A simulation scenario based mixed integer programming approach to airline reserve crew scheduling under uncertainty

The environment in which airlines operate is uncertain for many reasons, for example due to the effects of weather, traffic or crew unavailability (due to delay or sickness). This work focuses on airline reserve crew scheduling under crew absence uncertainty and delay for an airline operating a single hub and spoke network. Reserve crew can be used to cover absent crew or delayed connecting crew. A fixed number of reserve crew are available for scheduling and each requires a daily standby duty start time. This work proposes a mixed integer programming approach to scheduling the airline’s reserve crew. A simulation of the airline’s operations with stochastic journey time and crew absence inputs (without reserve crew) is used to generate input disruption scenarios for the mixed integer programming simulation scenario model (MIPSSM) formulation. Each disruption scenario corresponds to a record of all of the disruptions that may occur on the day of operation which are solvable by using reserve crew. A set of disruption scenarios form the input of the MIPSSM formulation, which has the objective of finding the reserve crew schedule that minimises the overall level of disruption over the set of input scenarios. Additionally, modifications of the MIPSSM are explored, a heuristic solution approach and a reserve use policy derived from the MIPSSM are introduced. A heuristic based on the proposed MIPSSM outperforms a range of alternative approaches. The heuristic solution approach suggests that including the right disruption scenarios is as important as the quantity of disruption scenarios that are added to the MIPSSM. An investigation into what makes a good set of scenarios is also presented

Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78-13.2) compared to 8.26 months (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn't reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs

Quantifying effects of radiotherapy-induced microvascular injury; review of established and emerging brain MRI techniques

Microvascular changes are increasingly recognised not only as primary drivers of radiotherapy treatment response in brain tumours, but also as an important contributor to short- and long-term (cognitive) side effects arising from irradiation of otherwise healthy brain tissue. As overall survival of patients with brain tumours is increasing, monitoring long-term sequels of radiotherapy-induced microvascular changes in the context of their potential predictive power for outcome, such as cognitive disability, has become increasingly relevant. Ideally, radiotherapy-induced significant microvascular changes in otherwise healthy brain tissue should be identified as early as possible to facilitate adaptive radiotherapy and to proactively start treatment to minimise the influence on these side-effects on the final outcome. Although MRI is already known to be able to detect significant long-term radiotherapy induced microvascular effects, more recently advanced MR imaging biomarkers reflecting microvascular integrity and function have been reported and might provide a more accurate and earlier detection of microvascular changes. However, the use and validation of both established and new techniques in the context of monitoring early and late radiotherapy-induced microvascular changes in both target-tissue and healthy tissue currently are minimal at best. This review aims to summarise the performance and limitations of existing methods and future opportunities for detection and quantification of radiotherapy-induced microvascular changes, as well as the relation of these findings with key clinical parameters. (C) 2019 Elsevier B.V. All rights reserved

Coulomb Blockade in a Silicon/Silicon-Germanium Two-Dimensional Electron Gas Quantum Dot

We report the fabrication and electrical characterization of a single electron transistor in a modulation doped silicon/silicon-germanium heterostructure. The quantum dot is fabricated by electron beam lithography and subsequent reactive ion etching. The dot potential and electron density are modified by laterally defined side gates in the plane of the dot. Low temperature measurements show Coulomb blockade with a single electron charging energy of 3.2 meV.Comment: Typos corrected; to appear in Appl. Phys. Let

Pests, pesticide use and alternative options in European maize production: current status and future prospects

Political efforts are made in the European Union (EU) to reduce pesticide use and to increase the implementation of integrated pest management (IPM). Within the EU project ENDURE, research priorities on pesticide reduction are defined. Using maize, one of the most important crops in Europe, as a case study, we identified the most serious weeds, arthropod pests, and fungal diseases as well as classes and amounts of pesticides applied. Data for 11 European maize growing regions were collected from databases, publications and expert estimates. Silage maize dominates in northern Europe and grain production in central and southern Europe. Crop rotations range from continuous growing of maize over several years to well-planned rotation systems. Weeds, arthropod pests and fungal diseases cause economic losses in most regions, even though differences exist between northern countries and central and southern Europe. Several weed and arthropod species cause increasing problems, illustrating that the goal of reducing chemical pesticide applications is challenging. Pesticides could potentially be reduced by the choice of varieties including genetically modified hybrids, cultural control including crop rotation, biological control, optimized application techniques for chemicals, and the development of more specific treatments. However, restrictions in the availability of alternative pest control measures, farm organization, and the training and knowledge of farmers need to be overcome before the adoption of environmentally friendly pest control strategies can reduce chemical pesticides in an economically competitive way. The complex of several problems that need to be tackled simultaneously and the link between different control measures demonstrates the need for IPM approaches, where pest control is seen in the context of the cropping system and on a regional scale. Multicriteria assessments and decision support systems combined with pest monitoring programs may help to develop region-specific and sustainable strategies that are harmonized within a EU framework

Clinical relevance of the radiation dose bath in lower grade glioma, a cross-sectional pilot study on neurocognitive and radiological outcome

AIM: To investigate the clinical relevance of the radiotherapy (RT) dose bath in patients treated for lower grade glioma (LGG). METHODS: Patients (n = 17) treated with RT for LGG were assessed with neurocognitive function (NCF) tests and structural Magnetic Resonance Imaging (MRI) and categorized in subgroups based on tumour lateralisation. RT dose, volumetric results and cerebral microbleed (CMB) number were extracted for contralateral cerebrum, contralateral hippocampus, and cerebellum. The RT clinical target volume (CTV) was included in the analysis as a surrogate for focal tumour and other treatment effects. The relationships between RT dose, CTV, NCF and radiological outcome were analysed per subgroup. RESULTS: The subgroup with left-sided tumours (n = 10) performed significantly lower on verbal tests. The RT dose to the right cerebrum, as well as CTV, were related to poorer performance on tests for processing speed, attention, and visuospatial abilities, and more CMB. In the subgroup with right-sided tumours (n = 7), RT dose in the left cerebrum was related to lower verbal memory performance, (immediate and delayed recall, r = −0.821, p = 0.023 and r = −0.937, p = 0.002, respectively), and RT dose to the left hippocampus was related to hippocampal volume (r = −0.857, p = 0.014), without correlation between CTV and NCF. CONCLUSION: By using a novel approach, we were able to investigate the clinical relevance of the RT dose bath in patients with LGG more specifically. We used combined MRI-derived and NCF outcome measures to assess radiation-induced brain damage, and observed potential RT effects on the left-sided brain resulting in lower verbal memory performance and hippocampus volume

Intradermal Electroporation of Naked Replicon RNA Elicits Strong Immune Responses

RNA-based vaccines represent an interesting immunization modality, but suffer from poor stability and a lack of efficient and clinically feasible delivery technologies. This study evaluates the immunogenic potential of naked in vitro transcribed Semliki Forest virus replicon RNA (RREP) delivered intradermally in combination with electroporation. Replicon-immunized mice showed a strong cellular and humoral response, contrary to mice immunized with regular mRNA. RREP-elicited induction of interferon-γ secreting CD8+ T cells and antibody responses were significantly increased by electroporation. CD8+ T cell responses remained substantial five weeks post vaccination, and antigen-specific CD8+ T cells with phenotypic characteristics of both effector and central memory cells were identified. The immune response during the contraction phase was further increased by a booster immunization, and the proportion of effector memory cells increased significantly. These results demonstrate that naked RREP delivered via intradermal electroporation constitute an immunogenic, safe and attractive alternative immunization strategy to DNA-based vaccines