Random Forest-Based Prediction of Stroke Outcome

[Abstract] We research into the clinical, biochemical and neuroimaging factors associated with the outcome of stroke patients to generate a predictive model using machine learning techniques for prediction of mortality and morbidity 3-months after admission. The dataset consisted of patients with ischemic stroke (IS) and non-traumatic intracerebral hemorrhage (ICH) admitted to Stroke Unit of a European Tertiary Hospital prospectively registered. We identified the main variables for machine learning Random Forest (RF), generating a predictive model that can estimate patient mortality/morbidity according to the following groups: (1) IS + ICH, (2) IS, and (3) ICH. A total of 6022 patients were included: 4922 (mean age 71.9 ± 13.8 years) with IS and 1100 (mean age 73.3 ± 13.1 years) with ICH. NIHSS at 24, 48 h and axillary temperature at admission were the most important variables to consider for evolution of patients at 3-months. IS + ICH group was the most stable for mortality prediction [0.904 ± 0.025 of area under the receiver operating characteristics curve (AUC)]. IS group presented similar results, although variability between experiments was slightly higher (0.909 ± 0.032 of AUC). ICH group was the one in which RF had more problems to make adequate predictions (0.9837 vs. 0.7104 of AUC). There were no major differences between IS and IS + ICH groups according to morbidity prediction (0.738 and 0.755 of AUC) but, after checking normality with a Shapiro Wilk test with the null hypothesis that the data follow a normal distribution, it was rejected with W = 0.93546 (p-value < 2.2e−16). Conditions required for a parametric test do not hold, and we performed a paired Wilcoxon Test assuming the null hypothesis that all the groups have the same performance. The null hypothesis was rejected with a value < 2.2e−16, so there are statistical differences between IS and ICH groups. In conclusion, machine learning algorithms RF can be effectively used in stroke patients for long-term outcome prediction of mortality and morbidity.This study was partially supported by grants from the Spanish Ministry of Science and Innovation (SAF2017-84267-R), Xunta de Galicia (Axencia Galega de Innovación (GAIN): IN607A2018/3), Instituto de Salud Carlos III (ISCIII) (PI17/00540, PI17/01103), Spanish Research Network on Cerebrovascular Diseases RETICS-INVICTUS PLUS (RD16/0019) and by the European Union FEDER program. T. Sobrino (CPII17/00027), F. Campos (CPII19/00020) are recipients of research contracts from the Miguel Servet Program (Instituto de Salud Carlos III). General Directorate of Culture, Education and University Management of Xunta de Galicia (ED431G/01,252 ED431D 2017/16), “Galician Network for Colorectal Cancer Research" (Ref. ED431D 2017/23), Competitive Reference Groups (ED431C 2018/49), Spanish Ministry of Economy and Competitiveness via funding of the unique installation BIOCAI (UNLC08-1E-002, UNLC13-13–3503), European Regional Development Funds (FEDER).Xunta de Galicia; IN607A2018/3Xunta de Galicia; ED431G/01,252Xunta de Galicia; ED431D 2017/1

Multiple phase and dielectric transitions on a novel multi-sensitive [TPrA][M(dca)3] (M: Fe2+, Co2+ and Ni2+) hybrid inorganic–organic perovskite family

