Multiobjective Design Optimization using Nash Games

International audienceIn the area of pure numerical simulation of multidisciplinary coupled systems, the computational cost to evaluate a configuration may be very high. A fortiori, in multi- disciplinary optimization, one is led to evaluate a number of different configurations to iterate on the design parameters. This observation motivates the search for the most in- novative and computationally efficient approaches in all the sectors of the computational chain : at the level of the solvers (using a hierarchy of physical models), the meshes and geometrical parameterizations for shape, or shape deformation, the implementation (on a sequential or parallel architecture; grid computing), and the optimizers (deterministic or semi-stochastic, or hybrid; synchronous, or asynchronous). In the present approach, we concentrate on situations typically involving a small number of disciplines assumed to be strongly antagonistic, and a relatively moderate number of related objective functions. However, our objective functions are functionals, that is, PDE-constrained, and thus costly to evaluate. The aerodynamic and structural optimization of an aircraft configuration is a prototype of such a context, when these disciplines have been reduced to a few major objectives. This is the case when, implicitly, many subsystems are taken into account by local optimizations. Our developments are focused on the question of approximating the Pareto set in cases of strongly-conflicting disciplines. For this purpose, a general computational technique is proposed, guided by a form of sensitivity analysis, with the additional objective to be more economical than standard evolutionary approaches

Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial

Abstract Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.</jats:p

Clinical assessment of Optivate®, a high-purity concentrate of factor VIII with von Willebrand factor, in the management of patients with haemophilia A

Factor VIII (FVIII) concentrates have revolutionized the treatment of patients with haemophilia A. Concerns over the transmission of viral infections through these products have been addressed through stringent, donor‐screening procedures and robust antiviral manufacturing steps. Bio Products Laboratory has developed a high‐purity FVIII product with von Willebrand factor, Optivate®. Its safety, tolerability and efficacy as prophylaxis and treatment of bleeds have been established in long‐term studies. Seventy previously treated patients with severe haemophilia A, with ≥20 exposure days, were recruited into two long‐term, multicentre, open‐label studies. The protocols were virtually identical. Patients received Optivate® either prophylactically or on‐demand. A mean of 159.0 EDs were experienced over 11 320 infusions. Under both conditions, Optivate® was well tolerated. Only 10% of patients experienced a treatment‐related adverse event; the most commonly reported were headache (4% of patients) and dizziness (3% of patients). The mean number of bleeds/patient over the 2 year treatment period was 23.5 during prophylactic use and 70.4 during on‐demand use. In patients treated prophylactically, clinical responses to breakthrough bleeds were rated by physicians as excellent or good and as very helpful or helpful by patients in 95% of bleeds. Clinical responses for on‐demand patients were rated as excellent or good by physicians and helpful or very helpful by the patients for 91% of bleeds. There were no viral transmissions or inhibitors. The studies confirm the clinical efficacy and safety of Optivate® in both prophylactic and on‐demand management of patients with haemophilia A

Modelling of natural convection flows with large temperature differences: A benchmark problem for low Mach number solvers. Part 2. Contributions to the June 2004 conference

In the second part of the paper, we compare the solutions produced in the framework of the conference “Mathematical and numerical aspects of low Mach number flows” organized by INRIA and MAB in Porquerolles, June 2004, to the reference solutions described in Part 1. We make some recommendations on how to produce good quality solutions, and list a number of pitfalls to be avoided

A five-year follow-up of untreated patients with chronic lymphocytic leukaemia treated with ofatumumab and chlorambucil: final analysis of the Complement 1 phase 3 trial

The Complement 1 trial investigated the efficacy and safety of ofatumumab + chlorambucil with chlorambucil monotherapy in patients with previously untreated chronic lymphocytic leukaemia (CLL). On long-term follow-up in the chemoimmunotherapy arm vs. the chemotherapy arm there was an estimated 12% (not significant) and 39% risk reduction in overall survival and progression-free survival, respectively. A high rate (61%) of treatment with next-line therapies in both the treatment arms may dilute any potential OS difference and confound the interpretation of the OS results. Addition of ofatumumab to chlorambucil demonstrated clinical benefit and tolerability as a frontline treatment option in patients unfit for fludarabine-containing therapy, with no new safety concerns. © 2020 British Society for Haematology and John Wiley &amp; Sons Lt