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In Project WASTEC, an experimental Reverse Osmosis (RO) desalination system was developed. It serves as a platform for testing new technologies. For this system, we solved two problems, which are described in this paper. Firstly, we developed and investigated strategies for scheduling chemical enhanced backwashing and chemical cleaning and secondly, due to the experimental nature of the project, several new technological developments with respect to materials and methods were integrated into the system and requires tools for evaluating the economic viability of the new technologies. In this task, the economics of membrane-based desalination will be investigated. Baseline systems of reverse osmosis and pretreatment systems (microfiltration and ultrafiltration) will be economically examined and compared for their investments and operational costs. Sensitivity of the different plant and membrane parameters to the cost will be studied. Results show that with respect to costs, for a 200m3/hr design capacity plant, a volume of water is produced by a MF process at a cost of $0.494 and at a cost of $0.486 by an ultrafiltration process microfiltration. The reverse osmosis process cannot be compared directly, but it required $ 0.49 / m3 for a plant with 56 m3/hour design capacity. The values are in line with the costs reported in literature for membrane-based filtration.

In the last decade remarkable progress has been made in development of suitable proof techniques for analysing randomised search heuristics. The theoretical investigation of these algorithms on classes of functions is essential to the understanding of the underlying stochastic process. Linear functions have been traditionally studied in this area resulting in tight bounds on the expected optimisation time of simple randomised search algorithms for this class of problems. Recently, the constrained version of this problem has gained attention and some theoretical results have also been obtained on this class of problems. In this paper we study the class of linear functions under uniform constraint and investigate the expected optimisation time of Randomised Local Search (RLS) and a simple evolutionary algorithm called (1+1) EA. We prove a tight bound of $\Theta(n^2)$ for RLS and improve the previously best known upper bound of (1+1) EA from $O(n^2 \log (Bw_{\max}))$ to $O(n^2\log B)$ in expectation and to $O(n^2 \log n)$ with high probability, where $w_{\max}$ and $B$ are the maximum weight of the linear objective function and the bound of the uniform constraint, respectively. Also, we obtain a tight bound of $O(n^2)$ for the (1+1) EA on a special class of instances. We complement our theoretical studies by experimental investigations that consider different values of $B$ and also higher mutation rates that reflect the fact that $2$-bit flips are crucial for dealing with the uniform constraint., Comment: Journal version to appear in Algorithmica

Hyperinflammation is frequently observed in patients with severe COVID-19. Inadequate and defective IFN type I responses against SARS-CoV-2, associated with autoantibodies in a proportion of patients, lead to severe courses of disease. In addition, hyperactive responses of the humoral immune system have been described. In the current study we investigated a possible role of neutralizing autoantibodies against anti-inflammatory mediators. Plasma from adult patients with severe and critical COVID-19 was screened by ELISA for antibodies against PGRN, IL-1-Ra, IL-10, IL-18BP, IL-22BP, IL-36-Ra, CD40, IFN-α2, IFN-γ, IFN-ω and serpinB1. Autoantibodies were characterized and the antigens were analyzed for immunogenic alterations. In a discovery cohort with severe to critical COVID-19 high titers of PGRN-autoantibodies were detected in 11 of 30 (36.7%), and of IL-1-Ra-autoantibodies in 14 of 30 (46.7%) patients. In a validation cohort of 64 patients with critical COVID-19 high-titer PGRN-Abs were detected in 25 (39%) and IL-1-Ra-Abs in 32 of 64 patients (50%). PGRN-Abs and IL-1-Ra-Abs belonged to IgM and several IgG subclasses. In separate cohorts with non-critical COVID-19, PGRN-Abs and IL-1-Ra-Abs were detected in low frequency (i.e. in < 5% of patients) and at low titers. Neither PGRN- nor IL-1-Ra-Abs were found in 40 healthy controls vaccinated against SARS-CoV-2 or 188 unvaccinated healthy controls. PGRN-Abs were not cross-reactive against SARS-CoV-2 structural proteins nor against IL-1-Ra. Plasma levels of both free PGRN and free IL-1-Ra were significantly decreased in autoantibody-positive patients compared to Ab-negative and non-COVID-19 controls. In vitro PGRN-Abs from patients functionally reduced PGRN-dependent inhibition of TNF-α signaling, and IL-1-Ra-Abs from patients reduced IL-1-Ra- or anakinra-dependent inhibition of IL-1ß signaling. The pSer81 hyperphosphorylated PGRN isoform was exclusively detected in patients with high-titer PGRN-Abs; likewise, a hyperphosphorylated IL-1-Ra isoform was only found in patients with high-titer IL-1-Ra-Abs. Thr111 was identified as the hyperphophorylated amino acid of IL-1-Ra. In longitudinally collected samples hyperphosphorylated isoforms of both PGRN and IL-1-Ra emerged transiently, and preceded the appearance of autoantibodies. In hospitalized patients, the presence of IL-1-Ra-Abs or IL-1-Ra-Abs in combination with PGRN-Abs was associated with a higher morbidity and mortality.To conclude, neutralizing autoantibodies to IL-1-Ra and PGRN occur in a significant portion of patients with critical COVID-19, with a concomitant decrease in circulating free PGRN and IL-1-Ra, indicative of a misdirected, proinflammatory autoimmune response. The break of self-tolerance is likely caused by atypical hyperphosphorylated isoforms of both antigens, whose appearances precede autoantibody induction. Our data suggest that these immunogenic secondary modifications are induced by the SARS-CoV-2-infection itself or the inflammatory environment evoked by the infection and predispose for a critical course of COVID-19.

BackgroundDespite numerous advances in the identification of risk factors for the development of severe coronavirus disease 2019 (COVID-19), factors that promote recovery from COVID-19 remain unknown. Natural killer (NK) cells provide innate immune defense against viral infections and are known to be activated during moderate and severe COVID-19. Killer immunoglobulin-like receptors (KIR) mediate NK cell cytotoxicity through recognition of an altered MHC-I expression on infected target cells. However, the influence of KIR genotype on outcome of patients with COVID-19 has not been investigated so far. We retrospectively analyzed the outcome associations of NK cell count and KIR genotype of patients with COVID-19 related severe ARDS treated on our tertiary intensive care unit (ICU) between February and June 2020 and validated our findings in an independent validation cohort of patients with moderate COVID-19 admitted to our tertiary medical center.ResultsMedian age of all patients in the discovery cohort (n = 16) was 61 years (range 50–71 years). All patients received invasive mechanical ventilation; 11 patients (68%) required extracorporeal membrane oxygenation (ECMO). Patients who recovered from COVID-19 had significantly higher median NK cell counts during the whole observational period compared to patients who died (121 cells/µL, range 16–602 cells/µL vs 81 cells/µL, range 6–227 cells/µL,p-value = 0.01). KIR2DS5 positivity was significantly associated with shorter time to recovery (21.6 ± 2.8 days vs. 44.6 ± 2.2 days,p-value = 0.01). KIR2DS5 positivity was significantly associated with freedom from transfer to ICU (0% vs 9%,p-value = 0.04) in the validation cohort which consisted of 65 patients with moderate COVID-19.ConclusionNK cells and KIR genotype might have an impact on recovery from COVID-19.

