Mathematical and statistical models are widely used in studying infectious disease. They provide important insights – including mechanisms of the spread of infectious disease, forecast epidemic size and duration, and effects of intervention strategies – which are useful in studying and combating infectious disease. Over the last couple of decades, modeling techniques have advanced tremendously due to improvements in computational power, data availability, and data accessibility; this enables researchers to use various modeling approaches to capture more realistic aspects of infectious disease epidemics. Despite having flexible modeling techniques, these approaches use different modeling assumptions to incorporate information and propagate uncertainty, often arriving at inconsistent conclusions. My work focuses on exploring and improving methods for modeling the spread of infectious disease; in particular, exploring the state of the art techniques for disease modeling in real epidemic outbreaks and simulation settings. Motivated by a synthetic forecasting challenge inspired by the 2014 West African Ebola outbreak, I compared simple Markov chain Monte Carlo approaches to simulated epidemics (Chapter 2). Using high-resolution data from an ongoing rabies contact- tracing study, I apply robust techniques to reassess global historical risk estimates of canine rabies (Chapter 3), and show that disease trait correlations bias generation time estimates, with implications for conclusions about control (Chapter 4). In Chapter 5, I developed a method to improve modeling trait relationships while incorporating phylogenetic relationships by reformulating phylogenetic mixed models to improve flexibility and speed. / Dissertation / Doctor of Philosophy (PhD)

Orientadora: Adolorata Aparecida Bianco Carvalho / Coorientador: Antonio Sergio Ferraudo / Banca: Angela Cleusa de Fátima Banzatto de Carvalho / Banca: Sonia Regina Pinheiro / Resumo: Um elevado número de tratamentos anti-rábicos profiláticos são efetuados, anualmente, em pessoas envolvidas em agravos com animais. Assim, este trabalho objetivou avaliar os registros e a conduta de profilaxia anti-rábica humana no Município de Jaboticabal, de 2000 a 2006, analisando as informações das fichas de atendimento e a distribuição geográfica dos agravos. Os dados foram tabulados em Excel e analisados com softwares EpiInfo e MapInfo. Também foi calculado o custo direto com as vacinas anti-rábicas humanas. Em 3056 fichas analisadas, computou-se um agravo para cada 160 habitantes, com maior ocorrência em residências e nos bairros da região central da cidade, e incremento de casos nos meses de janeiro, julho, agosto e dezembro. A faixa etária mais atingida foi de 0 a 15 anos, destacando-se o sexo masculino. Com relação à espécie animal envolvida, a canina foi a responsável pela maioria dos agravos, sendo 67,5% dos cães e 22,2% dos gatos declarados vacinados; os cães estavam sadios em 77,8% dos casos. Das pessoas agredidas, 81,6% receberam profilaxia pós-exposição, num total de 7.108 doses de vacina e a um custo aproximado de R$179.105,14. A análise detalhada dos dados, aliada ao fato de Jaboticabal ser considerada região controlada para a raiva, permitem questionar que 1.720 pessoas podem ter recebido vacina sem necessidade. Uma maior atenção deve ser dispensada aos registros de atendimento a agravos por animais, e uma análise acurada e mais criteriosa destes deve ser feita para que os tratamentos sejam instituídos adequadamente. Como a maioria dos acidentes ocorre em residências, portanto com cães e gatos domiciliados e vacinados, recomendam-se programas educativos para promoverem a posse responsável e o conhecimento dos cuidados que as pessoas devem ter com seus animais de estimação. / Abstract: A large number of rabies post-exposure treatment is annually given to humans attacked by animals. This study was aimed to evaluate the records and the conduct of rabies prophylaxis in humans, in the municipality of Jaboticabal, from 2000 to 2006, through the analysis of patients' records and geographic distribution of the accidents. The data were arranged in Excel® spreadsheets and were further analysed by EpiInfo® and MapInfo®. Also, the direct costs of given vaccines were calculated. From 3,056 patient's cards, it was observed 1 animal attack per 160 inhabitants, with higher occurence in residences, central neighborhoods and concentration of attacks in the months of January, July, August and December. The most affected age group was that of 0-15 years old, with predominance in males. As to animal species, dogs were responsible for causing the majority of accidents. 67.5% of dogs and 22.2% of cats had already been vaccinated before attacking. In 77.8% of occurences, the dogs were healthy. As to attacked humans, 81.6% of them received post-exposure prophylaxis, totalizing 7,108 antirabies vaccine doses at an approximate cost of R$179.105,14. Thorough data analysis and the fact that Jaboticabal lies in a rabies controlled region allow to question the administration of post-exposure vaccination in 1,720 persons. More attention should be payed to filling out and interpreting patient's records correctly, so that treatments can be properly established. As most attacks happen in the residences, where cats and dogs are usually domiciled and vaccinated, it is essencial to develop educational programs that promote responsible pet ownership and adequate pet handling and care. / Mestre

Orientador: Sonia Maria Alves Bueno / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Química / Made available in DSpace on 2018-08-09T16:21:01Z (GMT). No. of bitstreams: 1 Silva_PaulaTimoteoda_D.pdf: 1311022 bytes, checksum: 1652a409f13e2bb4e1a18a9dcb28d2fa (MD5) Previous issue date: 2007 / Resumo: Raiva ou hidrofobia é uma infecção viral que atinge o sistema nervoso central, ocorrendo em animais e humanos. As proteínas principais encontradas no vírus da raiva que atuam ativando o sistema imune são a nucleoproteína N (NPV) e a glicoproteína G, uma proteína transmembrana que forma o envelope viral e induz a produção de anticorpos neutralizantes que protegem contra o ataque viral. Este trabalho visou a purificação da glicoproteína G do vírus da raiva com cauda de polihistidina (GPV) a partir do lisado e do sobrenadante da cultura de células de inseto Drosophila melanogaster Schneider 2 (S2AcGPV2), transfectadas com o vetor pAc 5.1/V5-His A contendo o gene da GPV, empregando cromatografia de afinidade por íons metálicos imobilizados (IMAC). Os aspectos abordados neste trabalho foram a derivatização do gel de agarose com o agente quelante ácido iminodiacético (agarose-IDA) e a avaliação da seletividade, capacidade e reprodutibilidade do gel de agarose-IDA-Ni2+ na adsorção da GPV em função de diferentes sistemas tamponantes e de diferentes estratégias de dessorção de GPV (abaixamento de pH ou aumento da concentração de agente competitivo). A seletividade em cada sistema tamponante foi determinada por eletroforese SDSPAGE das frações dos picos de proteína obtidos nas cromatografias e a quantificação de GPV presente nas frações cromatográficas foi realizada através de ensaios do tipo ELISA. A melhor condição utilizada para a purificação da glicoproteína G foi a alimentação de lisado de células em coluna contendo agarose-IDA-Ni2+ equilibrada com tampão fosfato de sódio 20 mM, cloreto de sódio 500 mM, imidazol 2 mM pH 7,0. A lavagem foi realizada com tampão fosfato de sódio 20 mM, cloreto de sódio 500 mM, imidazol 2 mM pH 6,0 e a eluição por aumento de concentração de imidazol para 200 e 500 mM. Os resultados demonstraram a potencialidade de utilização do método de IMAC para a purificação da glicoproteína G do vírus da raiva / Abstract: Rabies or hydrophobia is a viral infection that affects the central nervous system, occuring in animals and humans. The main proteins found in rabies virus that activates the immunological system are the N nucleoprotein (NPV) and the G glycoprotein, a transmembrane protein that forms the spikes of the virus and induces virus-neutralizing antibodies that protect against infection. This research aimed at the purification of the rabies virus glycoprotein containing a polyhistidine tag (GPV) from lisate and supernatant of Drosophila melanogaster Schneider 2 (S2AcGPV2) cells culture, transfected with the vector pAc 5.1/V5-His A containing the GPV gene, using immobilized metal íon affinity chromatography (IMAC). The aspects developed in this project were the agarose gel derivatization with the chelating agent iminodiacetic acid (IDA) and the evaluation of the agarose-IDA-Ni2+ gel seletivity, capacity and reproductibility at the GPV adsorption, regarding different buffer systems and different GPV's desorption strategies (lowering the pH of the buffer or increasing the concentration of a competitive agent in the buffer). The seletivity in each buffer system was determined by performing SDS-PAGE electrophoresis on the chromatographic samples with the larger concentration of proteins, and the GPV quantification in these samples was determined by ELISA assays. The best results of purification were found when lisate was fed into an agarose-IDA-Ni2+ column equilibrated with 20 mM sodium phosphate buffer containing 500 mM sodium chloride and 2 mM imidazole pH 7,0. The washing step was proceeded with 20 mM sodium phosphate buffer containing 500 mM sodium chloride and 2 mM imidazole pH 6,0 and the elution proceeded by raising the imidazole concentration at the wash buffer to 200 e 500 mM. The results demonstrated the potencial of using IMAC to purify rabies virus G glycoprotein / Doutorado / Desenvolvimento de Processos Biotecnologicos / Mestre em Engenharia Química

Made available in DSpace on 2016-05-02T13:55:27Z (GMT). No. of bitstreams: 1 SoniaTerezaAngelo-Dissertacao.pdf: 3049204 bytes, checksum: e94b8691ed3c747a310a78102bc4cf24 (MD5) Previous issue date: 2011-05-25 / Dogs are transmitters of several zoonoses, and rabies has the highest epidemiological importance for being 100% lethal. Dog bites represented the most frequent notifiable injuries in Muzambinho, MG, in the 2005-2009 period, where many people were submitted to prophylaxis against rabies. This study evaluated the potential risk of rabies and respective injuries in the population. In September 2010, 427 questionnairies were randomly and systematically applied to residents of the 21 urban districts, who were classified according to their socioeconomic and cultural profiles. The survey of indicators pertinent to race, sex, form of acquisition, feeding, mobility, vaccination, sanitary conditions and fertility of the animals facilitated the construction of the epidemiological profile of the canine population in the urban area. The data were submitted to the chi-square test and multiple correspondence analysis in the R version 2.11.1 statistical software. It was found that 73% of the dogs were vaccinated at public health services; 9% at private services; while 18% were not vaccinated. Race and sex proved to be significant factors for the acquisition of dogs; 63% of the animals were received as presents, 11.5% were bought, and 25% adopted; 40.65% were adequately fed, while 59.35% were not properly fed. Regarding mobility, 60.5% of the animals were restricted, and 39.5% semi-restricted. The canine population density decreased with the socioeconomic situation of the owners. Only 20% of the dogs were castrated, and 80% presented no form of fertility control. Vaccination and fertility control proved to be inversely proportional indicators, with similar values in males and females. Sanitary conditions of dogs were better with upper class owners (69.5%), followed by lower class (26.5%), and middle class (5%). It was observed that the high incidence of canine aggression was related with limiting factors of welfare rather than symptoms of canine rabies, and that the full implementation of the actions of the municipal rabies prevention program could lead to a decrease of such accidents, with relevant reflections on the local public health. / Os cães são transmissores de diversas zoonoses, sendo a raiva a de maior importância epidemiológica, por ser 100% letal. Agressões caninas representam o agravo de maior notificação, em Muzambinho MG, no período de 2005-2009, onde expressivo número de pessoas é submetido a tratamentos profilático de raiva. O presente estudo foi idealizado com o propósito de avaliar o potencial de risco de raiva, que tais agravos representam à população do município. Durante o mês de setembro de 2010, foram aplicados 427 inquéritos, de forma aleatória e sistemática, a moradores residentes nos 21 bairros urbanos, os quais foram estratificados, segundo o seus perfis socioeconômico e cultural. O levantamento de indicadores referentes à raça, sexo, forma de aquisição, alimentação, mobilidade, vacinação, condições sanitárias e fertilidade desses animais possibilitou a construção do perfil epidemiológico da população canina, domiciliada na área urbana do município. Os dados foram analisados pelo teste Qui-quadrado e submetidos à avaliação de correspondência múltipla, no software estatístico R versão 2.11.1. O estudo demonstrou que 73% dos cães foram vacinados na rede pública, 9% na rede privada e 18% não foram vacinados. Comprovou-se que raça e sexo foram fatores significativos na aquisição de cães, sendo que 63% dos animais foram adquiridos como presente, 11,5 % através de compra e 25,5% por adoção. Verificou-se que 40,65% dos cães recebem alimentação adequada e 59,35%, inadequada. Quanto à mobilidade, 60,5% dos animais são restritos e 39,5% semirrestritos. A densidade populacional canina decresceu de acordo com a situação socioeconômica dos proprietários. Somente 20% dos cães são castrados e 80% dos animais não apresentam nenhuma forma de controle de fertilidade. Comprovou se que vacinação e controle de fertilidade são indicadores inversamente proporcionais e com valores equivalentes a machos e fêmeas. As condições sanitárias foram melhores em cães de proprietários de classe alta (69,5%), seguidos pelos de classe baixa (26,5%), e esses, pelos de classe média (5%). Observou-se que a alta incidência de agressões caninas está mais relacionada a fatores limitantes de bem-estar do que a sintomas de raiva canina e que o cumprimento integral das ações do programa de prevenção da raiva no município poderia contribuir para a diminuição de tais acidentes com relevantes reflexos na saúde pública local.

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In response to an epidemic of rabies in the mid-Atlantic region, the Virginia Department of Health and the Consolidated Laboratory Services in 1982, redesigned their submission forms for animals being tested for rabies in an effort to elicit detailed information about the epidemiology of rabies in Virginia. The information collected from those submission forms was used in a mathematical model analysis of the epidemiology of raccoon rabies in Virginia for the years 1984 through 1987. Eleven explanatory variables and one response variable (positivity for rabies) were examined. The objective of this study was to develop a model, through logistic regression, that would explain the epidemiology of rabies in raccoons in Virginia, and determine the risk factors for prediction for positivity for rabies in raccoons in Virginia. This information would aid further surveillance efforts, preventive education programs, and in formulating future oral vaccination programs in raccoons. Multiway contingency tables were constructed (involving 2,3,4,5,and 6 way interactions), and log-linear models were fitted using an iterative fitting process to generate maximum likelihood estimates. The goodness of fit of each model was judged using the likelihood-ratio-chi-square p value (0.01). The backward stepwise model selection process was performed on logit models to find the best fitting model (0.01). The final model consisted of a combination of 17 four variable term models. Eight of the eleven explanatory variables remained important risk factors in the prediction of positivity for rabies in raccoons. To validate the model, it was applied to data collected in the years 1988 through July 1989. The model fit at the 0.01 level. Parameter estimates were calculated for each term in the model. All eight variables had main order effects (direct) on the response variable (positivity for rabies). Three second order effects were evident: age and season, behavior and season, and year and season. Future studies will involve applications of this model to other species to further explore the epidemiology of rabies, and to refine the model for practical applications. / Ph. D.

Rabies is a zoonotic disease that is caused by a virus. Rabies infects domestic and wild animals, and is spread to people through close contact with infected saliva trough bites or scratches. The disease is present on nearly every continent of the world but most human deaths occur in Asia and Africa. Dogs continue to be the main carrier of rabies in Africa and Asia and are responsible for the human rabies deaths worldwide.People most at risk of rabies live in rural areas. The economic burden of rabies in the developing world takes large toll by means pre and post exposure prophylaxis treatments, cost of vaccine and other hidden costs. The study is set out to investigate the effectiveness of house-to-house rabies vaccination in Magabheni Township in KwaZulu-Natal province, a region that has experienced rabies outbreaks since 1976s. It is well-known that control of rabies at the animal source is a key to control of the disease in humans. However the main problem faced in the control of this zoonotic disease is that vaccination of dogs is not sustained, as a large percentage of dogs are not accessible. Due to some hiccups in existing strategies, there is always a significant percentage of the dog population that is not accessible. The strategy proposed and investigated is indeed labour intensive but result is a much higher percentage of dogs being accessed. In brief the observation and questionnaires as tools to generate data. The data obtained will be useful and can be considered as a strategy for rabies control in the country and probably the region

Doctor of Philosophy / Department of Biology / Samantha Wisely / Emerging infectious diseases play an increasingly critical role in many biological fields, including conservation biology and public health. Many emerging diseases originate in wildlife, most are caused by viruses, and often emergence is due to adaptation to and amplification in a new host, frequently in areas where ecological transformation is occurring. These emergence patterns suggest that the complex interactions among host, virus, and landscape drive disease emergence. Terrestrial rabies in striped skunks (Mephitis mephitis) in the central Great Plains is an excellent model system to investigate the interactions among the components of disease emergence: host ecology, pathogen properties, and landscape features. Striped skunks are not only numerous in the central Great Plains, they are also the reservoir for two genetically distinct rabies strains that co-occur in the region. Additionally, the landscape in the central Great Plains has undergone significant land use change over the last 70 years through increased urbanization and industrial agriculture practices. I used a combination of molecular and spatial techniques to investigate the interactions among host, pathogen, and landscape. Molecular epidemiology results indicated that rabies strains in the central Great Plains exhibit different epidemiological properties, while population genetic analyses indicated that striped skunks in the region are highly admixed and comprise a single population. Spatial analysis revealed that landscape features such as rivers are not a barrier to striped skunk dispersal, but differentially influence the movement of the two rabies strains. Because striped skunks are reservoirs for many diseases other than rabies and are ubiquitous throughout North America, I also examined the historical movements and distribution of striped skunks in North America using a phylogeographic approach. Results revealed that a combination of multiple Pleistocene dispersal events and Holocene admixture are responsible for the contemporary population structure of striped skunks in North America, and allowed me to place my regional-scale striped skunk rabies study into a larger biogeographic context. My results support the use of a holistic approach for studying emerging infectious diseases that includes studies of viral characteristics, host ecology and biogeography, and spatial features.

Orientador: Adolorata Aparecida Bianco Carvalho / Coorientador: Luiz Fernando Pereira Vieira / Coorientador: Andressa de Souza Pollo / Banca: Ricardo Augusto Dias / Banca: Hélio José Montassier / Banca: Luzia Helena Queiroz / Banca: Ingrid Bortolin Affonso Lux Hoppe / Resumo: A raiva é uma doença viral infecciosa aguda, de caráter zoonótico, que atinge todas as espécies de mamíferos. No meio urbano, os cães e os morcegos, em especial os insetívoros e os frugívoros, são vistos como principais agentes transmissores da enfermidade, e ao pensar na sua interação com os seres humanos, os cuidados se intensificam, tendo em vista o risco de propagação da doença. O avanço nos estudos epidemiológicos baseados na análise molecular do vírus da raiva, nas últimas décadas, permitiu a identificação de reservatórios e a distribuição geográfica das variantes. No entanto, dada a constante adaptação genética do vírus aos seus hospedeiros, o presente estudo objetivou realizar uma análise filogenética e filogeográfica do vírus da raiva (RABV) de amostras provenientes de diferentes estados do Brasil, identificados como positivos pelo Instituto Pasteur, São Paulo/SP. Para tanto, foram analisadas sequências parciais do gene codificador da nucleoproteína de 71 amostras de Sistema Nervoso Central (SNC) de morcegos insetívoros Nyctinomops spp. Observou-se na análise filogenética que 65 das 71 amostras agruparam-se em um mesmo clado juntamente com amostras de morcegos insetívoros do banco de dados, representando uma variante específica desse gênero de quiróptero. As outras seis amostras dividiram-se em outros clados mostrando haver proximidade genética entre isolados de morcegos hematófagos e não hematófagos e também entre estes e outros mamíferos silvestres. Ainda foi possí... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Rabies is an acute infectious viral disease of a zoonotic character that affects all the mammalian species. In the urban area, dogs and bats, especially the insetivorous and frugivorous, are seen as the main transmitters of the disease, and when their interaction with humans is analyzed, care is intensified according to the risk of rabies propagation. Advances in epidemiological studies based on the molecular analysis of the rabies virus in recent decades have allowed the identification of reservoirs and the geographical distribution of variants. However, given the constant genetic adaptation of the virus to the hosts, the present study aimed to perform a phylogenetic and phylogeographic analysis of rabies virus (RABV) from different states of Brazil, identified as positive by Pasteur Institute, São Paulo/SP. For this, partial sequences of the nucleoprotein gene of 71 samples from insectivorous bats Nyctinomops spp were analyzed. It was observed in the phylogenetic analysis that 65 of the 71 samples were grouped in the same cluster with samples of insectivorous bats from the GenBank database, representing a specific variant of this bat genus. The other six samples were divided into other clusters showing genetic proximity between hematophagous and nonhematophagous bats isolates and also between these and other wild mammals. It was possible to find a bat from the municipality of Tabuleiro do Norte/RN with RABV belonging to a variant related to crab-eating foxes (Cerdocyon thou... (Complete abstract click electronic access below) / Doutor