Les moteurs de fusées à ergols solides (SRMs) sont sensibles aux instabilités hydrodynamiques qui peuvent déclencher des oscillations auto-entretenues de pression de grandes amplitudes lorsqu’elles se couplent à l’un des modes acoustiques du système. Le moteur de ces instabilités est la formation de structures tourbillonnaires cohérentes synchronisées par des ondes acoustiques longitudinales. Pour certaines conditions de fonctionnement, les ondes acoustiques générées par l’interaction de ces tourbillons avec la tuyère amorcée du moteur renforcent l’oscillation acoustique. L’objectif des travaux menés dans cette thèse est de déterminer l’amplitude et la fréquence des oscillations de pression au cycle limite des instabilités. Celui-ci est atteint par saturation non linéaire des sources, qui est la conséquence de la formation de grosses structures cohérentes. Dans ce cas l’interaction tourbillon tuyère devient insensible à l’amplitude de l’onde du mode acoustique établi dans le foyer. Dans ces conditions, on peut se concentrer sur l’interaction d’un tourbillon avec la tuyère dans le mécanisme de production sonore. En considérant un écoulement incompressible et l’absence de frottement, un premier modèle analytique est développé permettant de déterminer la production sonore d’un tourbillon ingéré par une tuyère bidimensionnelle plane, lorsque le tourbillon est traité comme une ligne vorticité. Des expériences précédentes indiquent que le volume de la cavité autour de l’entrée d’une tuyère intégrée a une grande influence sur l’amplitude des oscillations de pression dans les grands SRMs. On montre que ceci est dû au champ de vitesse acoustique induit par la compressibilité du gaz dans la cavité qui produit une fluctuation de vitesse transverse à la trajectoire du tourbillon. Une seconde alternative au modèle analytique incompressible est développée en considérant toujours l’absence de frottement, mais un modèle compressible de l’interaction tourbillon-tuyère. Celui-ci repose sur un code aéroacoustique pour les écoulements internes basé sur les équations d’Euler (EIA) qui est utilisé ici pour la simulation de l’interaction tourbillon-tuyère. Une étude systématique de cette interaction a été menée pour une tuyère amorcée. Les résultats ont permis de proposer un modèle de sources localisées pour des ondes planes basé sur une analyse théorique des lois d’échelles de ces phénomènes. Les simulations de ces interactions tourbillons-tuyères ont été réalisées pour différents types de tuyères. En employant un bilan énergétique, un modèle avec un seul paramètre de contrôle est formulé, qui permet de reproduire qualitativement le comportement du cycle limite d’oscillations de pression observées dans des expériences réalisées avec des gaz froids décrites dans la littérature. Finalement le modèle Euler est utilisé pour comparer la production de son par interaction tourbillon-tuyère avec celle due à l’ingestion d’une onde d’entropie, appelée aussi tache d’entropie. Contrairement au cas des tourbillons, le bruit produit par ingestion de taches d’entropie n’est pas sensible au volume de la cavité d’une tuyère intégrée. Ces résultats indiquent que le bruit produit par les tourbillons est dominant dans le cas des SRMs étudiés. L’ensemble de ces travaux permet d’améliorer la compréhension des phénomènes d’interaction entre des non-homogénéités de l’écoulement et la tuyère. Elle permet surtout de déterminer quels sont les facteurs de l’écoulement et les éléments géométriques importants qui pilotent le niveau sonore produit par ces interactions. Les modèles développés dans ces travaux, avec divers degrés d’approximation et de complexité permettent d’enrichir la gamme des outils de conception des SRMs. / Solid Rocket Motors (SRMs) can display self-sustained acoustic oscillations driven by coupling between hydrodynamic instabilities of the internal flow and longitudinal acoustic standing waves. The hydrodynamic instabilities are triggered by the acoustic standing wave and results in the formation of coherent vortical structures. For nominal ranges of flow conditions the sound waves generated by the interaction between these vortices and the choked nozzle at the end of the combustion chamber reinforces the acoustic oscillation. Most available literature on this subject focuses on the threshold of instability using a linear model. The focus of this work is on the prediction of the limit-cycle amplitude. The limit-cycle is reached due to nonlinear saturation of the source, as a consequence of the formation of large coherent vortical structures. In this case the vortex-nozzle interaction becomes insensitive to the amplitude of the acoustic standing wave. Hence, one can focus on the sound generation of a vortex with the nozzle. Sound production can be predicted from an analytical two-dimensional planar incompressible frictionless model using the so-called Vortex Sound Theory. In this model the vorticity is assumed to be concentrated in a line vortex. Experiments indicate that the volume of cavities around so-called “integrated nozzles” have a large influence on the pulsation amplitude for large SRMs. This is due to the acoustical field normal to the vortex trajectory, induced