Implementation of open sea seaweed aquaculture has been pursued in Europe for high biomass production to be used for different purposes, including the biorefinery pipeline. Offshore cultiva...

Run-of-Mine stockpiles are essential components in the mining value chain because they can be used as temporary storage to balance inflow and outflow and provide an opportunity for blending material. Stockpile schedulers plan stockpile recovery to balance throughput and material specifications to deliver for the supply chain's next stage. There are technical limits on deliveries where "failure to meet" can lead to significant penalty fees, increased operational costs due to poor operational plans or over-delivery to material specifications. Currently, human experts determine the planning of stockpile recovery in practice. However, this approach is error prone due to the complex distribution of materials within a stockpile and the inability to foresee upcoming deliveries efficiently. In this paper, we model the stockpile recovery problem as a combinatorial optimization problem considering technical restrictions in real-world issues, and we investigate multiple scenarios and experiments. We apply deterministic and randomized greedy algorithms, as well as ant colony optimization algorithms integrated with local search. We compare all algorithms with a rule of thumb heuristic to evaluate our methodology's quality. Our findings show that ant colony optimization outperforms other algorithms, and the variant integrated with swap and insert local search operators finds the best solutions.

Introduction In this real-world study, the incidence of cardiovascular events (CV) including major adverse cardiac events (MACE), arterial occlusive events (AOE), and venous occlusive events (VOE) was evaluated in chronic myeloid leukemia (CML) patients treated with ponatinib or bosutinib in a US commercial database population. Materials and Methods CML patients aged ≥18 years with use of 1 or 2 prior tyrosine kinase inhibitors prescribed bosutinib or ponatinib were selected from the IBM® MarketScan® Research database. Cox proportional hazard model analyses were conducted to examine any difference in CV event risk. Results Ponatinib and bosutinib was associated with similar incidence and risk of CV events, including MACEs (HR: 1.02; 95% CI: 0.35, 3.01), AOEs (HR: 0.90; 95% CI: 0.43, 1.85) and VOEs (HR: 0.92; 95% CI: 0.44, 1.94). Conclusion Treatment with ponatinib or bosutinib was not associated with significant differences in the incidence of CV events in CML patients.

Evolutionary algorithms are adaptive algorithms that can alter their behaviour under changing circumstances. This makes them well-suited to act in interactive environments. We introduce a framework for human interactive animations based on EEG signals. EEG signals received through a brain computer interface headset are used as the fitness function and influence the animation based on the signals received. For our experimental investigation, we consider the recently introduced quasi-random animation process and alter the process through mutation operators that depend on the EEG signals received. Furthermore, the EEG signals trigger mutations and therefore alterations to the image animation process if their values are not in a predefined range. Our experimental study shows that a large variety of animations and intermediate images are obtainable in this way.

Dynamic optimisation occurs in a variety of real-world problems. To tackle these problems, evolutionary algorithms have been extensively used due to their effectiveness and minimum design effort. However, for dynamic problems, extra mechanisms are required on top of standard evolutionary algorithms. Among them, diversity mechanisms have proven to be competitive in handling dynamism, and recently, the use of neural networks have become popular for this purpose. Considering the complexity of using neural networks in the process compared to simple diversity mechanisms, we investigate whether they are competitive and the possibility of integrating them to improve the results. However, for a fair comparison, we need to consider the same time budget for each algorithm. Thus, instead of the usual number of fitness evaluations as the measure for the available time between changes, we use wall clock timing. The results show the significance of the improvement when integrating the neural network and diversity mechanisms depends on the type and the frequency of changes. Moreover, we observe that for differential evolution, having a proper diversity in population when using neural networks plays a key role in the neural network's ability to improve the results.

Dynamic optimization problems have gained significant attention in evolutionary computation as evolutionary algorithms (EAs) can easily adapt to changing environments. We show that EAs can solve the graph coloring problem for bipartite graphs more efficiently by using dynamic optimization. In our approach the graph instance is given incrementally such that the EA can reoptimize its coloring when a new edge introduces a conflict. We show that, when edges are inserted in a way that preserves graph connectivity, Randomized Local Search (RLS) efficiently finds a proper 2-coloring for all bipartite graphs. This includes graphs for which RLS and other EAs need exponential expected time in a static optimization scenario. We investigate different ways of building up the graph by popular graph traversals such as breadth-first-search and depth-first-search and analyse the resulting runtime behavior. We further show that offspring populations (e. g. a (1+$\lambda$) RLS) lead to an exponential speedup in $\lambda$. Finally, an island model using 3 islands succeeds in an optimal time of $\Theta(m)$ on every $m$-edge bipartite graph, outperforming offspring populations. This is the first example where an island model guarantees a speedup that is not bounded in the number of islands., Comment: To be presented at GECCO2020

Understanding the behaviour of heuristic search methods is a challenge. This even holds for simple local search methods such as 2-OPT for the Traveling Salesperson problem. In this paper, we present a general framework that is able to construct a diverse set of instances that are hard or easy for a given search heuristic. Such a diverse set is obtained by using an evolutionary algorithm for constructing hard or easy instances that are diverse with respect to different features of the underlying problem. Examining the constructed instance sets, we show that many combinations of two or three features give a good classification of the TSP instances in terms of whether they are hard to be solved by 2-OPT., 20 pages, 18 figures

Several important optimization problems in the area of vehicle routing can be seen as a variant of the classical Traveling Salesperson Problem (TSP). In the area of evolutionary computation, the traveling thief problem (TTP) has gained increasing interest over the last 5 years. In this paper, we investigate the effect of weights on such problems, in the sense that the cost of traveling increases with respect to the weights of nodes already visited during a tour. This provides abstractions of important TSP variants such as the Traveling Thief Problem and time dependent TSP variants, and allows to study precisely the increase in difficulty caused by weight dependence. We provide a 3.59-approximation for this weight dependent version of TSP with metric distances and bounded positive weights. Furthermore, we conduct experimental investigations for simple randomized local search with classical mutation operators and two variants of the state-of-the-art evolutionary algorithm EAX adapted to the weighted TSP. Our results show the impact of the node weights on the position of the nodes in the resulting tour.