The hybrid inorganic–organic [TPrA][M(dca)3] (M: Fe2+, Co2+ and Ni2+) compounds, where TPrA is the tetrapropylammonium cation and dca is the dicyanamide anion, are unique multi-sensitive compounds that display multiple phases and dielectric transitions. These materials exhibit up to three first-order structural transitions (between the polymorphs I, Ia, Ib and II) associated with the same number of dielectric transitions in the temperature range of 210–360 K. The mechanisms responsible for these dielectric responses are found to be novel within the hybrid perovskites, involving ionic displacements of the A-site cations (TPrA) and order/disorder processes of the X anions (dca). In addition, the phase transitions and dielectric transition temperatures can be tuned by applying external hydrostatic pressure or by inducing internal pressure by modifying the tolerance factor through ionic substitution in the B-sites. This multi-sensitive response towards temperature, external and internal pressure opens up promising technological applications for this family of materials, such as dielectric transductors or multistimuli-sensors, whose response can be modulated in a wide range of temperatures and pressuresThe authors are grateful for the financial support from Ministerio de Economía y Competitividad MINECO (MINECO) ENE2014-56237-C4-4-R and Xunta de Galicia under the project GRC2014/042. J. M. B.-G. also wants to thank Barrié Foundation for a predoctoral fellowship and S. Y.-V. to the Xunta de Galicia for a postdoctoral grant (Plan I2C)S

Ultrafast transient liquid assisted growth of high current density superconducting films

The achievement of high growth rates in YBaCuO epitaxial high-temperature superconducting films has become strategic to enable high-throughput manufacturing of long length coated conductors for energy and large magnet applications. We report on a transient liquid assisted growth process capable of achieving ultrafast growth rates (100 nm s −1) and high critical current densities (5 MA cm −2 at 77 K). This is based on the kinetic preference of Ba-Cu-O to form transient liquids prior to crystalline thermodynamic equilibrium phases, and as such is a non-equilibrium approach. The transient liquid-assisted growth process is combined with chemical solution deposition, proposing a scalable method for superconducting tapes manufacturing. Additionally, using colloidal solutions, the growth process is extended towards fabrication of nanocomposite films for enhanced superconducting properties at high magnetic fields. Fast acquisition in situ synchrotron X-ray diffraction and high resolution scanning transmission electron microscopy (STEM) become crucial measurements in disentangling key aspects of the growth process. High throughput manufacturing of long length coated conductors requires fast epitaxial growth of high-temperature superconducting films. Here, Soler et al. report an ultrafast growth rates and high critical current densities of YBaCuO films using a transient liquid-assisted growth method

Periodontitis is associated with subclinical cerebral and carotid atherosclerosis in hypertensive patients: A cross‑sectional study

Objective: To examine the relationship between periodontitis and subclinical intracranial atherosclerosis. The association of periodontitis with preclinical markers of atherosclerosis in other vascular territories was also explored. Material and methods: This was a cross-sectional study where 97 elderly subjects with a previous history of hypertension received an ultrasonographic evaluation to assess subclinical atherosclerosis in different vascular territories: (1) cerebral [pulsatility (PI) and resistance index (RI) of the middle cerebral artery], (2) carotid [intima-media thickness (IMT)], and (3) peripheral [ankle-brachial index (ABI)]. Additionally, participants underwent a full-mouth periodontal assessment together with blood sample collection to determine levels of inflammatory biomarkers (leukocytes, fibrinogen, and erythrocyte sedimentation rate), lipid fractions (total cholesterol and high- and low-density lipoprotein), and glucose. Results: Sixty-one individuals had periodontitis. Compared to subjects without periodontitis, those with periodontitis showed higher values of PI (1.24 ± 0.29 vs 1.01 ± 0.16), RI (0.70 ± 0.14 vs 0.60 ± 0.06), and IMT (0.94 ± 0.15 vs 0.79 ± 0.15) (all p < 0.001). No statistically significant differences were found neither for ABI or for other clinical and biochemical parameters. An independent association was found between periodontitis and increased intracranial atherosclerosis (ORadjusted = 10.16; 95% CI: 3.14-32.90, p < 0.001) and to a lesser extent with thicker carotid IMT (ORadjusted = 4.10; 95% CI: 1.61-10.48, p = 0.003). Conclusions: Periodontitis is associated with subclinical atherosclerosis in both intracranial and carotid arteries in elderly subjects with hypertension. Clinical relevance: The association of periodontitis with intracranial atherosclerosis implies that periodontitis patients might have greater chances to develop ischemic stroke in the futureOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This study was partially supported by grants from the Xunta de Galicia (TS: IN607A2018/3 and TS: IN607D 2020/09), Spanish Ministry of Science (TS: RTI2018-102165-B-I00 and RTC2019-007373-1), Institute of Health Carlos III (PI22/00938), and RICOR-ICTUS Network (RD21/0006/003). Furthermore, this study was also supported by grants from the Interreg Atlantic Area (TS: EAPA_791/2018_ NeuroATLANTIC project), Interreg V-A España Portugal (POCTEP) (TS: 0624_2IQBIONEURO_6_E), and the European Regional Development Fund. YL is supported by a Sara Borrell fellowship (CD22/00051), and TS (CPII17/00027) and FC (CPII19/00020) are recipients of Miguel Servet contracts, all of them funded by the Institute of Health Carlos IIIS

Influence of Sex on Stroke Prognosis: A Demographic, Clinical, and Molecular Analysis

Identifying the complexities of the effect of sex on stroke risk, etiology, and lesion progression may lead to advances in the treatment and care of ischemic stroke (IS) and non-traumatic intracerebral hemorrhage patients (ICH). We studied the sex-related discrepancies on the clinical course of patients with IS and ICH, and we also evaluated possible molecular mechanisms involved. The study's main variable was the patient's functional outcome at 3-months. Logistic regression models were used in order to study the influence of sex on different inflammatory, endothelial and atrial dysfunction markers. We recruited 5,021 patients; 4,060 IS (54.8% male, 45.2% female) and 961 ICH (57.1% male, 42.9% female). Women were on average 5.7 years older than men (6.4 years in IS, 5.1 years in ICH), and more likely to have previous poor functional status, to suffer atrial fibrillation and to be on anticoagulants. IS patients showed sex-related differences at 3-months regarding poorer outcome (55.6% women, 43.6% men, p &lt; 0.0001), but this relationship was not found in ICH (56.8% vs. 61.9%, p = 0.127). In IS, women had higher levels of NT-proBNP and 3-months worse outcome in both cardioembolic and non-cardioembolic stroke patients. Stroke patients showed sex-related differences in pre-hospital data, clinical variables and molecular markers, but only IS patients presented independent sex-related differences in 3-months poor outcome and mortality. There was a relationship between the molecular marker of atrial dysfunction NT-proBNP and worse functional outcome in women, resulting in a possible indicator of increased dysfunction

Extracellular Vesicles Enriched in Connexin 43 Promote a Senescent Phenotype in Bone and Synovial Cells Contributing to Osteoarthritis Progression

