Effects of sevoflurane postconditioning on cell death, inflammation and TLR expression in human endothelial cells exposed to LPS

Background: Sevoflurane is an anesthetic agent which also participates in protective mechanisms in sepsis, likely due to anti-inflammatory properties. A key tissue in sepsis is the endothelium, which expresses TLR2 and TLR4 receptors, known regulators of inflammatory mechanisms and potential therapeutic targets for this pathology. In this context, we explored the effect of sevoflurane postconditioning in an in vitro sepsis model. Methods: Primary cultures of human umbilical vein endothelial cells were used for two different experiments. In the first set, cultures were placed in an airtight incubation chamber and exposed to different concentrations of sevoflurane (0,1,3 or 7% vol,) for 1 hour. In the second set, lipopolysaccharide from Escherichia coli 0111:B4 (1 μg/mL) was added to culture medium for 3 hours and cells were subsequently exposed to sevoflurane (0,1,3 or 7% vol,) for 1 hour as explained before. In both cases, cell viability was measured by MTT and Trypan blue assays, TLR2 and TLR4 expression were analyzed by flow cytometry, and TNFα and IL-6 levels were quantified in cell culture media by an immunoassay immediately after exposure, at 6 and 24 hours. Results: Exposure to 3% sevoflurane decreased TLR2 at 24 hours and TLR4 at 6 and 24 hours (both p<0.05), whereas exposure to 7% decreased TLR4 expression at 6 hours (p<0.05). Both 3 and 7% sevoflurane decreased TNF-α and IL-6 levels at 24 hours (both p<0.05). In LPS-stimulated cultures, exposure to 3% sevoflurane was cytoprotective at 6 and 24 hours (p<0.05) compared with control, and decreased TLR2 and TLR4 expression at 24 hours (p<0.05); whereas 7% decreased TLR4 expression at 24 hours (p<0.05). Both 3% and 7% sevoflurane decreased TNF-α and IL-6 levels at 24 hours (both p<0.05). Conclusions: Postconditioning with the halogenated anesthetic agent sevoflurane after LPS stimulation shows a cytoprotective effect in an in vitro model, decreasing cell death and reducing TLR2 and TLR4 expression as well as levels of the inflammatory mediators TNF-α and IL-6 in human endothelial cells

Development and validation of a clinical score to estimate progression to severe or critical state in Covid-19 pneumonia hospitalized patients

The prognosis of a patient with Covid-19 pneumonia is uncertain. Our objective was to establish a predictive model of disease progression to facilitate early decision-making. A retrospective study was performed of patients admitted with Covid-19 pneumonia, classified as severe (admission to the intensive care unit, mechanic invasive ventilation, or death) or non-severe. A predictive model based on clinical, analytical, and radiological parameters was built. The probability of progression to severe disease was estimated by logistic regression analysis. Calibration and discrimination (receiver operating characteristics curves and AUC) were assessed to determine model performance. During the study period 1,152 patients presented with Covid-19 infection, of whom 229 (19.9%) were admitted for pneumonia. During hospitalization, 51 (22.3%) progressed to severe disease, of whom 26 required ICU care (11.4); 17 (7.4%) underwent invasive mechanical ventilation, and 32 (14%) died of any cause. Five predictors determined within 24 hours of admission were identified: Diabetes, Age, Lymphocyte count, SaO2, and pH (DALSH score). The prediction model showed a good clinical performance, including discrimination (AUC 0.87 CI 0.81, 0.92) and calibration (Brier score = 0.11). In total, 0%, 12%, and 50% of patients with severity risk scores ≤5%, 6-25%, and >25% exhibited disease progression, respectively. A simple risk score based on five factors predicts disease progression and facilitates early decision-making according to prognosis.Carlos III Health Institute, Spain, Ministry of Economy and Competitiveness (SPAIN) and the European Regional Development Fund (FEDER)Instituto de Salud Carlos II

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Multiple Scenario Generation of Subsurface Models:Consistent Integration of Information from Geophysical and Geological Data throuh Combination of Probabilistic Inverse Problem Theory and Geostatistics

