Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Oncoplastic breast conservation surgery is oncologically safe when compared to wide local excision and mastectomy

Background: Support for the oncological safety of oncoplastic breast conservation surgery (OBCS) is mostly based on evidence comparing recurrence rates after OBCS to wide local excision (WLE). However, OBCS is often indicated for larger cancers and oncological results should also be compared to patients treated with mastectomy. In this study we compared recurrence and survival following OBCS, mastectomy and WLE. Methods: Patients treated with OBCS between 2009 and 2012 were identified from a prospectively maintained database. For comparison, consecutive patients treated with WLE or mastectomy with or without immediate reconstruction (Ms ± IR) over the same time period were identified. Histological variables of patients were compared using Fisher Exact or Chi squared tests, and recurrence and survival were compared using Kaplan-Meier and Cox regression survival analysis. Results: 980 patients' data were analysed (OBCS: n = 104; WLE: n = 558; Ms ± IR: n = 318). Tumour size, grade, nodal status, ER, and PR expression of patients treated with OBCS were all significantly more adverse compared with patients treated with WLE (p < 0.001). These histological variables were similar in patients treated with Ms ± IR and OBCS. 5-year local recurrence rates were similar in all three groups (WLE: 3.4 per cent, OBCS: 2 per cent, Ms ± IR: 2.6 per cent; log rank = 0.973), while distant recurrence rates were higher after Ms ± IR and OBCS (Ms ± IR:13.1 per cent, OBCS:7.5 per cent, WLE:3.3 per cent; log rank: p < 0.001). Conclusion: OBCS is oncologically safe in patients even when histological results are similar to patients treated with Ms ± IR

Comparison of visual and automated assessment of microvessel density and their impact on outcome in primary operable invasive ductal breast cancer

Angiogenesis is essential for tumor growth and metastasis, and several studies have reported increased angiogenesis, as quantified by microvessel density, to be a powerful prognostic tool in breast cancer. Therefore, there is considerable interest in automated assessment of microvessel density with possible benefits in improved accuracy, increased precision, and handling workload. Visual and automated assessment of microvessel density (CD34+) and survival were examined in patients with primary operable invasive ductal breast cancer. Tissue microarrays (n = 356 patients) immunostained for microvessel density (CD34+) were scored visually and automatically with the Slidepath Tissue IA system (Dublin, Ireland). Visual and automated microvessel density (CD34+) were in agreement (interclass correlation coefficient = 0.69, P < .001). Visual but not the automated method for microvessel density (CD34+) was associated with locoregional treatment and metastasis. On univariate survival analysis, visual but not automated method for microvessel density (CD34+) was associated with recurrence-free and cancer-specific survival in patients with invasive ductal breast cancer (P < .01). Although automated assessment of microvessel density (CD34+) is in reasonable agreement, it poorly predicts outcome in patients with operable invasive ductal breast cancer

Comparison of visual and automated assessment of HER2 status and their impact on outcome in primary operable invasive ductal breast cancer

Aims: To compare visual and computerized image analysis of HER2 immunohistochemistry (IHC) with fluorescence in-situ hybridization (FISH) for HER2 status, and to examine the relationships with outcome in patients with primary operable invasive ductal breast cancer. <p/>Methods and results: Tissue microarrays for 431 breast cancer patients were used to compare different approaches to the assessment of HER2 status. The cores were scored visually and with the Slidepath Tissue IA system, using the NICE-approved scoring system for the HercepTest, as well as by FISH. The agreement between visual and image analysis of HER2 IHC was excellent [interclass correlation coefficient (ICCC) = 0.95, rs = 0.90, r = 0.91, k = 0.81, and P < 0.001]. The agreement of HER2 FISH with visual and image analysis of HER2 IHC was also excellent (ICCC = 0.95 and ICCC = 0.92, respectively). Univariate survival analysis showed equivalent associations of visual and image analysis of HER2 and HER2 FISH with both recurrence-free survival (all P < 0.01) and cancer-specific survival (all P < 0.05) in patients with invasive ductal breast cancer. <p/>Conclusions: Computerized image analysis of HER2 IHC gives results comparable to those obtained with visual assessment, with possible advantages in diagnostic pathology

Computed tomography analysis of the cranium of Champsosaurus lindoei and implications for choristoderan neomorphic ossification

Choristoderes are extinct neodiapsid reptiles that are well known for their unusual cranial anatomy, possessing an elongated snout and expanded temporal arches. Although choristodere skulls are well described externally, their internal anatomy remains unknown. An internal description was needed to shed light on peculiarities of the choristodere skull, such as paired gaps on the ventral surface of the skull that may pertain to the fenestra ovalis, and a putative neomorphic ossification in the lateral wall of the braincase. Our goals were: (i) to describe the cranial elements of Champsosaurus lindoei in three dimensions; (ii) to describe paired gaps on the ventral surface of the skull to determine if these are indeed the fenestrae ovales; (iii) to illustrate the morphology of the putative neomorphic bone; and (iv) to consider the possible developmental and functional origins of the neomorph. We examined the cranial anatomy of the choristodere Champsosaurus lindoei (CMN 8920) using high-resolution micro-computed tomography scanning. We found that the paired gaps on the ventral surface of the skull do pertain to the fenestrae ovales, an unusual arrangement that may be convergent with some plesiosaurs, some aistopods, and some urodeles. The implications of this morphology in Champsosaurus are unknown and will be the subject of future work. We found that the neomorphic bone is a distinct ossification, but is not part of the wall of the brain cavity or the auditory capsule. Variation in the developmental pathways of cranial bones in living amniotes was surveyed to determine how the neomorphic bone may have developed. We found that the chondrocranium and splanchnocranium show little to no variation across amniotes, and the neomorphic bone is therefore most likely to have developed from the dermatocranium; however, the stapes is a pre-existing cranial element that is undescribed in choristoderes and may be homologous with the neomorphic bone. If the neomorphic bone is not homologous with the stapes, the neomorph likely developed from the dermatocranium through incomplete fusion of ossification centres from a pre-existing bone, most likely the parietal.

3D Conceptual Design of R2D2, the Research Racetrack Dipole Demonstrator

International audienceR2D2, the Research Racetrack Dipole Demonstrator, is a short model being developed within a collaboration between CEA Paris-Saclay and CERN. The goal of the program is to develop key technologies for future high field 16 T Nb3Sn magnets for particle colliders. In the particular case of block-coil designs, two different cable grades are wound in the same coil layer, in order to maximize the current density, therefore to minimize the size of the magnet and the use of superconductor. One of the most challenging technologies with this grading concept, is the connection between two cables grades. CEA Paris-Saclay has proposed a concept of external joints, for which the cable exits are guided outside of the coil to perform the connections between the cable grades. The R2D2 project is aimed at demonstrating this technology in a representative demonstrator magnet, while simplifying and reducing the risks when possible, as an intermediate step towards 16 T magnets. In particular, the magnet is composed of single-layer racetrack coils, mainly to reduce the use of conductor and simplify some fabrication steps. However, the complexity inherent to the external joints requires a special focus in the design of the coil ends. To do so, the design of the magnet has been performed using a combination of CAD (Computer Aided Design), magnetic and mechanical 3D FEM (Finite-Elements Models). This paper will explain the design choices leading to a safe operation of the magnet in terms of peak fields and peak stresses