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Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-01-13T12:47:04Z No. of bitstreams: 1 elizamariaferreira.pdf: 2774756 bytes, checksum: 61a94ee557cce6b0fb63b18f2d57e8e4 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-01-25T17:29:48Z (GMT) No. of bitstreams: 1 elizamariaferreira.pdf: 2774756 bytes, checksum: 61a94ee557cce6b0fb63b18f2d57e8e4 (MD5) / Made available in DSpace on 2016-01-25T17:29:48Z (GMT). No. of bitstreams: 1 elizamariaferreira.pdf: 2774756 bytes, checksum: 61a94ee557cce6b0fb63b18f2d57e8e4 (MD5) Previous issue date: 2015-02-27 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O objetivo deste trabalho é estudar algumas aplicações da teoria de controle ótimo para problemas biológicos. Assim, apresentamos inicialmente o estudo de dois modelos diferentes: “Optimal Control of Biological Invasions in Lake Network”, proposto por Potapov et al. [13], e “Simulating Optimal Vaccination Times during Cholera Outbreaks” proposto por Modnak et al. [9]. Os modelos têm suas dinâmicas baseadas em equações diferenciais ordinárias e neles foi minimizado um funcional, com uma única e com várias restrições, respectivamente. No primeiro modelo a teoria de controle ótimo é usada para minimizar os custos com a prevenção juntamente com os custos gerados pelos danos da invasão biológica em estudo, e no segundo modelo aplica-se o controle ótimo para minimizar os custos da vacinação e tratamento dos indivíduos infectados durante um surto de cólera. Com base nos modelos propostos por Vieira e Takahashi em “A Sobrevivência do Vírus varicelazoster”, [16], e por Shulgin et al. em “Pulse vaccination strategy in the SIR epidemic model”, [14], propomos um modelo matemático que considera a vacinação da população como uma estratégia de controle da varicela. Nós usamos a teoria de controle ótimo para definir as condições necessárias para minimizar os custos da vacinação e tratamento dos indivíduos infectados com catapora ou com herpes zoster. A dinâmica é baseada em equações diferenciais ordinárias, que são as restrições sob as quais queremos minimizar o funcional utilizando a teoria de controle ótimo. / The goal of this work is to study some applications of the theory of optimal control for biological problems. Thus, initially we present the study of two different models: “Optimal Control of Biological Invasions in Lake Network” proposed by Potapov et al. [13], and “Simulating optimal Vaccination Times During Cholera Outbreaks” proposed by Modnak et al. [9]. The models have their dynamics based on ordinary differential equations and are minimizing the functional with a single and with several restrictions, respectively. The first model uses optimal control theory to minimize costs with prevention and together with the costs generated by the damage of the invasion, the second model applies optimal control to minimize costs in the vaccination and treatment of infected individuals during cholera outbreak. Based on models proposed by Vieira and Takahashi on “The Virus Survival varicella-zoster”, [16], and by Shulgin et al. in “Pulse vaccination strategy in the SIR epidemic model”, [14], we propose a mathematical model that considers a vaccination of the population as a varicella control strategy. We use the optimal control theory to define necessary conditions to minimize the costs of vaccination and treatment of infected individuals with chickenpox or with herpes zoster. The dynamics is based on ordinary differential equations which are the constraints under which we want to minimize the functional in the optimal control theory.

