Differential leukocyte expression of IFITM1 and IFITM3 in patients with severe pandemic influenza A(H1N1) and COVID-19

Interferon-induced transmembrane (IFITM) proteins mediate protection against enveloped viruses by blocking membrane fusion at endosomes. IFITM1 and IFITM3 are crucial for protection against influenza, and various single nucleotide polymorphisms altering their function have been linked to disease susceptibility. However, bulk IFITM1 and IFITM3 mRNA expression dynamics and their correlation with clinical outcomes have not been extensively addressed in patients with respiratory infections. In this study, we evaluated the expression of IFITM1 and IFITM3 in peripheral leukocytes from healthy controls and individuals with severe pandemic influenza A(H1N1) or coronavirus disease 2019 (COVID-19). Comparisons between participants grouped according to their clinical characteristics, underlying disease, and outcomes showed that the downregulation of IFITM1 was a distinctive characteristic of severe pandemic influenza A(H1N1) that correlated with outcomes, including mortality. Conversely, increased IFITM3 expression was a common feature of severe pandemic influenza A(H1N1) and COVID-19. Using a high-dose murine model of infection, we confirmed not only the downregulation of IFITM1 but also of IFITM3 in the lungs of mice with severe influenza, as opposed to humans. Analyses in the comparative cohort also indicate the possible participation of IFITM3 in COVID-19. Our results add to the evidence supporting a protective function of IFITM proteins against viral respiratory infections in humans.Introduction Methods - Human samples - IFITM expression in humans - Influenza infection in mice - IFITM expression in mice - Cytokine levels in mouse lungs - Study approval - Statistical analysis Results - Participant characteristics - IFITM1 and IFITM3 in patients with severe pandemic influenza A(H1N1) - High-dose influenza A (H1N1) virus infection downregulates IFITM expression in mice - IFITM1 and IFITM3 in severe COVID-19 Discussio

Cross-country migration linked to people who inject drugs challenges the long-term impact of national HCV elimination programmes

To the Editor: As of 2018, the majority of Western European countries – including Spain – have lifted restrictions to therapy based on disease severity in the context of HCV infections.1 Long overdue, most national elimination programmes now also include access to care for people who inject drugs (PWID), 2 who are at the core of ongoing HCV transmission.3 Macías et al.4 have recently shown in this Journal that high viral cure rates can be achieved in this group, hereby providing evidence that targeting PWID in treatment programmes is worthwhile. However, the extent to which such national efforts can reduce the HCV burden not only depends on the uptake into care and treatment success rates, it is also determined by the relative importance of within-country transmission and virus importation from elsewhere. As the chronic nature of most HCV infections hampers reliably reconstructing contact networks from patient interviews, virus genetic data can be a valuable alternative source of information for elucidating the geographic history of virus lineages (e.g. [5], [6]). Using such data, we have recently shown that for the most prevalent subtype among PWID in Spain (40%, 7), HCV1a, infections often link to infections abroad – in recent years >50% link to Western European countries, mostly European Union (EU) member states – as opposed to other infections ..

MIUSCAT: extended MILES spectral coverage. I. Stellar populations synthesis models

We extend the spectral range of our stellar population synthesis models based on the MILES and CaT empirical stellar spectral libraries. For this purpose we combine these two libraries with the Indo-U.S. to construct composite stellar spectra to feed our models. The spectral energy distributions (SEDs) computed with these models and the originally published models are combined to construct composite SEDs for single-age, single-metallicity stellar populations (SSPs) covering the range 3465 - 9469\AA at moderately high, and uniform, resolution (FWHM=2.51\AA). The colours derived from these SSP SEDs provide good fits to Galactic globular cluster data. We find that the colours involving redder filters are very sensitive to the IMF, as well as a number of features and molecular bands throughout the spectra. To illustrate the potential use of these models we focus on the NaI doublet at 8200 \AA and with the aid of the newly synthesized SSP model SEDs we define a new IMF-sensitive index that is based on this feature, which overcomes various limitations from previous index definitions for low velocity dispersion stellar systems. We propose an index-index diagram based on this feature and the neighboring CaII triplet at 8600 \AA, to constrain the IMF if the age and [Na/Fe] abundance are known. Finally we also show a survey-oriented spectrophotometric application which evidences the accurate flux calibration of these models for carrying out reliable spectral fitting techniques. These models are available through our user-friendly website.Comment: 16 pages, 17 figures, 2 tables; MNRAS in press. Model predictions available at our website: http://miles.iac.e

Human immunodeficiency virus/hepatits C virus coinfection in Spain: Elimination is feasible, but the burden of residual cirrhosis will be significant

Background We assessed the prevalence of antibodies against hepatitis C virus (HCV-Abs) and active HCV infection in patients infected with human immunodeficiency virus (HIV) in Spain in 2016 and compared the results with those of similar studies performed in 2002, 2009, and 2015. Methods The study was performed in 43 centers during October-November 2016. The sample was estimated for an accuracy of 2% and selected by proportional allocation and simple random sampling. During 2016, criteria for therapy based on direct-acting antiviral agents (DAA) were at least significant liver fibrosis, severe extrahepatic manifestations of HCV, and high risk of HCV transmissibility. Results The reference population and the sample size were 38904 and 1588 patients, respectively. The prevalence of HCV-Abs in 2002, 2009, 2015, and 2016 was 60.8%, 50.2%, 37.7%, and 34.6%, respectively (P trend <.001, from 2002 to 2015). The prevalence of active HCV in 2002, 2009, 2015, and 2016 was 54.0%, 34.0%, 22.1%, and 11.7%, respectively (P trend <.001). The anti-HCV treatment uptake in 2002, 2009, 2015, and 2016 was 23.0%, 48.0%, 59.3%, and 74.7%, respectively (P trend <.001). In 2016, HCV-related cirrhosis was present in 7.6% of all HIV-infected individuals, 15.0% of patients with active HCV, and 31.5% of patients who cleared HCV after anti-HCV therapy. Conclusions Our findings suggest that with universal access to DAA-based therapy and continued efforts in prevention and screening, it will be possible to eliminate active HCV among HIV-infected individuals in Spain in the short term. However, the burden of HCV-related cirrhosis will continue to be significant among HIV-infected individuals

Search for supersymmetry in proton-proton collisions at 13 TeV in final states with jets and missing transverse momentum

Results are reported from a search for supersymmetric particles in the final state with multiple jets and large missing transverse momentum. The search uses a sample of proton-proton collisions at s = 13 TeV collected with the CMS detector in 2016–2018, corresponding to an integrated luminosity of 137 fb, representing essentially the full LHC Run 2 data sample. The analysis is performed in a four-dimensional search region defined in terms of the number of jets, the number of tagged bottom quark jets, the scalar sum of jet transverse momenta, and the magnitude of the vector sum of jet transverse momenta. No significant excess in the event yield is observed relative to the expected background contributions from standard model processes. Limits on the pair production of gluinos and squarks are obtained in the framework of simplified models for supersymmetric particle production and decay processes. Assuming the lightest supersymmetric particle to be a neutralino, lower limits on the gluino mass as large as 2000 to 2310 GeV are obtained at 95% confidence level, while lower limits on the squark mass as large as 1190 to 1630 GeV are obtained, depending on the production scenario.Individuals have received support from the Marie-Curie program and the European Research Council and Horizon 2020 Grant, contract No. 675440 (European Union); the Leventis Foundation; the A.P. Sloan Foundation; the Alexander von Humboldt Foundation; the Belgian Federal Science Policy Office; the Fonds pour la Formation a la Recherche dans l’Industrie et dans l’Agriculture (FRIA-Belgium); the Agentschap voor Innovatie door Wetenschap en Technologie (IWT-Belgium); the F.R.S.-FNRS and FWO (Belgium) under the “Excellence of Science — EOS” — be.h project n. 30820817; the Ministry of Education, Youth and Sports (MEYS) of the Czech Republic; the Lendület (“Momentum”) Program and the J´anos Bolyai Research Scholarship of the Hungarian Academy of Sciences, the New National Excellence Program UNKP, the NKFIA research grants 123842, 123959, 124845, 124850 and 125105 (Hungary); the Council of Science and Industrial Research, India; the HOMING PLUS program of the Foundation for Polish Science, cofinanced from European Union, Regional Development Fund, the Mobility Plus program of the Ministry of Science and Higher Education, the National Science Center (Poland), contracts Harmonia 2014/14/M/ST2/00428, Opus 2014/13/B/ST2/02543, 2014/15/B/ST2/03998, and 2015/19/B/ST2/02861, Sonata-bis 2012/07/E/ST2/01406; the National Priorities Research Program by Qatar National Research Fund; the Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia María de Maeztu, grant MDM-2015-0509 and the Programa Severo Ochoa del Principado de Asturias; the Thalis and Aristeia programs cofinanced by EU-ESF and the Greek NSRF; the Rachadapisek Sompot Fund for Postdoctoral Fellowship, Chulalongkorn University and the Chulalongkorn Academic into Its 2nd Century Project Advancement Project (Thailand); the Welch Foundation, contract C-1845; and the Weston Havens Foundation (U.S.A.)

