Long-term neurodevelopmental outcome after fetal therapy

An increasing number of fetal diseases are being detected prior to birth due to major improvements in prenatal ultrasound examinations and the wide implementation of screening programs. For various diseases, fetal therapy may be a life-saving option or an alternative to postnatal treatment, to prevent permanent organ damage. A major breakthrough in fetal therapy was the introduction of intrauterine blood transfusion for severe fetal anemia in the early 1960s. Since then, fetal therapy has gradually evolved resulting in a dramatic increase in overall survival in several fetal diseases. In the Netherlands, fetal surgical interventions are concentrated in one center, the LUMC, a tertiary medical center which serves as the national referral center for fetal therapy. Although an increasing number of children are being born alive after fetal therapy, reliable data on the long-term neurodevelopmental outcome remain scarce. Follow-up studies are of paramount importance to increase our knowledge on the quality of long-term survival and to identify potential risk factors for adverse outcome. In this thesis, studies on the long-term neurodevelopmental outcome after fetal therapy for various fetal diseases are presented including intrauterine transfusion for fetal anemia, fetoscopic laser surgery for twin-twin transfusion syndrome and selective reduction in complicated monochorionic pregnancies.Willem Alexander Kinderfonds, Stichting Intrauteriene Diagnostiek en Behandeling, Sanquin Bloedvoorziening, Stichting Oranjekliniek, ChipSoft BV, Toshiba Medical Systems Nederland, KARL STORZ GmbH & Co. KG, Afdeling Neonatologie LUMC, Afdeling Kindergeneeskunde LUMC, Afdeling Verloskunde LUMCUBL - phd migration 201

Aetiology of Depression: Insights from epidemiological and genetic research

This thesis includes several population-based studies that explore the aetiology of depression, with a specific interest on biological factors, genetics and epigenetics, and physical health factors for depression. Unravelling the aetiology of depression could potentially answer some remaining questions about depression, and finally may explain why we consistently fail to develop effective management and treatment tools for depression. Therefore, this thesis aims to apply advanced epidemiological studies and to extend the existing knowledge on the aetiology of depression. Using population- based data, the studies described in this thesis examine several risk factors and predictors that may enlighten the pathophysiological mechanism that underlie the development of depression. Specifically, Chapter 2 of this thesis presents longitudinal studies that examine the impact of potential biomarkers, such as vitamin D (Chapter 2.1), and inflammatory markers (Chapter 2.2) on the occurrence of depression. Chapter 3 of this thesis presents two studies which apply advanced genetic epidemiological methods to study the genetics of depression. Chapter 4 focuses on the epigenetics of depression and presents the largest epigenome wide association population-based study so far. Moreover, we dedicated a chapter to the impact of physical health conditions such as myocardial infarct on depression (Chapter 5.1) as well as one to the physical consequences of depression such as cognitive decline (Chapter 5.2). Finally, Chapter 6 provides a more general discussion of the main findings in this thesis and addresses several methodological considerations of the studies. Clinical implications of the results in this thesis, and future directions are also presented

Accurate 3D shape and displacement measurement using a scanning electron microscope

With the current development of nano-technology, there exists an increasing demand for three-dimensional shape and deformation measurements at this reduced-length scale in the field of materials research. Images acquired by \ud Scanning Electron Microscope (SEM) systems coupled with analysis by Digital Image Correlation (DIC) is an interesting combination for development of a high magnification measurement system. However, a SEM is designed for visualization, not for metrological studies, and the application of DIC to the micro- or nano-scale with such a system faces the challenges of calibrating the imaging system and correcting the spatially-varying and \ud time-varying distortions in order to obtain accurate measurements. Moreover, the SEM provides only a single sensor and recovering 3D information is not possible with the classical stereo-vision approach. But the specimen being mounted on the mobile SEM stage, images can be acquired from multiple viewpoints and 3D reconstruction is possible using the principle of videogrammetry for recovering the unknown rigid-body motions undergone by \ud the specimen.\ud The dissertation emphasizes the new calibration methodology that has been developed because it is a major contribution for the accuracy of 3D shape and deformation measurements at reduced-length scale. It proves that, unlike previous works, image drift and distortion must be taken into account if accurate measurements are to be made with such a system. Necessary background and required theoretical knowledge for the 3D shape measurement using videogrammetry and for in-plane and out-of-plane deformation measurement are presented in details as well. In order to validate our work and demonstrate in particular the obtained measurement accuracy, experimental results resulting from different applications are presented throughout the different chapters. At last, a software gathering different computer vision applications has been developed.\ud Avec le développement actuel des nano-technologies, la demande en matière d'étude du comportement des matériaux à des échelles micro ou nanoscopique ne cesse d'augmenter. Pour la mesure de forme ou de déformations tridimensionnelles à ces échelles de grandeur,l'acquisition d'images à partir d'un Microscope électronique à Balayage (MEB) couplée à l'analyse par corrélation d'images numériques s'est avérée une technique intéressante. \ud Cependant, un MEB est un outil conçu essentiellement pour de la visualisation et son utilisation pour des mesures tridimensionnelles précises pose un certain nombre de difficultés comme par exemple le calibrage du système et la \ud correction des fortes distorsions (spatiales et temporelles) présentes dans les images. De plus, le MEB ne possède qu'un seul capteur et les informations tridimensionnelles souhaitées ne peuvent pas être obtenues par une approche classique de type stéréovision. Cependant, l'échantillon à analyser étant monté sur un support orientable, des images peuvent être acquises sous différents points de vue, ce qui permet une reconstruction tridimensionnelle en utilisant le principe de vidéogrammétrie pour retrouver à partir des seules images les mouvements inconnus du porte-échantillon.\ud La thèse met l'accent sur la nouvelle technique de calibrage et de correction des distorsions développée car c'est une contribution majeure pour la précision de la mesure de forme et de déformations 3D aux échelles de \ud grandeur étudiées. Elle prouve que, contrairement aux travaux précédents, la prise en compte de la dérive temporelle et des distorsions spatiales d'images \ud est indispensable pour obtenir une précision de mesure suffisante. Les principes permettant la mesure de forme par vidéogrammétrie et le calcul de déformations 2D et 3D sont aussi présentés en détails. Enfin, et dans le but de valider nos travaux et démontrer en particulier la précision de mesure obtenue, des résultats expérimentaux issus de différentes applications sont présentés.\ud \ud \u

A Deep Reinforcement Learning - based Hyperheuristic for the Flexible Traveling Repairman Problem with Drones

Masteroppgave i informatikkINF399MAMN-PROGMAMN-IN

Utilization and Unintended Effects of Antidepressants in an Ageing Population

To summarize, within this thesis, we aimed to study characteristics and unintended effects of antidepressant use in clinical practice in an ageing population. Prevalence of antidepressant use, mainly Selective Serotonin Reuptake Inhibitors (SSRIs), increased over a 20-year period within the Rotterdam Study. In contrast, incidence of antidepressant use decreased over the years. These opposing patterns were possible explained by a longer duration of treatment. Our results suggest that antidepressants are next to the traditional indications prescribed for a wide range of – possible off-label – indications such as neuropathic pain, stress and sleeping disorders. Moreover, there is room for improvement in the initiation (23% early drop-outs) and maintenance phase of treatment. Regarding the possible unintended effects: first, antidepressants were inconsistently associated with the prevalence and occurence of microbleeds. Second, SSRI use was in cross-sectional and longitudinal analyses associated with a good sleep quality. Third, we observed that use of SSRIs was associated with hyponatremia and was transient over time, however, neither use of tricyclic antidepressants, nor other antidepressants was associated with an increased risk of hyponatremia. Fourth, we observed no association between use of SSRIs and, change in, bone mineral density

Language-Based Analysis Of Differential Privacy

Differential privacy (Dwork, 2006; Dwork et al., 2006a) has achieved prominence over the past decade as a rigorous formal foundation upon which diverse tools and mechanisms for performing private data analysis can be built. The guarantee of differential privacy is that it protects privacy at the individual level: if the result of a differentially private query or operation on a dataset is publicly released, any individual present in that dataset can claim plausible deniability. This means that any participating individual can deny the presence of their information in the dataset based on the query result, because differentially private queries introduce enough random noise/bias to make the result indistinguishable from that of the same query run on a dataset which actually does not contain the individual’s information. Additionally, differential privacy guarantees are resilient against any form of linking attack in the presence of auxiliary information about individuals. Both static and dynamic tools have been developed to help non-experts write differentially private programs: static analysis tools construct a proof without needing to run the program; dynamic analysis tools construct a proof while running the program, using a dynamic monitor executed by the unmodified runtime system. The resulting proof may apply only to that execution of the program. Many of the static tools take the form of statically-typed programming languages, where correct privacy analysis is built into the soundness of the type system. Meanwhile dynamic systems typically take either a prescriptive or descriptive approach to analysis when running the program. This dissertation proposes new techniques for language-based analysis of differential privacy of programs in a variety of contexts spanning static and dynamic analysis. Our approach towards differential privacy analysis makes use of ideas from linear type systems and static/dynamic taint analysis. While several prior approaches towards differential privacy analysis exist, this dissertation proposes techniques which are designed to, in several regards, be more flexible and usable than prior work