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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
61

Singing Louder than a Mockingbird : Analyzing voice, racism and stereotypes in Harper Lee’s To Kill a Mockingbird with the aim of engaging Swedish EFL students to be critical towards an ethnic divide within literature

Moshayyadi, Maryam January 2018 (has links)
The aim of the present inquiry is to analyze the depiction of racism through given or withheld voice in Harper Lee’s novel To Kill a Mockingbird. A thematic analysis of marginalized and commonly occurring voices in the novel reveals discrepancies along an ethnic divide. Applying Critical Race theory affords the analytical tools of voice, ethnicity and stereotypes, while Critical Race Pedagogy provides the grounds for a discussion of how students can learn how to criticize ethnic hierarchies in classic works, such as To Kill a Mockingbird. The results of the inquiry show a clear hierarchy in which African American characters are often silenced. The critical lens focusing on voice, ethnicity and stereotypes, enables the reader to reach a more multifaceted examination of the novel by generating an in-depth view of racism. Discussing racist occurrences in a novel often lauded as the epitome of anti-racism in the EFL classroom, can possibly illustrate just how ingrained racism can be. As a result, the students may develop critical tools that, hopefully, empower them to raise their voices against racist acts in today’s society.
62

Trilhando caminhos para avaliar padrões espaciais de mortalidade e fragmentação em rodovias / Assessing spatial patterns of mortality and fragmentation caused by roads

Teixeira, Fernanda Zimmermann January 2015 (has links)
Atropelamentos de animais silvestres são a principal causa de mortalidade de origem antrópica de vertebrados terrestres. Além da mortalidade direta, as populações animais também são fragmentadas e isoladas por rodovias, que podem atuar como filtro ou barreira ao movimento da fauna. A indicação e implementação de medidas mitigadoras têm sido uma estratégia cada vez importante, ampliando a necessidade de desenvolver e qualificar métodos para avaliar os impactos e indicar áreas prioritárias. Essa tese de doutorado foi concebida com a preocupação de investigar certos temas relacionados à mortalidade e fragmentação por rodovias. No primeiro capítulo, discuto como a qualificação da pesquisa e do licenciamento podem colaborar com este cenário. No segundo capítulo, apresento uma revisão de diferentes métodos de análise espacial utilizados para testar se existe a presença de agregações de atropelamento e para localizar onde estão estas agregações. No terceiro capítulo, apresento os resultados de um modelo de simulação baseado em indivíduos, que mostra que a localização dos hotspots muda ao longo do tempo em função da diminuição das populações próximas a trechos de rodovias com maior letalidade, o que torna a mortalidade per capita um melhor indicador da necessidade de mitigação. No último capítulo avaliei o efeito da rede de rodovias na fragmentação de habitat nos campos sulinos do Rio Grande do Sul, e demonstro que considerar o efeito da rede de rodovias como uma barreira aos movimentos da fauna modifica de forma severa a percepção que temos sobre o status de conservação dos campos. Esta tese pode ter dois tipos principais de implicações: a aplicação direta dos resultados aqui apresentados nas avaliações dos impactos de rodovias e planejamento da mitigação, e a influência em novos rumos de pesquisa na ecologia de rodovias. / Roads are responsible for a series of impacts to ecosystems, and some authors point out that road-kills are the main cause of terrestrial vertebrate mortality from anthropogenic causes. Besides direct mortality, wildlife populations are also fragmented and isolated by roads, as they can act as barriers or filters to wildlife movement. Implementing mitigation measures had become an important conservation strategy, but the need to prioritize areas brings the urgency to develop and qualify methods to assess road impacts and indicate priority areas. This doctorate thesis was developed with the concern of investigating subjects related to wildlife mortality and fragmentation by roads. In the first chapter I discuss how qualifying research and environmental licensing may contribute in this scenario. In the second chapter, I present a review of different methods of spatial analysis that have been used to test the presence of clustering on road-kill data and to identify road-kill hotpots. In the third chapter, I present the results of simulations of an individual-based model that shows that the location of road-kill hotspots change in time due to population depression near high-risk road segments; making per capita mortality a better indicator of the need for mitigation. In the last chapter, I evaluated the effect of the road network on habitat fragmentation of South Brazilian grasslands in Rio Grande do Sul State, and I show that considering the road network as a barrier changes severely our perception about grassland conservation status. This thesis may have two types of implications: the direct applications of the results presented here in environmental impact assessment of roads and in mitigation planning, or the influence on new paths to study road effects on wildlife.
63