[Abstract] The accumulation of senescent cells is a key characteristic of aging, leading to the progression of age-related diseases such as osteoarthritis (OA). Previous data from our laboratory has demonstrated that high levels of the transmembrane protein connexin 43 (Cx43) are associated with a senescent phenotype in chondrocytes from osteoarthritic cartilage. OA has been reclassified as a musculoskeletal disease characterized by the breakdown of the articular cartilage affecting the whole joint, subchondral bone, synovium, ligaments, tendons and muscles. However, the mechanisms that contribute to the spread of pathogenic factors throughout the joint tissues are still unknown. Here, we show for the first time that small extracellular vesicles (sEVs) released by human OA-derived chondrocytes contain high levels of Cx43 and induce a senescent phenotype in targeted chondrocytes, synovial and bone cells contributing to the formation of an inflammatory and degenerative joint environment by the secretion of senescence-associated secretory associated phenotype (SASP) molecules, including IL-1ß and IL-6 and MMPs. The enrichment of Cx43 changes the protein profile and activity of the secreted sEVs. Our results indicate a dual role for sEVs containing Cx43 inducing senescence and activating cellular plasticity in target cells mediated by NF-kß and the extracellular signal-regulated kinase 1/2 (ERK1/2), inducing epithelial-to-mesenchymal transition (EMT) signalling programme and contributing to the loss of the fully differentiated phenotype. Our results demonstrated that Cx43-sEVs released by OA-derived chondrocytes spread senescence, inflammation and reprogramming factors involved in wound healing failure to neighbouring tissues, contributing to the progression of the disease among cartilage, synovium, and bone and probably from one joint to another. These results highlight the importance for future studies to consider sEVs positive for Cx43 as a new biomarker of disease progression and new target to treat OA.This work was supported in part through funding from Health Institute ‘Carlos III’ (ISCIII, Spain), the European Regional Development Fund, ‘A way of making Europe’ from the European Union (to MDM): grant PI19/00145; a grant from the Joint Transnational Call for Proposals for “European Innovative Research & Technological Development Projects in Nanomedicine” EURONANOMED III (AC21_2/00026) (to MDM); a grant from Xunta de Galicia (IN607B2020/12) (to MDM) and from H2020, Future and Emerging Technologies (grant 858014 “PANACHE”) to MDM. MV-E was funded with a predoctoral (ED481A-2015/188) and post-doctoral fellowship (IN606B-2019/004) from Xunta de Galicia. AG-C was funded with a predoctoral fellowship (FIS20/00310) from ISCIII. PC-F was funded with a post-doctoral fellowship and a grant from Xunta de Galicia (INB606B 2017/014 and IN606C 2021/006). We thank members of the CellCOM group for helpful technical suggestion, María Dolores Álvarez Alvariño (CHUS) for generously collecting tissue samples in the operating room after surgery and Arantxa Tabernero (INCYL, University of Salamanca) for kindly providing the human Cx43 plasmid used in this studyXunta de Galicia; IN607B2020/12Xunta de Galicia; ED481A-2015/188Xunta de Galicia; IN606B-2019/004Xunta de Galicia; INB606B 2017/014Xunta de Galicia; IN606C 2021/00

Temperature-Induced Changes in Reperfused Stroke: Inflammatory and Thrombolytic Biomarkers

Although hyperthermia is associated with poor outcomes in ischaemic stroke (IS), some studies indicate that high body temperature may benefit reperfusion therapies. We assessed the association of temperature with effective reperfusion (defined as a reduction of ≥8 points in the National Institute of Health Stroke Scale (NIHSS) within the first 24 h) and poor outcome (modified Rankin Scale (mRS) > 2) in 875 retrospectively-included IS patients. We also studied the influence of temperature on thrombolytic (cellular fibronectin (cFn); matrix metalloproteinase 9 (MMP-9)) and inflammatory biomarkers (tumour necrosis factor-alpha (TNF-α), interleukin 6 (IL-6)) and their relationship with effective reperfusion. Our results showed that a higher temperature at 24 but not 6 h after stroke was associated with failed reperfusion (OR: 0.373, p = 0.001), poor outcome (OR: 2.190, p = 0.005) and higher IL-6 levels (OR: 0.958, p 37.5 °C at 24 h, but not at 6 h after stroke, is correlated with reperfusion failure, poor clinical outcome, and infarct size. Mild hyperthermia (36.5–37.5 °C) in the first 6 h window might benefit drug reperfusion therapies by promoting clot lysisThis study was partially supported by grants from the Spanish Ministry of Science and Innovation (SAF2017-84267-R), Xunta de Galicia (Consellería Educación: IN607A2018/3), Instituto de Salud Carlos III (ISCIII) (PI17/00540 and PI17/01103), Spanish Research Network on Cerebrovascular Diseases RETICS-INVICTUS PLUS (RD16/0019), and by the European Union FEDER program. Furthermore, Tomás. Sobrino (CPII17/00027) and Francisco Campos (CPII19/00020) are recipients of research contracts from the Miguel Servet Program of Instituto de Salud Carlos III. María Pérez-Mato is a Sara Borrell Researcher (CD19/00033)S

Síntesis de nanopartículas de ferritas tipo MFe2O4 (M=Fe, Co, Cu) para su aplicación en superconductores

