Dissertations / Theses on the topic 'Combinatio'

A combinação de algoritmos tem despertado interesse para melhorar o desempenho de filtros adaptativos. Esse método consiste em combinar linearmente as saídas de dois filtros operando em paralelo com passos de adaptação diferentes para se obter um filtro com conver- gência rápida e um erro quadrático médio em excesso (EMSE - excess mean squared error) reduzido. Nesse contexto, foi proposta a combinação afim de dois algoritmos LMS (least-mean square), cujo parâmetro de mistura não fica restrito ao intervalo [0, 1] e por isso é considerada como uma generalização da combinação convexa. Neste trabalho, a combinação afim de dois algoritmos LMS é estendida para os algoritmos supervisionados NLMS (normalized LMS) e RLS (recursive least squares) e também para equalização autodidata, usando o CMA (constant modulus algorithm). Foi feita uma análise em regime da combinação afim desses algoritmos de forma unificada, considerando entrada branca ou colorida e ambientes estacionários ou não- estacionários. Através dessa análise, verificou-se que a combinação afim de dois algoritmos da mesma família pode apresentar uma redução de EMSE de até 3 dB em relação ao EMSE de seus filtros componentes e conseqüentemente ao EMSE da combinação convexa. Para garantir que a estimativa combinada seja pelo menos tão boa quanto a do melhor filtro componente, foram propostos e analisados três novos algoritmos para adaptação do parâmetro de mistura. Utilizando resultados da análise desses algoritmos em conjunto com os resultados da análise de transitório de filtros adaptativos, analisou-se o comportamento transitório da combinação afim. Através de simulações, observou-se uma boa concordância entre os resultados analíticos e os de simulação. No caso de equalização autodidata, também foi proposta uma combinação de dois equalizadores CMA com inicializações diferentes. Verificou-se através de simulações que em alguns casos a combinação afim é capaz de evitar a convergência para mínimos locais da função custo do módulo constante.
In order to improve the performance of adaptive filters, the combination of algorithms is receiving much attention in the literature. This method combines linearly the outputs of two filters operating in parallel with different step-sizes to obtain an adaptive filter with fast convergence and reduced excess mean squared error (EMSE). In this context, it was proposed an affine combination of two least-mean square (LMS) filters, whose mixing parameter is not restricted to the interval [0, 1]. Hence, the affine combination is a generalization of the convex combination. In this work, the affine combination of two LMS algorithms is extended to the supervised algorithms NLMS (normalized LMS) and RLS (recursive least squares), and also to blind equalization, using the constant modulus algorithm (CMA). A steady-state analysis of the affine combination of the considered algorithms is presented in a unified manner, assuming white or colored inputs, and stationary or nonstationary environments. Through the analysis, it was observed that the affine combination of two algorithms of the same family can provide a 3 dB EMSE gain in relation to its best component filter and consequently in relation to the convex combination. To ensure that the combined estimate is at least as good as the best of the component filters, three new algorithms to adapt the mixing parameter were proposed and analyzed. Using the analysis results of these algorithms in conjunction with the results of the transient analysis of adaptive filters, the transient behavior of the affine combination was analyzed. Through simulations, a good agreement between analytical and experimental results was always observed. In the blind equalization case, a combination of two CMA equalizers with different initializations was also proposed. The simulation results suggest that the affine combination can avoid local minima of the constant modulus cost function.

Combining multiple forecasts in order to generate a single, more accurate one is a well-known approach. A simple average of forecasts has been found to be robust despite theoretically better approaches, increasing availability in the number of expert forecasts, and improved computational capabilities. The dominance of a simple average is related to the small sample sizes and to the estimation errors associated with more complex methods. We study the role that expert correlation, multiple experts, and their relative forecasting accuracy have on the weight estimation error distribution. The distributions we find are used to identify the conditions when a decision maker can confidently estimate weights versus using a simple average. We also propose an improved expert weighting approach that is less sensitive to covariance estimation error while providing much of the benefit from a covariance optimal weight. These two improvements create a new heuristic for better forecast aggregation that is simple to use. This heuristic appears new to the literature and is shown to perform better than a simple average in a simulation study and by application to economic forecast data.

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Este estudo analisou o impacto das IFRS no reconhecimento e mensuração do goodwill, representado em aquisições, fusões e incorporações de empresas, sob a perspectiva da teoria institucional. Para isso, elaborou-se o índice do goodwill de 90 empresas brasileiras de diversos segmentos, listados na CVM, observando se os mesmos registraram diferenças significativas, considerando as mudanças ocorridas nos quatros anos antes e nos quatros anos após adoção das IFRS. Para avaliar as diferenças de médias identificadas nos índices do goodwill, utilizou-se o teste Anova – Fator único e o Kruskal-Wallis. Os resultados revelaram que a adoção das IFRS impactou no índice do goodwill das empresas, havendo diferenças significativas entre os valores desse índice, reconhecido e mensurado antes e posterior a adoção das IFRS para as empresas, não financeiras, brasileiras de capital aberto. Insere-se, assim, a mudança institucional que decorre da IAS 38, normatizando o tratamento contábil dos ativos intangíveis, quer no contexto internacional, quer, especificamente, no cenário brasileiro. Também o resultado revelou que, se existem diferenças significativas no índice entre o goodwill reconhecido e mensurado nas empresas com classificação de governança distinta, não houve influência significativa.
This study examined the impact of IFRS on the recognition and measurement of goodwill, represented in acquisitions, mergers and acquisitions of companies, from the perspective of institutional theory. For this, we elaborated the goodwill index 90 Brazilian companies from various sectors, listed in the CVM, noting whether they reported significant differences, considering the changes in the four years before and four years after adoption of IFRS. To evaluate the mean differences identified in the goodwill of the indices, we used ANOVA - single factor and the Kruskal-Wallis test. The results revealed that the adoption of IFRS impact on goodwill index of companies, with significant differences between the values of this index, recognized and measured before and after the adoption of IFRS for companies, non-financial, Brazilian publicly traded. Falls, so institutional change which arises from IAS 38, regulating the accounting treatment of intangible assets, whether in the international context, or, specifically, in the Brazilian scenario. Also the result showed that if there are significant differences in the index between the goodwill recognized and measured in companies with distinct governance rating, no significant influence.

A leucemia linfóide aguda (LLA) é a neoplasia hematológica mais comum na infância e representa uma doença heterogênea em relação à biologia e ao prognóstico e seu tratamento consiste principalmente em quimioterapia. Apesar dos avanços no tratamento, cerca de 20% dos pacientes apresentam recaída da doença e/ou óbito indicando a necessidade de terapias diferenciadas para esse grupo. Recentemente, drogas epigenéticas como inibidores de DNA metiltransferases (iDNMTs) tem mostrado efeitos anti-neoplásicos promissores para o tratamento de diversos tipos de neoplasias incluindo a LLA. Nos tumores, a hipermetilação gênica é encontrada em vários genes, incluindo genes de reparo do DNA, reguladores do ciclo celular e apoptose. Sendo assim, drogas desmetilantes estão sendo apontadas como promissores agentes para o tratamento do câncer. A Zebularina (ZB) é um iDNMT análogo de citidina que inibe a metilação do DNA. Esta droga tem mostrado resultados animadores para o tratamento de diversas neoplasias, incluindo glioblastoma, leucemia mielóide aguda, câncer de mama, próstata e outros. O objetivo deste trabalho foi avaliar os efeitos do tratamento com a ZB, associada ou não à quimioterápicos, em linhagens celulares pediátricas de LLA, por meio de ensaios funcionais como proliferação celular, capacidade clonogênica, apoptose e ciclo celular. Além disso, foi analisada a capacidade desmetilante da droga e a expressão dos genes DNMT1, DNMT3a e DNMT3b após o tratamento com a ZB. A ZB inibiu a proliferação celular de maneira dose e tempo-dependente e agiu sinergicamente quando combinada com o MTX em ambas as linhagens. Ela também diminuiu a capacidade clonogênica e aumentou a taxa de apoptose nas duas linhagens estudadas. Além disso, o tratamento com ZB causou uma parada na fase S do ciclo celular na linhagem ReH. A ZB foi capaz de desmetilar parcialmente o gene AhR e reduzir a expressão dos genes DNMT1, DNMT3a e DNMT3b. Todos os dados encontrados no presente trabalho sugerem que as drogas desmetilantes podem ser interessantes agentes para o tratamento da LLA pediátrica.
Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in childhood and represents a heterogeneous disease regarding its biology and prognosis. Its treatment consists mainly of chemotherapy. Despite advances in treatment, about 20% of patients experience disease recurrence and/or death indicating the need for differentiated therapies for this group. Recently, epigenetic drugs such as DNA methyltransferases inhibitors (iDNMTs) has shown antineoplastic and promising results for several types of tumors including ALL. Gene hypermethylation is found in several genes in tumors cells, including genes responsible for DNA repair, cell cycle and apoptosis regulators. Therefore, demethylating agents may be promising agents for cancer treatment. Zebularine (ZB) an iDNMT is a cytidine analogue that inhibits DNA methylation. This drug has shown promising results for the treatment of many cancers, including glioblastoma, acute myeloid leukemia, breast and prostate cancer and others. The aim of this study was to evaluate the effects of ZB treatment, associated or not with chemotherapeutic agents, in childhood ALL cell lines through functional tests such as cell proliferation, clonogenic capacity, apoptosis and cell cycle. In addition, we examined the demethylating ability of ZB and the expression of DNMT1, DNMT3a and DNMT3b genes after treatment with this agent. ZB inhibited cell proliferation in a dose- and time-dependent manner and showed synergistic effects when combined with MTX in both cell lines. ZB treatment also reduced clonogenic capacity and increased the number of apoptotic cells in both cell lines studied. Furthermore, treatment with ZB caused an S phase cell cycle arrest in ReH cell line. ZB was able to partially demethylate AhR gene and reduce the expression of genes DNMT1, DNMT3a and DNMT3b. These results suggest that demethylating drugs may be interesting agents for the treatment of childhood ALL.

As abordagens Tradicional e Ágil de gerenciamento de projetos são tidas como antagônicas, porém, há autores defendendo a combinação de práticas oriundas das duas abordagens. Por meio de uma Revisão Bibliográfica Sistemática, foram identificadas definições, benefícios esperados, fatores críticos e propostas de combinação, na forma de métodos e frameworks. Conclui-se que até o momento não há um termo comum, as definições são amplas e não auxiliam o desenvolvimento de métodos combinados. Analisou-se qualitativamente dez propostas utilizando os critérios de diferenciação identificadas em Eder et al. (2014). O resultado da análise indicou que as propostas não se diferenciavam da gestão Ágil ou não apresentavam informações para debater a combinação adotada. Identificou-se ainda duas estratégias de combinação: top-down e a bottom-up. Entre essas questões, optou-se por contribuir em duas áreas: a proposição de uma definição de abordagem híbrida ou combinada, e a recomendação de práticas para o uso dessa abordagem. O objetivo da pesquisa foi desenvolver um procedimento de planejamento de tempo combinado, baseado em uma definição nova de combinação. A concepção do procedimento utilizou a estratégia top-down e a proposta final é apresentada na forma de fluxo de atividades em um modelo de processos de negócio. Adotou-se o Estudo de Caso como método de investigação. O caso consiste em uma simulação de projeto com alunos da graduação do curso de Gestão de Projetos. Os dados foram coletados em duas dimensões, a primeira consiste na combinação de práticas, baseada nos seis critérios de Eder et al. (2014), e a segunda refere-se a usabilidade do procedimento. O resultado indicou que é viável combinar práticas. A usabilidade do procedimento pode ser considerada satisfatória para o contexto da aplicação, em termos de facilidade de uso e aprendizado. Recomenda-se como trabalhos futuros investigar a integração de outros processos de planejamento, como recursos e stakeholders, e desenvolver um procedimento considerando a estratégia bottom up.
The Traditional and Agile project management approaches are seen as polar opposites. However, the combination of agile and traditional practices could be preferable to the isolated use of either. Through a Systematic Literature Review (RBS), definitions, expected benefits, critical factors and combination proposals, among models, methods and frameworks, were summarized. The conclusion indicates the definitions present wide meaning and do not support the development of combined proposals. A qualitative analysis of ten combination proposals uses the criteria of differentiation of agile and traditional approaches identified in Eder et al. (2014). The result of the analysis indicated the proposals do not differ from Agile or lack of information to discuss the combination adopted. In addition, the analysis identifies two combination strategies: top-down and bottom-up. This dissertation contributes in two main areas: to propose a definition of hybrid or combined approach, and recommended practices for using this approach. The objective of the research was to develop a combined time planning procedure, based on a new definition of combination. The procedure used to design top-down strategy and the final proposal is presented as flow of activities in a business processes model. The research method adopts the case study. The case consists of a project simulation with under-graduate students of project management course. Two dimensions of analysis are used to assess the data, the first is the combination of practices, based on the six criteria of Eder et al. (2014), and the second relates to the procedure usability. The result indicated that it is viable to combine practices, the procedure usability can be considered satisfactory for the application context, in terms of use and learning facility. It is recommended as future work to investigate the integration of other planning processes, as resources and stakeholders, and develop a procedure considering the bottom-up strategy.