by the compressibility of the gas in this cavity. As an alternative to the incompressible analytical model a compressible frictionless model with an internal Euler Aeroacoustic (EIA) flow solver is used for simulations of vortex-nozzle interaction. A dedicated numerical simulation study focusing on elementary processes such as vortex-nozzle and entropy spot-nozzle interaction allows a systematic variation of relevant parameters and yields insight which would be difficult by means of limit cycle studies of the full engine. A systematic study of the vortex-nozzle interaction in the case of a choked nozzle has been undertaken. The results are summarized by using a lumped element model for plane wave propagation, which is based on theoretical scaling laws. From EIA simulations it appears that sound due to vortex-nozzle interaction is mainly generated during the approach phase and that for the relevant parameter range there is no impingement of the vortex on the nozzle wall as has been suggested in the literature. Using an energy balance approach, a single fit-parameter model is formulated which qualitatively predicts limit-cycle observations in cold gas-scale experiments reported in the literature. Finally the Euler model is used to compare the sound production by vortex-nozzle interaction with that due to the ingestion of an entropy non-uniformity also called entropy spot. In addition to insight, this study provides a systematic procedure to develop a lumped element model for the sound source due to non-homogeneous flow-nozzle interactions in SRMs. Such lumped models based on experimental data or a limited number of flow simulations can be used to ease the design of SRMs.

In Winter semester of 2005 the English Language Center (ELC) began plans to implement a content-based program for students at its highest proficiency level in order to provide them with more effective preparation for academic studies in English. Since that time, the program has undergone various changes to provide a more stable, cohesive, and responsive curriculum. There is a need, however, for greater teacher support and training. This paper outlines the process I underwent to create a handbook that would provide needed guidance and training for teachers in this program. This project involved an in-depth needs analysis of teachers and students in the program. Results from this analysis led to the selection of three basic principles that were used in the design and development of this project: (1) practicality, (2) instructiveness, and (3) sustainability. The resulting project is a binder organized into four tabs: (1) Program Overview, (2) The Basics of Content-based Instruction at the ELC, (3) Challenges and Strategies in CBI, and (4) Additional Resources. This resource was developed using Microsoft Word 2007 and includes a variety of graphics, text boxes and layouts to provide a professional and user-friendly product. An evaluation of the project based on the responses of three teachers who used the handbook during Winter semester 2009 revealed that it was a useful and needed resource for teaching content-based classes at the ELC. Further piloting is needed to verify these findings. It is recommended that in the future this resource be maintained by the ELC Coordinator assigned to oversee the content courses. As the ELC continues to refine the content curriculum, evaluation and revisions of this handbook should be carried out at regular intervals to ensure its continued relevance and accuracy over time.

Les matériaux à bande interdite électromagnétique (BIE) plus connus sous le nom de cristaux photoniques en optique, sont des structures périodiques possédant des propriétés intéressantes que l'on ne retrouve pas dans les matériaux conventionnels. Ces propriétés dépendent des paramètres géométriques de la structure, et des paramètres constitutifs de ses éléments ( E et μ). Ainsi, ils peuvent présenter un indice de réfraction négatif, posséder des bandes interdites ou encore être fortement anisotropes. Pour les dispositifs hyperfréquences, l'exploitation de ces propriétés s'avère très pertinente. Or, ces structures sont en général passives, et l'une des considérations actuelles vise à les rendre reconfigurables, afin d'étendre encore leur champ d'applications. L'originalité de ce travail consiste à utiliser les plasmas comme élément contrôlable. En effet, leurs paramètres physiques (E , diamètre etc.) varient en fonction des conditions de décharge. Pour l'étude de ce principe de reconfigurabilité, un dispositif de diviseur de puissance commutable à base d'un BIE a été défini. Différents plasmas de grand volume à des pressions allant de 40 à 760 torrs ont été étudiés puis intégrés dans le dispositif. Des mesures microondes ont alors mis en évidence le contrôle de la propagation de l'onde par le plasma. Cette thèse, à l'intersection de deux disciplines, plasma et microondes, a permis de valider le concept d'utilisation de plasmas localisés pour rendre reconfigurable certaines propriétés des structures BIE. Suite à cette validation, d'autres travaux sont d'ores et déjà entamés, afin d'améliorer les performances et d'explorer d'autres idées liant notamment métamatériaux et plasmas.

