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1.
Can J Rural Med ; 29(2): 71-79, 2024 Apr 01.
Artigo em Inglês, Francês | MEDLINE | ID: mdl-38709017

RESUMO

INTRODUCTION: The COVID-19 pandemic presented an unprecedented challenge for rural family physicians. The lessons learned over the course of 2 years have potential to help guide responses to future ecosystem disruption. This qualitative study aims to explore the leadership experiences of rural Canadian family physicians during the COVID-19 pandemic as both local care providers and community health leaders and to identify potential supports and barriers to physician leadership. METHODS: Semi-structured, virtual, qualitative interviews were completed with participants from rural communities in Canada from December 2021 to February 2022 inclusive. Participant recruitment involved identifying seed contacts and conducting snowball sampling. Participants were asked about their experiences during the COVID-19 pandemic, including the role of physician leadership in building community resilience. Data collection was completed on theoretical saturation. Data were thematically analysed using NVivo 12. RESULTS: Sixty-four participants took part from 22 rural communities in 4 provinces. Four key factors were identified that supported physician leadership towards rural resilience during ecosystem disruption: (1) continuity of care, (2) team-based care models, (3) physician well-being and (4) openness to innovative care models. CONCLUSION: Healthcare policy and practice transformation should prioritise developing opportunities to strengthen physician leadership, particularly in rural areas that will be adversely affected by ecosystem disruption. INTRODUCTION: La pandémie de COVID-19 a représenté un défi sans précédent pour les médecins de famille en milieu rural. Les leçons tirées au cours des deux années écoulées peuvent aider à orienter les réponses aux futures perturbations de l'écosystème. Cette étude qualitative vise à explorer les expériences de leadership des médecins de famille ruraux canadiens pendant la pandémie de COVID-19, en tant que prestataires de soins locaux et chefs de file de la santé communautaire, et à identifier les soutiens et les obstacles potentiels au leadership des médecins. MTHODES: Des entretiens qualitatifs virtuels semi-structurés ont été réalisés avec des participants issus de communautés rurales du Canada entre décembre 2021 et février 2022 inclus. Le recrutement des participants a consisté à identifier des contacts de base et à procéder à un échantillonnage boule de neige. Les participants ont été interrogés sur leurs expériences durant la pandémie de COVID-19, notamment sur le rôle du leadership des médecins dans le renforcement de la résilience des communautés. La collecte des données s'est achevée après saturation théorique. Les données ont été analysées thématiquement à l'aide de NVivo 12. RSULTATS: Soixante-quatre participants provenant de 22 communautés rurales de quatre provinces ont pris part à l'étude. Quatre facteurs clés ont été identifiés pour soutenir le leadership des médecins en faveur de la résilience rurale en cas de perturbation de l'écosystème: (1) la continuité des soins, (2) les modèles de soins en équipe, (3) le bien-être des médecins et (4) l'ouverture à des modèles de soins novateurs. CONCLUSION: La politique de santé et la transformation des pratiques devraient donner la priorité au développement d'opportunités pour renforcer le leadership des médecins, en particulier dans les zones rurales qui seront négativement affectées par la perturbation de l'écosystème.


Assuntos
COVID-19 , Liderança , Pandemias , Pesquisa Qualitativa , Serviços de Saúde Rural , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , Canadá , Serviços de Saúde Rural/organização & administração , Pneumonia Viral/epidemiologia , Médicos de Família , Feminino , Infecções por Coronavirus/epidemiologia , Betacoronavirus , Ecossistema , Masculino , População Rural
2.
J Infect Dev Ctries ; 18(4): 520-531, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38728643

RESUMO

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic caused global health, economic, and population loss. Variants of the coronavirus contributed to the severity of the disease and persistent rise in infections. This study aimed to identify potential drug candidates from fifteen approved antiviral drugs against SARS-CoV-2 (6LU7), SARS-CoV (5B6O), and SARS-CoV-2 spike protein (6M0J) using virtual screening and pharmacokinetics to gain insights into COVID-19 therapeutics. METHODOLOGY: We employed drug repurposing approach to analyze binding performance of fifteen clinically approved antiviral drugs against the main protease of SARS-CoV-2 (6LU7), SARS-CoV (5B6O), and SARS-CoV-2 spike proteins bound to ACE-2 receptor (6M0J), to provide an insight into the therapeutics of COVID-19. AutoDock Vina was used for docking studies. The binding affinities were calculated, and 2-3D structures of protein-ligand interactions were drawn. RESULTS: Rutin, hesperidin, and nelfinavir are clinically approved antiviral drugs with high binding affinity to proteins 6LU7, 5B6O, and 6M0J. These ligands have excellent pharmacokinetics, ensuring efficient absorption, metabolism, excretion, and digestibility. Hesperidin showed the most potent interaction with spike protein 6M0J, forming four H-bonds. Nelfinavir had a high human intestinal absorption (HIA) score of 0.93, indicating maximum absorption in the body and promising interactions with 6LU7. CONCLUSIONS: Our results indicated that rutin, hesperidin, and nelfinavir had the highest binding results against the proposed drug targets. The computational approach effectively identified SARS-CoV-2 inhibitors. COVID-19 is still a recurrent threat globally and predictive analysis using natural compounds might serve as a starting point for new drug development against SARS-CoV-2 and related viruses.


Assuntos
Antivirais , COVID-19 , Reposicionamento de Medicamentos , Simulação de Acoplamento Molecular , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2/efeitos dos fármacos , Humanos , Antivirais/farmacocinética , Antivirais/farmacologia , Antivirais/química , Glicoproteína da Espícula de Coronavírus/metabolismo , COVID-19/virologia , Pandemias , Betacoronavirus/efeitos dos fármacos , Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Proteases 3C de Coronavírus/química
3.
Zhonghua Yi Xue Za Zhi ; 104(20): 1812-1824, 2024 May 28.
Artigo em Chinês | MEDLINE | ID: mdl-38782749

RESUMO

Although COVID-19 no longer constitutes a "public health emergency of international concern", which still has being spreading around the world at a low level. Small molecule drugs are the main antiviral treatment for novel coronavirus recommended in China. Although a variety of small-molecule antiviral drugs against COVID-19 have been listed in China, there is no specific drug recommendation for special populations. Society of Bacterial Infection and Resistance of Chinese Medical Association, together with the National Clinical Research Center for Respiratory Disease, and the National Center for Respiratory Medicine, organized domestic experts in various fields such as respiratory, virology, infection, critical care, emergency medicine and pharmacy to release Expert Consensus on the Clinical Application of Oral Small-Molecule Antiviral Drugs against COVID-19. The main content of this consensus includes the introduction of seven small-molecule antiviral drugs against COVID-19, focusing on the drug recommendations for 14 special groups such as the elderly, patients with complicated chronic diseases, tumor patients, pregnant women, and children, and providing suggestions for clinicians to standardize drug use.


Assuntos
Antivirais , COVID-19 , Pandemias , SARS-CoV-2 , Antivirais/uso terapêutico , Humanos , Pneumonia Viral/tratamento farmacológico , Tratamento Farmacológico da COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Consenso , Betacoronavirus , Administração Oral , China , Gravidez
4.
Sci Rep ; 14(1): 11639, 2024 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773161

RESUMO

COVID-19 is a kind of coronavirus that appeared in China in the Province of Wuhan in December 2019. The most significant influence of this virus is its very highly contagious characteristic which may lead to death. The standard diagnosis of COVID-19 is based on swabs from the throat and nose, their sensitivity is not high enough and so they are prone to errors. Early diagnosis of COVID-19 disease is important to provide the chance of quick isolation of the suspected cases and to decrease the opportunity of infection in healthy people. In this research, a framework for chest X-ray image classification tasks based on deep learning is proposed to help in early diagnosis of COVID-19. The proposed framework contains two phases which are the pre-processing phase and classification phase which uses pre-trained convolution neural network models based on transfer learning. In the pre-processing phase, different image enhancements have been applied to full and segmented X-ray images to improve the classification performance of the CNN models. Two CNN pre-trained models have been used for classification which are VGG19 and EfficientNetB0. From experimental results, the best model achieved a sensitivity of 0.96, specificity of 0.94, precision of 0.9412, F1 score of 0.9505 and accuracy of 0.95 using enhanced full X-ray images for binary classification of chest X-ray images into COVID-19 or normal with VGG19. The proposed framework is promising and achieved a classification accuracy of 0.935 for 4-class classification.


Assuntos
COVID-19 , Aprendizado Profundo , Redes Neurais de Computação , SARS-CoV-2 , COVID-19/diagnóstico por imagem , COVID-19/virologia , COVID-19/diagnóstico , Humanos , SARS-CoV-2/isolamento & purificação , Radiografia Torácica/métodos , Pandemias , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/virologia , Pneumonia Viral/diagnóstico , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Betacoronavirus/isolamento & purificação , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X/métodos
5.
Anal Chem ; 96(19): 7360-7366, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38697955

RESUMO

During the coronavirus disease 2019 (COVID-19) pandemic, which has witnessed over 772 million confirmed cases and over 6 million deaths globally, the outbreak of COVID-19 has emerged as a significant medical challenge affecting both affluent and impoverished nations. Therefore, there is an urgent need to explore the disease mechanism and to implement rapid detection methods. To address this, we employed the desorption separation ionization (DSI) device in conjunction with a mass spectrometer for the efficient detection and screening of COVID-19 urine samples. The study encompassed patients with COVID-19, healthy controls (HC), and patients with other types of pneumonia (OP) to evaluate their urine metabolomic profiles. Subsequently, we identified the differentially expressed metabolites in the COVID-19 patients and recognized amino acid metabolism as the predominant metabolic pathway involved. Furthermore, multiple established machine learning algorithms validated the exceptional performance of the metabolites in discriminating the COVID-19 group from healthy subjects, with an area under the curve of 0.932 in the blind test set. This study collectively suggests that the small-molecule metabolites detected from urine using the DSI device allow for rapid screening of COVID-19, taking just three minutes per sample. This approach has the potential to expand our understanding of the pathophysiological mechanisms of COVID-19 and offers a way to rapidly screen patients with COVID-19 through the utilization of machine learning algorithms.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/diagnóstico , COVID-19/urina , COVID-19/virologia , SARS-CoV-2/isolamento & purificação , Pandemias , Masculino , Pneumonia Viral/diagnóstico , Pneumonia Viral/urina , Pneumonia Viral/virologia , Pessoa de Meia-Idade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/urina , Feminino , Betacoronavirus/isolamento & purificação , Espectrometria de Massas/métodos , Adulto , Metabolômica/métodos , Idoso , Aprendizado de Máquina
6.
Sci Total Environ ; 931: 172945, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38703849

