Bupivacaine ((R, S)-1-butyl-2-piperidylformo-2', 6'-xylidide), an anilide type local anaesthetic is manufactured in the standard racemic form and is widely used in the practice of regional anaesthesia. Despite its popularity as a local anesthetic, it has the potential to produce severe cardiotoxicity. Enantiomers, which are a pair of chiral isomers that are direct, nonsuperimposable mirror images of each other, vary in their chemical, pharmacological and toxicological profiles due to different stereospecific recognition in the body. Single enantiomeric drugs, when compared to racemic drugs, exert similar clinical effects but produce decreased risks of cardiac and neurotoxicity. This has led to the development of the single enantiomeric drugs ropivacaine ((S)-1-propyl-2-piperidylformo-2', 6'-xylidide) and levobupivacaine ((S)-1-butyl-2-piperidylformo-2', 6'-xylidide). Since local anaesthetics are extensively bound (>90%) to plasma protein in blood such as album and alpha1-acid-glycoprotein, it is only the free form of the flowing drug that can exert its pharmacological effects and are believed to be closely related to systemic toxicity. Although the safety and efficacy of these newer local anaesthetics have been ascertained in the literatures, but there are limited data on their pharmacokinetic profiles; thus it is envisioned that further pharmacokinetic trials would be required to elucidate their pharmacological and clinical effects. The aim of this thesis was to develop sensitive, reproducible and reliable methods of local anaesthetic assays to support such clinical trials. / The assays described in the thesis have been applied to numerous clinical research projects. Out of the various studies, the following will be discussed: Ropivacaine undergoes slower systemic absorption from the caudal epidural space in children than bupivacaine; Arterial and venous pharmacokinetics of ropivacaine with and without epinephrine after thoracic paravertebral block; Pharmacokinetics of levobupivacaine after thoracic paravertebral block. / The first method developed is the simultaneous determination of ropivacaine and bupivacaine in human plasma using high performance chromatography (HPLC). Most published methods of determining ropivacaine in human plasma use gas chromatography and a review of literature to date shows no data describing the use of HPLC to simultaneously determine both drugs. This is the first report describing a simple, isocratic, reversed-phase, liquid-liquid extraction procedure of high-performance liquid chromatographic method that allows the simultaneous detection of both local anaesthetics in one single injection. The chromatography was achieved using a reversed-phase chromatographic system with a Waters Novapak C18 column. 0.5 ml plasma was used for the sample preparation procedures. Bupivacaine and ropivacaine concentrations ranging from 10ng/ml to 3000 ng/ml and fixed amounts of pentycaine (internal standard) were spiked into the plasma samples for calculating the calibration graphs. Calibration graphs were linear over the range 10-3000 ng/ml (r=0.9978 for bupivacaine and r=0.9986 for ropivacaine). The within-day (intra-assay) coefficient of variation of the assay varied between 13.84% at 100 ng/ml, 1.84% at 500 ng/ml and 3.34% at 2000 ng/ml for bupivacaine; and 5.29% at 100 ng/ml, 1.38% at 500 ng/ml and 3.93% at 2000 ng/ml for ropivacaine. The between-day (inter-assay) coefficient of variation was 8.43% at 100 ng/ml, 4.06% at 500 ng/ml and 9.15% at 2000 ng/ml for bupivacaine, and 5.66% at 100 ng/ml, 4.40% at 500 ng/ml and 8.14% at 2000 ng/ml for ropivacaine. The limit of detection for both drugs was 10 ng/ml. / The fourth analytical technique describes the successful development of an ultrafiltration protein binding procedure to detect the free levels of the local anaesthetics in human plasma. Sample plasma was deposited in the ultrafiltration apparatus and ultrafiltrate containing the free local anaesthetics was forced thru a membrane under a fixed-angle rotor centrifugal force. Experiments were done to establish the optimum parameters for the ultrafiltration apparatus' binding capacities. The validated procedures use 0.5 ml plasma as the starting volume and it was deposited into the ultrafiltration apparatus. It was then subjected to 1750g centrifugal force for 20 minutes at centrifugal temperature of 37°C. The resultant ultrafiltrate was processed according to the described LC-MS/MS method to detect the free local anaesthetic levels. / The second analytical methodology describes the assay of levobupivacaine in human plasma using HPLC. Calibration graphs relating peak height ratios and concentrations were linear