Leflunomide is widely prescribed for Rheumatoid Arthritis (RA) patients in China. However, a number of RA patients still demonstrated progressive bone erosion (PBE+) after receiving Leflunomide in our clinical data. Moreover, the PBE+ is predicted by high baseline serum CRP level (CRPBH). Further, the changes of serum bone resorption marker (Tartrate-resistant acid phosphatase 5b, TRAP5b) strongly correlated with those of CRP in PBE+ RA patients during Leflunomide treatment. Those were consistently observed in collagen-induced-arthritis (CIA) rats. To precisely address the issue, we screened a series of marketed drugs combined with Leflunomide to inhibit CRP production and CRP-related osteoclastic signaling pathway using bioinformatics analysis. Ligustrazine was postulated as an optimal candidate drug. In vitro studies demonstrated that the combination of Ligustrazine and Leflunomide not only suppressed hepatic CRP production, but also suppressed CRP-related osteoclastic signaling and osteoclast activities. In vivo studies showed that the combination attenuated bone erosion in CIA rats. Further, the randomized parallel controlled clinical trial in 120 CRPBH RA patients showed that the combination therapy reduced serum CRP levels and attenuated bone erosion in those patients (ChiCTR-TRC-10001014). Together, this work presents a precision combination therapy for PBE+ in CRPBH RA patients.

Electromagnetic induction (EM) methods have been utilised in a recent surge of archaeological applications across continental Europe, Ireland and Scandinavia. Development of multi-exploration depth instruments and improvements to instrument stability have improved its reputation as an effective method for mapping archaeological remains. Despite these advances, EM methods are comparatively lacking in rigour when for British sites. Through a structured scheme of experimental analysis and fieldwork, this thesis develops an understanding of the responses of EM instruments over a range of British archaeology, including earthworks, field systems, burials, modern remains, and a Cistercian abbey; the results of which demonstrate its effective over a diversity of environments. The impact of instrument-based issues on the collected measurements was quantified through a scheme of experiments targeting instrument drift, calibration and elevation. Dedicated instrument operation and processing workflows were developed based on the collective field and experimental results, which recommend best practice guidelines for improving the quality and accuracy of collected data. The link between instrument measurements and buried archaeology was further developed through a structured analysis of the EM datasets with complementary earth resistance and magnetic results. The integration of the EM, earth resistance and magnetic datasets was utilised to develop an enhanced archaeological characterisation of subsurface features. While the earth resistance and magnetic methods generally responded to different aspects of the buried archaeology, the EM surveys were able to detect a range of responses evident in the results of the former methods. Therefore, the role of EM methods within this characterisation are shown to “bridge the gap” between the earth resistance and magnetic methods, while providing a comprehensive characterisation of the remains in their own right.

Resumo: 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. / Abstract: 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. / Orientador: Elisabeth Loshchagin Pizzolitto / Coorientador: Antonio Carlos Pizzolitto / Banca: Wilton Rogério Lustri / Banca: Izabel Yoko Ito / Mestre

The handling and utilization of products is an important factor in organization that strive towards and optimal operation, where different methods in the handling of products have a direct effect on the organizations results. This is a case study where a sawmill with a process that is repeated for each new order in the sorting- and packaging of timber. For each scenario, an operator is faced with a decision, where the result of the organization is directly affected by the decision that is made. The decision in question consist of an amount of trays of timber that must be combined in order to meet a constraint in the height of each delivered package. The purpose with this study is to investigate how optimization combined with process mapping can help the organization in maximizing its utilization of products. The study was performed with a mixed methods approach, where a process map was developed to gain understanding of the process. An optimization model was developed and run given collected data. In the process mapping it became clear that for each combination of trays, there is a downgrading in length and/or quality, which affects the total value of the combination. A comparison of the results between the optimization models’ and operators’ solutions showed a theoretical saving of 3 655 435 kr annually, and an increase in product utilization of 3,81 percentage in this process. The results of the study shows that optimization combined with process mapping is effective in the terms of minimizing costs dependent on a decision maker.

