Modified 3+3 design for phase I clinical trials

Phase I clinical trial is mainly designed to determine the maximum tolerated dose (MTD) of a new drug. Optimization of phase I trial design is crucial to minimize the number of enrolled patients exposed to unsafe dose levels and to provide reliable information to the later phases of clinical trials. Although it has been criticized about its inefficient MTD estimation, nowadays the traditional 3+3 method remains dominant in practice due to its simplicity and conservative estimation. There are many new designs that have been proven to generate more credible MTD estimation, such as the Continual Reassessment Method (CRM). Despite its accepted better performance, the CRM design is still not widely used in real trials. There are several factors that contribute to the difficulties of CRM adaption in practice. First, CRM is not widely accepted by the regulatory agencies such as FDA in terms of safety. It is considered to be less conservative and tend to expose more patients above the MTD level than the traditional design. Second, CRM is relatively complex and not intuitive for the clinicians to fully understand. Third, the CRM method take much more time and need statistical experts and computer programs throughout the trial. The current situation is that the clinicians still tend to follow the trial process that they are comfortable with. This situation is not likely to change in the near future. Based on this situation, we have the motivation to improve the accuracy of MTD selection while follow the procedure of the traditional design to maintain simplicity. We found that in 3+3 method, the dose transition and the MTD determination are relatively independent. Thus we proposed to separate the two stages. The dose transition rule remained the same as 3+3 method. After getting the toxicity information from the dose transition stage, we combined the isotonic transformation to ensure the monotonic increasing order before selecting the optimal MTD. To compare the operating characteristics of the proposed isotonic method and the other designs, we carried out 10,000 simulation trials under different dose setting scenarios to compare the design characteristics of the isotonic modified method with standard 3+3 method, CRM, biased coin design (BC) and k-in-a-row design (KIAW). The isotonic modified method improved MTD estimation of the standard 3+3 in 39 out of 40 scenarios. The improvement is much greater when the target is 0.3 other than 0.25. The modified design is also competitive when comparing with other selected methods. A CRM method performed better in general but was not as stable as the isotonic method throughout the different dose settings. The results demonstrated that our proposed isotonic modified method is not only easily conducted using the same procedure as 3+3 but also outperforms the conventional 3+3 design. It can also be applied to determine MTD for any given TTL. These features make the isotonic modified method of practical value in phase I clinical trials.^

Notas sobre la experiencia

Muchas lecturas, textos, debates, programas de investigación en teoría de la comunicación, cultura y arte incluyen un tópico recurrente que pasa desapercibido ante las distintas interpretaciones. Éste comenzó a inquietarnos lo suficiente como para prestar mayor atención a los planteos que de él teníamos. Por esta razón decidimos ensayar en estas líneas algunas ideas recuperadas en ciertas lecturas sobre la experiencia. ¿Por qué ocuparnos de la experiencia? Desde hace un tiempo cierto discurso contemporáneo (a veces caracterizado como posmoderno) repite/repetimos que la experiencia, el sentir en el presente, cambió en una dirección totalmente nueva. No pocos debates se concentran en describir este nuevo escenario, intentando responder la pregunta disparada por la línea anterior: ¿qué direcciones tomó la experiencia contemporánea? Y por supuesto el interrogante es acompañado por otra duda con una mirada más escéptica: la experiencia contemporánea ¿es más rica o profunda que en el pasado?

Simulation Model of Benthic Antarctic Assemblages (SIMBAA), link to PC-executable

SIMBAA is a spatially explicit, individual-based simulation model. It was developed to analyse the response of populations of Antarctic benthic species and their diversity to iceberg scouring. This disturbance is causing a high local mortality providing potential space for new colonisation. Traits can be attributed to model species, e.g. in terms of reproduction, dispersal, and life span. Physical disturbances can be designed in space and time, e.g. in terms of size, shape, and frequency. Environmental heterogeneity can be considered by cell-specific capacities to host a certain number of individuals. When grid cells become empty (after a disturbance event or due to natural mortality of of an individual), a lottery decides which individual from which species stored in a pool of candidates (for this cell) will recruit in that cell. After a defined period the individuals become mature and their offspring are dispersed and stored in the pool of candidates. The biological parameters and disturbance regimes decide on how long an individual lives. Temporal development of single populations of species as well as Shannon diversity are depicted in the main window graphically and primary values are listed. Examples for simulations can be loaded and saved as sgf-files. The results are also shown in an additional window in a dimensionless area with 50 x 50 cells, which contain single individuals depicted as circles; their colour indicates the assignment to the self-designed model species and the size represents their age. Dominant species per cell and disturbed areas can also be depicted. Output of simulation runs can be saved as images, which can be assembled to video-clips by standard computer programs (see GIF-examples of which "Demo 1" represents the response of the Antarctic benthos to iceberg scouring and "Demo 2" represents a simulation of a deep-sea benthic habitat).

