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Treballs Finals de Grau d'Enginyeria Biomèdica. Facultat de Medicina i Ciències de la Salut. Universitat de Barcelona. Curs: 2021-2022. Tutora: Carme Junqué Plaja, [cat] bla bla bla, [spa] ble ble ble

The detection of metastases in patients with a diagnosis of uveal melanoma (UM) is a controversial issue. While only 1% of the patients have detectable metastases at the time of diagnosis, up to 30% of them will develop liver metastases within 5 years of treatment. UM spreads hematogenously, therefore, blood biomarkers may be helpful for prognosis and monitoring the disease progression. Despite the great progress achieved thanks to the genetic analysis of UM biopsies, this is an invasive technique and is limited by the heterogeneity of the tumor. The present review considers the current understanding in the field regarding biomarkers for the diagnosis and prognosis of UM and its metastasis, primarily to the liver. General covered topics include non-conventional markers such as proteins previously identified in cutaneous melanoma and UM cell lines, circulating tumor cells, microRNAs (miRNA), and circulating DNA, and how each may be critical in the development of novel blood biomarkers for UM.

The detection of metastases in patients with a diagnosis of uveal melanoma (UM) is a controversial issue. While only 1% of the patients have detectable metastases at the time of diagnosis, up to 30% of them will develop liver metastases within 5 years of treatment. UM spreads hematogenously, therefore, blood biomarkers may be helpful for prognosis and monitoring the disease progression. Despite the great progress achieved thanks to the genetic analysis of UM biopsies, this is an invasive technique and is limited by the heterogeneity of the tumor. The present review considers the current understanding in the field regarding biomarkers for the diagnosis and prognosis of UM and its metastasis, primarily to the liver. General covered topics include non-conventional markers such as proteins previously identified in cutaneous melanoma and UM cell lines, circulating tumor cells, microRNAs (miRNA), and circulating DNA, and how each may be critical in the development of novel blood biomarkers for UM.

Manuel F Bande Rodríguez, 1, 2 Beatriz Fernandez Marta, 1 Nerea Lago Baameiro, 3 Maria Santiago-Varela, 1, 2 Paula Silva-Rodríguez, 2, 4 María Jose Blanco-Teijeiro, 1, 2 Maria Pardo Perez, 3 Antonio Piñeiro Ces 1, 2 1Unidad de Retina Quirúrgica y Tumores Intraoculares del Adulto (URQTIA), Servicio de Oftalmología Xerencia de Xestión Integrada de Santiago de Compostela, SERGAS, Santiago de Compostela, Spain; 2Tumores Intraoculares en el Adulto, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain; 3Grupo Obesidómica, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain; 4Fundación Pública Galega de Medicina Xenómica, Clinical University Hospital, SERGAS, Santiago de Compostela 15705, SpainCorrespondence: Manuel F Bande RodríguezUnidad de Retina Quirúrgica y Tumores Intraoculares del Adulto (URQTIA), Servicio de Oftalmología Xerencia de Xestión Integrada de Santiago de Compostela, SERGAS, Santiago de Compostela, SpainTel +34981951756Fax +34981956189Email verman017@hotmail.comAbstract: The detection of metastases in patients with a diagnosis of uveal melanoma (UM) is a controversial issue. While only 1% of the patients have detectable metastases at the time of diagnosis, up to 30% of them will develop liver metastases within 5 years of treatment. UM spreads hematogenously, therefore, blood biomarkers may be helpful for prognosis and monitoring the disease progression. Despite the great progress achieved thanks to the genetic analysis of UM biopsies, this is an invasive technique and is limited by the heterogeneity of the tumor. The present review considers the current understanding in the field regarding biomarkers for the diagnosis and prognosis of UM and its metastasis, primarily to the liver. General covered topics include non-conventional markers such as proteins previously identified in cutaneous melanoma and UM cell lines, circulating tumor cells, microRNAs (miRNA), and circulating DNA, and how each may be critical in the development of novel blood biomarkers for UM.Keywords: uveal melanoma, biomarker, circulating tumor cells, microRNAs, circulating DNA, exosome

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Additional file 1. Additional file table and figures.

Additional file 1. Additional findings that further support and/or give further detail to the main results.

Orientador: José Cândido Silveira Santos Filho Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Elétrica e de Computação Resumo: A hipertensão arterial é a principal causa de doenças cardiovasculares e, se não tratada, pode ser fator de risco de lesão de órgão-alvo, infarto, acidente vascular cerebral e outras doenças graves. Aferir a Pressão Arterial permite auxiliar no diagnóstico, prevenir situações de risco, monitorar predomínio populacional, controlar a doença e identificar fatores de risco associados à Hipertensão Arterial. Por meio da técnica de Monitorização Ambulatorial da Pressão Arterial (MAPA), é possível identificar a duração do efeito hipertensivo, apontar pacientes suspeitos e os fenômenos Whitecoat, Non-dipping e Morning Surge. Semelhante a outros segmentos da sociedade, a área médica também tem usufruído das técnicas de Inteligência Artificial na análise de grandes volumes de dados, transformando os métodos de diagnósticos e tratamentos, além de identificar potenciais ameaças à saúde pública. Considerando o cenário de gerenciamento de saúde populacional, onde se apura informações de um grande contexto populacional e objeto desta pesquisa, o uso de Aprendizado de Máquina – ramo da Inteligência Artificial -– se mostra adequado para inspeção de grandes volumes de dados, identificação de potenciais grupos de padrão, e formação de agrupamentos considerando que não há um rótulo explícito nos dados. A utilização do k-Means - algoritmo de clustering - no conjunto de dados de 21.137 pacientes permitiu a formação dos grupos, onde foram realizados estudos estatísticos descritivos para identificar características sociodemográficas. O algoritmo Random Forest também foi aplicado para identificar quais variáveis mais influenciaram o processo de classificação dos parâmetros Pressão Arterial Sistólica e Pressão Arterial Diastólica. Este estudo também ofereceu um pipeline analítico baseado em dados reais Abstract: Hypertension is the main cause of cardiovascular disease. If left untreated, it can be a risk factor for target organ damage, heart attacks, stroke and other serious diseases. Blood pressure measurement allows us to guide therapeutic approaches, monitor population predominance, and identify risk factors associated with Arterial Hypertension. The Ambulatory Blood Pressure Monitoring (ABPM) technique allows physicians to determine the duration of the hypertensive effect, identify suspicious patients, and recognize the Whitecoat, Non-dipping, and Morning Surge phenomena. Similarly to other segments of society, the medical field has also benefited from Artificial Intelligence techniques in analyzing large volumes of data. This has transformed diagnostic and treatment methods and allowed the identification of potential public health threatens. Considering the population health management scenario, where information from a large population is inspected, the use of Machine Learning – a branch of Artificial Intelligence – proves to be adequate to process large volumes of data, identify groups with similar patterns, and form clusters even though there was no explicit labels in the data. The application of k-Means - a clustering algorithm - in a dataset with 21.137 patients allowed the analysis of the results of each group, where studies were applied to identify sociodemographic characteristics. Random Forest - a Machine Learning classification technique - was also evaluated to identify which variables that most influence the classification process of parameters Systolic Blood Pressure and Diastolic Blood Pressure measures. This study also offered an analytical pipeline based on real data Mestrado Engenharia de Computação Mestra em Engenharia Elétrica CNPQ 130100/2020-0

BACKGROUND In order to study the feasibility of setting up a national trauma observatory in France, OBJECTIVE we compared the performance of several automatic language processing methods on a multi-class classification task of unstructured clinical notes. METHODS A total of 69,110 free-text clinical notes related to visits to the emergency departments of the University Hospital of Bordeaux, France, between 2012 and 2019 were manually annotated. Among those clinical notes 22,481 were traumas. We trained 4 transformer models (deep learning models that encompass attention mechanism) and compared them with the TF-IDF (Term- Frequency - Inverse Document Frequency) associated with SVM (Support Vector Machine) method. RESULTS The transformer models consistently performed better than TF-IDF/SVM. Among the transformers, the GPTanam model pre-trained with a French corpus with an additional auto-supervised learning step on 306,368 unlabeled clinical notes showed the best performance with a micro F1-score of 0.969. CONCLUSIONS The transformers proved efficient multi-class classification task on narrative and medical data. Further steps for improvement should focus on abbreviations expansion and multiple outputs multi-class classification.