over the range 10-3000 ng/ml (r=0.9995). The chromatography was achieved with an XTerra MS C18 column with the ultraviolet monitor set at 210 nm. The sample preparation steps were similar to the first analytical method, but with a different internal standard used. Precision and accuracy were assessed by performing analysis on replicate control plasma samples. The within-day (intra-assay) coefficient of variation of the assay varied between 4.25% at 50 ng/ml, 3.38% at 500 ng/ml, 3.76% at 1000 ng/ml and 3.14% at 2000 ng/ml. The between-day (inter-assay) coefficient of variation of the assay varied between 4.68% at 50 ng/ml, 4.94% at 500 ng/ml, 4.25% at 1000 ng/ml and 2.94% at 2000 ng/ml. The limit of detection was 10 ng/ml. / The third analytical methodology details the development and validation of a chiral analytical technique. This is the first report describing the development of a simple, isocratic, reversed-phase, liquid-liquid extraction procedure of a direct chiral method that allows the simultaneous detection of either free or total concentrations of bupivacaine enantiomers and ropivacaine in one single injection. It is also a novel technique to assay bupivacaine enantiomers with the use of vancomycin CSP column and liquid chromatography-mass spectrometry (LC-MS/MS) analysis, which achieved the lowest published detection limit with the lowest volume of plasma used. Calibration graphs were linear over the range 0.1-2000 ng/ml. Precision and accuracy were assessed by performing analysis on replicate control plasma samples. The within-day (intrassay) coefficient of variations of the assay for the drugs ropivacaine, levobupivacaine, dextrobupivacaine varied from 2.20% to 5.78%, 1.96% to 9.64%, 1.78% to 6.34%, respectively, for concentrations between 0.5 ng/ml to 2000 ng/ml. The between-day (interassay) coefficient of variations of the assay for the drugs ropivaciane, levobupivacaine, dextrobupivacaine varied from 3.66% to 9.61%, 3.18% to 8.34%, 2.22% to 10.59%, respectively, for concentrations between 0.5 ng/ml to 2000 ng/ml. The limit of detection was 0.05 ng/ml. / Wong Sum Yee April. / "November 2005." / Advisers: Manoj Karmakar; Tony Gin. / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6370. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 207-217). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Leung Kam Lun. / "July 2003." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (p. 187-201). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Conclusion. The missing data is a common problem in clinical trial. The methodology development is urgently needed to detect the difference of two treatments drug in patient quality of life. The modified pattern mixture model incorporating generalized estimating equation method or multiple imputation method provides a solution to tackle the non-ignorable missing data problem. Different clinical trials with various treatment schedules, missing data patterns will be formed. Further studies are needed to study the optimal choice of patterns under the methods. / Introduction. Health-related Quality of Life (HRQoL) has now been included as a major endpoint in many cancer clinical trials in addition to the traditional endpoints such as tumor response and survival. It refers to how illness or its treatment affects patients' ability to function and whether it induces symptoms. Toxicity, progression and death are common outcome affecting patient's QOL in cancer trial. Since this type of missing data are not occurred at random and are called non-ignorable missing data, conventional methods of analyses are not appropriate. It is important to develop general methods to deal with this problem so that treatment effectiveness for improving patient's QOL or those with serious side effect that is detrimental to patient's QOL can be identified. / Methods. The generalized estimating equation based on modified pattern mixture model is constructed to deal with non-ignorable missing data problem. We conducted a simulation study to examine performance of the model for different types of data. Two scenarios were examined. The first case assumes that two groups have quadratic trend but with different rates of change. The second case assumes that one group has linear trend with time while the other group has quadratic trend with time. Moreover, the second methodology is the multiple imputation based on modified pattern mixture model. The main idea is to resample the data within each pattern to create the full data set and use the standard method to analyze the data. Comparison between two methods was carried out in this study. / Recently, joint models for the QOL outcomes and the indicators of