The tuberculosis (TB) epidemic remains a major threat to public health globally, and is exacerbated by the escalating number of multi-drug resistant cases. These factors have highlighted the urgent need for new effective therapies or different approaches to augment the efficacy of current anti-TB drugs. Synergistic drug combinations present a feasible strategy towards expanding TB treatment options. Despite reported successes with combination screening, as well as the current reliance on combination therapy for TB, this approach remains largely underexplored. Evidence suggests that utilizing synergistic combinations might enable existing clinically-approved drugs to be readily re-purposed for TB treatment, including against multi-(MDR) and extensively- (XDR) drug resistant strains for current therapies are often ineffective. This thesis focused on the development and application of improved methods to identify and advance novel drug combinations for TB therapy. There were two key aspects to this work: firstly, exploring mechanisms of synergy between fusidic acid (FSA), a natural product antibiotic, and current anti-TB agents and, secondly, characterizing antibiotic action by delineating bacteriostatic and bactericidal compounds.

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Candida species are the most common etiologic agent of opportunistic fungal infections. Candida albicans is the most frequent species in candidiasis, however species of non-albicans species have emerged increasingly in hospitals in which the use of azoles as a prophylactic or therapeutic is common. C. glabrata is the species most relevant in this scenario, causing infections with high morbidity and mortality due to high rates of resistance to antifungal azoles, especially fluconazole, and reduced sensitivity to amphotericin B and echinocandins. The remarkable resistance of these species to antifungal agents requires the search for new therapeutic options. An alternative is the combination of drugs with different mechanisms of action. This study aimed to evaluate the in vitro susceptibility of Candida glabrata to conventional antifungal agents (amphotericin B, ketoconazole, itraconazole, fluconazole and voriconazole), and these associations with non-antifungal drugs (chlorpromazine, linezolid, minocycline, sulfamethoxazole, tacrolimus and diphenyl diselenide). Two groups of clinical isolates of C. glabrata were evaluated. The first group consists of fluconazole-sensitive clinical isolates (FS) (n = 30) and the second, derivative of the first, fluconazole-resistant clinical isolates (FR) (n = 30). Based on protocol M27-A3 (CLSI, 2008), the checkerboard method. In isolation, MICs (Minimum Inhibitory Concentration) for fluconazole ranged from 0.25 to ≥ 64.00 μg/mL (FS) and 64.00 to 256.00 μg/mL (FR); for amphotericin B ranged from 0.06 to 0.50 μg/mL (FS) and 0.03 to 0.50 μg/ mL (FR); for itraconazole 0.50 to 8.00 μg/ mL (FS) and 1.00 to 16.00 μg/mL (FR); for ketoconazole 0.13 to 2.00 μg/mL (FS) and 0.50 to 16.00 μg/mL (FR); for voriconazole 0.13 to 4.00 μg/mL (FS) and 1.00 to 16.00 μg/mL (FR). The combinations of tacrolimus with azoles showed significant synergism rates; for the group FS tacrolimus + ketoconazole (43%), tacrolimus + itraconazole (43%), tacrolimus + voriconazole (37%); for the group FR ketoconazole + tacrolimus (77% ) tacrolimus + itraconazole (73%), tacrolimus + voriconazole (63%). Linezolid combined with ketoconazole and voriconazole showed high rates of synergism against the FR group, 76.67% and 70%, respectively. Minocycline + amphotericin B obtained 46.67% (FS) and 36.67% (FR) of synergism; chlorpromazine + amphotericin B was synergistic for 40% of the FR. Chlorpromazine combined to azoles showed high rates of antagonism for resistant group, 76.67%, 70% and 80% for ketoconazole, itraconazole and voriconazole, respectively, for the sensitive group combinations had higher rates of indifference. Sulfamethoxazole evidenced a higher percentage of indifferent interactions associated with all tested antifungals, 70% (FS), 73.34% (FR) associated to ketoconazole, 60% (FS), 43.34% (FR) associated to itraconazole, 56.67% (FS), 66.67% (FR) ins association with voriconazole, 86.66% (FS), 80% (FR) associated to amphotericin B. Synergistic (76.66%) and indifferent (23.34%) interactions were observed for diphenyl diselenide + amphotericin B combination for the sensitive group. Diphenyl diselenide + fluconazole combination demonstrated indifferent (50%) and antagonistic (40%) interactions for sensitive group, whereas synergistic interactions were observed in 10% of the isolates. The most significant associations deserve in vivo evaluation in order to verify their potential in the treatment of infections caused by C. glabrata.
Candida spp é o mais frequente agente etiológico de infecções fúngicas oportunistas. Candida albicans é a espécie mais isolada nas candidíases, no entanto espécies de Candida não-albicans têm emergido de forma crescente nas unidades hospitalares em que o uso de azólicos de forma profilática ou terapêutica é frequente. C. glabrata é uma das espécies mais relevantes neste cenário, causando infecções com alta morbidade e mortalidade, devido às altas taxas de resistência frente aos antifúngicos azólicos, em especial ao fluconazol, e a reduzida sensibilidade a anfotericina B e equinocandinas. A marcante resistência desta espécie aos antifúngicos impõe a busca por novas possibilidades terapêuticas. Uma alternativa é a combinação entre fármacos com distintos mecanismos de ação. Este estudo objetivou avaliar a suscetibilidade in vitro de C. glabrata a antifúngicos convencionais (anfotericina B, fluconazol, cetoconazol, itraconazol e voriconazol) e associações destes, com fármacos e compostos não-antifúngicos (clorpromazina, linezolida, minociclina, sulfametoxazol, tacrolimus e disseleneto de difenila). Foram avaliados dois grupos de isolados clínicos de C. glabrata. O primeiro grupo composto de isolados sensíveis ao fluconazol (FS) (n=30) e o segundo, derivado do primeiro, isolados clínicos resistentes ao fluconazol (FR) (n=30). Com base no protocolo M27-A3 (CLSI, 2008), pelo método de checkerboard. Isoladamente, as CIMs (Concentrações Inibitórias Mínimas) para o fluconazol variaram de 0,25 - ≥64,00 μg/mL (FS) e 64,00 - 256,00 μg/mL (FR); para anfotericina B variaram de 0,06 - 0,50 μg/mL (FS) e 0,03 - 0,50 μg/mL (FR); para o itraconazol 0,50 - 8,00 μg/mL (FS) e 1,00 - 16,00 μg/mL (FR); para cetoconazol 0,13 - 2,00 μg/mL (FS) e 0,50 - 16,00 μg/mL (FR); para voriconazol 0,13 - 4,00 μg/mL (FS) e 1.00 - 16.00 μg/mL (FR). As combinações de tacrolimus com azólicos apresentaram consideráveis taxas de sinergismo; para o grupo FS tacrolimus + cetoconazol (43%), tacrolimus + itraconazol (43%), tacrolimus + voriconazol (37%). Para o grupo FR tacrolimus + cetoconazol (77%), tacrolimus + itraconazol (73%), tacrolimus + voriconazol (63%). Linezolida associada ao cetoconazol e ao voriconazol apresentou altas taxas de sinergismo frente ao grupo FR, 76,67% e 70%, respectivamente. Minociclina + anfotericina B obteve 46,67% (FS) e 36,67% (FR) de sinergismo; clorpromazina + anfotericina B foi sinérgica para 40% do grupo FR. Clorpromazina combinada aos azólicos apresentou altas taxas de antagonismo para o grupo resistente, 76,67%, 70% e 80% para cetoconazol, itraconazol e voriconazol, respectivamente; para o grupo sensível as combinações com clorpromazina tiveram maiores taxas de indiferença. Interações sinérgicas (76,66%) e indiferentes (23,34%) foram observadas na combinação de anfotericina B e disseleneto de difenila para o grupo sensível. A combinação de disseleneto de difenila com fluconazol apresentou indiferença (50%) e antagonismo (40%) para o grupo sensível, 10% dos isolados apresentaram sinergismo. Sulfametoxazol apresentou um maior porcentual de interações indiferentes, associado a todos os antifúngicos testados frente aos dois grupos, 70% (FS), 73,34% (FR) associado ao cetoconazol, 60% (FS), 43,34% (FR) associado ao itraconazol, 56,67% (FS), 66,67% (FR) na associação com voriconazol, 86,66% (FS), 80% (FR) associado à anfotericina B. As associações de maior relevância merecem avaliação in vivo, a fim de verificar o potencial das mesmas no tratamento de infecções por Candida glabrata.

The impact of particle size, size distribution, and particle shape on the rheology of precipitated calcium carbonate (PCC) based coatings was studied. Evaluating the interactions between different particle sizes and shapes leads to a better understanding of the packing fraction of PCC. HIgh packing fraction is desirable because of the positive impact on the fluidity of suspensions. Suspension with higher levels of fluidity can potentially load larger amounts of solids while keeping low viscosities. High solids suspensions are key factors to improve the efficiency of coating processes. To address this issue, PCC of different sizes and shapes where mixed in different ratiosto find mixtures with higher packing fractions that could result in coatings with lower viscosities. When coatings containing 90% of large particles and 10% by weight of small particles of different shape, viscosity decreases by 50% for one combination. The effect is caused by the higher packing fraction achieved. Future research is also described here.