Problemas de interacción suelo estructura en cimentaciones y muros de contención. Influencia de los fenómenos de despegue y deslizamiento

Los terremotos constituyen una de las más importantes fuentes productoras de cargas dinámicas que actúan sobre las estructuras y sus cimentaciones. Cuando se produce un terremoto la energía liberada genera movimientos del terreno en forma de ondas sísmicas que pueden provocar asientos en las cimentaciones de los edificios, empujes sobre los muros de contención, vuelco de las estructuras y el suelo puede licuar perdiendo su capacidad de soporte. Los efectos de los terremotos en estructuras constituyen unos de los aspectos que involucran por su condición de interacción sueloestructura, disciplinas diversas como el Análisis Estructural, la Mecánica de Suelo y la Ingeniería Sísmica. Uno de los aspectos que han sido poco estudiados en el cálculo de estructuras sometidas a la acciones de los terremotos son los efectos del comportamiento no lineal del suelo y de los movimientos que pueden producirse bajo la acción de cargas sísmicas, tales como posibles despegues y deslizamientos. En esta Tesis se estudian primero los empujes sísmicos y posibles deslizamientos de muros de contención y se comparan las predicciones de distintos tipos de cálculos: métodos pseudo-estáticos como el de Mononobe-Okabe (1929) con la contribución de Whitman-Liao (1985), y formulaciones analíticas como la desarrollada por Veletsos y Younan (1994). En segundo lugar se estudia el efecto del comportamiento no lineal del terreno en las rigideces de una losa de cimentación superficial y circular, como la correspondiente a la chimenea de una Central Térmica o al edificio del reactor de una Central Nuclear, considerando su variación con frecuencia y con el nivel de cargas. Finalmente se estudian los posibles deslizamientos y separación de las losas de estas dos estructuras bajo la acción de terremotos, siguiendo la formulación propuesta por Wolf (1988). Para estos estudios se han desarrollado una serie de programas específicos (MUROSIS, VELETSOS, INTESES y SEPARSE) cuyos listados y detalles se incluyen en los Apéndices. En el capítulo 6 se incluyen las conclusiones resultantes de estos estudios y recomendaciones para futuras investigaciones. ABSTRACT Earthquakes constitute one of the most important sources of dynamic loads that acting on structures and foundations. When an earthquake occurs the liberated energy generates seismic waves that can give rise to structural vibrations, settlements of the foundations of buildings, pressures on retaining walls, and possible sliding, uplifting or even overturning of structures. The soil can also liquefy losing its capacity of support The study of the effects of earthquakes on structures involve the use of diverse disciplines such as Structural Analysis, Soil Mechanics and Earthquake Engineering. Some aspects that have been the subject of limited research in relation to the behavior of structures subjected to earthquakes are the effects of nonlinear soil behavior and geometric nonlinearities such as sliding and uplifting of foundations. This Thesis starts with the study of the seismic pressures and potential displacements of retaining walls comparing the predictions of two types of formulations and assessing their range of applicability and limitations: pseudo-static methods as proposed by Mononobe-Okabe (1929), with the contribution of Whitman-Liao (1985), and analytical formulations as the one developed by Veletsos and Younan (1994) for rigid walls. The Thesis deals next with the effects of nonlinear soil behavior on the dynamic stiffness of circular mat foundations like the chimney of a Thermal Power Station or the reactor building of a Nuclear Power Plant, as a function of frequency and level of forces. Finally the seismic response of these two structures accounting for the potential sliding and uplifting of the foundation under a given earthquake are studied, following an approach suggested by Wolf (1988). In order to carry out these studies a number of special purposes computer programs were developed (MUROSIS, VELETSOS, INTESES and SEPARSE). The listing and details of these programs are included in the appendices. The conclusions derived from these studies and recommendations for future work are presented in Chapter 6.

