At the author’s request, the abstract has been removed due to the confidential nature of the thesis. It will be added once the embargo period has passed.

The study was conducted with a total of 13980 children of the 1995 birth cohort, who were living in Manitoba by the end of December, 2006. Higher frequency of RSV-associated LRTI before 2 years was associated with higher risks of asthma diagnosis at 7 and 11 years and also with risks of transient wheeze and early persistent asthma. Higher risk of asthma diagnosis was associated with more severe episode(s) of RSV-associated LRTI within the first 2 years of life. First clinically significant RSV-LRTI between 6 and 12 months was associated with the highest risks of asthma diagnosis at 7 and at 11 years. But first RSV-associated LRTI within the first 6 months of life was associated with the highest risk of asthma/transient wheezing before the age of 3 years and early persistent asthma and transient wheeze. These associations were diminishing with increasing age of the children of the study cohort.

The study was conducted with a total of 13980 children of the 1995 birth cohort, who were living in Manitoba by the end of December, 2006. Higher frequency of RSV-associated LRTI before 2 years was associated with higher risks of asthma diagnosis at 7 and 11 years and also with risks of transient wheeze and early persistent asthma. Higher risk of asthma diagnosis was associated with more severe episode(s) of RSV-associated LRTI within the first 2 years of life. First clinically significant RSV-LRTI between 6 and 12 months was associated with the highest risks of asthma diagnosis at 7 and at 11 years. But first RSV-associated LRTI within the first 6 months of life was associated with the highest risk of asthma/transient wheezing before the age of 3 years and early persistent asthma and transient wheeze. These associations were diminishing with increasing age of the children of the study cohort.

Hintergrund: Infektionen mit dem Respiratory Syncytial Virus (RSV) sind die häufigste virale Ursache für respiratorische Erkrankungen bei Säuglingen und Kleinkindern. Reinfektionen treten lebenslang auf. Es wurden zwei Typen (A und B) und mehrere Genotypen beschrieben. Die vorliegenden Daten über die molekulare Epidemiologie von RSV in Deutschland sind nur begrenzt. Material und Methoden: Zwischen Januar 2002 und Juli 2006 wurden 221 Nasenrachensekrete (NRS) von Kindern, welche in der Universitätskinderklinik Würzburg behandelt wurden, durch Routine-Untersuchung mit einem Immunfluoreszenztest auf RSV-Antigen positiv befunden. Die phylogenetische Analyse wurde aus Restmaterial von 211 NRS durchgeführt, indem die zweite variable Region des G-Gens amplifiziert und sequenziert wurde. Ergebnisse: Insgesamt war die Prävalenz von Typ A-Viren mit 69,5 % größer als die der Typ B-Viren mit 30,5 %. RSV Typ A war das dominierende Virus in allen Saisons außer in der Saison 2002-2003. Über den gesamten Beobachtungszeitraum traten drei A-Genotypen (GA2, GA5 und GA7) und vier B-Genotypen (GB3, SAB3, BA und ein neuer Genotyp) auf. Die Genotypen GA2, GA5, SAB3 und BA waren am häufigsten im Umlauf und in beinahe allen Saisons prävalent. Unter den B-Genotypen nahm der Anteil des Genotyps BA von 25 % (2002) auf 92 % (2005-2006) zu. Drei Typ B-Sequenzen wurden einem neuen Genotyp zugeordnet, welcher BWUE benannt wurde. Es wurde eine Reinfektion mit demselben Genotyp (GA5) bei einem Kind beobachtet, welches im Alter von 12 und 28 Monaten mit einer RSV-Infektion hospitalisiert war. Schlußfolgerung: Die Ergebnisse unserer Studie stehen in Einklang mit der molekularen Epidemiologie von RSV in anderen geographischen Regionen. Wir beobachteten sowohl Genotypen, welche über mehrere Saisons prävalent waren, als auch Genotypen, welche über den beobachteten Zeitraum zunehmend dominanter werdend andere Genotypen verdrängten. Zudem wurde ein neuer B-Genotyp entdeckt. / Title: Molecular epidemiology of respiratory syncytial virus infections in Underfranconia between 2002 and 2006 Background: The respiratory syncytial virus (RSV) es the most common viral cause of respiratory infections in infants and children. Reinfections occur lifelong. Two RSV subtypes (A and B) and several genotypes have been described. The available data on the molecular epidemiology of RSV in Germany are only limited. Material and methods: Between January 2002 and July 2006, 211 respiratory samples of infants and children treated in the Children’s Hospital of the University Würzburg were found to be positive for RSV antigen by routine testing with immunofluorescensce assays. Phylogenetic analysis was performed on 211 of these samples by amplification and sequencing of the second variable region of the RSV G gene. Results: The type distribution of the 211 RSV positive samples was 69,5 % type A and 30,5 % type B. RSV type A was the predominating virus in all seasons except for the winter season 2002/03. Over the whole observation period, three different A-genotypes (GA2, GA5, GA7) and four different B-genotypes (GB3, SAB3, BA and novel genotype) were detected. The RSV genotypes GA2, GA5, SAB3 and BA were most frequently found and were prevalent in almost all seasons. Among the B-genotypes, the proportion of the genotype BA increased from 25 % in 2002 to 91 % in 2005/06. Three type B sequences were assigned to a novel genotype, which was tentatively named BWUE. One reinfection with the same genotype (GA5) was observed in a child who was hospitalised with RSV infection at the age of 12 and 28 months. Conclusion: The results of our study are in agreement with the molecular epidemiology of RSV in other geographical regions. We observed both genotype persistence and genotype shifting during the observation period. In addition, we detected a novel B genotype.

Introduction Acute lower respiratory infection (ALRI) remains as a leading cause of childhood morbidity and mortality. With the continued universal vaccination campaign against bacterial pathogens, an increase in relative proportion of respiratory viruses contributing to ALRI is anticipated. Respiratory syncytial virus (RSV) has been recognised as the most common pathogen identified in young children presenting with ALRI as well as an important cause of hospital admission. This thesis aims to estimate the aetiological roles and attributable fractions of common respiratory viruses among ALRI cases and investigate the risk factors for RSV associated ALRI in young children. It also aims to estimate the global and regional incidence of RSV associated ALRI in both community and hospital based settings, and the possible boundaries for RSV associated ALRI mortality in children younger than five years old. Methods Systematic reviews were carried out separately for the following three research questions: aetiological roles of RSV and other common viruses in ALRI cases, risk factors for RSV associated ALRI and global/regional burden of RSV associated ALRI, formulating an overall picture of epidemiology of RSV associated ALRI in young children. They all focused on children younger than five years old. The identified studies were selected according to pre-defined inclusion and exclusion criteria. The whole process was conducted following the PRISMA guidelines for systematic review and meta-analysis. Unpublished data from RSV Global Estimates Network (RSV GEN) were collected from 45 leading researchers on paediatric pneumonia (primarily in developing countries). They either reanalysed data from their already published work with the pre-defined standardised case definitions or shared hitherto unpublished data from ongoing studies. Data from both systematic reviews and RSV GEN working group were included into further meta-analysis. Random effects model was consistently applied in all meta-analyses. Results There were 23 studies identified through literature search satisfying the eligibility criteria, investigated the viral aetiology of ALRI in young children. Strong evidence was observed for RSV in support of its causal contribution in children presenting with ALRI and the association was significant measured in odds ratio: 9.79 (4.98-19.27). Thus, the corresponding attributable fraction among the exposed was estimated as 90% (80%-95%), which means around 90% of RSV associated ALRI cases were in fact attributed to RSV in a causal path. In total, 27 studies (including 4 unpublished studies) were included and contributed to the analysis. Across these studies, 18 risk factors were described and 8 of them were observed to have significant associations with RSV infection: prematurity - gestational age < 37 weeks, low birth weight (< 2.5 kg), being male, having siblings, maternal smoking, history of atopy, no breastfeeding and crowding - > 7 persons in household. Overall, 304 studies met the selection criteria and were included to estimate the global and regional burden of RSV associated ALRI in young children. These included 73 published articles identified through Chinese language databases and 76 unpublished studies provided by RSV GEN working group, mainly from developing countries. It is estimated that in 2015, there were 33.0 (95% CI 20.6-53.2) million episodes of RSV associated ALRI occurring in children younger than 5 years old across the world. 30.5 (95% CI 19.5-47.9) million of them were in developing countries. 3.0 (95% CI 2.2-4.0) million cases were severe enough and warranted hospitalisation. Around 60,000 children died in the hospital settings with 99% of these deaths occurring in developing countries. The overall mortality from RSV associated ALRI was estimated about 131,000. Conclusion This thesis not only enhanced the epidemiological understanding of RSV in young children, but also provided important information for public health decision makers. It incorporated both data through systematic reviews of published articles in the past 20 years and more than 70 unpublished data sets shared by RSV GEN working group. The population based incidence, hospitalisation, mortality and risk factor data are essential to assess the various severity of illness in a specific age group and region, and inform local public health professionals regarding appropriate and prompt cases management, prevention and vaccine allocation strategies. National sentinel systems of RSV surveillance gathering structured and reasonably representative data are needed. Within the surveillance system, a universal definition regarding disease severity in various settings should be developed, and diagnostic methods with higher sensitivity and specificity should be applied.

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Made available in DSpace on 2014-06-11T19:26:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-02-09Bitstream added on 2014-06-13T19:53:58Z : No. of bitstreams: 1 rubio_ml_me_sjrp.pdf: 553575 bytes, checksum: e63be6b1c41d36a603fd12ca20a88442 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação para o Desenvolvimento da UNESP (FUNDUNESP) / Paramyxoviridae, é um vírus envelopado com tamanho médio de 120 a 300nm, de simetria helicoidal, que apresenta um genoma de RNA fita simples não segmentado de polaridade negativa. Este genoma codifica 11 proteínas, dentre as quais as glicoproteínas de membrana que são responsáveis pela infectividade do vírus. A proteína F, em associação com a proteína G e SH, é responsável pela fusão da membrana viral à célula que será infectada, ou seja, esta proteína proporciona a entrada e instalação do vírus na célula. Conhecer a forma de interação das proteínas da membrana viral com a célula que será infectada é importante para propor um mecanismo de inibição deste processo de infecção viral. Existem evidências que os glicosaminoglicanos são potenciais inibidores da infecção causada por vários vírus. A hipótese é de que este processo de inibição ocorra devido à ligação dos glicosaminoglicanos às proteínas da membrana viral, mais especificamente na proteína G, que apresenta um domínio de ligação para heparina, impedindo desta forma, que o vírus se ligue na célula hospedeira e que inicie o processo de infecção. O objetivo deste trabalho foi verificar a atuação de glicosaminoglicanos como potenciais inibidores da infecção viral. Esta análise foi realizada por meio de experimento de cultivo de células Hep2 na presença dos glicosaminoglicanos heparina e dextrana sulfatada que foram inoculadas com o vírus sincicial respiratório do tipo A (RSVA) e analisados por meio das técnicas de PCR e Imunofluorescência Indireta. Os resultados mostraram que a heparina e a dextrana sulfatada apresentam efeito inibitório da infecção viral em cultivo de células Hep2. / The respiratory sincicial virus (RSV) is part of Pneumovirus genus of the Paramyxoviridae family, is an enveloped virus with average size of 120 to 300nm, helical symmetry, that presents a genome consisting of a single strand, no segmented, RNA negative. This genome codifies for 11 proteins including the membrane glycoproteins which are responsible for the infectivity of the virus. Protein F in association with protein G and SH is responsible for the fusion of the viral membrane with the cell that will be infected, that is, this protein provides the entrance and the virus to settle in the cell. To know the form of interaction of viral membrane proteins with the cell that will be infected is important to propose a mechanism to inhibit of this process of viral infection. Evidences exist that the glycosaminoglycans are potential inhibitors of the infection caused by some viruses. The hypothesis is that this process of inhibition occurs more specifically due to the interation between glycosaminoglycans and the proteins of the viral membrane, more specifically in protein G, that presents a domain of linking for heparin, avoiding the virus to bind to the host cell and initiating the infection process. The aim of this work was to verify the performance of glycosaminoglycans as inhibitors of the viral infection. This analysis was accomplished through experiments of Hep2 cell culture in the presence of these glycosaminoglycans (heparin and dextran sulfate) that was inoculated with the respiratory sincicial virus type A (RSVA) and analyzed through the technique of PCR and Indirect Imunofluorecence. The results had shown that the heparin and the dextran sulfate presented an inhibitory effect of the viral infection in Hep2 cells culture.

Respiratory Syncytial Virus (RSV) infects the lower respiratory tract in children under the age of two years and is spread through droplet and contact with infected persons. An estimated 200,000 children suffer from complications of RSV annually worldwide. Palivizumab is a monoclonal antibody used to immunize children from RSV and has been on the market since 1988. In 2014, the American Academy of Pediatrics (AAP) updated its policy for recommendation of RSV in premature infants. The objective of this capstone is to propose an evaluation framework with an example of how it could have been applied to assess the impact of the AAP policy change on RSV vaccination use and RSV outcomes among premature infants. The proposed evaluation framework would be a unique link between birth certificate records and surveys of parents/guardians of 32 week gestation premature infants or less in the metropolitan Atlanta area. The birth certificate data would identify “at risk” infants and would allow for selection of a sample of parents/guardians, both pre-policy change (August 1, 2013 to July 30, 2014) and post-policy change (August 1, 2014 to July 30, 2015). The primary endpoints would be: initiation and completion of the RSV vaccine series and RSV infection rates. Moderating variables would be obtained from birth certificate data (e.g. mother’s education and race) and survey data (e.g. attitudes toward vaccine acceptance). The evaluation framework proposed in this Capstone can be used in future analyses of RSV vaccination policy changes. It can also be generalized to other geographic areas in the US and used for routine surveillance of RSV vaccination use and RSV outcomes.

The methodologies of systems design, rooted in engineering and in cognitivist conceptions of human action, have been stretched to the limit by the complexity of uses to which information and communication technologies are being turned. Within segments of the broader design community there has been a `turn to the social' - a perception that there is a need now for richer stories about the everyday practices systems designers build tools to support. This thesis is presented as a contribution to the corpus of `richer stories' about the what, how, why, when and where of information gathering. The thesis presents findings from an ethnographic study of newsroom information gathering at a UK daily newspaper. Adopting an analytical perspective based upon cultural-historical activity theory (CHAT), it describes and analyses journalistic information gathering on two mutually constitutive levels; that of activity and that of artefact mediation. Its starting point is that neither information gathering, nor the artefacts of information gathering, can be understood without consideration of the social, cultural and historical contexts within which they are situated. Ethnographic data is drawn upon to argue that journalistic information gathering can only be understood within the particular context of the `story lifecycle'. Stories are the principal object of journalistic enterprise, and the thesis examines in detail how everyday working practices are oriented towards this lifecycle. Based on an analysis of the artefacts of newsroom information gathering, and of the discourses of information systems designers, it is also argued that the discourses of systems designers over-emphasise the importance of the category `information'. In particular it is argued that sources are how journalists orient themselves in the vast, heterogeneous information spaces they simultaneously inhabit and populate. The background to these discussions is the often controversial relationship between ethnography, theory and systems design. This relationship is examined and it is argued that the CHAT perspective provides design ethnographers with an opportunity to move from ethnographic intuition to design insight. It is also argued that at a more pragmatic level, CHAT helps the fieldworker navigate the apparently never-ending mass of `potentially interesting material' any field experience throws up.