Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen

Optimizing cutting parameters in process planning of prismatic parts by using genetic algorithms

The determination of optimal cutting parameters, such as the number of passes, depth of cut for each pass, cutting speed and feed, which are applicable for assigned cutting tools, is one of the vital modules in process planning of metal parts, since the economy of machining operations plays an important role in increasing productivity and competitiveness. The present paper introduces a 'system software' developed to optimize the cutting parameters for prismatic parts. The system is mainly based on a powerful artificial intelligence (AI) tool, called genetic algorithms (GAs). It is implemented using C programming language and on a PC. It can be used as standalone system or as the integrated module of a process planning system called OPPS-PRI (Optimized Process Planning System for PRIsmatic parts) that was also developed for prismatic parts and implemented on a vertical machining centre (VMC). With the use of GAs, the impact and power of AI techniques have been reflected on the performance of the optimization system. The methodology of the developed optimization system is illustrated with practical examples throughout the paper

Dynamic optimization of multipass milling operations via geometric programming

This paper outlines the development of an optimization strategy to determine the optimum cutting parameters for multipass milling operations like plain milling and face milling. The developed strategy is based on the "maximum production rate" criterion and incorporates eight technological constraints. The optimum number of passes is determined via dynamic programming, and the optimal values of the cutting conditions are found based on the objective function developed for the typified criterion by using a non-linear programming technique called "geometric programming". This paper also underlies the importance of using optimization strategies rather than handbook recommendations as well as pointing out the superiority of the multipass over the single-pass optimization approach. (C) 1998 Elsevier Science Ltd. All rights reserved

OPPS-ROT: An optimised process planning system for rotational parts

This paper presents an optimised process planning system for rotational parts. The model of a part is drawn by using a CAD module prepared for this purpose. After the feature recognition module, machining operations are determined and the cutting tools are selected by using the knowledge base and machining topology. An optimum sequence of operations is found by minimising the number of tool changes and tool travelling distance to decrease the cost per operation. The optimum cutting conditions are determined and stored in a CAD/CAM data base, accordingly. The part programs are then automatically generated in standard ISO codes on the basis of specific CNC lathe controllers. The generated part programs as well as tool paths can also be verified by graphical simulation prior to actual machining. The system is intelligent and requires little manual intervention. It is implemented with C + + on a personal computer