Identification of circulating microRNA profiles associated with pulmonary function and radiologic features in survivors of SARS-CoV-2-induced ARDS

ABSTRACT There is a limited understanding of the pathophysiology of postacute pulmonary sequelae in severe COVID-19. The aim of current study was to define the circulating microRNA (miRNA) profiles associated with pulmonary function and radiologic features in survivors of SARS-CoV-2-induced ARDS. The study included patients who developed ARDS secondary to SARS-CoV-2 infection (n=167) and a group of infected patients who did not develop ARDS (n=33). Patients were evaluated 3 months after hospital discharge. The follow-up included a complete pulmonary evaluation and chest computed tomography. Plasma miRNA profiling was performed using RT-qPCR. Random forest was used to construct miRNA signatures associated with lung diffusing capacity for carbon monoxide (DLCO) and total severity score (TSS). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were conducted. DLCO<80% predicted was observed in 81.8% of the patients. TSS showed a median [P25;P75] of 5 [2;8]. The miRNA model associated with DLCO comprised miR-17-5p, miR-27a-3p, miR-126-3p, miR-146a-5p and miR-495-3p. Concerning radiologic features, a miRNA signature composed by miR-9-5p, miR-21-5p, miR-24-3p and miR-221-3p correlated with TSS values. These associations were not observed in the non-ARDS group. KEGG pathway and GO enrichment analyses provided evidence of molecular mechanisms related not only to profibrotic or anti-inflammatory states but also to cell death, immune response, hypoxia, vascularization, coagulation and viral infection. In conclusion, diffusing capacity and radiological features in survivors from SARS-CoV-2-induced ARDS are associated with specific miRNA profiles. These findings provide novel insights into the possible molecular pathways underlying the pathogenesis of pulmonary sequelae. Trial registration: ClinicalTrials.gov identifier: NCT04457505.. Trial registration: ISRCTN.org identifier: ISRCTN16865246..This work is supported by Instituto de Salud Carlos III (COV20/00110), co-funded by European Regional Development Fund (ERDF)/“A way to make Europe”. CIBERES is an initiative of the Instituto de Salud Carlos III. CIBERES is an initiative of the Instituto de Salud Carlos III. Suported by: Programa de donaciones "estar preparados" UNESPA (Madrid, Spain) and Fundación Francisco Soria Melguizo (Madrid, Spain).. Finançat per La Fundació La Marató de TV3, projecte amb codi 202108-30/-31. COVIDPONENT is funded by Institut Català de la Salut and Gestió de Serveis Sanitaris. MM is the recipient of a predoctoral fellowship (PFIS: FI21/00187) from Instituto de Salud Carlos III. MCGH is the recipient of a predoctoral fellowship from “University of Lleida”. DdGC has received financial support from Instituto de Salud Carlos III (Miguel Servet 2020: CP20/00041), co-funded by the European Social Fund (ESF)/“Investing in your future”. ENL and GL were funded by COVID1005 and ACT210085 from National Agency of Investigation & Development (ANID), Chile."Article signat per 27 autors/es: María C. García-Hidalgo, Jessica González, Iván D. Benítez, Paola Carmona, Sally Santisteve, Manel Pérez-Pons, Anna Moncusí-Moix, Clara Gort-Paniello, Fátima Rodríguez-Jara, Marta Molinero, Thalia Belmonte, Gerard Torres, Gonzalo Labarca, Estefania Nova-Lamperti, Jesús Caballero, Jesús F. Bermejo-Martin, Adrián Ceccato, Laia Fernández-Barat, Ricard Ferrer, Dario Garcia-Gasulla, Rosario Menéndez, Ana Motos ,Oscar Peñuelas, Jordi Riera, Antoni Torres, Ferran Barbé, David de Gonzalo-Calvo & on behalf of the CIBERESUCICOVID Project (COV20/00110 ISCIII)"Postprint (published version

Spatial-temporal variation of the Western Mediterranean Sea biodiversity along a latitudinal gradient