Apoptotic intestinal crypt cells are pathognomonic of acute intestinal graft versus host disease (GVHD). Serum levels of the apoptotic degradation product cytokeratin-18 fragments (CK18F) were associated with acute hepato-intestinal GVHD. Here we present a prospective clinical observational trial (NCT00935324) investigating serum levels of total CK18 (tCK18) and apoptotic CK18F to predict imminent acute hepato-intestinal GVHD and response to treatment. Total (t)CK18 and CK18F kinetics were measured before transplantation and in weekly intervals thereafter. In total 109 patients were enrolled. Acute hepato-intestinal GVHD grade I–IV was suspected in 36 patients (33%) at a median of 56 days post-transplant, 12 of these patients developed steroid-refractory GVHD. Both tCK18 and apoptotic CK18F increased at GVHD onset, and distinguished patients with suspected acute hepato-intestinal GVHD who were negative in intestinal histology. In patients with clinical acute hepato-intestinal GVHD, tCK18 significantly raised already 7–14 days before symptom onset. In receiver operator characteristics, areas under the curve at GVHD onset were 0.927 (p

Designing automatic drivers for car racing is an active field of research in the area of robotics and artificial intelligence. A controller called Ahura (a heuristic-based racer) for the open racing car simulator is proposed in this paper. Ahura includes five modules, namely steer controller, speed controller, opponent manager, dynamic adjuster, and stuck handler. These modules have 23 parameters all together that are tuned using an evolutionary strategy for a particular car to ensure fast and safe drive on different tracks. These tuned parameters are further modified by the dynamic adjuster module during the run according to the width, friction, and dangerous zones of the track. The dynamic adjustment enables Ahura to decide on-the-fly based on the current situation; hence, it eliminates the need for prior knowledge about the characteristics of the track. The driving performance of Ahura is compared with other state-of-the-art controllers on 40 tracks when they drive identical cars. Our experiments indicate that Ahura performs significantly better than other controllers in terms of damage and completion time especially on complex tracks (road tracks). Also, experiments show that the overtaking strategy of Ahura is safer and more effective compared to other controllers.

Background SAPHO syndrome has to be considered as a rare subtype of seronegative spondyloarthritis (SpA) showing typical manifestations with palmoplantar pustolosis and osteitis with hyperostosis; the clinical response of conventional or biological disease modifying drugs (DMARDs) in SAPHO syndrome are often disappointing. Whereas in SpA peripheral arthritis and inflammatory back pain represent the leading symptoms, the SAPHO patients often complain painful osteitis with hyperostosis in the sternal region as well as the palmoplantar pustulosis accompanied by synovitis preferentially in large joints including sacroiliitis. Recently, the detection of higher numbers of CD4+IL17+ lymphocytes in the peripheral blood of SAPHO patients has arisen the hypothesis that Th4/17 helper cells with their secretion of interleukin 17 (IL17) could be involved in the development of inflammation in SAPHO syndrome (1) Objectives Here we present an observational study of 12 SAPHO patients which were treated with the IL 17 blocking agent secukinumab. In addition, the fraction of CD4/17+ lymphocytes in peripheral blood specimen has been monitored on treatment. Methods Between January 2015 and February 2017 clinical activity of disease were measured in 37 SAPHO patients with a disease duration of 11 years (median). The disease activity were evaluated by the osteitis score and skin score (ranging from 0 to 6, assessed by physician), the HAQ score (ranging from 0 to 3, assessed by patient), and MRI of the osteitis lesion (activity score 0-3, analogously to 3 domains of OMERACT RAMRIS scoring synovitis, bone marrow edema, and erosions; assessed by radiologist). In this period of time 12 of them showed disease activity due to osteitis and/or skin disease, at which time the treatment of secukinumab at dosage of 300mg as monotherapy has been started, re-evaluated after at least 12 weeks (ranging from 12 to 18 weeks). For monitoring blood specimens were derived to assess the CD4+/IL17+ lymphocyte subpopulation using immunofluorescence technique commercial antibodies for CD4, IL17 (Boehringer Ingelheim, Germany). To analyse the differences between the disease activity scores prior to secukinumab treatment and after treatment we applied the nonparametric analysis according to Wilcoxon test. The p-value Results Secukinumab improved osteitis and palmoplantar pustolosis (osteitis score 3.8 to 2.4; p=0.007; PPP 3.4 to 2.4; p=0.071), the HAQ score was reduced from 1.25 to 1.0 (p=0.018), the MRI score from 2.08 to 1.58 (p=0.034). The reduction of at least two clinical activity parameters (osteitis, HAQ and/or MRI) after secukinumab treatment could be documented in all SAPHO patients who showed CD4+IL17+ lymphocytes in higher frequency of 0.4% of leukocytes of peripheral blood. Conclusion Secukinumab seems to control osteitis and PPP in SAPHO syndrome resulting in reduced burden of disease. High Th17 lymphocytes numbers seems to be associated with higher probability of clinical response to secukinumab. Reference: [1] Firinu D, Barca MP, Lorrai MM, Perra S, Cabras S, Muggianu E, Di Martino ML, Manconi PE, Del Giacco SR. TH17 cells are increased in the peripheral blood of patients with SAPHO syndrome. Autoimmunity. 2014Sep;47(6):389-94 Disclosure of Interests None declared

Diversity plays a crucial role in evolutionary computation. While diversity has been mainly used to prevent the population of an evolutionary algorithm from premature convergence, the use of evolutionary algorithms to obtain a diverse set of solutions has gained increasing attention in recent years. Diversity optimization in terms of features on the underlying problem allows to obtain a better understanding of possible solutions to the problem at hand and can be used for algorithm selection when dealing with combinatorial optimization problems such as the Traveling Salesperson Problem. We explore the use of the star-discrepancy measure to guide the diversity optimization process of an evolutionary algorithm. In our experimental investigations, we consider our discrepancy-based diversity optimization approaches for evolving diverse sets of images as well as instances of the Traveling Salesperson problem where a local search is not able to find near optimal solutions. Our experimental investigations comparing three diversity optimization approaches show that a discrepancy-based diversity optimization approach using a tie-breaking rule based on weighted differences to surrounding feature points provides the best results in terms of the star discrepancy measure.