Neutrinos with energies above 1017 eV are detectable with the Surface Detector Array of the Pierre Auger Observatory. The identification is efficiently performed for neutrinos of all flavors interacting in the atmosphere at large zenith angles, as well as for Earth-skimming \u3c4 neutrinos with nearly tangential trajectories relative to the Earth. No neutrino candidates were found in 3c 14.7 years of data taken up to 31 August 2018. This leads to restrictive upper bounds on their flux. The 90% C.L. single-flavor limit to the diffuse flux of ultra-high-energy neutrinos with an E\u3bd-2 spectrum in the energy range 1.0 7 1017 eV -2.5 7 1019 eV is E2 dN\u3bd/dE\u3bd &lt; 4.4 7 10-9 GeV cm-2 s-1 sr-1, placing strong constraints on several models of neutrino production at EeV energies and on the properties of the sources of ultra-high-energy cosmic rays

Calidad de vida y síntomas persistentes tras hospitalización por COVID-19. Estudio observacional prospectivo comparando pacientes con o sin ingreso en UCI

[Abstract] Background: Hospitalized COVID-19 patients are prone to develop persistent symptoms and to show reduced quality of life following hospital admission. Methods: Prospective cohort study of COVID-19 patients admitted to a hospital from March 1 to April 30, 2020. The primary outcome was to compare health related quality of life and persistent symptoms six months after hospital admission, of COVID-19 patients who required ICU admission with those who did not. Results: Among the 242 patients hospitalized during the defined period of time, 44 (18.2%) needed ICU admission. Forty (16.5%) patients died during hospital admission. Two hundred and two (83.5%) patients were discharged alive from the hospital. At six months, 183 (75.6%) patients completed the questionnaires (32 ICU patients and 151 non ICU patients). Ninety-six (52.4%) reported decreased quality of life and 143 (78.1%) described persistent symptoms. More ICU patients showed worsening of their quality of life (71.9 vs. 43.7%, P = 0.004). There were no differences in the proportion of patients with persistent symptoms between ICU and non ICU patients (87.5 vs. 76.2%, P = 0.159). ICU patients showed more frequently dyspnea on exertion (78.1 vs. 47.7%, P = 0.02), dyspnea on light exertion (37.5 vs. 4.6%, P < 0.001), and asthenia (56.3 vs. 29.1, P = 0.003). Conclusions: Survivors of COVID-19 needing hospitalization had persistent symptoms and a decline in the quality of life. ICU patients referred a large decrease of their quality of life compared with non ICU patients.[Resumen] Antecedentes/Contexto. Existe una tendencia en los pacientes hospitalizados por COVID-19 a desarrollar síntomas persistentes y a presentar una disminución en su calidad de vida tras el ingreso hospitalario. Métodos. Estudio de cohorte prospectivo de pacientes COVID-19 con ingreso hospitalario entre el 1 de marzo al 30 de abril de 2020. El objetivo primario fue comparar la calidad de vida relacionada con la salud y la presencia de síntomas persistentes seis meses después del ingreso, comparando los pacientes que requirieron ingreso en UCI con los que no lo precisaron. Resultados. De los 242 pacientes hospitalizados durante el período de estudio, 44 (18,2%) necesitaron ingreso en UCI. 40 (16,5%) pacientes fallecieron durante el ingreso hospitalario. 202 (83,5%) pacientes fueron dados de alta del hospital. A los seis meses, 183 (75,6%) pacientes completaron los cuestionarios (32 pacientes UCI y 151 pacientes no UCI). 96 (52,4%) refirieron disminución de la calidad de vida y 143 (78,1%) describieron síntomas persistentes. Un número mayor de pacientes de UCI mostraron un empeoramiento de su calidad de vida (71,9% vs 43,7%, P = 0,004). No hubo diferencias en la proporción de pacientes con síntomas persistentes entre los pacientes con UCI y sin UCI (87,5% vs 76,2%, P = 0,159). Los pacientes de UCI mostraron con mayor frecuencia disnea de esfuerzo (78,1% vs 47,7%, P = 0,02), disnea de pequeños esfuerzos (37,5% vs 4,6%, P < 0,001) y astenia (56,3 vs 29,1, P = 0,003). Conclusiones. Los supervivientes de COVID-19 que necesitaron hospitalización presentaron síntomas persistentes y un deterioro de su calidad de vida. Los pacientes de UCI refirieron una mayor disminución de su calidad de vida en comparación con los pacientes que no precisaron UCI

Measurement of the Fluctuations in the Number of Muons in Extensive Air Showers with the Pierre Auger Observatory

The successful installation, commissioning, and operation of the Pierre Auger Observatory would not have been possible without the strong commitment and effort from the technical and administrative staff in Malargue. We are very grateful to the following agencies and organizations for financial support: Argentina-Comision Nacional de Energia Atomica, Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT), Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Gobierno de la Provincia de Mendoza, Municipalidad de Malargue, NDM Holdings and Valle Las Lenas; in gratitude for their continuing cooperation over land access; Australia-the Australian Research Council; BrazilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Financiadora de Estudos e Projetos (FINEP), Fundacao de Amparo a Pesquisa do Estado de Rio de Janeiro (FAPERJ), Sao Paulo Research Foundation (FAPESP) Grants No. 2019/10151-2, No. 2010/07359-6, and No. 1999/05404-3, Ministerio da Ciencia, Tecnologia, Inovacoes e Comunicacoes (MCTIC); Ministry of Education, Youth and Sports of the Czech RepublicGrants No. MSMT CR LTT18004, No. LM2015038, No. LM2018102, No. CZ.02.1.01/0.0/0.0/16_013/0001402, No. CZ.02.1.01/0.0/0.0/18_046/0016010, and No. CZ.02.1.01/0.0/0.0/17_049/0008422; France-Centre de Calcul IN2P3/CNRS, Centre National de la Recherche Scientifique (CNRS), Conseil Regional Ile-de-France, Departement Physique Nucl ' eaire et Corpusculaire (PNC-IN2P3/CNRS), Departement Sciences de l'Univers (SDU-INSU/CNRS), Institut Lagrange de Paris (ILP) Grant No. LABEX ANR-10-LABX-63 within the Investissements d'Avenir Programme Grant No. ANR11-IDEX-0004-02; Germany-Bundesministerium fur Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG), Finanzministerium Baden-Wurttemberg, Helmholtz Alliance for Astroparticle Physics (HAP), Helmholtz-Gemeinschaft Deutscher Forschungszentren (HGF), Ministerium fur Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, Ministerium fur Wissenschaft, Forschung und Kunst des Landes Baden-Wurttemberg; Italy-Istituto Nazionale di Fisica Nucleare (INFN), Istituto Nazionale di Astrofisica (INAF), Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), CETEMPS Center of Excellence, Ministero degli Affari Esteri (MAE); Mexico-Consejo Nacional de Ciencia y Tecnologia (CONACYT) Grant No. 167733, Universidad Nacional Autonoma de Mexico (UNAM), PAPIIT DGAPA-UNAM; The Netherlands-Ministry of Education, Culture and Science, Netherlands Organisation for Scientific Research (NWO), Dutch national e-infrastructure with the support of SURF Cooperative; Poland-Ministry of Science and Higher Education, Grant No. DIR/WK/2018/11, National Science Centre, Grants No. 2013/08/M/ST9/00322, No. 2016/23/B/ST9/01635, and No. HARMONIA 5-2013/10/M/ST9/00062, UMO-2016/22/M/ST9/00198; Portugal -Portuguese national funds and FEDER funds within Programa Operacional Factores de Competitividade through Fundacao para a Ciencia e a Tecnologia (COMPETE); Romania-Romanian Ministry of Education and Research, the Program Nucleu within MCI (PN19150201/16N/2019 and PN19060102), and project PN-III-P1-1.2-PCCDI-2017-0839/19PCCDI/2018 within PNCDI III; Slovenia-Slovenian Research Agency, Grants No. P1-0031, No. P1-0385, No. I00033, No. N1-0111; Spain-Ministerio de Economia, Industria y Competitividad (FPA2017-85114-P and FPA2017-85197-P), Xunta de Galicia (ED431C 2017/07), Junta de Andalucia (SOMM17/6104/UGR), Feder Funds, RENATA Red Nacional Tematica de Astroparticulas (FPA2015-68783-REDT), and Maria de Maeztu Unit of Excellence (MDM-2016-0692); U.S.Department of Energy, Awards No. DE-AC0207CH11359, No. DE-FR02-04ER41300, No. DE-FG0299ER41107, and No. DE-SC0011689, National Science Foundation, Grant No. 0450696, The Grainger Foundation, Marie