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1.
Ther Innov Regul Sci ; 54(5): 1236-1255, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32865809

RESUMO

Two phase-III, double-blind, randomized clinical trials of remdesivir plus SOC (standard of care) versus placebo plus SOC have been conducted in Wuhan hospitals by Chinese investigators during the urgent COVID-19 epidemic [ClincalTrials.gov NCT04257656 and NCT04252664]. These trials have been highly anticipated worldwide. We expect investigators of the trials will soon report the clinical and laboratory findings from the medical perspective. This manuscript provides documentary style information on the process of monitoring key data and making recommendations to the sponsor and investigators based on analytical insights when dealing with the emergent situation from the statistical viewpoint. Having monitored data sequentially from 237 patients, we comment on the strength and weakness of the study design and suggest the treatment effect of remdesivir on severe COVID-19 cases. Our experience with using the Dynamic Data Monitoring (DDM) tool has demonstrated its efficiency and reliability in supporting DSMB's instantaneous review of essential data during the emergent situation. DDM, when used properly by disciplined statisticians, has shown its capability of exploring the trial data flexibly and, in the meantime, protecting the trial's scientific integrity.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Ensaios Clínicos Fase III como Assunto , Infecções por Coronavirus/tratamento farmacológico , Confiabilidade dos Dados , Pneumonia Viral/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/uso terapêutico , Alanina/efeitos adversos , Alanina/uso terapêutico , Antivirais/efeitos adversos , Betacoronavirus/patogenicidade , China , Comitês de Monitoramento de Dados de Ensaios Clínicos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Fatores de Tempo , Resultado do Tratamento
4.
Int J Rheum Dis ; 23(8): 1030-1039, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32881350

RESUMO

AIM: To describe the first Australian cases of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) disease (COVID-19) pneumonia treated with the interleukin-6 receptor antagonist tocilizumab. METHODS: Retrospective, open-label, real-world, uncontrolled, single-arm case series conducted in 2 tertiary hospitals in NSW, Australia and 1 tertiary hospital in Victoria, Australia. Five adult male patients aged between 46 and 74 years with type 1 respiratory failure due to COVID-19 pneumonia requiring intensive care unit (ICU) admission and biochemical evidence of systemic hyperinflammation (C-reactive protein greater than 100 mg/L; ferritin greater than 700 µg/L) were administered variable-dose tocilizumab. RESULTS: At between 13 and 26 days follow-up, all patients are alive and have been discharged from ICU. Two patients have been discharged home. Two patients avoided endotracheal intubation. Oxygen therapy has been ceased in three patients. Four adverse events potentially associated with tocilizumab therapy occurred in three patients: ventilator-associated pneumonia, bacteremia associated with central venous catheterization, myositis and hepatitis. All patients received broad-spectrum antibiotics, 4 received corticosteroids and 2 received both lopinavir/ritonavir and hydroxychloroquine. The time from first tocilizumab administration to improvement in ventilation, defined as a 25% reduction in fraction of inspired oxygen required to maintain peripheral oxygen saturation greater than 92%, ranged from 7 hours to 4.6 days. CONCLUSIONS: Tocilizumab use was associated with favorable clinical outcome in our patients. We recommend tocilizumab be included in randomized controlled trials of treatment for patients with severe COVID-19 pneumonia, and be considered for compassionate use in such patients pending the results of these trials.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Idoso , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Masculino , Pessoa de Meia-Idade , New South Wales , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Vitória
5.
Trials ; 21(1): 758, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883328

RESUMO

OBJECTIVES: Tocilizumab is a humanized monoclonal antibody which targets and inhibits interleukin-6 (IL-6) and has demonstrated efficacy in treating diseases associated with hyper-inflammation. Data are suggestive of tocilizumab as a potential treatment for patients with COVID-19 infection. The aim of this study is to determine the safety and efficacy of standard dose versus low dose tocilizumab in adults with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation on time to intubation, non-invasive ventilation and/or all-cause mortality. TRIAL DESIGN: This trial is a phase 2, open label, two-stage, multicentre, randomised trial. PARTICIPANTS: Adult subjects with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation requiring admission to hospital at St. Vincent's University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Inclusion criteria Aged 18 years or older. Confirmed SARS-CoV2 infection (as defined by positive PCR). Evidence of hyper inflammatory state as evidenced by at least three of the following: Documented temperature >38°C in the past 48 hours, IL6 >40 pg/ml, or in its absence D-dimer >1.5 µgFEU /ml, Elevated CRP (>100mg/L) and/or a three-fold increase since presentation, Elevated ferritin X5 ULN, Elevated LDH (above the ULN), Elevated fibrinogen (above the ULN). Pulmonary infiltrates on chest imaging. Moderate to severe respiratory failure as defined by PaO2/FiO2≤300mmHg. INTERVENTION AND COMPARATOR: Intervention for participants in this trial is SOC plus Tocilizumab compared to SOC alone (comparator). For Stage 1, following randomisation, subjects will receive either (Arm 1) SOC alone or (Arm 2) SOC plus Tocilizumab (standard single dose - 8mg/kg, infused over 60 minutes. Once stage 1 has fully recruited, subsequent participants will be enrolled directly into Stage 2 and receive either (Arm 1) SOC plus Tocilizumab (standard single dose - 8mg/kg, infused over 60 minutes or (Arm 2) SOC plus Tocilizumab (standard single dose - 4mg/kg, infused over 60 minutes). MAIN OUTCOMES: The primary endpoint for this study is the time to a composite primary endpoint of progression to intubation and ventilation, non-invasive ventilation or death within 28 days post randomisation. RANDOMISATION: Eligible patients will be randomised (1:1) using a central register. Randomisation will be performed through an interactive, web-based electronic data capturing database. In stage 1, eligible participants will be randomised (1:1) to (Arm 1) SOC alone or to (Arm 2) SOC with single dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. In stage 2, eligible participants will be randomised (1:1) to receive either (Arm 1) single, standard dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes or (Arm 2) reduced dose (4mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. BLINDING: This study is open label. The study will not be blinded to investigators, subjects, or medical or nursing staff. The trial statistician will be blinded for data analysis and will be kept unaware of treatment group assignments. To facilitate this, the randomisation schedule will be drawn up by an independent statistician and objective criteria were defined for the primary outcome to minimize potential bias. NUMBERS TO BE RANDOMISED: In stage 1, 90 subjects will be randomised 1:1, 45 to SOC and 45 subjects to SOC plus Tocilizumab (8mg/kg, infused over 60 minutes). In stage 2, sample size calculation for the dose evaluation stage will use data generated from stage 1 using the same primary endpoint as in stage 1. TRIAL STATUS: The COVIRL002 trial (Protocol version 1.4, 13th May 2020) commenced in May 2020 at St. Vincent's University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Recruitment is proceeding with the aim to achieve the target sample size on or before April 2021. TRIAL REGISTRATION: COVIRL002 was registered 25 June 2020 under EudraCT number: 2020-001767-86 and Protocol identification: UCDCRC/20/02. FULL PROTOCOL: The full protocol for COVIRL002 is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus/patogenicidade , Ensaios Clínicos Fase II como Assunto , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Progressão da Doença , Interações entre Hospedeiro e Microrganismos , Humanos , Intubação Intratraqueal , Irlanda , Estudos Multicêntricos como Assunto , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
6.
Trials ; 21(1): 766, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32891160

RESUMO

OBJECTIVES: To investigate the potential efficacy of Acacia Senegal extract Gum Arabic (GA) supplementation as immunomodulatory and anti-inflammatory dietary intervention among newly diagnosed COVID 19 Sudanese patients. To study the effect of GA on the level of cytokines, TNFα, IL8, IL6 IL10, CRP and the viral load. Secondary outcomes will be the effect of GA oral intake on mortality rate and days of hospital admission. TRIAL DESIGN: Quadruple blind, randomized placebo-controlled clinical trial Phase II & III. Prospective, two-arm, parallel-group, randomised (1:1 allocation ratio) superiority trial of oral GA among seropositive COVID-19 patients. PARTICIPANTS: Inclusion criteria: COVID-19 infected (newly diagnosed) as proved by real-time PCR within 72 hours of PCR. Age 8-90 years Both genders Exclusion criteria: Intubated patients on parenteral treatment Allergy to Gum Arabic The study will be conducted in COVID Isolation Centres and Soba University Hospital Khartoum State Sudan. INTERVENTION AND COMPARATOR: Experimental: Intervention Group This arm will receive 100% natural Gum Arabic provided in a powder form in 30-grams-dose once daily for four weeks Placebo Comparator: Control group: This group will be provided with pectin powder provided as one-gram-dose once daily for four weeks Both GA and placebo will be in addition to standard care treatment based on local clinical guidelines. MAIN OUTCOMES: Mean change from baseline score of Immune Response to end of the trial. Changes of the level of Tumor Necrosis Factor (TNFα), interleukin IL8, IL6, and IL10 from the baseline values (Four weeks from the start of randomization). Mortality rate: The percentage of deaths among COVID 19 patients received Gum Arabic compared to placebo (Four weeks from the start of randomization]). RANDOMISATION: Randomization (1:1 allocation ratio) and will be conducted using a sequence of computer-generated random numbers by an independent individual. Each participating centre will be assigned a special code generated by the computer. The randomization will be kept by the PI and a research assistant. BLINDING (MASKING): Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 110 eligible patients will be randomly assigned to either GA (n=55) or placebo (n=55) groups. TRIAL STATUS: Protocol Version no 2, 30th June 2020. Recruitment will start on 15th September 2020. The intended completion date is 15th January 2021. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04381871 . Date of trial registration: 11 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Goma Arábica/uso terapêutico , Fatores Imunológicos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Criança , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Feminino , Goma Arábica/efeitos adversos , Interações entre Hospedeiro e Microrganismos , Humanos , Fatores Imunológicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
7.
Elife ; 92020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32876563

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) and transmissible gastroenteritis virus (TGEV) are two highly infectious and lethal viruses causing major economic losses to pig production. Here, we report generation of double-gene-knockout (DKO) pigs harboring edited knockout alleles for known receptor proteins CD163 and pAPN and show that DKO pigs are completely resistant to genotype 2 PRRSV and TGEV. We found no differences in meat-production or reproductive-performance traits between wild-type and DKO pigs, but detected increased iron in DKO muscle. Additional infection challenge experiments showed that DKO pigs exhibited decreased susceptibility to porcine deltacoronavirus (PDCoV), thus offering unprecedented in vivo evidence of pAPN as one of PDCoV receptors. Beyond showing that multiple gene edits can be combined in a livestock animal to achieve simultaneous resistance to two major viruses, our study introduces a valuable model for investigating infection mechanisms of porcine pathogenic viruses that exploit pAPN or CD163 for entry.


Assuntos
Antígenos CD13/deficiência , Infecções por Coronavirus/prevenção & controle , Coronavirus/patogenicidade , Gastroenterite Suína Transmissível/prevenção & controle , Síndrome Respiratória e Reprodutiva Suína/prevenção & controle , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Receptores de Superfície Celular/deficiência , Vírus da Gastroenterite Transmissível/patogenicidade , Animais , Animais Geneticamente Modificados , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/imunologia , Composição Corporal , Antígenos CD13/genética , Antígenos CD13/imunologia , Coronavirus/imunologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Suscetibilidade a Doenças , Gastroenterite Suína Transmissível/genética , Gastroenterite Suína Transmissível/imunologia , Gastroenterite Suína Transmissível/virologia , Técnicas de Silenciamento de Genes , Interações entre Hospedeiro e Microrganismos , Indústria de Embalagem de Carne , Fenótipo , Síndrome Respiratória e Reprodutiva Suína/genética , Síndrome Respiratória e Reprodutiva Suína/imunologia , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Sus scrofa/genética , Suínos , Vírus da Gastroenterite Transmissível/imunologia , Ganho de Peso
8.
Dis Model Mech ; 13(9)2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32887790

