La scoliose idiopathique de l’adolescent (SIA) est une maladie dont la cause est encore inconnue, et qui génère des déformations complexes du rachis, du thorax et du bassin. La prévalence est de 4% dans la population adolescente au Québec. Cette pathologie affecte surtout les filles durant leur poussée de croissance pubertaire. Parmi plusieurs hypothèses émises, l’hypothèse neuroendocrinienne, impliquant une déficience en mélatonine comme agent étiologique de la SIA a suscité beaucoup d’intérêt. Cette hypothèse découle du fait que l’ablation de la glande pinéale chez le poulet produit une scoliose ressemblant sous plusieurs aspects à la pathologie humaine. La pertinence biologique de la mélatonine dans la scoliose est controversée, étant donné que la majorité des études chez l’homme n’ont pu mettre en évidence une diminution significative des niveaux de mélatonine circulante chez les patients scoliotiques. Nous avons démontré un dysfonctionnement dans la signalisation de la mélatonine au niveau des tissus musculo-squelettiques chez une série de patients atteints de SIA (Moreau & coll. 2004). Nous avons confirmé ce défaut chez un plus grand nombre de patients ainsi qu’en utilisant une nouvelle technologie (spectroscopie cellulaire diélectrique) n’ayant pas recours à un prétraitement des cellules donnant ainsi des résultats plus précis. Cette technique a montré la présence des mêmes groupes fonctionnels identifiés auparavant par la technique d’AMPc. Le dysfonctionnement de la signalisation de la mélatonine est dû à une phosphorylation accrue des protéines G inhibitrices. Ce défaut pourrait être causé par un déséquilibre de l’activité des kinases et phosphatases capables de réguler la phosphorylation des protéines Gi. Parmi ces kinases, PKCd a suscité initialement notre intérêt vu qu’elle peut phosphoryler les protéines Gi. Nous avons démontré que cette kinase interagit avec le récepteur de la mélatonine MT2 et que cette interaction varie selon le groupe fonctionnel auquel un patient SIA appartient. Par la suite nos travaux se sont dirigés vers la découverte d’effecteurs cellulaires régulés par la mélatonine et plus spécifiquement l’ostéopontine (OPN), compte tenu de son rôle présumé comme mécanorécepteur et dans certaines structures jouant un rôle dans la proprioception, le contrôle postural et la fonction vestibulaire. L’OPN a été identifiée initialement par sa surexpression au niveau protéique et de l’ARNm dans la musculature paraspinale uniquement chez les poulets scoliotiques. Nous avons également utilisé un autre modèle animal, la souris C57Bl/6 naturellement déficiente en mélatonine. Nous avons généré des souris bipèdes en amputant les membres antérieurs de souris OPN KO, des souris CD44 KO ainsi que des souris contrôles C57Bl/6. Nos résultats ont montré qu’aucune souris OPN KO (n=50) ou CD44 KO (n=60) ne développe la maladie, contrairement aux souris contrôles C57Bl/6 (n=50) dont 45% deviennent scoliotiques. Ces résultats nous ont poussés à investiguer le rôle de cette protéine dans l’étiopathogenèse de la maladie chez l’humain. Nos résultats ont montré une augmentation des niveaux circulants d’OPN chez les patients atteints de la SIA et que l’élevation en OPN corrélait avec la sévérité de la maladie. Nos études chez les enfants asymptomatiques nés de parents scoliotiques et qui sont plus à risque de développer la maladie ont aussi démontré des différences significatives au niveau des concentrations en OPN en comparaison avec les sujets sains. En effet, plusieurs enfants à risque présentaient des niveaux d’OPN supérieurs à 800ng/ml suggérant un plus grand risque de développer une scoliose indiquant aussi que l’augmentation des niveaux en OPN précède le début de la maladie. / Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis that affects a significant number of young teenagers, mainly females. Historically, several hypotheses were postulated to explain the aetiology of AIS. The neuroendocrine hypothesis involving a melatonin deficiency as the source for AIS has generated great interest. This hypothesis stems from the fact that experimental pinealectomy in chickens, and more recently in rats maintained in a bipedal mode, produces scoliosis. The biological relevance of melatonin in idiopathic scoliosis is controversial since no significant decrease in circulating melatonin level has been observed in a majority of studies. Analysis of melatonin signal transduction in musculoskeletal tissues of AIS patients demonstrated for the first time a defect occurring in a cell autonomous manner in different cell types isolated from AIS patients suffering of the most severe form of that disease. We confirmed this defect by analysing more AIS patients and by using a new technology (cellular dielectric spectroscopy) which gives more precise results because it allows the measurement and analysis of receptor activation without the need to pretreat cells. This technique showed the same functional classification into three functional groups as identified by cAMP technique. Melatonin signalling dysfunction is caused by phosphorylation of serine residues affecting the activity of G inhibitory (Gi) proteins normally associated with melatonin receptors present at the cell surface. This defect could be caused by an imbalance in the activity of kinases or phosphatases that can regulate Gi proteins phosphorylation. Among these kinases PKCd was initially of interest because it has been shown that it can phosphorylate Gi proteins. We showed that this kinase interacts with melatonin receptor MT2 and that this interaction varies from one functional group to another. Thereafter, we moved one step further to characterise downstream effector regulated by melatonin. This work has led to the identification of osteopontin (OPN) which is a relevant candidate because it can act as a mecanosensor and it is involved in proprioception, postural and vestibular control. OPN was initially identified in pinealectomized chickens where it was shown to be upregulated at protein and mRNA levels only in scoliotic ones. We also used another animal model, C57Bl/6 mice which are naturally deficient in melatonin. We generated bipedal mice by amputating forelimbs of OPN knock-out mice, CD44 knock-out mice as well as C57Bl/6 wild type mice. Our results showed that all bipedal mice OPN Knock-out or CD44 Knock-out did not develop scoliosis contrasting with C57Bl/6 wt mice where 45% develop scoliosis. These results prompted us to investigate the role of this protein in scoliosis etiopathogenesis in humans. We showed an increase in the OPN circulating levels in AIS patients and this elevation correlates with disease severity. Elevated plasma OPN levels were also found in the asymptomatic at-risk group (offspring of scoliotic patients), suggesting that these changes precede scoliosis onset.