International audience; Aim: With the objective to investigate the mechanisms underlying absence of spontaneous axonal regeneration following spinal cord injury (SCI) we employ a multimodal label-free imaging approach to monitor glial scar in a mice SCI model. Method: To determine the relevant structural signature, and the nanobiomechanical behavior of healthy and injured spinal cord tissue we combine the non-linear, multiphoton microscopy (MPM) technique with force measurements via atomic force microscopy (AFM). The glial scar at different post lesion time-points is investigated with these two techniques to monitor structural and elasticity (Young modulus) changes of the tissue.Results: 2-photon excited fluorescence (2PEF) and second harmonic generation (SHG) signals of excised mice SC injured tissues were recorded in MPM at 72h, 1week and 6 weeks post-lesion. The MPM images revealed the apparition of a strong SHG signal at 1week post injury, due to the formation of fibrillar collagen fibers (collagen type I) by the injury site in the glial scar. At 6 weeks’post-injury, the SHG signal is more intense and a higher number of fibers are detected in average. We further assessed the preferential orientation of the collagen bundles performing polarization dependent measurements of the SHG signal. The AFM based force spectroscopy measurements have been performed at the same post-lesion time-points to map the elastic properties of the healthy (grey and white matters) and injured (lesion) parts in the spinal cord tissue. The results suggested an increase of the lesion area stiffness over time that could be correlated with the apparition of fibrillar collagen observed in MPM, indicating the presence of a fibrotic process seven days after injury, that develops in time. As tissue stiffness is a regulator of neuronal growth, such kind of measurements might help to understand why adult mammalian axons do not regenerate after an injury. Our next step is to investigate the effect of a treatment (pharmacological transient depletion of microglia/macrophage in mice that underwent SCI) on the structure and mechanical properties of the lesion site at 1 week and 6 weeks post injury.

International audience; Spinal cord injuries (SCI) affect between 2.5 and 4 million patients worldwide yielding major handicaps and inducing high economical costs. A scar, called glial scar and composed of two main cellular populations i.e. astrocytes and microglia, inhibits axonal regeneration by forming a physical and chemical barrier. Currently, there is no curative treatment on any symptoms associated with SCI. In this context, with the objective to investigate the mechanisms underlying absence of spontaneous axonal regeneration following SCI, we employ a multimodal label-free imaging approach to monitor glial scar in a mice SCI model. Method: To determine the relevant structural signature and the nanobiomechanical behavior of healthy and injured spinal cord tissue, we combine the non-linear, multiphoton microscopy (MPM) technique with force measurements via atomic force microscopy (AFM). The glial scar at different key post lesion time-points is investigated with these two techniques to monitor structural and elasticity (Young modulus) changes of the tissue.Results: 2-photon excited fluorescence (2PEF) and second harmonic generation (SHG) signals of excised mice SC injured tissues were recorded in MPM at 72h,1 week and 6 weeks post-lesion. The MPM images revealed the apparition of a strong SHG signal at 1week post injury, due to the formation of fibrillar collagen fibers (collagen type I) by the injury site in the glial scar. At 6 weeks post-injury, the SHG signal is more intense and a higher number of fibers are detected in average. We further assessed the preferential orientation of the collagen bundles performing polarization dependent measurements of the SHG signal. The AFM based force spectroscopy measurements have been performed at the same post-lesion time-points to map the elastic properties of the healthy (grey and white matters) and injured (lesion) parts in the spinal cord tissue. The results suggested an increase of the lesion area stiffness over time that could be correlated with the apparition of fibrillar collagen observed in MPM, indicating the presence of a fibrotic process seven days after injury, that develops in time. As tissue stiffness is a regulator of neuronal growth, such kind of measurements might help to understand why adult mammalian axons do not regenerate after an injury. Our next step is to investigate the effect of a treatment (pharmacological transient depletion of microglia/macrophage in mice that underwent SCI) on the structure and mechanical properties of the lesion site at 2 weeks and 6 weeks post injury.

International audience; Spinal cord injuries (SCI) affect between 2.5 and 4 million patients worldwide (40 000 in France). Handicaps induced by SCI range from minimal sensory motor deficits to complete tetraplegia. Currently, there is no curative treatment on any symptoms associated with SCI. A scar, called glial and composed mainly of astrocytes and microglia, appears at the the injury site and inhibits axonal regeneration. This mechanism is poorly understood. Better monitoring of animal models of SCI in particular through the development of bioimaging translational tools are therefore mandatory.Our main objectives are to pursue and extend a multimodal imaging approach combining multiphoton spectroscopy (MPM), Atomic Force Microscopy (AFM) and Broadband coherent anti-Stokes Raman Spectroscopy (BCARS), a novel technique [1] based on Raman spectroscopy with faster image acquisitions [2], to better understand mechanisms that underlie the glial scar formation and the subsequent absence of spontaneous axonal regeneration following SCI, as well as to evaluate outcomes of therapeutic strategies that favor axonal regeneration in mice and non-human primates. MPM, conceived to specifically reveal non centro-symmetric structures with second harmonic generation (SHG) [3], provided a first evidence of the presence of collagen fibers as a biomarker of the injury site. AFM showed significant differences in Young Modulus between healthy and injured areas. These results must be supplemented with a deeper collagen characterization and axons imaging using MPM, as well as a treatment monitoring by co-localizing drugs within healthy/diseased tissues using BCARS [4].[1]. C. H. Camp Jr, Y. J. Lee, J. M. Heddleston, C. M. Hartshorn, A. R. Hight Walker, J. N. Rich, J. D. Lathia, M. T. Cicerone, Nat. Photonics 2014, 8, 627.[2]. C. M. Hartshorn, Y. J. Lee, C. H. Camp Jr, Z. Liu, J. M. Heddleston, N. Canfield, T. A. Rhodes, A. R. Hight Walker, P. J. Marsac, M. T. Cicerone, Anal. Chem. 2013, 85, 8102[3]. L. Mostaço-Guidolin, N.L. Rosin, T.L. Hackett, Int. J. Mol. 2017, 18(8), 1772. [4]. C. Zhang, D. Zhang, J.-X. Cheng, Annu. Rev. Biomed. Eng. 2015, 17, 415. [4]. C. Zhang, D. Zhang, J.-X. Cheng, Annu. Rev. Biomed. Eng. 2015, 17, 415.

