Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection

The coronavirus disease 2019 (COVID-19) pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is spread primary via respiratory droplets and infects the lungs. Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines (transformed or cancer cells) and species differences between animals and humans. Organoids are stem cell-derived self-organized three-dimensional culture in vitro and model the physiological conditions of natural organs. Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells (hESCs)-derived lung organoids, including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs. The infected cells were ciliated, club, and alveolar type 2 (AT2) cells, which were sequentially located from the proximal to the distal airway and terminal alveoli, respectively. Additionally, RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes, especially lipid metabolism, in addition to the well-known upregulation of immune response. Further, Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids. Therefore, human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.

Remdesivir para el tratamiento de COVID-19: una revisión sistemática viva / Remdesivir for the treatment of COVID-19: a living systematic review

OBJETIVO: Esta revisión sistemática viva tiene como objetivo entregar un resumen oportuno, riguroso y continuamente actualizado de la evidencia disponible sobre los efectos de remdesivir en pacientes con COVID-19. MÉTODOS: Se buscaron ensayos aleatorios que evaluaran el uso de remdesivir versus placebo o ningún tratamiento en pacientes con COVID-19. Se realizó una búsqueda en la plataforma L·OVE COVID-19 (Living OVerview of Evidence), un sistema que mantiene búsquedas regulares en bases de datos, registros de ensayos, servidores preprint y sitios web relevantes en COVID-19. Todas las búsquedas fueron realizadas hasta el 25 de agosto de 2020. No se aplicaron restricciones de fecha ni de idioma. Dos revisores evaluaron de forma independiente los artículos potencialmente elegibles, de acuerdo con criterios de selección predefinidos, y extrajeron los datos mediante un formulario estandarizado. Los resultados fueron combinados mediante un metanálisis utilizando modelos de efectos aleatorios y evaluamos la certeza de la evidencia utilizando el método GRADE. Una versión viva de esta revisión estará abiertamente disponible durante la pandemia de COVID-19. RESULTADOS: La búsqueda inicial arrojó 574 referencias. Finalmente, identificamos 3 ensayos aleatorios, que evaluaban el uso de remdesivir adicionado al tratamiento estándar versus tratamiento estándar. La evidencia es muy incierta acerca del efecto del remdesivir sobre la mortalidad (RR 0,7; IC del 95%: 0,46 a 1,05; certeza de la evidencia muy baja) y la necesidad de ventilación mecánica invasiva (RR 0,69; IC del 95%: 0,39 a 1,24; certeza de evidencia muy baja). Por otro lado, es probable que el uso de remdesivir produzca un aumento en la incidencia de efectos adversos en pacientes con COVID-19 (RR 1,29; IC del 95%: 0,58 a 2,84; evidencia de certeza moderada). CONCLUSIONES: La evidencia disponible sobre el papel del remdesivir en el tratamiento de pacientes con COVID-19 es insuficiente en relación a los desenlaces críticos para tomar decisiones, por lo que no es posible realizar un correcto balance entre los beneficios potenciales, los efectos adversos y los costos.

OBJECTIVE: Provide a timely, rigorous and continuously updated summary of the evidence on the role of remdesivir in the treatment of patients with COVID-19. METHODS: Eligible studies were randomized trials evaluating the effect of remdesivir versus placebo or no treatment. We conducted searches in the special L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs regular searches in databases, trial registries, preprint servers and websites relevant to COVID-19. All the searches covered the period until 25 August 2020. No date or language restrictions were applied. Two reviewers independently evaluated potentially eligible studies according to predefined selection criteria, and extracted data on study characteristics, methods, outcomes, and risk of bias, using a predesigned, standardized form. We performed meta-analyses using random-effect models and assessed overall certainty in evidence using the GRADE approach. A living, web-based version of this review will be openly available during the COVID-19 pandemic. RESULTS: Our search strategy yielded 574 references. Finally, we included three randomized trials evaluating remdesivir in addition to standard care versus standard care alone. The evidence is very uncertain about the effect of remdesivir on mortality (RR 0.7, 95% CI 0.46 to 1.05; very low certainty evidence) and the need for invasive mechanical ventilation (RR 0.69, 95% CI 0.39 to 1.24; very low certainty evidence). On the other hand, remdesivir likely results in a large increase in the incidence of adverse effects in patients with COVID-19 (RR 1.29, 95% CI 0.58 to 2.84; moderate certainty evidence). CONCLUSIONS: The evidence is insufficient for the outcomes critical for making decisions on the role of remdesivir in the treatment of patients with COVID-19, so it is impossible to balance potential benefits, if there are any, with the adverse effects and costs.

