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Abstract: A design analysis approach is developed for improving the stability of dynamic systems subject to non-conservative forces. It combines genetic algorithms, sequential quadratic programming (SQP), and dynamic mode tracking [...]

Summary: Background: Significantly more patients with moderate‐to‐severe plaque psoriasis treated with the interleukin (IL)‐17A inhibitor ixekizumab vs. the IL‐23p19 inhibitor guselkumab in the IXORA‐R head‐to‐head trial achieved 100% improvement in Psoriasis Area and Severity Index (PASI 100) at week 12. Objectives: To compare skin and nail clearance and patient‐reported outcomes for ixekizumab vs. guselkumab, up to week 24. Methods: IXORA‐R enrolled adults with moderate‐to‐severe plaque psoriasis, defined as static Physician's Global Assessment ≥ 3, PASI ≥ 12 and involved body surface area ≥ 10%. Statistical comparisons were performed using the Cochran–Mantel–Haenszel test stratified by pooled site. Time‐to‐first‐event comparisons were performed using Kaplan–Meier analysis, and P‐values were generated using adjusted log‐rank tests stratified by treatment group. Cumulative days at clinical and patient‐reported responses were compared by ancova. The trial was registered with ClinicalTrials.gov (NCT03573323). Results: Of the 1027 patients randomly assigned, 90% completed the trial (465 of 520 ixekizumab and 459 of 507 guselkumab). As early as week 2 and through week 16, more patients on ixekizumab achieved PASI 100 (P < 0·01). At week 24, ixekizumab was noninferior to guselkumab (50% vs. 52%, difference −2·3%), with no statistically significant difference in PASI 100 (P = 0·41). More patients receiving ixekizumab showed completely clear nails at week 24 (52% vs. 31%, P = 0·007). The median time to first PASI 50/75/90 and PASI 100 were 2 and 7·5 weeks shorter, respectively, for patients on ixekizumab vs. guselkumab (P < 0·001). Patients on ixekizumab also had a greater cumulative benefit, with more days at PASI 90 and 100, with Dermatology Life Quality Index of 0 or 1, and itch free (P < 0·05). The frequency of serious adverse events was 3% for each group, with no new safety signals. Conclusions: Ixekizumab was noninferior to guselkumab in complete skin clearance and superior in clearing nails at week 24. Ixekizumab cleared skin more rapidly in patients with moderate‐to‐severe plaque psoriasis, with a greater cumulative benefit, than guselkumab. Overall, the safety findings were consistent with the known safety profile for ixekizumab. What is already known about this topic?Patients with plaque psoriasis desire both high levels of clearance and rapid onset of treatment effects.Ixekizumab is a high‐affinity monoclonal antibody that selectively targets interleukin (IL)‐17A.In the 12‐week report of the IXORA‐R study, ixekizumab demonstrated significantly higher efficacy at early timepoints than the IL‐23p19 inhibitor guselkumab, with more patients achieving 100% improvement in Psoriasis Area and Severity Index (PASI 100) and improved quality of life as early as week 4. What does this study add?Patients on ixekizumab vs. guselkumab achieved similar levels of skin clearance and superior efficacy in the resolution of nail psoriasis at week 24.Patients on ixekizumab vs. guselkumab had a greater cumulative benefit, with more days at PASI 90 and 100, more days when psoriasis did not impact their quality of life, and more itch‐free days.The safety profiles of both drugs were consistent with those in previous studies. Linked Comment: Puig. Br J Dermatol 2021; 184:992–993. [ABSTRACT FROM AUTHOR]

