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Fibroblast Growth Factors and their receptors (FGFRs) comprise a cell signaling module that can stimulate signaling by Ras and the kinases Raf, MEK, and ERK to regulate animal development and homeostatic functions. In Caenorhabditis elegans, the sole FGFR ortholog EGL-15 acts with the GRB2 ortholog SEM-5 to promote chemoattraction and migration by the sex myoblasts (SMs) and fluid homeostasis by the hypodermis (Hyp7). Cell-specific differences in EGL-15 signaling were suggested by the phenotypes caused by egl-15(n1457), an allele that removes a region of its C-terminal domain (CTD) known to bind SEM-5. To determine how mutations altered EGL-15 activity in the SMs and Hyp7, we used the kinase reporter ERK-KTR to measure activation of the ERK ortholog MPK-1. Consequences of egl-15(n1457) were cell-specific, resulting in loss of MPK-1 activity in the SMs and elevated activity in Hyp7. Previous studies of Hyp7 showed that loss of the CLR-1 phosphatase causes a fluid homeostasis defect termed "Clear" that is suppressed by reduction of EGL-15 signaling, a phenotype termed "Suppressor of Clear" (Soc). To identify mechanisms that permit EGL-15 signaling in Hyp7, we conducted a genetic screen for Soc mutants in the clr-1; egl-15(n1457) genotype. We report the identification of SOC-3, a protein with putative SEM-5-binding motifs and PH and PTB domains similar to DOK and IRS proteins. In combination with the egl-15(n1457) mutation, loss of either soc-3, the GAB1 ortholog soc-1, or the SHP2 ortholog ptp-2, reduced MPK-1 activation. We generated alleles of soc-3 to test the requirement for the SEM-5-binding motifs, finding that residue Tyr356 is required for function. We propose that EGL-15-mediated SM chemoattraction relies solely on the direct interaction between SEM-5 and the EGL-15 CTD. In Hyp7, EGL-15 signaling uses two mechanisms: the direct SEM-5 binding mechanism; and an alternative, CTD-independent mechanism involving SOC-3, SOC-1, and PTP-2. This work demonstrates that FGF signaling uses distinct, tissue-specific mechanisms in development, and identifies SOC-3 as a potential adaptor that facilitates Ras pathway activation by FGFR.
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Chronic hepatitis C virus infection (HCV) causes liver inflammation and fibrosis, leading to the development of severe liver disease, such as cirrhosis or hepatocellular carcinoma (HCC). Approval of direct-acting antiviral drug combinations has revolutionized chronic HCV therapy, with virus eradication in >98% of the treated patients. The efficacy of these treatments is such that it is formally possible for cured patients to carry formerly infected cells that display irreversible transcriptional alterations directly caused by chronic HCV Infection. Combining differential transcriptomes from two different persistent infection models, we observed a major reversion of infection-related transcripts after complete infection elimination. However, a small number of transcripts were abnormally expressed in formerly infected cells. Comparison of the results obtained in proliferating and growth-arrested cell culture models suggest that permanent transcriptional alterations may be established by several mechanisms. Interestingly, some of these alterations were also observed in the liver biopsies of virologically cured patients. Overall, our data suggest a direct and permanent impact of persistent HCV infection on the host cell transcriptome even after virus elimination, possibly contributing to the development of HCC.
