A genetically modulated Toll-like receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome.

Dysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To investigate innate immune functions, we stimulated ex vivo peripheral blood cells from MIS-C patients with agonists of Toll-like receptors (TLR), key innate immune response initiators. We found severely dampened cytokine responses and elevated gene expression of negative regulators of TLR signaling. Increased plasma levels of zonulin, a gut leakage marker, were also detected. These effects were also observed in fully convalescent children months after MIS-C recovery. When we investigated the genetic background of patients in relation to TLR responsiveness, we found that cells from MIS-C children carrying rare heterozygous variants of lysosomal trafficking regulator (LYST) were less refractory to TLR stimulation and exhibited lysosomal and mitochondrial abnormalities with altered energy metabolism. Moreover, these rare LYST variant heterozygous carriers tended to exhibit unfavorable clinical laboratory indicators of inflammation, including more profound lymphopenia. The results of our observational study have several implications. First, TLR hyporesponsiveness may be associated with hyperinflammation and/or excessive or prolonged stimulation with gut-originated TLR ligands. Second, TLR hyporesponsiveness during MIS-C may be protective, since LYST variant heterozygous carriers exhibited reduced TLR hyporesponsiveness and unfavorable clinical laboratory indicators of inflammation. Thus, links may exist between genetic background, ability to establish a refractory immune state, and MIS-C clinical spectrum. Third, the possibility exists that prolonged TLR hyporesponsiveness is one of the mechanisms driving long coronavirus disease (COVID), which highlights the need to monitor long-term consequences of MIS-C

Closure and the Book of Virgil

Taking its initial inspiration from Lipking’s first foray into what is now known as ‘career criticism’ this chapter considers the ‘wheel of Virgil’ and the works of the poet’s ancient biographers in structuring structuring readers’ understanding of his three canonical works and of the connections between them. Rejecting the idea that the career pattern necessarily means that we must see Virgil as progressing towards ever greater acceptance of the political realities of his day, the chapter instead looks to different models of reading, in which attention to intratextual echoes prevents purely linear and teleological interpretations. It is proposed that the Book of Virgil demands a circular rather than a linear pattern of reading, and that the role played by the image of shade and darkness, and the word umbra in particular, is to unify the three works in rejecting the triumph of epic and empir

Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Prevalence and Associated Risk Factors in a Large Cohort of US Children.

BACKGROUND: Household transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may play a key role in times of increased infection, particularly among children. We aimed to determine the prevalence of SARS-CoV-2 antibodies and identify risk factors associated with SARS-CoV-2 antibody positivity in children. METHODS: Unvaccinated children aged 18 months to 11 years between August 2022 and June 2023 underwent oral fluid testing for SARS-CoV-2 antibodies. Caregivers completed electronic surveys at 4 major healthcare practices in Northern and Central New Jersey. Information was collected on demographics, household size, vaccination status, and prior SARS-CoV-2-related illness. Multivariable logistic regression determined individual and household-level factors associated with SARS-CoV-2 antibody positivity. RESULTS: A total of 870 children provided tests and corresponding surveys. Children were predominantly Hispanic (37%) or non-Hispanic Black (30%), and on average 5.7 years old. Overall SARS-CoV-2 antibody positivity was 68%. Risk factors for SARS-CoV-2 positivity include Hispanic or non-Hispanic Black race/ethnicity (adjusted odds ratios [aOR], 2.29 and 1.95 vs. White race/ethnicity; CONCLUSIONS: There is high burden of SARS-CoV-2 infection among children over time. Adult vaccination appears to be a protective factor in helping to mitigate coronavirus disease 2019 (COVID-19) infection among children. Increased vaccination of adults in the community can help inform COVID-19 prevention strategies for minors in the household