Electrical bioimpedance analysis and comparison in biological tissues through crystalloid solutions implementation.

Electrical bioimpedance is a non-invasive and radiation-free technique that was proposed to be used in different clinical areas, however, its practical use is limited due to its low capacity to discriminate between tissues. In order to overcome this limitation, our research group proposes to incorporate the contrast media into the electrical bioimpedance procedure. The main objective of the present study was to assess the crystalloid solutions as a possible contrast media to discriminate between different tissue types in the bioimpedance technique. Two medical-grade crystalloid solutions (Hartmann and NaCl 0.9%) were injected into three biological ex vivo models: kidney, liver, and brain. BIOPAC system was used to acquire bioimpedance data before and after the injections. The data was adjusted to the Debye electrical model. The analysis of measured values showed substantial bioimpedance disparities in tissues subjected to isotonic solutions. The NaCl solution exhibited more pronounced changes in electrical parameters compared to the Hartmann solution. Similarly, NaCl solution displayed superior discriminatory capabilities among tissues, with variations of 465%, 157%, and 206%. Distinct spectral modifications were identified, with tissues demonstrating unique responses at each frequency of analysis relative to untreated tissue. Variations in bandwidth alterations were discernible among tissues, providing clear distinctions. In conclusion, the research showed that the crystalloid solution exhibited greater sensitivity and superior tissue contrast at specific frequencies. This study's findings underscore the feasibility of implementing crystalloid solutions to enhance tissue discrimination, similar to the effects of contrast agents.

Interhospital Spread of blaVIM-1- and blaCTX-M-15-Producing K. pneumoniae ST15 on an IncR Plasmid in Southern Spain.

In 2014-2015, the main CTX-M-15- and OXA-48-producing clone in our region was ST15. Recently, K. pneumoniae ST15 isolates co-producing VIM-1 and CTX-M-15 were detected in several hospitals. The aim was to study the emergence and acquisition of this carbapenemase. Between 2017 and 2019, four hospitals submitted twenty-nine VIM-1- and CTX-M-15-producing K. pneumoniae ST15 isolates to our laboratory. Seven representatives of each XbaI PFGE pulsotype were sequenced using short- and long-read technologies. RAST, CGE databases, and Pathogenwatch were used for resistance determinants and capsule-type analysis. Plasmid comparison was performed with Easyfig2.1. Phylogenetic analysis included other contemporary ST15 isolates from Spain. The 29 isolates were clustered into seven different pulsotypes. The selected genomes, from three hospitals in two different provinces, were clustered together (fewer than 35 alleles) and differed by more than 100 alleles from other ST15 isolates obtained in the region. These seven isolates harbored one IncR plasmid (200-220 kb) with a common backbone and four regions flanked by IS26: one contained blaVIM-1, another contained blaCTX-M-15, the third contained blaOXA-1, and the fourth harbored heavy-metal-tolerance genes. The two initial plasmids, from two different centers, were identical, and rearrangement of four regions was observed in the five subsequent plasmids. Our findings showed the first intercenter dissemination of IncR plasmids carrying blaVIM-1, blaCTX-M-15, and metal-tolerance genes mediated by a new lineage of K. pneumoniae ST15. Two different capture events of the blaVIM-1 gene or different IS26-mediated plasmid rearrangements from a common ancestor may explain plasmid variations.

The CARBA-MAP study: national mapping of carbapenemases in Spain (2014-2018).

