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1.
Nature ; 592(7853): 277-282, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33545711

RESUMO

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.


Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19/terapia , COVID-19/virologia , Evolução Molecular , Mutagênese/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Idoso , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , Doença Crônica , Genoma Viral/efeitos dos fármacos , Genoma Viral/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Evasão da Resposta Imune/genética , Evasão da Resposta Imune/imunologia , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Imunização Passiva , Terapia de Imunossupressão , Masculino , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/imunologia , Mutação , Filogenia , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Fatores de Tempo , Carga Viral/efeitos dos fármacos , Eliminação de Partículas Virais , Soroterapia para COVID-19
3.
Clin Infect Dis ; 75(1): e97-e101, 2022 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34718446

RESUMO

Airborne severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected in a coronavirus disease 19 (COVID-19) ward before activation of HEPA-air filtration but not during filter operation; SARS-CoV-2 was again detected following filter deactivation. Airborne SARS-CoV-2 was infrequently detected in a COVID-19 intensive care unit. Bioaerosol was also effectively filtered.


Assuntos
COVID-19 , SARS-CoV-2 , Hospitais , Humanos
4.
Clin Trials ; 18(5): 615-621, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34154428

RESUMO

The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency.


Assuntos
Vacinas contra COVID-19/uso terapêutico , COVID-19 , Ensaios Clínicos como Assunto/normas , Pandemias , COVID-19/prevenção & controle , Ensaios Clínicos como Assunto/organização & administração , Humanos , Pandemias/prevenção & controle , Medicina Estatal , Reino Unido/epidemiologia
5.
BMC Infect Dis ; 20(1): 97, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005105

RESUMO

BACKGROUND: Salmonella species commonly causes infection in humans and on occasion leads to serious complications, such as mycotic aneurysms. Here, we present the first case reported of a patient with a mycotic aneurysm likely secondary to Salmonella Rissen infection. CASE PRESENTATION: The patient presented with 4 weeks of lower back pain, chills and a single episode of diarrhoea 2 months prior during a 14-day trip to Hong Kong and Taiwan. Magnetic resonance imaging revealed an aneurysmal left internal iliac artery with adjacent left iliacus rim-enhancing collection. A stool culture was positive for Salmonella Rissen ST 469 EBG 66 on whole genome sequencing. The patient underwent an emergency bifurcated graft of his internal iliac aneurysm and was successfully treated with appropriate antibiotics. CONCLUSIONS: This case highlights the importance of considering the diagnosis of a mycotic aneurysm in an unusual presentation of back pain with features of infection.


Assuntos
Aneurisma Infectado/cirurgia , Aneurisma Ilíaco/cirurgia , Infecções por Salmonella/cirurgia , Idoso , Aneurisma Infectado/diagnóstico por imagem , Aneurisma Infectado/tratamento farmacológico , Antibacterianos/uso terapêutico , Humanos , Aneurisma Ilíaco/diagnóstico por imagem , Aneurisma Ilíaco/tratamento farmacológico , Aneurisma Ilíaco/microbiologia , Artéria Ilíaca/diagnóstico por imagem , Artéria Ilíaca/microbiologia , Masculino , Salmonella/efeitos dos fármacos , Salmonella/isolamento & purificação , Salmonella/patogenicidade , Infecções por Salmonella/diagnóstico por imagem , Infecções por Salmonella/tratamento farmacológico
6.
J Infect Prev ; 23(5): 197-205, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36003131

RESUMO

Background: Healthcare-associated (HCA) SARS-CoV-2 infection is a significant contributor to the spread of the 2020 pandemic. Timely review of HCA cases is essential to identify learning to inform infection prevention and control (IPC) policies and organisational response. Aim: To identify key areas for improvement through rapid investigation of HCA SARS-CoV-2 cases and to implement change. Methods: Cases were identified based on date of first positive SARS-CoV-2 PCR sample in relation to date of hospital admission. Cases were reviewed using a structured gap analysis tool to identify key learning points. These were discussed in weekly multidisciplinary meetings to gain consensus on learning outcomes, level of harm incurred by the patient and required actions. Learning was then promptly fed back to individual teams and the organisation. Findings: Of the 489 SARS-CoV-2 cases admitted between 10th March and 23rd June 2020, 114 suspected HCA cases (23.3%) were reviewed; 58/489 (11.8%) were ultimately deemed to be HCA. Five themes were identified: individual patient vulnerability, communication, IPC implementation, policy issues and organisational response. Adaptations to policies based on these reviews were completed within the course of the initial phase of the pandemic. Conclusion: This approach enabled timely learning and implementation of control measures and policy development.

7.
J Infect ; 85(5): 557-564, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36058413

RESUMO

OBJECTIVES: To describe the risk factors for SARS-CoV-2 infection in UK healthcare workers (HCWs). METHODS: We conducted a prospective sero-epidemiological study of HCWs at a major UK teaching hospital using a SARS-CoV-2 immunoassay. Risk factors for seropositivity were analysed using multivariate logistic regression. RESULTS: 410/5,698 (7·2%) staff tested positive for SARS-CoV-2 antibodies. Seroprevalence was higher in those working in designated COVID-19 areas compared with other areas (9·47% versus 6·16%) Healthcare assistants (aOR 2·06 [95%CI 1·14-3·71]; p=0·016) and domestic and portering staff (aOR 3·45 [95% CI 1·07-11·42]; p=0·039) had significantly higher seroprevalence than other staff groups after adjusting for age, sex, ethnicity and COVID-19 working location. Staff working in acute medicine and medical sub-specialities were also at higher risk (aOR 2·07 [95% CI 1·31-3·25]; p<0·002). Staff from Black, Asian and minority ethnic (BAME) backgrounds had an aOR of 1·65 (95% CI 1·32 - 2·07; p<0·001) compared to white staff; this increased risk was independent of COVID-19 area working. The only symptoms significantly associated with seropositivity in a multivariable model were loss of sense of taste or smell, fever, and myalgia; 31% of staff testing positive reported no prior symptoms. CONCLUSIONS: Risk of SARS-CoV-2 infection amongst HCWs is highly heterogeneous and influenced by COVID-19 working location, role, age and ethnicity. Increased risk amongst BAME staff cannot be accounted for solely by occupational factors.


Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , COVID-19/epidemiologia , Pessoal de Saúde , Hospitais de Ensino , Humanos , Estudos Prospectivos , Fatores de Risco , Estudos Soroepidemiológicos , Reino Unido/epidemiologia
8.
Future Healthc J ; 8(1): e11-e14, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33791467

RESUMO

Social distancing during the coronavirus disease 2019 (COVID-19) pandemic has necessitated drastic changes in the practice of hospital medicine, including the cancellation of many educational activities. At the same time, the emergence of a new disease with a rapidly evolving knowledge base has mandated timely educational updates. To resolve this conflict in our hospital, we substituted 'traditional' grand rounds with 'virtual' grand rounds delivered over Zoom, consisting of a local situation report and operational update, followed by a specialty-specific clinical presentation on management of COVID-19. Attendance was greatly increased (mean 384 attendees) compared to traditional grand rounds (mean 44 attendees) and included a diverse audience of medical professionals. Feedback was overwhelmingly positive, with >80% of responders stating that the sessions would or might inform their clinical practice. COVID-19 has therefore provided an opportunity to modernise grand rounds, and develop a new model matching the needs of medical education beyond the pandemic.

9.
Cell Rep Med ; 1(5): 100062, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32838340

RESUMO

There is an urgent need for rapid SARS-CoV-2 testing in hospitals to limit nosocomial spread. We report an evaluation of point of care (POC) nucleic acid amplification testing (NAAT) in 149 participants with parallel combined nasal and throat swabbing for POC versus standard lab RT-PCR testing. Median time to result is 2.6 (IQR 2.3-4.8) versus 26.4 h (IQR 21.4-31.4, p < 0.001), with 32 (21.5%) positive and 117 (78.5%) negative. Cohen's κ correlation between tests is 0.96 (95% CI 0.91-1.00). When comparing nearly 1,000 tests pre- and post-implementation, the median time to definitive bed placement from admission is 23.4 (8.6-41.9) versus 17.1 h (9.0-28.8), p = 0.02. Mean length of stay on COVID-19 "holding" wards is 58.5 versus 29.9 h (p < 0.001). POC testing increases isolation room availability, avoids bed closures, allows discharge to care homes, and expedites access to hospital procedures. POC testing could mitigate the impact of COVID-19 on hospital systems.


Assuntos
Teste de Ácido Nucleico para COVID-19 , COVID-19/diagnóstico , Controle de Infecções/métodos , Testes Imediatos , SARS-CoV-2/isolamento & purificação , Adulto , Idoso , Teste de Ácido Nucleico para COVID-19/normas , Infecção Hospitalar/prevenção & controle , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Testes Imediatos/normas , SARS-CoV-2/genética
10.
Nat Immunol ; 8(6): 569-77, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17496896

RESUMO

DC-SIGN, a C-type lectin expressed on dendritic cells (DCs), can sequester human immunodeficiency virus (HIV) virions in multivesicular bodies. Here, using large-scale gene expression profiling and tyrosine-phosphorylated proteome analyses, we characterized signaling mediated by DC-SIGN after activation by either HIV or a DC-SIGN-specific antibody. Activation of DC-SIGN resulted in downregulation of genes encoding major histocompatibility complex class II, Jagged 1 and interferon-response molecules and upregulation of the gene encoding transcription factor ATF3. Phosphorylated proteome analysis showed that HIV- or antibody-stimulated DC-SIGN signaling was mediated by the Rho guanine nucleotide-exchange factor LARG and led to increased Rho-GTPase activity. Activation of LARG in DCs exposed to HIV was required for the formation of virus-T cell synapses. Thus, HIV sequestration by and stimulation of DC-SIGN helps HIV evade immune responses and spread to cells.


Assuntos
Moléculas de Adesão Celular/imunologia , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , HIV-1/fisiologia , Lectinas Tipo C/imunologia , Receptores de Superfície Celular/imunologia , Replicação Viral , Proteínas rho de Ligação ao GTP/metabolismo , Sequência de Aminoácidos , Diferenciação Celular , Células Cultivadas , Células Dendríticas/citologia , Ativação Enzimática , Perfilação da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/química , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Dados de Sequência Molecular , Fenótipo , Fosfosserina/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcrição Gênica/genética
11.
Immunity ; 23(6): 621-34, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16356860

RESUMO

Lentiviral Nef increases T cell signaling activity, but the molecular nature of the stimulus involved is incompletely described. We explored CD4 T cell lipid raft composition in the presence and absence of Nef. Here, the E2 ubiquitin-conjugating enzyme UbcH7, which acts in conjunction with c-Cbl, is absent from lipid rafts. This Nef-mediated exclusion is associated with failure of ubiquitination of activated Vav. In the presence of Nef, lipid raft Cdc42 is activated and forms a ternary complex between the c-Cbl-interacting protein p85Cool-1/betaPix and c-Cbl, displacing UbcH7 from rafts. Suppression of p85Cool-1/betaPix expression restores UbcH7 raft localization and Vav ubiquitination and diminishes Cdc42 activity. Moreover, p85Cool-1/betaPix knockdown attenuates HIV replication. Thresholds for activation of signaling involve the intricate balance of positive and negative regulators. Here we provide evidence for Nef disruption of a negative regulator of T cell signaling in promoting HIV replication.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Produtos do Gene nef/metabolismo , HIV , Microdomínios da Membrana/metabolismo , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Transdução de Sinais/imunologia , Enzimas de Conjugação de Ubiquitina/metabolismo , Replicação Viral/imunologia , Western Blotting , Linfócitos T CD4-Positivos/citologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Produtos do Gene nef/imunologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Imunoprecipitação , Microdomínios da Membrana/imunologia , Microscopia Confocal , Proteínas Proto-Oncogênicas c-cbl/imunologia , RNA Interferente Pequeno/genética , Fatores de Troca de Nucleotídeo Guanina Rho , Enzimas de Conjugação de Ubiquitina/imunologia , Proteína cdc42 de Ligação ao GTP/metabolismo , Produtos do Gene nef do Vírus da Imunodeficiência Humana
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