Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, and type 1 VWD is the most common VWD variant. Despite its frequency, diagnosis of type 1 VWD remains the subject of much debate. In order to study the spectrum of type 1 VWD in the United States, the Zimmerman Program enrolled 482 subjects with a previous diagnosis of type 1 VWD without stringent laboratory diagnostic criteria. VWF laboratory testing and full length VWF gene sequencing were performed for all index cases and healthy control subjects in a central laboratory. Bleeding phenotype was characterized using the ISTH Bleeding Assessment Tool. At study entry, 64% of subjects had VWF:Ag or VWF:RCo below the lower limit of normal, while 36% had normal VWF levels. VWF sequence variations were most frequent in subjects with VWF:Ag < 30 IU/dL (82%) while subjects with type 1 VWD and VWF:Ag ≥ 30 IU/dL had an intermediate frequency of variants (44%). Subjects whose VWF testing was normal at study entry had a similar rate of sequence variations as the healthy controls at 14% of subjects. All subjects with severe type 1 VWD and VWF:Ag ≤ 5 IU/dL had an abnormal bleeding score, but otherwise bleeding score did not correlate with VWF:Ag level. Subjects with a historical diagnosis of type 1 VWD had similar rates of abnormal bleeding scores compared to subjects with low VWF levels at study entry. Type 1 VWD in the United States is highly variable, and bleeding symptoms are frequent in this population

Efficient arithmetic on elliptic curves in characteristic 2

International audienceWe present normal forms for elliptic curves over a field of characteristic 2 analogous to Edwards normal form, and determine bases of addition laws, which provide strikingly simple expressions for the group law. We deduce efficient algorithms for point addition and scalar multiplication on these forms. The resulting algorithms apply to any elliptic curve over a field of characteristic 2 with a 4-torsion point, via an isomorphism with one of the normal forms. We deduce algorithms for duplication in time $2M + 5S + 2m_c$ and for addition of points in time $7M + 2S$, where $M$ is the cost of multiplication, $S$ the cost of squaring , and $m_c$ the cost of multiplication by a constant. By a study of the Kummer curves $\mathcal{K} = E/\{\pm1]\}$, we develop an algorithm for scalar multiplication with point recovery which computes the multiple of a point P with $4M + 4S + 2m_c + m_t$ per bit where $m_t$ is multiplication by a constant that depends on $P$

pi-NN Coupling Constants from NN Elastic Data between 210 and 800 Mev

High partial waves for $pp$ and $np$ elastic scattering are examined critically from 210 to 800 MeV. Non-OPE contributions are compared with predictions from theory. There are some discrepancies, but sufficient agreement that values of the $\pi NN$ coupling constants $g_0^2$ for $\pi ^0$ exchange and $g^2_{c}$ for charged $\pi$ exchange can be derived. Results are $g^2_0 = 13.91 \pm 0.13 \pm 0.07$ and $g^2_c = 13.69 \pm 0.15 \pm 0.24$, where the first error is statistical and the second is an estimate of the likely systematic error, arising mostly from uncertainties in the normalisation of total cross sections and $d\sigma/d\Omega$.Comment: 21 pages of LaTeX, UI-NTH-940

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation

ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease

Background: von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Accurate and timely diagnosis presents numerous challenges.Objective: These evidence-based guidelines of the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and other health care professionals in their decisions about VWD diagnosis.Methods: ASH, ISTH, NHF, and WFH established a multidisciplinary guideline panel that included 4 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Outcomes and Implementation Research Unit at the University of Kansas Medical Center (KUMC) supported the guideline-development process, including performing or updating systematic evidence reviews up to 8 January 2020. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subsequently subject to public comment.Results: The panel agreed on 11 recommendations.Conclusions: Key recommendations of these guidelines include the role of bleeding-assessment tools in the assessment of patients suspected of VWD, diagnostic assays and laboratory cutoffs for type 1 and type 2 VWD, how to approach a type 1 VWD patient with normalized levels over time, and the role of genetic testing vs phenotypic assays for types 2B and 2N. Future critical research priorities are also identified.Thrombosis and Hemostasi