Syftet med denna valideringsstudie är att värdera lämpligheten att överföra den manuella analysen av aktuell infektion av Varicella Zoster Virus (aVZV IgM) och Herpes Simplex Virus (aHSV IgM) med SIEMENS Enzygnost® till en av de automatiserade analysinstrumenten EUROIMMUN Analyzer I (ELISA) eller DiaSorin LIAISON® XL. Arbetet utfördes på Klinisk Mikrobiologi i Lund. Konsekutiva serumprover för VZV IgM (n=108) och för HSV IgM (n=116) från det vardagliga flödet analyserades, tillsammans med 10 PCR- eller serokonversion-konfirmerade positiva serumprover av primär infektion VZV och HSV samt 10 positiva för reaktiverad infektion av VZV och HSV. Utöver det användes 10 serumprover konfirmerade positiva för Cytomegalovirus (CMV) respektive 10 för Epstein-Barr Virus (EBV) för att testa korsreaktionen metoderna emellan. Resultatet från VZV-valideringen i Analyzer I samt LIAISON® XL gav en överensstämmelse på 93% respektive 94% av de konsekutiva proverna, 71% respektive 86% av de primärinfekterade proverna och 75% respektive 58% av de reaktiverade proverna, samt en korsreaktivitet (positiva och gränsvärden) på totalt 33% respektive 20% av proverna. Resultatet från HSV-valideringen i Analyzer I samt LIAISON® XL gav en överensstämmelse på 84% respektive 87% av de konsekutiva proverna, 82% respektive 18% av de primärinfekterade proverna och 40% respektive 10% av de reaktiverade proverna, samt en korsreaktivitet (positiva och gränsvärden) på totalt 67% respektive 47% av proverna. Enligt rekommendation efter utförandet av denna studie så bör analysen av HSV IgM uteslutas från båda automatiserade metoder medan VZV IgM bör kontrolleras något ytterligare i Analyzer I, med förhoppning om att denna metod kan vara känsligare. / The approach of this validation study is to evaluate the adequacy for transferring the manual analysis method of ongoing infection of Varicella Zoster Virus (aVZV IgM) and Herpes Simplex Virus (aHSV IgM) with SIEMENS Enzygnost® to one of the automated instruments EUROIMMUN Analyzer I (ELISA) or DiaSorin LIAISON® XL. The study was carried out at Clinical Microbiology in Lund. Consecutive serum samples for VZV IgM (n=108) and HSV IgM (n=116) from the daily local flow of tests were analyzed, along with 10 positive for primary infection of VZV and HSV, confirmed by PCR or seroconversion, and 10 with reactivated infection of VZV and HSV. Beyond those, 10 serum samples confirmed positive for Cytomegalovirus (CMV) respectively 10 for Epstein-Barr Virus (EBV) to test the cross-reaction between the three methods. The results from the validation of VZV in Analyzer I and LIAISON® XL gave an agreement of 93% and 94% respectively in the consecutive tests, 71% and 86% respectively in the primary infected tests and 75% and 58% respectively in the reactivated tests, and also a cross-reactivity (both positive and in between-values) at a total of 33% respectively 20% of the tests. The results from the validation of HSV in Analyzer I and LIAISON® XL gave an agreement of 84% and 87% respectively in the consecutive tests, 82% and 18% respectively in the primary infected tests and 40% and 10% respectively in the reactivated tests, and also a cross-reactivity (both positive and in between-values) at a total of 67% respectively 47% of the tests. According recommendations after the performance of this study, the analysis of HSV IgM should be excluded from both of the automated methods while VZV IgM should be controlled further in Analyzer I, with hopes that this new method could be more sensitive.

No description available.

Esta tese representa o aprofundamento do estudo das estimativas de custos, componente integrante e determinante das avaliações econômicas, enquanto parte do projeto de pesquisa Estudos de custo-efetividade da incorporação de novas vacinas à rotina do Programa Nacional de Imunizações: Rotavírus, Varicela, Pneumocócica conjugada, Meningocócica C conjugada e Hepatite A desenvolvido por solicitação do Programa Nacional de Imunização/PNI da Secretaria de Vigilância em Saúde/SVS do Ministério da Saúde, a partir de 2005. A tese teve como objetivo analisar as condições de uso, dificuldades e repercussões de diferentes métodos de estimativas de custos em estudos de custo-efetividade de vacinas de duas tecnologias específicas, vacinas contra rotavírus e varicela, assim como a relação entre as estimativas de custos e os resultados. As estimativas de custos estão condicionadas pelas características gerais da doença sob análise (aguda no caso de rotavírus e com seqüela no caso de varicela), assim como por questões metodológicas gerais (escolha teórico-conceitual, métodos e fontes de dados) e especificidades do caso brasileiro. Para esta tese, houve maior detalhamento das estimativas de custos diretos no cuidado da doença, com a inclusão de custos específicos do sistema de saúde suplementar para as duas doenças, inclusão de participação pública na dispensação de medicamentos no caso de rotavírus e inclusão de custos de medicamentos do sistema público de saúde no caso de varicela. Como resultado, houve aumento do custo total da doença estimado de 16% para rotavírus e 11% para varicela, assim como aumento de economia (custo total da doença evitado) de 18% e 16%, respectivamente, com a