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O presente estudo objetiva analisar como foram tratadas, no âmbito societário e fiscal, as reorganizações societárias conhecidas por drop down. Bastante comuns nos Estados Unidos, essas operações se caracterizam pelo aumento de capital que uma empresa produz em outra, ao transferir bens, direitos e/ou obrigações em troca de participação societária com controle acionário. Ademais, se assemelha à cisão em alguns aspectos, mas sem a redução do capital social ou a extinção da empresa cindida, o que induz alguns teóricos nacionais a denominarem como cisão branca. A essência do drop down - e consequentemente, a estratégia utilizada pelas empresas que optam por esse modelo de reestruturação societária - focaliza no core business, ou seja, concentra-se na atividade principal. A metodologia de pesquisa adotada para a construção desta dissertação, portanto, se estruturou em bases documentais, na qual constassem temas ligados à reestruturação ou à reorganização societária por intermédio da combinação de negócios que envolvessem as operações de drop down. Assim, o estudo pôde contribuir para a divulgação de novas formas de reorganizações societárias e sinalizar ao profissional contábil as formas de registros da operação e, posteriormente, auxiliar na divulgação das demonstrações contábeis. Os resultados obtidos revelaram que, mesmo não sendo muito conhecida no país, a operação de drop down vem ocorrendo como meio de reestruturação societária em empresas brasileiras. Também por meio da análise dos resultados, concluiu-se que, para as Companhias investigadas e/ou avaliadas pelos órgãos estaduais e do mercado de valores, a operação não foi objeto de questionamento por parte deles, haja vista que tão somente mensuraram como foram tratadas contábil e fiscalmente nas organizações selecionadas. Nas análises das empresas que não evidenciaram processos de avaliação pelos órgãos estaduais e pelo mercado de valores, identificou-se o foco no core business - a saber, a concentração de esforços nas atividades principais e a associação das empresas com as atividades afins. Igualmente, se observou se elas atentaram para as devidas contabilizações previstas nos pronunciamentos contábeis e nos registros contábeis da operação pretendida.
This study aims to analyze how corporate reorganizations known as drop down were treated in the corporate and fiscal scope. Quite common in the United States, these operations are characterized by the capital increase a company produces in another one, transferring assets, rights and/or obligations in exchange for share participation with share control. Moreover, in some aspects resembles a divestiture but without the reduction of equity capital or the termination of the divided company, which induces some national theorists call it white divestiture. The essence of drop down - and consequently the strategy used by companies that choose this corporate restructuring model - focuses on the core business, ie, focuses on the main business. The methodology adopted for the construction of this work, therefore, was built in document databases in which see covered in topics related to restructuring or reorganization through the business combination involving the drop down operations. Thus, the study could contribute to the spread of new forms of corporate restructuring and indicate to accounting professionals ways to record operations and, subsequently, assist in the disclosure of financial statements. The results revealed that, although not very known in the country, the drop-down operation has taken place as a means of corporate restructuring in Brazilian companies. Also by analyzing the results, it was concluded that, for companies investigated and/or evaluated by state agencies and the stock market, the operation was not a subject of questioning from them, given that only measured as they have been dealt accounting and fiscally in selected organizations. In the analyzes of companies which had no assessment procedures by state agencies and securities market, it was identified the focus on core business - namely, the concentration of efforts on core activities and the association of companies with similar activities. Likewise, it was observed if they attempted to the appropriate accountings provided in financial statements and accounting records of the intended operation.

ABSTRACT Shaw, BS, Shaw, I, and Brown, GA. Comparison of resistance and concurrent resistance and endurance training regimes in the development of strength. J Strength Cond Res 23(9): 2507–2514, 2009—Resistance and endurance training are often performed concurrently in most exercise programs and in rehabilitative settings in an attempt to acquire gains in more than 1 physiologic system. However, it has been proposed that by simultaneously performing these 2 modes of exercise training, the strength gains achieved by resistance training alone may be impaired. Thus, the aim of this study was to compare the effects of 16 weeks of resistance training and concurrent resistance and endurance training on muscular strength development in 38 sedentary, apparently healthy males (25 yr 6 8 mo). Subjects were age-matched and randomly assigned to either a control (Con) group (n = 12), resistance training (Res) group (n = 13), or concurrent resistance and endurance training (Com) group (n = 13). After 16 weeks, no changes were found in the strength of the subjects in the Con group. Resistance training and concurrent resistance and endurance training significantly (p # 0.05) improved strength in all of the 8 prescribed exercises. The data also indicated that 16 weeks of concurrent resistance training and endurance training was as effective in eliciting improvements in strength as resistance training alone in previously sedentary males. As such, concurrent resistance and endurance training does not impede muscular strength gains and can be prescribed simultaneously for the development of strength in sedentary, apparently healthy males and thus may invoke all the physiologic adaptations of resistance and endurance training at once.

O gênero Mallodeta Butler, exclusivamente neotropical, contava, no início deste estudo, com seis espécies: M. clavata (Walker) (espécie-tipo), M. sortita (Walker), M. consors (Walker), M. sanguipuncta Druce, M. cubana Gaede e M. simplex Rothschild. Estas espécies, mais Phoenicoprocta parthenii (Fabricius), outrora também considerada integrante daquele gênero, foram estudadas quanto às suas relações filogenéticas. A hipótese de monofiletismo de Mallodeta não foi corroborada, sendo as espécies historicamente associadas ao gênero doravante consideradas pertencentes a três clados: (i) Mallodeta, composto unicamente por sua espécie-tipo; (ii) Rezia Kirby gen. reval., composto por R. sortita comb. nov., R. consors comb. nov. e R. sanguipuncta, além de R. cardinale (Hampson), R. erythrarchos (Walker) comb. nov., R. cruenta (Perty) comb. nov. e R. hanga (Herrich-Schäffer) comb. nov., previamente tratadas em Cosmosoma Hübner; (iii) Antilleana gen. nov., composto por A. parthenii comb. nov., A. jamaicensis (Schaus) comb. nov., A. capistrata (Fabricius) comb. nov. e A. carminata (Hampson) comb. nov., todas anteriormente alocadas em Phoenicoprocta Druce. Dentre as conclusões taxonômicas, M. simplex foi tratada como sin. nov. de M. clavata, Glaucopis (Erruca) deyrolii Walker, 1854 sin. nov. de Rezia sortita, Laemocharis ignicolor Ménétriés sin. nov. de Rezia erythrarchos e M. cubana sin. nov. de A. capistrata. Todas as espécies tratadas no presente estudo foram redescritas, ilustradas e tiveram sua distribuição geográfica elucidada.
At the beginning of this study the genus Mallodeta Butler, exclusively neotropical, comprised six species: M. clavata (Walker) (type species), M. sortita (Walker), M. consors (Walker), M. sanguipuncta Druce, M. cubana Gaede and M. simplex Rothschild. These species besides Phoenicoprocta parthenii (Fabricius), formerly considered part of Mallodeta, had their phylogenetic relationships elucidated. The monophyly of Mallodeta was not corroborated, and the species historicaly associated to it should be considered, from now on, belonging to three different clades: (i) Mallodeta, composed exclusively by its type species; (ii) Rezia Kirby rev. gen, comprising R. sortita n. comb., R. consors n. comb. and R. sanguipuncta, plus R. cardinale (Hampson), R. erythrarchos (Walker) n. comb., R. cruenta (Perty) n. comb. and R. hanga (Herrich-Schäffer) n. comb., previously treated in the genus Cosmosoma Hübner; (iii) Antilleana n. gen., comprised by A. parthenii n. comb., A. jamaicensis (Schaus) n. comb., A. capistrata (Fabricius) n. comb. and A. carminata (Hampson) n. comb., formerly treated in Phoenicoprocta Druce. Among taxonomic conclusions we discovered M. simplex to be a n. syn. of M. clavata, Glaucopis (Erruca) deyrolii Walker, 1854 n. syn of Rezia sortita, Laemocharis ignicolor Ménétriés n. syn of Rezia erythrarchos and M. cubana n. syn. of A. capistrata. All species studied were redescribed, illustrated and had their geographical distribution elucidated.

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Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG
OBJECTIVE: To describe tuberculosis treatment rates of cure, failure and default of a self administered regimen, with rifampin, isoniazid, pyrazinamide and ethambutol in the first two months of treatment followed by isoniazid and rifampcina in the four last months (2RHZE/4RH) in four-drug fixed-dose combination (FDC), implemented in Brazil since 2010 to replace a regimen of separately administered rifampicin, isoniazid and pyrazinamide in the first two months of treatment followed by isoniazid and rifampcina for four months (2RHZ/4RH). METHODS: Descriptive study using prospectively collected data from medical records of TB cases, older than18 years of age undergoing treatment with 2RHZE/4RH in two units of primary health care in the metropolitan area of Goiânia. RESULTS: The study included 40 cases of TB. The cure rate was 67.5% (27/40), the abandonment was 17.5% (7/40) and there were no cases of failure. There was reports of adverse reactions in 47% (19/40) of the cases. Of these, 87% were mild and 13% were moderate. There was no need for change or suspension of the scheme. CONCLUSIONS: The cure rate in FDC 4RHZE/2RH scheme under self-administered regimen was similar to historical rates of cure with 2RHZ/4RH. The default rate in the sample studied was much higher than the rate recommended as appropriate (up to 5%).
INTRODUÇÃO: O esquema de tratamento da TB tem alta eficácia em torno de 95% e com possibilidade de cura de aproximadamente 100% dos casos e reduz rapidamente a transmissão, e assim pode-se reduzir a incidência da doença. Embora a distribuição da medicação seja gratuita em todo país pelo Sistema Único de Saúde, a efetividade do tratamento da TB varia muito nos diferentes locais. JUSTIFICAVA: Conhecer as taxas de sucesso de tratamento ,falência e abandono além de verificar a segurança do tratamento da TB com 4 medicamentos em apresentação dose fixa combinada. OBJETIVO: Descrever as taxas de cura, falência e abandono do tratamento da tuberculose com o esquema básico com rifampicina, isoniazida, pirazinamida e etambutol nos dois primeiros meses de tratamento seguidos de isoniazida e rifampcina por quatro meses (2RHZE/4RH), sob forma de comprimidos em dose fixa combinada (DFC), em regime auto administrado implementado no Brasil desde 2010, em substituição ao esquema utilizando cápsulas e comprimidos com rifampicina, isoniazida e pirazinamida nos dois primeiros meses de tratamento, seguidos de isoniazida e rifampcina por quatro meses (2RHZ/4RH). MÉTODOS: Estudo descritivo utilizando dados secundários coletados prospectivamente de prontuários de casos de TB, maiores de 18anos, submetidos ao tratamento com esquema básico para tuberculose, em duas Unidades Básicas de Saúde da região metropolitana de Goiânia. RESULTADOS: Foram incluídos no estudo 40 casos de TB. A taxa de cura foi de 67,5% (27/40), a de abandono de 17,5% (7/40) e a não ocorreram casos de falência. Houve relato de reações adversas em 47% (19/40) num total de 31 ocorrências. Dessas, 87% foram leves e 13% moderadas. Em nenhum caso houve necessidade de mudança ou suspensão do esquema. CONCLUSÕES: A taxa de cura do esquema 4RHZE/2RH em DFC sob regime autoadministrado foi semelhante às taxas históricas do tratamento com 2RHZ/4RH. A taxa de abandono na amostra estudada foi superior a taxa preconizada como adequada (até 5%).

