RESUMEN
The aim of this study was to examine the role of pre-existing dysphagia as a risk factor for COVID-19 severity among adults ≥50 years of age presenting to the emergency department (ED). This was a retrospective cohort study that used electronic health record data from two Midwestern EDs in the same health care system. The sample included patients ≥50 years of age who tested positive for SARS-COV-2 during an ED visit between March 15, 2020 and November 19, 2020. Patients were dichotomized based on documented history of dysphagia. The primary outcome was the highest World Health Organization COVID-19 clinical severity score within 30-days of ED arrival. Patients with a score of <4 were classified as non-severe whereas a score ≥4 was considered severe. Chi-square tests were used to assess differences in clinical severity scores between patients with and without dysphagia. A logistic regression model was created to estimate the odds of a severe COVID-19 clinical score. The sample included 126 patients without dysphagia and 40 patients with dysphagia. Patients with a history of dysphagia were more likely to develop severe COVID-19 disease compared to patients without (65.0% vs. 41.3%, p = 0.015). In multivariable analysis, patients with preexisting dysphagia (OR 2.38, 95% CI: 1.05-5.42; p = 0.038) and diabetes (OR 2.42 95% CI: 1.15-5.30; p = 0.021) had significantly increased odds of developing severe COVID-19. This study showed that a pre-existing diagnosis of dysphagia was independently associated with COVID-19 severity in adults ≥50 years of age.
RESUMEN
BACKGROUND: Type 2 (T2) inflammation drives airway dysfunction in many patients with asthma; yet, we lack a comprehensive understanding of the airway immune cell types and networks that sustain this inflammation. Moreover, defects in the airway immune system in patients with asthma without T2 inflammation are not established. OBJECTIVES: To determine the gene networks that sustain T2 airway inflammation in T2-high asthma and to explore the gene networks that characterize T2-low asthma. METHODS: Network analysis of sputum cell transcriptome expression data from 84 subjects with asthma and 27 healthy control subjects was used to identify immune cell type-enriched networks that underlie asthma subgroups. RESULTS: Sputum T2 gene expression was characterized by an immune cell network derived from multiple innate immune cells, including eosinophils, mast cells/basophils, and inflammatory dendritic cells. Clustering of subjects within this network stratified subjects into T2-high and T2-low groups, but it also revealed a subgroup of T2-high subjects with uniformly higher expression of the T2 network. These "T2-ultrahigh subjects" were characterized clinically by older age and more severe airflow obstruction and pathologically by a second T2 network derived from T2-skewed, CD11b+/CD103-/IRF4+ classical dendritic cells. Subjects with T2-low asthma were differentiated from healthy control subjects by lower expression of a cytotoxic CD8+ T-cell network, which was negatively correlated with body mass index and plasma IL-6 concentrations. CONCLUSIONS: Persistent airway T2 inflammation is a complex construct of innate and adaptive immunity gene expression networks that are variable across individuals with asthma and persist despite steroid treatment. Individuals with T2-low asthma exhibit an airway deficiency in cytotoxic T cells associated with obesity-driven inflammation.
Asunto(s)
Asma/inmunología , Perfilación de la Expresión Génica/métodos , Adulto , Asma/complicaciones , Asma/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Estudios de Casos y Controles , Células Dendríticas/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/inmunología , Obesidad/metabolismo , Esputo/inmunologíaRESUMEN
In our recent article [1], it has come to our attention that the sample labels are not consistent between Table 1, the data labels deposited in the Sequence Read Archive, and Additional file 1: Table S2. We are therefore providing an updated Additional file 1: Table S2 so identical samples now have the same label.
RESUMEN
BACKGROUND: Respiratory illness caused by viral infection is associated with the development and exacerbation of childhood asthma. Little is known about the effects of respiratory viral infections in the absence of illness. Using quantitative PCR (qPCR) for common respiratory viruses and for two genes known to be highly upregulated in viral infections (CCL8/CXCL11), we screened 92 asthmatic and 69 healthy children without illness for respiratory virus infections. RESULTS: We found 21 viral qPCR-positive and 2 suspected virus-infected subjects with high expression of CCL8/CXCL11. We applied a dual RNA-seq workflow to these subjects, together with 25 viral qPCR-negative subjects, to compare qPCR with sequencing-based virus detection and to generate the airway transcriptome for analysis. RNA-seq virus detection achieved 86% sensitivity when compared to qPCR-based screening. We detected additional respiratory viruses in the two CCL8/CXCL11-high subjects and in two of the qPCR-negative subjects. Viral read counts varied widely and were used to stratify subjects into Virus-High and Virus-Low groups. Examination of the host airway transcriptome found that the Virus-High group was characterized by immune cell airway infiltration, downregulation of cilia genes, and dampening of type 2 inflammation. Even the Virus-Low group was differentiated from the No-Virus group by 100 genes, some involved in eIF2 signaling. CONCLUSIONS: Respiratory virus infection without illness is not innocuous but may determine the airway function of these subjects by driving immune cell airway infiltration, cellular remodeling, and alteration of asthmogenic gene expression.
