Environmental factors are associated to hospital outcomes in COVID-19 patients during lockdown and post-lockdown in 2020: A nationwide study

Producción CientíficaThis study analyzed, at a postcode detailed level, the relation-ship between short-term exposure to environmental factors and hospital ad-missions, in-hospital mortality, ICU admission, and ICU mortality due to COVID-19 during the lockdown and post-lockdown 2020 period in Spain. Short-term exposure to air pollutants impacts COVID-19 out-comes during the lockdown, especially PM2.5, PM10, NO2, and SO2. These pollutants are associated with hospital admission, hospital mortality and ICU admission, while ICU mortality is mainly associated with PM2.5 and PM10. Our findings reveal the importance of monitoring air pollutants in respiratory infectious diseases.Ministerio de Ciencia e Innovación y Unión Europea – Next Generation EU (CB21/13/00044 y CB21/13/ 00051)Instituto Carlos III - FEDER. Río Hortega grant (CM20/00138

Development and application of computational techniques to drug discovery and structure-function relationships /

Departament responsable de la tesi: Departament de Bioquímica i Biologia MolecularEsta tesis doctoral presenta los resultados de la aplicación de varias técnicas computacionales al complejo campo del desarrollo de fármacos, particularmente en GPCRs, una de las familias más importantes de proteínas de membrana. La tesis está organizada en las siguientes secciones: introducción, métodos, objetivos, resultados y conclusiones. Introducción: incluye los fundamentos de biología molecular de los receptores de membrana acoplados a proteínas G.; clasificación, estructura, farmacología, señalización y activación. Métodos: describe las técnicas computaciones usadas en la tesis. Objetivos: describe los objetivos propuestos en el desarrollo de la tesis. Resultados: En esta sección se presentan los resultados obtenidos. En primer lugar se contextualice todo el trabajo hecho, se listan las contribuciones y se exponen resumidamente los diferentes resultados obtenidos. La siguientes subsecciones describen el trabajo realizado en los diferentes proyectos de manera detallada. Proyectos: LigandFinder Esta aplicación web proporciona una interfaz de fácil uso para realizar "virtual screening" rápido para encontrar nuevos compuestos similares a un set de compuestos de estructura conocida. Explora el espacio químico de una base de datos con más de 20 millones de compuestos. Hasta donde llega nuestro conocimiento, LigandFinder es la primera aplicación web de "virtual screening" capaz de usar varios ligandos como input. Estudio de los aminoácidos con azufre En este trabajo se estudian las interacciones de los aminoácidos con azufre en las proteínas de membrana. Las interacciones de estos aminoácidos entre ellos y con otros aminoácidos se extraen de una base de datos con estructuras refinadas, se agrupan, y se calcula la energía de interacción de las estructuras representativas usando cálculos químico cuánticos de alto nivel. GPCR-SAS Esta aplicación web se aprovecha de la similaridad estructural de las regiones transmembrana de la familia de las GPCRs para realizar cálculos estadísticos de las posiciones de secuencia o los motivos dentro de las hélices transmembrana. Es posible realizar estos cálculos en las clases A, B, C y F. Los cálculos estadísticos disponibles incluyen el cálculo de la conservación de una posición/posiciones/rango de posiciones, entropía, coevolución (covarianza) y correlación. Adicionalmente, hay la posibilidad de obtener una representación bidimensional de la conservación (snakeplot). La entrada extracelular otorga selectividad a los antogonistas de 5-HT7 con comportamiento antidepresivo en vivo. Este trabajo resalta la importancia de la poco conservada parte extracelular de los receptores de serotonina en la selectividad de sus ligandos. Se describe el modo de unión de un antagonista selectivo de 5-HT7 con comportamiento antidepresivo.This thesis present the results of various computational techniques applied to the complex world of drug development with a particular focus to its application to one of the most important membrane protein family, the GPCRs. The thesis is organized in the following sections: introduction, methods, objectives, results and conclusion. Introduction: covers the fundamentals of G-protein coupled receptors molecular biology; classification, structure, pharmacology, signaling and activation. Methods: describes the computational techniques used in the thesis. Results: In this section, the results obtained are presented. A first paragraph contextualizes all the work done, describing its objectives, stating the contribution of the author; moreover a brief introduction of each part of the results paragraphs. The following subsections contain a detailed explanation of all projects done in this thesis. Projects: LigandFinder This web application provides a user-friendly way to perform fast virtual screening to find new compounds similar to a set of compounds of known structure. It explores the chemical space of a database with more than 20M compounds. To our knowledge, LigandFinder is the first virtual screening web application able to use several ligands as input. Sulfur-containing amino acids study In this work the interactions of sulfur-containing amino acids (cysteine and methionine) in membrane proteins are studied. A refined crystal structures database is screened in order to find interactions of sulfur-containing residues with themselves and other residues. These interactions are clustered, and the interaction energy of representative structures is calculated through high-level quantum chemical calculations. GPCR-SAS This web application takes advantage of the structural similarity among GPCRs' transmembrane regions to perform statistical analysis of sequence positions or motifs within the transmembrane helices of GPCR A, B, C, and F classes. GPCRSAS provides different types of analysis such as position/positions/range of positions conservation, entropy, co-evolutionary (co-variance) and correlation analysis. Additionally, there is the possibility of drawing a snakeplot representation with conservation information. The extracellular entrance provides selectivity to 5-HT7 receptor antagonists with antidepressant -like behavior in vivo This work highlights the importance of the low conserved extracellular part of the serotonin receptors in ligand selectivity. The binding mode of a selective 5HT7 receptor antagonist with antidepressant activity is described, opening the way for a new generation of antidepressant drugs

Comparison of lossy filters and predistorted filters using novel software

Postprint (published version

HGF, IL-1α, and IL-27 Are Robust Biomarkers in Early Severity Stratification of COVID-19 Patients

Producción CientíficaPneumonia is the leading cause of hospital admission and mortality in coronavirus disease 2019 (COVID-19). We aimed to identify the cytokines responsible for lung damage and mortality. We prospectively recruited 108 COVID-19 patients between March and April 2020 and divided them into four groups according to the severity of respiratory symptoms. Twenty-eight healthy volunteers were used for normalization of the results. Multiple cytokines showed statistically significant differences between mild and critical patients. High HGF levels were associated with the critical group (OR = 3.51; p < 0.001; 95%CI = 1.95–6.33). Moreover, high IL-1α (OR = 1.36; p = 0.01; 95%CI = 1.07–1.73) and low IL-27 (OR = 0.58; p < 0.005; 95%CI = 0.39–0.85) greatly increased the risk of ending up in the severe group. This model was especially sensitive in order to predict critical status (AUC = 0.794; specificity = 69.74%; sensitivity = 81.25%). Furthermore, high levels of HGF and IL-1α showed significant results in the survival analysis (p = 0.033 and p = 0.011, respectively). HGF, IL-1α, and IL 27 at hospital admission were strongly associated with severe/critical COVID-19 patients and therefore are excellent predictors of bad prognosis. HGF and IL-1α were also mortality biomarkers.Instituto de Salud Carlos III (grant COV20/00491

Evaluation of cytokines as robust diagnostic biomarkers for COVID-19 detection

Producción CientíficaAntigen tests or polymerase chain reaction (PCR) amplification are currently COVID-19 diagnostic tools. However, developing complementary diagnosis tools is mandatory. Thus, we performed a plasma cytokine array in COVID-19 patients to identify novel diagnostic biomarkers. A discovery–validation study in two independent prospective cohorts was performed. The discovery cohort included 136 COVID-19 and non-COVID-19 patients recruited consecutively from 24 March to 11 April 2020. Forty-five cytokines’ quantification by the MAGPIX system (Luminex Corp., Austin, TX, USA) was performed in plasma samples. The validation cohort included 117 patients recruited consecutively from 15 to 25 April 2020 for validating results by ELISA. COVID-19 patients showed different levels of multiple cytokines compared to non-COVID-19 patients. A single chemokine, IP-10, accurately identified COVID-19 patients who required hospital admission (AUC: 0.962; 95%CI (0.933–0.992); p < 0.001)). The results were validated in an independent cohort by multivariable analysis (OR: 25.573; 95%CI (8.127–80.469); p < 0.001) and AUROC (AUC: 0.900; 95%CI (0.846–0.954); p < 0.001). Moreover, showing IP-10 plasma levels over 173.35 pg/mL identified COVID-19 with higher sensitivity (86.20%) than the first SARS-CoV-2 PCR. Our discover–validation study identified IP-10 as a robust biomarker in clinical practice for COVID-19 diagnosis at hospital. Therefore, IP-10 could be used as a complementary tool in clinical practice, especially in emergency departments.Instituto de Salud Carlos III (grant COV20/00491)Consejo Superior de Investigaciones científicas (grant CSIC-COV19-016/202020E155)Junta de Castilla y León (project COVID 07.04.467B04.74011.0)IBGM excellence programme (grant CLU-2029-02

Can the Cytokine Profile According to ABO Blood Groups Be Related to Worse Outcome in COVID-19 Patients? Yes, They Can

