Peripheral microcirculatory alterations are associated with the severity of acute respiratory distress syndrome in COVID-19 patients admitted to intermediate respiratory and intensive care units

COVID-19; Endothelial dysfunction; MicrocirculationCOVID-19; Disfunción endotelial; MicrocirculaciónCOVID-19; Disfunció endotelial; MicrocirculacióBackground COVID-19 is primarily a respiratory disease; however, there is also evidence that it causes endothelial damage in the microvasculature of several organs. The aim of the present study is to characterize in vivo the microvascular reactivity in peripheral skeletal muscle of severe COVID-19 patients. Methods This is a prospective observational study carried out in Spain, Mexico and Brazil. Healthy subjects and severe COVID-19 patients admitted to the intermediate respiratory (IRCU) and intensive care units (ICU) due to hypoxemia were studied. Local tissue/blood oxygen saturation (StO2) and local hemoglobin concentration (THC) were non-invasively measured on the forearm by near-infrared spectroscopy (NIRS). A vascular occlusion test (VOT), a three-minute induced ischemia, was performed in order to obtain dynamic StO2 parameters: deoxygenation rate (DeO2), reoxygenation rate (ReO2), and hyperemic response (HAUC). In COVID-19 patients, the severity of ARDS was evaluated by the ratio between peripheral arterial oxygen saturation (SpO2) and the fraction of inspired oxygen (FiO2) (SF ratio). Results Healthy controls (32) and COVID-19 patients (73) were studied. Baseline StO2 and THC did not differ between the two groups. Dynamic VOT-derived parameters were significantly impaired in COVID-19 patients showing lower metabolic rate (DeO2) and diminished endothelial reactivity. At enrollment, most COVID-19 patients were receiving invasive mechanical ventilation (MV) (53%) or high-flow nasal cannula support (32%). Patients on MV were also receiving sedative agents (100%) and vasopressors (29%). Baseline StO2 and DeO2 negatively correlated with SF ratio, while ReO2 showed a positive correlation with SF ratio. There were significant differences in baseline StO2 and ReO2 among the different ARDS groups according to SF ratio, but not among different respiratory support therapies. Conclusion Patients with severe COVID-19 show systemic microcirculatory alterations suggestive of endothelial dysfunction, and these alterations are associated with the severity of ARDS. Further evaluation is needed to determine whether these observations have prognostic implications. These results represent interim findings of the ongoing HEMOCOVID-19 trial. Trial registration ClinicalTrials.gov NCT04689477. Retrospectively registered 30 December 2020.The study has received funding from Fundació CELLEX Barcelona, Fundació Mir-Puig, Ajuntament de Barcelona, Agencia Estatal de Investigación (PHOTOMETABO, PID2019-106481RB-C31/10.13039/501100011033), the "Severo Ochoa" Programme for Centers of Excellence in R&D (CEX2019-000910-S), the Obra social “La Caixa” Foundation (LlumMedBcn), Generalitat de Catalunya (CERCA, AGAUR-2017-SGR-1380, RIS3CAT-001-P-001682 CECH), European Commission Horizon 2020 (FEDER, 688303/LUCA, 101016087/VASCOVID, 87114/LASERLAB-EUROPE V). We also acknowledge the collaboration and an instrument loan from Artinis (Netherlands)

LOS SILOS. SANTA BRÍGIDA [Material gráfico]

Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte, 201

VASCOVID: hybrid diffuse optical platform combined with a pulse-oximeter and an automatized inflatable tourniquet for the assessment of metabolism and endothelial health in the intensive care

VASCOVID project is developing and testing a hybrid diffuse optical monitor for evaluating endothelial function and metabolism in intensive care including COVID-19

Ultra-rare RTEL1 gene variants associate with acute severity of COVID-19 and evolution to pulmonary fibrosis as a specific long COVID disorder

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel coronavirus that caused an ongoing pandemic of a pathology termed Coronavirus Disease 19 (COVID-19). Several studies reported that both COVID-19 and RTEL1 variants are associated with shorter telomere length, but a direct association between the two is not generally acknowledged. Here we demonstrate that up to 8.6% of severe COVID-19 patients bear RTEL1 ultra-rare variants, and show how this subgroup can be recognized. Methods: A cohort of 2246 SARS-CoV-2-positive subjects, collected within the GEN-COVID Multicenter study, was used in this work. Whole exome sequencing analysis was performed using the NovaSeq6000 System, and machine learning methods were used for candidate gene selection of severity. A nested study, comparing severely affected patients bearing or not variants in the selected gene, was used for the characterisation of specific clinical features connected to variants in both acute and post-acute phases. Results: Our GEN-COVID cohort revealed a total of 151 patients carrying at least one RTEL1 ultra-rare variant, which was selected as a specific acute severity feature. From a clinical point of view, these patients showed higher liver function indices, as well as increased CRP and inflammatory markers, such as IL-6. Moreover, compared to control subjects, they present autoimmune disorders more frequently. Finally, their decreased diffusion lung capacity for carbon monoxide after six months of COVID-19 suggests that RTEL1 variants can contribute to the development of SARS-CoV-2-elicited lung fibrosis. Conclusion: RTEL1 ultra-rare variants can be considered as a predictive marker of COVID-19 severity, as well as a marker of pathological evolution in pulmonary fibrosis in the post-COVID phase. This notion can be used for a rapid screening in hospitalized infected people, for vaccine prioritization, and appropriate follow-up assessment for subjects at risk. Trial Registration NCT04549831 (www.clinicaltrial.org

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

Cerenkov luminescence imaging of human breast cancer: a Monte Carlo simulations study

Cerenkov luminescence imaging (CLI) is a novel molecular imaging technique based on the detection of Cerenkov light produced by beta particles traveling through biological tissues. In this paper we simulated using 18F and 90Y the possibility of detecting Cerenkov luminescence in human breast tissues, in order to evaluate the potential of the CLI technique in a clinical setting. A human breast digital phantom was obtained from an 18F-FDG CT-PET scan. The spectral features of the breast surface emission were obtained as well as the simulated images obtainable by a cooled CCD detector. The simulated images revealed a signal to noise ratio equal to 6 for a 300 s of acquisition time. We concluded that a dedicated human Cerenkov imaging detector can be designed in order to offer a valid low cost alternative to diagnostic techniques in nuclear medicine, in particular allowing the detection of beta-minus emitters used in radiotherapy

Accuracy and precision of tissue optical properties and hemodynamic parameters estimated by the BabyLux device: A hybrid time-resolved near-infrared and diffuse correlation spectroscopy neuro-monitor

We have investigated the accuracy and precision of “the BabyLux device”, a hybrid time-resolved near-infrared (TRS) and diffuse correlation spectroscopy (DCS) neuro-monitor for the pre-term infant. Numerical data with realistic noise were simulated and analyzed using the BabyLux device as a reference system and different experimental and analysis parameters. The results describe the limits for the precision and the accuracy to be expected. The dependence of these limits on different experimental conditions and choices of the analysis method is also described. Experiments demonstrate comparable values for precision with respect to the simulation results