International audience; Aim: Our main objective is to implement a multimodal (bio)physical approach to decipher mechanisms that underlie absence of spontaneous axonal regeneration following spinal cord injury (SCI) in mice and nonhuman primates. Method: A multimodal imaging strategy is employed combining state-of-the-art non-linear microscopy techniques (multiphoton - MPM and BCARS microscopy) with force spectroscopy measurements via atomic force microscopy (AFM). This approach enables to assess the relevant structural, morphological and spectral signature as well as the nanobiomechanical behavior of healthy and injured spinal cord tissue at cellular level. Results: We have first imaged excised mice SC tissues in 2-photon excited fluorescence and second harmonic generation (SHG). These MPM studies revealed the apparition of a strong SHG signal due to the formation of collagen I fibers by the injury site in the glial scar. AFM based force spectroscopy measurements have been also performed to map the elastic properties of the healthy and injured spinal cord tissue. Therefore, MPM data could be correlated with Young modulus elasticity results, indicating the presence of a fibrotic process 7 days after injury. As tissue stiffness is a regulator of neuronal growth, such kind of measurements will enable to understand why adult mammalian axons do not regenerate spontaneously after injury. Our next step will be to use a novel, emerging imaging technology that is the broadband coherent anti-Stokes Raman scattering (BCARS) microscopy for fast, label-free, highly selective and specific screening of spinal cord injury and potentially of drugs uptake into excised tissues. Combination of BCARS and MPM will first enable to retrieve information on the biological state of the cells/tissues that may underly the absence of spontaneous axonal regeneration following SCI (Raman neuronal markers: myelin, acetylcholine neurotransmitter, glutamate; MPM markers: collagen, neural axons, mitochondria,…). Second, it will permit to further correlate modification of these structural, morphological and spectral signatures in the context of therapeutic strategies.

TANK binding kinase 1 (TBK1) regulates IFN-I, NF-kappa B, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-kappa B. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD.

A partir das Teorias Feministas e dos Whiteness Studies (DiAngelo, 2018) (Moura, 2010 e Moura, et al., 2020) (Butler, 2018 [2015]) (Stubs et al., 2018) (Aruruzza et al., 2019) (Lugones, 2015), este ensaio tem como objetivo central identificar e analisar práticas artísticas e culturais decoloniais que permitem romper com espectativas normativas relativamente à performatividade dos seus corpos numa sociedade profundamente hierarquizada por uma desigualdade socio-espacial geradora de linhas abissais (Santos, 2007). Pretende-se discutir o potencial que práticas artísticas e culturais nas periferias urbanas podem ter na transformação das relações de desigualdade entre e dentro das culturas, descolonizando a linguagem e abrindo espaço para narrativas estigmatizadas, silenciadas e ocultas. Em vez de conceber as artes e a cultura como uma ferramenta civilizacional que pode "salvar" indivíduos de uma cultura desviante, o ensaio examina o potencial transformador da cultura e das artes por meio de sua contribuição para a descolonização de mentes e corpos. Partindo da hipótese de que práticas culturais como dança, música e teatro realizadas por sujeitos periféricos podem contribuir para uma redefinição da construção da identidade e do sentimento de pertencimento à cidade, e levando em conta as opressões interseccionais de gênero, raça e classe que informam a vida quotidiana, esta análise procura compreender se essas práticas podem ter um efeito emancipatório, potenciando as lutas feministas contemporâneas, nomeadamente no que diz respeito à disruptura dos modelos de masculinidade hegemónicos tradicionalmente associados a violência. (Moura, et al., 2020) (Miescher; Lindsay, 2003) (Mignolo, et al., 2006) (Quijano, 2005) (Segato, 2003).

The objective of Working Group (WG) 4 of the COST Action NET4Age-Friendly is to examine existing policies, advocacy, and funding opportunities and to build up relations with policy makers and funding organisations. Also, to synthesize and improve existing knowledge and models to develop from effective business and evaluation models, as well as to guarantee quality and education, proper dissemination and ensure the future of the Action. The Working Group further aims to enable capacity building to improve interdisciplinary participation, to promote knowledge exchange and to foster a cross-European interdisciplinary research capacity, to improve cooperation and co-creation with cross-sectors stakeholders and to introduce and educate students SHAFE implementation and sustainability (CB01, CB03, CB04, CB05). To enable the achievement of the objectives of Working Group 4, the Leader of the Working Group, the Chair and Vice-Chair, in close cooperation with the Science Communication Coordinator, developed a template (see annex 1) to map the current state of SHAFE policies, funding opportunities and networking in the COST member countries of the Action. On invitation, the Working Group lead received contributions from 37 countries, in a total of 85 Action members. The contributions provide an overview of the diversity of SHAFE policies and opportunities in Europe and beyond. These were not edited or revised and are a result of the main areas of expertise and knowledge of the contributors; thus, gaps in areas or content are possible and these shall be further explored in the following works and reports of this WG. But this preliminary mapping is of huge importance to proceed with the WG activities. In the following chapters, an introduction on the need of SHAFE policies is presented, followed by a summary of the main approaches to be pursued for the next period of work. The deliverable finishes with the opportunities of capacity building, networking and funding that will be relevant to undertake within the frame of Working Group 4 and the total COST Action. The total of country contributions is presented in the annex of this deliverable.

[ES] Fundamentos: La fragilidad es un problema de creciente magnitud entre los mayores que afecta en mayor proporción a mujeres. La actividad física mejora tanto la funcionalidad como la calidad de vida. Dadas las diferencias en la percepción de la calidad de vida y en la práctica de actividad física entre hombres y mujeres, se planteó como objetivo analizar la asociación entre calidad de vida y actividad física en mayores de 70 años prefrágiles y su relación con el sexo. Métodos: Estudio descriptivo en mayores de 70 años prefrágiles realizado entre junio de 2018 y marzo de 2020 en 12 centros de salud de Madrid. Se recogieron mediante entrevista clínica, variables de actividad física (cuestionario de Yale), calidad de vida (Euroqol-5D); variables sociodemográficas y de salud (comorbilidad, depresión y dolor). Se realizó análisis descriptivo y modelos de regresión lineal múltiple con calidad de vida como variable dependiente (total población y por sexo). Resultados: Participaron en el estudio 206 individuos (152 mujeres), con una edad media de 78 años. Las mujeres presentaron menos comorbilidad (32,3% versus 55,6%) y más dolor (60,5% versus 44,4%) que los hombres. La media de actividad física fue de 40 puntos (55,9% de la puntuación corresponde a pasear relajadamente). La calidad de vida fue de 0,74 según utilidades y de 68 en la EVA-EQ5D, sin diferencias según sexo. Pasear más de 5 horas/semana se asoció a mejor calidad de vida según utilidades (0,08, IC95%: 0,03 a 0,14), y según EVA (5,38, IC95%: 0,25 a 10,51). Conclusiones: La actividad física se asoció a una mejor calidad de vida en población prefrágil mayor de 70 años. [EN] Background: Frailty is an increasing problem among the elderly people and it is more frequent in women. Physical activity improves either the function and quality of life. Given the diferences reported by the literature about the quality of life perception and the physical activity practice between men and women, the aim of this study is to analyze the association between health related quality of life (HRQoL) and physical activity in a pre-frail population and to study its relationship with gender. Methods: Descriptive study in pre-frail individuals over 70 years old assigned to twelve primary care health centers carried out between 2018 Jun and 2020 March in Madrid. The studied variables were registered by clinical interview: Physical activity (Yale), HRQoL (EQ-5D-3L), sociodemographic and clinical variables (comorbidity, depression and pain). Descriptive analysis and multiple linear regression for the whole population and stratified by gender, using the quality of life as dependent variable. Results: The study involved 206 pre-frail individuals (152 women) wih an average age of 78 years. Women had less comorbidity (32.3% versus 55.6%) but more pain (60.5% versus 44.4%) than men. The median of physical activity was 40 points (55.9% of that score was attributable to relaxed walk). HRQoL was 0.74 in utility score and 68 in the EQ-VAS. No differences were found by gender. To walk more than 5 hours a week was found associated with better quality of life by EQ-5D utility score (0.08, IC95%: 0.03 to 0.14), and by EQ-VAS score (5.38, IC95%: 0.25 to 10.51). Conclusions: Physical activity was associated to better quality of life in a pre-frail population of individuals older than 70 years old. El presente estudio ha sido financiado por el Fondo de Investigaciones Sanitarias ISCIII (PI17/01887) y el Fondo Europeo de Desarrollo Regional (“Una forma de construir Europa”). Los financiadores no tuvieron ningún papel en el diseño del estudio o en la decisión de publicar el estudio Sí

The objective of Working Group (WG) 4 of the COST Action NET4Age-Friendly is to examine existing policies, advocacy, and funding opportunities and to build up relations with policy makers and funding organisations. Also, to synthesize and improve existing knowledge and models to develop from effective business and evaluation models, as well as to guarantee quality and education, proper dissemination and ensure the future of the Action. The Working Group further aims to enable capacity building to improve interdisciplinary participation, to promote knowledge exchange and to foster a cross-European interdisciplinary research capacity, to improve cooperation and co-creation with cross-sectors stakeholders and to introduce and educate students SHAFE implementation and sustainability (CB01, CB03, CB04, CB05). To enable the achievement of the objectives of Working Group 4, the Leader of the Working Group, the Chair and Vice-Chair, in close cooperation with the Science Communication Coordinator, developed a template (see annex 1) to map the current state of SHAFE policies, funding opportunities and networking in the COST member countries of the Action. On invitation, the Working Group lead received contributions from 37 countries, in a total of 85 Action members. The contributions provide an overview of the diversity of SHAFE policies and opportunities in Europe and beyond. These were not edited or revised and are a result of the main areas of expertise and knowledge of the contributors; thus, gaps in areas or content are possible and these shall be further explored in the following works and reports of this WG. But this preliminary mapping is of huge importance to proceed with the WG activities. In the following chapters, an introduction on the need of SHAFE policies is presented, followed by a summary of the main approaches to be pursued for the next period of work. The deliverable finishes with the opportunities of capacity building, networking and funding that will be relevant to undertake within the frame of Working Group 4 and the total COST Action. The total of country contributions is presented in the annex of this deliverable.

Simple Summary Contrary to other cancers, treatment of human uveal malignant melanoma metastases has not evolved sufficiently remaining as a great challenge in the field of ocular oncology. Although uveal melanoma is effectively controlled at the local level, the diagnosis of systemic disease in these patients makes its prognosis fatal, with survival rates of around 4–8 months. In this manuscript, we performed a systematic review studying comprehensively all the different treatment types for metastatic uveal melanoma disease in the last 40 years. We truly believe that our work shows a global vision of the situation, placing the reader in a concise and orderly manner in perspective of the current state of the subject. Abstract Introduction: More than 50% of patients with uveal melanoma end up developing metastases. Currently, there is no standard first-line treatment that facilitates proper management of the metastatic disease. Methods: A systematic review of the last 40 years in PubMed with an exhaustive and strict selection of studies was conducted, in which the unit of measurement was overall survival (OS) expressed in Kaplan–Meier curves or numerically. Results: After the selection process, 110 articles were included. Regional therapies, such as intra-arterial liver chemotherapy (OS: 2, 9–22 months), isolated liver perfusion (OS: 9, 6–27, 4 months), or selective internal radiation therapy (OS: 18 months in monotherapy and 26 months in combination with other therapies) showed some superiority when compared to systemic therapies, such as chemotherapy (OS: 4, 6–17 months), immunotherapy (OS: 5–19, 1 month), immunosuppression (OS: 11 months), or targeted therapy (OS: 6–12 months), without being significant. Conclusions: The results of this review suggest that there are no important differences in OS when comparing the different current treatment modalities. Most of the differences found seem to be explained by the heterogenicity of the different studies and the presence of biases in their design, rather than actual extensions of patient survival.

Manuel F Bande Rodríguez, 1, 2 Beatriz Fernandez Marta, 1 Nerea Lago Baameiro, 3 Maria Santiago-Varela, 1, 2 Paula Silva-Rodríguez, 2, 4 María Jose Blanco-Teijeiro, 1, 2 Maria Pardo Perez, 3 Antonio Piñeiro Ces 1, 2 1Unidad de Retina Quirúrgica y Tumores Intraoculares del Adulto (URQTIA), Servicio de Oftalmología Xerencia de Xestión Integrada de Santiago de Compostela, SERGAS, Santiago de Compostela, Spain; 2Tumores Intraoculares en el Adulto, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain; 3Grupo Obesidómica, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain; 4Fundación Pública Galega de Medicina Xenómica, Clinical University Hospital, SERGAS, Santiago de Compostela 15705, SpainCorrespondence: Manuel F Bande RodríguezUnidad de Retina Quirúrgica y Tumores Intraoculares del Adulto (URQTIA), Servicio de Oftalmología Xerencia de Xestión Integrada de Santiago de Compostela, SERGAS, Santiago de Compostela, SpainTel +34981951756Fax +34981956189Email verman017@hotmail.comAbstract: The detection of metastases in patients with a diagnosis of uveal melanoma (UM) is a controversial issue. While only 1% of the patients have detectable metastases at the time of diagnosis, up to 30% of them will develop liver metastases within 5 years of treatment. UM spreads hematogenously, therefore, blood biomarkers may be helpful for prognosis and monitoring the disease progression. Despite the great progress achieved thanks to the genetic analysis of UM biopsies, this is an invasive technique and is limited by the heterogeneity of the tumor. The present review considers the current understanding in the field regarding biomarkers for the diagnosis and prognosis of UM and its metastasis, primarily to the liver. General covered topics include non-conventional markers such as proteins previously identified in cutaneous melanoma and UM cell lines, circulating tumor cells, microRNAs (miRNA), and circulating DNA, and how each may be critical in the development of novel blood biomarkers for UM.Keywords: uveal melanoma, biomarker, circulating tumor cells, microRNAs, circulating DNA, exosome

National audience; Des modèles basés sur l'architecture Transformer qui intègrent une étape de pré-entrainement non supervisé à objectif prédictif, tels que le GPT-2 (Generative Pretrained Transformer 2) ont atteint récemment des succès remarquables. Nous avons adapté et mis en oeuvre un modèle de traitement automatique du langage naturel (NLP pour Natural Language Processing) permettant de déterminer si un texte libre clinique est de nature traumatique ou non. Nous avons comparé cette approche, nécessitant un nombre d'échantillons annotés réduit, à une approche entièrement supervisée. Nos résultats (basés sur l'AUC et le F1-score) montrent qu'il est possible d'adapter un modèle polyvalent tel que le GPT-2 pour créer un outil puissant de classification de notes de texte libre en français avec seulement un très faible nombre d'échantillons labélisés.

