Ce travail a pour objectif de développer et d’appliquer une méthode originale permettant de simuler l’écoulement dans un milieu poreux fracturé. Cette méthode repose sur une approche multicouches double continuum permettant de séparer le comportement des différents aquifères présents sur un site. La résolution des écoulements, basée sur la méthode des Eléments Finis de Crouzeix-Raviart, est associée à une méthode inverse (minimisation de type Quasi-Newton combinée à la méthode de l’état adjoint) et à une paramétrisation multi-échelle.La méthode est appliquée dans un premier temps sur l’aquifère fracturé du site expérimental de Poitiers. Les résultats montrent une bonne restitution du comportement de l’aquifère et aboutissent à des champs de transmissivité plus réguliers par rapport à ceux de l’approche simple continuum. L’application finale est réalisée sur le site de Cadarache (taille plus importante et données d’entrée moins denses). Le calage des deux aquifères présents sur le site est satisfaisant et montre que ceux-ci se comportent globalement de façon indépendante. Ce calage pourra être amélioré localement grâce à données de recharge plus fines. / The aim of this study is to develop and validate a new method for the simulation of flow in fractured porous media. This method is based on a multi-layered and dual continuum approach allowing to discriminate the behavior of different aquifers present on a site. The flow equations are solved using a Crouzeix-Raviart Finite Element method, in association with an inverse method (Quasi-Newton minimization combined with the adjoint state method) and a multi-scale parameterization.The method is first applied and validated on the fractured aquifer of the Hydrogeological Experimental Site of Poitiers. The results closely reproduce the flow behavior of the aquifer and lead to a transmissivity field much more homogeneous than the one obtained with a simple continuum approach. The final application is performed on the site of Cadarache (large scale problem with heterogeneously distributed input data). The model calibration of both aquifers is rather satisfactory and shows that their behavior is globally independent. It could locally be improved if more accurate groundwater recharge data is made available.

La fibrose pulmonaire idiopathique (FPI) et le syndrome de détresse respiratoire aiguë (SDRA) de l’adulte constituent des affections sévères du poumon distal, avec un pronostic sombre pour les patients. A ce jour, aucun traitement n’est réellement efficace. De manière intéressante, une hypoxie alvéolaire est retrouvée dans ces pathologies.La thérapie cellulaire utilisant des cellules souches mésenchymateuses humaines (CSMh) pourrait représenter un intérêt thérapeutique chez l’Homme. Cependant, leurs mécanismes d’action sont multiples et encore mal définis. Aussi, nous avons testé in vitro l’hypothèse selon laquelle les CSMh pourraient exercer un effet cytoprotecteur paracrine sur les cellules épithéliales alvéolaires (CEA) soumises à l’hypoxie.Dans une première étude, nous avons montré qu’une exposition prolongée à l’hypoxie telle que celle rencontrée au cours de la FPI induisait des modifications phénotypiques des CEA primaires de rat, évocatrices d’une transition épithélio-mésenchymateuse (TEM). On observe une perte progressive d’expression des marqueurs épithéliaux (TTF1, AQP5, ZO-1 et E-Cadhérine), couplée à l’apparition tardive de marqueurs mésenchymateux (α-SMA et Vimentine). Ces modifications phénotypiques s’accompagnent de l’expression dès les premières heures d’hypoxie de facteurs de transcription impliqués dans la TEM (SNAI1, TWIST1 et ZEB1) ou induits par l’hypoxie (HIF-1α et HIF-2α), et de protéines induisant la TEM (TGF-β1 et CTGF). La co-culture des CEA avec des CSMh en fond de puits prévient les modifications phénotypiques induites par l’hypoxie ainsi que l’expression des facteurs pro-TEM TWIST1, ZEB1, TGF-β1 et CTGF. Cet effet bénéfique des CSM est en partie expliqué par la sécrétion d’un facteur de croissance épithélial, le KGF.Dans une deuxième étude, nous avons confirmé que les CEA entraient en apoptose en condition hypoxique, via l’induction de deux voies de signalisations hypoxiques pro-apoptotiques. D’une part, les facteurs de transcription induits par l’hypoxie HIF sont stabilisés, et une cible pro-apoptotique, Bnip3, est induite. D’autre part, l’hypoxie induit une accumulation d’espèces réactives à l’oxygène délétère pour la cellule, perturbant l’équilibre redox de la cellule, endommageant l’ADN, et conduisant à l’apoptose. Cette accumulation pourrait résulter notamment d’une diminution de l’activité des enzymes anti-oxydantes