INTRODUCTION Les anévrismes cérébraux représentent une condition potentiellement mortelle. Ils sont traités par voie chirurgicale (« clipping ») ou endovasculaire (dont le « coiling »), et plusieurs essais cliniques randomisés comparant ces traitements utilisent les résultats angiographiques comme mesure du succès du traitement. Le développement d'une classification standardisée et applicable aux deux traitements et aux trois modalités angiographiques (conventionnelle, angioscan et angio-IRM) est nécessaire. Nos objectifs furent de revoir systématiquement les classifications existantes, d’évaluer la fiabilité inter/intra-observateur d’une nouvelle classification angiographique commune, et d’en vérifier la pertinence clinique. MÉTHODES Deux revues systématiques furent effectuées dans 5 bases de données pour recenser les classifications (et leur fiabilité, lorsque rapportée) pour chaque traitement. Les résultats d’angiographie conventionnelle post-clipping (n=30) ou coiling (n=30) de 60 patients furent évalués de manière indépendante, à l’aide d’une nouvelle classification à 3 catégories, par 19 cliniciens ayant diverses pratiques et expériences. Les observateurs devaient également indiquer la prise en charge clinique appropriée pour chaque cas: un suivi espacé, étroit, ou un retraitement. Quinze lecteurs ont procédé à une 2e évaluation des cas (présentée selon un ordre permuté) à 1 mois d’écart. Le même travail fut reconduit, dans un deuxième temps, par 24 observateurs avec 60 cas évalués par angioscan (n=30) ou angio-IRM (n=30). Les accords inter/intra-observateurs furent estimés avec la statistique Alpha de Krippendorff (aK); la corrélation entre le choix de classe et la prise en charge fut calculée avec un test V de Cramer. RÉSULTATS Soixante-dix classifications (44 post-clipping, 26 post-coiling) furent recensées dans la littérature. La fiabilité variait de 0.12 à 1.00, avec une hétérogénéité significative en termes d’observateurs et de patients. L’accord inter-observateur pour la classification retenue était substantiel pour les résultats d’angiographie conventionnelle (aK=0.76; 0.67–0.83) et des autres modalités (aK=0.63; 0.55–0.70); peu importe le traitement, la spécialité ou l’expérience des évaluateurs. La classe est fortement corrélée à la prise en charge (V de Cramer de 0,77 à 0,80 selon la modalité angiographique; p<0,001). CONCLUSION La classification proposée est fiable et pertinente cliniquement. Elle servira d’outil valide pour évaluer les résultats angiographiques d’anévrismes dans les futurs essais cliniques comparant les deux traitements, peu importe la modalité d’imagerie utilisée. / INTRODUCTION Intracranial aneurysms are a medical condition associated with serious morbidity and mortality when ruptured. They are mainly treated with surgical clipping or endovascular coiling, and randomized clinical trials comparing both treatments often use angiographic results as a surrogate outcome of treatment success. The development of a standardized, reliable method to report angiographic results, applicable to both treatments using any angiographic modality (Conventional [CA], Computed tomography [CTA], or magnetic resonance [MRA] angiography) is needed. We sought to systematically review existing methods of classifying treated aneurysms and to assess the inter-/intra-rater reliability of a new angiographic grading scale, as well as its clinical relevance. METHODS We conducted two separate systematic reviews in 5 databases to collect post-clipping and post-coiling grading scales, along with their reliability when reported. The CA of 60 cases of clipped (n=30) and coiled (n=30) aneurysms were independently evaluated by 19 raters of various backgrounds and experiences using a new 3-grade scale. Raters were also asked how they would manage each case (delayed, close follow-up, or retreatment). Fifteen raters performed a 2nd evaluation of the same cases (in a permuted order) at least one month apart. The same methodology was used to study the reliability of the scale when 60 noninvasive angiography cases of clipped (30 CTA) or coiled (30 MRA) aneurysms were evaluated by 24 raters. Inter and intra-rater agreements were assessed using Krippendorff’s Alpha statistics (aK), and the relationship between occlusion grade and clinical management using Cramer’s V test. RESULTS The systematic reviews found 70 grading scales (44 post-clipping, 26 post-coiling) with significant heterogeneity in terms of reliability (kappa values from 0.12 to 1.00), raters, and patients. Overall inter-rater agreement for the grading scale was substantial for CA results (aK=0.76; 0.67–0.83) as well as for noninvasive results (aK=0.63; 0.55–0.70); regardless of background, experience, or treatment used. A strong relationship was found between angiographic grades and management decisions (V=0.80±0.12 for CA; V=0.77±0.14 for CTA/MRA [p<0.001]). CONCLUSION A standardized 3-grade scale was found to be a reliable and clinically meaningful tool to compare the results of clipping and coiling of aneurysms using any angiographic modality. It could be used as a valid tool to adjudicate results of comparative randomized trials, and to standardize the reporting of aneurysm treatments.

