Network Construction and Graph Theoretical Analysis of Functional Language Networks in Pediatric Epilepsy

This dissertation introduces a new approach for assessing the effects of pediatric epilepsy on the language connectome. Two novel data-driven network construction approaches are presented. These methods rely on connecting different brain regions using either extent or intensity of language related activations as identified by independent component analysis of fMRI data. An auditory description decision task (ADDT) paradigm was used to activate the language network for 29 patients and 30 controls recruited from three major pediatric hospitals. Empirical evaluations illustrated that pediatric epilepsy can cause, or is associated with, a network efficiency reduction. Patients showed a propensity to inefficiently employ the whole brain network to perform the ADDT language task; on the contrary, controls seemed to efficiently use smaller segregated network components to achieve the same task. To explain the causes of the decreased efficiency, graph theoretical analysis was carried out. The analysis revealed no substantial global network feature differences between the patient and control groups. It also showed that for both subject groups the language network exhibited small-world characteristics; however, the patient’s extent of activation network showed a tendency towards more random networks. It was also shown that the intensity of activation network displayed ipsilateral hub reorganization on the local level. The left hemispheric hubs displayed greater centrality values for patients, whereas the right hemispheric hubs displayed greater centrality values for controls. This hub hemispheric disparity was not correlated with a right atypical language laterality found in six patients. Finally it was shown that a multi-level unsupervised clustering scheme based on self-organizing maps, a type of artificial neural network, and k-means was able to fairly and blindly separate the subjects into their respective patient or control groups. The clustering was initiated using the local nodal centrality measurements only. Compared to the extent of activation network, the intensity of activation network clustering demonstrated better precision. This outcome supports the assertion that the local centrality differences presented by the intensity of activation network can be associated with focal epilepsy.

Expression and purification of tau protein and its frontotemporal dementia variants using a cleavable histidine tag

Recombinant tau protein is widely used to study the biochemical, cellular and pathological aspects of tauopathies, including Alzheimer's disease and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTPD-17). Pure tau in high yield is a requirement for in vitro evaluation of the protein's physiological and toxic functions. However, the preparation of recombinant tau is complicated by the protein's propensity to aggregate and form truncation products, necessitating the use of multiple, time-consuming purification methods. In this study, we investigated parameters that influence the expression of wild type and FTPD-17 pathogenic tau, in an attempt to identify ways to maximise expression yield. Here, we report on the influence of the choice of host strain, induction temperature, duration of induction, and media supplementation with glucose on tau expression in Escherichia coli. We also describe a straightforward process to purify the expressed tau proteins using immobilised metal affinity chromatography, with favourable yields over previous reports. An advantage of the described method is that it enables high yield production of functional oligomeric and monomeric tau, both of which can be used to study the biochemical, physiological and toxic properties of the protein.

Effets des variations dans l’implantation d’un programme sur le risque cardiométabolique dans six CSSS de Montréal sur les résultats chez les patients

En 2011, l’Agence de la santé et des services sociaux de Montréal (ASSSM), en partenariat avec les Centres de santé et services sociaux (CSSS) de la région, a coordonné la mise en œuvre d’un programme de prévention et de prise en charge intégré sur le risque cardiométabolique. Ce programme, s’inspirant du Chronic Care Model et s’adressant aux patients atteints de diabète et d’hypertension artérielle, est d’une durée de deux ans et comporte une séquence de suivis individuels avec l’infirmière et la nutritionniste, de cours de groupe et de séances d’activité physique. L’objectif de ce mémoire est d’évaluer, à l’aide d’un devis quasi-expérimental, l’impact de la variation dans l’implantation de certains aspects du programme dans les six CSSS participant à l’étude sur les résultats de santé des patients. Cinq aspects du programme ont été retenus : les ressources, la conformité au processus clinique prévu dans le programme régional, la maturité du programme, la coordination interne au sein de l’équipe de soins et la coordination externe avec les médecins de 1re ligne. Des analyses de différence de différences, incluant des scores de propension afin de rendre les groupes comparables, ont été effectuées dans le but d’évaluer l’influence de ces aspects sur quatre indicateurs de santé : l’hémoglobine glyquée, l’atteinte de la cible de tension artérielle et l’atteinte de deux cibles d’habitudes de vie concernant la répartition des glucides alimentaires et la pratique d’activité physique. Les résultats indiquent que les indicateurs de santé sélectionnés se sont améliorés chez les patients participant au programme et ce, indépendamment des variations dans son implantation entre les CSSS participant à l’étude. Très peu d’analyses de différence de différences ont en effet relevé un impact significatif des variables d’implantation étudiées sur ces indicateurs. Les résultats suggèrent que les effets bénéfiques d’un tel programme sont davantage tributaires de la prestation des interventions auprès des patients que d’aspects organisationnels liés à son implantation.