Randomized search heuristics such as evolutionary algorithms are frequently applied to dynamic combinatorial optimization problems. Within this paper, we present a dynamic model of the classic Weighted Vertex Cover problem and analyze the performances of the two well-studied algorithms Randomized Local Search and (1+1) EA adapted to it, to contribute to the theoretical understanding of evolutionary computing for problems with dynamic changes. In our investigations, we use an edge-based representation based on the dual formulation of the problem and study the expected runtimes that the two algorithms require to maintain a 2-approximate solution when the given weighted graph is modified by an edge-editing or weight-editing operation. Considering the weights on the vertices may be exponentially large with respect to the size of the graph, the step size adaption strategy is incorporated. Our results show that both algorithms can recompute 2-approximate solutions for the studied dynamic changes efficiently

Evolutionary algorithms have been widely used in the area of creativity in order to help create art and music. We consider the recently introduced evolutionary image composition approach based on feature covariance matrices [1] which allows composing two images into a new one based on their feature characteristics. When using evolutionary image composition it is important to obtain a good weighting of interesting regions of the two images. We use colour-based segmentation based on K-Means clustering to come up with such a weighting of the images. Our results show that this preserves the chosen colour regions of the images and leads to composed images that preserve colours better than the previous approach based on saliency masks [1]. Furthermore, we evaluate our composed images in terms of aesthetic feature and show that our approach based on colour-based segmentation leads to higher feature values for most of the investigated features.

Robust model fitting plays a vital role in computer vision, and research into algorithms for robust fitting continues to be active. Arguably the most popular paradigm for robust fitting in computer vision is consensus maximisation, which strives to find the model parameters that maximise the number of inliers. Despite the significant developments in algorithms for consensus maximisation, there has been a lack of fundamental analysis of the problem in the computer vision literature. In particular, whether consensus maximisation is “tractable” remains a question that has not been rigorously dealt with, thus making it difficult to assess and compare the performance of proposed algorithms, relative to what is theoretically achievable. To shed light on these issues, we present several computational hardness results for consensus maximisation. Our results underline the fundamental intractability of the problem, and resolve several ambiguities existing in the literature.

Aims It is unknown whether different training modalities exert differential cellular effects. Telomeres and telomere-associated proteins play a major role in cellular aging with implications for global health. This prospective training study examines the effects of endurance training, interval training (IT), and resistance training (RT) on telomerase activity and telomere length (TL). Methods and results One hundred and twenty-four healthy previously inactive individuals completed the 6 months study. Participants were randomized to three different interventions or the control condition (no change in lifestyle): aerobic endurance training (AET, continuous running), high-intensive IT (4 × 4 method), or RT (circle training on 8 devices), each intervention consisting of three 45 min training sessions per week. Maximum oxygen uptake (VO2max) was increased by all three training modalities. Telomerase activity in blood mononuclear cells was up-regulated by two- to three-fold in both endurance exercise groups (AET, IT), but not with RT. In parallel, lymphocyte, granulocyte, and leucocyte TL increased in the endurance-trained groups but not in the RT group. Magnet-activated cell sorting with telomerase repeat-ampliflication protocol (MACS-TRAP) assays revealed that a single bout of endurance training—but not RT—acutely increased telomerase activity in CD14+ and in CD34+ leucocytes. Conclusion This randomized controlled trial shows that endurance training, IT, and RT protocols induce specific cellular pathways in circulating leucocytes. Endurance training and IT, but not RT, increased telomerase activity and TL which are important for cellular senescence, regenerative capacity, and thus, healthy aging.

In this paper, we perform theoretical analyses of the behaviour of an evolutionary algorithm and a randomised search algorithm on the dynamic vertex cover problem. The dynamic vertex cover problem has already been theoretically investigated for these two algorithms to some extent. We improve some of the existing results, i. e. we find a linear expected re-optimization time for a (1+1) EA to maintain a 2-approximation when edges are dynamically deleted from the graph. Furthermore, we investigate a different setting for the dynamic version of the problem, in which a dynamic change happens at each step with probability P D . We prove that when P D ≤ 1/(2+∊)em, where m is the number of edges of the graph, RLS and (1+1) EA find a 2-approximate solution from an arbitrary initial solution in expected time O(m log m). Furthermore, we prove that in expected time O(m) after the first dynamic change, they recompute a 2-approximate solution.

Parent selection in evolutionary algorithms for multi-objective optimization is usually performed by dominance mechanisms or indicator functions that prefer non-dominated points, while the reproduction phase involves the application of diversity mechanisms or other methods to achieve a good spread of the population along the Pareto front. We propose to refine the parent selection on evolutionary multi-objective optimization with diversity-based metrics. The aim is to focus on individuals with a high diversity contribution located in poorly explored areas of the search space, so the chances of creating new non-dominated individuals are better than in highly populated areas. We show by means of rigorous runtime analysis that the use of diversity-based parent selection mechanisms in the Simple Evolutionary Multi-objective Optimiser (SEMO) and Global SEMO for the well known bi-objective functions OneMinMax and Lotz can significantly improve their performance. Our theoretical results are accompanied by additional experiments that show a correspondence between theory and empirical results.

