Importance: Infectious diseases present an ever-changing threat to public health. Analysis of pathogen-linked mortality trends is elucidatory to infectious disease burden. Objective: To describe major shifts in United States infectious disease mortality trends from 1900-2013 with emphasis on recent changes for1980-2013. Design: Ecological study of infectious disease mortality in the United States. Setting: Infectious disease deaths were summed from Vital Statistic Reports from 1900-1967. Infectious disease deaths from 1968-2013 were extracted from the Centers for Disease Control and Prevention Wonder database and tallied. Participants: Deaths among United States residents from 1900-2013. Main Outcome Measures: Crude and age-adjusted mortality rates for key infectious diseases including emerging infections, specifically human immunodeficiency virus and certain vector-borne diseases, re-emerging diseases, specifically, vaccine-preventable diseases and pathogens with drug-resistant strains, and newly defined infectious diseases such as cervical cancer due to human papilloma virus. Results: While human immunodeficiency virus mortality has been declining since 1995 (average annual percent change = 10.6%, 95% Confidence Interval (CI) [-13.1, -7.9]), recent years have seen an increase in infectious disease mortality related to vector-borne diseases. Specifically, with the emergence of West Nile virus in the United States, vector-borne disease mortality increased from 34.5 deaths per year (1980-2001) to 141.7 deaths per year (2002-2013). Vaccine preventable disease mortality continues to decrease with an average annual percent change of 2.4%, 95% CI [-2.8, -2.0] from 1980-2013. Mortality due to drug-resistant strains of infectious diseases is increasing at an average annual percent change of 0.8%, 95% CI [0.1, 1.6] from 1980-2013. Finally, mortality due to a disease previously not classified as infectious, cervical cancer, has been decreasing at an average annual percent change of 1.4%, 95% CI [-1.7, -1.1] since 1980. Conclusions: Despite the overall downward trends in infectious disease mortality, they still account for 43 per 100,000 deaths annually in the United States. Specific diseases and disease groups evaluated in this study show inconsistent, but concerning, trends across emerging, re-emerging, and newly defined infectious diseases, indicating that infectious diseases remain a public health concern.

Infectious diseases are a major cause of morbidity and mortality worldwide. Streptococcus pneumoniae and Neisseria meningitidis are major causes of severe bacterial disease which can manifest as invasive disease such as bacteraemia and meningitis. Exposure to these pathogens is relatively widespread, yet only a minority of individuals develop invasive disease. A host genetic component to infectious disease susceptibility has been implied from twin and adoptee studies. A role for rare large effect genetic variants in predisposition to infection has been demonstrated through the study of individuals with primary immunodeficiencies. However, a majority of these studies have been undertaken in individuals with a history of recurrent disease or in multi-case families. The relative role of rare genetic variants of moderate to large effect at the population level has not been widely explored. This thesis presents effort made using next generation sequencing methods to identify rare genetic variants that lead to increased susceptibility to bacterial disease focussing on meningococcal disease, pleural infection(empyema), pneumococcal disease and sepsis phenotypes. Using an exome sequencing approach in 13 cases with invasive meningococcal disease, a novel mutation leading to a complement deficiency and increased risk of meningococcal infection was identified and functionally validated in one individual. This mutation in the CFP gene was demonstrated as leading to impaired properdin secretion. Further analysis implicated loss of function mutations in CD4 and ZAP70 as novel loci for meningococcal disease susceptibility. A case control association analysis for sepsis susceptibility highlighted the possible role for small Rho GTPases in sepsis pathology. By aggregating all rare predicted deleterious mutations in a gene, four genes in this pathway, (ROCK2, ARHGAP18, FYN and CDC42BPG) were implicated as having an excess of rare deleterious variants in sepsis samples compared to population controls. A similar approach identified low frequency genetic variants in the CD109 gene as predisposing to empyema susceptibility in children. Finally, preliminary evidence from adult individuals with invasive pneumococcal disease points to a potential role of the RNASE7 gene in invasive pneumococcal disease susceptibility. This association was primarily due to a predicted deleterious missense mutation present in cases and absent in controls. Taken together, these results have identified a number of potential loci with rare variants associated with susceptibility to severe phenotypes of bacterial diseases.