Purpose: This study primarily investigates the effects and influence of frustration in children with childhood apraxia of speech (CAS) in the setting of intensive treatment. Additionally, the study examines the interrater reliability of the frustration rating scale used in an intensive CAS treatment study. Methods: Frustration and treatment data obtained from 17 participants (between 4;0-9;11 years) with CAS in an intensive treatment research study were retrospectively used to determine potential relationships related to frustration in treatment (target complexity, temporal conditions, session number, CAS severity). Interrater reliability of the frustration rating scale was assessed with 34 randomly selected treatment session videos scored by a blinded second rater and compared to original scores. Results: Interrater reliability of the scale was poor to fair but had relatively close agreement within one scale point. Frustration levels were observed to decrease over the course of the treatment period but were typically greater in the afternoon sessions compared to morning. Participants in the complex target treatment condition with lower frustration also exhibited better outcomes than those with greater frustration. No other relationships were observed. Conclusions: Due to relatively poor interrater reliability of frustration scoring system used to obtain data used in the current study, results of the study should be interpreted cautiously. There may be a relationship between frustration levels in children with CAS and treatment conditions and outcomes, but other factors may influence both variables and further investigation into frustration is necessary to draw stronger conclusions. / Public Health

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

La dystrophie musculaire de Duchenne est une maladie génétique qui résulte de diverses mutations dans le gène DMD, codant pour la protéine dystrophine. 70% des patients ont une délétion d'exons ou de parties d'exons provoquant un changement dans le cadre de lecture, résultant en l'apparition d'un codon stop et en l'absence de la protéine dystrophine. Plusieurs traitements potentiels ont été explorés dans les dernières années pour cette maladie, dont le système CRISPR-Cas9, un outil génétique permettant d'éliminer un segment d'ADN à l'aide de la protéine nucléase Cas9 et de deux guides d'ARN ciblant des séquences précises d'ADN. Le plus grand défi avec l'utilisation de cette technologie est sa livraison in vivo. Les vésicules extracellulaires sont des particules membranaires lipidiques qui jouent un rôle dans la communication intercellulaire et sont retrouvées dans tous les biofluides chez les mammifères. Elles pourraient donc être une alternative intéressante pour la livraison du système CRISPR-Cas9. J'ai participé à des travaux de purification de vésicules extracellulaires de sérum par chromatographie par exclusion de taille. Ces vésicules extracellulaires ont été chargées avec la protéine Cas9 et des guides ARN, puis, des injections intramusculaires ont été effectuées dans le Tibialis anterior de trois lignées de souris (Ai9, RAG-mdx et mdx/hDMD) pour établir l'efficacité du traitement. Les résultats ont montré que les vésicules extracellulaires chargées avec la Cas9 et des guides d'ARN provoquent une édition de l'ADN efficace dans le Tibialis anterior des trois lignées de souris utilisées et la restauration de l'expression de la protéine dystrophine dans les fibres musculaires du Tibialis anterior des souris RAG-mdx, modèle pour la dystrophie musculaire de Duchenne. Le traitement a ensuite été modifié pour permettre le ciblage des vésicules extracellulaires aux organes affectés par la dystrophie musculaire de Duchenne, soit le cœur et les muscles squelettiques. Des peptides de ciblage ont été sélectionnés dans la littérature et insérés dans la membrane des vésicules extracellulaires marquées de façon fluorescente à l'aide d'un segment lipidique stéaryl. Les résultats de l'expérience effectuée avec les vésicules extracellulaires ciblées n'ont pas été concluants en raison d'un marquage mal adapté des vésicules injectées, mais de futures expériences permettront d'élucider leur efficacité. L'ajustement du traitement pour permettre une injection systémique rejoignant le cœur et les muscles squelettiques est indispensable à l'application de celui-ci à la clinique. / Duchenne muscular dystrophy is a genetic disease that affects one in 3500 boys and results from mutations in the DMD gene, which codes for dystrophin protein. 70% of patients have an exon deletion, which results in a shift in the reading frame, the apparition of a stop codon, and the absence of the dystrophin protein. Many different potential treatments have been explored for Duchenne muscular dystrophy, including the CRISPRCas9 system. This technology allows for the modification of genomic DNA through a Cas9 nuclease and two guide RNAs designed to target a specific DNA sequence. The biggest challenge with using the CRISPR system is delivery. The classic vectors for CRISPR, such as AAV, can cause many adverse effects like immunological responses. Extracellular vesicles are membranous particles that play a role in intercellular communication and are found in all mammalian biofluids. They are thus an interesting alternative for the delivery of the Cas9 protein and its guide RNAs. I have participated in a research project aiming to purify serum extracellular vesicles by size-exclusion chromatography and to load them with Cas9 and two guide RNAs. These extracellular vesicles were then injected intramuscularly into the Tibialis anterior muscles of three mouse strains (Ai9, RAG-mdx and mdx/hDMD) to assess treatment efficiency. The injection of Cas9 and guide RNA-loaded extracellular vesicles produced efficient gene editing as well as dystrophin expression restauration. To modify the treatment for systemic injection, targeting peptides were added to EV membrane through a lipid stearyl segment. This was done to target the extracellular vesicles to Duchenne muscular dystrophy-affected organs: heart and skeletal muscles. Results of the targeted-extracellular vesicle experiment were inconclusive, however, with more experiments, the efficacy of the targeting peptides should be determinable. It is essential to adjust this treatment to allow for targeted systemic delivery for it to be applicable to the clinic.