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Antivirales , Hepacivirus , Hepatitis C Crónica , Humanos , Antivirales/farmacología , Antivirales/uso terapéutico , Hepacivirus/genética , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Transcriptoma , Infección Persistente/virología , Perfilación de la Expresión Génica , Hígado/virología , Hígado/patología , Carcinoma Hepatocelular/virología , Transcripción Genética/efectos de los fármacosRESUMEN
Mutation of the GABRA1 gene is associated with neurodevelopmental defects and epilepsy. GABRA1 encodes for the α1 subunit of the γ-aminobutyric acid type A receptor (GABAAR), which regulates the fast inhibitory impulses of the nervous system. Multiple model systems have been developed to understand the function of GABRA1, but these models have produced complex and, at times, incongruent data. Thus, additional model systems are required to validate and substantiate previous results. We sought to provide initial phenotypic analysis of a novel germline mutant allele. Our analysis provides a solid foundation for the future use of this allele to characterize gabra1 functionally and pharmacologically using zebrafish. We investigated the behavioral swim patterns associated with a nonsense mutation of the zebrafish gabra1 (sa43718 allele) gene. The sa43718 allele causes a decrease in gabra1 mRNA expression, which is associated with light induced hypermotility, one phenotype previously associated with seizure like behavior in zebrafish. Mutation of gabra1 was accompanied by decreased mRNA expression of gabra2, gabra3, and gabra5, indicating a reduction in the expression of additional α sub-units of the GABAAR. Although multiple sub-units were decreased, larvae continued to respond to pentylenetetrazole (PTZ), indicating that a residual GABAAR exists in the sa43718 allele. Proteomics analysis demonstrated that mutation of gabra1 is associated with abnormal expression of proteins that regulate synaptic vesicle fusion, vesicle transport, synapse development, and mitochondrial protein complexes. These data support previous studies performed in a zebrafish nonsense allele created by CRISPR/Cas9 and validate that loss of function mutations in the gabra1 gene result in seizure-like phenotypes with abnormal development of the GABA synapse. Our results add to the existing body of knowledge as to the function of GABRA1 during development and validate that zebrafish can be used to provide complete functional characterization of the gene.
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Alelos , Receptores de GABA-A , Proteínas de Pez Cebra , Pez Cebra , Animales , Pez Cebra/genética , Pez Cebra/crecimiento & desarrollo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Mutación con Pérdida de Función , Codón sin Sentido/genética , Mutación de Línea Germinal , Fenotipo , Convulsiones/genética , Convulsiones/patologíaRESUMEN
PURPOSE: There is evidence that COVID-19 can have a clinically significant effect on the right ventricle (RV). Our objective was to enhance the efficiency of assessing RV dilation for diagnosing ACP by utilizing both linear measurements and qualitative assessment and its usefulness as an independent predictor of mortality. METHODS: This is an observational, retrospective and single-center study of the Intensive Care Unit of the Sanatorio de Los Arcos in Buenos Aires, Argentina from March 2020 to January 2022. All patients admitted with acute respiratory distress syndrome due to COVID-19 pneumonia (C-ARDS) on mechanical ventilation who were assessed by transthoracic echocardiography (TTE) were included. RESULTS: A total of 114 patients with C-ARDS requiring invasive mechanical ventilation were evaluated by echocardiography. 12.3% had RV dilation defined as a RV basal diameter greater than 41 mm, and 87.7% did not. Acute cor pulmonale (ACP) defined as RV dilation associated with paradoxical septal motion was found in 6.1% of patients. 7% had right ventricular systolic dysfunction according to qualitative evaluation. The different RV echocardiographic variables were studied with a logistic regression model as independent predictors of mortality. In the multivariate analysis, both the RV basal diameter and the presence of ACP showed to be independent predictors of in-hospital mortality with OR of 3.16 (95% CI 1.36-7.32) and 3.64 (95% CI 1.05-12.65) respectively. CONCLUSION: An increase in the RV basal diameter and the presence of ACP measured by TTE are independent predictors of in-hospital mortality in patients with C-ARDS.
