Probabilistic Inequalities and Bootstrap Percolation

This dissertation focuses on two topics. In the first part of we address a number of extremal probabilistic questions:The Littlewood-Offord problem: we provide an alternative and very elementary proof of a classical result by Erdos that avoids using Sperner\u27s Theorem. We also give a new simple proof of Sperner\u27s Theorem itself.Upper bounds for the concentration function: answering a question of Leader and Radcliffe we obtain optimal upper bounds for the concentration function of a sum of real random variables when individual concentration information about the summands is given. The result can be viewed as the optimal form of a well-known Kolmogorov-Rogozin inequality.Small ball probabilities for sums of random vectors with bounded density: we provide optimal upper bounds the probability that a sum of random vectors lies inside a small ball and derive an upper bound for the maximum density of this sum. In particular, our work extends a result of Rogozin who proved the best possible result in one dimension and improves some recent results proved by Bobkov and Chystiakov.Two extremal questions of bounded symmetric random walks: we obtain optimal upper bounds for the probability that a sum of independent bounded symmetric random variables exceeds a given value or hits it.The second part of the dissertation is concerned with a problem in Bootstrap Percolation. Let G be a graph and let I be a set of initially infected vertices. The set of infected vertices is updated as follows: if a healthy vertex has the majority of its neighbours infected it itself becomes infected.In the description of the bootstrap process above the superscripts of the sets correspond to the time steps when infections occur. If the process ends up infecting all of the vertices we say that percolation occurs.In this dissertation we shall investigate this process on the Erdos-Renyi random graph G(n,p). In this graph on n vertices each edge is included independently with probability p. We shall be interested in the smallest cardinality, say m=m(n), of a uniformly chosen initially infected set of vertices I, such that the probability of percolation at least 1/2. We call this quantity the critical size of the initially infected set. In the regime p\u3eclog (n)/n (the connectivity threshhold) we prove sharp upper and lower bounds for m that match in the first two terms of the asymptotic expansion

Mediastinal neoplasms in patients with Graves disease: a possible link between sustained hyperthyroidism and thymic neoplasia?

Background Anterior mediastinal masses are a rare but well documented finding in Graves disease. The vast majority of these lesions represents benign thymic hypertrophy and regress after treatment of the hyperthyroidism. A small percentage of these cases however represent neoplastic/malignant diseases which require further treatment. Cases 12 year old boy with one year history of refractory Graves disease was found to have an anterior mediastinal mass and underwent curative thyroidectomy for sustained hyperthyroidism. Cervical lymphadenopathy was detected during the procedure and biopsy was obtained. A 23 year old woman who presented with a one month history of hyperthyroid symptoms, was diagnosed with Graves disease and also was found to have an anterior mediastinal mass on imaging. Biopsy of the anterior mediastinal mass was obtained and subsequently the patient underwent robotic thymectomy. Histologic examination and immunophenotyping of the cervical lymph node in a 12 year old boy revealed neoplastic proliferation of T lymphoblasts diagnostic of T lymphoblastic leukemia/lymphoma. Examination of the anterior mediastinal mass biopsy in the 23 year old woman revealed type B1 thymoma which was confirmed after examination of the subsequent robotic thymectomy specimen. Conclusion This is the first reported case of T cell lymphoblastic lymphoma and the third reported case of thymoma associated with sustained hyperthyroidism due to Graves disease. These cases indicate that an anterior mediastinal mass in a patient with active Graves disease may be due to a neoplastic cause, which may require definitive treatment. Caution should be exercised when dismissing a mediastinal mass as benign thymic hyperplasia in patients with active Graves disease

SPECIFIC PRECAUTIONS FOR AVOIDING MICROORGANISM TRANSMISSION: DEVELOPMENT AND VALIDATION OF AN EDUCATIONAL GUIDE

This study aimed to develop and validate the content of the educational guide for individuals under specific precautions for avoiding microorganism transmission. It is a methodological study performed in three phases, in two hospitals (public and private) in the city of São Paulo, from May to July 2015, using the theoretical framework of Vulnerability. In the first phase, a questionnaire was applied for capturing the adult individuals’ perceptions regarding specific precautions. In the second phase, the educational guide was elaborated. In the third phase, the guide was submitted to specialists in specific precautions and vulnerability for content validation. Interviews were held with 39 individuals, an average of seven days after the institution of the specific precautions, 32 (82%) of whom were under contact precautions. The guide was developed to provide better knowledge of aspects usually neglected by professionals, and to encourage person-centred care. All items had a content validity index of above 75%. The guide presents potential to support professionals in the development of educational actions for adult patients subject to specific precautions.O objetivo deste estudo foi desenvolver e validar o conteúdo do roteiro educativo para indivíduos em precauções específicas para evitar a transmissão de microrganismos. Estudo metodológico, desenvolvido em três fases,em dois hospitais (público e privado) na cidade de São Paulo, no período de maio a julho de 2015, utilizando o referencial teórico de Vulnerabilidade. Na primeira fase, aplicou-se questionário para captação das percepções dos indivíduos adultos sobre precauções específicas. Na segunda fase, elaborou-se o roteiro educativo. Na terceira fase, foi submetido a especialistas em precauções específicas e vulnerabilidade para validação de conteúdo. Foram entrevistados39 indivíduos em média sete dias após a instituição das precauções específicas, 32 (82%) em precaução para contato. O roteiro foi desenvolvido para proporcionar maior conhecimento nos aspectos usualmente negligenciados pelos profissionais e estimular o cuidado centrado no indivíduo. Todos os itens tiveram um índice de validade de conteúdo acima de 75%. O roteiro apresenta potencial para instrumentalizar profissionais na elaboração de ações educativas para pacientes adultos em precauções específicas.La finalidad de este estudio fue desarrollar y validar el contenido de guion educativo de precauciones específicas con fines de evitar la transmisión de microorganismos. Es un estudio metodológico, hecho entres fases, en dos hospitales (público y privado) en la ciudad de São Paulo, en periodo de mayo a julio de 2015, utilizándose referencial teórico de Vulnerabilidad. Fue aplicado cuestionario para captación de percepciones de los individuos adultos acerca de precauciones específicas en la primera fase. En la segunda fase, se elaboró guion educativo. En la tercera fase, ello fue sometido a especialistas en precauciones específicas y vulnerabilidad para validación de contenido. Fueron entrevistados 39 individuos, en media siete días después de la institución de las medidas preventivas específicas, 32 (82%) en precaución para contacto. El guion fue desarrollado para proporcionar más conocimiento acerca de los aspectos generalmente negligenciados por los profesionales y estimular el cuidado centrado en el individuo. Todos los puntos tuvieron índice de validad de contenido superior a75%. El guiones una potencial herramienta a los profesionales en la elaboración de acciones educativas para pacientes adultos en precauciones específicas

Genetic background and evolution of relapses in aggressive B-cell lymphomas

Relapses of aggressive B-cell lymphomas pose a higher risk to affected patients because of potential treatment resistance and usually rapid tumor growth. Recent advances, such as targeting Bruton tyrosine kinase, have provided promising results in small numbers of cases, but treatment for the majority of patients remains challenging and outcomes are generally poor. A number of recent studies have utilized state-of-the-art genomic technologies in an attempt to better understand tumor genome evolution during relapse and to identify relapse-specific genetic alterations. It has been found that in some settings (e.g. diffuse large B-cell lymphomas in immunocompromised patients, secondary diffuse large B-cell lymphomas as Richter transformations) a significant part of the recurrences are clonally-unrelated de novo neoplasms, which might have distinct genomic and drug sensitivity profiles as well as different prognoses. Similar to earlier findings in indolent lymphomas, genetic tumor evolution of clonally-related relapsing aggressive B-cell lymphomas is predominantly characterized by two patterns: early divergence from a common progenitor and late divergence/linear evolution from a primary tumor. The clinical implications of these distinct patterns are not yet clear and will require additional investigation; however, it is plausible that these two patterns of recurrence are linked to different treatment-resistance mechanisms. Attempts to identify drivers of relapses result in a very heterogeneous list of affected genes and pathways as well as epigenetic mechanisms and suggest many ways of how recurrent tumors can adapt to treatment and expand their malignant properties

Assessing agriculture vulnerabilities for the design of effective measures for adaptation to climate change (AVEMAC project)