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Para melhor avaliar a transmissÃo interfamiliar da infecÃÃo por H. pylori durante a infÃncia, foi investigada a prevalÃncia de infecÃÃo por H. pylori em famÃlias de uma comunidade urbana pobre de Fortaleza no Cearà com alta prevalÃncia de H. pylori . A infecÃÃo por H. pylori foi investigada em 570 membros de 128 famÃlias dessa comunidade, atravÃs do teste respiratÃrio marcado com 13C-urÃia em crianÃas e atravÃs do teste ELISA em mÃes e outros parentes adultos. A prevalÃncia geral da infecÃÃo por H. pylori em todos os indivÃduos analisados foi 65.9% (376/570) a qual aumentou com a idade (p <0,001) variando de 28,9%, em crianÃas de 6 meses a 5 anos, para 82% em adultos com mais de 40 anos. A existÃncia de infecÃÃo materna e o nÃmero de irmÃos infectados foram fatores de risco independentes para a infecÃÃo por H. pylori na infÃncia (OR = 2,2, IC95% = 1,0-4,6 e OR = 4.3, IC95% = 2,3-8,1, respectivamente). O nÃmero de irmÃos, nÃmero de irmÃos mais novos, e o nÃmero de irmÃos mais novos infectados tambÃm foram associados à infecÃÃo na infÃncia atravÃs da anÃlise univariada. O nÃmero de irmÃos mais novos infectados permaneceu independentemente associado com a infecÃÃo (p = 0,000), mesmo apÃs o controle de todas as variÃveis acima citadas, alÃm do status H. pylori de irmÃos e mÃes, idade, nÃmero de pessoas por quarto, e nÃmero de crianÃas no mesmo domicÃlio / To further evaluate interfamilial transmission of H. pylori infection during childhood, we investigated the prevalence of H. pylori infection in family members from a poor H. pylori high prevalence urban community in the Northeast of Brazil. H pylori infection was investigated in 570 members of 128 households, by 13C-urea breath test in children and by ELISA in mothers and other adult relatives. The overall prevalence of H. pylori infection 65.9% (376/570) increased with age (p < 0.001) and ranged from 28.9%, in children aged 6 months to 5 years to 82% in adults over 40 years. An H. pylori positive mother and the number of infected siblings are independent risk factors for childhood H. pylori infection (OR = 2.2, 95% CI = 1.0-4.6 and OR = 4.3, 95% CI = 2.3-8.1, respectively). The number of siblings, number of younger siblings, and number of infected younger siblings were also associated with the infection in the univariate analysis. The number of infected younger siblings remained independently associated with the infection (p=0.000), even after controlling for all the above cited variables, in addition to the H. pylori status of siblings and mothers, age, number of people per room, and number of children in the household. The transmission of H. pylori occurs from infected mothers to their offspring and among siblings, notably from younger siblings to the older ones.

Orientadores: Clarice Weis Arns, Helena Lage Ferreira / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-26T04:15:51Z (GMT). No. of bitstreams: 1 Martini_MatheusCavalheiro_D.pdf: 16763908 bytes, checksum: 65c4aed6451181f383a10560fce87e51 (MD5) Previous issue date: 2014 / Resumo: O vírus da Bronquite Infecciosa (VBI), pertencente à família Coronaviridae, é um importante patógeno à sanidade e fatores econômicos da produção avícola no Brasil e no mundo. O VBI possui múltiplos sorotipos e o frequente surgimento de novas variantes é um dos principais problemas relacionados a este vírus. Este trabalho tem como objetivo a investigação experimental da patogênese de um isolado de pombo (Columba/Brazil/2007/Unicamp/67T), caracterizado molecularmente pelo gene S1 como VBI sorotipo Massachusetts, e seus efeitos in vivo, em galinhas e camundongos. O presente estudo foi dividido em duas partes, na primeira um grupo de aves "specific pathogen free" (SPF) foi inoculado pela via óculo-nasal com a amostra viral proveniente de pombo. Os animais, de um dia de vida, foram sacrificados nos dias 2, 4, 5, 7, 9, 11, 14, 21, 28, 35 e 42 dias pós-inoculação (dpi). Foram coletados suabes de traqueia, seio nasal e cloaca, além de órgãos como pulmão, íleo, pró-ventrículo (coletado entre 7 e 21 dpi), rim, tonsilas cecais (coletada a partir de 4dpi) e testículos (coletado a partir de 5 dpi). Sinais clínicos respiratórios como espirros, estertores, corrimento nasal, além de letargia, diarreia e perda de coordenação foram observados principalmente no 5dpi. A inibição da atividade ciliar ocorreu concomitantemente ao pico de sinais clínicos das aves. Foi analisado tropismo tecidual, através da quantidade de RNA viral