Inter-Rater Variability in the Evaluation of Lung Ultrasound in Videos Acquired from COVID-19 Patients

Lung ultrasound (LUS) allows for the detection of a series of manifestations of COVID-19, such as B-lines and consolidations. The objective of this work was to study the inter-rater reliability (IRR) when detecting signs associated with COVID-19 in the LUS, as well as the performance of the test in a longitudinal or transverse orientation. Thirty-three physicians with advanced experience in LUS independently evaluated ultrasound videos previously acquired using the ULTRACOV system on 20 patients with confirmed COVID-19. For each patient, 24 videos of 3 s were acquired (using 12 positions with the probe in longitudinal and transverse orientations). The physicians had no information about the patients or other previous evaluations. The score assigned to each acquisition followed the convention applied in previous studies. A substantial IRR was found in the cases of normal LUS (kappa = 0.74), with only a fair IRR for the presence of individual B-lines (kappa = 0.36) and for confluent B-lines occupying < 50% (kappa = 0.26) and a moderate IRR in consolidations and B-lines > 50% (kappa = 0.50). No statistically significant differences between the longitudinal and transverse scans were found. The IRR for LUS of COVID-19 patients may benefit from more standardized clinical protocols.

Carbapenemase-Encoding Genes and Colistin Resistance in Gram-Negative Bacteria During the COVID-19 Pandemic in Mexico: Results from the Invifar Network.

In this study, we report the carbapenemase-encoding genes and colistin resistance in Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa in the second year of the COVID-19 pandemic. Clinical isolates included carbapenem-resistant K. pneumoniae, carbapenem-resistant E. coli, carbapenem-resistant A. baumannii, and carbapenem-resistant P. aeruginosa. Carbapenemase-encoding genes were detected by PCR. Carbapenem-resistant K. pneumoniae and carbapenem-resistant E. coli isolates were analyzed using the Rapid Polymyxin NP assay. mcr genes were screened by PCR. Pulsed-field gel electrophoresis and whole-genome sequencing were performed on representative isolates. A total of 80 carbapenem-resistant E. coli, 103 carbapenem-resistant K. pneumoniae, 284 carbapenem-resistant A. baumannii, and 129 carbapenem-resistant P. aeruginosa isolates were recovered. All carbapenem-resistant E. coli and carbapenem-resistant K. pneumoniae isolates were included for further analysis. A selection of carbapenem-resistant A. baumannii and carbapenem-resistant P. aeruginosa strains was further analyzed (86 carbapenem-resistant A. baumannii and 82 carbapenem-resistant P. aeruginosa). Among carbapenem-resistant K. pneumoniae and carbapenem-resistant E. coli isolates, the most frequent gene was blaNDM (86/103 [83.5%] and 72/80 [90%], respectively). For carbapenem-resistant A. baumannii, the most frequently detected gene was blaOXA-40 (52/86, 60.5%), and for carbapenem-resistant P. aeruginosa, was blaVIM (19/82, 23.2%). For carbapenem-resistant A. baumannii, five indistinguishable pulsotypes were detected. Circulation of K. pneumoniae New Delhi metallo-ß-lactamase (NDM) and E. coli NDM was detected in Mexico. High virulence sequence types (STs), such as K. pneumoniae ST307, E. coli ST167, P. aeruginosa ST111, and A. baumannii ST2, were detected. Among K. pneumoniae isolates, 18/101 (17.8%) were positive for the Polymyxin NP test (two, 11.0% positive for the mcr-1 gene, and one, 5.6% with disruption of the mgrB gene). All E. coli isolates were negative for the Polymyxin NP test. In conclusion, K. pneumoniae NDM and E. coli NDM were detected in Mexico, with the circulation of highly virulent STs. These results are relevant in clinical practice to guide antibiotic therapies considering the molecular mechanisms of resistance to carbapenems.

Severe Intractable Headache as a Presentation of COVID-19 in a 23-Year-Old.