RESUMO

The coagulation process has a high potential as a treatment method that can handle pathogenic viruses including emerging enveloped viruses in drinking water treatment process which can lower infection risk through drinking water consumption. In this study, a surrogate enveloped virus, bacteriophage Փ6, and surrogate non-enveloped viruses, including bacteriophage MS-2, T4, ՓX174, were used to evaluate removal efficiencies and mechanisms by the conventional coagulation process with alum, poly­aluminum chloride, and ferric chloride at pH 5, 7, and 9 in turbid water. Also, treatability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recent virus of global concern by coagulation was evaluated as SARS-CoV-2 can presence in drinking water sources. It was observed that an increase in the coagulant dose enhanced the removal efficiency of turbidity and viruses, and the condition that provided the highest removal efficiency of enveloped and non-enveloped viruses was 50 mg/L of coagulants at pH 5. In addition, the coagulation process was more effective for enveloped virus removal than for the non-enveloped viruses, and it demonstrated reduction of SARS-CoV-2 Omicron BA.2 over 0.83-log with alum. According to culture- and molecular-based assays (qPCR and CDDP-qPCR), the virus removal mechanisms were floc adsorption and coagulant inactivation. Through inactivation with coagulants, coagulants caused capsid destruction, followed by genome damage in non-enveloped viruses; however, damage to a lipid envelope is suggested to contribute to a great extend for enveloped virus inactivation. We demonstrated that conventional coagulation is a promising method for controlling emerging and re-emerging viruses in drinking water.


Assuntos
SARS-CoV-2 , Purificação da Água , Purificação da Água/métodos , SARS-CoV-2/fisiologia , COVID-19 , Água Potável/virologia , Água Potável/química , Compostos de Alúmen , Microbiologia da Água , Betacoronavirus/fisiologia , Floculação , Compostos de Alumínio , Compostos Férricos/química
7.
BMC Med Ethics ; 25(1): 63, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38778293

RESUMO

BACKGROUND: The COVID-19 pandemic forced governments, multilateral public health organisations and research institutions to undertake research quickly to inform their responses to the pandemic. Most COVID-19-related studies required swift approval, creating ethical and practical challenges for regulatory authorities and researchers. In this paper, we examine the landscape of ethics review processes in Africa during public health emergencies (PHEs). METHODS: We searched four electronic databases (Web of Science, PUBMED, MEDLINE Complete, and CINAHL) to identify articles describing ethics review processes during public health emergencies and/or pandemics. We selected and reviewed those articles that were focused on Africa. We charted the data from the retrieved articles including the authors and year of publication, title, country and disease(s) reference, broad areas of (ethical) consideration, paper type, and approach. RESULTS: Of an initial 4536 records retrieved, we screened the titles and abstracts of 1491 articles, and identified 72 articles for full review. Nine articles were selected for inclusion. Of these nine articles, five referenced West African countries including Liberia, Guinea and Sierra Leone, and experiences linked to the Ebola virus disease. Two articles focused on South Africa and Kenya, while the other two articles discussed more general experiences and pitfalls of ethics review during PHEs in Africa more broadly. We found no articles published on ethics review processes in Africa before the 2014 Ebola outbreak, and only a few before the COVID-19 outbreak. Although guidelines on protocol review and approval processes for PHEs were more frequently discussed after the 2014 Ebola outbreak, these did not focus on Africa specifically. CONCLUSIONS: There is a gap in the literature about ethics review processes and preparedness within Africa during PHEs. This paper underscores the importance of these processes to inform practices that facilitate timely, context-relevant research that adequately recognises and reinforces human dignity within the quest to advance scientific knowledge about diseases. This is important to improve fast responses to PHEs, reduce mortality and morbidity, and enhance the quality of care before, during, and after pandemics.


Assuntos
COVID-19 , Emergências , Pandemias , Saúde Pública , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , Saúde Pública/ética , África/epidemiologia , Revisão Ética , Betacoronavirus , Doença pelo Vírus Ebola/epidemiologia , Infecções por Coronavirus/epidemiologia , Ética em Pesquisa
8.
Neurosciences (Riyadh) ; 29(2): 133-138, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38740405

RESUMO

Bilateral femoral neuropathy is rare, especially that caused by bilateral compressive iliopsoas, psoas, or iliacus muscle hematomas. We present a case of bilateral femoral neuropathy due to spontaneous psoas hematomas developed during COVID-19 critical illness. A 41-year-old patient developed COVID-19 pneumonia, and his condition deteriorated rapidly. A decrease in the hemoglobin level prompted imaging studies during his intensive care unit (ICU) stay. Bilateral psoas hematomas were identified as the source of bleeding. Thereafter, the patient complained of weakness in both upper and lower limbs and numbness in the lower limb. He was considered to have critical illness neuropathy and was referred to rehabilitation. Electrodiagnostic testing suggested bilateral femoral neuropathy because of compression due to hematomas developed during the course of his ICU stay. The consequences of iliopsoas hematomas occurring in the critically ill can be catastrophic, ranging from hemorrhagic shock to severe weakness, highlighting the importance of recognizing this entity.


Assuntos
COVID-19 , Neuropatia Femoral , Hematoma , Músculos Psoas , SARS-CoV-2 , Humanos , COVID-19/complicações , Hematoma/diagnóstico por imagem , Hematoma/etiologia , Hematoma/complicações , Masculino , Adulto , Neuropatia Femoral/etiologia , Músculos Psoas/diagnóstico por imagem , Estado Terminal , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico por imagem , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico por imagem , Pandemias , Betacoronavirus
9.
Biol Pharm Bull ; 47(5): 930-940, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38692871

RESUMO

The coronavirus disease 2019 (COVID-19) is caused by the etiological agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19, with the recurrent epidemics of new variants of SARS-CoV-2, remains a global public health problem, and new antivirals are still required. Some cholesterol derivatives, such as 25-hydroxycholesterol, are known to have antiviral activity against a wide range of enveloped and non-enveloped viruses, including SARS-CoV-2. At the entry step of SARS-CoV-2 infection, the viral envelope fuses with the host membrane dependent of viral spike (S) glycoproteins. From the screening of cholesterol derivatives, we found a new compound 26,27-dinorcholest-5-en-24-yne-3ß,20-diol (Nat-20(S)-yne) that inhibited the SARS-CoV-2 S protein-dependent membrane fusion in a syncytium formation assay. Nat-20(S)-yne exhibited the inhibitory activities of SARS-CoV-2 pseudovirus entry and intact SARS-CoV-2 infection in a dose-dependent manner. Among the variants of SARS-CoV-2, inhibition of infection by Nat-20(S)-yne was stronger in delta and Wuhan strains, which predominantly invade into cells via fusion at the plasma membrane, than in omicron strains. The interaction between receptor-binding domain of S proteins and host receptor ACE2 was not affected by Nat-20(S)-yne. Unlike 25-hydroxycholesterol, which regulates various steps of cholesterol metabolism, Nat-20(S)-yne inhibited only de novo cholesterol biosynthesis. As a result, plasma membrane cholesterol content was substantially decreased in Nat-20(S)-yne-treated cells, leading to inhibition of SARS-CoV-2 infection. Nat-20(S)-yne having a new mechanism of action may be a potential therapeutic candidate for COVID-19.


Assuntos
Antivirais , COVID-19 , Colesterol , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacologia , Humanos , COVID-19/virologia , Colesterol/metabolismo , Células Vero , Chlorocebus aethiops , Glicoproteína da Espícula de Coronavírus/metabolismo , Animais , Internalização do Vírus/efeitos dos fármacos , Betacoronavirus/efeitos dos fármacos , Pandemias , Tratamento Farmacológico da COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Enzima de Conversão de Angiotensina 2/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia
10.
Trials ; 25(1): 328, 2024 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-38760804

RESUMO

BACKGROUND: The SARS CoV-2 pandemic has resulted in more than 1.1 million deaths in the USA alone. Therapeutic options for critically ill patients with COVID-19 are limited. Prior studies showed that post-infection treatment of influenza A virus-infected mice with the liponucleotide CDP-choline, which is an essential precursor for de novo phosphatidylcholine synthesis, improved gas exchange and reduced pulmonary inflammation without altering viral replication. In unpublished studies, we found that treatment of SARS CoV-2-infected K18-hACE2-transgenic mice with CDP-choline prevented development of hypoxemia. We hypothesize that administration of citicoline (the pharmaceutical form of CDP-choline) will be safe in hospitalized SARS CoV-2-infected patients with hypoxemic acute respiratory failure (HARF) and that we will obtain preliminary evidence of clinical benefit to support a larger Phase 3 trial using one or more citicoline doses. METHODS: We will conduct a single-site, double-blinded, placebo-controlled, and randomized Phase 1/2 dose-ranging and safety study of Somazina® citicoline solution for injection in consented adults of any sex, gender, age, or ethnicity hospitalized for SARS CoV-2-associated HARF. The trial is named "SCARLET" (Supplemental Citicoline Administration to Reduce Lung injury Efficacy Trial). We hypothesize that SCARLET will show that i.v. citicoline is safe at one or more of three doses (0.5, 2.5, or 5 mg/kg, every 12 h for 5 days) in hospitalized SARS CoV-2-infected patients with HARF (20 per dose) and provide preliminary evidence that i.v. citicoline improves pulmonary outcomes in this population. The primary efficacy outcome will be the SpO2:FiO2 ratio on study day 3. Exploratory outcomes include Sequential Organ Failure Assessment (SOFA) scores, dead space ventilation index, and lung compliance. Citicoline effects on a panel of COVID-relevant lung and blood biomarkers will also be determined. DISCUSSION: Citicoline has many characteristics that would be advantageous to any candidate COVID-19 therapeutic, including safety, low-cost, favorable chemical characteristics, and potentially pathogen-agnostic efficacy. Successful demonstration that citicoline is beneficial in severely ill patients with SARS CoV-2-induced HARF could transform management of severely ill COVID patients. TRIAL REGISTRATION: The trial was registered at www. CLINICALTRIALS: gov on 5/31/2023 (NCT05881135). TRIAL STATUS: Currently enrolling.


