New hybrid quadrature schemes for weakly singular kernels applied to isogeometric boundary elements for 3D Stokes flow

This work proposes four novel hybrid quadrature schemes for the efficient and accurate evaluation of weakly singular boundary integrals (1/r kernel) on arbitrary smooth surfaces. Such integrals appear in boundary element analysis for several partial differential equations including the Stokes equation for viscous flow and the Helmholtz equation for acoustics. The proposed quadrature schemes apply a Duffy transform-based quadrature rule to surface elements containing the singularity and classical Gaussian quadrature to the remaining elements. Two of the four schemes additionally consider a special treatment for elements near to the singularity, where refined Gaussian quadrature and a new moment-fitting quadrature rule are used. The hybrid quadrature schemes are systematically studied on flat B-spline patches and on NURBS spheres considering two different sphere discretizations: An exact single-patch sphere with degenerate control points at the poles and an approximate discretization that consist of six patches with regular elements. The efficiency of the quadrature schemes is further demonstrated in boundary element analysis for Stokes flow, where steady problems with rotating and translating curved objects are investigated in convergence studies for both, mesh and quadrature refinement. Much higher convergence rates are observed for the proposed new schemes in comparison to classical schemes

A general isogeometric finite element formulation for rotation-free shells with embedded fibers and in-plane bending

This paper presents a general, nonlinear finite element formulation for rotation-free shells with embedded fibers that captures anisotropy in stretching, shearing, twisting and bending -- both in-plane and out-of-plane. These capabilities allow for the simulation of large sheets of heterogeneous and fibrous materials either with or without matrix, such as textiles, composites, and pantographic structures. The work is a computational extension of our earlier theoretical work (Duong et al., 2021) that extends existing Kirchhoff-Love shell theory to incorporate the in-plane bending resistance of initially straight or curved fibers. The formulation requires only displacement degrees-of-freedom to capture all mentioned modes of deformation. To this end, isogeometric shape functions are used in order to satisfy the required $C^1$-continuity for bending across element boundaries. The proposed formulation can admit a wide range of material models, such as surface hyperelasticity that does not require any explicit thickness integration. To deal with possible material instability due to fiber compression, a stabilization scheme is added. Several benchmark examples are used to demonstrate the robustness and accuracy of the proposed computational formulation.Comment: This version updates the paper format and adjust the units in figure axes, results unchange

A general theory for anisotropic Kirchhoff-Love shells with embedded fibers and in-plane bending

In this work we present a generalized Kirchhoff-Love shell theory that can capture anisotropy not only in stretching and out-of-plane bending, but also in in-plane bending. This setup is particularly suitable for heterogeneous and fibrous materials such as textiles, biomaterials, composites and pantographic structures. The presented theory is a direct extension of existing Kirchhoff-Love shell theory to incorporate the in-plane bending resistance of fibers. It also extends existing high gradient Kirchhoff-Love shell theory for initially straight fibers to initially curved fibers. To describe the additional kinematics of multiple fiber families, a so-called in-plane curvature tensor -- which is symmetric and of second order -- is proposed. The effective stress tensor and the in-plane and out-of-plane moment tensors are then identified from the mechanical power balance. These tensors are all second order and symmetric for general materials. The constitutive equations for hyperelastic materials are derived from different expressions of the mechanical power balance. The weak form is also presented as it is required for computational shell formulations based on rotation-free finite element discretizations.Comment: This version updates reference list and improves text editing, results unchange

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Funder: Breast Cancer Now (BCN); doi: https://doi.org/10.13039/100009794Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH)Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2009-223175, HEALTH-F2-2009-223175Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); doi: https://doi.org/10.13039/501100000024Funder: Quebec Breast cancer Foundation Genome QuebecFunder: U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (NLM); doi: https://doi.org/10.13039/100000092Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))Funder: European Union’s Horizon 2020Funder: Deutsche Krebshilfe (German Cancer Aid); doi: https://doi.org/10.13039/501100005972Funder: BCAST - European Union’s Horizon 2020Funder: Breast Cancer Now; doi: https://doi.org/10.13039/501100007913Abstract: Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8). Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation