Du fondamental à la clinique, cette thèse a été construite autour d’un seul mot clefs : KCC2, grâce à plusieurs projets collaboratifs. Ce co-transporteur d’ion est une molécule à plusieurs facettes dont la multiplicité des rôles et ses implications dans diverses pathologies font d’elle un élément clef de l’organisme vivant. En plus des études phylogénétiques et thérapeutiques effectuées au cours de cette période, mon principal travail a été de déterminer le rôle physio-pathologiques in vitro et in vivo d’un mécanisme de régulation post-traductionnelle de KCC2. Nous avons dans un premier temps montré que la déphosphorylation des Thréonines (Thr) 906 et 1007 in vitro était un puissant activateur de la protéine. En effet, nous avons montré que l’état de phosphorylation des sites dicté par la voie Wnk-Spak/OSR1 était impliqué dans le niveau d’expression en surface de la protéine. Par la suite, nous avons pu révéler que les souris porteuses d’une mutation phospho-mimétique Glu906 et Glu1007 “(KCC2E/+)” sur un allèle de la protéine, présentaient un décalage de l’émergence de la force inhibitrice GABAergique, une altération de la balance excitation/inhibition, ainsi qu’une augmentation de la susceptibilité à générer des crises. De plus, ces même souris développent des troubles de la communication chez le jeune ainsi qu’un défaut de sociabilité chez l’adulte, deux symptômes clefs des TSA. Ces résultats suggèrent que la régulation post-traductionnelle est un mécanisme physio-pathologique clef de la protéine. / From basic to clinical aspects, this thesis comprises different collaborative projects focusing on KCC2. KCC2 is a complex protein with multiple roles and implications in various pathologies that makes this molecule a key element of living organisms. In addition to the phylogenetic and therapeutic studies performed during this period, my main work has been to determine the in vitro and in vivo physio-pathological role of a KCC2 post-translational regulatory mechanism. We first showed in vitro that dephosphorylation of Threonines (Thr) 906 and 1007 was a potent activator of the protein. We have shown that phosphorylation state by the Wnk-Spak/OSR1 pathway of these two residues is implicated in the level surface expression of KCC2. Subsequently we have revealed that mice carrying in one allele a phospho-mimetic mutations Glu906 and Glu1007 “(KCC2E/+)”, preventing the developmental dephosphorylation at these sites, exhibited a delayed onset of fast synaptic GABA inhibition, a decreased ratio of spontaneous GABA- to glutamate-driven post-synaptic responses, and a significantly reduced flurothyl-induced seizure threshold. Furthermore, KCC2E/+ pups and adult mice, respectively, exhibited impaired communication and sociability, classic ASD phenotypes. These results suggest that post-translational regulation is a key physio-pathological mechanism of KCC2.

This study expands on the work of ElHajjar and HajAli (2003) on a quantitative thermoelastic strain analysis method for composite materials. Computational models for various prepreg and thicksection composites are validated with experiments using this quantitative strain analysis method. This study provides this thermomechanical calibrations for prepreg S2glass/epoxy, Carbon/epoxy, and pultruded Eglass/polyester. A research collaboration with the Institute of Paper Science and Technology (IPST) focused on infrared thermography for defect detection in wood and fibrous materials and structural systems. This study provides some detailed information on various testing setups for fiber and corrugated board systems to analyze anomalies and manufacturing defects. Quantitative infrared thermography is suggested as a preferred method for assessing the bond quality in corrugated paper systems. Methods for tracking fullfield thermal data during fatigue have been developed for FRP composites. The temperature changes on the surface of an FRP composite caused by damage during fatigue are tracked and thermoelastic stress analysis (TSA) technique is developed to relate the surface deformation to the IR emission. Infrared thermography is developed for fatigue damage detection in FRP composites with stochastic methods for analyzing this fullfield data. Future damage detection techniques in aging aircraft will require quantitative and noncontact nondestructive evaluation (NDE) methods especially for composite components. Infrared (IR) thermograpy techniques are qualitatively used to assess and indirectly infer the durability of structural systems. A research collaboration with Lockheed Martin for nondestructive evaluation of composite lap shear joints led to a development of thermoelastic stress analysis techniques for evaluation aerospace structures. Infrared thermography is used to investigate failure initiation and progression in composite lap shear joints.

O uso inadequado de antimicrobianos é fator determinante para disseminação da resistência bacteriana. Vários países têm usado como estratégias políticas de restrição para tornar o uso mais racional. Principalmente em hospitais, onde a utilização é mais prevalente. Embora o uso empírico seja a opção de tratamento em muitas condições clínicas, sabe-se que exames microbiológicos de cultura e teste de sensibilidade antimicrobiana (TSA), podem orientar uma prescrição mais racional. Para se avaliar a adequação de prescrições de antimicrobianos de uso restrito no Hospital São Vicente de Paulo de Passo Fundo, considerando resultados de exames microbiológicos e protocolos clínicos da instituição, foram analisadas 372 prescrições de pacientes internados. O tipo de infecção foi a única justificativa apresentada para o uso de antimicrobianos, sendo a maior freqüência para infecções do trato respiratório inferior (59,4%) seguido das do trato urinário (10,8%). O tratamento inicial empírico ocorreu em 89% dos casos. Dos pacientes com uso empírico (331/372), 66,7% apresentaram pneumonia. Nesta situação, devido à dificuldade de coleta de material, o tratamento é baseado nos prováveis agentes causadores e o uso empírico é aceitável. O exame de cultura foi solicitado em menos da metade das prescrições 48,7%(181/372), e o TSA foi realizado nos casos de cultura positiva (121/181). O resultado do TSA apontou que o tratamento inicial prescrito estava adequado em 76% dos casos (92/121). A necessidade de troca do esquema terapêutico inicial foi identificada em 12,7% (23/181) dos casos que realizaram cultura e TSA. A troca de esquema ocorreu em 65,2% (15/23) dos casos, nos demais o médico optou por não alterar devido à resposta clínica do paciente. Das prescrições avaliadas conforme protocolos, 71,9% (192/267) demonstraram indicação terapêutica de acordo com a recomendação. De acordo com os protocolos, observou-se uma freqüência maior de adequação das prescrições e das condutas laboratoriais quando comparada com outros estudos. Estes resultados podem estar associados às políticas de restrição de uso adotadas pela instituição. / The inadequated use of antimicrobials is the determinant fact to the dissemination of the resistance of the bacteria. Many countries have used as a strategy the politics of the restriction to become this use more rational, mainly in the hospitals, where the utilization is more prevalent. Although the empiricist use is the option of the treatment in many clinical conditions, we know that microbiological exams of culture and the test of antimicrobial sensibility (TSA) can conduct to a more rational prescription. To evaluate the adjustment of the prescriptions of antimicrobials in restrict use at São Vicente de Paulo Hospital, in Passo Fundo, and considering the results of the microbiological exams and clinical protocols of the institution, 372 interned patients prescriptions were analyzed. The type of the infection was the unique justify showed to the use of the antimicrobials, being the biggest frequency to the infections in the lower respiratory tract (59.4%), followed by the urinary tract (10.8%). The initial empiricist treatment occurred in 89% of the cases. Within the patients with the empiricist use (331/372), 66.7% showed pneumonia. In this situation, due to the difficulty of the material collecting, the treatment is based in the probable causer agents and the empiricist use is acceptable. The exam of the culture was required in the less of the half prescriptions (48.7%) (181/372) and TSA was executed in the cases of the positive culture (121/181). The results of TSA showed that the initial treatment prescribed was adjusted in 76% of the cases (92/121). The necessity of the changing of the initial therapeutic scheme was identified in 12.7% (23/181) of the cases where the culture and TSA were found. In the others, the doctor opted to not to modify it due to the clinical answer of the patient. According protocols, evaluated prescriptions 71.9% (192/267) showed therapeutic indication according the recommendation. According with the protocols, it was observed a major frequency of adaptation of the prescriptions and of the lab behaviors when it is compared with other studies. These results can be associated with the restriction policies of adopted using for the institution.