Trilhando caminhos para avaliar padrões espaciais de mortalidade e fragmentação em rodovias / Assessing spatial patterns of mortality and fragmentation caused by roads

Teixeira, Fernanda Zimmermann January 2015 (has links)
Atropelamentos de animais silvestres são a principal causa de mortalidade de origem antrópica de vertebrados terrestres. Além da mortalidade direta, as populações animais também são fragmentadas e isoladas por rodovias, que podem atuar como filtro ou barreira ao movimento da fauna. A indicação e implementação de medidas mitigadoras têm sido uma estratégia cada vez importante, ampliando a necessidade de desenvolver e qualificar métodos para avaliar os impactos e indicar áreas prioritárias. Essa tese de doutorado foi concebida com a preocupação de investigar certos temas relacionados à mortalidade e fragmentação por rodovias. No primeiro capítulo, discuto como a qualificação da pesquisa e do licenciamento podem colaborar com este cenário. No segundo capítulo, apresento uma revisão de diferentes métodos de análise espacial utilizados para testar se existe a presença de agregações de atropelamento e para localizar onde estão estas agregações. No terceiro capítulo, apresento os resultados de um modelo de simulação baseado em indivíduos, que mostra que a localização dos hotspots muda ao longo do tempo em função da diminuição das populações próximas a trechos de rodovias com maior letalidade, o que torna a mortalidade per capita um melhor indicador da necessidade de mitigação. No último capítulo avaliei o efeito da rede de rodovias na fragmentação de habitat nos campos sulinos do Rio Grande do Sul, e demonstro que considerar o efeito da rede de rodovias como uma barreira aos movimentos da fauna modifica de forma severa a percepção que temos sobre o status de conservação dos campos. Esta tese pode ter dois tipos principais de implicações: a aplicação direta dos resultados aqui apresentados nas avaliações dos impactos de rodovias e planejamento da mitigação, e a influência em novos rumos de pesquisa na ecologia de rodovias. / Roads are responsible for a series of impacts to ecosystems, and some authors point out that road-kills are the main cause of terrestrial vertebrate mortality from anthropogenic causes. Besides direct mortality, wildlife populations are also fragmented and isolated by roads, as they can act as barriers or filters to wildlife movement. Implementing mitigation measures had become an important conservation strategy, but the need to prioritize areas brings the urgency to develop and qualify methods to assess road impacts and indicate priority areas. This doctorate thesis was developed with the concern of investigating subjects related to wildlife mortality and fragmentation by roads. In the first chapter I discuss how qualifying research and environmental licensing may contribute in this scenario. In the second chapter, I present a review of different methods of spatial analysis that have been used to test the presence of clustering on road-kill data and to identify road-kill hotpots. In the third chapter, I present the results of simulations of an individual-based model that shows that the location of road-kill hotspots change in time due to population depression near high-risk road segments; making per capita mortality a better indicator of the need for mitigation. In the last chapter, I evaluated the effect of the road network on habitat fragmentation of South Brazilian grasslands in Rio Grande do Sul State, and I show that considering the road network as a barrier changes severely our perception about grassland conservation status. This thesis may have two types of implications: the direct applications of the results presented here in environmental impact assessment of roads and in mitigation planning, or the influence on new paths to study road effects on wildlife.
64

Trilhando caminhos para avaliar padrões espaciais de mortalidade e fragmentação em rodovias / Assessing spatial patterns of mortality and fragmentation caused by roads