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X-ray diffraction (XRD) profile fitting (Rietveld method) was used in this study to characterize the microstructure for seven microalloyed steels, which were produced through thermomechanical controlled processing (TMCP). Microstructure characterization was conducted through the strip thickness. The microstructural variables studied include subgrain size, dislocation density, texture index and weight percent of retained austenite. The subgrain size was also analyzed by electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM). The effects of processing parameters, including coiling temperature, cooling rate and alloying elements, on the microstructure were also investigated. It was found that decreasing the coiling temperature resulted in a finer subgrain size and higher dislocation densities. The texture index was observed to increase with decreasing coiling temperature. The subgrain size decreased and dislocation density increased as the amount of alloying elements (Ni, Mo and Mn) were increased. The amount of retained austenite increased at the strip center with increasing coiling temperature and increasing C and Ni content. / Materials Engineering

Cancer metastasis, the spread of cancer from the primary site to distant regions in the body, is the major cause of cancer mortality, accounting for almost 90% of cancer related deaths. During metastasis, cancer cells from the primary tumor initially probe the surrounding fibrous tumor microenvironment (TME) prior to detaching and subsequently migrating towards the blood vessels for further dissemination. It has widely been acknowledged that the biophysical cues provided by the fibrous TME greatly facilitate the metastatic cascade. Consequently, there has been a tremendous wealth of work devoted towards elucidating different modes of cancer cell migration. However, our knowledge of how cancer cells at the primary tumor site initially sense their fibrous surroundings prior to making the decision to detach and migrate remains in infancy. In part, this is due to the lack of a fibrous in vitro platform that allows for precise, repeatable manipulation of fiber characteristics. In this study, we use the non-electrospinning, Spinneret based Tunable Engineered Parameters (STEP) technique to manufacture suspended nanofiber networks with exquisite control on fiber dimensions and network architecture and use these networks to investigate how single cancer cells biophysically sense fibers mimicking in vivo dimensions. Using high spatiotemporal resolution imaging (63x magnification/1-second imaging interval), we report for the first time, that cancer cells sense individual fibers by coiling (i.e. wrapping around the fiber axis) at the tip of a cell protrusion. We find that coiling dynamics are mediated by both the fiber curvature and the metastatic capacity of the cancer cells with less aggressive cancer cells showing diminished coiling. Based on these results, we explore the possibility of using coiling in conjunction with other key biophysical metrics such as cell migration dynamics and forces exerted in the development of a genetic marker independent, biophysical predictive tool for disease progression. Finally, we identify the membrane curvature sensing Insulin Receptor tyrosine kinase Substrate protein of 53 kDa (IRSp53) as a key regulator of protrusive activity with IRSp53 knockout (KO) cells exhibiting significantly slower protrusion dynamics and diminished coil width compared to their wild-type (WT) counterparts. We demonstrate that the hindered protrusive activity ultimately translates to impaired contractility, alteration in the nucleus shape and slower migration dynamics, thus highlighting the unique role of IRSp53 as a signal transducer – linking the protrusive activity at the cell membrane to changes in cytoskeletal contractility. Overall, these findings offer novel perspectives to our understanding of how cancer cells biophysically sense their fibrous surroundings. The results from this study could ultimately pave the way for elucidating the precise fiber configurations that either facilitate or hinder cancer cell invasion, allowing for the development of new therapeutics in the long term that could inhibit the metastatic cascade at a relatively nascent stage and yield a more promising prognosis in the perennial fight against cancer. / Doctor of Philosophy / Cancer is a leading cause of death worldwide. Almost ninety percent of cancer related deaths arise from the spreading of cancer cells from the primary tumor site to secondary sites in the body – a processed termed as metastasis. The environment surrounding a tumor (tumor microenvironment) is highly fibrous in nature and can assist in the metastatic process by providing biophysical cues to the cells at the tumor boundary. These cells sense the presence of the surrounding fibers by extending "arms" termed as protrusions, and then eventually detach from the primary tumor and start migrating through the fibrous microenvironment. While numerous studies have investigated the various modes of cell migration in fibrous environments, there is very little information regarding how cancer cells use protrusions to initially sense the fibers prior to detaching. In this study, we used the Spinneret based Tunable Engineered Parameters (STEP) technique to manufacture suspended nanofiber networks with robust control on fiber diameter and network architecture and use these networks to systematically investigate how single cancer cells biophysically sense fibers that mimic in vivo dimensions. We discovered that cancer cells sense individual fibers by "wrapping-around" the axis of the fiber at the tip of the protrusion – a phenomenon we refer to as coiling. We found both the fiber diameter as well as the invasive capacity of cells can influence the coiling mechanics. Based on these results, we explored the use of coiling in conjunction with other key biophysical metrics such as the cell migration speed and how much force a cell can exert to develop a biophysical predictor for cancer cell aggressiveness. Finally, given that cells sense the fiber curvature by coiling, we explored the role of a key curvature sensing protein Insulin Receptor tyrosine kinase Substrate protein of 53 kDa (IRSp53) in mediating coiling activity and found that knocking out (KO) IRSp53 results in reduced coiling and slower protrusions compared to wild-type (WT) cells. Furthermore, IRSp53 KO cells showed impaired contractility which led to an alteration in the nucleus shape and slower migration dynamics thus highlighting the role of IRSp53 in linking changes at the cell membrane to the underlying cell cytoskeleton. The results from this study could ultimately help us understand what type of fiber conditions around a primary tumor would either help or delay the emergence of the tumor boundary cells and thus allow for the development of therapeutics that could significantly slow down the metastatic process at a relatively early stage.