In the first part of this dissertation, the phenomenon of self-sustained pressure os-cillations due to the flow past a circular, axisymmetric cavity, associated with inline gate valves, was investigated. In many engineering applications, such as flows through open gate valves, there exists potential for coupling between the vortex shedding from the up-stream edge of the cavity and a diametral mode of the acoustic pressure fluctuations. The effects of the internal pipe geometry immediately upstream and downstream of the shal-low cavity on the characteristics of partially trapped diametral acoustic modes were in-vestigated numerically and experimentally on a scaled model of a gate valve mounted in a pipeline that contained convergence-divergence sections in the vicinity of the valve. The resonant response of the system corresponded to the second acoustic diametral mode of the cavity. Excitation of the dominant acoustic mode was accompanied by pressure oscillations, and, in addition to that, as the angle of the converging-diverging section of the main pipeline in the vicinity of the cavity increased, the trapped behavior of the acoustic diametral modes diminished, and additional antinodes of the acoustic pressure wave were observed in the main pipeline. In addition to that, the effect of shallow chamfers, introduced at the upstream and/or downstream cavity edges, was investigated in the experimental system that con-tained a deep, circular, axisymmetric cavity. Through the measurements of unsteady pressure and associated acoustic mode shapes, which were calculated numerically for several representative cases of the internal cavity geometry, it was possible to identify the configuration that corresponded to the most efficient noise suppression. This arrangement also allowed calculation of the azimuthal orientation of the acoustic modes, which were classified as stationary, partially spinning or spinning. Introduction of shallow chamfers at the upstream and the downstream edges of the cavity resulted in changes of azimuthal orientation and spinning behaviour of the acoustic modes. In addition, introduction of splitter plates in the cavity led to pronounced change in the spatial orientation and the spinning behaviour of the acoustic modes. The short splitter plates changed the behaviour of the dominant acoustic modes from partially spinning to stationary, while the long split-ter plates enforced the stationary behaviour across all resonant acoustic modes. Finally, the evolution of fully turbulent, acoustically coupled shear layers that form across deep, axisymmetric cavities and the effects of geometric modifications of the cavity edges on the separated flow structure were investigated using digital particle image velocimetry (PIV). Instantaneous, time- and phase-averaged patterns of vorticity pro-vided insight into the flow physics during flow tone generation and noise suppression by the geometric modifications. In particular, the first mode of the shear layer oscillations was significantly affected by shallow chamfers located at the upstream and, to a lesser degree, the downstream edges of the cavity. In the second part of the dissertation, the performance of aortic heart valve pros-thesis was assessed in geometries of the aortic root associated with certain types of valve diseases, such as aortic valve stenosis and aortic valve insufficiency. The control case that corresponds to the aortic root of a patient without valve disease was used as a reference. By varying the aortic root geometry, it was possible to investigate corresponding changes in the levels of Reynolds shear stress and establish the possibility of platelet activation and, as a result of that, the formation of blood clots. / Graduate / 0541 / 0546 / 0548 / 0986 / alexbn024@gmail.com

In the first part of this dissertation, the phenomenon of self-sustained pressure os-cillations due to the flow past a circular, axisymmetric cavity, associated with inline gate valves, was investigated. In many engineering applications, such as flows through open gate valves, there exists potential for coupling between the vortex shedding from the up-stream edge of the cavity and a diametral mode of the acoustic pressure fluctuations. The effects of the internal pipe geometry immediately upstream and downstream of the shal-low cavity on the characteristics of partially trapped diametral acoustic modes were in-vestigated numerically and experimentally on a scaled model of a gate valve mounted in a pipeline that contained convergence-divergence sections in the vicinity of the valve. The resonant response of the system corresponded to the second acoustic diametral mode of the cavity. Excitation of the dominant acoustic mode was accompanied by pressure oscillations, and, in addition to that, as the angle of the converging-diverging section of the main pipeline in the vicinity of the cavity increased, the trapped behavior of the acoustic diametral modes diminished, and additional antinodes of the acoustic pressure wave were observed in the main pipeline. In addition to that, the effect of shallow chamfers, introduced at the upstream and/or downstream cavity edges, was investigated in the experimental system that con-tained