Las toxicidades limitantes de dosis fuero una neutropenia febril grado 4 (en el brazo de docetaxel) y una neutropenia grado 3 en el brazo de gemcitabina. La combinación de carlumab no tuvo un impacto El cáncer es una enfermedad altamente frecuente y con alta mortalidad. El desarrollo de fármacos contra el cáncer se ha caracterizado por su ineficiencia, con una de las tasas de aprobación de fármacos más baja entre las diferentes especialidades médicas. El principal motivo de esta baja tasa de éxito es la falta de eficacia de los nuevos fármacos que entran al desarrollo clínico. Se han planteado diferentes estrategias para mejorar la eficiencia del desarrollo de fármacos, incluyendo la combinación de fármacos antitumorales, el desarrollo en paralelo de biomarcadores y la optimización del diseño de los ensayos clínicos usando modelización basada en farmacocinética y farmacodinamia Esta tesis es un compendio de dos artículos que evalúan estrategias para optimizar el desarrollo de fármacos mediante la combinación de agentes antitumorales. El primer proyecto es la evaluación preclínica en xenoinjertos derivados de pacientes (PDX) la combinación de inhibidores de PI3K-mTOR con diferentes agentes antitumorales y el segundo es el ensayo clínico fase I evaluando carlumab, un anticuerpo anti CCL2, en combinación con diferentes quimioterapias en pacientes con tumores sólidos avanzados. Proyecto 1: se seleccionaron tres modelos de PDX con deficiencia en PTEN: un PDX de cáncer de mama triple negativo (TNBC), otro de carcinoma de ovario de bajo grado KRAS G12R mutado y otro de adenocarcinoma de pulmón con mutaciones en KRAS G12C y TP53 R181P. En estos modelos se evaluaron dos inhibidores de PI3K-mTOR—PF-04691502 and PF-05212384— en combinación con cisplatino, paclitaxel o dacomitinib. La adición de los inhibidores de PI3K-mTOR a cisplatino o paclitaxel aumentó la actividad de la quimioterapia en los modelos de TNBC y LGSOC; sin embargo, no se objetivó este efecto en modelo de adenocarcinoma de pulmón con mutación de KRAS y TP53. Se objetivó modulación farmacodinámica de pAKT y pS6 en los grupos tratados con inhibidores de PI3K-mTOR. Nuestra investigación sugiere que añadir un inhibidor de PI3K-mTOR puede aumentar el efecto inhibitorio sobre el crecimiento de la quimioterapia en modelos PDX con deficiencia en PTEN. Sin embargo, este beneficio no se observó en el modelo de adenocarcinoma KRAS y TP53 mutado. En el futuro se deberá ahondar en el papel de la pérdida de PTEN en la actividad de estas combinaciones. Proyecto 2: se trata de un ensayo clínico fase Ib evaluando carlumab, un anticuerpo monoclonal contra CCL-2, en combinación con cuatro regímenes de quimioterapia (docetaxel, gemcitabina, carboplatino + paclitaxel y doxorrubicina liposomal pegilda (PLD). En este estudio participaron 53 pacientes en los que o bien los agentes quimioterápicos eran parte del tratamiento convencional o no tenían otras opciones de tratamiento convencional: docetaxel (n=15), gemcitabina (n=12), carboplatino + paclitaxel (n=12) y PLD (n=14). Las toxicidades limitantes de dosis incluyeron una neutropenia febril grado 4 (en el brazo de docetaxel) y una neutropenia grado 3 (en el brazo de gemcitabina). De acuerdo a los brazos de tratamiento, las toxicidades grado 3 o mayores más frecuentes fueron: neutropenia (6/15) y neutropenia febril (4/15) en el brazo de docetaxel, neutropenia (2/12) en el brazo de gemcitabina, neutropenia (4/12), trombocitopenia (4/12) y anemia (2/12) en el brazo de carboplatino-paclitaxel y anemia (3/14) y mucositis (2/14) en el brazo de PLD. Se objetivo una respuesta parcial y 18 estabilizaciones de la enfermedad (38%). La adición de carlumab no tuvo cambios relevantes en el perfil farmacocinético de ninguna de las quimioterapias evaluadas. Los niveles de CCL2 libres descendieron inmediatamente tras el tratamiento con carlumab, pero aumentaron con las administraciones posteriores, sugiriendo que carlumab secuestraba CCL2 de manera temporal. No se objetivaron anticuerpos anti-droga que justificasen dicho efecto. No se objetivaron cambios en las células tumorales circulantes ni en las células circulantes endoteliales. En 3 de 19 pacientes evaluables se objetivó una reducción del 30% en los niveles de N-telopeptido de colágeno tipo I en orina (uNTx). Carlumab es seguro administrado a dosis de 10 o 15 mg/kg en combinación con quimioterapia convencional y tiene buena tolerancia. Sin embargo, no se alcanza una inhibición sostenida de CCL2, ni se han objetivado un número de respuestas significativas.
Cancer is a highly frequent disease associated to high mortality. Drug development in Oncology has shown to be inefficient, having one of the lowest success rate of drugs entering in phase I trials that finally achieves marketed authorization. The main reason for this high failure rate is lack of efficacy. Different strategies have been adopted to improved anti-cancer drug development with the aim of improving patient care. This strategies include the combinatorial use of agents, biomarker co-development, and optimization of clinical trial design with the use of pharmacokinetic-pharmacodynamic modeling. This thesis is presented as compendium of work integrating two projects; the first project preclinically evaluates the combination of two PI3K-mTOR inhibitors and chemotherapy or the pan-HER inhibitor dacomitinib in patient derived xenografts. The second project evaluates de monoclonal antibody anti-CCL2 carlumab in patient derived xenografts. Project 1: Three PDXs were selected for their lack of PTEN expression by immunohistochemistry: a triple-negative breast cancer (TNBC), a KRAS G12R low-grade serous ovarian cancer (LGSOC), and KRAS G12C and TP53 R181P lung adenocarcinoma (LADC). Two dual PI3K-mTOR inhibitors were evaluated—PF-04691502 and PF-05212384—in combination with cisplatin, paclitaxel, or dacomitinib. The addition of PI3K-mTOR inhibitors to cisplatin or paclitaxel increased the activity of chemotherapy in the TNBC and LGSOC models; whereas no added activity was observed in the LADC model. Pharmacodynamic modulation of pS6 and pAKT was observed in the group treated with PI3K-mTOR inhibitor. Our research suggests that the addition of a PI3K-mTOR inhibitor may enhance tumor growth inhibition when compared to chemotherapy alone in PTEN-deficient PDXs. However, this benefit was absent in the KRAS and TP53 mutant LADC model. The role of PTEN deficiency in the antitumor activity of these combinations should be further investigated in the clinic. Project 2 is a first-in-human phase 1b study of carlumab with one of four chemotherapy regimens (docetaxel, gemcitabine, paclitaxel+carboplatin, and pegylated liposomal doxorubicin HCl [PLD]). Fifty-three patients with advanced solid tumors for which ≥1 of these regimens was considered standard of care or for whom no other treatment options existed participated in the study: docetaxel (n=15), gemcitabine (n=12), paclitaxel or carboplatin (n=12), or PLD (n=14). Dose-limiting toxicities included one grade 4 febrile neutropenia (docetaxel arm) and one grade 3 neutropenia (gemcitabine arm). The most common drug-related grade ≥3 adverse events were docetaxel arm—neutropenia (6/15) and febrile neutropenia (4/15); gemcitabine arm—neutropenia (2/12); paclitaxel+carboplatin arm—neutropenia, thrombocytopenia (4/12 each), and anemia (2/12); and PLD arm—anemia (3/14) and stomatitis (2/14). One partial response and 18 (38 %) stable disease responses were observed. Combination treatment with carlumab had no clinically relevant pharmacokinetic effect on any of the chemotherapeutic agents tested. Free CCL2 declined immediately post-treatment with carlumab but increased with further chemotherapy administrations in all arms, suggesting that carlumab could sequester CCL2 for only a short time. Neither antibodies against carlumab nor consistent changes in circulating tumor cells (CTCs) or circulating endothelial cells (CECs) enumeration were observed. Three of 19 evaluable patients showed a 30 % decrease from baseline urinary cross-linked N-telopeptide of type I collagen (uNTx). Carlumab could be safely administered at 10 or 15 mg/kg in combination with standard-of-care chemotherapy and was well-tolerated, although no long-term suppression of serumCCL2 or significant tumor responses were observed.

MATERIAL I MÈTODES: En el primer estudi es van analitzar els resultats de l’aplicació del Test Combinat (bioquímica materna de primer trimestre (f-β-hCG i PAPP-A) i la mesura de la translucència nucal (TN) d’ambdós fetus a les 11-14 s) per a la detecció de trisomia 21 en 100 gestacions gemel•lars. Es va comparar l’ efectivitat del Test Combinat amb el cribratge exclusivamnet ecogràfic mitjançant la medició de la TN. En un segon temps es van analitzar els resultats obtinguts amb el Test Combinat en 161 gestacions gemel•lars. Es va analitzar també la distribució dels marcadors bioquímics de primer trimestre en funció de la corionicitat i del tipus de reproducció (espontània o assistida). En el segon estudi es van valorar els resultats obtinguts en totes les gestacions gemel•lars (monocorials i dicorials) amb un o ambdós fetus amb una TN extrema (> percentil 99) diagnosticats durant l’ecografia de primer trimestre, en un període de 4 anys. CONCLUSIONS: . Dels resultats del primer estudi es desprèn que l’aplicació del Test Combinat permet en les gestacions gemel•lars, disminuir els falsos positius obtinguts amb l’aplicació del cribratge exclusiu ecogràfic (14.3% de les gestacions vs 5.1%) i que els marcadors bioquímics de primer trimestre presenten uns valors significativament disminuits en les gestacions monocorials respecte a les gestacions dicorials. Els resultats del segon estudi mostren que la prevalença d’una TN extrema és major en els fetus procedents d’una gestació monocorial i que una TN extrema en algun dels fetus s’associa a resultats obstètrics desfavorables (80%) tant en les gestacions monocorials com dicorials. PARAULES CLAU: Gestació gemel•lar; Test Combinat; cribratge de trisomia 21; cribratge de primer trimestre; translucència nucal; translucència nucal augmentada; cariotip normal; defectes estructurals; síndrome de transfusió feto-fetal.
Methods: In the first study, free-β-hCG and PAPP-A were determined at 8-12 weeks and fetal nuchal translucency (NT) was measured at 11-14 weeks in 100 twin pregnancies. The individual risks for trisomy 21 were estimated using NT alone and the Combined Test and the effectiveness of both tests was compared. Subsequently, the results of the combined test were evaluated in 161 twin pregnancies with an assessment on the distribution of the biochemical markers ant NT thickness according to chorionicity and the mode of conception. In the second study a consecutive sample of 206 twin pregnancies (166 dichorionic and 40 monochorionic) were scanned for NT. In those with a NT>99th percentile and a normal karyotype, extensive follow-up was performed and perinatal outcome was recorded. Results:. In the first study, two pregnancies with trisomy 21 were detected by both methods. The false positive rate achieved by NT screening (11.2% of pregnancies) was substantially reduced when first trimester biochemistry was added (5.1%). With the application of the Combined Test in 161 pregnancies, all trisomy 21 pregnancies were identified (3 pregnancies) for a false-positive rate of 6.4%. Fβ-hCG and PAPP-A were significantly decreased in monochorionic pregnancies and PAPP-A was significantly decreased in pregnancies conceived by assisted reproduction. In the second study in 10 pregnancies one of the fetuses had a NT> 99th percentile, 5 DC (1.5%) and 5 MC (6.3%) with a normal karyotype. Among these, six structurally abnormalities were diagnosed (3 in dichorionics and 3 in monochorionics), and two intrauterine fetal demises occurred (1 in dichorionics and 1 in monochorionics). Normal perinatal outcome was observed in two pregnancies, one dichorionic and one monochorionic. Conclusion: The Combined Test maintains the detection rate achieved by NT screening for trisomy 21 in twin pregnancies, but false positive rates are reduced. The differences in the biochemical markers related to chorionicity or the mode of conception must be confirmed in further studies. NT>99th percentile with a normal karyotype was associated with a high rate of fetal abnormalities anf fetal demise irrespective of chorionicity KEY WORDS: Twin pregnancy; Combined Test; Down syndrome screening; first trimester screening; nuchal translucency; increased nuchal translucency; normal karyotype; fetal abnormalities; twin-twin transfusion syndrome

