Medicamentos biológicos são obtidos a partir de fluidos biológicos ou tecidos de origem animal por procedimentos biotecnológicos e, a partir do vencimento das suas patentes, surge a possibilidade da produção de suas cópias, os chamados biossimilares. Este tema, além de polêmico, por ainda apresentar divergências de entendimento da classe científica, também engloba 4 das 5 classes terapêuticas de medicamentos mais vendidas, e apresenta evolução crescente no mercado farmacêutico. Com o aumento da demanda, cresce o interesse na produção de medicamentos biológicos de alta qualidade, com a mesma eficácia, porém a preços mais baixos. Dessa forma, é possível entender a responsabilidade das regulamentações, principalmente no que diz respeito aos biossimilares, a fim de que eles respeitem os requisitos mínimos necessários para serem comparáveis ao seu medicamento biológico novo. Assim, este trabalho teve como objetivo avaliar questões técnico-regulatórias e os requisitos de qualidade para registro de medicamentos biológicos e biossimilares humanos frente a diferentes Autoridades Sanitárias mundiais. A análise foi baseada em três moléculas biológicas, sendo a clássica heparina e moléculas novas, filgrastim e infliximabe. Foi constatado que na teoria, a legislação brasileira é baseada em regulamentos internacionais, especialmente da Federal and Drug Administration (FDA) e European Medicines Agency (EMA), e que na prática, o Brasil tem se mostrado mais conservador na extrapolação de indicação e na aprovação dos biossimilares. Ainda, foi possível notar que independente do país, as Farmacopeias ainda necessitam de aprimoramento com relação a este tema, pois em sua maioria, não existe padronização dos parâmetros e testes a serem realizados. Pesquisa demonstrou que o conhecimento sobre biossimilares ainda não está consolidado entre profissionais médicos e que, portanto, há necessidade de programas para esclarecimentos, com a finalidade de estimular seu uso, quando possível e com custos mais interessantes. / Biological drugs are obtained from biological fluids or animals tissues by biotechnological procedures and, from the expiration of their patents, the possibility of producing their \"copies\", the so-called biosimilars, arises. In addition to being a controversial subject, as it still presents divergences of understanding by the scientific class, it also encompasses 4 of the 5 therapeutic classes of best-selling drugs, and it presents an increasing evolution in the pharmaceutical market. As demand increases, interest in the production of high-quality biological drugs with the same effectiveness, but at lower prices, also increases. In this way, it is possible to understand the responsibility of regulations, especially with regard to biosimilars, so that they comply with the minimum requirements needed to be comparable to their reference biological medicine. Thus, the objective of this project was to evaluate technical and regulatory topics, as well as quality requirements for the registration of human biological and biosimilar medicines under the perspective of different Health Authorities around the world. The analysis was based on three biological molecules, being the classic heparin and new molecules, filgrastim and infliximab. It was found that in theory, Brazilian regulation is based on international regulations, especially the Federal and Drug Administration (FDA) and the European Medicines Agency (EMA), and that in practice, Brazil has been more conservative in the extrapolation of indication and approval of biosimilars. Also, it was possible to note that, regardless the country, Pharmacopoeias still need to be improved for this topic, since in general, there is no standardization of the parameters and tests to be performed. Research showed that the knowledge about biosimilars is not yet consolidated among doctors and that, therefore, there is a need for clarification programs, with the purpose of stimulating their use, when possible and at lower costs.

