Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial.

BACKGROUND Patients with isolated locoregional recurrences (ILRR) of breast cancer have a high risk of distant metastasis and death from breast cancer. We aimed to establish whether adjuvant chemotherapy improves the outcome of such patients. METHODS The CALOR trial was a pragmatic, open-label, randomised trial that accrued patients with histologically proven and completely excised ILRR after unilateral breast cancer who had undergone a mastectomy or lumpectomy with clear surgical margins. Eligible patients were enrolled from hospitals worldwide and were centrally randomised (1:1) to chemotherapy (type selected by the investigator; multidrug for at least four courses recommended) or no chemotherapy, using permuted blocks, and stratified by previous chemotherapy, oestrogen-receptor and progesterone-receptor status, and location of ILRR. Patients with oestrogen-receptor-positive ILRR received adjuvant endocrine therapy, radiation therapy was mandated for patients with microscopically involved surgical margins, and anti-HER2 therapy was optional. The primary endpoint was disease-free survival. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00074152. FINDINGS From Aug 22, 2003, to Jan 31, 2010, 85 patients were randomly assigned to receive chemotherapy and 77 were assigned to no chemotherapy. At a median follow-up of 4·9 years (IQR 3·6-6 ·0), 24 (28%) patients had disease-free survival events in the chemotherapy group compared with 34 (44%) in the no chemotherapy group. 5-year disease-free survival was 69% (95% CI 56-79) with chemotherapy versus 57% (44-67) without chemotherapy (hazard ratio 0·59 [95% CI 0·35-0·99]; p=0·046). Adjuvant chemotherapy was significantly more effective for women with oestrogen-receptor-negative ILRR (pinteraction=0·046), but analyses of disease-free survival according to the oestrogen-receptor status of the primary tumour were not statistically significant (pinteraction=0·43). Of the 81 patients who received chemotherapy, 12 (15%) had serious adverse events. The most common adverse events were neutropenia, febrile neutropenia, and intestinal infection. INTERPRETATION Adjuvant chemotherapy should be recommended for patients with completely resected ILRR of breast cancer, especially if the recurrence is oestrogen-receptor negative. FUNDING US Department of Health and Human Services, Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, Australian and New Zealand Breast Cancer Trials Group, Swedish Cancer Society, Oncosuisse, Cancer Association of South Africa, Foundation for Clinical Research of Eastern Switzerland (OSKK), Grupo Español de Investigación en Cáncer de Mama (GEICAM), and the Dutch Breast Cancer Trialists' Group (BOOG).

Childhood cancer survivor cohorts in Europe.

With the advent of multimodality therapy, the overall five-year survival rate from childhood cancer has improved considerably now exceeding 80% in developed European countries. This growing cohort of survivors, with many years of life ahead of them, has raised the necessity for knowledge concerning the risks of adverse long-term sequelae of the life-saving treatments in order to provide optimal screening and care and to identify and provide adequate interventions. Childhood cancer survivor cohorts in Europe. Considerable advantages exist to study late effects in individuals treated for childhood cancer in a European context, including the complementary advantages of large population-based cancer registries and the unrivalled opportunities to study lifetime risks, together with rich and detailed hospital-based cohorts which fill many of the gaps left by the large-scale population-based studies, such as sparse treatment information. Several large national cohorts have been established within Europe to study late effects in individuals treated for childhood cancer including the Nordic Adult Life after Childhood Cancer in Scandinavia study (ALiCCS), the British Childhood Cancer Survivor Study (BCCSS), the Dutch Childhood Oncology Group (DCOG) LATER study, and the Swiss Childhood Cancer Survivor Study (SCCSS). Furthermore, there are other large cohorts, which may eventually become national in scope including the French Childhood Cancer Survivor Study (FCCSS), the French Childhood Cancer Survivor Study for Leukaemia (LEA), and the Italian Study on off-therapy Childhood Cancer Survivors (OTR). In recent years significant steps have been taken to extend these national studies into a larger pan-European context through the establishment of two large consortia - PanCareSurFup and PanCareLIFE. The purpose of this paper is to present an overview of the current large, national and pan-European studies of late effects after childhood cancer. This overview will highlight the strong cooperation across Europe, in particular the EU-funded collaborative research projects PanCareSurFup and PanCareLIFE. Overall goal. The overall goal of these large cohort studies is to provide every European childhood cancer survivor with better care and better long-term health so that they reach their full potential, and to the degree possible, enjoy the same quality of life and opportunities as their peers.

