Chaos in non lineal Alfven waves using the DNLS equations

The electro-dynamical tethers emit waves in structured denominated Alfven wings. The Derivative Nonlineal Schrödinger Equation (DNLS) possesses the capacity to describe the propagation of circularly polarized Alfven waves of finite amplitude in cold plasmas. The DNLS equation is truncated to explore the coherent, weakly nonlinear, cubic coupling of three waves near resonance, one wave being linearly unstable and the other waves damped. In this article is presented a theoretical and numerical analysis when the growth rate of the unstable wave is next to zero considering two damping models: Landau and resistive. The DNLS equation presents a chaotic dynamics when is consider only three wave truncation. The evolution to chaos possesses three routes: hard transition, period-doubling and intermittence of type I.

Modelling of landslides propagation with SPH : effects of rheology and pore water pressure

El estudio desarrollado en este trabajo de tesis se centra en la modelización numérica de la fase de propagación de los deslizamientos rápidos de ladera a través del método sin malla Smoothed Particle Hydrodynamics (SPH). Este método tiene la gran ventaja de permitir el análisis de problemas de grandes deformaciones evitando operaciones costosas de remallado como en el caso de métodos numéricos con mallas tal como el método de los Elementos Finitos. En esta tesis, particular atención viene dada al rol que la reología y la presión de poros desempeñan durante estos eventos. El modelo matemático utilizado se basa en la formulación de Biot-Zienkiewicz v - pw, que representa el comportamiento, expresado en términos de velocidad del esqueleto sólido y presiones de poros, de la mezcla de partículas sólidas en un medio saturado. Las ecuaciones que gobiernan el problema son: • la ecuación de balance de masa de la fase del fluido intersticial, • la ecuación de balance de momento de la fase del fluido intersticial y de la mezcla, • la ecuación constitutiva y • una ecuación cinemática. Debido a sus propiedades geométricas, los deslizamientos de ladera se caracterizan por tener una profundidad muy pequeña frente a su longitud y a su anchura, y, consecuentemente, el modelo matemático mencionado anteriormente se puede simplificar integrando en profundidad las ecuaciones, pasando de un modelo 3D a 2D, el cual presenta una combinación excelente de precisión, sencillez y costes computacionales. El modelo propuesto en este trabajo se diferencia de los modelos integrados en profundidad existentes por incorporar un ulterior modelo capaz de proveer información sobre la presión del fluido intersticial a cada paso computacional de la propagación del deslizamiento. En una manera muy eficaz, la evolución de los perfiles de la presión de poros está numéricamente resuelta a través de un esquema explicito de Diferencias Finitas a cada nodo SPH. Este nuevo enfoque es capaz de tener en cuenta la variación de presión de poros debida a cambios de altura, de consolidación vertical o de cambios en las tensiones totales. Con respecto al comportamiento constitutivo, uno de los problemas principales al modelizar numéricamente deslizamientos rápidos de ladera está en la dificultad de simular con la misma ley constitutiva o reológica la transición de la fase de iniciación, donde el material se comporta como un sólido, a la fase de propagación donde el material se comporta como un fluido. En este trabajo de tesis, se propone un nuevo modelo reológico basado en el modelo viscoplástico de Perzyna, pensando a la viscoplasticidad como a la llave para poder simular tanto la fase de iniciación como la de propagación con el mismo modelo constitutivo. Con el fin de validar el modelo matemático y numérico se reproducen tanto ejemplos de referencia con solución analítica como experimentos de laboratorio. Finalmente, el modelo se aplica a casos reales, con especial atención al caso del deslizamiento de 1966 en Aberfan, mostrando como los resultados obtenidos simulan con éxito estos tipos de riesgos naturales. The study developed in this thesis focuses on the modelling of landslides propagation with the Smoothed Particle Hydrodynamics (SPH) meshless method which has the great advantage of allowing to deal with large deformation problems by avoiding expensive remeshing operations as happens for mesh methods such as, for example, the Finite Element Method. In this thesis, special attention is given to the role played by rheology and pore water pressure during these natural hazards. The mathematical framework used is based on the v - pw Biot-Zienkiewicz formulation, which represents the behaviour, formulated in terms of soil skeleton velocity and pore water pressure, of the mixture of solid particles and pore water in a saturated media. The governing equations are: • the mass balance equation for the pore water phase, • the momentum balance equation for the pore water phase and the mixture, • the constitutive equation and • a kinematic equation. Landslides, due to their shape and geometrical properties, have small depths in comparison with their length or width, therefore, the mathematical model aforementioned can then be simplified by depth integrating the equations, switching from a 3D to a 2D model, which presents an excellent combination of accuracy, computational costs and simplicity. The proposed model differs from previous depth integrated models by including a sub-model able to provide information on pore water pressure profiles at each computational step of the landslide's propagation. In an effective way, the evolution of the pore water pressure profiles is numerically solved through a set of 1D Finite Differences explicit scheme at each SPH node. This new approach is able to take into account the variation of the pore water pressure due to changes of height, vertical consolidation or changes of total stress. Concerning the constitutive behaviour, one of the main issues when modelling fast landslides is the difficulty to simulate with the same constitutive or rheological model the transition from the triggering phase, where the landslide behaves like a solid, to the propagation phase, where the landslide behaves in a fluid-like manner. In this work thesis, a new rheological model is proposed, based on the Perzyna viscoplastic model, thinking of viscoplasticity as the key to close the gap between the triggering and the propagation phase. In order to validate the mathematical model and the numerical approach, benchmarks and laboratory experiments are reproduced and compared to analytical solutions when possible. Finally, applications to real cases are studied, with particular attention paid to the Aberfan flowslide of 1966, showing how the mathematical model accurately and successfully simulate these kind of natural hazards.

On a mathematical model of tumor growth based on cancer stem cells

We consider a simple mathematical model of tumor growth based on cancer stem cells. The model consists of four hyperbolic equations of first order to describe the evolution of different subpopulations of cells: cancer stem cells, progenitor cells, differentiated cells and dead cells. A fifth equation is introduced to model the evolution of the moving boundary. The system includes non-local terms of integral type in the coefficients. Under some restrictions in the parameters we show that there exists a unique homogeneous steady state which is stable.

