Introdução: A cada ano, cresce o número de exames solicitados no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP (HCFMRP-USP), devido, principalmente, ao aumento da demanda de exames complementares, com a alegação de que se trata de um hospital de ensino. Entretanto, dúvidas são levantadas sobre a real necessidade de muitos exames solicitados por razões acadêmicas no binômio atendimento/ensino, sem, contudo, contribuírem efetivamente para a tomada de decisão em face de um problema clínico do paciente. Por outro lado,as dificuldades orçamentárias enfrentadas pelas instituições públicas de saúde, particularmente nestes últimos anos, em virtude da crise econômica que assola o país, com reflexos importantes em nosso meio. Desta forma, avaliar a utilização racional dos pedidos de exames laboratoriais é medida fundamental para identificar o uso indiscriminado dessas ferramentas de diagnóstico e conduta clínica em um hospital de grande porte. Objetivo: Este trabalho teve por objetivo quantificar e apresentar o custo dos exames totais solicitados nos anos de 2012 a 2014 nos laboratórios do HCRP de acordo com o local de atendimento: enfermaria, ambulatório e unidades de terapia intensiva (UTI); verificar, dentre os dez exames mais solicitados, o percentual daqueles cujos resultados não acessados pelos médicos; e estimar o custo dos exames não acessados. Metodologia: Estudo de corte transversal, retrospectivo, realizado no período de 2012 a 2014 no HCFMRP-USP, unidade Campus. Foram avaliados exames realizados em dezessete laboratórios, solicitados pelas enfermarias, ambulatórios e UTIs. Resultados: Verificou-se um aumento de 9,19% na solicitação de exames de 2012 a 2014. Com relação aos exames não acessados no mesmo período, houve uma redução de 18,52% nas UTIs, porém um aumento de 16,60% nas enfermarias e de 68,94% nos ambulatórios.O gasto total dos dez exames mais solicitados e não acessados nos três locais solicitantes foi de R$ 270 241,21 de 2012 a 2014. Os dados demonstram que novas estratégias devem ser realizadas para evitar ou ao menos reduzir esse desperdício financeiro. Implantação de protocolos clínicos, educação continuada aos médicos e revisão do rol de exames disponíveis são ações que podem contribuir para o uso racional dos exames complementares. / Introduction: Every year, the number of laboratorial tests performed at the Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP (HCFMRP-USP)) increases, mainly due to the increment in the demand for complementary tests, with the argument that the institution is a university hospital. However, questions have been raised about the real necessity of ordering so many tests for academic (assistance / teaching) purposes, without effectively contributing to the clinical decision making. On the other hand, it is well known that public health institutions have been facing budget problems in light of the economic crisis hitting the country, with serious consequences to health. Therefore, the assessment of the rational use of laboratory test orders is essential to detect an indiscriminate use of these diagnostic and therapeutic tools in a large hospital. Aim: This study aimed to quantify all laboratory tests ordered to the laboratories of the GH-USPMS from 2012 to 2014, by three locations: wards, outpatient department, and intensive care units (ICUs); to determine among the ten most ordered exams, the percentage of test results that were not checked by the physicians; and to estimate the costs of these tests. Methods: This was a retrospective, crosssectional studied, carried out at the GH-USPMS, Campus, from 2012 to 2014. Tests performed at the seventeen laboratories of this institution, ordered by the wards, outpatient department and ICUs were assessed. Results: There was a 9.19% increase in the number of laboratory tests ordered from 2012 to 2014. Regarding the number of test results not accessed by the physicians during the same period, there was a decrease by 18.52% at the ICUs, but an increase by 16.60% in the wards and 68.94% in the outpatient department. The total cost of the ten most ordered tests whose results were not checked by the physicians was 270,241.21 BRL from 2012 to 2014. These findings show that new strategies to prevent, or at least reduce financial waste should be employed. In addition, the implementation of clinical protocols, continuing education for physicians, and the revision of the menu of tests available may contribute to the rational use of complementary tests.