Comparaison populationnelle des résultats périopératoires entre la néphro-urétérectomie ouverte et laparoscopique aux États-Unis

Introduction : La néphro-urétérectomie radicale (NUR) représente le traitement primaire pour les patients atteints d’une tumeur des voies excrétrices supérieures (TVES) non métastatique. Une approche ouverte ou laparoscopique peut être considérée. Malgré la présence de plusieurs études comparant les résultats périopératoires et oncologiques entre ces deux approches, aucunes études se basent sur une cohorte populationnelle. Objectif : Notre but est d’évaluer la morbidité péri-opératoire entre la NUR ouverte et laparoscopique en utilisant une cohorte populationnelle. Méthode : Nous avons utilisé la base de donnée Nationwide Inpatient Sample (NIS) pour identifier tous les patients atteints d’une TVES non métastatique, traités par NUR ouverte ou laparoscopique, entre 1998 et 2009. Au total, 7401 (90,8%) et 754 (9,2%) patients ont subi une NUR ouverte et laparoscopique, respectivement. Dans le but de contrôler les différences inhérentes entre les deux groupes, nous avons utilisé une analyse par appariement sur les scores de propension. Ainsi, 3016 (80%) patients avec NUR ouverte étaient appariés à 754 (20%) patients avec NUR laparoscopique. Intervention : Tous les patients ont subi une NUR. Mesures : Les taux de complications intra-opératoires et post-opératoires, de transfusions sanguines, d’hospitalisation prolongée et de mortalité intrahospitalière ont été mesurés. Des analyses de régression logistique on été utilisées pour notre cohorte, après appariement sur les scores de propension. Résultats et Limitations : Pour les patients traités par approche ouverte vs. laparoscopique, les taux suivants furent calculés : transfusions sanguines : 15 vs. 10% (p<0,001); complications intra-opératoires : 4,7 vs. 2,1% (p=0,002); complications post-opératoires : 17 vs. 15% (p=0,24); durée d’hospitalisation prolongée (≥ 5 jours) : 47 vs. 28% (p<0,001); mortalité intra-hospitalière 1,3 vs. 0,7% (p=0,12). Sur les analyses par régression logistique, les patients ayant été traités par NUR laparoscopique avaient moins de chance de recevoir une transfusion sanguine (odds ratio [OR]: 0,6, p<0,001), de subir une complication intra-opératoire (OR: 0,4, p=0,002), et d’avoir une durée prolongée d’hospitalisation (OR: 0,4, p<0,001). Globalement les taux de complications postopératoires étaient équivalents. Toutefois, l’approche laparoscopique était associée à moins de complications pulmonaires (OR: 0,4, p=0,007). Cette étude est limitée par sa nature rétrospective. Conclusion: Après ajustement de potentiels biais de sélection, la NUR par approche laparoscopique est associée à moins de complications intraopératoires et péri-opératoires comparée à la NUR par approche ouverte.

