RESUMO
The coronavirus disease 2019 (COVID-19) pandemic has claimed over 7 million lives worldwide, providing a stark reminder of the importance of pandemic preparedness. Due to the lack of approved antiviral drugs effective against coronaviruses at the start of the pandemic, the world largely relied on repurposed efforts. Here, we summarise results from randomised controlled trials to date, as well as selected in vitro data of directly acting antivirals, host-targeting antivirals, and immunomodulatory drugs. Overall, repurposing efforts evaluating directly acting antivirals targeting other viral families were largely unsuccessful, whereas several immunomodulatory drugs led to clinical improvement in hospitalised patients with severe disease. In addition, accelerated drug discovery efforts during the pandemic progressed to multiple novel directly acting antivirals with clinical efficacy, including small molecule inhibitors and monoclonal antibodies. We argue that large-scale investment is required to prepare for future pandemics; both to develop an arsenal of broad-spectrum antivirals beyond coronaviruses and build worldwide clinical trial networks that can be rapidly utilised.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Pandemias , Agentes de Imunomodulação , Antivirais/uso terapêuticoRESUMO
Sepsis is a life-threatening condition involving a dysregulated immune response to infectious agents that cause injury to host tissues and organs. Current treatments are limited to early administration of antibiotics and supportive care. While appealing, the strategy of targeted inhibition of individual molecules in the inflammatory cascade has not proved beneficial. Non-targeted, systemic immunosuppression with steroids has shown limited efficacy and raises concern for secondary infection. Iminosugars are a class of small molecule glycomimetics with distinct inhibition profiles for glycan processing enzymes based on stereochemistry. Inhibition of host endoplasmic reticulum resident glycoprotein processing enzymes has demonstrated efficacy as a broad-spectrum antiviral strategy, but limited consideration has been given to the effects on host glycoprotein production and consequent disruption of signalling cascades. This work demonstrates that iminosugars inhibit dengue virus, bacterial lipopolysaccharide and fungal antigen-stimulated cytokine responses in human macrophages. In spite of decreased inflammatory mediator production, viral replication is suppressed in the presence of iminosugar. Transcriptome analysis reveals the key interaction of pathogen-induced endoplasmic reticulum stress, the resulting unfolded protein response and inflammation. Our work shows that iminosugars modulate these interactions. Based on these findings, we propose a new therapeutic role for iminosugars as treatment for sepsis-related inflammatory disorders associated with excess cytokine secretion.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Sepse/tratamento farmacológico , Resposta a Proteínas não Dobradas/efeitos dos fármacos , 1-Desoxinojirimicina/farmacologia , 1-Desoxinojirimicina/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antígenos de Fungos/imunologia , Células Cultivadas , Vírus da Dengue/imunologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/microbiologia , Lipopolissacarídeos/imunologia , Macrófagos , Cultura Primária de Células , Sepse/imunologia , Sepse/microbiologia , Receptor 4 Toll-Like/metabolismo , Resposta a Proteínas não Dobradas/imunologiaRESUMO
BACKGROUND: Zika virus (ZIKV) has become a global threat with immediate need for accurate diagnostics, efficacious vaccines and therapeutics. Several ZIKV envelope (Env)-based vaccines have been developed recently. However, many commercially available ZIKV Env are based on the African lineage and produced in insect cells. Here, we sought to produce Asian-lineage ZIKV Env in mammalian cells for research and clinical applications. METHODS: We designed various gene expression constructs to optimize the production of ZIKV using prM-Env and full or C-terminal truncations of Env; with or without a rat CD4 fusion partner to allow large-scale production of soluble protein in mammalian HEK293 cells. Protein expression was verified by mass spectrometry and western-blot with a pan-flavivirus antibody, a ZIKV Env monoclonal antibody and with immune sera from adenoviral (ChAdOx1) ZIKV Env-vaccinated mice. The resulting Env-CD4 was used as a coating reagent for immunoassay (ELISA) using both mouse and human seropositive sera. RESULTS: Replacement of the C-terminus transmembrane Env domain by a rat CD4 and addition of prM supported optimal expression and secretion of Env. Binding between the antigens and the antibodies was similar to binding when using commercially available ZIKV Env reagents. Furthermore, antibodies from ZIKV patients bound ZIKV Env-CD4 in ELISA assays, whereas sera from healthy blood donors yielded minimal OD background. The serological outcomes of this assay correlated also with ZIKV neutralisation capacity in vitro. CONCLUSIONS: Results obtained from this study indicate the potential of the Asian-lineage Zika Env-CD4 and Env proteins in ELISA assays to monitor humoral immune responses in upcoming clinical trials as well as a sero-diagnostic tool in ZIKV infection.
Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Proteínas Recombinantes de Fusão/imunologia , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/isolamento & purificação , Zika virus/imunologia , Animais , Antígenos CD4/genética , Ensaio de Imunoadsorção Enzimática/métodos , Células HEK293 , Humanos , México , Camundongos , Testes de Neutralização/métodos , Ratos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo , Zika virus/genéticaRESUMO
Defending against future pandemics requires vaccine platforms that protect across a range of related pathogens. Nanoscale patterning can be used to address this issue. Here, we produce quartets of linked receptor-binding domains (RBDs) from a panel of SARS-like betacoronaviruses, coupled to a computationally designed nanocage through SpyTag/SpyCatcher links. These Quartet Nanocages, possessing a branched morphology, induce a high level of neutralizing antibodies against several different coronaviruses, including against viruses not represented in the vaccine. Equivalent antibody responses are raised to RBDs close to the nanocage or at the tips of the nanoparticle's branches. In animals primed with SARS-CoV-2 Spike, boost immunizations with Quartet Nanocages increase the strength and breadth of an otherwise narrow immune response. A Quartet Nanocage including the Omicron XBB.1.5 'Kraken' RBD induced antibodies with binding to a broad range of sarbecoviruses, as well as neutralizing activity against this variant of concern. Quartet nanocages are a nanomedicine approach with potential to confer heterotypic protection against emergent zoonotic pathogens and facilitate proactive pandemic protection.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Animais , Anticorpos Neutralizantes/imunologia , SARS-CoV-2/imunologia , Anticorpos Antivirais/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/química , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/química , COVID-19/prevenção & controle , COVID-19/imunologia , COVID-19/virologia , Humanos , Vacinação/métodos , Camundongos , Nanopartículas/química , FemininoRESUMO
Defending against future pandemics may require vaccine platforms that protect across a range of related pathogens. The presentation of multiple receptor-binding domains (RBDs) from evolutionarily-related viruses on a nanoparticle scaffold elicits a strong antibody response to conserved regions. Here we produce quartets of tandemly-linked RBDs from SARS-like betacoronaviruses coupled to the mi3 nanocage through a SpyTag/SpyCatcher spontaneous reaction. These Quartet Nanocages induce a high level of neutralizing antibodies against several different coronaviruses, including against viruses not represented on the vaccine. In animals primed with SARS-CoV-2 Spike, boost immunizations with Quartet Nanocages increased the strength and breadth of an otherwise narrow immune response. Quartet Nanocages are a strategy with potential to confer heterotypic protection against emergent zoonotic coronavirus pathogens and facilitate proactive pandemic protection.
