Liver radioembolization: Computational particle–hemodynamics studies in a patient-specific hepatic artery under literature-based cancer scenarios.

Liver radioembolization is a promising treatment for combating primary and metastatic liver tumors. It consists of administering radioactive microspheres via an intraarterially placed microcatheter with the aim of lodging these microspheres, which are driven by the arterial bloodstream, in the tumoral bed. The position of the microcatheter and the microsphere injection velocity are decided during a pretreatment assessment, by which the treatment is mimicked via the infusion of macroaggregated albumin microparticles. It is assumed that the pretreatment microcatheter placement and microsphere injection velocity are reproduced during the treatment. Even though it is a safe and effective treatment, some complications (e.g., radiation-induced hepatitis or pneumonitis, gastrointestinal ulcers, etc.) may arise due to nontarget radiation, which can occur due to differences between pretreatment and treatment injection conditions related to microcatheter placement, the injection itself, and the patient’s bloodstream. In terms of microcatheter placement, there are a number of parameters that can vary from pretreatment to treatment. Of those, the ones that are of special interest in this thesis are the longitudinal and radial position of the microcatheter tip, the microcatheter’s distal direction, the expandable-tip presence (for antireflux catheters only), and the tip orientation (for angled-tip microcatheters only). As for the injection itself, of the parameters that can be modified, this thesis is most concerned with two of them: the quantity and size of the microagent, and the particle injection velocity. With regard to the bloodstream, the arterial blood flow conditions might vary, e.g., due to microsphere-caused embolization of arterioles, leading to a reflux of microspheres. Any alteration in these parameters may be responsible for nontarget radiation and therefore radiation-induced complications. In order to reduce these radiation-induced complications, it has been suggested that the pretreatment injection conditions be matched as closely as possible during treatment. An alternative solution is to modify the design of microcatheters. For instance, it has been reported that using an antireflux catheter has eliminated particle reflux. The aim of this thesis is to analyze the influence of the abovementioned parameters on microsphere distribution via computational fluid–particle dynamics simulations. The thesis is divided into four major studies, each of which follows the same numerical strategy (i.e., the liver radioembolization is simulated in a patient-specific hepatic artery model under literature-based liver cancer scenarios). The first study analyzes the pretreatment as an actual treatment surrogate, the second analyzes the influence of an antireflux catheter, the third investigates the influence of the microcatheter distal direction and the injection point and velocity, and the last one explores the influence of an angled-tip microcatheter. Furthermore, prior to conducting these four studies, a methodology was developed to define realistic boundary conditions for numerical simulations in hepatic arteries. For the study on the pretreatment, results suggest that microcatheter placement is of paramount importance, both in terms of its location in the artery (near a bifurcation or not) and in the longitudinal shifting in microcatheter tip locations between pretreatment and actual treatment. Moreover, the higher the cancer burden, the better the tumor targeting because of the enhanced particle transport power. For the study on antireflux catheter influence, the main conclusion that can be drawn is that injecting from a sufficiently long and tortuous artery branch may ensure a downstream particle distribution that matches flow split, almost regardless of catheter type due to the likely adequate conditions for microsphere redistribution in the bloodstream. With regard to the third study, despite the importance of microcatheter tip position, microcatheter direction and injection velocity seem also to play an important role in particle distribution; results show that unintentional modifications to microcatheter tip and direction and injection velocity during tumor targeting may influence procedure outcome. The final study involving the angled-tip microcatheter shows that the higher the injection velocity the more spread out the particle distribution across cross-sectional areas of artery lumen. Moreover, when only focusing on tip orientation, it is not possible to accurately predict which branch of the bifurcation will take the particles because the complex geometry of hepatic arteries makes the bloodstream take the form of helical and chaotic streamlines. This means that the particle pathlines are not initially intuitive, even though the particle distribution will be similar to flow split.La radioembolización hepática es un tratamiento para combatir