Assuntos
COVID-19 , Citidina Difosfato Colina , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Humanos , Citidina Difosfato Colina/uso terapêutico , Método Duplo-Cego , SARS-CoV-2/efeitos dos fármacos , COVID-19/complicações , Tratamento Farmacológico da COVID-19 , Ensaios Clínicos Fase II como Assunto , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Pneumonia Viral/complicações , Resultado do Tratamento , Hipóxia/tratamento farmacológico , Masculino , Pandemias , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/complicações , Hospitalização , Feminino , Betacoronavirus , Ensaios Clínicos Fase I como Assunto , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/virologia , Administração Intravenosa , Adulto
11.
J Virol ; 98(5): e0176223, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38563762

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and is responsible for the largest human pandemic in 100 years. Thirty-four vaccines are currently approved for use worldwide, and approximately 67% of the world population has received a complete primary series of one, yet countries are dealing with new waves of infections, variant viruses continue to emerge, and breakthrough infections are frequent secondary to waning immunity. Here, we evaluate a measles virus (MV)-vectored vaccine expressing a stabilized prefusion SARS-CoV-2 spike (S) protein (MV-ATU3-S2PΔF2A; V591) with demonstrated immunogenicity in mouse models (see companion article [J. Brunet, Z. Choucha, M. Gransagne, H. Tabbal, M.-W. Ku et al., J Virol 98:e01693-23, 2024, https://doi.org/10.1128/jvi.01693-23]) in an established African green monkey model of disease. Animals were vaccinated with V591 or the control vaccine (an equivalent MV-vectored vaccine with an irrelevant antigen) intramuscularly using a prime/boost schedule, followed by challenge with an early pandemic isolate of SARS-CoV-2 at 56 days post-vaccination. Pre-challenge, only V591-vaccinated animals developed S-specific antibodies that had virus-neutralizing activity as well as S-specific T cells. Following the challenge, V591-vaccinated animals had lower infectious virus and viral (v) RNA loads in mucosal secretions and stopped shedding virus in these secretions earlier. vRNA loads were lower in these animals in respiratory and gastrointestinal tract tissues at necropsy. This correlated with a lower disease burden in the lungs as quantified by PET/CT at early and late time points post-challenge and by pathological analysis at necropsy.IMPORTANCESevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the largest human pandemic in 100 years. Even though vaccines are currently available, countries are dealing with new waves of infections, variant viruses continue to emerge, breakthrough infections are frequent, and vaccine hesitancy persists. This study uses a safe and effective measles vaccine as a platform for vaccination against SARS-CoV-2. The candidate vaccine was used to vaccinate African green monkeys (AGMs). All vaccinated AGMs developed robust antigen-specific immune responses. After challenge, these AGMs produced less virus in mucosal secretions, for a shorter period, and had a reduced disease burden in the lungs compared to control animals. At necropsy, lower levels of viral RNA were detected in tissue samples from vaccinated animals, and the lungs of these animals lacked the histologic hallmarks of SARS-CoV-2 disease observed exclusively in the control AGMs.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Vírus do Sarampo , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Animais , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Chlorocebus aethiops , SARS-CoV-2/imunologia , SARS-CoV-2/genética , COVID-19/prevenção & controle , COVID-19/imunologia , COVID-19/virologia , Vírus do Sarampo/imunologia , Vírus do Sarampo/genética , Vacinas contra COVID-19/imunologia , Humanos , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangue , Vetores Genéticos , Células Vero , Pandemias/prevenção & controle , Feminino , Betacoronavirus/imunologia , Betacoronavirus/genética , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Pneumonia Viral/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Infecções por Coronavirus/veterinária , Vacinas Virais/imunologia , Vacinas Virais/genética , Vacinas Virais/administração & dosagem , Modelos Animais de Doenças
12.
J Virol ; 98(5): e0045124, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38591877

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a wide range of hosts, including hippopotami, which are semi-aquatic mammals and phylogenetically closely related to Cetacea. In this study, we characterized the binding properties of hippopotamus angiotensin-converting enzyme 2 (hiACE2) to the spike (S) protein receptor binding domains (RBDs) of the SARS-CoV-2 prototype (PT) and variants of concern (VOCs). Furthermore, the cryo-electron microscopy (cryo-EM) structure of the SARS-CoV-2 PT S protein complexed with hiACE2 was resolved. Structural and mutational analyses revealed that L30 and F83, which are specific to hiACE2, played a crucial role in the hiACE2/SARS-CoV-2 RBD interaction. In addition, comparative and structural analysis of ACE2 orthologs suggested that the cetaceans may have the potential to be infected by SARS-CoV-2. These results provide crucial molecular insights into the susceptibility of hippopotami to SARS-CoV-2 and suggest the potential risk of SARS-CoV-2 VOCs spillover and the necessity for surveillance. IMPORTANCE: The hippopotami are the first semi-aquatic artiodactyl mammals wherein SARS-CoV-2 infection has been reported. Exploration of the invasion mechanism of SARS-CoV-2 will provide important information for the surveillance of SARS-CoV-2 in hippopotami, as well as other semi-aquatic mammals and cetaceans. Here, we found that hippopotamus ACE2 (hiACE2) could efficiently bind to the RBDs of the SARS-CoV-2 prototype (PT) and variants of concern (VOCs) and facilitate the transduction of SARS-CoV-2 PT and VOCs pseudoviruses into hiACE2-expressing cells. The cryo-EM structure of the SARS-CoV-2 PT S protein complexed with hiACE2 elucidated a few critical residues in the RBD/hiACE2 interface, especially L30 and F83 of hiACE2 which are unique to hiACE2 and contributed to the decreased binding affinity to PT RBD compared to human ACE2. Our work provides insight into cross-species transmission and highlights the necessity for monitoring host jumps and spillover events on SARS-CoV-2 in semi-aquatic/aquatic mammals.