Background The SAPHO syndrome has to be considered as a rare subtype of the disease entity of the seronegative spondylarthritis. The characteristic defining symptoms are synovitis, acne, palmoplantar pustulosis (PPP), and hyperostosis with osteitis. In general, most of SAPHO patients complete the diagnostic criteria for spondylarthritis and/or psoriatic arthritis. The etiology of SAPHO syndrome remains unclear so far, autoimmune dysregulations potentially triggered by bacterial infection with propionibacterium acnes has been discussed. Firinu D et. al (Ref.) has previously published data of higher Th17+ lymphocytes in the periphereal blood in SAPHO patients compared with psoriatic arthritis patients or healthy controls. Activation of the TH17 pathway leads to pro-inflammatory effects mediated by interleukin 17 with stimulation of osteoblast, macrophages, and fibroblasts with the consequences of secretion f pro-inflammatory cytokines such as interleukin 6 and 1, TNF alpha, and MMPs. The interleukin 17 blocking agent secukinumab has been introduced in the armentarium of antirheumatic drugs against seronegative spondylarthritis including psoriatic arthritis. Objectives To evaluate the count of Th17+ lymphocytes in patients with SAPHO syndrome and psoriatic arthritis before and under treatment with secukinumab. Methods Periphereal blood was derived from 4 patients with SAPHO syndrome and 4 patients with psoriatic arthritis, respectively before and under 12 week treatment with secukinumab 300mg (dosage: 4 times weekly, then monthly). All patients had received at least one conventional DMARDs and one TNF blocking agent in their medical history. All patients showed active disease with elevated scores of DAS28 and/or HAQ, for SAPHO patients the activity scores of osteitis (from 0 to 6) and PPP (0–6) were estimated by physician. The blood specimen were separated in EDTA containing tubes to separate lymphocytes, which were measured using FACS analysis to evaluate the fraction of Th 17+/CD4+ lymphocytes. The Ethics Committee of Saarland has proven the study, all patients gave their consent to take part in the study. Results The Th17+lymphocytes were not detectable in 4 patients with psoriatic arthritis and 2 of 4 SAPHO patients before and under 12 week treatment with secukinumab. In 2 of 4 SAPHO patients the fractions of Th17+ lymphocytes were prominent prior to secukinumab application; after treatment duration of 12 weeks one of both developed a depletion of Th17+ cells (figure), the other SAPHO patient a Th17+ cell reduction. Only the two SAPHO patients with diminishing Th17+ lymphocytes have developed treatment response evaluated by reduction of HAQ score (from 1.75 to 1.25), osteitis score (4.5 to 3.0), and PPP score (5.0 to 4.0). Three of 4 psoriatic arthritis patients showed reduced diseases activity under treatment with secukinumab (DAS28 score from 4.22 to 3.45, HAQ 2.25 to 1.5). Conclusions The measurement of Th17+lymphocytes in the periphereal blood of SAPHO patients could be suggested for further evaluation as possible predictor of treatment response by secukinumab. References Firinu D, Barca MP, Lorrai MM, Perra S, Cabras S, Muggianu E, Di Martino ML, Manconi PE, Del Giacco SR. TH17 cells are increased in the peripheral blood of patients with SAPHO syndrome. Autoimmunity. 2014 Sep;47(6):389–94. doi: 10.3109/08916934.2014.906582. Epub 2014 Apr 10. Disclosure of Interest None declared

Evolutionary algorithms have recently been used to create a wide range of artistic work. In this paper, we propose a new approach for the composition of new images from existing ones, that retain some salient features of the original images. We introduce evolutionary algorithms that create new images based on a fitness function that incorporates feature covariance matrices associated with different parts of the images. This approach is very flexible in that it can work with a wide range of features and enables targeting specific regions in the images. For the creation of the new images, we propose a population-based evolutionary algorithm with mutation and crossover operators based on random walks. Our experimental results reveal a spectrum of aesthetically pleasing images that can be obtained with the aid of our evolutionary process.

We consider the weighted minimum vertex cover problem and investigate how its dual formulation can be exploited to design evolutionary algorithms that provably obtain a 2-approximation. Investigating multi-valued representations, we show that variants of randomized local search and the (1+1)EA achieve this goal in expected pseudo-polynomial time. In order to speed up the process, we consider the use of step size adaptation in both algorithms and show that RLS obtains a 2-approximation in expected polynomial time while the one+one still encounters a pseudo-polynomial lower bound.

Many evolutionary and constructive heuristic approaches have been introduced in order to solve the Travelling Thief Problem (TTP). However, the accuracy of such approaches is unknown due to their inability to find global optima. In this paper, we propose three exact algorithms and a hybrid approach to the TTP. We compare these with state-of-the-art approaches to gather a comprehensive overview on the accuracy of heuristic methods for solving small TTP instances.

We investigate how well-performing local search algorithms for small or medium size instances can be scaled up to perform well for large inputs. We introduce a parallel kernelization technique that is motivated by the assumption that graphs in medium to large scale are composed of components which are on their own easy for state-of-the-art solvers but when hidden in large graphs are hard to solve. To show the effectiveness of our kernelization technique, we consider the well-known minimum vertex cover problem and two state-of-the-art solvers called NuMVC and FastVC. Our kernelization approach reduces an existing large problem instance significantly and produces better quality results on a wide range of benchmark instances and real world graphs.

INTRODUCTION: Chronic myeloid leukemia (CML) is a bone marrow and blood disorder accounting for 15% of adult leukemia. Tyrosine kinase inhibitors (TKIs) have been the standard of care for CML treatment. However, an association between TKI use and cardiovascular events has been observed. Ponatinib and bosutinib are introduced to provide more options for patients who failed their first-line treatment. The incidence of major adverse cardiac events (MACEs), arterial occlusive events (AOEs), and venous occlusive events (VOEs) were assessed among CML patients who were prescribed ponatinib vs bosutinib. METHODS: A retrospective observational study was conducted among adult CML patients aged ≥18 years with use of 1 or 2 prior TKIs who were prescribed bosutinib or ponatinib. Study patients were selected from the IBM® MarketScan® Research database from July 2012-June 2017. The index date was defined as the index drug prescription date, identified based on TKI use during the identification period (January 2013-December 2016) in a hierarchical order based on the sequence of treatment lines: ponatinib and bosutinib without ponatinib. Continuous health plan enrollment for ≥6 months pre-index date (baseline period) and at least 6 months post-index date (follow-up period) was required. Cardiovascular (CV) events (MACEs, AOEs, VOEs) using ICD-9/10-CM diagnosis codes occurring through the earliest of index TKI discontinuation, switch to another TKI, or end of follow-up period, were calculated as the number of events per 100 person-years (PYs). Inverse probability of treatment weighting (IPTW) was applied to adjust for differences in baseline characteristics between the treatment cohorts. Kaplan-Meier (KM) and Cox proportional hazard model analyses were conducted on the adjusted sample to examine any difference in CV event risk. RESULTS: After applying the selection criteria, 79 and 109 patients were included in the ponatinib and bosutinib cohorts, respectively. Mean ages were 53 years (ponatinib cohort) and 58 years (bosutinib cohort). The average Charlson Comorbidity Index (CCI) scores - defined by categorizing comorbidities using diagnosis codes - were 1.23 for ponatinib and 1.81 for the bosutinib cohort. Common baseline comorbid conditions included anemia (ponatinib: 49%; bosutinib 34%), hypertension (ponatinib: 33%, bosutinib: 46%), and diabetes (ponatinib: 15%; bosutinib: 29%). Some patients were observed to have CV events, specifically MACEs (ponatinib 8%; bosutinib 16%) and AOEs (ponatinib 15%; bosutinib 28%), before index ponatinib or bosutinib use. In the follow-up period, ponatinib patients were associated with a similar incidence of MACEs (14.70 vs 10.46 per 100 PYs; p=0.464), AOEs (29.56 vs 34.50 per 100 PYs; p=0.632), and VOEs (36.21 vs 34.70 per 100 PYs; p=0.890) compared to bosutinib patients. After applying IPTW, similar risks of the CV events (MACE, AOEs, VTEs) were observed in the KM analysis (Figure 1) expressed as time to CV event. After adjusting for additional confounders using Cox models, compared to those with bosutinib use, ponatinib patients were associated with similar rate of MACEs (Hazard Ratio [HR]: 1.02; 95% CI: 0.34, 3.01), AOEs (HR: 0.90; 95% CI: 0.43, 1.85), and VOEs (HR: 0.92; 95% CI: 0.44, 1.94). CONCLUSION: Among CML patients treated with ponatinib or bosutinib in second or third line, similar risks of cardiovascular events (MACE, AOEs, VTEs) were observed in the follow-up in this study in a community setting. Figure 1 Disclosures Levy: Takeda (Millennium Pharmaceuticals): Consultancy. Xie:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Takeda Pharmaceutical Corporation. . Wang:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Takeda Pharmaceutical Company. . Neumann:Millennium Pharmaceuticals (Takeda): Employment, Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Srivastava:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Naranjo:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Xu:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Zhang:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Takeda Pharmaceutical Corporation.. Dalal:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd.