tumores hepáticos primarios y metástasis hepáticas. Consiste en administrar microesferas radiactivas mediante un microcatéter situado en la arteria hepática, de modo que esas microesferas, que son llevadas por la corriente sanguínea, se depositan en la malla tumoral. La posición del microcatéter y la velocidad de inyección de las partículas se deciden durante el pretratamiento, mediante el cual se emula el tratamiento por medio de la infusión de micropartículas de macroagregados de albúmina. Se supone que tanto la posición del microcatéter como la velocidad de inyección se repiten durante el tratamiento. Aunque sea un tratamiento seguro y efectivo, pueden aparecer complicaciones (hepatitis, neumonitis, úlceras gastrointestinales, etc.) por la irradiación de zonas que no debían irradiarse. Esta irradiación no deseada puede deberse a diferencias entre las condiciones de la inyección del pretratamiento y las del tratamiento. Esas condiciones son: el posicionamiento del microcatéter, la inyección y el flujo sanguíneo. En lo que respecta al posicionamiento del microcatéter, los parámetros que pueden variar del pretratamiento al tratamiento, entre otros, son: las posiciones longitudinal y radial de la punta del microcatéter, el direccionamiento distal del microcatéter, la presencia de una punta expandible (para el caso del catéter antirreflujo) y la orientación de la punta del microcatéter (sólo para los microcatéteres con la punta a 45º). En cuanto a la inyección, los parámetros que pueden ser alterados son: el tamaño y la cantidad del microagente inyectado, y la velocidad de inyección de las partículas, entre otros. En cuanto al flujo sanguíneo, éste puede variar, por ejemplo, debido a la embolización de las arteriolas, lo que puede conllevar el reflujo de partículas. La variación de los citados parámetros puede ocasionar irradiación no deseada, lo que conlleva complicaciones debidas a dicha irradiación. Para reducir estas complicaciones, por un lado se ha recomendado ajustar, durante el tratamiento, la posición del microcatéter y la velocidad de inyección definidas durante el pretratamiento. Por otro lado, se han propuesto diferentes diseños de microcatéteres. Por ejemplo, el reflujo de partículas se ha eliminado gracias al catéter antirreflujo. El objetivo de esta tesis es analizar la influencia de los parámetros citados en la distribución de microesferas mediante simulaciones numéricas del flujo de sangre con transporte de partículas. La tesis se divide en cuatro estudios que siguen la misma estrategia de simulación; es decir, la radioembolización es simulada en un modelo de arteria hepática específica de paciente bajo unos escenarios de cáncer basados en la literatura. El primer estudio analiza las diferencias que pueden darse entre el pretratamiento y el tratamiento. El segundo, estudia la influencia del catéter antirreflujo. El tercero, la influencia de la dirección distal del microcatéter, del punto de inyección y de la velocidad de inyección; y el cuarto, la influencia del microcatéter acabado con la punta a 45º. Además, antes de llevar a cabo estos cuatro estudios se tuvo que desarrollar una metodología para definir condiciones de contorno realistas aplicables a simulaciones numéricas en arterias hepáticas. En lo que respecta al estudio sobre el pretratamiento, los resultados muestran que la posición del microcatéter es muy importante, tanto en su posición en la arteria (cerca o lejos de una bifurcación) como en pequeños movimientos longitudinales de la punta del microcatéter entre el pretratamiento y el tratamiento. Además, cuanto mayor es el volumen de cáncer, tanto mayor es la capacidad de llegar a los tumores porque aumenta la capacidad de transportar las partículas. En cuanto al estudio sobre el catéter antirreflujo, la conclusión principal es que inyectar en una arteria lo suficientemente larga y tortuosa posibilita el alineamiento de las partículas con el flujo; de modo que, sea cual sea el catéter empleado para la inyección, la distribución de partículas tiende a parecerse a la distribución del flujo de sangre. Con respecto al tercer estudio, se concluye que a pesar de la importancia de la posición de la punta del microcatéter, también son importantes tanto la dirección distal del microcatéter como la velocidad de inyección de las partículas. Así, variaciones involuntarias de cualquiera de los tres parámetros puede conllevar resultados no deseados en el tratamiento. Por último, el cuarto estudio muestra que cuanto mayor es la velocidad de inyección de las partículas, más esparcidas viajan las partículas en el lumen de la arteria. Además, fijándose únicamente en la orientación de la punta del microcatéter no es posible predecir la rama de la bifurcación que van a tomar las partículas porque la complejidad de la geometría de las arterias hepáticas hace que el flujo sanguíneo tome estructuras hemodinámicas helicoidales y caóticas, por lo que la trayectoria de las partículas no es intuitiva, aunque la distribución de las partículas será similar a la del flujo de sangre

Where is the value of cluster associations for SMEs?

Purpose: To explore the role played by policies for co-operation and networking, such as cluster initiatives. We empirically examine not only the direct effect of cluster initiatives on firms’ innovation performance, but also potential moderation and mediation effects with regards effort in other internal innovation activities. Methodology: We analyze the case of the long-running and stable Basque Cluster policy. We built using SABI an extensive sample of 1779 industrial SMEs, 132 of which are members of cluster associations. Findings: The results show that cluster associates do not have more innovation than non-cluster associates. It also rejects the moderation role of other innovation activities (such as technology management, environmental management or R&D activities). However, the results give support to the mediation role of cluster associations in enhancing the value of innovation activities. Practical implications: The results presented are relevant both for policy-makers seeking to achieve an optimal mix of ‘general cooperation’ and ‘activity-specific’ policies, as well as for the managers of firms who may accelerate the impacts of their innovation efforts by being members of cooperation networks. Research limitations: There are two main limitations to the empirical analysis. Firstly, the impossibility of identifying the year in which cluster associates formally register to the cluster association through secondary sources could entail a degree of endogeneity in the direct and moderation models. Secondly, we measure innovation as labour productivity growth, which is acknowledged as only a partial measure of innovation. More generally we acknowledge that evaluations of soft policies such as that reported in this paper should be combined with complementary qualitative analysis. Originality: Few empirical analyses have been conducted to empirically assess the efficiency of the Basque cluster policy. The research does not support the idea that cluster associates increase innovation per se. However, it reinforces the view that cluster associations can be conceived as a focal network or broker of knowledge. In particular, this could be interpreted in terms of the success of the cluster initiative as a mechanism for generating or demonstrating a certain degree of trust among firms that already engage in innovation activities, supporting in turn benefits from the exchange of their knowledge.Peer Reviewe

Dieta de pichones de cotorra Myiopsitta m. monachus (Aves: Psittacidae) en la Provincia de Buenos Aires

Dieta de pichones de Cotorra Myiopsitta m. monachus (Aves: Psittacidae) en la Provincia de Buenos Aires. El objetivo de este trabajo fue conocer la composición de la dieta aportada por los progenitores a los pichones durante su permanencia en el nido. Se analizaron los buches de 32 pichones de cotorra cuyos nidos fueron sometidos a control químico, procedentes de Gándara, Cañuelas y Villanueva (Provincia de Buenos Aires). Cada buche fue pesado con balanza analítica. Los distintos ítems integrantes de la dieta fueron separados bajo lupa binocular y pesados. La determinación se realizó en base a caracteres morfológicos externos e internos. Se observó que el 99.5% correspondió a componente vegetal, mientras que el componente mineral sólo se encontró representado en un 0.5%. En la fracción vegetal se destacaron cuatro familias siendo Asteracea y Poacea las de mayor porcentaje (96%)

Human Erythroid Progenitors Are Directly Infected by SARS-CoV-2: Implications for Emerging Erythropoiesis in Severe COVID-19 Patients

We document here that intensive care COVID-19 patients suffer a profound decline in hemoglobin levels but show an increase of circulating nucleated red cells, suggesting that SARS-CoV-2 infection either directly or indirectly induces stress erythropoiesis. We show that ACE2 expression peaks during erythropoiesis and renders erythroid progenitors vulnerable to infection by SARS-CoV-2. Early erythroid progenitors, defined as CD34-CD117+CD71+CD235a-, show the highest levels of ACE2 and constitute the primary target cell to be infected during erythropoiesis. SARS-CoV-2 causes the expansion of colony formation by erythroid progenitors and can be detected in these cells after 2 weeks of the initial infection. Our findings constitute the first report of SARS-CoV-2 infectivity in erythroid progenitor cells and can contribute to understanding both the clinical symptoms of severe COVID-19 patients and how the virus can spread through the circulation to produce local inflammation in tissues, including the bone marrow

Eventos no epilépticos psicógenos: El desafío constante de su diagnóstico y tratamiento.

Psychogenic Non-Epileptic Events (PNEE) are paroxysmal episodes described as behavioral changes, sensory- sensitive disturbances, or motor manifestations that resemble epileptic seizures without showing underlying epileptiform activity, are not deliberately produced by the individual, and respond to multifactorial biopsychosocial mechanisms. Epidemiological information is limited due to the heterogeneous nature of the affected population, and to the limited accessibility to the video electroencephalogram (vEEG) necessary for its diagnosis. In such context, the convergence of two important elements is necessary: a detailed clinical history (clinical characteristics suggestive of PNEE, and identification of the associated factors), and the absence of electroencephalographic “ictal” changes in the vEEG. A psychological evaluation provides additional information, relevant for the diagnostic corroboration and management. The diagnosis must be made in a timely manner, to avoid complications in its evolution and treatment. A positive and encouraging attitude to the patient is vital when informing him/her of the diagnosis, as it also is the coordination between the treating neurologist and mental health professionals involved in the management and monitoring of the case. Cognitive behavioral psychotherapy, associated with psychopharmacotherapy -when needed-- constitute the most effective treatment approach for these patients. There are limited studies on the current epidemiological and clinical evolution of patients with PNEE in Latin America, and additional research regarding this problem is much needed, given its impact on the quality of life of the patients and on the cost of its management in the health care systems.Los eventos no epilépticos psicógenos (ENEP) son episodios paroxísticos descritos como cambios conductuales, alteraciones sensorio-sensitivas, o manifestaciones motoras que se asemejan a las crisis epilépticas pero sin mostrar actividad epileptiforme subyacente, no son producidos deliberadamente por el individuo, y responden a mecanismos multifactoriales de índole biopsicosocial. La información epidemiológica es limitada debido a la naturaleza heterogénea de la población afectada, así como a la escasa accesibilidad al videoelectroencefalograma (vEEG) necesario para su diagnóstico. En este contexto, es necesaria la convergencia de dos elementos importantes: historia clínica detallada (características clínicas sugerentes de ENEP e identificación de los factores asociados) y la ausencia de cambios electroencefalográficos en el vEEG durante el episodio. La evaluación psicológica provee información adicional relevante para la corroboración diagnóstica y para su manejo. El diagnóstico debe realizarse de manera oportuna, para evitar complicaciones en su evolución y tratamiento. Es vital una actitud positiva y alentadora hacia el/la paciente al momento de comunicarle su diagnóstico, así como la coordinación entre el neurólogo tratante y los profesionales de salud mental involucrados en el manejo y seguimiento del caso. La psicoterapia cognitiva conductual, asociada a psicofármacoterapia -cuando pertinente-, constituyen el tratamiento más eficaz de estos pacientes. Existen limitados estudios en Latinoamérica sobre aspectos epidemiológicos y clínico-evolutivos de pacientes con ENEP, por lo que más investigación y publicaciones respecto a esta problemática son indispensables dado su impacto sobre la calidad de vida de los pacientes y sobre el costo de su manejo en los sistemas de salud

Revisión bioestratigráfica de las pizarras del Ordovícico Medio en el noroeste de España (zonas Cantábrica, Asturoccidental-leonesa y Centroibérica septentrional)

A complete review of more than one hundred Middle Ordovician fossil localities, distributed within the north western part of the Hesperian Massif, shows that the sedimentation of the dark shales (Luarca Fo rmation and equivalents) that overlie Arenig quartzites with Cruziana (the 'Armorican Quartzite' facies) was not as uniform as it has been supposed for the whole NW Spain. These shales were mainly deposited during the Oretanian in the West Asturian-Leonese Zone and in nort h e rn Central-Iberian Zone (Domain of the Ollo de Sapo Antiform). In these zones, the top of the unit is close to the Oretanian/Dobrotivian boundary, without any fossils with proved Dobrotivian age. In the Cantabrian Zone, clay sedimentation started in the latest Oretanian and continued during the Dobrotivian. Several local or regional stratigraphic gaps are proposed and characterized for the whole study area. In addition, the most recent paleog e ographical reconstructions proposed are discussed, in accordance with new paleoecological and paleobiog e ographical data. These data indicate that sedimentation took place in open shelf areas, relative ly deeper than in the southern Central Iberian shelf, and with trough areas where some mesopelagic elements are recorded. We identified a total of 97 different fossil taxa (67 from Oretanian rocks and 45 from Dobrotivian rocks), remarkable among which are the first known appearance of certain trilobites and ostracodes, the latest record of other taxa, and also the presence of some taxa in common with Avalonia and Baltica, that were previously unknown from any area of SW Europe

Lattice models and Landau theory for type II incommensurate crystals

Ground state properties and phonon dispersion curves of a classical linear chain model describing a crystal with an incommensurate phase are studied. This model is the DIFFOUR (discrete frustrated phi4) model with an extra fourth-order term added to it. The incommensurability in these models may arise if there is frustration between nearest-neighbor and next-nearest-neighbor interactions. We discuss the effect of the additional term on the phonon branches and phase diagram of the DIFFOUR model. We find some features not present in the DIFFOUR model such as the renormalization of the nearest-neighbor coupling. Furthermore the ratio between the slopes of the soft phonon mode in the ferroelectric and paraelectric phase can take on values different from -2. Temperature dependences of the parameters in the model are different above and below the paraelectric transition, in contrast with the assumptions made in Landau theory. In the continuum limit this model reduces to the Landau free energy expansion for type II incommensurate crystals and it can be seen as the lowest-order generalization of the simplest Lifshitz-point model. Part of the numerical calculations have been done by an adaption of the Effective Potential Method, orginally used for models with nearest-neighbor interaction, to models with also next-nearest-neighbor interactions.Comment: 33 pages, 7 figures, RevTex, submitted to Phys. Rev.