SOD, en hypoxie. Le manque d’oxygène entraine également l’expression de CHOP, facteur de transcription pro-apoptotique impliqué dans le stress du réticulum endoplasmique, qui va13inhiber l’expression de la protéine anti-apoptotique Bcl-2. Nous avons montré que la culture des CEA en présence de milieu conditionné de CSMh (mc-CSMh) permet de prévenir partiellement l’apoptose des CEA en hypoxie, en modulant la voie de signalisation HIF, et en prévenant l’accumulation et les effets délétères des ROS. L’effet protecteur des CSM impliquerait le KGF comme observé lors de la première étude, mais également le HGF.Ces deux études indiquent que les CSMh sont susceptibles d’exercer des effets cytoprotecteurs paracrines vis-à-vis des CEA soumises à l’hypoxie aiguë ou prolongée, en limitant d’une part les modifications phénotypiques évocatrices de TEM, et d’autre part l’apoptose des CEA via la modulation des voies de signalisations hypoxiques. La sécrétion par les CSMh de KGF et de HGF, facteurs de croissance épithéliaux connus pour leurs effets bénéfiques sur les CEA, explique en partie les effets protecteurs paracrines des CSMh. Nos résultats suggèrent que les effets cytoprotecteurs des CSMh vis-à-vis des CEA pourraient contribuer aux effets bénéfiques des CSMh observés in vivo dans différents modèles animaux de fibrose induite, ou lors d’agressions alvéolaires aiguës. / Acute or chronic alveolar injuries provoke massive apoptosis of alveolar epithelial cells (AEC) that compromises an efficient repair of the alveolar epithelium and leads to lung diseases such as ARDS or IPF. These disorders are commonly associated with local alveolar hypoxia aggravating their progression through the stimulation of AEC apoptosis. Administration of allogenic mesenchymal stem cells (MSCs) has been shown to limit lung inflammation and fibrosis in murine models of alveolar injury, through a still poorly understood paracrine mechanism. In a first study, we showed that long term exposure of AEC in hypoxia leads to phenotypic alterations which looks like epithelio-mesenchymal transition (EMT). Co-culture with MSCs prevent hypoxia-induced EMT.In a second work, we studied whether MSC could protect AEC from hypoxia-induced apoptosis and the mechanisms involved. hMSC-conditioned media (hMSC-CM) significantly reduced hypoxia-induced apoptosis of AEC. Such a anti-apoptotic effect was also obtained with ROS scavenger N-acetylcystein or HIF1a inhibitor YC-1. hMSC-CM decreased the protein expression of HIF1α and HIF2α and of their pro-apoptotic target Bnip3 in hypoxic AEC. hMSC-CM also reduced ROS accumulation in hypoxic AEC by enhancing the activity of anti-oxidant enzymes and prevented the induction of CHOP, a pro-apoptotic factor induced by ROS signaling. The paracrine effect of hMSC was partly dependent on KGF and HGF secretion. hMSC prevent via a paracrine effect hypoxia-induced apoptosis of AEC by modulating hypoxic and ROS signaling.These two studies show that MSCs exert cytoprotective effects in vitro against hypoxia-induced apoptosis and EMT in AEC

The aims of this thesis were to evaluate caries-preventive measures from a societal perspective, to demonstrate the use of resources in preventive dentistry, to develop and discuss techniques suitable for evaluating dental care costs and outcomes, and to test costs and consequences within a health economic decision model adapted to preventive dental care. The thesis is based on three separate studies with three separate cohorts. In the first study, performed at a single dental clinic, analysis was made of data on dental caries progression over four years in 92 adolescents, along with the use of resources for preventive treatment. In the second study, data from the intervention study “Evaluation of caries-preventive measures” (performed between 1995 and 1999 at 26 dental health clinics throughout Sweden) were used for economic evaluation. Three different approaches to calculating unit cost were discussed, each of which reflect the differences in treatment costs as influenced by the practitioner’s level of skill and competence (salary) and by methods of handling overhead cost allocation. These methods seem useful for evaluating costs in cost-effectiveness analysis (CEA) and cost-benefit analysis (CBA). The CEA showed an incremental cost-effectiveness over four years of SEK 2 043* per averted decayed (D) enamel (e) and dentine caries, missing (M) and filled (F) surface (S) (DeMFS). In the third study, 82 19-year-old individuals agreed to participate in a pilot exploratory case-control study. Individuals with high caries experience formed the test group while the control group consisted of individuals with no caries experience. To explore whether any differences existed between these two groups in perceived oral health-related quality of life (OHRQOL), two OHRQOL measures were used. Additionally, the willingness of these individuals to pay (WTP) for a preventive strategy was elicited using the contingent valuation method (CVM) within a cost-benefit approach. Using these WTP values, the cost-benefit analyses showed positive net social benefit (NSB) values for both study groups, meaning that the benefits of prevention exceeded the costs. A new outcome measure, Value of Statistical Oral Health (VOSOH), was also presented. Consideration was also made, within the economic framework fundamental to this thesis, of the trend away from a strictly bio-medical paradigm towards a biopsychosocial perspective. The health economic decision model encompasses a number of different techniques for comparing costs with consequences, each with its own advantages and disadvantages and each with its own field of application. These techniques should be seen as complementary rather than competing. Preventive dentistry plays a central role in Swedish dental health care, and it is important that resources are used properly. Accurate evaluation methods are necessary in order to improve the basis for public decision-making; the methods proposed in this thesis seem to be of potential use in this endeavour. *SEK8.54 = US$1 (December 1999).

Ce travail a pour objectif de développer et d'appliquer une méthode originale permettant de simuler l'écoulement dans un milieu poreux fracturé. Cette méthode repose sur une approche multicouches double continuum permettant de séparer le comportement des différents aquifères présents sur un site. La résolution des écoulements, basée sur la méthode des Eléments Finis de Crouzeix-Raviart, est associée à une méthode inverse (minimisation de type Quasi-Newton combinée à la méthode de l'état adjoint) et à une paramétrisation multi-échelle.La méthode est appliquée dans un premier temps sur l'aquifère fracturé du site expérimental de Poitiers. Les résultats montrent une bonne restitution du comportement de l'aquifère et aboutissent à des champs de transmissivité plus réguliers par rapport à ceux de l'approche simple continuum. L'application finale est réalisée sur le site de Cadarache (taille plus importante et données d'entrée moins denses). Le calage des deux aquifères présents sur le site est satisfaisant et montre que ceux-ci se comportent globalement de façon indépendante. Ce calage pourra être amélioré localement grâce à données de recharge plus fines.

Limb outgrowth is controlled by a specialized group of cells called the apical ectodermal ridge (AER), a thickening of the limb epithelium, at its distal tip. This specialized thickening of ectodermal cells is responsible for maintaining the underlying mesenchymal cells in an undifferentiated and proliferative state, and its structure is preserved through a fine-tuned balance between proliferation and apoptosis. This equilibrium is genetically controlled but little is known about the molecules involved in this process. Several authors have been shown that both fibroblast growth factor (FGF) and Erk pathway activation are crucial for AER function. Recently, FLRT3, a transmembrane protein able to interact with FGF receptors, has been implicated in the triggering of ERK activity by FGFs. In this thesis, we show that flrt3 expression is restricted to the AER, co-localizing its expression with fgf8 and pERK activity. Loss-of-function studies demonstrate that silencing of flrt3 affects the integrity of the AER and, subsequently, its proper function during limb bud outgrowth. Our data also indicate that flrt3 expression is not regulated by FGF activity in the AER, whereas ectopic WNT3A is able to induce flrt3 expression. Overall, our findings confirm flrt3 as a key player during chicken limb development, being necessary but not sufficient for proper AER formation and maintenance under the control of BMP and WNT signalling. During limb bud development, AER structure is maintained through a fine-tuned balance between proliferation and programmed cell death and this equilibrium is genetically controlled, although little is known about the molecules involved in that process. In this thesis we present evidences involving oct4, required to establish and maintain the pluripotent cell population necessary for embryogenesis in mouse and human, in the control of the proliferative balance within the AER cells. Overexpression of otc4 in the limb ectoderm disrupts the ratio apoptosis/proliferation and, moreover, oct4 expression is under the