Effect of viral storm in patients admitted to intensive care units with severe COVID-19 in Spain: a multicentre, prospective, cohort study

Background: The contribution of the virus to the pathogenesis of severe COVID-19 is still unclear. We aimed to evaluate associations between viral RNA load in plasma and host response, complications, and deaths in critically ill patients with COVID-19. Methods: We did a prospective cohort study across 23 hospitals in Spain. We included patients aged 18 years or older with laboratory-confirmed SARS-CoV-2 infection who were admitted to an intensive care unit between March 16, 2020, and Feb 27, 2021. RNA of the SARS-CoV-2 nucleocapsid region 1 (N1) was quantified in plasma samples collected from patients in the first 48 h following admission, using digital PCR. Patients were grouped on the basis of N1 quantity: VIR-N1-Zero ([removed]2747 N1 copies per mL). The primary outcome was all-cause death within 90 days after admission. We evaluated odds ratios (ORs) for the primary outcome between groups using a logistic regression analysis. Findings: 1068 patients met the inclusion criteria, of whom 117 had insufficient plasma samples and 115 had key information missing. 836 patients were included in the analysis, of whom 403 (48%) were in the VIR-N1-Low group, 283 (34%) were in the VIR-N1-Storm group, and 150 (18%) were in the VIR-N1-Zero group. Overall, patients in the VIR-N1-Storm group had the most severe disease: 266 (94%) of 283 patients received invasive mechanical ventilation (IMV), 116 (41%) developed acute kidney injury, 180 (65%) had secondary infections, and 148 (52%) died within 90 days. Patients in the VIR-N1-Zero group had the least severe disease: 81 (54%) of 150 received IMV, 34 (23%) developed acute kidney injury, 47 (32%) had secondary infections, and 26 (17%) died within 90 days (OR for death 0·30, 95% CI 0·16–0·55; p<0·0001, compared with the VIR-N1-Storm group). 106 (26%) of 403 patients in the VIR-N1-Low group died within 90 days (OR for death 0·39, 95% CI 0·26–0·57; p[removed]11 página

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

CARB-ES-19 Multicenter Study of Carbapenemase-Producing Klebsiella pneumoniae and Escherichia coli From All Spanish Provinces Reveals Interregional Spread of High-Risk Clones Such as ST307/OXA-48 and ST512/KPC-3

ObjectivesCARB-ES-19 is a comprehensive, multicenter, nationwide study integrating whole-genome sequencing (WGS) in the surveillance of carbapenemase-producing K. pneumoniae (CP-Kpn) and E. coli (CP-Eco) to determine their incidence, geographical distribution, phylogeny, and resistance mechanisms in Spain.MethodsIn total, 71 hospitals, representing all 50 Spanish provinces, collected the first 10 isolates per hospital (February to May 2019); CPE isolates were first identified according to EUCAST (meropenem MIC &gt; 0.12 mg/L with immunochromatography, colorimetric tests, carbapenem inactivation, or carbapenem hydrolysis with MALDI-TOF). Prevalence and incidence were calculated according to population denominators. Antibiotic susceptibility testing was performed using the microdilution method (EUCAST). All 403 isolates collected were sequenced for high-resolution single-nucleotide polymorphism (SNP) typing, core genome multilocus sequence typing (cgMLST), and resistome analysis.ResultsIn total, 377 (93.5%) CP-Kpn and 26 (6.5%) CP-Eco isolates were collected from 62 (87.3%) hospitals in 46 (92%) provinces. CP-Kpn was more prevalent in the blood (5.8%, 50/853) than in the urine (1.4%, 201/14,464). The cumulative incidence for both CP-Kpn and CP-Eco was 0.05 per 100 admitted patients. The main carbapenemase genes identified in CP-Kpn were blaOXA–48 (263/377), blaKPC–3 (62/377), blaVIM–1 (28/377), and blaNDM–1 (12/377). All isolates were susceptible to at least two antibiotics. Interregional dissemination of eight high-risk CP-Kpn clones was detected, mainly ST307/OXA-48 (16.4%), ST11/OXA-48 (16.4%), and ST512-ST258/KPC (13.8%). ST512/KPC and ST15/OXA-48 were the most frequent bacteremia-causative clones. The average number of acquired resistance genes was higher in CP-Kpn (7.9) than in CP-Eco (5.5).ConclusionThis study serves as a first step toward WGS integration in the surveillance of carbapenemase-producing Enterobacterales in Spain. We detected important epidemiological changes, including increased CP-Kpn and CP-Eco prevalence and incidence compared to previous studies, wide interregional dissemination, and increased dissemination of high-risk clones, such as ST307/OXA-48 and ST512/KPC-3

Global Impairment of Immediate-Early Genes Expression in Rett Syndrome Models and Patients Linked to Myelination Defects

Rett syndrome (RTT) is a severe neurodevelopmental disease caused almost exclusively by mutations to the MeCP2 gene. This disease may be regarded as a synaptopathy, with impairments affecting synaptic plasticity, inhibitory and excitatory transmission and network excitability. The complete understanding of the mechanisms behind how the transcription factor MeCP2 so profoundly affects the mammalian brain are yet to be determined. What is known, is that MeCP2 involvement in activity-dependent expression programs is a critical link between this protein and proper neuronal activity, which allows the correct maturation of connections in the brain. By using RNA-sequencing analysis, we found several immediate-early genes (IEGs, key mediators of activity-dependent responses) directly bound by MeCP2 at the chromatin level and upregulated in the hippocampus and prefrontal cortex of the Mecp2-KO mouse. Quantification of the IEGs response to stimulus both in vivo and in vitro detected an aberrant expression pattern in MeCP2-deficient neurons. Furthermore, altered IEGs levels were found in RTT patient's peripheral blood and brain regions of post-mortem samples, correlating with impaired expression of downstream myelination-related genes. Altogether, these data indicate that proper IEGs expression is crucial for correct synaptic development and that MeCP2 has a key role in the regulation of IEGs

Toxicological evaluation of a propolis extract

La tintura de propóleos es un fitofármaco que tiene asociados diversos efectos farmacológicos: acción antimicrobiana, analgésica, antinflamatoria, antioxidante y cicatrizante. Según las normativas establecidas por la Organización para la Cooperación Económica y el Desarrollo (OECD), los ensayos toxicológicos constituyen un requerimiento para el registro de los fármacos, lo cual garantiza determinar un margen de seguridad para el uso de los productos que se evalúan. Para el estudio de toxicidad aguda oral se emplearon ratas Sprague-Dawley de ambos sexos, realizándose un ensayo límite donde se clasificó al extracto de propóleos en la categoría "sin clasificar", al ser administrado a una dosis de 2 g/Kg por vía oral en ratas. El estudio de irritabilidad dérmica se desarrolló en conejos albinos F1 machos, obteniéndose un índice de irritación primario igual a cero, con el cual se clasifica al producto como no irritante.The propolis extract is a phytomedicine. It is well know that propolis is associated with some pharmacological effects, as antimicrobian, analgesic, antinflammatory, antioxidant and healing actions. According to the normative setted dawn by OECD, toxicological assays are one of the requirements for drug registration, which guarantees the determination of a security margin for the use of the evaluated product. For acute toxicity studies, Sprague Dawley rats of both sexes were used in a limit assay carried out with propolis extract, on the basis of which was set into the unclassified category, when being administrated in one dose of 2 g/kg (p.o) in rats. The dermal irritability assay was carried out in albino rabbits F1. A primary irritation index equal to zero was obtained, which classifies the product as not irritating.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Toxicological evaluation of a propolis extract

La tintura de propóleos es un fitofármaco que tiene asociados diversos efectos farmacológicos: acción antimicrobiana, analgésica, antinflamatoria, antioxidante y cicatrizante. Según las normativas establecidas por la Organización para la Cooperación Económica y el Desarrollo (OECD), los ensayos toxicológicos constituyen un requerimiento para el registro de los fármacos, lo cual garantiza determinar un margen de seguridad para el uso de los productos que se evalúan. Para el estudio de toxicidad aguda oral se emplearon ratas Sprague-Dawley de ambos sexos, realizándose un ensayo límite donde se clasificó al extracto de propóleos en la categoría "sin clasificar", al ser administrado a una dosis de 2 g/Kg por vía oral en ratas. El estudio de irritabilidad dérmica se desarrolló en conejos albinos F1 machos, obteniéndose un índice de irritación primario igual a cero, con el cual se clasifica al producto como no irritante.The propolis extract is a phytomedicine. It is well know that propolis is associated with some pharmacological effects, as antimicrobian, analgesic, antinflammatory, antioxidant and healing actions. According to the normative setted dawn by OECD, toxicological assays are one of the requirements for drug registration, which guarantees the determination of a security margin for the use of the evaluated product. For acute toxicity studies, Sprague Dawley rats of both sexes were used in a limit assay carried out with propolis extract, on the basis of which was set into the unclassified category, when being administrated in one dose of 2 g/kg (p.o) in rats. The dermal irritability assay was carried out in albino rabbits F1. A primary irritation index equal to zero was obtained, which classifies the product as not irritating.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Oral acute toxicity assay of a phytomedicine elaborated with an extract of Musa paradisiaca pseudo-stem