La dengue est une maladie virale des régions tropicales et subtropicales, transmise par les moustiques du genre Aedes. Le virus de la dengue (DENV) appartient à la famille des Flaviviridae, genre Flavivirus. Si la plupart des infections sont asymptomatiques ou se traduisent par un syndrome fébrile sans gravité, le virus peut aussi causer une maladie plus sévère caractérisée par une fuite plasmatique, avec ou sans hémorragie. Sans prise en charge adéquate, les formes les plus sévères peuvent évoluer vers un syndrome de choc, potentiellement mortel. Il n’existe pas de traitement spécifique de la dengue mais une réhydratation adaptée et débutée précocement permet de réduire la survenue de formes sévères de la maladie. Malheureusement, les symptômes initiaux de la dengue avant la survenue des éventuelles complications ne sont pas spécifiques et seul un diagnostic biologique basé sur la détection du génome viral, de l’antigène NS1 ou des anticorps anti-DENV dans le sang des patients permet de confirmer la nature exacte de l’infection. La dengue constitue à l’heure actuelle un problème majeur de santé publique du fait de son expansion mondiale et de l’augmentation annuelle du nombre de cas sévères. Pour assurer la surveillance épidémiologique et le contrôle de la maladie, il est indispensable de développer des outils diagnostiques performants et faciles à mettre en œuvre, à la fois utilisables par les médecins de toutes les structures médicales, des simples centres de soins de santé primaire aux centres de référence, et utilisables lors d’enquêtes épidémiologiques pour l’investigation de nouvelles épidémies. Le travail de cette thèse a porté sur plusieurs aspects de cette problématique. Dans une première partie, un test commercial de diagnostic rapide (TDR) permettant la détection simultanée de la NS1 et des IgG et IgM anti-DENV, a été évalué, en laboratoire spécialisé et sur le terrain, afin de comparer, à partir des mêmes échantillons, les performances du test dans deux situations différentes. La sensibilité s’est révélée plus faible lors de l’utilisation sur le terrain que lors de l’utilisation en laboratoire de référence. La majorité des discordances a été observées pour la détection des IgG et des IgM. L’impact de la mise à disposition du test sur la prise en charge des patients a également été évalué et il s’est avéré qu’au cours de cette étude les pédiatres cambodgiens ont ignorés les résultats du test rapide et ont préféré suivre leur instinct clinique.Un second volet a porté sur la faisabilité d’utiliser les urines et la salive en remplacement du sang veineux pour les tests employés en routine pour le diagnostic de la dengue. Les urines et la salive sont des fluides biologiques plus faciles à prélever que le sang veineux ce qui présente un avantage majeur pour les enquêtes épidémiologiques mais peut également secourir les médecins lorsqu’un prélèvement de sang veineux est difficile à obtenir, par exemple chez les enfants. Bien que les performances des différentes méthodes de diagnostic ne soient pas aussi bonnes avec de l’urine et la salive qu’avec du plasma, les résultats obtenus par PCR en temps réel et avec les ELISAs de détection des anticorps anti-DENV démontrent l’intérêt potentiel de ces deux fluides biologiques pour détecter les infections par le DENV lorsqu’il est difficile d’obtenir du sang veineux. Plusieurs TDR commerciaux développés pour permettre la détection de la NS1 et des anticorps anti-DENV (IgM, IgG et IgA) dans les urines et la salive ont été évalués mais les performances obtenues se sont révélées peu satisfaisantes.Une dernière partie du travail a été consacrée à l’étude de la protéinurie comme marqueur pronostic potentiel de sévérité de la dengue. Ce marqueur biologique ne s’est pas révélé être utile pour diagnostiquer précocement les formes sévères de la maladie. / Dengue is a viral disease transmitted by Aedes species mosquitoes, in tropical and subtropical regions. Dengue virus (DENV) belongs to the family Flaviviridae, genus Flavivirus. Although most DENV infections are asymptomatic or result in a self-limited febrile illness, severe diseases characterized by plasma leakage, with or without hemorrhage, can also occur. Patients with a severe dengue can rapidly progress into a life-threatening shock syndrome if no efficient clinical management is provided. There is no specific treatment available for dengue