Submitted by Filipe dos Santos (fsantos@pucsp.br) on 2018-10-05T12:15:00Z No. of bitstreams: 1 Ruy Veridiano Patu Rebello-Pinho.pdf: 1247599 bytes, checksum: c44c5bdfc39b4b689b84b1dd0766568e (MD5) / Made available in DSpace on 2018-10-05T12:15:00Z (GMT). No. of bitstreams: 1 Ruy Veridiano Patu Rebello-Pinho.pdf: 1247599 bytes, checksum: c44c5bdfc39b4b689b84b1dd0766568e (MD5) Previous issue date: 2018-08-31 / The purpose of this dissertation is to emphasize the existence of the duty of legal independence of the registrar and the notary, who are responsible of a legal function constitutionally decentralized by the Charter of 1988 and disciplined by Law 8935/94, the Law of Notaries and Registrars. Independence is not a state of the person, but takes place contemporaneously in an argumentative intersubjective process of cooperative order. This mechanism of decentralization of powers and competences outside the structure of the State, gives an independent legal professional a bundle of legal responsibilities to be exercised through an administrative and technical organization, so that along legal independence, that all legal profession implies, goes the management and administration of its resources under private law. Every legal function must be accountable to the society and to be supervised; by law, the inspection and technical standardization of the services is attributed to the Judiciary. In order to concentrate the finite judicial powers in its nuclear activity, the Judiciary has an important role in ensuring the legal independence of the registrar and the notary as legal duties to society / O objetivo desta dissertação é sublinhar a existência do dever de independência jurídica do registrador e do notário, que exercem função jurídica descentralizada constitucionalmente pela Carta de 1988 e disciplinada pela Lei 8935/94, a Lei dos Notários e dos Registradores. Independência que não é um estado da pessoa, mas que ocorre, na contemporaneidade, em um processo intersubjetivo argumentativo de ordem cooperativa. Esse mecanismo de descentralização de poderes e competências para fora da estrutura do Estado, atribui a um profissional do Direito independente um feixe de responsabilidades jurídicas a serem exercidas por meio de uma organização administrativa e técnica, de modo que ao lado da independência jurídica, que toda profissão jurídica implica, se encontra a gestão e administração de seus recursos em regime de direito privado. Toda função jurídica deve prestar contas à sociedade e ser fiscalizada; por lei, a fiscalização e a uniformização técnica das serventias é de atribuição do Poder Judiciário. A fim de concentrar as energias judiciárias, que são finitas, em sua atividade nuclear, o Poder Judiciário tem importante atuação no sentido de garantir a independência jurídica do registrador e do notário como deveres jurídicos para com a sociedade

Este trabalho descreve uma técnica para alinhamento de imagens de documentos antigos. Para que seja possível alinhar duas imagens da mesma página de um documento uma técnica de registro de imagens é utilizada. As imagens mencionadas possuem diferenças de aquisição que incluem translação, rotação e distorções geométricas. A técnica de registro de imagens é dividida em três etapas. A primeira é a seleção de pontos de controle. Nessa etapa, as imagens das páginas são segmentadas em linhas de texto e, em seguida, cada linha de texto é segmentada em palavras. Dessa forma, cada ponto de controle corresponde ao início de uma palavra no texto. Na segunda etapa é realizada uma correspondência entre os pontos de controle extraídos das duas imagens. Essa etapa é necessária, uma vez que a seleção de pontos apresenta algumas falhas e os dois conjuntos de pontos de controle não são iguais. Por fim, na última etapa, a imagem destino é então mapeada utilizando funções Thin Plate Spline - TPS para que coincida com a imagem de referência. / This work describes a technique to anciente document images alignment. To be possible to align a couple of images of the same document pages, a image registration approach is used. These mentioned images have acquisition differences like translation, rotation and geometric distorsions. The image registration approach is divided in three stages. The first one is the control points selection. In this stage, images of the pages are segmented in text lines and then each one of them is segmented in words. Therefore, each selected control point corresponds to the begin of a text word. In the second stage, a matching is performed between extracted control points of both images. This stage is quite necessary because points selection presents some faults and both control points sets are not equals. Finally, in the last stage, target image is mapped using thin plate spline functions to coincide it with the reference image.

Image guided surgery (IGS), which has been developing fast recently, benefits significantly from the superior accuracy of robots and magnetic resonance imaging (MRI) which is a great soft tissue imaging modality. Teleoperation is especially desired in the MRI because of the highly constrained space inside the closed-bore MRI and the lack of haptic feedback with the fully autonomous robotic systems. It also very well maintains the human in the loop that significantly enhances safety. This dissertation describes the development of teleoperation approaches and implementation on an example system for MRI with details of different key components. The dissertation firstly describes the general teleoperation architecture with modular software and hardware components. The MRI-compatible robot controller, driving technology as well as the robot navigation and control software are introduced. As a crucial step to determine the robot location inside the MRI, two methods of registration and tracking are discussed. The first method utilizes the existing Z shaped fiducial frame design but with a newly developed multi-image registration method which has higher accuracy with a smaller fiducial frame. The second method is a new fiducial design with a cylindrical shaped frame which is especially suitable for registration and tracking for needles. Alongside, a single-image based algorithm is developed to not only reach higher accuracy but also run faster. In addition, performance enhanced fiducial frame is also studied by integrating self-resonant coils. A surgical master-slave teleoperation system for the application of percutaneous interventional procedures under continuous MRI guidance is presented. The slave robot is a piezoelectric-actuated needle insertion robot with fiber optic force sensor integrated. The master robot is a pneumatic-driven haptic device which not only controls the position of the slave robot, but also renders the force associated with needle placement interventions to the surgeon. Both of master and slave robots mechanical design, kinematics, force sensing and feedback technologies are discussed. Force and position tracking results of the master-slave robot are demonstrated to validate the tracking performance of the integrated system. MRI compatibility is evaluated extensively. Teleoperated needle steering is also demonstrated under live MR imaging. A control system of a clinical grade MRI-compatible parallel 4-DOF surgical manipulator for minimally invasive in-bore prostate percutaneous interventions through the patient’s perineum is discussed in the end. The proposed manipulator takes advantage of four sliders actuated by piezoelectric motors and incremental rotary encoders, which are compatible with the MRI environment. Two generations of optical limit switches are designed to provide better safety features for real clinical use. The performance of both generations of the limit switch is tested. MRI guided accuracy and MRI-compatibility of whole robotic system is also evaluated. Two clinical prostate biopsy cases have been conducted with this assistive robot.