Severe acute respiratory syndrome coronavirus type 2 is a novel betacoronavirus with a new genome sequence that causes coronavirus disease 2019 (COVID-19), which primarily affects the lungs, thus causing pneumonia which can progress to severe acute respiratory distress syndrome. New emerging cases of extrapulmonary manifestations of COVID-19 include gastrointestinal, cardiac, renal, and/or central nervous system involvement. Although an ischemic stroke converting to a hemorrhagic stroke is more commonly seen, spontaneous intracranial hemorrhage (ICH) in hospitalized COVID-19 patients is on the rise. This case report describes a 23-year-old female who tested positive (via a polymerase chain reaction test) for COVID-19 and presented with new onset of severe intractable headache. The investigation suggested COVID-19 as the most probable cause of this patients' spontaneous ICH. This case emphasizes the importance of adding COVID-19 to the differential diagnosis of hemorrhagic cerebrovascular accidents in patients with a spontaneous ICH of unclear etiology and, in the process, performing COVID testing.

Advances in the Development of SARS-CoV-2 Mpro Inhibitors.

Since the outbreak of COVID-19, one of the strategies used to search for new drugs has been to find inhibitors of the main protease (Mpro) of the virus SARS-CoV-2. Initially, previously reported inhibitors of related proteases such as the main proteases of SARS-CoV and MERS-CoV were tested. A huge effort was then carried out by the scientific community to design, synthesize and test new small molecules acting as inactivators of SARS-CoV-2 Mpro. From the chemical structure view, these compounds can be classified into two main groups: one corresponds to modified peptides displaying an adequate sequence for high affinity and a reactive warhead; and the second is a diverse group including chemical compounds that do not have a peptide framework. Although a drug including a SARS-CoV-2 main protease inhibitor has already been commercialized, denoting the importance of this field, more compounds have been demonstrated to be promising potent inhibitors as potential antiviral drugs.

Advances in the Developing of SARS-CoV-2 Mpro Inhibitors (preprint)

Since the outbreak of COVID-19, one of the strategies used to search for new drugs has been to find inhibitors of the main protease (Mpro) of virus SARS-CoV-2. Initially, previously reported inhibitors of related proteases like the main proteases of SARS-CoV and MERS-CoV were tested. Then a huge effort has been done by the scientific community to design, synthesize and test new small molecules acting as inactivators of SARS-CoV-2 Mpro. From the structure view, these compounds can be classified into two main groups: one corresponds to modified peptides displaying an adequate sequence for high affinity and a reactive warhead, and the second one is a diverse group including chemical compounds which do not have a peptide framework. Although a drug including a SARS-CoV-2 main protease has already been commercialized, denoting the importance of this field, more compounds have been demonstrated to be promising potent inhibitors as potential antiviral drugs.

How does the beach ecosystem change without tourists during COVID-19 lockdown?

Urban tourist beach ecosystems provide the essential service of recreation. These ecosystems also support critical ecological functions where biodiversity conservation is not usually a priority. The sudden lockdown due to the COVID-19 pandemic created a unique opportunity to evaluate the effects of human absence in these urban-coastal ecosystems. This study examined bioindicators from 29 urban tourist beaches in seven Latin-American countries and assesses their response to lockdown about some relevant anthropogenic stressors such as pollution, noise, human activities, and user density. The presence of animals and plants, as well as the intensity of stressors, were assessed through a standardized protocol during lockdown conditions. Additionally, the environmental conditions of the beaches before and during lockdown were qualitatively compared using multivariate non-parametric statistics. We found notable positive changes in biological components and a clear decrease in human stressors on almost all the beaches. Dune vegetation increased on most sites. Similarly, high burrow densities of ghost crabs were observed on beaches, except those where cleaning activity persisted. Because of the lockdown, there was an exceptionally low frequency of beach users, which in turn reduced litter, noise and unnatural odors. The observed patterns suggest that tourist beaches can be restored to natural settings relatively quickly. We propose several indicators to measure changes in beaches once lockdown is relaxed. Adequate conservation strategies will render the recreational service of tourist beaches more environmental-friendly.