Teixeira, Fernanda Zimmermann January 2015 (has links)
Atropelamentos de animais silvestres são a principal causa de mortalidade de origem antrópica de vertebrados terrestres. Além da mortalidade direta, as populações animais também são fragmentadas e isoladas por rodovias, que podem atuar como filtro ou barreira ao movimento da fauna. A indicação e implementação de medidas mitigadoras têm sido uma estratégia cada vez importante, ampliando a necessidade de desenvolver e qualificar métodos para avaliar os impactos e indicar áreas prioritárias. Essa tese de doutorado foi concebida com a preocupação de investigar certos temas relacionados à mortalidade e fragmentação por rodovias. No primeiro capítulo, discuto como a qualificação da pesquisa e do licenciamento podem colaborar com este cenário. No segundo capítulo, apresento uma revisão de diferentes métodos de análise espacial utilizados para testar se existe a presença de agregações de atropelamento e para localizar onde estão estas agregações. No terceiro capítulo, apresento os resultados de um modelo de simulação baseado em indivíduos, que mostra que a localização dos hotspots muda ao longo do tempo em função da diminuição das populações próximas a trechos de rodovias com maior letalidade, o que torna a mortalidade per capita um melhor indicador da necessidade de mitigação. No último capítulo avaliei o efeito da rede de rodovias na fragmentação de habitat nos campos sulinos do Rio Grande do Sul, e demonstro que considerar o efeito da rede de rodovias como uma barreira aos movimentos da fauna modifica de forma severa a percepção que temos sobre o status de conservação dos campos. Esta tese pode ter dois tipos principais de implicações: a aplicação direta dos resultados aqui apresentados nas avaliações dos impactos de rodovias e planejamento da mitigação, e a influência em novos rumos de pesquisa na ecologia de rodovias. / Roads are responsible for a series of impacts to ecosystems, and some authors point out that road-kills are the main cause of terrestrial vertebrate mortality from anthropogenic causes. Besides direct mortality, wildlife populations are also fragmented and isolated by roads, as they can act as barriers or filters to wildlife movement. Implementing mitigation measures had become an important conservation strategy, but the need to prioritize areas brings the urgency to develop and qualify methods to assess road impacts and indicate priority areas. This doctorate thesis was developed with the concern of investigating subjects related to wildlife mortality and fragmentation by roads. In the first chapter I discuss how qualifying research and environmental licensing may contribute in this scenario. In the second chapter, I present a review of different methods of spatial analysis that have been used to test the presence of clustering on road-kill data and to identify road-kill hotpots. In the third chapter, I present the results of simulations of an individual-based model that shows that the location of road-kill hotspots change in time due to population depression near high-risk road segments; making per capita mortality a better indicator of the need for mitigation. In the last chapter, I evaluated the effect of the road network on habitat fragmentation of South Brazilian grasslands in Rio Grande do Sul State, and I show that considering the road network as a barrier changes severely our perception about grassland conservation status. This thesis may have two types of implications: the direct applications of the results presented here in environmental impact assessment of roads and in mitigation planning, or the influence on new paths to study road effects on wildlife.
65

Training Security Professionals in Social Engineering with OSINT and Sieve

Meyers, Jared James 01 June 2018 (has links)
This research attempts to create a novel process, Social Engineering Vulnerability Evaluation, SiEVE, to use open source data and open source intelligence (OSINT) to perform efficient and effectiveness spear phishing attacks. It is designed for use by "œred teams" and students learning to conduct a penetration test of an organization, using the vector of their workforce. The SiEVE process includes the stages of identifying targets, profiling the targets, and creating spear phishing attacks for the targets. The contributions of this research include the following: (1) The SiEVE process itself was developed using an iterative process to identify and fix initial shortcomings; (2) Each stage of the final version of the SiEVE process was evaluated in an experiment that compared performance of students using SiEVE against performance of those not using SiEVE in order to test effectiveness of the SiEVE process in a learning environment; Specifically, the study showed that those using the SiEVE process (a) did not identify more targets, (b) did identify more information about targets, and (c) did lead to more effective spear phishing attacks. The findings, limitations, and future work are discussed in order to provide next steps in developing formalized processes for red teams and students learning penetration testing.
66

