A note on the cracked plates reinforced by a line stiffener

The problem of a cracked plate reinforced by a line stiffener is reconsidered. The original solution of this problem was given in the literature. Also, a variation of the problem with debonding between the plate and the stiffener near the cracked region was reported in the literature. However, the special case of the problem in which the crack tip terminates at the stiffener does not appear to have been studied. In practice, the solution may be necessary in order to assess the crack arrest effectiveness of the stiffener. The problem of a stiffened plate with a crack is reformulated, the asymptotic stress state near the crack tip terminating at the stiffener is examined, and numerical results are given for various stiffness constants

A pressurized cylindrical shell with a fixed end which contains an axial part-through or through crack

A cylindrical shell having a very stiff and plate or a flange is considered. It is assumed that near the end the cylinder contains an axial flaw which may be modeled as a part through surface crack or a through crack. The effect of the end constraining on the stress intensity factor which is the main fracture mechanics parameter is studied. The applied loads acting on the cylinder are assumed to be axisymmetric. Thus the crack problem under consideration is symmetric with respect to the plane of the crack and consequently only the Mode 1 stress intensity factors are nonzero. With this limitation, the general perturbation problem for a cylinder with a built in end containing an axial crack is considered. Reissner's shell theory is used to formulate the problem. The part through crack problem is treated by using a line spring model. In the case of a crack tip terminating at the fixed end it is shown that the integral equations of the shell problem has the same generalized Cauchy kernel as the corresponding plane stress elasticity problem

The crack problem in a reinforced cylindrical shell

A partially reinforced cylinder containing an axial through crack is considered. The reinforcement is assumed to be fully bonded to the main cylinder. The composite cylinder is thus modelled by a nonhomogeneous shell having a step change in the elastic properties at the z = 0 plane, z being the axial coordinate. Using a Reissner type transverse shear theory the problem is reduced to a pair of singular integral equations. In the special case of a crack tip touching the bimaterial interface it is shown that the dominant parts of the kernels of the integral equations associated with both membrane loading and bending of the shell reduce to the generalized Cauchy kernel obtained for the corresponding plane stress case. The integral equations are solved and the stress intensity factors are given for various crack and shell dimensions. A bonded fiberglass reinforcement which may serve as a crack arrestor is used as an example

A cylindrical shell with an arbitrarily oriented crack

The general problem of a shallow shell with constant curvatures is considered. It is assumed that the shell contains an arbitrarily oriented through crack and the material is specially orthotropic. The nonsymmetric problem is solved for arbitrary self equilibrating crack surface tractions, which, added to an appropriate solution for an uncracked shell, would give the result for a cracked shell under most general loading conditions. The problem is reduced to a system of five singular integral equations in a set of unknown functions representing relative displacements and rotations on the crack surfaces. The stress state around the crack tip is asymptotically analyzed and it is shown that the results are identical to those obtained from the two dimensional in plane and antiplane elasticity solutions. The numerical results are given for a cylindrical shell containing an arbitrarily oriented through crack. Some sample results showing the effect of the Poisson's ratio and the material orthotropy are also presented

The crack problem in a reinforced cylindrical shell

In this paper a partially reinforced cylinder containing an axial through crack is considered. The reinforcement is assumed to be fully bonded to the main cylinder. The composite cylinder is thus modelled by a nonhomogeneous shell having a step change in the elastic properties at the z=0 plane, z being the axial coordinate. Using a Reissner type transverse shear theory the problem is reduced to a pair of singular integral equations. In the special case of a crack tip touching the bimaterial interface it is shown that the dominant parts of the kernels of the integral equations associated with both membrane loading and bending of the shell reduce to the generalized Cauchy kernel obtained for the corresponding plane stress case. The integral equations are solved and the stress intensity factors are given for various crack and shell dimensions. A bonded fiberglass reinforcement which may serve as a crack arrestor is used as an example

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

Human genetic and immunological determinants of critical COVID-19 pneumonia

SARS-CoV-2 infection is benign in most individuals but, in ˜10% of cases, it triggers hypoxemic COVID-19 pneumonia, which becomes critical in ˜3% of cases. The ensuing risk of death (˜1%) doubles every five years from childhood onward and is ˜1.5 times greater in men than in women. What are the molecular and cellular determinants of critical COVID-19 pneumonia? Inborn errors of type I IFNs, including autosomal TLR3 and X-linked TLR7 deficiencies, are found in ˜1-5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing autoantibodies neutralizing IFN-α, –β, and/or –ω, which are more common in men than in women, are found in ˜15-20% of patients with critical pneumonia over 70 years old, and a lower proportion in younger patients. Thus, at least 15% of cases of critical COVID-19 pneumonia can apparently be explained. The TLR3- and TLR7-dependent production of type I IFNs by respiratory epithelial cells and plasmacytoid dendritic cells, respectively, is essential for host defense against SARS-CoV-2. In ways that can depend on age and sex, insufficient type I IFN immunity in the respiratory tract during the first few days of infection may account for the spread of the virus, leading to pulmonary and systemic inflammation

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-α and/or IFN-ω are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or IFN-ω (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or IFN-ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases