<p>The methodology leverages medical notes already annotated according to the General Assessment of Functioning (GAF) scale to develop a disease severity PDM for schizophrenia, bipolar type I or mixed bipolar and non-psychotic patients.</p>

Indiana University-Purdue University Indianapolis (IUPUI) / Psychiatric patients require continuous monitoring on par with their severity status. Unfortunately, current assessment instruments are often time-consuming. The present thesis introduces several passive digital markers (PDMs) that can help reduce this burden by automating the assessment using medical notes. The methodology leverages medical notes already annotated according to the General Assessment of Functioning (GAF) scale to develop a disease severity PDM for schizophrenia, bipolar type I or mixed bipolar and non-psychotic patients. Topic words that are representative of three disease severity levels (severe impairment, serious impairment, moderate to no impairment) are identified and the top 50 words from each severity level are used to summarize the raw text of the medical notes. The summary of the text is processed by a classifier that generates a disease severity level. Two classifiers are considered: BERT PDM and Clinical BERT PDM. The evaluation of these classifiers showed that the BERT PDM delivered the best performance. The PDMs developed using the BERT PDM can assign medical notes from each encounter to a severe impairment level with a positive predictive value higher than 0.84. These PDMs are generalizable and their development was facilitated by the availability of a substantial number of medical notes from multiple institutions that were annotated by several health care providers. The methodology introduced in the present thesis can support the automated monitoring of the progression of the disease severity for psychiatric patients by digitally processing the medical note produced at each encounter without additional burden on the health care system. Applying the same methodology to other diseases is possible subject to availability of the necessary data.

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In Sweden, three principles prescribed by law compose the ethical platform aiming to ensure a fair distribution of healthcare resources. The goals of each of the three principles are to 1: ensure equal care, regardless of personal characteristics or social function; 2: give priority to patients of bad health; 3: base priority decisions on cost-effectiveness. The weights given to the last two principles yield different implications on which pharmaceuticals and medical procedures to subsidize and can be seen as an equity-efficiency trade-off. Knowledge of the Swedish public's views on this balance has been stated to be of large value to decision-makers, to be used as a basis for priority decisions. However, no such information exists to date. A large share of studies from other countries has moreover provided counter-intuitive estimates, possibly indicating a need for methodological development. In this thesis, I provide a suggestion on a discrete choice approach to quantify opinions on how to weight disease severity and cost-effectiveness in healthcare prioritization. In addition, I present a novel method to use the estimates to rank treatments. The design is furthermore tested in a pilot study, being the first to investigate this question in a Swedish setting. The results indicate that the population values both the amount and distribution of health created, favoring individuals suffering from severe conditions, which is seen as in line with a priori expectations. The thesis contributes to the literature aiming to quantify opinions on healthcare prioritization.

By increasing fruit exposure to sunlight and influencing fruit development, leaf thinning in the fruit zone can improve grape quality and lower disease incidence; however, further investigations on the timing, varietal response and intensity are needed to optimize results and to better understand underlying physiologic responses. Fruit zone leaf thinning was applied at different timing and intensities to evaluate its effect on cluster health and fruit composition in Cabernet Sauvignon and Chardonnay. Treatments consisted of control (C), pre-bloom leaf thinning (PB) and two levels of fruit-set leaf thinning (three leaves, PF3 and six leaves, PF6). In an additional project on Cabernet Sauvignon, two levels of hedging (17th node, NH and 12th node, H) were integrated with no leaf thinning (L) and fruit set leaf thinning (LR, three leaves). All leaf thinning treatments consistently reduced disease incidence