Dimensionamiento de una instalación eléctrica de un edificio de oficinas y almacén de productos farmacéuticos

En el presente proyecto se realiza el diseño y cálculo de la instalación eléctrica y el cálculo de luminarias, de un edificio de oficinas y almacén de productos farmacéuticos. Este diseño se precisa para el correcto desarrollo de la actividad de la nave industrial objeto de la instalación. Mediante la utilización de programas informáticos se pretende diseñar una guía para agilizar los procesos de dimensionamiento y cálculo para este tipo de proyectos. Al contar estos programas con una normativa totalmente actualizada, también agilizan el proceso de adecuación a la norma. En el cálculo de luminarias se consigue un cálculo muy aproximado de la potencia requerida, además de asegurar las condiciones lumínicas necesarias. También se tiene un cálculo muy exacto del circuito eléctrico que es fácil modificar a futuras ampliaciones. ABSTRACT The project´s aim is to make the design and calculations of the electrical and lighting installations, for a pharmaceutical warehouse. This design is necessary to ensure proper operational activity of the industrial warehouse, subject to the installation. By means of computer programs, it is intended to design a guide in order to speed up the processes of calculations and sizing of the electric wiring for this type of project. These programs are also fully updated, and therefore, the processes of adaptation to the legislation and regulations are made easier. In the calculation of the lighting, the software achieves a close approximation of the required power as well as ensuring the necessary light conditions. With this software we also achieve a very accurate calculation of the electrical circuit that is easy to modify to future expansions.

Estudio de la aplicabilidad de las aproximaciones uniformes al análisis de series históricas : aplicación al caso de los precios del cobre

El objetivo de este proyecto de investigación es comparar dos técnicas matemáticas de aproximación polinómica, las aproximaciones según el criterio de mínimos cuadrados y las aproximaciones uniformes (“minimax”). Se describen tanto el mercado actual del cobre, con sus fluctuaciones a lo largo del tiempo, como los distintos modelos matemáticos y programas informáticos disponibles. Como herramienta informática se ha seleccionado Matlab®, cuya biblioteca matemática es muy amplia y de uso muy extendido y cuyo lenguaje de programación es suficientemente potente para desarrollar los programas que se necesiten. Se han obtenido diferentes polinomios de aproximación sobre una muestra (serie histórica) que recoge la variación del precio del cobre en los últimos años. Se ha analizado la serie histórica completa y dos tramos significativos de ella. Los resultados obtenidos incluyen valores de interés para otros proyectos. Abstract The aim of this research project is to compare two mathematical models for estimating polynomial approximation, the approximations according to the criterion of least squares approximations uniform (“Minimax”). Describes both the copper current market, fluctuating over time as different computer programs and mathematical models available. As a modeling tool is selected main Matlab® which math library is the largest and most widely used programming language and which is powerful enough to allow you to develop programs that are needed. We have obtained different approximating polynomials, applying mathematical methods chosen, a sample (historical series) which indicates the fluctuation in copper prices in last years. We analyzed the complete historical series and two significant sections of it. The results include values that we consider relevant to other projects