RESUMO

The spread of the novel virus SARS coronavirus 2 (SARS-CoV-2) was explosive, with cases first identified in December 2019, and >22 million people infected and >775,000 deaths as of August 2020. SARS-CoV-2 can cause severe respiratory disease in humans leading to coronavirus disease 2019 (COVID-19). The development of effective clinical interventions, such as antivirals and vaccines that can limit or even prevent the burden and spread of SARS-CoV-2, is a global health priority. Testing of leading antivirals, monoclonal antibody therapies and vaccines against SARS-CoV-2 will require robust animal and cell models of viral pathogenesis. In this Special Article, we discuss the cell-based and animal models of SARS-CoV-2 infection and pathogenesis that have been described as of August 2020. We also outline the outstanding questions for which researchers can leverage animal and cell-based models to improve our understanding of SARS-CoV-2 pathogenesis and protective immunity. Taken together, the refinement of models of SARS-CoV-2 infection will be critical to guide the development of therapeutics and vaccines against SARS-CoV-2 to end the COVID-19 pandemic.


Assuntos
Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Animais , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Células Cultivadas , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Modelos Animais de Doenças , Interações entre Hospedeiro e Microrganismos , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico , Especificidade da Espécie , Técnicas de Cultura de Tecidos , Vacinas Virais/uso terapêutico
9.
Drug Discov Ther ; 14(4): 161-170, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32908071

RESUMO

Coronavirus disease 2019 (COVID-19) is found to be associated with various comorbidities which include cardiovascular diseases, hypertension, and diabetes. The impaired regulation of renin-angiotensin-aldosterone system (RAAS) has been seen in COVID-19 patients, but whether RAAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), are responsible for worsening of clinical conditions remains unknown. Herein, we review the role of angiotensin-converting enzyme 2 (ACE2) expression in disease progression, its association with comorbidities and COVID-19, and summarize the clinical evidence for several potential directions for future research work on ACEIs/ARBs in COVID-19 patients.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Sistema Renina-Angiotensina , Internalização do Vírus , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Comorbidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/enzimologia , Interações entre Hospedeiro e Microrganismos , Humanos , Pandemias , Segurança do Paciente , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/enzimologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Internalização do Vírus/efeitos dos fármacos
10.
Drug Discov Ther ; 14(4): 171-176, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32908072

RESUMO

The healthcare sector has been overwhelmed by the global rise in the number of COVID-19 cases. The primary care physicians at the forefront of this pandemic are being provided with multiple guidelines (state, national, international). The aim of this review was to examine the existing guidelines for congruence and critically analyze them in light of current evidence. A discordance was noted between the national and state guidelines with respect to indication, duration and dosage of antivirals, steroids/immunomodulators, anticoagulation and convalescent plasma. The lack of concordance between various guidelines mandates the need for a unified national guideline that is regularly updated.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Guias de Prática Clínica como Assunto/normas , Padrões de Prática Médica/normas , Anticoagulantes/uso terapêutico , Antivirais/efeitos adversos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Imunização Passiva , Fatores Imunológicos/uso terapêutico , Índia/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Esteroides/uso terapêutico
11.
J Nippon Med Sch ; 87(4): 240-242, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32908116

RESUMO

OBJECTIVE: Little is known about COVID-19 patients who have not traveled to infected areas or had direct contact with infected persons. This report describes the clinical features of 28 such patients with confirmed COVID-19 infection. METHODS: Data on clinical characteristics during hospitalization were collected. RESULTS: Epidemiological exposures were investigated among patients reporting no travel to infected areas or direct contact with a case-patient. Patients presented with various symptoms, increased levels of inflammatory markers, and consolidation or ground-glass opacification on computed tomography scans. CONCLUSIONS: The present report contributes critical information on the clinical presentation of COVID-19 patients without typical epidemiological exposures.


Assuntos
Betacoronavirus/patogenicidade , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Adulto , Idoso , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Feminino , Hospitalização , Interações entre Hospedeiro e Microrganismos , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Valor Preditivo dos Testes , Fatores de Risco , Tomografia Computadorizada por Raios X
12.
Comput Math Methods Med ; 2020: 1352982, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32908574

RESUMO

The current emergence of coronavirus (SARS-CoV-2) puts the world in threat. The structural research on the receptor recognition by SARS-CoV-2 has identified the key interactions between SARS-CoV-2 spike protein and its host (epithelial cell) receptor, also known as angiotensin-converting enzyme 2 (ACE2). It controls both the cross-species and human-to-human transmissions of SARS-CoV-2. In view of this, we propose and analyze a mathematical model for investigating the effect of CTL responses over the viral mutation to control the viral infection when a postinfection immunostimulant drug (pidotimod) is administered at regular intervals. Dynamics of the system with and without impulses have been analyzed using the basic reproduction number. This study shows that the proper dosing interval and drug dose both are important to eradicate the viral infection.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Modelos Biológicos , Pneumonia Viral/tratamento farmacológico , Ácido Pirrolidonocarboxílico/análogos & derivados , Tiazolidinas/administração & dosagem , Número Básico de Reprodução , Betacoronavirus/genética , Betacoronavirus/imunologia , Simulação por Computador , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Relação Dose-Resposta a Droga , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Conceitos Matemáticos , Mutação , Pandemias , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Ácido Pirrolidonocarboxílico/administração & dosagem , Receptores Virais/fisiologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T Citotóxicos/imunologia
13.
Nat Commun ; 11(1): 4403, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879312

RESUMO

Bacteriophage genomes rapidly evolve via mutation and horizontal gene transfer to counter evolving bacterial host defenses; such arms race dynamics should lead to divergence between phages from similar, geographically isolated ecosystems. However, near-identical phage genomes can reoccur over large geographical distances and several years apart, conversely suggesting many are stably maintained. Here, we show that phages with near-identical core genomes in distant, discrete aquatic ecosystems maintain diversity by possession of numerous flexible gene modules, where homologous genes present in the pan-genome interchange to create new phage variants. By repeatedly reconstructing the core and flexible regions of phage genomes from different metagenomes, we show a pool of homologous gene variants co-exist for each module in each location, however, the dominant variant shuffles independently in each module. These results suggest that in a natural community, recombination is the largest contributor to phage diversity, allowing a variety of host recognition receptors and genes to counter bacterial defenses to co-exist for each phage.


Assuntos
Bacteriófagos/genética , Camada de Gelo/virologia , Metagenoma , Cianobactérias/virologia , Ecossistema , Transferência Genética Horizontal , Genes Virais , Genoma Viral , Interações entre Hospedeiro e Microrganismos/genética , Camada de Gelo/microbiologia , Metagenômica , Filogenia
14.
Sci Immunol ; 5(51)2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943497

RESUMO

COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells (PBMCs) of hospitalized patients during the peak of the COVID-19 pandemic in the UK. Here, we report key immune signatures present shortly after hospital admission that were associated with the severity of COVID-19. Immune signatures were related to shifts in neutrophil to T cell ratio, elevated serum IL-6, MCP-1 and IP-10, and most strikingly, modulation of CD14+ monocyte phenotype and function. Modified features of CD14+ monocytes included poor induction of the prostaglandin-producing enzyme, COX-2, as well as enhanced expression of the cell cycle marker Ki-67. Longitudinal analysis revealed reversion of some immune features back to the healthy median level in patients with a good eventual outcome. These findings identify previously unappreciated alterations in the innate immune compartment of COVID-19 patients and lend support to the idea that therapeutic strategies targeting release of myeloid cells from bone marrow should be considered in this disease. Moreover, they demonstrate that features of an exaggerated immune response are present early after hospital admission suggesting immune-modulating therapies would be most beneficial at early timepoints.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata , Monócitos/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Biomarcadores/sangue , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Ciclo-Oxigenase 2/imunologia , Ciclo-Oxigenase 2/metabolismo , Progressão da Doença , Feminino , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/imunologia , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Estudos Prospectivos , Índice de Gravidade de Doença , Reino Unido/epidemiologia
16.
Adv Physiol Educ ; 44(4): 545-549, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32880484

RESUMO

It is important to reinforce physiology and pathophysiology concepts during clinical rotations, which traditionally occur after the foundational sciences in the US medical school system. We took an opportunistic approach when the COVID-19 pandemic forced our content into virtual delivery mode, as clinical medical education required a shift to nonpatient contact. We describe our experience in building a 2-wk course that consisted of online small groups during week 1 and panels and cases during week 2. The physiology content involved faculty-vetted resources, along with both discrete and open-ended focus questions for each learning objective. The course also included mechanical ventilation, and the physiologist utilized discussion points and developed a formative quiz to emphasize the physiology correlates, in addition to the very clinical aspects of mechanical ventilation. There were pathophysiology opportunities with pneumonia, acute respiratory distress syndrome, systemic inflammatory response syndrome, and multiple-organ system dysfunction among the clinical correlates. Review and recall of the foundational sciences occurred, allowing links between the pre-clerkship and clerkship years that were previously undiscovered in our institution. This virtually delivered medical curriculum related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 is timely, carries high student interest, and can benefit medical students and the communities they serve.


Assuntos
Betacoronavirus/patogenicidade , Instrução por Computador , Infecções por Coronavirus/fisiopatologia , Educação a Distância , Educação de Graduação em Medicina , Pulmão/fisiopatologia , Fisiologia/educação , Pneumonia Viral/fisiopatologia , Infecções por Coronavirus/terapia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Pulmão/virologia , Pandemias , Pneumonia Viral/terapia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Faculdades de Medicina
17.
Nat Commun ; 11(1): 4475, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901029

RESUMO

Tissue resident memory CD8+ T cells (Trm) are poised for immediate reactivation at sites of pathogen entry and provide optimal protection of mucosal surfaces. The intestinal tract represents a portal of entry for many infectious agents; however, to date specific strategies to enhance Trm responses at this site are lacking. Here, we present TMDI (Transient Microbiota Depletion-boosted Immunization), an approach that leverages antibiotic treatment to temporarily restrain microbiota-mediated colonization resistance, and favor intestinal expansion to high densities of an orally-delivered Listeria monocytogenes strain carrying an antigen of choice. By augmenting the local chemotactic gradient as well as the antigenic load, this procedure generates a highly expanded pool of functional, antigen-specific intestinal Trm, ultimately enhancing protection against infectious re-challenge in mice. We propose that TMDI is a useful model to dissect the requirements for optimal Trm responses in the intestine, and also a potential platform to devise novel mucosal vaccination approaches.


Assuntos
Microbioma Gastrointestinal/imunologia , Imunidade nas Mucosas , Administração Oral , Animais , Antígenos/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Quimiotaxia/imunologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Imunidade nas Mucosas/efeitos dos fármacos , Memória Imunológica , Listeria monocytogenes/crescimento & desenvolvimento , Listeria monocytogenes/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/administração & dosagem , Estreptomicina/administração & dosagem
18.
J Stroke Cerebrovasc Dis ; 29(10): 105047, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912511

RESUMO

COVID-19 is a pandemic disease which predominantly affects the respiratory system, however it also causes multi-organ dysfunction in a subset of patients. There is a growing evidence that it increases the propensity of strokes in younger patients. Besides producing a prothrombotic state, arterial dissection could be one of its many manifestations, increasing the risks of stroke. Herein, we report the first case of spontaneous bilateral vertebral artery dissection in a patient with COVID-19. 39-year female presented with spontaneous bilateral vertebral artery dissections without any instigating traumatic events and no history of connective tissue disorders. Whether this patient's vertebral artery dissections were triggered by exaggerated inflammatory response or arteriopathy secondary to COVID-19 remains speculative. Nonetheless, arterial dissection could be one of it's complications. It is important for the physicians to be aware of different clinical manifestations of COVID-19 as we manage these patients with no historical experience, to provide adequate care.


Assuntos
Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Acidente Vascular Cerebral/etiologia , Dissecação da Artéria Vertebral/etiologia , Adulto , Anticoagulantes/administração & dosagem , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Feminino , Interações entre Hospedeiro e Microrganismos , Humanos , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/virologia , Dissecação da Artéria Vertebral/diagnóstico por imagem , Dissecação da Artéria Vertebral/tratamento farmacológico , Dissecação da Artéria Vertebral/virologia
19.
J Stroke Cerebrovasc Dis ; 29(10): 105077, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912524

RESUMO

BACKGROUND: As Covid-19 evolved into a world-wide pandemic, hospitals reported marked declines in strokes, only to be followed by reports of increased numbers of young people presenting with large-vessel occlusions. We reviewed our patient data-base to determine if similar or other novel trends were present. RESULTS: Our Thrombectomy Stroke Center experienced marked declines in ED visits from 2,349 in early March to 1,178 in late April, stroke alerts dropped from 34 to 14 during the same period. Average monthly stroke admissions dropped from 34 in 2019 to 23 in 2020. Nonetheless, in March, we had 12 patients eligible for tPA, which is twice the typical caseload and was unexpected given the low overall stroke presentations. Although the neurointervention caseload was low, the patients were significantly younger. Of the acute intervention patients in March, 5 of the 12 patients were ≤ 60 years old, and two were in their 30's. These trends are similar to those reported elsewhere but were highly unusual for our center as our catchment area is predominantly Caucasian with 34 % of the population > 65 years of age. CONCLUSIONS: Even in low risk centers Covid-19 will likely impart unique stroke presentations. It will be imperative to determine the mechanisms responsible for these changes so we can institute effective strategies for optimal stroke prevention as well as maintain timely acute interventions.


Assuntos
Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Idoso , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Feminino , Florida/epidemiologia , Interações entre Hospedeiro e Microrganismos , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/terapia , Acidente Vascular Cerebral/virologia , Trombectomia , Terapia Trombolítica , Fatores de Tempo
20.
J Stroke Cerebrovasc Dis ; 29(10): 105114, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912527

RESUMO

BACKGROUND: Little is known about the effect of the Coronavirus disease 2019 pandemic on stroke care and the impact of the epidemic on acute stroke hospitalizations has not been described. METHODS: We analyze the stroke admission rate in three hospitals in New York City from January 1, 2020 through April 17, 2020, identifying all cases of acute ischemic stroke, intraparenchymal hemorrhage and subarachnoid hemorrhage. RESULTS: We confirmed 518 cases of out-of-hospital stroke. During the baseline period up to February 25, 2020, the daily stroke admission rate was stable, with the slope of the regression describing the number of admissions over time equal to -0.33 (se = 1.21), not significantly different from 0 (p = 0.79), with daily admissions averaging 41. During the pandemic period, the slope was -4.4 (se = 1.00); i.e., the number of stroke admissions decreased an average of 4.4 per week, (p = 0.005), with weekly admissions averaging 23, a reduction of 44% versus baseline. This general result was not different by patient age, sex, or race/ethnicity. CONCLUSIONS: The weekly stroke admission rate started declining two weeks prior to the local surge of coronavirus admissions. The consequences of lack of diagnosis and treatment of a large proportion of acute stroke patients are likely severe and lasting.


Assuntos
Infecções por Coronavirus/terapia , Assistência à Saúde/tendências , Hemorragias Intracranianas/terapia , Admissão do Paciente/tendências , Pneumonia Viral/terapia , Acidente Vascular Cerebral/terapia , Idoso , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Feminino , Interações entre Hospedeiro e Microrganismos , Humanos , Hemorragias Intracranianas/diagnóstico , Hemorragias Intracranianas/epidemiologia , Hemorragias Intracranianas/virologia , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Prognóstico , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/virologia , Hemorragia Subaracnóidea/epidemiologia , Hemorragia Subaracnóidea/terapia , Fatores de Tempo
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