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COVID-19 , Enfermedad Cardiopulmonar , Síndrome de Dificultad Respiratoria , Disfunción Ventricular Derecha , Humanos , COVID-19/complicaciones , Estudios Retrospectivos , Ecocardiografía , Enfermedad Cardiopulmonar/complicacionesRESUMEN
PURPOSE: The passive leg raising test (PLR) is a noninvasive method widely adopted to assess fluid responsiveness. We propose to explore if changes in the carotid flow assessed by echo-Doppler can predict fluid responsiveness after a PLR. METHODS: We conducted a performance diagnostic study in two intensive care units from Argentina between February and April 2022. We included patients with signs of tissular hypoperfusion that required fluid resuscitation. We labeled the patients as fluid responders when we measured, after a fluid bolus, an increase greater than 15% in the left ventricle outflow tract (LVOT) VTI in an apical 5-chamber view and we compared those results with the carotid flow (CF) velocity-time integral (VTI) from the left supraclavicular region in a semi-recumbent position and during the PLR. RESULTS: Of the 62 eligible patients, 50 patients (80.6%) were included. The area under the ROC curve for a change in CF VTI during the PLR test was 0.869 (95% CI 0.743-0.947). An increase of at least of 11% in the CF VTI with the PLR predicted fluid-responsiveness with a sensitivity of 77.3% (95% CI 54.6-92.2%) and specificity of 78.6% (95% CI 59-91.7%). The positive predictive value was 73.9% (95% CI 57.4-85.6%) and the negative predictive value was 81.5% (95% CI 66.5-90.7%). The positive likelihood ratio was 3.61 and the negative likelihood ratio was 0.29. CONCLUSION: An increase greater than 11% in CF VTI after a PLR may be useful to predict fluid responsiveness among critically ill patients.
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Unidades de Cuidados Intensivos , Pierna , Humanos , Pierna/diagnóstico por imagen , Curva ROCRESUMEN
Plus-strand RNA viruses are proficient at remodeling host cell membranes for optimal viral genome replication and the production of infectious progeny. These ultrastructural alterations result in the formation of viral membranous organelles and may be observed by different imaging techniques, providing nanometric resolution. Guided by confocal and electron microscopy, this study describes the generation of wide-field volumes using cryogenic soft-X-ray tomography (cryo-SXT) on SARS-CoV-2-infected human lung adenocarcinoma cells. Confocal microscopy showed accumulation of double-stranded RNA (dsRNA) and nucleocapsid (N) protein in compact perinuclear structures, preferentially found around centrosomes at late stages of the infection. Transmission electron microscopy (TEM) showed accumulation of membranous structures in the vicinity of the infected cell nucleus, forming a viral replication organelle containing characteristic double-membrane vesicles and virus-like particles within larger vesicular structures. Cryo-SXT revealed viral replication organelles very similar to those observed by TEM but indicated that the vesicular organelle observed in TEM sections is indeed a vesiculo-tubular network that is enlarged and elongated at late stages of the infection. Overall, our data provide additional insight into the molecular architecture of the SARS-CoV-2 replication organelle.
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COVID-19 , ARN Viral , Humanos , ARN Viral/metabolismo , COVID-19/diagnóstico por imagen , SARS-CoV-2 , Replicación Viral , Núcleo Celular/metabolismo , Tomografía por Rayos X/métodosRESUMEN
Variants in the MMACHC gene cause combined methylmalonic acidemia and homocystinuria cblC type, the most common inborn error of intracellular cobalamin (vitamin B12) metabolism. cblC is associated with neurodevelopmental, hematological, ocular, and biochemical abnormalities. In a subset of patients, mild craniofacial dysmorphia has also been described. Mouse models of Mmachc deletion are embryonic lethal but cause severe craniofacial phenotypes such as facial clefts. MMACHC encodes an enzyme required for cobalamin processing and variants in this gene result in the accumulation of two metabolites: methylmalonic acid (MMA) and homocysteine (HC). Interestingly, other inborn errors of cobalamin metabolism, such as cblX syndrome, are associated with mild facial phenotypes. However, the presence and severity of MMA and HC accumulation in cblX syndrome is not consistent with the presence or absence of facial phenotypes. Thus, the mechanisms by which mutations in MMACHC cause craniofacial defects are yet to be completely elucidated. Here we have characterized the craniofacial phenotypes in a zebrafish model of cblC (hg13) and performed restoration experiments with either a wildtype or a cobalamin binding deficient MMACHC protein. Homozygous mutants did not display gross morphological defects in facial development but did have abnormal chondrocyte nuclear organization and an increase in the average number of neighboring cell contacts, both phenotypes were fully penetrant. Abnormal chondrocyte nuclear organization was not associated with defects in the localization of neural crest specific markers, sox10 (RFP transgene) or barx1. Both nuclear angles and the number of neighboring cell contacts were fully restored by wildtype MMACHC and a cobalamin binding deficient variant of the MMACHC protein. Collectively, these data suggest that mutation of MMACHC causes mild to moderate craniofacial phenotypes that are independent of cobalamin binding.