The main purpose of this study was to develop a three-tier test for assessing ninth-grade students&rsquo / misconceptions about simple electric circuits. The first tier of an item on the test presents an ordinary multiple choice question, the second tier presents a set of reasons for the response given to the first tier, and the third tier questions if examinees are confident for their responses to the first two tiers. The study was carried in Polatli, the biggest outlying district of capital Ankara. In the light of the related literature, interviews were conducted by the researcher so as to collect information about students&rsquo / understanding of simple electric circuits. Thereby, a list of misconceptions was acquired and it was used for developing an open-ended questionnaire. Next, the questionnaire was examined by two physics teachers and an instructor from METU for establishing content validity. The questionnaire was administered to 99 ninth-grade students and their responses were categorized in the purpose of determining the distracters of the three-tier test / the Simple Electric Circuit Diagnostic Test (SECDT). At last, the SECDT was developed and administered to 124 ninth-grade students. The validity of the SECDT was established by means of quantitative methods in addition to the qualitative methods. A positive correlation coefficient was estimated between student scores and confidence levels, that is, successful students on the SECDT were more confident for their responses than unsuccessful students. This result means that the SECDT works properly, for example, students generally understood the items and found their reasoning among the distracters. Also, what items measure was investigated by means of factor analysis, and three reasonable factors were obtained. Furthermore, proportions of false positives and negatives were estimated and found as 17.47 % and 10.82 %, respectively. As well as, Cronbach alpha reliability coefficient of student scores was estimated as 0.69, but the reliability coefficient of student misconception scores was estimated as 0.33. Consequently, the SECDT scores are valid and reliable measure of students&rsquo / qualitative understanding of simple electric circuits / however, misconception scores may not be reliable.

Abstract Emergency medical services (EMS) are designed to provide prompt response, on-scene treatment and transport for definitive care in patients with acute illness or injury. In recent years, the growing number of missions for non-urgent matters has challenged emergency care to design risk assessment protocols and tools to support decision-making and resource management at both dispatch and on-scene. The present study was designed to examine the efficacy of a criteria based dispatch protocol and National Early Warning Score (NEWS) in the Finnish EMS system. In addition, the aim of the research was to obtain data on patient allocation and mortality in the Northern Finnish population. The study data included 13,354 EMS missions from a six-month cohort (1.1.2014 - 30.6.2014) of prehospital emergency patients in two hospital districts – Kainuu and Länsi-Pohja – in Northern Finland, using a retrospective, observational design. Prehospital data including patient clinical physiological variables were combined with the national Finnish registries (Care Registry for Health Care, Intensive Care Consortium Database and Cause of Death Registry) in order to examine risk assessment in EMS and prehospital patient outcomes. Based on the result, the risk assessment at the dispatch was correct in 67.5% of the cases and four out of ten EMS missions did not lead to transportation by an ambulance. The use of the Finnish dispatch protocol resulted in an overall rate of 23% of over-triage and a 9% rate of under-triage. The highest NEWS category showed a good sensitivity for 1-day mortality but failed to adequately discriminate patients in need of intensive care or who died within 30-days in a large, unselected, typical EMS population. In conclusion, the criteria based dispatch protocol resulted in over-triage of a quarter of missions and in a significant rate of EMS missions without ambulance transportation. In addition, the predictive value of prehospital NEWS regarding the patient´s risk of death and need for intensive care was low. / Tiivistelmä Ensihoitopalvelu on suunniteltu tarjoamaan nopeaa vastetta, paikalla tapahtuvaa hoitoa ja kuljetusta lopulliseen hoitopaikkaan potilaille, joilla on akuutti sairaus tai vamma. Viime vuosien lisääntyneet yhteydenotot ei-kiireellisissä asioissa on johtanut riskinarviotyökalujen kehittämiseen tukemaan päätöksentekoa ja resurssienhallintaa hätäpuhelun aikana ja tapahtumapaikalla. Tässä tutkimuksessa tarkasteltiin kriteeripohjaista hätäpuhelun käsittelyä sekä varhaisen varoituspistejärjestelmän (NEWS) tehokkuutta suomalaisessa ensihoitojärjestelmässä. Lisäksi tutkimuksen tavoitteena oli saada tietoa ensihoitopotilaiden hoitotuloksista ja kuolleisuudesta Pohjois-Suomessa. Tutkimukseen sisältyi 13 354 ensihoitotehtävää kuuden kuukauden kohortista (1.1.2014 – 30.6.2014) kahden sairaanhoitopiirin alueelta – Kainuu ja Länsi-Pohja – Pohjois-Suomessa käyttämällä retrospektiivistä havainnoivaa tutkimusmenetelmää. Ensihoidon aikana kerätty tieto, mukaan lukien potilaan kliiniset fysiologiset arvot, yhdistettiin kansallisiin rekistereihin (hoitoilmoitusrekisteri, tehohoitokonsortion laatutietokanta sekä kuolinsyyrekisteri) jotta ensihoitopotilaiden riskinarviota ja hoitotuloksia voitiin tutkia. Tutkimustulosten mukaan 67.5 prosentissa tapauksista riskinarvio hätäkeskuksessa oli oikea ja neljä kymmenestä ensihoitotehtävästä ei johtanut kuljetukseen ambulanssilla. Suomalaisen hälytysprotokollan käyttö johti yliarviointiin 23 prosentissa tapauksista ja aliarviointiin 9 prosentissa tapauksista. Korkeariskin NEWS-luokan herkkyys 1-päivän kuolleisuudelle oli hyvä, mutta se ei kyennyt erottelemaan riittävän hyvin potilaita, jotka tarvitsivat tehohoitoa tai kuolivat 30 päivän sisällä suuressa ei-valikoidussa tyypillisessä ensihoitopotilasväestössä. Yhteenvetona todettiin, että kriteeripohjaisen riskinarvion käyttö johti yliarvioon neljänneksestä tapauksista sekä huomattavaan ensihoitotehtävämäärään ilman ambulanssikuljetusta. Lisäksi ensihoidon aikana käytetyn varhaisen varoituspistejärjestelmän ennusteellinen arvo potilaan kuolemanriskin ja tehohoidon tarpeeseen oli matala.

