Manufacturability and Analysis of Topologically Optimized Continuous Fiber Reinforced Composites

Researchers are unlocking the potential of Continuous Fiber Reinforced Composites for producing components with greater strength-to-weight ratios than state of the art metal alloys and unidirectional composites. The key is the emerging technology of topology optimization and advances in additive manufacturing. Topology optimization can fine tune component geometry and fiber placement all while satisfying stress constraints. However, the technology cannot yet robustly guarantee manufacturability. For this reason, substantial post-processing of an optimized design consisting of manual fiber replacement and subsequent Finite Element Analysis (FEA) is still required. To automate this post-processing in two dimensions, two (2) algorithms were developed. The first one is aimed at filling the space of a topologically optimized component with fibers of prescribed thickness. The objective is to produce flawless fiber paths, meaning no self-intersections, no tight turns, and no overlapping between fibers. It does so by leveraging concepts from elementary geometry and the Signed Distance Function of a topologically optimized domain. The manufacturable fiber paths are represented using Non-Uniform Rational Basis Splines, which can be readily conveyed to a 3D-printer as The second algorithm then calls a meshing routine to spatially discretize the topologically optimized domain. It takes input from the first algorithm to automatically create and append, orientations and material flags to the spatial elements produced by the meshing routine. Finally, it generates output that is then input to FEA software. The software is written in the C-programming language using the PETSc library. A load case is validated against MSC NASTRAN

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

BackgroundWe 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 similar to 80% of cases.MethodsWe 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.ResultsNo 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=1.1x10(-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=2.1x10(-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=3.4x10(-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=7.7x10(-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=1.68x10(-5)).ConclusionsRare 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