In vitro efficacy assessment of targeted antimalarial drugs synthesized following in silico design

Matlebjane, Dikeledi M.A. January 2017 (has links)
Malaria is a major public health problem that affects millions of lives globally. The increased burden of malaria requires new interventions that will address the eradication of the disease. Current interventions include vector control by using insecticide-treated bed nets and indoor residual spraying, and antimalarial drugs to control the parasite. Parasite resistance has been reported for the currently used effective antimalarial drugs. To pre-empt the impact of parasite resistance a continued development of new antimalarial drugs that have novel mechanisms of action should be pursued. Antimalarial drug discovery requires that potential antimalarial drugs should have different drug targets to those already targeted, to lower the chances of resistance. Potential antimalarial drugs should preferably provide a single radical cure to prevent reproduction at all life cycle stages. This study tested the effects of in silico designed compounds targeting plasmodial Ca2+- dependent protein kinases (CDPK) 1 & 4, FIKK kinases and bromodomain proteins on the Plasmodium parasite. These enzymes are involved in gene regulation and are important factors during gene transcription. In P. falciparum the gatekeeper kinases contain small hydrophobic pockets near the ATP-binding site. These hydrophobic pockets allow for selective inhibition of these proteins at the ATP-binding site. The compounds were tested in vitro to determine their antiplasmodial activity. These compounds are shown to be potential inhibitors of the intra-erythrocytic P. falciparum parasites as three of the compounds showed selective cytotoxic activity at less than 1 μM against the chloroquine sensitive laboratory strains (3D7 and NF54). Even though the proteins targeted by these compounds have been previously indicated to play a role at specific stages during the parasite’s life cycle, the compounds tested here were not able to target the sexual gametocyte stages of the Plasmodium parasite. Further optimisation of these compounds should be performed to improve activity against both the asexual and sexual stages of the parasites. / Dissertation (MSc)--University of Pretoria, 2017. / Pharmacology / MSc / Unrestricted
67

Information Security Training and Serious Games

Agrianidis, Anastasios January 2021 (has links)
The digital transformation of the 21st century has led to a series of new possibilities and challenges, where one major concern of many major organizations and enterprises is promoting Information Security Awareness and Training (ISAT) for their employees. This aspect of Information Security (IS) can promote cybersecurity in the work environment against threats related to the human factor. Apart from traditional methods as workshops and seminars, researchers study the effect of gamification on ISAT, by proposing customized digital games to train employees regardless their IT skills. This thesis is trying to propose what techniques and approaches can be considered to train people throughout a full threat progression by studying the features of previous efforts. For this purpose, a literature study based on the principles of a systematic literature review (SLR) is essential to gather the available data and review their characteristics. More specifically, the solutions of the researchers are analyzed against the seven steps of the Lockheed Martin Cyber Kill Chain (LM CKC), where each game is classified to one or more phases, according to the training they offer. Thus, some tools can provide a wide range of training, covering many aspects of the CKC, while others are targeting a specific IS topic. The results also suggest that popular attacks involving social engineering, phishing, password and anti-malware software are addressed by many games, mainly in the early stages of the CKC and are focus on trainees without professional IT background. On the other hand, in the last two phases of the CKC, the majority of categorized games involves countermeasures that IS specialists must launch to prevent the security breach. Therefore, this study offers insight on the characteristics of serious games, which can influence an ISAT program, tailored to the enterprise’s distinct IS issue(s) and the IT background of the trainees.
68

Lysine Acetylation and Small Molecule Epigenetic Inhibition Reveal Novel Mechanisms Controlling Cellular Susceptibility to HIV-1 Infection

Lucera, Mark B. 27 January 2016 (has links)
No description available.
69

UAV:ernas möte med en högteknologisk motståndare : en fallstudie av konfikten i Ukraina