a deep, circular, axisymmetric cavity. Through the measurements of unsteady pressure and associated acoustic mode shapes, which were calculated numerically for several representative cases of the internal cavity geometry, it was possible to identify the configuration that corresponded to the most efficient noise suppression. This arrangement also allowed calculation of the azimuthal orientation of the acoustic modes, which were classified as stationary, partially spinning or spinning. Introduction of shallow chamfers at the upstream and the downstream edges of the cavity resulted in changes of azimuthal orientation and spinning behaviour of the acoustic modes. In addition, introduction of splitter plates in the cavity led to pronounced change in the spatial orientation and the spinning behaviour of the acoustic modes. The short splitter plates changed the behaviour of the dominant acoustic modes from partially spinning to stationary, while the long split-ter plates enforced the stationary behaviour across all resonant acoustic modes. Finally, the evolution of fully turbulent, acoustically coupled shear layers that form across deep, axisymmetric cavities and the effects of geometric modifications of the cavity edges on the separated flow structure were investigated using digital particle image velocimetry (PIV). Instantaneous, time- and phase-averaged patterns of vorticity pro-vided insight into the flow physics during flow tone generation and noise suppression by the geometric modifications. In particular, the first mode of the shear layer oscillations was significantly affected by shallow chamfers located at the upstream and, to a lesser degree, the downstream edges of the cavity. In the second part of the dissertation, the performance of aortic heart valve pros-thesis was assessed in geometries of the aortic root associated with certain types of valve diseases, such as aortic valve stenosis and aortic valve insufficiency. The control case that corresponds to the aortic root of a patient without valve disease was used as a reference. By varying the aortic root geometry, it was possible to investigate corresponding changes in the levels of Reynolds shear stress and establish the possibility of platelet activation and, as a result of that, the formation of blood clots. / Graduate / 0541 / 0546 / 0548 / 0986 / alexbn024@gmail.com

Le traitement du virus de l'hépatite C (VHC) a connu une révolution récente, rapide et exemplaire grâce à l'arrivée des agents antiviraux directs (AAD) en plusieurs vagues depuis 2011, détrônant ainsi la bithérapie interféron-pégylé/ribavirine. Ces nouveaux traitements ont été rapidement confrontés à des limites concernant leur efficacité et leur tolérance notamment à leurs débuts avec les inhibiteurs de la protéase NS3/4A de première génération. L'arrivée de nouveaux AAD sur le marché lors d'une 2ème vague en 2014 a permis toutefois de surpasser celles-ci et de devenir le traitement de référence du VHC.Leur efficacité remarquable a laissé naître l'idée d'une potentielle élimination du VHC grâce à l'utilisation universelle de ces traitements. Cependant, leur coût élevé et les comportements à risque observés dans des sous-groupes de population (utilisateurs de drogues intraveineuses et homosexuels) restent encore des problématiques cruciales à surmonter pour espérer atteindre les objectifs fixés par l'Organisation Mondiale de la Santé en 2030 concernant l'élimination du VHC. De plus ces traitements, permettant l'élimination virale quasi-systématique et donc consécutivement une diminution du risque de complications hépatiques, ont été récemment confrontés à une polémique concernant un potentiel risque de récidive précoce de carcinome hépatocellulaire (CHC) suite à une exposition à ces derniers.Le travail présenté dans cette thèse s'articule autour de trois problématiques ayant toutes pour objectif principal d'optimiser l'utilisation de ces traitements dans l'optique de contrôler l'histoire naturelle de la maladie à l'échelle individuelle et à l'échelle populationnelle par l'intermédiaire de diverses méthodes statistiques.Nos résultats ont permis de montrer au sein d’une première problématique ayant exploré l'efficacité et la tolérance de ces traitements antiviraux à l’échelle individuelle: (i) une efficacité antivirale moindre que celle annoncée dans les essais de phase III des inhibiteurs de protéase de première génération(télaprévir et bocéprévir), (ii) un effet indésirable significatif des inhibiteurs de protéase de première génération sur la fonction rénale, (iii) une tolérance moins bonne de ces premières molécules que lors du traitement par bithérapie avec une incidence accrue d'anémie probablement liée à un surdosage en ribavirine induit par les inhibiteurs de protéase et (iv) une efficacité antivirale remarquable des AAD arrivés depuis 2014 sans impact des caractéristiques du patient ni des dosages pharmacologiques sur la réponse virologique. Dans un second temps, la problématique d'un risque de récidive de CHC accru après un traitement par AAD a également été explorée par l'analyse d'une cohorte locale, celle-ci ayant conclu à l'absence de risque accru comparé à un groupe de patients non exposés. Enfin, nos travaux basés