Abstract The aim of the South Karelian Allergy Research Project (SKARP) was to quantify the occurrence of children’s food allergy and food-associated hypersensitivity symptoms and their associated factors. The study population comprised all children born between April 2001 and March 2006 and living in the province of South Karelia, in the south-eastern part of Finland. The questionnaire survey was conducted in co-operation with the child health clinics in the area in 2005–2006. Concurrently with but independently of the questionnaire study, the results of allergy tests regarding the same child population were collected from patient records. The participation rates in the questionnaire study were 54% (644/1194) among the newborn infants and 69% (3308/4779) among the children aged 1 to 4 years. The lifetime prevalence of parent-reported food allergies was 9% and that of parent-perceived food-associated hypersensitivity symptoms 21% by the age of 4 years. In addition, another 19% of children adhered to an elimination diet without previous symptoms associated with any food items. The prevalence of children with such diets decreased by age. Up to the age of 4 years, 19% of the participants had undergone a food allergy test and 8% of the participants had obtained a positive result in these tests. Physician-diagnosed food allergies and food allergies based on the tests were more common for milk, egg and cereals than for other food items. The tested children and those with a positive test result were only slightly overrepresented among the participants. Allergic manifestations in either biological parent doubled and in both biological parents tripled the incidence of a positive food allergy test. The spring season coinciding with the end of the first trimester of pregnancy predicted sensitisation to food items in the children. In early childhood, food allergies and food hypersensitivities were found to be common in a child population. New population-based knowledge regarding the inheritance of these conditions was obtained. Additionally, an association was observed between the timing of the 11th gestational week in spring and the sensitisation to food items, the detailed reasons and immunological mechanisms of which must be confirmed in further studies. / Tiivistelmä Etelä-Karjalan allergiatutkimus (EKAT) käynnistettiin selvittämään lasten ruoka-allergioiden ja ruokayliherkkyysoireiden esiintyvyyttä ja niihin liittyviä tekijöitä. Tutkimusväestöön kuuluivat kaikki ne Etelä-Karjalan maakunnan alueella asuvat lapset, jotka olivat syntyneet huhtikuun 2001 ja maaliskuun 2006 välisenä aikana. Kyselyaineisto kerättiin yhteistyössä alueen neuvoloiden kanssa vuosina 2005–2006. Kyselytutkimuksen kanssa samanaikaisesti mutta siitä riippumattomasti kerättiin samaa lapsiväestöä koskevat allergiatestitulokset alueen potilasrekistereistä. Kyselytutkimuksen osallistumisaste oli vastasyntyneiden ikäluokassa 54 % (644/1194) ja isommilla lapsilla 69 % (3308/4779). Kolmannen ikävuoden loppuun mennessä vanhemmat ilmoittivat 9 %:lla lapsista todetun ruoka-allergiaa ja lisäksi 21 %:lla ruokayliherkkyys perustui ainoastaan vanhempien havaintoihin. Näiden lisäksi 19 % lapsista vältti yhtä tai useampaa ruoka-ainetta ilman, että minkään ruoka-aineen olisi todettu aiheuttaneen oireita. Dieettien noudattajien osuus väheni selvästi tarkasteltaessa ikäluokkia yksivuotiaista neljävuotiaisiin. Kolmannen ikävuoden loppuun mennessä ruoka-allergiatestattuja oli 19 % ja positiivisen testituloksen saaneita 8 % tutkimukseen osallistuneista. Lääkärin toteamat ja testeihin perustuneet ruoka-allergiat olivat tavallisempia maidolle, kananmunalle ja viljoille kuin muille ruoka-aineille. Allergiatestatuilla ja positiivisen testituloksen saaneilla oli vain lievä yliedustus kyselytutkimukseen osallistujien joukossa verrattuna kyselyyn vastaamattomiin. Allergiset sairaudet toisella biologisella vanhemmalla kaksinkertaistivat ja molemmilla vanhemmilla kolminkertaistivat positiivisen ruoka-allergiatestin ilmaantuvuuden. Raskauden ensimmäisen kolmanneksen lopun ajoittuminen kevääseen ennakoi syntyvän lapsen herkistymistä ruoka-aineille. Varhaislapsuuden ruoka-allergioiden ja -yliherkkyyksien todettiin olevan tavallisia väestössä. Näiden sairauksien periytyvyydestä saatiin uutta väestötietoa. Lisäksi havaittiin yhteys 11. raskausviikon ajoittumisen kevääseen ja ruoka-aineille herkistymisen välillä. Yhteyden yksityiskohtaiset syytekijät ja immunologiset mekanismit täytyy ehdottomasti vahvistaa jatkotutkimuksin.

