Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Preregistration in infant research - A primer

Preregistration, the act of specifying a research plan in advance, is becoming more common in scientific research. Infant researchers contend with unique problems that might make preregistration particularly challenging. Infants are a hard‐to‐reach population, usually yielding small sample sizes, they can only complete a limited number of trials, and they can be excluded based on hard‐to‐predict complications (e.g., parental interference, fussiness). In addition, as effects themselves potentially change with age and population, it is hard to calculate an a priori effect size. At the same time, these very factors make preregistration in infant studies a valuable tool. A priori examination of the planned study, including the hypotheses, sample size, and resulting statistical power, increases the credibility of single studies and adds value to the field. Preregistration might also improve explicit decision making to create better studies. We present an in‐depth discussion of the issues uniquely relevant to infant researchers, and ways to contend with them in preregistration and study planning. We provide recommendations to researchers interested in following current best practices

An economic analysis of community-level fast food prices and individual-level fast food intake: A longitudinal study

While dietary intake is shaped by cost, there is minimal research on the association between community-level food prices and dietary intake

EDS, HRTEM/STEM, and X-ray absorption spectroscopy studies of co-substituted maghemite nanoparticles

A detailed study of the composition and structure of Co-doped maghemite nanoparticles with systematically varying composition has been carried out by transmission electron microscopy (TEM) techniques, such as high-resolution TEM, scanning TEM, and energy-dispersive X-ray spectrometry, and by X-ray absorption spectroscopy at the Fe and Co K-edges, analyzing both the extended X-ray absorption fine structure and the X-ray absorption near-edge structure regions. The latter techniques, in particular, allow us to determine the degree of inversion of divalent and trivalent metal ions among the octahedral and tetrahedral sites in the spinel structure of the nanoparticles and give detailed information on atomic distances. The samples consist of single-crystal nanoparticles with a composition corresponding to the Fe/Co ratio used in the synthesis. The degree of inversion is quite similar for all samples and close to the value found in a pure cobalt ferrite bulk sample. © 2013 American Chemical Society