L’évaluation des déterminants des paramètres hémodynamiques centraux à l’aide de la cohorte populationnelle CARTaGENE

Les maladies cardiovasculaires ont un impact considérable sur la vie des Canadiens, et de nombreux efforts ont permis d’identifier différents facteurs de risque associés à cette condition. L’hypertension artérielle représente un de ces facteurs modifiables les plus importants. Quoique l’hypertension est définie à l’aide de mesures de pression artérielle en périphérie, il devient de plus en plus apparent que la mesure de pression centrale et de ses composantes auraient des avantages au niveau de la prédiction de la survenue d’événements cardiovasculaires. Le présent mémoire vise à mieux caractériser deux déterminants de cette pression centrale, le traitement antihypertenseur à base de bêtabloqueurs et l’insuffisance rénale chronique précoce. En utilisant les données recueillies dans la banque de données populationnelle CARTaGENE, il a été possible à l’aide d’analyses statistiques par appariement basé sur le coefficient de propension de démontrer que l’utilisation d’agents antihypertensifs de type bêtabloqueurs était associée à un profil hémodynamique central défavorable. Ainsi, les individus recevant ces agents avaient une pression centrale et une amplification artérielle plus élevées que des individus du groupe contrôle apparié et ce, malgré une pression périphérique identique. Cet effet semblait être incomplètement expliqué par la réduction du rythme cardiaque associé à l’utilisation de bêtabloqueurs. Aussi, il a été démontré que l’insuffisance rénale chronique de stade 3 (débit de filtration glomérulaire estimé entre 30 et 60 mL/min/1.73m2) n’était pas associée à une élévation des paramètres hémodynamiques centraux, contrairement à ce qui avait déjà été décrit chez des individus avec insuffisance rénale chronique plus avancée. De plus, le niveau d’albuminurie ne serait également pas associé à un changement du profil central dans un sous-groupe de la cohorte CARTaGENE.

Regional diversity and economic performance

This thesis consists of an introductory chapter and four individual papers. In each paper the relationship between some form of spatial diversity and economic performance is analyzed. Diversity is treated as a potential source of externality effects, mainly in the form of knowledge spillovers. The first paper studies the impact of a broad range of spatial externalities on the productivity of manufacturing plants. While finding positive effects of specialization and competition, there is no support for positive spillovers of either related or unrelated industry diversity. The second paper argues that relatedness should be framed at the level of individuals and consequently should be measured in terms of, for example, education and occupation rather than industry belonging. The results show that educational- and occupational related diversity matter for regional productivity growth, while related industry diversity is positively related to employment growth. The third paper analyzes the importance of neighborhood related diversity, in terms of both industries and education, and internal human capital for firms’ propensity to innovate. The findings support that education and skills are strongly related to firm innovation. Additionally, firms in metropolitan regions are more innovative in neighborhoods with more related diversity in industries, while firms in rural regions seem to benefit more from related diversity in education. In the fourth paper, the location factor of interest is segregation, which may be regarded as inverse diversity. The results show that neighborhood segregation has a negative effect on individual employment. However, it is not the spatial separation of individuals with different backgrounds that causes lower employment but rather the distress of segregated neighborhoods.

Entrepreneurship: a long way to go

Entrepreneurship education has emerged as one popular research domain in academic fields given its aim at enhancing and developing certain entrepreneurial qualities of undergraduates that change their state of behavior, even their entrepreneurial inclination and finally may result in the formation of new businesses as well as new job opportunities. This study attempts to investigate the Colombian student´s entrepreneurial qualities and the influence of entrepreneurial education during their studies.

Impacto del Programa de Alimentación Escolar en el Trabajo Infantil: Una aproximación desde la toma de decisiones familiares

Esta investigación analiza el impacto del Programa de Alimentación Escolar en el trabajo infantil en Colombia a través de varias técnicas de evaluación de impacto que incluyen emparejamiento simple, emparejamiento genético y emparejamiento con reducción de sesgo. En particular, se encuentra que este programa disminuye la probabilidad de que los escolares trabajen alrededor de un 4%. Además, se explora que el trabajo infantil se reduce gracias a que el programa aumenta la seguridad alimentaria, lo que consecuentemente cambia las decisiones de los hogares y anula la carga laboral en los infantes. Son numerosos los avances en primera infancia llevados a cabo por el Estado, sin embargo, estos resultados sirven de base para construir un marco conceptual en el que se deben rescatar y promover las políticas públicas alimentarias en toda la edad escolar.

Diferencias regionales en las estructuras de ingresos laborales en Colombia

Dada la persistencia de las diferencias en ingresos laborales por regiones en Colombia, el presente artículo propone cuantificar la magnitud de este diferencial que es atribuida a la diferencia en estructuras de mercado laboral, entendiendo esta última como la diferencia en los retornos a las características de la fuerza laboral. Para ello se propone el uso de un método de descomposición del tipo Oaxaca- Blinder y se compara a Bogotá –la ciudad con mayores ingresos laborales- con otras ciudades principales. Los resultados obtenidos al conducir el ejercicio de descomposición muestran que las diferencias en estructura están a favor de Bogotá y que estas explican más de la mitad de la diferencia total, indicando que si se quieren reducir las disparidades de ingresos laborales entre ciudades no es suficiente con calificar la fuerza laboral y que es necesario indagar por las causas que hacen que los retornos a las características difieran entre ciudades.

Essays in Applied Insurance Economics

The papers included in this thesis deal with a few aspects of insurance economics that have seldom been dealt with in the applied literature. In the first paper I apply for the first time the tools of the economics of crime to study the determinants of frauds, using data on Italian provinces. The contributions to the literature are manifold: -The price of insuring has a positive correlation with the propensity to defraud -Social norms constraint fraudulent behavior, but their strength is curtailed in economic downturns -I apply a simple extension of the Random Coefficient model, which allows for the presence of time invariant covariates and asymmetries in the impact of the regressors. The second paper assesses how the evolution of macro prudential regulation of insurance companies has been reflected in their equity price. I employ a standard event study methodology, deriving the definition of the “control” and “treatment” groups from what is implied by the regulatory framework. The main results are: -Markets care about the evolution of the legislation. Their perception has shifted from a first positive assessment of a possible implicit “too big to fail” subsidy to a more negative one related to its cost in terms of stricter capital requirement -The size of this phenomenon is positively related to leverage, size and on the geographical location of the insurance companies The third paper introduces a novel methodology to forecast non-life insurance premiums and profitability as function of macroeconomic variables, using the simultaneous equation framework traditionally employed macroeconometric models and a simple theoretical model of insurance pricing to derive a long term relationship between premiums, claims expenses and short term rates. The model is shown to provide a better forecast of premiums and profitability compared with the single equation specifications commonly used in applied analysis.

Disturbi dell'informazione, nuovi media e libertà di manifestazione del pensiero

L’elaborato affronta il tema della massiccia diffusione di disinformazione tramite internet sotto il profilo del diritto costituzionale, nell’ottica di indagare se le dimensioni del fenomeno richiedano l’elaborazione di principi e soluzioni nuove ovvero se i paradigmi costituzionali enucleati dalla tradizione costituzionalistica con riferimento alla libertà d’espressione forniscano gli strumenti sufficienti per un intervento efficace. In tale ottica, il lavoro premette una ricostruzione del fenomeno della disinformazione nel tentativo di individuare il perimetro socio-cognitivo e tecnologico entro cui la medesima prolifera, descrivendo gli elementi che distinguono l’informazione diffusa dai nuovi media rispetto a quella veicolata dai media mainstream. Ciò premesso, lo studio passa a delineare lo “statuto costituzionale” del falso, indagando la rilevanza che la menzogna assume sotto il profilo costituzionale nel suo rapporto con la libertà di manifestazione del pensiero negli ordinamenti interno, europeo e statunitense. L’analisi prosegue poi con l’esame delle politiche di contrasto alla disinformazione introdotte da singoli Stati (prevalentemente Germania, Francia e Italia), Unione europea, e piattaforme, con l’obiettivo di mettere in luce vantaggi e limiti dei modelli di eteroregolamentazione, coregolamentazione e autoregolamentazione. Da ultimo, l’elaborato scompone alcune delle azioni e misure passate in rassegna e le analizza con la lente d’ingrandimento della libertà di manifestazione del pensiero, ordinandone i contenuti secondo la specifica propensione a comprimere la libertà d’espressione. L’indagine si conclude con alcuni brevi spunti conclusivi che evidenziano l’esigenza, in base ai principi costituzionali analizzati, che eventuali interventi normativi siano se del caso volti alla regolazione delle piattaforme, ovvero dei “contenitori”, lasciano i contenuti al libero scambio delle idee.

Structural and biophysical characterization of RAD52 as novel pharmacological target for synthetic lethality

RAD52 is a protein involved in various DNA reparation mechanisms. In the last few years, RAD52 has been proposed as a novel pharmacological target for cancer synthetic lethality strategies. Hence, this work has the purpose to investigate RAD52 protein, with biophysical and structural tools to shed light on proteins features and mechanistic details that are, up to now poorly described, and to design novel strategies for its inhibition. My PhD work had two goals: the structural and functional characterization of RAD52 and the identification of novel RAD52 inhibitors. For the first part, RAD52 was characterized both for its DNA interaction and oligomerization state together with its propensity to form high molecular weight superstructures. Moreover, using EM and Cryo-EM techniques, additional RAD52 structural hallmarks were obtained, valuable both for understanding protein mechanism of action and for drug discovery purpose. The second part of my PhD project focused on the design and characterization of novel RAD52 inhibitors to be potentially used in combination therapies with PARPi to achieve cancer cells synthetic lethality, avoiding resistance occurrence and side effects. With this aim we selected and characterized promising RAD52 inhibitors through three different approaches: 19F NMR fragment-based screening; virtual screening campaign; aptamers computational design. Selected hits (fragments, molecules and aptamers) were investigated for their binding to RAD52 and for their mechanism of inhibition. Collected data highlighted the identification of hits worthy to be developed into more potent and selective RAD52 inhibitors. Finally, a side project carried out during my PhD is reported. GSK-3β protein, an already validated pharmacological target was investigated using biophysical and structural biology tools. Here, an innovative and adaptable drug discovery screening pipeline able to directly identify selective compounds with binding affinities not higher than a reference binder was developed.

Enhanced financial literacy through financial education and its impact on financial behaviour

This dissertation aims to contribute to the ongoing discourse on the effect an enhanced financial literacy, through financial education, has on financial behaviour. We posit that financial literacy is enhanced through financial education courses, but it also significantly impacts the financial behaviour of individuals. Moreover, we argue that improved financial literacy plays a significant role in mitigating behavioural biases and an asset price bubble. Chapter 1 analyzes the impact of a financial education course in enhancing financial literacy in a high- school context. Students at specific schools in Tirana, Albania, are delivered a financial education course, which lasts one academic year. To understand the impact of this financial education course in enhancing financial literacy, PISA (2012) questionnaire on financial literacy is delivered to the students before and after the course is delivered. Chapter 2 analysis the impact of financial literacy in mitigating behavioural biases. We focus on the impact that enhanced financial literacy through the financial education course and financial education plays in reducing the propensity to mental accounting bias. Chapter 3 investigates how financial literacy affects the propensity to an asset price bubble occurrence. We posit that enhanced financial literacy through financial education reduces the probability of an asset price bubble occurrence. We find that financial literacy enhanced through financial education has a significant impact in the financial behaviour of the individuals.