compared to control vines in both varieties, with the reduction extent varying between 2017 and 2018. Yield was not negatively affected by leaf thinning treatments, even though PB reduced cluster compactness by decreasing the number of berries per cluster of Chardonnay in 2017. Control vines tended to have greater titratable acidity than defoliated vines, while Brix and pH responses varied between seasons. No direct positive correlation was found between sunlight exposure and norisoprenoids concentration. Post fruit set leaf thinning PF6 consistently increase free norisoprenoids at harvest, while pre-bloom defoliation never did. Heterogeneous responses were observed for bound and total norisoprenoids. In Cabernet Sauvignon free, bound and total 1,1,6-trimethyl-1,2-dihydronaphtalene (TDN) was consistently increased by PF3. Hedging negatively influenced Brix and anthocyanins accumulation in 2017, and increased free norisoprenoids while decreasing the bound and total fraction. Results revealed that a high level of stress possiblt caused by excess sunlight and/or reduced photosynthesis might negatively affect norisoprenoids glycosylation. / Master of Science in Life Science / This project evaluates the effect of a grapevine canopy management practice on grape quality. The objective was to find a suitable technique to expose the fruits to sunlight in order to increase grape aroma concentration and improve grape sanitary status of Virginia vineyards. Leaves were removed from the fruit zone with different intensities at two grape developmental stages, in two varieties (Chardonnay and Cabernet Sauvignon). Treatments consisted of control, three leaves removed before blooming (PB) and three or six leaves removed after fruit set (PF3 and PF6 respectively) In an additional project with Cabernet Sauvignon, the effect of canopy height was integrated with the fruit zone defoliation. Results showed that the removal of leaves from the fruit zone is effective in improving grape sanitary status at harvest, with the improvement extent depending on the season climatic conditions and on the amount of leaves removed. Crop yield was not negatively affected by treatments. Non defoliated grapes tended to have greater acidity at harvest, while sugar responses were inconsistent. Aroma compounds responded heterogeneously to fruit zone defoliation, but volatile odorants were consistently greatest in the most exposed grapes (PF6) compared to all other treatments at harvest. Pre-bloom defoliation instead, never increased volatile aroma compounds compared to control at harvest. Generally, non-volatile odorants were greater in less severely defoliated vines or control. An overall positive effect was observed with PF3. Canopy height was demonstrated to be able to indirectly affect grape quality and composition, with the short canopy reducing grape’s sugar and color content and increasing grape’s volatile aroma compounds concentration at harvest in 2017. The removal of three or six leaves from the fruit zone in post fruit set could be a suitable practice to improve grape quality in the Virginia environment.

Introdução: O transplante de células-tronco hematopoiéticas (TCTH) tornou-se um procedimento terapêutico mundialmente aceito sobretudo pelo impacto positivo na sobrevida e na qualidade de vida dos pacientes com doenças onco-hematológicas. No entanto, a mortalidade ainda é alta e influenciada por fatores de natureza individual e terapêutica. Objetivo: Analisar a mortalidade relacionada ao transplante (MRT) nos pacientes submetidos ao TCTH e seus fatores associados. Método: Coorte prospectiva realizada com 60 pacientes internados na unidade de TCTH do Hospital de Clínicas da Universidade Estadual de Campinas. Os dados foram obtidos pela análise diária dos prontuários. A variável dependente foi a MRT e as variáveis independentes foram demográficas e de evolução clínicas, incluindo escore de risco pré-TCTH (EBMT) e o SAPS II. Na análise dos dados foram utilizados os testes Qui-quadrado, Exato de Fisher, o teste t de Student e Mann-Whitney. Na análise da MRT utilizou-se o método de kaplan-Meier e o Modelo de Cox. Considerou-se nível de significância igual a 5%. Resultados: A MRT foi de 15% aos cem dias do TCTH, de 18,9% no grupo de pacientes de TCTH alogênico e de 8,7% para os de TCTH autólogo. A infecção foi a principal causa de óbito. Na amostra, o tempo médio de sobrevida dos pacientes foi de 83,2 dias (DP 32,7). No grupo de pacientes não sobreviventes a maioria pertencia ao sexo masculino, com média de idade de 48,7 anos e diagnóstico principal de leucemia. Quanto à gravidade destes pacientes, o escore de