Prevalence and management of familial hypercholesterolaemia in patients with acute coronary syndromes.

AIMS We aimed to assess the prevalence and management of clinical familial hypercholesterolaemia (FH) among patients with acute coronary syndrome (ACS). METHODS AND RESULTS We studied 4778 patients with ACS from a multi-centre cohort study in Switzerland. Based on personal and familial history of premature cardiovascular disease and LDL-cholesterol levels, two validated algorithms for diagnosis of clinical FH were used: the Dutch Lipid Clinic Network algorithm to assess possible (score 3-5 points) or probable/definite FH (>5 points), and the Simon Broome Register algorithm to assess possible FH. At the time of hospitalization for ACS, 1.6% had probable/definite FH [95% confidence interval (CI) 1.3-2.0%, n = 78] and 17.8% possible FH (95% CI 16.8-18.9%, n = 852), respectively, according to the Dutch Lipid Clinic algorithm. The Simon Broome algorithm identified 5.4% (95% CI 4.8-6.1%, n = 259) patients with possible FH. Among 1451 young patients with premature ACS, the Dutch Lipid Clinic algorithm identified 70 (4.8%, 95% CI 3.8-6.1%) patients with probable/definite FH, and 684 (47.1%, 95% CI 44.6-49.7%) patients had possible FH. Excluding patients with secondary causes of dyslipidaemia such as alcohol consumption, acute renal failure, or hyperglycaemia did not change prevalence. One year after ACS, among 69 survivors with probable/definite FH and available follow-up information, 64.7% were using high-dose statins, 69.0% had decreased LDL-cholesterol from at least 50, and 4.6% had LDL-cholesterol ≤1.8 mmol/L. CONCLUSION A phenotypic diagnosis of possible FH is common in patients hospitalized with ACS, particularly among those with premature ACS. Optimizing long-term lipid treatment of patients with FH after ACS is required.

Transregional Interactions between Jansenists, other Catholics, and Protestants in Seventeenth Century Northern Europe

This paper discusses the theological and cultural exchanges between Catholic clergy and theologians, and specifically between the neo-Augustinian-minded, the so-called “Jansenists”, and other Catholics, in Northern Europe during the seventeenth century. It also explores the Jansenists’ encounters and theological engagement with Protestantism. In this period, interaction and transfer between French Jansenist Catholics and other Catholics in other countries took place in various ways: 1. Via traveling and migration: French theologians and clergy returned home from their travels with reports about the situation of Catholicism and Protestantism in other countries; moreover, in the second half of the 17th century, French Jansenists fled to the northern Netherlands. 2. Via networking: it is little known that for a brief period on the North Sea island of Nordstrand, adherents to Port-Royal were buying land, and clergy of the Flemish Oratory provided pastoral care for the island’s Catholics. This project was not successful, but at the end it strengthened the network between French “Jansenists” and Catholics in the Dutch Republic. 3. Via publications by leading Jansenists and their counterparts. In this paper, the focus is on the view of Protestantism held by Jansenist writers.

