Unsupervised CT lung image segmentation of a mycobacterium tuberculosis infection model

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that produces pulmonary damage. Radiological imaging is the preferred technique for the assessment of TB longitudinal course. Computer-assisted identification of biomarkers eases the work of the radiologist by providing a quantitative assessment of disease. Lung segmentation is the step before biomarker extraction. In this study, we present an automatic procedure that enables robust segmentation of damaged lungs that have lesions attached to the parenchyma and are affected by respiratory movement artifacts in a Mycobacterium Tuberculosis infection model. Its main steps are the extraction of the healthy lung tissue and the airway tree followed by elimination of the fuzzy boundaries. Its performance was compared with respect to a segmentation obtained using: (1) a semi-automatic tool and (2) an approach based on fuzzy connectedness. A consensus segmentation resulting from the majority voting of three experts' annotations was considered our ground truth. The proposed approach improves the overlap indicators (Dice similarity coefficient, 94% ± 4%) and the surface similarity coefficients (Hausdorff distance, 8.64 mm ± 7.36 mm) in the majority of the most difficult-to-segment slices. Results indicate that the refined lung segmentations generated could facilitate the extraction of meaningful quantitative data on disease burden.The research leading to these results received funding from the Innovative Medicines Initiative (www.imi.europa.eu) Joint Undertaking under grant agreement no. 115337, whose resources comprise funding from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution. This work was partially funded by projects TEC2013-48552-C2-1-R, RTC-2015-3772-1, TEC2015-73064-EXP and TEC2016-78052-R from the Spanish Ministerio de Economía, Industria y Competitividad, TOPUS S2013/MIT-3024 project from the regional government of Madrid and by the Department of Health, UK

Lineal and cartesian graphics modes of representations in understanding of numerical sequence concept in secondary school students

Esta investigación forma parte de un trabajo cuyo objetivo es la compresión del concepto de sucesión numérica en los estudiantes de secundaria. El enfoque proporcionado por distintos investigadores en relación a los modos de representación y las aportaciones de Piaget y García en relación al desarrollo de un esquema a través de los niveles intra, inter y trans, nos proporciona información sobre el desarrollo de la comprensión del concepto de sucesión numérica a través del uso de los modos de representación gráficos, lineal y cartesiano, por parte de los estudiantes en la resolución de una tarea.The present paper is part of research that addresses the compression of the concept of numerical sequence in secondary school students. The perspective provided by the work of Piaget & Garcia related to the development of a scheme through several levels (intra, inter and trans), it provides empirical evidence of how the students’ use of the modes of representations when solving a task provides information of the development of understanding. This use allows us to go deep about the stages in the development of numerical sequence concep

Competencias en enfermeras especialistas y en enfermeras de práctica avanzada

10 p.Objetivo: Analizar la distribución de competencias avanzadas en enfermeras especialistas y enfermeras de práctica avanzada y evaluar su asociación con algunas características de superfil profesional.Método: Estudio transversal analítico multicéntrico. Se incluyeron enfermeras que ejercían como Enfermeras de Práctica Avanzada y enfermeras Especialistas. Se midió su nivel de competencias avanzadas percibidas, así como variables de caracterización profesional.Resultados: Doscientas setenta y siete enfermeras participaron (149 ejercían práctica avanzada y 128 especialistas), con una media de 13,88 (11,05) años como especialista y 10,48 (5,32) años como Enfermera de Práctica Avanzada. Un 28,8% tenía nivel de máster o doctorado. El 50,2% ejercía en atención primaria, el 24,9% en hospitales y el 22,7% en salud mental. El nivel global autopercibido fue elevado en las distintas competencias, siendo las dimensiones más bajas las de investigación, práctica basada en la evidencia, gestión de la calidad y seguridad y liderazgo y consultoría. Las Enfermeras de Práctica Avanzada obtuvieron mayor nivel competencial de forma global y en las dimensiones de liderazgo y consultoría, relaciones interprofesionales, gestión de cuidados y promoción de salud. No hubo diferencias en función de la experiencia o la posesión de nivel de máster o de doctorado. En las Enfermeras de Práctica Avanzada el contexto de práctica no influía en los niveles competenciales, aunque en las enfermeras especialistas sí, a favor de las que ejercían en salud mental.Conclusiones: Las enfermeras especialistas y de práctica avanzada tienen competencias distintas que deberían ser gestionadas adecuadamente para el desarrollo de los servicios enfermeros avanzados y especializados

Bespoken nanoceria: A new effective treatment in experimental hepatocellular carcinoma