detectado, pelo trato digestório. Os maiores títulos de RNA viral foram detectados na tonsila cecal, seguida pelo íleo (ambos no 5dpi) e cloaca (no 2dpi). Além disso, houve detecção de RNA viral no rim e trato respiratório, com maior título de RNA viral na traqueia. Os órgãos que apresentaram maiores danos teciduais através do exame histopatológico foram o rim, íleo e traqueia (todos no 5dpi). Por fim, as aves inoculadas com a amostra do VBI oriundo de pombo produziram anticorpos entre os dias 14 e 21dpi, detectados no soro destes animais através do ELISA. Na segunda parte do trabalho, a capacidade de replicação de diferentes variantes do VBI em camundongos foi avaliada. Para tanto, camundongos das linhagens Balb/C e A/J foram inoculados pela via nasal com duas amostras do sorotipo Massachussets (Mass) e com a variante brasileira (BR-I), e sacrificados no 3, 10 e 14 dpi. Não foram observados sinais clínicos nem lesões macroscópicas graves. O RNA viral foi detectado em todos os órgãos coletados, sendo os principais órgãos de replicação o seio nasal e pulmão (no 3dpi) para os camundongos da linhagem A/J e pulmão e duodeno (ambos no 3dpi) na linhagem de camundongos Balb/C, nos quais os títulos virais detectados foram mais altos. Pneumonia intersticial, edema e infiltrado mononuclear foram as principais alterações histopatológicas observadas no 3dpi em camundongos inoculados com as diferentes variantes. A presença da nucleoproteína viral, pela imunohistoquímica, foi detectada no duodeno, traqueia e pulmão de camundongos no 3dpi nas duas linhagens de camundongos. Os anticorpos contra o coronavírus aviário foram detectados somente no 3dpi. Assim, os resultados do presente estudo demonstraram que a variante Massachussets, com origem de pombo, causa a doença clínica em aves comerciais não vacinadas e pode replicar em modelo mamífero por um curto período de tempo, ressaltando a importância da vacinação e o papel potencial dos roedores como possível reservatório e carreador do vírus / Abstract: Infectious bronchitis virus (IBV) belonging to the family Coronaviridae is an important pathogen to sanity and economics of poultry production in Brazil and worldwide. The VBI has multiple serotypes and the frequent emergence of new variants is one of the main problems related to this virus. This work aims to experimentally investigate the pathogenesis of pigeon sample (Columba/Brazil/2007/Unicamp/67T), molecularly characterized by S1 gene as IBV Massachusetts serotype, and its effects in vivo in chickens and mice. This study was divided into two parts. In the first part, a group of birds "specific pathogen free" (SPF) was inoculated by oculo-nasal route with the viral sample from pigeon. The animals with one-day-old, were sacrificed on 2, 4, 5, 7, 9, 11, 14, 21, 28, 35 and 42 days post-inoculation (dpi). Tracheal swabs, nasal sinus and cloaca were collected, and organs such as lung, ileum, pro-ventricular (collected between 7 and 21dpi), kidney, caecal tonsils (collected from 4dpi) and testes (collected from 5 dpi). Clinical signs such as sneezing, rales, nasal discharge, lethargy, diarrhea, and loss of coordination were observed mainly in the 5dpi. Inhibition of ciliary activity occurred concomitantly with the peak of clinical signs of birds. Tissue tropism was analyzed by the amount of viral RNA detected by the gastrointestinal tract. The higher titers of viral RNA were detected in the cecal tonsil, followed by the ileum (both in 5dpi) and cloaca (in 2dpi). In addition, viral RNA was detected in the kidney and respiratory tract, with highest titer of viral RNA in the trachea. The organs that showed severe tissue damage by histopathology were the kidney, ileum and trachea (all in 5dpi). Finally, the birds inoculated with the sample originated from IBV Pigeon produced antibodies between 14 and 21dpi, detected in the serum of these animals by ELISA. In the second part, the replication capacity of different variants of IBV in mice was evaluated. For this, mice of strains BALB/C and A/J were inoculated intranasally with two strains of Massachusetts (Mass) serotype and the Brazilian variant (BR-I), and sacrificed at 3, 10 and 14 dpi. No clinical signs or severe macroscopic lesions were observed. The viral RNA was detected in all organs collected, higher tittles were detected on sinus and lung (in 3dpi) for mice of strain A/J and on lung and duodenum (both in 3dpi) in the line of Balb/C; in this line the viral titles were higher than the strain A/J. Interstitial pneumonia, edema and mononuclear cell infiltration were the main histopathological changes observed in 3dpi in inoculated mice with different variants. The presence of viral nucleoprotein, immunohistochemistry was detected in the duodenum, trachea and lungs of mice in 3dpi in both mice strains. Antibodies against avian coronaviruses have been detected only in 3dpi. Thus, the results of this study demonstrate that the Massachusetts variant, originating from pigeon, cause clinical disease in commercial poultry unvaccinated and can replicate in mammalian model for a short period of time, emphasizing the importance of vaccination and the potential role of rodents as possible reservoir and the carrier virus / Doutorado / Microbiologia / Doutora em Genética e Biologia Molecular