RESUMO
Severe acute respiratory syndrome coronavirus 2 is the causative pathogen of the COVID-19 pandemic which as of March 29, 2021, has claimed 2â¯776â¯175 lives worldwide. Vaccine development efforts focus on the viral trimeric spike glycoprotein as the main target of the humoral immune response. Viral spikes carry glycans that facilitate immune evasion by shielding specific protein epitopes from antibody neutralization, and antigen efficacy is influenced by spike glycoprotein production in vivo. Therefore, immunogen integrity is important for glycoprotein-based vaccine candidates. Here, we show how site-specific glycosylation differs between virus-derived spikes, wild-type, non-stabilized spikes expressed from a plasmid with a CMV promoter and tPA signal sequence, and commonly used recombinant, engineered spike glycoproteins. Furthermore, we show that their distinctive cellular secretion pathways result in different protein glycosylation and secretion patterns, including shedding of spike monomeric subunits for the non-stabilized wild-type spike tested, which may have implications for the resulting immune response and vaccine design.
RESUMO
Most enveloped viruses rely on the host cell endoplasmic reticulum (ER) quality control (QC) machinery for proper folding of glycoproteins. The key ER α-glucosidases (α-Glu) I and II of the ERQC machinery are attractive targets for developing broad-spectrum antivirals. Iminosugars based on deoxynojirimycin have been extensively studied as ER α-glucosidase inhibitors; however, other glycomimetic compounds are less established. Accordingly, we synthesized a series of N-substituted derivatives of valiolamine, the iminosugar scaffold of type 2 diabetes drug voglibose. To understand the basis for up to 100,000-fold improved inhibitory potency, we determined high-resolution crystal structures of mouse ER α-GluII in complex with valiolamine and 10 derivatives. The structures revealed extensive interactions with all four α-GluII subsites. We further showed that N-substituted valiolamines were active against dengue virus and SARS-CoV-2 in vitro. This study introduces valiolamine-based inhibitors of the ERQC machinery as candidates for developing potential broad-spectrum therapeutics against the existing and emerging viruses.
Assuntos
Antivirais/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Imino Açúcares/farmacologia , Inositol/análogos & derivados , alfa-Glucosidases/metabolismo , Animais , Antivirais/síntese química , Antivirais/metabolismo , Sítios de Ligação , Chlorocebus aethiops , Cristalografia por Raios X , Vírus da Dengue/efeitos dos fármacos , Retículo Endoplasmático/enzimologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/metabolismo , Humanos , Imino Açúcares/síntese química , Imino Açúcares/metabolismo , Inositol/síntese química , Inositol/metabolismo , Inositol/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Ligação Proteica , SARS-CoV-2/efeitos dos fármacos , Células Vero , alfa-Glucosidases/químicaRESUMO
Basigin, or CD147, has been reported as a coreceptor used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to invade host cells. Basigin also has a well-established role in Plasmodium falciparum malaria infection of human erythrocytes, where it is bound by one of the parasite's invasion ligands, reticulocyte binding protein homolog 5 (RH5). Here, we sought to validate the claim that the receptor binding domain (RBD) of SARS-CoV-2 spike glycoprotein can form a complex with basigin, using RH5-basigin as a positive control. Using recombinantly expressed proteins, size exclusion chromatography and surface plasmon resonance, we show that neither RBD nor full-length spike glycoprotein bind to recombinant human basigin (expressed in either Escherichia coli or mammalian cells). Further, polyclonal anti-basigin IgG did not block SARS-CoV-2 infection of Vero E6 cells. Given the immense interest in SARS-CoV-2 therapeutic targets to improve treatment options for those who become seriously ill with coronavirus disease 2019 (COVID-19), we would caution the inclusion of basigin in this list on the basis of its reported direct interaction with SARS-CoV-2 spike glycoprotein. IMPORTANCE Reducing the mortality and morbidity associated with COVID-19 remains a global health priority. Vaccines have proven highly effective at preventing infection and hospitalization, but efforts must continue to improve treatment options for those who still become seriously ill. Critical to these efforts is the identification of host factors that are essential to viral entry and replication. Basigin, or CD147, was previously identified as a possible therapeutic target based on the observation that it may act as a coreceptor for SARS-CoV-2, binding to the receptor binding domain of the spike protein. Here, we show that there is no direct interaction between the RBD and basigin, casting doubt on its role as a coreceptor and plausibility as a therapeutic target.
Assuntos
Basigina/metabolismo , COVID-19/metabolismo , COVID-19/virologia , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Animais , Basigina/imunologia , COVID-19/imunologia , Linhagem Celular , Chlorocebus aethiops , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ligação Proteica/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Células Vero , Internalização do VírusRESUMO
The antiviral mechanism of action of iminosugars against many enveloped viruses is hypothesized to be a consequence of misfolding of viral N-linked glycoproteins through inhibition of host endoplasmic reticulum α-glucosidase enzymes. Iminosugar treatment of dengue virus (DENV) infection results in reduced secretion of virions and hence lower viral titres in vitro and in vivo. We investigated whether iminosugars might also affect host receptors important in DENV attachment and uptake and immune responses to DENV. Using a primary human macrophage model of DENV infection, we investigated the effects of maturation with IL-4, DENV-infection and treatment with N-butyl-1-deoxynojirimycin (NB-DNJ) or N-(9-methoxynonyl)-1-DNJ (MON-DNJ) on expression of 11 macrophage receptors. Whereas iminosugars did not affect surface expression of any of the receptors examined, DENV infection significantly reduced surface IFNγ receptor amongst other changes to total receptor expression. This effect required infectious DENV and was reversed by iminosugar treatment. Treatment also affected signalling of the IFNγ receptor and TNFα receptor. In addition, iminosugars reduced ligand binding to the carbohydrate receptor-binding domain of the mannose receptor. This work demonstrates that iminosugar treatment of primary macrophages affects expression and functionality of some key glycosylated host immune receptors important in the dengue life cycle.
Assuntos
Antivirais/farmacologia , Imino Açúcares/farmacologia , Macrófagos/efeitos dos fármacos , Receptores de Interferon/genética , Células Cultivadas , Dengue/virologia , Vírus da Dengue , Regulação para Baixo , Interações entre Hospedeiro e Microrganismos , Humanos , Interleucina-4/farmacologia , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Macrófagos/virologia , Receptor de Manose , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais , Receptor de Interferon gamaRESUMO
Iminosugars have therapeutic potential against a range of diseases, due to their efficacy as glycosidase inhibitors. A major challenge in the development of iminosugar drugs lies in making a compound that is selective for the glycosidase associated with a given disease. We report the synthesis of ToP-DNJ, an antiviral iminosugar-tocopherol conjugate. Tocopherol was incorporated into the design of the iminosugar in order to direct the drug to the liver and immune cells, specific tissues of interest for antiviral therapy. ToP-DNJ inhibits ER α-glucosidase II at low micromolar concentrations and selectively accumulates in the liver in vivo. In cellular assays, the drug showed efficacy exclusively in immune cells of the myeloid lineage. Taken together, these data demonstrate that inclusion of a native metabolite into an iminosugar provides selectivity with respect to target enzyme, target cell, and target tissue.