Técnicas de diseño de pruebas en sistemas embebidos

El software es, cada vez más, una parte muy importante de cualquier circuito electrónico moderno, por ejemplo, un circuito realizado con algún tipo de microprocesador debe incorporar un programa de control por pequeño que sea. Al utilizarse programas informáticos en los circuitos electrónicos modernos, es muy aconsejable, por no decir imprescindible, realizar una serie de pruebas de calidad del diseño realizado. Estas pruebas son cada vez más complicadas de realizar debido al gran tamaño del software empleado en los sistemas actuales, por este motivo, es necesario estructurar una serie de pruebas con el fin de realizar un sistema de calidad, y en algunos casos, un sistema que no presente ningún peligro para el ser humano o el medio ambiente. Esta propuesta consta de la explicación de las técnicas de diseño de pruebas que existen actualmente (por lo menos las más básicas ya que es un tema muy extenso) para realizar el control de calidad del software que puede contener un sistema embebido. Además, muchos circuitos electrónicos, debido a su control o exigencia hardware, es imprescindible que sean manipulados por algún programa que requiera más que un simple microprocesador, me refiero a que se deban controlar por medio de un pequeño programa manipulado por un sistema operativo, ya sea Linux, AIX, Unix, Windows, etc., en este caso el control de calidad se debería llevar a cabo con otras técnicas de diseño. También se puede dar el caso que el circuito electrónico a controlar se deba hacer por medio de una página web. El objetivo es realizar un estudio de las actuales técnicas de diseño de pruebas que están orientadas al desarrollo de sistemas embebidos. ABSTRACT. Software is increasingly a very important part of any modern electronic circuit, for example, a circuit made with some type of microprocessor must incorporate a control program no matter the small it is. When computer programs are used in modern electronic circuits, it is quite advisable if not indispensable to perform a series of quality tests of the design. These tests are becoming more and more difficult to be performed due to the large size of the software used in current systems, which is why it is necessary to structure a series of tests in order to perform a quality system, and in some cases, a system with no danger to humans or to the environment. This proposal consists of an explanation of the techniques used in the tests (at least the most basic ones since it is a very large topic) for quality control of software which may contain an embedded system. In addition, a lot of electronic circuits, due to its control or required hardware, it is essential to be manipulated by a program that requires more than a simple microprocessor, I mean that they must be controlled by means of a small program handled by an operating system, being Linux, AIX, Unix, Windows, etc., in this case the quality control should be carried out with other design techniques. The objective is to study the current test design techniques that are geared to the development of embedded systems. It can also occur that the electronic circuit should be controlled by means of a web page.

Análisis del comportamiento de uniones metálicas viga-soporte mediante modelo de elementos finitos y comparación de resultados con el modelo de nudos y barras