Introduction: Infections caused by carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa, including isolates producing acquired carbapenemases, constitute a prevalent health problem worldwide. The primary objective of this study was to determine the distribution of the different carbapenemases among carbapenemase-producing Enterobacterales (CPE, specifically Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae complex, and Klebsiella aerogenes) and carbapenemase-producing P. aeruginosa (CPPA) in Spain from January 2014 to December 2018. Methods: A national, retrospective, cross-sectional multicenter study was performed. The study included the first isolate per patient and year obtained from clinical samples and obtained for diagnosis of infection in hospitalized patients. A structured questionnaire was completed by the participating centers using the REDCap platform, and results were analyzed using IBM SPSS Statistics 29.0.0. Results: A total of 2,704 carbapenemase-producing microorganisms were included, for which the type of carbapenemase was determined in 2692 cases: 2280 CPE (84.7%) and 412 CPPA (15.3%), most often using molecular methods and immunochromatographic assays. Globally, the most frequent types of carbapenemase in Enterobacterales and P. aeruginosa were OXA-48-like, alone or in combination with other enzymes (1,523 cases, 66.8%) and VIM (365 cases, 88.6%), respectively. Among Enterobacterales, carbapenemase-producing K. pneumoniae was reported in 1821 cases (79.9%), followed by E. cloacae complex in 334 cases (14.6%). In Enterobacterales, KPC is mainly present in the South and South-East regions of Spain and OXA-48-like in the rest of the country. Regarding P. aeruginosa, VIM is widely distributed all over the country. Globally, an increasing percentage of OXA-48-like enzymes was observed from 2014 to 2017. KPC enzymes were more frequent in 2017-2018 compared to 2014-2016. Discussion: Data from this study help to understand the situation and evolution of the main species of CPE and CPPA in Spain, with practical implications for control and optimal treatment of infections caused by these multi-drug resistant organisms.

Anticancer Potential of Flavonoids: An Overview with an Emphasis on Tangeretin.

Natural compounds with pharmacological activity, flavonoids have been the subject of an exponential increase in studies in the field of scientific research focused on therapeutic purposes due to their bioactive properties, such as antioxidant, anti-inflammatory, anti-aging, antibacterial, antiviral, neuroprotective, radioprotective, and antitumor activities. The biological potential of flavonoids, added to their bioavailability, cost-effectiveness, and minimal side effects, direct them as promising cytotoxic anticancer compounds in the optimization of therapies and the search for new drugs in the treatment of cancer, since some extensively antineoplastic therapeutic approaches have become less effective due to tumor resistance to drugs commonly used in chemotherapy. In this review, we emphasize the antitumor properties of tangeretin, a flavonoid found in citrus fruits that has shown activity against some hallmarks of cancer in several types of cancerous cell lines, such as antiproliferative, apoptotic, anti-inflammatory, anti-metastatic, anti-angiogenic, antioxidant, regulatory expression of tumor-suppressor genes, and epigenetic modulation.

Long-lasting effect of belantamab mafodotin in heavily pretreated multiple myeloma.

Belantamab mafodotin (BLMF) is an interesting therapeutic alternative for multiple myeloma (MM) patients pretreated with immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. Scientific evidence on BLMF provides immature data about progression-free survival and overall survival by short follow-up of patients with poor prognoses. Cases with long follow-ups could provide additional information about BLMF. This case reports a patient with MM treated with BLMF who had received nine previous lines of therapy with a follow-up of 11 months. No complete response was obtained. However, no disease progression was observed and the patient was still alive at the end of this work. BLMF showed manageable adverse effects. Our patient presented advanced disease, good functional status at the beginning of BLMF treatment, and elevated levels of lactate dehydrogenase during BLMF therapy. The influence of these last two factors was not evaluated in clinical trials. This relationship should be assessed more deeply in future studies.

Electrical Impedance Tomography to Measure Spirometry Parameters in Chronic Obstructive Pulmonary Disease Patients / Tomografía por Impedancia Eléctrica para Medir Parámetros de Espirometría en Pacientes con Enfermedad Pulmonar Obstructiva Crónica

ABSTRACT Spirometry is a test for the diagnosis of chronic obstructive pulmonary disease. It is a technique that can be intolerant due to the essential use of a mouthpiece and a clamp. This study proposes the use of electrical impedance tomogra phy to measure respiratory parameters. Patients underwent spirometry and three respiratory exercises. The imped ance signals were convolved, and the resultant was analyzed by fast Fourier transform. The frequency spectrum was divided into seven segments (R1 to R7). Each segment was represented in terms of quartiles (Q25%, Q50%, Q75%). Each quartile of each segment was correlated with the spirometric parameters to obtain a fitting equation. FVC was correlated 70% with the 3 quartiles of R7, 3 equations were obtained with a fit of 60%. FEV1 correlated 70% with the Q50% of R7, obtaining an equation with a fit of 40%. FEV1/FVC correlated 69% with Q75% of R2, obtaining an equation with a fit of 60%. Spirometric parameters can be estimated from the implied carrier frequency components of the ventilatory impedance signal.

RESUMEN La espirometría es una prueba para el diagnóstico de enfermedad pulmonar obstructiva crónica. Es una técnica que puede resultar intolerante debido al uso imprescindible de una boquilla y una de pinza. Este estudio propone el uso de la tomografía de impedancia eléctrica para medir los parámetros respiratorios. Los pacientes realizaron una espi rometría y tres ejercicios respiratorios. Las señales de impedancia fueron convolucionadas, y la resultante se analizó mediante una transformada rápida de Fourier. El espectro en frecuencias se dividió en siete segmentos (R1 a R7). Cada segmento se representó en términos de cuartiles (Q25%, Q50%, Q75%). Cada cuartil de cada segmento se co rrelacionó con los parámetros espirométricos para obtener una ecuación de ajuste. La FVC se correlacionó en un 70% con los 3 cuartiles de R7, se obtuvieron 3 ecuaciones con un ajuste del 60%. El FEV1 se correlacionó en un 70% con el Q50% de R7, obteniéndose una ecuación con un ajuste del 40%. El FEV1/FVC se correlacionó en un 69% con el Q75% de R2, obteniéndose una ecuación con un ajuste del 60%. Los parámetros espirométricos pueden ser estimados a partir de los componentes de frecuencia portadora implícitos de la señal de impedancia ventilatoria.

"K-Powder" Exposure during Adolescence Elicits Psychiatric Disturbances Associated with Oxidative Stress in Female Rats.

Ketamine, also called 'K-powder' by abusers, an analog of phencyclidine, primarily acts as an antagonist of N-methyl-D-aspartic acid (NMDA) receptors, therapeutically used as an anesthetic agent. Ketamine also stimulates the limbic system, inducing hallucinations and dissociative effects. At sub-anesthetic doses, ketamine also displays hallucinatory and dissociative properties, but not loss of consciousness. These behavioral consequences have elicited its recreational use worldwide, mainly at rave parties. Ketamine is generally a drug of choice among teenagers and young adults; however, the harmful consequences of its recreational use on adolescent central nervous systems are poorly explored. Thus, the aim of the present study was to characterize the behavioral and biochemical consequences induced by one binge-like cycle of ketamine during the early withdrawal period in adolescent female rats. Adolescent female Wistar rats (n = 20) received intraperitoneally administered ketamine (10 mg/kg/day) for 3 consecutive days. Twenty-four hours after the last administration of ketamine, animals were submitted to behavioral tests in an open field, elevated plus-maze, and forced swimming test. Then, animals were intranasally anesthetized with 2% isoflurane and euthanized to collect prefrontal cortex and hippocampus to assess lipid peroxidation, antioxidant capacity against peroxyl radicals, reactive oxygen species, reduced glutathione, and brain-derived neurotrophic factor (BDNF) levels. Our results found that 24 h after recreational ketamine use, emotional behavior disabilities, such as anxiety- and depression-like profiles, were detected. In addition, spontaneous ambulation was reduced. These negative behavioral phenotypes were associated with evidence of oxidative stress on the prefrontal cortex and hippocampus.

Detrusor pressure monitoring by electrical bioimpedance in the neurogenic bladder of adult patients.

PURPOSE: Detrusor pressure-volume relationship evaluation by urodynamics provides useful clinical information; however, it is invasive, and requires specific installations. An alternative technique proposed by our research group is the electrical bioimpedance (BI) which is an easily performed and non-invasive method. In this work, we assess the relationship between BI and detrusor bladder pressure in adults with neurogenic lower urinary tract dysfunction. METHODS: A prospective observational study was conducted. 20 patients (11 females and 9 male) previously diagnosed with neurogenic bladder were included. All participants underwent simultaneously a urodynamic evaluation (UDS) and BI determination, and both examination signals were recorded and subjected to Shapiro-Wilks statistical test. A correlational statistical test was used to compare the pressure parameters (detrusor, vesical and abdominal) with their respective BI determinations. Subsequently, a linear regression test was performed to evaluate the concordance between BI and their respective pressure values. RESULTS: From the 20 correlations, between detrusor bladder pressure (PDET) and abdominal bioimpedance determinations (ZABD), obtained for all participants, 16 evidenced significant results over 90% (p < 0.05). CONCLUSIONS: A significantly high correlation between abdominal bioimpedance determinations and the detrusor bladder pressures was evidenced. These results should be confirmed in a larger group of participants.