control of wnt-canonical pathway. We also describe a special localization and behaviour of proliferating cells in the AER in response to oct4 activity. We, therefore, describe a role for oct4 as a factor able to maintain a niche of cells that is responsible for the renewal of the AER. / El crecimiento del esbozo de la extremidad está controlado por un grupo especializado de células denominado Cresta Ectodérmica Apical (CEA), un engrosamiento del epitelio del miembro en su borde más distal. Este engrosamiento es responsable del mantenimiento de las células del mesodermo distal en un estado indiferenciado y proliferativo. Diferentes estudios muestran que la actividad de los factores de crecimiento fibroblástico (FCF) y de la vía Erk son cruciales para la correcta funcionalidad de la CEA. Recientemente se ha implicado a FLRT3, una proteína transmembranal capaz de interaccionar con los receptores de los FCF, en la activación de la vía Erk por los mismos. En esta tesis describimos cómo la expresión de flrt3 se restringe a la CEA, colocalizándose su expresión con fgf8 y la actividad de la vía Erk. Los experimentos de pérdida de función demuestran que la inhibición de flrt3 afecta la integridad de la CEA y, consecuentemente, a su función durante el desarrollo del esbozo del miembro. Nuestros datos también indican que la expresión de flrt3 no está regulada a través de los FCF en la CEA, sin embargo, la activación ectópica de WNT3A es capaz de inducir la expresión de flrt3. En conjunto, nuestros resultados demuestran que flrt3 es una molécula clave durante el desarrollo de las extremidades de pollo, siendo necesaria, pero no suficiente, para la correcta formación y mantenimiento de la CEA bajo el control de la señalización a través de BMP y WNT. Durante el desarrollo de las extremidades, la estructura de la CEA se mantiene a través de un fino control del balance entre la proliferación y apoptosis. Este equilibrio se encuentra genéticamente controlado aunque se sabe muy poco acerca de las moléculas involucradas en este proceso. En esta tesis presentamos evidencias en las que oct4, molécula necesaria para establecer y mantener la población de células pluripotentes necesarias durante la embriogénesis en ratón y humanos, controla la tasa de proliferación en las células de la CEA. La expresión ectópica de oct4 en el ectodermo del esbozo de la extremidad perturba la razón entre la apoptosis y la proliferación y, además, su expresión está controlada por la actividad de la vía canónica de los Wnt. También describimos en este trabajo la localización y comportamiento especiales de las células de la CEA en proliferación como respuesta a la actividad de oct4. Por consiguiente, podemos inferir que el rol de oct4 será el de un factor necesario para mantener un nicho celular responsable por la renovación de la CEA.

Made available in DSpace on 2015-02-24T19:48:44Z (GMT). No. of bitstreams: 1 SilvanaPPG_TESE_pag119_final.pdf: 4384081 bytes, checksum: f4e3889e03bd2b77ef4e8f1b271723a8 (MD5) Previous issue date: 2012-08-06 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / The Northeast relief was described by the Pediplanation Model. This action discards the theoretical basis of post-Cretaceous tectonic evolution of the landscape. Through this model the Massif Pereiro - MP, Borborema Province, was established as part of the Tablelands Area Residual Sertanejos. The present work aims to establish the post- Cretaceous morphotectonic evolution of the MP by geomorphological and geological mapping using Geographic Information System, Remote Sensing and dating of sediments by Single Aliquot Regenerative-dose (SAR). The MP is contained in the core semi-arid, annual precipitation of 600-800 mm / year. The MP is NE-SW, is limited by Shear Zone Jaguaribe (ZCJ) and Portalegre Shear Zone (ZCPa), the same attitude, and crossed by several other shear zones. These shear zones show evidence of brittle Cenozoic reactivation, mostly as normal faults and shallow crustal level. The Quaternary sedimentation around the MP focuses on fault escarpments in a general pattern cascade, where ages decrease from the summits of the steep foothills. The ages of 51 sediment samples indicate a correlation with global climate following pulses: Last Interestadial-UI, the Last Glacial Maximum - LGM and the transition Pleistocene / Holocene, while the latter focus on 18 of 51 samples dated. This study also finds evidence of a new quaternary basin, here called Merejo Basin. Through these results it is concluded that no evidence of post-Cretaceous tectonic evolution of morphological MP, as their retreat along the fault scarps, invariably following the trend