A technological framework based on automatic messaging for improving adherence of diabetic patients

En todo el mundo se ha observado un crecimiento exponencial en la incidencia de enfermedades crónicas como la hipertensión y enfermedades cardiovasculares y respiratorias, así como la diabetes mellitus, que causa un número de muertes cada vez mayor en todo el mundo (Beaglehole et al., 2008). En concreto, la prevalencia de diabetes mellitus (DM) está aumentando de manera considerable en todas las edades y representa un serio problema de salud mundial. La diabetes fue la responsable directa de 1,5 millones de muertes en 2012 y 89 millones de años de vida ajustados por discapacidad (AVAD) (OMS, 2014). Uno de los principales dilemas que suelen asociarse a la gestión de EC es la adherencia de los pacientes a los tratamientos, que representa un aspecto multifactorial que necesita asistencia en lo relativo a: educación, autogestión, interacción entre los pacientes y cuidadores y compromiso de los pacientes. Medir la adherencia del tratamiento es complicado y, aunque se ha hablado ampliamente de ello, aún no hay soluciones “de oro” (Reviews, 2002). El compromiso de los pacientes, a través de la participación, colaboración, negociación y a veces del compromiso firme, aumentan las oportunidades para una terapia óptima en la que los pacientes se responsabilizan de su parte en la ecuación de adherencia. Comprometer e involucrar a los pacientes diabéticos en las decisiones de su tratamiento, junto con expertos profesionales, puede ayudar a favorecer un enfoque centrado en el paciente hacia la atención a la diabetes (Martin et al., 2005). La motivación y atribución de poder de los pacientes son quizás los dos factores interventores más relevantes que afectan directamente a la autogestión de la atención a la diabetes. Se ha demostrado que estos dos factores desempeñan un papel fundamental en la adherencia a la prescripción, así como en el fomento exitoso de un estilo de vida sana y otros cambios de conducta (Heneghan et al., 2013). Un plan de educación personalizada es indispensable para proporcionarle al paciente las herramientas adecuadas que necesita para la autogestión efectiva de la enfermedad (El-Gayar et al. 2013). La comunicación efectiva es fundamental para proporcionar una atención centrada en el paciente puesto que influye en las conductas y actitudes hacia un problema de salud ((Frampton et al. 2008). En este sentido, la interactividad, la frecuencia, la temporalización y la adaptación de los mensajes de texto pueden promover la adherencia a un régimen de medicación. Como consecuencia, adaptar los mensajes de texto a los pacientes puede resultar ser una manera de hacer que las sugerencias y la información sean más relevantes y efectivas (Nundy et al. 2013). En este contexto, las tecnologías móviles en el ámbito de la salud (mHealth) están desempeñando un papel importante al conectar con pacientes para mejorar la adherencia a medicamentos recetados (Krishna et al., 2009). La adaptación de los mensajes de texto específicos de diabetes sigue siendo un área de oportunidad para mejorar la adherencia a la medicación y ofrecer motivación a adultos con diabetes. Sin embargo, se necesita más investigación para entender totalmente su eficacia. Los consejos de texto personalizados han demostrado causar un impacto positivo en la atribución de poder a los pacientes, su autogestión y su adherencia a la prescripción (Gatwood et al., 2014). mHealth se puede utilizar para ofrecer programas de asistencia de autogestión a los pacientes con diabetes y, al mismo tiempo, superar las dificultades técnicas y financieras que supone el tratamiento de la diabetes (Free at al., 2013). El objetivo principal de este trabajo de investigación es demostrar que un marco tecnológico basado en las teorías de cambios de conducta, aplicado al campo de la mHealth, permite una mejora de la adherencia al tratamiento en pacientes diabéticos. Como método de definición de una solución tecnológica, se han adoptado un conjunto de diferentes técnicas de conducta validadas denominado marco de compromiso de retroacción conductual (EBF, por sus siglas en inglés) para formular los mensajes, guiar el contenido y evaluar los resultados. Los estudios incorporan elementos del modelo transteórico (TTM, por sus siglas en inglés), la teoría de la fijación de objetivos (GST, por sus siglas en inglés) y los principios de comunicación sanitaria persuasiva y eficaz. Como concepto general, el modelo TTM ayuda a los pacientes a progresar a su próxima fase de conducta a través de mensajes de texto motivados específicos y permite que el médico identifique la fase actual y adapte sus estrategias individualmente. Además, se adoptan las directrices del TTM para fijar objetivos personalizados a un nivel apropiado a la fase de cambio del paciente. La GST encierra normas que van a ponerse en práctica para promover la intervención educativa y objetivos de pérdida de peso. Finalmente, los principios de comunicación sanitaria persuasiva y eficaz aplicados a la aparición de los mensajes se han puesto en marcha para aumentar la efectividad. El EBF tiene como objetivo ayudar a los pacientes a mejorar su adherencia a la prescripción y encaminarlos a una mejora general en la autogestión de la diabetes mediante mensajes de texto personalizados denominados mensajes de retroacción automáticos (AFM, por sus siglas en inglés). Después de una primera revisión del perfil, consistente en identificar características significativas del paciente basadas en las necesidades de tratamiento, actitudes y conductas de atención sanitaria, el sistema elige los AFM personalizados, los aprueba el médico y al final se transfieren a la interfaz del paciente. Durante el tratamiento, el usuario recopila los datos en dispositivos de monitorización de pacientes (PMD, por sus siglas en inglés) de una serie de dispositivos médicos y registros manuales. Los registros consisten en la toma de medicación, dieta y actividad física y tareas de aprendizaje y control de la medida del metabolismo. El compromiso general del paciente se comprueba al estimar el uso del sistema y la adherencia del tratamiento y el estado de los objetivos del paciente a corto y largo plazo. El módulo de análisis conductual, que consiste en una serie de reglas y ecuaciones, calcula la conducta del paciente. Tras lograr el análisis conductual, el módulo de gestión de AFM actualiza la lista de AFM y la configuración de los envíos. Las actualizaciones incluyen el número, el tipo y la frecuencia de mensajes. Los AFM los revisa periódicamente el médico que también participa en el perfeccionamiento del tratamiento, adaptado a la fase transteórica actual. Los AFM se segmentan en distintas categorías y niveles y los pacientes pueden ajustar la entrega del mensaje de acuerdo con sus necesidades personales. El EBF se ha puesto en marcha integrado dentro del sistema METABO, diseñado para facilitar al paciente diabético que controle sus condiciones relevantes de una manera menos intrusiva. El dispositivo del paciente se vincula en una plataforma móvil, mientras que una interfaz de panel médico permite que los profesionales controlen la evolución del tratamiento. Herramientas específicas posibilitan que los profesionales comprueben la adherencia del paciente y actualicen la gestión de envíos de AFM. El EBF fue probado en un proyecto piloto controlado de manera aleatoria. El principal objetivo era examinar la viabilidad y aceptación del sistema. Los objetivos secundarios eran también la evaluación de la eficacia del sistema en lo referente a la mejora de la adherencia, el control glucémico y la calidad de vida. Se reclutaron participantes de cuatro centros clínicos distintos en Europa. La evaluación del punto de referencia incluía datos demográficos, estado de la diabetes, información del perfil, conocimiento de la diabetes en general, uso de las plataformas TIC, opinión y experiencia con dispositivos electrónicos y adopción de buenas prácticas con la diabetes. La aceptación y eficacia de los criterios de evaluación se aplicaron para valorar el funcionamiento del marco tecnológico. El principal objetivo era la valoración de la eficacia del sistema en lo referente a la mejora de la adherencia. En las pruebas participaron 54 pacientes. 