Comparación entre cinco técnicas de PCR para el diagnóstico del SARS-CoV-2 / Comparison between five PCR techniques for the diagnosis of SARS-CoV-2

Introducción. Desde que aparecieron los primeros casosde SARS-CoV-2 son numerosas las técnicas que se han desarrollado para el diagnóstico o seguimiento de la infección,tanto técnicas directas como serológicas. La elección de unabuena herramienta diagnóstica es fundamental para el controlepidemiológico. El objetivo ha sido comparar cinco técnicascomercializadas de RT-PCR a tiempo real, en sensibilidad, especificidad y concordancia para la detección del SARS-CoV-2.Material y métodos. Se compararon cinco kits comerciales de RT-PCR para la detección del SARS-CoV-2. Se tomaronocho muestras positivas conocidas que se sometieron a sietediluciones o concentraciones diferentes y otras 135 muestrasnegativas para determinar valores de sensibilidad, especificidad y concordancia.Resultados. La sensibilidad, especificidad, valor predictivopositivo (VPP) y valor predictivo negativo (VPN) para las técnicas de Palex, Roche y GeneXpert respecto a Seegene fueronidénticas, correspondientes a 98,21%, 100%, 100% y 99,26%respectivamente. Para Becton Dickinson la sensibilidad fue del89,28%, la especificidad del 100%, el VPP del 100% y el VPNdel 95,74%. La concordancia mediante el índice Kappa paraPalex, Roche y GeneXpert fue del 0,9892, mientras que la concordancia para Becton Dickinson fue con un índice Kappa de0,9215.Conclusión. Todos los kits de RT-PCR comerciales presentaron elevadas sensibilidades y especificidades, así como VPP,VPN y concordancia. (AU)

Introduction. Since the first cases of SARS-CoV-2appeared, there have been numerous techniques that havebeen developed for the diagnosis or monitoring of infection, both direct and serological techniques. Choosing agood diagnostic tool is essential for epidemiological control. The objective was to compare five commercializedRT-PCR techniques in real time, in sensitivity, specificityand agreement for the detection of SARS-CoV-2.Material and methods. Five commercial RT-PCR kitsfor the detection of SARS-CoV-2 were compared. Eightknown positive samples were taken and subjected to seven different dilutions or concentrations, and another 135negative samples were used to determine sensitivity, specificity, and agreement values.Results. The sensitivity, specificity, positive predictivevalue (PPV) and negative predictive value (NPV) for thePalex, Roche and GeneXpert techniques with respect toSeegene were identical, corresponding to 98.21%, 100%,100% and 99.26% respectively. For Becton Dickinson thesensitivity was 89.28%, the specificity of 100%, the PPVof 100% and the NPV of 95.74%. The agreement using theKappa index for Palex, Roche and GeneXpert was 0.9892,while the agreement for Becton Dickinson was with aKappa index of 0.9215.Conclusion. All commercial RT-PCR kits had highsensitivities and specificities, as well as PPV, NPV, andconcordance. (AU)

HLA in Las Alpujarras Mts., South-East Spain: A Renaissance process of population artificial substitution.

Spain was invaded in 711 CE by mostly Berber North Africans carrying Muslim religion to a mostly Christian/Catholic Kingdom. A fight to expel Muslims soon started and were apparently driven out of Iberia (Spain) starting in 1492 CE. However, many of these expelled people were of Iberian old ancestry that had become Muslims at Las Alpujarras Mts. (South-East Spain). Also, Muslim North Africans converted to Christianity either remained there or came back after they more definetively were expelled by 1609 CE. Las Alpujarras region was also repopulated by northern Spaniards mostly from Galicia. Our HLA study of present day Alpujarrans shows that typical North Spain and European Atlantic façade HLA extended haplotypes are very frequent in nowadays Las Alpujarras region, i. e.: HLA-(A*29-B*44)-DRB1*07:01-DQA1*02:01-DQB1*02:01 and (A*02-B*27)-DRB1*15:01-DQA1*01:02-DQB1*06:02. It is concluded that repopulation had a noticeable success even in today Alpujarran population.