The availability of attenuated, bitypic, genetic recombinant strains of herpes simplex virus (HSV) made possible the following investigations. The recombinant virus, D5E1, exhibited limited, short-lived replication in the central nervous system of mice and guinea pigs. Nevertheless, this virus was sufficient to stimulate substantial levels of neutralizing antibody and localized cellular immunity in genital tissue. Immunization with D5El protected mice and/or guinea pigs against (HSV) type l and 2 infections when the challenge virus was given by a variety of pathways. In particular, it reduced vaginal virus shedding, inflammation, and acute and latent infection of the regional ganglia. The degree of protection in mice was influenced by the strain of rodent, the route of challenge and type of wild virus. Vaccination of newborn mice with live, attenuated virus also resulted in protection against HSV-2 subsequently inoculated into the footpad. The ability of recombinant HSV strains to establish latent ganglionic infection was related to their virulence, the route of inoculation and the genetic strain of the mouse. The D5E1 vaccine failed to establish latent disease by itself, but nevertheless conferred good protection against HSV type 1 or 2 challenge of immunized mice or guinea pigs.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality in the U.S. and worldwide. Atherosclerosis, the buildup of plaque in the arteries, is a common cause of CVD. For many years, research in atherosclerosis was focused on lipid metabolism and the accumulation of low-density lipoprotein in the arteries. While this research set public health guidelines for lipid management, lipid concentration was not the only factor influencing atherosclerosis and CVD events. Many scientists, as far back as the 1850’s recognized the role of inflammation in the progression of atherosclerotic disease. The continuous low levels of immune activation in the body contribute to atherosclerosis. Research in animal models and epidemiologic studies have shown the involvement of both the innate and the adaptive immune systems in plaque development and to elucidate the roles of monocytes and T cells. In addition to animal studies and epidemiologic research, CVD and atherosclerotic research has extended to genetic analysis in the search for associations with risk factors and outcomes. The first chapter is a review of the literature studying the immune system’s involvement in atherosclerosis. Beginning with an examination of the impact of CVD and atherosclerosis, the basic pathophysiology, and the involvement of the innate and adaptive immune systems through animal models and epidemiology. Some of the significant cohort studies in CVD and genome wide association studies are also discussed. Chapter 2 examines the associations of soluble interleukin 2 receptor alpha (sIL-2Rα) with clinical events in the Cardiovascular Health Study and genetic variants. Interleukin 2 (IL-2) and its receptor regulate both tolerance and immunity, IL-2 induces the proliferation and differentiation of T cells, part of the adaptive immune system. The results showed an association between sIL-2Rα and CVD events. The genome-wide association study found 52 variants to be significantly associated with sIL-2Rα in European Americans. Chapter 3 assesses the involvement of the innate immune system in atherosclerosis through the associations of soluble CD163 (sCD163). CD163 is a marker of macrophage activation, specifically associated with M2 macrophages. In CHS, sCD163 levels were analyzed for associations with cardiovascular events and genetic variants. sCD163 was found to be associated with CVD risk factors and with cardiovascular events. In a genome-wide association study six variants in European Americans and three variants in African Americans were found to be significant. Chapter 4 summarizes the results and discusses some bench to bedside translational science already seen in atherosclerosis treatment and prevention. Continued investigation of markers of T-cell and monocyte differentiation in animal models and cohort studies may lead to opportunities for the prevention of atherosclerosis and/or treatment through an increased understanding of the biology and genetics of the innate and adaptive immune.

