<p> Anaphylaxis is a potentially life-threatening systemic allergic reaction [1]. We aimed to determine the overall anaphylaxis incidence rate, the incidence of specific causes of anaphylaxis over time, and epinephrine auto-injector prescribing trends in Olmsted County, Minnesota. </p><p> Using the resources of the Rochester Epidemiology Project, a comprehensive records linkage system, we performed a population-based incidence study in Olmsted County, Minnesota, from 2001 through 2010. All cases with a diagnosis of anaphylactic shock and 20% of cases diagnosed with venom/bee sting, food allergy, and medication reactions were manually reviewed. Anaphylaxis incident cases were required to meet the National Institute of Allergy and Infectious Disease / Food Allergy and Anaphylaxis Network (NIAID/FAAN) diagnostic criteria. We also extracted all outpatient epinephrine prescriptions for all Olmsted County residents during 2003-2010 to further explore treatment of anaphylaxis. The sampling faction was accounted for in determining the reported number of anaphylaxis incidence cases. Incidence rates per 100,000 person-years were calculated using the adjusted number of incident cases of anaphylaxis (and likewise the number patients with a prescription) as the numerator and age- and sex-specific counts of the population of Olmsted County as the denominator. The relationships of age group, sex, and year of anaphylaxis with incidence rates were assessed by fitting Poisson regression models using the SAS procedure GENMOD. </p><p> We identified six hundred and thirty-one cases of anaphylaxis (51% male). The median age was 31 years (interquartile range 19-44). Incidence rates differed by year of diagnosis (p&lt;0.001) and by age group (p&lt;0.001). The overall age- and sex-adjusted incidence rate was 42 (95%CI 38.7 - 45.3) per 100,000 person-years. Four hundred and sixty eight cases (74%) of anaphylaxis were evaluated in the emergency department, 71 cases (11%) were admitted to the emergency department observation unit, and 92 cases (15%) were admitted to the hospital. Prescription data showed that the overall age- and sex-adjusted incidence rate of epinephrine prescriptions was 330 per 100,000 person-years (95% CI 320-340). Age-adjusted incidence rates for women and men were 369 (95% CI 354-385) and 288 (95% CI 274-302) per 100,000 person-years, respectively. Prescription incidence rates differed by year of diagnosis (p&lt;0.001), age group (p&lt;0.001), and sex (p&lt;0.001). The incidence rate of outpatient prescription decreased by year during 2003-2005 then became constant during 2005-2010. </p><p> Our master&rsquo;s degree thesis concludes that the overall anaphylaxis incidence rate was 42 per 100,000 person-years during 2001-2010 in the Olmsted County. The food, venom, and medication were the leading causes for anaphylaxis for younger age, middle age and the elderly, respectively. The majority of anaphylaxis cases were treated in the emergency department. The incidence rate of outpatient epinephrine prescriptions, which was 330 per 100, 000 person-years, decreased from 2003-2005 and reached plateau. Our study used updated diagnostic criteria for anaphylaxis and epinephrine prescription to demonstrate the flattening of the incidence. We would like to emphasize the clinicians to be aware of trend of anaphylaxis and supply of epinephrine in the community.</p>

<p> A personal belief exemption (PBE) has allowed parents to exempt their children from immunization when they are opposed to it based on their personal beliefs. As the number of PBE increased over the past few years, there was an increase in incidence of vaccine preventable diseases such as measles and pertussis among kindergartens. The current study examined the association between the percentages of PBEs filed by parents of kindergarten and three socio-demographic variables of schools including ethnicity, income level, and religious affiliation. The statistical findings showed that the percentages of PBE were lower among Asian Americans and Hispanics than Caucasians, higher among the religiously affiliated schools than religiously affiliated schools, and higher among south Orange County (OC) schools than north OC schools. The findings can help public health field detect which risk factors correlate the percentage of PBE and develop interventions more effectively and can help limit future outbreaks.</p>