Strengths and Weaknesses of Docking Simulations in the SARS-CoV-2 Era: the Main Protease (Mpro) Case Study.

The scientific community is working against the clock to arrive at therapeutic interventions to treat patients with COVID-19. Among the strategies for drug discovery, virtual screening approaches have the capacity to search potential hits within millions of chemical structures in days, with the appropriate computing infrastructure. In this article, we first analyzed the published research targeting the inhibition of the main protease (Mpro), one of the most studied targets of SARS-CoV-2, by docking-based methods. An alarming finding was the lack of an adequate validation of the docking protocols (i.e., pose prediction and virtual screening accuracy) before applying them in virtual screening campaigns. The performance of the docking protocols was tested at some level in 57.7% of the 168 investigations analyzed. However, we found only three examples of a complete retrospective analysis of the scoring functions to quantify the virtual screening accuracy of the methods. Moreover, only two publications reported some experimental evaluation of the proposed hits until preparing this manuscript. All of these findings led us to carry out a retrospective performance validation of three different docking protocols, through the analysis of their pose prediction and screening accuracy. Surprisingly, we found that even though all tested docking protocols have a good pose prediction, their screening accuracy is quite limited as they fail to correctly rank a test set of compounds. These results highlight the importance of conducting an adequate validation of the docking protocols before carrying out virtual screening campaigns, and to experimentally confirm the predictions made by the models before drawing bold conclusions. Finally, successful structure-based drug discovery investigations published during the redaction of this manuscript allow us to propose the inclusion of target flexibility and consensus scoring as alternatives to improve the accuracy of the methods.

Local Analysis of Air Quality Changes in the Community of Madrid before and during the COVID-19 Induced Lockdown

This paper examines the effect of the COVID-19 induced lockdown upon six pollutants, CO, NO, NO2, PM10, PM2.5, and O3, in the Spanish community of Madrid. The paper relies on clustering methods and multiple regression techniques to control for a battery of potential confounding factors. The results show that the nationwide lockdown, decreed on 13 March by the Spanish government, exerted a statistically significant effect upon most pollution indicators. The estimates range from approximately −82% (NO and NO2) to −3% (CO). Reversely, the COVID-19 induced lockdown raised O3 levels by an average of 20%. By using data from 43 stations spread out among the region, the paper provides a local level analysis. This analysis reveals substantial differences across areas and across pollutants. This observation indicates that any successful approach to improve air quality in the region must be multidimensional.

The fate of SARS-COV-2 in WWTPS points out the sludge line as a suitable spot for detection of COVID-19.

SARS-CoV-2 genetic material is detectable in the faeces of a considerable part of COVID-19 cases and hence, in municipal wastewater. This fact was confirmed early during the spread of the COVID-19 pandemic and prompted several studies that proposed monitoring its incidence by wastewater. This paper studies the fate of SARS-CoV-2 genetic material in wastewater treatment plants using RT-qPCR with a two-fold goal: i) to check its presence in the water effluent and in the produced sludge and ii) based on the understanding of the virus particles fate, to identify the most suitable spots for detecting the incidence of COVID-19 and monitor its evolution. On the grounds of the affinity of enveloped virus towards biosolids, we hypothesized that the sludge line acts as a concentrator of SARS-CoV-2 genetic material. Sampling several spots in primary, secondary and sludge treatment at the Ourense (Spain) WWTP in 5 different days showed that, in effect, most of SARS-CoV-2 particles cannot be detected in the water effluent as they are retained by the sludge line. We identified the sludge thickener as a suitable spot for detecting SARS-CoV-2 particles thanks to its higher solids concentration (more virus particles) and longer residence time (less sensitive to dilution caused by precipitation). These findings could be useful to develop a suitable strategy for early warning of COVID-19 incidence based on WWTP monitoring.