MATERIAL I MÈTODES: En el primer estudi es van analitzar els resultats de l’aplicació del Test Combinat (bioquímica materna de primer trimestre (f-β-hCG i PAPP-A) i la mesura de la translucència nucal (TN) d’ambdós fetus a les 11-14 s) per a la detecció de trisomia 21 en 100 gestacions gemel•lars. Es va comparar l’ efectivitat del Test Combinat amb el cribratge exclusivamnet ecogràfic mitjançant la medició de la TN. En un segon temps es van analitzar els resultats obtinguts amb el Test Combinat en 161 gestacions gemel•lars. Es va analitzar també la distribució dels marcadors bioquímics de primer trimestre en funció de la corionicitat i del tipus de reproducció (espontània o assistida). En el segon estudi es van valorar els resultats obtinguts en totes les gestacions gemel•lars (monocorials i dicorials) amb un o ambdós fetus amb una TN extrema (> percentil 99) diagnosticats durant l’ecografia de primer trimestre, en un període de 4 anys. CONCLUSIONS: . Dels resultats del primer estudi es desprèn que l’aplicació del Test Combinat permet en les gestacions gemel•lars, disminuir els falsos positius obtinguts amb l’aplicació del cribratge exclusiu ecogràfic (14.3% de les gestacions vs 5.1%) i que els marcadors bioquímics de primer trimestre presenten uns valors significativament disminuits en les gestacions monocorials respecte a les gestacions dicorials. Els resultats del segon estudi mostren que la prevalença d’una TN extrema és major en els fetus procedents d’una gestació monocorial i que una TN extrema en algun dels fetus s’associa a resultats obstètrics desfavorables (80%) tant en les gestacions monocorials com dicorials. PARAULES CLAU: Gestació gemel•lar; Test Combinat; cribratge de trisomia 21; cribratge de primer trimestre; translucència nucal; translucència nucal augmentada; cariotip normal; defectes estructurals; síndrome de transfusió feto-fetal.
Methods: In the first study, free-β-hCG and PAPP-A were determined at 8-12 weeks and fetal nuchal translucency (NT) was measured at 11-14 weeks in 100 twin pregnancies. The individual risks for trisomy 21 were estimated using NT alone and the Combined Test and the effectiveness of both tests was compared. Subsequently, the results of the combined test were evaluated in 161 twin pregnancies with an assessment on the distribution of the biochemical markers ant NT thickness according to chorionicity and the mode of conception. In the second study a consecutive sample of 206 twin pregnancies (166 dichorionic and 40 monochorionic) were scanned for NT. In those with a NT>99th percentile and a normal karyotype, extensive follow-up was performed and perinatal outcome was recorded. Results:. In the first study, two pregnancies with trisomy 21 were detected by both methods. The false positive rate achieved by NT screening (11.2% of pregnancies) was substantially reduced when first trimester biochemistry was added (5.1%). With the application of the Combined Test in 161 pregnancies, all trisomy 21 pregnancies were identified (3 pregnancies) for a false-positive rate of 6.4%. Fβ-hCG and PAPP-A were significantly decreased in monochorionic pregnancies and PAPP-A was significantly decreased in pregnancies conceived by assisted reproduction. In the second study in 10 pregnancies one of the fetuses had a NT> 99th percentile, 5 DC (1.5%) and 5 MC (6.3%) with a normal karyotype. Among these, six structurally abnormalities were diagnosed (3 in dichorionics and 3 in monochorionics), and two intrauterine fetal demises occurred (1 in dichorionics and 1 in monochorionics). Normal perinatal outcome was observed in two pregnancies, one dichorionic and one monochorionic. Conclusion: The Combined Test maintains the detection rate achieved by NT screening for trisomy 21 in twin pregnancies, but false positive rates are reduced. The differences in the biochemical markers related to chorionicity or the mode of conception must be confirmed in further studies. NT>99th percentile with a normal karyotype was associated with a high rate of fetal abnormalities anf fetal demise irrespective of chorionicity KEY WORDS: Twin pregnancy; Combined Test; Down syndrome screening; first trimester screening; nuchal translucency; increased nuchal translucency; normal karyotype; fetal abnormalities; twin-twin transfusion syndrome

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Sporotrichosis is a subcutaneous mycosis that affects humans and animals, and it is caused by dimorphic melanized fungi belonging to the genus Sporothrix. Sporotrichosis is mainly acquired by traumatic implantation of the fungus into the dermis through scratches inflicted by domestic animals or by handling plants. This study approaches: a) the in vitro susceptibility of Sporothrix schenckii complex species to photodynamic inactivation using methylene blue as a photosensitizer and laser as the light source; b) the combination of amphotericin B plus posaconazole in a murine model of systemic infection by S. brasiliensis and S. schenckii sensu stricto, seeking to enhance the treatment of disseminated sporotrichosis; c) the interference of fungal melanin in the in vitro susceptibility of S. brasiliensis and S. schenckii sensu stricto to amphotericin B and itraconazole. In the photodynamic therapy study we have applied methylene blue as a photosensitizing agent and Light emitting diode (InGaAlP) against Sporothrix schenckii complex species in an in vitro assay. The viability of the conidia was determined through the counting of colony forming units. The activity of amphotericin B and posaconazole alone or in combination was evaluated by using a microdilution checkerboard method. For the in vivo study, OF-1 mice were intravenously (i.v.) infected with a lethal inoculum of 2 x 107 CFU/animal. Two strains of S. brasiliensis and two of S. schenckii were tested. Animals received amphotericin i.v. at suboptimal dose i.e., 0.3 mg/kg, in combination with oral posaconazole at 2.5 mg/kg, 5 mg/kg or 10 mg/kg BID. Results were compared with their respective monotherapies and efficacy was evaluated by prolongation of survival and reduction of tissue burden in spleen and liver. In the study of the interference of melanin in the susceptibility of S. brasiliensis and S. schenckii sensu stricto, yeast cells were cultivated in minimal medium with or without L-DOPA in order to induce the production of melanin. Microdilution and time-kill methods were used to determine the antifungal activity against yeast cells with different amounts of melanin. The laser light (InGaAlP) together with a methylene blue photosensitizer were able to significantly reduce the growth of all the tested Sporothrix strains. In vitro data demonstrated a synergistic effect of the combination and although posaconazole alone was effective against sporotrichosis, efficacy was increased when combined with amphotericin B. The maximum efficacy of the combinations was obtained with posaconazole 5 mg/kg. The killing assay showed that melanization protected isolates within the Sporothrix schenckii complex from amphotericin B, particularly in the lower concentrations tested. The conclusions of the present study are: a) the in vitro inhibition of Sporothrix spp. isolates by laser light deserves in vivo experimental and clinical studies since it may be a promising treatment for cutaneous and subcutaneous sporotrichosis; b) posaconazole in combination with suboptimal doses of amphotericin B could be an option in the treatment of disseminated sporotrichosis especially when itraconazole or amphotericin B at optimal doses are contraindicated; c) combination studies of amphotericin B with inhibitors of melanin are required in order to avoid this effect.
A esporotricose é uma micose subcutânea que afeta homens e animais, e é causada por fungos dimórficos melanizados pertencentes ao gênero Sporothrix. Pode ser principalmente adquirida por implantação traumática do fungo na derme através da arranhadura de animais domésticos ou manipulação de plantas contaminadas. O presente estudo investigou: a) a suscetibilidade in vitro de espécies do Complexo Sporothrix schenckii à inativação fotodinâmica; b) a combinação de anfotericina B e posaconazol em modelo murino de infecção sistêmica por S. brasiliensis e S. schenckii stricto sensu, buscando melhorar o tratamento da esporotricosse disseminada; c) a interferência da melanina fúngica na suscetibilidade in vitro de S. brasiliensis e S. schenckii stricto sensu à anfotericina B e itraconazol. No estudo da terapia fotodinâmica foi aplicado azul de metileno como fotossensibilizador e emissão de luz diiodo (InGaAlP) frente espécies do complexo Sporothrix schenckii em ensaio in vitro. A viabilidade dos conídios foi determinada através de contagem de unidades formadoras de colônia (UFC). A atividade da anfotericina B e posaconazol sozinhos ou combinados foi avaliada segundo a técnica de microdiluição em caldo e técnica de checkerboard. No estudo in vivo, camundongos OF-1 foram infectados com um inóculo de 2 x 107 UFC/animal. Foram utilizadas duas cepas de S. brasiliensis e duas cepas de S. schenckii. Os animais receberam doses de 0.3 mg/kg de anfotericina B em combinação com 2.5 mg/kg e 5 mg/kg de posaconazol. Os resultados foram comparados com as respectivas monoterapias e a eficácia foi avaliada através do prolongamento da sobrevivência e redução da carga fúngica no fígado e baço. No estudo da interferência da melanina na suscetibilidade de S. brasiliensis e S. schenckii stricto sensu à anfotericina B e itraconazol, células leveduriformes foram cultivadas em meio mínimo com e sem L-DOPA. Métodos de microdiluição e tempo de morte foram utilizados para determinar a atividade dos antifúngicos frente às células com diferentes quantidades de melanina. A luz laser (InGaAlP) em conjunto com o azul de metileno foram capazes de reduzir significativamente o crescimento de todas as cepas de Sporothrix testadas. Os dados in vitro demonstraram um efeito sinérgico da combinação de posaconazol e anfotericina B, e, apesar de o posaconazol 5 mg/kg sozinho apresentar eficácia contra a esporotricose, teve sua eficiência aumentada quando combinado com anfotericina B 0,3 mg/kg. A técnica de tempo de morte mostrou que a melanização protegeu os isolados do complexo Sporothrix schenckii da anfotericina B, particularmente na concentração mais baixa testada. Desta forma, as conclusões do presente estudo são: a) a inibição fotodinâmica in vitro de isolados de Sporothrix merece estudos experimentais e clínicos, uma vez que pode ser um tratamento promissor para a esporotricose cutânea e subcutânea; b) o posaconazol em combinação com dose baixa de anfotericina B pode ser uma opção para o tratamento de esporotricose disseminada, especialmente quando itraconazol e anfotericina B são contraindicados; c) estudos de combinação de anfotericina B com inibidores de melanina são necessários a fim de evitar o efeito protetor da melanina contra as defesas do organismo e contra antifúngicos.

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Universidade Estadual Paulista (UNESP)
A produção de beta-lactamase de espectro estendido (ESBL) em membros da família Enterobacteriaceae pode conferir resistência a cefalosporinas de amploespectro, aztreonam e penicilinas. Devido a esse fenômeno, a detecção exata dos produtores de ESBL é essencial para a seleção apropriada da antibioticoterapia. Para detectar a produção de beta-lactamase de espectro estendido (ESBL) em bacilos Gram-negativos, foi usado um teste de triagem com os discos de aztreonam (ATM), ceftazidima (CAZ), cefotaxima (CTX) e ceftriaxona (CRO) sobre 300 cepas, das quais trinta e cinco eram suspeitas da presença de ESBL. A produção de ESBL foi demonstrada por três métodos fenotípicos confirmatórios de fácil utilização. Os três testes fenotípicos para confirmar a produção de ESBL incluíram o teste do sinergismo (double disk), E-test? ESBL e disco combinado. Os discos utilizados no teste do sinergismo e do disco combinado foram: aztreonam (30?g-ATM), cefotaxima (30?g-CTX), ceftazidima (30?g-CAZ), cefpodoxima (10?g-CPD) ceftriaxone (30?g-CRO) e amoxicilina+ácido clavulânico(30?g-AMC), cefotaxima+ácido clavulânico (30?g-10?g), ceftazidima+ácido clavulânico (30?g- 10?g), cefpodoxima+ácido clavulânico (10?g-1? g). Para E-test foram utilizadas fitas contendo as cefalosporinas: ceftazidima versus ceftazidima/ácido clavulânico; cefotaxima versus cefotaxima/ácido clavulânico. Os testes fenotípicos confirmaram a presença de ESBL em cinco cepas de enterobactérias (1,66%). Todos os métodos são de fácil execução, contudo o método do Etest requer experiência para interpretar os resultados. Os três testes oferecem uma solução viável para confirmar a produção de ESBL no laboratório clínico.
The production of extended spectrum beta-lactamase (ESBL) in the members of the family Enterobacteriaceae can check resistance to cephalosporins of extended-spectrum, aztreonam and penicilins. Due to this phenomenon, the exact detection of the producers of ESBL are essential for the appropriate selection of antimicrobial therapy. To detect the production of extended spectrum beta-lactamase (ESBL) in Gram-negative bacilli, a test of screening was used with the discs of aztreonam (ATM), ceftazidime (CAZ), cefotaxime (CTX) e ceftriaxone (CRO) in 300 strains, of which thirty-five were suspicious of the presence of ESBL. The production of ESBL was demonstrated by three phenotypic methods confirmed of easy utilization. The three phenotypic tests to confirm the production of ESBL included the test of sinergy (double disk), E-test? ESBL and combination disk. The disks used on the test sinergy and the combination disk were: aztreonam (30?g-ATM), cefotaxime (30?g-CTX), ceftazidime (30?g-CAZ), cefpodoxime (10?g-CPD) ceftriaxone (30?g- CRO) e amoxicillin+clavulanic acid (30?g-AMC), cefotaxime+clavulanic acid (30?g- 10? g), ceftazidime+clavulanic acid (30?g-10? g), cefpodoxime+clavulanic acid (10?g- 1? g). For E-test, were utilized strips containing the cephalosporins: ceftazidime and ceftazidime/clavulanic acid; cefotaxime and cefotaxime/clavulanic acid. The phenotypic tests confirmed the presence of ESBL in five strains Enterobacteriaceae (1,66%). All of the methods are of easy execution; however, the method of Etest requires experiment to interpret the results. The three tests offer a viable solution to confirm the production of ESBL on a clinic laboratory.