of the shear zones. The erosion of cliffs in large time scale is controlled by weakness zones generated by faults on the other hand the erosion of cliffs in short time, with the formation of deposits and colluvial horizons pedogenizados, has climate control. It was also found that in the study area there is a preponderance of past and current tectonic erosion processes on the morphological evolution / O relevo do Nordeste foi descrito por meio do modelo de pediplana??o. Esta base te?rica descarta a atua??o da tect?nica p?s-cret?cea na evolu??o da paisagem. Atrav?s deste modelo o Maci?o do Pereiro MP, Prov?ncia Borborema, foi definido como parte do Dom?nio dos Planaltos Residuais Sertanejos. O presente trabalho tem por objetivo estabelecer a evolu??o morfotect?nica p?s-cret?cea do MP, atrav?s da cartografia geol?gica e geomorfol?gica com uso de Sistema de Informa??o Geogr?fica, Sensoriamento Remoto e data??o de sedimentos por Single Aliquot Regenerative-dose (SAR). O MP est? contido no n?cleo semi?rido, de precipita??o anual entre 600 a 800 mm/ano. O MP tem dire??o NE-SW, ? limitado pela Zona de Cisalhamento de Jaguaribe (ZCJ) e Zona de Cisalhamento Portalegre (ZCPa), de mesma atitude, e atravessado por v?rias outras zonas de cisalhamento. Estas zonas de cisalhamento apresentam evid?ncias de reativa??o fr?gil cenozoica, na sua maioria como falhas normais e de n?vel crustal raso. A sedimenta??o quatern?ria em torno do MP se concentra em escarpas de falhas, em um padr?o geral em cascata, onde as idades diminuem das cimeiras aos sop?s das escarpas. As idades de 51 amostras de sedimentos indicam correla??o com seguintes pulsos clim?ticos globais: ?ltimo Interestadial- UI, o ?ltimo M?ximo Glacial - UMG e a transi??o Pleistoceno/Holoceno, sendo que nesta ?ltima concentram-se 18 das 51 amostras datadas. O presente trabalho tamb?m encontra evid?ncias de uma nova bacia quatern?ria, aqui denominada de Bacia Merejo. Atrav?s destes resultados conclui-se que h? evidencia de tect?nica p?s-cret?cea na evolu??o morfol?gica do MP, pois as suas escarpas recuam paralelamente ?s falhas, seguindo invariavelmente o trend das zonas de cisalhamento. A eros?o das escarpas em grande escala de tempo ? controlada pelas zonas de fraqueza geradas pelos falhamentos, por outro lado ? eros?o das escarpas em curtos espa?os de tempos, com a forma??o dos dep?sitos coluvionares e horizontes pedogenizados, possui controle clim?tico. Concluise ainda que na ?rea de estudo haja a preponder?ncia da tect?nica pret?rita e atual sobre os processos erosivos na evolu??o morfol?gica

No description available.

<p>  </p> <p>With the discovery and treatment of any disease comes the important question of its genetic prevalence. This is especially important for animals under strict breeding control, such as dogs, because this can provide essential information regarding breeding pair decisions. Thus, the focus of this thesis is to investigate the genetic prevalence of three different diseases: 1) Factor VII Deficiency (FVIID), 2) Collie Eye Anomaly (CEA), and 3) Progressive Rod-Cone Degeneration-Progressive Retinal Atrophy (prcd-PRA). Factor VII Deficiency (FVIID) is a clotting disorder observed in both humans and dogs, characterized by impeded function of the Factor VII protein. In dogs, FVIID is caused by a single nucleotide substitution (c.407G>A) in the <em>F7 </em>gene. This mutation, identified in a colony of research Beagles, is also present in dogs with a wide variety of distantly-related breed backgrounds and in mixed-breed dogs, suggesting an ancient, ancestral origin. Given the relatively common presence of this variant, it was hypothesized that this genetic mutation could be contributing to excessive bleeding in canine autopsy cases that could not be attributed to typical causes. DNA from formalin-fixed paraffin-embedded tissues (n = 67 cases) were Sanger sequenced for the FVIID c.407G>A mutation, and all were determined to be homozygous wild-type. Therefore, the tested variant is not associated with the unexplained bleeding in these cases, and it is not a logical diagnostic test to apply to similar cases in the future.</p> <p><br></p> <p>CEA and prcd-PRA are ophthalmic genetic diseases of concern often included in commercial genetic testing panels. A large dataset spanning 15+ years provided by a commercial partner company (OptiGen/Wisdom Panel, Kinship) encompassed dogs tested for the CEA-associated <em>NHEJ1</em> deletion (n = 33,834 dogs) and the prcd-PRA causal mutation in <em>PRCD</em> (n = 86,667 dogs). Disease trends were observed graphically and analyzed with Chi-square goodness-of-fit testing and regression modeling for disease status and genotype classification. Both diseases had a statistically significant change in genotype frequencies from the first year of data to the last; both diseases also had a negative association between progression of time and overall probability of a dog being disease-positive or a carrier/heterozygous. This suggests that genetic testing results are being incorporated into breeding decisions, although affected dogs were still being identified by the end of this study. Different breeds, AKC groups, FCI groups, genetic clades, and geography were also investigated to determine impact on overall disease trend. </p>