Assuntos
Antivirais/química , Antivirais/farmacologia , Retículo Endoplasmático/enzimologia , Inibidores de Glicosídeo Hidrolases/farmacologia , 1-Desoxinojirimicina/química , Administração Oral , Animais , Antivirais/síntese química , Vírus da Dengue/efeitos dos fármacos , Inibidores de Glicosídeo Hidrolases/administração & dosagem , Inibidores de Glicosídeo Hidrolases/química , Células HL-60 , Hepacivirus/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Fígado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Ratos , Distribuição Tecidual , Tocoferóis/química , alfa-Glucosidases/metabolismoRESUMO
It has long been thought that iminosugar antiviral activity is a function of inhibition of endoplasmic reticulum-resident α-glucosidases, and on this basis, many iminosugars have been investigated as therapeutic agents for treatment of infection by a diverse spectrum of viruses, including dengue virus (DENV). However, iminosugars are glycomimetics possessing a nitrogen atom in place of the endocyclic oxygen atom, and the ubiquity of glycans in host metabolism suggests that multiple pathways can be targeted via iminosugar treatment. Successful treatment of patients with glycolipid processing defects using iminosugars highlights the clinical exploitation of iminosugar inhibition of enzymes other than ER α-glucosidases. Evidence correlating antiviral activity with successful inhibition of ER glucosidases together with the exclusion of alternative mechanisms of action of iminosugars in the context of DENV infection is limited. Celgosivir, a bicyclic iminosugar evaluated in phase Ib clinical trials as a therapeutic for the treatment of DENV infection, was confirmed to be antiviral in a lethal mouse model of antibody-enhanced DENV infection. In this study we provide the first evidence of the antiviral activity of celgosivir in primary human macrophages in vitro, in which it inhibits DENV secretion with an EC50 of 5 µM. We further demonstrate that monocyclic glucose-mimicking iminosugars inhibit isolated glycoprotein and glycolipid processing enzymes and that this inhibition also occurs in primary cells treated with these drugs. By comparison to bicyclic glucose-mimicking iminosugars which inhibit glycoprotein processing but do not inhibit glycolipid processing and galactose-mimicking iminosugars which do not inhibit glycoprotein processing but do inhibit glycolipid processing, we demonstrate that inhibition of endoplasmic reticulum-resident α-glucosidases, not glycolipid processing, is responsible for iminosugar antiviral activity against DENV. Our data suggest that inhibition of ER α-glucosidases prevents release of virus and is the primary antiviral mechanism of action of iminosugars against DENV.
Assuntos
Antivirais/metabolismo , Vírus da Dengue/crescimento & desenvolvimento , Retículo Endoplasmático/enzimologia , Inibidores Enzimáticos/metabolismo , Imino Açúcares/metabolismo , Indolizinas/metabolismo , alfa-Glucosidases/metabolismo , Animais , Células Cultivadas , Vírus da Dengue/fisiologia , Retículo Endoplasmático/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Imino Açúcares/química , Indolizinas/química , Macrófagos/efeitos dos fármacos , Macrófagos/virologia , Modelos Moleculares , Estrutura Molecular , Liberação de Vírus/efeitos dos fármacosRESUMO
The antiviral activity of UV-4 was previously demonstrated against dengue virus serotype 2 (DENV2) in multiple mouse models. Herein, step-wise minimal effective dose and therapeutic window of efficacy studies of UV-4B (UV-4 hydrochloride salt) were conducted in an antibody-dependent enhancement (ADE) mouse model of severe DENV2 infection in AG129 mice lacking types I and II interferon receptors. Significant survival benefit was demonstrated with 10-20 mg/kg of UV-4B administered thrice daily (TID) for seven days with initiation of treatment up to 48 h after infection. UV-4B also reduced infectious virus production in in vitro antiviral activity assays against all four DENV serotypes, including clinical isolates. A set of purified enzyme, in vitro, and in vivo studies demonstrated that inhibition of endoplasmic reticulum (ER) α-glucosidases and not the glycosphingolipid pathway appears to be responsible for the antiviral activity of UV-4B against DENV. Along with a comprehensive safety package, these and previously published data provided support for an Investigational New Drug (IND) filing and Phases 1 and 2 clinical trials for UV-4B with an indication of acute dengue disease.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Inibidores de Glicosídeo Hidrolases/farmacologia , Dengue Grave/tratamento farmacológico , alfa-Glucosidases/metabolismo , 1-Desoxinojirimicina/administração & dosagem , 1-Desoxinojirimicina/farmacologia , 1-Desoxinojirimicina/uso terapêutico , Animais , Anticorpos Antivirais/sangue , Anticorpos Facilitadores/efeitos dos fármacos , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Células Cultivadas , Chlorocebus aethiops , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Drogas em Investigação , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/enzimologia , Inibidores de Glicosídeo Hidrolases/administração & dosagem , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Humanos , Concentração Inibidora 50 , Camundongos , Monócitos/virologia , Receptores de Interferon/deficiência , Sorogrupo , Dengue Grave/virologia , Células VeroRESUMO
Home telehealth can improve clinical outcomes for conditions that are common among patients with spinal cord injury (SCI). However, little is known about the costs and potential savings associated with its use. We developed clinical scenarios that describe common situations in treatment or prevention of pressure ulcers. We calculated the cost implications of using telehealth for each scenario and under a range of reasonable assumptions. Data were gathered primarily from US Department of Veterans Affairs (VA) administrative records. For each scenario and treatment method, we multiplied probabilities, frequencies, and costs to determine the expected cost over the entire treatment period. We generated low-, medium-, and high-cost estimates based on reasonable ranges of costs and probabilities. Telehealth care was less expensive than standard care when low-cost technology was used but often more expensive when high-cost, interactive devices were installed in the patient's home. Increased utilization of telehealth technology (particularly among rural veterans with SCI) could reduce the incidence of stage III and stage IV ulcers, thereby improving veterans' health and quality of care without increasing costs. Future prospective studies of our present scenarios using patients with various healthcare challenges are recommended.
RESUMO
Following the emergence and global spread of a novel H1N1 influenza virus in 2009, two A(H1N1)pdm/09 influenza vaccines produced from the A/California/07/09 H1N1 strain were selected and used for the national immunisation programme in the United Kingdom: an adjuvanted split virion vaccine and a non-adjuvanted whole virion vaccine. In this study, we assessed the immune responses generated in inbred large white pigs (Babraham line) following vaccination with these vaccines and after challenge with A(H1N1)pdm/09 virus three months post-vaccination. Both vaccines elicited strong antibody responses, which included high levels of influenza-specific IgG1 and haemagglutination inhibition titres to H1 virus. Immunisation with the adjuvanted split vaccine induced significantly higher interferon gamma production, increased frequency of interferon gamma-producing cells and proliferation of CD4(-)CD8(+) (cytotoxic) and CD4(+)CD8(+) (helper) T cells, after in vitro re-stimulation. Despite significant differences in the magnitude and breadth of immune responses in the two vaccinated and mock treated groups, similar quantities of viral RNA were detected from the nasal cavity in all pigs after live virus challenge. The present study provides support for the use of the pig as a valid experimental model for influenza infections in humans, including the assessment of protective efficacy of therapeutic interventions.
Assuntos
Adjuvantes Imunológicos/farmacologia , Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Subpopulações de Linfócitos T/imunologia , Animais , Linhagem Celular , Proliferação de Células , Cães , Ensaio de Imunoadsorção Enzimática , ELISPOT , Citometria de Fluxo , Fluoresceínas , Imunoglobulina G/sangue , Leucócitos Mononucleares , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas , Succinimidas , Sus scrofaRESUMO
The reliability and validity of assessments and diagnoses made via home telehealth was measured in 42 patients with spinal cord injury. Two telehealth modalities were investigated: telephone-only contact and videoconferencing. The results were compared with a reference (gold-standard) method, the in-person assessment and diagnosis of skin integrity and pressure ulcers. The agreement on the presence of a pressure ulcer was excellent for both telephone and videoconferencing approaches (92% for telephone, 97% for videoconferencing). The diagnoses of the stage of pressure ulcer (on an ordinal scale of 0-4) made via telephone and videoconferencing showed substantial to almost perfect agreement with the in-person diagnoses (Spearman's rho of 0.76 and 0.83, respectively). There was a tendency for the measurements of wound volume to be somewhat larger in the telephone and videoconferencing modalities compared to those made in-person. Bland-Altman plots showed that videoconferencing gave substantially narrower 95% limits of agreement. The findings of the study indicate that telephone contact can be a useful tool for identifying the presence of a pressure ulcer, but videoconferencing is required to obtain an evaluation reasonably close to that of a home visit.