A previsão de demanda que combina métodos quantitativos e a opinião de especialistas é uma técnica amplamente utilizada na tentativa de aproximar a previsão da demanda real. A presente dissertação apresenta uma revisão bibliográfica sobre combinação de previsões e propõe um método combinado a partir de métodos quantitativos e opinião de especialistas. A revisão sistemática da literatura foi realizada em trabalhos atuais e de relevância para o tema em estudo, com o auxílio de cinco bases de dados. O referencial teórico, que totaliza 38 publicações, apresenta conceitos teóricos sobre combinação de previsões, bem como exemplifica, através de aplicações práticas, como esta técnica está sendo utilizada pelas empresas. Com base nesta revisão foi possível estruturar um método combinado de previsão de demanda. O método proposto não só combina matematicamente as previsões quantitativas e qualitativas, como também pondera, através da matriz de comparações do método AHP (Analytic Hierarchy Process), a opinião de cada especialista responsável por gerar as previsões qualitativas. Esta dissertação, além de descrever detalhadamente o método proposto, ilustra a aplicação deste através de um estudo de caso realizado em uma empresa metal-mecânica. Tal estudo foi realizado para diferentes modelos de produtos, considerando um horizonte de previsão de doze meses. Ao final, o método AHP mostrou-se uma forma eficiente de ponderação da opinião dos especialistas. O resultado mostra que a previsão combinada proposta apresentou os menores erros entre as previsões analisadas, não só melhorando a acurácia total da previsão em mais de 23%, como também aumentando a acurácia para a maioria dos meses analisados e dos modelos testados. A partir da revisão bibliográfica e do método proposto, oportunidades para estudos futuros foram identificadas. / Demand forecasting that combines quantitative methods and judgmental adjustments is a technique widely used in the attempt to approximate forecast to actual demand. This thesis presents a literature review on combination of forecasts, and proposes a combined method using quantitative methods and expert opinion. A systematic literature review has been carried out analyzing works that were considered relevant to the topic under study, gathered from five databases. The review, which is comprised of 38 references, introduces theoretical concepts about combination of forecast, and exemplifies through practical applications how companies are using this technique. Based on this review it was possible to structure a combination model. The model presented not only combines mathematically the quantitative and qualitative forecast, but also assigns importance weights to experts using the comparison matrices of AHP (Analytic Hierarchy Process). We describe in details the model proposed and illustrate it through a practical application in a manufacturing industry. The case study considers several products in a 12-month forecast horizon. AHP has proven to be efficient for assigning weights to experts. Using the combination model proposed in this thesis we obtained improvements in the overall forecast accuracy of more than 23%; accuracy was also improved for the majority of periods and products analyzed. The literature review and proposed model led to the proposition of several opportunities for future research.

A realização de previsões de volatilidade é uma atividade de suma importância para empresas e agentes econômicos, entretanto utilizar-se de apenas um modelo para obtê-las pode não ser suficiente para incorporar todo o conhecimento associado ao ambiente de previsões. As técnicas de combinação de previsões podem incorporar todo o conhecimento associado ao ambiente de previsão. As técnicas de combinação têm como objetivo principal incorporar vários modelos com a finalidade de reduzir as medidas de erro de previsão. Este trabalho apresenta uma comparação da acurácia dos modelos individuais e das técnicas de combinação. Os modelos individuais incluídos nas técnicas de combinação são os modelos da família GARCH, o modelo de Alisamento Exponencial e o de Volatilidade Estocástica. Já as técnicas de combinação escolhidas foram a técnica de combinação por média aritmética, a técnica de combinação de pesos fixos proposta por Granger e Ramanathan (1984), a técnica de combinação com pesos móvel de Terui e Djik (2002). / The realization of forecasts of volatility is an activity of extreme importance for companies and economy agents, however to utilize only one model to obtain them could be insuficient to incorporate all the knowledge associated to the ambient of previsions. The technics of combination of forecasts have as its main objective to incorporate various models with the finality to reduce the measures of error of prediction. This work presents a comparision of the acuracy of the individual models and of the combination technics. The individual models included on the technics of combination are the models of the family GARCH, the model of Exponentially Weighted Moving Averages. Thus the technics of combination chosen were the technic of combination by arithmetic average, the technic of fixed weights proposed by Granger and Ramanathan (1984), the technic of combination of movable weights of Terui e Djik (2002).

