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Marie, le paradigme de foi de la Nouvelle Alliance Luc exprime sa théologie à travers la narration, rendant l'analyse de ses techniques narratives fort utile pour découvrir les thèmes de son œuvre ainsi que les relations entre eux. L'analyse narrative est particulièrement fructueuse dans les deux premiers chapitres du troisième évangile, sept épisodes entrelacés de matériel exclusif à l'auteur, connu comme le « prologue de l'enfance ». Racontant les naissances parallèles de Jean et de Jésus, ce prologue relie les deux Testaments, montrant que ces naissances miraculeuses sont le début de l'accomplissement des promesses anciennes. Celles-ci annonçaient les ministères de Jean et de Jésus dans lesquels les promesses s'accompliraient pleinement. Ces récits sont structurés par un cadre de promesses et d'accomplissements auquel les acteurs humains répondent selon divers degrés de foi et d'interprétation juste. Non seulement le prologue met-il en valeur l'action divine, la gloire et l'humilité paradoxale de l'incarnation, mais on y retrouve aussi l'axe de la réponse humaine. En effet, tout comme la réponse de foi d'Abraham à la promesse divine fait de lui le père de la première Alliance, la réponse de foi de Marie à une promesse sans précédent et encore plus impossible fait d'elle le modèle de croyant de la Nouvelle Alliance. Dans la seconde phase du prologue, Marie demeure modèle par son choix de méditer. À travers plusieurs techniques narratives, l'évangéliste invite le lecteur à s'identifier à ce personnage humble et empathique. Entourée d'une constellation d'anciens vénérables, dignes représentants du meilleur de l'Ancienne Alliance (Zacharie, Élizabeth, Siméon et Anne) la jeune Marie brille comme le paradigme du croyant de la Nouvelle Alliance qui reconnaît la grâce de Dieu, embrasse sa promesse et médite longtemps sur tout ce qui la bouleverse et l'émerveille de l'action divine, la repassant et la conservant dans son cœur. / Mary, the paradigm of the New Testament believer Luke expresses his theology through narration, making close attention to his narrative techniques essential to discover both his major themes and the relations between them. Narrative criticism is particularly useful in the first two chapters of the third gospel, seven interwoven episodes of material exclusive to this gospel, known as Luke's "infancy prologue". Recounting the parallel births of John and Jesus, the prologue looks both back to the Old Covenant hopes and forward to the ministries of John and Jesus to show that these births are answers to the ancient promises. The stories of John and Jesus are structured around a framework of promise and fulfillment to which human actors respond with varying degrees of faith and correct interpretation. In addition to showcasing divine visitation, and the paradoxical glory and humility of the incarnation, the prologue develops the axis of the human response. Just as Abraham's response of faith to the divine promise makes him the father of the covenant people, so Mary's response of faith to an even more impossible and unprecedented promise makes her the first of the new covenant people. Mary's faith shines brightly after Zachariah's doubt; it is praised by spirit-filled prophecy, expressed in song. In the second phase of the prologue, through several narrative techniques, the narrator invites identification with this humble and empathetic character, especially in her choice to ruminate what she cannot fathom. Surrounded by a constellation of venerable elders, representatives of the best of the Old Covenant--Zechariah, Elisabeth, Simeon and Anne--young Mary shines as the believer of the New Covenant who recognizes the undeserved favour of God, embraces his promise and chooses to treasure all that amazes and overwhelms her of divine action in her life.

Salmonella enterica sérovar Typhi (Typhi) est une bactérie pathogène spécifique à l’homme. Typhi est l’agent étiologique de la fièvre typhoïde chez l’humain, causant plus de 16 millions de nouveaux cas par année et plus de 600 000 morts. Il a été démontré que pour causer une infection systémique, Salmonella doit nécessairement survivre dans les macrophages de l'hôte. Paradoxalement, S. enterica sérovar Typhimurium, très apparenté à Typhi (près de 90 % d’homologie), n’a pas la capacité de se disséminer dans l’organisme humain et peut infecter plusieurs espèces animales. Nous avons antérieurement identifié 36 gènes uniques à Typhi (absents chez Typhimurium) situés sur 15 régions différentes et exprimés sélectivement lors de l’infection de macrophages humains. Ainsi, l’une de ces régions a suscité notre attention, soit la région sty4217-4222 et plus particulièrement le produit du gène sty4221, une aminotransférase hypothétique. Ce dernier gène est d’intérêt dû à l’homologie qu’il détient avec une hémolysine connue (Hly) produite par Treponema denticola, possédant elle-même une activité d’aminotransférase. Chez T. denticola, Hly dégrade la cystéine et produit du H2S qui est toxique pour l’hôte. Notre hypothèse est que la spécificité d’hôte et la capacité de produire une infection systémique de Typhi sont dues à l’expression de gènes qui ne se retrouvent pas chez d’autres salmonelles. Le but de cette étude était donc de caractériser le gène sty4221 quant à son activité hémolytique, cytotoxique et tenter de déterminer son rôle dans la virulence de cette bactérie. Le gène sty4221 a été cloné sous le contrôle d’un promoteur inductible à l’arabinose et exprimé par E. coli. L’activité hémolytique du clone a été déterminée par simple observation sur gélose sang. Ce clone a également permis d’observer l’effet cytotoxique du surnageant de culture sur différentes lignées cellulaires, par quantification de la relâche de LDH. Le gène sty4221 a été muté chez la souche sauvage de Typhi, ISP1820, l’implication pathogénique du gène a ainsi pu être étudiée. Des tests de phagocytose, d’invasion et de survie dans des macrophages humains ont été effectués, ainsi que des tests d’adhésion et d’invasion sur des cellules HeLa. Par ailleurs, une première tentative de purification de la protéine a été entreprise. En somme, nous savons maintenant que STY4221 a des propriétés hémolytiques, augmentées par la présence de cystéine. De plus, STY4221 a un effet cytotoxique sur les macrophages THP-I, mais aucun effet sur les HeLa. Or, sty4221 ne semble pas impliqué dans les étapes d’adhésion, d’invasion, de phagocytose ou de survie. La caractérisation de sty4221 permettra sans doute d’approfondir nos connaissances sur les toxines trouvées uniquement chez Typhi. / Salmonella enterica serovar Typhi (Typhi) is a human restricted pathogen causing typhoid fever, a systemic infection. Annually, at least 16 million new cases with 600, 000 associated deaths are reported. It has been demonstrated that Salmonella has to survive in the macrophages of its host, in order to produce a systemic disease. This ability to cause a disseminated infection in human is unique to Typhi. Our laboratory had isolated 36 genes that were unique to Typhi (absent from Typhimurium’s genome), and that were expressed during human macrophages infection. One of these genes, sty4221, a putative aminotransferase, was of high interest since it shares sequence similarities with a known hemolysin (Hly), which also possesses an aminotransferase activity. That hemolysin is produced by Treponema denticola, it catabolizes cysteine and produces H2S, a toxic metabolite for the host. Our hypothesis is that host specificity and the ability to cause a systemic infection might be explained by the expression of genes that are not found in other salmonellas. The goal of this study was to characterize the gene sty4221, in terms of hemolytic and cytotoxic activity and to determine its role in virulence. The sty4221gene has been cloned in a vector under an arabinose inducible promoter and transformed in a strain of E. coli. The hemolytic activity has been investigated on blood-agar medium. To evaluate the cytotoxicity of the STY4221 protein on human cultured cells, direct observation by photonic microscopy was done. The cytotoxicity activity on human cultured cells has been quantitatively measured with a lactate dehydrogenase release assay. Moreover, the sty4221 gene has been deleted in order to study its implication in the infection and the survival within human macrophages and for adhesion/invasion on epithelial. Protein purification was also attempted. We now know that protein STY4221 has a hemolytic activity that is enhanced by cysteine. Also, we proved that the expression of sty4221 has a cytotoxic effect on THP-I macrophages, but not on epithelial HeLa cells. Meanwhile, sty4221 does not seem to be important during adhesion, invasion, infection nor survival. The characterization of protein STY4221 might extend the list of known exotoxin of Typhi.

Salmonella enterica sérovar Typhi (Typhi) est une bactérie pathogène spécifique à l’homme. Typhi est l’agent étiologique de la fièvre typhoïde chez l’humain, causant plus de 16 millions de nouveaux cas par année et plus de 600 000 morts. Il a été démontré que pour causer une infection systémique, Salmonella doit nécessairement survivre dans les macrophages de l'hôte. Paradoxalement, S. enterica sérovar Typhimurium, très apparenté à Typhi (près de 90 % d’homologie), n’a pas la capacité de se disséminer dans l’organisme humain et peut infecter plusieurs espèces animales. Nous avons antérieurement identifié 36 gènes uniques à Typhi (absents chez Typhimurium) situés sur 15 régions différentes et exprimés sélectivement lors de l’infection de macrophages humains. Ainsi, l’une de ces régions a suscité notre attention, soit la région sty4217-4222 et plus particulièrement le produit du gène sty4221, une aminotransférase hypothétique. Ce dernier gène est d’intérêt dû à l’homologie qu’il détient avec une hémolysine connue (Hly) produite par Treponema denticola, possédant elle-même une activité d’aminotransférase. Chez T. denticola, Hly dégrade la cystéine et produit du H2S qui est toxique pour l’hôte. Notre hypothèse est que la spécificité d’hôte et la capacité de produire une infection systémique de Typhi sont dues à l’expression de gènes qui ne se retrouvent pas chez d’autres salmonelles. Le but de cette étude était donc de caractériser le gène sty4221 quant à son activité hémolytique, cytotoxique et tenter de déterminer son rôle dans la virulence de cette bactérie. Le gène sty4221 a été cloné sous le contrôle d’un promoteur inductible à l’arabinose et exprimé par E. coli. L’activité hémolytique du clone a été déterminée par simple observation sur gélose sang. Ce clone a également permis d’observer l’effet cytotoxique du surnageant de culture sur différentes lignées cellulaires, par quantification de la relâche de LDH. Le gène sty4221 a été muté chez la souche sauvage de Typhi, ISP1820, l’implication pathogénique du gène a ainsi pu être étudiée. Des tests de phagocytose, d’invasion et de survie dans des macrophages humains ont été effectués, ainsi que des tests d’adhésion et d’invasion sur des cellules HeLa. Par ailleurs, une première tentative de purification de la protéine a été entreprise. En somme, nous savons maintenant que STY4221 a des propriétés hémolytiques, augmentées par la présence de cystéine. De plus, STY4221 a un effet cytotoxique sur les macrophages THP-I, mais aucun effet sur les HeLa. Or, sty4221 ne semble pas impliqué dans les étapes d’adhésion, d’invasion, de phagocytose ou de survie. La caractérisation de sty4221 permettra sans doute d’approfondir nos connaissances sur les toxines trouvées uniquement chez Typhi. / Salmonella enterica serovar Typhi (Typhi) is a human restricted pathogen causing typhoid fever, a systemic infection. Annually, at least 16 million new cases with 600, 000 associated deaths are reported. It has been demonstrated that Salmonella has to survive in the macrophages of its host, in order to produce a systemic disease. This ability to cause a disseminated infection in human is unique to Typhi. Our laboratory had isolated 36 genes that were unique to Typhi (absent from Typhimurium’s genome), and that were expressed during human macrophages infection. One of these genes, sty4221, a putative aminotransferase, was of high interest since it shares sequence similarities with a known hemolysin (Hly), which also possesses an aminotransferase activity. That hemolysin is produced by Treponema denticola, it catabolizes cysteine and produces H2S, a toxic metabolite for the host. Our hypothesis is that host specificity and the ability to cause a systemic infection might be explained by the expression of genes that are not found in other salmonellas. The goal of this study was to characterize the gene sty4221, in terms of hemolytic and cytotoxic activity and to determine its role in virulence. The sty4221gene has been cloned in a vector under an arabinose inducible promoter and transformed in a strain of E. coli. The hemolytic activity has been investigated on blood-agar medium. To evaluate the cytotoxicity of the STY4221 protein on human cultured cells, direct observation by photonic microscopy was done. The cytotoxicity activity on human cultured cells has been quantitatively measured with a lactate dehydrogenase release assay. Moreover, the sty4221 gene has been deleted in order to study its implication in the infection and the survival within human macrophages and for adhesion/invasion on epithelial. Protein purification was also attempted. We now know that protein STY4221 has a hemolytic activity that is enhanced by cysteine. Also, we proved that the expression of sty4221 has a cytotoxic effect on THP-I macrophages, but not on epithelial HeLa cells. Meanwhile, sty4221 does not seem to be important during adhesion, invasion, infection nor survival. The characterization of protein STY4221 might extend the list of known exotoxin of Typhi.

The presented thesis is devoted to the experimental and numerical analysis of concrete fracture under the mixed-mode I/II load. This phenomenon was analysed on various concrete grades and types which are used in the fabrication of precast concrete structural elements. Subsequently, the Brazilian disc test with central specimen was used in experimental and numerical parts. The numerical part employs both linear elastic fracture mechanics (LEFM) approach and non-linear material model to assess the concrete fracture and failure under the mixed mode I/II load. The LEFM part is dedicated to evaluation the geometry functions and higher order terms of the Williams’ expansion, while the non-linear analysis is dedicated to crack initiation and propagation throughout the specimen using the concrete damage plasticity model. The experimental part is dedicated to the analysis of the mixed mode-mode I/II fracture resistance by the generalised tangential stress (GMTS) criterion with focus set on the governing role of the critical distance rC. Furthermore, the experimental part validates the applicability of the Williams’ expansion on the concrete. For this, experimentally measured displacements by digital image correlation technique were used to calculate the Williams’s expansion terms. Lastly, the thesis deals with the influence of the aggressive environment on the material’s fracture toughness and on the fracture resistance under the mixed mode I/II has been studied.

L’analyse de la réponse du lecteur (reader-response) est une théorie littéraire qui étudie la réception d’oeuvres littéraires et le rôle du lecteur dans leur interprétation. Inspirée par la version postformaliste de la stylistique affective de Stanley Fish et par l’adaptation de cette méthode pour l’étude de la littérature biblique de Robert Hurley, cette thèse passe des lecteurs théoriques (implicite, modèle, idéal...) aux « lecteurs réels » pour analyser les effets du récit des origines de Jésus en Mt 1-2. Quels sont les effets ressentis lors de la lecture de Mt 1-2 ? Par une approche méthodologique novatrice, cette thèse répondra à cette question en décrivant les effets de ce texte dans une lecture au ralenti. Le texte comme objet d’analyse cède la place à la lecture comme un processus se déroulant dans le temps avec une attention à la tension ressentie par le jeu du suspense, de la curiosité et de la surprise. La description de l’expérience de lecture montre les transformations produites au moment même où le lecteur redonne présence concrète au texte par son acte interprétatif. Le ralentissement de la lecture permet de souligner la présence de dispositifs textuels qui demandent une implication active du lecteur tels que l’ironie, la métaphore et les textes autophages. Polysémique, Mt 1-2 a permis une grande diversité de réponses chez ses lecteurs. Les nombreux espaces d’indétermination du texte ont généré diverses expériences de lecture. Parmi les éléments ambigus explorés, on retrouve : la présence de cinq femmes dans une généalogie patriarcale (1,1- 16), un décompte du nombre de générations (1,17) différent de la liste d’engendrements (1,2-16), la discontinuité généalogique entre Joseph et Jésus (1,16), la « justice » équivoque de Joseph (1,19), la nature de l’astre que suivent les mages (2,2.9) et la citation « Ναζωραῖος κληθήσεται » qui n’a aucun référent connu (2,23). Cette recherche montre un éclatement des interprétations au sujet de ces questions. Au lieu de combler les apories textuelles, cette thèse propose de regarder les réponses des « vrais lecteurs » que sont les Pères de l’Église et les exégètes du XIXe au XXIe siècle. Leurs écrits sont des réponses au texte lu. Ces réponses sont présentées non pas pour trouver la meilleure interprétation, mais pour comprendre l’effet de la lecture du texte sur ces lecteurs. En tablant sur les effets produits par le texte, il appert que dès les premiers versets, l’Évangile selon Matthieu cherche à dérouter ses lecteurs pour les préparer à lire un récit déconcertant. Telle une énigme, la généalogie désoriente ses lecteurs pour mieux les guider dans leur quête de Jésus et de ses origines. Mt 1,1-17 subvertit le messianisme davidique en revisitant l’histoire d’Israël pour proposer l’identité de Jésus comme messie à la fois issu de David et différent de lui. L’attention aux masculinités de ses personnages fait partie des aspects novateurs de cette thèse. Alors que la plupart des études ne font qu’effleurer le contexte vétérotestamentaire des cinq citations du récit autour des origines de Jésus (1,18-2,23), cette thèse propose d’analyser les effets de l’interaction entre le contexte narratif en Matthieu et les contextes narratifs des oeuvres citées. De manière originale, ces citations sont présentées comme des métalepses qui en quelques mots, incitent les lecteurs à penser au monde narratif complet d’où ils sont tirés. Cette pratique s’oppose à la stratégie interprétative habituelle qui voit ces citations comme des « mots crochets » au sein d’un modèle interprétatif centré sur la prédiction et l’accomplissement de paroles prophétiques. Les résultats de cette étude intertextuelle soulignent que l’accomplissement de ces citations porte aussi un rapport de renversement. L’étude des lecteurs inscrits ne permet pas de comprendre la richesse de l’expérience de la lecture. Le rôle du lecteur réel comme créateur de sens a été sous-estimé en études bibliques. Le dialogue entre lecteurs présenté dans cette thèse souligne la pluralité interprétative. Il permet de découvrir les effets du récit des origines de Jésus en Mt 1-2 par les rapports possibles entre ce texte et ses lecteurs. / Reader-response is a literary theory which studies the reception of literary works and the role of the reader in their interpretation. Inspired by Stanley Fish’s post-formalist version of affective stylistics and Robert Hurley’s adaptation of that method for the study of biblical literature, this thesis shifts attention from the responses of theoretically constructed readers (implicit, model, ideal…) to the responses of a “real reader” to the narrative of the origins of Jesus in Matt. 1-2. What effects does Matt. 1-2 produce? This research question is answered by using an innovative methodological approach: the author describes what happens as one slows down the reading event, reporting on the effects produced by each successive word, phrase and sentence. The “text as object” dissolves in a dynamic reading experience which takes place in time, generating suspense, curiosity and surprise. The description of the reading experience shows the transformations produced at the very moment the reader gives concrete expression to the text by his interpretive act. Slowing down the reading process brings the essential, active role of the reader into view in the operation of such textual devices and strategies as irony, metaphor and the self-consuming artifact. Historically, the great diversity of reading experiences recorded in successive exegeses may partially be explained by the many gaps of Matt. 1-2. Among the ambiguous elements explored are: the presence of five women in a patriarchal genealogy (1:1-16), the number of generations (1:17) that is different from the list of generations (1:2-16), the genealogical discontinuity between Joseph and Jesus (1:16), the equivocal "justice" of Joseph (1:19), the nature of the star followed by the magi (2:2,9), and the quotation "Nαζωραῖος κληθήσεται" which has no known source (2:23). A review of available research underscores the considerable confusion that this text has stirred up. Instead of filling in textual aporias, this thesis proposes to look at the answers of the "real readers" that are Church Fathers and exegetes of the twentieth and twenty-first centuries. Their writings are responses to the textual devices of the read text. These responses are not presented with a view to finding the one right interpretation, but in order to understand the effects this text produces in readers. Based on the effects produced by the text, it appears that from the first verses, the Gospel according to Matthew seeks to disorient its readers, preparing them for the disconcerting narrative that follows. Like an enigma, the genealogy throws its readers off balance as they begin their quest for Jesus and his origins. Matt. 1:1-17 subverts Davidic messianism by revisiting the history of Israel to propose Jesus as a Messiah, both from David and different from him. One of the innovative aspects of this thesis is to pay attention to the ways in which these male characters express their masculinities. While most studies merely scratch the context of the Old Testament quoted in Matt. 1:17-2:23, this thesis proposes to analyze the effects of the interaction between the narrative context in Matthew and the narrative contexts of the works cited. In an original way, these quotations are presented as metalepses. Using a few words, they encourage readers to think of the complete narrative world from which these words are drawn. This procedure is contrary to the usual interpretative strategy which treats these quotations as "hook words" within an interpretive model centered on the prediction and fulfillment of prophecies. The results of this intertextual study underscores the fact that the relationship between text and intertext modifies our understanding of both. Studies which concentrate on the “inscribed reader” do not to justice to the richness of the reading experience. The role of the real reader as a creator of meaning has been underestimated in biblical studies. The dialogue between real readers, past and present, emphasizes the interpretative plurality that makes it possible to discover the effects of the story of the origins of Jesus in Matt. 1-2, highlighting some of the possible relations between this text and reader.

Foram analisadas 197.032 doações no período de janeiro de 1998 a junho de 2008, realizadas no Banco de Sangue do Hospital de Clínicas de Porto Alegre. Os doadores de sangue foram triados por um teste de enzimaimunoensaio (EIE) de terceira geração para HTLV I/II. Também foram realizados testes para hepatites B e C, HIV 1/2, sífilis e doença de Chagas. Os dados das fichas cadastrais foram revisados após o diagnóstico do doador. Como teste confirmatório, foi utilizado o Western Blot (WB). Foram excluídos os doadores considerados negativos após a confirmação dos testes iniciais. Ao todo, 204 doadores foram reagentes para HTLV I ou II. A prevalência de HTLV I/II foi de 0,1%, sendo 0,08% do tipo I e 0,02% do tipo II. A média de idade foi de 38 anos; 73,5% dos doadores eram brancos e 53,9% do sexo feminino. Cerca de 65% deles completaram o ensino fundamental e apenas 1% o ensino superior; 59,3% eram procedentes de Porto Alegre. A frequência de casados e solteiros foi de 40,2% e 42,4%, respectivamente, sendo os demais separados, divorciados ou viúvos. Os soropositivos para HTLV apresentaram ainda 30,4% de coinfecção com os outros marcadores testados. AntiHCV e anti-HBc foram os marcadores com maior prevalência (19,1% e 18,6%, respectivamente), seguidos por VDRL (2,94%), anti-HIV 1/2 (2,45%) e doença de Chagas (1,96%). / A total of 197,032 donors from the Blood Bank of Hospital de Clínicas de Porto Alegre, in southern Brazil, were assessed from January 1998 to June 2008. Blood donors were screened for HTLV I/II using a third-generation enzyme immunoassay (EIA). Tests for hepatites B and C, HIV 1 and 2, syphilis and Chagas disease were also performed. The information on blood donor forms was reviewed after the diagnosis. The Western Blot (WB) was used as confirmatory test. Seronegative donors were excluded from the study after initial test results were confirmed. Two hundred and four donors were positive for HTLV I or II. The prevalence of HTLV I/II was 0.1% (0.08% for HTLV I and 0.02% for HTLV II). The mean age was 38 years, 73.5% were whites and there was a female predominance (53.9%). Approximately 65% of seropositive individuals had attended elementary school, only 1% had college education, and 59.3% came from Porto Alegre. The frequency of married and single individuals was similar (40.2 and 42.4%, respectively), whereas the remaining donors were separated, divorced or widowed. This population also showed 30.4% of coinfection, according to the other tested markers. Anti-HCV and anti-HBc were the most prevalent markers (19.1 and 18.6%, respectively), followed by VDRL (2.94%), anti-HIV 1/2 (2.45%), Chagas disease (1.96%).