sur la modélisation de la transmission du VHC en France dans la population coinfectée VIH-VHCont montré qu'un taux annuel de traitement par AAD de 50% était nécessaire dans la population homosexuelle ayant des pratiques à haut-risque de transmission pour contrer l'épidémie actuellement observée.Nos travaux ont donc permis d'apporter des données pour optimiser l'utilisation des nouveaux traitements anti-VHC par l'intermédiaire de diverses approches statistiques et ont apporté des éléments de réponse aux grandes problématiques actuelles. L'efficacité exemplaire et la tolérance quasi-parfaite des dernières molécules antivirales permettent une utilisation universelle de ces traitements dans toutes les populations de patients. Des études complémentaires robustes sont cependant nécessaires pour apporter des arguments à la question de la récidive du CHC. Des efforts sont également attendus concernant l'accès au traitement, la diminution des coûts associés et un dépistage renforcé du VHC pour espérer pouvoir éradiquer un jour cette maladie. / The arrival of direct-acting antivirals agents (DAAs) has spurred a rapid revolution in the treatment of hepatitis C virus (HCV), supplanting the previous standard of care, i.e. pegylated interferon and ribavirin. These new treatments are associated with an increased rate of virological response however they rapidly faced some limits more particularly at the beginning with the first generation NS3/4A protease inhibitors. From 2014 on the second wave of DAA was available for treatment of chronic HCV infection and surpassed previous encountered limits. These treatments are nowadays the gold standard for HCV treatment in high-income countries.The idea of HCV eradication recently emerged since DAA treatment are highly effective. However, their associated high cost and recent high-risk behaviors associated with an increased risk of HCV transmission (among intravenous drug users and homosexuals) have been reported. These issues need therefore to be addressed in order to achieve the objectives of the World Health Organization for 2030 of an HCV eradication. Moreover, these treatments allow a sustained virological response in almost all patients and consequently reduce the risk of liver-related complications, but a recent controversy regarding a potential increased risk of hepatocellular carcinoma after DAA treatment has been raised.Three issues will be extensively discussed in this manuscript regarding how these treatments can be used to optimize their effect on HCV natural history at the individual and population level through different statistical approaches.As regards the first issue, this project allowed us to demonstrate regarding the tolerance and efficacy of DAA treatment: (i) a lower antiviral efficacy than previously reported in the phase III trials for first generationprotease inhibitor regimen (telaprevir and boceprevir), (ii) impairment of renal function during first generation protease inhibitor treatment, (iii) an increased rate of reported side effects during first-generation protease inhibitor treatment and more particularly anemia, potentially related to an increased ribavirin biodisponibility induced by protease inhibitor intake and (iv) a remarkable antiviral efficacy of second generation DAAs without impact of patients' characteristics norpharmacology on virological response rate. The recent issue regarding a higher risk of HCC recurrence after DAA treatment was also explored through a local cohort study and no impact of DAA treatment was observed when comparing DAA-exposed vs non DAA-exposed patients. Finally, we conducted amodelling study on HCV transmission in the coinfected HIV-HCV French population and our results suggested that an annual DAA treatment coverage rate of 50% was required in the homosexual population with high-risk behaviors to counter the recent observed epidemic in this population.Our different works provide new insights on how to optimize the use of DAA treatment through several statistical approaches and bring new elements for discussion on the recent controversy. The new DAA have an excellent efficacy and tolerance profile and should be universally used in all populations without restriction. However, further studies are required to explore on a deeper level the question regarding HCC recurrence after DAA treatment. Efforts are also still needed regarding DAA treatment access, associated costs and HCV screening to reach the objective of HCV eradication

