The present thesis presents several theoretical studies on the dynamical processes of physicochemical interest involving superfluid helium (4He) nanodroplets. It has been developed a theoretical approach and computationally implemented. This consists in the first stage on the theoretical study of chemical reaction dynamics in superfluid helium nanodroplets. The description of the system is fully quantum and consists in a hybrid method in which different theoretical approaches are combined to describe the different components of the system. The liquid helium (superfluid) has been described through the Density Functional Theory (DFT), using a phenomenological energy functional. Atomic and molecular impurities have been described by means of standard quantum dynamics. The methodology developed in the present thesis has been applied to the study of various physicochemical processes of interest. These studies con be grouped as: - Study of the structure, energy and electronic spectroscopy of helium nanodroplets doped with atomic oxygen in different electronic states. In this work, the influence of the electronic state of oxygen and energy structure of the drop has been determined to be the induction of anisotropy on the helium density (for the open-shell cases), as well as the high quality of helium nanodroplets acting as a matrix for high-resolution spectroscopy confirmed. - Investigation on the dynamics of the photodissociation of homonuclear diatomic molecules in superfluid helium nanodroplets. In this context, the method developed has been initially applied to the case of molecular chlorine. Some interesting results related with the energy exchange phenomenon and generation of quantum (confined) resonances due tot the interaction of the molecules with the helium nanodroplet have been reported. Moreover, the relaxation process of the nanodroplet after the photodissociation has been also studied. This methodology developed has been also applied to the case of two halogen homonuclear diatomic molecules more, Br2 and I2. Different phenomenology and mechanism have been found for these cases, even producing full recombination for the biggest droplet considered. Furthermore, in order to determine the role played by the mass of the atoms of the diatomic homonuclear molecule on this process, we have studied the photodissociation dynamics of prototypic “isomers” of Cl2. - We have modeled the process of the capture of a neon atom by superfluid helium nanodroplets. We have restricted to the case of zero angular momentum as a first approach to the problem at the quantum level. We obtained the time scale of this process. Also, it was found that the energy exchange does not take place at any time, but until the velocity is low enough (Landau’s critical velocity) there is no mechanism for the exchange energy. This leads to a constant (mean) velocity of the quantum particle (Ne atom), since the friction force is zero. The resulting wave packet in momentum representation has a Gaussian type profile. - The synthesis reaction of a dimer of van der Waals (Ne2) in helium nanodroplets has been investigated. This process starts with a drop initially doped with Ne atom. Then, a second Ne atom is captured, which initiates the process of the synthesis. We have restricted to the zero angular momentum case for computational reasons. A great variety of phenomenology (reaction mechanisms) depending on the collision velocity and the droplet size has been found. / La present Tesi doctoral comprèn diferents estudis teòrics sobre processos fisicoquímics relacionats amb nanogotes d'heli (4He) superfluid. Per a la seva realització s'ha desenvolupat la metodologia teòrica i implementat a nivell computacional. Es tracta d'un primer estudi teòric en qual s'estudia la dinàmica de reaccions químiques en nanogotes d'heli superfluid. La descripció del sistema és completament quàntica, combinant diferents aproximacions teòriques per descriure els components del sistema. L'heli líquid s'ha descrit a través de la teoria del funcional de la densitat (DFT), utilitzant un funcional fenomenològic. Les impureses atòmiques i moleculars s'han descrit mitjançant dinàmica quàntica. La metodologia desenvolupada ha estat aplicada a l'estudi de diversos processos d'interès quimicofísic. Aquests són: - Estudi de l'estructura, energètica i espectroscòpia electrònica de nanogotes d'heli dopades amb oxigen atòmic en diferents estats electrònics. - Estudi de la dinàmica de la fotodissociació de molècules diatòmiques homonuclears en nanogotes d'heli superfluid. El mètode desenvolupat s'ha aplicat inicialment al cas del clor molecular. Posteriorment s'ha realitzat els casos del brom i el iode, així com d'"isòtops" artificials del clor amb l'objecte de determinar la influència de la massa sobre aquest tipus de processos. S’ha pogut determinar la formació de ressonàncies quàntiques, les qual s’han estudiat amb detall posteriorment. - Modelització del procés de captura d'un àtom de neó per part de nanogotes d'heli superfluid. S'ha estudiat el cas de moment angular nul com una primera aproximació a la problemàtica a nivell quàntic. - Reacció de síntesi d'un dímer de van der Waals (Ne2) en nanogotes d'heli. Partint d'una gota inicialment dopada amb un àtom de Ne, la captura d'un segon àtom de Ne inicia el procés de la síntesi. S'ha determinat una gran varietat de fenomenologia (mecanismes de reacció) segons la velocitat de col·lisió i la mida de la gota.

Tesi realitzada a l'Institut de Recerca Biomèdica de Barcelona (IRBB) / Los iminoazúcares son productos estructuralmente análogos a los azúcares convencionales en los que un nitrógeno se sitúa sustituyendo al oxígeno endocíclico. Son sustratos capaces de mimetizar la conformación y la carga del intermedio oxocarbonio generado durante la ruptura del enlace glicosídico de los sustratos naturales confiriéndoles la posibilidad de actuar como inhibidores de glicosidasas y otras proteínas como glicosiltransferasas, glicógeno fosforilasas o N-ribosiltransferasas. Por ello, son compuestos con aplicación terapéutica para el tratamiento de una gran variedad de enfermedades entre las que destacan diabetes, cáncer, virus, enfermedades bacterianas o enfermedades de depósito lisosomal (LSD). Incluso se pueden hallar iminoazúcares que se utilizan como fármacos como el Glyset® o el Zavesca®. Los iminoazúcares presentan una gran complejidad estructural. Son moléculas pequeñas con un esqueleto polihidroxilado, distintos tamaños del anillo que contiene el nitrógeno, número variable de centros quirales y distintos tipos de sustituyentes. La mayoría de aproximaciones sintéticas a estos productos están basadas en el chiral pool, partiendo de otros azúcares o aminoácidos. Los N-acetil iminoazúcares son derivados que incluyen en su estructura una acetamida y se han revelado como un tipo de sustratos con una gran selectividad por hexosaminidasas con potencias ente el rango milimolar y nanomolar. Esto les da un interés especial para su aplicación en el tratamiento de varias LSD (como el síndrome de Tay-Sachs, Sandhoff, Fabry o Schindler- Kanzaki), y en el control de los niveles de O-GlcNAc (relacionado con osteoartritis, cáncer, Parkinson o diabetes). En la presente tesis doctoral, se ha trabajado en el desarrollo de metodología sintética para la obtención de 2-acetamido-1,2-didesoxinojirimicina (DNJNAc) y varios de sus