El fitofármaco elaborado a partir del extracto de pseudotallo de Musa paradisiaca es un producto natural que presenta además en su composición miel de abejas (edulcorante) y propóleos (preservante). Entre los requisitos para el registro de medicamentos se encuentran los ensayos toxicológicos, los cuales garantizan un margen de seguridad para el empleo de los productos que son evaluados, según las normativas establecidas por la OECD. Para el estudio de toxicidad aguda oral se emplearon ratas Sprague- Dawley de ambos sexos, realizándose un ensayo límite donde se concluyó que el producto se clasifica en la categoría sin clasificar al ser administrado a una dosis única de 2000 mg/Kg por vía oral en ratas.The phytomedicine elaborated with a Musa paradisiaca pseudostalk extract is a natural product that also contains honeybee (edulcorant) and propolis (preservative). According to the normative setted down by OECD, toxicological assay is one of the requeriments for the drug registration which guarantees a security margin for the use of the evaluated product. For the study of acute oral toxicity, rats Sprague-Dawley of both sexes were used; a limit assay was carried out and the product was classified into unclassified category when being administrated in one dose of 2 g/Kg (p.o.) in rats.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Oral acute toxicity assay of a phytomedicine elaborated with an extract of Musa paradisiaca pseudo-stem

El fitofármaco elaborado a partir del extracto de pseudotallo de Musa paradisiaca es un producto natural que presenta además en su composición miel de abejas (edulcorante) y propóleos (preservante). Entre los requisitos para el registro de medicamentos se encuentran los ensayos toxicológicos, los cuales garantizan un margen de seguridad para el empleo de los productos que son evaluados, según las normativas establecidas por la OECD. Para el estudio de toxicidad aguda oral se emplearon ratas Sprague- Dawley de ambos sexos, realizándose un ensayo límite donde se concluyó que el producto se clasifica en la categoría sin clasificar al ser administrado a una dosis única de 2000 mg/Kg por vía oral en ratas.The phytomedicine elaborated with a Musa paradisiaca pseudostalk extract is a natural product that also contains honeybee (edulcorant) and propolis (preservative). According to the normative setted down by OECD, toxicological assay is one of the requeriments for the drug registration which guarantees a security margin for the use of the evaluated product. For the study of acute oral toxicity, rats Sprague-Dawley of both sexes were used; a limit assay was carried out and the product was classified into unclassified category when being administrated in one dose of 2 g/Kg (p.o.) in rats.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Oral acute toxicity assay of a phytomedicine elaborated with an extract of Musa paradisiaca pseudo-stem

El fitofármaco elaborado a partir del extracto de pseudotallo de Musa paradisiaca es un producto natural que presenta además en su composición miel de abejas (edulcorante) y propóleos (preservante). Entre los requisitos para el registro de medicamentos se encuentran los ensayos toxicológicos, los cuales garantizan un margen de seguridad para el empleo de los productos que son evaluados, según las normativas establecidas por la OECD. Para el estudio de toxicidad aguda oral se emplearon ratas Sprague- Dawley de ambos sexos, realizándose un ensayo límite donde se concluyó que el producto se clasifica en la categoría sin clasificar al ser administrado a una dosis única de 2000 mg/Kg por vía oral en ratas.The phytomedicine elaborated with a Musa paradisiaca pseudostalk extract is a natural product that also contains honeybee (edulcorant) and propolis (preservative). According to the normative setted down by OECD, toxicological assay is one of the requeriments for the drug registration which guarantees a security margin for the use of the evaluated product. For the study of acute oral toxicity, rats Sprague-Dawley of both sexes were used; a limit assay was carried out and the product was classified into unclassified category when being administrated in one dose of 2 g/Kg (p.o.) in rats.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Global Impairment of Immediate-Early Genes Expression in Rett Syndrome Models and Patients Linked to Myelination Defects

Rett syndrome (RTT) is a severe neurodevelopmental disease caused almost exclusively by mutations to the MeCP2 gene. This disease may be regarded as a synaptopathy, with impairments affecting synaptic plasticity, inhibitory and excitatory transmission and network excitability. The complete understanding of the mechanisms behind how the transcription factor MeCP2 so profoundly affects the mammalian brain are yet to be determined. What is known, is that MeCP2 involvement in activity-dependent expression programs is a critical link between this protein and proper neuronal activity, which allows the correct maturation of connections in the brain. By using RNA-sequencing analysis, we found several immediate-early genes (IEGs, key mediators of activity-dependent responses) directly bound by MeCP2 at the chromatin level and upregulated in the hippocampus and prefrontal cortex of the Mecp2-KO mouse. Quantification of the IEGs response to stimulus both in vivo and in vitro detected an aberrant expression pattern in MeCP2-deficient neurons. Furthermore, altered IEGs levels were found in RTT patient’s peripheral blood and brain regions of post-mortem samples, correlating with impaired expression of downstream myelination-related genes. Altogether, these data indicate that proper IEGs expression is crucial for correct synaptic development and that MeCP2 has a key role in the regulation of IEGs