O uso inadequado de antimicrobianos é fator determinante para disseminação da resistência bacteriana. Vários países têm usado como estratégias políticas de restrição para tornar o uso mais racional. Principalmente em hospitais, onde a utilização é mais prevalente. Embora o uso empírico seja a opção de tratamento em muitas condições clínicas, sabe-se que exames microbiológicos de cultura e teste de sensibilidade antimicrobiana (TSA), podem orientar uma prescrição mais racional. Para se avaliar a adequação de prescrições de antimicrobianos de uso restrito no Hospital São Vicente de Paulo de Passo Fundo, considerando resultados de exames microbiológicos e protocolos clínicos da instituição, foram analisadas 372 prescrições de pacientes internados. O tipo de infecção foi a única justificativa apresentada para o uso de antimicrobianos, sendo a maior freqüência para infecções do trato respiratório inferior (59,4%) seguido das do trato urinário (10,8%). O tratamento inicial empírico ocorreu em 89% dos casos. Dos pacientes com uso empírico (331/372), 66,7% apresentaram pneumonia. Nesta situação, devido à dificuldade de coleta de material, o tratamento é baseado nos prováveis agentes causadores e o uso empírico é aceitável. O exame de cultura foi solicitado em menos da metade das prescrições 48,7%(181/372), e o TSA foi realizado nos casos de cultura positiva (121/181). O resultado do TSA apontou que o tratamento inicial prescrito estava adequado em 76% dos casos (92/121). A necessidade de troca do esquema terapêutico inicial foi identificada em 12,7% (23/181) dos casos que realizaram cultura e TSA. A troca de esquema ocorreu em 65,2% (15/23) dos casos, nos demais o médico optou por não alterar devido à resposta clínica do paciente. Das prescrições avaliadas conforme protocolos, 71,9% (192/267) demonstraram indicação terapêutica de acordo com a recomendação. De acordo com os protocolos, observou-se uma freqüência maior de adequação das prescrições e das condutas laboratoriais quando comparada com outros estudos. Estes resultados podem estar associados às políticas de restrição de uso adotadas pela instituição. / The inadequated use of antimicrobials is the determinant fact to the dissemination of the resistance of the bacteria. Many countries have used as a strategy the politics of the restriction to become this use more rational, mainly in the hospitals, where the utilization is more prevalent. Although the empiricist use is the option of the treatment in many clinical conditions, we know that microbiological exams of culture and the test of antimicrobial sensibility (TSA) can conduct to a more rational prescription. To evaluate the adjustment of the prescriptions of antimicrobials in restrict use at São Vicente de Paulo Hospital, in Passo Fundo, and considering the results of the microbiological exams and clinical protocols of the institution, 372 interned patients prescriptions were analyzed. The type of the infection was the unique justify showed to the use of the antimicrobials, being the biggest frequency to the infections in the lower respiratory tract (59.4%), followed by the urinary tract (10.8%). The initial empiricist treatment occurred in 89% of the cases. Within the patients with the empiricist use (331/372), 66.7% showed pneumonia. In this situation, due to the difficulty of the material collecting, the treatment is based in the probable causer agents and the empiricist use is acceptable. The exam of the culture was required in the less of the half prescriptions (48.7%) (181/372) and TSA was executed in the cases of the positive culture (121/181). The results of TSA showed that the initial treatment prescribed was adjusted in 76% of the cases (92/121). The necessity of the changing of the initial therapeutic scheme was identified in 12.7% (23/181) of the cases where the culture and TSA were found. In the others, the doctor opted to not to modify it due to the clinical answer of the patient. According protocols, evaluated prescriptions 71.9% (192/267) showed therapeutic indication according the recommendation. According with the protocols, it was observed a major frequency of adaptation of the prescriptions and of the lab behaviors when it is compared with other studies. These results can be associated with the restriction policies of adopted using for the institution.

O uso inadequado de antimicrobianos é fator determinante para disseminação da resistência bacteriana. Vários países têm usado como estratégias políticas de restrição para tornar o uso mais racional. Principalmente em hospitais, onde a utilização é mais prevalente. Embora o uso empírico seja a opção de tratamento em muitas condições clínicas, sabe-se que exames microbiológicos de cultura e teste de sensibilidade antimicrobiana (TSA), podem orientar uma prescrição mais racional. Para se avaliar a adequação de prescrições de antimicrobianos de uso restrito no Hospital São Vicente de Paulo de Passo Fundo, considerando resultados de exames microbiológicos e protocolos clínicos da instituição, foram analisadas 372 prescrições de pacientes internados. O tipo de infecção foi a única justificativa apresentada para o uso de antimicrobianos, sendo a maior freqüência para infecções do trato respiratório inferior (59,4%) seguido das do trato urinário (10,8%). O tratamento inicial empírico ocorreu em 89% dos casos. Dos pacientes com uso empírico (331/372), 66,7% apresentaram pneumonia. Nesta situação, devido à dificuldade de coleta de material, o tratamento é baseado nos prováveis agentes causadores e o uso empírico é aceitável. O exame de cultura foi solicitado em menos da metade das prescrições 48,7%(181/372), e o TSA foi realizado nos casos de cultura positiva (121/181). O resultado do TSA apontou que o tratamento inicial prescrito estava adequado em 76% dos casos (92/121). A necessidade de troca do esquema terapêutico inicial foi identificada em 12,7% (23/181) dos casos que realizaram cultura e TSA. A troca de esquema ocorreu em 65,2% (15/23) dos casos, nos demais o médico optou por não alterar devido à resposta clínica do paciente. Das prescrições avaliadas conforme protocolos, 71,9% (192/267) demonstraram indicação terapêutica de acordo com a recomendação. De acordo com os protocolos, observou-se uma freqüência maior de adequação das prescrições e das condutas laboratoriais quando comparada com outros estudos. Estes resultados podem estar associados às políticas de restrição de uso adotadas pela instituição. / The inadequated use of antimicrobials is the determinant fact to the dissemination of the resistance of the bacteria. Many countries have used as a strategy the politics of the restriction to become this use more rational, mainly in the hospitals, where the utilization is more prevalent. Although the empiricist use is the option of the treatment in many clinical conditions, we know that microbiological exams of culture and the test of antimicrobial sensibility (TSA) can conduct to a more rational prescription. To evaluate the adjustment of the prescriptions of antimicrobials in restrict use at São Vicente de Paulo Hospital, in Passo Fundo, and considering the results of the microbiological exams and clinical protocols of the institution, 372 interned patients prescriptions were analyzed. The type of the infection was the unique justify showed to the use of the antimicrobials, being the biggest frequency to the infections in the lower respiratory tract (59.4%), followed by the urinary tract (10.8%). The initial empiricist treatment occurred in 89% of the cases. Within the patients with the empiricist use (331/372), 66.7% showed pneumonia. In this situation, due to the difficulty of the material collecting, the treatment is based in the probable causer agents and the empiricist use is acceptable. The exam of the culture was required in the less of the half prescriptions (48.7%) (181/372) and TSA was executed in the cases of the positive culture (121/181). The results of TSA showed that the initial treatment prescribed was adjusted in 76% of the cases (92/121). The necessity of the changing of the initial therapeutic scheme was identified in 12.7% (23/181) of the cases where the culture and TSA were found. In the others, the doctor opted to not to modify it due to the clinical answer of the patient. According protocols, evaluated prescriptions 71.9% (192/267) showed therapeutic indication according the recommendation. According with the protocols, it was observed a major frequency of adaptation of the prescriptions and of the lab behaviors when it is compared with other studies. These results can be associated with the restriction policies of adopted using for the institution.