Background: The coronavirus disease 2019 (COVID-19) presents diagnostic evaluation and patient management challenges, including uncertainty regarding the role of imaging tests. This series of reviews from the suite of Cochrane ‘living systematic reviews’ aims to evaluate the accuracy of chest imaging (computed tomography (CT), X-ray and ultrasound) for diagnosis and management of individuals with suspected COVID-19. Methods: The Bern COVID-19 Living Database, Cochrane COVID-19 Register, and CDC Library were searched through 30 September 2020 (for review version 3) and 17 February 2021 (for review version 4). Diagnostic accuracy studies involving participants with suspected COVID-19 were included. Screening, data extraction, and risk of bias assessments (using the QUADAS-2 tool) were completed independently, in duplicate. Pooled accuracy estimates and 95% confidence intervals (CIs) were determined using a bivariate random effects model. Results: In the third version of the review, chest CT (41 studies, 16133 participants, 8110 (50%) cases) had a pooled sensitivity of 87.9% (95%CI 84.6-90.6) and specificity of 80.0% (74.9-84.3). Chest X-ray (9 studies, 3694 participants, 2111 (57%) cases) had a pooled sensitivity of 80.6% (69.1-88.6) and specificity of 71.5% (59.8-80.8). Ultrasound of the lungs (5 studies, 446 participants, 211 (47%) cases) had a pooled sensitivity of 86.4% (72.7-93.9) and specificity of 54.6% (35.3-72.6). Indirect comparisons showed that chest CT gave higher specificity (P=0.0052) and similar sensitivity (P=0.77) compared to ultrasound. There were no differences (P≥0.05) in accuracy between CT and X‐ray, or X‐ray and ultrasound. In the fourth version of the review, chest CT (69 studies, 28285 participants, 14342 (51%) cases) had a pooled sensitivity of 86.9% (83.6-89.6) and specificity of 78.3% (73.7-82.3). Chest X‐ray (17 studies, 8530 participants, 5303 (62%) cases) had a pooled of sensitivity=73.1% (64.1-80.5) and specificity of 73.3% (61.9-82.2). Ultrasound of the lungs (15 studies, 2410 participants, 1158 (48%) cases) had a pooled sensitivity of 88.9% (84.9-92.0) and specificity of 72.2% (58.8-82.5). Indirect comparisons showed that chest CT and ultrasound had similar sensitivities (P=0.42), and each gave higher sensitivities than X-ray (P=0.0003 and P=0.001, respectively). All modalities had similar specificities (P≥0.05). Conclusion: The most recent evidence indicates that both chest CT and ultrasound of the lungs are sensitive and moderately specific for diagnosing individuals with suspected COVID-19, while chest X-ray is moderately sensitive and moderately specific. Chest CT and ultrasound may be useful for ruling out COVID‐19, but not for distinguishing COVID-19 from other illnesses. Research assessing the prognostic value of imaging for predicting morbidity and mortality in individuals with COVID-19 is underway and will also be published in the suite of Cochrane ‘living' systematic reviews.

Although classroom assessment is one of the most frequent practices carried out by teachers in all educational programs, limited research has been conducted to investigate the dependability and validity of criterion-referenced tests (CRTs). The main purpose of this study is to develop a criterion-referenced test for first-year Japanese university students in a general English program. To this end, four research questions are formulated: (a) To what extent do the criterion-referenced items function effectively?; (b) To what extent do the facets of persons, items, sections, classes, and subtests contribute to the total score variation in two CRT forms?; (c) To what extent are two CRT forms dependable when administered as pretests and posttests?; and (d) To what extent are two CRT forms valid when administered as pretests and posttests? Two CRT forms made up of vocabulary (k = 25), listening (k = 20), and reading (k = 25) subtests were administered to 249 students using a counterbalanced design. Criterion-referenced item analyses showed that most items were working well for criterion-referenced purposes. Both univariate and multivariate generalizability studies indicated that the most of the variance was accounted for by the interaction effect, followed by the items effect, and then by the persons effect. FACETS analyses showed the separation for all the facets accounted for in the analyses and showed that item separation was greater than person separation. This indicated that the students' ability estimates were similar due to their having taken a placement test, whose results were used to form proficiency-based classes. Both univariate and multivariate decision studies indicated that the CRT forms were moderately to highly dependable. The content validity of the CRT forms was supported because the test content was strongly linked to what was taught in class. The construct validity was supported mainly because a fair amount of score gain was observed. This study elucidates how the statistical analyses used in this study can be applied to CRT development, and how CRT development can be carried out as part of curriculum development. / Educational Administration

This doctoral thesis is dealing with the correlation of morphological, immunohistochemical and genetical findings in malignant tumors of salivary glands. The first half of the thesis comprises the summary of current knowledge about salivary malignancies. The second half is presenting the research itself. The research results are divided into three parts. The first part is presenting the method of "2-step diagnostic test" of malignant tumors. This screening test aims to find new, so far not described gene aberrations with a focus on malignant tumors of salivary glands. This method takes place in two consecutive steps. In the first step the material is examined by an immunohistochemical mixture of antibodies, which non-specifically detects aberration in the genes NTRK1-3, ALK and ROS1. In the second step all positive cases are subjected to highly sensitive and specific molecular-genetic examination by the method of next generation sequencing (NGS) using the Archer kit. In the second part of the work there has been designed the approach to the cytological diagnosis of salivary secretory carcinoma by the fine-needle aspiration (FNA). This part is describing to the details the cytomorphology of secretory carcinoma in both, Pap smears and cell blocks, from which additional immunocytochemical and genetic...