The Mediterranean Sea is a large marine ecosystem with high heterogeneity in both environmental and ecological characteristics. It presents clear gradients from north to south and west to east. It is also an important area in terms of biodiversity and conservation of vulnerable species, and it suffers from several cumulative human impacts, such as fishing and climate change. Previous studies have characterized spatial and temporal patterns of species distributions and biodiversity indicators. However, a comprehensive analysis combining a wide representation of biodiversity indicators is still missing. In this study, we examined spatial and temporal changes of marine communities along a latitudinal gradient over the continental shelf ecosystems (25–500 m depth) of the Western Mediterranean Sea, from the Gulf of Lion in the north to the Gibraltar Strait in the south. We used information from the MEDITS trawl scientific surveys from 1994 to 2018, and we calculated relevant indicators to investigate spatial and temporal patterns in the region. We selected several indicators measuring alpha (species richness, Shannon diversity index and Pielou evenness index) and beta (decomposing both turnover and nestedness) diversity, as well as previously studied indicators identified to be sensitive to fishing and climate change impacts (biomass-based and trophic-level based metrics). We assessed differences in these indicators for the surveyed community as a whole and for fish, crustaceans and cephalopods, separately, over five regions. Our results show clear latitudinal gradients in some indicators: we observe a reversed pattern between richness (decreasing from south to north) and biomass trends (increasing from south to north) for the demersal community. We also found a generalized increase in β-diversity in most regions with time, and a decline in the trophic level of the surveyed community. In addition, we identify a remarkable increase in several indicators when only considering the cephalopods group, and a general low environmental status for the North Catalan Sea. We discuss our results considering the differences between regions and taxa related to the fishing activity and environmental dynamics that can act at different scales. This in-depth analysis illustrates how to use a selection of indicators that combine the capacity to detect ecological changes from regional to sub-regional scales.En prensa2,69

Decapod crustacean assemblages on trawlable grounds in the northern Alboran Sea and Gulf of Vera

This study analyses the samples collected annually (2012 to 2018) on circalittoral and bathyal soft bottoms (30 to 800 m) by the MEDITS surveys in the northern Alboran Sea (including Alboran Island) and the Gulf of Vera to determine the composition, structure and distribution of decapod crustacean assemblages. A total of 94 decapod crustacean species were identified. Non-metric multidimensional scaling showed depth to be the main factor for distinguishing four main decapod assemblages: the inner shelf (30-100 m depth), outer shelf (101-200 m), upper slope (201-500 m) and middle slope (501-800 m). PERMANOVA analyses revealed further significant depth-related differences between three established geographical sectors of the study area (northern Alboran Sea, Gulf of Vera and Alboran Island). Generalized additive model analyses were used to assess the bathymetrical, geographical and environmental effects on the ecological indices of each assemblage. Results showed that depth and the geographical effect were the main drivers in all cases. Decreases in abundance and increases in species richness, Shannon-Wiener diversity and Pielou’s evenness indices with depth were detected. This study shows the primacy of depth and geographical effect on the distribution of decapod species in the study area, in alignment with findings from other parts of the Mediterranean Sea.Versión del editor1,00

Emergence of ceftazidime/avibactam resistance in KPC-8–producing Klebsiella pneumoniae in South America

Klebsiella pneumoniae is one of the so-called ESKAPE pathogens. These organisms are the main cause of nosocomial infections worldwide, causing life-threatening infections amongst critically ill and immunocompromised individuals. They are characterized by drug resistance mechanisms. Klebsiella pneumoniae carbapenemase (KPC)-producing isolates display resistance to multiple antimicrobial agents, usually including last-resort alternative options, leading to an urgent need to develop new drugs or combinations. In Argentina sequence type (ST) 258 harbouring bla KPC-2 emerged in 2010 and remained prevalent until the last few years, when the emergence of different STs such as ST25, ST11 and ST307 appeared likely to change the local epidemiology.Fil: García, J.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Nastro, Marcela. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Cejas, Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquimica. Instituto de Investigaciones En Bacteriologia y Virologia Molecular; ArgentinaFil: Santana, G.. No especifíca;Fil: Mancino, M.B.. No especifíca;Fil: Hidalgo, M.. No especifíca;Fil: Maccallini, G.. No especifíca;Fil: Vay, C.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Radice, Marcela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquimica. Instituto de Investigaciones En Bacteriologia y Virologia Molecular; ArgentinaFil: Dabos, L.. Université Paris Sud; FranciaFil: Famiglietti, Angela María Rosa. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Rodríguez, H.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentin

The Influence of Oxytocin and Prolactin During a First Episode of Psychosis: The Implication of Sex Differences, Clinical Features, and Cognitive Performance

Background Approximately 3% of the population suffers a first episode of psychosis (FEP), and a high percentage of these patients subsequently relapse. Because the clinical course following a FEP is hard to predict, it is of interest to identify cognitive and biological markers that will help improve the diagnosis, treatment, and outcome of such events and to define new therapeutic targets. Here we analyzed the plasma oxytocin and prolactin levels during an FEP, assessing their correlation with clinical and cognitive features. Methods The oxytocin and prolactin in plasma was measured in 120 FEP patients and 106 healthy controls, all of whom were subjected to a clinical and neuropsychological assessment. Most patients were under antipsychotics. Statistical analyses aimed to identify factors associated with the FEP and to search for associations between the variables. This study is preliminary and exploratory because the P-values were not corrected for multiple comparisons. Results FEP patients had less oxytocin, more prolactin, and a poor premorbid IQ, and they performed worse in sustained attention. Male patients with higher prolactin levels experienced more severe psychotic symptoms and required higher doses of antipsychotics. Low oxytocin was associated with poor sustained attention in women, whereas low oxytocin and high prolactin in men correlated with better performance in sustained attention. Conclusion Low oxytocin, high prolactin, and poor premorbid IQ and sustained attention are factors associated with an FEP, representing potential therapeutic targets in these patients. These biological factors and cognitive domains might play an important role during a FEP, which could help us to develop new strategies that improve the outcomes of this disorder and that should perhaps be gender specific