26 fueron asignados al grupo de intervención y equipados con tecnología móvil donde estaba instalado el EBF: 14 pacientes tenían T1DM y 12 tenían T2DM. El grupo de control estaba compuesto por 25 pa cientes que fueron tratados con atención estándar, sin el empleo del EBF. La intervención profesional tanto de los grupos de control como de intervención corrió a cargo de 24 cuidadores, entre los que incluían diabetólogos, nutricionistas y enfermeras. Para evaluar la aceptabilidad del sistema y analizar la satisfacción de los usuarios, a través de LimeSurvey, se creó una encuesta multilingüe tanto para los pacientes como para los profesionales. Los resultados también se recopilaron de los archivos de registro generados en los PMD, el panel médico profesional y las entradas de la base de datos. Los mensajes enviados hacia y desde el EBF y los archivos de registro del sistema y los servicios de comunicación se grabaron durante las cinco semanas del estudio. Se entregaron un total de 2795 mensajes, lo que supuso una media de 107,50 mensajes por paciente. Como se muestra, los mensajes disminuyen con el tiempo, indicando una mejora global de la adherencia al plan de tratamiento. Como se esperaba, los pacientes con T1DM recibieron más consejos a corto plazo, en relación a su estado. Del mismo modo, al ser el centro de T2DM en cambios de estilo de vida sostenible a largo plazo, los pacientes con T2DM recibieron más consejos de recomendación, en cuanto a dietas y actividad física. También se ha llevado a cabo una comparación de la adherencia e índices de uso para pacientes con T1DM y T2DM, entre la primera y la segunda mitad de la prueba. Se han observado resultados favorables para el uso. En lo relativo a la adherencia, los resultados denotaron una mejora general en cada dimensión del plan de tratamiento, como la nutrición y las mediciones de inserción de glucosa en la sangre. Se han llevado a cabo más estudios acerca del cambio a nivel educativo antes y después de la prueba, medidos tanto para grupos de control como de intervención. Los resultados indicaron que el grupo de intervención había mejorado su nivel de conocimientos mientras que el grupo de control mostró una leve disminución. El análisis de correlación entre el nivel de adherencia y las AFM ha mostrado una mejora en la adherencia de uso para los pacientes que recibieron los mensajes de tipo alertas, y unos resultados no significativos aunque positivos relacionados con la adherencia tanto al tratamiento que al uso correlacionado con los recordatorios. Por otra parte, los AFM parecían ayudar a los pacientes que no tomaban suficientemente en serio su tratamiento en el principio y que sí estaban dispuestos a responder a los mensajes recibidos. Aun así, los pacientes que recibieron demasiadas advertencias, comenzaron a considerar el envío de mensajes un poco estresante. El trabajo de investigación llevado a cabo al desarrollar este proyecto ofrece respuestas a las cuatro hipótesis de investigación que fueron la motivación para el trabajo. • Hipótesis 1 : es posible definir una serie de criterios para medir la adherencia en pacientes diabéticos. • Hipótesis 2: es posible diseñar un marco tecnológico basado en los criterios y teorías de cambio de conducta mencionados con anterioridad para hacer que los pacientes diabéticos se comprometan a controlar su enfermedad y adherirse a planes de atención. • Hipótesis 3: es posible poner en marcha el marco tecnológico en el sector de la salud móvil. • Hipótesis 4: es posible utilizar el marco tecnológico como solución de salud móvil en un contexto real y tener efectos positivos en lo referente a indicadores de control de diabetes. La verificación de cada hipótesis permite ofrecer respuesta a la hipótesis principal: La hipótesis principal es: es posible mejorar la adherencia diabética a través de un marco tecnológico mHealth basado en teorías de cambio de conducta. El trabajo llevado a cabo para responder estas preguntas se explica en este trabajo de investigación. El marco fue desarrollado y puesto en práctica en el Proyecto METABO. METABO es un Proyecto I+D, cofinanciado por la Comisión Europea (METABO 2008) que integra infraestructura móvil para ayudar al control, gestión y tratamiento de los pacientes con diabetes mellitus de tipo 1 (T1DM) y los que padecen diabetes mellitus de tipo 2 (T2DM). ABSTRACT Worldwide there is an exponential growth in the incidence of Chronic Diseases (CDs), such as: hypertension, cardiovascular and respiratory diseases, as well as diabetes mellitus, leading to rising numbers of deaths worldwide (Beaglehole et al. 2008). In particular, the prevalence of diabetes mellitus (DM) is largely increasing among all ages and constitutes a major worldwide health problem. Diabetes was directly responsible for 1,5 million deaths in 2012 and 89 million Disability-adjusted life year (DALYs) (WHO 2014). One of the key dilemmas often associated to CD management is the patients’ adherence to treatments, representing a multi-factorial aspect that requires support in terms of: education, self-management, interaction between patients and caregivers, and patients’ engagement. Measuring adherence is complex and, even if widely discussed, there are still no “gold” standards ((Giardini et al. 2015), (Costa et al. 2015). Patient’s engagement, through participation, collaboration, negotiation, and sometimes compromise, enhance opportunities for optimal therapy in which patients take responsibility for their part of the adherence equation. Engaging and involving diabetic patients in treatment decisions, along with professional expertise, can help foster a patient-centered approach to diabetes care (Martin et al. 2005). Patients’ motivation and empowerment are perhaps the two most relevant intervening factors that directly affect self-management of diabetes care. It has been demonstrated that these two factors play an essential role in prescription adherence, as well as for the successful encouragement of a healthy life-style and other behavioural changes (Heneghan et al. 2013). A personalised education plan is indispensable in order to provide the patient with the appropriate tools needed for the effective self-management of the disease (El-Gayar et al. 2013). Effective communication is at the core of providing patient-centred care since it influences behaviours and attitudes towards a health problem (Frampton et al. 2008). In this regard, interactivity, frequency, timing, and tailoring of text messages may promote adherence to a medication regimen. As a consequence, tailoring text messages to patients can constitute a way of making suggestions and information more relevant and effective (Nundy et al. 2013). In this context, mobile health technologies (mHealth) are playing significant roles in improving adherence to prescribed medications (Krishna et al. 2009). The tailoring of diabetes-specific text messages remains an area of opportunity to improve medication adherence and provide motivation to adults with diabetes but further research is needed to fully understand their effectiveness. Personalized text advices have proven to produce a positive impact on patients’ empowerment, self-management, and adherence to prescriptions (Gatwood et al. 2014). mHealth can be used for offering self-management support programs to diabetes patients and at the same time surmounting the technical and