Curie-IRSES/EPLANET, European Particle Physics Latin American Network, and UNESCO.We present the first measurement of the fluctuations in the number of muons in extensive air showers produced by ultrahigh energy cosmic rays. We find that the measured fluctuations are in good agreement with predictions from air shower simulations. This observation provides new insights into the origin of the previously reported deficit of muons in air shower simulations and constrains models of hadronic interactions at ultrahigh energies. Our measurement is compatible with the muon deficit originating from small deviations in the predictions from hadronic interaction models of particle production that accumulate as the showers develop.Argentina-Comision Nacional de Energia AtomicaANPCyTConsejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET)Gobierno de la Provincia de MendozaMunicipalidad de MalargueNDM HoldingsValle Las LenasAustralian Research CouncilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ)Fundacao de Apoio a Pesquisa do Distrito Federal (FAPDF)Financiadora de Inovacao e Pesquisa (Finep)Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio De Janeiro (FAPERJ)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) 2019/10151-2 2010/07359-6 1999/05404-3Ministerio da Ciencia, Tecnologia, Inovacoes e Comunicacoes (MCTIC)Ministry of Education, Youth & Sports - Czech Republic MSMT CR LTT18004 LM2015038 LM2018102 CZ.02.1.01/0.0/0.0/16_013/0001402 CZ.02.1.01/0.0/0.0/18_046/0016010 CZ.02.1.01/0.0/0.0/17_049/0008422France-Centre de Calcul IN2P3/CNRSCentre National de la Recherche Scientifique (CNRS)Region Ile-de-FranceCentre National de la Recherche Scientifique (CNRS)Departement Sciences de l'Univers (SDU-INSU/CNRS)French National Research Agency (ANR) LABEX ANR-10-LABX-63 ANR11-IDEX-0004-02Federal Ministry of Education & Research (BMBF)German Research Foundation (DFG)Finanzministerium Baden-WurttembergHelmholtz Alliance for Astroparticle Physics (HAP)Helmholtz AssociationMinisterium fur Innovation, Wissenschaft und Forschung des Landes Nordrhein-WestfalenMinisterium fur Wissenschaft, Forschung und Kunst des Landes Baden-WurttembergItaly-Istituto Nazionale di Fisica Nucleare (INFN)Istituto Nazionale Astrofisica (INAF)Ministry of Education, Universities and Research (MIUR)CETEMPS Center of ExcellenceMinistry of Foreign Affairs and International Cooperation (Italy)Consejo Nacional de Ciencia y Tecnologia (CONACyT) 167733Universidad Nacional Autonoma de Mexico (UNAM), PAPIIT DGAPA-UNAMNetherlands-Ministry of Education, Culture and ScienceNetherlands Organization for Scientific Research (NWO)Dutch national e-infrastructureSURF CooperativePoland-Ministry of Science and Higher Education DIR/WK/2018/11National Science Centre, Poland 2013/08/M/ST9/00322 2016/23/B/ST9/01635 HARMONIA 5-2013/10/M/ST9/00062 UMO-2016/22/M/ST9/00198Portugal -Portuguese national fundsFEDER funds within Programa Operacional Factores de Competitividade through Fundacao para a Ciencia e a Tecnologia (COMPETE)Romania-Romanian Ministry of Education and Research, the Program Nucleu within MCI PN19150201/16N/2019 PN19060102Romania-Romanian Ministry of Educatio n and Research, the Program Nucleu within PNCDI III PN-III-P1-1.2-PCCDI-2017-0839/19PCCDI/2018Slovenian Research Agency - Slovenia P1-0031 P1-0385 I00033 N1-0111Spain-Ministerio de Economia, Industria y Competitividad FPA2017-85114-P FPA2017-85197-PXunta de Galicia European Commission ED431C 2017/07Junta de Andalucia SOMM17/6104/UGREuropean CommissionRENATA Red Nacional Tematica de Astroparticulas FPA2015-68783-REDTMaria de Maeztu Unit of Excellence MDM-2016-0692United States Department of Energy (DOE) DE-AC0207CH11359 DE-FR02-04ER41300 DE-FG0299ER41107 DE-SC0011689National Science Foundation (NSF) 0450696Grainger FoundationMarie Curie-IRSES/EPLANETEuropean Particle Physics Latin American NetworkUNESC