Benralizumab does not elicit therapeutic effect in patients with chronic spontaneous urticaria: results from the phase 2b multinational, randomised, double-blind, placebo-controlled ARROYO trial.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a relatively common skin disease associated with hives and angio-oedema. Eosinophils play a role in CSU pathogenesis. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, has been shown to induce nearly complete depletion of eosinophils. OBJECTIVES: To determine the clinical efficacy and safety of benralizumab in patients with CSU who were symptomatic despite H1 antihistamine treatment. METHODS: The 24-week, randomised, double-blind, placebo-controlled, phase 2b portion of the ARROYO trial enrolled adult patients with CSU who were currently on H1 antihistamine treatment. Patients were randomised to one of five treatment groups according to benralizumab dose and regimen for a 24-week treatment period. The primary endpoint was change from baseline in ISS7 at Week 12. The key secondary endpoint was change from baseline in UAS7 at Week 12. Additional secondary endpoints included other metrics to assess CSU at Week 24; blood eosinophil levels; and pharmacokinetics and immunogenicity assessments. Exploratory subgroup analyses were conducted to explore responses according to demographics, clinical features and biomarkers. Safety was assessed in all treatment groups. RESULTS: Of 155 patients, 59 were randomised to benralizumab 30 mg, 56 to benralizumab 60 mg and 40 to placebo. Baseline and disease characteristics were consistent with what was expected for patients with CSU. There were no significant differences in change from baseline in ISS7 score at Week 12 between benralizumab and placebo (benralizumab 30 mg vs. placebo, least-squares mean difference -1.01, 95% confidence interval -3.28 to 1.26; benralizumab 60 mg vs. placebo, least-squares mean difference -1.79, 95% confidence interval -4.09 to 0.50) nor in change from baseline in UAS7 score at Week 12 between benralizumab and placebo (benralizumab 30 mg vs. placebo, P = 0.4016; benralizumab 60 mg vs. placebo, P = 0.0819). Depletion of blood eosinophil levels was observed at Week 24 in patients treated with benralizumab. All other secondary endpoints and exploratory/subgroup analyses indicated no significant differences between benralizumab and placebo. Safety results were consistent with the known profile of benralizumab. CONCLUSIONS: Although benralizumab resulted in near-complete depletion of blood eosinophils, there was no clinical benefit over placebo.

Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Benralizumab, a monoclonal antibody against the interleukin-5α receptor expressed on eosinophils, may be an option for treating EGPA. METHODS: We conducted a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial to evaluate the efficacy and safety of benralizumab as compared with mepolizumab. Adults with relapsing or refractory EGPA who were receiving standard care were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecified noninferiority margin, -25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety. RESULTS: A total of 140 patients underwent randomization (70 assigned to each group). The adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], -13 to 18; P = 0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per microliter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per microliter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively. CONCLUSIONS: Benralizumab was noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. (Funded by AstraZeneca; MANDARA ClinicalTrials.gov number, NCT04157348.).

Defense against Adversarial Swarms with Parameter Uncertainty.

This paper addresses the problem of optimal defense of a high-value unit (HVU) against a large-scale swarm attack. We discuss multiple models for intra-swarm cooperation strategies and provide a framework for combining these cooperative models with HVU tracking and adversarial interaction forces. We show that the problem of defending against a swarm attack can be cast in the framework of uncertain parameter optimal control. We discuss numerical solution methods, then derive a consistency result for the dual problem of this framework, providing a tool for verifying computational results. We also show that the dual conditions can be computed numerically, providing further computational utility. Finally, we apply these numerical results to derive optimal defender strategies against a 100-agent swarm attack.

Bernstein Polynomial-Based Method for Solving Optimal Trajectory Generation Problems.

This paper presents a method for the generation of trajectories for autonomous system operations. The proposed method is based on the use of Bernstein polynomial approximations to transcribe infinite dimensional optimization problems into nonlinear programming problems. These, in turn, can be solved using off-the-shelf optimization solvers. The main motivation for this approach is that Bernstein polynomials possess favorable geometric properties and yield computationally efficient algorithms that enable a trajectory planner to efficiently evaluate and enforce constraints along the vehicles' trajectories, including maximum speed and angular rates as well as minimum distance between trajectories and between the vehicles and obstacles. By virtue of these properties and algorithms, feasibility and safety constraints typically imposed on autonomous vehicle operations can be enforced and guaranteed independently of the order of the polynomials. To support the use of the proposed method we introduce BeBOT (Bernstein/Bézier Optimal Trajectories), an open-source toolbox that implements the operations and algorithms for Bernstein polynomials. We show that BeBOT can be used to efficiently generate feasible and collision-free trajectories for single and multiple vehicles, and can be deployed for real-time safety critical applications in complex environments.

Comparison of activities of daily living (ADLs) in two different one arm drive wheelchairs: a study of individuals/participants with hemiplegia.

AIMS: This pilot study measured activities of daily living performance in individuals/participants with hemiplegia propelling both a standard dual handrim Action 3 wheelchair and a standard Action 3 wheelchair with a Neater Uni-Wheelchair kit attachment. The kit consists of a steerable front. RESEARCH QUESTIONS: Does the use of the NUW affect the performance quality of activities of daily living in individuals/participants with hemiplegia. Is there a difference in the motor and process skills during activities of daily living performance, and in the time taken to complete the activities. METHODS: Four individuals/participants with hemiplegia were used in a cross over, repeated measures trial. Assessment of Motor and Process Skills of users undertaking making a bed and laying a table "Swedish style", tasks were measured and time taken to complete each task were recorded. RESULTS: Bed making completion time was quicker in the Neater Uni-wheelchair (p < 0.03). Motor skills were significantly higher than the process ability skills (p < 0.05). CONCLUSION: Activities of daily living tasks in the Neater Uni-wheelchair were completed more efficiently with no loss in quality of motor and process skills performance. This suggests that the Neater Uni-wheelchair is a viable alternative to current one arm drive provision. Implications for Rehabilitation Inappropriate wheelchair provision can result in capacity limitation and poorer quality of ADL motor skill as well-lowered process performance skill. AMPS can help to explain motor and process skill differences in complex activities.

An induction programme for health visitors.

Bradford South and West PCT developed a comprehensive induction programme for newly-qualified health visitors in order to enhance the support offered to these practitioners. This study examined the experiences of a group of health visitors who have undergone this programme and compared it with the experiences of health visitors who did not receive a structured induction. The data were collected by means of two focus groups and were analysed using framework analysis. The findings indicated that the induction programme was very valuable to newly-qualified health visitors, as well as those new to the PCT. Health visitors who had taken part in the programme felt privileged to have had this opportunity. The programme helped them adjust to their new roles and made the transference to personal accountability easier. The provision of peer support and preceptorship enhanced learning and effective decision-making, and encouraged reflection. The health visitors who had not received a structured induction felt they had been at a distinct disadvantage and welcomed the new programme. There was a consensus of opinion that the induction programme would have a positive impact on the recruitment and retention of health visitors and should continue to be developed.