Le trouble du spectre de l’autisme (TSA) et la déficience intellectuelle (DI) sont des troubles du développement qui affectent un grand nombre de familles partout dans le monde (American Psychiatric Association, 2013). Des études démontrent que les enfants ayant une DI ou un TSA manifestent plus de comportements problématiques que les enfants dans la population en générale. Les agressions physiques et verbales, la destruction de bien, les crises, l’opposition et l’automutilation interfèrent souvent avec les habiletés de l’individu, l’empêchant de bien fonctionner et causant souvent des dommages ou des blessures (Matson et al., 2009; Mazurek et al., 2013; Minshawi et al., 2014). Pour bien cerner l’importance de réduire les comportements problématiques, plusieurs études démontrent les conséquences graves qui peuvent en découler (Caron, Fleury, Godbout et Desranleau, 2005 ; Taylor, Oliver et Murphy, 2011). Ces conséquences peuvent limiter ou mettre à risque l’utilisation optimale de nombreuses ressources découlant de la communauté et réduire la capacité de la personne accompagnée à s’occuper de ses besoins et limitent son potentiel d’intégration sociale et communautaire (Richards, Moss, Nelson et Oliver, 2016). Les interventions comportementales peuvent aider les familles d’enfants ayant un TSA ou une DI qui se retrouvent bien souvent stressées et isolées socialement, s’exposant à des dangers réels, comme faire subir de mauvais traitements physiques à leurs enfants si elles ne reçoivent aucune aide (Bessette Gorlin, McAlpine, Garwick et Wieling, 2016; Chan et Lam, 2016). Cependant, l’accessibilité aux services pour traiter ces difficultés comportementales est souvent limitée à cause des coûts élevés des services privés, de l’isolement géographique, du manque de personnel ou encore des listes d’attente pour les services publics. Parmi les nouveaux moyens technologiques utilisés pour offrir des services précoces aux familles, on retrouve les formations interactives offertes en ligne, simples à utiliser, efficaces et très peu coûteuses (Higbee et al. 2016; Pollard, Higbee, Akers et Brodhead, 2014). Des résultats iii d’études soutiennent qu’il est possible d’impliquer de manière efficace les parents en tant qu’agents de changement dans la réduction des comportements problématiques de leurs enfants par différentes interventions comportementales, directives verbales et écrites, modelage par vidéo et exercices de répétitions (Gerencser, Higbee, Akers et Contreras, 2017; Ilg et al., 2016; Lanovaz, Rapp, Maciw, Dorion et Pelletier, 2016). L’objectif de notre étude était d’examiner les résultats préliminaires d’une formation interactive en ligne développée pour soutenir les parents d’enfants ayant un TSA ou une DI dans la réduction de comportements problématiques. Les objectifs de ce projet pilote portait principalement sur trois variables de réponse : (1) l’identification d’une fonction plausible d’un comportement problématique (2) la sélection d’une intervention fonctionnelle et (3) la satisfaction du parent vis-à-vis de cette formation. Les résultats de ce projet pilote suggèrent une amélioration sur des tâches d’identification de fonctions comportementales plausibles et de sélection d’interventions fonctionnelles ainsi qu’une excellente validité sociale. L’utilisation d’une formation interactive comme ressource aux parents semble être une avenue novatrice et intéressante à explorer. Il serait cependant nécessaire de reproduire l’étude afin de pouvoir valider les résultats / Autism spectrum disorders (ASD) and intellectual disability (ID) are developmental disorders that affect many families around the world (American Psychiatric Association, 2013). Several studies have shown that children with ASD or ID engage in more challenging behavior than children without disability. Aggression, destruction, opposition, and self-injury often interfere with individual skills, preventing those who emit these behavior from functioning adequately in their natural environment and often causing them harm or injury (Matson, Wilkins & Macken, 2008; Mazurek, Kanne & Wodka,2013; Minshawi & al., 2014). Several studies have outlined the serious consequences that can result from these behaviors (Caron, Fleury, Godbout & Desranleau, 2005; Taylor, Oliver & Murphy, 2011). These consequences can limit or put at risk the optimal use of community resources and reduce the persons’ capacity to address their needs and limit their potential for social and community integration (Richards, Moss, Nelson & Oliver, 2016). Behavioral interventions can help families who are often stressed, socially isolated and confronted to risks if they do not receive access to adequate services (Bessette, Gorlin, McAlpine, Garwick & Wieling, 2016; Chan & Lam, 2016). However, accessibility to services to address these behavioral difficulties is often limited due to the high costs of private services, geographic isolation, shortage of staff, or waiting lists for public services. Interactive web training is an easy-to-use, efficient and affordable approach, which can be used to address these issues (Higbee & al., 2016; Pollard, Higbee, Akers & Brodhead, 2014). Research findings suggest that parents can be effectively involved as agents of change and play a meaningful role in the reduction of their children’s challenging behavior when trained adequately using verbal v and written instructions, video modeling and exercises (Gerencser, Higbee, Akers & Contreras, 2017; Ilg & al., 2016; Lanovaz, Rapp, Maciw, Dorion & Pelletier, 2016). The objective of our study was to document the effects of an interactive web training developed to support parents of children with ASD or ID in the reduction of challenging behavior. The objectives of this pilot project focused on three response variables (1) identifying a function of challenging behavior, (2) selecting a functional intervention, and (3) parents’ satisfaction with the training. The results indicated an improvement on behavioral function identification tasks and functional intervention selection tasks as well as an excellent social validity. The use of interactive web training as a resource for parents seems to be an interesting avenue for treatment, but it is necessary to replicate our study in order to validate the results.

Les Troubles du Spectre Autistique (TSA) forment un groupe hétérogène de troubles neurodéveloppementaux caractérisés par des déficits de l’interaction sociale et de la communication ainsi que la présence de comportements répétitifs et d’intérêts restreints. Les TSA affectent environ un individu sur 68. Ils se manifestent généralement durant les trois premières années de vie mais, pour certains cas, les symptômes sont reconnus plus tard, quand les exigences sociales augmentent. Les études de jumeaux et la récurrence des troubles dans certaines familles démontrent l’importance des facteurs génétiques dans la vulnérabilité aux TSA. Cependant, l’architecture génétique des TSA reste difficile à caractériser car elle est extrêmement hétérogène et il est très compliqué d’identifier, pour chacun des patients, la combinaison d’allèles à risque. Notre laboratoire a identifié la première voie génétique associée aux TSA – la voie NLGN-NRXN-SHANK- qui joue un rôle clé dans la plasticité synaptique. Il existe un nombre de plus en plus grand de gènes associés aux TSA mais peu d’études ont été réalisées sur des cohortes épidémiologiques et dans des populations isolées. L'analyse des données de génotypage et de séquençage d’exome de 357 individus issus des îles Féroé (36 patients, 136 apparentés des patients, 185 témoins) nous a permis de mettre en évidence un nombre plus important de Variations du Nombre de Copies (CNVs), un coefficient de consanguinité supérieur, un plus grand nombre de mutations homozygotes et délétères ainsi qu’un Polygenic Risk Score (ASD-PRS) supérieur chez les patients TSA comparés aux individus témoins. Notre analyse confirme le rôle de plusieurs loci associés aux TSA (NRXN1, ADNP, délétion 22q11) et a permis d’identifier de nouvelles mutations tronquant la protéine (GRIK2, ROBO1, NINL et IMMP2L) ou récessives (KIRREL3 et CNTNAP2) affectant des gènes déjà associés aux TSA. Nous avons également mis en évidence trois nouveaux gènes candidats jouant un rôle important dans la plasticité synaptique (RIMS4, KALRN et PLA2G4A) à travers la présence de mutations de novo délétères chez des patients sans déficience intellectuelle. Au total, nous avons pu identifier une cause génétique expliquant les TSA pour 11% des patients et au moins une mutation fortement délétère dans des gènes candidats chez 39% des patients. Aucune cause génétique n'a pu être trouvée chez 50% des patients. En résumé, notre étude permet de mieux comprendre l’architecture génétique des TSA dans les populations isolées en soulignant à la fois l'impact des variants communs et des variants rares mais également en révélant le rôle de nouveaux gènes pour les TSA. Ces gènes codent pour des protéines essentielles pour le neurodéveloppement et l’identification de ces facteurs impliqués dans la formation et l'entretien des synapses pourrait ainsi fournir de nouvelles pistes afin de mieux comprendre les bases biologiques des TSA et de découvrir de nouvelles stratégies thérapeutiques. Il est cependant nécessaire de comprendre plus avant l'impact de la combinaison de différentes mutations sur la fonction neuronale afin de mieux caractériser l’architecture génétique des TSA. / Autism Spectrum Disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders characterized by deficits in social interaction and communication as well as the presence of repetitive behaviors and restricted interests. ASD affects approximately one in 68 individuals. They usually occur during the first three years of life but, in some cases, symptoms are recognized later, when social demands increase. There is a strong genetic component to ASD, as indicated by the recurrence risk in families and twin studies. However, the genetic architecture of ASD remains largely unknown because of its extreme heterogeneity. It is very challenging to identify, for each patient, the combination of risk alleles. Our laboratory identified the first genetic pathway associated with ASD – the NLGN-NRXN-SHANK pathway – playing a key role in synaptogenesis during development. There are an increasing number of genes associated with ASDs but few studies have been conducted on epidemiological cohorts and isolated populations. Here, we investigated 357 individuals from the Faroe Islands including 36 patients with ASD, 136 of their relatives and 185 non-ASD controls. Data from SNP array and whole exome sequencing revealed that patients had a higher burden of copy-number variants, higher inbreeding status, higher load of homozygous deleterious mutations, and a higher ASD polygenic risk score compared to controls. We confirmed the role of several ASD-associated loci (NRXN1, ADNP, 22q11 deletion) and identified new truncating (GRIK2, ROBO1, NINL and IMMP2L) or recessive variants (KIRREL3 and CNTNAP2) affecting genes already associated with ASD. We have also identified three novel candidate genes playing key roles in synaptic plasticity (RIMS4, KALRN and PLA2G4A) carrying deleterious de novo mutations in patients without intellectual disability. Overall, for 11% of individuals with ASD, a known genetic cause was identified, for 39% at least one strongly deleterious mutation was identified in a compelling candidate gene and for 50% no obvious genetic cause was detected. In summary, our study provides a better understanding of the genetic architecture of ASD in isolated populations by highlighting both the impact of common and rare variants but also by revealing the role of new genes for ASD. These genes code for proteins that are essential for neurodevelopment. The identification of these factors involved in synapse formation and maintenance could provide new leads to better understand the biological basis of ASD and find novel therapeutic strategies. However, it is necessary to further understand the combined impact of different mutations on neuronal function in order to better characterize the genetic architecture of ASD.