Made available in DSpace on 2016-04-27T16:57:02Z (GMT). No. of bitstreams: 1 Vivaldo de Souza Bartolomeu.pdf: 1726401 bytes, checksum: aca4194ead87c19ca09df39e6a761c4b (MD5) Previous issue date: 2010-10-06 / Secretaria da Educação do Estado de São Paulo / The goal of this research is to examine the learning and difficulties of high school seniors students with the real numbers. For this, was made a diagnostic test with 54 students, with 18 from 1st year, 18 from 2nd year and 18 from 3rd year of high school seniors; everyone from State Public School System. This research has a qualitative approach, referenced by LUCKESI (2005) and his analyses show a blank between student learning and Mathematics knowledge, then is proposed a change on the methods to teach real numbers, according with DIAS (2002). The results revealed that most of the students are not familiar with this topic, although the Real number was taught at High School. It is necessary to review this teaching process with Real Numbers / A presente pesquisa tem como objetivo verificar os conhecimentos e dificuldades dos estudantes do ensino médio relacionados ao conjunto dos números reais. Para isso, foi realizado uma avaliação diagnóstica com 54 alunos, sendo 18 do 1ºano, 18 do 2º ano e 18 do 3º ano do Ensino Médio; oriundos da Rede Pública Estadual - na resolução de questões envolvendo conceitos relativos a números reais. Trata-se de um estudo qualitativo, embasado por LUCKESI (2005) e suas considerações teóricas a respeito da avaliação e seus desdobramentos. As análises das respostas revelam uma lacuna na aprendizagem discente frente a este conteúdo matemático, propõe-se então uma revisão do processo de ensino de números reais, afinal para DIAS (2002), saber o conceito de números reais é fundamental ao ensino de matemática. Os resultados obtidos revelam que a maioria dos sujeitos participantes não tem esses conceitos claramente definidos, embora componham oficialmente a formação de qualquer estudante do Ensino Fundamental. Sendo necessária uma revisão do processo de ensino-aprendizagem dos números reais

INTRODUCTION Taenia solium cysticercosis (CC) and taeniosis are zoonotic diseases mainly occurring in developing countries of Asia, Africa and Latin America. Humans are the only definitive host of the parasite harbouring the adult tapeworm in the small intestine (taeniosis). Gravid proglottids containing thousands of eggs are daily shed with the faeces in the environment. The pig intermediate host, through its coprophagic behaviour, may consume contaminated human faeces and consequently, ingest eggs that will further develop into the larval stage of the parasite in the muscles and the brain (cysticerci), causing porcine CC. Humans acquire infection with the adult tapeworm by consumption of undercooked or raw pork infected with cysticerci. Humans can also become infected by the cysts by accidental ingestion of T. solium eggs and develop human CC. In humans, cysts may lodge in muscles, subcutaneous tissues, eyes and/or central nervous system causing ocular CC and neurocysticercosis (NCC) in the two latter cases, respectively. While mainly asymptomatic in pigs, CC and particularly NCC may be responsible of severe health disorders in humans, seizures and epilepsy being the most common ones. In the last decade T. solium became the study target of research groups throughout the world and is now more in the focus of international health and animal health organizations. However, the disease remains neglected and many data gaps still hinder a comprehensive estimation of its burden. Therefore, the general objective of this thesis is the development of tools to estimate the impact of T. solium CC on both public health and veterinary public health in regions where the parasite occurs. For this purpose, four specific objectives are followed focusing on taeniosis, porcine and human CC in different endemic areas of the world. Firstly, a stochastic model is developed allowing the estimation of the monetary and health (disability adjusted life year, DALY) burden of CC in three endemic provinces of Cameroon and the identification of data gaps increasing the uncertainty around the disease burden estimates (Objective 1). Secondly, because there is incomplete knowledge on many CC burden assessment parameters, two protocols are designed to study specific factors that may affect the transmission dynamics of the parasite, and possibly, the disease burden estimation. Because the latter estimation may depend on the age of diseased individuals, a community-based study aims at determining the occurrence of human CC and at studying the age-related infection and transmission patterns of the parasite among a population living in an endemic area of Ecuador (Objective 2). The objective of a second field study conducted in the Democratic Republic of Congo is to determine the occurrence of porcine CC at different levels of the pig trade chain in order to detect any variation in the apparent prevalence figures of the disease (Objective 3). Finally, because none of the available tests for the diagnosis of human CC is a gold standard limiting the estimation of the disease occurrence to the apparent prevalence, and since sensitivity and specificity of the diagnostic tests have only been evaluated in clinical settings, i.e. infected diseased versus uninfected non-diseased individuals, a Bayesian approach is used to estimate the true prevalence of human CC and the performances of available immunological tools for its diagnosis in the framework of an epidemiological study (including uninfected and infected diseased and non-diseased individuals) (Objective 4). RESULTS 1. Development of a stochastic model for the estimation of the economic and health (DALY) burden of T. solium cysticercosis The first experimental section of this thesis aims at developing a stochastic model for the estimation of the monetary and health (DALY) burden of CC, taking 3 endemic provinces of Cameroon as example. Both cost and DALY estimations are applied. All necessary parameters are collected and imported in R software. Different probability distributions are used according to the type of information available for each of the parameters. Monte Carlo simulation techniques allow drawing a set of parameters from the underlying distributions through serial iterations. The number of people with NCC-associated epilepsy represents 1.0% of the local population, whereas the number of pigs diagnosed with CC corresponds to 5.6% of the local pig population. The total annual costs due to T. solium CC in West-Cameroon is estimated at 10,255,202 Euro (95% CR 6,889,04814,754,044), of which 4.7% are due to losses in pig husbandry and 95.3% to direct and indirect expenses associated with human CC. The average number of DALYs lost is 9.0 per thousand persons per year (95% CR 2.820.4; meaning that 9 years of life in perfect health per thousand inhabitants of this area are lost due to CC). This study provides the first estimates of the impact of CC in Cameroon and allows identifying the related economical, clinical and epidemiological necessary parameters and related data gaps. Moreover, the stochastic approach developed here allowed quantifying the uncertainty around the estimates due to the lack of knowledge on this neglected disease. 