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Errores Innatos del Metabolismo de los Aminoácidos , Pez Cebra , Animales , Ratones , Pez Cebra/genética , Condrocitos/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/genética , Vitamina B 12/genética , Vitamina B 12/metabolismo , Mutación , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Since the mid-20th century, the so-called Great Acceleration (sensu Steffen et al., 2007, https://doi.org/10.1579/0044-7447(2007)36[614:TAAHNO]2.0.CO;2) has amplified processes of ecosystem degradation, extinction of biological species, displacement of local peoples, losses of languages, and cultural diversity. These losses are still underperceived by the academic community, and by a global society that is disconnected from biocultural diversity. To reconnect society with biocultural diversity, we integrate temporal and spatial dimensions of seasonal cycles, by combining two conceptual frameworks: ecological calendars and the "3Hs" model of the biocultural ethic (sensu Rozzi, 2012, https://doi.org/10.5840/enviroethics20123414). The latter values the vital links between human and other-than-human co-inhabitants, their life habits (e.g., cultural practices of humans or life cycles of other-than-human species), and the structure and processes of their shared habitats. This integration enhances an understanding of links between cultural practices and the life cycles of biocultural keystone species. As a synthesis, we use the term biocultural calendars to emphasize their co-constitutive nature that result from interactions between dynamic biophysical and cultural processes embedded in specific ecosystems and cultures. These calendars link astronomical, biological, and cultural seasonal cycles that sustain life and enhance the integration of Indigenous and scientific knowledge to confront challenges of climate change faced from local to global scales. To illustrate this integration, we examine cultural practices and socio-environmental changes across four contrasting ethnolinguistic communities in southwestern South America, from southern to northern Chile along a marked climatic gradient to show the broad application of the concept of biocultural calendars.
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BACKGROUND: Real-time ultrasound (US)-guided venipuncture has become the standard of care due to its reduced complications and higher success rate. There are various techniques for US-guided cannulation of the internal jugular vein (IJV); the transversal and longitudinal views are the most widely used. There is a less commonly used technique that combines the benefits of both methods. DISCUSSION: Two main techniques for central line US-guided cannulation of the IJV are based on the location of the probe relative to the vessel and are known as the transversal view and the longitudinal view. The transversal view may make it difficult to identify the tip of the needle as it enters the vein, and the longitudinal view may not allow for visualization of surrounding structures. A third and less commonly used technique, the short axis in-plan view, aims to combine the benefits of both previous methods. In this technique, the entire needle can be tracked in real time as it enters the IJV, while also providing visualization of surrounding structures. CONCLUSIONS: The short axis in-plane view technique for central venous line placements allows for real-time US-guided needle venipuncture with simultaneous visualization of surrounding structures.
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Cateterismo Venoso Central , Catéteres Venosos Centrales , Humanos , Venas Yugulares/diagnóstico por imagen , Ultrasonografía Intervencional/métodos , Cateterismo Venoso Central/métodos , UltrasonografíaRESUMEN
Mutations in the HCFC1 transcriptional co-factor protein are the cause of cblX syndrome and X-linked intellectual disability (XLID). cblX is the more severe disorder associated with intractable epilepsy, abnormal cobalamin metabolism, facial dysmorphia, cortical gyral malformations, and intellectual disability. In vitro, murine Hcfc1 regulates neural precursor (NPCs) proliferation and number, which has been validated in zebrafish. However, conditional deletion of mouse Hcfc1 in Nkx2.1 + cells increased cell death, reduced Gfap expression, and reduced numbers of GABAergic neurons. Thus, the role of this gene in brain development is not completely understood. Recently, knock-in of both a cblX (HCFC1) and cblX-like (THAP11) allele were created in mice. Knock-in of the cblX-like allele was associated with increased expression of proteins required for ribosome biogenesis. However, the brain phenotypes were not comprehensively studied due to sub-viability. Therefore, a mechanism underlying increased ribosome biogenesis was not described. We used a missense, a nonsense, and two conditional zebrafish alleles to further elucidate this mechanism during brain development. We observed contrasting phenotypes at the level of Akt/mTor activation, the number of radial glial cells, and the expression of two downstream target genes of HCFC1, asxl1 and ywhab. Despite these divergent phenotypes, each allele studied demonstrates with a high degree of face validity when compared to the phenotypes reported in the literature. Collectively, these data suggest that individual mutations in the HCFC1 protein result in differential mTOR activity which may be associated with contrasting cellular phenotypes.