Pollen and macroremains from four profiles from site Samerberg 1

Pollen and macrofossil analysis of lake sediments revealed the complete development of vegetation from Riss late-glacial to early Würm glacial times at Samerberg (12°12' E, 47°45' N, 600 m a.s.l) on the northern border of the Alps. The pollen bearing sediments overlie three stratigraphic units, at the base a ground-moraine, then a 13 m thick layer of pollen free silt and clay, and then a younger moraine; all the sediments including the pollen bearing sediments, lie below the Würm moraine. The lake, which had developed in an older glacial basin, became extinct, when the ice of the river Inn glacier filled its basin during Würm full-glacial time at the latest. One interglacial, three interstadials, and the interdigitating treeless periods were identified at Samerberg. Whereas the cold periods cannot be distinguished from one another pollenanalytically, the interglacial and the two older interstadials have distinctive characteristics. A shrub phase with Juniperus initiated reforestation and was followed by a pine phase during the interglacial and each of the three interstadials. The further development of the interglacial vegetation proceeded with a phase when deciduous trees (mainly Quercus, oak) and hazel (Corylus) dominated, though spruce (Picea) was present at the same time in the area. A phase with abundant yew (Taxus) led to an apparently long lasting period with dominant spruce and fir (Abies) accompanied by some hornbeam (Carpinus). The vegetational development shows the main characteristics of the Riss/Würm interglacial, though certain differences in the vegetational development in the northern alpine foreland are obvious. These differences may result from the existence of an altitudinal zonation of the vegetation in the vicinity of the site and are the expression of its position at the border of the Alps. A greater age (e.g. the Holsteinian) can be excluded by reason of the vegetational development, and is also not indicated at first sight from the geological and stratigraphical data of the site. Characteristic of the Riss/Würm vegetational development in southern Germany - at least in the region between Lake Starnberg/Samerberg/Salzach - is the conspicuous yew phase. According to absolute pollen counts, yew not only displaced the deciduous species, but also displaced spruce preferentially, thus indicating climatic conditions less favourable for spruce, caused by mild winters (Ilex spreading!) and by short-term low precipitation, indicated by the reduced sedimentation rate. The oldest interstadials is bipartite, as due to the climatic deterioration the early vegetational development, culminating in a spruce phase, had been interrupted by another expansion of pine. A younger spruce-dominated period with fir and perhaps also with hornbeam and beech (Fagus) followed. An identical climatic development has been reported from other European sites with long pollen sequences (see chapter 6.7). However, different tree species are found in the same time intervals in Middle Europe during Early Würm times. Sediments of the last interglacial (Eem or Riss/Würm) have been found in all cases below the sediments of the bipartite interstadial, and in addition one more interstadial occurs in the overlying sediments. This proves that Eem and Riss/Würm of the north-european plain resp. of the alpine foreland are contemporaneous interglacials although this has been questioned by some authors. The climax vegetation of the second interstadial was a spruce forest without fir and without more demanding deciduous tree species. The vegetational development of the third interstadial is recorded fragmentary only. But it has been established that a spruce forest was present. The oldest interstadial must correspond to the danish Brørup interstadial as it is expressed in northern Germany, the second one to the Odderade interstadial. A third Early Würm interstadial, preserved fragmentarily at Samerberg, is known from other sites. The dutch Amersfoort interstadial most likely is the equivalent to the older part of the bipartite danish Brørup interstadial.

Skilled emigration and exchange rate : theory and empirics

In this paper we build a theoretical model on the wage effect of skilled emigration to the fluctuations in real exchange rate through the relative prices of nontradables. Our theoretical model predicts that skilled emigration is associated with an increase in the prices of nontradable, which in turn appreciates the exchange rate. We provide robust empirical support to a higher skilled emigration associated with higher prices in nontradables and appreciation of the real effective exchange rate. Based on two samples of countries with 51 and 67 observations, in 1990 and 2000 respectively, we find robust empirical support to a higher skilled emigration associated with higher prices in nontradables and appreciation of the REER. In addition, the support for the remittance-channel of the Dutch disease is also significant; overall, our findings corroborate the remittance-based Dutch disease phenomenon by providing an additional channel through which the labor mobility across borders affects the real exchange rate volatility.

La forma del agua. Temas e invariantes en el jardín y el paisaje. Análisis de casos (Holanda-España, 1548-1648)