Para el proyecto y cálculo de estructuras metálicas, fundamentalmente pórticos y celosías de cubierta, la herramienta más comúnmente utilizada son los programas informáticos de nudos y barras. En estos programas se define la geometría y sección de las barras, cuyas características mecánicas son perfectamente conocidas, y sobre las cuales obtenemos unos resultados de cálculo concretos en cuanto a estados tensionales y de deformación. Sin embargo el otro componente del modelo, los nudos, presenta mucha mayor complejidad a la hora de establecer sus propiedades mecánicas, fundamentalmente su rigidez al giro, así como de obtener unos resultados de estados tensionales y de deformación en los mismos. Esta “ignorancia” sobre el comportamiento real de los nudos, se salva generalmente asimilando a los nudos del modelo la condición de rígidos o articulados. Si bien los programas de cálculo ofrecen la posibilidad de introducir nudos con una rigidez intermedia (nudos semirrígidos), la rigidez de cada nudo dependerá de la geometría real de la unión, lo cual, dada la gran variedad de geometrías de uniones que en cualquier proyecto se nos presentan, hace prácticamente inviable introducir los coeficientes correspondientes a cada nudo en los modelos de nudos y barras. Tanto el Eurocódigo como el CTE, establecen que cada unión tendrá asociada una curva momento-rotación característica, que deberá ser determinada por los proyectistas mediante herramientas de cálculo o procedimientos experimentales. No obstante, este es un planteamiento difícil de llevar a cabo para cada proyecto. La consecuencia de esto es, que en la práctica, se realizan extensas comprobaciones y justificaciones de cálculo para las barras de las estructuras, dejando en manos de la práctica común la solución y puesta en obra de las uniones, quedando sin justificar ni comprobar la seguridad y el comportamiento real de estas. Otro aspecto que conlleva la falta de caracterización de las uniones, es que desconocemos como afecta el comportamiento real de éstas en los estados tensionales y de deformación de las barras que acometen a ellas, dudas que con frecuencia nos asaltan, no sólo en la fase de proyecto, sino también a la hora de resolver los problemas de ejecución que inevitablemente se nos presentan en el desarrollo de las obras. El cálculo mediante el método de los elementos finitos, es una herramienta que nos permite introducir la geometría real de perfiles y uniones, y nos permite por tanto abordar el comportamiento real de las uniones, y que está condicionado por su geometría. Por ejemplo, un caso típico es el de la unión de una viga a una placa o a un soporte soldando sólo el alma. Es habitual asimilar esta unión a una articulación. Sin embargo, el modelo por elementos finitos nos ofrece su comportamiento real, que es intermedio entre articulado y empotrado, ya que se transmite un momento y el giro es menor que el del apoyo simple. No obstante, la aplicación del modelo de elementos finitos, introduciendo la geometría de todos los elementos estructurales de un entramado metálico, tampoco resulta en general viable desde un punto de vista práctico, dado que requiere invertir mucho tiempo en comparación con el aumento de precisión que obtenemos respecto a los programas de nudos y barras, mucho más rápidos en la fase de modelización de la estructura. En esta tesis se ha abordado, mediante la modelización por elementos finitos, la resolución de una serie de casos tipo representativos de las uniones más comúnmente ejecutadas en obras de edificación, como son las uniones viga-pilar, estableciendo el comportamiento de estas uniones en función de las variables que comúnmente se presentan, y que son: •Ejecución de uniones viga-pilar soldando solo por el alma (unión por el alma), o bien soldando la viga al pilar por todo su perímetro (unión total). •Disposición o no de rigidizadores en los pilares •Uso de pilares de sección 2UPN en cajón o de tipo HEB, que son los tipos de soporte utilizados en casi el 100% de los casos en edificación. Para establecer la influencia de estas variables en el comportamiento de las uniones, y su repercusión en las vigas, se ha realizado un análisis comparativo entre las variables de resultado de los casos estudiados:•Estados tensionales en vigas y uniones. •Momentos en extremo de vigas •Giros totales y relativos en nudos. •Flechas. Otro de los aspectos que nos permite analizar la casuística planteada, es la valoración, desde un punto de vista de costos de ejecución, de la realización de uniones por todo el perímetro frente a las uniones por el alma, o de la disposición o no de rigidizadores en las uniones por todo el perímetro. Los resultados a este respecto, son estrictamente desde un punto de vista económico, sin perjuicio de que la seguridad o las preferencias de los proyectistas aconsejen una solución determinada. Finalmente, un tercer aspecto que nos ha permitido abordar el estudio planteado, es la comparación de resultados que se obtienen por el método de los elementos finitos, más próximos a la realidad, ya que se tiene en cuenta los giros relativos en las uniones, frente a los resultados obtenidos con programas de nudos y barras. De esta forma, podemos seguir usando el modelo de nudos y barras, más versátil y rápido, pero conociendo cuáles son sus limitaciones, y en qué aspectos y en qué medida, debemos ponderar sus resultados. En el último apartado de la tesis se apuntan una serie de temas sobre los que sería interesante profundizar en posteriores estudios, mediante modelos de elementos finitos, con el objeto de conocer mejor el comportamiento de las uniones estructurales metálicas, en aspectos que no se pueden abordar con los programas de nudos y barras. For the project and calculation of steel structures, mainly building frames and cover lattices, the tool more commonly used are the node and bars model computer programs. In these programs we define the geometry and section of the bars, whose mechanical characteristics are perfectly known, and from which we obtain the all calculation results of stresses and displacements. Nevertheless, the other component of the model, the nodes, are much more difficulty for establishing their mechanical properties, mainly the rotation fixity coefficients, as well as the stresses and displacements. This "ignorance" about the real performance of the nodes, is commonly saved by assimilating to them the condition of fixed or articulated. Though the calculation programs offer the possibility to introducing nodes with an intermediate fixity (half-fixed nodes), the fixity of every node will depend on the real connection’s geometry, which, given the great variety of connections geometries that in a project exist, makes practically unviable to introduce the coefficients corresponding to every node in the models of nodes and bars. Both Eurocode and the CTE, establish that every connection will have a typical moment-rotation associated curve, which will have to be determined for the designers by calculation tools or experimental procedures. Nevertheless, this one is an exposition difficult to carry out for each project. The consequence of this, is that in the practice, in projects are extensive checking and calculation reports about the bars of the structures, trusting in hands of the common practice the solution and execution of the connections, resulting without justification and verification their safety and their real behaviour. Another aspect that carries the lack of the connections characterization, is that we don´t know how affects the connections real behaviour in the stresses and displacements of the bars that attack them, doubts that often assault us, not only in the project phase, but also at the moment of solving the execution problems that inevitably happen in the development of the construction works. The calculation by finite element model is a tool that allows us to introduce the real profiles and connections geometry, and allows us to know about the real behaviour of the connections, which is determined by their geometry. Typical example is a beam-plate or beam-support connection welding only by the web. It is usual to assimilate this connection to an articulation or simple support. Nevertheless, the finite element model determines its real performance, which is between articulated and fixed, since a moment is transmitted and the relative rotation is less than the articulation’s rotation. Nevertheless, the application of the finite element model, introducing the geometry of all the structural elements of a metallic structure, does not also turn out to be viable from a practical point of view, provided that it needs to invest a lot of time in comparison with the precision increase that we obtain opposite the node and bars programs, which are much more faster in the structure modelling phase. In this thesis it has been approached, by finite element modelling, the resolution of a representative type cases of the connections commonly used in works of building, since are the beam-support connections, establishing the performance of these connections depending on the variables that commonly are present, which are: •Execution of beam-support connections welding only the web, or welding the beam to the support for the whole perimeter. •Disposition of stiffeners in the supports •Use 2UPN in box section or HEB section, which are the support types used in almost 100% building cases. To establish the influence of these variables in the connections performance, and the repercussion in the beams, a comparative analyse has been made with the resulting variables of the studied cases: •Stresses states in beams and connections. •Bending moments in beam ends. •Total and relative rotations in nodes. •Deflections in beams. Another aspect that the study allows us to analyze, is the valuation, from a costs point of view, of the execution of connections for the whole perimeter opposite to the web connections, or the execution of stiffeners. The results of this analyse, are strictly from an economic point of view, without prejudice that the safety or the preferences of the designers advise a certain solution. Finally, the third aspect that the study has allowed us to approach, is the comparison of the results that are obtained by the finite element model, nearer to the real behaviour, since the relative rotations in the connections are known, opposite to the results obtained with nodes and bars programs. So that, we can use the nodes and bars models, more versatile and quick, but knowing which are its limitations, and in which aspects and measures, we must weight the results. In the last part of the tesis, are relationated some of the topics on which it would be interesting to approach in later studies, with finite elements models, in order to know better the behaviour of the structural steel connections, in aspects that cannot be approached by the nodes and bars programs.