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Discapacidad Intelectual , Pez Cebra , Animales , Ratones , Codón sin Sentido , Células Ependimogliales/metabolismo , Fenotipo , Proteínas Represoras/genética , Serina-Treonina Quinasas TOR/genética , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Mutation of the GABRA1 gene is associated with neurodevelopmental defects and epilepsy. GABRA1 encodes for the α1 subunit of the gamma-aminobutyric acid type A receptor (GABAAR), which regulates the fast inhibitory impulses of the nervous system. Multiple model systems have previously been developed to understand the function of GABRA1 during development, but these models have produced complex and at times incongruent data. Thus, additional model systems are required to validate and substantiate previously published results. We investigated the behavioral swim patterns associated with a nonsense mutation of the zebrafish gabra1 (sa43718 allele) gene. The sa43718 allele causes a decrease in gabra1 mRNA expression, which is associated with light induced hypermotility, one phenotype associated with seizure like behavior in zebrafish. Mutation of gabra1 was accompanied by decreased mRNA expression of gabra2, gabra3, and gabra5, indicating a reduction in the expression of additional alpha sub-units of the GABAAR. Although multiple sub-units were decreased in total expression, larvae continued to respond to pentylenetetrazole (PTZ) indicating that a residual GABAAR exists in the sa43718 allele. Proteomics analysis demonstrated that nonsense mutation of gabra1 is associated with abnormal expression of proteins that regulate proton transport, ion homeostasis, vesicle transport, and mitochondrial protein complexes. These data support previous studies performed in a zebrafish nonsense allele created by CRISPR/Cas9 and validate that loss of function mutations in the gabra1 gene result in seizure like phenotypes with abnormal function of inhibitory synapses.
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Variants in the MMACHC gene cause combined methylmalonic acidemia and homocystinuria cblC type, the most common inborn error of intracellular cobalamin (vitamin B12) metabolism. cblC is associated with neurodevelopmental, hematological, ocular, and biochemical abnormalities. In a subset of patients, mild craniofacial dysmorphia has also been described. Mouse models of Mmachc deletion are embryonic lethal but cause severe craniofacial phenotypes such as facial clefts. MMACHC encodes an enzyme required for cobalamin processing and variants in this gene result in the accumulation of two metabolites: methylmalonic acid (MMA) and homocysteine (HC). Interestingly, other inborn errors of cobalamin metabolism, such as cblX syndrome, are associated with mild facial phenotypes. However, the presence and severity of MMA and HC accumulation in cblX syndrome is not consistent with the presence or absence of facial phenotypes. Thus, the mechanisms by which mutation of MMACHC cause craniofacial defects have not been completely elucidated. Here we have characterized the craniofacial phenotypes in a zebrafish model of cblC ( hg13 ) and performed restoration experiments with either wildtype or a cobalamin binding deficient MMACHC protein. Homozygous mutants did not display gross morphological defects in facial development, but did have abnormal chondrocyte intercalation, which was fully penetrant. Abnormal chondrocyte intercalation was not associated with defects in the expression/localization of neural crest specific markers, sox10 or barx1 . Most importantly, chondrocyte organization was fully restored by wildtype MMACHC and a cobalamin binding deficient variant of MMACHC protein. Collectively, these data suggest that mutation of MMACHC causes mild to moderate craniofacial phenotypes that are independent of cobalamin binding.