but an accurate and early fluid therapy substantially reduces the occurrence of severe forms of the disease. Dengue symptoms are typically non-specific until or unless complications develop. Only a biologic diagnosis based on DENV genome, NS1 antigen or anti-DENV antibodies detection enables to confirm dengue cases. Dengue is now a major public health problem due to both its geographical spread and the increase in the number of severe cases. New diagnostic tools are necessary to ensure epidemiological surveillance and control of the disease. These tools need to be effective and easy to use in every medical settings, from the smallest primary health centers to the biggest reference centers, and also usable for epidemiologic studies, e.g. for epidemic investigations. The work presented in this thesis was dedicated to this problematic.In a first part of the work, a rapid diagnostic test (RDT), designed to detect NS1 antigen, anti-DENV IgG and IgM, was evaluated, both in a specialized laboratory and in the field, in order to compare the test performances in two different settings, with the same samples. Interestingly, sensitivity was lower when the test was used in the field compared to the sensitivity of the test when performed in the specialized laboratory. Discordances were mainly observed for IgM and IgG detection. Impact of the use of the RDT on clinical management was also assessed during the field study and it revealed that Cambodian pediatricians ignored the results of the RDT and followed their clinical instinct.A second part of the work was dedicated to the assessment of the usefulness of urine and saliva for dengue diagnostic. Dengue diagnostic normally requires a venous blood sample that can be difficult to obtain in certain conditions such as in children or during epidemiological studies. Urine and saliva are easier to collect as the procedure is non-invasive. We showed that, although the performances of the different diagnostic methods were not as good in saliva and urine as in plasma specimens, the results obtained by qRT-PCR and by anti-DENV antibody ELISA could well justify the use of these two body fluids to detect dengue infection in situations when the collection of blood samples is difficult. Performances of commercial RDTs developed for NS1 and anti-DENV antibodies (IgM, IgG and IgA) detection in urine and saliva specimens were not satisfactory.In the last part of the thesis, the potential use of proteinuria as a prognostic marker of severity was assessed but it didn’t prove to be a useful marker for risk prediction.

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The asymptomatic nature of chlamydial infection renders the differential diagnosis of acute and chronic infection difficult. An untreated Chlamydia trachomatis infection can become chronic, result in disease sequelae such as salpingitis and pelvic inflammatory disease (PID), and ultimately culminate in tubal occlusion and infertility. Diagnostic tests for C. trachomatis such as nucleic acid amplification testing (PCR), antigen detection and serological methods have variable performance capabilities with respect to sensitivity, specificity and stage of infection. The use of PCR as a diagnostic tool is somewhat limited, as specimen collection is routinely sampled from the lower genital tract; hence, infections in the fallopian tube where inflammatory damage is most significant, escape detection. Furthermore, PCR can only detect selected Chlamydia DNA sequences from readily accessible sites of the genital tract, and therefore cannot differentiate between acute and chronic infection. Other serological assays aim to discriminate the various stages of C. trachomatis infection through identification of key antigens. The efficacy of these assays however is impeded due to cross-reactivity between chlamydial species and the subsequent antibody response against the target antigen is not restricted to patients with a specific stage of infection. To identify antibody responses capable of differentiating various states of chlamydial infection, samples were collected from both men and women given the variability of immune responses between the two genders. Samples were assigned to a patient group according to infection status and then probed against protein extracts of HEp-2 cells infected with C. trachomatis serovar L2 and HEp-2 cells pre-treated with IFN-γ and