Producción CientíficaSevere status of coronavirus disease 2019 (COVID-19) is extremely associated to cytokine release. Moreover, it has been suggested that blood group is also associated with the prevalence and severity of this disease. However, the relationship between the cytokine profile and blood group remains unclear in COVID-19 patients. In this sense, we prospectively recruited 108 COVID-19 patients between March and April 2020 and divided according to ABO blood group. For the analysis of 45 cytokines, plasma samples were collected in the time of admission to hospital ward or intensive care unit and at the sixth day after hospital admission. The results show that there was a risk of more than two times lower of mechanical ventilation or death in patients with blood group O (log rank: p = 0.042). At first time, all statistically significant cytokine levels, except from hepatocyte growth factor, were higher in O blood group patients meanwhile the second time showed a significant drop, between 20% and 40%. In contrast, A/B/AB group presented a maintenance of cytokine levels during time. Hepatocyte growth factor showed a significant association with intubation or mortality risk in non-O blood group patients (OR: 4.229, 95% CI (2.064–8.665), p < 0.001) and also was the only one bad prognosis biomarker in O blood group patients (OR: 8.852, 95% CI (1.540–50.878), p = 0.015). Therefore, higher cytokine levels in O blood group are associated with a better outcome than A/B/AB group in COVID-19 patients.Instituto de Salud Carlos III (grant COV20/00491)Junta de Castilla y León (grant 18IGOF

Nature of viruses and pandemics: Coronaviruses

Coronaviruses (CoVs) have the largest genome among RNA viruses and store large amounts of information without genome integration as they replicate in the cell cytoplasm. The replication of the virus is a continuous process, whereas the transcription of the subgenomic mRNAs is a discontinuous one, involving a template switch, which resembles a high frequency recombination mechanism that may favor virus genome variability. The origin of the three deadly human CoVs SARS-CoV, MERS-CoV and SARS-CoV-2 are zoonotic events. SARS-CoV-2 has incorporated in its spike protein a furine proteolytic site that facilitates the activation of the virus in any tissue, making this CoV strain highly polytropic and pathogenic. Using MERS-CoV as a model, a propagation-deficient RNA replicon was generated by removing E protein gene (essential for viral morphogenesis and involved in virulence), and accessory genes 3, 4a, 4b and 5 (responsible for antagonism of the innate immune response) to attenuate the virus: MERS-CoV-Δ[3,4a,4b,5,E]. This RNA replicon is strongly attenuated and elicits sterilizing protection after a single immunization in transgenic mice with the receptor for MERS-CoV, making it a promising vaccine candidate for this virus and an interesting platform for vector-based vaccine development. A strategy could be developed for the design of RNA replicon vaccines for other human pathogenic coronaviruses.This work was supported by grants from the Government of Spain (PID2019-107001RB-I00 AEI/FEDER, UE; SEV 2017-0712 and PIE_INTRAMURAL_LINEA 1-202020E079), the CSIC (PIE_INTRAMURAL-202020E043), the European Commission (ISOLDA_848166 H2020-SC1-2019-Two-Stage-RTD, RIA; MANCO_101003651 H2020-SC1-PHE-CORONAVIRUS-2020 RIA), and the U.S. National Institutes of Health (NIH_2P01AI060699).Peer reviewe

Effects of intubation timing in patients with COVID-19 throughout the four waves of the pandemic : a matched analysis

The primary aim of our study was to investigate the association between intubation timing and hospital mortality in critically ill patients with COVID-19-associated respiratory failure. We also analysed both the impact of such timing throughout the first four pandemic waves and the influence of prior non-invasive respiratory support on outcomes. This is a secondary analysis of a multicentre, observational and prospective cohort study that included all consecutive patients undergoing invasive mechanical ventilation due to COVID-19 from across 58 Spanish intensive care units (ICU) participating in the CIBERESUCICOVID project. The study period was between 29 February 2020 and 31 August 2021. Early intubation was defined as that occurring within the first 24 h of intensive care unit (ICU) admission. Propensity score (PS) matching was used to achieve balance across baseline variables between the early intubation cohort and those patients who were intubated after the first 24 h of ICU admission. Differences in outcomes between early and delayed intubation were also assessed. We performed sensitivity analyses to consider a different timepoint (48 h from ICU admission) for early and delayed intubation. Of the 2725 patients who received invasive mechanical ventilation, a total of 614 matched patients were included in the analysis (307 for each group). In the unmatched population, there were no differences in mortality between the early and delayed groups. After PS matching, patients with delayed intubation presented higher hospital mortality (27.3% versus 37.1%, p =0.01), ICU mortality (25.7% versus 36.1%, p=0.007) and 90-day mortality (30.9% versus 40.2%, p=0.02) when compared to the early intubation group. Very similar findings were observed when we used a 48-hour timepoint for early or delayed intubation. The use of early intubation decreased after the first wave of the pandemic (72%, 49%, 46% and 45% in the first, second, third and fourth wave, respectively; first versus second, third and fourth waves p<0.001). In both the main and sensitivity analyses, hospital mortality was lower in patients receiving high-flow nasal cannula (n=294) who were intubated earlier. The subgroup of patients undergoing NIV (n=214) before intubation showed higher mortality when delayed intubation was set as that occurring after 48 h from ICU admission, but not when after 24 h. In patients with COVID-19 requiring invasive mechanical ventilation, delayed intubation was associated with a higher risk of hospital mortality. The use of early intubation significantly decreased throughout the course of the pandemic. Benefits of such an approach occurred more notably in patients who had received high-flow nasal cannul