Iterative Temporal Motion Planning for Hybrid Systems in Partially Unknown Environments

This paper considers the problem of motion planning for a hybrid robotic system with complex and nonlinear dynamics in a partially unknown environment given a temporal logic specification. We employ a multi-layered synergistic framework that can deal with general robot dynamics and combine it with an iterative planning strategy. Our work allows us to deal with the unknown environmental restrictions only when they are discovered and without the need to repeat the computation that is related to the temporal logic specification. In addition, we define a metric for satisfaction of a specification. We use this metric to plan a trajectory that satisfies the specification as closely as possible in cases in which the discovered constraint in the environment renders the specification unsatisfiable. We demonstrate the efficacy of our framework on a simulation of a hybrid second-order car-like robot moving in an office environment with unknown obstacles. The results show that our framework is successful in generating a trajectory whose satisfaction measure of the specification is optimal. They also show that, when new obstacles are discovered, the reinitialization of our framework is computationally inexpensive

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Background Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations

Low-Dimensional Projections for SyCLoP

Abstract — This paper presents an extension to SyCLoP, a multilayered motion planning framework that has been shown to successfully solve high-dimensional problems with differential constraints. SyCLoP combines traditional sampling-based planning with a high-level decomposition of the workspace through which it attempts to guide a low-level tree of motions. We investigate a generalization of SyCLoP in which the highlevel decomposition is defined over a given low-dimensional projected subspace of the state space. We begin with a manually-chosen projection to demonstrate that projections other than the workspace can potentially work well. We then evaluate SyCLoP’s performance with random projections and projections determined from linear dimensionality reduction over elements of the state space, for which the results are mixed. As we will see, finding a useful projection is a difficult problem, and we conclude this paper by discussing the merits and drawbacks of various types of projections. I

Reactive Landing of Gas-Phase Ions as a Tool for the Fabrication of Metal Oxide Surfaces for In Situ Phosphopeptide Enrichment

Zirconium, titanium, and hafnium oxide-coated stainless steel surfaces are fabricated by reactive landing of gas-phase ions produced by electrospray ionization of group IVB metal alkoxides. The surfaces are used for in situ enrichment of phosphopeptides before analysis by matrix-assisted laser desorption ionization (MALDI) mass spectrometry. To evaluate this method we characterized ZrO2 (zirconia) surfaces by (1) comparison with the other group IVB metal oxides of TiO2 (titania) and HfO2 (hafnia), (2) morphological characterization by SEM image analysis, and (3) dependence of phosphopeptide enrichment on the metal oxide layer thickness. Furthermore, we evaluated the necessity of the reactive landing process for the construction of useful metal oxide surfaces by preparing surfaces by electrospray deposition of Zr, Ti, and Hf alkoxides directly onto polished metal surfaces at atmospheric pressure. Although all three metal oxide surfaces evaluated were capable of phosphopeptide enrichment from complex peptide mixtures, zirconia performed better than hafnia or titania as a result of morphological characteristics illustrated by the SEM analysis. Metal oxide coatings that were fabricated by atmospheric pressure deposition were still capable of in situ phosphopeptide enrichment, although with inferior efficiency and surface durability. We show that zirconia surfaces prepared by reactive landing of gas-phase ions can be a useful tool for high throughput screening of novel phosphorylation sites and quantitation of phosphorylation kinetics

Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro.