Manufacturing of aircraft parts is often complex and time-consuming, which has led to an increased interest in new manufacturing technologies in the Swedish industry such as additive manufacturing (AM). Additive manufacturing techniques could be a solution to meet the aircrafts’ demand since it contributes to an efficient manufacturing and allows a just-in-time production of complex metal parts in their final shape. However, the use of AM aluminum for aircraft applications is in a development phase and no surface treatment process exists. Thereby, it is of high interest to further investigate surface treatments for AM alloys. Currently at Saab AB, conventional aluminum alloys are generally anodized in tartaric sulphuric acid (TSA) to improve the corrosion resistance and adhesion properties of the metal. On the behalf of Saab AB, there is also an interest in establishing powder coating as a surface treatment. This master thesis’ purpose is to investigate the anodizing and adhesion properties for the two additive manufacturing alloys - AlSi10Mg and ScalmalloyⓇ, and compare it with the conventionally produced Al alloy 2024-T3. The anodization and the powder coating is examined by using following characterization techniques: profilometry, light microscopy, scanning electron microscopy and contact angle measurements. The results from the experimental part indicated successful anodizations for all the alloys and good adhesion properties for powder coating. This research is a first step in contributing to a better understanding of the anodic coating and adhesion properties for the AM samples ScalmalloyⓇ and AlSi10Mg

Abstract in English with Afrikaans and SeTswana translation / Evidence from relevant literature indicates that abandoned and failed projects have become prevalent in the Botswana context. Poor stakeholder management has been identified as a salient contributor to this challenge. To this end, various stakeholder management (SM) frameworks, models and methodologies have been developed. Nevertheless, the increasing incidence of project failure and abandonment in the Botswana construction industry indicates significant underperformance of these SM methodologies. A cursory appraisal of SM models highlights the linearity of the stakeholder relationship management (SRM) curve, i.e. between the client, consultants and contractors, with SRM responsibilities being domiciled with the client or their representative in most cases. Also, the dynamics associated with changes in stakeholder attributes during project delivery are not catered for by extant SM and relationship management models. In addition, extant SM models focus on the relationship between the project stakeholders on the one hand and the external stakeholders on the other, and others cater for project stakeholders alone. This implies that the models currently deployed for SM in the Botswana construction context remain defective. Contracting organisations (contractors) have been blamed for their inability to manage relationships with projects and external stakeholders during project delivery. Yet, these entities are not at the epicentre of SRM on construction projects. This study provides answers to the gaps highlighted. As its central objective, this study set out to develop and validate a contractor-driven stakeholder relationship management framework (CSRMF) for the Botswana construction industry. The emergent framework which leverages on the attributes of the customer relationship model (CRM) overcomes the shortcomings mentioned previously. An interpretivist philosophical paradigm was adopted in this qualitative case study research study based on pre-determined case selection criteria. Owing to the need to attain analytic generalisation through adherence to replication logic, a multi-case study research design was utilised. Six contractor organisations categorised according to scale and operating within Gaborone were selected. The unit of analysis centred on the relationship between the contracting organisations and other project stakeholders on selected projects being procured and delivered under a diverse range of contracting strategies. Data was collected through a sequential multi-method approach in which semi-structured interviews were conducted with project managers representing these construction contracting organisations on the selected projects. To enable replication, care was taken to select two contracting organisations per level – large, medium and small according to prevalent grades. Samples across the different sizes of the contractors allowed for better generalisability. Relevant projects and organisational documents were reviewed. Furthermore, data from the various stages was analysed using the qualitative content analysis technique. The findings of the study show that most of the contractors in Botswana related to their project stakeholders without a model or framework when handling relationship management with project stakeholders. These findings are a reflection of the small, medium and large construction contractors in the Botswana construction industry. There was further indication that the small, medium and large contractors had a way of managing stakeholder relationships and resolving conflicts, and thus the level of experience and knowledge within the contracting firm had a significant influence on how they managed their project stakeholder relationships in the course of project procurement and delivery. In addition, the study findings demonstrate that the nature of contracting strategy had a significant influence on how various categories of contractors related to their stakeholders on construction projects. The traditional method was found to be the main procurement strategy used in the Botswana construction industry, and this approach was fairly rigid to implement effective contractor-driven stakeholder relationship management. Other procurement strategies, such as design-and-build, and construction management are used in Botswana with their positive and negative impacts on contractors’ capability to manage their project stakeholder relationships and related matters effectively. Further evaluation of the findings led to the identification of key success factors for CSRMF development to foster effective contractor-stakeholder relationship management. These key success factors are effective communication, collaboration, engagement and cooperation among clients and contractors and consultants’ commitment; employee (stakeholder) engagement and satisfaction and capacity building; in-depth understanding of all project stakeholders and their importance and influence; and strategies to manage their relationship effectively in the course of project design, procurement and delivery. Based on the evaluation of formulated propositions and analysis of empirical data and results tested