El espacio geográfico, entendido como territorio que da soporte a la vida y a la civilización, ha estado siempre fuertemente supeditado a la presencia de agua. Desde la Prehistoria el hombre otorgó al agua, junto a otros elementos que aseguraban o protegían su vida, un valor superior, por encima de lo humano. Paralelamente y de manera natural, el jardín, en sus inicios en estrecha relación con la agricultura y con el paisaje, fue el ámbito idóneo para la creación de nuevas formas acuáticas artificiales. Este proceso dio lugar a un extenso repertorio de formas compositivas que parece que tuvo en el Renacimiento un punto de inflexión, en el que se observa como la mayoría de recursos y configuraciones básicas del agua estaban ya plenamente establecidas. Esta evolución y sus resultados ha sido el objeto de la primera parte de la tesis: su objetivo ha sido analizar cómo el agua configura, cualifica o puede llegar a construir el jardín y el territorio en el que se inserta, así como establecer las posibles relaciones entre estos dos ámbitos de estudio. Aunque la historia es su fundamento, el planteamiento aquí ha sido más bien conceptual; estudiando los componentes acuáticos desde un punto de vista fundamentalmente compositivo. Esta indagación previa ha sido indispensable para llegar a entender en profundidad los modos en los que el agua se muestra en el jardín y en el paisaje renacentista y manierista, momentos en que se insertan los dos casos de estudio que constituyen la segunda parte de la tesis. Sin caer en un determinismo geográfico extremo, puede admitirse que el jardín, como manifestación cultural intrínsecamente ligada al entorno, depende fuertemente del territorio en el que se asienta; hecho particularmente evidente en aquellas regiones en las que su especial geografía ha sido un claro factor condicionante de su historia. Por ello, Holanda y España han sido las dos localizaciones elegidas para profundizar en este estudio; no tanto por su estrecha relación política y cultural, sino por su profundo y sugerente contraste de medio físico y climático. La Península Ibérica, geográficamente el término del mundo conocido en Occidente hasta el final de la Edad Media, y por esta circunstancia convertida en destino, en territorio de permanencia y fusión, estará además supeditada en la mayoría de su territorio a la falta de agua, siendo a la vez heredera directa del universo y la tradición del jardín meridional originario de Oriente. En el extremo opuesto, Holanda, espacio de transición entre el mar y la tierra firme “real”, es un territorio permeado de humedad y surcado con generosidad por grandes ríos. El país, con una relación ambivalente con el agua, unas veces como amenaza y otras como fuente de nuevas oportunidades, será por el contrario especialmente favorable para el desarrollo de un modelo de jardín septentrional. Un jardín del norte, que no obstante, no surgirá de despejar los bosques, como en el arquetipo nórdico, sino que crecerá sobre planicies antes saturadas de agua o directamente anegadas. El marco temporal de los dos casos concretos ha considerado como fecha inicial 1548, momento en el que Felipe II, aún príncipe, realizó su primer viaje a los Países Bajos, y entró en contacto con el modelo holandés. La extensa producción posterior de jardines de Felipe II, siempre con el agua como protagonista, tuvo como destacado referente la adaptación al suelo y la geografía hispánicos de dicho modelo. Como fecha final se fija 1648, justo un siglo después, fecha coincidente con la firma de la Paz de Westfalia, tratado que supone la total reorganización política del territorio europeo y la pérdida de la hegemonía española en Europa. En Holanda sólo dos años después nacerá Guillermo III de Orange, estatúder de las Provincias Unidas, también futuro rey de Inglaterra, Escocia e Irlanda. Para entonces en Holanda ya se había asistido al desarrollo de un arte propio de jardín, íntimamente ligado al agua, sorprendentemente no demasiado bien conocido y que será uno de los temas de esta investigación. Finalmente, se propone una lectura conjunta de toda esta serie de intervenciones que tienen como argumento el agua, en la que se integra la información procedente de distintos campos de estudio, cada una con su metodología particular. El resultado es una tesis en la que el jardín y el territorio son tratados desde un nuevo y enriquecedor punto de vista. ABSTRACT Geographical space, understood as the territory that provides support to human life and civilization, has always been strongly subjected to the presence of water. From Prehistory man gave to water, along with other elements that ensured or protected life, a higher value than the merely human. At the same time and in a natural way, the garden, in its beginnings with a close relationship with agriculture and landscape, soon developed as the appropriate ground for the creation of new artificial aquatic forms, in a process that seems to have a turning point in the Renaissance, when most of the basic waterworks and resources were already fully established. This development and its outcomes are the subjects of the first part of the thesis: its scope has been to analyse how water configures, qualifies and might even help to construct the garden or landscape attached to it; and to establish the possible links between these two fields of study. Although history based, the point of view here is mainly conceptual, studying the water components understood as composite elements. This exploratory research has been essential to deeply understand the water patterns shown in the Renaissance and Mannerist garden and landscape, periods in which the two case studies are inserted. Without falling in extreme determinism, it can be accepted however, that garden, as a cultural expression linked to environment, is strongly dependant on territorial setting; something particularly evident in those areas where specific geography has been a clear history conditioning factor. This is the reason that leads to choose the Netherlands and Spain to deepen this study, no so much for their interesting cultural and politics relations as for the suggestive and profound contrast of their physical environment and climate. The Iberian Peninsula, geographically the limit of the known world in Occident until the end of the Medium Age, and by this circumstance understood as endpoint, more a destination than a crossroad, a territory of permanence and fusion, but also subjected to water shortage; is thus associated with the universe and tradition of the meridional garden imported from Orient. In the opposite, the Netherlands, a transitional space between the sea and the “real” firm land, is a territory permeated by water and crossed by big rivers. Always with an ambivalent relationship with water, sometimes seen as a threat and sometimes as a source of new opportunities, it was in the other hand the adequate land for the development of a special model of Northern garden. A garden that will not arise, however, from the clearing of woods as in the Nordic archetype, but that will grow on plains originally saturated of water or directly waterlogged. The timeframe of the two cases has 1548 as the initial year, moment in which Philip II, yet prince, made his first trip to the Low Lands and imbibed the Dutch garden model. The later and bountiful garden works of the king, always with the water as the main focus, adapted the imported model to the Spanish ground and geography. The final date is fixed in 1648, just a century after, in coincidence with the Westfalia Peace; a treaty that implied the total political reorganization of the European territory and the end of the Spanish hegemony in the continent. In Holland, only two years later, William III of Orange, Stadtholder of the United Provinces and also future king of England, Scotland and Ireland, was born. But by then the Netherlands had developed an own garden art, closely linked to water. This type garden, surprisingly not very well known, and its relationship with water, will be other of the addressing questions of this work. Finally, the investigation merges the different interventions that have water as an argument, integrating all the fields considered with their particular methodological approaches. The final result is a thesis in which garden and territory are treated from a new and enriching perspective.