Cystoisosporosis is a leading diarrheal disease in suckling piglets. With the confirmation of resistance against the only available drug toltrazuril, there is a substantial need for novel therapeutics to combat the infection and its negative effects on animal health. In closely related apicomplexan species, bumped kinase inhibitors (BKIs) targeting calcium-dependent protein kinase 1 (CDPK1) were shown to be effective in inhibiting host-cell invasion and parasite growth. Therefore, the gene coding for Cystoisospora suis CDPK1 (CsCDPK1) was identified and cloned to investigate activity and thermal stabilization of the recombinant CsCDPK1 enzyme by BKI 1369. In this comprehensive study, the efficacy, safety and pharmacokinetics of BKI 1369 in piglets experimentally infected with Cystoisospora suis (toltrazuril-sensitive, Wien-I and toltrazuril-resistant, Holland-I strains) were determined in vivo and in vitro using an established animal infection model and cell culture, respectively. BKI 1369 inhibited merozoite proliferation in intestinal porcine epithelial cells-1 (IPEC-1) by at least 50% at a concentration of 40 nM, and proliferation was almost completely inhibited (>95%) at 200 nM. Nonetheless, exposure of infected cultures to 200 nM BKI 1369 for five days did not induce structural alterations in surviving merozoites as confirmed by transmission electron microscopy. Five-day treatment with BKI 1369 (10 mg/kg BW twice a day) effectively suppressed oocyst excretion and diarrhea and improved body weight gains in treated piglets without obvious side effects for both toltrazuril-sensitive, Wien-I and resistant, Holland-I C. suis strains. The plasma concentration of BKI 1369 in piglets increased to 11.7 μM during treatment, suggesting constant drug accumulation and exposure of parasites to the drug. Therefore, oral applications of BKI 1369 could potentially be a therapeutic alternative against porcine cystoisosporosis. For use in pigs, future studies on BKI 1369 should be directed towards ease of drug handling and minimizing treatment frequencies

Southern Barrier Ranges-Northern Murray Basin, New South Wales

S.M. Hill, D.S. West, G. Shirtliff, A.B. Senior, B.E.R. Maly, G.L. Jones, M. Holzapfel, K.A. Foster, S.C. Debenham, R. Dann, J. Brachmani

Iterative Temporal Planning in Uncertain Environments with Partial Satisfaction Guarantees

Abstract This work introduces a motion-planning framework for a hybrid system with general continuous dynamics to satisfy a temporal logic specification consisting of co-safety and safety components in a partially unknown environment. The framework employs a multi-layered synergistic planner to generate trajectories that satisfy the specification and adopts an iterative replanning strategy to deal with unknown obstacles. When the discovery of an obstacle renders the specification unsatisfiable, a division between the constraints in the specification is considered. The co-safety component of the specification is treated as a soft constraint, whose partial satisfaction is allowed, while the safety component is viewed as a hard constraint, whose violation is forbidden. To partially satisfy the co-safety component, inspirations To appear in the IEEE Transaction on Robotics, 2016. 2 are taken from indoor-robotic scenarios, and three types of (unexpressed) restrictions on the ordering of sub-tasks in the specification are considered. For each type, a partial satisfaction method is introduced, which guarantees the generation of trajectories that do not violate the safety constraints while attending to partially satisfying the co-safety requirements with respect to the chosen restriction type. The efficacy of the framework is illustrated through case studies on a hybrid car-like robot in an office environment

Iterative temporal planning in uncertain environments with partial satisfaction guarantees

This paper introduces a motion-planning framework for a hybrid system with general continuous dynamics to satisfy a temporal logic specification consisting of cosafety and safety components in a partially unknown environment. The framework employs a multilayered synergistic planner to generate trajectories that satisfy the specification and adopt an iterative replanning strategy to deal with unknown obstacles. When the discovery of an obstacle renders the specification unsatisfiable, a division between the constraints in the specification is considered. The cosafety component of the specification is treated as a soft constraint, whose partial satisfaction is allowed, while the safety component is viewed as a hard constraint, whose violation is forbidden. To partially satisfy the cosafety component, inspirations are taken from indoor-robotic scenarios, and three types of (unexpressed) restrictions on the ordering of subtasks in the specification are considered. For each type, a partial satisfaction method is introduced, which guarantees the generation of trajectories that do not violate the safety constraints while attending to partially satisfying the cosafety requirements with respect to the chosen restriction type. The efficacy of the framework is illustrated through case studies on a hybrid car-like robot in an office environment