Use of remdesivir for patients with Covid-19: a review article

SUMMARY The etiological agent of COVID-19, which causes severe respiratory diseases such as pneumonia and pulmonary insufficiency, has been confirmed as a new coronavirus, now known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There is currently no authorized medication for the treatment of COVID-19. No vaccines have been authorized. Thus, this study aimed at conducting a review of the use of Remdesivir in patients with COVID-19. The following electronic databases were used MEDLINE, SCIELO, LILACS, and PUBMED. On May 1, Remdesivir received emergency use authorization from the Food and Drug Administration. Remdesivir is currently the most promising molecule in the treatment of COVID-19, taking into account its broad antiviral spectrum (considering the genetic sequences of the virus, it is expected to maintain activity against SARS-CoV-2). There is in vitro and in vivo information available for coronaviruses, as well as an extensive clinical safety database (from a clinical trial of the Ebola virus and in the context of the Monitored Emergency Use of Unregistered and Investigational Interventions - MEURI). Further studies are relevant as available data on the efficacy and safety of Remdesivir against SARS-nCoV-2 are limited.

RESUMO O agente etiológico da COVID-19, que causa doenças respiratórias graves, como pneumonia e insuficiência pulmonar, foi confirmado como um novo coronavírus, agora conhecido como coronavirus de síndrome respiratória aguda grave 2 (SARS-CoV-2). Não existem atualmente medicamentos autorizados para o tratamento de COVID-19, nem estão também autorizadas quaisquer vacinas. Assim, o estudo teve como objetivo realizar uma revisão sobre a utilização de Remdesivir em pacientes com COVID-19. As seguintes bases de dados eletrônicas foram utilizadas MEDLINE, SCIELO, LILACS e PUBMED. Em primeiro de maio, o Redemsivir recebeu autorização de uso de emergência da Food and Drug Administration. Remdesivir é presentemente a molécula promissora no tratamento da COVID-19 tendo em conta o seu largo espetro antiviral (considerando as sequências genéticas do vírus, é expectável que mantenha atividade contra o SARS-CoV-2). A informação in vitro e in vivo está disponível para os coronavírus, assim como a extensiva base de dados de segurança clínica (proveniente de ensaio clínico do vírus Ebola e no contexto do Monitored Emergency Use of Unregistered and Investigational Interventions - MEURI). A realização de novos estudos torna-se relevantes uma vez que os dados disponíveis são limitados sobre eficácia e segurança do Remdesivir contra SARS-nCoV-2.

Tratamiento exitoso con Remdesivir y corticoides en un paciente con neumonía asociada a COVID-19: reporte de un caso / Successful treatment with Remdesivir and corticosteroids in a patient with COVID-19-associated pneumonia: a case report

El síndrome respiratorio agudo grave coronavirus 2 (SARS-CoV-2) se ha diseminado rápidamente a lo largo del mundo causando una mortalidad significativa en pacientes de alto riesgo con manifestaciones severas. A la fecha, Remdesivir ha sido el único antiviral autorizado por la FDA para uso de emergencia. Una de las posibles complicaciones de esta infección es el desarrollo de tormenta de citoquinas, para la cual no existe un tratamiento óptimo. Presentamos el caso de un varón de 48 años sin antecedentes médicos que acudió al hospital con disnea, tos, fiebre subjetiva y diarrea durante 10 días. La reacción de cadena polimerasa nasofaríngea fue positiva para SARS-CoV-2. Su estado respiratorio empeoró rápidamente hasta el punto de requerir oxígeno suplementario a través cánula nasal de alto flujo con 80% de FiO2. La tomografía computarizada de tórax mostró opacidades confluyentes en vidrio esmerilado en los lóbulos superiores, acompañadas de opacidades irregulares alveolares en los lóbulos inferiores bilateralmente. Se inició terapia con hidroxicloroquina, la cual se cambió a Remdesivir cuando estuvo disponible. Luego se inició metilprednisolona como tratamiento de una posible tormenta de citoquinas. La oxigenación del paciente mejoró significativamente en los días posteriores y fue dado de alta sin requerir oxigeno adicional y saturando 96% en medio ambiente. Nuestro caso ilustra el papel de Remdesivir en el tratamiento de la neumonía grave por COVID-19. También observamos un posible beneficio clínico de los corticoides en tormenta de citoquinas. Se necesitan más estudios para evaluar la eficacia de esta estrategia terapéutica.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread throughout the world causing significant mortality in high risk patients with severe manifestations. To date, Remdesivir has been the only antiviral authorized by FDA as therapy for emergency use. One of the potential complications of this infection is cytokine storm, which optimal treatment remains unknown. We present the case of a 48-year-old man with no past medical history who presented to the hospital with dyspnea, cough, subjective fever, and diarrhea for 10 days. Nasopharyngeal PCR was positive for SARS-CoV-2. His respiratory status rapidly worsened to the point of requiring supplemental oxygen by high flow nasal cannula with FiO2 of 80%. Chest computed tomography showed confluent ground glass opacities in upper lobes accompanied by patchy airspace opacities in lower lobes bilaterally. He was started on hydroxychloroquine, which was switched to Remdesivir when it became available. Then, methylprednisolone was initiated for suspected cytokine storm. The patient's oxygenation improved significantly over the following days and he was discharged home with no oxygen supplementation and saturating 96% on room air. Our case illustrates the role of Remdesivir for the treatment of severe COVID-19 pneumonia. We also observed a possible clinical benefit of corticosteroids in the context of suspected cytokine storm. Further studies are needed to evaluate this therapeutic strategy.