People often create novel lexical expressions to efficiently communicate their thoughts to others. Noun-noun phrases, also known as conceptual combinations, serve as an example of these novel expressions. Most of the research on conceptual combination has focused on structural features of the phrases. However, other research has demonstrated that discourse context can also influence how these phrases are interpreted. Across two experiments, we demonstrate that discourse context has a greater influence on how people interpret these combinations than does a structural level manipulation. We also examine the strength of this contextually based-effect over a series of time delays. The findings from this study indicate that, while structural features of a given conceptual combination influence how that combination is interpreted, the discourse surrounding the novel combination plays a more influential role in the resulting interpretation. The influence of context is more pronounced than has been suggested in much of the research on conceptual combination.

This thesis looks at conceptual combination, in particular it investigates how noun noun compounds are interpreted. Several themes run throughout the work. Real compounds (e.g. coat hanger, crab apple) are compared to novel ones (e.g. banjo cactus, zip violin). Also, compounds are examined in each of the possible permutations of artefacts (A) (e.g. coat, banjo) and natural kinds (N) (e.g. crab, cactus), (AA, AN, NA and NN).Experiments 1 - 4 examine noncompositionality in noun noun compounds. Possible sources of noncompositionality are investigated using both feature listing and feature rating tasks. Although some differences were found, results were similar between different types of compound, evidence of noncompositionality being found in each. The results also confirm that most of the meaning of a noun noim compound is derived from the second constituent (noun2).Experiments 5 and 6 look at two different types of compoimd interpretation - slot filling and property mapping. In experiment 5, slot filling is found to be the preferred interpretation type overall, but property mapping is more common in compounds composed of two natural kinds (NN). Experiment 6 examines possible factors influencing the choice between slot filling and property mapping interpretations. It was found that constituent similarity plays an important role, and also that this interacts with whether or not the constituents have important properties which clash. Experiment 7 looks at compound identification. Results suggest that the first constituent (nounl) may be critical in such tasks. Experiment 8 compares the importance of nounl and noun2 in determining the type of interpretation given to a compound. Neither position is found to be more influential than the other, although relational information does seem to be associated with specific nouns in each position. Throughout the thesis findings are related to current theories of conceptual combination, such as prototype models, the concept specialisation model and theories of compound interpretation by analogy.

INTRODUÇÃO O consumo de álcool combinado com bebidas energéticas (AmED) tem se mostrado associado tanto a um padrão pesado de ingestão de bebidas alcoólicas, quanto a comportamentos de risco no trânsito (CRTs) entre jovens adultos. Devido ao grave impacto causado pelas incapacidades e mortes no trânsito serem decorrentes de comportamentos previsíveis e em grande parte evitáveis, o presente estudo procura investigar a influência do consumo de AmED sobre os comportamentos de risco no trânsito entre os motoristas de caminhão. MÉTODOS Dados de uma amostra de profissionais que trafegavam pelas rodovias do Estado de São Paulo entre junho de 2012 e setembro de 2013 (N=535) foram separados em três grupos: (a) os que afirmaram ingerir AmED (n=90), (b) que relataram consumir apenas bebidas alcoólicas (n=326) e (c) o restante da amostra (n=445). Análises bivariadas foram realizadas com os relatos positivos nos últimos 12 meses que antecederam a pesquisa. O nível de significância foi estipulado para um alfa de 5% e, posteriormente, a analise múltipla utilizou a regressão logística. RESULTADOS Comparando os condutores que ingeriram AmED com os que consumiram apenas bebidas alcoólicas, os primeiros tiveram mais chances de possuir idades entre 20 e 24 anos (OR=3,3), de trabalhar como profissional a menos de 5 anos (OR=2,5), apresentaram maiores riscos de dirigir sem cinto de segurança (OR=2,2), em alta velocidade (OR=1,9), ter brigado ou discutido no trânsito (OR=2,1), ter consumido bebidas alcoólicas em um padrão pesado (OR=3,4), bebendo mais doses alcoólicas por ocasião (mediana 5 vs 2 doses, p < 0,008); em maior frequência (OR=1,9), bebendo mais frequentemente no padrão binge drinking (OR=2,3) e consumindo drogas ilícitas em maior frequência (OR=2,3), além de maiores chances de apresentar uma qualidade de sono ruim (OR=1,7). Comparados ao restante da amostra, observou-se que os motoristas de caminhão que ingeriram AmED apresentaram maior risco de dirigir sem cinto de segurança (OR=2,2), em alta velocidade (OR=1,9), alcoolizado (OR=2,6), de brigar ou discutir no trânsito (OR=2,0), apresentaram maiores chances de ingerir mais doses alcoólicas por ocasião (medianas 5 vs 2 doses, p < 0,001), beber mais frequentemente (OR=2,6), inclusive no padrão binge drinking (OR=2,1), também em maior frequência em binge drinking (OR=3,2), consumir álcool em um padrão pesado (OR=3,4) e usar drogas ilícitas (OR=2,6). A regressão logística ajustada por idade indicou que os motoristas que brigaram ou discutiram no trânsito (OR=2,2), que dirigiram sem cinto de segurança (OR=1,9) e que relataram o uso de drogas ilícitas nos últimos 12 meses (OR=2,0) tiveram maiores chances de ter ingerido AmED. CONCLUSÃO O estudo indica uma associação entre a ingestão conjunta de álcool com bebidas energéticas e maiores chances de apresentar CRTs. São necessários investimentos em pesquisas e ações preventivas voltadas para essa população
INTRODUCTION: Consumption of alcohol mixed with energy drinks (AmED) has been shown associated with both a heavy pattern of alcohol intake as well as the traffic risk behaviors (TRB) among young adults. Due to the serious impact caused by disabilities and traffic deaths arising from predictable and largely preventable behaviors, the present study investigates the influence of AmED consumption on traffic risk behaviors among truck drivers. METHODS: Data from a sample of professional driving along the highways of the State of São Paulo (Brazil) between June 2012 and September 2013 (N=535) were divided into three groups: (a) those who reported drinking AmED (n=90), (b) who reported consuming alcohol only (n=326) and (c) the rest of the sample (n=445). Bivariate analyzes were performed with positive reports in the last 12 months preceding the survey. The level of significance was set for an alpha of 5% and, subsequently, it was made a multiple logistic regression analysis. RESULTS: Comparing the drivers who drink AmED with those who consumed only alcohol, the first were more likely to have between 20 and 24 years (OR=3.3), to work as a professional less than five years (OR=2.5), had higher risks of driving without a seat belt (OR=2.2), in high speed (OR=1.9), have a fight or discussion in traffic (OR=2.1), having consumed alcohol in a heavy pattern (OR=3.4), drinking more alcoholic drinks per occasion (median 5 vs 2 doses, p < 0.008); at higher frequency (OR=1.9), more often in binge drinking (OR=2.3), consuming illicit drugs more frequently (OR=2.3), as well as more likely to have a bad quality sleep (OR=1.7). Compared to the rest of the sample, it was found that truck drivers who drink AmED had higher risk of driving without a seat belt (OR=2.2), in high speed (OR=1.9), drunk (OR=2 , 6), to fight or discuss in traffic (OR=2.0), were more likely to consume more alcoholic drinks per occasion (median 5 vs 2 doses, p < 0.001), drinking more often (OR=2.6), including in binge drinking (OR=2.1), also in higher frequency in binge drinking (OR=3.2), consuming alcohol in a heavy pattern (OR=3.4) and use illicit drugs (OR=2 6). Logistic regression adjusted for age indicated that drivers who fought or discussed in traffic (OR = 2.2), which drove without a seat belt (OR = 1.9) and that reported using illicit drugs in the last 12 months (OR = 2.0) had higher chances of having ingested AmED. CONCLUSION: This study indicates an association between the combined intake of alcohol with energy drinks and more likely to have TRBs. Investment is needed in research and preventive actions for this population

Commodities primárias, tais como metais, petróleo e agricultura, constituem matérias-primas fundamentais para a economia mundial. Dentre os metais, destaca-se o alumínio, usado em uma ampla gama de indústrias, e que detém o maior volume de contratos na London Metal Exchange (LME). Como o preço não está diretamente relacionado aos custos de produção, em momentos de volatilidade ou choques econômicos, o impacto financeiro na indústria global de alumínio é significativo. Previsão de preços do alumínio é fundamental, portanto, para definição de política industrial, bem como para produtores e consumidores. Este trabalho propõe um modelo ótimo de previsões para preços de alumínio, por meio de combinações de previsões e de seleção de modelos através do Model Confidence Set (MCS), capaz de aumentar o poder preditivo em relação a métodos tradicionais. A abordagem adotada preenche uma lacuna na literatura para previsão de preços de alumínio. Foram ajustados 5 modelos individuais: AR(1), como benchmarking, ARIMA, dois modelos ARIMAX e um modelo estrutural, utilizando a base de dados mensais de janeiro de 1999 a setembro de 2014. Para cada modelo individual, foram geradas 142 previsões fora da amostra, 12 meses à frente, por meio de uma janela móvel de 36 meses. Nove combinações de modelos foram desenvolvidas para cada ajuste dos modelos individuais, resultando em 60 previsões fora da amostra, 12 meses à frente. A avaliação de desempenho preditivo dos modelos foi realizada por meio do MCS para os últimos 60, 48 e 36 meses. Um total de 1.250 estimações foram realizadas e 1.140 variáveis independentes e suas transformadas foram avaliadas. A combinação de previsões usando ARIMA e um ARMAX foi o único modelo que permaneceu no conjunto de modelos com melhor acuracidade de previsão para 36, 48 e 60 meses a um nível descritivo do MCS de 0,10. Para os últimos 36 meses, o modelo combinado proposto apresentou resultados superiores em relação a todos os demais modelos. Duas co-variáveis identificadas no modelo ARMAX, preço futuro de três meses e estoques mundiais, aumentaram a acuracidade de previsão. A combinação ótima apresentou um intervalo de confiança pequeno, equivalente a 5% da média global da amostra completa analisada, fornecendo subsídio importante para tomada de decisão na indústria global de alumínio. iii
Primary commodities, including metals, oil and agricultural products are key raw materials for the global economy. Among metals, aluminum stands out for its large use in several industrial applications and for holding the largest contract volume on the London Metal Exchange (LME). As the price is not directly related to production costs, during volatility periods or economic shocks, the financial impact on the global aluminum industry is significant. Aluminum price forecasting, therefore, is critical for industrial policy as well as for producers and consumers. This work has proposed an optimal forecast model for aluminum prices by using forecast combination and the Model Confidence Set for model selection, resulting in superior performance compared to tradicional methods. The proposed approach was not found in the literature for aluminum price forecasting. Five individual models were developed: AR(1) for benchmarking, ARIMA, two ARIMAX models and a structural model, using monthly data from January 1999 to September 2014. For each individual model, 142 out-of-sample, 12 month ahead, forecasts were generated through a 36 month rolling window. Nine foreast combinations were deveoped for each individual model estimation, resulting in 60 out-of-sample, 12 month ahead forecasts. Model predictive performace was assessed through the Model Confidence Set for the latest 36, 48, and 60 months, through 12-month ahead out-of-sample forecasts. A total of 1,250 estimations were performed and 1,140 independent variables and their transformations were assessed. The forecast combination using ARMA and ARIMAX was the only model among the best set of models presenting equivalent performance at 0.10 MCS p-value in all three periods. For the latest 36 months, the proposed combination was the best model at 0.1 MCS p-value. Two co-variantes, identified for the ARMAX model, namely, 3-month forward price and global inventories increased forecast accuracy. The optimal forecast combination has generated a small confidence interval, equivalent to 5% of average aluminum price for the entire sample, proving relevant support for global industry decision makers.