risco pré-TCTH (EBMT) foi de 4,1 pontos e do SAPS II geral foi de 52,6 pontos, o que correspondeu a um risco médio de morte de de 38,4%. Os fatores associados à MRT, em cem dias, foram faixa etária (p=0,0306), presença de infecção (p=0,0216), número de infecções (p=0,0386), ocorrência de enxertia (p<0,0001), uso de ventilação mecânica (p<0,0001) e de drogas vasoativas (p<0,0001). O índice de gravidade SAPS II foi fator preditor para MRT (p=0,0001). Conclusão: O índice de gravidade SAPS II, preditor para MRT em cem dias, mostrou que o paciente submetido ao TCTH é grave e necessita de cuidado especializado e intensivo. / Hematopoietic stem cells transplantation (HSCT) has become a therapeutic procedure accepted worldwide, particularly because of its positive impact on survival and quality of life of patients with onco-hematological diseases. However, the mortality is still high and it is influenced by factors of individual and therapeutic kinds. Objective: To analyze the transplant-related mortality (TRM) on patients submitted to HSCT and its associated factors. Methodology: Prospective cohort study with 60 patients hospitalized in the HSTC unit of the Clinical Hospital of the State University of Campinas (Unicamp). Data was obtained by daily analysis of the medical records. The dependent variable was the TRM and the independent variables were demographic and clinical development, including pre-HSCT risk score (EBMT) and SAPS II. For data analysis were used the Chi-square, Fishers exact tests, Students t-test, Mann-Whitney. On TRM analysis were used Kaplan-Meier and Cox Model method. It was considered a significance level of 5%. Results: The TRM was 15% to a hundred days of HSCT, 18,9% to allogeneic HSCT patients and 8,7% to autologous HSCT. Infection was the main cause of death. In the sample, the median survival time of the patients was 83,2 days (DP 32,7). In the group of non-surviving patients the most were male, with an average age of 48,7 years and the main diagnosis was leukemia. Regarding to the severity of these patients, the pre-HSCT risk score (EBMT) was 4,1 points and general SAPS II was 52,6 points, which corresponds to an average death risk of 38,4%. The TRM associated factors on a hundred days were age (p=0,0306), presence of infection (p=0,0216), number of infections (p=0,0386), occurrence of grafting (p<0,0001), mechanical ventilation use (p<0,0001) and vasoactive drugs (p<0,0001). The severity rate SAPS II was a predictive factor for TRM (p=0,0001). Conclusion: The severity rate SAPS II was predictive for TRM on a hundred days and showed that the patient submitted to HSCT is severe and demands specialized and intensive care.

Introdução: O transplante de células-tronco hematopoiéticas (TCTH) tornou-se um procedimento terapêutico mundialmente aceito sobretudo pelo impacto positivo na sobrevida e na qualidade de vida dos pacientes com doenças onco-hematológicas. No entanto, a mortalidade ainda é alta e influenciada por fatores de natureza individual e terapêutica. Objetivo: Analisar a mortalidade relacionada ao transplante (MRT) nos pacientes submetidos ao TCTH e seus fatores associados. Método: Coorte prospectiva realizada com 60 pacientes internados na unidade de TCTH do Hospital de Clínicas da Universidade Estadual de Campinas. Os dados foram obtidos pela análise diária dos prontuários. A variável dependente foi a MRT e as variáveis independentes foram demográficas e de evolução clínicas, incluindo escore de risco pré-TCTH (EBMT) e o SAPS II. Na análise dos dados foram utilizados os testes Qui-quadrado, Exato de Fisher, o teste t de Student e Mann-Whitney. Na análise da MRT utilizou-se o método de kaplan-Meier e o Modelo de Cox. Considerou-se nível de significância igual a 5%. Resultados: A MRT foi de 15% aos cem dias do TCTH, de 18,9% no grupo de pacientes de TCTH alogênico e de 8,7% para os de TCTH autólogo. A infecção foi a principal causa de óbito. Na amostra, o tempo médio de sobrevida dos pacientes foi de 83,2 dias (DP 32,7). No grupo de pacientes não sobreviventes a maioria pertencia ao sexo masculino, com média de idade de 48,7 anos e diagnóstico principal de leucemia. Quanto à gravidade destes pacientes, o escore de risco pré-TCTH (EBMT) foi de 4,1 pontos e do SAPS II geral foi de 52,6 pontos, o que correspondeu a um risco médio de morte de de 38,4%. Os fatores associados à MRT, em cem dias, foram faixa etária (p=0,0306), presença de infecção (p=0,0216), número de infecções (p=0,0386), ocorrência de enxertia (p<0,0001), uso de ventilação mecânica (p<0,0001) e de drogas vasoativas (p<0,0001). O índice de gravidade SAPS II foi fator preditor para MRT (p=0,0001). Conclusão: O índice de gravidade SAPS II, preditor para MRT em cem dias, mostrou que o paciente submetido ao TCTH é grave e necessita de cuidado especializado e intensivo. / Hematopoietic stem cells transplantation (HSCT) has become a therapeutic procedure accepted worldwide, particularly because of its positive impact on survival and quality of life of patients with onco-hematological diseases. However, the mortality is still high and it is influenced by factors of individual and therapeutic kinds. Objective: To analyze the transplant-related mortality (TRM) on patients submitted to HSCT and its associated factors. Methodology: Prospective cohort study with 60 patients hospitalized in the HSTC unit of the Clinical Hospital of the State University of Campinas (Unicamp). Data was obtained by daily analysis of the medical records. The dependent variable was the TRM and the independent variables were demographic and clinical development, including pre-HSCT risk score (EBMT) and SAPS II. For data analysis were used the Chi-square, Fishers exact tests, Students t-test, Mann-Whitney. On TRM analysis were used Kaplan-Meier and Cox Model method. It was considered a significance level of 5%. Results: The TRM was 15% to a hundred days of HSCT, 18,9% to allogeneic HSCT patients and 8,7% to autologous HSCT. Infection was the main cause of death. In the sample, the median survival time of the patients was 83,2 days (DP 32,7). In the group of non-surviving patients the most were male, with an average age of 48,7 years and the main diagnosis was leukemia. Regarding to the severity of these patients, the pre-HSCT risk score (EBMT) was 4,1 points and general SAPS II was 52,6 points, which corresponds to an average death risk of 38,4%. The TRM associated factors on a hundred days were age (p=0,0306), presence of infection (p=0,0216), number of infections (p=0,0386), occurrence of grafting (p<0,0001), mechanical ventilation use (p<0,0001) and vasoactive drugs (p<0,0001). The severity rate SAPS II was a predictive factor for TRM (p=0,0001). Conclusion: The severity rate SAPS II was predictive for TRM on a hundred days and showed that the patient submitted to HSCT is severe and demands specialized and intensive care.

Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome in Europe. After inhalation of virus shed by bank voles, the virus systemically targets the vascular endothelium leading to vascular dysfunction and leakage. Many patients with PUUV infection experience cardiopulmonary manifestations but the underlying mechanisms have not been determined. The aims of the studies presented were to describe cardiopulmonary manifestations, investigate pathogenetic mechanisms including presence of virus in the lungs and the local immune response in PUUV infection. The results showed cardiopulmonary involvement of varying severity in almost all studied patients. High-resolution computed tomography frequently revealed vascular leakage into the lungs or pleural cavities. Pulmonary function tests generally showed reduced gas diffusing capacity, evidenced in patients as dyspnea, poor oxygenation and frequent need of oxygen treatment. Among patients who were not fully recovered at 3 months follow-up, remaining decreased gas diffusing capacity was highly common. Echocardiography revealed mainly right heart dysfunction which was related to manifestations within the lungs, in terms of increased estimated pulmonary vascular resistance, mild to moderate pulmonary hypertension, and reduced right ventricular systolic function in patients with more pronounced lung involvement, as indicated by need of oxygen treatment. Analyses on bronchoalveolar lavage (BAL) and bronchial biopsies revealed a highly activated cytotoxic T cell (CTL) response in the lungs. The CTL response was not balanced by the expansion of regulatory T cells and high numbers of CTLs were associated with more severe disease. PUUV RNA was detected in almost all patients’ BAL samples and the viral load was inversely correlated to the number of CTLs. Three patients presenting with severe and fatal cardiopulmonary distress were also described. Autopsies revealed PUUV protein in vascular endothelium in all investigated organs, including the heart and lungs, along with a massive CTL response mainly in the lungs. In conclusion, cardiopulmonary involvement of varying severity was present in almost all patients with PUUV infection. Cytotoxic immune responses could contribute to disease development but also help in clearing the infection. Long lasting fatigue after hantavirus infection may be explained by remaining manifestations within the lungs.