Vascular access in patients with peripheral arterial disease undergoing TAVI: the hostile registry

BACKGROUND The optimal access route in patients with severe peripheral artery disease (PAD) undergoing TAVI remains undetermined. OBJECTIVE To compare clinical outcomes with transfemoral access (TFA), transthoracic access (TTA), and non-thoracic alternative access (TAA) in TAVI patients with severe PAD. METHODS Patients with PAD and hostile femoral access (TFA impossible, or possible only after percutaneous treatment) undergoing TAVI at 28 international centers were included in this registry. The primary endpoint was the propensity-adjusted risk of 30-day major adverse events (MAE) defined as the composite of all-cause mortality, stroke/transitory ischemic attack (TIA) or main access site-related VARC 3 major vascular complications. Outcomes were also stratified according to the severity of PAD using a novel risk score (Hostile score). RESULTS Among the 1,707 patients included in the registry, 518 (30.3%) underwent TAVI with TFA after percutaneous treatment, 642 (37.6%) with TTA, and 547 (32.0%) with TAA (mostly transaxillary). Compared with TTA, both TFA (adjusted HR=0.58, 95%CI 0.45-0.75) and TAA (adjusted HR=0.60, 95%CI 0.47-0.78) were associated with lower 30-day rates of MAE, driven by fewer access site-related complications. Composite risks at 1 year were also lower with TFA and TAA compared with TTA. TFA compared with TAA was associated with lower 1-year risks of stroke/TIA (adjusted HR=0.49, 95%CI 0.24-0.98), a finding confined to patients with low Hostile scores (Pinteraction=0.049). CONCLUSIONS Among patients with PAD undergoing TAVI, both TFA and TAA were associated with lower 30-day and 1-year rates of MAE compared with TTA, but 1-year stroke/TIA rates were higher with TAA compared with TFA.

Nuovi approcci al trattamento della valvulopatia aortica

Background L’incidenza di malattie valvolari aortiche è in costante aumento. La terapia definitiva è chirurgica o interventistica, determinando un evidente miglioramento della qualità di vita, a fronte di un rischio operatorio ormai estremamente basso. Le linee guida internazionali più recenti pongono in classe I entrambe le procedure nella fascia di età fra 65 e 80 anni. Materiali e metodi È stata effettuata un’analisi retrospettiva dei pazienti di età compresa fra 65 e 80 anni, sottoposti a sostituzione valvolare aortica isolata chirurgica con bioprotesi sutureless (gruppo SU-AVR), oppure trans-catetere (gruppo TAVR), presso Maria Cecilia Hospital tra gennaio 2011 e dicembre 2021. Mediante propensity score matching sono stati analizzati, nei due gruppi risultanti, gli outcomes di mortalità e complicanze intraospedaliere, a 30 giorni, ad un anno e attuariale. Risultati Sono stati inclusi nello studio 638 pazienti, di cui 338 (52.98%) nel gruppo SU-AVR e 300 (47.02%) nel gruppo TAVR. Dopo propensity score matching, sono stati ottenuti due gruppi di pazienti (124 per gruppo) senza differenze statisticamente significative nelle comorbidità preoperatorie. La mortalità a 30 giorni è risultata sovrapponibile nei 2 gruppi. Il gruppo TAVR ha mostrato un’incidenza significativamente maggiore di impianto di pacemaker definitivo e di danni vascolari maggiori, mentre il gruppo SU-AVR ha mostrato una maggior incidenza di fibrillazione atriale, di trasfusioni e di insufficienza renale. La mortalità per tutte le cause a un anno è risultata significativamente maggiore per il gruppo TAVR e il divario continua ad aumentare con il tempo. Conclusioni La sostituzione valvolare aortica trans-catetere (TAVR) mostra risultati molto buoni nel breve termine nei pazienti fra 65 e 80 anni di età. Al follow-up a medio termine, tuttavia, i risultati preliminari mostrano un miglior outcome dei pazienti sottoposti a sostituzione valvolare chirurgica, sia in termini di mortalità per qualsiasi causa che di eventi cardiovascolari e cerebrovascolari maggiori.