Contribution of two diagnosis tools to support interface situation during production launch

Organised by: Cranfield UniversityFirms are urged to constantly introduce new products. Hence, the New Product Development process should be mastered, especially its final phase, the production launch. This paper addresses the critical issue of the information exchange during production launch. Two diagnosis tools considering production launch as a key interface are presented. They permit to examine the information flows, to highlight their weaknesses and hence to find solutions for further improvements. This paper also presents the results of a case study where the diagnosis tools were implemented during a switchgear development project.Mori Seiki – The Machine Tool Compan

Chebyshev Polynomials on Generalized Julia Sets

Let (fn)n=1∞ be a sequence of non-linear polynomials satisfying some mild conditions. Furthermore, let Fm(z) : = (fm∘ fm - 1⋯ ∘ f1) (z) and ρm be the leading coefficient of Fm. It is shown that on the Julia set J(fn), the Chebyshev polynomial of degree deg Fm is of the form Fm(z) / ρm- τm for all m∈ N where τm∈ C. This generalizes the result obtained for autonomous Julia sets in Kamo and Borodin (Mosc. Univ. Math. Bull. 49:44–45, 1994). © 2015, Springer-Verlag Berlin Heidelberg

Orthogonal Polynomials Associated with Equilibrium Measures on ℝ

Let K be a non-polar compact subset of ℝ and μK denote the equilibrium measure of K. Furthermore, let Pn(⋅;μK) be the n-th monic orthogonal polynomial for μK. It is shown that ∥Pn(⋅;μK)∥L2(μK), the Hilbert norm of Pn(⋅;μK) in L2(μK), is bounded below by Cap(K)n for each n∈ ℕ. A sufficient condition is given for(∥Pn(⋅;μK)∥L2(μK)/Cap(K)n)n=1∞ to be unbounded. More detailed results are presented for sets which are union of finitely many intervals. © 2016, Springer Science+Business Media Dordrecht

Some open problems concerning orthogonal polynomials on fractals and related questions

We discuss several open problems related to analysis on fractals: Estimates of the Green functions, the growth rates of the Markov factors with respect to the extension property of compact sets, asymptotics of orthogonal polynomials and the Parreau-Widom condition, Hausdorff measures and the Hausdorff dimension of the equilibrium measure on generalized Julia sets. © 2017, Padova University Press. All rights reserved

Some asymptotics for extremal polynomials

We review some asymptotics for Chebyshev polynomials and orthogonal polynomials. Our main interest is in the behaviour of Widom factors for the Chebyshev and the Hilbert norms on small sets such as generalized Julia sets. © Springer International Publishing Switzerland 2016

Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase.

UnlabelledMigalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified.Trial registrationClinicalTrials.gov NCT01196871

Thermal Particle Creation in Cosmological Spacetimes: A Stochastic Approach

The stochastic method based on the influence functional formalism introduced in an earlier paper to treat particle creation in near-uniformly accelerated detectors and collapsing masses is applied here to treat thermal and near-thermal radiance in certain types of cosmological expansions. It is indicated how the appearance of thermal radiance in different cosmological spacetimes and in the two apparently distinct classes of black hole and cosmological spacetimes can be understood under a unifying conceptual and methodological framework.Comment: 17 pages, revtex (aps, eqsecnum), submitted to PRD, April 199

Presenting signs and patient co-variables in Gaucher disease : outcome of the Gaucher Earlier Diagnosis Consensus (GED-C) Delphi initiative

© 2018 The Authors. Internal Medicine Journal by Wiley Publishing Asia Pty Ltd on behalf of Royal Australasian College of Physicians.Background: Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognise the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities. Aim: The Gaucher Earlier Diagnosis Consensus (GED-C) initiative aimed to identify signs and co-variables considered most indicative of early type 1 and type 3 GD, to help non-specialists identify ‘at-risk’ patients who may benefit from diagnostic testing. Methods: An anonymous, three-round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5-point Likert scales and scoring thresholds defined a priori. Results: For type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone-related manifestations, anaemia, hyperferritinaemia, hepatomegaly and gammopathy) and two major co-variables (family history of GD and Ashkenazi-Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances and kyphosis) and one major co-variable (family history of GD) were identified. Lack of disease awareness, overlooking mild early signs and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis. Conclusion: The signs and co-variables identified in the GED-C initiative as potentially indicative of early GD will help to guide non-specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD.Peer reviewedFinal Published versio

Long-term safety and efficacy of pegunigalsidase alfa: A multicenter 6-year study in adult patients with Fabry disease

Purpose: Fabry disease (FD) is a rare lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding α-galactosidase (α-Gal)-A. We evaluated long-term safety/efficacy of pegunigalsidase alfa, a novel PEGylated α-Gal-A enzyme replacement therapy (ERT) now approved for FD. Methods: In a phase-1/2 dose-ranging study, 15 ERT-naive adults with FD completed 12 months of pegunigalsidase alfa and enrolled in this 60-month open-label extension of 1 mg/kg pegunigalsidase alfa infusions every 2 weeks. Results: Fifteen patients enrolled (8 males; 7 females); 10 completed ≥48 months (60 months total treatment), and 2 completed 60 months (72 months total treatment). During treatment, most treatment-emergent adverse events were mild/moderate in severity and all infusion-related reactions were mild/moderate in severity. Four patients were transiently positive for anti-pegunigalsidase alfa IgG. Patients showed continuous reduction in plasma lyso-Gb3 concentrations with mean (standard error) reduction of 76.1 [25.1] ng/mL from baseline to month 24. At 60 months, the estimated glomerular filtration rate slope was comparable to that observed in patients treated with other ERTs. Cardiac function assessments revealed stability; no cardiac fibrosis was observed. Conclusion: In this first long-term assessment of pegunigalsidase alfa administration in patients with FD, we found favorable safety/efficacy. Our data suggest long-term continuous benefits of pegunigalsidase alfa treatment in adults with FD