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Asma/genética , Interacciones Huésped-Patógeno/genética , Infecciones por Virus ARN/genética , Infecciones por Virus ARN/virología , Virus ARN , Infecciones del Sistema Respiratorio/genética , Infecciones del Sistema Respiratorio/virología , Transcriptoma , Asma/complicaciones , Asma/inmunología , Estudios de Casos y Controles , Niño , Perfilación de la Expresión Génica , Regulación Viral de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Interacciones Huésped-Patógeno/inmunología , Humanos , Infecciones por Virus ARN/complicaciones , Infecciones por Virus ARN/inmunología , Virus ARN/genética , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/virología , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/inmunología , Análisis de Secuencia de ARNRESUMEN
Bifunctional electrophiles have been used in various chemopreventive, chemotherapeutic, and bioconjugate applications. Many of their effects in biological systems are traceable to their reactive properties, whereby they can modify nucleophilic sites in DNA, proteins, and other cellular molecules. Previously, we found that two different bifunctional electrophiles--diethyl acetylenedicarboxylate and divinyl sulfone--exhibited a strong enhancement of toxicity when compared with analogous monofunctional electrophiles in both human colorectal carcinoma cells and baker's yeast. Here, we have compared the toxicities for a broader panel of homobifunctional electrophiles bearing diverse electrophilic centers (e.g., isothiocyanate, isocyanate, epoxide, nitrogen mustard, and aldehyde groups) to their monofunctional analogues. Each bifunctional electrophile showed at least a 3-fold enhancement of toxicity over its monofunctional counterpart, although in most cases, the differences were even more pronounced. To explain their enhanced toxicity, we tested the ability of each bifunctional electrophile to cross-link recombinant yeast thioredoxin 2 (Trx2), a known intracellular target of electrophiles. The bifunctional electrophiles were capable of cross-linking Trx2 to itself in vitro and to other proteins in cells exposed to toxic concentrations. Moreover, most cross-linkers were preferentially reactive with thiols in these experiments. Collectively, our results indicate that thiol-reactive protein cross-linkers in general are much more potent cytotoxins than analogous monofunctional electrophiles, irrespective of the electrophilic group studied.
Asunto(s)
Reactivos de Enlaces Cruzados/química , Tiorredoxinas/química , Aldehídos/química , Aldehídos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Reactivos de Enlaces Cruzados/toxicidad , Compuestos Epoxi/química , Compuestos Epoxi/toxicidad , Humanos , Isocianatos/química , Isocianatos/toxicidad , Mecloretamina/química , Mecloretamina/toxicidad , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismoRESUMEN
Thioredoxin protects cells against oxidative damage by reducing disulfide bonds in improperly oxidized proteins. Previously, we found that the baker's yeast cytosolic thioredoxin Trx2 undergoes cross-linking to form several protein-protein complexes in cells treated with the bifunctional electrophile divinyl sulfone (DVSF). Here, we report that the peroxiredoxin Tsa1 and the thioredoxin reductase Trr1, both of which function in a redox relay network with thioredoxin, become cross-linked in complexes with Trx2 upon DVSF treatment. Treatment of yeast with other bifunctional electrophiles, including diethyl acetylenedicarboxylate (DAD), mechlorethamine (HN2), and 1,2,3,4-diepoxybutane (DEB), resulted in the formation of similar cross-linked complexes. Cross-linking of Trx2 and Tsa1 to other proteins by DVSF and DAD is dependent on modification of the active site Cys residues within these proteins. In addition, the human cytosolic thioredoxin, cytosolic thioredoxin reductase, and peroxiredoxin 2 form cross-linked complexes to other proteins in the presence of DVSF, although each protein shows different susceptibilities to modification by DAD, HN2, and DEB. Taken together, our results indicate that bifunctional electrophiles potentially disrupt redox homeostasis in yeast and human cells by forming cross-linked complexes between thioredoxins and their redox partners.