The purpose of this study was to construct a career meta-competency model for sustained employability in the contemporary world of work. This study explored a convenience sample (N = 304) of early career employees’ personality preferences (measured by the Myers-Briggs Type Indicator), self-esteem (measured by the Culture-free Self-esteem Inventories for Adults) and emotional intelligence (measured by the Assessing Emotions Scale), as a composite set of their personality attributes, in relation to their employability attributes (measured by the Employability Attributes Scale). The participants comprised 81% blacks and 64% females employed in the business management field in managerial/supervisory (53%) and staff (28%) level positions. Their ages ranged between 25 and 40 years (early adulthood and establishment phase) (79%). The correlations, canonical correlations and multiple regression results indicated that the participants’ personality attributes were significantly and positively related to their employability attributes. Structural Equation Modelling indicated a moderate fit between the theoretically hypothesised career meta-competency model and the empirically tested structural model. The results indicated job level as a significant moderator of the relationship between the participants’ personality and employability attributes. Middle management level was associated with an inverse relationship between the personality and employability attributes. Staff and middle managers did not significantly differ regarding their mean scores on these variables. On a theoretical level, the study deepened understanding of the cognitive, affective, conative and interpersonal behavioural dimensions of the hypothesised career meta-competency model. On an empirical level, the study produced an empirically tested career meta-competency model in terms of the various behavioural dimensions. On a practical level, career v counselling and development interventions for guiding employees’ sustained employability in terms of the career meta-competency behavioural dimensions were recommended. / Industrial and Organisational Psychology / D. Com. (Industrial and Organisational Psychology)

INTRODUÇÃO: A combinação de sepse e insuficiência renal com necessidade de diálise é bastante comum nas Unidades de Terapia Intensiva e esta situação tem elevada mortalidade. Um desafio neste cenário é prescrever a dose correta dos antimicrobianos para o tratamento destas infecções. Em pacientes críticos e hemodinamicamente instáveis que necessitam de terapia renal substitutiva, um dos métodos mais utilizados é a diálise contínua, entretanto, recentemente, tem-se utilizado a diálise de baixa eficiência - conhecida como SLED, da abreviação do inglês \"sustained low-efficiency dialysis\". Esta modalidade de terapia renal substitutiva combina características da hemodiálise contínua com a intermitente, utilizando o equipamento da diálise intermitente, com menores fluxos sanguíneos e de dialisato, e com vantagem de menor custo. Apesar do fluxo mais baixo, por ser utilizado tempo mais prolongado, a SLED frequentemente resulta em maior clearance e especula-se que a remoção dos fármacos seria maior. Há escassez de estudos que avaliaram a farmacocinética e farmacodinâmica de antimicrobianos em pacientes submetidos à SLED.OBJETIVOS: Avaliar adequação farmacodinâmica de meropenem e vancomicina em pacientes submetidos a diálise estendida de baixa eficiência. Avaliar a depuração paramêtros farmacocinéticos durante a sessão de SLED. MÉTODOS: Foi realizado estudo prospectivo descritivo observacional com coleta de material biológico julho de 2012 a julho de 2014 HC-FMUSP. Foram incluídos pacientes submetidos à SLED em uso de vancomicina e/ou meropenem. Foram coletadas amostras de sangue seriadas (tempos: imediatamente antes do início da sessão de diálise, 0,5h, 1h, 2h, 4h após o início do tratamento e ao final da sessão). A quantificação dos antimicrobianos foi realizada através dos métodos analíticos de quantificação em Cromatografia Líquida de Alta Eficiência (CLAE). Os parâmetros farmacocinéticos foram calculados apenas durante a sessão de diálise utilizando-se o software WinNonlin. A área sob a curva foi determinada para a vancomicina. Para o meropenem, calculou-se o tempo acima da MIC. Resultados: Foram incluídos 24 pacientes tratados com vancomicina e 21 com meropenem eforam obtidas 170 amostras de plasma. As concentrações médias de vancomicina sérica e meropenem: antes da sessão de SLED foram 24,5 e 28,0 ?g / ml, respectivamente; e após SLED 14 e 6 ?g / ml, respectivamente. A depuração média foi de 41% para a vancomicina e 78% para o meropenem. Para vancomicina, 22 (96%), 19 (83%) e 16 (70%) pacientes teriam atingido o alvo (AUC0-24 > 400) considerando-se MIC 0,5; <= 1mg/l e <= 2 mg/l respectivamente. Para meropenem, 19 (95%), 18 (90%) e 11 (55%) pacientes teriam atingido a meta (70% de tempo acima da CIM) se infectados com isolados com MIC <= 1, <= 4 e <= 8 mg/l, respectivamente. Conclusões: Em pacientes críticos, meropenem evancomicina foram removidas durante o SLED. Entretando, a maioria dos pacientes alcançaria alvo PK-PD, excepto para CIMs mais altas. Sugerimos doses de manutenção de 1g a cada 12 ou 8 horaspara meropenem. Para a vancomicina, deve-se utilizar abordagem mais individualizada com monitorização sérica, uma vez que ensaios comerciais são disponíveis / Background: Antibiotic dosing is a challenge in critically ill patients undergoing renal replacement therapy. Our aim was to evaluate pharmacokinetics and pharmacodynamics of meropenem and vancomycin in patients undergoing SLED.Methods: ICU patients undergoing SLED, receiving meropenem and/or vancomycin, were prospectively evaluated. Blood samples were collected at the start of SLED and 0.5; 1; 2; 4 and 6 hours later. Antimicrobial levels were determined by HPLC. Noncompartimental pharmacokinetic analysis was performed. Area under the curve was determined for vancomycin. For