Background and aims: Despite the availability of new-generation drugs, hepatocellular carcinoma (HCC) is still the third most frequent cause of cancer-related deaths worldwide. Cerium oxide nanoparticles (CeO2 NPs) have emerged as an antioxidant agent in experimental liver disease because of their antioxidant, anti-inflammatory, and antisteatotic properties. In the present study, we aimed to elucidate the potential of CeO2 NPs as therapeutic agents in HCC. Approach and results: HCC was induced in 110 Wistar rats by intraperitoneal administration of diethylnitrosamine for 16 weeks. Animals were treated with vehicle or CeO2 NPs at weeks 16 and 17. At the eighteenth week, nanoceria biodistribution was assessed by mass spectrometry (MS). The effect of CeO2 NPs on tumor progression and animal survival was investigated. Hepatic tissue MS-based phosphoproteomics as well as analysis of principal lipid components were performed. The intracellular uptake of CeO2 NPs by human ex vivo perfused livers and human hepatocytes was analyzed. Nanoceria was mainly accumulated in the liver, where it reduced macrophage infiltration and inflammatory gene expression. Nanoceria treatment increased liver apoptotic activity, while proliferation was attenuated. Phosphoproteomic analysis revealed that CeO2 NPs affected the phosphorylation of proteins mainly related to cell adhesion and RNA splicing. CeO2 NPs decreased phosphatidylcholine-derived arachidonic acid and reverted the HCC-induced increase of linoleic acid in several lipid components. Furthermore, CeO2 NPs reduced serum alpha-protein levels and improved the survival of HCC rats. Nanoceria uptake by ex vivo perfused human livers and in vitro human hepatocytes was also demonstrated. Conclusions: These data indicate that CeO2 NPs partially revert the cellular mechanisms involved in tumor progression and significantly increase survival in HCC rats, suggesting that they could be effective in patients with HCC. © 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.J.P.L.’s lab is sponsored by Grant PID2020-118527RB-I00 funded by MCIN/AEI/10.13039/ 501100011039; Grant PDC2021-121735-I00 funded by MCIN/AEI/10.13039/501100011039 and by the “European Union Next Generation EU/PRTR”, the Regional Government of Castile and León (CSI144P20). J.P.L. and P.L.S. are supported by the Carlos III Health Institute (PIE14/00066). AGN laboratory and human patients’ studies are supported by an ISCIII project grant (PI18/01242). The Human Genotyping unit is a member of CeGen, PRB3, and is supported by grant PT17/0019 of the PE I + D + i 2013–2016, funded by ISCIII and ERDF. SCLl is supported by MINECO/FEDER research grants (RTI2018-094130-B-100). CH was supported by the Department of Defense (DoD) BCRP, No. BC190820; and the National Cancer Institute (NCI) at the National Institutes of Health (NIH), No. R01CA184476. Lawrence Berkeley National Laboratory (LBNL) is a multi-program national laboratory operated by the University of California for the DOE under contract DE AC02-05CH11231. The Proteomics Unit belongs to ProteoRed, PRB3-ISCIII, supported by grant PT17/0019/0023 of the PE I + D +i, 2017–2020, funded by ISCIII and FEDER. RCC is funded by fellowships from the Spanish Regional Government of Castile and León. NGS is a recipient of an FPU fellowship (MINECO/FEDER). hiPSC-CM studies were funded in part by the “la Caixa” Banking Foundation under the project code HR18-00304 and a Severo Ochoa CNIC Intramural Project (Exp. 12-2016 IGP) to J.J.S

Mutational spectrum of GNAL, THAP1 and TOR1A genes in isolated dystonia: study in a population from Spain and systematic literature review