Enhancement of the catalytic activity of Mg/Al layered double hydroxide for glycerol oligomers production.

In this study, the impact of rehydration on the catalytic properties of Mg/Al layered double hydroxides (LDH) for glycerol oligomerization was assesed. Although previous works have employed other LDH derived materials in this reaction, little information on recyclability is published. After observing the initial results on how basicity and surface area were related to the catalytic activty, an LDH modification strategy was developed with the addition of acetic acid. Changes on the basic site distribution were noticed and consequently, selectivity to diglycerol was improved. The best catalytic performance (reaction with 4 wt% cat., at 240 °C for 8 hours) led to 64% of glycerol conversion (XGly) and 37% of diglycerol selectivity (Sdi). Aditionally, reciclying of modified LDH was better than the non acid treated material, presenting higher yield of diglycerol. Catalyst deactivation was related to the harsh reaction conditions and to the blockage of active species by impurities. Loss of metallic species by leaching to the reaction products was not oberseved, an advantage in comparison with previous works.

Scheduling deferrable electric appliances in smart homes: a bi-objective stochastic optimization approach.

In the last decades, cities have increased the number of activities and services that depends on an efficient and reliable electricity service. In particular, households have had a sustained increase of electricity consumption to perform many residential activities. Thus, providing efficient methods to enhance the decision making processes in demand-side management is crucial for achieving a more sustainable usage of the available resources. In this line of work, this article presents an optimization model to schedule deferrable appliances in households, which simultaneously optimize two conflicting objectives: the minimization of the cost of electricity bill and the maximization of users satisfaction with the consumed energy. Since users satisfaction is based on human preferences, it is subjected to a great variability and, thus, stochastic resolution methods have to be applied to solve the proposed model. In turn, a maximum allowable power consumption value is included as constraint, to account for the maximum power contracted for each household or building. Two different algorithms are proposed: a simulation-optimization approach and a greedy heuristic. Both methods are evaluated over problem instances based on real-world data, accounting for different household types. The obtained results show the competitiveness of the proposed approach, which are able to compute different compromising solutions accounting for the trade-off between these two conflicting optimization criteria in reasonable computing times. The simulation-optimization obtains better solutions, outperforming and dominating the greedy heuristic in all considered scenarios.

Dinâmica comparada: fluxos dos escravizados africanos em São Paulo, Minas Gerais e Maranhão (1804-1848) / Comparative dynamics: flows of enslaved Africans in São Paulo, Minas Gerais and Maranhão (1804-1848) / Dinámica comparada: flujos de africanos esclavizados en São Paulo, Minas Gerais y Maranhão (1804-1848)

Analisamos comparativamente informes demográficos de qualidade aceitável acerca dos escravizados nascidos na África para Minas Gerais, São Paulo e Maranhão de 1804 a 1848. As parcelas dos nascidos na África em relação aos escravizados e às razões de sexo de todos os cativos, de acordo com as idades, auxiliaram-nos a remontar a dinâmica retrospectiva da chegada dos africanos às regiões. Supondo certas hipóteses e procedimentos, a partir das coortes etárias, estimamos as proporções de africanos e as razões de sexo da população cativa para os períodos anteriores aos das listas nominativas de habitantes. A dinâmica retrospectiva da introdução de africanos reconstruída mostrou-se bastante correlacionada à história econômica das diferentes regiões estudadas.

We compare the surviving enslaved people present in demographic censuses of acceptable quality for Minas Gerais, São Paulo and Maranhão from 1804 to 1848. The share of those born in Africa in relation to slaves and the sex ratio of all captives according to their ages helped us find the retrospective dynamics of the arrival of Africans to these regions. When using age cohorts, we estimate, assuming certain hypotheses and procedures, the proportions of Africans and the sex ratios of the captive population for periods prior to those of the nominative lists of inhabitants. The retrospective dynamics of the reconstructed introduction of these Africans proved to be closely correlated with the economic history of the different regions analyzed.