meropenem, time above MIC was calculated. Results: 24 patients receiving vancomycin and 21 receiving meropenem were included; 170 plasma samples were obtained. Median serum vancomycin and meropenem concentrations: before SLED were 24.5 and 28.0 ?g/ml, respectively; and after SLED 14 and 6 ?g/ml, respectively. Mean removal was 41% for vancomycin and 78% for meropenem. For vancomycin, 22 (96%), 19(83%) and 16(70%) patients would have achieved the target (AUC0-24>400) considering MIC 0.5; <= 1mg/l and <= 2 mg/l, respectively. For meropenem, 19 (95%), 18 (90%) and 11(55%) patients would have achieved the target (70% of time above MIC) if infected with isolates with MIC <= 1, <= 4 and <= 8mg/l, respectively. Conclusions: In critically ill patients, meropenem and vancomycin were removed during SLED. Despite this, overall high PK/PD target attainment was obtained, except for higher MICs. We suggest maintenance doses of 1g tid or bid for meropenem. For vancomycin, more individualized approach using therapeutic drug monitoring should be used, as commercial assays are available

O objetivo do presente trabalho foi desenvolver e avaliar péletes para compor sistema multiparticulado contendo ácido ascórbico, bem como validar metodologia analítica por cromatografia líquida de alta eficiência (CLAE) para aplicação em ensaio de dissolução destas formas farmacêuticas. A técnica de extrusão-esferonização foi utilizada por ser de fácil aplicação a nível laboratorial e industrial obtendo-se péletes matriciais, compostos de Methocel® K4M, Methocel® K100M e Eudragit® L 100, e péletes de liberação convencionais, para revestimento em leito fluidizado com Kollicoat® SR 30 D como agente regulador da liberação do fármaco. O sistema multiparticulado foi preparado na forma de comprimido pela compressão dos péletes com menor nível de revestimento, avaliando-se o nível de força aplicada e a presença da Microcel® 101 como protetor da camada de revestimento. Os péletes obtidos foram caracterizados quanto à esfericidade por análise imagem, friabilidade, dureza e perfil de dissolução comparativo com apresentações comerciais. Os péletes matriciais foram obtidos com grau de dificuldade variável em função do polímero utilizado, porém apresentaram esfericidade e resistência mecânica adequadas. O perfil de dissolução destas formulações demonstrou que não houve controle na liberação do fármaco, mesmo naquelas onde havia maior concentração de polímero. Os péletes revestidos com três níveis de polímero (5,07; 8,26 e 10,35% em relação à massa do pélete) apresentaram boas características granulométricas e o perfil de dissolução daqueles revestidos com 5,07% de polímero demonstrou semelhança com o da apresentação comercial. O perfil de dissolução comparativo entre os péletes isolados e os comprimidos obtidos sem a presença de excipiente mostrou que ocorre dano na camada de revestimento nos maiores níveis de força de compressão aplicada. Para os comprimidos obtidos a partir da mistura de péletes e Microcel® 101 este fato não foi observado, indicando que a presença do excipiente é fundamental para a manutenção da integridade da camada de revestimento além de promover a desintegração parcial dos comprimidos. / The present work aimed to develop and evaluate pellets to compound a multiparticulate system containing ascorbic acid, as well as, validate analytic methodology through high performance liquid chromatography and evaluate the essay of dissolution from these dosage forms. The extrusion-spheronization technique was used for its laboratorial and industrial application to obtain matrix pellets compounds of Methocel® K4M, Methocel® K100M, Eudragit® L 100, and conventional release pellets, for fluid bed coating with Kollicoat® SR 30 O as a regular occurrence release agent for the drug. The multiple system was prepared in tablets through the compression of the pellets with a lower coating levei, evaluating its applied compression force and the presence of Microcel® 101 as a protector of the coating layer. The obtained pellets were characterized according to its roundness through image analysis, friability, hardness and dissolution profile compared with those marketed products. The matrix pellets were obtained on varied difficulty degree due to the polymer utilized, even through they presented adequate spheroid and mechanical properties. The dissolution profile of these formulations didn\'t show any control in the release of the drug even in those, which had a high concentration of the polymer. The pellets coated with three polymers leveis (5,07%, 8,26% and 10,35% related to the pellets mass) presented good sphericity, and the dissolution profile of those pellets coated with 5,07% polymer demonstrated similarity with those ones marketed products. The comparative dissolution profile among isolated pellets and the tablets obtained without excipients presence, showed that damage right occur on the higher compression force levei is applied. This fact is not observed on the tablets obtained from the pellets blend and Microcel®101, which indicates that the presence of the excipients is fundamental for the maintenance and integrity of the coating layer, moreover, it causes the partial disintegration of the tablets.