diastereoisómeros. Para ello, se ha sintetizado un intermedio clave partiendo del 2,4-pentadien-1-ol a escala multigramo y desde él se han explorado varias metodologías para introducir una 2- acetamida en el esqueleto piperidínico del sustrato. La exploración de la apertura regioselectiva de epóxidos, sulfitos cíclicos y sulfatos cíclicos ha permitido la obtención de DNJNAc y la síntesis de varios derivados haciendo modificaciones tanto en la amina endocíclica como en la amina en C2. Los distintos productos obtenidos se han evaluado como inhibidores de glicosidasas y la mayoría han mostrada una elevada selectividad por β-N-acetilglucosaminidasas con potencias en el rango bajo micromolar. El mismo intermedio clave se ha utilizado para la introducción de equivalentes sintéticos del amoníaco mediante la sustitución alílica catalizada por paladio. La aplicación posterior de las reacciones de dihidroxilación ha permitido obtener por primera vez la 2-acetamido-1,2- didesoxialonojirimicina (DAJNAc) con buenos rendimientos globales en sólo 7 pasos sintéticos. Este sustrato ha resultados ser un inhibidor específico de β-N-acetilglucosaminidasas en el rango bajo micromolar demostrando que este tipo de enzimas también acepta configuraciones distintas a las del sustrato natural. También se han sintetizado derivados de DAJNAc situando tioureas y iminotiozolidinas en la amina endocíclica consiguiendo en algunos casos actividad submicromolar frente a β-N-acetilglucosaminidasas. Los resultados obtenidos se utilizarán en un estudio SAR. La enfermedad de Sanfilippo es un tipo de LSD que presenta 4 subvariedades (A, B, C y D) caracterizada por la imposibilidad de degradar el heparan sulfato. En la presente tesis se ha desarrollado satisfactoriamente una metodología sintética para la obtención de los productos necesarios para el diagnóstico de las variedades A y D mediante mediante ensayos enzimáticos fluorimétricos. En 2010, se identificó EPI001 como un inhibidor selectivo del receptor androgénico (AR) que constituye un target para el cáncer de próstata resistente a castración. Esta molécula es una mezcla de cuatro estereoisómeros. Se ha desarrollado una síntesis estereoselectiva de cada uno de ellos y se han analizado sus interacciones con el AR humano mediante técnicas de STD-RMN. El conocimiento generado se está aplicando para el diseño racional de nuevos inhibidores. / Iminosugars are structural analogs of monosaccharides in which the oxygen ring atom has been replaced by nitrogen. The biological activity of these compounds may be related to their capacity to mimic the glycosyloxocarbenium cation in their protonated state, a species postulated to be close to the transition state in the reaction of enzymatic glycoside hydrolysis. Among iminosugars, the analogs of N-acetylhexosamines have result to be selective inhibitors of hexosaminidases which give them high potential for the treatment of acquired and genetic diseases such as lysosomal storage diseases (LSD) such as Sandhoff, Tay-Sachs and Schindler-Kanzaki syndromes, osteoarthritis, allergy or Alzheimer. In addition, acetamido iminosugars have become candidates for the development of pharmacological chaperones for the treatment of some LSD. In our investigation group a synthesis to obtain a key scaffold was designed and used to obtain the known iminosugars 1-desoxymannojirimycin and swainsonine. The main goal of this thesis was to introduce an amino functionality at the C2 position of the glycosidic piperidinic skeleton using this scaffold. To do this, two different approaches have been explored. First, opening reaction of epoxides, cyclic sulphites and cyclic sulphates allowed us to obtain the already know 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and new N-ureido derivatives which have been tested as hexosaminidase inhibitors with good selectivities and potencies. Second, allylic palladium substitution and dihydroxylations allowed us to get the new 2- acetamido-1,2-dideoxyallojirimycin (DAJNAc) a new potent and selective hexosaminidase inhibitor with high overall yields in few synthetic steps. A small library of N-derivatives of DAJNAc has been build and the compounds have been testes as hexosaminidase inhibitors. Furthermore, high valuable intermediates have been obtained to get the gulo conformer by regioselective opening reactions of epoxides. Sanfilippo disease is an LSD variety which is nowadays diagnose by fluorimetric enzyme assays. A synthesis to get the substrates to make those assays in the A and D diseases subtypes has been successfully developed. Finally, EPI001 was recognized as an irreversible inhibitor of the androgenic receptor related with prostate cancer. The four stereoisomers of EPI001 have been synthesized. Their interaction with the AR has been analyzed by STD-NMR. The obtained results are currently being used in the rational design of more potent inhibitors of the AR.

The study of the electrochemical oxidation behaviour of tin in alkaline media, the development of anodic self-ordered tin oxide nanostructures and its application to laboratory scale devices have been the main focus of this PhD Thesis. The passivation process of Sn has been studied from an electrochemical approach covering the whole range from hydrogen evolution to the final passivation of the metal. The oxides formed in each relevant potential region have been characterized by ex situ techniques and a mechanism for the process has been proposed by correlating composition, morphology and electronic properties. Three main processes have been identified: the formation of a SnO·nH2O primary passive layer; the hydroxyl induced etching of tin and concurrent SnO precipitation; and the final passivation due to the growth of Sn(IV) based oxides. Also, in situ techniques like EC-STM were used to gain more knowledge on the growth mechanism, especially for the first oxidation process. Before the onset of the peak, the formation of islands and metal dissolution and redeposition phenomena were observed. The composition of these islands is still under study. The knowledge gained while attaining this first goal is used for the design of protocols to develop self-ordered anodic tin oxide structures. In this view, several electrolytes were explored to find one that allows growing self-ordered tin oxide structures without the actual limitations of the films prepared in oxalic acid or NaOH: clogged pores and cracks on its cross-section. Once proper structures were attained in the new Na2S and NH4F electrolyte, applications such as gas sensing or photoelectrochemical water splitting were attempted in order to assess their value. The as-grown nanochannelled tin oxide structures are in general amorphous so an appropriate thermal treatment is required to convert them into SnO2, which is a material commonly applied in hydrogen sensors. Our layers proved to have superior characteristics by detecting H2 concentrations as low as 9 ppm and by operating at relatively low temperatures (80 ºC). The performance is comparable to that of noble-metal doped SnO2 particles or single SnO2 nanowires and superior to that of other self-ordered structures prepared in non-optimized conditions or oxalic acid. The opening of the pores provides a higher specific area whereas the continuity of the channels improves the conducting properties and the transference of electrons through the structure. By