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

L'entreprise et l'economie du XXe siecle. Etude internationale & l'initiative. Tome 2 : la fornation des decisions et l'entreprise. Deuxieme edition. Tome 3 : La croif sance de l'entreprise et le profit.

H45-46Paris, Presses Universitaires de France, 1956-1968.

Science shaping the future?

Full report `Science shaping the future? Technology Foresight and its impact' held at GPE/0987SIGLEAvailable from British Library Document Supply Centre-DSC:7673.163(97) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Image-guided spine surgery: state of the art and future directions

Navigation technology is a widely available tool in spine surgery and has become a part of clinical routine in many centers. The issue of where and when navigation technology should be used is still an issue of debate. It is the aim of this study to give an overview on the current knowledge concerning the technical capabilities of image-guided approaches and to discuss possible future directions of research and implementation of this technique. Based on a Medline search total of 1,462 publications published until October 2008 were retrieved. The abstracts were scanned manually for relevance to the topics of navigated spine surgery in the cervical spine, the thoracic spine, the lumbar spine, as well as ventral spine surgery, radiation exposure, tumor surgery and cost-effectivity in navigated spine surgery. Papers not contributing to these subjects were deleted resulting in 276 papers that were included in the analysis. Image-guided approaches have been investigated and partially implemented into clinical routine in virtually any field of spine surgery. However, the data available is mostly limited to small clinical series, case reports or retrospective studies. Only two RCTs and one metaanalysis have been retrieved. Concerning the most popular application of image-guided approaches, pedicle screw insertion, the evidence of clinical benefit in the most critical areas, e.g. the thoracic spine, is still lacking. In many other areas of spine surgery, e.g. ventral spine surgery or tumor surgery, image-guided approaches are still in an experimental stage. The technical development of image-guided techniques has reached a high level as the accuracies that can be achieved technically meet the anatomical demands. However, there is evidence that the interaction between the surgeon (‘human factor’) and the navigation system is a source of inaccuracy. It is concluded that more effort needs to be spend to understand this interaction