Master of Science / Department of Diagnostic Medicine/Pathobiology / Ying Fang / Seneca Valley Virus (SVV) causes vesicular disease in pigs. Vesicular lesions on the snout and coronary band of hoof mostly resemble lesions caused by Foot-and-Mouth Disease Virus (FMDV), which may lead to the foreign animal disease investigation. In 2015, Brazil experienced major outbreaks of SVV; then in July, sporadic cases of SVV were reported in United States and became a concern in swine industry. A reverse-genetic system serves as a major tool to study pathogenesis of the virus. In our study, a full-length cDNA infectious clone, pKS15-01-Clone, was constructed from an emerging Seneca Valley Virus (SVV; strain KS15-01). To explore the potential use as a viral backbone for expressing marker genes, the enhanced green fluorescent protein (EGFP)-tagged reporter virus (vKS15-01-EGFP) was generated using reverse genetics. Compared to the parental virus, the pKS15-01-Clone derived virus (vKS15-01-Clone) replicated efficiently in vitro and in vivo, and induced similar levels of neutralizing antibody and cytokine responses in infected animals. In contrast, the vKS15-01-EGFP virus showed impaired growth ability and induced lower level of immune response in infected animals. Lesions on the dorsal snout and coronary bands were observed in all pigs infected by parental virus KS15-01, but not in pigs infected with vKS15-01-Clone or vKS15-01-EGFP viruses. These results demonstrated that the infectious clone and EGFP reporter virus will be important tools in further elucidating the SVV pathogenesis and development of control measures.

The effect of infectious diseases on the population in the developing countries is of utmost concern. Malaria, tuberculosis (TB) and human immunodeficiency virus (HIV) are the three major infectious disease threats. They account for approximately half of the mortality caused by infectious diseases, which is almost half of the mortality in the developing countries. With no vaccine likely in the foreseeable future, drugs remain the best means of controlling infectious diseases. In the industrialized nations at the present time, some 50% of all prescribed drugs are derived or synthesized from natural products (animals, marine species, plants and micro-organisms). It has been estimated that plants are the most important source of medicine for more than 80% of the world’s population. As previous work on the leaves of Croton steenkampianus gave promising results and revealed that it still contained bioactive compounds that could be isolated, it was chosen for further work. The bioassay guided fractionation of the ethanol crude extract using silica and Sephadex column chromatography resulted in the isolation of six compounds: three flavoniods (quercetin, tamarixetin and eriodictyol), one new indane (1) (2,6-dimethyl-1-oxo-4 indanecarboxylic acid) and two new diterpenes (steenkrotin A (2) and steenkrotin B (3)) with novel skeletons. The structure of the compounds was determined using NMR, IR, UV, MS and X-ray crystallography. Ethanol crude extract, quercetin, steenkrotin A, steenkrotin B and the indane were tested against four strains of Plasmodium falciparum (D6, D10, Dd2 and W2). Quercetin showed good antiplasmodial activity against the D10 and Dd2 strains. The antiplasmodial activity of steenkrotin A and crude extract were moderate. The antimalarial activity of steenkrotin A in particular is promising, as it showed more activity against resistant strains. The indane, and steekrotin B were not active against the strains of P. falciparum used (IC50 > 10 μg/m). The IC50 of the compounds improved when they were combined with chloroquine. However, the IC50 of chloroquine was still the lowest. The compounds showed moderate bioactivity against Bacillus cereus and Escherichia coli. The three new compounds (1, 2 and 3) tested against Mycobacterium (H37Rv) were not active (IC50 > 10 μg/ml). The indane (1) showed anti-HIV activity at 50 μg/ml against reverse transcriptase. The antioxidant activity of the compounds tested ranged from weak to excellent (>280.00 μg/ml for compound 1 and 2 to 0.05 μg/ml for quercetin). The cytotoxicity of the compounds and extract were determined against Vero cells lines. Their IC50 values ranged from 34.0 to 305.9 ìg/ml, which is higher and better than that of chloroquine. The IC50 values obtained are: chloroquine (25.0), quercetin (33.6), steenkrotin A (35.0), ethanol extract (45.0), tamarixetin (53.8), indane (248.2) and steenkrotin B (305.9). / Thesis (PhD)--University of Pretoria, 2009. / Plant Science / unrestricted