drop-outs are used in longitudinal studies to correct for non-ignorable missing. Two broad classes of joint models, selection model and pattern mixture model, were used. Most of the methodology has been developed in the selection model while the pattern mixture model has attracted less attention due to the identifiability problem. Although pattern mixture model has its own limitation, a modified version of this model incorporating Generalized Estimating Equation can be used in practice. / Result. The power of generalized estimating equation alone is higher than pattern mixture model when the missing data is missing at random. Moreover, the bias of generalized estimating equation is less than that of pattern mixture model when the missing data is missing at random. However, the pattern mixture model performs well when the missing data is missing not at random. On the other hand, the modified pattern mixture model has higher power than the standard pattern mixture model if one group has quadratic trend and other group has linear trend. However, the power of modified pattern mixture model is similar or worst than the standard when the data is both quadratic trends with different rates of change. On the other hand, the results of multiple imputation based on modified pattern mixture model were similar but the power was less than the generalized estimating equation model. / Mo Kwok Fai. / "August 2006." / Adviser: Benny Zee. / Source: Dissertation Abstracts International, Volume: 68-09, Section: B, page: 6051. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 91-93). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

O objetivo deste trabalho é analisar como os falantes administram o fluxo da informação no português brasileiro (PB). De acordo com Lambrecht 1994, a administração do fluxo da informação está calcada basicamente em três funções: função com foco no predicado (tópico-comentário), função com foco no argumento (identificacional) e função com foco em toda a sentença (que pode ser de reportar um evento ou apresentacional). Para chegar a essas funções, Lambrecht utiliza seis noções independentes, mas interrelacionadas: pressuposição e asserção pragmática, ativação e identificabilidade de referentes e tópico e foco. O presente trabalho defende a idéia de que existe uma máxima pragmática cognitivamente motivada que leva o falante a primeiro introduzir um referente, para então dizer algo sobre ele. O quadro teórico no qual a pesquisa se desenvolve é o da Lingüística Cognitiva, dentro da qual, mais especificamente, incluem-se estudos da área da Pragmática Discursiva, que tem por objeto o estudo da estrutura da informação. Essa área investiga as relações entre a estrutura formal das sentenças (sintática e prosódica) e as suposições do falante sobre o estado mental do ouvinte. Os dados utilizados para a análise baseiam-se em um corpus formado pela transcrição de dez narrativas orais, feitas a partir do filme História da Pêra, elaborado por Chafe 1980. A partir dessas narrativas, foi possível chegar a um quadro que descreve a estruturação da informação no português brasileiro. A principal particularidade do PB em relação à estruturação da informação consiste na manifestação formal das construções com foco em toda a sentença. / This thesis aims at investigating how users organize information flow in Brazilian Portuguese (BP). According to Lambrecht 1994, the management of information flow is primarily based on three functions: predicate-focus structure (topic-comment), argumentfocus structure (identificational) and sentence-focus structure (event reporting or apresentational). His analysis comprises six independent but inter-related notions: pragmatic pressuposition and pragmatic assertion, identifiability and activation, topic and focus. I intend to explore the idea that there is a cognitively motivated pragmatic maxim, which induces the speaker to introduce a referent first, and then say something about it. The theoretical background is the one of Cognitive Linguistics, more specifically Discourse Pragmatics, which comprises the study of information structure. This studies are based on the observation that the structure of a sentence reflects the speakers´s assumption about the hearer´s state of knowledge and counscionusness at the time of utterance. To achieve my goals, I used a corpus composed by transcriptions of ten oral narratives, estimulated by the Pear Story movie, produced by Chafe 1980. With the empirical study, it was possible to describe how information is structured in Brazilian Portuguese. When it comes to information structure, the main specificity of BP is the formal manifestation of sentence-focus structures.