in this study, the findings also support the following analytical generalisations: the construction contracting organisations in Botswana do not have any SRM frameworks in place for engaging with stakeholders in their different projects; contractors in Botswana recognise the need to do better in managing their project stakeholder relationships; and there is an apparent gap in technical skills and limited ability of contractors to manage relationships with project stakeholders. Premised on the findings, a contractor-driven stakeholder relationship management framework was developed. The CSRMF was validated by two focus groups, namely sampled project managers from the semi-structured interviews, and relevant professionals and other academics in the industry. The validation was done to assess the relevance of the CSRMF in their management of relations. The CSRMF will provide guidance for bridging the gaps identified. It will be adopted and utilised by contractors to achieve efficiencies in the management of relationships with stakeholders, thus saving time and costs and securing improved quality and, most of all, client satisfaction. / Volgens die literatuur misluk die meeste projekte in Botswana. Swak bestuur deur die belanghebbendes in die projekte is die hoofrede hiervoor. Talle raamwerke, modelle en metodologieë gemik op doeltreffende bestuur van belanghebbendes (BB) is as oplossing vir hierdie probleem voorgestel. Dat al hierdie BB-metodologieë egter gebrekkig is, blyk uit ʼn toename in die aantal mislukte projekte in die konstruksiebedryf wat laat vaar is. ʼn Oppervlakkige ondersoek van die BB-modelle het aan die lig gebring dat die belanghebbendeverhoudingsbestuur- (BVB) kromme afgeplat is. Hierdie kromme gee ʼn aanduiding van die verhouding tussen die kliënt, konsultante en kontrakteurs. Belanghebbendeverhoudingsbestuur berus meestal by kliënte of hulle verteenwoordigers. Die bestaande BB- en verhoudingsbestuurmodelle maak geensins vir veranderinge in die eienskappe van belanghebbendes tydens die lewering van ʼn projek voorsiening nie. Hierbenewens fokus sommige BB-modelle op die verhouding tussen eksterne belanghebbendes en projekbelanghebbendes, en party slegs op projekbelanghebbendes. Om hierdie rede is die modelle wat tans in Botswana se konstruksiebedryf toegepas word, ontoereikend. Kontrakteurorganisasies word dikwels daarvan beskuldig dat hulle nie tydens die lewering van ʼn projek in staat is om hulle verhouding tussen eksterne en projekbelanghebbendes te bestuur nie. Hierdie groepe staan egter nie in die brandpunt van konstruksieprojekte se BVB nie. Hierdie studie poog om oplossings te bied vir die tekortkomings wat aangetoon is. Die oogmerk is ʼn raamwerk vir kontrakteurgedrewe belanghebbendeverhoudingsbestuur (RKBVB) vir die konstruksiebedryf in Botswana. Hierdie raamwerk steun op die kliënteverhoudingsmodel (KVM) om die gemelde tekortkomings te verbeter. Hierdie kwalitatiewe gevallestudie berus op vooraf vasgestelde kriteria vir die keuse van gevalle. Daarby word ʼn interpretatiewe filosofiese paradigma in hierdie studie gevolg. Aangesien analitiese veralgemening volgens die eise van replikasielogika die doelwit was, behels die navorsingsontwerp veelvuldige gevallestudies. Ses kontrakteurorganisasies in Gaborone wat volgens ʼn skaal gekategoriseer is, is gekies. Die verhouding tussen hierdie kontrakteurorganisasies en die belanghebbendes in projekte wat volgens ʼn verskeidenheid kontrakstrategieë verkry en gelewer is, was die ontledingseenheid. Data is volgens ʼn sekwensiële multimetodebenadering ingewin, en halfgestruktureerde onderhoude is met die projekbestuurders van hierdie ix konstruksiemaatskappye gevoer. Om replisering te vergemaklik, is twee kontrakteurorganisasies volgens hulle vlak – groot, middelslag en klein en graad gekies. Die onderskeid op grond die grootte van die kontrakteurs het tot veralgemening meegehelp. Insae is in die projek- en maatskappydokumente verkry. Die data wat in elke stadium ingewin is, is volgens die kwalitatiewe tegniek ontleed. Op grond van die bevindings het die meeste kontrakteurs sonder enige model of raamwerk hulle verhouding met die projekbelanghebbendes bestuur. Hulle verteenwoordig alle klein, middelslag en groot konstruksiekontrakteurs in Botswana. Die gebrek aan kennis en ervaring in die bestuur van hulle verhouding met belanghebbendes en die beslegting van geskille in die verkryging en lewering van projekte was ooglopend. Daar is voorts bevind dat die aard van die kontraktuele strategie ʼn beduidende invloed gehad het op hoe die onderskeie kategorieë van kontrakteurs verhoudings met die belanghebbendes in konstruksieprojekte aanknoop. Verder is bevind dat die konstruksiebedryf tradisionele verkrygingstrategie meestal volg. Hierdie strategie is taamlik rigied en bevorder nie juis kontrakteurgedrewe belanghebbendeverhoudingsbestuur nie. Ander verkrygingstrategieë, soos die ontwerp-en-boustrategie, en konstruksiebestuur word in Botswana toegepas, en kan kontrakteurs se vermoë om hulle verhouding met die belanghebbendes in projekte en aanverwantesake doeltreffend te bestuur, enersyds bevorder en andersyds belemmer. Verskeie suksesfaktore vir kontakteur-belanghebberverhoudingsbestuur (KBVB) is op grond van die bevindings onderskei, te wete effektiewe kommunikasie, medewerking, betrokkenheid en samewerking tussen kliënte en kontrakteurs asook konsultante se verbintenis; werknemer (belanghebbendes) se betrokkenheid, bevrediging en kapasiteitsbou; ʼn grondige begrip van alle belanghebbendes in ʼn projek en van hulle belang en invloed; en strategieë om verhoudings effektief in die ontwerp, verkryging en lewering van ʼn projek effektief te bestuur. Die bevindings, wat op die beoordeling van die geformuleerde voorstelle en ʼn ontleding van die empiriese data berus, het tot die volgende analitiese veralgemenings gelei: konstruksiemaatskappye in Botswana het geen BVB-raamwerk waarvolgens hulle met belanghebbers in projekte omgaan nie; hulle besef dat hulle hul verhouding met belanghebbendes in projekte beter behoort te bestuur; en kontrakteurs beskik blykbaar nie oor die tegniese vaardighede en vermoëns om hulle verhouding met belanghebbendes in projekte te bestuur nie. x ʼn Raamwerk vir kontrakteurgedrewe belanghebberverhoudingsbestuur (RKBVB) is op grond van die bevindings ontwikkel. Die RKBVB is deur twee fokusgroepe gevalideer, naamlik projekbestuurders enersyds en beroepslui en akademici in die bedryf andersyds, ten einde die relevansie van die RKBVB te toets. Die raamwerk help kontrakteurs om die genoemde probleme op te los. Aangesien dit kontrakteurs sal help om hulle verhouding met belanghebbendes doeltreffend te bestuur, sal dit nie alleen tyd en geld spaar nie, maar ook die gehalte van hulle werk en bowenal kliënttevredenheid verbeter. / Bosupi go tswa mo dikwalong tse di maleba bo supa gore diporojeke