The cultivation of flowers is, in Brazil, very recent and little known species have a high ornamental potential, Cartamus is such a species and there are cultivars for the production of oil and as well as for ornamental pourposes. Being a recent crop in Brazil, little is known about its associated diseases, specially those that affect the seeds and the soil borne, such as white mold that causes great losses to several crops. Six experiments were conducted with the objectives of testing the reaction of the crop to isolates of Sclerotinia sclerotiorum, the biocontrol of S. sclerotiorum and of pathogens associated to the seeds, and the effect of the biocontrollers on cartamus plant growth. Isolates of the pathogen from chrisantemum, lettuce, soybean, and carrots, as well as isolates of Trichoderma sp. (ETSR 20 e TC 1.15) and comercial products of Trichoderma spp. (Agrotrich and Trichodel®) were used. In the reaction test, the cartamus crop was more severely attacked by the isolate obtained from lettuce, which when incorporated to commercial substrate did not promote the development of the disease in plant, but reduced plant growth. Trichodel® was the product that promoted the highest growth of plants when incorporated to the substrate, even in the absence of the pathogen. The product more efficient in controlling seed pathogens was Agrotrich. In the growth of seedlings, the isolates ETSR20 and TC1.15 were the best, when applied to the seeds and the latter promoted the best emergency of seeds in commercial substrate. Therefore, the Trichoderma based products can be used in the control of seed pathogens and growth promotion of cartamus plants as seed or substrate treatment. There are differences in disease severity on cartamus among isolates of S. sclerotiorum from different crops and its presence reduces the crop s growth, even in the absence of visible symptoms / A floricultura, no Brasil, é relativamente recente, existindo espécies pouco conhecidas com alto potencial ornamental. O cártamo é uma delas e possui cultivares tanto para a produção de óleo quanto para ornamentação. Por ser uma cultura recente no Brasil, pouco se conhece sobre as doenças associadas a ela, especialmente as que afetam as sementes e as veiculadas pelo solo, como o mofo branco, que causa grandes prejuízos a diversas culturas. Seis experimentos foram conduzidos com o objetivo de testar a reação da cultura a isolados de Sclerotinia sclerotiorum, o biocontrole de patógenos associados às sementes e de Sclerotinia sclerotiorum e o efeito dos biocontroladores no crescimento de plantas de cártamo. Foram utilizados isolados de Sclerotinia sclerotiorum das culturas do crisântemo, alface, soja e cenoura, e isolados de Trichoderma spp. (ETSR 20 e TC 1.15) e formulados comerciais à base de Trichoderma spp. (Agrotrich e Trichodel®). No teste de reação, a cultura do cártamo foi mais severamente atacada pelo isolado proveniente da alface, o qual, quando incorporado ao substrato comercial, não promoveu o desenvolvimento da doença nas plantas, porém prejudicou seu crescimento. Trichodel® foi o produto que maior crescimento proporcionou às plantas quando incorporado ao substrato, mesmo sem a presença do patógeno. O produto mais eficiente no controle dos patógenos das sementes foi o formulado comercial Agrotrich. No crescimento de plântulas, os isolados ETSR 20 e TC 1.15 se sobressaíram quando aplicados às sementes e este obteve melhor resultado na emergência de plântulas em substrato. Assim, os produtos a base de Trichoderma são viáveis para controle de patógenos de sementes e crescimento de plantas tanto no tratamento de sementes como do substrato. Existem diferenças na severidade da doença em cártamo entre isolados de Sclerotinia sclerotiorum oriundos de diferentes culturas e sua presença reduz o crescimento da cultura, mesmo na ausência de sintomas visíveis

The objective of the study is to analyze the factors associated with the severity of pruritus in patients with terminal chronic kidney disease undergoing hemodialysis. The methodology used is based on a cross-sectional study in patients receiving hemodialysis at the Centro Nacional de Salud Renal. Severe pruritus was defined as a score on the visual analogue scale greater than or equal to 7, and the strength of association with the possible risk factors was assessed by calculating prevalence ratios. Regarding the results, 264 patients were included, 59.9% were male, with a mean time on hemodialysis of 10.26 ± 7.14 years. 75% experienced pruritus, of this group, 1 in 3 presented severe pruritus. Hyperphosphatemia and the use of antihistamines were associated with a higher prevalence of severe pruritus (RP 1.71, 95% CI 1.09-267 and RP 2.39, 95% CI 1.51-3.75, respectively). The positive serology for Hepatitis C Virus was described as a protective factor for presenting severe pruritus (RP 0.55, 95% CI 0.33 - 0.89). In conclusion, severe uremic pruritus is a frequent problem in patients with chronic terminal kidney disease who have hyperphosphatemia and treatment with antihistamines independently of the time they have been on hemodialysis. / Revisión por pares