financial difficulties involved in diabetes treatment (Free et al. 2013). The main objective of this research work is to demonstrate that a technological framework, based on behavioural change theories, applied to mHealth domain, allows improving adherence treatment in diabetic patients. The framework, named Engagement Behavioural Feedback Framework (EBF), is built on top of validated behavioural techniques to frame messages, guide the definition of contents and assess outcomes: elements from the Transtheoretical Model (TTM), the Goal-Setting Theory (GST), Effective Health Communication (EHC) guidelines and Principles of Persuasive Technology (PPT) were incorporated. The TTM helps patients to progress to a next behavioural stage, through specific motivated text messages, and allow clinician’s identifying the current stage and tailor its strategies individually. Moreover, TTM guidelines are adopted to set customised goals at a level appropriate to the patient’s stage of change. The GST was used to build rules to be applied for enhancing educational intervention and weight loss objectives. Finally, the EHC guidelines and the PPT were applied to increase the effectiveness of messages. The EBF aims to support patients on improving their prescription adherence and persuade them towards a general improvement in diabetes self-management, by means of personalised text messages, named Automatic Feedback Messages (AFM). After a first profile screening, consisting in identifying meaningful patient characteristics based on treatment needs, attitudes and health care behaviours, customised AFMs are selected by the system, approved by the professional, and finally transferred into the patient interface. During the treatment, the user collects the data into a Patient Monitoring Device (PMD) from a set of medical devices and from manual inputs. Inputs consist in medication intake, diet and physical activity, metabolic measurement monitoring and learning tasks. Patient general engagement is checked by estimating the usage of the system and the adherence of treatment and patient goals status in the short and the long term period. The Behavioural Analysis Module, consisting in a set of rules and equations, calculates the patient’s behaviour. After behavioural analysis is accomplished, the AFM library and the dispatch setting are updated by the AFM Manager module. Updates include the number, the type and the frequency of messages. The AFMs are periodically supervised by the professional who also participates to the refinement of the treatment, adapted to the current transtheoretical stage. The AFMs are segmented in different categories and levels and patients can adjust message delivery in accordance with their personal needs. The EBF was integrated to the METABO system, designed to facilitate diabetic patients in managing their disease in a less intrusive approach. Patient device corresponds in a mobile platform, while a medical panel interface allows professionals to monitoring the treatment evolution. Specific tools allow professional to check patient adherence and to update the AFMs dispatch management. The EBF was tested in a randomised controlled pilot. The main objective was to examine the feasibility and acceptance of the system. Secondary objectives were also the assessment of the effectiveness of system in terms of adherence improvement, glycaemic control, and quality of life. Participants were recruited from four different clinical centres in Europe. The baseline assessment included demographics, diabetes status, profile information, knowledge about diabetes in general, usage of ICT platforms, opinion and experience about electronic devices and adoption of good practices with diabetes. Acceptance and the effectiveness evaluation criteria were applied to evaluate the performance of the technological framework. The main objective was the assessment of the effectiveness of system in terms of adherence improvement. Fifty-four patients participated on the trials. Twenty-six patients were assigned in the intervention group and equipped with mobile where the EBF was installed: 14 patients were T1DM and 12 were T2DM. The control group was composed of 25 patients that were treated through a standard care, without the usage of the EBF. Professional’s intervention for both intervention and control groups was carried out by 24 care providers, including endocrinologists, nutritionists, and nurses. In order to evaluate the system acceptability and analyse the users’ satisfaction, an online multi-language survey, using LimeSurvey, was produced for both patients and professionals. Results were also collected from the log-files generated in the PMDs, the professional medical panel and the entries of the data base. The messages sent to and from the EBF and the log-files of the system and communication services were recorded over 5 weeks of the study. A total of 2795 messages were submitted, representing an average of 107,50 messages per patient. As demonstrated, messages decrease over time indicating an overall improvement of the care plan’s adherence. As expected, T1DM patients were more loaded with short-term advices, in accordance with their condition. Similarly, being the focus of T2DM on long-term sustainable lifestyle changes, T2DM received more reminders advices, as for diet and physical activity. Favourable outcomes were observed for treatment and usage adherences of the intervention group: for both the adherence indices, results denoted a general improvement on each care plan’s dimension, such as on nutrition and blood glucose input measurements. Further studies were conducted on the change on educational level before and after the trial, measured for both control and intervention groups. The outcomes indicated the intervention group has improved its level of knowledge, while the control group denoted a low decrease. The correlation analysis between the level of adherences and the AFMs showed an improvement in usage adherence for patients who received warnings message, while non-significantly yet even positive indicators related to both treatment and usage adherence correlated with the Reminders. Moreover, the AFMs seemed to help those patients who did not take their treatment seriously enough in the beginning and who were willing to respond to the messages they received. Even though, patients who received too many Warnings, started to consider the message dispatch to be a bit stressful. The research work carried out in developing this research work provides responses to the four research hypothesis that were the motivation for the work: •Hypothesis 1: It is possible to define a set of criteria to measure adherence in diabetic patients. •Hypothesis 2: It is possible to design a technological framework, based on the aforementioned criteria and behavioural change theories, to engage diabetic patients in managing their disease and adhere to care plans. •Hypothesis 3: It is possible to implement the technological framework in the mobile health domain. •Hypothesis 4: It is possible to use the technological framework as a mobile health solution in a real context and have positive effects in terms of diabetes management indicators. The verification of each hypothesis allowed us to provide a response to the main hypothesis: The Main Hypothesis is: It is possible to improve diabetic adherence through a mHealth technological framework based on behavioural change theories. The work carried out to answer these questions is explained in this research work. The framework was developed and applied in the METABO project. METABO is an R&D project, co-funded by the European Commission (METABO 2008) that integrates mobile infrastructure for supporting the monitoring, management, and treatment of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) patients.