Background Dislocation of catheters within the tissue is a challenge in continuous regional anesthesia. A novel self-coiling catheter design is available and has demonstrated a lower dislocation rate in a cadaver model. The dislocation rate and effect on postoperative pain of these catheters in vivo has yet to be determined and were the subjects of this investigation. Methods After ethics committee approval 140 patients undergoing elective distal lower limb surgery were enrolled in this prospective randomized controlled trial. Preoperatively, patients were randomly assigned and received either the conventional (n = 70) or self-coiling catheter (n = 70) for ultrasound-guided popliteal sciatic nerve block in short axis view and by the in-plane approach from lateral to medial. The primary outcome was pain intensity after surgery and on the following three postoperative days. Secondary outcomes investigated were dislocation rate in situ determined by sonography, catheter movement visible from outside, opioid consumption as well as leakage at the puncture site. Results All catheters were successfully inserted. The study population of self-coiling catheters had significantly lower mean numeric rating scale values than the reference cohort on the first (p = 0.01) and second postoperative days (p < 0.01). Sonographic evaluation demonstrated, 42 standard catheters (60%) and 10 self-coiling catheters (14.3%) were dislocated in situ within the first three postoperative days. The externally visible movement of the catheters at insertion site did not differ significantly between groups through the third postoperative day. The opioid consumption was significantly lower in the self-coiling catheter group on the day of surgery and on the second and third postoperative days (p = 0.04, p = 0.03 and p = 0.04, respectively). Conclusion The self-coiling catheter offers a better postoperative pain control and a lower dislocation rate within the tissue when blocking the popliteal sciatic nerve compared to a conventional catheter. Further trials in large patient cohorts are warranted to investigate the potential beneficial effects of self-coiling catheters for other localisations and other application techniques.

In der vorliegenden Arbeit wird ein prozessübergreifendes Simulationsmodell für die Temperatur- und Gefügeentwicklung im Band und Coil beim reversierenden Warmwalzen entwickelt. In der Software werden die erstmals aufgestellten Modelle der Bandab- und aufwicklung implementiert. Die Temperatur- und Gefügeveränderungen im gewalzten Warmband werden lokal und prozessübergreifend betrachtet. Die für das gesamte Modell notwendigen Koeffizienten zur Beschreibung der Wärmeübertragung wurden mittels der inversen Methode bestimmt. Die Bestimmung der radialen Wärmeübertragung im Coil erfolgte mit Hilfe von Laboruntersuchungen in Abhängigkeit von der Temperatur, der Banddicke und des radialen Druckes. Die Validierung des Modells für die Temperatur- und Gefügeentwicklung erfolgte am Beispiel des reversierenden Warmwalzens der Magnesiumlegierung AZ31. Zu diesem Zweck wurden Versuche zu Temperaturmessungen in den einzelnen Phasen der Prozesskette durchgeführt. Die Ermittlung der Einflüsse der Umformbedingungen auf die Temperatur- und Gefügeentwicklung während des reversierenden Warmbandwalzens erfolgte abschließend mit Hilfe des entwickelten Modells. Die Ergebnisse zeigen auf, wie sich die Walzbedingungen auf die Entwicklung der Temperatur und des Gefüges auswirken.