Medical images have been used increasingly for diagnosis, treatment planning, monitoring disease processes, and other medical applications. A large variety of medical imaging modalities exists including CT, X-ray, MRI, Ultrasound, etc. Frequently a group of images need to be compared to one another and/or combined for research or cumulative purposes. In many medical studies, multiple images are acquired from subjects at different times or with different imaging modalities. Misalignment inevitably occurs, causing anatomical and/or functional feature shifts within the images. Computerized image registration (alignment) approaches can offer automatic and accurate image alignments without extensive user involvement and provide tools for visualizing combined images. This dissertation focuses on providing automatic image registration strategies. After a through review of existing image registration techniques, we identified two registration strategies that enhance the current field: (1) an automated rigid body and affine registration using voxel similarity measurements based on a sequential hybrid genetic algorithm, and (2) an automated deformable registration approach based upon a linear elastic finite element formulation. Both methods streamlined the registration process. They are completely automatic and require no user intervention. The proposed registration strategies were evaluated with numerous 2D and 3D MR images with a variety of tissue structures, orientations and dimensions. Multiple registration pathways were provided with guidelines for their applications. The sequential genetic algorithm mimics the pathway of an expert manually doing registration. Experiments demonstrated that the sequential genetic algorithm registration provides high alignment accuracy and is reliable for brain tissues. It avoids local minima/maxima traps of conventional optimization techniques, and does not require any preprocessing such as threshold, smoothing, segmentation, or definition of base points or edges. The elastic model was shown to be highly effective to accurately align areas of interest that are automatically extracted from the images, such as brains. Using a finite element method to get the displacement of each element node by applying a boundary mapping, this method provides an accurate image registration with excellent boundary alignment of each pair of slices and consequently align the entire volume automatically. This dissertation presented numerous volume alignments. Surface geometries were created directly from the aligned segmented images using the Multiple Material Marching Cubes algorithm. Using the proposed registration strategies, multiple subjects were aligned to a standard MRI reference, which is aligned to a segmented reference atlas. Consequently, multiple subjects are aligned to the segmented atlas and a full fMRI analysis is possible.

"This thesis presents a single-slice based fast stereotactic registration and tracking technique along with a corresponding modular system for guiding robotic mechanism or interventional instrument to perform needle-based interventions under live MRI guidance. The system can provide tracking of full 6 degree-of-freedom (DOF) in stereotactic interventional surgery based upon a single, rapidly acquired cross-sectional image. The whole system is constructed with a modular data transmission software framework and mechanical structure so that it supports remote supervision and manipulation between a 3D Matlab tracking user interface (UI) and an existing MRI robot controller by using the OpenIGTLink network communication protocol. It provides better closed-loop control by implementing a feedback output interface to the MRI-guided robot. A new compact fiducial frame design is presented, and the fiducial is wrapped with a passive resonant coil. The coil resonates at the Larmor frequency for 3T MRI to enhance signal strength and enable for rapid imaging. The fiducial can be attached near the distal end of the robot and coaxially with a needle so as to visualize target tissue and track the surgical tool synchronously. The MRI-compatible design of fiducial frame, robust tracking algorithm and modular interface allow this tracking system to be conveniently used on different robots or devices and in different size of MRI bores. Several iterations of the tracking fiducial and passive resonant coils were constructed and evaluated in a Phillips Achieva 3T MRI. To assess accuracy and robustness of the tracking algorithm, 25 groups of images with different poses were successively scanned along specific sequence in and MRI experiment. The translational RMS error along depth is 0.271mm with standard deviation of 0.277mm for totally 100 samples. The overall angular RMS error is less than 0.426 degree with standard deviation of 0.526 degree for totally 150 samples. The passive resonant coils were shown to significantly increase signal intensity in the fiducial relative to the surroundings and provide for rapid imaging with low flip angles. "