TPS7061 Background: Therapies for adults with newly diagnosed Ph+ ALL are limited and associated with poor outcomes. PON, a potent TKI, is active against native BCR-ABL1 and all identified single resistance mutations, including T315I, which confers resistance to other TKIs (Zhou. Chem Biol Drug Des 2011;77). In the phase 2 PACE study, PON had a 41% major hematologic response rate in heavily pretreated Ph+ ALL, but responses were not durable mainly due to compound mutations (Cortes. Blood 2018;132; Pritchard. Blood 2016;128). As PON suppresses single BCR-ABL1 resistance mutations, resistance in Ph+ ALL is acquired through compound mutations. Decreased likelihood of compound mutations with first-line PON in Ph+ ALL may lead to more durable responses compared with PON in later lines of therapy. In a phase 2 study of PON with CT in newly diagnosed Ph+ ALL, long-term outcomes were improved vs first/second-generation TKIs (Jabbour. Lancet Haematol 2018;5). The PhALLCON trial compares first-line PON vs IM with reduced-intensity CT. Methods: This open-label trial (NCT03589326) is enrolling 230–320 pts (≥18 y) with newly diagnosed Ph+ or BCR-ABL1–positive ALL (p190/p210) and ECOG status ≤2. Pts are randomized 2:1 to PON 30 mg/d or IM 600 mg/d PO with reduced-intensity CT in induction (cycles [C] 1-3), consolidation (C4-9), and maintenance (C10-20). PON dose is reduced to 15 mg once pt achieves minimal residual disease–negative (MRD−) complete remission (CR). After 20C, pts stay on single-agent PON/IM. CNS prophylaxis: 2x/mo in C1-6. Primary endpoint: MRD− (BCR-ABL/ABL1 ≤0.01%) CR (end of induction). Key secondary endpoint: EFS; others in the Table. Subgroup analysis: pts with/without HSCT. Exploratory endpoints include mutation status. Initiated Aug 2018; to include ~110 sites in ≤35 countries. Currently, 5 active sites (4 US, 1 Spain); accrual ongoing. Clinical trial information: NCT03589326. [Table: see text]

Meta-heuristics are frequently used to tackle NP-hard combinatorial optimization problems. With this paper we contribute to the understanding of the success of 2-opt based local search algorithms for solving the traveling salesperson problem (TSP). Although 2-opt is widely used in practice, it is hard to understand its success from a theoretical perspective. We take a statistical approach and examine the features of TSP instances that make the problem either hard or easy to solve. As a measure of problem difficulty for 2-opt we use the approximation ratio that it achieves on a given instance. Our investigations point out important features that make TSP instances hard or easy to be approximated by 2-opt.

Randomized search heuristics are frequently applied to NP-hard combinatorial optimization problems. The runtime analysis of randomized search heuristics has contributed tremendously to our theoretical understanding. Recently, randomized search heuristics have been examined regarding their achievable progress within a fixed-time budget. We follow this approach and present a fixed-budget analysis for an NP-hard combinatorial optimization problem. We consider the well-known Traveling Salesperson Problem (TSP) and analyze the fitness increase that randomized search heuristics are able to achieve within a given fixed-time budget. In particular, we analyze Manhattan and Euclidean TSP instances and Randomized Local Search (RLS), (1+1) EA and (1+[Formula: see text]) EA algorithms for the TSP in a smoothed complexity setting, and derive the lower bounds of the expected fitness gain for a specified number of generations.

Renewable forms of energy are becoming increasingly important to consider, as the global energy demand continues to grow. Wave energy is one of these widely available forms, but it is largely unexploited. A common design for a wave energy converter is called a point absorber or buoy. The buoy typically floats on the surface or just below the surface of the water, and captures energy from the movement of the waves. It can use the motion of the waves to drive a pump to generate electricity and to create potable water. Since a single buoy can only capture a limited amount of energy, large-scale wave energy production necessitates the deployment of buoys in large numbers called arrays. However, the efficiency of arrays of buoys is affected by highly complex intra-buoy interactions. The contributions of this article are two-fold. First, we present an approximation of the buoy interactions model that results in a 350-fold computational speed-up to enable the use inside of iterative optimisation algorithms, Second, we study arrays of fully submerged three-tether buoys, with and without shared mooring points.

Understanding the behaviour of heuristic search methods is a challenge. This even holds for simple local search methods such as 2-OPT for the Traveling Salesperson problem. In this paper, we present a general framework that is able to construct a diverse set of instances that are hard or easy for a given search heuristic. Such a diverse set is obtained by using an evolutionary algorithm for constructing hard or easy instances that are diverse with respect to different features of the underlying problem. Examining the constructed instance sets, we show that many combinations of two or three features give a good classification of the TSP instances in terms of whether they are hard to be solved by 2-OPT.