This final report of the AVEMAC study presents an assessment of the potential vulnerability of European agriculture to changing climatic conditions in the coming decades. The analysis is based on weather data generated from two contrasting realizations of the A1B emission scenario of the Intergovernmental Panel on Climate Change (IPCC) for the time horizons 2020 and 2030. These two realizations (obtained from two different general circulation models, downscaled using regional climate models and biascorrected) represent the warmest and coldest realizations of the A1B scenario over Europe as estimated by the ENSEMBLES project. The future weather data fed two types of analyses. The first analysis consisted in computing static agro-meteorological indicators as proxies of potential vulnerabilities of agricultural systems, expressed as changes in the classification of agricultural areas in Europe under climate constraints. The second analysis relied on biophysical modelling to characterize crop specific plant responses derived from crop growth simulations at different production levels (potential production, water-limited production, and production limited by diseases). Assessing the importance of vulnerability to climate change requires not only the localisation of relative yield changes, but also the analysis of the impact of the change on the acreage affected. Consequently, the simulation results of the impact assessment on crops were further processed to estimate the potential changes in production at sub-national (NUTS2) level. This was achieved by relating the simulation results to farm typologies in order to identify which types of systems are likely to be affected by reductions in production. The analyses of this study must be considered as a first step only, since they have neither included adaptation strategies that the farmer can take in response to changes in climate, nor a bio-economic evaluation of estimated vulnerabilities. Therefore, the main aspects and the requirements for a possible future integrated analysis at EU27 level to address climate change and agriculture with the target of providing policy support are also presented in this report. Eventually the results of this study shall help the formulation of appropriate policy options and the development of adequate policy instruments to support the adaptation to climate change of the EU agricultural sector.JRC.H.4-Monitoring Agricultural Resource

Integration of Baseline Metabolic Parameters and Mutational Profiles Predicts Long-Term Response to First-Line Therapy in DLBCL Patients: A Post Hoc Analysis of the SAKK38/07 Study.

Accurate estimation of the progression risk after first-line therapy represents an unmet clinical need in diffuse large B-cell lymphoma (DLBCL). Baseline (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) parameters, together with genetic analysis of lymphoma cells, could refine the prediction of treatment failure. We evaluated the combined impact of mutation profiling and baseline PET/CT functional parameters on the outcome of DLBCL patients treated with the R-CHOP14 regimen in the SAKK38/07 clinical trial (NCT00544219). The concomitant presence of mutated SOCS1 with wild-type CREBBP and EP300 defined a group of patients with a favorable prognosis and 2-year progression-free survival (PFS) of 100%. Using an unsupervised recursive partitioning approach, we generated a classification-tree algorithm that predicts treatment outcomes. Patients with elevated metabolic tumor volume (MTV) and high metabolic heterogeneity (MH) (15%) had the highest risk of relapse. Patients with low MTV and favorable mutational profile (9%) had the lowest risk, while the remaining patients constituted the intermediate-risk group (76%). The resulting model stratified patients among three groups with 2-year PFS of 100%, 82%, and 42%, respectively (p < 0.001)

Legislation of direct-to-consumer genetic testing in Europe: a fragmented regulatory landscape

Despite the increasing availability of direct-to-consumer (DTC) genetic testing, it is currently unclear how such services are regulated in Europe, due to the lack of EU or national legislation specifically addressing this issue. In this article, we provide an overview of laws that could potentially impact the regulation of DTC genetic testing in 26 European countries, namely Austria, Belgium, Cyprus, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, the Netherlands and the United Kingdom. Emphasis is placed on provisions relating to medical supervision, genetic counselling and informed consent. Our results indicate that currently there is a wide spectrum of laws regarding genetic testing in Europe. There are countries (e.g. France and Germany) which essentially ban DTC genetic testing, while in others (e.g. Luxembourg and Poland) DTC genetic testing may only be restricted by general laws, usually regarding health care services and patients’ rights

Histological and immunohistochemical features of the spleen in persistent polyclonal B-cell lymphocytosis closely mimic splenic B-cell lymphoma

Persistent polyclonal B-cell lymphocytosis (PPBL) is rare and intriguing hematological disorder predominantly reported in young to middle- aged smoking women. It is characterized by persistent moderate polyclonal B-cell lymphocytosis with circulating hallmark binucleated lymphocytes and elevated polyclonal serum IgM. Most patients have benign clinical course on long-term follow-up. Some pathologic features of PPBL may resemble malignant lymphoma, including morphology as well as frequent cytogenetic and molecular abnormalities. Significant symptomatic splenomegaly requiring splenectomy is very unusual for this disorder; therefore there is a lack of descriptions of the morphologic features of the spleen in the literature. We present here one of the first detailed descriptions of the morphologic and immunohistochemical features of the spleen from a young female with PPBL who developed massive splenomegaly during 6-year follow up. Splenectomy was performed for symptomatic relief and suspicion of malignant process. The morphological and immunohistochemical features of the spleen closely mimicked involvement by B-cell lymphoma, however there was no monotypic surface light chain restriction seen by flow cytometry and no clonal rearrangement of IgH gene was detected by molecular analysis. Evaluating a splenectomy sample in cases like this may present a diagnostic challenge to pathologists. Therefore, correlation with B cell clonality studies (by flow cytometry and molecular analysis), clinical findings and peripheral blood morphology searching for characteristic binucleated lymphocytes is essential to avoid misdiagnosing this benign process as B-cell lymphoma. We also present here a literature review on pathogenesis of PPBL