La tecnología actual ha permitido que en los últimos años la nanociencia y la nanotecnología sean puntos críticos en el desarrollo del conocimiento. En estos momentos se desarrollan sistemas de dimensiones nanométricas que son interesantes debido a sus potenciales aplicaciones en diferentes ámbitos como en química, física, biología, materiales, medicina, cosmética... Dentro de estos sistemas nanoscópicos se encuentran las nanopartículas, estructuras con un tamaño inferior a los 100nm de longitud. En esta clasificación existen a su vez diferentes categorías, como las nanopartículas metálicas, semiconductoras, magnéticas, etc. y es exactamente en esta última tipoogía donde se centra este estudio. Este proyecto de investigación desarrolla la síntesis de magnetita (Fe3O4), ferrita de cobalto (CoFe2O4) y ferrita de cobre (CuFe2O4) con la finalidad de utilizarlas como dopante en superconductores. El método sintético utilizado es del tipo solvotérmico y se lleva a cabo en trietilenglicol, el cual actúa a la vez como disolvente y como estabilizante de las nanopartículas. Las partículas así obtenidas son dispersables en medios polares como el etanol absoluto. Los precursores de este método sintético son los respectivos acetilacetonatos metálicos debido a que el ligando orgánico descompone en productos volátiles. Existen diferentes factores que afectan a la síntesis, tales como la velocidad de ascenso de la temperatura, la agitación, la presencia de agua, la temperatura de descomposición de los precursores, etc. Algunos de estos factores han sido estudiados con detalle y aplicados con tal de optimizar el método experimental. Las nanopartículas sintetizadas han sido analizadas mediante diversas técnicas físicas con tal de establecer diferentes parámetros, tales como su composición fnal, su pureza, su estructura, sus propiedades magnéticas, etc. Estas técnicas son diversas: desde la espectroscopia infrarroja hasta medidas mediante SQUID, pasando por rayos X, microscopía electrónica y termogravimetría. Los resultados han sido favorables en la síntesis de la magnetita y también en la ferrita de cobalto, ya que las nanopartículas obtenidas son homogéneas, fácilmente dispersables en algoholes, estables por largos períodos de teimpo, rápidas de sintetizar, etc. El único problema observado ha sido la síntesis de ferrita de cobre la cual se ha de optimizar, ya que el producto final ha resultado ser una mezcla de tres compuesto diferentes

An Influenza A/H1N1/2009 Hemagglutinin Vaccine Produced in Escherichia coli

The A/H1N1/2009 influenza pandemic made evident the need for faster and higher-yield methods for the production of influenza vaccines. Platforms based on virus culture in mammalian or insect cells are currently under investigation. Alternatively, expression of fragments of the hemagglutinin (HA) protein in prokaryotic systems can potentially be the most efficacious strategy for the manufacture of large quantities of influenza vaccine in a short period of time. Despite experimental evidence on the immunogenic potential of HA protein constructs expressed in bacteria, it is still generally accepted that glycosylation should be a requirement for vaccine efficacy.We expressed the globular HA receptor binding domain, referred to here as HA(63-286)-RBD, of the influenza A/H1N1/2009 virus in Escherichia coli using a simple, robust and scalable process. The recombinant protein was refolded and purified from the insoluble fraction of the cellular lysate as a single species. Recombinant HA(63-286)-RBD appears to be properly folded, as shown by analytical ultracentrifugation and bio-recognition assays. It binds specifically to serum antibodies from influenza A/H1N1/2009 patients and was found to be immunogenic, to be capable of triggering the production of neutralizing antibodies, and to have protective activity in the ferret model.Projections based on our production/purification data indicate that this strategy could yield up to half a billion doses of vaccine per month in a medium-scale pharmaceutical production facility equipped for bacterial culture. Also, our findings demonstrate that glycosylation is not a mandatory requirement for influenza vaccine efficacy