Linezolid for infective endocarditis. A structured approach based on a national database experience

Current data on the frequency and efficacy of linezolid (LNZ) in infective endocarditis (IE) are based on small retrospective series. We used a national database to evaluate the effectiveness of LNZ in IE. This is a retrospective study of IE patients in the Spanish GAMES database who received LNZ. We defined 3 levels of therapeutic impact: LNZ 50% of the total treatment, and > 50% of the LNZ doses prescribed in the first weeks of treatment), and LNZ ? 7 days not fulfilling the high-impact criteria (LNZ-NHI). Effectiveness of LNZ was assessed using propensity score matching and multivariate analysis of high-impact cases in comparison to patients not treated with LNZ from the GAMES database matched for age-adjusted comorbidity Charlson index, heart failure, renal failure, prosthetic and intracardiac IE device, left-sided IE, and Staphylococcus aureus. Primary outcomes were in-hospital mortality and one-year mortality. Secondary outcomes included IE complications and relapses

Early rise in central venous pressure during a spontaneous breathing trial: A promising test to identify patients at high risk of weaning failure?

Background The spontaneous breathing trial (SBT) assesses the risk of weaning failure by evaluating some physiological responses to the massive venous return increase imposed by discontinuing positive pressure ventilation. This trial can be very demanding for some critically ill patients, inducing excessive physical and cardiovascular stress, including muscle fatigue, heart ischemia and eventually cardiac dysfunction. Extubation failure with emergency reintubation is a serious adverse consequence of a failed weaning process. Some data suggest that as many as 50% of patients that fail weaning do so because of cardiac dysfunction. Unfortunately, monitoring cardiovascular function at the time of the SBT is complex. The aim of our study was to explore if central venous pressure (CVP) changes were related to weaning failure after starting an SBT. We hypothesized that an early rise on CVP could signal a cardiac failure when handling a massive increase on venous return following a discontinuation of positive pressure ventilation. This CVP rise could identify a subset of patients at high risk for extubation failure. Methods Two-hundred and four mechanically ventilated patients in whom an SBT wa

A blood microRNA classifier for the prediction of ICU mortality in COVID-19 patients: a multicenter validation study

Background: The identification of critically ill COVID-19 patients at risk of fatal outcomes remains a challenge. Here, we first validated candidate microRNAs (miRNAs) as biomarkers for clinical decision-making in critically ill patients. Second, we constructed a blood miRNA classifier for the early prediction of adverse outcomes in the ICU. Methods: This was a multicenter, observational and retrospective/prospective study including 503 critically ill patients admitted to the ICU from 19 hospitals. qPCR assays were performed in plasma samples collected within the first 48 h upon admission. A 16-miRNA panel was designed based on recently published data from our group. Results: Nine miRNAs were validated as biomarkers of all-cause in-ICU mortality in the independent cohort of critically ill patients (FDR < 0.05). Cox regression analysis revealed that low expression levels of eight miRNAs were associated with a higher risk of death (HR from 1.56 to 2.61). LASSO regression for variable selection was used to construct a miRNA classifier. A 4-blood miRNA signature composed of miR-16-5p, miR-192-5p, miR-323a-3p and miR-451a predicts the risk of all-cause in-ICU mortality (HR 2.5). Kaplan‒Meier analysis confirmed these findings. The miRNA signature provides a significant increase in the prognostic capacity of conventional scores, APACHE-II (C-index 0.71, DeLong test p-value 0.055) and SOFA (C-index 0.67, DeLong test p-value 0.001), and a risk model based on clinical predictors (C-index 0.74, DeLong test-p-value 0.035). For 28-day and 90-day mortality, the classifier also improved the prognostic value of APACHE-II, SOFA and the clinical model. The association between the classifier and mortality persisted even after multivariable adjustment. The functional analysis reported biological pathways involved in SARS-CoV infection and inflammatory, fibrotic and transcriptional pathways. Conclusions: A blood miRNA classifier improves the early prediction of fatal outcomes in critically ill COVID-19 patients.11 página