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

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

A patient with hereditary angioedema and systemic lupus erythematosus: Coincidence or coexistence?

Angioedema is classified into two major groups: mast cell-mediated (histaminergic) and bradykinin-mediated angioedema. Hereditary angioedema and acquired angioedema are well-defined groups of bradykinin-mediated angioedema. Both hereditary angioedema and acquired angioedema demonstrate a similar clinical presentation and can be challenging to differentiate. The prevalence of autoimmune diseases is higher in patients with HAE and lupus is an autoimmune disease associated with HAE. In this case, we aimed to present a male patient who was monitored with the diagnosis of HAE and developed systemic lupus erythematosus (SLE) in the follow-up and to discuss whether the patient had hereditary angioedema and concomitant lupus, or acquired angioedema secondary to SLE. [Med-Science 2020; 9(2.000): 512-4

THE EFFECT OF TREATMENT TIME ON DIMENSIONALLY STABILITY, MOISTURE CONTENT AND MECHANICAL PROPERTIES OF HEAT TREATED ANATOLIAN CHESTNUT (CASTANEA SATIVA MILL.) WOOD

In this study, the effect of treatment time on dimensional stability, moisture content, and mechanical properties of heat-treated Anatolian chestnut (Castanea sativa Mill.) were investigated. Test specimens were subjected to a temperature of 180 degrees C at atmospheric pressure for five different treatment times (2, 4, 6, 8, and 12 hours). After the heat treatment of the specimens was completed, their moisture contents at relative humidity (RH) conditions of 45, 55, 65, 80, and 95\%, their dimensional stabilities, their mechanical properties, e.g., bending strength, modulus of elasticity, and compression strength, were determined. The data obtained were analyzed using variance analysis, and then the statistical analysis of Tukey's test was conducted. The results showed that heat treatment resulted in decreased (i.e., improved) moisture content, enhanced dimensional stability, and reductions of the mechanical properties. The decrease of mechanical properties that resulted from the 12-hour test was greater than the reductions observed for the tests that lasted 2, 4, 6, and 8 hours

Cyanoacrylate Associated Foreign Body Granulomatous Gastritis: A Report Of Three Cases

Granulomas are rarely seen in gastric biopsies mostly as an involvement of granulomatous diseases like sarcoidosis, Crohn's disease, infections, neoplasms, and vasculitis. Here, we claim cyanoacrylate as a foreign body type granuloma-causing agent in the stomach after vascular embolisation. We present cyanoacrylate associated gastric changes of three cases: two endoscopic biopsies and one gastric resection. In two cases, cyanoacrylate associated ulcers and granulomatous inflammation were observed in gastric mucosal biopsies following endoscopic examination after 7 months and 6 years of the glue injections, respectively. In the third case, the cyanoacrylate injection was performed 2 months prior to the surgery. Then the patient underwent distal pancreatectomy for pancreatic adenocarcinoma and during the operation a gastric mass was resected with a suspicion of tumoral infiltration. These three cases demonstrated that glue exposure causes active chronic inflammation with foreign body type granulomas, mucosal ulceration, and bleeding in the gastric mucosa. Even further, it can induce mass formation in the injection sites.PubMe