O ácido politiofeno acético (PTAA) é um derivado do politiofeno bastante versátil. Sua solubilidade em alguns solventes orgânicos e em soluções básicas aquosas lhe confere extensa processabilidade na forma de filmes finos, característica importante para dispositivos e sensores. Neste trabalho, investigou-se a formação de filmes de PTAA com as técnicas de automontagem e Langmuir-Blodgett (LB). Os filmes automontados foram preparados com dois policátions, hidrocloreto de poli-alilamina (PAH) e cloreto de poli-dialildimetilamônio (PDAC). O crescimento dos filmes depende do pH das soluções e do tipo de policátion, sugerindo dependência do mecanismo de crescimento com as interações específicas polímeropolímero. A conformação do PTAA em filme tem correlação com sua conformação em solução, apontando para um efeito de memória. Por outro lado, a energia de superfície destes filmes não sofre influência da arquitetura nem dessas diferenças conformacionais. Ou seja, embora o volume do filme possa ser distinto, as superfícies possuem propriedades semelhantes. A morfologia dos filmes foi caracterizada a partir de imagens de AFM utilizando conceitos de geometria fractal e estatística. A dimensão fractal dos filmes é semelhante, indicando o mesmo processo de crescimento dos filmes, independentemente das condições da deposição. Os filmes obtidos em pH ácido tinham tamanho de grão e comprimentos de correlação maiores, sugerindo a deposição de cadeias mais enoveladas. Foi possível fabricar filmes autossustentados sem degradação aparente do material a partir de filmes automontados de PAH/PTAA, entrecruzando termicamente os grupos ácido carboxílico e amina. Este é o primeiro relato de filmes deste tipo com derivado do politiofeno. Os filmes LB de PTAA foram obtidos sem adjuvantes, mas as condições de deposição precisam ser aprimoradas. Para explorar a elevada afinidade química entre compostos contendo enxofre e metais pesados, filmes foram utilizados para detecção espectroscópica e eletroquímica. Espectros de fotoluminescência e UV-Vis demonstraram que os metais interagem apenas com os estados excitados resultando na supressão da fluorescência; no entanto, sem especificidade e apenas para longos períodos de exposição. Espectros de FTIR mostraram a presença dos sais na matriz dos filmes. Por sua vez, voltametrias cíclicas permitiram detectar Pb+2 e Hg+2, mas a irreversibilidade dos processos eletroquímicos, causando alargamento dos picos de oxirredução, inviabiliza a detecção simultânea. / Polythiophene acetic acid (PTAA) is a versatile polythiophene derivative. Its solubility in some organic solvents and in basic aqueous solutions makes it attractive for processing thin films, an important feature for the fabrication of devices and sensors. In this thesis, we investigate the formation of PTAA films using the layer-by-layer (LbL) and the Langmuir- Blodgett (LB) techniques. The LbL films were prepared with poly(allylamine hydrochloride) (PAH) and poly(diallydimethylammonium chloride) (PDAC), with film growth depending on the pH of the solutions and type of polycation, thus indicating that the growth mechanism depends on polymer-polymer interactions. The conformation of the PTAA molecules in solid state was correlated with that in solution, in a kind of memory effect. The surface energy of the films was not affected by the film architecture or different conformations. The film morphology was characterized with AFM images using concepts of fractal geometry and statistics. The fractal dimension was similar for all films, and therefore the overall growth obeys the same process regardless of the deposition conditions. Nevertheless, films obtained at acidic pH exhibited larger grain size and correlation lengths than those produced at basic pHs, suggesting deposition of more coiled chains. It was also possible to fabricate selfsustained films without apparent PTAA degradation from the PAH/PTAA LbL films, upon thermal crosslinking of carboxylic acid and amine groups. This is the first report of such films with a polythiophene derivative. LB films of PTAA were obtained without co-spreading materials, but the deposition conditions need to be optimized. To explore the high chemical affinity between PTAA and compounds containing sulfur and heavy metals, some films were used for spectroscopic and electrochemical detection. The UV-Vis and photoluminescence spectra indicated that the metals affect only the excited states, leading to fluorescence quenching after long exposure times and without specificity for the metals. The FTIR spectra pointed to salts in the films. Pb+2 and Hg+2 ions could be detected using cyclic voltammetry, but their simultaneous detection was hampered by the irreversibility of the electrochemical processes which caused broadening of the oxi-reduction peaks.