Can drug repurposing strategies be the solution to the COVID-19 crisis?

Introduction: The COVID-19 pandemic resulted in disastrous human and economic costs, mainly due to the initial lack of specific treatments. Complementary to immunotherapies, drug repurposing is possibly the best option to arrive at COVID-19 treatments in the short term.Areas covered: Repurposing prospects undergoing clinical trials or with some level of evidence emerging from clinical studies are overviewed. The authors discuss some possible intellectual property and commercial barriers to drug repurposing, and strategies to facilitate equitable access to incoming therapeutic solutions, highlighting the importance of collaborative drug discovery models. Based on a critical analysis of the available literature about in silico screens against SARS-CoV-2 main protease, the authors illustrate how frequently overconfident conclusions are being drawn in COVID-19-related literature.Expert opinion: Most of the current clinical trials on potential COVID-19 treatments are, in fact, drug repurposing examples. In October 2020, the FDA approved a repurposed antiviral, remdesivir, as the first treatment for COVID-19. Considering the high expectations invested in approaching therapeutic solutions, the scientific community must be careful not to raise unrealistic expectations. Today more than ever, the conclusions drawn in scientific reports have to be fully supported by the level of evidence, avoiding any sort of unfounded speculation.

Development of a hyperimmune equine serum therapy for COVID-19 in Argentina

The disease named COVID-19, caused by the SARS-CoV-2 coronavirus, is currently generating a global pandemic. Vaccine development is no doubt the best long-term immunological approach, but in the current epidemiologic and health emergency there is a need for rapid and effective solutions. Convalescent plasma is the only antibody-based therapy available for COVID-19 patients to date. Equine polyclonal antibodies (EpAbs) put forward a sound alternative. The new generation of processed and purified EpAbs containing highly purified F(ab’)2 fragments demonstrated to be safe and well tolerated. EpAbs are easy to manufacture allowing a fast development and scaling up for a treatment. Based on these ideas, we present a new therapeutic product obtained after immunization of horses with the receptor-binding domain of the viral Spike glycoprotein. Our product shows around 50 times more potency in in vitro seroneutralization assays than the average of convalescent plasma. This result may allow us to test the safety and efficacy of this product in a phase 2/3 clinical trial to be conducted in July 2020 in the metropolitan area of Buenos Aires, Argentina. La enfermedad denominada COVID-19 es causada por el coronavirus SARS-CoV-2 y es actualmente considerada una pandemia a nivel global. El desarrollo de vacunas es sin duda la mejor estrategia a largo plazo, pero debido a la emergencia sanitaria, existe una necesidad urgente de encontrar soluciones rápidas y efectivas para el tratamiento de la enfermedad. Hasta la fecha, el uso de plasma de convalecientes es la única inmunoterapia disponible para pacientes hospitalizados con COVID-19. El uso de anticuerpos policlonales equinos (EpAbs) es otra alternativa terapéutica interesante. La nueva generación de EpAbs incluyen el procesamiento y purificación de los mismos y la obtención de fragmentos F(ab’)2 con alta pureza y un excelente perfil de seguridad en humanos. Los EpAbs son fáciles de producir, lo cual permite el desarrollo rápido y la elaboración a gran escala de un producto terapéutico. En este trabajo mostramos el desarrollo de un suero terapéutico obtenido luego de la inmunización de caballos utilizando el receptor-binding domain de la glicoproteína Spike del virus. Nuestro producto mostró ser alrededor de 50 veces más potente en ensayos de seroneutralización in vitro que el promedio de los plasmas de convalecientes. Estos resultados nos permitirían testear la seguridad y eficacia de nuestro producto en ensayos clínicos de fase 2/3 a realizarse a partir de julio de 2020 en la zona metropolitana de Buenos Aires, Argentina.