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The agriculture, activity of primal importance for the human being, it is indeed a route of access for the application of the chemical knowledge towards its practice. Besides that, a sort of theoric concern that also configurated itself as one of the outlines on which was delineated the agricultural practices at the end of XVIII century and beginning of the XIX century, aiming the thecnincal development. Humphry Davy, who during his his career developed several studies with latent practical concerns, starts in 1802 one cycle of lectures about agricultural chemistry, supported by the Board of Agriculture, which extended until 1812, culminating with the publication of the book Elements of Agriculture in 1813. Davy, is usually known by his works with eletriciy and the posterior identification of several chemical elements. In his researchs, showed great interest towards nature and the composition of the matter, what was not different on agricultural researchs. Under the light of current historiography of science, this work intends to analyze how Humphry Davy used to explain the phenomena linked to vegetation, besides of the relevance of his books to agricultural practices
A agricultura, atividade de fundamental importância para o ser humano, é uma via de acesso à aplicação do conhecimento químico à prática. Além disso, uma certa preocupação teórica também se configurou como um dos contornos em que se delineava a prática agrícola do final do século XVIII e início do século XIX, com vistas ao melhoramento técnico. Humphry Davy, que durante sua carreira desenvolveu vários estudos com latente preocupação prática, inicia em 1802 um ciclo de palestras sobre química agrícola, apoiadas pelo Board of Agriculture, que se estenderam até 1812, culminando com a publicação do livro Elements of Agriculture em 1813. Davy é normalmente conhecido por seus trabalhos envolvendo eletricidade e a posterior identificação de vários elementos químicos. Em suas pesquisas, manifestava grande interesse em relação à natureza e à composição da matéria, o que não se mostrou diferente nas pesquisas agrícolas. À luz da atual historiografia da ciência, este trabalho pretende analisar como Humphry Davy explicava os fenômenos ligados à vegetação, além da relevância do seu livro às práticas agrícolas

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CAPES
Segmentar imagens de maneira automática é um grande desafio. Apesar do ser humano conseguir fazer essa distinção, em muitos casos, para um computador essa divisão pode não ser tão trivial. Vários aspectos têm de ser levados em consideração, que podem incluir cor, posição, vizinhanças, textura, entre outros. Esse desafio aumenta quando se passa a utilizar imagens médicas, como as ressonâncias magnéticas, pois essas, além de possuírem diferentes formatos dos órgãos em diferentes pessoas, possuem áreas em que a variação da intensidade dos pixels se mostra bastante sutil entre os vizinhos, o que dificulta a segmentação automática. Além disso, a variação citada não permite que haja um formato pré-definido em vários casos, pois as diferenças internas nos corpos dos pacientes, especialmente os que possuem alguma patologia, podem ser grandes demais para que se haja uma generalização. Mas justamente por esse possuírem esses problemas, são os principais focos dos profissionais que analisam as imagens médicas. Este trabalho visa, portanto, contribuir para a melhoria da segmentação dessas imagens médicas. Para isso, utiliza a ideia do Bagging de gerar diferentes imagens 2D para segmentar a partir de uma única imagem 3D, e conceitos de combinação de classificadores para uni-las, para assim conseguir resultados estatisticamente melhores, se comparados aos métodos populares de segmentação. Para se verificar a eficácia do método proposto, a segmentação das imagens foi feita utilizando quatro técnicas de segmentação diferentes, e seus resultados combinados. As técnicas escolhidas foram: binarização pelo método de Otsu, o K-Means, rede neural SOM e o modelo estatístico GMM. As imagens utilizadas nos experimentos foram imagens reais, de ressonâncias magnéticas do cérebro, e o intuito do trabalho foi segmentar a matéria cinza do cérebro. As imagens foram todas em 3D, e as segmentações foram feitas em fatias 2D da imagem original, que antes passa por uma fase de pré-processamento, onde há a extração do cérebro do crânio. Os resultados obtidos mostram que o método proposto se mostrou bem sucedido, uma vez que, em todas as técnicas utilizadas, houve uma melhoria na taxa de acerto da segmentação, comprovada através do teste estatístico T-Teste. Assim, o trabalho mostra que utilizar os princípios de combinação de classificadores em segmentações de imagens médicas pode apresentar resultados melhores.
Automatic image segmentation is still a great challenge today. Despite the human being able to make this distinction, in most of the cases easily and quickly, to a computer this task may not be that trivial. Several characteristics have to be taken into account by the computer, which may include color, position, neighborhoods, texture, among others. This challenge increases greatly when it comes to using medical images, like the MRI, as these besides producing images of organs with different formats in different people, have regions where the intensity variation of pixels is subtle between neighboring pixels, which complicates even more the automatic segmentation. Furthermore, the above mentioned variation does not allow a pre-defined format in various cases, because the internal differences between patients bodies, especially those with a pathology, may be too large to make a generalization. But specially for having this kind of problem, those people are the main targets of the professionals that analyze medical images. This work, therefore, tries to contribute to the segmentation of medical images. For this, it uses the idea of Bagging to generate different 2D images from a single 3D image, and combination of classifiers to unite them, to achieve statistically significant better results, if compared to popular segmentation methods. To verify the effectiveness of the proposed method, the segmentation of the images is performed using four different segmentation techniques, and their combined results. The chosen techniques are the binarization by the Otsu method, K-Means, the neural network SOM and the statistical model GMM. The images used in the experiments were real MRI of the brain, and the dissertation objective is to segment the gray matter (GM) of the brain. The images are all in 3D, and the segmentations are made using 2D slices of the original image that pass through a preprocessing stage before, where the brain is extracted from the skull. The results show that the proposed method is successful, since, in all the applied techniques, there is an improvement in the accuracy rate, proved by the statistical test T-Test. Thus, the work shows that using the principles of combination of classifiers in medical image segmentation can obtain better results.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, February 2016.
Cataloged from PDF version of thesis. "September 2015."
Includes bibliographical references (pages 128-131).
Immunotherapy is a broad treatment strategy that harnesses the immune system to fight off a particular condition or disease. Cancer immunotherapy is the specific application of agents designed to interact or stimulate the immune system to fight off tumors. Treatments as diverse as passive antibody therapy, cytokine support, and comprehensive adoptive T cell transfer make up the broad field of immunotherapeutics. Due to the naturally complex interactions inherent in the immune system, there are many options for therapeutic intervention, however, this same complexity makes it extremely difficult to optimize treatment strategies. Because of this, research into developing new immunotherapies, optimizing existing immunotherapies, and designing new combinations of immunotherapies is still critical in the fight against cancer. Although there have been ongoing successes of individual immunotherapies in the clinic, the complexity and interdependence of the immune system suggests that any single therapeutic intervention will be insufficient to reject established malignancies. Increased interest in applying combinations of immunotherapies in the clinic requires more thorough preclinical work to guide the designs of these studies. The work presented in this thesis focuses on developing combinations of immunotherapies to treat preclinical models of cancer, as well as studying the underlying mechanism of tumor control. T cells are potent mediators of cytotoxicity and when properly used in adoptive cell transfer (ACT) protocols, can be highly effective in the treatment of cancer. ACT consists of three steps: 1) harvesting and purifying T cells from the patient, 2) enriching or modifying the T cells to become tumor specific, and 3) reinfusing the T cells along with supporting therapies. Therapies given alongside ACT are often adjuvants designed to enhance T cell response. However, focusing therapies only on enhancing the activity of the transferred T cells may miss out on synergistic effects when other parts of the immune system are simultaneously engaged. To study the effect of adjuvant therapy on ACT, a preclinical murine model was analyzed. Large, established B16F10 tumors were controlled when pmel-1 T cells were given with a course of supportive MSA-IL2 cytokine therapy, however, no cures were observed. When a course of TA99 antibody therapy was added alongside ACT, a high rate of cures was observed. Flow cytometry of both circulating and tumor infiltrating pmel-1 cells showed massive expansion and activation. Additionally, tumor infiltration of neutrophils, NK cells, and DCs were greatly enhanced by adjuvant therapy. DCs in the tumor draining lymph nodes were largely unchanged by the therapies. Engagement of the humoral immune response was also observed in both treatment cases. Surprisingly, antibody therapy did not substantially alter any of the mechanistic observations made in this study, despite its critical role in achieving cures of tumors. While ACT is a highly effective therapy, its clinical applicability is hindered by the complexity of performing T cell transplants and manipulations. A more optimal solution would involve purely injectable treatments that could elicit the same level of tumor specific T cell response in conjunction with potent recruitment of the adaptive immune system against tumors. To achieve this, working in collaboration with the Irvine Lab, combinations of immunotherapy using up to four different components were tested to identify critical factors in the successful rejection of established tumors in preclinical models. The four components of tumor targeting antibody, cytokine support, checkpoint blockade, and cancer vaccine acted synergistically to reject tumors from B16F10, TC-1, and DD-Her2/neu cell lines. The cancer vaccine elicited large numbers of tumor-specific T cells, and acted as a replacement for ACT. By analyzing subset combinations of this full treatment, the roles of each therapeutic component were identified. CD8 T cells and cross-presenting DCs were critical to curing subcutaneous tumors. Cytokine therapy was indispensable for effective tumor control, promoted immune cell infiltration into the tumor, and led to an increase in DCs. In combination with the other therapies, vaccination against a tumor antigen elicited a strong immunological memory response that was able to reject subsequent tumor rechallenge, as well as promote antigen spreading to new epitopes. Successful combinations were demonstrated to be dependent on the recruitment of both the adaptive and innate branches of the immune system. Finally, the efficacy of this combination of treatments was demonstrated by controlling the growth of induced tumors in a BRaf/Pten model. Combination immunotherapy promises a future where synergistic treatments are specifically tailored to individual cancers leading to highly effective responses. However, determining the optimal combination of therapies, the complexity of dosing strategies, and the availability of targeted treatments are all barriers that must be overcome. The analysis presented here will make a significant contribution to the body of knowledge on immunotherapy as it has shown the importance of combining orthogonal immunotherapies in order to get durable cures to established tumors. These results will hopefully encourage combinations of orthogonally acting therapies based on T cells to achieve stronger clinical responses. By determining the necessary requirements for a strong, synergistic response to tumorous growths, more effective combination immunotherapy protocols may be designed in the future.
by Cary F. Opel.
Ph. D.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Search for new therapeutic alternatives for leishmaniasis is considered essential by the World Health Organization, due to the high toxicity of the drugs currently used, its high cost and the risk of resistance. In Brazil, it is used three drugs to treat leishmaniasis: meglumine antimoniate and two formulations of amphotericin B (deoxycholate and liposomal). This study is a piggy-back evaluation linked to a multicentric clinical trial with the objective to perform a decision analysis between the treatment regimens for visceral leishmaniasis, for both adults and children. For this end, it was performed analysis of the data obtained in the state of Sergipe from 62 patients randomized to treatment with meglumine antimoniate (group A), considered the first line treatment in Brazil, amphotericin B deoxycholate (group B), liposomal amphotericin B (group C) and the combined regimen of meglumine antimoniate with liposomal amphotericin B (group D), in order to conduct a decision analysis from among these therapeutic regimens for both adults and children. To this end, two scenarios were considered: scenario 1 is the currently prevailing in Brazil, where patients are always treated as possible on an outpatient basis with meglumine antimoniate, although with a smaller monitoring on its potentially lethal side effects and a possible lower adherence to treatment. In the scenario 2, patients are hospitalized during the treatment period, with a better monitoring of clinical and laboratory parameters of the patient, although with a higher risk of nosocomial infections and increasing treatment costs. In terms of security, there is an emphasis on amphotericin B deoxycholate as the one that presents a greater amount of serious and potentially lethal adverse reactions, with an average of 2 severe reactions per patient. From the viewpoint of cost-efficacy, for scenario 1 the meglumine antimoniate remains the treatment of choice for both adults and children. However, in scenario 2, the combination of drugs (group D) presented itself as the most costeffective for both adults and children. From this study it became clear, from a safety point of view for the patient, the need to evaluate both therapeutic regimens, particularly amphotericin B deoxycholate, such as the treatment scenarios for visceral leishmaniasis.
A busca por novas alternativas terapêuticas para as leishmanioses é considerada essencial pela Organização Mundial da Saúde, em virtude da elevada toxicidade dos medicamentos atualmente utilizados, seu alto custo e o risco de resistência. No Brasil, utilizam-se três drogas para o tratamento da leishmaniose: o antimoniato de meglumina e as formulações de anfotericina B (desoxicolato e lipossomal). Este estudo é uma análise econômica atrelada a um ensaio clínico multicêntrico, com o objetivo de se realizar uma análise de decisão entre os esquemas terapêuticos para a leishmaniose visceral, tanto para adultos como para crianças. Para tal, foram utilizados os dados obtidos do estado de Sergipe, onde foram acompanhados 62 pacientes, randomizados para tratamento com antimoniato de meglumina (grupo A), considerado o esquema de primeira escolha no Brasil, anfotericina B desoxicolato (grupo B), anfotericina B lipossomal (grupo C) e o esquema terapêutico combinado de antimoniato de meglumina com anfotericina B lipossomal (grupo D). Na análise de decisão, foram considerados dois cenários: o cenário 1, atualmente existente no Brasil, no qual os pacientes são tratados sempre que possível ambulatorialmente com o antimoniato de meglumina, porém com um menor acompanhamento de suas reações adversas potencialmente letais e uma possível menor adesão ao tratamento. Já no cenário 2, os pacientes são internados durante todo o período do tratamento, com um melhor monitoramento dos parâmetros clínicos e laboratoriais do paciente, porém com um risco maior de infecções hospitalares e aumento de custos do tratamento. No quesito segurança, há um destaque para a anfotericina B desoxicolato como sendo a que apresenta uma maior quantidade de reações adversas graves e potencialmente letais, com uma média de 2 reações graves/paciente. Já no ponto de vista de custo-eficácia, para o cenário 1 o antimoniato de meglumina continua sendo o tratamento de primeira escolha, tanto para adultos como para crianças. Porém, no cenário 2, a combinação de medicamentos (grupo D) se apresentou como o mais custo-eficaz tanto para adultos como para crianças. Deste estudo evidenciou-se, do ponto de vista de segurança ao paciente, a necessidade de reavaliação tanto dos esquemas terapêuticos, particularmente a anfotericina B desoxicolato, como dos cenários de tratamento para a leishmaniose visceral.