Andersson, Liam January 2019 (has links)
UAV:er används frekvent i samhället och med detta har den kommersiella marknaden växt. Därför är det rimligt att de används i större utsträckning i konflikter, vilket innebär att konflikter där båda parter har UAV:er som kan klassas som relativt högteknologiska möts blir troligare. Ukraina och Rysslands användande av UAV i Ukraina kan räknas som denna typ av konflikt.  I uppsatsen är det UAV:er av den militära typen som diskuteras. Skillnaden mellan dessa och civila typer är framförallt räckvidd, flygtid och kvalitén på sensorerna.För att undersöka hur UAV:er nyttjas och taktiseras med i denna typ av konflikter har följande frågeställning använts: Hur påverkas nyttjandet av UAV:er i en konflikt mellan två högteknologiska motståndare?Genom att analysera beslutsprocessen med hjälp av OODA-loopen och bekämpningskedjan har författaren kunnat dra följande slutsatser om nyttjandet i denna typ av konflikt. Uppsatsen är genomförd som en fallstudie där metoderna kvalitativ textanalys och intervju använts Slutsatsen är att den multiplikator som UAV varit i Ukraina visar på att de kommer fortsätta användas i framtida konflikter. Trots att telekrig varit aktivt mot just UAV:erna och att de saknar motmedel mot störningen har de fortsatt att nyttjas, den multiplikatoreffekt de bidrar med kan motiveras stridsekonomiskt och väger tyngre än de problem som störningen innebär. / UAV: s are in more frequent use as a result of a growing commercial market. This increases the probability of UAV: s in conflicts. This means that conflicts where both sides have access to UAV: s that are relatively high-tech becomes more likely. Ukraine and Russia’s use of UAV: s in Ukraine can be described as this kind of conflict. In this paper it is primarily military UAV: s that are discussed. The difference between these and their civilian counterparts are range, flight time and the quality of the sensors. In order to understand how the use of UAV: s is being affected, the following question needs to be answered.  How is the use of UAV: s affected in a conflict between two high-tech opponents? This was answered by analysing the decision-making process using the OODA loop and the kill chain. The paper is a case study which uses qualitative text analysis and an interview.The conclusion of this paper is that UAV: s has acted as a force multiplier in Ukraine and they will be used in future conflicts. Despite the electronic warfare against the UAV: s and the fact that they are missing systems for counteracting the disturbance both sides continue to use UAV: s. The force multiplier that is gained from using UAV: s is justified from a battle economic standpoint despite being hindered by electronic warfare.
70

Modelagem farmacocinética/farmacodinâmica (PK/PD) para caracterização do efeito do ciprofloxacino em infecções com biofilmes de Pseudomonas aeruginosa / Pharmacokinetic/Pharmacodynamic (PK/PD) model to characterize ciprofloxacin effect in pseudomonas aeruginosa biofilm infection

Torres, Bruna Gaelzer Silva January 2016 (has links)
Biofilmes são comunidades bacterianas complexas encapsuladas em matrizes poliméricas autoproduzidas e podem se desenvolver em superfícies inertes ou tecidos vivos. A formação do biofilme é um importante fator de virulência, pois permite à bactéria resistir às respostas do hospedeiro e à terapia antimicrobiana. Devido a essa elevada resistência aos antimicrobianos, é difícil estabelecer uma estratégia eficaz para o tratamento de infecções com formação de biofilmes, levando a falhas na erradicação das mesmas. Nesse contexto, o objetivo do presente estudo é desenvolver um modelo farmacocinético/farmacodinâmico (PK/PD) para descrever o efeito do ciprofloxacino (CIP) na presença de biofilmes de Pseudomonas aeruginosa (ATCC 27853), visto que a modelagem PK/PD de antimicrobianos é uma ferramenta útil na escolha de regimes posológicos que atinjam o efeito bactericida máximo, minimizando o desenvolvimento de resistência. Para atingir esse objetivo, inicialmente um método analítico por CLAE/fluorescência foi desenvolvido para quantificar o CIP em amostras de plasma e microdialisado. O método desenvolvido foi simples, rápido e com sensibilidade adequada para corretamente caracterizar a farmacocinética plasmática e pulmonar do CIP. Posteriormente, um modelo animal de infecção pulmonar crônica foi adaptado da literatura e padronizado, permitindo a investigação da distribuição pulmonar do CIP em ratos Wistar sadios e infectados. Para tal, bactérias foram imobilizadas em beads de alginato a fim de manter a infecção por até 14 dias com cargas bacterianas superiores à 108 UFC/pulmão. Estudo de microdiálise foi então conduzido para avaliar as concentrações livres de CIP após administração intravenosa de 20 mg/kg. A análise não-compartimental (NCA) e a modelagem farmacocinética populacional (PopPK) dos dados foram realizadas nos softwares Phoenix® e NONMEM®, respectivamente. Diferenças significativas foram observadas no clearance plasmático (1,59 ± 0,41 L/h/kg e 0,89 ± 0,44 L/h/kg) e na constante de eliminação (0,23 ± 0,04 h-1 e 0,14 ± 0,08 h-1) para ratos sadios e infectados, resultando em uma exposição plasmática maior nos animais infectados (ASC0-∞ = 27,3 ± 12,1 μg·h/mL) quando comparados com os animais sadios (ASC0-∞ = 13,3 ± 3,5 μg·h/mL) ( = 0,05). Apesar da maior exposição plasmática, quando comparados com os animais saudáveis (fT = 1,69), animais infectados apresentaram uma penetração pulmonar quatro vezes menor (fT = 0,44). Diferenças na constante de eliminação pulmonar não foram observadas. Dados plasmáticos e pulmonares foram simultaneamente descritos por modelo PopPK constituído de compartimentos venoso e arterial, dois compartimentos representativos de duas regiões pulmonares distintas e dois compartimentos periféricos, representando outros tecidos que não os pulmões. Um clearance pulmonar foi adicionado ao modelo apenas para os dados de microdiálise dos animais infectados (CLlung = 0,643 L/h/kg) afim de explicar a exposição tecidual diminuída. O modelo desenvolvido descreveu, com sucesso, os dados plasmáticos e teciduais de animais sadios e infectados, permitindo a correta caracterização das alterações observadas na disposição plasmática e pulmonar do CIP decorrentes da infecção com biofilme. Para os estudos de farmacodinâmica, o efeito bactericida do CIP frente a biofilmes e células planctônicas de P. aeruginosa foi simultaneamente avaliado através do uso de curvas de morte bacteriana. Para a construção destas curvas, biofilmes de P. aeruginosa foram formados na superfície de blocos de acrílico e sua formação foi confirmada pelo ensaio cristal violeta e por microscopia eletrônica de varredura. Os blocos foram expostos a concentrações constantes de CIP (de 0,0625 a 10 μg/mL) e, em tempos pré-determinados, células planctônicas e de biofilmes eram amostradas para quantificação. Um modelo semi-mecanístico que incorpora um modelo Emax sigmoidal foi utilizado para descrever o efeito do CIP frente a ambos estilos de vida bacteriano. Uma subpopulação pré-existente com menor suscetibilidade ao CIP foi incluída no modelo e o efeito do CIP nesta subpopulação também foi descrito pelo modelo Emax sigmoidal. A comparação dos parâmetros estimados pelo modelo demonstrou que o efeito in vitro do CIP é maior para as células planctônicas (EC50 = 0,259 mg/L e 0,123 mg/L e Emax = 2,25 h-1 e 5,59 h-1 para biofilmes e planctônicas, respectivamente). A potência estimada do CIP para a subpopulação resistente foi muito menor para ambos estilos de vida bacteriano (EC50 = 2,71 mg/L e 1,15 mg/L para biofilmes e planctônicas, respectivamente). Os modelos desenvolvidos podem ser utilizados para a simulação de cenários não testados e servir