Airborne multi-sensor imaging is increasingly used to examine vegetation properties. The advantage of using multiple types of sensor is that each detects a different feature of the vegetation, so that collectively they provide a detailed understanding of the ecological pattern. Specifically, Light Detection And Ranging (LiDAR) devices produce detailed point clouds of where laser pulses have been backscattered from surfaces, giving information on vegetation structure; hyperspectral sensors measure reflectances within narrow wavebands, providing spectrally detailed information about the optical properties of targets; while aerial photographs provide high spatial-resolution imagery so that they can provide more feature details which cannot be identified from hyperspectral or LiDAR intensity images. Using a combination of these sensors, effective techniques can be developed for mapping species and inferring leaf physiological processes at ITC-level. Although multi-sensor approaches have revolutionised ecological research, their application in mapping individual tree crowns is limited by two major technical issues: (a) Multi-sensor imaging requires all images taken from different sensors to be co-aligned, but different sensor characteristics result in scale, rotation or translation mismatches between the images, making correction a pre-requisite of individual tree crown mapping; (b) reconstructing individual tree crowns from unstructured raw data space requires an accurate tree delineation algorithm. This thesis develops a schematic way to resolve these technical issues using the-state-of-the-art computer vision algorithms. A variational method, called NGF-Curv, was developed to co-align hyperspectral imagery, LiDAR and aerial photographs. NGF-Curv algorithm can deal with very complex topographic and lens distortions efficiently, thus improving the accuracy of co-alignment compared to established image registration methods for airborne data. A graph cut method, named MCNCP-RNC was developed to reconstruct individual tree crowns from fully integrated multi-sensor imagery. MCNCP-RNC is not influenced by interpolation artefacts because it detects trees in 3D, and it detects individual tree crowns using both hyperspectral imagery and LiDAR. Based on these algorithms, we developed a new workflow to detect species at pixel and ITC levels in a temperate deciduous forest in the UK. In addition, we modified the workflow to monitor physiological responses of two oak species with respect to environmental gradients in a Mediterranean woodland in Spain. The results show that our scheme can detect individual tree crowns, find species and monitor physiological responses of canopy leaves.

O setor público brasileiro tem grande influência na economia, considerando o volume de tributos que arrecada e também pelo volume de bens públicos que administra, os quais, em matéria contábil, em parte, representam ativos patrimoniais. Este trabalho teve como objetivo propor um modelo de identificação e de classificação de Ativos para as entidades do setor público, harmonizando os conceitos constitucionais, legais e normativos, especialmente com as Normas Brasileiras de Contabilidade Aplicáveis ao Setor Público. Procurou-se evidenciar a possível convergência de conceitos de Ativos para entidades do setor público, as definições de bens da União e dos Estados, assim definidos no artigo 20 e 31 da Constituição Federal de 1988, bem como a convergência de conceitos de Ativos de entidades setor privado para com os de bens públicos. Para tanto, realizou-se uma revisão bibliográfica quanto à conceituação de bens, de bens públicos, de ativos e do patrimônio público, previstas nos diversos regramentos constitucionais e legais do país e na literatura. O trabalho resultou na identificação das diversas classes de ativos públicos, na estruturação de um modelo de identificação e classificação dos bens, com exemplos de utilização, visando a facilitar e qualificar os procedimentos de registro e o relevo dos bens públicos. O que, o caso, poderá ser útil para o entendimento dos eventos contábeis relacionados à identificação e sua classificação. / The Brazilian public sector has great influence on the economy, considering the amount of taxes it collects, and also by the volume of public goods that manages, which in accounting matters partly represent corporate assets. This study aimed to propose a model for the identification and classification of assets for the public sector entities, harmonizing the constitutional, legal and regulatory concepts, especially with the Brazilian Accounting Standards applicable to the Public Sector. It was essayed to evidence the possible convergence of Assets concepts for public sector entities to the (União) Federal Government and States assets definitions, as delineated in the Article 20 and 31 of the 1988’s Federal Constitution and the convergence of assets concepts of entities from private sector towards public goods. For that a literature review was conducted on the concept of goods, public goods, assets and public property, under the various constitutional and legal specific regulations of the country and in the literature. The work resulted in the identification of several classes of public assets and in the structuring of a model for identification and classification of goods, with examples of use, in order to facilitate and qualify registration procedures and disclosure of public goods, which could be useful for the understanding of accounting events related to their identification and classification.

L’objectif principal d’une Arthroplastie Totale de Hanche (ATH) est de réduire la douleur en reproduisant les propriétés mécaniques de l’articulation de la hanche à l'aide d'implants artificiels, qui assurent également une fonctionnalité optimale. Ce travail traite de la navigation de l’ATH, à base d’échographie, en mettant l'accent sur la navigation de l'implant fémoral. La conception d'un système de navigation pour l’ATH, basé sur l’échographie peropératoire et CT préopératoire et focalisant sur l’implant fémoral, est proposée. Il fournit un feed back visuel et quantitatif sur l'insertion de l'implant. Le pipeline de navigation proposé inclut : la calibration de la sonde, la segmentation tenant compte de la géométrie d’acquisition, et le recalage profitant de la forme quasi symétrique du fémur. La précision est évaluée en termes cliniques.Les temps d'exécution et la précision obtenus sont encourageants et rendent le pipeline proposé valable pour être évalué en utilisant des données réelles des patients. Une fois notre étude réussie le défi peropératoire, d’autres applications telles que l'arthroplastie totale de l'épaule et l'ablation du cancer osseux peuvent en profiter. / The principal aim of a Total Hip Arthroplasty (THA) is to reduce pain by reproducing the hip joint mechanical properties using artificial implants. This work addresses the ultrasound based navigation of THA, with a focus on the femoral implant. Using a calibrated 3D ultrasound probe, the aim is to image and recognize the femur after implant insertion, then to provide quantitative and visual navigation instructions for optimal implant placement. US bone interfaces are estimated per line of sight, then mapped to CT model profiting from the femur symmetry. The inaccuracy of the proposed navigation system is quantified in clinical terms. The obtained runtimes and accuracies make the proposed pipeline worthy to be tested in the OR. Once the proposed pipeline succeeds the intraoperative challenge, navigated bone tumor ablation and total shoulder arthroplasty can profit from our work.

Three independent studies drawing on the cases from different spaces and times comprise this research project, but they share a common theme: how do expansive reforms that open up paths to political participation take place? The first paper takes up the case of the motor voter reform, which allows people to register to vote at driver's license offices. The reform was widely legislated by U.S. states before the passage of the National Voter Registration Act in 1993. The paper investigates the factors that helped promote the reform at the state level by breaking down the reforms along two dimensions: the voter registration location and the implementation method. Motor voter legislation could either stand alone or be accompanied by agency-based registration (ABR), which includes registration at social service public agencies that primarily serve the poor. A reform could be implemented in an active or passive way. While ABR and active implementation had the potential to mobilize previously alienated socioeconomic groups, motor voter reform itself and passive implementation were expected to have a partisan-neutral and limited impact, respectively. Using data collected from the archived materials of the leading advocacy organization of the reform, Human SERVE, I test the following three general hypotheses statistically: 1) the Democratic Party is interested in mobilizing the poor, 2) electoral competition enhances mobilization efforts by parties, and 3) liberal political culture promotes inclusive electoral institutions. All three hypotheses find some support in the empirical analysis. The second paper focuses on a candidate selection method reform in contemporary Japan. Throughout the first decade of the twenty first century, the (then) opposition Democratic Party of Japan (DPJ) used kôbo, an open-recruitment candidate selection method, which was purported to open up the party nomination to non-traditional outsider aspirants. The DPJ's action presented a puzzle: searching for low-electability amateur candidates instead of traditional quality candidates seemed paradoxical for a party preparing to take over power. The paper reveals that using kôbo was a transitional strategy for a young party building itself under the mixed-member majoritarian system. I argue that recruiting "fresh faces" was not what really motivated the use of kôbo, by showing how kôbo increasingly produced insider candidates over time. The third paper investigates the development of direct primary in nineteenth century Pennsylvania. The historical origins of the U.S. primaries have mostly been discussed in terms of statewide legislations around the Progressive Era, which made the primaries mandatory for the two major parties. This paper focuses instead on the voluntary adoption phase that took place under the party by-laws, paying special attention to the case of Pennsylvania after 1842. I argue that the party elites of county organizations initiated the introduction of the primaries in order to prevent defection and to preserve party unity. As the vote share of a party increased, the party nomination became more valuable, and more people competed for nomination. More disgruntled nomination losers would run as independents, hurting the electoral prospects of a given party in the general election. For party leaders, whose overwhelming concern was the maintenance of party unity, the direct primary system offered a solution by presenting the primary winner as a focal candidate to the party voters. The primaries made it harder for losers to defect later, with the transparent features of their procedures. Thus, the stronger the party, the more likely it was to adopt the direct primary. The paper tests this hypothesis empirically with an original data set built from hundreds of archived local newspapers. To my knowledge, this is the first study on nineteenth century county-level party activities to use comprehensive data covering most counties from a single state. The findings have broader implications as to how party competition affects the choice of candidate selection methods, and the role which competition among elites plays in the democratization of the intraparty decision-making mechanism.