2. Study on the age-related infection and transmission patterns of human CC in an endemic area The second experimental part of this thesis aims at estimating the apparent prevalence of human CC in an endemic area of Ecuador using both serological antigen and antibody detection methods. Besides a high exposure to the parasite (25% of the sampled population had antibodies directed against T. solium cysticerci) contrasting with a low level of active infection (2.9% had circulating parasite antigens), this study shows that positivity patterns of both diagnostic tests strongly depend on the age of the subjects. The proportion of individuals showing antibodies directed against the larval stage of the parasite significantly increases till the age of 40 to become stable later. Simulation models incorporating insights from cohort study data and basic immunology principles are developed to explain the variations in antibody detection positivity pattern and to reflect the dynamics of exposure to the parasite. The simulations suggest a continual exposure to the parasite through all age categories but a variation of the rate of seroreversion depending on the number of exposures, or in other words, on the immunological status of the individuals. The models also indicate that at least 14% of the population of the community is yearly exposed to the parasite. On the other hand, the proportion of individuals infected by living cysticerci is significantly higher in the elderly. These findings agree with clinical observations in Mexico and Brazil. Immunosenescence could explain such an observation since a weaker immune system in the elderly would facilitate the establishment and maintenance of viable cysticerci in the muscles and in the brain in comparison with fully immunocompetent younger individuals. Our findings indicate that age-related CC infection may influence the CC burden estimates. 3. Occurrence of porcine cysticercosis at different levels of the pig trade flow in a suspected endemic area Based on the use of the enzyme-linked immunosorbent assay for the detection of circulating antigens of T. solium metacestodes (B158/B60 Ag-ELISA), the third experimental section of this thesis reports an apparent prevalence of about 40% of active CC in a pig population in a rural area of Bas-Congo (where pigs are reared) and in a pig population in different markets of Kinshasa (where pork is sold). This work also indicates that the marketing of cysticercotic pig may influence the transmission of the parasite. Indeed, while no significant difference is found in the proportion of active infections between the two sites, the intensity of infection is significantly higher in pigs sampled in the villages in Bas-Congo as compared to those in the markets in Kinshasa. It seems that massively infected animals are excluded at a certain level in the pig trade chain. Preliminary informal surveys on common practices in pig husbandry and pig trading indicate that pig farmers and/or buyers select the low infected animals and exclude those who are positive by tongue inspection at village level. More heavily infected pigs are subsequently used for villagers own consumption or sold at local (clandestine) markets. The influence of the cysticercotic pig marketing should be considered when estimating the animal disease burden. Accurate burden estimates will allow establishing and implementing effective food safety policies and regulations or improving the existent ones in order to control and prevent CC and taeniosis. 4. Estimation of the performances of available immunodiagnostic tools for the diagnosis of human CC in the framework of an epidemiological study The last experimental section of this thesis focuses on the use of Bayesian models to estimate the true prevalence of infection with and exposure to T. solium, and the characteristics of serological tests, namely the enzyme-linked immunosorbent assay for the detection of circulating antigens of the metacestode of T. solium (B158/B60 Ag-ELISA), the enzyme-linked immunoelectrotransfer blot assay (EITB) for the detection of antibodies directed against 7 specific T. solium glycoprotein antigens, and the ELISA for the detection of antibodies directed against crude cyst fluid extracts (Ab-ELISA), used in an epidemiological study setting (including uninfected and infected diseased and non-diseased individuals) in an Ecuadorian endemic area. The EITB and B158/B60 Ag-ELISA sensitivity and specificity estimates in the latter conditions are comparable to the same estimates in clinical settings. However, the present study demonstrates the importance of clearly defining a case when conducting such an exercise. Indeed, the sensitivity and specificity of EITB and B158/B60 Ag-ELISA are high for estimating the true prevalence of exposure to (proportion of individuals who have been in contact with the parasite during the precedent year, with or without development of cysticerci, and with or without (cured individuals) current infection with living cysticerci) and infection with T. solium (proportion of individuals currently infected with living cysticerci), respectively, but drop the other way around. In conclusion, since no gold standard test for human CC diagnosis is available, this study provides a tool for estimation of the true CC prevalence, which is essential for the disease burden assessment. CONCLUSIONS AND PERSPECTIVES Even though the World Health Organization (WHO) already drew the map of the global distribution of T. solium, data remain very limited in several parts of the world. Through a literature review and four experimental sections, this thesis shows that the burden of human and porcine CC may be non negligible and deserves a more global assessment. Moreover, this work allows depicting the disease data gaps more precisely and proposes some tools to deal with the lack of knowledge on this neglected zoonosis. The threat of misusing limited data is a fact and one could reject more global burden estimates based hereon. However, this should not be the main issue. The main concerns should rather focus on how to obtain estimates when only fragmentary data are available. For this purpose, two approaches may be considered: (1) a prospective approach aiming at developing more accurate taeniosis and CC diagnostic tools and at collecting more standardized data from different endemic areas of the world; (2) a retrospective approach aiming at using existing data in innovative ways, such as simulation, Bayesian and stochastic models and expert elicitation, may be a valid alternative. In conclusion, the development of new diagnostic and estimation tools is in progress to compensate for the lack of knowledge on taeniosis/CC and for the diagnostic test and study design limitations (including financial, technical and ethical restrictions). Efforts should be made to increase their availability to developing countries and to standardize study designs in order to produce reliable estimates to assess the global burden of T. solium CC. Once burden estimates are available, the cost-effectiveness of prevention and control programs can be tested and help national and international policy- and decision- makers in setting priorities in public health and veterinary public health policy, services and research. INTRODUCTION La cysticercose (CC) et la taeniose dues à Taenia solium sont des maladies zoonotiques sévissant principalement dans les pays en voie de développement dAsie, dAfrique et dAmérique Latine. LHomme est le seul hôte définitif du parasite, infesté par le ver