P2Y12 inhibitors in acute coronary syndromes: Which and when.

Acute coronary syndromes (ACS) are the commonest acute manifestation of coronary artery disease and a major cause of hospitalization and death. Plaque rupture and subsequent platelet activation are the key factors in its pathogenesis. Platelet inhibitors are crucial in the management of ACS. Aspirin remains the standard antiplatelet but use of dual antiplatelet drugs is beneficial in ACS. Platelet P2Y12 receptor inhibitors are an important group of antiplatelet compounds that can be combined with aspirin in the management of ACS. P2Y12 inhibitors may belong to the thienopyridine or nonthienopyridine group of compounds. The former (clopidogrel, prasugrel) combine irreversibly with the receptor and therefore have a prolonged duration of action. On the other hand, the non-thienopyridine compounds (ticagrelor, elinogrel) have a reversible action and hence a shorter duration of action. Several new compounds in this group have become or are likely to become available. The newer agents have a more uniform and complete antiplatelet effect and are much less likely to be affected by genetic variability of CYP2C19 enzyme activity compared with that of clopidogrel. Large phase 3 trials have shown that ticagrelor and prasugrel reduce major cardiovascular events in ACS compared to clopidogrel when given in addition to aspirin. This is accompanied by some increase in bleeding. This review discusses the properties, clinical profile and possible place of P2Y12 receptor inhibitors in clinical practice.

Osteoporosis: estudio de un tratamiento homeopático / Osteoporosis: study of an homeopathic treatment

Se plantea investigar la eficacia de un tratamiento homeopático para la osteoporosis. Para ello se somete a una población de mujeres postmenopáusicas a un estudio prospectivo de un año de duración, en base a un protocolo de tratamiento. El incremento óseo se evalúa a través de controles densitométricos y subjetivos. Los resultados objetivos corroboran la eficacia del tratamiento propuesto en un grado que podría ser comparable a los mejores tratamientos alopáticos, aunque la respuesta no es uniforme

Demostración del papel de la estimulación de receptores purinérgicos en el efecto electrofisiológico de los compuestos adenilicos en el hombre / The electrophysiological actions of ampare medrate through purinergic receptor stimulation

Para estudiar el mecanismos de acción del AMP en el nodo A-V, se estudiaron 10 pacientes con taquicardia supraventricular por re-entrada (TVS) que incluía el nodo AV en su circuito.. El promedio de edad fue 32.8 + ou - 11.1 años. La taquicardia se indujo por estimulación auricular programada y se realizaron registros electrofisiológicos intracavitarios en todos los casos. En la primera etapa la administración de AMP suprimió la arrtmia en todos los casos en un tiempo promedio de 15.2 + ou - 2.6 seg., con una dosis de 0.095 + ou - 0.037mg/kg. En la segunda etapa la administración de atropina (0.04mg/kg.) no impidió la supresión de la arritmia. La dosis de AMP fue 0.122 + ou - 0.045mg/kg (P3NDS) y el tiempo promedio 16.2 + ou - 2.2 (p=NDS). En la tercera etapa: la administración de AMP no interrumpió la arritmia inducida bajo el efecto de atropina y aminofilina (4mg/kg) en 8 de los pacientes. En uno de los restantes la dosis necesarias fue 0.250mg/kg., y en el otro fue 0.075mg/kg. No hubo efectos colaterales graves. Se demuestra que la acción del AMP está mediada por estimulación agonista de receptores purinérgicos en el nodo AV