adjusting the annealing conditions, SnO2 nanochannelled structures with absorption in the visible range were prepared. A band gap of 2.4 eV was achieved for self-ordered tin oxide structures annealed at 200 ºC in Argon atmosphere due to the improved crystallinity, with respect to as-grown samples, together with the conservation of the Sn2+ defects and oxygen vacancies. These layers could have potential applications in photoelectrochemical water splitting or photocatalysis. Despite the enhancement in collecting visible light, the structures were found to be unstable in the photoanode working conditions. The further oxidation occurring during the photoelectrochemical performance seems to arise from the Sn2+ defects and vacancies themselves. An alternative approach to build up photoanodes is proposed. The system combines the good conducting properties and the high surface area of antinomy doped nanochannelled SnO2 structures with the stability and good visible absorption of hematite nanoparticles. By building up this host-guest system some of the limitations of hematite like its poor conductivity and extremely short hole diffusion length are overcome. Although the role of SnO2 here is just as charge collector, the overall performance of the photoanodes is shown to be strongly dependent on its characteristics. Photocurrents attained are in line with the values reported for other reported hematite nanostructured electrodes. / Aquesta tesi doctoral s’estructura en dos grans blocs: d’una banda es pretén estudiar el procés d’oxidació electroquímica i passivació de l’estany en solucions alcalines per tal d’entendre els processos que hi estan involucrats, i de l’altre desenvolupar nanoestructures anòdiques d’òxid d’estany amb aplicacions reals en dispositius com sensors de gasos o ànodes per a la fotòlisi de l’aigua. L’estudi fonamental de la passivació de l’estany s’ha dut a terme combinant tècniques electroquímiques clàssiques amb mètodes de caracterització ex situ per a determinar la composició i morfologia dels òxids formats en la zona activa i passiva de potencial. Amb això s’ha pogut establir que el primer procés anòdic correspon a la formació d’una pel·lícula amorfa de SnO·nH2O mitjançant un mecanisme de dissolució-precipitació, seguidament té lloc la precipitació de cristalls de SnO com a producte de l’atac preferencial tant de la primera capa com del metall, i finalment l’elèctrode passiva gràcies a l’aparició d’un òxid a la interfase Sn/SnO que conté Sn(IV). El primer procés anòdic s’ha seguit també amb tècniques in situ com el EC-STM per a extreure informació sobre els canvis que tenen lloc a la superfície a nivell nanomètric. L’anodització autoorganitzada és un mètode habitual per a obtenir nanotubs o nanopors de manera relativament senzilla en metalls com el Ti o el Al, però per al cas de l’estany es troba encara en una fase molt preliminar. Així doncs, es va treballar en el desenvolupament i l’optimització d’un nou electròlit basat en Na2S i NH4F fins a assolir estructures d’òxid d’estany en forma de nanocanals amb pors totalment oberts i sense fissures en la secció (estructures multicapa). Un cop tractades tèrmicament aquestes pel·lícules van demostrar una molt bona resposta per a la detecció de H2 (9 ppm a temperatures de 80 ºC). Altrament, es van construir fotoànodes combinant les nanoestructures de SnO2 dopades amb Sb i nanopartícules de Fe2O3. La eficiència final d’aquests fotoelèctrodes en la producció de H2 a partir de l’aigua depèn fortament del dopatge amb Sb.

Tesi realitzada a l'Institut de Recerca Biomèdica de Barcelona (IRBB) / Amyloid-beta protein (Aß) is strongly linked to the aetiology of Alzheimer’s disease (AD). Even though Aß has a central role in AD, this protein is normally produced in healthy humans. It is the aberrant processing of Aß that determines its accumulation and aggregation into large oligomer species that evolve into the fibrillar structures deposited in amyloid plaques in the brain of AD patients. The neurotoxicity observed in AD has been attributed to the oligomeric intermediates, although their stoichiometry and structure still remain unknown. This is the reason why no AD therapeutic approaches tackling Aß aggregation have arrived to the market yet. In the present thesis, we have determined the stoichiometry and the structure of the oligomers formed in the early stages of Aß aggregation. Due to their highly dynamic nature, we have first obtained their covalent counterparts through the use of a photo-induced crosslinking methodology. Successful isolation of cross-linked Aß dimers and trimers has been achieved by means of a disaggregating treatment coupled to size exclusion chromatography. The combined study of these isolated cross-linked species through ion mobility coupled to electrospray ionization mass spectrometry, circular dichroism and molecular dynamics simulations, has shown that Aß dimers and trimers possess a globular shape without defined secondary structure. Moreover, we have proved that these cross-linked oligomers induce calcium influx, an intracellular marker for neurotoxicity, in primary neuroglial cultures, and that these cross-linked species effectively modulate Aß aggregation. Additionally, we have demonstrated that classical SDS-PAGE analysis provides misleading results when determining oligomer stoichiometry. The present thesis was also aimed at providing insights into the role of Aß amyloid fibrils in AD. Aß fibrils had been previously shown to be in dynamic equilibrium with soluble Aß species. The objective was to find evidences on the nature of these soluble species in equilibrium with Aß fibrils. Determination of their stoichiometry has been achieved by incubating Aß fibrils with insulin degrading enzyme, an enzyme which we have demonstrated to specifically proteolyze monomeric Aß. Subsequent analysis of Aß fibrils by hydrogen/deuterium exchange monitored by mass spectrometry has revealed that Aß fibrils are in equilibrium with monomers and low molecular weight oligomers. This equilibrium has been proved to be highly dependent on the physicochemical properties of Aß fibrils. / La proteïna beta amiloide (Aß) es troba estretament lligada a la malaltia d’Alzheimer (MA). Tot i el seu rol central en la malaltia, Aß es produeix de forma regular en humans sans. És el processament aberrant de la proteïna que en determina la seva acumulació i agregació, primer en intermedis oligomèrics transitoris que evolucionen cap a les estructures fibril·lars que composen les plaques amiloides dipositades al cervell dels malalts de la MA. La neurotoxicitat associada a la malaltia s’atribueix a les espècies intermèdies, per bé que se’n desconeix l’estequiometria i l’estructura. En la present tesi doctoral, hem determinat l’estequiometria i l’estructura dels oligòmers d’Aß formats en els estadiatges inicials de l’agregació. Hem provat que aquests oligòmers mostren neurotoxicitat en cultius neuronals primaris. Addicionalment, hem demostrat que el clàssic anàlisi per electroforesi en gel proporciona resultats confusos a l’hora de determinar l’estequiometria dels oligòmers. Els resultats presentats en la tesi doctoral també mostren evidències de que les fibres amiloides d’Aß es troben en equilibri amb monòmers i oligòmers de baix pes molecular. Aquest equilibri ha demostrat ser dependent de les propietats fisicoquímiques de les pròpies fibres d’Aß.