We consider how well-known branching approaches for the classical minimum vertex cover problem can be turned into randomized initialization strategies with provable performance guarantees and investigate them by experimental investigations. Furthermore, we show how these techniques can be built into local search components and analyze a basic local search variant that is similar to a state-of-the-art approach called NuMVC. Our experimental results for the two local search approaches show that making use of more complex branching strategies in the local search component can lead to better results on various benchmark graphs.

Evolutionary algorithms have been used in many ways to generate digital art. We study how evolutionary processes are used for evolutionary art and present a new approach to the transition of images. Our main idea is to define evolutionary processes for digital image transition, combining different variants of mutation and evolutionary mechanisms. We introduce box and strip mutation operators which are specifically designed for image transition. Our experimental results show that the process of an evolutionary algorithm in combination with these mutation operators can be used as a valuable way to produce unique generative art.

Evolutionary algorithms have been widely used to tackle multi-objective optimization problems. Incorporating preference information into the search of evolutionary algorithms for multi-objective optimization is of great importance as it allows one to focus on interesting regions in the objective space. Zitzler et al. have shown how to use a weight distribution function on the objective space to incorporate preference information into hypervolume-based algorithms. We show that this weighted information can easily be used in other popular EMO algorithms as well. Our results for NSGA-II and SPEA2 show that this yields similar results to the hypervolume approach and requires less computational effort.

Research on conditions to develop new innovations within emerging renewable energy industries is often done with a national focus. However, recent research on international entrepreneurship has revealed that firms operate on international levels very early in their life time. Thus, based on former research on international entrepreneurship and case examples, we build the propositions that firms in the marine energy industry use internationalization as a strategy to overcome industry barriers. Our primary source of data is a unique dataset from a global survey of all the companies in the marine energy industry who are aiming to commercialize a wave or tidal energy device. This paper is organized in two steps: first we identified the most challenging industry barriers perceived by companies. Second we use these to form propositions which we assess through empirical data. The two most challenging barriers perceived by the companies are need for capital and need for supportive political schemes. Our findings reveal that internationalization certainly is a common strategy to access capital and attractive support schemes in foreign countries. The early internationalization has implications for researchers, managers and policy makers.

Introduction: We recently showed that vitamin D deficiency leads to decreased overall survival of DLBCL-patients treated with rituximab-chemotherapy (Bittenbring et al, JCO, 2014). We hypothesized that rituximab-mediated NK cell-cytotoxicity is more effective at higher vitamin D levels. This was confirmed by vitamin D substitution of healthy volunteers, which increased their rituximab-mediated cytotoxicity in vitro against the Daudi lymphoma cell line. To unveil the molecular mechanisms behind this finding, resting NK cells before and after vitamin D supplementation were isolated from those volunteers and a whole transcriptome analysis was performed. Methods: We collected PBMCs from eight healthy volunteers with vitamin D deficiency before and after vitamin D substitution to > 30 ng/ml 25-OH vitamin D3. NK cells were isolated from PBMCs by magnetic depletion of all non-NK cells. Purity of the CD16+ cells was confirmed by flow cytometry. After isolating total RNA, we performed a microarray analysis using an Affymetrix Gene-Chip 2.0 ™. The signals were normalized using the LMA algorithm. For pathway analysis, gene set enrichment analysis (GSEA) was used. A two-step approach was chosen. Firstly, we separated 7.705 genes due to their involvement in the NK cell-mediated immune response according to the Gene Ontology database, irrespective of their differential expression. This dataset was used separately for specific analysis of the NK cell-cytotoxicity pathway to increase sensitivity. Secondly, the complete data set of 48.145 genes was used in an exploratory analysis in an attempt to screen for other dysregulated pathways involved in the immune response and vitamin D homeostasis. We used gene sets provided from the Molecular Signature Database. A significance level of < 0.05 for p and False Discovery Rate (FDR) was chosen. Real-time quantitative PCR was performed to confirm the results. Results: The NK cell-associated cytotoxicity pathway was found to be significantly upregulated after restoration of normal vitamin D levels in the specific analysis. The most significantly overexpressed genes in the gene set were five IFN-α subtypes (IFN-α2, IFN-α4, IFN-α6, IFN-α7, and IFN-α10) as well as IFN-κ. The exploratory analysis showed an upregulation of the response to type I interferon pathway and regulation of type I interferon mediated signaling pathway. The most upregulated genes in those pathways were again the IFN-α subtypes mentioned above. Other pathways involved in the immune response were found to be downregulated after vitamin D substitution, like interferon gamma response; cytokine production and chemotaxis. The common denominator of these pathways was the downregulation of three toll-like receptor genes (TLR-8, TLR-7, TLR-2). Conclusion: The increased expression of specific IFN-α subtypes could explain the increased rituximab-mediated NK cell-cytotoxicity after vitamin D substitution in deficient individuals. To the best of our knowledge, this is the first study to suggest a role for vitamin D in IFN-α regulation. TLRs are known to stimulate cytokine production in NK cells including IFN-α. It can be assumed, that the observed upregulation of IFN-α genes after vitamin D substitution leads to a negative feedback on positive regulators of cytokine production like TLR, causing their downregulation once vitamin D levels are restored. This implies a comprehensive role of vitamin D in IFN-α biosynthesis in human NK cells. Disclosures Stilgenbauer: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