An ICT-based closed-loop model to improve care for heart failure patients

Durante las últimas décadas se ha producido un fenómeno global de envejecimiento en la población. Esta tendencia se puede observar prácticamente en todos los países del mundo y se debe principalmente a los avances en la medicina, y a los descensos en las tasas de fertilidad y mortalidad. El envejecimiento de la población tiene un gran impacto en la salud de los ciudadanos, y a menudo es la causa de aparición de enfermedades crónicas. Este tipo de enfermedades supone una amenaza y una carga importantes para la sociedad, especialmente en aspectos como la mortalidad o los gastos en los sistemas sanitarios. Entre las enfermedades cardiovasculares, la insuficiencia cardíaca es probablemente la condición con mayor prevalencia y afecta a 23-26 millones de personas en todo el mundo. Normalmente, la insuficiencia cardíaca presenta un mal pronóstico y una tasa de supervivencia bajas, en algunos casos peores que algún tipo de cáncer. Además, suele ser la causa de hospitalizaciones frecuentes y es una de las enfermedades más costosas para los sistemas sanitarios. La tendencia al envejecimiento de la población y la creciente incidencia de las enfermedades crónicas están llevando a una situación en la que los sistemas de salud no son capaces de hacer frente a la demanda de la sociedad. Los servicios de salud existentes tendrán que adaptarse para ser efectivos y sostenibles en el futuro. Es necesario identificar nuevos paradigmas de cuidado de pacientes, así como mecanismos para la provisión de servicios que ayuden a transformar estos sistemas sanitarios. En este contexto, esta tesis se plantea la búsqueda de soluciones, basadas en las Tecnologías de la Información y la Comunicación (TIC), que contribuyan a realizar la transformación en los sistemas sanitarios. En concreto, la tesis se centra en abordar los problemas de una de las enfermedades con mayor impacto en estos sistemas: la insuficiencia cardíaca. Las siguientes hipótesis constituyen la base para la realización de este trabajo de investigación: 1. Es posible definir un modelo basado en el paradigma de lazo cerrado y herramientas TIC que formalice el diseño de mejores servicios para pacientes con insuficiencia cardíaca. 2. El modelo de lazo cerrado definido se puede utilizar para definir un servicio real que ayude a gestionar la insuficiencia cardíaca crónica. 3. La introducción, la adopción y el uso de un servicio basado en el modelo definido se traducirá en mejoras en el estado de salud de los pacientes que sufren insuficiencia cardíaca. a. La utilización de un sistema basado en el modelo de lazo cerrado definido mejorará la experiencia del usuario de los pacientes. La definición del modelo planteado se ha basado en el estándar ISO / EN 13940- Sistema de conceptos para dar soporte a la continuidad de la asistencia. Comprende un conjunto de conceptos, procesos, flujos de trabajo, y servicios como componentes principales, y representa una formalización de los servicios para los pacientes con insuficiencia cardíaca. Para evaluar el modelo definido se ha definido un servicio real basado en el mismo, además de la implementación de un sistema de apoyo a dicho servicio. El diseño e implementación de dicho sistema se realizó siguiendo la metodología de Diseño Orientado a Objetivos. El objetivo de la evaluación consistía en investigar el efecto que tiene un servicio basado en el modelo de lazo cerrado sobre el estado de salud de los pacientes con insuficiencia cardíaca. La evaluación se realizó en el marco de un estudio clínico observacional. El análisis de los resultados ha comprendido métodos de análisis cuantitativos y cualitativos. El análisis cuantitativo se ha centrado en determinar el estado de salud de los pacientes en base a datos objetivos (obtenidos en pruebas de laboratorio o exámenes médicos). Para realizar este análisis se definieron dos índices específicos: el índice de estabilidad y el índice de la evolución del estado de salud. El análisis cualitativo ha evaluado la autopercepción del estado de salud de los pacientes en términos de calidad de vida, auto-cuidado, el conocimiento, la ansiedad y la depresión, así como niveles de conocimiento. Se ha basado en los datos recogidos mediante varios cuestionarios o instrumentos estándar (i.e. EQ-5D, la Escala de Ansiedad y Depresión (HADS), el Cuestionario de Cardiomiopatía de Kansas City (KCCQ), la Escala Holandesa de Conocimiento de Insuficiencia Cardíaca (DHFKS), y la Escala Europea de Autocuidado en Insuficiencia Cardíaca (EHFScBS), así como cuestionarios dedicados no estandarizados de experiencia de usuario. Los resultados obtenidos en ambos análisis, cuantitativo y cualitativo, se compararon con el fin de evaluar la correlación entre el estado de salud objetivo y subjetivo