Hyperspectral imaging (HSI) in abdominal surgery is a new non-invasive tool for the assessment of the perfusion and oxygenation of various tissues and organs. Its benefit in pancreatic surgery is still unknown. The aim of this study was to evaluate the key impact of using HSI during pancreatoduodenectomy (PD). In total, 20 consecutive patients were included. HSI was recorded during surgery as part of a pilot study approved by the local Ethics Committee. Data were collected prospectively with the TIVITA® Tissue System. Intraoperative HS images were recorded before and after gastroduodenal artery (GDA) clamping. We detected four patients with celiac artery stenosis (CAS) caused by a median arcuate ligament (MAL). In two of these patients, a reduction in liver oxygenation (StO2) was discovered 15 and 30 min after GDA clamping. The MAL was divided in these patients. HSI showed an improvement of liver StO2 after MAL division (from 61% to 73%) in one of these two patients. There was no obvious decrease in liver StO2 in the other two patients with CAS. HSI, as a non-invasive procedure, could be helpful in evaluating liver and gastric perfusion during PD, which might assist surgeons in choosing the best surgical approach and in improving patients’ outcomes.

付記する学位プログラム名: 京都大学卓越大学院プログラム「メディカルイノベーション大学院プログラム」 / 京都大学 / 新制・課程博士 / 博士(医科学) / 甲第25007号 / 医科博第154号 / 新制||医科||10(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 遊佐 宏介, 教授 萩原 正敏, 教授 齋藤 潤 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Professional preparation is important for individuals in any profession, as well as the profession itself. It is one of the hallmarks of any profession. Many sets of standards for the curriculum of student affairs preparation programs have been promoted throughout the years. Most recently the Council for the Advancement of Standards in Higher Education (CAS) published a set of standards that outline areas of competency for student affairs professionals. The purpose of this study was to measure the degree to which recent graduates of student affairs preparation programs reported learning about the important foundational elements of the profession. I examined learning based on standards for student affairs preparation programs defined by CAS and compared amounts of reported learning from alumni based on the programs' adherence to the CAS standards (compliant v. non-compliant). To that end, I administered a 67 item questionnaire to recent graduates from student affairs preparation programs. The findings of the present study reveal that a majority of alumni from student affairs preparation programs report having a clear understanding of 57 of 60 identified foundational learning outcomes. Additionally, there was no statistically significant difference between reported learning of alumni from CAS compliant and non-compliant programs based on these foundational learning outcomes on 58 of the 60 items. Data suggest that alumni from CAS compliant programs are more likely to feel confidence in their preparation in 48 of the 60 outcomes presented in the survey. Additionally, the results indicated that alumni from non-compliant programs were more likely to report higher levels of learning based on involvement theory and understanding the level of data a variable in quantitative analysis. / Master of Arts