El objetivo general del proyecto es obtener información estadística sobre las características de los alumnos de la asignatura de Expresión Gráfica (EG) del Grado en Tecnologías Industriales (GETI) y su percepción respecto a la asignatura. También se pretende conocer la percepción de coordinadores de otras asignaturas del GETI de la ETSEIB respecto a los conocimientos que se adquieren en EG. Se realizaron diferentes encuestas mediante plataformas digitales a estudiantes y coordinadores. Sobre los aspectos sociodemográficos, académicos y experiencias previas se realizó la encuesta Caracterización del estudiante (CE). Se les pasó también el Mental Cutting Test (MCT) y se obtuvo su nota de EG. Además, se preguntó tanto a los estudiantes de primero (encuesta TAM1) como a los de cuarto (encuesta TAM4) la percepción que tenían sobre la asignatura de EG. Para valorar la percepción de los coordinadores de otras asignaturas se les pasó la Encuesta 112 sobre competencias y conocimientos adquiridos por los estudiantes. Se hizo un análisis descriptivo de las variables y posteriormente se realizó un estudio de las asociaciones entre ellas. Los resultados principales son que la nota de EG y la nota de MCT tiene una correlación entre ellas y que además pueden depender del sexo del estudiante, si cursó Dibujo Técnico en Bachillerato, si tiene experiencia con programas CAD 3D, el tiempo de desplazamiento a la universidad, la autopercepción de habilidades espaciales (HE) del alumno y la autopercepción de resolución de problemas gráficos del alumno. Además, existe correlación entre las variables, Nota EG-Nota Dibujo Técnico Bachillerato, Nota EGNota 1er cuatrimestre ETSEIB y Nota EG-Nota suspenso de la última convocatoria de los repetidores. Respecto a la percepción del estudiante sobre la asignatura EG, tanto los alumnos de primero como los de cuarto curso del GETI valoran como “Bastante” y “Mucho” los conocimientos adquiridos en EG para resolver problemas geométricos y la utilización de SolidWorks en la asignatura de EG. Además, no hay diferencias significativas entre las respuestas por sexo del alumno en el TAM 1, pero sí que las hay entre alumnos aprobados y suspendidos. Respecto a la valoración de las competencias adquiridas por los coordinadores de otras asignaturas del GETI, opinan que las competencias valoradas como “Bastante” y “Muy importantes” que los estudiantes han adquirido son: “guionizar la presentación oral del diseño”, “capacidad de trabajo en grupo homogéneo” y “capacidad de análisis de problemas”. Respecto a las competencias valoradas como “Muy importantes” opinan que los estudiantes no han adquirido “definir la métrica de los conjuntos de piezas”, “realizar la representación visual en la posición (render estático)” y “capacidad de defensa del proyecto escrito” y de los conocimientos de delineación son “la representación normalizada de escalas”, “la representación normalizada de acotación” y los “conjuntos y despieces”.

International audience; Chronic kidney disease (CKD) is characterized by a gradual decline in renal function that progresses toward end-stage renal disease (ESRD). Podocytes are highly specialized glomerular epithelial cells, which form with the glomerular basement membrane (GBM) and capillary endothelium, the glomerular filtration barrier (GFB). GBM is an extracellular matrix (ECM) that acts as a mechanical support and provides biophysical signals that control normal podocytes behavior in the process of glomerular filtration. Thus the modulus of elasticity E or stiffness of “ECM” represents an essential characteristic that controls podocyte functions. The biophysical properties of hydrolyzed Polyacrylamide (PAAm) gels resemble to in vivo ECM and thus provide an opportunity to be applied as ECM-like membranes to study cellular behaviors. Therefore, hydrolyzed PAAm hydrogels were investigated for their potential use as new ECM-like constructs to engineer a basement membrane that form with cultured human podocytes a functional glomerular-like filtration barrier. Such ECM-like polyacrylamide hydrogel construct will provide the unique opportunity of understanding in an in vivo-like setting podocyte cells biological responses by controlling the physical properties of the PAAm membranes. In this work, several PAAm hydrogel layers were prepared by changing the crosslinker concentration. The macromolecular microstructure and stiffness were evaluated by Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) techniques respectively. Accordingly, the mechanical properties and the polymeric network porosity can be effectively controlled by modulating the crosslinker concentration as well as the swelling degree. Moreover, modulating gel stiffness significantly influenced podocyte behavior including morphology, actin cytoskeleton reorganization. In conclusion, podocytes response to the variation of the mechanical properties of the membranes correlated with the hydrogels stiffness. This work addresses the complexity of podocytes behavior which will further enhance our knowledge to develop a kidney-on-chip model much needed to study kidney function in both health and disease states.

This article belongs to the Section Molecular Medicine., Interleukin-7 receptor subunit alpha (IL7RA) rs6897932 polymorphism IS related to CD4+ recovery after combination antiretroviral therapy (cART), but no studies so far have analyzed its potential impact in patients with very low CD4+ T-cells count. We aimed to analyze the association between IL7RA rs6897932 polymorphism and CD4+ T-cells count restoration in HIV-infected patients starting combination antiretroviral therapy (cART) with CD4+ T-cells count 20% and was in Hardy–Weinberg equilibrium (p = 0.550). Of 411 patients, 256 carried the CC genotype, while 155 had the CT/TT genotype. The CT/TT genotype was associated with a higher slope of CD4+ T-cells recovery (arithmetic mean ratio; AMR = 1.16; p = 0.016), higher CD4+ T-cells increase (AMR = 1.19; p = 0.004), and higher CD4+ T-cells count at the end of follow-up (AMR = 1.13; p = 0.006). Besides, rs6897932 CT/TT was related to a higher odds of having a value of CD4+ T-cells at the end of follow-up ≥500 CD4+ cells/mm3 (OR = 2.44; p = 0.006). After multiple testing correction (Benjamini–Hochberg), only the increase of ≥ 400 CD4+ cells/mm3 lost statistical significance (p = 0.052). IL7RA rs6897932 CT/TT genotype was related to a better CD4+ T-cells recovery and it could be used to improve the management of HIV-infected patients starting cART with CD4+ T-cells count, This study has been (partially) funded by grants RD12/0017/0031 and D16/0025/0013 to JMB, and RD12/0017/0024 and RD16CIII/0002/0002 to SR as part of the Health Research and Development Strategy, State Plan for Scientific and Technical Research and Innovation (2008–2011; 2013–2016) and co-financed by Institute of Health Carlos III, ISCIII—Sub-Directorate General for Research Assessment and Promotion and European Regional Development Fund (ERDF). MA Jiménez-Sousa is funded by project RD16CIII/0002/0002; MA Navarrete-Muñoz is co-funded by RD16/0025/0013 project and Intramural Research Scholarship from IIS-FJD. N Rallón is a Miguel Servet investigator from the ISCIII [grant number CP14/00198].