infected with C. trachomatis serovar L2. (persistence cell culture) Serological analysis revealed the presence of five antigens (denoted bands A, B, C, D and M) which were shown to be differential between patient groups. Identification of bands B and C by N-terminal sequencing provided two possible candidates for each antigen, ie. CT727 and CT396 (band B) and CT157 and CT423 (band C). In contrast, band M which was unique to males was a PmpB (probable outer membrane protein B) fragment. The four target antigens (CT157, CT423, CT727 and CT396) were expressed as recombinant proteins using autoinduction media and were subsequently probed by both male and female sera to evaluate their diagnostic potential. Results showed that two chlamydial antigenic targets (CT157 and CT727) have the potential to discriminate between acute and chronic C. trachomatis infection. However, since only a small number of samples (n = 3) were used for this aspect of the study, the findings should simply be viewed as preliminary. In females, sensitivity and specificity values were derived using various combinations of the four target antigens into a panel format for the purpose of detecting chronic C. trachomatis infections. The preferred format was B + C with a sensitivity and specificity of 80% and 84% respectively. Using the IFN-γ-mediated persistence model, only two of the five antigenic targets were shown to be differentially expressed. PmpB in males and CT157 (the most likely band C candidate) in females were shown to be up-regulated to varying degrees in samples across the patient groups. We also demonstrated that no other chlamydial antigens are up-regulated during a persistent C. trachomatis infection. In conclusion, although combinations of bands A, B, C, D and M differentiate between male and female patient groups under normal chlamydial growth conditions, during IFN-γ-induced persistence, only bands C (CT157) and M (CT413 - PmpB) are up-regulated thus suggesting a potential role in chronic C. trachomatis infection.

Introdução: A cada ano, cresce o número de exames solicitados no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP (HCFMRP-USP), devido, principalmente, ao aumento da demanda de exames complementares, com a alegação de que se trata de um hospital de ensino. Entretanto, dúvidas são levantadas sobre a real necessidade de muitos exames solicitados por razões acadêmicas no binômio atendimento/ensino, sem, contudo, contribuírem efetivamente para a tomada de decisão em face de um problema clínico do paciente. Por outro lado,as dificuldades orçamentárias enfrentadas pelas instituições públicas de saúde, particularmente nestes últimos anos, em virtude da crise econômica que assola o país, com reflexos importantes em nosso meio. Desta forma, avaliar a utilização racional dos pedidos de exames laboratoriais é medida fundamental para identificar o uso indiscriminado dessas ferramentas de diagnóstico e conduta clínica em um hospital de grande porte. Objetivo: Este trabalho teve por objetivo quantificar e apresentar o custo dos exames totais solicitados nos anos de 2012 a 2014 nos laboratórios do HCRP de acordo com o local de atendimento: enfermaria, ambulatório e unidades de terapia intensiva (UTI); verificar, dentre os dez exames mais solicitados, o percentual daqueles cujos resultados não acessados pelos médicos; e estimar o custo dos exames não acessados. Metodologia: Estudo de corte transversal, retrospectivo, realizado no período de 2012 a 2014 no HCFMRP-USP, unidade Campus. Foram avaliados exames realizados em dezessete laboratórios, solicitados pelas enfermarias, ambulatórios e UTIs. Resultados: Verificou-se um aumento de 9,19% na solicitação de exames de 2012 a 2014. Com relação aos exames não acessados no mesmo período, houve uma redução de 18,52% nas UTIs, porém um aumento de 16,60% nas enfermarias e de 68,94% nos ambulatórios.O gasto total dos dez exames mais solicitados e não acessados nos três locais solicitantes foi de R$ 270 241,21 de 2012 a 2014. Os dados demonstram que novas estratégias devem ser realizadas para evitar ou ao menos reduzir esse desperdício financeiro. Implantação de protocolos clínicos, educação continuada aos médicos e revisão do rol de exames disponíveis são ações que podem contribuir para o uso racional dos exames complementares. / Introduction: Every year, the number of laboratorial tests performed at the Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP (HCFMRP-USP)) increases, mainly due to the increment in the demand for complementary tests, with the argument that the institution is a university hospital. However, questions have been raised about the real necessity of ordering so many tests for academic (assistance / teaching) purposes, without effectively contributing to the clinical decision making. On the other hand, it is well known that public health institutions have been facing budget problems in light of the economic crisis hitting the country, with serious consequences to health. Therefore, the assessment of the rational use of laboratory test orders is essential to detect an indiscriminate use of these diagnostic and therapeutic tools in a large hospital. Aim: This study aimed to quantify all laboratory tests ordered to the laboratories of the GH-USPMS from 2012 to 2014, by three locations: wards, outpatient department, and intensive care units (ICUs); to determine among the ten most ordered exams, the percentage of test results that were not checked by the physicians; and to estimate the costs of these tests. Methods: This was a retrospective, crosssectional studied, carried out at the GH-USPMS, Campus, from 2012 to 2014. Tests performed at the seventeen laboratories of this institution, ordered by the wards, outpatient department and ICUs were assessed. Results: There was a 9.19% increase in the number of laboratory tests ordered from 2012 to 2014. Regarding the number of test results not accessed by the physicians during the same period, there was a decrease by 18.52% at the ICUs, but an increase by 16.60% in the wards and 68.94% in the outpatient department. The total cost of the ten most ordered tests whose results were not checked by the physicians was 270,241.21 BRL from 2012 to 2014. These findings show that new strategies to prevent, or at least reduce financial waste should be employed. In addition, the implementation of clinical protocols, continuing education for physicians, and the revision of the menu of tests available may contribute to the rational use of complementary tests.

Clostridium difficile is the most common bacterial cause of infectious diarrhoea in healthcare environments and in 2014 was responsible for 13,785 infections in the UK. C. difficile infection (CDI) is spread via the faecal-oral route and by contact with contaminated surfaces. However, despite the healthcare concerns no tests are available to validate if sufficient cleaning has been conducted. In addition, Polymerase Chain Reaction (PCR) and Enzyme Immunoassays (EIAs)-based tests used to diagnose CDI lack sensitivity and specificity and hence false negative results are commonly obtained. To overcome these concerns the aim of the PhD research has been to develop the first diagnostic test that exploits the specific interactions of C. difficile bacteriophages (phages), viruses that specifically infect and kill C. difficile. In order to develop a C. difficile phage-based test, first suitable phages that can be used for the test were identified and this was conducted by screening 35 different C. difficile phages against 160 clinically relevant C. difficile isolates. Five phages were found to infect the most number of isolates and were investigated further to identify whether a phage-based diagnostic could be developed based on phages binding (adsorption) to different C. difficile subgroups. However, for all five phages, adsorption rates were not consistently high for C. difficile subgroups in comparison to other common bacteria found in similar locations to C. difficile. Therefore, to increase specificity of the phage-based diagnostic test a new approach was taken by tagging two phages with luminescence luxAB genes (reporter phages), which would be expressed once C. difficile cells were infected with the phages. To design the C. difficile reporter phages, non-essential phage genes were replaced with the luxAB genes, but this study revealed mutagenesis of C. difficile was troublesome and extensive optimisation was required. In addition, once the reporter phages had successfully been constructed the luxAB genes were unstable within the phage genome and were lost during phage replication. Despite extensive optimisation and due to time constrains the luxAB genes were not stabilised within the phages but future work will focus on stabilising the genes.