Background Active Learning using smartphone technology can be implemented as a tool for teaching medical students (MS) and residents (Rs). The use of technology would increase participation and enhance student learning by engaging them in solving ID clinical case scenarios. Our objective was to describe the methods used and to share the opinions of the users of such active learning methods. Methods The smartphone applications used were Socrative and WhatsApp. We used Socrative during the Universidad Peruana de Ciencias Aplicadas (UPC) ID course for MS in two different ways. In selected lectures (4 of 32), teacher paced questions were asked based on clinical scenarios related to the topic reviewed, and by voluntary homework questionnaires (student paced). At the British American Hospital (BAH) Medicine Department (MS and Rs) Socrative was used similarly: during some noon lectures (teacher paced questions) and during the baseline MS exam and Rs mid-year exam and voluntary homework questions (student paced). WhatsApp is currently used at the BAH with questions send from Monday to Friday. MS /Rs answer individually via WhatsApp to the mentor in charge. The right answer is given the next day. Questions using WhatsApp deal with recent cases seen at the Wards or in the outpatient clinic, and are designed so that the MS/Rs must do quick literature searches in order to provide the right answer. Results Forty-one MS/Rs answered the survey on Socrative use, 25 of 48 (52%) of UPC MS and 16 (89%) MS/Rs from the BAH. Forty (97%) believed using Socrative had influenced their learning and all but 2 believed it promoted participation from the class. 36 (87.8%) would like to have Socrative used in other lectures and 35 (85%) in other courses. Only one person voted against Socrative use in courses or lectures. With regards to WhatsApp use 16 MS/Rs from BAH answered the survey. Six had used before WhatsApp as a teaching tool. All felt the methodology was useful for learning and promoting reading and would recommend this methodology to promote learning on a student paced way. Conclusion Socrative and WhatsApp can be used for teaching ID through MS/Rs smartphones. Most MS/Rs who were surveyed recommended the use of such methods in their education.

This thesis examines the potential interface that exists between health information, specifically electronic health record (EHR) systems, and notifiable disease surveillance in Canada. It aims to highlight the benefits and barriers experienced by the current national notifiable disease surveillance strategy, as well as to highlight the successes and roadblocks to the successful implementation and adoption of EHR technologies in Canada. Qualitative methodologies, which include the 16 semi-structured interviews conducted with four key stakeholder groups, including public health experts, physicians, health administrators and academics that are concerned with EHR adoption and public health were used to obtain data. Data from interviews was analysed using grounded theory methodology and then verified using member checking and other data validation methods. Emergent themes from obtained data indicated that there is a large potential for the improvement of the current notifiable disease through the use of EHR technologies: however, the barriers currently faced by both the notifiable disease surveillance system and the state of implementation and adoption of EHR technologies prevent this from occurring. These barriers include political, financial, human, security/privacy, and technology barriers. Differences between stakeholder groups were explored, and potential solutions and insights into existing barriers were provided. The information gained from this study provides insight into the efficiency of the current infectious disease surveillance system and the progress of and need for the implementation of EHRs nationwide. In addition, the results of this study provide stakeholders with a deeper understanding of the barriers facing the use of EHR technologies for infectious disease surveillance and provide a starting place to address these issues. The results of this study can help to inform policy regarding public health surveillance and EHR implementation and adoption.