Uso de un sistema para la gestión del aprendizaje (LMS) de código libre en la Universidad Tecnológica del Suroeste de Guanajuato (UTSOE)

The use of the Information and Communication Technologies (ICT) in Learning Environment allows achieving the maximum interaction between Teachers and Students.The Virtual Learning Environments are computer programs that benefit the learning facilitating the communication between users. Open Source software allow to create the own online modular learning environment with a fast placed in service. In the present paper the use of a Learning Management Systems (LMS) as continuous education tool is proposed.

Improving Crop Models: Incorporating New Processes, New Approaches, and Better Calibrations

Early ancestors of crop simulation models (De Wit, 1965; Monteith, 1965; Duncan et al., 1967) were born before primitive personal computers were available (e.g. Apple II released in 1977, IBM PC released in 1981). Paleo-computer programs were run in mainframes with the support of punch cards. As computers became more available and powerful, crop models evolved into sophisticated tools summarizing our understanding of how crops operate. This evolution was triggered by the need to answer new scientific questions and improve the accuracy of model simulations, especially under limiting conditions.

Characteristic enrichment of DNA repeats in different genomes

Using computer programs developed for this purpose, we searched for various repeated sequences including inverted, direct tandem, and homopurine–homopyrimidine mirror repeats in various prokaryotes, eukaryotes, and an archaebacterium. Comparison of observed frequencies with expectations revealed that in bacterial genomes and organelles the frequency of different repeats is either random or enriched for inverted and/or direct tandem repeats. By contrast, in all eukaryotic genomes studied, we observed an overrepresentation of all repeats, especially homopurine–homopyrimidine mirror repeats. Analysis of the genomic distribution of all abundant repeats showed that they are virtually excluded from coding sequences. Unexpectedly, the frequencies of abundant repeats normalized for their expectations were almost perfect exponential functions of their size, and for a given repeat this function was indistinguishable between different genomes.

A high-resolution annotated physical map of the human chromosome 13q12-13 region containing the breast cancer susceptibility locus BRCA2.

Various types of physical mapping data were assembled by developing a set of computer programs (Integrated Mapping Package) to derive a detailed, annotated map of a 4-Mb region of human chromosome 13 that includes the BRCA2 locus. The final assembly consists of a yeast artificial chromosome (YAC) contig with 42 members spanning the 13q12-13 region and aligned contigs of 399 cosmids established by cross-hybridization between the cosmids, which were selected from a chromosome 13-specific cosmid library using inter-Alu PCR probes from the YACs. The end sequences of 60 cosmids spaced nearly evenly across the map were used to generate sequence-tagged sites (STSs), which were mapped to the YACs by PCR. A contig framework was generated by STS content mapping, and the map was assembled on this scaffold. Additional annotation was provided by 72 expressed sequences and 10 genetic markers that were positioned on the map by hybridization to cosmids.

