l’enfant

Acute respiratory failure is the leading cause of hospital admissions in the pediatric intensive care unit and is associated with significant morbidity and mortality. Since the pediatric population is characterized by a great heterogeneity in terms of age and respiratory pathology, individualization of therapeutic management is essential. Different minimally invasive methods have been described to assess the patient's work of breathing in acute respiratory failure. Objectives - The main objective of the project was to assess the diagnostic and therapeutic contribution of the measurement of the work of breathing in children with acute hypercapnic respiratory failure. Methods - We used in the present work three tools to assess the work of breathing: oesogastric pressures, electrical activity of the diaphragm monitoring and oxygen consumption measurements. Results - We highlighted how these different methods are valuable during the ICU stay: (i) in the early phase of the disease to initiate or withdraw noninvasive ventilation and to optimize its settings; (ii) in the recovery phase to evaluate the patient-ventilator interaction; (iii) during the weaning process to early detect an increase in work of breathing.  Conclusion - Throughout the disease process, the work of breathing assessment can be useful to enhance our understanding of the pathophysiology of lung disease, to optimize mechanical ventilation settings and adapt therapeutic interventions.

Keyphrases: Mechanical ventilation, Respiratory mechanics, Work of breathing, Acute respiratory failure, Electrical activity of the diaphragm, Indirect calorimetry, Esophageal pressure, Children, Pediatrics
Évaluation de l'innocuité et de l'efficacité d'un dérivé synthétique marqué de l'adrénomédulline dans l'imagerie moléculaire pulmonaire chez l'humain

Background. The pulmonary circulation is submitted to large physiologic hemodynamic variations and possesses numerous important metabolic functions mediated through its vast endothelial surface. Unfortunately, no test is currently available that can directly evaluate endothelial integrity and pulmonary perfusion gradients at the same time. We developed PulmoBind, a chelated derivative of human adrenomedullin labeled with 99m-Tc for nuclear medicine SPECT imaging. By specifically binding to its endothelial receptors, abundantly expressed in human alveolar capillaries, PulmoBind can provide a non-invasive evaluation of pulmonary function that can help in the diagnosis of disorders affecting the pulmonary circulation. This thesis represents my doctoral work to determine the safety of PulmoBind in humans and its capacity to generate good quality imaging for diagnosis purposes. Methods. Twenty healthy participants were included into escalating doses groups of 5 mCi (n=5), 10 mCi (n=5) or 15 mCi (n=10) 99mTc-PulmoBind. Vital signs were closely monitored and safety biochemistry and hematology parameters obtained. SPECT imaging was serially performed and 99mTc-PulmoBind dosimetric and spatial distribution analysis accomplished. Imaging quality of the lungs was assessed serially. Results. Radiochemical purity of 99mTc-PulmoBind was greater than 95%. There were no safety concerns at the 3 dosages studied. Imaging revealed a predominant and prolonged lung uptake with mean peak pulmonary extraction of 58% ± 7% (mean ± SD) of the injected dose. PulmoBind was well tolerated and resulted in no clinically significant adverse events. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent quality tomographic imaging of the lungs. The postural lung perfusion gradient was detectable. Indeed, dorsal activity was 18.1 ± 2.1% greater than ventral activity, and caudal activity was 25.7 ± 1.6% greater than cranial activity. The intensity of PB activity followed a normal distribution while macro aggregated albumin (MAA) activity was importantly skewed and bimodal. Conclusion. 99mTc-PulmoBind up to a dose of 15 mCi is safe and provides good quality lung perfusion imaging that can reveal the heterogeneity of the pulmonary perfusion. Therefore, the safety and efficacy of this agent could be tested in disorders of the pulmonary circulation such as pulmonary arterial hypertension.

Keyphrases: Phase I, SPECT, Innocuité, RAMP, Receptor activity modifying protein, Hypertension pulmonaire, HTAP, Calcitonin receptor-like receptor, Adrenomedullin, Nuclear medicine, Radiotracer, Molecular imaging, Clinical study, Pulmonary arterial hypertension, Pulmonary circulation, Safety, Molecular marker, Nuclear physics, Diagnostic imaging, Pulmonary endothelium, Pulmonary hypertension, Dosimetry
Exploration et analyse éthique des facteurs influençant la priorisation des patients, ainsi que la fréquence et la durée des traitements en physiothérapie musculosquelettique

Background: In the context of an aging population, physiotherapy needs are growing due to an increased prevalence of chronic disease and disability. Physiotherapy professionals are required to make decisions regarding allocation and use of their services because of this increased need coupled with a scarcity of resources. These decisions involve prioritization of patients, and choices regarding frequency and duration of treatment. Many factors – some justifiable and some not – can influence these decisions, including clinical factors, as well as non-clinical factors. Two preliminary studies help to better comprehend the complexity of decisions associated with resource allocation. Objective: To explore and ethically analyze factors that can influence the prioritization of patients, as well as the frequency and duration of treatment in musculoskeletal physiotherapy. Method: This project is anchored in a empirical bioethics approach. The empirical part of the project uses a mixed methods approach: a national survey with clinical vignettes and semi-structured interviews. To integrate the quantitative and qualitative results, a conceptual analysis was conducted using two different analytical frameworks: distributive justice and complexity. Results: The study did not find bias on the part of physiotherapy professionals in relation to patients’ personal characteristics (age, sex, socioeconomic status) when allocating resources for a patient with the same clinical profile, but attitudes and behaviours of patients did have an influence on the distribution of services. This project confirms that even though physiotherapy professionals do not demonstrate explicit bias regarding patient acuity or insurance status, some populations are still disadvantaged in their access to physiotherapy, notably patients with chronic pain and those who are not covered by insurance. Further, the distribution of services is closely related to the funding source providing payment for treatments. Patients covered by a workers compensation board for a work accident receive a higher frequency of treatment. Conclusion: Physiotherapy professionals do not acknowledge biases in their resource allocation decisions, although there was bias in the provision of physiotherapy services resulting in overtreatment for some groups and under-treatment for others. These inequalities highlight the need for more research in order to develop national and provincial policies to ensure equity in the allocation of physiotherapy resources. It is imperative that the factors influencing the prioritization of patients, and the frequency and duration of treatment in musculoskeletal physiotherapy, be scrutinized so that the decision models being used are ethically justified and applied in a transparent, systematic and responsible way.

Keyphrases: physiotherapy, bioethics, ethical principles, prioritization, frequency, duration, resource allocation, musculoskeletal