Nanotechnology is the multidisciplinary science consisting in modifying the matter at the nanometre scale. Due to the unique properties exhibited by nanomaterials, the number of investigations devoted to obtain new materials and their applications has increased dramatically. However, the potential risk associated to nanomaterials and nanostructures continues being poorly understood. Different gaps of information were identified including their environmental occurrence, fate, behaviour and toxicity. In addition, some nanomaterials can also be emitted by natural events or incidental sources. Under this context, this doctoral Thesis presents the study of the occurrence and toxicity of nanomaterials and nanostructures in the environment, focusing on pristine and functionalized fullerenes and volatile dimethylsiloxanes. Different extraction procedures for the analysis of pristine and functionalized fullerenes in different environmental compartments were developed: (i) For the investigation of their occurrence in air particulate two extraction procedures are presented, based on ultrasound assisted solvent extraction with toluene with recoveries from 60 to 70 %, and using accelerated solvent extraction with recoveries ranging from the 70 to 113 %; (ii) for the investigation of soils using a long-term ultrasound assisted solvent extraction with toluene; (iii) for the simultaneous analysis of fullerenes in the particulate and dissolved phases of water samples. Two analytical methods based on liquid chromatography coupled to mass spectrometry for the analysis of fullerenes in environmental samples were developed. The first one employed C18 analytical column with toluene:methanol as mobile phase and an ESI source in negative ionization conditions coupled to a triple quadrupole analyzer. The second method consisted in the use of pyrenylpropyl stationary phase columns with toluene as mobile phase. LC was coupled to HRMS with an APPI source. The main improvements of the second approach were in terms of lower matrix effect, better sensibility and selectivity. The occurrence of pristine and non-polar functionalized fullerenes was evaluated in several compartments. - Air particulate: The concentrations of C60 ranged from 10 pg/m3 to 50 ng/m3 in the Mediterranean Sea atmosphere, and between the MLOQ and 63 pg/m3 in air particulate of Barcelona city. - Soils: Samples were taken in Saudi Arabia and Brazil, close to potential emission points. The concentrations of pristine fullerenes were in the pg/g–ng/g levels, showing the incidental emission these compounds and subsequent deposition. - Freshwater and sediments from the Llobregat River. The relationship between the occurrence of natural colloids and the sedimentation of fullerenes because of heteroaggregation and flocculation was studied. Pristine fullerenes were detected in all the compartments while functionalized fullerenes were detected very rarely. The results show that incidental combustion sources are the main contributor to the environment, in contrast to nanotechnology. The occurrence of siloxanes was studied in several environmental compartments. According to our results the intensive manufacture and application of cVMS such as in personal care products, industry, nano-emulsions, etc. lead to the emission of these compounds at global-scale: - Wastewater: Siloxanes were detected in almost all influent and effluent samples at concentrations up to 24 µg/L. In general, for VMS relevant elimination rates during WW treatments were shown. - Fish: Fish directly sampled in the Xúquer River and fish for human consumption collected in different markets stores were analysed. Market fish presented higher levels, which can be attributed to contamination during food manipulation, storage and ambient air. - Samples from the Antarctic region: VMS were found in all types of the analyzed samples (krill, phytoplankton, soil and vegetation). These results reveal for first time the potential long-range environmental transport of VMS and their posterior cool-deposition supported by the snow scavenging during winter time and their posterior liberation to sea water and soils during the Antarctic summer. The acute toxicity of carbon nanomaterials (fullerene soot, carbon nanotubs and graphene) dispersed in artificial estuary medium in ecologically relevant conditions was studied using two standardized acute toxicity tests. The results are to fullerenes aggregation in presence of humic acid and salts. The presence of fullerene soot is relevant because inhibited the activity of most of the organic co-contaminants due to their sorption properties. / El desenvolupament de la nanotecnologia ha generat una miríada de nous materials que, sumats als nanomaterials presents de forma natural al medi ambient, generen un seguit d’incerteses. La present tesi va tenir l’objectiu de contribuir en l’estudi d’aquests nanomaterials i nanoestructures determinant la presència de ful·lerens i siloxans de mida nanomètrica en el medi ambient. Es van desenvolupar mètodes d’anàlisi per a ful·lerens en diverses matrius ambientals: particulat atmosfèric, sòls, sediments, aigües de riu i de depuradora. Per al seu anàlisi instrumental, es van desenvolupar dos mètodes. El primer, basat en cromatografia de líquids amb columnes de fase estacionària C18 i fase mòbil toluè-metanol, acoblada a espectrometria de masses en tàndem amb font d’electrosprai. El segon mètode, basat en cromatografia de líquid amb columna de fase estacionària de pirenilrpopil i toluè com a fase mòbil, acoblada a espectrometria de masses d’alta resolució amb font de fotoionització a pressió atmosfèrica. La segona metodologia millorava les prestacions de la primera en termes d’efecte matriu, selectivitat i sensibilitat. Es va determinar la presència de ful·lerens en particulat atmosfèric, sòls i sediments i aigua de riu. Es van detectar ful·lerens no funcionalitzats a nivells traça en la majoria de mostres, podent-se localitzar fonts d’emissió. Els ful·lerens funcionalitzats es van detectar esporàdicament, demostrant la preponderància dels processos accidentals en front de la nanotecnologia. Es van analitzar els siloxans en diversos compartiments ambientals. Els resultats d’aquesta tesi demostren com l’ús intensiu d’aquests compostos en productes domèstics, aplicacions industrials, nano-emulsions, etc, contribueix a la seva emissió al medi ambient a escala global. Es van detectar siloxans en totes les mostres d’aigües residuals analitzades, en mostres de peix de mercat i de riu i en mostres remotes de l’Antàrtida. Es va modelitzar la seva deposició. Finalment es va estudiar la toxicitat aguda de tres nanomaterials de carboni (pols de ful·lerens, nanotubs de carboni i grafè) dispersos en medi artificial d’estuari i en condicions ecològicament rellevants. Es van emprar dos tests estandarditzats de toxicitat aguda i es va determinar que la toxicitat dels agregats resultants ve determinada per la presència d’àcids húmics i salinitat del medi. També es va observar com la presència de pols de ful·lerè inhibia l’activitat d’altres co-contaminants orgànics presents en el medi.