La Terre est une planète en constante évolution et sa surface ne cesse de se transformer. Ses déformations soulèvent des questionnements. Depuis plusieurs années, le L2G de l’ESGT s’intéresse à l’étude des déformations par inter comparaison de techniques. Il dispose en cela de différents procédés de mesure. Puis au fil du temps, le laboratoire s’interroge sur l’intérêt de réaliser une combinaison entre différentes techniques de mesure afin d’observer des déformations fines et précises (quelques millimètres).L’objectif de cette thèse est de démontrer l’intérêt de combiner des mesures GNSS et des mesures topométriques, celles-ci semblant être les plus utilisées, et de les concrétiser. Les résultats présentés sont basés sur des simulations et sur des campagnes de mesures combinées des techniques de GNSS et de topométrie effectuée sur un réseau test d’une étendue locale. Les calculs évoluent en fonction de la distance de la ligne de base et en modifiant les durées de sessions de mesures. Nous montrons qu’une combinaison par cumul des équations normales améliore la précision du positionnement non seulement par rapport à l’utilisation de chaque technique séparée, mais également par rapport aux méthodes classiques basées sur la combinaison des coordonnées issues des techniques de GNSS et de topométrie. / The Earth is a constantly evolving planet and its surface keeps transforming. Its deformations raise questions. For several years, the L2G at ESGT has been interested in the study of deformations through inter comparison of techniques. For this, it has various measurement processes. Then, with time, the laboratory is now pondering about the interest of combining various techniques of measurement in order to observe fine and precise deformations (a few millimeters).The aim of this PhD thesis is to demonstrate the interest of combining GNSS and topometric measurements, the latter being apparently the most commonly used. The presented results are based on simulations and campaigns of combined measurement through the use of GNSS and topometric techniques made on a model network of a local area. Thecalculations made are dependent both on the distance of the baseline and the alteration of the session length.We show that a combination through the accumulation of the normal equations improves the localisation accuracy regarding not only the use of every separate technique but also the more classic methods based on the coordinates combination provided by GNSS and topometric techniques.

A.baumannii é um importante patógeno em infecções nosocomiais principalmente por sua capacidade de se tornar resistente aos antimicrobianos. Surtos de A.baumannii resistente aos carbapenêmicos (ABRC) têm sido descritos em todo mundo. Devido à emergência de resistência aos antimicrobianos e ausência de novas opções de tratamento, as polimixinas reemergiram como opção de terapia contra infecções causadas por A.baumannii. O uso de polimixina é associado a maior mortalidade e menor eficácia comparada a outros antimicrobianos. Alguns estudos in vitro têm avaliado a combinação de polimixina com outros antimicrobianos a fim de aumentar a eficácia dos tratamentos. O objetivo deste estudo foi avaliar o sinergismo entre a polimixina B com outros antimicrobianos em isolados de ABRC, pelo método de Curvas Tempo-Morte bacteriana (Time- Kill Curves). Os isolados foram provenientes de banco de amostras e foram avaliadas as combinações de polimixina B com carbapenêmicos (imipenem e meropenem), tigeciclina, rifampicina, amicacina e ceftazidima. As combinações foram testadas nos tempo 0, 30’, 1,4,12 e 24 h. Sinergismo entre polimixina B foi demonstrado contra todos antimicrobianos para ambos isolados, exceto para ceftazidima e imipenem no isolado 1. Nosso estudo mostrou que tigeciclina, amicacina e rifampicina são agentes mais ativos combinados com polimixina B, sendo assim estes agentes podem apresentar efeito benéfico em combinação com a polimixina no tratamento de ABRC. / A.baumannii is an important pathogen in nosocomial infections primarily for its ability to become resistant to antimicrobials. Outbreaks carbapenem- resistant A.baumannii (CRAB) has been described worldwide. Due to the emergence of antimicrobial resistance and the absence of new treatment options, the polymyxins reemerged as an option therapy against infections caused by A.baumannii. The use of polymyxin is associated with higher mortality and lower effectiveness compared to other antimicrobials. In vitro studies have evaluated the combination of polymyxin with other antimicrobial agents to enhance the effectiveness of the treatments. This study was to evaluate the synergy between polymyxin B with other antimicrobials in isolates from ABRC, by Time-Kill Curves. The isolates were from stool samples and were evaluated combinations of polymyxin B with carbapenems (imipenem and meropenem), tigecycline, rifampin, amikacin and ceftazidime. The combinations were tested at time 0, 30 ', 1,4,12 and 24 h. Synergism between polymyxin B was demonstrated against all antimicrobials for both isolates, except for ceftazidime and imipenem in isolated 2. Our study showed that tigecycline, amikacin and rifampicin more active agents are combined with polymyxin B, and thus these agents may have a beneficial effect in combination with a polymyxin in treating CRAB.