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Traumatic brain injury (TBI) is a worldwide public health concern given its significant morbidity and mortality, years of potential life lost, reduced quality of life and elevated healthcare costs. The primary injury occurs at the moment of impact, but secondary injuries might develop as a result of brain hemodynamic abnormalities, hypoxia, and hypotension. The cerebral edema and hemorrhage of the injured tissues causes a decrease in cerebral perfusion pressure (CPP), which leads to higher risk of cerebral ischemia, herniation and death. In this setting, our role as physicians is to minimize damage by the optimization of the CPP and therefore to reduce mortality and improve neurological outcomes. Performing a transcranial doppler ultrasound (TCD) allows to estimate cerebral blood flow velocities and identify states of low flow and high resistance. We propose to include TCD as an initial assessment and further monitoring tool for resuscitation guidance in patients with severe TBI. We present an Ultrasound-Guided Cardio-cerebral Resuscitation (UGCeR) protocol in Patients with Severe TBI.
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Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Humanos , Lesiones Encefálicas/complicaciones , Calidad de Vida , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/terapia , Ultrasonografía Doppler Transcraneal/métodos , Ultrasonografía Intervencional , Circulación Cerebrovascular , Presión IntracranealRESUMEN
PURPOSE: The velocity time integral (VTI) of the left ventricular outflow tract (LVOT) obtained in the apical view by echocardiography can be regarded as a surrogate for the stroke volume. In critically ill patients it is often difficult to obtain an appropriate apical view to assess the VTI. The subcostal view is more accessible, but while it allows a qualitative assessment of the heart, is not adequate for estimating a reliable LVOT VTI, given the inappropriate angle between the Doppler signal and the flow through the LVOT. We present a new modified subcostal view that allows a proper LVOT VTI measurement. METHODS: This is a single-centre experimental, retrospective, and observational study using data from patients in a tertiary-care centre. We included adult patients admitted to the intensive care unit in the period from June 2020 to January 2022, who were evaluated by echocardiography and whose LVOT VTI was measured aligned with the Doppler signal in both the apical five-chamber view and the modified subcostal view. RESULTS: A total of 30 patients were evaluated in the study period by ultrasonography. The Bland-Altman method analysis of the LVOT VTI measured in the apical view compared with that obtained in the subcostal view showed a bias of 0.8 (95% CI 0.39-1.21) with a 95% limit of agreement between - 1.35 (95% CI - 2.06 to - 0.64) and 2.96 (95% CI 2.25-3.67). The percentage error was calculated to be 23%. The Pearson correlation coefficient for the two forms of measurements showed an R value of 0.98 (95% CI 0.96-0.99). CONCLUSION: The LVOT VTI measured in a modified subcostal view is useful for estimating the value of the LVOT VTI obtained in an apical view.
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Ventrículos Cardíacos , Función Ventricular Izquierda , Adulto , Humanos , Estudios Retrospectivos , Ventrículos Cardíacos/diagnóstico por imagen , Volumen Sistólico , UltrasonografíaRESUMEN
Transthoracic echocardiography (TTE) is a fundamental tool for hemodynamic monitoring in critical patients. It allows evaluating the left ventricle's stroke volume based on the measurement of the velocity-time integral (VTI) of the left ventricle outflow tract (LVOT). However, in the intensive care unit obtaining adequate echocardiographic views may present a challenge. We propose to measure, as a surrogate of the stroke volume, the carotid flow with a novel technique. This is an observational, prospective, and simple blind study, conducted in the intensive care unit of Sanatorio de los Arcos and Hospital Aleman, in Buenos Aires, Argentina. We measured the carotid systodiastolic flow (CSD) VTI and the carotid systolic flow (CS) VTI at the level of the left supraclavicular fossa and we compared it with the LVOT VTI obtained by TTE. We evaluated 43 subjects. Spearman's correlation coefficient between LVOT VTI and CS VTI was 0.81 (95% CI 0.67-0.89) and between LVOT VTI and CSD VTI was 0.89 (95% CI 0.81-0.94). The Bland-Altman method analysis of the 5-chamber apical window LVOT VTI compared to the CSD VTI showed a bias of - 0.2 (95% CI - 0.82 to 0.43), with a concordance interval between - 4.2 (95% CI - 5.2 to - 3.1) and 3.8 cm (95% CI 2.7 to 4.9). The percentage error was 37.9%. Almost 100% of the values fell within the concordance limits, and no trend was observed in bias across the spectrum of mean variables. Although the CSD VTI could not be interchangeable with the LVOT VTI, it could be considered as its surrogate.