Assuntos
Enzima de Conversão de Angiotensina 2 , Microscopia Crioeletrônica , Ligação Proteica , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Animais , Humanos , Artiodáctilos/virologia , COVID-19/virologia , COVID-19/metabolismo , Sítios de Ligação , Betacoronavirus/genética , Betacoronavirus/metabolismo
13.
J Virol ; 98(5): e0034924, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38639488

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel coronavirus severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has rapidly spread worldwide since its emergence in late 2019. Its ongoing evolution poses challenges for antiviral drug development. Coronavirus nsp6, a multiple-spanning transmembrane protein, participates in the biogenesis of the viral replication complex, which accommodates the viral replication-transcription complex. The roles of its structural domains in viral replication are not well studied. Herein, we predicted the structure of the SARS-CoV-2 nsp6 protein using AlphaFold2 and identified a highly folded C-terminal region (nsp6C) downstream of the transmembrane helices. The enhanced green fluorescent protein (EGFP)-fused nsp6C was found to cluster in the cytoplasm and associate with membranes. Functional mapping identified a minimal membrane-associated element (MAE) as the region from amino acids 237 to 276 (LGV-KLL), which is mainly composed of the α-helix H1 and the α-helix H2; the latter exhibits characteristics of an amphipathic helix (AH). Mutagenesis studies and membrane flotation experiments demonstrate that AH-like H2 is required for MAE-mediated membrane association. This MAE was functionally conserved across MERS-CoV, HCoV-OC43, HCoV-229E, HCoV-HKU1, and HCoV-NL63, all capable of mediating membrane association. In a SARS-CoV-2 replicon system, mutagenesis studies of H2 and replacements of H1 and H2 with their homologous counterparts demonstrated requirements of residues on both sides of the H2 and properly paired H1-H2 for MAE-mediated membrane association and viral replication. Notably, mutations I266A and K274A significantly attenuated viral replication without dramatically affecting membrane association, suggesting a dual role of the MAE in viral replication: mediating membrane association as well as participating in protein-protein interactions.IMPORTANCESevere acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) assembles a double-membrane vesicle (DMV) by the viral non-structural proteins for viral replication. Understanding the mechanisms of the DMV assembly is of paramount importance for antiviral development. Nsp6, a multiple-spanning transmembrane protein, plays an important role in the DMV biogenesis. Herein, we predicted the nsp6 structure of SARS-CoV-2 and other human coronaviruses using AlphaFold2 and identified a putative membrane-associated element (MAE) in the highly conserved C-terminal regions of nsp6. Experimentally, we verified a functionally conserved minimal MAE composed of two α-helices, the H1, and the amphipathic helix-like H2. Mutagenesis studies confirmed the requirement of H2 for MAE-mediated membrane association and viral replication and demonstrated a dual role of the MAE in viral replication, by mediating membrane association and participating in residue-specific interactions. This functionally conserved MAE may serve as a novel anti-viral target.


Assuntos
SARS-CoV-2 , Proteínas não Estruturais Virais , Replicação Viral , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , SARS-CoV-2/metabolismo , Humanos , Proteínas não Estruturais Virais/metabolismo , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/química , COVID-19/virologia , Membrana Celular/metabolismo , Animais , Chlorocebus aethiops , Betacoronavirus/genética , Betacoronavirus/fisiologia , Betacoronavirus/metabolismo , Células HEK293 , Células Vero , Pandemias , Sequência de Aminoácidos
14.
Comput Biol Med ; 175: 108485, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38653063

RESUMO

Various studies have linked several diseases, including cancer and COVID-19, to single nucleotide variations (SNV). Although single-cell RNA sequencing (scRNA-seq) technology can provide SNV and gene expression data, few studies have integrated and analyzed these multimodal data. To address this issue, we introduce Interpretable Single-cell Multimodal Data Integration Based on Variational Autoencoder (ISMI-VAE). ISMI-VAE leverages latent variable models that utilize the characteristics of SNV and gene expression data to overcome high noise levels and uses deep learning techniques to integrate multimodal information, map them to a low-dimensional space, and classify disease cells. Moreover, ISMI-VAE introduces an attention mechanism to reflect feature importance and analyze genetic features that could potentially cause disease. Experimental results on three cancer data sets and one COVID-19 data set demonstrate that ISMI-VAE surpasses the baseline method in terms of both effectiveness and interpretability and can effectively identify disease-causing gene features.