This study examines multigrade teaching in selected schools in Canada and its implications for improving multigrade teaching in South Africa, where over 50 % of primary schools are multigrade and the teachers have not received preparation in multigrade teaching. The case study method was adopted because it allowed for 'an intensive, holistic description and analysis' of the multigrade classroom. The approach is interpretivist, based on the assumption that social phenomena are 'socially constituted' and 'valuationally based'. Research techniques included a literature review, interviews and observations. Four classrooms with grade combinations ranging from two grades to eight grades (Kindergarten to grade 7) were studied. Despite problems such as the lack of official recognition, inadequate teacher education and support - problems common to both Canada and South Africa - the Canadian teachers managed their classrooms effectively. This was indicated by their understanding of the children's needs, their integration of the curriculum for teaching across the grades and the learning areas, their use of effective instructional strategies and their involyement of parents in the classroom. A reason for their success may be that their teacher education includes child-centred, activity based approaches, integration of the curriculum, critical thinking, flexibility and effective instructional strategies, which they may adapt for effective multigrade teaching. The study found that successful multigrade teaching depended on the teacher. For South Africa, this may imply that intervention programmes should focus on relevant preparation and support for multigrade teachers. The emphasis on material resources in the implementation of Curriculum 2005 has not been balanced with adequate training on policy, curriculum and instructional strategies. Teacher education should include methodologies that are experiential, reflective and participatory. A variety of instructional strategies should be employed in the multigrade classroom. The respondents in the study believed further that multigrade teaching is more beneficial than single-grade teaching because it caters for the diversity of needs amongst children and allows for peer tutoring, thereby exploiting Vygotsky's theory of the 'zone of proximal development'. Thus, instead of viewing multigrade teaching as a temporary phenomenon, it should be viewed as an opportunity for improving school effectiveness.

Em 2007 foi sancionada a Lei no 11.638, que possibilitou a adoção das Normas Internacionais de Relato Financeiro (International Financial Reporting Standards - IFRS) no Brasil. A convergência às IFRS trouxe diversas inovações, incluindo dentre elas a contabilização das aquisições de empresas, normatizadas pelo Pronunciamento Técnico CPC 15 - Combinações de negócio, que tornou obrigatória a aplicação do método de aquisição. Por esse novo modelo, a entidade adquirente contabiliza os ativos identificáveis adquiridos e os passivos assumidos da adquirida pelos seus respectivos valores justos. Já o ágio por expectativa de rentabilidade futura (goodwill) passa a ser mensurado pela parcela do valor justo da contraprestação transferida que não foi individualmente identificada, sendo realizado exclusivamente por meio do teste de impairment. Esta tese tem o objetivo de identificar fatores determinantes no percentual do custo de aquisição alocado como goodwill nas combinações de negócios realizadas e divulgadas pelas 101 empresas que compõe o Índice Brasil Amplo (IBr-A) durante o período entre 2009 e 2015. Foram identificados e coletados, em grande parte, manualmente, dados sobre 442 combinações de negócios, e utilizaram-se efetivamente as 307 observações em que foi reconhecido goodwill. Foi empregada uma técnica multivariada de dependência conhecida como modelos hierárquicos lineares ou modelos multinível (HLM), cuja característica basilar é a captura da estrutura aninhada dos dados, considerando a variabilidade dos dados dentro dos 39 segmentos econômicos das empresas da amostra deste estudo. Os resultados indicaram a existência de uma estrutura hierárquica, na qual o segmento econômico de atuação da adquirente explicou em torno de 15% da variabilidade no percentual do custo de aquisição alocado como goodwill. Durante a pesquisa foram testadas cinco variáveis relacionadas a fatores de 1o nível (percentual de remuneração variável da diretoria, relevância da aquisição, número de analistas, contraprestação em ações e o aproveitamento fiscal do goodwill) e outras duas relacionadas ao 2o nível (índice de imobilização e market-to-book ratio do segmento). Individualmente, dentre as variáveis de 1o nível, apenas o número de analistas acompanhando as ações da adquirente apresentou associação com o percentual de goodwill. As interações entre o aproveitamento fiscal e o índice de imobilização médio do segmento com o número de analistas também apresentaram associação.
In 2007, the approval of the Law 11.638 made the adoption of the International Accounting Reporting Standard (IFRS) possible in Brazil. The convergence to the IFRS brought several innovations, among then, the accounting for business combinations, regulated by the Pronunciamento Técnico CPC 15 - Combinações de negócios, which made the acquisition method mandatory. Under this new model, the acquirer measures the identifiable acquired assets and the assumed liabilities by their respective fair values. The goodwill, in turn, is the portion of the fair value of the consideration transferred that are not individually identified, and it is realized exclusively by the impairment test. This thesis aims to identify the determining factors in the percentage of the acquisition cost allocated as goodwill in the business combinations realized and disclosed by the 101 companies which comprises the Índice Brasil Amplo (IBr-A) in the period from 2009 to 2015. It was identified and, in great part, hand collected, data about 442 business combinations, and the 307 observationsin which a goodwill was recognized were effectively used. It was used a multivariate dependency technique known as Hierarchical Linear Models or Multilevel Models (HLM), thathas the fundamental characteristic of capturing the nested data structure, considering the variability within the 39 economic segments of the firms of this study\'s sample. The results indicated the presence of a hierarchical structure, in which the segment that the acquirer operates explains about 15% of the variability in the percentage of acquisition cost allocated as goodwill. During the research five first level variables were tested (variable remuneration percentage of the acquirer\'s directors, acquisition relevance, number of analysts, stock consideration and the goodwill tax allowance), as well as two related to the second level (properties, plants and equipment to total asset and market-to-book value of the segment). Individually, among the first level variables, only the number of analyst following the acquirer shares presented an association with the percentage of goodwill. The interactions between the use of the tax allowance and the properties, plants and equipment to total asset with the number of analyst also presented an association.

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Financiadora de Estudos e Projetos
In credit scoring problems, the interest is to associate to an element who request some kind of credit, a probability of default. However, traditional models uses samples biased because the data obtained from the tenderers has only clients who won a approval of a request for previous credit. In order to reduce the bias sample of these models, we use strategies to extract information about individuals rejected to be able to infer a response, good or bad payer. This is what we call the reject inference. With the use of these strategies, we also use the bagging technique (bootstrap aggregating), which consist in generate models based in some bootstrap samples of the training data in order to get a new predictor, when these models is combined. In this work we will discuss about some of the combination methods in the literature, especially the method of combination by logistic regression, although little used but with interesting results.We'll also discuss some strategies relating to reject inference. Analyses are given through a simulation study, in data sets generated and real data sets of public domain.
Em problemas de credit scoring, o interesse é associar a um elemento solicitante de algum tipo de crédito, uma probabilidade de inadimplência. No entanto, os modelos tradicionais utilizam amostras viesadas, pois constam apenas de dados obtidos dos proponentes que conseguiram a aprovação de uma solicitação de crédito anterior. Com o intuito de reduzir o vício amostral desses modelos, utilizamos estratégias para extrair informações acerca dos indivíduos rejeitados para que nele seja inferida uma resposta do tipo bom/- mau pagador. Isto é o que chamamos de inferência dos rejeitados. Juntamente com o uso dessas estratégias utilizamos a técnica bagging (bootstrap aggregating ), que é baseada na construção de diversos modelos a partir de réplicas bootstrap dos dados de treinamento, de modo que, quando combinados, gera um novo preditor. Nesse trabalho discutiremos sobre alguns dos métodos de combinação presentes na literatura, em especial o método de combinação via regressão logística, que é ainda pouco utilizado, mas com resultados interessantes. Discutiremos também as principais estratégias referentes à inferência dos rejeitados. As análises se dão por meio de um estudo simulação, em conjuntos de dados gerados e em conjuntos de dados reais de domínio público.

One of the most common social media platforms of today is Twitter, an open community where content easily could be spread by sharing so called tweets and where the relationship between users is not constrained by accepting the other user. This report discusses the complexity in merging social media and dance by studying a project which used crowdsourcing through Twitter to collect choreographic ideas for a new ballet piece. In order to examine Twitter as a tool in a creative process, a questionnaire was sent to Twitter users and email interviews were held with those responsible for the project of study. The questionnaire showed that most of the Twitter users enjoyed creating and being part of a creative process. However, some of those with an occupation within the dance world voiced concerns about untrained people creating choreography. From the interviews it was found that a lot of thought had to be put into the structure of the project and that the project’s main motivator was to inspire and create with the help of people around the world. It was found in the research that Twitter is a suiting platform for a crowdsourced project since a large and varying group of participants is reached. Twitter allows for the Twitter users to participate regardless of location or occupation as well as bringing good publicity to the dance world.
Twitter är idag en av de största plattformarna inom sociala medier. Plattformen är ett öppet forum där användare enkelt kan sprida material genom så kallade tweets och där användarnas relationer inte kräver att den ena parten accepterar den andre. Denna rapport behandlar komplexiteten i att kombinera sociala medier och dans, genom studien av ett projekt som använde sig av crowdsourcing via Twitter för att samla idéer till ett nytt balettverk. För att kunna utvärdera Twitter som ett verktyg i en kreativ process skickades ett frågeformulär ut till twitteranvändare. Dessutom hölls e-mailintervjuer med dem som var ansvariga för projektet. Formuläret visade att de flesta twitteranvändarna uppskattade att få skapa och ta del av en kreativ process. Dock fanns det negativa åsikter bland användare inom dansvärlden, att otränade personer inte bör koreografera. E-mailintervjuerna visade att mycket tanke hade lagts på strukturen av projektet och att drivkrafterna för att driva ett sådant projekt var att inspirera och skapa tillsammans med hela världen. Genom undersökningen visade det sig att Twitter är en passande plattform för ett crowdsourcat projekt eftersom ett stort antal deltagare kan nås oberoende av var de befinner sig samtidigt som det medför bra publicitet för dansvärlden.