Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: A novel syndrome

Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: A novel syndrome.BackgroundAutosomal-dominant forms of hematuria have been mostly related to mutations in the COL4A3/COL4A4 genes. Patients with thin basement membrane (BM) disease do not have extrarenal manifestations, while those with Alport syndrome often present with hearing loss, anterior lenticonus, and dot-and-fleck retinopathy.MethodsWe performed a phenotypic study and a candidate gene approach in a four-generation family presenting with autosomal-dominant hematuria associated with extrarenal manifestations. Renal biopsy was analyzed for determination of BM thickness and expression of chains of type IV collagen. Linkage to 18 candidate genes/loci was investigated using polymorphic microsatellite markers.ResultsIn all affected patients, hematuria without proteinuria was associated with muscular contractures and retinal arterial tortuosities responsible for retinal hemorrhages. Cardiac arrythmia, Raynaud phenomena, and brain MRI abnormalities were also observed. Despite the presence of red cells in tubule sections, no glomerular abnormalities were found by electron microscopy. Expression of type IV collagen chains and glomerular BM thickness was normal. We searched for a molecular defect affecting either BM or angiogenesis. Linkage analyses of genes encoding BM components (COL4A3/COL4A4, COL6A1, COL6A2, COL6A3, FBLN1), and angiogenic factors or their receptors (VHL, ANPT1, ANPT2, TIE, TEK, NOTCH2, NOTCH3, NOTCH4, DLL4, JAG1, JAG2) and of the facio-sapulo-humeral dystrophy and 3q21 loci failed to show segregation of the disease with those gene loci.ConclusionWe have identified a new inherited hematuria syndrome associated with retinal vessel tortuosities and contractures. We recommend performing a fundus examination in patients with familial hematuria and episodes of visual impairment, as well as a urinary analysis in patients with retinal arterial tortuosity or congenital muscular contractures

MQGeometry-1.0: a multi-layer quasi-geostrophic solver on non-rectangular geometries

International audienceAbstract. This paper presents MQGeometry, a multi-layer quasi-geostrophic (QG) equation solver for non-rectangular geometries. We advect the potential vorticity (PV) with finite volumes to ensure global PV conservation using a staggered discretization of the PV and stream function (SF). Thanks to this staggering, the PV is defined inside the domain, removing the need to define the PV on the domain boundary. We compute PV fluxes with upwind-biased interpolations whose implicit dissipation replaces the usual explicit (hyper-)viscous dissipation. The discretization presented here does not require tuning of any additional parameter, e.g., additional eddy viscosity. We solve the QG elliptic equation with a fast discrete sine transform spectral solver on rectangular geometry. We extend this fast solver to non-rectangular geometries using the capacitance matrix method. Subsequently, we validate our solver on a vortex-shear instability test case in a circular domain, on a vortex–wall interaction test case, and on an idealized wind-driven double-gyre configuration in an octagonal domain at an eddy-permitting resolution. Finally, we release a concise, efficient, and auto-differentiable PyTorch implementation of our method to facilitate future developments on this new discretization, e.g., machine-learning parameterization or data-assimilation techniques

Finite-volume discretization of the quasi-geostrophic equations with implicit dissipation

We present in this work a new discretization of the multi-layer quasi-geostrophic (QG) model that relies on implicit dissipation rather than additional explicit dissipation.It is first based on the staggered discretization of the potential vorticity (PV) and the stream-function in order to solve the PV advection with a finite volume method.This ensures the exact material conservation of the PV.We compute PV fluxes with a WENO-5 interpolation whose implicit dissipation replaces the usual explicit (hyper-)viscous dissipation.We propose a new method for solving reversibly the elliptic equation which is nontrivial with this staggered discretization.The presented discretization does not require the tuning of any additional parameter, \textit{e.g.} additional hyper-viscosity.We test the proposed method on a challenging idealized wind-driven double-gyre configuration at eddy-resolving, eddy-permitting, and non-eddy-resolving resolutions.In the eddy-permitting and non-eddy-resolving resolutions, our method produces an eastward jet contrary to usual discretizations without parametrization.Moreover, our method produces statistics that have a stronger coherence across resolutions than usual discretizations.We release a very short, concise, and efficient PyTorch implementation of our method to facilitate future data assimilation or machine-learning developments upon this new discretization

COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps

<i>Background</i>: COL4A3, COL4A4, and COL4A5 are the only collagen genes that have been implicated in inherited nephropathies in humans. However, the causative genes for a number of hereditary multicystic kidney diseases, myopathies with cramps, and heritable intracranial aneurysms remain unknown.<p></p> <i>Methods</i>: We characterized the renal and extrarenal phenotypes of subjects from three families who had an autosomal dominant hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC), which we propose is a syndrome. Linkage studies involving microsatellite markers flanking the COL4A1–COL4A2 locus were performed, followed by sequence analysis of COL4A1 complementary DNA extracted from skin-fibroblast specimens from the subjects.<p></p> <i>Results</i>: We identified three closely located glycine mutations in exons 24 and 25 of the gene COL4A1, which encodes procollagen type IV 1. The clinical renal manifestations of the HANAC syndrome in these families include hematuria and bilateral, large cysts. Histologic analysis revealed complex basement-membrane defects in kidney and skin. The systemic angiopathy of the HANAC syndrome appears to affect both small vessels and large arteries.<p></p> <i>Conclusions</i>: COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps.<p></p&gt

Management of Severe Bleeding in Patients Treated with Direct Oral Anticoagulants

International audienceThe use of prothrombin complex concentrates and the role of plasma concentration of anticoagulants in the management of bleeding in patients treated with direct oral anticoagulants are still debated. Our aim was to describe management strategies and outcomes of severe bleeding events in patients treated with direct oral anticoagulants.METHODS:We performed a prospective cohort study of 732 patients treated with dabigatran, rivaroxaban, or apixaban hospitalized for severe bleeding, included prospectively in the registry from June 2013 to November 2015.RESULTS:Bleeding was gastrointestinal or intracranial in 37% (212 of 732) and 24% (141 of 732) of the cases, respectively. Creatinine clearance was lower than 60 ml/min in 61% (449 of 732) of the cases. The plasma concentration of direct oral anticoagulants was determined in 62% (452 of 732) of the cases and was lower than 50 ng/ml or higher than 400 ng/ml in 9.2% (41 of 452) and in 6.6% (30 of 452) of the cases, respectively. Activated or nonactivated prothrombin complex concentrates were administered in 38% of the cases (281 of 732). Mortality by day 30 was 14% (95% CI, 11 to 16).CONCLUSIONS:Management of severe bleeding in patients treated with direct oral anticoagulants appears to be complex. The use of prothrombin complex concentrates differs depending on bleeding sites and direct oral anticoagulant plasma concentrations. Mortality differs according to bleeding sites and was similar to previous estimates

Rituximab vs ocrelizumab in relapsing-remitting multiple sclerosis

IMPORTANCE Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening by 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, a chimeric monoclonal anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab. OBJECTIVE To evaluate whether the effectiveness of rituximab is noninferior to ocrelizumab in relapsing-remitting MS. DESIGN, SETTING, AND PARTICIPANTS This was an observational cohort study conducted between January 2015 and March 2021. Patients were included in the treatment group for the duration of study therapy and were recruited from the MSBase registry and Danish MS Registry (DMSR). Included patients had a history of relapsing-remitting MS treated with ocrelizumab or rituximab, a minimum 6 months of follow-up, and sufficient data to calculate the propensity score. Patients with comparable baseline characteristics were 1:6 matched with propensity score on age, sex, MS duration, disability (Expanded Disability Status Scale), prior relapse rate, prior therapy, disease activity (relapses, disability accumulation, or both), magnetic resonance imaging lesion burden (missing values imputed), and country. EXPOSURE Treatment with ocrelizumab or rituximab after 2015. MAIN OUTCOMES AND MEASURES Noninferiority comparison of annualized rate of relapses (ARRs), with a prespecified noninferiority margin of 1.63 rate ratio. Secondary end points were relapse and 6-month confirmed disability accumulation in pairwise-censored groups. RESULTS Of the 6027 patients with MS who were treated with ocrelizumab or rituximab, a total of 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled the inclusion criteria and were included in the analysis (898 MSBase, 715 DMSR). A total of 710 patients treated with ocrelizumab (414 MSBase, 296 DMSR) were matched with 186 patients treated with rituximab (110 MSBase, 76 DMSR). Over a pairwise censored mean (SD) follow-up of 1.4 (0.7) years, the ARR ratio was higher in patients treated with rituximab than in those treated with ocrelizumab (rate ratio, 1.8; 95% CI, 1.4-2.4; ARR, 0.20 vs 0.09; P < .001). The cumulative hazard of relapses was higher among patients treated with rituximab than those treated with ocrelizumab (hazard ratio, 2.1; 95% CI, 1.5-3.0). No difference in the risk of disability accumulation was observed between groups. Results were confirmed in sensitivity analyses. CONCLUSION In this noninferiority comparative effectiveness observational cohort study, results did not show noninferiority of treatment with rituximab compared with ocrelizumab. As administered in everyday practice, rituximab was associated with a higher risk of relapses than ocrelizumab. The efficacy of rituximab and ocrelizumab administered at uniform doses and intervals is being further evaluated in randomized noninferiority clinical trials