HIV-1 persists to be a major health problem worldwide. A prophylactic or therapeutic vaccine offers the best hope to restrain the HIV-1 epidemic, however a consistent correlate of immune protection is yet to be found. HLA class I expression and their restricting HIV-1 specific CD8+ T cell responses have been shown to play a vital role in the control of HIV-1 infection. The interactions between HIV-1 and CD8⁺ T cell responses are complex and the mechanisms involved in the success or failure to control viraemia remain uncertain. Thus, the aim of these studies was to help define what CD8+ T cell responses a vaccine needs to induce to achieve durable immune control of HIV-1 infection. Focusing initially on HLA-B*35, an allele that has consistently been associated with rapid HIV-1 disease progression in the context of B clade infection, this study shows substantial differences in markers of HIV-1 disease outcome associated with different HLA-B*35 subtypes. Preliminary data suggest that effective targeting of a single epitope in Gag may be associated with HLA-B*35 mediated control of HIV-1 disease progression. Increased breadth of the Gag- specific CD8⁺ T cell responses is found to be associated with decreasing viral loads. These data therefore support the Gag hypothesis, and suggest that targeting of certain regions of the HIV-1 genome may have a positive effect in disease outcome, even for individuals carrying “detrimental” alleles. The extensive diversity of the HIV-1 genome and rapid viral adaptation are the main chal- lenges to vaccine design. Previous studies have suggested that effective CD8⁺ T cell responses drive selection of escape mutations that reduce viral replication capacity (VRC). There is also evidence that certain escape mutations can be transmitted from one host to another allow- ing for its accumulation in a population. The second study looked at the impact of HLA driven evolution of HIV-1 in VRC at a population level. This study compared two ART-naïve HIV-1 B clade infected cohorts, in Mexico and Barbados, in which protective HLA alleles (HLA- B*27/57/58:01/81:01) are expressed at 10% and 35% respectively, to analyze differences in VRC at a population level. Viral loads (VL) were found to be significantly higher in Mexico compared to Barbados and median CD4⁺ T cell counts significantly lower. Analysis of VRC in a subset of subjects in each cohort matched by CD4⁺ T cell counts between 300-500 cells/μl revealed that VL and VRC was significantly higher in the Mexican subset. This VRC difference was associated with accumulations in Barbados of eight previously described Gag escape mutation where fitness cost has previously been implicated. Accumulation remained significant in mismatched subjects. These data suggest that VLs and disease progression rates may differ between distinct populations as a result of the frequency of protective alleles in the respective populations, and that CD4⁺ T cell count-based guidelines to initiate antiretroviral therapy (ART) may need to be modified accordingly, to optimize the effectiveness of treatment-for-prevention strategies and reduce HIV-1 transmission rates to the absolute minimum. The final project aimed to improve the HIV-1 replication fitness assays currently used in the context of C clade infection. In order to achieve this, we attempted to design a clade C infectious molecular clone for the testing of gal-pol gene regions. However, the clones produced were not replication competent. Sequence analysis showed a large quantity of stop codons, most located within env which may explain the lack of infectivity. Chapter 5 describes the methodology used in the construction of the clade C isolate and suggests future work. Although we were unsuccessful in producing a replication competent virus, the construction of a C clade backbone which replicates efficiently remain an aim due to its importance for research directed to the analysis of genetic determinants of C clade virus. Data presented in this thesis suggest that vaccine-induced immune responses should aim to focus on vulnerable regions of the virus. These are conserved regions that can not escape without a high fitness cost and with a complex and difficult selection of compensatory mutations. Although much work remains to be done to achieve an effective CD8⁺ T cell based vaccine, hope remains that the induction of HIV control may be possible.

Submitted by Vivian Narana Ribeiro El Achkar null (vivian.narana@gmail.com) on 2018-03-13T17:45:45Z No. of bitstreams: 1 Tese Doutorado Vivian Narana Ribeiro El Achkar 2018.pdf: 2729366 bytes, checksum: 456859c4eee05d53290891b79a9d2732 (MD5) / Approved for entry into archive by Silvana Alvarez null (silvana@ict.unesp.br) on 2018-03-20T20:39:50Z (GMT) No. of bitstreams: 1 elachkar_vnr_dr_sjc.pdf: 2729366 bytes, checksum: 456859c4eee05d53290891b79a9d2732 (MD5) / Made available in DSpace on 2018-03-20T20:39:51Z (GMT). No. of bitstreams: 1 elachkar_vnr_dr_sjc.pdf: 2729366 bytes, checksum: 456859c4eee05d53290891b79a9d2732 (MD5) Previous issue date: 2018-01-17 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A papilomatose laríngea (PL) é uma doença rara e grave, dividida em dois grupos: juvenil (PLJ) e adulta (PLA), ambas causadas pelo papilomavírus humano (HPV). Seu curso pode ser agressivo, com inúmeras