tse di phuagantsweng le tse di padileng di dintsi kwa Botswana. Go supilwe botsamaisi jo bo bokoa jwa baamegi jaaka setshwaedi se segolo mo kgwetlhong eno. Ka ntlha ya seno, go tlhamilwe matlhomeso a le mmalwa a botsamaisi jwa baamegi (SM), dikao le mekgwa. Le fa go le jalo, koketsego ya ditiragalo tsa go pala le go phuaganngwa ga diporojeke mo indasetering ya kago kwa Botswana e supa tiragatso e e bokowa thata ya mekgwa eno ya SM. Tshekatsheko ya ka bonako ya dikao tsa SM e bontsha tatelano ya segoro sa botsamaisi jwa dikamano le baamegi (SRM), k.g.r. magareng ga modirelwa, baemedi le bakonteraka, mme maikarabelo a SRM a patagantswe le badirelwa gongwe baemedi ba bona mo mabakeng a le mantsi. Gape dintlha tse di amanang le diphetogo mo diponagalong tsa baamegi mo tsamaong ya tlamelo ya porojeke ga di a akarediwa mo dikaong tsa ga jaana tsa SM le botsamaisi jwa dikamano. Go tlalaletsa foo, dikao tsa ga jaana tsa SM di totile dikamano magareng ga baamegi ba diporojeke ka fa letsogong je lengwe, le baamegi ba kwa ntle ka fa go je lengwe, mme tse dingwe di lebelela baamegi ba diporojeke fela. Seno se kaya gore dikao tse di dirisiwang ga jaana mo dikonterakeng tsa Botswana ga di a siama. Ditlamo tsa kago (bakonteraka) di latofalediwa go palelwa ke go tsamaisa dikamano tsa diporojeke le baamegi ba kwa ntle ka nako ya tsamaiso ya diporojeke. Fela, ditheo tseo ga di mo mookong wa SRM mo diporojekeng tsa kago. Thutopatlisiso e neela dikarabo tsa ditlhaelo tse di supilweng. Maikaelelomagolo a thutopatlisiso e ne e le go tlhamela le go tlhomamisetsa indaseteri ya kago ya Botswana letlhomeso la botsamaisi jwa dikamano tsa baamegi (CSRMF) le le tsamaisiwang ke mokonteraka. Letlhomeso le le tlhagelelang le le dirisang diponagalo tsa sekao sa dikamano tsa badirisi (CRM) le fenya ditlhaelo tse di kailweng fa pejana. Go dirisitswe mokgwa wa filosofi o o ikaegileng ka go ranola le go tlhaloganya mo thutopatlisisong eno e e lebelelang mabaka mme go dirisitswe mokgwa wa go tlhopha dikgetse o o sweditsweng pele. Ka ntlha ya botlhokwa jwa go lebelela gore a diphitlhelelo tsa tshekatsheko di ka fetisega ka go obamela ntlha ya ntsifatso, go dirisitswe thadiso ya thutopatlisiso ya dikgetsidintsi. Go tlhophilwe ditheo di le thataro tsa dikonteraka tse di arogantsweng go ya ka seelo mme di dira kwa Gaborone. Tokololo e ne e ikaegile ka dikamano magareng ga ditheo tsa kago le baamegi ba bangwe ba diporojeke mo diporojekeng tse di tlhophilweng tse di rebotsweng le go xii diragadiwa ka ditogamaano tse di farologaneng tsa kago. Go kokoantswe data ka molebo wa mekgwamentsi o o dirang ka tatelano moo go dirilweng dipotsolotso tse di batlileng di rulagane le batsamaisi ba diporojeke ba ba neng ba emetse ditheo tseno tsa kago mo diporojekeng tse di tlhophilweng. Go kgontsha ntsifatso, go etswe tlhhoko gore go tlhophiwa ditheo tse pedi tsa kago mo legatong lengwe le lengwe – le legolo, le le magareng le le lennye go ya ka dikaroganyo tse di gona. Go dirisa disampole go ralala dikonteraka tsa bogolo jo bo farologaneng go dirile gore go akaretsa go nne botoka. Go sekasekilwe diporojeke le dikwalo tse di maleba tsa ditheo Mo godimo ga moo, go lokolotswe go tswa mo dateng ya magato a a farologaneng go dirisiwa thekeniki ya go lokolola diteng go lebeletswe mabaka. Diphitlhelelo tsa thutopatlisiso di bontsha gore bontsi jwa dikonteraka mo Botswana bo amana le baamegi ba diporojeke kwa ntle ga sekao gongwe letlhomeso fa bo tsamaisa dikamano le baamegi. Diphitlhelelo tseno di bontsha dikonteraka tse dinnye, tse dimagareng le tse dikgolo mo indasetering ya kago ya Botswana. Gape go na le sesupo se sengwe sa gore dikonteraka tse dinnye, tse dimagareng le tse dikgolo di na le tsela ya go tsamaisa dikamano le baamegi le go rarabolola dikgotlhang, mme ka jalo seelo sa maitemogelo le kitso mo difemeng tsa kago se na le tlhotlheletso mo go reng di tsamaisa jang dikamano tsa tsona le baamegi ba diporojeke mo tsamaong ya theko le tiragatso ya porojeke. Go tlaleletsa, diphitlhelelo tsa thutopatlisiso di bontsha gore mofuta wa togamaano ya konteraka o na le tlhotlheletso e e bonalang mo go reng dikarolo tsa dikonteraka di amanang jang le baamegi ba tsona mo diporojekeng tsa kago. Mokgwa wa tlwaelo o fitlhetswe e le togamaano e kgolo ya theko e e dirisiwang mo indasetering ya kago ya Botswana, mme mokgwa ono o tsepame thata go ka diragatsa botsamaisi jo bo nonofileng jwa kamano ya baamegi e e tsamaisiwang ke mokonteraka. Go dirisiwa ditogamaano tse dingwe tsa go reka di tshwana le thadisa-o-age, le botsamaisi jwa kago mo Botswana ka ditlamorago tsa tsona tse di siameng le tse di sa siamang mo bokgoning jo bo nonofileng jwa mokonteraka go tsamaisa dikamano tsa gagwe tsa baamegi ba porojeke le dintlha tse dingwe tse di amanang. Tshekatsheko e nngwe ya diphitlhelelo e lebisitse kwa go supiweng ga dintlha tsa botlhokwa tsa katlego tsa go tlhamiwa ga CSRMF gore go nne le botsamaisi jo bo bokgoni jwa kamano ya mokonteraka le baamegi. Dintlha tseno tsa botlhokwa tsa katlego ke tlhaeletsano e e bokgoni, tirisanommogo, therisano le tirisano magareng ga badirelwa le bakonteraka mmogo xiii le maitlamo a moemedi; therisano le badiri (baamegi) le kgotsofalo mmogo le katiso; go tlhaloganya go go boteng ga baamegi botlhe ba porojeke mmogo le botlhokwa le tlhotlheletso ya bona; le ditogamaano tsa go tsamaisa dikamano ka bokgoni mo tsamaong ya thadiso ya porojeke, theko le tiragatso. Go ikaegilwe ka tshekatsheko ya ditshitshinyo tse di dirilweng le tokololo ya data ya maitemogelo le dipholo tse di tlhatlhobilweng mo thutopatlisisong eno, diphitlhelelo di tshegetsa dikakaretso tse di latelang: ditheo tsa dikonteraka kwa Botswana ga di na matlhomeso ape a SRM go rerisana le baamegi mo diporojekeng tse di farologaneng; bakonteraka ba Botswana ba lemoga tlhokego ya go dira botoka go tsamaisa dikamano tsa bona le baamegi ba diporojeke; mme go na le phatlha e e bonalang ya bokgoni jwa setegeniki le bokgoni jo bo lekanyediitsweng jwa bakonteraka go tsamaisa dikamano tsa bona le baamegi ba diporojeke. Go ikaegilwe ka diphitlhelelo, go tlhamilwe letlhomeso la botsamaisi jwa dikamano tsa baamegi tse di tsamaisiwang ke mokonteraka. Letlhomeso (CSRMF) le tlhomamisitswe ke ditlhopha tse pedi tse go buisanweng natso, e leng, batsamaisi ba diporojeke ba ba neng ba le mo sampoleng go tswa mo dipotsolotsong tse di batlileng di rulagane, le baporofešenale ba ba maleba mmogo le barutegi ba bangwe mo indasetering. Tlhomamiso e ne e direlwa go sekaseka bomaleba jwa CSRMF mo tsamaisong ya dikamano. Letlhomeso (CSRMF) le tlaa tlamela ka kaedi ya go fokotsa phatlha e e supilweng. Le tlaa amogelwa le go dirisiwa ke bakonteraka go fitlhelela dinonofo mo tsamaisong ya dikamano le baamegi, mme ka go rialo ba boloka nako le ditshenyegelo le go netefatsa boleng jo bo tokafetseng le, go feta tsotlhe, kgotsofalo ya badirelwa. / Business Management / D. B. L.