introdução de cada vacina. Apesar do maior detalhamento das estimativas de custos ter reduzido a razão de custo-efetividade incremental em 20% para rotavírus e 4% para varicela, o nível de custo-efetividade dos dois programas de vacinação não foi alterado. Os resultados das avaliações econômicas de vacinação contra rotavírus e varicela mostraram-se mais sensíveis às estimativas de custos do programa de vacinação, em especial o preço da vacina, apontando a relevância do custo da tecnologia sob análise para incorporação em comparação aos demais custos / This thesis represents a deeper study of the cost estimates, an integrant and determinative component of economic evaluations, as part of the project Costeffectiveness studies of the incorporation of new vaccines into the routine of the National Immunisation Program: Rotavirus, Varicella, Pneumococcal conjugate, Meningococcal C conjugate and Hepatitis A. The project has been developed on the request of the National Immunisation Program/PNI of the Secretary of Sanitary Surveillance/SVS of the Ministry of Health since 2005. The objective of the thesis was to analyse the conditions of use, difficulties and repercussions of different cost estimates methods in the cost-effectiveness studies of two specific technologies, vaccines against rotavirus and varicella, as well as the relationship between the cost estimates and the results. The cost estimates are conditioned by general characteristics of the disease under analysis (acute in the case of rotavirus and with long-term disability in the case of varicella), general methodological issues (theoretical choice, methods and sources of data) and specificities to the Brazilian case. This thesis brings a more detailed estimation of direct medical costs, with the inclusion of specific costs of the private health care system for the two diseases, inclusion of public participation for dispensing drugs in the case of rotavirus and inclusion of drugs costs in the public health care system in the case of varicella. As a result, there was an estimated disease total cost increase of 16% for rotavirus and 11% for varicella, as well as increase of savings (disease total cost avoided) of 18% and 16%, respectively, with the introduction of each vaccine. Although the more detailed cost estimates have reduced the incremental cost-effectiveness ratio by 20% for rotavirus and 4% for varicella, the cost-effectiveness level of the two vaccination programs was not altered. The results of the economic evaluations of vaccination against rotavirus and varicella were more sensitive to the vaccination program cost estimates, especially the vaccine price, pointing out the relevance of the cost of the technology under analysis for incorporation comparatively to the other costs

Made available in DSpace on 2016-03-15T19:38:04Z (GMT). No. of bitstreams: 1 ANA LEDA SILVA MORAES.pdf: 1708515 bytes, checksum: 8e07dd190f9a5fd165c14e35c2c626b0 (MD5) Previous issue date: 2016-02-01 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Epidemiology is the science that studies the occurrence of diseases in a population. The results of these studies allow a comprehension of a disease propagation and enable actions in order to control epidemics. There are many mathematical models used in epidemiological studies; in which SIR-like models are the most used. In this model, the population is divided into three groups: S - susceptible individuals to infection, I - infected individuals, and R - recovered individuals. The proposal of this thesis is, based on a new SIR model, taking into consideration the effect of recovered individuals on the propagation of contagious diseases and on the recovery of sick individuals. This can be relevant to the study of propagation of typical diseases in children, since immune individuals can catalyze the encounters among susceptible children and infected children, as well as to contribute to the recovery of sick individuals. The predictive ability of the proposed model is evaluated from the records refering to the incidence of chickenpox in Belgium, Germany and Italy, in a pre-vaccination era. / Epidemiologia é a ciência que estuda as ocorrências de doenças numa população. Os resultados desses estudos permitem uma compreensão do comportamento da incidência da doença e possibilita ações a fim de controlar epidemias. Há vários modelos matemáticos que são utilizados para estudos epidemiológicos, sendo modelos do tipo SIR os mais empregados. Nesse modelo, divide-se a população em três classes: 𝑆 - indivíduos suscetíveis à infecção, 𝐼 - indivíduos infectados, e 𝑅 - indivíduos recuperados. A proposta desta dissertação é, a partir de um novo modelo SIR, levar em consideração o efeito de indivíduos recuperados na propagação de doenças contagiosas e na recuperação de indivíduos doentes. Isso pode ser relevante no estudo da propagação de infecções típicas de crianças, já que indivíduos imunes podem servir como catalisador de encontros entre crianças suscetíveis e crianças infectadas, bem como contribuir para a recuperação de indivíduos doentes. A capacidade preditiva do modelo proposto é avaliada a partir dos registros referentes à incidência de varicela na Alemanha, Bélgica e Itália, numa era pré-vacinação.

Esta tese representa o aprofundamento do estudo das estimativas de custos, componente integrante e determinante das avaliações econômicas, enquanto parte do projeto de pesquisa Estudos de custo-efetividade da incorporação de novas vacinas à rotina do Programa Nacional de Imunizações: Rotavírus, Varicela, Pneumocócica conjugada, Meningocócica C conjugada e Hepatite A desenvolvido por solicitação do Programa Nacional de Imunização/PNI da Secretaria de Vigilância em Saúde/SVS do Ministério da Saúde, a partir de 2005. A tese teve como objetivo analisar as condições de uso, dificuldades e repercussões de diferentes métodos de estimativas de custos em estudos de custo-efetividade de vacinas de duas tecnologias específicas, vacinas contra rotavírus e varicela, assim como a relação entre as estimativas de custos e os resultados. As estimativas de custos estão condicionadas pelas características gerais da doença sob análise (aguda no caso de rotavírus e com seqüela no caso de varicela), assim como por questões metodológicas gerais (escolha teórico-conceitual, métodos e fontes de dados) e especificidades do caso brasileiro. Para esta tese, houve maior detalhamento das estimativas de custos diretos no cuidado da doença, com a inclusão de custos específicos do sistema de saúde suplementar para as duas doenças, inclusão de participação pública na dispensação de medicamentos no caso de rotavírus e inclusão de custos de medicamentos do sistema público de saúde no caso de varicela. Como resultado, houve aumento do custo total da doença estimado de 16% para rotavírus e 11% para varicela, assim como aumento de economia (custo total da doença evitado) de 18% e 16%, respectivamente, com a introdução de cada vacina. Apesar do maior detalhamento das estimativas de custos ter reduzido a razão de custo-efetividade incremental em 20% para rotavírus e 4% para varicela, o nível de custo-efetividade dos dois programas de vacinação não foi alterado. Os resultados das avaliações econômicas de vacinação contra rotavírus e varicela mostraram-se mais sensíveis às estimativas de custos do programa de vacinação, em especial o preço da vacina, apontando a relevância do custo da tecnologia sob análise para incorporação em comparação aos demais custos / This thesis represents a deeper study of the cost estimates, an integrant and determinative component of economic evaluations, as part of the project Costeffectiveness studies of the incorporation of new vaccines into the routine of the National Immunisation Program: Rotavirus, Varicella, Pneumococcal conjugate, Meningococcal C conjugate and Hepatitis A. The project has been developed on the request of the National Immunisation Program/PNI of the Secretary of Sanitary Surveillance/SVS of the Ministry of Health since 2005. The objective of the thesis was to analyse the conditions of use, difficulties and repercussions of different cost estimates methods in the cost-effectiveness studies of two specific technologies, vaccines against rotavirus and varicella, as well as the relationship between the cost estimates and the results. The cost estimates are conditioned by general characteristics of the disease under analysis (acute in the case of rotavirus and with long-term disability in the case of varicella), general methodological issues (theoretical choice, methods and sources of data) and specificities to the Brazilian case. This thesis brings a more detailed estimation of direct medical costs, with the inclusion of specific costs of the private health care system for the two diseases, inclusion of public participation for dispensing drugs in the case of rotavirus and inclusion of drugs costs in the public health care system in the case of varicella. As a result, there was an estimated disease total cost increase of 16% for rotavirus and 11% for varicella, as well as increase of savings (disease total cost avoided) of 18% and 16%, respectively, with the introduction of each vaccine. Although the more detailed cost estimates have reduced the incremental cost-effectiveness ratio by 20% for rotavirus and 4% for varicella, the cost-effectiveness level of the two vaccination programs was not altered. The results of the economic evaluations of vaccination against rotavirus and varicella were more sensitive to the vaccination program cost estimates, especially the vaccine price, pointing out the relevance of the cost of the technology under analysis for incorporation comparatively to the other costs

Age stratified seroepidemiological studies play a crucial role in the design and assessment of vaccination strategies. An existing multiplex bead immunoassay for measles, mumps, rubella and varicella zoster virus antibodies together with a newly developed multiplex bead immunoassay for herpes simplex virus type 1 and type 2 antibodies were used to investigate the age-related seroepidemiology of these viruses in England during 2012.To develop the HSV-1 and HSV-2 antibody assay, attempts were made to produce full length of HSV-1 and HSV-2 glycoprotein G using a baculovirus vector expression system. While HSV-1 gG protein was produced, the proteins were extensively aggregated. Native glycoprotein G molecules undergo partial removal of HSV-1 signal sequence and HSV-1 short membrane anchor sequence during post translational modification. It is possible that such post translational modification is not performed when protein is processed in insect cell