Assuntos
COVID-19 , Aprendizado Profundo , Neoplasias , SARS-CoV-2 , Humanos , COVID-19/genética , SARS-CoV-2/genética , Neoplasias/genética , Análise de Célula Única/métodos , Polimorfismo de Nucleotídeo Único , Pandemias , Pneumonia Viral/genética , Infecções por Coronavirus/genética , Betacoronavirus/genética
15.
Viruses ; 16(4)2024 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-38675987

RESUMO

Consistent with the biochemistry of coronaviruses as well established over decades, SARS-CoV-2 makes its initial attachment to host cells through the binding of its spike protein (SP) to sialylated glycans (containing the monosaccharide sialic acid) on the cell surface. The virus can then slide over and enter via ACE2. SARS-CoV-2 SP attaches particularly tightly to the trillions of red blood cells (RBCs), platelets and endothelial cells in the human body, each cell very densely coated with sialic acid surface molecules but having no ACE2 or minimal ACE2. These interlaced attachments trigger the blood cell aggregation, microvascular occlusion and vascular damage that underlie the hypoxia, blood clotting and related morbidities of severe COVID-19. Notably, the two human betacoronaviruses that express a sialic acid-cleaving enzyme are benign, while the other three-SARS, SARS-CoV-2 and MERS-are virulent. RBC aggregation experimentally induced in several animal species using an injected polysaccharide caused most of the same morbidities of severe COVID-19. This glycan biochemistry is key to disentangling controversies that have arisen over the efficacy of certain generic COVID-19 treatment agents and the safety of SP-based COVID-19 vaccines. More broadly, disregard for the active physiological role of RBCs yields unreliable or erroneous reporting of pharmacokinetic parameters as routinely obtained for most drugs and other bioactive agents using detection in plasma, with whole-blood levels being up to 30-fold higher. Appreciation of the active role of RBCs can elucidate the microvascular underpinnings of other health conditions, including cardiovascular disease, and therapeutic opportunities to address them.


Assuntos
COVID-19 , Polissacarídeos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , COVID-19/metabolismo , COVID-19/virologia , SARS-CoV-2/metabolismo , Polissacarídeos/metabolismo , Animais , Glicoproteína da Espícula de Coronavírus/metabolismo , Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Eritrócitos/metabolismo , Eritrócitos/virologia , Pandemias , Microvasos/metabolismo , Microvasos/virologia , Ligação Viral , Tratamento Farmacológico da COVID-19 , Células Endoteliais/metabolismo , Células Endoteliais/virologia , Enzima de Conversão de Angiotensina 2/metabolismo , Agregação Eritrocítica
16.
Diabetes Metab Syndr ; 18(3): 102991, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38569447

RESUMO

BACKGROUND AND AIMS: The impact of the coronavirus disease 2019 (COVID-19) pandemic on pregnant women, especially those with gestational diabetes mellitus (GDM), has yet to be fully understood. This review aims to examine the interaction between GDM and COVID-19 and to elucidate the pathophysiological mechanisms underlying the comorbidity of these two conditions. METHODS: We performed a systematic literature search using the databases of PubMed, Embase, and Web of Science with appropriate keywords and MeSH terms. Our analysis included studies published up to January 26, 2023. RESULTS: Despite distinct clinical manifestations, GDM and COVID-19 share common pathophysiological characteristics, which involve complex interactions across multiple organs and systems. On the one hand, infection with severe acute respiratory syndrome coronavirus 2 may target the pancreas and placenta, resulting in ß-cell dysfunction and insulin resistance in pregnant women. On the other hand, the hormonal and inflammatory changes that occur during pregnancy could also increase the risk of severe COVID-19 in mothers with GDM. Personalized management and close monitoring are crucial for treating pregnant women with both GDM and COVID-19. CONCLUSIONS: A comprehensive understanding of the interactive mechanisms of GDM and COVID-19 would facilitate the initiation of more targeted preventive and therapeutic strategies. There is an urgent need to develop novel biomarkers and functional indicators for early identification and intervention of these conditions.


Assuntos
COVID-19 , Diabetes Gestacional , Pandemias , Complicações Infecciosas na Gravidez , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , COVID-19/complicações , Gravidez , Diabetes Gestacional/epidemiologia , Feminino , Complicações Infecciosas na Gravidez/virologia , Complicações Infecciosas na Gravidez/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Betacoronavirus
17.
Int J Biol Macromol ; 267(Pt 1): 131427, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38583833

RESUMO

Due to the health emergency created by SARS-CoV-2, the virus that causes the COVID-19 disease, the rapid implementation of a new vaccine technology was necessary. mRNA vaccines, being one of the cutting-edge new technologies, attracted significant interest and offered a lot of hope. The potential of these vaccines in preventing admission to hospitals and serious illness in people with comorbidities has recently been called into question due to the vaccines' rapidly waning immunity. Mounting evidence indicates that these vaccines, like many others, do not generate sterilizing immunity, leaving people vulnerable to recurrent infections. Additionally, it has been discovered that the mRNA vaccines inhibit essential immunological pathways, thus impairing early interferon signaling. Within the framework of COVID-19 vaccination, this inhibition ensures an appropriate spike protein synthesis and a reduced immune activation. Evidence is provided that adding 100 % of N1-methyl-pseudouridine (m1Ψ) to the mRNA vaccine in a melanoma model stimulated cancer growth and metastasis, while non-modified mRNA vaccines induced opposite results, thus suggesting that COVID-19 mRNA vaccines could aid cancer development. Based on this compelling evidence, we suggest that future clinical trials for cancers or infectious diseases should not use mRNA vaccines with a 100 % m1Ψ modification, but rather ones with the lower percentage of m1Ψ modification to avoid immune suppression.