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Ecocardiografía , Ventrículos Cardíacos , Humanos , Volumen Sistólico , Estudios Prospectivos , Ventrículos Cardíacos/diagnóstico por imagen , CorazónRESUMEN
Mechanical ventilation in prone position is a strategy that increases oxygenation and reduces mortality in severe ARDS. The hemodynamic and cardiovascular assessment of these patients is essential. Transthoracic echocardiography (TTE) is a widely used tool to assess hemodynamics in critical care, but the prone position is thought to limit adequate TTE views and goal-oriented measurements. The aim of this study is to show the feasibility of the hemodynamic assessment by transthoracic echocardiography during prone position ventilation (PPV). This is a retrospective, observational study, carried out in the intensive care unit (ICU) of a tertiary-care center in Buenos Aires, Argentina. We included all the adult patients admitted to the ICU between March 2020 and August 2021 who had a TTE examination in PPV due to ARDS. During the study period, we evaluated by TTE a total of 35 patients requiring PPV. The vast majority of the patients had COVID-19 pneumonia (91.4%). In 33 out of 35 (94.3%) cases, it was able to achieve an adequate apical four chamber view. We assessed qualitatively the systolic function of left ventricle (LV) and right ventricle (RV) in all of the successfully evaluated patients. We measured the RV basal diameter (94.3%), RV/LV ratio (77.1%), tricuspid annular plane systolic excursion (TAPSE) (91.4%), and septal mitral annular plane systolic excursion (MAPSE) (88.5%) in most of them. Also, we quantified the left ventricle outflow tract velocity time integral (LVOT VTI) in a large part (68.5%) of the examinations. Transthoracic echocardiography is a useful tool for the hemodynamic assessment of patients in prone position under mechanical ventilation.
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COVID-19 , Síndrome de Dificultad Respiratoria , Adulto , Humanos , Estudios Retrospectivos , Posición Prona , Respiración Artificial , Función Ventricular Derecha , Valor Predictivo de las Pruebas , EcocardiografíaRESUMEN
Severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) pose a threat to global public health. The 3C-like main protease (Mpro), which presents structural similarity with the active site domain of enterovirus 3C protease, is one of the best-characterized drug targets of these viruses. Here we studied the antiviral activity of the orally bioavailable enterovirus protease inhibitor AG7404 against SARS-CoV-1 and SARS-CoV-2 from a structural, biochemical, and cellular perspective, comparing it with the related molecule rupintrivir (AG7800). Crystallographic structures of AG7404 in complex with SARS-CoV-1 Mpro and SARS-CoV-2 Mpro and of rupintrivir in complex with SARS-CoV-2 Mpro were solved, revealing that all protein residues interacting with the inhibitors are conserved between the two proteins. A detailed analysis of protein-inhibitor interactions indicates that AG7404 has a better fit to the active site of the target protease than rupintrivir. This observation was further confirmed by biochemical FRET assays showing IC50 values of 47 µM and 101 µM for AG7404 and rupintrivir, respectively, in the case of SARS-CoV-2 Mpro. Equivalent IC50 values for SARS-CoV-1 also revealed greater inhibitory capacity of AG7404, with a value of 29 µM vs. 66 µM for rupintrivir. Finally, the antiviral activity of the two inhibitors against SARS-CoV-2 was confirmed in a human cell culture model of SARS-CoV-2 infection, although rupintrivir showed a higher potency and selectivity index in this assay.