de los pacientes. Los resultados de la validación demostraron que el modelo propuesto tiene efectos positivos en el cuidado de los pacientes con insuficiencia cardíaca y contribuye a mejorar su estado de salud. Asimismo, ratificaron al modelo como instrumento válido para la definición de servicios mejorados para la gestión de esta enfermedad. ABSTRACT During the last decades we have witnessed a global aging phenomenon in the population. This can be observed in practically every country in the world, and it is mainly caused by the advances in medicine, and the decrease of mortality and fertility rates. Population aging has an important impact on citizens’ health and it is often the cause for chronic diseases, which constitute global burden and threat to the society in terms of mortality and healthcare expenditure. Among chronic diseases, Chronic Heart Failure (CHF) or Heart Failure (HF) is probably the one with highest prevalence, affecting between 23 and 26 million people worldwide. Heart failure is a chronic, long-term and serious condition with very poor prognosis and worse survival rates than some type of cancers. Additionally, it is often the cause of frequent hospitalizations and one of the most expensive conditions for the healthcare systems. The aging trends in the population and the increasing incidence of chronic diseases are leading to a situation where healthcare systems are not able to cope with the society demand. Current healthcare services will have to be adapted and redefined in order to be effective and sustainable in the future. There is a need to find new paradigms for patients’ care, and to identify new mechanisms for services’ provision that help to transform the healthcare systems. In this context, this thesis aims to explore new solutions, based on ICT, that contribute to achieve the needed transformation within the healthcare systems. In particular, it focuses on addressing the problems of one of the diseases with higher impact within these systems: Heart Failure. The following hypotheses represent the basis to the elaboration of this research: 1. It is possible to define a model based on a closed-loop paradigm and ICT tools that formalises the design of enhanced healthcare services for chronic heart failure patients. 2. The described closed-loop model can be exemplified in a real service that supports the management of chronic heart failure disease. 3. The introduction, adoption and use of a service based on the outlined model will result in improvements in the health status of patients suffering heart failure. 4. The user experience of patients when utilizing a system based on the defined closed-loop model will be enhanced. The definition of the closed-loop model for health care support of heart failure patients have been based on the standard ISO/EN 13940 System of concepts to support continuity of care. It includes a set of concept, processes and workflows, and services as main components, and it represent a formalization of services for heart failure patients. In order to be validated, the proposed closed-loop model has been instantiated into a real service and a supporting IT system. The design and implementation of the system followed the user centred design methodology Goal Oriented Design. The validation, that included an observational clinical study, aimed to investigate the effect that a service based on the closed-loop model had on heart failure patients’ health status. The analysis of results comprised quantitative and qualitative analysis methods. The quantitative analysis was focused on determining the health status of patients based on objective data (obtained in lab tests or physical examinations). Two specific indexes where defined and considered in this analysis: the stability index and the health status evolution index. The qualitative analysis assessed the self-perception of patients’ health status in terms of quality of life, self-care, knowledge, anxiety and depression, as well as knowledge levels. It was based on the data gathered through several standard instruments (i.e. EQ-5D, the Hospital Anxiety and Depression Scale, the Kansas City Cardiomyopathy Questionnaire, the Dutch Heart Failure Knowledge Scale, and the European Heart Failure Self-care Behaviour Scale) as well as dedicated non-standardized user experience questionnaires. The results obtained in both analyses, quantitative and qualitative, were compared in order to assess the correlation between the objective and subjective health status of patients. The results of the validation showed that the proposed model contributed to improve the health status of the patients and had a positive effect on the patients’ care. It also proved that the model is a valid instrument for designing enhanced healthcare services for heart failure patients.

La arquitectura de Víctor Eusa

El arquitecto Víctor Eusa (Pamplona, 1894-1990) es la figura central de la arquitectura en Navarra durante la mayor parte del siglo XX. Desde 1920, año en que termina sus estudios en Madrid, hasta 1973, año de su jubilación, produjo centenares de obras y proyectos en esta región española, con esporádicas intervenciones en otras zonas, como las provincias vecinas de Guipúzcoa, Vizcaya y Zaragoza. Su periodo activo coincide con el de la construcción del II Ensanche de Pamplona. La cantidad y calidad de su producción hacen posible establecer una identificación entre la obra de Eusa y la ciudad entonces existente. Sus obras principales son auténticos hitos urbanos que caracterizan el Ensanche. El archivo personal del arquitecto se perdió desgraciadamente en los años setenta del pasado siglo. Este trabajo de investigación ha partido de la recopilación de la documentación gráfica existente en archivos públicos y privados, que ha dado como fruto la catalogación de las obras y proyectos de Víctor Eusa, que constituye el tomo II de la tesis. En el tomo I se analiza la trayectoria del arquitecto y la evolución formal de su lenguaje, a partir de su formación académica y las sucesivas influencias que jalonan sus primeros años de profesión: sus viajes por Europa y Oriente, Otto Wagner y la Sezession vienesa, Perret y el hormigón armado, el Art-Déco y la Exposición de París de 1925, Dudok y la arquitectura holandesa, etc. Todo ello fructifica en una arquitectura expresionista muy personal, basada en la geometría de líneas rectas y quebradas, que combina el ladrillo y el hormigón como sus materiales preferidos. Su madurez se alcanza a finales de los años veinte y se prolonga hasta la guerra civil española. En este periodo se concentran sus obras más conocidas: Casa de Misericordia, Iglesia de los Paúles, Colegio de Escolapios, edificios de viviendas en plaza Príncipe de Viana y calle García Castañón, Seminario, Casino Eslava,… Después del 36, sus responsabilidades públicas sucesivas como arquitecto municipal de Pamplona y como arquitecto provincial de la Diputación Foral de Navarra introducen en su obra una nueva dimensión urbana. ABSTRACT The architect Víctor Eusa (Pamplona, 1894-1990) was the central figure in architecture in Navarra for most of the 20th century. From 1920, when he finished his studies in Madrid, to his retirement in 1973, he was responsible for hundreds of buildings in Navarra, as well as occasional projects in the neighbouring provinces of Guipúzcoa, Vizcaya and Zaragoza. His career as an architect developed in parallel with the second phase of urban expansion in Pamplona. In terms of both quantity and quality, this new district can be seen as an embodiment of Eusa's work, and his most outstanding buildings form the landmarks which give character to this area. Unfortunately, Eusa's personal archive was lost in the 1970s. By collecting and analyzing the graphic information available in public archives, the author of this dissertation was able to compile a catalogue of Eusa's work and projects, which is provided in volume II. Volume I focuses on Eusa's career and the formal development of his language, starting from his academic training and tracing the successive influences that were at work during his early years as an architect: his journeys through Europe and the East, Otto Wagner and the Vienna Secession, Perret and reinforced concrete, Art-Déco and the Paris Exhibition of 1925, Dudok and the Dutch architecture represented in the magazines Wendingen and De Stijl, and many others. All of this came together in Eusa's highly personal expressionist style, based on a geometry of straight and zigzag lines, combining his favourite materials, brick and concrete. His mature period consolidated by end of the 1920s and lasted until the Spanish Civil War. After 1936, Eusa's responsibilities as municipal architect for Pamplona and later as head of architecture for Navarra enabled him to develop his talents in the area of urban design.

Imaging of spin waves in atomically designed nanomagnets

The spin dynamics of all ferromagnetic materials are governed by two types of collective phenomenon: spin waves and domain walls. The fundamental processes underlying these collective modes, such as exchange interactions and magnetic anisotropy, all originate at the atomic scale. However, conventional probing techniques based on neutron1 and photon scattering2 provide high resolution in reciprocal space, and thereby poor spatial resolution. Here we present direct imaging of standing spin waves in individual chains of ferromagnetically coupled S = 2 Fe atoms, assembled one by one on a Cu2N surface using a scanning tunnelling microscope. We are able to map the spin dynamics of these designer nanomagnets with atomic resolution in two complementary ways. First, atom-to-atom variations of the amplitude of the quantized spin-wave excitations are probed using inelastic electron tunnelling spectroscopy. Second, we observe slow stochastic switching between two opposite magnetization states3, 4, whose rate varies strongly depending on the location of the tip along the chain. Our observations, combined with model calculations, reveal that switches of the chain are initiated by a spin-wave excited state that has its antinodes at the edges of the chain, followed by a domain wall shifting through the chain from one end to the other. This approach opens the way towards atomic-scale imaging of other types of spin excitation, such as spinon pairs and fractional end-states5, 6, in engineered spin chains.

Controlled Complete Suppression of Single-Atom Inelastic Spin and Orbital Cotunneling

The inelastic portion of the tunnel current through an individual magnetic atom grants unique access to read out and change the atom’s spin state, but it also provides a path for spontaneous relaxation and decoherence. Controlled closure of the inelastic channel would allow for the latter to be switched off at will, paving the way to coherent spin manipulation in single atoms. Here, we demonstrate complete closure of the inelastic channels for both spin and orbital transitions due to a controlled geometric modification of the atom’s environment, using scanning tunneling microscopy (STM). The observed suppression of the excitation signal, which occurs for Co atoms assembled into chains on a Cu2N substrate, indicates a structural transition affecting the dz2 orbital, effectively cutting off the STM tip from the spin-flip cotunneling path.

Odell, Richard, 2 autographed letters signed to John Winthrop; Southampton, Long Island, 1652 November 16-1653

Correspondence concerning an illness, which Odell believed was palsy or the King's evil (scrofula), that afflicted his five-year-old daughter. Odell writes that her symptoms included loss of speech and feeling in her right side, and a throat blockage, and he requests advice from Winthrop on the course of treatment the family should pursue. Odell writes again in 1653 thanking Winthrop for the ointment and electuary he had prescribed for the child. Her symptoms had persisted, however, and he requested further advice. Odell adds several lines regarding rumors of an insurrection of a Native American tribe, inquiring if Winthrop has any information regarding "how matters stand & between the Dutch & the English."

Delft, Netherlands, ca. 1695 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Delfi Batavorum vernacule Delft, F. de Wit excudit. It was published ca. 1695. Scale [ca. 1:3,800]. Covers a portion of Delft, Netherlands. Map in Latin and Dutch. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Dutch National Grid: RD (Rijksdriehoekstelsel) GCS Amersfoort (Bessel 1841) coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, drainage, built-up areas and selected buildings, fortifications, ground cover, and more. Includes also index.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

Dordrecht, Netherlands, ca. 1695 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Dordracum vulgo Dortt, F. de Wit excudit. It was published ca. 1695. Scale [ca. 1:4,830]. Covers a portion of Dordrecht, Netherlands. Map in Latin and Dutch.The image inside the map neatline is georeferenced to the surface of the earth and fit to the Dutch National Grid: RD (Rijksdriehoekstelsel) GCS Amersfoort (Bessel 1841) coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, drainage, built-up areas and selected buildings, fortifications, ground cover, and more. Includes also index.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.