Analizamos comparativamente a los sobrevivientes esclavizados presentes en los informes demográficos evaluados como de calidad aceptable para Minas Gerais, São Paulo y Maranhão entre 1804 y 1848. La proporción de los nacidos en África en relación con los esclavizados y la proporción de sexos de todos los cautivos, según las edades, nos ayudaron a trazar la dinámica retrospectiva de la llegada de africanos a estas regiones. Utilizando las cohortes de edad, estimamos, asumiendo ciertas hipótesis y procedimientos, las proporciones de africanos y las proporciones de sexos de la población cautiva para períodos anteriores a las listas nominativas de habitantes. La dinámica retrospectiva de la introducción reconstruida de africanos demostró estar altamente correlacionada con la historia económica de las diferentes regiones estudiadas.

Traumatic rupture of diaphragm with splenic herniation. An unusual cause of hemothorax.

The traumatic diaphragmatic hernia is considered a rare clinic condition and represents a diagnostic challenge. Its presentation is mainly a surgical emergency, leading to scarce time for complementary image studies. We present a case of a 21-year-old male who suffered a penetrating wound in the left hemitorax from whom is suspected to have a traumatic visceral herniation into the thoracic cavity by chest X-ray, confirming a splenic herniation with intrathoracic hemorrhage, as well as the proposal of a management algorithm for this defiant cases.

La hernia diafragmática traumática es poco frecuente en la clínica y representa un reto diagnóstico, ya que su aparición es principalmente de emergencia y esto propicia poco tiempo para la realización de estudios de imagen complementarios. Presentamos el caso de un varón de 21 años que sufrió una herida penetrante en el hemitórax izquierdo con sospecha de herniación traumática diafragmática de vísceras abdominales al tórax por radiografía, y en el quirófano se confirmó una herniación esplénica con hemorragia intratorácica. Se propone un algoritmo de manejo en estos casos tan desafiantes.

Synthesis and experimental/computational characterization of sorghum procyanidins-gelatin nanoparticles.

In this research, sorghum procyanidins (PCs) and procyanidin B1 (PB1) were encapsulated in gelatin (Gel) to form nanoparticles as a strategy to maintain their stability and bioactivity and for possible applications as inhibitors of metalloproteinases (MMPs) of the gelatinase type. Encapsulation was carried out by adding either PCs or PB1 to an aqueous solution of A- or B-type Gel (GelA or GelB) at different concentrations and pH. Under this procedure, the nanoparticles PCs-GelA, PCs-GelB, PB1-GelA, and PB1-GelB were synthesized and subsequently characterized by experimental and computational methods. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed that all types of nanoparticles had sizes in the range of 22-138 nm and tended to adopt an approximately spherical morphology with a smooth surface, and they were immersed in a Gel matrix. Spectral analysis indicated that the nanoparticles were synthesized by establishing hydrogen bonds and hydrophobic interactions betweenGel and the PCs or PB1. Study of simulated gastrointestinal digestion suggested that PCs were not released from the Gel nanoparticles, and they maintained their morphology (SEM analysis) and antioxidant activity determined by Trolox-equivalent antioxidant capacity (TEAC) assay. Computational characterization carried out through molecular docking studies of PB1 with Gel or (pro-)metalloproteinase-2 [(pro-)MMP-2], as a model representative of the PCs, showed very favorable binding energies (around -5.0 kcal/mol) provided by hydrogen bonds, van der Waals interactions, and desolvation. Additionally, it was found that PB1 could act as a selective inhibitor of (pro-)MMP-2.

Antibody response in patients admitted to the hospital with suspected SARS-CoV-2 infection: results from a multicenter study across Spain.

AIM: To evaluate the serological response against SARS-CoV-2 in a multicenter study representative of the Spanish COVID pandemic. METHODS: IgG and IgM + IgA responses were measured on 1466 samples from 1236 Spanish COVID-19 patients admitted to the hospital, two commercial ELISA kits (Vircell SL, Spain) based on the detection of antibodies against the viral spike protein and nucleoprotein, were used. RESULTS: Approximately half of the patients presented antibodies (56.8% were IgM + IgA positive and 43.0% were IgG positive) as soon as 2 days after the first positive PCR result. Serological test positivity increased with time from the PCR test, and 10 days after the first PCR result, 91.5% and 88.0% of the patients presented IgM + IgA and IgG antibodies, respectively. CONCLUSION: The high values of sensitivity attained in the present study from a relatively early period of time after hospitalization support the use of the evaluated serological assays as supplementary diagnostic tests for the clinical management of COVID-19.