Le trouble du spectre de l’autisme (TSA) est une pathologie due à des anomalies neurodéveloppementales. Syndrome le plus souvent diagnostiqué dans la petite enfance, il affecte principalement l’interaction sociale et cause: des troubles de langage, de la communication et du comportement. Sa prévalence sans cesse croissante atteint en 2018 1.52% au Canada[1]. Cette prévalence est quatre fois plus élevée chez les garçons comparativement aux filles[2]. À ce jour, il n’existe pas de traitement spécifique au TSA, cependant des interventions psychologiques et médications sont proposées pour réduire des symptômes tel que l’agressivité et l’anxiété qui y sont associés. L’étiologie du TSA est peu ou mal connue. Néanmoins, des hypothèses sont avancées suivant trois facteurs. Génétique, biologique et environnementale. Concernant ce dernier facteur, l’on peut citer l’exposition in utéro aux médicaments et ce projet porte son intérêt sur ce point et plus précisément l’acétaminophène. C’est l’un des analgésiques le plus utilisé dans le soulagement de la douleur et le traitement de la fièvre. Il est souvent recommandé aux femmes durant la grossesse pour le soulagement de la douleur et le traitement de la fièvre. Cette forte consommation d’acétaminophène chez la femme enceinte : environ 65%-75% aux États-Unis[3], soulève une réelle problématique sachant qu’il est démontré que le principe actif est détectable dans des échantillons de plasma de cordon ombilical[4]. La possibilité que l’acétaminophène traverse le placenta et soit présent dans la circulation sanguine du bébé n’est pas exclue[4],[5]. Il est important d’effectuer davantage de recherche sur le sujet afin d’évaluer le réel impact d’une telle exposition. Sachant les limites d’inclusion des femmes enceintes dans les essais cliniques randomisées, nous avons mené une étude de cohorte populationnelle et les données utilisées proviennent de quatre bases de données administratives québécoises, dont le jumelage a permis de mettre sur pied la cohorte des grossesses du Québec (CGQ) avec un suivi longitudinal entre 1998 et 2015. Ainsi, ce projet méthodologique vise principalement à explorer et illustrer les limites de l’utilisation des bases de données administratives pour mesurer l’exposition aux médicaments en vente libre. Ceci en utilisant comme cas pratique, l’évaluation du risque de TSA chez des enfants exposés à l’acétaminophène durant la phase gestationnelle comparativement aux enfants non exposés. La littérature rapporte que les données quant à l’utilisation des médicaments en vente libre sont souvent sous-estimées par rapport à la réalité. L’utilisation bases de données administratives afin de mesurer l’exposition de certains médicaments en vente libre, introduirait une erreur de classification importante[6]. Sachant que la collecte de données se base sur les prescriptions complétées en pharmacie. Dans la pratique clinique courante, ces médicaments sont peu prescrits par les médecins et peu compléter auprès du pharmacien. Le cas pratique utilisé dans ce projet confirme cette hypothèse. En effet, l’exposition in utéro d’acétaminophène est sous-estimée à 94% (Supplemental Table 5). Seulement 6 % (38/648) des enfants exposés sont capturés au sein de la CGQ ce qui ne reflète pas la réalité clinique d’utilisation d’acétaminophène en grossesse. Ce résultat démontre l’introduction d’un biais d’information (erreur de classification) qui expliquerait totalement ou en partie l’estimé mesuré. En effet, notre étude montre qu’il n’y a pas d’augmentation statistiquement significative entre le risque de TSA et la consommation d’acétaminophène in-utero (aHR : 1.10 IC 95% 0.93-1.30). Parallèlement, une analyse de sous cohorte a été effectuée. Celle-ci, utilisait des questionnaires auto-rapportées par les mères afin de mesurer l’exposition à l’acétaminophène. Pour cette analyse secondaire, un effet protecteur est mesuré (aHR : 0.78 IC 95% 0.41-1.47). Des analyses de sensibilités sur l’issue ont pu confirmer la robustesse de ces estimés, validant ainsi nos résultats. En conclusion, ce projet d’étude a permis de mesurer l’ampleur des erreurs de classifications associées à l’utilisation des bases de données administratives pour des questions de recherches impliquant des médicaments en vente libre. Cependant, au regard de ces défis méthodologiques, il est difficile de mesurer l’association entre l’utilisation d’acétaminophène et le risque de TSA dans notre cohorte. Notre étude ne démontre pas d’association statistiquement significative, ce qui est contradictoire aux antécédentes études ayant des méthodes de mesures d’exposition différentes. / Autism Spectrum Disorder (ASD) is a pathology caused by neurodevelopmental abnormalities. A syndrome most often diagnosed in early childhood, ASD mainly affects social interaction and causes language, communication, and behavioral disorders. Its ever-increasing prevalence reached a rate of 1.52% in Canada in 2018[1]. This prevalence is four times higher in boys compared to girls[2]. Nowadays, there is no specific treatment for ASD, however, psychological interventions and medications are proposed to reduce symptoms such as aggression and anxiety. The etiology of ASD is unknown. Nevertheless, hypotheses are put forward to explain the ASD mechanism via the genetic, biological, and environmental approach. The last factor includes in-utero exposure to medications and the present project focuses on this point and more specifically acetaminophen[3]. This research focuses on this point and, more specifically, on acetaminophen. It is one of the most widely used analgesics in pain and fever treatment, which is why it is often recommended to women during pregnancy. This high consumption of acetaminophen in pregnant women: approximately 65%-75% in the United States [4], raises a real problem, knowing that it has been demonstrated that the active ingredient is detectable in cord plasma samples [5]. It is possible that acetaminophen crosses the placenta and is present in the baby’s bloodstream[4], [5]. It is important to carry out more research on the subject in order to assess the true impact of such exposure. Knowing the limits of the inclusion of pregnant women in randomized clinical trials, we conducted a population-based cohort study. The data came from four Quebec administrative databases, their pairing allowing the establishment of the Quebec pregnancy cohort (QPC) with a longitudinal follow-up between 1998 and 2015. Thus, this methodological project mainly aims to explore and illustrate the limits of the use of administrative databases to measure exposure of over-the-counter medications. Using as a practical example, the assessment of the risk of ASD in children exposed to acetaminophen during the gestational phase compared to unexposed children. The literature reports that data on the use of over-the-counter medications are often underestimated compared to reality. The use of administrative databases to measure exposure to over-the-counter medications would introduce major misclassification[6]. Knowing that data are collected based on prescriptions filled in pharmacies. In the current clinical practice, these medications are rarely prescribed by physicians and rarely filled by pharmacists. The practical case used in this project confirms this hypothesis. In-utero exposure to acetaminophen is underestimated at 94% (Supplemental Table 5). Only 6% (38/648) of exposed children are captured within the QPC, which does not reflect the clinical reality of acetaminophen use in pregnancy. This result demonstrates the introduction of an information bias (misclassification) which would totally or partially explain the measured estimate. Indeed, our study shows that there is no statistically significant increase between the risk of ASD and the consumption of acetaminophen in utero (aHR: 1.10 95% CI 0.93-1.30). At the same time, a sub-cohort analysis was carried out. This used questionnaires self-reported by mothers to measure exposure to acetaminophen. For this secondary analysis, a protective effect is measured (aHR: 0.78 95% CI 0.41-1.47). Sensitivity analyses on issue were able to confirm the robustness of these results, thus validating our results. Through this study, we were able {Citation} to measure the magnitude of misclassifications associated with the use of administrative databases for research questions involving over-the-counter drugs. However, given these methodological challenges, it is difficult to measure the association between the use of acetaminophen in pregnancy and the risk of ASD in our cohort. Our study does not demonstrate a statistically significant association, which is contradictory to previous studies with exposure measurement methods approaching reality.