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Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Humanos , Antivirales/química , Cisteína Endopeptidasas/metabolismo , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , Simulación del Acoplamiento MolecularRESUMEN
PURPOSE: The passive leg raising test (PLR) produces a reversible increase in venous return and, if the patient's ventricles are preload dependent, in the cardiac output. As this effect occurs in seconds, the transthoracic echocardiography is optimal for its real time assessment. The utility of the PLR for monitoring fluid responsiveness through the measurement of the left ventricle outflow tract velocity-time integral (LVOT VTI) in an apical 5-chamber view is well stablished. To achieve this view in critically ill patients is often challenging. The aim of this study is to explore the accuracy for predicting fluid responsiveness of the change in the right ventricle outflow tract velocity-time integral (RVOT VTI) from a subcostal view during a PLR. METHODS: This is a diagnostic accuracy study carried out in two centers in Argentina. We included patients admitted to the intensive care unit from January 2022 to April 2022, that required fluid expansion due to signs of tissular hypoperfusion. We measured the RVOT VTI from a subcostal view in a semi-recumbent position and during the PLR, and the LVOT VTI in an apical 5-chamber view before and after a fluid bolus. If the LVOT VTI increased by 15% after the fluid bolus, the patients were considered fluid responders. RESULTS: We included 43 patients. The area under the ROC curve for a change in the RVOT VTI during the PLR was 0.879 (95% CI 0.744-0.959). A change of 15.36% in the RVOT VTI with the PLR predicted fluid responsiveness with a sensitivity of 85.7% (95% CI 57.2%-98.2%) and specificity of 93.1% (95% CI 77.2-99.2). The positive predictive value was 85.7% (95% CI 60.8%-95.9%) and the negative predictive value was 93.1% (95% CI 78.8%-98%). The positive likelihood ratio was 12.43 and the negative predictive value was 0.15. CONCLUSION: The RVOT VTI change during a PLR is suitable for the prediction of fluid responsiveness in critically ill patients.
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Early inhabitants along the hyperarid coastal Atacama Desert in northern Chile developed resilience strategies over 12,000 years, allowing these communities to effectively adapt to this extreme environment, including the impact of giant earthquakes and tsunamis. Here, we provide geoarchaeological evidence revealing a major tsunamigenic earthquake that severely affected prehistoric hunter-gatherer-fisher communities ~3800 years ago, causing an exceptional social disruption reflected in contemporary changes in archaeological sites and triggering resilient strategies along these coasts. Together with tsunami modeling results, we suggest that this event resulted from a ~1000-km-long megathrust rupture along the subduction contact of the Nazca and South American plates, highlighting the possibility of Mw ~9.5 tsunamigenic earthquakes in northern Chile, one of the major seismic gaps of the planet. This emphasizes the necessity to account for long temporal scales to better understand the variability, social effects, and human responses favoring resilience to socionatural disasters.
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PURPOSE: Severe Covid-19 pneumonia frequently presents with infective complications as bacterial and fungal infections, nosocomial maxillary sinusitis is one of them. We describe the role of ultrasonography in the diagnosis of nosocomial maxillary sinusitis in patients undergoing mechanical ventilation due to severe Covid-19 pneumonia. METHODS: Patients with severe pneumonia due to Covid-19 requiring mechanical ventilation and had maxillary sinus occupation by ultrasonography were retrospectively enrolled at intensive care unit of Sanatorio De los Arcos, Buenos Aires, Argentina, between March 2020 and May 2021. RESULTS: We evaluated a total of 171 patients with severe Covid-19 pneumonia requiring mechanical ventilation during the study period. We included 26 patients that had maxillary sinus occupation by ultrasonography (15.2%). Out of the 26 patients, in 17 the diagnosis was confirmed by surgical drainage of the maxillary sinus with positive cultures with a positive predictive value of 85%. In 34.6% of the cases the maxillary sinus disease was unilateral and in 38.4% bilateral. A sinus computed tomography (CT) was performed in 30.7% of the patients. Most of the patients underwent to surgical drainage without a CT scan (66.7%). CONCLUSIONS: Ultrasonography is a useful tool for the detection of maxillary sinus infection in patients with severe Covid-19 pneumonia and avoids to perform a CT scan and, therefore, unnecessary transfers.