adulte au niveau de lintestin grêle (taeniose). Des proglottis gravides, contenant des milliers dufs sont quotidiennement évacués avec les matières fécales humaines dans lenvironnement. Le porc, hôte intermédiaire coprophage, peut consommer ces matières fécales contaminées et, par conséquent, ingérer des ufs qui se développeront en stade larvaire au niveau des muscles et du cerveau (les cysticerques), causant ainsi la CC porcine. LHomme, en consommant de la viande de porc infestée (de cysticerques) crue ou mal cuite, sinfeste par le ver adulte bouclant ainsi le cycle. LHomme peut également sinfester par ingestion accidentelle dufs et développer la CC humaine. Chez ce dernier, les cysticerques peuvent se loger dans les muscles, le tissu sous-cutané, les yeux et le système nerveux central, causant, dans ces deux derniers cas, respectivement, la CC oculaire et la neurocysticercose (NCC). Alors que la CC est généralement asymptomatique chez le porc, la CC et tout particulièrement la NCC peuvent être responsables daffections sévères chez lHomme, les convulsions et crises dépilepsie étant les plus fréquentes dentre elles. Durant les dernières décennies, T. solium est devenu le sujet détude principal de plusieurs groupes de recherche à travers le monde ainsi que dorganisations internationales de santé publique et de santé animale. Cependant, le manque de données épidémiologiques et cliniques empêche toujours une estimation précise de son impact réel sur la santé. Cest pourquoi, lobjectif principal de cette thèse est de développer des outils permettant destimer limpact de la CC due à T. solium sur la santé publique et la santé publique vétérinaire. Dans ce but, quatre objectifs spécifiques sont fixés. Premièrement, un modèle stochastique est développé pour estimer limpact économique de la CC due à T. solium et son impact sur la santé (« disability adjusted life year », DALY) dans trois provinces du Cameroun. Cette première étude vise également à identifier les données lacunaires qui augmentent lincertitude autour des estimations (Objectif 1). Sur cette base, deux études épidémiologiques sont conduites dans des communautés endémiques dAfrique et dAmérique Latine, focalisées sur certains facteurs pouvant avoir une influence sur la transmission du parasite, et ainsi sur son impact sur la santé. Puisque lestimation de limpact de la CC sur la santé peut dépendre de lâge des individus malades, une étude de terrain a pour but détudier les relations entre la prévalence apparente de la CC et lâge des individus exposés et infestés dans une zone endémique dEquateur (Objectif 2). Une seconde étude de terrain vise à déterminer loccurrence de la CC porcine à différents niveaux de la filière de production et de commercialisation de la viande de porc dans une zone suspectée endémique de la République Démocratique du Congo (RDC) afin de détecter déventuelles variations de la prévalence apparente de la maladie (Objectif 3). Finalement, vu que la sensibilité et la spécificité des tests pour le diagnostic de la CC humaine ont uniquement été évaluées dans le cadre détudes cliniques, cest-à-dire chez des patients souffrant de CC versus des individus non infestés et asymptomatiques, et vu quaucun de ces tests nest un test parfait (test ayant une sensibilité et une spécificité de 100%), une approche bayésienne est appliquée pour estimer les performances de tests immunologiques disponibles dans le cadre dune étude épidémiologique, incluant des individus non infestés et infestés avec ou sans symptômes (Objectif 4). RESULTATS 1. Développement dun modèle stochastique pour lestimation de limpact économique et de limpact sur la santé (DALY) de la cysticercose due à T. solium Le coût monétaire et le nombre dannées de vie en bonne santé perdues en raison dune mortalité prématurée et/ou de la morbidité dues à la cysticercose (CC) (DALY) sont tous deux estimés dans trois provinces de lOuest du Cameroun. Tous les paramètres épidémiologiques et économiques nécessaires sont collectés et importés dans le logiciel R. Différentes distributions de probabilité sont utilisées en fonction du type dinformation disponible pour chacun dentre eux. Des techniques de simulation de Monte Carlo permettent les estimations finales sur la base des distributions de probabiltés. En tenant compte dune prévalence dépilepsie de 3,6%, le nombre dindividus souffrant dépilepsie associée à la NCC sélève à 1,0% de la population locale. Dautre part, le nombre de porcs diagnostiqués comme infestés correspond à 5,6% de la population porcine locale. Le coût annuel total associé à la CC à lOuest du Cameroun est estimé à 10255202 Euros (95% de la région de confidence (RC) : 6889048-14754044 Euros), desquels 4,7% sont dus aux pertes liées à la production porcine. Le coût par cas de CC humaine séleve à 194 Euros (95% RC : 147-253 Euros). Le nombre moyen de DALYs perdus par 1000 personnes et par an est de 9,0 (95% RC : 2,8 20,4). Cette étude permet une première quantification de limpact de la CC au Cameroun, recense les paramètres économiques, cliniques et épidémiologiques nécessaires à cette fin et le manque de données leur étant lié. De plus, lapproche stochastique utilisée ici permet de quantifier lincertitude autour de ces estimations due au manque de connaissance de cette maladie négligée. 2. Etude de la relation entre la prévalence et la transmission de la cysticercose et lâge des individus exposés et infestés La seconde section expérimentale de cette thèse a pour objectif destimer la prévalence apparente de la CC humaine dans une région endémique de lEquateur en utilisant des techniques sérologiques de détection dantigènes et danticorps. En plus dune exposition élevée au parasite (25% des individus ont des anticorps dirigés contre les cysticerques) contrastant avec une faible proportion dindividus infestés par des cysticerques vivants (3% des individus ont des antigènes circulants de cysticerques), cette étude montre que la positivité aux tests sérologiques dépend de lâge des individus. En effet, la proportion dindividus montrant une réaction humorale dirigée contre le stade larvaire du parasite augmente significativement jusquà lâge de 40 ans pour se stabiliser ensuite. Des modèles de simulation intégrant des données issues dune étude longitudinale ainsi que des principes de bases dimmunologie sont développés dans le but dexpliquer ces variations et de refléter certains aspects de la dynamique dexposition au parasite. Ces simulations suggèrent un taux dexposition au parasite stable à travers les différentes catégories dâge, mais une variation du taux de séroréversion dépendant du nombre de contacts préalables avec le parasite ou, en dautres mots, du statut immunologique des individus. Les modèles indiquent également quau moins 14% de la population sont annuellement exposés au parasite. Dautre part, la proportion des individus infestés par des cysticerques vivants est significativement plus élevée chez les personnes âgées de plus de 60 ans. Limmunosénescence pourrait expliquer ce phénomène, puisque un système immunitaire plus faible chez les personnes âgées pourrait faciliter létablissement et le maintien de cysticerques vivants au sein des muscles et du cerveau. Nos observations indiquent que lâge des individus malades pourrait influencer lestimation de limpact de la CC. 3. Occurrence de la cysticercose porcine à différents niveaux de la filière de la production de viande porcine dans une zone suspectée endémique Sur la base de lutilisation dun test immuno-enzymatique (« enzyme-linked immunosorbent assay », ELISA) pour la détection dantigènes circulants de cysticerques (B158/B60 Ag-ELISA), la troisième section expérimentale de cette thèse permet destimer une prévalence denviron 40% de CC active au sein dune population de porcs élevés traditionnellement dans une zone rurale de la province du Bas-Congo (RDC) et dans une population de porcs vendus et abattus sur différents marchés de Kinshasa (RDC). Ce travail démontre aussi linfluence du commerce de la viande de porc infestée sur la transmission du parasite. En effet, alors quaucune différence significative nest observée entre les proportions de porcs infestés sur les des deux sites détude, lintensité de linfestation est significativement plus élevée chez les porcs des villages que chez les porcs des marchés. Il semble ainsi que les animaux hautement infestés sont exclus à un certain stade de la filière de production et de commercialisation de la viande de porc. Des enquêtes préliminaires réalisées auprès des éleveurs de porcs et des vendeurs de viande de porc indiquent que les éleveurs et/ou les acheteurs de porcs sélectionnent les animaux faiblement infestés et excluent les animaux positifs au langueyage (inspection de la langue) dans les villages. Les porcs hautement infestés sont, par conséquent, consommés par les villageois ou vendus sur des marchés clandestins. Linfluence possible de la filière de la production et de la commercialisation de la viande porcine sur la prévalence apparente de la CC observée dans cette étude devrait être prise en considération lorsque lon évalue limpact de la maladie sur la santé et la production animale. Des estimations précises de cet impact permettront la mise en place de mesures de contrôle et de prévention adéquates de la CC et de la taeniose. 4. Estimation des performances doutils sérologiques pour le diagnostic de la cysticercose humaine dans le cadre dune étude épidémiologique La dernière section expérimentale de cette thèse vise lutilisation de modèles bayésiens pour lestimation de la prévalence réelle dinfestation par et dexposition à T. solium, et des caractéristiques (sensibilité et spécificité) de trois tests sérologiques, à savoir , un ELISA pour la détection dantigènes circulants de cysticerques de T. solium (B158/B60 Ag-ELISA), un autre test immuno-enzymatique (« enzyme-linked immunoelectrotransfer blot assay », EITB) pour la détection danticorps dirigés contre sept glycoprotéines spécifiques à T. solium, et un ELISA pour la détection danticorps dirigés contre le liquide vésiculaire brut de cysticerques (Ab-ELISA), appliqués dans le cadre dune étude épidémiologique (incluant des individus non infestés et infestés avec ou sans symptômes) dans une région endémique de lEquateur. Les performances de lEITB et du B158/B60 Ag-ELISA sont comparables à celles obtenues dans le cadre détudes cliniques. Cependant, cette étude démontre limportance dune définition claire de ce quest « un cas » lorsque lon sadonne à un tel exercice. En effet, la sensibilité et la spécificité de lEITB et du B158/B60 Ag-ELISA sont élevées lorsquil sagit destimer la prévalence dexposition à T. solium (proportion dindividus ayant été en contact avec le parasite durant lannée précédente, avec ou sans établissement de cysticerques et, avec ou sans présence concomitante de cysticerques vivants) et dinfestation par le parasite (proportion dindividus actuellement infestés par des cysticerques vivants), respectivement, mais chutent dans le cas contraire. En conclusion, vu quaucun test parfait nest disponible à ce jour pour le diagnostic de la CC humaine, cette étude propose un outil destimation de la prévalence réelle de la maladie. Cette estimation est essentielle pour lévaluation de limpact de la CC. CONCLUSIONS ET PERSPECTIVES Même si lOrganisation Mondiale de la Santé (OMS) a déjà dressé une carte de la distribution globale de la CC due à T. solium, les données concernant celle-ci restent limitées et incomplètes dans beaucoup de régions endémiques du globe. A travers une étude de la littérature et quatre sections expérimentales, cette thèse montre que limpact de la CC porcine et humaine peut être non négligeable. De plus, ce travail permet de décrire de façon quantitative le manque de connaissance sur la maladie et propose quelques outils permettant dy pallier. Le risque de mal interpréter ou dextrapoler à tort des données incomplètes existe. Il pourrait donc être légitime de rejeter toute estimation plus globale de limpact dune maladie qui serait basée sur ces données. Cependant, le manque de données ne devrait pas signifier « estimation impossible » mais devrait plutôt soulever la question suivante: « Comment pouvons-nous y pallier? ». Pour cela, deux approches sont envisageables : (1) une approche prospective visant à développer des techniques plus performantes pour le diagnostic de la taeniose et de la CC et à permettre la collecte de données standardisées dans différentes zones endémiques du monde ; (2) une approche rétrospective ayant pour but dutiliser les données existantes de manière innovatrice, cest-à-dire en utilisant par exemple des modèles de simulation, des modèles bayésiens ou l« élicitation dexpert ». En conclusion, de nouveaux outils diagnostiques et techniques destimation sont en développement et en cours de validation pour pallier au manque de connaissances, aux limitations des protocoles détudes de recherches scientifiques (incluant les restrictions financières, techniques et éthiques) et/ou aux limitations des tests diagnostiques mais, de considérables efforts devraient être fournis afin de mettre ces outils à la disposition des pays en voie de développement et de standardiser les protocoles de recherche pour permettre une estimation globale de limpact de la CC. Une fois disponible, cette estimation pourra aider les décideurs politiques et les bailleurs de fonds à fixer les priorités en termes de lois, services et recherche scientifiques en santé publique et santé publique vétérinaire.

Systematic reviews on diagnostic test accuracy studies provide an overview of the current literature in a systematic and transparent manner. They are the highest level of evidence in clinical research, therefore they are critical to decision-making in the healthcare setting. Cancer is the primary source of mortality in Canada, however early detection of tumors can improve the survival rates and long-term health outcomes of patients. The primary method of cancer diagnosis is histopathological assessment, however, its use remains controversial. It is an invasive procedure and requires resources and clinical expertise not readily available. Noninvasive clinical imaging has been studied as a clinically desirable method for cancer diagnosis, however its diagnostic accuracy has yet to be established in the medical setting. With the increased role of DTA research in medicine, the current literature needs to be summarized in an effective way to properly educate and influence clinical decision-making. The objective of this thesis is to address the current evidence gaps in DTA research by conducting several systematic reviews to evaluate the accuracy of diagnostic methods in cancer-related imaging. The last chapter of the thesis will provide a critical reflection on the current landscape of DTA studies in cancer-related imaging, based on the findings of the reviews in the thesis.