Este trabalho investiga os efeitos semânticos e pragmáticos de um tipo específico de foco que chamamos foco sobreinformativo e como ele afeta relações de escopo entre sintagmas quantificadores em português brasileiro. Discutimos como a estrutura informacional e o escopo de quantificadores interagem, com atenção especial a vários tipos de quantificadores, como universais, existenciais, e cardinais. Relações de escopo em português brasileiro foram investigadas em Negrão (1999), que concluiu trata-se de uma língua bastante rígida nesse aspecto, não permitindo inversão de escopo na maioria dos casos. Tal trabalho, entretanto, se restringiu a contextos neutros. Nosso objetivo é investigar como o foco sobreinformativo pode afetar essa aparente rigidez. No decorrer do trabalho fornecemos análises sintáticas e semânticas detalhadas da interação entre quantificação e focalização e uma caracterização pragmática dos contextos em que o foco sobreinformativo é lícito. / This work investigates the semantic and pragmatic effects of a specific kind of focus which we call over-informative focus and how it affects scope relations among quantifier phrases in Brazilian Portuguese. We discuss how information structure and quantifier scope interact paying attention to many types of quantifiers such as universals, existential and cardinals. Scope relations in Brazilian Portuguese were investigated by Negrão (1999), who have concluded that the language is very rigid disallowing scope inversion in most cases. Her work, however, was restricted to neutral (out-of-the-blue) contexts. Our goal is to investigate how over-informative focus affects this apparent rigidity. Throughout this work, we give a detailed syntactic and semantic analysis of the interaction between quantification and focalization and a pragmatic characterization of contexts in which over informative focus is licit.

A necessidade de extrair conhecimento útil e inovador de grandes massas de dados textuais, tem motivado cada vez mais a investigação de métodos para Mineração de Textos. Dentre os métodos existentes, destacam-se as iniciativas para organização de conhecimento por meio de hierarquias de tópicos, nas quais o conhecimento implícito nos textos é representado em tópicos e subtópicos, e cada tópico contém documentos relacionados a um mesmo tema. As hierarquias de tópicos desempenham um papel importante na recupera ção de informação, principalmente em tarefas de busca exploratória, pois permitem a análise do conhecimento de interesse em diversos níveis de granularidade e exploração interativa de grandes coleções de documentos. Para apoiar a construção de hierarquias de tópicos, métodos de agrupamento hierárquico têm sido utilizados, uma vez que organizam coleções textuais em grupos e subgrupos, de forma não supervisionada, por meio das similaridades entre os documentos. No entanto, a maioria dos métodos de agrupamento hierárquico não é adequada em cenários que envolvem coleções textuais dinâmicas, pois são exigidas frequentes atualizações dos agrupamentos. Métodos de agrupamento que respeitam os requisitos existentes em cenários dinâmicos devem processar novos documentos assim que são adicionados na coleção, realizando o agrupamento de forma incremental. Assim, neste trabalho é explorado o uso de métodos de agrupamento incremental para o aprendizado não supervisionado de hierarquias de tópicos em coleções textuais dinâmicas. O agrupamento incremental é aplicado na construção e atualização de uma representação condensada dos textos, que mantém um sumário das principais características dos dados. Os algoritmos de agrupamento hierárquico podem, então, ser aplicados sobre as representa ções condensadas, obtendo-se a organização da coleção textual de forma mais eficiente. Foram avaliadas experimentalmente três estratégias de agrupamento incremental da literatura, e proposta uma estratégia alternativa mais apropriada para hierarquias de tópicos. Os resultados indicaram que as hierarquias de tópicos construídas com uso de agrupamento incremental possuem qualidade próxima às hierarquias de tópicos construídas por métodos não incrementais, com significativa redução do custo computacional / The need to extract new and useful knowledge from large textual collections has motivated researchs on Text Mining