Determination of absorption curves, dissolution profiles and establishment of in vitro-in vivo correlation by in silico methods using GastroPlusTM and DDDPlusTM

The use of computer programs to predict drug absorption in humans and to simulate dissolution profiles has become a valuable tool in the pharmaceutical area. The objective of this study was to use in silico methods through software GastroPlusTM and DDDPlusTM to simulate drug absorption curves and dissolution profiles, and to establish in vitro-in vivo correlations (IVIVCs). The work presented herein is divided into five chapters and includes the drugs ketoprofen, pyrimethamine, metronidazole, fluconazole, carvedilol and doxazosin. In Chapter 1, simulated plasma curves for ketoprofen matrix tablets are presented and IVIVC was established. The use of simulated intrinsic dissolution tests for pyrimethamine and metronidazole as a tool for biopharmaceutics classification is detailed in Chapter 2. In Chapter 3, simulation of plasma curves for fluconazole capsules with different dissolution profiles is demonstrated as a tool for biowaiver. IVIVC studies were also conducted for carvedilol immediate-release tablets from dissolution profiles in Chapter 4. Chapter 5 covers the application of simulated dissolution tests for development of doxazosin extended-release formulations. Simulation of plasma curves and IVIVC using the software GastroPlusTM as well as intrinsic dissolution tests and dissolution profiles using the software DDDPlusTM proved to be a tool of wide application in predicting biopharmaceutical characteristics of drugs and formulations, allowing the reduction of time and costs of experimental laboratory work.

PCRELAP5 - Programa de cálculo para os dados de entrada do código RELAP5

Após os acidentes nucleares ocorridos no mundo, critérios e requisitos extremamente rígidos para a operação das instalações nucleares foram determinados pelos órgãos internacionais que regulam essas instalações. A partir da ocorrência destes eventos, as operadoras de plantas nucleares necessitam simular alguns acidentes e transientes, por meio de programas computacionais específicos, para obter a licença de operação de uma planta nuclear. Com base neste cenário, algumas ferramentas computacionais sofisticadas têm sido utilizadas como o Reactor Excursion and Leak Analysis Program (RELAP5), que é o código mais utilizado para a análise de acidentes e transientes termo-hidráulicos em reatores nucleares no Brasil e no mundo. Uma das maiores dificuldades na simulação usando o código RELAP5 é a quantidade de informações geométricas da planta necessárias para a análise de acidentes e transientes termo-hidráulicos. Para a preparação de seus dados de entrada é necessário um grande número de operações matemáticas para calcular a geometria dos componentes. Assim, a fim de realizar estes cálculos e preparar dados de entrada para o RELAP5, um pré-processador matemático amigável foi desenvolvido, neste trabalho. O Visual Basic for Applications (VBA), combinado com o Microsoft Excel, foi utilizado e demonstrou ser um instrumento eficiente para executar uma série de tarefas no desenvolvimento desse pré-processador. A fim de atender as necessidades dos usuários do RELAP5, foi desenvolvido o Programa de Cálculo do RELAP5 PCRELAP5 onde foram codificados todos os componentes que constituem o código, neste caso, todos os cartões de entrada inclusive os opcionais de cada um deles foram programados. Adicionalmente, uma versão em inglês foi criada para PCRELAP5. Também um design amigável do PCRELAP5 foi desenvolvido com a finalidade de minimizar o tempo de preparação dos dados de entrada e diminuir os erros cometidos pelos usuários do código RELAP5. Nesse trabalho, a versão final desse pré-processador foi aplicada com sucesso para o Sistema de Injeção de Emergência (SIE) da usina Angra 2.

High-speed polynomial basis multipliers over GF(2(m)) for special pentanomial.

Efficient hardware implementations of arithmetic operations in the Galois field are highly desirable for several applications, such as coding theory, computer algebra and cryptography. Among these operations, multiplication is of special interest because it is considered the most important building block. Therefore, high-speed algorithms and hardware architectures for computing multiplication are highly required. In this paper, bit-parallel polynomial basis multipliers over the binary field GF(2(m)) generated using type II irreducible pentanomials are considered. The multiplier here presented has the lowest time complexity known to date for similar multipliers based on this type of irreducible pentanomials.