Assuntos
COVID-19 , Neoplasias , Pseudouridina , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Neoplasias/imunologia , Pseudouridina/metabolismo , Vacinas contra COVID-19/imunologia , Animais , Vacinas de mRNA , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Pneumonia Viral/prevenção & controle , Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia
18.
Gene ; 915: 148427, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38575097

RESUMO

The descendants of the B lineage are the most predominant variants among the SARS-CoV-2 virus due to the incorporation of new mutations augmenting the infectivity of the virus. There is a substantial increase in the transition transversion bias, nucleotide diversity and purifying selection on the spike protein in the descendants of the B lineage of the SARS-CoV-2 virus on a temporal scale. A strong bias for C-to-U substitutions is found in the genes encoding spike protein in this lineage. The positive selection has operated on the spike gene of B lineages and its sub-lineages. The B.1 lineage has undergone positive selection on site 501 of the receptor binding domain ultimately reflected in a key substitution N501Y in its three descendant lineages namely B.1.1.7, B.1.351 and P.1. The intensity of purifying selection on the multiple sites of the spike gene has increased substantially in the sub-lineages of B.1 in a timescale. The binding site 501 on the spike protein in B lineage is found to coevolve with other amino acid sites. This study sheds light on the evolutionary trajectory of the B lineage into highly infectious descendants in the recent past under the influence of positive and purifying selection exerted by natural immunity and vaccination of the host.


Assuntos
COVID-19 , Evolução Molecular , SARS-CoV-2 , Seleção Genética , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Humanos , Sítios de Ligação , COVID-19/virologia , Filogenia , Mutação , Betacoronavirus/genética , Substituição de Aminoácidos
19.
Environ Int ; 187: 108658, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38640612

RESUMO

During the unprecedented COVID-19 city lockdown, a unique opportunity arose to dissect the intricate dynamics of urban air quality, focusing on ultrafine particles (UFPs) and volatile organic compounds (VOCs). This study delves into the nuanced interplay between traffic patterns and UFP emissions in a subtropical urban setting during the spring-summer transition of 2021. Leveraging meticulous roadside measurements near a traffic nexus, our investigation unravels the intricate relationship between particle number size distribution (PNSD), VOCs mixing ratios, and detailed vehicle activity metrics. The soft lockdown era, marked by a 20-27% dip in overall traffic yet a surprising surge in early morning motorcycle activity, presented a natural experiment. We observed a consequential shift in the urban aerosol regime: the decrease in primary emissions from traffic substantially amplified the role of aged particles and secondary aerosols. This shift was particularly pronounced under stagnant atmospheric conditions, where reduced dilution exacerbated the influence of alternative emission sources, notably solvent evaporation, and was further accentuated with the resumption of normal traffic flows. A distinct seasonal trend emerged as warmer months approached, with aromatic VOCs such as toluene, ethylbenzene, and xylene not only increasing but also significantly contributing to more frequent particle growth events. These findings spotlight the criticality of targeted strategies at traffic hotspots, especially during periods susceptible to weak atmospheric dilution, to curb UFP and precursor emissions effectively. As we stand at the cusp of widespread vehicle electrification, this study underscores the imperative of a holistic approach to urban air quality management, embracing the complexities of primary emission reductions and the resultant shifts in atmospheric chemistry.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , COVID-19 , Cidades , Monitoramento Ambiental , Material Particulado , SARS-CoV-2 , Emissões de Veículos , Compostos Orgânicos Voláteis , COVID-19/epidemiologia , Material Particulado/análise , Compostos Orgânicos Voláteis/análise , Emissões de Veículos/análise , Poluentes Atmosféricos/análise , Poluição do Ar/estatística & dados numéricos , Humanos , Estações do Ano , Pandemias , Tamanho da Partícula , Aerossóis/análise , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia
20.
Obstet Gynecol ; 143(6): e149-e152, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38574363

RESUMO

BACKGROUND: Since the onset of the coronavirus disease (COVID-19) pandemic, a variety of long-COVID-19 symptoms and autoimmune complications have been recognized. CASES: We report three cases of autoimmune premature poor ovarian response in patients aged 30-37 years after mild to asymptomatic COVID-19 before vaccination, with nucleotide antibody confirmation. Two patients failed to respond to maximum-dose gonadotropins for more than 4 weeks, despite a recent history of response before having COVID-19. After a month of prednisone 30 mg, these two patients had normal follicle-stimulating hormone (FSH) levels, high oocyte yield, and blastocyst formation in successful in vitro fertilization cycles. All three patients have above-average anti-müllerian hormone levels that persisted throughout their clinical ovarian insufficiency. Two patients had elevated FSH levels, perhaps resulting from FSH receptor blockade. One patient, with a history of high response to gonadotropins 75 international units per day and below-normal FSH levels, had no ovarian response to more than a month of gonadotropins (525 international units daily), suggesting autoimmune block of the FSH glycoprotein and possible FSH receptor blockade. CONCLUSION: Auto-antibody production in response to COVID-19 before vaccination may be a rare cause of autoimmune poor ovarian response. Although vaccination is likely protective, further study will be required to evaluate the effect of vaccination and duration of autoimmune FSH or FSH receptor blockade.


Assuntos
COVID-19 , Insuficiência Ovariana Primária , Receptores do FSH , SARS-CoV-2 , Humanos , Feminino , COVID-19/imunologia , COVID-19/complicações , Insuficiência Ovariana Primária/imunologia , Insuficiência Ovariana Primária/tratamento farmacológico , Adulto , SARS-CoV-2/imunologia , Pandemias , Hormônio Foliculoestimulante/sangue , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Betacoronavirus
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