ABSTRACT
Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variants impacting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Treg cells induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.
ABSTRACT
Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infections that occurs in the pediatric population. We sought to characterize T cell responses in MIS-C compared to COVID-19 and pediatric hyperinflammatory syndromes. MIS-C was distinct from COVID-19 and hyperinflammatory syndromes due to an expansion of T cells expressing TRBV11-2 that was not associated with HLA genotype. Children diagnosed with MIS-C, but who were negative for SARS-CoV-2 by PCR and serology, did not display Vß skewing. There was no difference in the proportion of T cells that became activated after stimulation with SARS-CoV-2 peptides in children with MIS-C compared to convalescent COVID-19. The frequency of SARS-CoV-2-specific TCRs and the antigens recognized by these TCRs were comparable in MIS-C and COVID-19. Expansion of Vß11-2+ T cells was a specific biomarker of MIS-C patients with laboratory confirmed SARS-CoV-2 infections. Children with MIS-C had robust antigen-specific T cell responses to SARS-CoV-2.
Subject(s)
COVID-19 , Connective Tissue Diseases , COVID-19/complications , Child , Humans , SARS-CoV-2 , Systemic Inflammatory Response Syndrome , T-LymphocytesABSTRACT
Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized in association with increased Notch1 expression. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variant impacting inflammation and autoimmunity pathways, including dominant negative mutations in the Notch1 regulators NUMB and NUMBL . Notch1 signaling in Treg cells induced CD22, leading to their destabilization in an mTORC1 dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.
ABSTRACT
Technological skills development is a central issue for a country’s educational and social policies. Throughout their school career, from primary to secondary education and later in higher education, students have the opportunity to build and develop various skills, including technological. Considering the different needs and different uses that these skills encompass, these will certainly be necessary and useful in students’ academic and professional life. This study reports on an investigation of technological skills development in higher education. It aims to analyze the relevance of technologies integration, which technological skills are built and developed by higher education students, and what their perception about the importance of technological skills is. Based on a literature review, an online questionnaire was designed and applied to 217 students from three public higher education institutions located in the North, Center, and South of Portugal. This intended to verify which areas of technological skills (from the European Digital Competence Framework for Citizens) are most developed and to understand respective repercussions. It is concluded that the balanced development of students’ technological skills in higher education is crucial for their personal, social, and professional future and consequently, for their quality of life, with the integration of digital technologies being relevant in the change of the academic work organization, in the relations between learners, teachers, and institutions, and in the new ways of teaching and learning.
ABSTRACT
OBJECTIVES: Healthcare workers face distinct occupational challenges that affect their personal health, especially during a pandemic. In this study we compare the characteristics and outcomes of Covid-19 patients who are and who are not healthcare workers (HCW). METHODS: We retrospectively analyzed a cohort of 2,842 adult patients with known HCW status and a positive SARS-CoV-2 RT-PCR test presenting to a large academic medical center emergency department (ED) in New York State from March 21 2020 through June 2020. Early in the pandemic we instituted a policy to collect data on patient occupation and exposures to suspected Covid-19. The primary outcome was hospital admission. Secondary outcomes were ICU admission, need for invasive mechanical ventilation (IMV), and mortality. We compared baseline characteristics and outcomes of Covid-19 adult patients based on whether they were or were not HCW using univariable and multivariable analyses. RESULTS: Of 2,842 adult patients (mean age 53+/-19 years, 53% male) 193 (6.8%) were HCWs and 2,649 (93.2%) were not HCWs. Compared with non-HCW, HCWs were younger (43 vs 53 years, P<0.001), more likely female (118/193 [61%] vs 1211/2649 [46%], P<0.001), and more likely to have a known Covid-19 exposure (161/193 [83%] vs 946/2649 [36%], P<0.001), but had fewer comorbidities. On presentation to the ED, HCW also had lower frequencies of tachypnea (12/193 [6%] vs 426/2649 [16%], P<0.01), hypoxemia (15/193 [8%] vs 564/2649 [21%], P<0.01), bilateral opacities on imaging (38/193 [20%] vs 1189/2649 [45%], P<0.001), and lymphocytopenia (6/193 [3%] vs 532/2649 [20%], P<0.01) compared to non-HCWs. Direct discharges home from the ED were more frequent in HCW 154/193 (80%) vs 1275/2649 (48%) p<0.001). Hospital admissions (38/193 [20%] vs 1264/2694 [47%], P<0.001), ICU admissions (7/193 [3%] vs 321/2694 [12%], P<0.001), need for IMV (6/193 [3%] vs 321/2694 [12%], P<0.001) and mortality (2/193 [1%] vs 219/2694 [8%], P<0.01) were lower than among non-HCW. After controlling for age, sex, comorbidities, presenting vital signs and radiographic imaging, HCW were less likely to be admitted (OR 0.6, 95%CI 0.3-0.9) than non HCW. CONCLUSIONS: Compared with non HCW, HCW with Covid-19 were younger, had less severe illness, and were less likely to be admitted.