[Objective] We aimed to investigate the prevalence of TOR1A, GNAL and THAP1 variants as the cause of dystonia in a cohort of Spanish patients with isolated dystonia and in the literature.[Methods] A population of 2028 subjects (including 1053 patients with different subtypes of isolated dystonia and 975 healthy controls) from southern and central Spain was included. The genes TOR1A, THAP1 and GNAL were screened using a combination of high-resolution melting analysis and direct DNA resequencing. In addition, an extensive literature search to identify original articles (published before 10 August 2020) reporting mutations in TOR1A, THAP1 or GNAL associated to dystonia was performed.[Results] Pathogenic or likely pathogenic variants in TOR1A, THAP1 and GNAL were identified in 0.48%, 0.57% and 0.29% of our patients, respectively. Five patients carried the variation p.Glu303del in TOR1A. A very rare variant in GNAL (p.Ser238Asn) was found as a putative risk factor for dystonia. In the literature, variations in TOR1A, THAP1 and GNAL accounted for about 6%, 1.8% and 1.1% of published dystonia patients, respectively.[Conclusions] There is a different genetic contribution to dystonia of these three genes in our patients (about 1.3% of patients) and in the literature (about 3.6% of patients), probably due the high proportion of adult-onset cases in our cohort. As regards age at onset, site of dystonia onset, and final distribution, in our population there is a clear differentiation between DYT-TOR1A and DYT-GNAL, with DYT-THAP1 likely to be an intermediate phenotype.This work was supported by the Carlos III Health Institute-European Regional Development Fund (ISCIII-FEDER) [PI14/01823, PI16/01575, PI18/01898, PI19/01576], the Andalusian Regional Ministry of Economics, Innovation, Science and Employment [CVI-02526, CTS-7685], the Andalusian Regional Ministry of Health and Welfare [PI-0741-2010, PI-0471-2013, PE-0210-2018, PI-0459-2018, PE-0186-2019], and the Alicia Koplowitz and Mutua Madrileña Foundations. Pilar Gómez-Garre was supported by the "Miguel Servet" program [MSII14/00018] (from ISCIII-FEDER) and “Nicolás Monardes” program [C-0048-2017] (from the Andalusian Regional Ministry of Health). Silvia Jesús was supported by the "Juan Rodés" program [B-0007-2019] and Daniel Macías-García by the “Río Hortega” program [CM18/00142] (both from ISCIII-FEDER). María Teresa Periñán was supported by the Spanish Ministry of Education [FPU16/05061]. Cristina Tejera was supported by VPPI-US from the University of Seville.Peer reviewe

Targeting NAE1-mediated protein hyper-NEDDylation halts cholangiocarcinogenesis and impacts on tumor-stroma crosstalk in experimental models.

[EN] BACKGROUND & AIMS: Cholangiocarcinoma (CCA) comprises a heterogeneous group of malignant tumors associated with dismal prognosis. Alterations in post-translational modifications (PTMs), including NEDDylation, result in abnormal protein dynamics, cell disturbances and disease. Herein, we investigate the role of NEDDylation in CCA development and progression. METHODS: Levels and functions of NEDDylation, together with response to pevonedistat (NEDDylation inhibitor) or CRISPR/Cas9 against NAE1 were evaluated invitro, invivo and/or in patients with CCA. The development of preneoplastic lesions in Nae1+/- mice was investigated using an oncogene-driven CCA model. The impact of NEDDylation in CCA cells on tumor-stroma crosstalk was assessed using CCA-derived cancer-associated fibroblasts (CAFs). Proteomic analyses were carried out by mass-spectrometry. RESULTS: The NEDDylation machinery was found overexpressed and overactivated in human CCA cells and tumors. Most NEDDylated proteins found upregulated in CCA cells, after NEDD8-immunoprecipitation and further proteomics, participate in the cell cycle, proliferation or survival. Genetic (CRISPR/Cas9-NAE1) and pharmacological (pevonedistat) inhibition of NEDDylation reduced CCA cell proliferation and impeded colony formation invitro. NEDDylation depletion (pevonedistat or Nae1+/- mice) halted tumorigenesis in subcutaneous, orthotopic, and oncogene-driven models of CCA invivo. Moreover, pevonedistat potentiated chemotherapy-induced cell death in CCA cells invitro. Mechanistically, impaired NEDDylation triggered the accumulation of both cullin RING ligase and NEDD8 substrates, inducing DNA damage and cell cycle arrest. Furthermore, impaired NEDDylation in CCA cells reduced the secretion of proteins involved in fibroblast activation, angiogenesis, and oncogenic pathways, ultimately hampering CAF proliferation and migration. CONCLUSION: Aberrant protein NEDDylation contributes to cholangiocarcinogenesis by promoting cell survival and proliferation. Moreover, NEDDylation impacts the CCA-stroma crosstalk. Inhibition of NEDDylation with pevonedistat may represent a potential therapeutic strategy for patients with CCA. LAY SUMMARY: Little is known about the role of post-translational modifications of proteins in cholangiocarcinoma development and progression. Herein, we show that protein NEDDylation is upregulated and hyperactivated in cholangiocarcinoma, promoting tumor growth. Pharmacological inhibition of NEDDylation halts cholangiocarcinogenesis and could be an effective therapeutic strategy to tackle these tumors.This article is based upon work from the COST Action CA18122 European Cholangiocarcinoma Network supported by COST (European Cooperation in Science and Technology: www.cost.eu)

Residual pulmonary infiltrates, symptoms and diffusion impairment at one‐year after severe COVID‐19 infection have different associated factors

Menendez R, Mendez R, Latorre A, Gonzalez-Jimenez P, Peces-Barba G, Molina M, et al. Residual pulmonary infiltrates, symptoms and diffusion impairment at 1-year after severe COVID-19 infection have different associated factors. J Intern Med. 2023;00:1-13. Introduction. After severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia, patients may show lung sequelae on radiology and functional impairment at the 1-year followup. We aimed to describe the persistence of symptoms, radiological alterations, or reduced diffusing capacity of the lung for carbon monoxide (DLCO) at 1-year follow-up in patients from the Spanish Registry RECOVID. Methods. RECOVID collected symptom and radiological and functional lung tests data on hospitalized patients with coronavirus disease 2019 during the acute phase and at the 6- and 12-month follow-up visits. Results. Of the 2500 enrolled survivors (90% admitted to the ward), 1874 had follow-up visits for up to a year. Of these, 42% continued to present with symptoms, 27% had radiological sequelae and 31% had reduced DLCO. Independently associated factors included female sex, asthma and the requirement for invasive or non-invasive mechanical ventilation. Complete radiological resolution was 72.2% at 12 months; associated factors with incomplete recovery were age, male sex, oxygen or respiratory support, corticosteroids and an initial SpO(2)/FiO(2) = 2. Reduced D-LCO was observed in 31% of patients at 12 months; associated factors were older age, female sex, smoking habit, SpO(2)/FiO(2) = 2 and the requirement of respiratory support.At 12 months, a proportion of the asymptomatic patients showed reduced D-LCO (9.5%), radiological findings (25%) or both (11%). Conclusions. The factors associated with symptom persistence, incomplete radiological resolution and D-LCO <80% differed according to age, sex, comorbidities and respiratory support. The burden of symptoms, reduced D-LCO and incomplete radiological resolution were considerable in patients with SARS-CoV-2 pneumonia at the 1-year follow-up after hospitalisation

Deliverable D2.1 - Ecosystem analysis and 6G-SANDBOX facility design

This document provides a comprehensive overview of the core aspects of the 6G-SANDBOX project. It outlines the project's vision, objectives, and the Key Performance Indicators (KPIs) and Key Value Indicators (KVIs) targeted for achievement. The functional and non-functional requirements of the 6G-SANDBOX Facility are extensively presented, based on a proposed reference blueprint. A detailed description of the updated reference architecture of the facility is provided, considering the requirements outlined. The document explores the experimentation framework, including the lifecycle of experiments and the methodology for validating KPIs and KVIs. It presents the key technologies and use case enablers towards 6G that will be offered within the trial networks. Each of the platforms constituting the 6G-SANDBOX Facility is described, along with the necessary enhancements to align them with the project's vision in terms of hardware, software updates, and functional improvements

SARS-CoV-2 viral load in nasopharyngeal swabs is not an independent predictor of unfavorable outcome

The aim was to assess the ability of nasopharyngeal SARS-CoV-2 viral load at first patient’s hospital evaluation to predict unfavorable outcomes. We conducted a prospective cohort study including 321 adult patients with confirmed COVID-19 through RT-PCR in nasopharyngeal swabs. Quantitative Synthetic SARS-CoV-2 RNA cycle threshold values were used to calculate the viral load in log10 copies/mL. Disease severity at the end of follow up was categorized into mild, moderate, and severe. Primary endpoint was a composite of intensive care unit (ICU) admission and/or death (n = 85, 26.4%). Univariable and multivariable logistic regression analyses were performed. Nasopharyngeal SARS-CoV-2 viral load over the second quartile (≥ 7.35 log10 copies/mL, p = 0.003) and second tertile (≥ 8.27 log10 copies/mL, p = 0.01) were associated to unfavorable outcome in the unadjusted logistic regression analysis. However, in the final multivariable analysis, viral load was not independently associated with an unfavorable outcome. Five predictors were independently associated with increased odds of ICU admission and/or death: age ≥ 70 years, SpO2, neutrophils > 7.5 × 103/µL, lactate dehydrogenase ≥ 300 U/L, and C-reactive protein ≥ 100 mg/L. In summary, nasopharyngeal SARS-CoV-2 viral load on admission is generally high in patients with COVID-19, regardless of illness severity, but it cannot be used as an independent predictor of unfavorable clinical outcome