Hacia un análisis cuantitativo de la Ciudad Informal: una aproximación desde la Habitabilidad Básica y la experiencia en Makeni (Sierra Leona)

La importantísima expansión urbana que sufren las principales ciudades de los países en vías de desarrollo, es el mayor reto que afronta la habitabilidad a nivel mundial. Dentro de la teoría general de la Habitabilidad Básica (HaB-ETSAM-UPM, 1995) la ordenación del territorio y el planeamiento urbanístico son las herramientas determinantes para orientar coherentemente los procesos de urbanización, como se reconoce también desde las principales esferas técnicas a nivel internacional. Pero tales herramientas deben enfocarse a una construcción eficiente del territorio, actuando desde una aproximación multidisciplinar, flexible y directa, que incida en las prioridades específicas de cada contexto. Para ello, resulta fundamental comprender a fondo las realidades específicas de estos ámbitos. La ciudad es un fenómeno complejo en esencia. El tejido construido, en constante proceso de cambio, es el caparazón visible que alberga una maravillosa mezcla entrelazada de espacios, funciones, flujos, personas.... Cada ciudad, diferente y única, se integra en su medio, se adapta a geografías, contextos y climas distintos, evoluciona según dinámicas propias, en incomprensibles (o casi) procesos evolutivos. El estudio de la ciudad, supone siempre una simplificación de la misma. La realidad urbana, por detallado que sea nuestro análisis, siempre contendrá indescifrables relaciones que se nos escapan. En cambio, necesitamos de métodos analíticos que nos ayuden a comprender algo esa complejidad. Acercarnos en ese análisis, es un paso previo fundamental para la formulación de respuestas. En este plano, de avance en la comprensión del hecho urbano, se sitúa este trabajo. Se pone el acento en el enfoque cuantitativo, profundizando en datos básicos concretos, siempre aceptando de partida que esta información es una componente mínima, pero esperamos que sustantiva, de un fenómeno inabordable. Y es esta búsqueda de comprensión material y cuantitativa de la ciudad, el objetivo esencial de la investigación. Se pretende proporcionar una base detallada de aquéllos aspectos fundamentales, que pueden ser medidos en los entornos urbanos y que nos proporcionan información útil para el diagnóstico y las propuestas. Para ello, se aportan rangos y referencias deseables, a través de una herramienta para la comprensión y la valoración de cada contexto, la Matriz de Indicadores. Esta herramienta se concibe desde la reflexión a la aplicación práctica, a la utilidad directa, al aporte concreto para quien pueda servir. Ésta es la voluntad decidida con la que se aborda este trabajo, centrado en los entornos urbanos donde el aporte técnico es prioritario: la Ciudad Informal. La Ciudad Informal, entendida aquí como aquélla que se desarrolla sin los medios suficientes (técnicos, económicos e institucionales) que proporciona la planificación, aquélla por donde la habitabilidad precaria se extiende. Es la ciudad que predomina en los países en vías de desarrollo, en los contextos de bajos recursos, allí donde, precisamente, se concentran los principales déficits y necesidades a nivel global. El enfoque nace de la teoría de la Habitabilidad Básica, de la definición de mínimos posibles para, desde allí, construir el espacio necesario para el desarrollo humano. Éste es el ámbito genérico objeto del trabajo que, a su vez, se nutre, de forma muy importante, de la experiencia directa en la ciudad de Makeni, en Sierra Leona. Esta ciudad nos sirve de prototipo experimental en un doble sentido. Por un lado, sirve como espacio empírico en el que chequear la metodología de valoración cuantitativa; y, por otro, el conocimiento de esta ciudad de tamaño medio africana, que se ha ido adquiriendo en los últimos cinco años, es una base directa para el desarrollo teórico de la propia metodología, que ayuda a atisbar lo esencial en contextos similares. El encaje de todo este recorrido se ha articulado desde una experiencia académica que, como docente, he coordinado directa e intensamente. Experiencia muy enriquecedora, que ha sumado muchas manos y mucho aprendizaje en este tiempo. Teoría y práctica en planeamiento urbano se alternan en el trabajo, nutriéndose la una de la otra y a la inversa. Trabajo que nace desde la pasión por la ciudad y el urbanismo. Desde la búsqueda por comprender y desde la vocación de actuar, de intentar mejorar y hacer más habitables los entornos urbanos. Especialmente allí donde las dificultades se agolpan y el camino se alarga, se llena de polvo. Acumular preguntas a cada paso. Cada vez más preguntas. Las respuestas, si existen, aparecen entrelazadas en dinámicas indescifrables de las que queremos formar parte. Fundirnos por momentos en la misma búsqueda, acompañarla. Sentirnos cerca de quiénes comienzan de cero casi cada día. Y otra vez, arrancar. Y compartir, desde el conocimiento, si acaso es que se puede. Y la ciudad. Brutal, imponente, asfixiante, maravillosa, imposible. Creación colectiva insuperable, de energías sumadas que se cosen sin patrón aparente. O sin más razón que la del propio pulso de la vida. Así se siente Makeni. ABSTRACT The important urban growth suffering major cities of developing countries, is the biggest challenge facing the global habitability. Within the general theory of Basic Habitability (HAB-ETSAM-UPM, 1995) spatial planning and urban planning are the crucial tools to consistently guide the urbanization process, as also recognized from the main technical areas worldwide. But such tools should focus on an efficient construction of the territory, working from a multidisciplinary, flexible and direct approach, that affects the specific priorities of each context. To do this, it is essential to thoroughly understand the specific realities of these areas. The city is essentially a complex phenomenon. The urban fabric in constant flux, is the visible shell that houses a wonderful mixture interlocking spaces, functions, flows, people.... Every city, different and unique, is integrated into its environment, adapted to geographies, contexts and climates, it evolves according to its own dynamics, along (almost) incomprehensible evolutionary processes. The study of the city, is always a simplification of it. The urban reality, even studied from a detailed analysis, always contain undecipherable relationships that escape us. Instead, we need analytical methods that help us understand something that complexity. Moving forward in this analysis is an essential first step in formulating responses. At this level, progressing in understand the urban reality, is where this work is located. The emphasis on the quantitative approach is placed, delving into specific basic data, starting always accepting that this information is just a minimal component, but we hope that substantive, of an intractable phenomenon. And it is this search for materials and quantitative understanding of the city, the main objective of the research. It is intended to provide a detailed basis of those fundamental aspects that can be measured in urban environments that provide us useful information for the diagnosis and proposals. To do this, desirable ranges and references are provided, through a tool for understanding and appreciation of each context, the Indicator Matrix. This tool is conceived from reflection to practical application, to a direct utility, concrete contribution to who can serve. This is the firm resolve with which this work is addressed, centered in urban environments where the technical contribution is a priority: the Informal City. The Informal City, understood here as the urban areas developed without the sufficient resources (technical, economic and institutional) which planning provides, where it is extended the precarious habitability. It is the city that prevails in developing countries, in low-resource settings, where, precisely, the main gaps and needs in the global context are concentrated. The approach stems from the theory of Basic Habitability, the definition of possible minimum, to build the necessary space for human development. This is the generic scope of the work object, that is also based in the direct experience in the town of Makeni, Sierra Leone. This city serves as an experimental prototype in two ways. On the one hand, it serves as a space where empirically check the quantitative assessment methodology; and, secondly, the knowledge of this African city of medium size, which has been acquired in the last five years, is a direct basis for the theoretical development of the methodology itself, which helps to glimpse the essence in similar contexts. The engagement of this whole journey has been articulated from an academic experience, directly and intensely coordinated as teacher. Enriching experience that has added many hands and much learning at this time. Theory and practice in urban planning are mixed at work, enriching the one of the other and vice versa. Work is born from the passion for the city and urbanism. From the search for understanding and from the vocation of acting, trying to improve and make more livable urban environments. Especially where the difficulties are crowded and the road is so long, full of dust. To accumulate questions at every turn. More and more questions. The answers, if do exist, appears inside indecipherable dynamics in which we want to be involved. Merge at times in the same search. Feel close to those who start from scratch almost every day. And again, move forward. And share, from knowledge, if possible. And the city. Brutal, impressive, suffocating, wonderful, impossible. Unsurpassed collective creation, combined energy mix that are sewn with no apparent pattern. Or for no reason other than the pulse of life itself. As it feels the city of Makeni.