Effectiveness, safety/tolerability of OBV/PTV/r ± DSV in patients with HCV genotype 1 or 4 with/without HIV-1 co-infection, chronic kidney disease (CKD) stage IIIb/V and dialysis in Spanish clinical practice – preliminary data Vie-KinD study

Poster presentatio

Effectiveness and Safety of the Sequential Use of a Second and Third Anti-TNF Agent in Patients with Inflammatory Bowel Disease: Results from the Eneida Registry

Background: The effectiveness of the switch to another anti-tumor necrosis factor (anti-TNF) agent is not known. The aim of this study was to analyze the effectiveness and safety of treatment with a second and third anti-TNF drug after intolerance to or failure of a previous anti-TNF agent in inflammatory bowel disease (IBD) patients. Methods: We included patients diagnosed with IBD from the ENEIDA registry who received another anti-TNF after intolerance to or failure of a prior anti-TNF agent. Results: A total of 1122 patients were included. In the short term, remission was achieved in 55% of the patients with the second anti-TNF. The incidence of loss of response was 19% per patient-year with the second anti-TNF. Combination therapy (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.8-3; P < 0.0001) and ulcerative colitis vs Crohn''s disease (HR, 1.6; 95% CI, 1.1-2.1; P = 0.005) were associated with a higher probability of loss of response. Fifteen percent of the patients had adverse events, and 10% had to discontinue the second anti-TNF. Of the 71 patients who received a third anti-TNF, 55% achieved remission. The incidence of loss of response was 22% per patient-year with a third anti-TNF. Adverse events occurred in 7 patients (11%), but only 1 stopped the drug. Conclusions: Approximately half of the patients who received a second anti-TNF achieved remission; nevertheless, a significant proportion of them subsequently lost response. Combination therapy and type of IBD were associated with loss of response. Remission was achieved in almost 50% of patients who received a third anti-TNF; nevertheless, a significant proportion of them subsequently lost response

A Proposed Approach to Chronic Airway Disease (CAD) Using Therapeutic Goals and Treatable Traits: A Look to the Future

© 2020 Pérez de Llano et al.Chronic airflow obstruction affects a wide range of airway diseases, the most frequent of which are asthma, COPD, and bronchiectasis; they are clearly identifiable in their extremes, but quite frequently overlap in some of their pathophysiological and clinical characteristics. This has generated the description of new mixed or overlapping disease phenotypes with no clear biological grounds. In this special article, a group of experts provides their perspective and proposes approaching the treatment of chronic airway disease (CAD) through the identification of a series of therapeutic goals (TG) linked to treatable traits (TT) – understood as clinical, physiological, or biological characteristics that are quantifiable using biomarkers. This therapeutic approach needs validating in a clinical trial with the strategy of identification of TG and treatment according to TT for each patient independently of their prior diagnosis

Cardiac responses to β‐adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity

Background and Purpose: Despite the importance of mitochondrial Ca2+ to metabolic regulation and cell physiology, little is known about the mechanisms that regulate Ca2+ entry into the mitochondria. Accordingly, we established a system to determine the role of the mitochondrial Ca2+ uniporter in an isolated heart model, at baseline and during increased workload following β-adrenoceptor stimulation. Experimental Approach: Cardiac contractility, oxygen consumption and intracellular Ca2+ transients were measured in ex vivo perfused murine hearts. Ru360 and spermine were used to modify mitochondrial Ca2+ uniporter activity. Changes in mitochondrial Ca2+ content and energetic phosphate metabolite levels were determined. Key Results: The addition of Ru360, a selective inhibitor of the mitochondrial Ca2+ uniporter, induced progressively and sustained negative inotropic effects that were dose-dependent with an EC50 of 7 μM. Treatment with spermine, a uniporter agonist, showed a positive inotropic effect that was blocked by Ru360. Inotropic stimulation with isoprenaline elevated oxygen consumption (2.7-fold), Ca2+-dependent activation of pyruvate dehydrogenase (5-fold) and mitochondrial Ca2+ content (2.5-fold). However, in Ru360-treated hearts, this parameter was attenuated. In addition, β-adrenoceptor stimulation in the presence of Ru360 did not affect intracellular Ca2+ handling, PKA or Ca2+/calmodulin-dependent PK signalling. Conclusions and Implications: Inhibition of the mitochondrial Ca2+ uniporter decreases β-adrenoceptor response, uncoupling between workload and production of energetic metabolites. Our results support the hypothesis that the coupling of workload and energy supply is partly dependent on mitochondrial Ca2+ uniporter activity.Centro de Investigaciones Cardiovasculare