A previsão de demanda é uma das principais ferramentas para a eficiência do gerenciamento das organizações, afetando diretamente a lucratividade do negócio. O atual nível competitivo das empresas requer previsões cada vez mais acuradas, sedo estas um diferencial para o sucesso empresarial. Neste contexto, a combinação de previsões se tornou um dos principais métodos empregados no intuito de melhorar a precisão das previsões. Através de uma revisão da literatura sobre as abordagens da combinação de previsões, identificou-se uma carência de estudos comparativos que incorporem modelos de regressão para a combinação de previsões. Assim, o objetivo principal desta dissertação é combinar três previsões individuais (redes neurais, modelos ARIMA e modelos de alisamento exponencial) via média simples, variância mínima e modelos de regressão, comparando as três previsões combinadas com suas previsões individuais. Estas comparações serão avaliadas em duas situações: em séries simuladas (estacionárias) e em uma série de dados reais (não estacionária) de uma empresa que realiza auditorias médicas. As medidas empregadas para a escolha do método mais preciso são MAE, MAPE, RMSE e o coeficiente U de Theil. Os resultados obtidos enfatizam a melhoria das previsões quando estas são combinadas por regressão, tanto para séries convergentes quanto para a série divergente. / Forecasting is a key tool for ensuring the efficiency of management in organizations, directly affecting business profitability. The current competitive corporative level requires increasingly accurate predictions. In this context, the combination of forecasts has improved forecast accuracy. Through a literature review on the approaches of combining forecasts, we identified a lack of comparative studies that incorporate regression models for combining forecasts. Thus, the main objective of this dissertation is to combine three individual forecasts (neural networks, ARIMA models and exponential smoothing models) via simple average, minimum variance and regression models, comparing the three combined forecasts with their individual forecasts. These comparisons are evaluated in two situations: in simulated series (converging) and in series of real data (divergent) from a company that performs medical audits. The measures used to identify the best method are MAE, MAPE, RMSE and Theil’s U coefficient. Results from combined methods improved the predictions in both convergent and divergent series.

A obtenção de previsões com maior acuracidade é uma necessidade constantemente requerida, em tempos onde há imensa disponibilidade de dados e recursos computacionais cada dia mais eficientes. Tais critérios possibilitaram o desenvolvimento de muitas técnicas de previsão individual ou de métodos de combinação que são considerados eficientes no intuito de reduzir erros. O desenvolvimento de novas técnicas, por sua vez, promove questionamentos quanto à identificação de quantas ou quais técnicas de previsão individual combinar. A literatura não é unânime ao tentar responder a estes questionamentos e indica a importância da correlação entre os erros de previsão na precisão da combinação. Posto isso, esta tese apresenta uma alternativa aos métodos atuais de combinar previsões, contemplando a correlação entre os erros de previsão, além de propor uma forma de identificar técnicas de previsão que sejam distintas quanto à modelagem de características da série de dados. Para identificar grupos de técnicas de previsão individual que sejam similares, utilizou-se a Análise de Agrupamentos em erros gerados por 15 técnicas de previsão que modelaram uma mesma série de dados real com tendência e sazonalidade. O resultado indicou a formação de 3 agrupamentos. Como alternativa aos métodos atuais de combinar previsão e selecionar a quantidade adequada de técnicas, utilizou-se a Análise de Componentes Principais. O método proposto mostrou-se viável quando comparado com outros métodos de combinação e quando submetido à modelagem de séries com maior variabilidade. / The obtaining of more accurate forecasts is a necessity often required in times where there is a huge availability of data and computing resources becoming more efficient every day. These criteria allowed the development of many individual forecasting techniques or combination methods that are considered efficient in order to reduce errors. The development of new techniques, in turn, promotes questioning as the identification of how many or which techniques to combine individual forecasts. The literature is not unanimous when trying to answer these questions and indicates the importance of the correlation between forecast errors on the accuracy of the combination. That said, this presents an alternative to current methods of combining forecasts, considering the correlation between forecast errors, and propose a way to identify predictive techniques that are different about the modeling features of the data series. To identify groups of individual forecasting techniques that are similar, it was used the cluster analysis on errors generated by 15 forecasting techniques that shaped the same series of real data with trend and seasonality. The result indicated the formation of 3 clusters. As an alternative to current methods of combining forecasting and selecting the appropriate amount of techniques, it was used the Principal Component Analysis. The proposed method has proved feasible when compared to other methods of combining and when subjected to modeling of series with greater variability.