Background: Although low-grade serous ovarian cancer (LGSC) is rare, case-fatality rates are high as most patients present with advanced disease and current cytotoxic therapies are not overly effective. Recognizing that these cancers may be driven by MAPK pathway activation, MEK inhibitors (MEKi) are being tested in clinical trials. LGSC respond to MEKi only in a subgroup of patients, so predictive biomarkers and better therapies will be needed. Methods: We evaluated a number of patient-derived LGSC cell lines, previously classified according to their MEKi sensitivity. Two cell lines were genomically compared against their matching tumors samples. MEKi-sensitive and MEKi-resistant lines were compared using whole exome sequencing and reverse phase protein array. Two treatment combinations targeting MEKi resistance markers were also evaluated using cell proliferation, cell viability, cell signaling, and drug synergism assays. Results: Low-grade serous ovarian cancer cell lines recapitulated the genomic aberrations from their matching tumor samples. We identified three potential predictive biomarkers that distinguish MEKi sensitive and resistant lines: KRAS mutation status, and EGFR and PKC-alpha protein expression. The biomarkers were validated in three newly developed LGSC cell lines. Sub-lethal combination of MEK and EGFR inhibition showed drug synergy and caused complete cell death in two of four MEKi-resistant cell lines tested. Conclusions: KRAS mutations and the protein expression of EGFR and PKC-alpha should be evaluated as predictive biomarkers in patients with LGSC treated with MEKi. Combination therapy using a MEKi with EGFR inhibition may represent a promising new therapy for patients with MEKi-resistant LGSC.

Let’s Go Engineering nace del análisis de la situación actual en España, donde faltan profesionales de la ingeniería para cubrir las necesidades del mercado. Adicionalmente a ésto encontramos la falta de diversidad en el mundo de la ingeniería. Con esto in mente y tras llevar a cabo algunas charlas en centros educativos de Primaria y Secundaria sobre esta problemática, un equipo de Schneider Electric decidió impulsar y desarrollar de forma voluntaria 'Let's Go Engineering', un programa dirigido a estudiantes en últimos cursos de la escuela primaria, cuyo objetivo es colaborar activamente con los centros educativos de las principales ciudades españolas, para crear un espacio de influencia y así contribuir a despertar vocaciones de ingeniería y romper los estereotipos de género asociados a estas carreras. El programa 'Let's Go Engineering' se realiza durante un curso escolar y se compone de varias fases, a lo largo de las cuales se realizan diferentes actividades que pretenden despertar la creatividad de los estudiantes y mostrar el impacto humanitario y beneficio social de la tecnología. Cada clase incluida en el programa se prepara de forma conjunta entre el equipo que integra 'Let's Go Engineering' y el profesorado en las aulas. Además, se hace un acompañamiento a las familias a través de las AMPAs, para que sean conocedores de la realidad, contribuyan a romper estereotipos y sean también agentes del cambio en la mentalidad de las nuevas generaciones. 'Let's Go Engineering', inició el mes de septiembre 2018, con una periodicidad variable de las imparticiones de actividades de entre 15 días y un mes. El programa cuenta con un equipo de más de 40 voluntarios de Schneider Electric y con la colaboración de profesores especializados, universidades públicas como la Universitat Politècnica de Catalunya (UPC), y empresas Partners de Schneider Electric

Background: Vitamin D is a fundamental regulator of host defenses by activating genes related to innate and adaptive immunity. In this study, we analyzed the association among single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene, with clinical patterns of AIDS progression in antiretroviral treatment (ART)-naive HIV-infected patients. Methods: We conducted a retrospective study in 667 HIV-infected patients, who were classified within three groups according to their AIDS progression pattern (183 long-term non-progressors (LTNPs), 334 moderate progressors (MPs), and 150 rapid progressors (RPs)). Five VDR SNPs (rs11568820, rs4516035, rs2228570, rs1544410, and rs7975232) were genotyped using Agena Bioscience's MassARRAY platform. Results: Significant association results were found for rs2228570. Within all HIV patients, the presence of T allele at VDR rs2228570 SNP was protective against AIDS progression (ordinal outcome) under additive (adjusted odds ratio (aOR) = 0.75; p = 0.009), dominant (aOR = 0.69; p = 0.015), and codominant (aOR = 0.56; p = 0.017) inheritance models. In addition, the same allele was protective under additive and codominant inheritance models when we compared with LTNPs vs. RPs [aOR = 0.64 (p = 0.019) and aOR = 0.37 (p = 0.018), respectively] and when we compared MPs vs. RPs [aOR = 0.72 (p = 0.035) and aOR = 0.45 (p = 0.028), respectively]. Conclusions: The VDR rs2228570 T allele was related to a lower AIDS progression pattern in ART-naive HIV-infected patients. These findings expand upon the knowledge about HIV pathogenesis in untreated HIV-infected patients with different clinical outcomes., This work has been (partially) funded by the RD16/0025/0019 and RD16CIII/0002/0002, projects as part of Accion Estrategica en Salud, Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (2013-2016) and cofinanced by Instituto de Salud Carlos III (Subdireccion General de Evaluacion) and Fondo Europeo de Desarrollo Regional (FEDER), RETIC PT17/0015/0042, Fondo de Investigacion Sanitaria (FIS) (grant number PI16/01863, PI17/01115, PI17CIII/00003), EPIICAL Project and Comunidad de Madrid B2017/BMD-3703. Programa de Investigacion de la Consejeria de Sanidad de la Comunidad de Madrid to JLJ. CIBER-BBN is an initiative funded by the VI National R& D& i Plan 2008-2011, Iniciativa Ingenio 2010, the Consolider Program, and CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. COST CA17140 Cancer Nanomedicine-Front the Bench to Bebside. AFR are supported and funded by Instituto de Salud Carlos III [grant number CP14/0010].

Mes travaux portent principalement sur le développement, l’adaptation, l’implémentation et l’application de méthodes statistiques de sélection de modèle. Ma principale contribution consiste à adapter des méthodes de l'apprentissage statistique supervisé qui sont devenues très populaires lors de la dernière décennie, les régressions pénalisées de type Lasso, à l'analyse de données issues d'études épidémiologiques. L'enjeu est de s'attaquer aux problèmes des données volumineuses (\textit{Big Data}) tout en respectant les objectifs et spécificités de la discipline. Le volume important se réfère ici au fait que le nombre d'observations et/ou le nombre de variables est bien plus important que celui qui était classique dans le domaine, sans exclure le cas où le nombre de variables est supérieur au nombre d'observations (données de grande dimension). Le contexte de la pratique épidémiologique est en plein changement avec les évolutions technologiques et la conséquente disponibilité croissante des Big Data. Le Système National des Données de Santé (SNDS), regroupant les principales bases de données de santé publique existantes en France, constitue un exemple de Big Data en santé. Le données ``omiques'' (génomiques, transcriptomiques, protéomiques, métabolomiques, microbiomiques, mycobiomiques, viromiques,$\ldots$) issues des avancées des techniques de séquençage à haut débit constituent un autre exemple de Big Data en santé. Enfin, les mesures de l'\textit{exposome} (par opposition aux facteurs génétiques), qui désigne en épidémiologie l’ensemble des expositions environnementales que subit un individu au long de sa vie peut également constituer une source de Big Data.Ce document s'articule autour de trois chapitres. Il résume mon activité de recherche depuis 2005, soit depuis mon recrutement à l’Université de Bordeaux après ma thèse. Le premier chapitre est une introduction générale dans laquelle je contextualise, motive et énonce la problématique abordée tout au long de mes recherches. Le deuxième chapitre est consacré à mes travaux en lien avec les études sur les traumatismes accidentels et expositions médicamenteuses à partir des données du SNDS. Le troisième chapitre est consacré à mes travaux en lien avec des études biomédicales: la prédiction de la charge virale censurée par un seuil de détection à partir des mutations du VIH, d'une part, et l'automatisation de la détection des seuils d'anomalie des hémogrammes en population générale, d'autre part.