On sonic anemometer measurement theory

In this paper a model for the measuring process of sonic anemometers (ultrasound pulse based) is presented. The differential equations that describe the travel of ultrasound pulses are solved in the general case of non-steady, non-uniform atmospheric flow field. The concepts of instantaneous line-average and travelling pulse-referenced average are established and employed to explain and calculate the differences between the measured turbulent speed (travelling pulse-referenced average) and the line-averaged one. The limit k1l=1 established by Kaimal in 1968, as the maximum value which permits the neglect of the influence of the sonic measuring process on the measurement of turbulent components is reviewed here. Three particular measurement cases are analysed: A non-steady, uniform flow speed field, a steady, non-uniform flow speed field and finally an atmospheric flow speed field. In the first case, for a harmonic time-dependent flow field, Mach number, M (flow speed to sound speed ratio) and time delay between pulses have revealed themselves to be important parameters in the behaviour of sonic anemometers, within the range of operation. The second case demonstrates how the spatial non-uniformity of the flow speed field leads to an influence of the finite transit time of the pulses (M≠0) even in the absence of non-steady behaviour of the wind speed. In the last case, a model of the influence of the sonic anemometer processes on the measurement of wind speed spectral characteristics is presented. The new solution is compared to the line-averaging models existing in the literature. Mach number and time delay significantly distort the measurement in the normal operational range. Classical line averaging solutions are recovered when Mach number and time delay between pulses go to zero in the new proposed model. The results obtained from the mathematical model have been applied to the calculation of errors in different configurations of practical interest, such as an anemometer located on a meteorological mast and the transfer function of a sensor in an atmospheric wind. The expressions obtained can be also applied to determine the quality requirements of the flow in a wind tunnel used for ultrasonic anemometer calibrations.

A INFLUÊNCIA DAS PRÁTICAS PEDAGÓGICAS DOCENTES E DAS BARREIRAS DISCENTES SOBRE O DESENVOLVIMENTO DA CRIATIVIDADE DO FUTURO ADMINISTRADOR

As empresas que almejam garantir e melhorar sua posição dentro de em um mercado cada vez mais competitivo precisam estar sempre atualizadas e em constante evolução. Na busca contínua por essa evolução, investem em projetos de Pesquisa & Desenvolvimento (P&D) e em seu capital humano para promover a criatividade e a inovação organizacional. As pessoas têm papel fundamental no desenvolvimento da inovação, mas para que isso possa florescer de forma constante é preciso comprometimento e criatividade para a geração de ideias. Criatividade é pensar o novo; inovação é fazer acontecer. Porém, encontrar pessoas com essas qualidades nem sempre é tarefa fácil e muitas vezes é preciso estimular essas habilidades e características para que se tornem efetivamente criativas. Os cursos de graduação podem ser uma importante ferramenta para trabalhar esses aspectos, características e habilidades, usando métodos e práticas de ensino que auxiliem no desenvolvimento da criatividade, pois o ambiente ensino-aprendizagem pesa significativamente na formação das pessoas. O objetivo deste estudo é de identificar quais fatores têm maior influência sobre o desenvolvimento da criatividade em um curso de graduação em administração, analisando a influência das práticas pedagógicas dos docentes e as barreiras internas dos discentes. O referencial teórico se baseia principalmente nos trabalhos de Alencar, Fleith, Torrance e Wechsler. A pesquisa transversal de abordagem quantitativa teve como público-alvo os alunos do curso de Administração de uma universidade confessional da Grande São Paulo, que responderam 465 questionários compostos de três escalas. Para as práticas docentes foi adaptada a escala de Práticas Docentes em relação à Criatividade. Para as barreiras internas foi adaptada a escala de Barreiras da Criatividade Pessoal. Para a análise da percepção do desenvolvimento da criatividade foi construída e validada uma escala baseada no referencial de características de uma pessoa criativa. As análises estatísticas descritivas e fatoriais exploratórias foram realizadas no software Statistical Package for the Social Sciences (SPSS), enquanto as análises fatoriais confirmatórias e a mensuração da influência das práticas pedagógicas e das barreiras internas sobre a percepção do desenvolvimento da criatividade foram realizadas por modelagem de equação estrutural utilizando o algoritmo Partial Least Squares (PLS), no software Smart PLS 2.0. Os resultados apontaram que as práticas pedagógicas e as barreiras internas dos discentes explicam 40% da percepção de desenvolvimento da criatividade, sendo as práticas pedagógicas que exercem maior influencia. A pesquisa também apontou que o tipo de temática e o período em que o aluno está cursando não têm influência sobre nenhum dos três construtos, somente o professor influencia as práticas pedagógicas.