The present Doctoral Thesis constitutes a comprehensive study of the removal of food azo dyes in aqueous matrices by single and coupled electrochemical separation and destruction technologies. First, the work was focused on the selection of the most appropriate technology and the progressive optimization of operation conditions for the effective and efficient removal of each dye. The degradation of Ponceau 4R, Carmoisine, Allura Red AC and their mixtures was studied by different electrochemical advanced oxidation processes (EAOPs) such as electro-oxidation (EO), electro-Fenton (EF) and photoelectro-Fenton (PEF) using BDD or Pt anode and stainless steel (SS) or air-diffusion cathode (ADE). Different aspects including decolorization and mineralization of solutions were studied in details. The results revealed that PEF is the most efficient and promising process to degrade food azo dyes at lab-scale. Complete decolorization and almost total mineralization with 96-98% TOC abatement was attained, with electrolysis time depending on the initial dye content and applied current. The kinetic decay of dye always obeyed a pseudo-first-order reaction. In view of the promising results obtained by PEF, the study of the degradation of dyes was scaled-up to a 2.5 L pre-pilot plant, which allowed demonstrating the viability of the solar photoelectro-Fenton to mineralize the dyes within a short time. Analyses of dyes and their mixtures treated by EAOPs allowed the identification of some intermediates and end products, and plausible reaction sequences were proposed to explain the transformation of each compound. The mineralization of dyes led to the conversion of the heteroatoms (N and S) present in the molecules to inorganic ions such as ammonium, nitrate and sulfate. The degradation of Tartazine solution was studied by electrocoagulation (EC), which is a process of high industrial interest, several EAOPs and the sequential combination of EC/EAOPs. The findings demonstrated that the sequential EC (Fe/SS) / PEF (BDD/ADE) treatment favors both, the fast color removal and the destruction of the remaining persistent organic matter in the pre-treated solution by PEF. The complete decolorization and mineralization of solutions were thus achieved within relatively short time periods thanks to coagulation by Fe(OH)n and oxidation by electrogenerated hydroxyl radical and active chlorine species. / La presente Tesis Doctoral se ha enfocado en el estudio exhaustivo de la eliminación de colorantes alimentarios azoicos en matrices acuosas mediante tecnologías electroquímicas de separación y de destrucción usadas individualmente o acopladas. En primer lugar se centró el trabajo en la elección de la tecnología más apropiada y la optimización progresiva de las condiciones de operación para una eliminación eficaz y eficiente de cada colorante. Se estudió la degradación de los colorantes Ponceau 4R, Carmoisina, Rojo Allura AC y de sus mezclas mediante diferentes procesos electroquímicos de oxidación avanzada (EAOPs) como la electrooxidación (EO), electro-Fenton (EF) y fotoelectro-Fenton (FEF), utilizando un ánodo de BDD o Pt y un cátodo de difusión de aire o acero inoxidable (SS), y evaluando diferentes aspectos relacionados con la decoloración y la mineralización. Los resultados revelaron que el proceso FEF es el más eficiente y prometedor para la degradación de los colorantes alimentarios a escala de laboratorio. Se alcanzó la decoloración total y una mineralización casi completa (96-98%), dependiendo el tiempo de electrolisis de la concentración inicial de colorante y de la corriente aplicada. En todos los casos, la cinética de degradación del colorante obedeció a una reacción de pseudo primer orden. En vista de los resultados prometedores obtenidos mediante FEF, el estudio de la degradación de los colorantes se amplió al uso de una planta pre-piloto de 2,5 L que permitió demostrar la viabilidad del proceso fotoelectro-Fenton solar (SFEF) para mineralizar los colorantes en tiempos cortos. Los análisis de las disoluciones de colorantes y de sus mezclas tratadas por EAOPs permitieron identificar los intermedios y productos finales, permitiendo así proponer esquemas de reacción para explicar la transformación de cada compuesto estudiado. La mineralización de los colorantes condujo a la conversión de los heteroátomos (N y S) presentes en las moléculas en iones inorgánicos, tales como nitrato, amonio y sulfato. Se estudió la degradación del colorante Tartrazina presente en una disolución de agua sintética mediante electrocoagulación (EC), que es un proceso de alto interés industrial, varios EAOPs, así como a través de la combinación secuencial EC/EAOPs. Los resultados demostraron que la combinación secuencial EC (Fe/SS) / FEF (BDD/ADE) favorece tanto la decoloración total como la destrucción completa de la materia orgánica persistente en la solución pre-tratada por FEF. Se consiguió una rápida decoloración y mineralización total de las disoluciones gracias a la coagulación por Fe(OH)n y la oxidación por radicales hidroxilo y/o especies de cloro activo electrogeneradas. El tratamiento combinado permitió superar los inconvenientes de la EC y el tiempo largo requerido por los EAOPs individuales, lo que condujo a una mayor rentabilidad de las tecnologías electroquímicas gracias a un menor consumo energético.

Tesi realitzada a l'Institut de Diagnosi Ambiental i Estudis de l'Aigua (IDAEA-CSIC) / Atmospheric aerosols have played a key role in the development of the Earth’s atmosphere. Without atmospheric particles rainfall would be nonexistent and the climate would be very different. However, anthropogenic emissions have changed the chemical composition of atmospheric aerosols significantly through emissions of particles and precursor gases, particularly since the industrial revolution. Moreover, numerous studies have demonstrated that atmospheric aerosols, both natural and anthropogenic, do not only influence Earth’s climate, but also have adverse effects on human health, ecosystems, as well as on air quality. The global distribution of the aerosols is very uneven; therefore atmospheric particles have very different concentrations and composition depending on the region. In southern Europe, and in particular in the western Mediterranean region, the meteorological conditions with higher temperatures and lower precipitation, together with the abrupt topography around the Mediterranean Sea, hinder aerosol dispersion and prevent atmospheric wet-scavenging processes. Moreover, Mediterranean region is highly influenced by both anthropogenic emissions from shipping, power generation, industrial processes and road traffic, among others sources, and natural emissions from African dust outbreaks, soil resuspension, wildfires, sea spray, and vegetation. All these particular and complex atmospheric dynamics result in higher concentrations of aerosols around the Mediterranean Basin than in northern Europe. A detailed study of the physical, optical and chemical properties of the continental background aerosols measured at Montsec (MSC) monitoring station is presented in this work. The MSC mountain site (1570 m a.s.l.) was established during the development of this thesis; it is located in the western Mediterranean and became a member of the GAW (Global Atmosphere Watch) network in 2014. Aerosol properties (particle mass (PM), particle number (N), absorption (σap), scattering (σsp) and chemical composition) from MSC were found to be comparable in magnitude to those from other remote sites in Europe, when removing African dust outbreaks influence. This suggests that a continental background designation for MSC site is applicable. Nevertheless, some differences between MSC and other European remote sites highlight the importance of new particle formation (NPF) processes as a source of particles, the lower contribution of combustion and industrial processes, the greater impact of shipping emissions, and the higher influence of biogenic emissions. Moreover, these differences corroborate the important contribution of long-range transport of mineral dust and reveal a high impact of regional dust resuspension in the western Mediterranean region. Continental background aerosols in this region are affected by natural and anthropogenic emissions which results in a PM1 (PM of diameter less than 1 µm) comprised of (in decreasing concentrations) organic matter, sulfate, ammonium, mineral matter, nitrate, elemental carbon, sea salt and trace elements. The foremost PM1-10 (PM of diameter between 1 and 10 µm) constituent is mineral matter, followed by organic matter, nitrate, sulfate, sea salt, ammonium and elemental carbon. Comparison of σap measurements with those of elemental carbon revealed an average mass absorption cross section (MAC) at MSC of 9.1 m-2 g-1 . A clear seasonal variation is observed for the majority of the aerosol parameters measured at MSC, with the highest values in summer and the lowest in winter, except for nitrate, in agreement with previous studies in the western Mediterranean. The reduced human activity at the weekend is reflected in the concentrations of PM1 and BC with a delay of one day (minimum on Sunday and Monday), which confirms that MSC is located at a sufficient distance from direct anthropogenic emissions, although it is still affected by them. The intra-day variation of PMx, BC, σsp and PM1 major inorganic components (sulfate, nitrate, ammonium and chloride) shows poorly defined daily patterns in summer but clearer in winter, whereas concentrations of N and submicron organic aerosol show marked diurnal cycles throughout the year and regardless of the air mass origin, with a clear increase around midday. / Els aerosols atmosfèrics han jugat un paper crucial en el desenvolupament de l’atmosfera terrestre. Sense les partícules atmosfèriques la pluja no hauria existit i el clima seria molt diferent. No obstant això, les emissions antropogèniques han canviat de forma significativa la composició química dels aerosols atmosfèrics degut a l’emissió de partícules i de gasos precursors. A més a més, nombrosos estudis han demostrat que els aerosols atmosfèrics, tant naturals com antropogènics, no només influencien el clima de la Terra, sinò que també provoquen efectes perjudicials per la salut humana, els ecosistemes i la qualitat de l’aire. En aquesta tesi doctoral es presenta un estudi detallat de les propietats físiques, òptiques i químiques dels aerosols de fons continental mitjançant les mesures realitzades a l’estació del Montsec (MSC, 1570 m s.n.m.). Aquesta estació de muntanya està situada a l’oest del Mediterrani, es va establir durant el desenvolupament d’aquesta tesi i forma part de la xarxa GAW (Global Atmosphere Watch) des de 2014. Les propietats dels aerosols (massa (PM), nombre (N), absorció (σap), dispersió (σsp) i composició química) mesurades al MSC van presentar magnituds comparables a les obtingudes a altres llocs remots d’Europa, una vegada eliminada la influència de les intrusions de pols sahariana. Per tant, la designació de fons continental és aplicable per a l’estació del MSC. Tanmateix, algunes diferències entre les propietats mesurades al MSC i les mesurades a altres estacions remotes europees van revelar que els processos de formació de noves partícules (angl., new particle formation, NPF) com a font de partícules són molt importants a la regió oest del Mediterrani. També van destacar que els processos industrials i de combustió tenen una menor contribució a la matèria particulada (angl., particulate matter, PM) ambiental, mentre que les emissions biogèniques i dels vaixells tenen un major impacte. A més a més, van corroborar que el transport de llarga distància de la pols del Sàhara és la font natural de partícules més important en aquesta regió, i van revelar que la pols de resuspensió regional té un impacte considerable.

Tesi realitzada a l'Institut de Química Avançada de Catalunya (IQAC-CSIC) / Las emulsiones son dispersiones de dos líquidos inmiscibles que, generalmente están estabilizadas por moléculas tensioactivas. Cuando la fracción en volumen de fase dispersa es superior o igual a 0,74 (valor que corresponde al máximo empaquetamiento de gotas esféricas indeformables y monodispersas) se denominan altamente concentradas. Dichas emulsiones tienen una elevada relación superficie/volumen, además de regiones hidrófilas y lipófilas bien definidas que permiten la incorporación de moléculas de diferente naturaleza. Por todo ello, tienen aplicaciones en el campo farmacéutico, cosmético, alimentario, en síntesis de materiales, etc. En la mayoría de aplicaciones, los procesos de difusión desempeñan un papel importante y por este motivo, se han estudiado los mecanismos de difusión para determinar la influencia de las propiedades de las emulsiones en dichos mecanismos. Sin embargo, no se ha estudiado de forma simultánea la influencia que los factores de composición y formación podrían ejercer sobre los procesos de liberación. Por este motivo, el objetivo principal de esta tesis, ha sido el de modelizar la formulación de emulsiones altamente concentradas de tipo W/O estudiando la relación entre el tamaño de gota, sus propiedades reológicas y la liberación de moléculas activas, incorporadas en la fase dispersa, a soluciones receptoras. Para alcanzar dicho objetivo, se seleccionaron componentes biocompatibles y biodegradables para formar emulsiones altamente concentradas de tipo W/O. De este modo, se seleccionaron tensioactivos derivados de ésteres como el poligliceril-2 diisoestearato (IS-202P), el monoleato de sorbitán (Span80) y un polioxietileno de sorbitano (Tween80), de alcoholes etoxilados (Brij52), del aceite de ricino (CremophorWO7), y dos tensioactivos poliméricos de bloque o copolímeros (SynperonicL2 y PluronicL121). Como componentes oleosos, se seleccionaron hidrocarburos alifáticos (aceite de parafina y escualano), un éster derivado del ácido oleico (decil oleato) y un triglicérido derivado de los ácidos grasos caprílico/cáprico (triglicéridos de cadena media). Se realizaron estudios de formación de emulsiones altamente concentradas, caracterizando las emulsiones formadas, que permitieron seleccionar un sistema modelo (solución acuosa/Span80/aceite de parafina), además del método de adición del componente acuoso a la mezcla del componente oleoso y tensioactivo, como el más apropiado para formar las emulsiones. Asimismo, se seleccionaron tres moléculas activas modelo el metilparabeno, etilparabeno y propilparabeno, ya que se podían incorporar en la fase dispersa de emulsiones altamente concentradas seleccionadas, sin modificar las propiedades de dichas emulsiones. Una vez seleccionados el sistema y las moléculas activas modelo, se aplicaron dos diseños de experimentos. El primero, un diseño central compuesto, permitió relacionar el tamaño de gota y las propiedades reológicas con variables de composición y formación de las emulsiones en ausencia de parabenos. El segundo, un diseño factorial fraccionado permitió la obtención de un modelo empírico para modelizar la formulación de emulsiones altamente concentradas, optimizando su tamaño de gota, sus propiedades reológicas, así como la liberación de las moléculas activas incorporadas. Se realizó un estudio comparativo de la formulación optimizada variando el aceite y el componente tensioactivo, determinando que influía más la estructura del tensioactivo que la polaridad del componente oleoso. También se realizó un estudio preliminar de escalado de la formulación óptima poniendo de manifiesto que, a pesar de la complejidad de los procesos de difusión que tienen lugar en las emulsiones altamente concentradas, en el escalado se obtuvieron resultados de liberación razonablemente similares. Mediante la utilización de diseños de experimentos y seleccionado un sistema modelo de tipo componente acuoso/tensioactivo no iónico/componente oleoso, se ha optimizado la formulación de emulsiones altamente concentradas de tipo W/O, obteniendo un modelo empírico que ha permitido optimizar el tamaño de gota, propiedades reológicas y modular el perfil de liberación de moléculas activas incorporadas en el componente acuoso de dichas emulsiones. / Emulsions are dispersions of two immiscible liquids, generally stabilized with surfactants. When the volume fraction of the disperse phase exceeds 0.74 (the maximum packing of spherical, undistorted and monodisperse droplets), emulsions are classified as highly concentrated emulsions. In most applications of highly concentrated emulsions, diffusion processes have an important role, and as a consequence, diffusion of active molecules incorporated in the disperse phase of emulsions has been studied to find out their relationship with emulsion properties. However, there is still a lack of knowledge on the relationship among composition and formation factors with diffusion processes. The main objective of this thesis has been to model the formulation of highly concentrated W/O emulsions, studying the relationship between droplet size, rheological properties and the release of active molecules, incorporated in the dispersed phase, to receptor solutions. To achieve this objective, the selected surfactants were: sorbitane monooleate (Span80) and polyglyceryl-2 diisostearate (IS-202P). The oil components were aliphatic hydrocarbons (paraffin oil and squalene). Methylparaben, ethylparaben and propylparaben were chosen as model active molecules. Their incorporation in the aqueous phase of emulsions did not modify emulsion properties. An experimental design was performed to optimize the formulation of emulsions in the model aqueous solution/Span80/paraffin oil system. The optimized formulation was compared with other systems by varying oil and surfactant components, concluding that the influence of surfactant structure was more important than the oil polarity. Furthermore, a preliminary scale up study was carried out with the optimized formulation and the results for the two scales considered were reasonably similar. Using design of experiments and selecting a model aqueous/nonionic surfactant/oil system, an empirical model has been obtained that has allowed to optimize emulsion droplet size, their rheological properties and the release of active molecules incorporated in the aqueous phase of these highly concentrated W/O emulsions.

In this Doctoral Thesis a new stereoselective Ni(II)–mediated catalytic system for the SN1–like addition of chiral N­acyl thiazolidinethiones to electrophiles able to deliver cationic species under acidic conditions has been developed. Importantly, the nickel(II) complexes used along our studies are structurally simple, commercially available and easy to handle. These complexes coordinate to thioimides to generate an intermediate that, after deprotonation, afford a putative nickel(II) enolate, which is the real nucleophile. In Chapter 1, a totally stereoselective addition of N­acyl thiazolidinethiones to trimethyl orthoformate activated by TESOTf has been optimized. The use of this Lewis acid is also crucial for the activation of the catalyst. For N­arylacetyl thiazolidinethiones, reactions with 2.5 mol% of (Ph3P)2NiCl2 and a temperature between –20 ºC and 0 ºC was required. Instead, when other N­acyl groups were used, up to 20 mol% of (Ph3P)2NiCl2 was necessary. Alternatively, a 2.5–5 mol% of (Me3P)2NiCl2 can be used, as long as the reaction temperature is –20 ºC to avoid the appearance of byproducts. The resultant adducts are obtained between 71–94% yield and they can be converted easily in enantiomerically pure compounds with a wide array of different functional groups. This method has been applied successfully to the stereoselective synthesis of the side chain of (–)­pyridovericin and the C11–C19 fragment of (+)­peloruside A, with overall yields of 44% and 4%, respectively. In Chapter 2, the Ni(II)­mediated catalytic system was next applied to commercially available cationic salts such as 1,3­benzodithiolylium tetrafluoroborate, the Eschemoser’s salt and the tropylium tetrafluoroborate. Although the results were not highly satisfactory, the obtention of the corresponding adducts support a SN1 mechanism. Furthermore, a new stereoselective Ni(II) catalyzed alkylation reaction with diarylcarbenium methyl ethers has been developed. The reaction proceeds smoothly provided that the carbocationic intermediate is stable enough. The Mayr’s scale of electrophilicity accounts for this evidence. In Chapter 3, the catalytic system has been applied to acetals, which involved the challenging construction of two new stereocenters in a single reaction. The reaction provides the corresponding anti adducts with aromatic, a,ß­unsaturated and Co–propargylic acetals in low to moderate yields. The stereoselectivity of these additions strongly depends on the structure of the acetal. Particularly, acetals that furnish stable oxonium cations give the best stereocontrol, up to 83:17 diastereomeric ratio. Finally, Chapter 4 refers to our studies on the use of chiral N­glycolyl thiazolidinethiones in the Ni(II) catalyzed reaction to prepare anti­a,ß­dihydroxycarboxyl compounds from aromatic, a,ß­unsaturated cobalt–derived propargylic acetals in moderate to high yields. Therefore, this method provides a new method towards enantiomerically pure 1,2,3­trioxygenated systems. The diastereomeric ratios observed in these reactions resulted to be from good (75:25) to excellent (94:6). A thorough analysis of the reaction conditions uncovered that acetals difficult to be activated require an excess of Lewis acid or acetal. All together, these results proved that the Lewis acid–mediated addition of chiral N­acyl thiazolidinethiones to a wide range of electrophiles catalyzed by structurally simple, commercially available and easy to handle nickel(II) complexes is a very efficient method for the stereoselective construction of carbon–carbon bonds. Likely, such a transformation proceeds through a SN1–like mechanism in which a putative nickel(II) enolate adds to a cationic intermediate generated in situ from orthoesters, acetals or ethers. The chiral auxiliary can be removed easily to afford an important number of enantiomerically pure compounds. The synthetic potential of this new method has been demonstrated in the preparation of the side chain of pyridovericin and the C11–C19 fragment of peloruside A. / En la presente tesis doctoral se ha desarrollado un nuevo sistema catalítico estereoselectivo basado en complejos de níquel(II) para la adición tipo SN1 de N­acil tiazolidintionas quirales a electrófilos capaces de generar especies carbocatiónicas en condiciones ácidas. Los complejos de níquel(II) usados a lo largo de los respectivos estudios son estructuralmente simples, comercialmente disponibles y baratos, y fáciles de manipular y almacenar. En el Capítulo 1 se ha optimizado y desarrollado una adición totalmente estereoselectiva catalizada por complejos de tipo (R3P)2NiCl2 de N­acil tiazolidintionas a ortoformiato de trimetilo activado por un ácido de Lewis, lo que permite la introducción de un grupo formilo en la posición ß. Esta reacción pasa por la generación catalítica de un presunto enolato de níquel(II). Mientras que la reacción con N­arilacetil tioimidas funcionan satisfactoriamente con un 2.5 mol% de (Ph3P)2NiCl2, otro tipo de N­acil tioimidas requieren de una carga del 5 mol% de (Me3P)2NiCl2. Esta reacción ha sido aplicada en la preparación de la cadena lateral de la (–)­piridovericina y el fragmento C11–C19 de la pelorusida A. En el Capítulo 2, este sistema catalítico fue aplicado a diferentes sales carbocatiónicas comercialmente disponibles con resultados moderados. No obstante, la obtención de los aductos de adición demuestra la viabilidad del sistema hacia otros electrófilos mediante una reacción del tipo SN1. Aprovechando la potencialidad de este sistema catalítico, se ha desarrollado una nueva reacción de alquilación estereoselectiva con diarilmetil metil éteres. La reacción funciona increíblemente bien siempre y cuando los intermedios carbocatiónicos sean lo suficientemente estables. En el Capítulo 3 se desarrolla la adición de enolatos de níquel(II) de N­propanoíltiazolidintionas generadas en cantidades catalíticas a acetales, que fue extrapolada posteriormente a N­hidroxiacetil tioimidas debidamente protegidas en el Capítulo 4. Estas reacciones proporcionan aductos con dos nuevos centros estereogénicos con estereoquímica relativa anti. El método es aplicable a acetales aromáticos, a,ß–insaturados y propargílicos cobaltados y, en el caso de la N­propanoíltiazolidintiona, se obtienen rendimientos de moderados a buenos y relaciones diastereoméricas modestas (60:40–83:17) Estos resultados son notablemente mejores por lo que hace al uso de N­hidroxiacetil tioimidas (Capítulo 4), que muestran diastereoselectividades que llegan al valor de 94:6.