International audience; We consider the problem of learning a low dimensional representation for compositional data. Compositional data consists of a collection of nonnegative data that sum to a constant value. Since the parts of the collection are statistically dependent, many standard tools cannot be directly applied. Instead, compositional data must be first transformed before analysis. Focusing on principal component analysis (PCA), we propose an approach that allows low dimensional representation learning directly from the original data. Our approach combines the benefits of the log-ratio transformation from compositional data analysis and exponential family PCA. A key tool in its derivation is a generalization of the scaled Bregman theorem, that relates the perspective transform of a Bregman divergence to the Bregman divergence of a perspective transform and a remainder conformal divergence. Our proposed approach includes a convenient surrogate (upper bound) loss of the exponential family PCA which has an easy to optimize form. We also derive the corresponding form for nonlinear autoencoders. Experiments on simulated data and microbiome data show the promise of our method.

Simple Summary The development of uveal melanoma is a multifactorial and multi-step process, in which abnormal gene expression plays a key role. Recently, several studies have highlighted the role of non-coding RNAs in the progression of uveal melanoma by affecting different signaling pathways. As important agents in the regulation of genes, non-coding RNAs have enormous potential to open up therapeutic pathways, predict response to treatment, and anticipate patient outcome for uveal melanoma. This review aims to provide a comprehensive view of what we know about ncRNAs in uveal melanoma currently. Abstract Uveal melanoma (UM) is the most common primary intraocular tumor in adulthood. Approximately 50% of patients develop metastatic disease, which typically affects the liver and is usually fatal within one year. This type of cancer is heterogeneous in nature and is divided into two broad groups of tumors according to their susceptibility to develop metastasis. In the last decade, chromosomal abnormalities and the aberrant expression of several signaling pathways and oncogenes in uveal melanomas have been described. Recently, importance has been given to the association of the mentioned deregulation with the expression of non-coding RNAs (ncRNAs). Here, we review the different classes of ncRNAs—such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs)—and their contribution to the development of UM. Special attention is given to miRNAs and their regulatory role in physiopathology and their potential as biomarkers. As important agents in gene regulation, ncRNAs have a huge potential for opening up therapeutic pathways, predicting response to treatment, and anticipating patient outcome for UM.

International audience; Microgels display specific features attracting a high research interest in several applications such as bioactives, drug delivery or protein purification. Whey protein microgels (WPM) are obtained by promoting whey protein intramolecular cross-linking through heat treatment. Temperature-induced protein denaturation and aggregation involves several kinds of interactions such as electrostatic repulsions and disulfide bonds. In the present work, the WPM particles topography and nanomechanical properties were investigated at native pH (6.5) and acid pH (5.5 and 3.0) by atomic force microscopy (AFM) in contact mode in a liquid environment. Prior to AFM analysis, WPM particles were captured on a gold substrate via low energy interactions by means of specific monoclonal antibodies. The 2D AFM images clearly showed a swelling of WPM particles induced by pH decrease. At native pH, they displayed an average width and height of 192 ± 27 nm and 44 ± 9 nm, respectively. A decrease in pH to 5.5 led to a significant (p

A micromechanical characterisation of biomaterials for bone tissue engineering is essential to understand the quality of the newly regenerated bone, enabling the improvement of tissue regeneration strategies. A combination of micro-computed tomography (microCT) in conjunction with in situ mechanical testing and digital volume correlation (DVC) has become a powerful technique to investigate the internal deformation of bone structure at a range of dimensional scales. However, in order to obtain accurate three-dimensional (3D) strain measurement at tissue level, high-resolution images must be acquired, and displacement/strain measurement uncertainties evaluated. The aim of this study was to optimise imaging parameters, image post-processing and DVC settings to enhance computation based on ‘zero-strain’ repeated high-resolution synchrotron microCT (SR-microCT) scans of trabecular bone and bone-biomaterial systems. Low exposures to SR X-ray radiation were required to minimize irradiation-induced tissue damage, resulting in the need of advanced 3D filters on the reconstructed images to reduce DVC-measured strain errors. Furthermore, the computation of strain values only in the hard phase (i.e. bone, biomaterial) allowed the exclusion of large artifacts localised in the bone marrow. This study demonstrated the suitability of a local DVC approach based on SR-microCT images to investigate the micromechanics of trabecular bone and bone-biomaterial composites at tissue level with a standard deviation of the errors in the region of 100 microstrain after a thorough optimisation of DVC computation.

International audience; Luminescent nanodiamonds (ND) are attractive tools for nanoscale biologic cellular imaging allowing both photoluminescence (PL) and magnetic resonance imaging [1]. Recent technological developments enable to fabricate bright NDs with high content of nitrogen-vacancy centres [2] that are anticipated to serve as a cell probes. In this work we present novel method of NDs detection in cellular environment. We demonstrate simultaneous visualization of NDs and of the non- labeled nucleus of living cells based on Raman and PL detection as a new tool for the localization of internalized nanoparticles.To this end, NDs of size ranging from ultra-small particles ~ 5 nm to 60 nm were used, prepared from Ib synthetic diamond. Cells used for this experiment were from mammalian breast cancer (MCF7). We report on accomplishing to successfully internalize ND particles in MCF7 cells. We show that ND internalization can be monitored by Raman imaging method using K-mean cluster analysis. Whilst standard Raman imaging methods of NDs make use of the sp3 diamond Raman signal, which limits their use to 100 nm size particles or bigger [3], here we employ Raman imaging in a novel way to detect small near-IR cellular probe. Changes of cells stiffness were detected by force measurement in atomic force microscopy after incubating cells with NDs, suggesting cell membrane hardening upon ND uptake.[1] L. Moore, M. Nesladek et al., Nanoscale (2014)[2] J. Havlik, M. Gulka, M. Nesladek et al., Nanoscale (2013) [3] C.-Y. Cheng et al., Applied Physics Letter (2007)

International audience; In this work, a combination of optical and electrochemical studies are performed in order to elaborate a suitable porous silicon (PSi) substrate for biosensing and biomaterial applications. We report on the electrochemical behavior of PSi multilayer stabilized by thermal oxidation, applying electrochemical impedance spectroscopy and cyclic voltammetry measurements. The strength of the method is evidenced when adsorption of small (12-mer) peptides is monitored. Our aim is to combine the advantages offered by the large sensing area of the PSi multilayers and the high sensitivity of the electrochemical technique for improved biosensing.

International audience; Mineralization of calcium phosphate crystals was examined on porous silicon (PSi) scaffolds with respect to the dependence of crystal formation on the average pore size of PSi. PSi multilayer wafers fabricated by electrochemical etching were moni- tored via their reflectivity spectra over time in a biologically relevant osteogenic solution. The evolution of the mean refractive index of the PSi scaffold is the signature of the in situ crystals nucleation within the pores. Crystals were then characterized using atomic force microscopy (AFM), scanning electron microscopy (SEM) and Raman micro-spectroscopy. The results in- dicate that the average pore size of PSi highly influences nucleation and crystal formation.