Pseudomonassp. CBB1 degraded caffeine via C-8 oxidation. Previously, a novel quinone-dependent caffeine dehydrogenase (Cdh) was shown to catalyze the oxidation of caffeine to 1,3,7-trimethyluric acid (TMU). Initial metabolite analysis using resting cells and partially purified extract of CBB1 identified transient accumulation 1,3,7-trimethyl-5-hydroxyisourate (TM-HIU), and 3,6,8-trimethylallantoin (TMA). TMA structure was confirmed; chiral analysis revealed that it was racemic. In contrast, a time-course reaction showed that one of the enantiomers of TMA accumulated nine times, and racemized in three hours. Based on this, it was proposed that TMU was converted to TM-HIU and enantiomeric TMA. A 43-kDa NADH-dependent TMU mononxygenase (TmuM) was purified and shown to convert TMU to unstable TM-HIU. The enzyme belonged to a new family of FAD-dependent monooxygenases. The enzyme was specific for methyluric acid with no activity on uric acid. Homology model of TmuM revealed a larger, more hydrophobic active site compared to analogous uricase in the uric acid pathway. Genes encoding heterotrimeric Cdh (cdhA,B,C) and TmuM (tmuM), were located on a 25.2-kb fragment in CBB1 genome. Gene cluster analysis relative to similar cluster in uric acid degrading organisms identified five more putative genes of the C-8 oxidation pathway, namely tmuH, tmuD, orf1, orf2, and orf3. First three genes were assigned encoding TM-HIU hydrolase (TM-HIU to TM-OHCU), TM-OHCU decarboxylase (TM-OHCU to stereospecific TMA (proposed S-(+)-TMA)), and trimethylallantoinase (stereospecific TMA to TMAA), respectively. Further, orf2 and orf3 are proposed to encode for YlbA and ArgE like hydrolase and deacetylase, which convert TMAA to glyoxylate, di- and monomethylurea. This is the first report of (a) TMA structure (b) TMU monooxygenase and TM-HIU (hydroxylation product of TMU), and (c) complete delineation of C-8 oxidation pathway by a combination of enzymology and cluster analysis. Excessive consumption of caffeine in various forms has created a need for a rapid diagnostic test, esp. for nursing mothers and infants. Cdh was hypothesized to be suitable for this test. Sensitivity of the test was shown to be 1 ppm. A colorimetric test with partially purified Cdh and INT-dye was optimized to detect within a minute, caffeine in drugs, nursing mother's milk, and differentiate decaffeinated beverages.

Les nourrissons âgés de moins de trois mois ont la particularité d’être à relativement haut risque d’infections bactériennes sévères (IBS), majoritairement représentées par les infections urinaires et en particulier celles plus invasives (IBI) que sont les méningites et les bactériémies. On ne dispose actuellement pas d’outil suffisamment fiable et d’un rapport coût-bénéfice bien évalué pour différencier les nourrissons fébriles porteurs d’une affection virale banale de ceux porteurs d’une infection bactérienne.Le travail doctoral avait pour objectifs d’évaluer l’épidémiologie et les pratiques de prise en charge françaises des infections bactériennes de l’enfant fébrile âgé de moins de trois mois admis aux urgences pédiatriques ainsi que des outils diagnostiques, tels que la bandelette urinaire et la procalcitonine dans cette population. Plus de 2000 nourrissons ont été inclus dans une étude prospective observationnelle multicentrique (PRONOUR) sur une période de trente mois d’octobre 2008 à Mars 2011.Nous avons dans un premier temps décrit les modalités de prise en charge de ces jeunes nourrissons fébriles et montré que les pratiques étaient hétérogènes entre les centres participants et variaient par rapport aux recommandations existantes.Nous avons dans un second temps, étudié les pratiques de dépistage des infections urinaires, IBS la plus fréquente dans cette tranche d’âge, et en particulier les performances de la bandelette urinaire. La majorité des urines étaient prélevées par poche collectrice et la bandelette urinaire avait une sensibilité pour la détection d’infection urinaire comparable à celle de l’analyse par microscopie avec cette méthode de recueil.Puis, nous avons réévalué les performances des algorithmes décisionnels existants pour la détection des enfants à faible risque d’IBS dans une nouvelle population (PRONOUR). Nous avons montré qu’ils avaient une valeur prédictive négative satisfaisante comme précédemment décrit, mais une faible valeur prédictive positive pour la distinction des enfants porteurs ou non d’une IBS.Enfin, les performances de la procalcitonine (PCT) dans la détection des IBS et IBI ont été calculées et comparées avec celles d’autres marqueurs inflammatoires usuels. La capacité discriminative de la PCT était excellente pour le diagnostique d’IBI et meilleure que celles des autres marqueurs inflammatoires. Pour la détection d’une IBS, la PCT avait des performances similaires à celles de la