Phase I clinical trials in oncology aim to evaluate the toxicity risk of new therapies and identify a safe but also effective dose for future studies. Traditional Phase I trials of chemotherapies focus on estimating the maximum tolerated dose (MTD). The rationale for finding the MTD is that better therapeutic effects are expected at higher dose levels as long as the risk of severe toxicity is acceptable. With the advent of a new generation of cancer treatments such as the molecularly targeted agents (MTAs) and immunotherapies, higher dose levels no longer guarantee increased therapeutic effects, and the focus has shifted to estimating the optimal biological dose (OBD). The OBD is a dose level with the highest biologic activity with acceptable toxicity. The search for OBD requires joint evaluation of toxicity and efficacy. Although several seamleass phase I/II designs have been published in recent years, there is not a consensus regarding an optimal design and further improvement is needed for some designs to be widely used in practice. In this dissertation, we propose a modification to an existing seamless phase I/II design by Wages and Tait (2015) for locating the OBD based on binary outcomes, and extend it to time to event (TITE) endpoints. While the original design showed promising results, we hypothesized that performance could be improved by replacing the original adaptive randomization stage with a different randomization strategy. We proposed to calculate dose assigning probabilities by averaging all candidate models that fit the observed data reasonably well, as opposed to the original design that based all calculations on one best-fit model. We proposed three different strategies to select and average among candidate models, and simulations are used to compare the proposed strategies to the original design. Under most scenarios, one of the proposed strategies allocates more patients to the optimal dose while improving accuracy in selecting the final optimal dose without increasing the overall risk of toxicity. We further extend this design to TITE endpoints to address a potential issue of delayed outcomes. The original design is most appropriate when both toxicity and efficacy outcomes can be observed shortly after the treatment, but delayed outcomes are common, especially for efficacy endpoints. The motivating example for this TITE extension is a Phase I/II study evaluating optimal dosing of all-trans retinoic acid (ATRA) in combination with a fixed dose of daratumumab in the treatment of relapsed or refractory multiple myeloma. The toxicity endpoint is observed in one cycle of therapy (i.e., 4 weeks) while the efficacy endpoint is assessed after 8 weeks of treatment. The difference in endpoint observation windows causes logistical challenges in conducting the trial, since it is not acceptable in practice to wait until both outcomes for each participant have been observed before sequentially assigning the dose of a newly eligible participant. The result would be a delay in treatment for patients and undesirably long trial duration. To address this issue, we generalize the time-to-event continual reassessment method (TITE-CRM) to bivariate outcomes with potentially non-monotonic dose-efficacy relationship. Simulation studies show that the proposed TITE design maintains similar probability in selecting the correct OBD comparing to the binary original design, but the number of patients treated at the OBD decreases as the rate of enrollment increases. We also develop an R package for the proposed methods and document the R functions used in this research. The functions in this R package assist implementation of the proposed randomization strategy and design. The input and output format of these functions follow similar formatting of existing R packages such as "dfcrm" or "pocrm" to allow direct comparison of results. Input parameters include efficacy skeletons, prior distribution of any model parameters, escalation restrictions, design method, and observed data. Output includes recommended dose level for the next patient, MTD, estimated model parameters, and estimated probabilities of each set of skeletons. Simulation functions are included in this R package so that the proposed methods can be used to design a trial based on certain parameters and assess performance. Parameters of these scenarios include total sample size, true dose-toxicity relationship, true dose-efficacy relationship, patient recruit rate, delay in toxicity and efficacy responses.

A new type of heterogeneous carbon fiber bunch bipolar plate developed in our lab is applied to portable pure hydrogen proton exchange membrane fuel cell stacks. Several different types of bipolar plate structures have been designed, and the voltages and currents of these fuel cell stacks are measured to compare their performance. The new type of heterogeneous carbon fiber bunch bipolar plate is well in low contact resistance, weight low, small volume and the flexible geometry shape. Due to its flexible structure of carbon fiber bunch, the compressing pressure is small while assembling stack so that the electrode can not be over compressed and out of shape. Therefore the high porosity of diffusion layer can be keep and reaction gas can enter and distribute to all reaction areas easily. For using to portable equipments, a small 6-cell flat type of fuel cell stack are developed firstly. The total weight is about 75g and the total volume is about 68cm . The second stack is cylinder-type(I) fuel cell stack. The total weight is about 60g and the total volume is about 71cm . The third stack is cylinder-type (II). The total weight has been reduced to about 20g and the total volume has been reduced to about 30cm . Above three kinds of the 6-cell stacks the total electrode area is 13.5cm . Using Nafion, the catalyst content anode Pt 0.4mg/cm , cathode Pt 1.0mg/cm , On room temperature and inlet hydrogen gauge pressure 0.15atm air-breathing, total output power of the cylinder (II) can reach 1.85W, and the power density of unit area can reach about 137mW/cm^2.

Zugl.: Bochum, Univ., Diss., 2007 u.d.T.: Pirke, Klaus: Zeugnisse zur Entstehung der industriellen Kulturlandschaft Ruhrgebiet