BACKGROUND: Biological assays for the quantification of markers may suffer from a lack of sensitivity and thus from an analytical detection limit. This is the case of human immunodeficiency virus (HIV) viral load. Below this threshold the exact value is unknown and values are consequently left-censored. Statistical methods have been proposed to deal with left-censoring but few are adapted in the context of high-dimensional data. METHODS: We propose to reverse the Buckley-James least squares algorithm to handle left-censored data enhanced with a Lasso regularization to accommodate high-dimensional predictors. We present a Lasso-regularized Buckley-James least squares method with both non-parametric imputation using Kaplan-Meier and parametric imputation based on the Gaussian distribution, which is typically assumed for HIV viral load data after logarithmic transformation. Cross-validation for parameter-tuning is based on an appropriate loss function that takes into account the different contributions of censored and uncensored observations. We specify how these techniques can be easily implemented using available R packages. The Lasso-regularized Buckley-James least square method was compared to simple imputation strategies to predict the response to antiretroviral therapy measured by HIV viral load according to the HIV genotypic mutations. We used a dataset composed of several clinical trials and cohorts from the Forum for Collaborative HIV Research (HIV Med. 2008;7:27-40). The proposed methods were also assessed on simulated data mimicking the observed data. RESULTS: Approaches accounting for left-censoring outperformed simple imputation methods in a high-dimensional setting. The Gaussian Buckley-James method with cross-validation based on the appropriate loss function showed the lowest prediction error on simulated data and, using real data, the most valid results according to the current literature on HIV mutations. CONCLUSIONS: The proposed approach deals with high-dimensional predictors and left-censored outcomes and has shown its interest for predicting HIV viral load according to HIV mutations.

Conclusiones: Los resultados del análisis del sueño en los niños con TDAH resultan dispares según se midan por métodos objetivos o subjetivos. A través de la actigrafía no se encuentran alteraciones en el sueño, mientras que, por métodos subjetivos, los niños diagnosticados de TDAH presentan, mayor somnolencia excesiva diurna y más problemas en el inicio y mantenimiento del sueño. Las alteraciones subjetivas del sueño pueden estar mediadas por factores biopsicosociales, como la comorbilidad y la patología mental parental. Para una correcta evaluación del sueño en niños diagnosticados de TDAH, es importante el análisis socio-familiar y la combinación de varios métodos de medida. Fecha de lectura de Tesis: 17 de diciembre 2018. Introducción: Los problemas del sueño son comunes en niños diagnosticados de TDAH, sin embargo, los estudios que examinan dicha asociación muestran resultados inconsistentes. - Objetivos: Caracterización de los patrones de sueño en niños de reciente diagnóstico de TDAH sin tratamiento farmacológico comparado con niños sanos utilizando actigrafía y la escala Sleep Disorder Scale for Children (SDSC). Análisis de la influencia de los factores biopsicosociales en las características del sueño de los niños TDAH y controles sanos. - Resultados: El 55% de los niños con TDAH presentaba alteraciones en el sueño según la puntuación total de la escala SDSC en comparación con un 3.33% de los sanos. Los niños con TDAH presentan según las subescalas de SDSC, mayores problemas en el inicio y mantenimiento del sueño (p

The European pig industry is heavily dependent on imported protein feedstuffs, particularly soybean meal (SBM). Increased and more efficient use of locally produced protein sources, such as rapeseed (RS), could alleviate the dependency on imports and improve the sustainability and self-sufficiency of pig production in Europe. Because feed represents up to 70% of the total cost for pig producers, small improvements in feed efficiency (FE) when using rapeseed meal (RSM) could enhance production profitability. Digestive and metabolic efficiencies are key factors affecting the net FE in pigs. Alternative protein feedstuffs, including RSM, are typically more fibrous compared with SBM, and can contain other antinutritional factors that could compromise FE. Two experiments were thus conducted to assess the effects of replacing SBM with RS coproducts on energy and nutrient digestibility and metabolism in pigs. The present thesis includes three papers, Papers I and II are based on data collected from Experiment 1 while Paper III is based on data collected from Experiment 2. Svineproduksjonen i Europa er i dag svært avhengig av importerte proteinråvarer, særlig soyamel (SBM). Økt og mer effektiv bruk av lokalproduserte proteinkilder, som rapsfrø (RS), kan redusere avhengigheten av importerte råvarer, og øke bærekraften og selvforsyningen av europeisk svineproduksjon. Fôret representerer opptil 70% av den totale kostnaden i svineproduksjonen, og dermed kan små forbedringer av fôreffektiviteten (FE) ved bruk av rapsfrømel (RSM) bidra til økt lønnsomhet for produsentene. Fordøyelighet og metabolisme er sentrale faktorer som påvirker omsetningen av næringstoffer hos gris. Alternative proteinfôrmidler, som RSM, er typisk mer fiberrike sammenlignet med SBM, og kan også inneholde andre anti-næringsstoffer som kan redusere fôreffektiviteten. Det ble derfor gjennomført to forsøk for å vurdere effekten av å erstatte SBM med coprodukter av rapsfrø, på fordøyelighet og metabolisme av energi og næringsstoffer hos gris. Disse forsøkene er samlet i tre artikler i denne avhandlingen. Artikkel I og II er basert fra data fra det første forsøket, mens artikkel III er basert på forsøk nummer to.

CoRIS cohort., [Background] We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regimens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) and to investigate factors associated with the choice of each regimen., [Methods] We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between sociodemographic and clinical characteristics and the choice of the initial regimen., [Results] Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegravir (RAL) (5.6%). Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4100.000 copies/mL. TDF/FTC+DTG was more frequent in those with CD4100.000 copies/mL. TDF/FTC+RAL and TDF/FTC+bDRV were also more frequent among patients with CD4, [Conclusions] The choice of initial ART regimens is consistent with Spanish guidelines’ recommendations, but is also clearly influenced by physician’s perception based on patient’s clinical and sociodemographic variables and by the prescribing hospital location., The RIS cohort (CoRIS) is supported by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (RD06/006, RD12/0017/0018 and RD16/0002/0006) as part of the Plan Nacional I+D+i and cofinanced by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER). This study was funded by ViiV Healthcare.

International audience

International audience; The morphology and the nanomechanical properties of single casein micelles (CMs) in their native state were investigated using AFM in liquid environment. A novel immobilization method of CMs using low energy interactions was developed and compared with a well-known chemical immobilization method involving direct covalent bonds.For the classic method, CMs were covalently bound via carbodiimide chemistry to a gold-sputtered glass surface precoated with carboxyl groups. For the proposed method an indirect immobilization of CMs was realized via anti-human phospho-Ser/Thr/Tyr mouse monoclonal antibody covalently bound onto a gold-coated slide via carbodiimide chemistry. In both methods, immobilized CMs were then analyzed by AFM in their native environment represented by a simulated milk ultrafiltrate at room temperature.With the classic method of immobilization, some CMs remained mobile in liquid condition during the probe sample interaction. Conversely, with the novel method, CMs were well immobilized allowing the extraction of both surface topography and elastic properties by AFM in liquid. Morphologic characteristics were obtained from 2D and 3D images (Figure1). Data analyses allowed the calculation of diameters, heights and contact angles of native CMs. They are characterized by a mean width of 148 ± 8 nm and a mean height of 42 ± 1 nm. Low forces were applied on immobilized CM to calculate force-vs-indentation curves fitted using Hertz theory in order to determine Young Moduli (E*) which represents elasticity. Their elasticity distribution exhibited a unimodal trend, with an elasticity pic centered at 269 ± 14 kPa.