como uma ferramenta para guiar a escolha dos regimes posológicos adequados, contribuindo para o sucesso terapêutico no tratamento de infecções associadas à biofilmes. / Biofilms are complex bacterial communities enclosed in self-produced polymeric matrices that can develop in inert surfaces or living tissues. Biofilm formation is an important virulence factor that allows bacteria to resist host responses and antibacterial agents. Due to this high resistance to antibiotics, it is difficult to establish an efficacious strategy for treatment of infections with biofilm formation leading to failure in infection eradication. In this context, the goal of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the antimicrobial effect of ciprofloxacin (CIP) in the presence of biofilms of Pseudomonas aeruginosa (ATCC 27853), since PK/PD modeling for antibacterial agents can be a useful tool to choose dosing regimens and to achieve the maximum bactericidal effect, minimizing the development of resistance. To reach this goal, firstly an analytical method based on HPLC/fluorescence was developed in order to quantify CIP in plasma and lung microdialysate. The developed method was simple, fast and with enough sensibility to proper characterize CIP plasma and lung pharmacokinetics. Secondly, an animal model of chronic lung infection was adapted from literature and standardized, allowing the analysis of CIP lung distribution in infected and healthy Wistar rats. Bacteria were immobilized in alginate beads prior to inoculation to Wistar rats in order to sustain the pneumonia for 14 days, maintaining a bacterial load superior to 108 CFU/lung. A microdialysis study was then conducted to evaluate free CIP concentrations after an intravenous administration of 20 mg/kg. Non-compartimental analysis (NCA) and populational PK modeling (PopPK) of the data were performed in Phoenix® and NONMEM®, respectively. Statistical differences were observed in the plasma clearance (1.59 ± 0.41 L/h/kg and 0.89 ± 0.44 L/h/kg) and elimination rate constant (0.23 ± 0.04 h-1and 0.14 ± 0.08 h-1) for healthy and infected rats, respectively, resulting in a significantly higher CIP plasma exposure in infected rats (AUC0-∞ = 27.3 ± 12.1 μg·h/mL) compare to healthy animals (AUC0-∞ = 13.3 ± 3.5 μg·h/mL) ( = 0.05). Besides the plasma exposure, a four times lower pulmonary penetration was observed in infected rat’s lungs (fT = 0.44) in comparison to healthy animals (fT = 1.69), with no significant differences in the lung elimination rate constant. Plasma and lung data were simultaneously fitted using a PopPK model consisting of an arterial and a venous compartment, two compartments representing different regions of the lungs and two peripheral distribution compartments, representing tissues other than lungs. A lung clearance was added to the model for infected animals (CLlung = 0.643 L/h/kg) to explain the lower tissue exposure. The model successfully described the plasma and microdialysis data from both, healthy and infected rats and allowed to correctly describe the changes in CIP plasma and lung disposition in biofilm infections. For the pharmacodynamic studies, CIP bactericidal effect against Pseudomonas aeruginosa biofilms and planktonic shedding cells were simultaneously evaluated using the time-kill curves approach. For the time-kill curves construction, P. aeruginosa biofilms were formed in acrylic blocks, which was confirmed by the crystal violet assay and scanning electron microscopy. The blocks were placed in flasks containing Mueller-Hinton growth medium and exposed to constant CIP concentrations (ranging from 0.0625 to 10 μg/mL). At pre-determined time points, biofilm and planktonic cells were sampled for bacterial counting. A mechanism-based model which incorporates a sigmoidal Emax model was used to describe the CIP effect against P.aeruginosa in both llifestyles, biofilm and planktonic. The presence of a pre-existing resistant subpopulation was included in the model and also modeled with a sigmoidal Emax model to describe CIP effect in this subpopulation. Comparison of the parameter estimates showed that the in vitro effect of CIP is higher for planktonic cells (EC50 = 0.259 mg/L and 0.123 mg/L and Emax = 2.25 h-1 and 5.59 h-1 for biofilm and planktonic cells, respectively). CIP potency was much lower for the resistant subpopulation, for both bacteria lifestyles (EC50 = 2.71 mg/L and 1.15 mg/L for biofilm and planktonic, respectively). The developed models can be used to simulate untested scenarios and serve as a tool to guide dosing regimen selection, contributing for the therapeutic success of treatments of biofilm-associated infections.

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