La evaluación económica de tecnologías sanitarias supone un conjunto de herramientas que tienen como finalidad examinar las consecuencias que tiene, en el corto y largo plazo, la utilización de las tecnologías sanitarias en los individuos y en la sociedad en su conjunto. Puesto que existen múltiples alternativas donde asignar dichos recursos, la evaluación económica trata de poner al alcance de los decisores del ámbito sanitario aquella información relevante desde el punto de vista de la eficiencia. Es por ello que la estadística se ha convertido en una pieza clave cada vez más necesaria para mejorar y desarrollar nuevos métodos para la evaluación económica. Actualmente las revisiones sistemáticas y su metanálisis de estudios de evaluación económica consisten en una descripción narrativa de los estudios realizando sólo el metanálisis de cada uno de sus componentes y obviando la relación existente entre costes y efectos. En esta tesis se ha desarrollado un nuevo método para llevar a cabo el metanálisis de estudios coste-efectividad, bautizándolo como COMER (del inglés, Comparative Eficiency Research). El metanálisis propuesto consiste en la estimación del beneficio monetario neto incremental total (TINB), ponderación de los beneficios monetarios netos incremental (INB) de cada estudio a partir de la inversa de la varianza. Para validar el método se estudió cómo incorporar la estructura de dependencia entre costes y efectos mediante las distribuciones cópulas. De tal forma que se simuló la distribución Frank Copula con dependencia positiva donde se asoció a las distribuciones marginales la distribución lognormal para costes y la distribución gamma para desutilidades. Se crearon cohortes hipotéticas variando el tamaño muestral y asumiendo tres escenarios con todas las combinaciones posibles: alternativa coste-efectiva, alternativa no coste-efectiva y alternativa dominante. Se comparó el resultado del COMER con resultado teórico en función del ratio coste-efectividad incremental y el INB, asumiendo un margen de error de 2.000 y 500 unidades monetarias, respectivamente. Adicionalmente, se estimó cual sería el tamaño muestral mínimo para poder obtener mediante COMER una estimación ajustada con un probabilidad alta (>70%). También se evaluó en qué medida el tamaño muestral permite alcanzar la convergencia a la τ de Kendall original. Para poder aplicarse esta aproximación del metanálisis mediante el TINB será necesario que en las evaluaciones económicas futuras se incorpore como resultado la matriz de covarianzas de la diferencia de costes y efectos. En el capítulo 1 de la tesis se hace una revisión de los conceptos de evaluación económica ahondando en qué métodos estadísticos se aplican en cada caso, así como cuál es el uso de los metanálsis. En este mismo capítulo se describen la teoría subyacente en las distribuciones cópulas y la utilización residual en el ámbito de la evaluación económica. En el capítulo 2 se indican tanto el objetivo general como los objetivos específicos de estudiar como incorporar la simulación a nivel de paciente en un estudio coste-efectividad de microsimulación y como incorporar la estructura de correlación en las simulaciones basado en regresiones. En el capítulo 3 se incluyen los informes de los directores de la tesis para los cuatro artículos incluidos en la misma. En el capítulo 4 se realiza la discusión de los cuatro artículos, profundizando en el método COMER. Los artículos propiamente se pueden localizar en el capítulo 6, así como un resumen de los mismos. Se han incorporado dos apéndices con el código en R que permiten ejecutar el método. / Economic evaluation of health technologies (EEHT) entails a set of tools which aim to examine the short and long-term consequences of using health technologies on individuals and society. Since there are numerous alternatives for allocating those resources, EEHT make relevant information from the efficiency perspective available to the people who make decisions in the health field. For this reason, the statistic is more necessary to improve and develop new methods for economic evaluation. Currently, systematic review and met-analysis of economic evaluations studies lies only in a narrative description with a meta-analysis of compound and forget structure relation between cost and effects. In this thesis, I have developed a new method to carry out a meta-analysis for cost-effectiveness studies, defined as COMparative Efficiency Research (COMER). Meta-analysis consists in the creation of total incremental net benefit (TINB), the weighting of incremental net benefits (INB), from the inverse variance of each study. Validation was carried out by simulating dependence structure between cost and effects by copula distribution. I have simulated a Frank copula distribution with positive dependence associated to a log-normal distribution for costs and gamma distribution for disutilities. Hypothetical cohorts were created by varying sample size and assuming three scenarios: cost-effective alternative, non-cost-effective alternative and dominant. The COMER result was compared to the theoretical one in function of the incremental cost-effectiveness ratio and the INB, assuming a margin of error of 2,000 and 500 monetary units, respectively. Additionally, I estimated what the minimum sample size would be to obtain through COMER an adjusted estimation with a high probability (>70%) and when simulations converged to the original τ of Kendall. This meta-analysis approximation by TINB can be used as long as the covariance matrix of the difference between costs and effects will be available. Chapter 1 is a review of EEHT concepts linked with statistical methods, the use of meta-analysi and copula distribution theory. Chapter 2 shows main objective and focus on how to include simulations at patient level in cost-effectiveness microsimulations study and correlation dependence with regressions. Chapter 3 includes Thesis Directors report for four articles. Chapter 4 discusses the articles and deepens the COMER method.