methods. Among the existing methods, initiatives for the knowledge organization by topic hierarchies are very popular. In the topic hierarchies, the knowledge is represented by topics and subtopics, and each topic contains documents of similar content. They play an important role in information retrieval, especially in exploratory search tasks, allowing the analysis of knowledge in various levels of granularity and interactive exploration of large document collections. Hierarchical clustering methods have been used to support the construction of topic hierarchies. These methods organize textual collections in clusters and subclusters, in an unsupervised manner, using similarities among documents. However, most existing hierarchical clustering methods is not suitable for scenarios with dynamic text collections, since frequent clustering updates are necessary. Clustering methods that meet these requirements must process new documents that are inserted into textual colections, in general, through incremental clustering. Thus, we studied the incremental clustering methods for unsupervised learning of topic hierarchies for dynamic text collections. The incremental clustering is used to build and update a condensed representation of texts, which maintains a summary of the main features of the data. The hierarchical clustering algorithms are applied in these condensed representations, obtaining the textual organization more efficiently. We experimentally evaluate three incremental clustering algorithms available in the literature. Also, we propose an alternative strategy more appropriate for construction of topic hieararchies. The results indicated that the topic hierarchies construction using incremental clustering have quality similar to non-incremental methods. Furthermore, the computational cost is considerably reduced using incremental clustering methods

Esta pesquisa investiga propriedades da estrutura sentencial do português brasileiro, mais precisamente aquelas que desencadeiam a inversão de constituintes para a periferia à esquerda da sentença. Sustenta-se num corpus para a obtenção de dados descritivos, constituído por dez peças de teatro, sendo cada uma delas escrita por um escritor nascido no Brasil numa década diferente, abrangendo dois séculos: XIX e XX. O objetivo desta pesquisa é identificar os tipos de constituintes que ocupam a periferia esquerda de sentenças e o porquê de ocuparem tal posição, isto é, se desempenham alguma função discursiva como tópico, foco ou se simplesmente se encontram em proeminência estrutural, a fim de entender melhor como a estrutura da informação interage com a sintaxe desse dialeto. Dessa forma, o estudo das funções discursivas desempenhadas pelo sujeito, tanto na ordem SV como na ordem VS, também precisou ser considerado. O quadro teórico adotado para sua realização sustenta-se nas implementações do programa minimalista em Chomsky (2000, 2001 e 2004) feitas à Teoria de Princípios e Parâmetros. Além disso, como proposta cartográfica, adota-se Rizzi (2002, 2004) e, como conceito de tópico e de foco, o proposto em Lambrecht (1996). / This research investigates properties of the Brazilian Portuguese sentence structure, more precisely those that trigger the inversion of constituents to the left-periphery of the sentence. It is based on a corpus as a means of acquiring descriptive data, composed of ten plays, being each of them written by a writer born in a different decade, comprising two centuries: XIX and XX. The aim of this research is to identify the types of constituents that occupy the leftperiphery of sentences and why they do so (if they fulfill any discourse function like topic, focus or if they are merely in structural prominence), in order to cast light upon the way the information structure interacts with the syntax of that dialect. For that reason, it was also necessary to investigate the discourse functions played by the subject both in SV and VS orders. The theoretical framework used for the accomplishment of that task is based on the implementations made by the Minimalist Program (Chomsky - 2000, 2001 and 2004) to the Theory of Principles and Parameters. Besides, as cartographic proposal, it adopts Rizzi (2002, 2004) and, as concept of topic and focus, those proposed in Lambrecht (1996).

Esta pesquisa nasce na vontade de sistematizar uma experiência com o jogo teatral e suas variações, em função da prática teatral no trabalho de formação de atores iniciantes. O percurso se dá no encontro da necessidade de explorar o processo de criação e a apropriação do texto dramático em seu primeiro contato com a obra. Proponho articular os instrumentos de condução do trabalho a partir do foco na \"espontaneidade\" como potência para a mobilização do instante da criação cênica. No universo do lúdico, investiguei o sentido e a veracidade da potência do jogo teatral no processo de criação e na relação outra do ator com o texto dramático, analisando as possibilidades positivas e negativas da experiência vivida. Assim, monta-se uma prática reflexiva que mantém ativo o impulso advindo da efemeridade da espontaneidade, a força da imaginação e como tudo se relaciona no processo de criação do ator iniciante. / This search is born from the need of a development action by the drama scene at the beginners performers shaping. There is an indispensable link between the creation process improvement and the drama topic preparation at the prime rehearsal. However, in my point of view, it is important to manage direction ways of the labor by the individual natural gifts to act powerfully at the play. Inside the playful universe I found out the real sense of this theater power reconnaissance at the creation process and the characters link with the drama topic. The real experience showed me results with advantages and disadvantages. From now on, I create an analysis habit to encourage an action belonging to the natural ephemerality, the creativity and how everything is attached to the beginner performer creation process.

Probabilistic models of text are a useful tool for enabling the analysis of large collections of digital text. For example, Latent Dirichlet Allocation can quickly produce topical summaries of large collections of text documents. Many important uses cases of such models include human interaction during the inference process for these models of text. For example, the Interactive Topic Model extends Latent Dirichlet Allocation to incorporate human expertiese during inference in order to produce topics which are better suited to individual user needs. However, interactive use cases of probabalistic models of text introduce new constraints on inference - the inference procedure must not only be accurate, but also fast enough to facilitate human interaction. If the inference is too slow, then the human interaction will be harmed, and the interactive aspect of the probalistic model will be less useful. Unfortunately, the most popular inference algorithms in use today either require strong approximations which can degrade the quality of some models, or require time-consuming sampling. We explore the use of Iterated Conditional Modes, an algorithm which is able to obtain locally optimal maximum a posteriori estimates, as an alternative to popular inference algorithms such as Gibbs sampling or mean field variational inference. Iterated Conditional Modes algorithm is not only fast enough to facilitate human interaction, but can produce better maximum a posteriori estimates than sampling. We demonstrate the superior performance of Iterated Conditional Modes on a wide variety of models. First we use a DP Mixture of Multinomials model applied to the problem of web search result cluster, and show that not only can we outperform previous methods in clustering quality, but we can achieve interactive runtimes when performing inference with Iterated Conditional Modes. We then apply Iterated Conditional Modes to the Interactive Topic Model. Not only is Iterated Conditional Modes much faster than the previous published Gibbs sampler, but we are better able to incorporate human feedback during inference, as measured by accuracy on a classification task using the resultant topic model. Finally, we utilize Iterated Conditional Modes with MomResp, a model used to aggregate multiple noisy crowdsourced data. Compared with Gibbs sampling, Iterated Conditional Modes is better able to recover ground truth labels from simulated noisy annotations, and runs orders of magnitude faster.

Prior research on text collections of religious documents has demonstrated that viable recommender systems in the area are lacking, if not non-existent, for some datasets. For example, both www.LDS.org and scriptures.byu.edu are websites designed for religious use. Although they provide users with the ability to search for documents based on keywords, they do not provide the ability to discover documents based on similarity. Consequently, these systems would greatly benefit from a recommender system. This work provides a framework for evaluating recommender systems and is flexible enough for use with either website. Such a framework would identify the best recommender system that provides users another way to explore and discover documents related to their current interests, given a starting document. The framework created for this thesis, RelRec, is attractive because it compares two different recommender systems. Documents are considered relevant if they are among the nearest neighbors, where "nearest" is defined by a particular system's similarity formula. We use RelRec to compare output of two particular recommender systems on our selected data collection. RelRec shows that LDA recommeder outperforms the TF-IDF recommender in terms of coverage, making it preferable for LDS-based document collections.