Since the establishment of People's Republic of China in 1949, Chinese think tanks have experienced significant development during the transformative process of China's political reform and modernization, and their influence has become more notable than before. However, think tanks historically have been given little attention by the public as well as social scientists in China, so scholarly study on Chinese think tanks is limited. This thesis explores the political roles and characteristics of Chinese think tanks by investigating the transformation and classification of Chinese think tanks from 1949 to the present. Furthermore, through a case study of one of the significant projects in contemporary China—the Three Gorges Project—this thesis examines the performance and influence of three Chinese nonpolitical think tanks—the Chinese Academy of Social Science (CASS), the Chinese Academy of Sciences (CAS), and the Chinese Academy of Engineering (CAE) on the process of government policy-making in China. Based on this analysis of Chinese think tanks, I draw the conclusion that professionalism and institutionalization are very urgent requirements for contemporary China's think tanks. / Master of Arts

Le contexte hospitalier est en perpétuel mouvement. Les infirmières ont besoin d'être soutenues pour modifier leur pratique et exercer leur autonomie. À partir de la théorie du leadership de Bass (1985) et du modèle conceptuel en soins infirmiers de Virginia Henderson (1969), cette étude descriptive de type de cas examine l'exercice du leadership transformationnel des infirmières-chefs dans un contexte de modifications à la pratique infirmière et identifie des facteurs organisationnels qui facilitent ou entravent son exercice. Deux échantillons ont été formés, soit trois infirmières-chefs et dix-neuf infirmières. Des entrevues individuelles semi-structurées ont été réalisées et la pratique infirmière a été observée. Les résultats démontrent que la capacité à exercer le leadership transformationnel dans un contexte bureaucratisé est limitée. Celui-ci prend davantage forme dans les moyens utilisés que dans le développement d'une vision et dans l'implication des infirmières.

<p dir="ltr">The CRISPR-Cas systems, originally evolved as bacterial and archaeal adaptive immune systems against viral infections, have been ingeniously repurposed for genome editing. The ongoing evolutionary competition between bacteria and phages has given rise to the diversification of CRISPR-Cas systems, which can be broadly classified into two classes and six types. Among these, the versatile CRISPR type V family stands out as a promising source for discovering new CRISPR-Cas effectors to expand the genome editing toolbox. However, before proceeding to genome editing applications, it is imperative to get a comprehensive understanding of the mechanisms underlying how Cas effectors function as programmable RNA-guided nucleases. Structural studies play a pivotal role in elucidating these mechanisms, providing a clear picture of processes such as DNA recognition and cleavage.</p><p><br></p><p dir="ltr">In the first part of this thesis, we embarked on determining the cryo-EM structures of an extraordinarily small type V-F CRISPR-Cas effector, Cas12f. Our findings unveiled that Cas12f functions as an asymmetric dimer. Through structural analysis and mutagenesis experiments, we elucidated the mechanisms of PAM recognition and substrate cleavage by Cas12f. Furthermore, we provided insights into the activation mechanism of Cas12f by monitoring its conformational changes before and after the crRNA-target DNA heteroduplex formation. Our results contribute to our understanding of the type V Cas effector nucleases and hold promise for possible applications of genome editing.</p><p><br></p><p dir="ltr">In the second part, we focused on study of CRISPR-associated transposons (CASTs). Specifically, we delved into Cas12k, a component of the type V-K CRISPR-Cas system, which is a naturally inactivated nuclease but is interestingly associated with transposons and is capable for guiding transposition. We determined the structure of Cas12k in complex with the guide RNA and target DNA. Our studies revealed target site recognition mechanism and the structural features of Cas12k critical for downstream CIRPSR-guided DNA transposition.</p><p><br></p><p dir="ltr">Lastly, we directed our attention towards the ancestor of CRISPR type V systems, TnpB, which serves as a minimal programmable RNA-guided DNA nuclease originating from the IS200/IS605-like transposon family. To reveal the molecular mechanisms of substrate recognition and cleavage, multiple approaches including artificial dimers was introduced to obtained the cryo-EM structure of <i>Isdra2</i> TnpB-gRNA-target DNA ternary complex. Furthermore, our exploration extended to the investigation of newly emerged TnpB variants. Among these variants, one was identified as a naturally occurring transcription repressor. We attained the cryo-EM structure of this variant at 3.12 Å and currently working on understanding its mechanism.</p>