culture. Attempts to produce an HSV-2 glycoprotein G were not successful. It is possible that the high GC-content of HSV-2 glycoprotein G led to poor fidelity of copying the PCR amplification sequence. Commercially available truncated HSV-1 gG and HSV-2 gG were therefore used to develop a duplex microbead immunoassay for the simultaneous detection of specific HSV antibodies in human sera. The resultant assays performed with low sensitivity and specificity (HSV-1 of 89% and 66%, respectively and for HSV-2 of 79% and 85%, respectively) compared to the reference HerpeSelect ELISA.The MMRV multiplex bead immunoassay proved rapid, and required minimal sample volume to semi-quantify MMRV specific antibodies. The seroepidemiology of MMR results was compared with previous seroepidemiological studies performed in 1996 in England. The comparison showed an increase in the proportion of individuals who were positive for mumps and measles antibodies in the 2012 survey. The proportion of individuals positive for rubella was essentially unchanged. The increase in the proportion of individuals positive for mumps and measles antibodies in 2012 show the effectiveness of the change in MMR vaccination policy for England from 1996 onward. For VZV, the proportion of individuals who were positive for varicella antibodies between the 1996 and 2012 serological surveys were essentially unchanged. The comparison showed that most young children are susceptible to VZV. At this level of immunity, it can be expected that varicella will continue to produce epidemics of infection in the population, unless varicella vaccination is implemented as a part of routine childhood vaccination.

Background: The prevalence of herpes zoster (HZ) is high in patients with rheumatic diseases. Systemic lupus erythematosus (SLE) doubles the risk for developing HZ. However, little is known about natural humoral immunity against varicella zoster virus (VZV) in patients with SLE. Hence, we compared VZV IgG antibody concentrations in a group of SLE patients with healthy controls and patients with rheumatoid arthritis (RA). Methods: n = 56 patients with SLE, n = 54 patients with RA, and n = 56 healthy controls were included in this study. The VZV IgG antibody concentration was measured using an enzyme-linked immunosorbent assay (ELISA). The antibody concentrations were compared between the groups. Results: Overall IgG antibody titers for VZV in SLE patients were comparable to healthy controls but higher when compared to patients with rheumatoid arthritis (p = 0.0012). In consequence, antibody levels in controls were higher than in RA patients (p = 0.0097). Stratification by age revealed highest titers among SLE patients in the fourth life decade (p = 0.03 for controls, p = 0.0008 for RA patients) whereas RA patients in their sixth decade had the lowest antibody concentration (p = 0.03 for controls, p = 0.04 for SLE patients). Regarding the individual HZ history, antibody levels of SLE patients with a positive history exceeded all other groups. Conclusions: Although humoral VZV immunity in SLE patients is comparable to healthy controls it seems to be pronounced in young SLE patients between 30 and 39. The lowest VZV IgG levels were found in RA patients. HZ seems to induce antibody production, particularly in patients with SLE. Immunological processes might contribute to VZV antibody levels in SLE patients, but further investigations are needed to substantiate this hypothesis. Even though the increased HZ prevalence seems to be independent of humoral immunity in SLE patients, reduced humoral immunity might contribute to HZ in RA patients. The available HZ subunit vaccination might be an appropriate way to reduce the HZ risk in patients with rheumatic diseases.

Many infectious diseases are spread through interactions between susceptible and infectious individuals. Keeping track of where each exposure to the disease took place, when it took place, and which individuals were involved in the exposure can give public health officials important information that they may use to formulate their interventions. Further, knowing which individuals in the population are at the highest risk of becoming infected with the disease may prove to be a useful tool for public health officials trying to curtail the spread of the disease. Epidemiological models are needed to allow epidemiologists to study the population dynamics of transmission of infectious agents and the potential impact of infectious disease control programs. While many agent-based computational epidemiological models exist in the literature, they focus on the spread of disease rather than exposure risk. These models are designed to simulate very large populations, representing individuals as agents, and using random experiments and probabilities in an attempt to more realistically guide the course of the modeled disease outbreak. The work presented in this thesis focuses on tracking exposure risk to chickenpox in an elementary school setting. This setting is chosen due to the high level of detailed information realistically available to school administrators regarding individuals' schedules and movements. Using an agent-based approach, contacts between individuals are tracked and analyzed with respect to both individuals and locations. The results are then analyzed using a combination of tools from computer science and geographic information science.