recidivas, risco de malignização, disseminação pulmonar e obstrução das vias aéreas. Para identificar os casos mais agressivos e nortear os tratamentos foram desenvolvidas escalas laringoscópicas, dentre elas; a escala desenvolvida por Derkay et al. (1998). O objetivo deste projeto foi caracterizar a PL e correlacionar suas características clínico-patológicas com com a escala laringoscópica de Derkay. Os dados e biópsias de 36 pacientes com PLJ e 56 com PLA foram coletados e analisados por meio da microscopia de luz. Os pacientes foram separados em grupos de acordo com os índíces de Derkay: ≥20 para os mais agressivos e <20 para os casos menos agressivos. Foram realizadas reações de imuno-histoquímicas anti- Fator XIIIa, CD3, CD4, CD8, CD15, CD20, CD68, FoxP3 e MUM-1. As células inflamatórias foram quantificadas. Todas as características clínico-patológicas e os resultados da reação imuno-histoquímica encontrados foram comparados entre os grupos propostos através do teste estatístico de Qui-Quadradro e correlacionados através do teste de correlação de Spearman. O nível de significância considerado foi de 5%. Ao comprar a severidade entre os grupos PLJ e PLA, o grupo PLJ foi considerado mais agressivo (P=0,02). Os pacientes entre as amostras com score ≥20 apresentaram maior incidência de traqueostomia e dificuldade respiratória grave. As displasias de alto grau foram associadas à presença de células FatorXIII+ e CD68+ (P<0,05) e tanto para PLJ quanto para PLA não houve associação destas displasias com a severidade (P=0,55 e P=0,87, respectivamente). A média do índice de Derkay para as amostras com mitoses acima da camada basal e atípicas foi 10,65 (± 5,93), maior do que a média das amostras que não apresentavam esta característica (8,02 ± 4,64), sendo estatisticamente significante (P=0,03). Amostras de PLA apresentaram maior quantidade de células CD3+. CD8+ e MUM1+ (P<0,05). A presença de CD15+ é diretamente proporcional ao índice de Derkay (P<0,05), enquanto MUM-1 é inversamente proporcional (P=0,01). Baseados nestes resultados, conclui-se que a PL é mais severa no pacientes jovens; mitoses atípicas e nas camadas mais superiores do epitélio foram mais frequentes na PLJ e estas foram correlacionadas com a maior severidade. As células inflamatórias também foram relacionadas a severidade e diferiram entre os grupos PLJ e PLA. / Laryngeal papillomatosis (LP) is a rare and serious disease, divided into two groups: juvenile (JLP) and adult (ALP), both caused by the human papillomavirus (HPV). Its course can be aggressive, with numerous relapses, risk of malignancy, pulmonary dissemination and airway obstruction. To identify the most aggressive cases and guide the treatments, laryngoscopic scales were developed, among them; the scale developed by Derkay et al. (1998). The objective of this project was to characterize LP and to correlate its clinical-pathological characteristics with Derkay's laryngoscopic scale. The data and biopsies of 36 patients with JLP and 56 patients with ALP were collected and analyzed by light microscopy. The patients were separated into groups according to the Derkay indices: ≥20 for the most aggressive and <20 for the less aggressive cases. Anti-Factor XIIIa, CD3, CD4, CD8, CD15, CD20, CD68, FoxP3 and MUM-1 immunohistochemical reactions were performed and the inflammatory cells were quantified. All the clinical-pathological characteristics and the results of the immunohistochemical reaction were compared between the groups proposed using the Chi-Square test and correlated through the Spearman correlation test. The significance level considered was 5%. When comparing aggressivity between the JLP and ALP groups, the JLP group was considered more aggressive (P = 0.02). Patients among the samples with score ≥20 had a higher incidence of tracheostomy and severe respiratory distress. High-grade dysplasias were associated with the presence of Factor XIII+ and CD68+ cells (P <0.05), and for both JLP and ALP there was no association of these dysplasias with aggressivity (P = 0.55 and P = 0.87, respectively). The mean of the Derkay index for the samples with mitoses above the basal and atypical layer was 10.65 (± 5.93), higher than the mean of the samples that did not show this characteristic (8.02 ± 4.64), (P = 0.03) being statistically significant. The ALP samples showed higher quantities of CD3+ cells, CD8+ and MUM1+ (P <0.05). The presence of CD15+ is directly proportional to the Derkay index (P <0.05), while MUM-1 is inversely proportional (P = 0.01). Based on these results, it is concluded that LP is more aggressive in young patients; atypical mitoses and in the uppermost layers of the epithelium were more frequent in JLP and these were correlated with aggressivity. Inflammatory cells were also related to aggressiveness and differed between the groups PLJ e PLA. / FAPESP: 2016/24019-0