The growing demand for clean water has led to the adoption of the EU Water Framework Directive (Directive 2000/60 EC). New legislation has a major impact on the water management and the national economy and provides numerous requirements, including "good status" of all water bodies. The Framework Directive also implies the need for an economic analysis of the optimal process to achieve good status by using the cost-effectiveness analysis (CEA). The application of this method in water management is struggling with a number of methodological complications. One of the affected areas in the Czech Republic is the catchment of the Orlik Reservoir that faces excessive eutrophication. Eutrophication is caused by excessive introduction of phosphorus. The main sources of phosphorus are municipal wastewater, aquaculture and agriculture. As illustrated by professional research mentioned in this work and the actual processing of CEA of the catchment of the Orlik Reservoir, a wide range of methodological problems can be avoided by using appropriate tools. This thesis also presents that achieving of good status of the catchment would require annual cost of CZK 602 million. The most significant cost bearers are according to the CEA fisheries and municipalities.

Tesis por compendio / [ES] El brote de Coronavirus SARS-CoV-2 representó un reto para la economía, la vida social y los servicios sanitarios. Justo cuando más se necesitaba la información para la planificación económica, los servicios de vigilancia y notificación no fueron capaces de ofrecer, a pesar de esfuerzos extraordinarios, datos consistentes, como así reconocieron los propios orga-nismos gubernamentales. Esta tesis incluye tres artículos publicados durante los brotes de COVID-19 y una investi-gación adicional fuera del conjunto de publicaciones. La investigación tiene como objetivo general proporcionar información a través de estimaciones alternativas. Para ello se han utilizado varias metodologías, entre ellas los modelos matemáticos de predicción epidemio-lógica, el Mejor Ajuste de Valores Relacionados (BARV), los análisis de diferentes encues-tas y la metodología bibliométrica, aprovechando u ofreciendo alternativas a los métodos bayesianos más complejos, las simulaciones de Monte Carlo o las cadenas de Markov, aun-que algunos datos obtenidos se apoyan parcialmente en estas metodologías. Cada artículo aborda un tema esencial relacionado con la pandemia COVID-19. La primera publicación se centra en los datos epidemiológicos básicos. Se refiere al primer brote de COVID-19, estimando su duración, incidencia, prevalencia, tasa de fallecimientos sobre infectados (IFR) y tasa de fallecimientos sobre casos (confirmados) (CFR). Como dato destacado de este trabajo, se previó que la seroprevalencia era demasiado baja para que la inmunidad de rebaño desempeñara algún papel. Aunque el valor obtenido fue aproxima-damente un 2% inferior al que demostró posteriormente un estudio poblacional (Instituto Carlos III), la conclusión sobre la inmunidad de rebaño no cambió, y los resultados confir-maron la idoneidad del enfoque. La segunda publicación se centró en las cuestiones legales y las noticias falsas, analizando la reticencia de la población a vacunarse, el impacto de las falsas noticas en estos comporta-mientos, las posibilidades legales de hacer obligatoria la vacuna y las posibles acciones contra los profesionales de la salud que publican noticias falsas. La principal conclusión fue que, aunque se podría encontrar una vía legal para la obligatoriedad de la vacunación, y para la persecución gubernamental de las noticias falsas, la opinión ciudadana parece prefe-rir que la administración no tome la iniciativa, por lo que se recomienda promover y fomen-tar la concienciación ciudadana. La tercera publicación presentó un modelo matemático simplificado para la estimación del coste-efectividad de la vacuna contra la COVID-19. Se actualizan los datos de dos fechas para la estimación de los costes directos para el sistema sanitario debidos a la COVID-19, computando el coste por ciudadano y por Producto Interior Bruto (PIB), así como el coste-efectividad de la vacuna. La estimó razón de coste-efectividad incremental (RCEI) para dos dosis por persona a un coste de 30 euros cada dosis (incluida la administración). Asumien-do al 70% de efectividad y con el 70% de la población vacunada resultó ser de 5.132 euros (4.926 - 5.276) por año de vida ajustado a calidad (AVAC) ganado (a 17 de febrero de 2021). Una cifra que desciende cada día de pandemia activa. Se incluyó una investigación adicional, no incorporada en el conjunto de artículos, centrada en los recursos humanos y la educación. Se analizaron los temas preocupan al personal de primera línea, es decir, a la enfermería, y cómo la pandemia ha afectado a sus publicaciones científicas, como índice de los cambios en el clima laboral que sufre este colectivo. Median-te un estudio bibliométrico comparativo entre las publicaciones de 2019 y 2020, se analizó el cambio de temas y ámbitos como reflejo del impacto del COVID-19 en el personal de enfermería. Así se comprobó que, en los ámbitos de enfermería de atención especializada, y sobre todo e / [CA] El brot de Coronavirus SARS-CoV-2 va representar un repte per a l'economia, la vida soci-al i els serveis sanitaris. Quan més es necessitava la informació per a la planificació econò-mica, malgrat esforços extraordinaris, els serveis de vigilància i notificació no van ser capa-ços d'oferir dades consistents, com així van reconèixer els mateixos organismes governa-mentals. Aquesta tesi inclou tres articles publicats durant els brots de COVID-19 i una investigació addicional fora del conjunt de publicacions. La investigació té com a objectiu general pro-porcionar informació a través d'estimacions alternatives. Per a això s'han utilitzat diverses metodologies, entre elles els models matemàtics de predicció epidemiològica, el Millor Ajust de Valors Relacionats (BARV), les anàlisis de diferents enquestes i la metodologia bibliomètrica, aprofitant o oferint opcions alternatives als mètodes bayesians més comple-xos, les simulacions de Montecarlo o les cadenes de Markov, tot i que algunes dades obtin-gudes es recolzen parcialment en aquestes metodologies. Cada article aborda un tema essen-cial relacionat amb la pandèmia COVID-19. La primera publicació se centra en les dades epidemiològiques bàsiques. Es refereix al pri-mer brot de COVID-19, calculant la seua durada, incidència, prevalença, taxa de defuncions sobre infectats (IFR) i taxa de defuncions sobre casos (confirmats) (CFR). Com a dada des-tacada d'aquest treball, es va preveure que la seroprevalença era massa baixa perquè la im-munitat de ramat exercirà algun paper. Tot i que el valor obtingut va ser aproximadament un 2% inferior al demostrat posteriorment en un estudi poblacional (Institut Carles III), la conclusió sobre la immunitat de ramat no va canviar, i els resultats van confirmar la idoneï-tat de l'enfocament. La segona publicació es va centrar en les qüestions legals i les notícies falses, analitzant la reticència de la població a vacunar-se, l'impacte de les falses notícies en aquests comporta-ments, les possibilitats legals de fer obligatòria la vacuna i les possibles accions contra els professionals de la salut que publiquen notícies falses. La principal conclusió va ser que, tot i que es podria trobar una via legal per l'obligatorietat de la vacunació, i per la persecució governamental de les notícies falses, l'opinió ciutadana sembla preferir que l'administració no prenga la iniciativa, per la qual cosa es recomana promoure i fomentar la conscienciació ciutadana. La tercera publicació va presentar un model matemàtic simplificat per a l'estimació del cost-efectivitat de la vacuna contra la COVID-19. S'actualitzen les dades de dues dates per a l'estimació dels costos directes per al sistema sanitari deguts a la COVID-19, computant el cost per ciutadà i per Producte Interior Brut (PIB), així com el cost-efectivitat de la vacuna. La va estimar raó de cost-efectivitat incremental (RCEI) per dues dosis per persona a un cost de 30 euros cada dosi (inclosa l'administració). Assumint al 70% d'efectivitat i amb el 70% de la població vacunada va resultar ser de 5.132 euros (4.926 - 5.276) per any de vida ajustat a qualitat (AVAQ) (a 17 de febrer de 2021). Una xifra que descendeix cada dia de pandèmia activa. Es va afegir una investigació addicional, no inclosa en el conjunt d'articles, centrada en els recursos humans i l'educació. Es van analitzar els temes que preocupen al personal de pri-mera línia, és a dir, a la infermeria, i com la pandèmia ha afectat les seues publicacions cien-tífiques, com a índex dels canvis en el clima laboral que pateix aquest col·lectiu. Mitjançant un estudi bibliomètric comparatiu entre les publicacions de 2019 i 2020, es va analitzar el canvi de temes i camps com a reflex de l'impacte del COVID-19 en el personal d'infermeria. Així es va comprovar que en els àmbits d'infermeria d'atenció especialitzada, i sobretot en atenció primària, els principals problemes detectat / [EN] The SARS-CoV-2 Coronavirus outbreak has posed a challenge to the economy, social life, and health services. Just when information was most needed for economic planning, moni-toring, and reporting services were unable, despite extraordinary efforts to provide con-sistent data, as government agencies themselves acknowledged. This thesis includes three articles published during the COVID-19 outbreaks and additional research outside the publication set. The overall aim of the research is to provide infor-mation through alternative estimates. Several methodologies have been used, including mathematical models for epidemiological prediction, Best Adjustment of Related Values (BARV), analyses of different surveys and bibliometric methodology, taking advantage of or offering an alternative to, more complex options such as Bayesian methods, Monte Carlo simulations or Markov chains, although some data obtained are partially supported by these methodologies. Each article addresses a key issue related to the COVID-19 pandemic. The first publication focuses on basic epidemiological data. It refers to the first outbreak of COVID-19, estimating its duration, incidence, prevalence, Infection Fatality Rate (IFR) and Case Fatality Rate (CFR). As a highlight of this work, the seroprevalence was anticipated to be too low for herd immunity to play a role. Although the value obtained was approximate-ly 2% lower than that subsequently demonstrated by a population-based study (Instituto Carlos III), the conclusion on herd immunity remained unchanged, and the results con-firmed the appropriateness of the approach. The second publication focuses on legal issues and fake news, analysing reluctance to be vaccinated in the population, the impact of fake news on these behaviours, the legal possi-bilities of making vaccination mandatory, and possible actions against health professionals who publish fake news. The main conclusion was that, although a legal avenue could be found for mandatory vaccination and for governmental prosecution of fake news, public opinion seems to prefer that the authorities do not take the initiative, therefore it recom-mends promoting and encouraging public awareness. The third publication presented a simplified mathematical model for estimating the cost-effectiveness of the COVID-19 vaccine. Data from two dates were obtained for the estimation of the direct costs to the health system due to COVID-19, computing the cost per citizen and per Gross Domestic Product (GDP), as well as the cost-effectiveness of the vaccine. The estimated incremental cost-effectiveness ratio (ICER) was calculated for two doses per person at a cost of 30 euros per dose (including administration). Assuming 70% effectiveness and with 70% of the population vaccinated, it was found to be 5,132 euros (4,926 - 5,276) per quality-adjusted life year (QALY) gained (as of 17 February 2021). The figure decreases with each day of the active pandemic. Additional research not included in the set of articles focuses on human resources and education. It analyses the concerns of frontline staff, i.e., nurses, and how the pandemic has affected their scientific publications, as an index of the changes in the work climate experienced by this group. Through a comparative bibliometric study of publications in 2019 and 2020, the change in topics and fields was analysed, as a reflection of the impact of COVID-19 on nursing staff. It was found that in the fields of specialised care nursing and above all in primary care, the main problems detected are those related to protective measures and psychological factors, while the publications of nursing staff in nursing homes showed an increase in topics related to management and organisation. Finally, some aspects of the implementation of telecommuting and distance learning have been reviewed. Some of the boosts in this field resulting from the pandemic could be very useful and remain in the future, such as the incorporation of telewo / Marco Franco, JE. (2021). What have we learned from the economic impact of the Covid-19 outbreak? Critical analysis of economic factors and recommendations for the future [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/174883 / TESIS / Compendio