ANALISANDO A RELAÇÃO DOS VOLUMES DE EXPORTAÇÃO E DE IMPORTAÇÃO, PIB, TAXAS DE CÂMBIO E INFLAÇÃO NO PERÍODO DE 2004 A 2014.

Esta dissertação visa deslumbrar uma análise macroeconômica do Brasil, especialmente no que se refere à relação dos índices mensais dos volumes das exportações e das importações com os volumes mensais do PIB, da Taxa SELIC e as Taxas de Câmbio, conforme dados coletados no período de janeiro de 2004 a dezembro de 2014, através de pesquisa literária referente aos históricos sobre cada conceito envolvido no âmbito da macroeconomia das varáveis estudadas. Foi realizado um estudo de caso embasado em dados de sites governamentais, no período delimitado, empregando-se o método de regressão linear, com base na Teoria da correlação de Pearson, demonstrando os resultados obtidos no período do estudo para as varáveis estudadas. Desta maneira, conseguiu-se estudar e analisar como as variáveis dependentes (resposta): volume das exportações e volume das importações estão relacionadas com as varáveis independentes (explicativas): PIB, Taxa Selic e taxa de Câmbio. Os resultados apurados no presente estudo permitem identificar que existe correlação moderada e negativa, quando analisadas a Taxa Selic e a Taxa de Câmbio com os volumes das exportações e das importações, enquanto o PIB apresenta correlação forte e positiva na análise com os volumes das exportações e das importações

Activating mutations in the extracellular domain of the fibroblast growth factor receptor 2 function by disruption of the disulfide bond in the third immunoglobulin-like domain

Multiple human skeletal and craniosynostosis disorders, including Crouzon, Pfeiffer, Jackson–Weiss, and Apert syndromes, result from numerous point mutations in the extracellular region of fibroblast growth factor receptor 2 (FGFR2). Many of these mutations create a free cysteine residue that potentially leads to abnormal disulfide bond formation and receptor activation; however, for noncysteine mutations, the mechanism of receptor activation remains unclear. We examined the effect of two of these mutations, W290G and T341P, on receptor dimerization and activation. These mutations resulted in cellular transformation when expressed as FGFR2/Neu chimeric receptors. Additionally, in full-length FGFR2, the mutations induced receptor dimerization and elevated levels of tyrosine kinase activity. Interestingly, transformation by the chimeric receptors, dimerization, and enhanced kinase activity were all abolished if either the W290G or the T341P mutation was expressed in conjunction with mutations that eliminate the disulfide bond in the third immunoglobulin-like domain (Ig-3). These results demonstrate a requirement for the Ig-3 cysteine residues in the activation of FGFR2 by noncysteine mutations. Molecular modeling also reveals that noncysteine mutations may activate FGFR2 by altering the conformation of the Ig-3 domain near the disulfide bond, preventing the formation of an intramolecular bond. This allows the unbonded cysteine residues to participate in intermolecular disulfide bonding, resulting in constitutive activation of the receptor.

An antagonistic vascular endothelial growth factor (VEGF) variant inhibits VEGF-stimulated receptor autophosphorylation and proliferation of human endothelial cells

Vascular endothelial growth factor (VEGF) is a potent mitogen with a unique specificity for endothelial cells and a key mediator of aberrant endothelial cell proliferation and vascular permeability in a variety of human pathological situations, such as tumor angiogenesis, diabetic retinopathy, rheumatoid arthritis, or psoriasis. VEGF is a symmetric homodimeric molecule with two receptor binding interfaces lying on each pole of the molecule. Herein we report on the construction and recombinant expression of an asymmetric heterodimeric VEGF variant with an intact receptor binding interface at one pole and a mutant receptor binding interface at the second pole of the dimer. This VEGF variant binds to VEGF receptors but fails to induce receptor activation. In competition experiments, the heterodimeric VEGF variant antagonizes VEGF-stimulated receptor autophosphorylation and proliferation of endothelial cells. A 15-fold excess of the heterodimer was sufficient to inhibit VEGF-stimulated endothelial cell proliferation by 50%, and a 100-fold excess resulted in an almost complete inhibition. By using a rational approach that is based on the structure of VEGF, we have shown the feasibility to construct a VEGF variant that acts as an VEGF antagonist.

Solution of the pulse width modulation problem using orthogonal polynomials and Korteweg-de Vries equations

The mathematical underpinning of the pulse width modulation (PWM) technique lies in the attempt to represent “accurately” harmonic waveforms using only square forms of a fixed height. The accuracy can be measured using many norms, but the quality of the approximation of the analog signal (a harmonic form) by a digital one (simple pulses of a fixed high voltage level) requires the elimination of high order harmonics in the error term. The most important practical problem is in “accurate” reproduction of sine-wave using the same number of pulses as the number of high harmonics eliminated. We describe in this paper a complete solution of the PWM problem using Padé approximations, orthogonal polynomials, and solitons. The main result of the paper is the characterization of discrete pulses answering the general PWM problem in terms of the manifold of all rational solutions to Korteweg-de Vries equations.