C-réactive protein.La prise en charge des nourrissons fébriles âgés de moins de trois mois est hétérogène et pourrait être améliorée par de nouveaux outils prédictifs La prise en charge des nourrissons fébriles âgés de moins de trois mois est hétérogène et pourrait être améliorée par de nouveaux outils prédictifs tels que l’utilisation de la procalcitonine et de la bandelette urinaire dans cette tranche d’âge. / The prevalence of severe bacterial infections (SBI),mainly represented by urinary tract infections is relatively high in infants less than three months of age and particularly those more invasive (IBI) that are meningitis and bacteremia. Current strategies to distinguish young infants with SBIs from those with viral infections are not absolutely reliable and their cost-effectiveness and the associated iatrogenic morbidity have not been extensively evaluated.The purposes of the study were to characterize the spectrum of disease, clinical outcomes and management of febrile infants aged three months or younger admitted to pediatric emergency department in France and to evaluate the performances of diagnostics tests that are urinary dipstick test and procalcitonin assay in this population. A prospective multicenter cohort study was conducted in 15 French pediatric emergency departments over a period of 30 months between October 2008 and March 2011(PRONOUR). More than 2000 infants were enrolled.First, we have described the management of these young febrile infants. We have showed that practices were heterogeneous between the participating centers and varied from the current guidelines.We have analyzed screening strategies of urinary tract infection, the most common SBI in this age group, and in particular we aimed to assess the test performances of urine dipstick test. Most of urine specimens were collected by bag. Dipstick tests on bag urine samples detected urinary tract infections in infants aged 7 to 92 days similarly to microscopy.Then, we have re-evaluated the performances of current strategies for identifying infants at low risk for SBI in a new population (PRONOUR). We have showed that current protocols maintained their good previously reported negative predictive values but have low positive predictive values to detect young infants with SBIs.Finally, the performances parameters of procalcitonine (PCT) for detecting SBI and IBI in this population were calculated and compared with usual biomarkers. Procalcitonin has better diagnostic accuracy than CRP for detecting IBI. The two tests perform similarly for identifying SBI in febrile infants aged 7 to 91 days.The management of febrile infants less than three months of age varied between centers should be improved by new predictive tests. The performance of PCT testing should encourage the development of decision-making rules incorporating PCT and urinary dipstick test.

The aim of this study is to describe, analyse and interpret the reading comprehension of language teacher students at the beginning of their university studies through a diagnostic reading comprehension test as a prognosis of their ability to manage their studies. The research questions are: 1. What form has the diagnostic reading comprehension test of the development project used at the beginning of the teacher education for language teacher students? 2. What does the diagnostic reading comprehension test at the beginning of the studies indicate about the success in the reading comprehension of academic course literature of the language teacher students? 3. What do the language teacher students’ reflections show about the reading comprehension test and about their insight into their own reading comprehension of academic course literature? 4. To what extent can a connection be shown between the results of the diagnostic reading comprehension test and the study results of the language teacher students? The research study represents a mixed method strategy and is a descriptive case study. A diagnostic reading comprehension test has been given to a group of language teacher students at the beginning of their first term. The students were also asked to reflect on the test and their reading ability. According to the study the diagnostic reading comprehension test used in the development project, and analysed in this study, must be altered to meet desired claims before used again. For example should the test include more reflective questions and more people should be included in the test process. This research contributes to new knowledge about teacher students’ comprehension of academic texts as well as new knowledge about a reading comprehension test.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13560号 / 論医博第2289号 / 新制||医||1067(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 森信 暁雄, 教授 村井 俊哉, 教授 林 康紀 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM