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Jacques Delors, the former French Finance Minister and President of the European Commission, who died in December at age 98, was the driving force behind two of the European Union's (EU) most remarkable accomplishments–the single market for goods, services and people, and the European Monetary Union that led to the introduction in 2000 of the euro, the EU's common currency. Today the euro and the single market are deeply embedded, but 30 years ago travelers had to exchange money at every European border. Shops in many European countries had to price their goods in multiple currencies. Technical standards were not mutually recognized, so goods were held up at borders. Investing in another EU member state was often cumbersome. In 1986, Mr. Delors began to change all that when he spearheaded passage of the Single European Act through the 12 member nations. By January 1, 1993 the SEA resulted in the scrapping of non-tariff barriers and border checks and the mutual acceptance of technical standards. Europe's future, Mr. Delors believed, depended on the efficiencies that would spring from a broader and deeper union. The ability to easily sell goods and services and to invest freely in all member states transformed the European Community (EC) and later the EU into an economic powerhouse. The euro made doing business in Europe cheaper, more predictable, and far less risky. A common currency and more freedom to travel among countries also generated a sense among citizens that they were European as well as French, German, or Belgian. This was something new. But in supercharging the push toward a more dynamic and ever-closer union, Mr. Delors set in motion another force–a fierce blowback from nationalists who feared their sovereignty was being impinged by a technocratic cabal in faraway Brussels. Greater competition among European companies unsettled many workers, who viewed this as a threat to their long-established and deeply cherished workplace traditions. The tensions unleashed by these more dynamic economic conditions would eventually lead first to the Euro-crisis in 2009, when Greece nearly tumbled out of the euro and the euro itself almost collapsed. Next came Brexit. There is little doubt that the creation of the single market provided a powerful jolt for the European economy. The European Central Bank estimates that real per capita growth has climbed by 12%-22% since the single market's creation, with smaller countries enjoying greater gains than the larger countries. The introduction of the euro brought lower inflation and lower interest rates. But as with all dramatic economic policy changes, there were losers as well as winners. Less-competitive companies cosseted in the previously protected environments of some member states went out of business. Something similar took place in the United States after the implementation of major trade agreements such as NAFTA and the Uruguay Round, which created the World Trade Organization. Most people gained through greater efficiency and more consumer choice. But there were those who did not fare as well. The benefits were dispersed across the entire economy while the losses were concentrated in specific industries or companies. Those who gained may not have appreciated how and why this was the case, but those who lost knew for certain.Mr. Delors wrestled for many decades with the question of how to help those who drew the short straw from economic transformation. He favored open markets and budgetary restraint. But he also believed markets–and international trade–needed to be regulated and that open economic policies were not sustainable without social measures to offset the jarring impact of enhanced international competition. In 1988, he proposed a "Social Dimension" to the internal market plan, which included the right to bargain collectively and protections for temporary workers. Workers were to be represented in company decision making and every worker was entitled to lifelong education. There was fierce opposition, notably from Margaret Thatcher's Britain, and the plan never got off the ground. As the move toward a monetary union gathered pace, these anxieties became more deep seated. Britain, Denmark, and Sweden opted out of the euro and London retained its constraints on free travel. But even with these exceptions, many in Britain believed the die had been cast and so began the inexorable descent into Brexit and the country leaving the EU in 2020. Anti-Europe hostility arose in Poland and continues today in Hungary. If he underestimated the full magnitude of the nationalists' opposition, Mr. Delors was under no illusions about the fragility of the monetary union project. Apart from British resistance to a single currency, there was another serious impediment to adoption of the Euro. France wanted the power of Germany's currency (the Deutsche mark) to be curbed through a common currency and a common central bank. Yet Germany's historical aversion to inflation made it wary of the budgetary policies of its freer-spending neighbors and wanted European-wide budgetary discipline. The result was a flimsy compromise wherein governments pledged to keep their budget deficits and overall debt burdens within agreed limits. Mr. Delors knew the lopsided economic structure of the Maastricht Treaty posed real danger down the road, but he considered the prize of greater Europe unity to be worth the risk. Many countries never achieved those limits and as membership in the Euro increased, the strain on the currency bubbled over. Only adroit leadership from then European Central Bank President Mario Draghi in 2010 prevented the demise of the euro. Mr. Delors recognized early in his career that underlying social tensions could doom grand economic and political projects. But for much of his career, his appreciation of the need for sound regulation and a social compact was not globally embraced. He foresaw the seismic political and social tremors that economic integration would spark, and he suggested policies that would make such integration more widely acceptable. Were his policy prescriptions the right way to address the burgeoning opposition to opening trade and investment? We will never know because they were never enacted. Some EU countries–notably Denmark–implemented programs to cushion the impact of globalization. Others have been slow off the mark. The US has for years used the Trade Adjustment Assistance program to retrain workers who have been displaced by import competition. But the TAA program has few fans and is widely perceived to be ineffective. The inability of Western governments to address domestic grievances on trade has contributed to a sharp rise in nationalism and the disintegration of support for trade and closer economic integration in much of Europe and the US. The World Trade Organization's negotiating agenda has been gutted. Brussels' efforts to strike trade deals with the US, Mercosur and India have ground to a halt. The US has no plans to negotiate trade agreements for the foreseeable future. Managed trade is the order of the day. Had a social dimension been incorporated into the EU's single market program and subsequently, in global WTO negotiations, might public support for trade be more ardent? We don't know the answer, but what seems clear is that Mr. Delors was asking the right questions.
Treball Final de Màster Universitari en Cooperació al Desenvolupament (Pla de 2015) (A distància). Codi: SRP531. Curs acadèmic: 2019-2020 ; Partiendo del abordaje conceptual sobre el desarrollo que aporta Bosier (2005) entendido como un proceso endógeno que comprende la capacidad de transformación del sistema socioeconómico, pero además la habilidad de los grupos humanos para reaccionar frente a los desafíos externos, de promover aprendizajes sociales y sobre todo innovar localmente, este trabajo presenta los detalles de un programa diseñado con el fin de dar cumplimiento a las macro estrategias de desarrollo nacionales, así como a los bien conocidos Objetivos de Desarrollo Sostenible (ODS). El Banco de iniciativas de participación ciudadana para el fortalecimiento de la democracia participativa -BIP- se configura como una estrategia del Ministerio del Interior de Colombia para identificar las organizaciones sociales, comunales y comunitarias que propenden hacia el desarrollo social y político de Colombia, reconocer sus iniciativas y proyectos para orientar la asignación democrática y participativa de estímulos financieros. En este sentido, el ejercicio de patrocinar con recursos económicos la ejecución de iniciativas de participación ciudadana se convierte en instrumento útil tanto para dar cumplimiento Plan Nacional de Desarrollo del gobierno colombiano, como para aportar al logro de los objetivos 10, 11 y 16 de los ODS enfocados en reducir las desigualdades, lograr que las ciudades y los asentamientos humanos sean inclusivos y sostenibles, y que se fortalezca la participación de los países en desarrollo en las instituciones de gobernanza mundial. Reconociendo la heterogeneidad socio-económica y política que caracteriza a las organizaciones sociales de base en el territorio colombiano, y buscando sinergias efectivas entre el Estado y la sociedad civil, se identificó en este caso que la teoría de gobernanza local resulta ser un modelo de participación y concurrencia multinivel y multiactor con el potencial para generar impactos duraderos con posterioridad a la implementación de las iniciativas en mención. Sin embargo, esto requerirá organizaciones sólidas, resilientes e innovadoras para integrar escenarios colaborativos que impulsen no solo el crecimiento sino también el desarrollo endógeno de las comunidades. Para ello, la Corporación Red Constructores de Paz, en adelante CRCP, como organización sin ánimo de lucro que ha consolidado un nombre alrededor de procesos juveniles de incidencia local y participación comunitaria en el Departamento de Cundinamarca, firmó un Convenio de Asociación (F-127) con el Ministerio del Interior con el fin de aunar esfuerzos para fortalecer las organizaciones sociales de base colombianas en varios frentes: con capacitación en formulación y ejecución de iniciativas, financiación de iniciativas y la generación de espacios para intercambiar experiencias entre pares. En este contexto, mi labor como Coordinadora Técnica en el grupo Gerencia de Proyectos de la CRCP bajo la supervisión directa del Gerente, consistió principalmente en brindar las herramientas técnicas, metodológicas y pedagógicas pertinentes para alcanzar cada una de las metas trazadas con el Banco de Iniciativas BIP. Los productos a mi cargo variaban a medida que avanzábamos en la ejecución de la estrategia, abarcando desde la construcción de los términos de referencia de la primera convocatoria BIP, aporte al diseño de materiales pedagógicos para el componente de formación, consolidación de informes de gestión e incluso apoyo logístico en la realización del Encuentro Nacional de Iniciativas Participativas. En síntesis, esta experiencia ha representado para mí el escenario ideal para adquirir y multiplicar saberes valiosísimos de la mano colegas, altos representantes de la institucionalidad colombiana y actores de múltiples procedencias (líderes sociales, representantes de juventudes municipales, académicos, entre otros) otorgándome además el privilegio de dimensionar el DESARROLLO a partir de elementos más cercanos, reales, y cotidianos. ; Based on the conceptual approach to development provided by Bosier (2005), understood as an endogenous process that includes the capacity for transformation of the socio-economic system, but also the ability of human groups to react to external challenges, to promote social learning and, above all, to innovate locally, this paper presents the details of a programme designed to give effect to national macro development strategies as well as the well-known Sustainable Development Goals (SDGs). The Bank of Citizen Participation Initiatives for the Strengthening of Participatory Democracy (BIP) is configured as a strategy of the Ministry of the Interior of Colombia to identify social and communal organizations that promote the social and political development of Colombia, recognize their initiatives and projects to guide the democratic and participatory allocation of financial incentives. In this regard, the exercise of financially sponsoring the implementation of citizen participation initiatives becomes a useful instrument both to implement the Colombian Government's National Development Plan and to contribute to the achievement of objectives 10, 11 and 16 SDGs focusing on reducing inequalities, making cities and human settlements inclusive and sustainable, and strengthening the participation of developing countries in global governance institutions. Recognizing the socio-economic and political heterogeneity that characterizes grassroots social organizations in Colombian territory, and seeking effective synergies between the State and civil society, it was identified in this case that the theory of local governance turns out to be a model of multilevel and multiactor participation and concurrence with the potential to generate lasting impacts after the implementation of the initiatives in question. However, this will require strong, resilient and innovative organizations to integrate collaborative scenarios that drive not only growth but also the endogenous development of communities. To this end, the Corporación Red Constructores de Paz, hereinafter CRCP, as a non-profit organization that has consolidated a name around youth processes of local advocacy and community participation in the Department of Cundinamarca, signed a Partnership Agreement (F127) with the Ministry of the Interior to join efforts to strengthen Colombian grass-roots social organizations on several fronts: with training in the formulation and implementation of initiatives, funding of initiatives and the creation of spaces for exchanging experiences between peers. In this context, my work as Technical Coordinator in the CRCP Project Management Group under the direct supervision of the Manager was mainly focused on providing the technical tools, relevant methodological and pedagogical approaches to achieving each of the goals set with the BIP. The products under my resposability varied as we advanced in the implementation of the strategy, from the construction of the terms and conditions for the first BIP call, to contribution to the design of teaching materials for the training component, and consolidation of management reports or even logistical support in the implementation of the National Meeting of Participatory Initiatives.Ultimately, this experience has represented the ideal scenario for me to acquire and multiply valuable knowledge at the hands of colleagues, high representatives of colombian institutions and actors from many backgrounds (social leaders, representatives of municipal youth, academics, among others) also granting me the privilege of dimensioning DEVELOPMENT from closer, real, and day to day elements.
As the history of this land continues to unfold, we come to the time when the capitol of the State was moved to a new city to the north of Baghdad, which was called Samarra, and this was the opportunity taken by the Khalifahs to build new palaces and excavate new canals and open more land for cultivation. In this paper details on the building of Sammara by Khalifah al- Mu'tasim, son of Khalifah Harun al- Rashid and moving the capitol to it from Baghdad in the year 836 and remaining as such until 892 are given. One of the main reasons which led al-Muʿtaṣim to build Samarra and moving to it was the problems raised by the presence of his Turkish slave-soldiers in Baghdad and the friction they had created with the population. Al-Muʿtaṣim construction works in Samarra, the various public buildings, and numerous palaces he constructed here are described. As the city was located on the eastern bank of the Tigris, water supply could not be drawn to it by gravity since its location was higher than the river and even higher than the Katul Kisrawi canal adjoining to it from the east. Therefore, the irrigation works of al- Muʿtaṣim were concentrated on the western bank of the Tigris, which he had already connected it to the right bank by building a bridge. The main irrigation work he embarked upon was the construction of Nahr Ishaqi Canal. This old canal dated to the Partho- Sassanid era but it had to be re-excavated and remodeled since it was already filled up by sediments and abandoned. More over the canal had to be extended for a very long distance downstream to irrigate all the qati'as he had given to his top generals and courtiers to develop into cultivations and farms. These farms then produced all sorts of crops and fruits while the large date palm orchards planted here gave the best types of dates. Moreover, the canal in its downward route supplied water to the large tract of land that al- Mu'tasim had reserved for the encampment of his Maghariba troops which was called "Istablat". Details of the barracks, housing quarters, stables and training arena of the encampment are presented in addition to the three branch canals off taking from Nahr Ishaqi, which were to irrigate also the extensive pastureland that was reserved for the 140,000 cavalry horses to graze in. The canal was then followed to its end in the other old canal called al- Dujail canal. The works of al- Mu'tasim, however, were no match to what his grandson al- Mutawakkil had done which are described. This Khalifah was determined to irrigate Samarra by gravity from the Tigris and to have plentiful water supply to the city and to his palaces and to his many artificial ponds. He embarked on a daring project by constructing a dual kariz and open channel conduit system taking water from the Tigris at a location forty kilometers north of Samarra and running for great part of its length along the Katul Kisrawi canal adapting to the hilly topography of the land. The scheme was then described following its course after crossing the Katul by an aqueduct to an earth reservoir. This reservoir was built to retain the incoming water before distributing it to the main city dual Kariz, and to the canal supplying the Dakka palace. In addition to the flood escape channel that was known as the Nahr Murayr which took off from the west side of the reservoir and passed down to the Tigris where it poured. The main city Kariz system is followed i and the details of its branching network are fully described. Such details covered the water supply to the racing courses, the Dar Khilafa palace and its unique pools intended for the Khalifah's pleasure and the water supply to Abu Dulaf Mosque congregational mosque with its famous fountain. Having finished in the Tigris at al- Matira this stream could not irrigate the 5000 hectares of land of al- Hayr, or the wild animal reserve created by al- Mutawakkil to practice his hobby of hunting, as this land was above its course. The al- Hayr was so important to al- Mutawakkil that he excavated a new canal directly from the Katul, which commanded the whole area, called it Nahr al Nyzak and gave from its final reach a branch to another palace he built there and supplied one more of his favorite ponds adjoined to it. The construction works of al- Mutawakkil were not confined to Samarra but he extended this to build a new city 18 kilometers to the north of Samarra and called it al- Mutawakkiliyya, and here he again built new government compound, a mosque and gave qati'as to his sons, generals and may more people to build houses and palaces. He built for himself another palace and called it al Ja'fari. To supply the new city with water, he ordered the excavation of a new canal, which he called Nahr al Ja'fari. The intake of this canal was on the Tigris River some forty kilometer north of Tikrit and it followed a course parallel to the river for a considerable distance before it crossed the Katul Kisrawi by an aqueduct and then entered the city. This project proved an engineering failure as the ground, which had to be dug, was extremely hard and the work had to be stopped after spending twenty five million dirham. While some of these works may be considered as grand works, they were very costly and deprived public works such as irrigation networks from their share necessary for their maintenance and proper functioning. This extravagance coupled with political intrigues led to the assassination of al- Mutawakkil in a plot that was planned by his own son. This point marked the beginning of the decline of al- Khilafa which took some more time till it finally collapsed in 1258 fall of Baghdad on the hands of the Mongols. In addition to Samarra and its irrigation work described also the Nahr Dujail canal flowing on the western bank of the Tigris not far downstream from Samarra. Much older than Samarra itself, it was irrigating a large tract of land extending to Baghdad. In description of the course of the canal followed its western branch, which had gone out of use at the Abbasid times and also concentrated attention on the eastern branch that was known as Nahr Batatiya. It irrigated the Tusuj of Maskin before it reached the northern parts of Baghdad and branched into a dense network of watercourses that supplied al- Harbbiyyah quarter. Further details are presented of the various places and parts of this quarter that benefited from these watercourses before the full supply was exhausted. The details as given augment therefore the description of the canal networks serving Baghdad (the round city and the Karkh districts) that had originated from Nahr Isa. The Abbasid Khilafa after it had experienced its golden era began after the assassination of al- Mutawakkil, a long process of slow but steady decline due to multiplicity of reasons. ; Validerad;2020;Nivå 1;2020-04-24 (alebob)
Tesis llevada a cabo para conseguir el grado de Doctor por la Universidad de la RIoja.--2020-04-03.--Sobresaliente Cum Laude ; [ES] Actualmente, las enfermedades fúngicas de la madera de la vid son muy graves y han sido señaladas en muchos foros como una de las principales preocupaciones actuales del sector vitivinícola, si no la mayor. Entre estas enfermedades destaca la enfermedad del pie negro, cuya incidencia es creciente en viveros de vid y en nuevas plantaciones. Esta enfermedad está causada por numerosas especies con formas asexuales del tipo "Cylindrocarpon". El pie negro ha sido extensamente estudiado en España durante los últimos años. Sin embargo, la constante reclasificación y ampliación taxonómica de las especies asociadas a la enfermedad, la restricción en la aplicación de fungicidas y la emergencia en el uso de técnicas de secuenciación de nueva generación ha hecho necesario una revisión y actualización de los conocimientos obtenidos hasta ahora. En esta tesis se ha estudiado en detalle la biología y ecología de la enfermedad, y se han evaluado diversas estrategias de control. En primer lugar, se han caracterizado una amplia colección de aislados asociados al pie negro obtenidos de vides asintomáticas. Estos aislados fueron analizados mediante el estudio de sus caracteres fenotípicos y la secuenciación de los genes his3, tef1 y tub2 y la región ITS. Como resultado, se describieron dos nuevas especies asociadas al pie negro de la vid: Dactylonectria riojana e Ilyonectria vivaria, y por primera vez se han aislado de vid Ilyonectria pseudodestructans y Neonectria quercicola, elevando a 17 el total de especies fúngicas asociadas con la enfermedad en España. Además, se ha desarrollado un medio semi-selectivo, basado en un trabajo ya publicado, para identificar y cuantificar propágulos viables de hongos asociados al pie negro en muestras de suelo. El uso de este medio ha permitido confirmar la presencia de inóculo en campos de vivero en rotación y en viñedos adultos. Además, se ha establecido una relación positiva entre Unidades Formadoras de Colonias (UFC) de los patógenos de la enfermedad del pie negro y la concentración de CaCO3 en el suelo. A continuación, se ha caracterizado el microbioma fúngico y bacteriano de la rizosfera de 5 portainjertos en dos viñedos localizados en La Rioja y Navarra mediante secuenciación de amplicones. Los resultados mostraron que el genotipo es determinante en la selección del microbioma residente en la rizosfera en el viñedo adulto (25 años), mientras que este factor no influía en la selección del microbioma en el viñedo joven (7 años). Sin embargo, diversas especies bacterianas y fúngicas se encontraron en ambos viñedos, lo que demuestra la existencia de un microbioma conservado en el viñedo, independientemente de la región geográfica. Además, se ha observado una correlación positiva entre la abundancia relativa de patógenos de la enfermedad del pie negro obtenida mediante secuenciación masiva de amplicones y la obtenida mediante qPCR. También se ha comprobado que la rizosfera de los portainjertos "140 R" y "161-49 C" contiene menor cantidad de estos patógenos que los portainjertos "1103 P", "110 R" y "41 B". Por último, en cuanto a medidas de control, se ha comparado la eficacia de la biofumigación con mostaza blanca con el empleo de propamocarb + fosetyl-Al, así como el efecto de la aplicación de Tusal®, un producto comercial basado en las especies Trichoderma atroviride T11 y Trichoderma asperellum T25. Se ha confirmado que la biofumigación con Brassica sp. es una alternativa prometedora al uso de fungicidas químicos para el control de la enfermedad del pie negro, mientras que la aplicación de Trichoderma spp. sobre las raíces antes de la plantación resultó ser inefectiva para el manejo de la enfermedad. ; [EN] Grapevine trunk diseases (GTDs) are a growing concern in the wine sector worldwide. Among them, black-foot disease (BFD) has increased its incidence in grapevine nurseries and newly established vineyards. BFD is caused by numerous Cylindrocarpon-like asexual morphs species. This disease has been widely studied in Spain in recent years. However, the constant reclassification and taxonomic expansion of the species associated with BFD, the restriction in the application of fungicides, and the emergence in the use of high-throughput sequencing techniques has made necessary a review and an update of the knowledge obtained so far. In this Ph.D. thesis, the biology and ecology of the disease was studied in detail. The evaluation of different control strategies to improve disease management was also investigated. Firstly, a wide collection of isolates associated to BFD, which were obtained from asymptomatic vines, were characterized. These isolates were studied with morphological and cultural characteristics as well as phylogenetic analyses of combined DNA sequences of the his3, tef1 and tub2 genes, and the ITS region. Two new species associated with the disease were described: Dactylonectria riojana and Ilyonectria vivaria. Ilyonectria pseudodestructans and Neonectria quercicola were isolated for the first time from grapevine in Spain, raising the total number of fungal species associated to BFD in our country to 17. The development of a semi-selective medium based on previous research allowed the identification and quantification of viable propagules of fungi associated with BFD from soil samples. The presence of BFD inoculum in rotating nursery fields and in mature vineyards was confirmed. Moreover, a positive correlation was established between Colony Forming Units (CFU) of BFD pathogens and the CaCO3 concentration in soil. On the other hand, the fungal and bacterial microbiome of the rhizosphere of 5 rootstocks in two vineyards located in La Rioja and Navarra has been characterized by high-throughput amplicon sequencing (HTAS). The results showed that grapevine rootstock genotype was the most important factor in shaping the microbiome in a mature vineyard (25-year-old), but not in a young vineyard (7-year-old). However, several bacterial and fungal species were found in both vineyards, demonstrating the existence of a "core" microbiome conserved in the vineyard, regardless of the geographic region. In addition, a positive correlation has been observed between the relative abundance of BFD pathogens obtained by HTAS and by qPCR. Moreover, the rhizosphere compartment of the "140 R" and "161-49 C" rootstocks harboured lower number of these pathogens than the "1103 P", "110 R" and "41 B" rootstocks. Finally, regarding control measures, the efficacy of white mustard biofumigation was compared with the use of propamocarb + fosetyl-Al, as well as the effect of Tusal® (Trichoderma atroviride T11 + Trichoderma asperellum T25) application. Biofumigation with Brassica sp. is a promising alternative to the use of chemical fungicides for BFD control, while the application of commercial products based on Trichoderma sp. on the roots before planting resulted ineffective for disease management. ; Funding for the present research was provided by the National Institute for Agricultural Research and Experimentation (INIA) project "Desarrollo de nuevas estrategias de manejo integrado de las enfermedades fúngicas de la madera de la vid (RTA2015-00015- C02)" and its related contract "FPI2015-0035". In addition, the work has also been supported by the Regional Projects that annually the Department of Agriculture, Livestock, Rural World, Territory and Population of the Government of La Rioja has funded.
This thesis illustrates and puts in context two of the main research projects I worked on during my Ph.D. program, in collaboration with several national and international co-authors from "La Sapienza" and other prestigious universities. Both research lines concern spatial and spatio-temporal analysis of geo-referenced datasets, which is of broad and current interest in the statistical research literature and applications. My focus on such an area of statistics was not meditated before the start of the program. However, while pursuing my original research interests in the broader domain of Bayesian statistics, I realized there was an ever-increasing demand for viable and efficient statistical methods to analyze spatial and spatio-temporal data. That is a consequence of the extraordinary technological development that interested data collection systems during the last few decades. The innovative, cutting-edge technologies conceive new devices that can record and store data and information about the most diverse phenomena, possibly at a fine spatial scale and with high temporal resolution. Such capabilities were just a dream up to 20 or 30 years ago. Spatial statistics methods are rapidly evolving to face this surge of novel data structure in various application fields: geology, meteorology, ecology, epidemiology, economics, politics, and more. The first chapter of this thesis introduces the general idea behind spatial statistics, that is the branch of statistics devoted to analyzing and modeling temporal and spatial structure in time and/or geo-referenced datasets. A brief historical introduction of its developments is provided, starting from the first (sometimes unwitting) applications of its logic to practical and theoretical problems at the end of the XIX century. Many methods and techniques in this domain evolved independently, driven by the specific needs of the application fields in which they were developed. The historical excursus leads to a coarse (but reasonable) distinction in three main areas: continuous spatial variations, discrete spatial variations, spatial point patterns. These areas present further facets within themselves, making spatial statistics an incredibly diverse and rich topic. A really comprehensive review would require an entire book to be written and maybe a lifetime to be thoroughly studied. Therefore, in the following Chapters, the discussion is focused on specific areas and techniques used in the studies. Only those tools that proved valuable for the analysis performed in Alaimo Di Loro et al.(2021) and Kalair et al. (2020) are extensively treated. The second chapter focuses on analyzing continuous spatial variation, which is the modeling of outcomes varying continuously over some space. First, the most relevant properties for continuous spatial processes are introduced; second, some of the most common methodologies for performing spatial interpolation of the mean trend and stochastic modeling of the residuals are listed and sketched. In particular, the chapter digresses on Spline Regression as a valid technique to catch the first-order structure in spatial data. Soon after, the Geo-Statistical methods and the Bayesian Hierarchical framework are claimed as invaluable tools to attain the simultaneous estimation of the first and second-order structure of a process. Extension to spatio-temporal contexts is not as trivial as it may seem but must be approached with due care. An extensive discussion about the possible pitfalls and viable solutions is included in the same chapter. Finally, the problems arising in the analysis of Big spatial data are highlighted in the last section, where The Nearest Neighbor Gaussian Process (NNGP, Datta et al. (2016a,b)) model is introduced as a highly scalable framework for providing full inference on massive spatial and spatio-temporal datasets. The third chapter includes an extended version of the paper Alaimo Di Loro et al. (2021), currently under-review and published as a pre-print. It describes how the aforementioned technological development has strongly affected human tracking and monitoring capabilities, generating substantial interest in monitoring human activity. New non-intrusive wearable devices, such as wrist-worn sensors that monitor gross motor activity (miniature accelerometers), can continuously record individual activity levels, producing massive amounts of high-resolution measurements. Analyzing such data needs to account for spatial and temporal information on trajectories or paths traversed by subjects wearing such devices. Inferential objectives include estimating a subject's physical activity levels along a given trajectory, identifying trajectories that are more likely to produce higher levels of physical activity for a given subject, and predicting expected levels of physical activity in any proposed new trajectory for a given set of health attributes. We argue that the underlying process is more appropriately modeled as a stochastic evolution through time while accounting for spatial information separately. Building upon recent developments in this field, we construct temporal processes using directed acyclic graphs (DAG) on the line of the NNGP, include spatial dependence through penalized spline regression, and develop optimized implementations of the collapsed Markov chain Monte Carlo (MCMC) algorithm. The resulting Bayesian hierarchical modeling framework for the analysis of spatial-temporal actigraphy data proves able to deliver fully model-based inference on trajectories while accounting for subject-level health attributes and spatial-temporal dependencies. We undertake a comprehensive analysis of an original dataset from the Physical Activity through Sustainable Transport Approaches in Los Angeles (PASTA-LA) study to formally ascertain spatial zones and trajectories exhibiting significantly higher physical activity levels. Suggestions for further extensions and improvements on the currently adopted methodology are discussed in the last section of the chapter. Chapter four undergoes a paradigm shift and introduces the basic theory and tools of spatial point patterns analysis. Some common probabilistic models for point processes are briefly discussed, with some of their properties and limitations highlighted. The rest of the chapter is instead entirely focused on the Hawkes process and its spatio-temporal extension. It is a particular kind of self-exciting point process that presents a strong inter-dependence structure. While conceived in Hawkes (1971a), its use in the statistical application has been for a long time limited to the analysis of earthquakes dynamic. The recent escalation of data at the high temporal resolution, sometimes accompanied by spatial information, has favored its use in modeling events dynamics in diverse fields: finance, society, biology, etc. In particular, its defining properties are presented and state-of-the-art estimation methods of the spatio-temporal version are introduced. In the fifth chapter, the semi-parametric Hawkes process with a periodic background originally introduced in Zhuang and Mateu (2019) is outlined. While very recent, it has already revealed itself very useful to model phenomena that are likely to present a cyclic pattern. It assumes that primary events occur as an effect of the background intensity, while secondary events are associated with the self-excitation effect. There are sound motivations that justify its utilization in the context of road accident dynamics, e.g.: excitation may occur when a driver, reacting to the disruption of one accident, triggers a subsequent accident upstream of the first one. The proposed framework is tested on two original applications on two original sets of data: the first one, somewhat preliminary, involves the modeling and analysis of road accidents that occurred on the urban road network of Rome, in Italy; the second is instead a conclusive analysis recently published in (Kalair et al., 2020), conducted on a collection of road accidents occurred on the M25 London Orbital, in the United Kingdom. Adaptations of the original methodology to the road accident setting were deemed necessary in both cases to consider specific features of car accidents and the geometry of the underlying space. The final results permit a fruitful interpretation of the temporal and spatial background that detects the typical commuting behavior in the Roman and Londoners communities. The self-excitation component appears to have slightly different intensities in the two contexts, suggesting excitation mechanisms that vary between urban networks and motorways. Finally, the sixth chapter summarizes all the main passages in the thesis, highlighting the previous chapters' original contributions. It also tries to summarize a take-home message about statistical modeling's fundamental importance as a scientific tool to formulate and verify hypotheses that must not be discouraged by new challenges and technological advancements.
A renewed AUDITIO! World Hearing Day is coming and we couldn't have chosen a better time to welcome the new AUDITIO. After many months of work, AEDA has managed to renew its journal in a unique way. A team, led by Dr. Raul Sánchez, brand new Editor-in-Chief of the journal, began to work with the aim of renovating, modernizing and adapting the journal to the needs of the 21st century. It may surprise you but AUDITIO is a pioneering journal in audiology as it was designed, by the Fundación Canaria Dr. Barajas in 2001, as a free access electronic journal. I assure you that in 2001 this format was quite a novelty and this fact has marked its existence. The distribution of AUDITIO through the internet among the Spanish-speaking community made it the most widely distributed Audiology journal in the Spanish language and therefore one of the most widely read journals. AUDITIO has always maintained its academic orientation and has successfully fulfilled its goal: the free dissemination of Audiology. So why did it have to be renewed? It was a demand from our associates and a thorn in many of us. So much so that it became a goal of my action program for the legislature of the Presidency in the 2020 elections. The reason for this demand was clear: its lack of periodicity. In the last five years AUDITIO has suffered ups and downs and a lack of regularity, due to a lower reception of publications. It has not been due to lack of work from its Editor-in-Chief, Dr. Bartolomé, who knew how to surround herself with a great team of reviewers, was able to encourage university students and masterfully handled her contacts with prestigious researchers to maintain the greatest possible regularity. We should all thank her for her effort, dedication and results, but AUDITIO was slowly getting sick and we were unable to detect it and we were unable to find solutions. And in the face of illness, renew or die. It was the cruel reality that AEDA had to face. And after delving into the reasons, we discovered that AUDITIO still had possibilities and we decided to bet on it and mark a turning point. AUDITIO and audiology in Spanish deserve it. Because audiology is one of the disciplines of science with the greatest scientific production and we must base its future development on it. AUDITIO must maintain its unique role, as a means of expression within audiology in the Spanish language. A key element in the promotion of clinical practice based on scientific evidence and the speaker of knowledge in audiology in the Spanish language where to publish new research, projects, clinical practice guides, conference summaries, etc. An agile, young and dynamic communication medium, adjusted to the highest scientific rigor. AUDITIO is worth it and must have its space in our discipline and our language (the 2nd most widely spoken mother tongue in the world). Today, World Hearing Day, begins a new era for AUDITIO. A journal whose publications will be easily found by readers, a modern journal, according to the needs of authors and readers. For this, we aspire strongly and adopt the Open Journal System (for content management, applications, reviews and production), we register all content with Digital Object Identifiers (DOI), we adapt the journal to FECYT quality standards and adjust the contents for a better indexing of Google Scholar, RedIB, PubMed, WoS, Scielo, etc. A new time, new standards, an objective within the reach of this Board of Directors, an effort by AEDA associates and a brilliant job, catalyzed by its member and editor-in-chief/managing editor of the journal, Raul Sánchez-López. Congratulations to all! ; ¡AUDITIO se renueva! Llega el Día Mundial de la audición y no podíamos haber elegido mejor momento para dar la bienvenida a la nueva AUDITIO. Tras muchos meses de trabajo, AEDA ha conseguido renovar de manera única su revista científica. Un equipo, liderado el Dr. Raul Sánchez, flamante Editor Jefe de la revista, empezó a trabajar con el objetivo de renovar, modernizar y adaptar la revista a las necesidades del siglo XXI. Puede que les sorprenda pero AUDITIO es una revista pionera en audiología pues fue diseñada, por la Fundación Canaria Dr. Barajas en 2001, como una revista electrónica de acceso libre. Les aseguro que en 2001 este formato era toda una novedad y este hecho ha marcado su existencia. La distribución de AUDITIO a través de internet entre la comunidad hispanohablante la convirtió en la revista de Audiología de mayor difusión en lengua española y por tanto, una de las revistas más leídas. AUDITIO siempre ha mantenido su orientación académica y ha cumplido con éxito su objetivo: la divulgación gratuita de la Audiología. Entonces, ¿por qué tenía que ser renovada?. Era una demanda de nuestros asociados y una espina clavada en muchos de nosotros. Tanto que se convirtió en un objetivo de mi programa de actuación para la legislatura de Presidencia en las elecciones del 2020. El motivo de esa demanda era claro: su falta de periodicidad. En el último lustro AUDITIO ha sufrido altibajos y la falta de regularidad, por una menor recepción de publicaciones. No ha sido por falta de trabajo de su Editora Jefe, la Dra. Bartolomé, que supo rodearse de un gran equipo de revisores, supo incentivar a los universitarios y manejó con maestría sus contactos con prestigiosos investigadores para mantener la mayor regularidad posible. Todos debemos agradecerle su esfuerzo, dedicación y resultados pero AUDITIO enfermaba lentamente y no supimos detectarlo ni fuimos capaces de encontrar soluciones. Y ante la enfermedad, renovar o morir. Era la cruel realidad que AEDA tenía que afrontar. Y tras profundizar en los motivos, descubrimos que AUDITIO aun tenía posibilidades y decidimos apostar por ella y marcar un punto de inflexión. AUDITIO y la audiologia en español lo merece. Porque la audiología es una de las disciplinas de la ciencia con mayor producción científica y en ella debemos fundamentar su desarrollo futuro. AUDITIO debe mantener su papel único, como medio de expresión dentro de la audiología en lengua española. Un elemento clave en la promoción de la práctica clínica basada en la evidencia científica y el altavoz del conocimiento en audiología en lengua española donde publicar nuevas investigaciones, proyectos, guías de la práctica clínica, resúmenes de congresos etc. Un medio de comunicación ágil, joven y dinámico, ajustado al mayor rigor científico. AUDITIO merece la pena y debe tener su espacio en nuestra disciplina y nuestra lengua (la 2ª lengua materna más hablada en el mundo). Hoy, Día Mundial de la Audición, empieza una nueva era para AUDITIO. Una revista cuyas publicaciones serán fácilmente localizables por los lectores, una revista moderna, acorde a las necesidades de autores y lectores. Para ello, aspiramos fuerte y adoptamos el sistema Open Journal System (para la gestión de contenido, postulaciones, revisiones y producción), registramos todo el contenido con Digital Object Identifiers (DOI), adecuamos la revista a los estándares de calidad de FECYT y ajustamos los contenidos para una mejor indexación de Google Scholar, RedIB, PubMed, WoS, Scielo, etc. Un nuevo tiempo, un salto de calidad, un objetivo al alcance de esta Junta Directiva, un esfuerzo de los asociados de AEDA y un brillante trabajo, catalizado por su vocal y Director Jefe de la revista, Dr. Raul Sánchez-López. ¡Enhorabuena a todos!
The Atlantic salmon (Salmo salar) is an iconic fish species with a widespread historic abundance, but recent decades have witnessed a dramatic decline in wild stocks due to a variety of anthropogenic factors, especially overfishing and loss of habitat. To mitigate the impacts of these anthropogenic effects, millions of hatchery-reared Atlantic salmon are released yearly into rivers through stocking programs, which aim to augment the productivity of wild populations. However, these stocked fish are reared under uniform and stimulus-poor hatchery conditions and consequently, they are behaviourally naïve at time of release. For example, hatchery-reared salmonids often show impaired foraging and antipredator behaviour compared to wild conspecifics, which contributes to the observed high post-release mortality rates in stocked fish. Although the effects of the hatchery environment on fish behaviour are relatively well described, the brain, which is the key organ that translates environmental stimuli into appropriate behavioural responses, remains gravely understudied. The few studies which have investigated the impact of the hatchery environment on the fish central nervous system have mostly mapped the expression of neuroplasticity and neurogenesis genes in the entire brain, or large brain structures, such as the whole telencephalon. However, the brain is a complex organ, composed of a plethora of neural subpopulations, each with distinct functionalities and characteristics. When quantifying whole-brain levels of neuroplasticity markers, one studies a conglomerate of many different neural subregions, and regional differences can therefore not be detected. The aim of this thesis is to gain a better insight into the neural differences between wild and hatchery-reared fish, specifically within neural subpopulations of the telencephalon, and how innovative hatchery protocols can improve the neurobiology, behaviour and post-release survival of hatchery-reared salmon. First, we made a detailed characterisation of the neurobiology of juvenile wild and hatchery-reared Atlantic salmon parr. This was achieved by quantifying the expression of the neuroplasticity marker brain-derived neurotrophic factor (bdnf) and the neural activity marker cfos in five neural populations within the telencephalon of wild and hatchery-reared juvenile salmon under both basal and acute-stress conditions (Paper I). We found that expression of bdnf and cfos varied greatly between the studied telencephalic subregions, confirming that these subregions have a distinct responsiveness to environmental stimuli. Compared to wild fish, hatchery-reared fish of the same genetic origin showed higher post-stress neural activation in the ventral area of the dorsolateral pallium (Dlv), which is an important brain region associated with relational memory and spatial orientation. Furthermore, wild fish displayed stress-induced upregulation of bdnf in the dorsomedial pallium (Dm), which regulates emotional learning and stress reactivity, while this was not the case for hatchery-reared individuals. This study showed that targeting telencephalic subregions can reveal expression patterns that escape detection when studying the entire telencephalon as a whole. Moreover, we demonstrated that the hatchery environment affects neuroplasticity and neural activation in brain regions which are important for learning processes and stress reactivity, providing a neuronal foundation for the behavioural differences observed between wild and hatchery-reared fish. After we had characterised neural differences in telencephalic subregions between wild and hatchery-reared salmon, we assessed whether structural environmental enrichment (EE) of the rearing environment could increase region-specific neural plasticity and stocking success in hatchery-reared salmon (Paper II). After seven weeks of treatment, EE-reared parr showed higher post-release freshwater survival rates compared to control individuals, which were reared in standard uniform hatchery tanks. This improved stocking performance did not, however, appear to be linked to significant changes in the expression of telencephalic plasticity markers. Although structural EE has shown some, albeit inconsistent, beneficial effects on fish stocking success across studies, hatchery managers are reluctant to implement this measure in their hatcheries because of hygienic and operational limitations. Therefore, it is important to develop alternative rearing methods which can enhance fish neural development and are more practical to implement in the hatchery. One of these alternative rearing methods is swimming exercise, which has previously been linked to increased post-release survival in salmonids. As running exercise is associated with increased neural plasticity in mammals, we investigated in Paper III whether swimming exercise could serve as an alternative rearing strategy to promote Atlantic salmon neural plasticity and cognition. After eight weeks of sustained swimming, we found increased expression of neuroplasticity-related transcripts in the telencephalon transcriptome of exercised salmon. However, we did not find any evidence for increased cognition in exercised fish, in terms of their ability to solve a spatial orientation task in a maze test. While previous studies have reported positive physiological effects of swimming exercise, such as improved growth efficiency and stress reduction, this is the first time that exercise-enhanced neural plasticity has been reported in salmonids, building a case for exploring further the potential of implementing swimming exercise to improve the stocking success of reared salmonids. In summary, the results presented in this thesis advance the field of applied fish neurobiology in a stocking context by characterising telencephalic neural plasticity markers in Atlantic salmon on a more detailed level than previously studied. We demonstrate that EE can improve juvenile salmon survival during freshwater residency, but that the effects of EE on neural plasticity are limited in the studied telencephalic regions. We identify swimming exercise as a promising novel tool to improve neural plasticity in salmon, and we remark that exercise has additional physiological benefits and is relatively easy to implement in hatcheries. We therefore suggest that future work should aim at validating the potential use of exercise in the optimisation of hatchery conditions for stocking programs, and that further research is needed to increase our understanding on the link between the rearing environment, the brain and behaviour. ; Laks (Salmo salar) er en ikonisk fiskeart som historisk sett har funnes i overflod, men som de siste tiår har opplevd en dramatisk nedgang i villpopulasjonen. Denne nedgangen skyldes hovedsakelig antropogene faktorer som overfisking og habitatinnskrenkning. Som en motkraft til den minkende populasjon blir det gjennom kultiveringsprogrammer satt ut millioner av fisk fra klekkerier og ut i elvene årlig. Disse fiskene er imidlertid vokst opp under uniforme og stimuluslave omgivelser, noe som gjør dem atferdsmessig naive i møte med elven. For eksempel viser utsatt laks nedsatt forings- og antipredatorevne sammenlignet med villaks, noe som bidrar til høyere dødelighet hos denne gruppen. Selv om klekkerimiljøets effekter på atferd er relativt godt beskrevet, så er hjernen, selve hovedorganet som omsetter omgivelsenes stimuli til en passende atferd, fremdeles underbeskrevet. De få studiene som har undersøkt påvirkningen fra klekkerimiljøet på fiskens sentrale nervesystem har stort sett kartlagt uttrykket av gener involvert i nevroplastisitet og nevrogenese i enten hele hjernen eller større hjernestrukturer, som telencephalon. Hjernen er imidlertid et komplekst organ, sammensatt av et utall nevrale subpopulasjoner, hver med distinkte funksjonaliteter og karakteristikker som driver ulike atferder. Når man kvantifiserer markører for nevroplastisitet på helhjerne-nivå, så studerer man et konglomerat av ulike nevrale regioner på samme tid og kan dermed ikke detektere eventuelle regionale forskjeller. Hensikten bak denne avhandlingen var dels å bedre forståelsen av potensielle nevrale forskjeller mellom klekkeri- og villfisk, og dels å undersøke om innovative klekkeriprotokoller kan forbedre nevrobiologien, atferden og overlevelsen til kultivert laks etter elveutsettelsen. Arbeidet startet med en detaljert karakterisering av nevrobiologien til kultivert og vill parr (juvenil laks). Dette ble oppnådd ved å kvantifisere genuttrykket av en nevroplastisitetsmarkør, brain-derived neurotrophic factor (bdnf), og en nevral aktivitetsmarkør, cfos, i fem ulike nevrale populasjoner innad i telencephalon til parr av klekkeri- og villaks under både basale- og akutte stress-tilstander (Artikkel I). Her fant vi at genuttrykket av bdnf og cfos varier sterkt mellom de ulike delene av telencephalon, noe som bekrefter at disse delene har distinkte responser til omgivelsene. Sammenlignet med villfisk har klekkerifisk, med det samme genetiske opphav som villfisken, høyere nevral aktivering etter stress i den ventrale delen av det dorsolaterale pallium (Dlv), et viktig område av hjernen assosiert med deklarativ hukommelse og romlig orientering. Videre hadde villfisken en stressindusert oppregulering av bdnf i det dorsomediale pallium (Dm), et område som regulerer emosjonell læring og stressreaktivitet, mens dette ikke var tilfelle for klekkerifisken. Dette studiet illustrerte at å undersøke delregioner av telencephalon kan avsløre mønstre som blir maskert ved å undersøke telencephalon som en enhet. I tillegg ble det vist at klekkerimiljøet påvirker nevroplastisiteten og den nevrale aktiviteten i hjerneområder viktige for læreprosesser og stressreaktivitet, noe som gir et nevralt fundament for de atferdsmessige forskjeller som blir observert mellom vill og kultivert fisk. Etter karakteriseringen av de nevrale forskjellene i telencephalons delregioner mellom vill og kultivert laks, undersøkte vi videre om strukturell berikelse av oppvekstmiljøet (EE) kunne bedre den regionspesifikke nevrale plastisiteten og kultiveringssuksessen av klekkerilaksen (Artikkel II). Etter syv ukers behandling viste EE-oppfostret parr høyere overlevelse etter utsetting i ferskvann enn kontrollindivider oppfostret i standard uniforme klekkeritanker. Den forbedrede kultiveringen ble imidlertid ikke gjenspeilet i signifikante endringer i telencephalons genuttrykk av plastisitetsmarkører. Selv om strukturell EE har demonstrert å gi noen, dog inkonsekvente, fordelaktige effekter på kultivering i flere studier, er klekkeriledere motvillige til å implementere dette grunnet de hygieniske og operasjonelle begrensinger de kan føre med seg. Det er derfor viktig å utvikle alternative oppfostringsmetoder som kan bedre fiskens nevrale utvikling og samtidig være mer praktisk å innføre i produksjonen. Ett slikt alternativ er svømmetrening, noe som tidligere har blitt knyttet til økt overlevelse hos laksefisk etter utsetting. Ettersom løping er assosiert med økt nevroplastisitet i pattedyr, undersøkte vi i Artikkel III om svømming kunne virke som en alternativ strategi for å bedre laksens nevroplastisitet og kognisjon. Etter åtte uker med vedvarende svømming fant vi økt uttrykk av nevroplastisitet-relaterte gentranskripter i telencephalons transkriptom hos de trente laksene. Vi testet deres evne til romlig orientering i en labyrinttest, men fant ingen bevis for økt kognisjon hos den trente fisken. Til tross for at tidligere studier har rapportert positive fysiologiske effekter av svømmetrening, slik som økt vekst eller stressreduksjon, så er dette første gang at trenings-stimulert nevroplastisitet har blitt rapportert i laksefisk, noe som indikerer at svømmetrening bør utforskes som en potensiell måte å øke utsettingssuksessen av klekkerilaks. Oppsummert bidrar resultatene i denne avhandlingen til en avansering av den anvendte fiskenevrobiologien i kultiveringssammenheng gjennom å karakterisere telencephalons nevroplastisitetsmarkører i laks på et mer detaljert nivå enn tidligere beskrevet. Vi viser at EE kan forbedre overlevelsen til parr i ferskvann, men at effektene av EE på nevroplastisitet er avmålte i de områder av telencephalon som ble studert her. Videre demonstrerer vi svømmetrening som et lovende nytt verktøy for forbedring av nevroplastisiteten i laks, samtidig som vi understreker at trening har ytterligere fysiologiske fortrinn og er relativt lett å få implementert i klekkeriene. Vi foreslår derfor at fremtidige arbeid har som mål å validere den potensielle nytten av trening i optimaliseringen av klekkeribetingelsene for kultivering og at fremtidige undersøkelser søker å forstå sammenhengen mellom oppvekstmiljøet, hjernen og atferd. ; De Atlantische zalm (Salmo salar) is een iconische vissoort die oorspronkelijk in overvloed voorkwam, maar door menselijk handelen zijn de wereldwijde aantallen in de afgelopen decennia sterk gedaald, met name door overbevissing en verlies van leefgebied. Om afnemende wilde zalmpopulaties te ondersteunen worden jaarlijks miljoenen Atlantische zalmen gekweekt en vervolgens in rivieren vrijgelaten via uitzettingsprogramma's. De omstandigheden in de kwekerijen zijn echter zeer uniform en prikkelarm, wat tot gevolg heeft dat de vis zich naïef gedraagt na vrijlating in de natuur. Vaak vertonen gekweekte zalmen bijvoorbeeld minder efficïent foerageergedrag en vallen ze snel ten prooi aan predators, en mede daardoor hebben ze een lage overlevingskans in het wild. De effecten van het kweken op het gedrag van vissen zijn redelijk goed beschreven, maar de effecten op de hersenen – het orgaan dat omgevingsprikkels vertaalt in geschikt gedrag – zijn tot nu toe sterk onderbelicht gebleven. De weinige studies die de impact van de kwekerijomgeving op het centraal zenuwstelsel van vissen hebben bestudeerd, hebben met name de expressie van neuroplasticitiets- en neurogenesegenen in kaart gebracht in de gehele hersenen, of in grote hersenstructuren zoals de gehele voorhersenen (telencephalon). De hersenen zijn echter een zeer complex orgaan en bestaan uit een overvloed aan neurale subpopulaties, ieder met verschillende functionaliteiten en kenmerken die specifieke typen gedrag aansturen. Bij het kwantificeren van neuroplasticiteitsmarkers in de gehele hersenen bestudeert men een verzameling van al deze neurale populaties, en nuances tussen hersengebieden kunnen niet worden gedetecteerd. Het doel van dit proefschrift is om een beter inzicht te krijgen in de neurale verschillen in subregio's van het telencephalon tussen wilde zalm en gekweekte zalm, en hoe innovatieve kweekmethoden verbeteringen kunnen bewerkstelligen in de neurobiologie, het gedrag en de overleving van gekweekte zalm. Allereerst hebben we een gedetailleerde karakterisatie gemaakt van de neurobiologie van juveniele wilde zalm en kweekzalm. Daarvoor hebben we de expressie van de neuroplasticiteitsmarker bdnf en de neurale activiteitsmarker cfos gekwantificeerd in vijf neurale subregio's van het telencephalon in wilde zalm en kweekzalm, zowel voor als na blootstelling aan een acute stressor (Paper I). We ontdekten dat de expressie van bdnf en cfos sterk varieerde tussen de bestudeerde subregio's, hetgeen bevestigt dat deze regio's ieder individuele eigenschappen hebben met betrekking tot hun reactie op externe stimuli. Vergeleken met wilde vis vertoonde de kweekvis van dezelfde genetische oorsprong na blootstelling aan stress een hogere neurale activering in het ventrale gebied van het dorsolaterale pallium (Dlv), een hersengebied dat belangrijk is voor relationeel geheugen en ruimtelijke oriëntatie. Gestresste wilde zalm vertoonde een verhoogde expressie van bndf in het dorsomediale pallium (Dm), dat belangrijk is voor het emotioneel geheugen en de stressrespons, terwijl dit niet het geval was voor gekweekte zalm. Deze studie toont aan dat het bestuderen van neurale subregio's in het telencephalon bepaalde expressiepatronen kan onthullen die niet gedetecteerd kunnen worden wanneer het telencephalon in zijn geheel bestudeerd wordt. Verder hebben we aangetoond dat het kweken van invloed is op de neuroplasticiteit en neurale activatie in hersenregio's die belangrijk zijn voor leerprocessen en de stressrespons. Deze resultaten kunnen een mogelijke verklaring geven voor de gedragsverschillen die worden waargenomen tussen wilde zalm en gekweekte zalm. Nadat we de neurale verschillen tussen wilde zalm en gekweekte zalm hadden gekarakteriseerd in de subregio's van het telencephalon, hebben we in Paper II onderzocht of de hersenplasticiteit en overlevingskansen van gekweekte zalm kunnen worden verbeterd door de kwekerij te verrijken met objecten als stenen en planten ('milieuverrijking'). Na zeven weken in een verrijkte omgeving hadden gekweekte zalmen een significant hogere overlevingskans na uitzetting in de rivier, vergeleken met een controlegroep die onder standaard omstandigheden was gekweekt. De verhoogde overlevingskans leek echter niet gepaard te gaan te met significante veranderingen in hersenplasticiteit. Hoewel milieuverrijking een aantal (maar inconsistente) gunstige effecten heeft laten zien op het succes van uitzettingsprogramma's, zijn de eigenaren van kwekerijen terughoudend om milieuverrijking te implementeren vanwege hygiënische en operationele bezwaren. Het is daarom belangrijk om alternatieve kweekmethoden te ontwikkelen die een gunstig effect hebben op de neurale ontwikkeling van vissen, zonder praktische nadelen mee te brengen voor kwekerijen. Een van deze alternatieve kweekmethoden is het implementeren van zwemtraining, waarvan in eerdere studies al is gebleken dat het de overlevingskans van uitgezette zalm ten goede kan komen. Daarnaast is bekend dat rennen positieve effecten heeft op hersenplasticiteit in zoogdieren, maar de neurologische effecten van zwemtraining zijn nog nooit grondig onderzocht in vis. Daarom hebben we in Paper III onderzocht of zwemtraining de hersenplasticiteit en cognitie van Atlantische zalm kan bevorderen. Na acht weken zwemtraining vonden we verhoogde expressie van hersenplasticiteit-gerelateerde genen in het telencephalon van getrainde zalm. Echter, we hebben geen bewijs gevonden van verhoogde cognitie in getrainde vissen met betrekking tot het ruimtelijk geheugen bij het oplossen van een doolhof. Hoewel eerdere studies positieve fysiologische effecten van zwemtraining in vissen beschrijven, zoals een efficiëntere lichaamsgroei en verminderde stress, is dit de eerste keer dat is aangetoond dat zwemtraining ook de hersenplasticiteit van zalmen kan bevorderen. Daarom lijkt zwemtraining een veelbelovende methode om de overlevingskansen van uitgezette zalm te bevorderen. De resultaten die gepresenteerd worden in dit proefschrift leveren een bijdrage op het terrein van de toegepaste visneurobiologie doordat we de expressie van hersenplasticiteitsmarkers in het telencephalon van Atlantische zalm op een meer gedetailleerd niveau hebben gekarakteriseerd dan ooit tevoren. We laten zien dat milieuverrijking de overlevingskans van jonge zalm in de zoetwaterfase kan verbeteren, maar dat effecten van milieuverrijking op hersenplasticiteit beperkt zijn in de bestudeerde regio's van het telencephalon. We identificeren zwemtraining als een veelbelovende alternatieve kweekmethode om de hersenplasticiteit in zalm te bevorderen, en merken daarnaast op dat zwemtraining toegevoegde fysiologische voordelen biedt en relatief eenvoudig te implementeren is in de kwekerij. Daarom stellen we voor dat toekomstige studies zich richten op de validatie van zwemtraining als methode om kweekomstandigheden te optimaliseren, en dat verder onderzoek de samenhang tussen kweekomstandigheden, hersenen en gedrag nauwkeuriger in kaart brengt. ; The European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 642893: Improved Production Strategies for Endangered Freshwater Species, "IMPRESS" The Europeun Union's Horizon 2020 research and innovation programme under grant agreement no. 652831 (AQUAEXCEL2020) for providing Transnational Access to Wageningen University & Research for Paper III The Research Council of Norway under the HAVBRUK programme, project number 268075/E40, for supplying a travel grant to support the work presented in Paper III COST Action FA1304 "Swimming of fish and implications for migration and aquaculture (FITFISH)" for funding the short-term scientific mission that led to Paper III The Physiology Division of the American Fisheries Society for providing a travel award to attend the 13th International Congress on the Biology of Fish in Calgary, Canada
Background A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. Methods Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita. Findings In 2016, HAQ Index performance spanned from a high of 97.1 (95% UI 95.8-98.1) in Iceland, followed by 96.6 (94.9-97.9) in Norway and 96.1 (94.5-97.3) in the Netherlands, to values as low as 18.6 (13.1-24.4) in the Central African Republic, 19.0 (14.3-23.7) in Somalia, and 23.4 (20.2-26.8) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91.5 (89.1-936) in Beijing to 48.0 (43.4-53.2) in Tibet (a 43.5-point difference), while India saw a 30.8-point disparity, from 64.8 (59.6-68.8) in Goa to 34.0 (30.3-38.1) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4.8-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20.9-point to 17.0-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17.2-point to 20.4-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries. Interpretation GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle-SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view and subsequent provision of quality health care for all populations. ; Bill & Melinda Gates Foundation. Barbora de Courten is supported by a National Heart Foundation Future Leader Fellowship (100864). Ai Koyanagi's work is supported by the Miguel Servet contract financed by the CP13/00150 and PI15/00862 projects, integrated into the National R + D + I and funded by the ISCIII —General Branch Evaluation and Promotion of Health Research—and the European Regional Development Fund (ERDF-FEDER). Alberto Ortiz was supported by Spanish Government (Instituto de Salud Carlos III RETIC REDINREN RD16/0019 FEDER funds). Ashish Awasthi acknowledges funding support from Department of Science and Technology, Government of India through INSPIRE Faculty scheme Boris Bikbov has received funding from the European Union's Horizon 2020 research and innovation programme under Marie Sklodowska-Curie grant agreement No. 703226. Boris Bikbov acknowledges that work related to this paper has been done on the behalf of the GBD Genitourinary Disease Expert Group. Panniyammakal Jeemon acknowledges support from the clinical and public health intermediate fellowship from the Wellcome Trust and Department of Biotechnology, India Alliance (2015–20). Job F M van Boven was supported by the Department of Clinical Pharmacy & Pharmacology of the University Medical Center Groningen, University of Groningen, Netherlands. Olanrewaju Oladimeji is an African Research Fellow hosted by Human Sciences Research Council (HSRC), South Africa and he also has honorary affiliations with Walter Sisulu University (WSU), Eastern Cape, South Africa and School of Public Health, University of Namibia (UNAM), Namibia. He is indeed grateful for support from HSRC, WSU and UNAM. EUI is supported in part by the South African National Research Foundation (NRF UID: 86003). Ulrich Mueller acknowledges funding by the German National Cohort Study grant No 01ER1511/D, Gabrielle B Britton is supported by Secretaría Nacional de Ciencia, Tecnología e Innovación and Sistema Nacional de Investigación de Panamá. Giuseppe Remuzzi acknowledges that the work related to this paper has been done on behalf of the GBD Genitourinary Disease Expert Group. Behzad Heibati would like to acknowledge Air pollution Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran. Syed Aljunid acknowledges the National University of Malaysia for providing the approval to participate in this GBD Project. Azeem Majeed and Imperial College London are grateful for support from the Northwest London National Insititute of Health Research (NIHR) Collaboration for Leadership in Applied Health Research & Care. Tambe Ayuk acknowledges the Institute of Medical Research and Medicinal Plant Studies for office space provided. José das Neves was supported in his contribution to this work by a Fellowship from Fundação para a Ciência e a Tecnologia, Portugal (SFRH/BPD/92934/2013). João Fernandes gratefully acknowledges funding from FCT–Fundação para a Ciência e a Tecnologia (grant number UID/Multi/50016/2013). Jan-Walter De Neve was supported by the Alexander von Humboldt Foundation. Kebede Deribe is funded by a Wellcome Trust Intermediate Fellowship in Public Health and Tropical Medicine (201900). Kazem Rahimi was supported by grants from the Oxford Martin School, the NIHR Oxford BRC and the RCUK Global Challenges Research Fund. Laith J Abu-Raddad acknowledges the support of Qatar National Research Fund (NPRP 9-040-3-008) who provided the main funding for generating the data provided to the GBD-IHME effort. Liesl Zuhlke is funded by the national research foundation of South Africa and the Medical Research Council of South Africa. Monica Cortinovis acknowledges that work related to this paper has been done on the behalf of the GBD Genitourinary Disease Expert Group. Chuanhua Yu acknowleges support from the National Natural Science Foundation of China (grant number 81773552 and grant number 81273179) Norberto Perico acknowledges that work related to this paper has been done on behalf of the GBD Genitourinary Disease Expert Group. Charles Shey Wiysonge's work is supported by the South African Medical Research Council and the National Research Foundation of South Africa (grant numbers 106035 and 108571). John J McGrath is supported by grant APP1056929 from the John Cade Fellowship from the National Health and Medical Research Council and the Danish National Research Foundation (Niels Bohr Professorship). Quique Bassat is an ICREA (Catalan Institution for Research and Advanced Studies) research professor at ISGlobal. Richard G White is funded by the UK MRC and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement that is also part of the EDCTP2 programme supported by the European Union (MR/P002404/1), the Bill & Melinda Gates Foundation (TB Modelling and Analysis Consortium: OPP1084276/OPP1135288, CORTIS: OPP1137034/OPP1151915, Vaccines: OPP1160830), and UNITAID (4214-LSHTM-Sept15; PO 8477-0-600). Rafael Tabarés-Seisdedos was supported in part by grant number PROMETEOII/2015/021 from Generalitat Valenciana and the national grant PI17/00719 from ISCIII-FEDER. Mihajlo Jakovljevic acknowleges contribution from the Serbian Ministry of Education Science and Technological Development of the Republic of Serbia (grant OI 175 014). Shariful Islam is funded by a Senior Fellowship from Institute for Physical Activity and Nutrition, Deakin University and received career transition grants from High Blood Pressure Research Council of Australia. Sonia Saxena is funded by various grants from the NIHR. Stefanos Tyrovolas was supported by the Foundation for Education and European Culture, the Sara Borrell postdoctoral program (reference number CD15/00019 from the Instituto de Salud Carlos III (ISCIII–Spain) and the Fondos Europeo de Desarrollo Regional. Stefanos was awarded with a 6 months visiting fellowship funding at IHME from M-AES (reference no. MV16/00035 from the Instituto de Salud Carlos III). S Vittal Katikreddi was funded by a NHS Research Scotland Senior Clinical Fellowship (SCAF/15/02), the MRC (MC_UU_12017/13 & MC_ UU_12017/15) and the Scottish Government Chief Scientist Office (SPHSU13 & SPHSU15). Traolach S Brugha has received funding from NHS Digital UK to collect data used in this study. The work of Hamid Badali was financially supported by Mazandaran University of Medical Sciences, Sari, Iran. The work of Stefan Lorkowski is funded by the German Federal Ministry of Education and Research (nutriCARD, Grant agreement number 01EA1411A). Mariam Molokhia's research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We also thank the countless individuals who have contributed to GBD 2016 in various capacities. ; Peer reviewed
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After six years of U.S. "maximum pressure," Iran's economy continues to defy dire predictions of economic collapse that motivated Trump's hasty 2018 withdrawal from the Iran nuclear deal (also known as the JCPOA). The Biden administration's continuation of the same policy since 2021 is similarly based on the logic that the weaker Iran's economy is, the more likely Tehran will bend to Washington's will. The economy's resilience is evidenced by the fact that in the first nine months of the Iranian fiscal year (March 21 to December 20, 2023), GDP grew by a 6.7% annual rate, and it is very likely to finish the year in two months with a growth rate exceeding the World Bank and IMF forecasts of about 4%.But, after more than a decade of decline in their living standards, resilience is not what ordinary Iranians are looking for. As a result of Trump's reimposition of sanctions in 2018, Iran's economic growth fell by 13.6 percentage points, from a positive annual growth rate of 9.5% during 2016-2017, when the JCPOA had eased U.S. sanctions, to negative 4.1% per year during 2018-2019.Since 2020, and helped by rising oil revenues, the economy has recovered some, growing steadily, if slowly, by about 4% per year. Even the damage from the Covid-19 pandemic, which was mostly on employment, has been repaired, and employment is now back to its pre-pandemic level. But, as Israel's war on Gaza continues, renewed tensions and proxy fights with the U.S. could put these fragile gains at risk of a reversal.Flawed recoveryThis modest growth has done little to dampen deep dissatisfaction with the economy among ordinary Iranians. Living standards have not yet recovered to their pre-Trump level, and inflation remains very high. In 2022, real household expenditures per capita were 7.7% below their 2017 level, far below where Iranians expected to be now based on two decades of rising real consumption before sanctions tightened in 2011. Inflation is an even larger source of popular discontent. For reasons that are not peculiar to Iranian society, people show more concern with rising prices than real incomes. They are unhappy with rising prices even if their incomes are keeping up with inflation. In 2018, with poor prospects from oil exports, the rial lost 2/3 of its value in a short time and caused prices to spike. Inflation rose from 8.1% in 2017 to 26.7% in 2018 and has remained above 30% since. Since the beginning of the Iranian year, a new Central Bank governor has tried to reduce inflation to below 30%, a very modest goal, but so far he has not succeeded. Last month, inflation was at 36.5% annual rate despite tightened credit and fiscal austerity, which shows itself in a stagnant real estate market.This mixed record is what hardliners are presenting to voters in the March 1 parliamentary elections and the record that President Ebrahim Raisi will be defending when he stands for re-election in June 2025. And this is no ordinary re-election because hardliners, who view the Raisi administration as the first "revolutionary government" since the founding of the Islamic Republic, hope to deliver on their promise of economic prosperity. They need to convince voters that their strategy of giving up on the nuclear deal and turning to the East (read China and Russia) can do better than the record of reformist presidents Mohammad Khatami (1997-2005) and Hassan Rouhani (2013-2021), whom they consider pro-west and "neo-liberal".Both Khatami and Rouhani were re-elected with bigger margins to their second terms. For President Raisi to do the same in 2025 he needs the robust growth rate of the past year to continue in 2024. As I argued last November, meeting this challenge is an important reason why Iranian hardliners are unwilling to get drawn into the Israel-Hamas conflict.Darker clouds on the horizon threaten economic recoveryBesides the fact that economies grow faster when they are recovering from a trough, the growth should slow down in 2024. In addition, rising tensions in the region worsen the prospect for growth. Iran may be intent on not getting involved, but protecting its fragile recovery from an expanding regional conflict may be increasingly difficult. Iran's allies in the "resistance front" in Yemen, Iraq, Syria, and Lebanon are challenging U.S. and Israeli forces. Even if Iran stays out of the fray, the conflict is bound to have a negative effect on Iran's recovery, if only because Washington would try harder to limit Iran's oil exports and refuse Iran access to its previously frozen funds.This month Iran angered Iraq and Pakistan after it bombed two locations in these countries, ostensibly taking revenge for a terrorist attack a month ago in Kerman that killed over 100 bystanders. Adding a third nuclear power to the two that it is already in conflict with – the U.S. and Israel – may show Iran's military resolve but also increases the risk of conflict.Rising tensions have caused the rial, which enjoyed months of stability, to lose 10% of its value in the free market just in the past two weeks. If the rial continues to lose value, the task of bringing inflation down to below 30% will become much harder in the coming months.More lax enforcement of oil sanctions since Biden's election, intended to keep Iran from increasing its stockpile of enriched uranium and obtain the release of U.S. hostages, has allowed Tehran to sell more oil. More oil revenues have been the largest factor in Iran's economic recovery. According to the Statistical Center of Iran, in the last three years the value added of the oil and gas sector has grown three times as fast as the GDP. So, if Washington decides to police Iran' oil exports more aggressively, growth will suffer.Finally, in the longer run, the financial components of U.S. sanctions prevent Iran from taking advantage of its deep devaluations by increasing its non-oil exports. Devaluations have reduced the cost of unskilled Iranian labor in export markets to about $10 per day, half the average unskilled wage in China. Devaluations helped Iran substitute its own products for imports, but there are limits to this substitution, especially with the domestic demand depressed to fight inflation. A fuller economic recovery from the loss of oil exports requires exporting more manufactures and services, which financial sanctions make costly and difficult.Escaping sanctions?Iran's recent diplomatic successes have reduced its isolation but will not translate into economic growth in the short term. In 2023, Iran, aided by China, repaired its broken diplomatic relations with its Persian Gulf neighbors; gained entry into BRICS, an organization that includes rising non-aligned global players; and joined the Shanghai Cooperation Organization that, at least in one observer's opinion, is a "game changer." While these developments bode well for Iran's ability to resist U.S. sanctions in the long run, they are unlikely to translate into more investment and economic growth in the short run.What these successes have accomplished so far is to convince Iranian hardliners that their strategy of resistance to U.S. pressure has raised the Islamic Republic's global stature, just as the West has tried to isolate it. They see the emerging multipolar world as one in which unilateral sanctions lose their sting and one that allows Iran to turn its newfound geopolitical capital into economic growth.
Mención Internacional en el título de doctor ; One of the foremost and challenging subfields of MRI is cardiac magnetic resonance imaging (CMR). CMR is becoming an indispensable tool in cardiovascular medicine by acquiring data about anatomy and function simultaneously. For instance, it allows the non-invasive characterization of myocardial tissues via parametric mapping techniques. These mapping techniques provide a spatial visualization of quantitative changes in the myocardial parameters. Inspired by the need to develop novel high-quality parametric sequences for 3T, this thesis's primary goal is to introduce an accurate and efficient 3D single breath-hold MR methodology for measuring cardiac parametric mapping at 3T. This thesis is divided into two main parts: i) research and development of a new 3D T1 saturation recovery mapping technique (3D SACORA), together with a feasibility study regarding the possibility of adding a T2 mapping feature to 3D SACORA concepts, and ii) research and implementation of a deep learning-based post-processing method to improve the T1 maps obtained with 3D SACORA. In the first part of the thesis, 3D SACORA was developed as a new 3D T1 mapping sequence to speed up T1 mapping acquisition of the whole heart. The proposed sequence was validated in phantoms against the gold standard technique IR-SE and in-vivo against the reference sequence 3D SASHA. The 3D SACORA pulse sequence design was focused on acquiring the entire left ventricle in a single breath-hold while achieving good quality T1 mapping and stability over a wide range of heart rates (HRs). The precision and accuracy of 3D SACORA were assessed in phantom experiments. Reference T1 values were obtained using IR-SE. In order to further validate 3D SACORA T1 estimation accuracy and precision, T1 values were also estimated using an in-house version of 3D SASHA. For in-vivo validation, seven large healthy pigs were scanned with 3D SACORA and 3D SASHA. In all pigs, images were acquired before and after administration of MR contrast agent. The phantom results showed good agreement and no significant bias between methods. In the in-vivo experiments, all T1-weighted images showed good contrast and quality, and the T1 maps correctly represented the information contained in the T1-weighted images. Septal T1s and coefficients of variation did not considerably differ between the two sequences, confirming good accuracy and precision. 3D SACORA images showed good contrast, homogeneity and were comparable to corresponding 3D SASHA images, despite the shorter acquisition time (15s vs. 188s, for a heart rate of 60 bpm). In conclusion, the proposed 3D SACORA successfully acquired a whole-heart 3D T1 map in a single breath-hold at 3T, estimating T1 values in agreement with those obtained with the IR-SE and 3D SASHA sequences. Following the successful validation of 3D SACORA, a feasibility study was performed to assess the potential of modifying the acquisition scheme of 3D SACORA in order to obtain T1 and T2 maps simultaneously in a single breath-hold. This 3D T1/T2 sequence was named 3D dual saturation-recovery compressed SENSE rapid acquisition (3D dual-SACORA). A phantom of eight tubes was built to validate the proposed sequence. The phantom was scanned with 3D dual-SACORA with a simulated heart rate of 60 bpm. Reference T1 and T2 values were estimated using IR-SE and GraSE sequences, respectively. An in-vivo study was performed with a healthy volunteer to evaluate the parametric maps' image quality obtained with the 3D dual-SACORA sequence. T1 and T2 maps of the phantom were successfully obtained with the 3D dual-SACORA sequence. The results show that the proposed sequence achieved good precision and accuracy for most values. A volunteer was successfully scanned with the proposed sequence (acquisition duration of approximately 20s) in a single breath-hold. The saturation time images and the parametric maps obtained with the 3D dual-SACORA sequence showed good contrast and homogeneity. The septal T1 and T2 values are in good agreement with reference sequences and published work. In conclusion, this feasibility study's findings open the door to the possibility of using 3D SACORA concepts to develop a successful 3D T1/T2 sequence. In the second part of the thesis, a deep learning-based super-resolution model was implemented to improve the image quality of the T1 maps of 3D SACORA, and a comprehensive study of the performance of the model in different MR image datasets and sequences was performed. After careful consideration, the selected convolutional neural network to improve the image quality of the T1 maps was the Residual Dense Network (RDN). This network has shown outstanding performance against state-of-the-art methods on benchmark datasets; however, it has not been validated on MR datasets. In this way, the RDN model was initially validated on cardiac and brain benchmark datasets. After this validation, the model was validated on a self-acquired cardiac dataset and on improving T1 maps. The RDN model improved the images successfully for the two benchmark datasets, achieving better performance with the brain dataset than with the cardiac dataset. This result was expected as the brain images have more well-defined edges than the cardiac images, making the resolution enhancement more evident. On the self-acquired cardiac dataset, the model also obtained an enhanced performance on image quality assessment metrics and improved visual assessment, particularly on well-defined edges. Regarding the T1 mapping sequences, the model improved the image quality of the saturation time images and the T1 maps. The model was able to enhance the T1 maps analytically and visually. Analytically, the model did not considerably modify the T1 values while improving the standard deviation in both myocardium and blood. Visually, the model improved the T1 maps by removing noise and motion artifacts without losing resolution on the edges. In conclusion, the RDN model was validated on three different MR datasets and used to improve the image quality of the T1 maps obtained with 3D SACORA and 3D SASHA. In summary, a 3D single breath-hold MR methodology was introduced, including a ready to-go 3D single breath-hold T1 mapping sequence for 3T (3D SACORA), together with the ideas for a new 3D T1/T2 mapping sequence (3D dual-SACORA); and a deep learning-based post-processing implementation capable of improving the image quality of 3D SACORA T1 maps. ; This thesis has received funding from the European Union Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement N722427. ; Programa de Doctorado en Multimedia y Comunicaciones por la Universidad Carlos III de Madrid y la Universidad Rey Juan Carlos ; Presidente: Carlos Alberola López.- Secretario: María Jesús Ledesma Carbayo.- Vocal: Nathan Mewton
Lo scopo di questa ricerca applicata è quello di indagare l'opinione degli imprenditori vitivinicoli in merito alla collaborazione con l'università, orientata all'innovazione sostenibile, oltre a comprendere se e in quale misura le certificazioni sostenibili influenzino la percezione edonica di un vino da parte di consumatori esperti. Come viene esposto nel primo capitolo, l'esigenza di attuare pratiche sostenibili, sia dal punto di vista ambientale, che da quello economico e sociale, è stata incentivata dalla pubblicazione, nel 1972, di Blueprint to Survive da parte di The Ecologist. Nello stesso anno, la commissione Brundtland introduceva il concetto di sviluppo sostenibile, che mira a soddisfare i bisogni del presente, senza compromettere la possibilità alle generazioni future di soddisfare i propri. Nel contesto europeo sono state adottate diverse misure per la sua diffusione, come l'adesione dell'Unione Europea all'Agenda 2030 e ai suoi diciassette Obiettivi di Sviluppo Sostenibile, per eliminare la povertà garantendo l'uguaglianza tra tutti gli Stati membri: essa ribadisce l'importanza delle tre dimensioni dello sviluppo sostenibile - economica, sociale e ambientale - e diffonde valori quali il perseguimento della pace e della giustizia. Nel settore agroalimentare, l'Unione Europea ha sviluppato politiche specifiche per incoraggiare lo sviluppo sostenibile, come la Politica Agricola Comunitaria (PAC) e Horizon 2020, le quali, insieme ad altri programmi, forniscono fondi per attività di ricerca innovative, promuovendo la crescita sostenibile e la creazione di posti di lavoro. Nel secondo capitolo, si approfondiscono le potenzialità del rapporto università/piccole-medie imprese vitivinicole, per promuovere l'innovazione orientata alla sostenibilità. Secondo Silvestre e Ţîrcă (2019), l'innovazione è considerata un fattore chiave che contribuisce alla sostenibilità. Per facilitare tale processo, la collaborazione tra gli stakeholders del territorio è ritenuta fondamentale; per favorire lo sviluppo di tecnologie eco-efficienti, può essere rilevante coinvolgere attori che non fanno parte dell'attività produttiva, ad esempio le università (Chen, 2008; Noci and Verganti, 1999). Nel settore vitivinicolo, troviamo diversi esempi dei benefici derivanti da questa relazione, come il caso di studio di Giuliani e Bell (2005), in cui vengono sottolineati gli aspetti positivi del cluster tra stakeholders. Nell'ambito del progetto The Wine Lab, sono state condotte interviste semi-strutturate con le aziende vinicole, per comprendere le loro difficoltà e verificare se, da parte loro, vi sia o meno una propensione a creare le basi per questo rapporto, al fine di promuovere innovazione e sostenibilità nelle loro attività. Per l'analisi dei dati è stato utilizzato il metodo della Grounded Theory. Una volta raccolti e trascritti i dati delle interviste, sono state realizzate delle categorie attraverso il line-by-line coding (Glaser e Strauss, 1967; Charmaz, 2006). In termini di difficoltà, è emerso che uno dei problemi principali è la burocrazia, seguita dalla gestione sostenibile (che si traduce in mancanza di personale e fondi, posizione della cantina e clima avverso), dal marketing e dalla promozione sul mercato nazionale e internazionale, dalla mancanza di interazione tra imprese e stakeholders sul territorio e dalla necessità di innovazione. Secondo la maggior parte degli intervistati, è necessario incoraggiare la collaborazione tra cantine e stakeholders, in quanto può facilitare lo scambio di conoscenze e implementare pratiche innovative e sostenibili. Gli studenti sono stati percepiti come gli elementi chiave per la costruzione di questa rete. L'ultimo capitolo di questo elaborato, infine, approfondisce il punto di vista del consumatore esperto, andando ad indagare quanto le certificazioni sostenibili presenti in etichetta influenzino la percezione edonica del vino. Le etichette dei vini sono fondamentali per comunicare tutte le loro caratteristiche e sono considerate indispensabili ai fini della scelta del consumatore (Müller et al.,2010; Goodman, 2009). L'obiettivo principale delle certificazioni sostenibili è quello di informare il consumatore che alcuni produttori praticano un'agricoltura biologica o eco-friendly e cercano di differenziarli attraverso l'informazione sull'etichetta del vino (Dans et al., 2019; Sogari et al., 2015). Nel settore vitivinicolo, c'è una forte attenzione ai vini sostenibili, ma riguardo la percezione sensoriale, la conoscenza è scarsa (Troiano et al., 2016, Schaufele e Hamm, 2018). Pertanto, per analizzare il secondo quesito di questa ricerca, è stato realizzato un focus group ad undici studenti del corso di Wine Export Management dell'Università di Camerino, seguito da un expectation test. Durante il focus group, è stato chiesto ai partecipanti di esprimere la loro opinione sul vino sostenibile, le loro aspettative, i vantaggi e gli svantaggi e le analisi del contesto di mercato. Dalla discussione è emersa la possibilità di guardare alla sostenibilità con un approccio storico, socioeconomico, ambientalista ed etico. Si sostiene, inoltre, che nella scelta tra vino convenzionale e sostenibile, è l'esperienza del consumatore che fa la differenza: chi opta per questa opzione, si aspetta una qualità migliore. A livello sensoriale, non esistono differenze. In seguito, i partecipanti sono stati invitati a aderire all'expectation test, che prevedeva l'assaggio di tre tipologie di Montepulciano d'Abruzzo, uno convenzionale, uno con logo biologico europeo e uno con logo biodinamico Demeter, della stessa annata e prezzo, in tre fasi differenti: il blind test, l'expected test e il labelled test. Per ogni fase è stata fornita una scala a nove punti per valutare l'indice di gradimento; in particolare, 1 = Estremamente sgradevole, 9 = Estremamente gradevole. I dati sono stati elaborati utilizzando l'analisi della varianza one way ANOVA tra i diversi valori, per comprendere le differenze di percezione dei vini scelti nelle tre diverse fasi. L'analisi dei dati sottolinea che in ogni stadio del test, la percezione tra le varie etichette subisce un piccolo margine di variazione. Nel complesso, l'etichetta biologica possiede il maggior gradimento, soprattutto nella fase expected. Questo risultato potrebbe essere giustificato dal fatto che gli assaggiatori sono esperti del settore; pertanto, l'aspetto sensoriale risulta più rilevante rispetto alla presenza o meno di certificazioni sull'etichetta. Un mese dopo, i partecipanti sono stati contattati ed invitati ad esprimere un'opinione su quanto appreso sulle certificazioni e su quale sia stato per loro l'elemento più importante di questa esperienza. Ciò che è emerso è che le etichette sostenibili sono mezzi di comunicazione per il consumatore e che un'etichetta con logo biologico o biodinamico ha certamente più "appeal" rispetto ad un vino convenzionale; tuttavia, essi potrebbero anche apparire controproducenti, in quanto alcuni consumatori considerano i vini sostenibili di minor qualità rispetto a quelli convenzionali. Ciononostante, è stato riconosciuto che le etichette sostenibili sono un pilastro importante del sistema agroalimentare nazionale e globale e rappresentano un veicolo di promozione che deve essere incoraggiato. I partecipanti hanno descritto l'esperienza in maniera positiva, affermando di aver compreso che, nella fase di acquisto, l'etichetta è fondamentale nella scelta del vino e che essa è in grado di influenzare la percezione del prodotto. Infine, hanno preso coscienza di come le tendenze possano condizionare il mercato: se non c'è una reale conoscenza del significato dei loghi e i consumatori non sono esperti del settore, sceglieranno quello che, ad oggi, risulta più di tendenza.
Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation. ; The authors would like to thank the many colleagues who contributed to collection and phenotypic characterisation of the clinical samples, as well as genotyping and analysis of the GWA data. Special mentions are as follows: CGSB participating cohorts: Some of the data utilised in this study were provided by the Understanding Society: The UK Household Longitudinal Study, which is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The data were collected by NatCen and the genome wide scan data were analysed by the Wellcome Trust Sanger Institute. The Understanding Society DAC have an application system for genetics data and all use of the data should be approved by them. The application form is at: https://www.understandingsociety.ac.uk/about/health/data. The Airwave Health Monitoring Study is funded by the UK Home Office, (Grant number 780-TETRA) with additional support from the National Institute for Health Research Imperial College Health Care NHS Trust and Imperial College Biomedical Research Centre. We thank all participants in the Airwave Health Monitoring Study. This work used computing resources provided by the MRC- funded UK MEDical Bioinformatics partnership programme (UK MED-BIO) (MR/L01632X/1). Paul Elliott wishes to acknowledge the Medical Research Council and Public Health England (MR/L01341X/1) for the MRC-PHE Centre for Environment and Health; and the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141). Paul Elliott is supported by the UK Dementia Research Institute which receives its funding from UK DRI Ltd funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Paul Elliott is associate director of the Health Data Research UK London funded by a consortium led by the UK Medical Research Council. SHIP (Study of Health in Pomerania) and SHIP-TREND both represent population-based studies. SHIP is supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung (BMBF); grants 01ZZ9603, 01ZZ0103, and 01ZZ0403) and the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG); grant GR 1912/5-1). SHIP and SHIP-TREND are part of the Community Medicine Research net (CMR) of the Ernst-Moritz-Arndt University Greifswald (EMAU) which is funded by the BMBF as well as the Ministry for Education, Science and Culture and the Ministry of Labor, Equal Opportunities, and Social Affairs of the Federal State of Mecklenburg-West Pomerania. The CMR encompasses several research projects that share data from SHIP. SNP typing of SHIP and SHIP-TREND using the Illumina Infinium HumanExome BeadChip (version v1.0) was supported by the BMBF (grant 03Z1CN22). LifeLines authors thank Behrooz Alizadeh, Annemieke Boesjes, Marcel Bruinenberg, Noortje Festen, Ilja Nolte, Lude Franke, Mitra Valimohammadi for their help in creating the GWAS database, and Rob Bieringa, Joost Keers, René Oostergo, Rosalie Visser, Judith Vonk for their work related to data-collection and validation. The authors are grateful to the study participants, the staff from the LifeLines Cohort Study and Medical Biobank Northern Netherlands, and the participating general practitioners and pharmacists. LifeLines Scientific Protocol Preparation: Rudolf de Boer, Hans Hillege, Melanie van der Klauw, Gerjan Navis, Hans Ormel, Dirkje Postma, Judith Rosmalen, Joris Slaets, Ronald Stolk, Bruce Wolffenbuttel; LifeLines GWAS Working Group: Behrooz Alizadeh, Marike Boezen, Marcel Bruinenberg, Noortje Festen, Lude Franke, Pim van der Harst, Gerjan Navis, Dirkje Postma, Harold Snieder, Cisca Wijmenga, Bruce Wolffenbuttel. The authors wish to acknowledge the services of the LifeLines Cohort Study, the contributing research centres delivering data to LifeLines, and all the study participants. Niek Verweij was supported by NWO VENI (016.186.125). Fenland authors thank Fenland Study volunteers for their time and help, Fenland Study general Practitioners and practice staff for assistance with recruitment, and Fenland Study Investigators, Co-ordination team and the Epidemiology Field, Data and Laboratory teams for study design, sample/data collection and genotyping. We thank all ASCOT trial participants, physicians, nurses, and practices in the participating countries for their important contribution to the study. In particular we thank Clare Muckian and David Toomey for their help in DNA extraction, storage, and handling. We would also like to acknowledge the Barts and The London Genome Centre staff for genotyping the Exome Chip array. The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. We would also like to thank the Barts Genome Centre staff for their assistance with this project. Patricia B. Munroe, Mark J. Caulfield, and Helen R. Warren wish to acknowledge the NIHR Cardiovascular Biomedical Research Unit at Barts and The London, Queen Mary University of London, UK for support. Mark J. Caulfield are Senior National Institute for Health Research Investigators. EMBRACE Collaborating Centres are: Coordinating Centre, Cambridge: Daniel Barrowdale, Debra Frost, Jo Perkins. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Marc Tischkowitz, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James's Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy's Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Gemma Serra-Feliu. Cheshire & Merseyside Clinical Genetics Service, Liverpool: Ian Ellis, Claire Foo. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Alex Henderson, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Nazneen Rahman, Elizabeth Bancroft, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Jenny Pope, Sibel Saya, Natalie Taylor, Zoe Kemp and Angela George. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. Understanding Society Scientific Group is funded by the Economic and Social Research Council (ES/H029745/1) and the Wellcome Trust (WT098051). Paul D.P. Pharoah is funded by Cancer Research UK (C490/A16561). SHIP is funded by the German Federal Ministry of Education and Research (BMBF) and the German Research Foundation (DFG); see acknowledgements for details. F.W. Asselbergs is funded by the Netherlands Heart Foundation (2014T001) and supported by UCL Hospitals NIHR Biomedical Research Centre. The LifeLines Cohort Study, and generation and management of GWAS genotype data for the LifeLines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. Niek Verweij is supported by Horizon 2020, Marie Sklodowska-Curie (661395) and ICIN-NHI. Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK's Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Genotyping was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, and the Royal Society of Edinburgh. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. Paul W. Franks is supported by Novo Nordisk, the Swedish Research Council, Påhlssons Foundation, Swedish Heart Lung Foundation (2020389), and Skåne Regional Health Authority. Nicholas J Wareham, Claudia Langenberg, Robert A Sacott, and Jian'an Luan are supported by the MRC (MC_U106179471 and MC_UU_12015/1). The BRIGHT study was supported by the Medical Research Council of Great Britain (Grant Number G9521010D); and by the British Heart Foundation (Grant Number PG/02/128). The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. The Exome Chip genotyping was funded by Wellcome Trust Strategic Awards (083948 and 085475). We would also like to thank the Barts Genome Centre staff for their assistance with this project. The ASCOT study and the collection of the ASCOT DNA repository was supported by Pfizer, New York, NY, USA, Servier Research Group, Paris, France; and by Leo Laboratories, Copenhagen, Denmark. Genotyping of the Exome Chip in ASCOT-SC and ASCOT-UK was funded by the National Institutes of Health Research (NIHR). Anna F. Dominiczak was supported by the British Heart Foundation (Grant Numbers RG/07/005/23633, SP/08/005/25115); and by the European Union Ingenious HyperCare Consortium: Integrated Genomics, Clinical Research, and Care in Hypertension (grant number LSHM-C7-2006-037093). Nilesh J. Samani is supported by the British Heart Foundation and is a Senior National Institute for Health Research Investigator. Panos Deloukas is supported by the British Heart Foundation (RG/14/5/30893), and NIHR, where his work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Centre which is funded by the National Institute for Health Research (NIHR). The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z, 090532 & 098381) the NIHR (RP-PG-0407-10371), the NIHR Official Development Assistance (ODA, award 16/136/68), the European Union FP7 (EpiMigrant, 279143) and H2020 programs (iHealth-T2D, 643774). We acknowledge support of the MRC-PHE Centre for Environment and Health, and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards. The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the Imperial College Healthcare NHS Trust, the NHS, the NIHR or the Department of Health. We thank the participants and research staff who made the study possible. JC is supported by the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award (NMRC/STaR/0028/2017). The research was supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility and ERC grant 323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC to T.M. Frayling. Hanieh Yaghootkar is funded by Diabetes UK RD Lawrence fellowship (grant:17/0005594) Anna Dominiczak was funded by a BHF Centre of Research Excellence Award (RE/13/5/30177) GSCAN participating cohorts: The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators: B. Porjesz, V. Hesselbrock, H. Edenberg, L. Bierut. The study includes eleven different centers: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, J. Nurnberger Jr., T. Foroud); University of Iowa (S. Kuperman, J. Kramer); SUNY Downstate (B. Porjesz); Washington University in St. Louis (L. Bierut, J. Rice, K. Bucholz, A. Agrawal); University of California at San Diego (M. Schuckit); Rutgers University (J. Tischfield, A. Brooks); Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA (L. Almasy), Virginia Commonwealth University (D. Dick), Icahn School of Medicine at Mount Sinai (A. Goate), and Howard University (R. Taylor). Other COGA collaborators include: L. Bauer (University of Connecticut); J. McClintick, L. Wetherill, X. Xuei, Y. Liu, D. Lai, S. O'Connor, M. Plawecki, S. Lourens (Indiana University); G. Chan (University of Iowa; University of Connecticut); J. Meyers, D. Chorlian, C. Kamarajan, A. Pandey, J. Zhang (SUNY Downstate); J.-C. Wang, M. Kapoor, S. Bertelsen (Icahn School of Medicine at Mount Sinai); A. Anokhin, V. McCutcheon, S. Saccone (Washington University); J. Salvatore, F. Aliev, B. Cho (Virginia Commonwealth University); and Mark Kos (University of Texas Rio Grande Valley). A. Parsian and M. Reilly are the NIAAA Staff Collaborators. COGA investigators continue to be inspired by their memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, P. Michael Conneally, Raymond Crowe, and Wendy Reich, for their critical contributions. COGA investigators are very grateful to Dr. Bruno Buecher without whom this project would not have existed. The authors also thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. ASTERISK, a GECCO sub-study, also thanks all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. As part of the GECCO sub-studies, CPS-II authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. Another GECCO sub-study, HPFS and NHS investigators would like to acknowledge Patrice Soule and Hardeep Ranu of the Dana Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS, HPFS under the supervision of Dr. Immaculata Devivo and Dr. David Hunter, Qin (Carolyn) Guo and Lixue Zhu who assisted in programming for NHS and HPFS. HPFS and NHS investigators also thank the participants and staff of the Nurses' Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. PLCO, a substudy within GECCO, was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, and additionally supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS1, CGEMS pancreatic cancer scan (PanScan)2, 3, and the Lung Cancer and Smoking study4. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. The authors thank Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff or the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services, Inc., Ms. Barbara O'Brien and staff, Westat, Inc., and Drs. Bill Kopp and staff, SAIC-Frederick. Most importantly, we acknowledge the study participants for their contributions to making this study possible. We also thank all participants and staff of the André and France Desmarais Montreal Heart Institute's (MHI) Biobank. The genotyping of the MHI Biobank was done at the MHI Pharmacogenomic Centre and funded by the MHI Foundation. HRS is supported by the National Institute on Aging (NIA U01AG009740). The genotyping was funded separately by the National Institute on Aging (RC2 AG036495, RC4 AG039029). Our genotyping was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the University of Michigan School of Public Health. CHDExome+ participating cohorts: BRAVE: The BRAVE study genetic epidemiology working group is a collaboration between the Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK, the Centre for Control of Chronic Diseases, icddr,b, Dhaka, Bangladesh and the National Institute of Cardiovascular Diseases, Dhaka, Bangladesh. CCHS, CIHDS, and CGPS collaborators thank participants and staff of the Copenhagen City Heart Study, Copenhagen Ischemic Heart Disease Study, and the Copenhagen General Population Study for their important contributions. EPIC-CVD: CHD case ascertainment and validation, genotyping, and clinical chemistry assays in EPIC-CVD were principally supported by grants awarded to the University of Cambridge from the EU Framework Programme 7 (HEALTH-F2-2012-279233), the UK Medical Research Council (G0800270) and British Heart Foundation (SP/09/002), and the European Research Council (268834). We thank all EPIC participants and staff for their contribution to the study, the laboratory teams at the Medical Research Council Epidemiology Unit for sample management and Cambridge Genomic Services for genotyping, Sarah Spackman for data management, and the team at the EPIC-CVD Coordinating Centre for study coordination and administration. MORGAM: The work by MORGAM collaborators has been sustained by the MORGAM Project's recent funding: European Union FP 7 projects ENGAGE (HEALTH-F4-2007-201413), CHANCES (HEALTH-F3-2010-242244) and BiomarCaRE (278913). This has supported central coordination, workshops and part of the activities of the The MORGAM Data Centre, at THL in Helsinki, Finland. MORGAM Participating Centres are funded by regional and national governments, research councils, charities, and other local sources. PROSPER: collaborators have received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° HEALTH-F2-2009-223004 PROMIS: The PROMIS collaborators are are thankful to all the study participants in Pakistan. Recruitment in PROMIS was funded through grants available to investigators at the Center for Non-Communicable Diseases, Pakistan (Danish Saleheen and Philippe Frossard) and investigators at the University of Cambridge, UK (Danish Saleheen and John Danesh). Field-work, genotyping, and standard clinical chemistry assays in PROMIS were principally supported by grants awarded to the University of Cambridge from the British Heart Foundation, UK Medical Research Council, Wellcome Trust, EU Framework 6-funded Bloodomics Integrated Project, Pfizer. We would like to acknowledge the contributions made by the following individuals who were involved in the field work and other administrative aspects of the study: Mohammad Zeeshan Ozair, Usman Ahmed, Abdul Hakeem, Hamza Khalid, Kamran Shahid, Fahad Shuja, Ali Kazmi, Mustafa Qadir Hameed, Naeem Khan, Sadiq Khan, Ayaz Ali, Madad Ali, Saeed Ahmed, Muhammad Waqar Khan, Muhammad Razaq Khan, Abdul Ghafoor, Mir Alam, Riazuddin, Muhammad Irshad Javed, Abdul Ghaffar, Tanveer Baig Mirza, Muhammad Shahid, Jabir Furqan, Muhammad Iqbal Abbasi, Tanveer Abbas, Rana Zulfiqar, Muhammad Wajid, Irfan Ali, Muhammad Ikhlaq, Danish Sheikh and Muhammad Imran. INTERVAL: Participants in the INTERVAL randomised controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was funded by the National Institute of Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk/) and the NIHR Cambridge Biomedical Research Centre (www.cambridge-brc.org.uk). The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics, UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194), and NIHR Research Cambridge Biomedical Research Centre. A complete list of the investigators and contributors to the INTERVAL trial is provided in reference.
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Foreign policy mandarins have spent years fighting over what to make of former President Donald Trump. At heart, is he a hawk or a dove? Does he hope to be a new Nixon, capable of seeking detente with enemies despite (or even because of) his mean streak? Or perhaps a new Reagan, focused on achieving "peace through strength"?I might ask it a different way: Who cares? New political science research suggests that Trump's personal views are not the most important part of the puzzle. In short, it's the advisers, stupid. This may sound like received wisdom, but its implications are profound. Researchers created an unprecedented dataset of minutes from presidential meetings related to foreign policy during the Cold War. Using complex statistical methods, they found that the relative hawkishness of a president's advisers is a remarkably good predictor of whether a leader will make "conflictual decisions" regarding an adversary.The differences can be stark. If you assemble the most hawkish group of presidential advisers from the Cold War, the model predicts they would make six times as many aggressive choices as the least hawkish group. Over the course of a presidency, that could mean hundreds of extra moves liable to spark new conflicts or escalate simmering disputes."Who dominates the room [...] does seem to have a systematic effect" on whether presidents choose hawkish or dovish paths, said Tyler Jost, a professor at Brown University who co-led the project.Now, Trump has a unique opportunity. The new research finds that hawkishness is surprisingly consistent from administration to administration; in fact, it varies more within administrations than between them — a statistical testament to the power of the so-called foreign policy "blob." Perhaps more than any president in recent memory, Trump has the chance to ditch advocates of global primacy and hire proponents of a more restrained U.S. foreign policy.Indeed, the former president is spoiled for choice. Most candidates for posts in a new Trump administration now agree that Washington should shift its focus to Asia by pursuing real retrenchment in Europe and the Middle East. Sen. J.D. Vance (R-Ohio) — a close Trump ally and top vice presidential candidate — has slammed U.S. military adventurism, called for a negotiated settlement in Ukraine, and even voted in favor of removing U.S. troops from Syria in December.New think tanks have popped up to support this viewpoint, and some old conservative stalwarts have refashioned themselves as America Firsters who want to help shape a different, more populist vision of U.S. foreign policy. These groups are creating staffing pipelines for a new brand of conservative foreign policy, and the consequences of their investment could go far beyond 2024.The transition battleThe Heritage Foundation wants you to know that it's changed. Once a premier home for neocons and uber hawks, the eminence grise of conservative politics now loudly calls for the U.S. to pull back from the Middle East and Europe, all while railing against inefficient military spending.Heritage's shift reflects broader changes in the conservative movement dating back to Trump's first election in 2016. "The real America First foreign policy position recognizes that the last few decades were characterized by a series of blunders," argued Micah Meadowcroft, the research director at the conservative Center for Renewing America (CRA) and a former staffer in the Trump White House. "Our leadership class messed up badly" during the so-called unipolar moment by launching a global crusade against terrorism and ignoring China's rise, Meadowcroft told RS.Conservative realists hope that recognizing this shift will allow the U.S. to focus all of its attention on preparing for — and hopefully deterring — a war with China over Taiwan. "China remains the single greatest threat to American interests in the world today, and we just haven't been acting like it," said Alex Velez-Green, a former adviser to Sen. Josh Hawley (R-Mo.) now based at Heritage. "My view is that a new administration will really need to prioritize it."The key question is how to strike a balance between deterrence and provocation. Velez-Green draws on a "peace through strength" tradition exemplified by Elbridge Colby, a prominent China hawk who appears poised to get a major role in a new Trump administration. While all hope to avoid war, other realists have argued for a more conservative approach to Beijing's rise.Regardless of the reasons behind this broader shift, conservatives have made big investments in order to shape its path. The most influential effort is Heritage's Project 2025, an initiative that has raised millions of dollars to identify potential staffers for a second Trump administration and plan policies to help vault it back into the White House.For supporters of a more restrained foreign policy, Project 2025 has a lot to offer. While any Heritage program is bound to make up a big tent of conservative views, "the leadership of Project 2025 is a lot more aligned to a more Trumpian strain of America First, which is a more narrow, national-interest oriented idea," said Sumantra Maitra of the CRA, who has advised on the effort. Will Ruger, who Trump nominated as his ambassador to Afghanistan, welcomed Heritage's shift toward a "much more prudential approach to American foreign policy."But there are still some reasons to doubt Heritage's restraint bona fides. Project 2025's transition manifesto makes clear that the conservative tone setter is not quite ready to drop its commitment to fighting global terrorism and keeping down America's parochial enemies, however weak they may now be.Of course, Heritage is far from the only game in town. Its foreign policy team has often found common cause with the CRA, a right-wing think tank with restraint-oriented views on international affairs that Maitra said will be a "key player" in the planning for a second Trump term. Trump himself reportedly read and at least partially endorsed Maitra's CRA paper calling for a major down-sizing of the U.S. role in NATO.On the other side, traditional hawks at organizations like the American Enterprise Institute and the Hoover Institute continue to hold sway in both mainstream and conservative media, as Meadowcroft pointed out. But many prominent hard-line hawks — like one-time Trump adviser John Bolton — have had a sufficiently large break with the MAGA movement to make them persona non grata in any future Trump White House.The America First Policy Institute (AFPI) appears determined to split the difference. Like Heritage, AFPI has questioned the wisdom of continued U.S. aid to Ukraine and pushed hard for Europe to shoulder more of the burden of its own defense. But the startup policy outfit — created as something of a White House in waiting — has a bit of a neocon streak when it comes to the Middle East, with a particular focus on countering Iranian influence and supporting Israel.There is no love lost between Heritage and AFPI, as journalist Sam Adler-Bell recently noted in the New York Times. "A.F.P.I. partisans see Heritage as a latecomer to the Trump train, establishment wolves in 'America First' clothing," Adler-Bell wrote. "Some at Heritage see A.F.P.I. as a redoubt of precisely those unreliable Trump appointees — grifters and RINOs — who trade on their relationships with the president to ensure they can continue to run the show." This antipathy helps to explain why AFPI has a separate Trump staffing effort, known as the America First Transition Project.One should note, however, that the two don't always disagree. They share some staff and have both kept strong ties to more traditional foreign policy shops. Part of this stems from the fact that even the more dovish members of the GOP national security world are more hawkish on, say, the Middle East and Venezuela than hard-line realists. But, on balance, restrainers are more skeptical of AFPI than their old foes at Heritage.It remains unclear which side has Trump's ear. AFPI associates — including Fred Fleitz, Keith Kellogg, and John Ratcliffe — often show up on lists of current and potential future Trump advisers. He also reportedly consults with former Secretary of State Mike Pompeo and Sen. Tom Cotton (R-Ark.), who rank among the most hawkish figures in American politics. (Pompeo's habit of calling himself a "realist" is a particular point of frustration for many America Firsters.)But, as efforts like Project 2025 demonstrate, Trump will no longer be stuck with old-school options on every front. There are no hardcore restrainers known to be in the running for major roles, but the former president is reportedly considering Richard Grenell and Kash Patel — both of whom have a somewhat less interventionist streak — for top jobs in his administration. And, as just about everyone I spoke with noted, there's still plenty of time for other potential nominees to gain ground before the election."The bench is deeper, and therefore there are more folks to turn to if a president wants to go in a restraint direction," said Ruger.Trump 2.0Much of the planning for a second Trump administration revolves around staffing. This laser focus is a response to his first term, in which advisers and officials often took steps to block the implementation of the president's preferred policies.Take Syria. When Trump ordered that U.S. troops be withdrawn from the country in 2019, the move sparked an uproar among policy experts who argued that it would leave our Kurdish allies in the lurch. Jim Jeffrey — then the special envoy to Syria — persuaded Trump to leave a token force in the country but later revealed that "we were always playing shell games to not make clear to our leadership how many troops we had there."Trump world is looking to make sure that never happens again. Heritage wants a new administration to make sweeping personnel changes that would allow Trump to replace thousands of federal bureaucrats with more sympathetic cadres.This is both an opportunity and a challenge for restrainers. On the "challenge" side, Trump has increasingly signaled that he wants to use military force against Mexican cartels, a proposal that most realists reject as dangerous and counterproductive. And, as Jost of Brown University notes, presidents don't just select their advisers based on hawkishness. They have to make decisions about which advisers will appease which constituencies in their base, among other considerations. In Trump's case, loyalty to the president appears to be another key criterion.But loyalty to Trump doesn't get your nomination through Congress. For many top jobs, nominees will have to persuade the old-school hawks in the Senate that they won't change too much about the status quo. Restraint-oriented nominees will, however, get help from the growing group of young America Firsters on Capitol Hill, not to mention the changing of the guard symbolized by Sen. Mitch McConnell's (R-Ky.) decision to step down from leadership.It will be up to Trump to decide whether he picks less controversial candidates for these positions or simply relies on "acting" appointees, as he did at the end of his first term. The former president will have much more room to maneuver when it comes to the National Security Council, whose leaders don't require confirmation.These challenges aside, the decisions that Trump makes in a potential second term could have a massive, lasting impact on the direction of conservative foreign policy. To better understand how, a quick history lesson is in order.In 2007, Democratic foreign policy big wigs founded the Center for a New American Security (CNAS), a hawkish center-left think tank first conceived as a government in waiting for Hillary Clinton. When Barack Obama beat Clinton in the primaries, he made the fateful decision to soften his stance on the Iraq War and staff up his team with CNAS acolytes.The CNAS crew — in addition to Clinton herself — earned powerful roles in Obama's administration that allowed them to steer the president away from his anti-war rhetoric on the campaign trail. The result was a vicious or virtuous cycle, depending on where you stand. The more hawkish CNAS staffers got coveted government experience (and connections) that put weight behind their arguments. Once they left government, they took their place as the sages of liberal foreign policy, with many returning in 2020 to staff the Biden administration.Obama's decision may have been practical. The progressive foreign policy landscape was, and in many ways still is, short on funding and candidates for high-level jobs. But Trump has the virtue of a genuine choice. The former president probably won't reject staffers based on their hawkishness — but perhaps he should. Research suggests it just might prevent the next war before it happens.
Publisher's version (útgefin grein) ; Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors. ; Peterlongo laboratory is supported by Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732) to P. Peterlongo and by a fellowship from Fondazione Umberto Veronesi to G. Figlioli. Surrallés laboratory is supported by the ICREA-Academia program, the Spanish Ministry of Health (projects FANCOSTEM and FANCOLEN), the Spanish Ministry of Economy and Competiveness (projects CB06/07/0023 and RTI2018-098419-B-I00), the European Commission (EUROFANCOLEN project HEALTH-F5-2012-305421 and P-SPHERE COFUND project), the Fanconi Anemia Research Fund Inc, and the "Fondo Europeo de Desarrollo Regional, una manera de hacer Europa" (FEDER). CIBERER is an initiative of the Instituto de Salud Carlos III, Spain. BCAC: we thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. ABCFS thank Maggie Angelakos, Judi Maskiell, Tu Nguyen-Dumont is a National Breast Cancer Foundation (Australia) Career Development Fellow. ABCS thanks the Blood bank Sanquin, The Netherlands. Samples are made available to researchers on a non-exclusive basis. BCEES thanks Allyson Thomson, Christobel Saunders, Terry Slevin, BreastScreen Western Australia, Elizabeth Wylie, Rachel Lloyd. The BCINIS study would not have been possible without the contributions of Dr. Hedy Rennert, Dr. K. Landsman, Dr. N. Gronich, Dr. A. Flugelman, Dr. W. Saliba, Dr. E. Liani, Dr. I. Cohen, Dr. S. Kalet, Dr. V. Friedman, Dr. O. Barnet of the NICCC in Haifa, and all the contributing family medicine, surgery, pathology and oncology teams in all medical institutes in Northern Israel. The BREOGAN study would not have been possible without the contributions of the following: Manuela Gago-Dominguez, Jose Esteban Castelao, Angel Carracedo, Victor Muñoz Garzón, Alejandro Novo Domínguez, Maria Elena Martinez, Sara Miranda Ponte, Carmen Redondo Marey, Maite Peña Fernández, Manuel Enguix Castelo, Maria Torres, Manuel Calaza (BREOGAN), José Antúnez, Máximo Fraga and the staff of the Department of Pathology and Biobank of the University Hospital Complex of Santiago-CHUS, Instituto de Investigación Sanitaria de Santiago, IDIS, Xerencia de Xestion Integrada de Santiago-SERGAS; Joaquín González-Carreró and the staff of the Department of Pathology and Biobank of University Hospital Complex of Vigo, Instituto de Investigacion Biomedica Galicia Sur, SERGAS, Vigo, Spain. BSUCH thanks Peter Bugert, Medical Faculty Mannheim. CBCS thanks study participants, co-investigators, collaborators and staff of the Canadian Breast Cancer Study, and project coordinators Agnes Lai and Celine Morissette. CCGP thanks Styliani Apostolaki, Anna Margiolaki, Georgios Nintos, Maria Perraki, Georgia Saloustrou, Georgia Sevastaki, Konstantinos Pompodakis. CGPS thanks staff and participants of the Copenhagen General Population Study. For the excellent technical assistance: Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, Dorthe Kjeldgård Hansen. The Danish Cancer Biobank is acknowledged for providing infrastructure for the collection of blood samples for the cases. Investigators from the CPS-II cohort thank the participants and Study Management Group for their invaluable contributions to this research. They also acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, as well as cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. The CTS Steering Committee includes Leslie Bernstein, Susan Neuhausen, James Lacey, Sophia Wang, Huiyan Ma, and Jessica Clague DeHart at the Beckman Research Institute of City of Hope, Dennis Deapen, Rich Pinder, and Eunjung Lee at the University of Southern California, Pam Horn-Ross, Peggy Reynolds, Christina Clarke Dur and David Nelson at the Cancer Prevention Institute of California, Hoda Anton-Culver, Argyrios Ziogas, and Hannah Park at the University of California Irvine, and Fred Schumacher at Case Western University. DIETCOMPLYF thanks the patients, nurses and clinical staff involved in the study. The DietCompLyf study was funded by the charity Against Breast Cancer (Registered Charity Number 1121258) and the NCRN. We thank the participants and the investigators of EPIC (European Prospective Investigation into Cancer and Nutrition). ESTHER thanks Hartwig Ziegler, Sonja Wolf, Volker Hermann, Christa Stegmaier, Katja Butterbach. FHRISK thanks NIHR for funding. GC-HBOC thanks Stefanie Engert, Heide Hellebrand, Sandra Kröber and LIFE - Leipzig Research Centre for Civilization Diseases (Markus Loeffler, Joachim Thiery, Matthias Nüchter, Ronny Baber). The GENICA Network: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany [HB, Wing-Yee Lo], German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) [HB], Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy - EXC 2180 - 390900677 [HB], Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian Baisch], Institute of Pathology, University of Bonn, Germany [Hans-Peter Fischer], Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany [Ute Hamann], Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany [TB, Beate Pesch, Sylvia Rabstein, Anne Lotz]; and Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany [Volker Harth]. HABCS thanks Michael Bremer. HEBCS thanks Heidi Toiminen, Kristiina Aittomäki, Irja Erkkilä and Outi Malkavaara. HMBCS thanks Peter Hillemanns, Hans Christiansen and Johann H. Karstens. HUBCS thanks Shamil Gantsev. KARMA thanks the Swedish Medical Research Counsel. KBCP thanks Eija Myöhänen, Helena Kemiläinen. LMBC thanks Gilian Peuteman, Thomas Van Brussel, EvyVanderheyden and Kathleen Corthouts. MABCS thanks Milena Jakimovska (RCGEB "Georgi D. Efremov), Katerina Kubelka, Mitko Karadjozov (Adzibadem-Sistina" Hospital), Andrej Arsovski and Liljana Stojanovska (Re-Medika" Hospital) for their contributions and commitment to this study. MARIE thanks Petra Seibold, Dieter Flesch-Janys, Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers and Stefan Nickels. MBCSG (Milan Breast Cancer Study Group) thanks Daniela Zaffaroni, Irene Feroce, and the personnel of the Cogentech Cancer Genetic Test Laboratory. We thank the coordinators, the research staff and especially the MMHS participants for their continued collaboration on research studies in breast cancer. MSKCC thanks Marina Corines and Lauren Jacobs. MTLGEBCS would like to thank Martine Tranchant (CHU de Québec Research Center), Marie-France Valois, Annie Turgeon and Lea Heguy (McGill University Health Center, Royal Victoria Hospital; McGill University) for DNA extraction, sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. NBHS thanks study participants and research staff for their contributions and commitment to the studies. We would like to thank the participants and staff of the Nurses' Health Study and Nurses' Health Study II for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The study protocol was approved by the institutional review boards of the Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. The authors assume full responsibility for analyses and interpretation of these data. OFBCR thanks Teresa Selander and Nayana Weerasooriya. ORIGO thanks E. Krol-Warmerdam, and J. Blom for patient accrual, administering questionnaires, and managing clinical information. PBCS thanks Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao and Michael Stagner. The ethical approval for the POSH study is MREC /00/6/69, UKCRN ID: 1137. We thank staff in the Experimental Cancer Medicine Centre (ECMC) supported Faculty of Medicine Tissue Bank and the Faculty of Medicine DNA Banking resource. PREFACE thanks Sonja Oeser and Silke Landrith. PROCAS thanks NIHR for funding. RBCS thanks Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens, Anja Kromwijk-Nieuwlaat, Annette Heemskerk, the Erasmus MC Family Cancer Clinic. We thank the SEARCH and EPIC teams. SKKDKFZS thanks all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study. We thank the SUCCESS Study teams in Munich, Duessldorf, Erlangen and Ulm. SZBCS thanks Ewa Putresza. UCIBCS thanks Irene Masunaka. UKBGS thanks Breast Cancer Now and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. CIMBA: we are grateful to all the families and clinicians who contribute to the studies; Sue Healey, in particular taking on the task of mutation classification with the late Olga Sinilnikova; Maggie Angelakos, Judi Maskiell, Helen Tsimiklis; members and participants in the New York site of the Breast Cancer Family Registry; members and participants in the Ontario Familial Breast Cancer Registry; Vilius Rudaitis and Laimonas Griškevičius; Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management; Bent Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of participants; Alicia Barroso, Rosario Alonso and Guillermo Pita; all the individuals and the researchers who took part in CONSIT TEAM (Consorzio Italiano Tumori Ereditari Alla Mammella), thanks in particular: Giulia Cagnoli, Roberta Villa, Irene Feroce, Mariarosaria Calvello, Riccardo Dolcetti, Giuseppe Giannini, Laura Papi, Gabriele Lorenzo Capone, Liliana Varesco, Viviana Gismondi, Maria Grazia Tibiletti, Daniela Furlan, Antonella Savarese, Aline Martayan, Stefania Tommasi, Brunella Pilato, Isabella Marchi, Elena Bandieri, Antonio Russo, Daniele Calistri and the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy. FPGMX: members of the Cancer Genetics group (IDIS): Ana Blanco, Miguel Aguado, Uxía Esperón and Belinda Rodríguez. We thank all participants, clinicians, family doctors, researchers, and technicians for their contributions and commitment to the DKFZ study and the collaborating groups in Lahore, Pakistan (Noor Muhammad, Sidra Gull, Seerat Bajwa, Faiz Ali Khan, Humaira Naeemi, Saima Faisal, Asif Loya, Mohammed Aasim Yusuf) and Bogota, Colombia (Diana Torres, Ignacio Briceno, Fabian Gil). Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study is a study from the National Cancer Genetics Network UNICANCER Genetic Group, France. We wish to pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet initiated and coordinated GEMO until she sadly passed away on the 30th June 2014. The team in Lyon (Olga Sinilnikova, Mélanie Léoné, Laure Barjhoux, Carole Verny-Pierre, Sylvie Mazoyer, Francesca Damiola, Valérie Sornin) managed the GEMO samples until the biological resource centre was transferred to Paris in December 2015 (Noura Mebirouk, Fabienne Lesueur, Dominique Stoppa-Lyonnet). We want to thank all the GEMO collaborating groups for their contribution to this study. Drs.Sofia Khan, Irja Erkkilä and Virpi Palola; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Netherlands Cancer Institute (coordinating center), Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, M.K. Schmidt, N.S. Russell, D.J. Jenner; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, C.M. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C.J. van Asperen, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, M.J. Koudijs; Amsterdam Medical Center, NL: C.M. Aalfs, H.E.J. Meijers-Heijboer; VU University Medical Center, Amsterdam, NL: K. van Engelen, J.J.P. Gille; Maastricht University Medical Center, NL: E.B. Gómez-Garcia, M.J. Blok; University of Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL): S. Siesling, J.Verloop; The nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA): A.W. van den Belt-Dusebout. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection. Overbeek; the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Zoltan Matrai, Miklos Kasler, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study; HVH (University Hospital Vall d'Hebron) the authors acknowledge the Oncogenetics Group (VHIO) and the High Risk and Cancer Prevention Unit of the University Hospital Vall d'Hebron, Miguel Servet Progam (CP10/00617), and the Cellex Foundation for providing research facilities and equipment; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; Dr Martine Dumont for sample management and skillful assistance; Catarina Santos and Pedro Pinto; members of the Center of Molecular Diagnosis, Oncogenetics Department and Molecular Oncology Research Center of Barretos Cancer Hospital; Heather Thorne, Eveline Niedermayr, all the kConFab investigators, research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab; the investigators of the Australia New Zealand NRG Oncology group; members and participants in the Ontario Cancer Genetics Network; Kevin Sweet, Caroline Craven, Julia Cooper, Amber Aielts, and Michelle O'Conor; Christina Selkirk; Helena Jernström, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Öfverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza; from Umeå University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellström Pigg, Richard Rosenquist; from Linköping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren; Cecilia Zvocec, Qun Niu; Joyce Seldon and Lorna Kwan; Dr. Robert Nussbaum, Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad and Salina Chan; Carole Pye, Patricia Harrington and Eva Wozniak. OSUCCG thanks Kevin Sweet, Caroline Craven, Julia Cooper, Michelle O'Conor and Amber Aeilts. BCAC is funded by Cancer Research UK [C1287/A16563, C1287/A10118], the European Union's Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST respectively), and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation or writing of the report. Genotyping of the OncoArray was funded by the NIH Grant U19 CA148065, and Cancer UK Grant C1287/A16563 and the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and, the Ministère de l'Économie, Science et Innovation du Québec through Genome Québec and the PSRSIIRI-701 grant, and the Quebec Breast Cancer Foundation. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]. The Australian Breast Cancer Tissue Bank (ABCTB) was supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation. The AHS study is supported by the intramural research program of the National Institutes of Health, the National Cancer Institute (grant number Z01-CP010119), and the National Institute of Environmental Health Sciences (grant number Z01-ES049030). The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BCEES was funded by the National Health and Medical Research Council, Australia and the Cancer Council Western Australia. For the BCFR-NY, BCFR-PA, BCFR-UT this work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. BCINIS study was funded by the BCRF (The Breast Cancer Research Foundation, USA). The BREast Oncology GAlician Network (BREOGAN) is funded by Acción Estratégica de Salud del Instituto de Salud Carlos III FIS PI12/02125/Cofinanciado FEDER; Acción Estratégica de Salud del Instituto de Salud Carlos III FIS Intrasalud (PI13/01136); Programa Grupos Emergentes, Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur. Xerencia de Xestion Integrada de Vigo-SERGAS, Instituto de Salud Carlos III, Spain; Grant 10CSA012E, Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain; Grant EC11-192. Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; and Grant FEDER-Innterconecta. Ministerio de Economia y Competitividad, Xunta de Galicia, Spain. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). Sample collection and processing was funded in part by grants from the National Cancer Institute (NCI R01CA120120 and K24CA169004). CBCS is funded by the Canadian Cancer Society (grant # 313404) and the Canadian Institutes of Health Research. CCGP is supported by funding from the University of Crete. The CECILE study was supported by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Sécurité Sanitaire, de l'Alimentation, de l'Environnement et du Travail (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev and Gentofte Hospital. The American Cancer Society funds the creation, maintenance, and updating of the CPS-II cohort. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398, K05 CA136967, UM1 CA164917, and U01 CA199277). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. The University of Westminster curates the DietCompLyf database funded by Against Breast Cancer Registered Charity No. 1121258 and the NCRN. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation, the Stavros Niarchos Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). FHRISK is funded from NIHR grant PGfAR 0707-10031. The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837, coordinator: Rita K. Schmutzler, Cologne). This work was also funded by the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, 14575/2470). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The GEPARSIXTO study was conducted by the German Breast Group GmbH. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and the German Cancer Research Center (DKFZ). The HABCS study was supported by the Claudia von Schilling Foundation for Breast Cancer Research, by the Lower Saxonian Cancer Society, and by the Rudolf Bartling Foundation. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. The HMBCS was supported by a grant from the German Research Foundation (Do 761/10-1). The HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017), and by the Russian Foundation for Basic Research and the Federal Agency for Scientific Organizations for support the Bioresource collections and RFBR grants 14-04-97088, 17-29-06014 and 17-44-020498. E.K was supported by the program for support the bioresource collections №007-030164/2 and study was performed as part of the assignment of the Ministry of Science and Higher Education of Russian Federation (№АААА-А16-116020350032-1). Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. The KARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. LMBC is supported by the 'Stichting tegen Kanker'. DL is supported by the FWO. The MABCS study is funded by the Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov" and supported by the German Academic Exchange Program, DAAD. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419, 110826, 110828], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5 × 1000"). The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057 and 396414, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. The MEC was support by NIH grants CA63464, CA54281, CA098758, CA132839 and CA164973. The MISS study is supported by funding from ERC-2011-294576 Advanced grant, Swedish Cancer Society, Swedish Research Council, Local hospital funds, Berta Kamprad Foundation, Gunnar Nilsson. The MMHS study was supported by NIH grants CA97396, CA128931, CA116201, CA140286 and CA177150. MSKCC is supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The Northern California Breast Cancer Family Registry (NC-BCFR) and Ontario Familial Breast Cancer Registry (OFBCR) were supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The Carolina Breast Cancer Study was funded by Komen Foundation, the National Cancer Institute (P50 CA058223, U54 CA156733, U01 CA179715), and the North Carolina University Cancer Research Fund. The NHS was supported by NIH grants P01 CA87969, UM1 CA186107, and U19 CA148065. The NHS2 was supported by NIH grants UM1 CA176726 and U19 CA148065. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Genotyping for PLCO was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The POSH study is funded by Cancer Research UK (grants C1275/A11699, C1275/C22524, C1275/A19187, C1275/A15956 and Breast Cancer Campaign 2010PR62, 2013PR044. PROCAS is funded from NIHR grant PGfAR 0707-10031. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). SEARCH is funded by Cancer Research UK [C490/A10124, C490/A16561] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. The Sister Study (SISTER) is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES049033). The Two Sister Study (2SISTER) was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES102245), and, also by a grant from Susan G. Komen for the Cure, grant FAS0703856. SKKDKFZS is supported by the DKFZ. The SMC is funded by the Swedish Cancer Foundation and the Swedish Research Council [grant 2017-00644 for the Swedish Infrastructure for Medical Population-based Life-course Environmental Research (SIMPLER)]. The SZBCS is financially supported under the program of Minister of Science and Higher Education "Regional Initiative of Excellence" in years 2019-2022, Grant No 002/RID/2018/19. The TNBCC was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation. The UCIBCS component of this research was supported by the NIH [CA58860, CA92044] and the Lon V Smith Foundation [LVS39420]. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The USRT Study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. CIMBA CIMBA: The CIMBA data management and data analysis were supported by Cancer Research – UK grants C12292/A20861, C12292/A11174. ACA is a Cancer Research -UK Senior Cancer Research Fellow. GCT and ABS are NHMRC Research Fellows. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation. BCFR: UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. BFBOCC: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015 and Nr. P-MIP-19-164. BIDMC: Breast Cancer Research Foundation. BMBSA: Cancer Association of South Africa (PI Elizabeth J. van Rensburg). CNIO: Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). COH-CCGCRN: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under grant number R25CA112486, and RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. CONSIT TEAM: Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 no.15547) to P. Radice. Funds from Italian citizens who allocated the 5 × 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '5 × 1000') to S. Manoukian. UNIROMA1: Italian Association for Cancer Research (AIRC; grant no. 21389) to L. Ottini. DFKZ: German Cancer Research Center. EMBRACE: Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester (IS-BRC-1215-20007). The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: NIH/NCI grant P30-CA006927. The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by R0 1CA140323, R01 CA214545, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. Ana Vega is supported by the Spanish Health Research Foundation, Instituto de Salud Carlos III (ISCIII), partially supported by FEDER funds through Research Activity Intensification Program (contract grant numbers: INT15/00070, INT16/00154, INT17/00133), and through Centro de Investigación Biomédica en Red de Enferemdades Raras CIBERER (ACCI 2016: ER17P1AC7112/2018); Autonomous Government of Galicia (Consolidation and structuring program: IN607B), and by the Fundación Mutua Madrileña (call 2018). GC-HBOC: German Cancer Aid (grant no 110837, Rita K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, 14575/2470). GEMO: Ligue Nationale Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program, the French National Institute of Cancer (INCa) (grants AOR 01 082, 2013-1-BCB-01-ICH-1 and SHS-E-SP 18-015) and the Fondation ARC pour la recherche sur le cancer (grant PJA 20151203365). GEORGETOWN: the Survey, Recruitment and Biospecimen Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008) and the Fisher Center for Hereditary Cancer and Clinical Genomics Research. HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS: Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBON: the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HUNBOCS: Hungarian Research Grants KTIA-OTKA CK-80745 and NKFI_OTKA K-112228. HVH (University Hospital Vall d'Hebron) This work was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds: FIS PI12/02585 and PI15/00355. ICO: The authors would like to particularly acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad) and "Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa" (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563, P18/01029, and CIBERONC) and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338, 2017SGR449, and PERIS Project MedPerCan), and CERCA program. IHCC: PBZ_KBN_122/P05/2004. ILUH: Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund. INHERIT: Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. IOVHBOCS: Ministero della Salute and "5 × 1000" Istituto Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. MAYO: NIH grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. Marc Tischkowitz is supported by the funded by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). MSKCC: the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). NCI: the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD. NNPIO: the Russian Foundation for Basic Research (grants 17-54-12007, 17-00-00171 and 18-515-45012). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. OSUCCG: was funded by the Ohio State University Comprehensive Cancer Center. PBCS: Italian Association of Cancer Research (AIRC) [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. SMC: the Israeli Cancer Association. SWE-BRCA: the Swedish Cancer Society. UCHICAGO: NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance and the Breast Cancer research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR: Cancer Researc h UK. UPENN: National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. ; Peer Reviewed
In April 2002 the European Central Bank (ECB) and the Center for Financial Studies (CFS) launched the ECB-CFS Research Network to promote research on "Capital Markets and Financial Integration in Europe". The ECB-CFS research network aims at stimulating top-level and policy-relevant research, significantly contributing to the understanding of the current and future structure and integration of the financial system in Europe and its international linkages with the United States and Japan. This report summarises the work done under the network after two years. Over time the network formed a coherent and growing group of researchers interested in the integration of European financial markets, while using light organisational structures and budgets. The members of this evolving group met repeatedly at the events organised by the network to present the latest results of their research and to share views on policy options. In this sense, the "network of people" intended at the start was created. Overall, the network aroused great interest, as leading academic researchers, researchers from the main policy institutions and high-level policy makers participated actively in it by presenting research results, through speeches and in policy panels. It also stimulated a new research field on securities settlement systems, an area of high policy relevance and interest to the ECB that had not attracted much interest in the research community beforehand. Also, the network seems to have triggered several related outside initiatives by international institutions, such as the IMF or the OECD. During its first two years the network was organised around three workshops and a final symposium on 10-11 May 2004. To focus research resources and to ensure medium-term policy relevance, a limited number of areas have been given top priority: bank competition and the geographical scope of banking; international portfolio choices and asset market linkages between Europe, the United States and Japan; European bond markets; European securities settlement systems; and the emergence and evolution of new markets in Europe (in particular start-up financing markets). In order to stimulate further research focused on the priority fields of the network, the ECB Lamfalussy research fellowships were established. These fellowships sponsor projects proposed by young researchers, both a dvanced doctoral students and younger professors. Five Lamfalussy fellowships were granted in 2003 and five more in 2004. The first papers from this program have already been issued in the ECB working paper series or are forthcoming. One of them won the prize for the best paper written by a Ph.D. student at the 2004 European Finance Association Meetings in Maastricht. Results of the network in the five top priority areas can be summarised as follows: Bank competition and the geographical scope of banking. First, integration does not appear to be very advanced in many retail banking markets. Second, some of the inherent characteristics of traditional loan and deposit business constrain the cross-border expansion of commercial banking, even in a common currency area. Hence, the implementation of some policies to foster cross-border integration in retail banking may be ineffective. Third, theoretical research suggests that supervisory structures may not be neutral towards further European banking integration. Finally, a stronger role of area-wide competition policies could be beneficial for further banking integration. This would also stimulate economic growth, as more competition in the banking sector induces financially dependent firms to grow more. European bond markets. While the government bond market has integrated rapidly with the EMU convergence process, its full integration has not yet been achieved. The introduction of a common electronic trading platform reduced transaction costs substantially, but yield spreads of long-term sovereign bonds of the euro area are still heterogeneous. This is largely explained by different sensitivities to an international risk factor, whereas liquidity differentials only play a role in conjunction with this latter factor. Somewhat surprisingly in this context, the dynamically developing corporate bond market exhibits a relatively high level of integration. There is also increasing evidence that the introduction of the euro has contributed to a reduction in the cost of capital in the euro area, in particular through the reduction of corporate bond underwriting fees. As a result, firms may wish to increase bond financing relative to equity financing. The development of a larger corporate bond market is also important for monetary policy. For example, US evidence suggests that the rating of corporate bonds may contribute to the persistence of recessions, as rating agencies´ policies affect firms asymmetrically in their access to the bond market over the business cycle. US evidence also suggests that liquidity conditions in stock and bond markets tend to be positively correlated. European securities settlement systems. European securities settlement infrastructures are highly fragmented and further integration and/or consolidation would exploit economies of scale that could greatly benefit investors. It is not clear, however, whether direct public intervention in favour of consolidation would lead to the highest level of efficiency, for example because of the existence of strong vertical integration between trading and securities platforms ("silos"). In contrast, promoting open access to clearing and settlement systems could lead to consolidation and the highest level of efficiency. Finally, regarding concerns about unfair practices by Central Securities Depositories (CSDs) toward custodian banks, regulatory interventions favouring custodian banks should be discouraged, as long as CSDs are not allowed to price discriminate between custodian banks and investor banks. The emergence and evolution of new markets in Europe (in particular start-up financing markets). While fairly well integrated, "new markets" and start-up financing are less developed and integrated in Europe than in the United States. However, new markets and venture capitalists are the most important intermediaries for the financing of projects with high risk but with potentially very high return. The analysis carried out within the network reveals that European start-up financiers are mostly institutional investors, while US venture capitalists are mostly rich individuals. Also, new markets are essential for the development of start-up finance in Europe, as they provide an exit strategy for start-up financiers who can then sell new successful projects using initial public offerings. Finally, the legal framework affects the development of venture capital firms. For example, very strict personal bankruptcy laws constrain early stage entrepreneurs, reducing demand for venture capital finance. International portfolio choices and asset market linkages between Europe, the United States and Japan. At a global scale, asset market linkages have increased recently. For example, major economies such as the United States and the euro area have become more financially interdependent. This phenomenon can be observed in stock and bond markets as well as in money markets, where the main direction of spillovers has recently been from the US to the euro area. Country-specific shocks now play a smaller role in explaining stock return variations of firms whose sales are internationally diversified. Increases in firmby-firm market linkages are a global phenomenon, but they are stronger within the euro area than in the rest of the world. Various other phenomena also increase market linkages and therefore the likelihood that financial shocks spread across countries. One example is the use of global bonds. Finally, the nowadays more direct access of unsophisticated investors to financial markets may increase volatility. Other areas. Financial integration affects financial structures, but it does not need to lead to their convergence across countries. Financial structures matter for growth, as market-oriented financial systems benefit all sectors and firms, whereas bank-based systems primarily benefit younger firms that depend on external finance. Moreover, good corporate governance increases firms' value. In particular, the dual board system, where the monitoring and advising roles of the board of directors are separated, is found to dominate the single board structure. Therefore, the further development of the European single market should strongly require good corporate governance. In general, well designed institutions foster entrepreneurial activity, partly by relaxing capital constraints. The results of the network clearly illustrated the substantial effects the introduction of the euro had on euro area financial markets. In addition to the effects on bond markets, stock markets and the cost of capital summarised above, research produced showed that the single currency had its strongest effects on money markets, whose unsecured segment is now completely integrated. Without any doubt the euro generally enhanced the liquidity and efficiency of euro area financial markets, and ongoing initiatives such as the European Union's Financial Services Action Plan will help to continue this process. In sum, in the first two years the network has established itself as the hub for the research debate on European financial integration. Some of the best papers produced by the network, leading to the conclusions mentioned above, are currently being considered for publication in two special issues of academic journals. An issue of the Oxford Review of Economic Policy on "European financial integration" is published contemporaneously with this report, and an issue of the Review of Finance is planned for next year. The current policy context, the gradual progress of integration as well as the creation of other related non-ECB or non-CFS initiatives on financial integration suggest that this topic will remain high on the agendas of policy makers and academics for the years to come. Therefore, the ECB Executive Board and the CFS decided to continue the network, refocusing its priorities. Three priority areas have been added: 1) The relationship between financial integration and financial stability, 2) EU accession, financial development and financial integration, and 3) financial system modernisation and economic growth in Europe. These three areas have become particularly important at the current juncture, but have not received particularly strong attention in the first two years of the network. For example, the area of financial stability research was highlighted by the ECB research evaluators as an area deserving further development. Moreover, despite the results found in the first two years of the network, new developments remain to be further explored in the earlier priority areas. A three-year extension is envisaged, running from after the May 2004 symposium until 2007, with two events to be held per year. The threeyear period is long enough to consider the first effects of the Financial Services Action Plan. It also constitutes a realistic horizon for the ambitious agenda implied by the three new priorities. The generally light organisational structure and working of the network will not be changed. In addition, given the value of the Lamfalussy fellowship research program in inducing further research in the areas of the network, the program has also been extended for all the research topics in the area of the network.