This study develops new solution methodologies for the flexible job shop scheduling problem (F-JSSP). As a first step towards dealing with this complex problem, mathematical modellings have been used; two novel effective position- and sequence-based mixed integer linear programming (MILP) models have been developed to fully characterise operations of the shop floor. The developed MILP models are capable of solving both partially and totally F-JSSPs. Size complexities, solution effectiveness and computational efficiencies of the developed MILPs are numerically explored and comprehensively compared vis-à-vis the makespan optimisation criterion. The acquired results demonstrate that the proposed MILPs, by virtue of its structural efficiencies, outperform the state-of-the-art MILPs in literature. The F-JSSP is strongly NP-hard; hence, it renders even the developed enhanced MILPs inefficient in generating schedules with the desired quality for industrial scale problems. Thus, a meta-heuristic that is a hybrid of Artificial Immune and Simulated Annealing (AISA) Algorithms has been proposed and developed for larger instances of the F-JSSP. Optimality gap is measured through comparison of AISA’s suboptimal solutions with its MILP exact optimal counterparts obtained for small- to medium-size benchmarks of F-JSSP. The AISA’s results were examined further by comparing them with seven of the best-performing meta-heuristics applied to the same benchmark. The performed comparative analysis demonstrated the superiority of the developed AISA algorithm. An industrial problem in a mould- and die-making shop was used for verification. [ABSTRACT FROM PUBLISHER]

Summary: Background: Patients with psoriasis value rapid and complete skin clearance. No head‐to‐head studies have focused on early responses to interleukin (IL)‐17 vs. IL‐23 inhibitors. Objectives: To compare early and complete skin clearance by the IL‐17A inhibitor ixekizumab vs. the IL‐23p19 inhibitor guselkumab. Methods: IXORA‐R, a 24‐week, randomized, double‐blinded study, enrolled adults with moderate‐to‐severe plaque psoriasis [static Physician's Global Assessment of Disease (sPGA) score of ≥ 3, Psoriasis Area and Severity Index (PASI) ≥ 12, and ≥ 10% body surface area]. Patients were randomized (1 : 1) to receive the approved dose of subcutaneous ixekizumab or guselkumab. Primary end point was 100% improvement in PASI (PASI 100) at week 12. Major secondary end points included other levels of improved PASI and sPGA at different time points. Comparisons were made using the Cochran–Mantel–Haenszel test with a multiple testing strategy. Nonresponder imputation was used for missing data. After the completion of the study, the final secondary end point (PASI 100 at 24 weeks) and safety data through week 24 will be reported. Results: In total, 1027 patients were randomized. The primary end point PASI 100 at week 12 was met [215/520 ixekizumab (41%); 126/507 guselkumab (25%); P < 0·001]. All major secondary end points measured up to week 12 were met, including PASI 50 at week 1 and PASI 75 at week 2. Serious adverse event frequency was 3% for each group; no new safety signals were identified. Conclusions: Ixekizumab was superior to guselkumab for rapidly improving signs and symptoms in patients with moderate‐to‐severe plaque psoriasis by week 12. Adverse events were similar to previous ixekizumab and guselkumab studies. Compared with the IL‐23 inhibitor guselkumab, ixekizumab can offer complete skin clearance more rapidly to patients with moderate‐to‐severe plaque psoriasis. What's already known about this topic? Patients with plaque psoriasis desire both high levels of clearance and rapid onset of treatment effects.Ixekizumab, a high‐affinity monoclonal antibody that selectively targets interleukin (IL)‐17A, has demonstrated greater and faster skin clearance than etanercept and ustekinumab, with consistent long‐term efficacy, safety and durability of response.Clinical trial data and systematic reviews have suggested that IL‐17 inhibitors can improve a patient's psoriasis more rapidly than IL‐23 inhibitors. What does this study add? The head‐to‐head study design directly compares the efficacy and speed of response of ixekizumab and the IL‐23 inhibitor guselkumab in moderate‐to‐severe plaque psoriasis.The primary end point was met, showing superiority of ixekizumab over guselkumab for achieving complete skin clearance at week 12.The safety profile of ixekizumab was consistent with previous studies.Ixekizumab can deliver patients complete skin clearance and improved quality of life more rapidly than guselkumab. Linked Comment:Veysey. Br J Dermatol 2020; 182:1321–1322. Plain language summary available online [ABSTRACT FROM AUTHOR]