Es werden verschiedene Stetigkeitskonzepte, die in der statistischen Theorie und Methodik eine Rolle spielen, erläutert.

Cables are highly nonlinear structural members under transverse loading. This nonlinearity is mainly due to the close relationship between the final geometry under transverse loads and the resulting stresses in its equilibrium state rather than the material properties. In practice, the cables are usually used as isolated single-segment elements fixed at the ends. Various studies and solution procedures suggested by researchers are available in the literature for such isolated cables. However, not much work is available for continuous cables with multiple supports. In this study, a multi-segment continuous cable is defined as a cable fixed at the ends and supported by a number of stationary roller supports in between. Total cable length is assumed constant and the intermediate supports are assumed to be frictionless. Therefore, the critical issue is to find the distribution of the cable length among its segments in the final equilibrium state. Since the solution of single-segment cables is available the additional condition to be satisfied for multi-segment continuous cables with multiple supports is to have stress continuity at intermediate support locations where successive cable segments meet. A predictive/corrective iteration procedure is proposed for this purpose. The solution starts with an initially assumed distribution of total cable length among the segments and each segment is analyzed as an independent isolated single-segment cable. In general, the stress continuity between the cable segments will not be satisfied unless the assumed distribution of cable length is the correct distribution corresponding to final equilibrium state. In the subsequent iterations the segment lengths are readjusted to eliminate the unbalanced tensions at segment junctions. The iterations are continued until the stress continuity is satisfied at all junctions. Two alternative approaches are proposed for the segment length adjustments: Direct stiffness method and tension distribution method. Both techniques have been implemented in a software program for the analysis of multi-segment continuous cables and some sample problems are analyzed for verification. The results are satisfactory and compares well with those obtained by the commercial finite element program ANSYS.

L’un des nombreux défis pour l’industrie pharmaceutique est de développer des procédés compétitifs pour produire des principes actifs de hautes qualités à bas coût. Pour ce faire, plusieurs sociétés se tournent vers la chimie en flux continu et les avantages qu’elle présente comparé au batch traditionnel. C’est pourquoi ces travaux de thèse se centrent sur le développement d’un procédé continu allant des matières premières au principe actif. La première étape pour parvenir à ce but fut de collecter des données sur le procédé batch industriel actuel. Il se compose de trois étapes de réactions chimiques, une de séparation chromatographique et une étape de cristallisation. A partir de là, la chimie de chaque réaction a été adaptée pour profiter au mieux des avantages du flux continu. La dissipation de chaleur étant plus efficace qu’en batch il fut possible de développer une réaction exothermique sans solvant à haute température. Une étude cinétique a été réalisée afin de modéliser cette réaction. Ensuite, cet outil fut utilisé pour déterminer les conditions opératoires optimales théoriques de la réaction et en guider l’optimisation ainsi que la conception du futur réacteur. La deuxième partie de ce travail se focalise sur la cristallisation en continu du principe actif avec la technique des jets impactant. Il est nécessaire d’avoir un contrôle précis sur la distribution de taille de particules (DTP) et la morphologie des cristaux. En effet, le principe actif peut cristalliser sous deux formes compétitives : cristaux cubiques ou en forme d’aiguilles. Les cubes sont la forme désirée. La technique des jets impactant a été sélectionnée car c’est un procédé continu qui permet la génération de fines particules avec une DTP resserrée. La sursaturation est généralement crée en impactant un jet de solution de principe actif avec un jet d’anti-solvant. Ici, le solvant et l’anti-solvant sont les mêmes. Seule une large différence de température entre les deux jets génère la sursaturation. En testant différentes conditions opératoires, une « zone cubique » a été définie, où seuls des cristaux de forme désirée sont générés. Une fois la nucléation maîtrisée, le murissement et la séparation solide-liquide furent étudiés pour développer un procédé complet de cristallisation. En combinant les recherches sur le développement des réactions chimiques et l’étape de cristallisation, un procédé continu complet fut proposé et comparé au procédé batch actuel afin d’évaluer les bénéfices apportés par la transposition en flux continu à la production du principe actif. / One of the many challenges in the pharmaceutical industry is to develop competitive processes to generate high quality active pharmaceutical ingredient (API) at low cost. To achieve this goal, many companies are looking towards flow chemistry and the advantages it affords, compared to traditional batch production. It is why this PhD work is focused on developing a continuous process from the raw materials to the API. The first step to achieve this goal was to collect data on the actual industrial batch process. It is composed of five steps, three steps of chemical reactions, one chromatographic separation and a crystallization step. From this starting point, the chemistry of each reaction was adapted to better use the advantages of flow chemistry. Thus, as the heat recovery in a continuous reactor is more efficient than in batch, it was possible to develop an exothermal reaction in neat conditions and at high temperature. A kinetic study was undertaken to gather knowledge on the reaction and develop a reaction model. This tool was used to find theoretical optimal operating conditions (temperature, residence time…) to guide the optimisation of the reaction and to design the future industrial reactor. The second part of this work is focused on the continuous crystallization of the API using the two impinging jets technology. It is required to have a tight control upon the morphology of the crystals and the particle size distribution (CSD). Indeed, the targeted API may crystallize under two competitive forms: cubic and needle crystals. The cubic form is the desired one. The two impinging jets technique was selected, since it is a continuous process able to generate small particles with a narrow CSD. The supersaturation is traditionally generated by impacting a jet of API solution with an anti-solvent one. Here, the solvent and the antisolvent are identical and only a large temperature difference between both streams is used to create the supersaturation. By screening different operating conditions, a “cubic zone” could be defined. Within this zone, only the desired crystal form is generated. Once the nucleation was under control, crystal growth and solid-liquid separation were studied to develop a complete crystallization process. By combining the research on the development of the chemical reactions and the crystallization step a full continuous process was proposed and was compared to the current batch one in order to evaluate the benefits brought by the flow chemistry to the API production.

Les anticorps monoclonaux sont une classe de bio médicaments en plein essor. Leur production est largement étudiée afin d’obtenir des rendements de plus en plus élevés et de réduire les coûts. Cette thèse décrit le développement d’un procédé complet en continu, de la production d’anticorps recombinants par des cellules mammifères jusqu’à leur purification. L’objectif est de coupler la culture cellulaire en mode perfusion à la purification par chromatographie semi-continue. Le développement du procédé se fait en bioréacteur avec une lignée de cellules d’ovaires de hamster chinois (CHO-DP12) transformée pour produire un anticorps anti-Interleukine 8 utilisée, comme modèle. Après adaptation, les cellules ont été cultivées en mode batch afin de connaitre le comportement de la lignée en environnement contrôlé. Ensuite, un procédé de perfusion de 2L de culture avec recyclage cellulaire a été mis en place. Le principal enjeu est de maintenir un état stationnaire avec une concentration cellulaire constante et déterminer le débit optimal d’alimentation spécifique par cellule (CSPR). Plusieurs méthodes ont été testées et comparées pour la détermination de ce CSPR optimal. Le procédé de culture en perfusion a ensuite été maintenu pendant 24 jours à des concentrations cellulaires de 10, 20 et 40 millions de cellules par mililitres. Les anticorps produit par différents modes de culture ont été caractérisés (batch, fed-batch et perfusion). Les N-glycosylations, les variants de charge ainsi que la thermo-stabilité des anticorps ont été étudiés. Les résultats montrent que les anticorps produits présentent des caractéristiques similaires quel que soit le mode de production.Pour la purification, une étude préliminaire a permis de caractériser le comportement du filtrat sur la résine chromatographique d’affinité MabSelect Sure LX en chromatographie classique. Un procédé semi-continu a été simulé grâce au logiciel BioSC® Predict puis testé et optimisé sur le chromatographe BioSC®. Il comprend la purification de l’anticorps mais aussi les étapes de nettoyages et de sanitisation. Un premier essai de couplage production/purification a pu être réalisé avec succès pendant 32h et a permis d’obtenir un niveau de pureté similaire à la chromatographie classique. La productivité a été augmentée de 23% (en grammes d’anticorps purifié par litre de résine et par jour) et le volume de tampon utilisé a été réduit de 25%. De plus, le couplage production/purification a permis de s’affranchir du stockage de volumes importants de filtrat (7,2L de filtrat par jour de production en perfusion). Enfin, une étude de coût de production, à l’échelle « laboratoire », a été réalisée afin de déterminer, en fonction de la productivité du clone et de la quantité d’anticorps à produire, la différence de rentabilité entre une production en batch ou en perfusion à différents CSPR. / Monoclonal antibodies are a biopharmaceuticals class of growing interest. Their production is widely studied to obtain higher yields and to reduce costs. This thesis describes the development of a complete continuous process, from the production of recombinant antibodies by mammalian cells until their purification. The objective is to connect cell culture in perfusion mode to a semi-continuous chromatographic purification. The development of the process was done in a bioreactor with a Chinese hamster ovary cell line (CHO-DP12) transformed to produce an anti-interleukin-8 antibody used as a cell model. After adaptation, the cells were cultured in batch mode in order to study the behavior of the cell line in controlled environment. Then, a 2L culture perfusion process with cell recycling was set up. The main challenge is to maintain a steady state with constant cell concentration and to determine the optimal cell-specific perfusion rate (CSPR). Several methods were tested and compared for the determination of this optimal CSPR. The perfusion process was maintained for 24 days at cell concentrations of 10, 20 and 40 million cells per mililiters. The antibody produced by different culture methods was compared (batch, fed-batch and perfusion). The N-glycosylations, the charge variants as well as the thermo-stability of the antibody were studied. The results show that the produced antibody have similar characteristics whatever the chosen production mode. For purification process, we performed a preliminary study to characterize the behavior of the supernatant on the chromatographic affinity resin MabSelect Sure LX. A semi-continuous process was simulated through BioSC® Predict software and then tested and optimized on the BioSC® chromatograph. It includes antibody purification but also cleaning and sanitizing steps. A first production/purification coupling test was successfully carried out for 32 h. It provides antibodies at a purity level similar to that of the conventional chromatography. Productivity was increased by 23% (in grams of purified antibody per liter of resin per day) and the volume of buffer used was reduced by 25%. In addition, production/purification coupling prevented storage of large volumes of supernatant (7,2L of supernatant per production day in perfusion mode). Finally, a cost-of-production study, at research scale, was carried out to determine, depending on the productivity of the clone and the antibodies amount, the difference of costs between batch or perfusion production according to different CSPRs.

Purpose – It is argued that traditional audit methods are becoming outdated in terms of delivering sufficient assurance on business objectives, whereby, a paradigm shift towards continuous auditing (CA) is proposed and perceived as necessary both by academia, standard-setting groups, and business society. However, the practical prevalence of CA is insignificant in relation to the expectations depicted. Therefore, the purpose of this paper is to examine why this is the case by means of investigating what factors that motivate an adoption of CA amongst various internal audit functions (IAFs). Design/methodology/approach – The study draws on the Technology Acceptance Model (TAM), and data are obtained through semi-structured interviews capturing internal auditors’ attitude towards CA, and what factors that influence an adoption. Findings – There is a shattered view on CA amongst IAFs, where the proponents embrace it as a set of value-adding methodologies whilst the opponents argue that it falls outside their responsibility and threaten the independence of the function. Thus, why CA has not been leveraged to its full potential is, in contrast to previous research, not solely attributable to practical factors but also due to the IAFs’ vast differences in approach to CA as a concept. Practical implications – The study has brought attention to the distinguished disparity found in internal auditors’ attitude towards CA. Ultimately, doubts, whether CA should be leveraged by IAFs has come to light. These are hurdles that need to be considered, both by academia, standard-setting groups, and business society if the leap for CA ought to continue. Originality/value – The use of semi-structured interviews contributes to in-depth understandings and insights of the internal auditors’ attitudes towards CA. Moreover, such an approach is more likely to capture the stance towards CA in greater detail than that possible of previous large-scale surveys.

Multirepo model přístupu ke správě a verzování zdrojového kódu, jež zahrnuje použití mnoha oddělených repozitářů verzovacích systémů, je poslední dobou často zmiňován v odborné literatuře. Jednou z jeho nevýhod je množství zdlouhavých, nezajímavých a repetitivních úkonů, které je nutno provádět při hromadných operacích tvořících transakce napříč těmito repozitáři. Multirepo repozitáře navíc umožňují využití široké škály technologií, což jen umocňuje riziko lidské chyby, ke které při ručně prováděných hromadných operacích může dojít. V rámci této práce je navrženo, implementováno a otestováno řešení pro automatizaci operací prováděných napříč množstvím repozitářů uspořádaných v multirepo modelu, což s nimi uživatelům zlepšuje zkušenost.

Pulse crops included in a crop rotation can reduce nitrogen (N) requirements via biological N2 fixation (BNF) and provide greater carbon (C) inputs to soil than non-pulse crops in rotation. The goal of this research was to estimate the BNF and C input to soil by various pulse crops (chickpea, lentil and field pea) grown in rotation with pulse crops and non-pulse crops. Soil cores from three crop rotations (chickpea-wheat, lentil-wheat and pea-wheat) were collected from Swift Current, SK. Additional soil cores from two rotations (canola-wheat and wheat-canola) were extracted from a field used for commercial cropping in Central Butte, SK. The 15N dilution method and continuous labelling with depleted 13CO2 were used to estimate BNF and 13C input to soil by pulse crops grown in a greenhouse. The continuous labelling with depleted 13CO2 was effective in depleting 13C in plants. The movement of 13C from plant to soil C pools via rhizodeposition was also observed. However, an accurate amount of 13C transferred was not measurable. Different pulse crop performed differently in rotation. Pea had the greatest amount of BNF and produced the most residue-C (pods, stems, leaves and roots) compared to chickpea and lentil. The crop grown in the first year of the three-year rotation also influenced the pulse crops grown in the third year of the rotation. Cropping the same first year and third year pulse crop in rotation (chickpea-wheat-chickpea and lentil-wheat-lentil) performed better than growing different first year and third year pulse crops in rotation (pea-wheat-chickpea and pea-wheat-lentil). Pulse crops grown immediately after wheat yielded better and fixed more N than those after canola. Growing a pulse crop after canola is not recommended in this soil zone.

After hot rolling, the presense of segregation in the center of wire-rod can lead to a nonuniform transformation, resulting in bands of martensite in the microstructure. This is considered to be a defect, called center-martensite, because it can cause cracks and breaks during wire drawing. To identify the mechanism for the formation of center-martensite in wire-rod, the structure, macrosegregation and microsegregation in unworked billets were characterized. Based on measurements of secondary dendrite arm spacings, cooling rates during solidification were estimated. It appears that the macrosegregation of carbon and manganese in the billets manifests itself as the microsegregation in wire-rod, which is an agent in forming the center-martensite. Thus, electromagnetic stirring is proposed as a means to reduce the macrosegregation in the billet and, thereby, reduce the occurrence of center-martensite in wire-rod.

Master of Science / Department of Clinical Sciences / Thomas Schermerhorn / The use of continuous blood glucose monitors (CBGMs) has recently come into favor in human medicine for the control and monitoring of the diabetic patient. It allows for a higher degree of accuracy of the true glucose curve throughout a 72-hour period. With this information, physicians are better equipped to treat and manage diabetic patients. Recently, this modality has been verified for use in veterinary patients including cats and dogs. This is an excellent source of information, especially in the management of difficult to regulate veterinary patients. This device has potential for use in various applications, particularly for the monitoring of patients with various diseases under general anesthesia. In order to ensure accurate results do occur when an animal is under general anesthesia, the continuous blood glucose monitor was evaluated on apparently healthy patients under anesthesia for routine procedures such as ovariohysterectomies and orchiectomies. In this manner, the monitor was tested on anesthetized patients that had the potential to experience hypothermia, hypotension, and other anesthesia-associated complications that can be typical of patients that could benefit from the CGMS.

Recent research has implicated working memory in unconscious tasks, controversially shifting the viewpoint of conscious access necessitating working memory functions (Soto, Mäntylä & Silvanto, 2011). The aim of this study was to investigate the flexibility of unconscious working memory using continuous flash suppression (CFS). Participants (n=18) completed a simple delayed-match-to-sample (DMS) task. Two conditions required the matching of either objects or spatial locations. CFS was used to render stimuli invisible and the perceptual awareness scale (PAS) helped to determine subjective conscious experience. Analysis determined no significant findings in d’ or reaction times. This confirmed the null hypothesis, that there would not be an affect on working memory due to presentation of visually suppressed information. These results may have been due to a lack of effect, complexity or procedural issues. Further research is needed to elucidate these non-significant results. This is especially critical since alternative methods examining unconscious working memory have found significant results.