Subtraction hybridization identifies a transformation progression-associated gene PEG-3 with sequence homology to a growth arrest and DNA damage-inducible gene

Cancer is a progressive multigenic disorder characterized by defined changes in the transformed phenotype that culminates in metastatic disease. Determining the molecular basis of progression should lead to new opportunities for improved diagnostic and therapeutic modalities. Through the use of subtraction hybridization, a gene associated with transformation progression in virus- and oncogene-transformed rat embryo cells, progression elevated gene-3 (PEG-3), has been cloned. PEG-3 shares significant nucleotide and amino acid sequence homology with the hamster growth arrest and DNA damage-inducible gene gadd34 and a homologous murine gene, MyD116, that is induced during induction of terminal differentiation by interleukin-6 in murine myeloid leukemia cells. PEG-3 expression is elevated in rodent cells displaying a progressed-transformed phenotype and in rodent cells transformed by various oncogenes, including Ha-ras, v-src, mutant type 5 adenovirus (Ad5), and human papilloma virus type 18. The PEG-3 gene is transcriptionally activated in rodent cells, as is gadd34 and MyD116, after treatment with DNA damaging agents, including methyl methanesulfonate and γ-irradiation. In contrast, only PEG-3 is transcriptionally active in rodent cells displaying a progressed phenotype. Although transfection of PEG-3 into normal and Ad5-transformed cells only marginally suppresses colony formation, stable overexpression of PEG-3 in Ad5-transformed rat embryo cells elicits the progression phenotype. These results indicate that PEG-3 is a new member of the gadd and MyD gene family with similar yet distinct properties and this gene may directly contribute to the transformation progression phenotype. Moreover, these studies support the hypothesis that constitutive expression of a DNA damage response may mediate cancer progression.

Synergistic inhibition of tumor growth in a murine mammary adenocarcinoma model by combinational gene therapy using IL-12, pro-IL-18, and IL-1β converting enzyme cDNA

We report here that a cancer gene therapy protocol using a combination of IL-12, pro-IL-18, and IL-1β converting enzyme (ICE) cDNA expression vectors simultaneously delivered via gene gun can significantly augment antitumor effects, evidently by generating increased levels of bioactive IL-18 and consequently IFN-γ. First, we compared the levels of IFN-γ secreted by mouse splenocytes stimulated with tumor cells transfected with various test genes, including IL-12 alone; pro-IL-18 alone; pro-IL-18 and ICE; IL-12 and pro-IL-18; and IL-12, pro-IL-18, and ICE. Among these treatments, the combination of IL-12, pro-IL-18, and ICE cDNA resulted in the highest level of IFN-γ production from splenocytes in vitro, and similar results were obtained when these same treatments were delivered to the skin of a mouse by gene gun and IFN-γ levels were measured at the skin transfection site in vivo. Furthermore, the triple gene combinatorial gene therapy protocol was the most effective among all tested groups at suppressing the growth of TS/A (murine mammary adenocarcinoma) tumors previously implanted intradermally at the skin site receiving DNA transfer by gene gun on days 6, 8, 10, and 12 after tumor implantation. Fifty percent of mice treated with the combined three-gene protocol underwent complete tumor regression. In vivo depletion experiments showed that this antitumor effect was CD8+ T cell-mediated and partially IFN-γ-dependent. These results suggest that a combinatorial gene therapy protocol using a mixture of IL-12, pro-IL-18, and ICE cDNAs can confer potent antitumor activities against established TS/A tumors via cytotoxic CD8+ T cells and IFN-γ-dependent pathways.

Oryza sativa PSK gene encodes a precursor of phytosulfokine-α, a sulfated peptide growth factor found in plants

Phytosulfokine-α [PSK-α, Tyr(SO3H)-Ile-Tyr(SO3H)-Thr-Gln], a sulfated mitogenic peptide found in plants, strongly promotes proliferation of plant cells in culture at very low concentrations. Oryza sativa PSK (OsPSK) cDNA encoding a PSK-α precursor has been isolated. The cDNA is 725 base pairs long, and the 89-aa product, preprophytosulfokine, has a 22-aa hydrophobic region that resembles a cleavable leader peptide at its NH2 terminus. The PSK-α sequence occurs only once within the precursor, close to the COOH terminus. [Ser4]PSK-α was secreted by transgenic rice Oc cells harboring a mutated OsPSK cDNA, suggesting proteolytic processing from the larger precursor, a feature commonly found in animal systems. Whereas PSK-α in conditioned medium with sense transgenic Oc cells was 1.6 times as concentrated as in the control case, antisense transgenic Oc cells produced less than 60% of the control level. Preprophytosulfokine mRNA was detected at an elevated constitutive level in rice Oc culture cells on RNA blot analysis. Although PSK-α molecules have never been identified in any intact plant, reverse transcription–PCR analysis demonstrated that OsPSK is expressed in rice seedlings, indicating that PSK-α may be important for plant cell proliferation both in vitro and in vivo. DNA blot analysis demonstrated that OsPSK homologs may occur in dicot as well as monocot plants.

Novel Ras antagonist blocks human melanoma growth

During past decades, knowledge of melanoma biology has increased considerably. Numerous therapeutic modalities based on this knowledge are currently under investigation. Advanced melanoma, nevertheless, remains a prime example of poor treatment response that may, in part, be the consequence of activated N-Ras oncoproteins. Besides oncogenic Ras, wild-type Ras gene products also play a key role in receptor tyrosine kinase growth factor signaling, known to be of importance in oncogenesis and tumor progression of a variety of human neoplasms, including malignant melanoma; therefore, it is reasonable to speculate that a pharmacological approach that curtails Ras activity may represent a sensible approach to inhibit melanoma growth. To test this concept, the antitumor activity of S-trans, trans-farnesylthiosalicylic acid (FTS), a recently discovered Ras antagonist that dislodges Ras from its membrane-anchoring sites, was evaluated. The antitumor activity of FTS was assessed both in vitro and in vivo in two independent SCID mouse xenotransplantation models of human melanoma expressing either wild-type Ras (cell line 518A2) or activated Ras (cell line 607B). We show that FTS (5–50 μM) reduces the amounts of activated N-Ras and wild-type Ras isoforms both in human melanoma cells and Rat-1 fibroblasts, interrupts the Ras-dependent extracellular signal-regulated kinase in melanoma cells, inhibits the growth of N-Ras-transformed fibroblasts and human melanoma cells in vitro and reverses their transformed phenotype. FTS also causes a profound and statistically significant inhibition of 518A2 (82%) and 607B (90%) human melanoma growth in SCID mice without evidence of drug-related toxicity. Our findings stress the notion that FTS may qualify as a novel and rational treatment approach for human melanoma and possibly other tumors that either carry activated ras genes or rely on Ras signal transduction more heavily than nonmalignant cells.