INTRODUCTION: Chronic myeloid leukemia (CML) is a bone marrow and blood disorder accounting for 15% of adult leukemia. A shift in CML management has occurred over the past decade with the introduction of tyrosine kinase inhibitors (TKIs), changing CML status from fatal to a chronic, lifelong illness. However, an association between TKI use and cardiovascular events has been observed. This study aimed to compare major adverse cardiac events (MACE), arterial occlusive events (AOEs), and venous thrombotic events (VTEs) among CML patients in chronic phase (CP-CML) treated with different TKIs. METHODS: A retrospective observational study of adult (aged ≥18 years) CP-CML patients prescribed a TKI was conducted using the IBM® MarketScan® Research Databases from July 2012-June 2017. The index date was defined as the index drug prescription date, identified based on TKI use during the identification period (January 2013-December 2016) in hierarchical order: ponatinib, bosutinib without ponatinib, and other TKIs (imatinib, dasatinib, nilotinib) excluding ponatinib and bosutinib. Patients were required to have continuous health plan enrollment for ≥6 months pre-index date (baseline period) and at least 6 months post-index date (follow-up period). Patients with use of one or two previous TKI(s) before the index date were examined separately. Cardiovascular events occurring through the earliest of discontinuation of index TKI, switch to another TKI, or end of follow-up period using ICD-9/10-CM diagnosis codes were calculated as the number of events per 100 person-years. MACE was defined as a composite of stroke (hemorrhagic stroke and ischemic stroke), myocardial infarction, and inpatient death; AOEs included cardiovascular, cerebrovascular, and peripheral vascular events; VTEs included pulmonary embolism and deep vein thrombosis. RESULTS: After applying the selection criteria, 161 patients had one previous use of a TKI, with 50 ponatinib, 80 bosutinib and 31 other TKI patients. Mean ages were 54, 57, and 58 years for ponatinib, bosutinib, and other TKI cohorts, respectively. Most ponatinib patients initiated treatment with a dose of 45 mg (60%); most bosutinib patients initiated with a dose of 500 mg (53%) . For patients with use of one previous TKI, the average Charlson Comorbidity Index score was 1.4 for ponatinib, 1.8 for bosutinib and 0.8 for other TKI patients. Common baseline comorbid conditions by drug included anemia (ponatinib: 50%; bosutinib 31%; other TKI: 19%), hypertension (ponatinib: 32%, bosutinib: 43%, other TKI: 29%), and diabetes (ponatinib: 16%; bosutinib: 28%; other TKI: 10%). CP-CML patients were observed to have cardiovascular events prior to index TKI use, especially MACE (ponatinib: 4%, bosutinib: 16%, other TKI: 3%), and AOEs (ponatinib: 12%; bosutinib: 25%; other TKI: 19%). During the follow-up period, no significant differences were found for cardiovascular events across patients with TKI use (Table 1); the incidence of MACE was 4.7-8.3, AOEs: 25.8-33.3, and VTE: 2.3-9.1 (in 100 person-years). For those with use of two types of TKIs before the index date, 29 ponatinib, 29 bosutinib, and 4 other TKI patients were identified, with an average age of 51, 59, and 65 years, respectively. A similar trend was observed for patients with use of two prior TKIs. CONCLUSION: CP-CML patients treated with different TKIs (ponatinib, bosutinib, imatinib, dasatinib, and nilotinib) did not have different incidence of cardiovascular events (MACE, AOEs, VTEs) in this small cohort of real-world patients with ≥6-month of follow-up. The results were consistent among patients with prior use of one and two TKI types. Disclosures Levy: Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Xie:STATinMED Research: Employment. Wang:STATinMED Research: Employment. Neumann:Takeda (Millennium Pharmaceuticals, Inc.): Employment. Srivastava:Takeda (Millennium Pharmaceuticals, Inc.): Employment. Naranjo:Takeda (Millennium Pharmaceuticals, Inc.): Employment. Zhang:STATinMED Research: Employment. Dalal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA: Employment, Equity Ownership.

Vitamin D deficiency is frequently observed in human cancer patients and a prognostic relevance could be shown for some entities. Additionally, it is known that vitamin D can stimulate the patients' antitumor immunity. However, valid epidemiological data for head and neck squamous cell carcinoma (HNSCC) patients are sparse and functional studies on a possible connection between vitamin D and the patients' immune system are missing. 25-OH vitamin D serum levels were analyzed in 231 HNSCC patients and 232 healthy controls and correlated with clinical data and patient survival. Intra- and peritumoral infiltration with T-cell, NK-cell and macrophage populations was analyzed in 102 HNSCC patients by immunohistochemistry. In 11 HNSCC patients, NK-cells were isolated before and after vitamin D substitution and analyzed for their cytotoxic activity directed against a HNSCC cell line. Vitamin D serum levels were significantly lower in HNSCC patients compared with healthy controls. Low vitamin D levels were associated with lymphatic metastasis and a negative HPV status and were a significant predictor of poor overall survival. HNSCC patients with severe vitamin D deficiency showed significantly altered intra- and peritumoral immune cell infiltrate levels. After vitamin D substitution, the patients' NK cells showed a significant rise in cytotoxic activity. Taken together, we could show that Vitamin D deficiency is highly prevalent in HNSCC patients and is a predictor of poor survival. Vitamin D substitution used as an adjuvant in immune therapies such as cetuximab and nivolumab treatment could support antitumorigenic immune responses, thus contributing to the improvement of the patients' prognosis in the context of a multimodal therapy.

During product development, shape-based similarity search helps the engineering teams to discover parts and assemblies already existing in their company's component databases that match the ones required for the new product. Therefore, similarity search constitutes an important means to keep the overall number of components designed, managed and maintained by a company at the lowest possible level. This helps reducing the efforts for engineering design, manufacturing planning, managing the master data, and consequently lowers the product costs. In this paper, we present a new approach for shape-based similarity search utilising 3D PDF as the unique neutral format for determining various types of shape descriptors. We find that this method significantly reduces the implementation efforts for analysing 3D geometries originating from various CAD systems. In addition, it permits to tackle novel use cases for shape-based similarity search due to the versatile characteristics of the 3D PDF format.

This study evaluates response-adapted treatment of chronic myelogenous leukaemia (CML) in chronic phase using molecular response criteria. bcr-abl/G6PDH ratios were assessed by Light-Cycler quantitative real-time polymerase chain reaction (PCR( in 277 peripheral blood samples from 33 patients, before and every 3 months during therapy. Sixty-six per cent (22/33) of the patients fulfiled our molecular response criterion of ≥1 log decrease in bcr-abl transcript after 6 or ≥2 log decrease after 9 and every following 3 months. Dose escalation was necessary for 33% (11/33) of the patients. Of these, 54% (6/11) achieved a reduction of bcr-abl mRNA by ≥2 log (n = 3) or ≥3 log (n = 3) with 800 mg Imatinib. Forty-five per cent (5/11) showed insufficient molecular response with 800 mg Imatinib and received Nilotinib. In conclusion, the assessment of molecular response permits an individual patient-tailored treatment of CML in first chronic phase, resulting in the majority of patients achieving a major molecular response after 2 years of therapy. Copyright © 2008 John Wiley & Sons, Ltd.

Es wird ein neu entwickeltes geometrisches Normal zur Prüfung von Röntgen-Mikro-Computertomografiemesssystemen (μCT-Messsystemen) sowie ein Verfahren zur Herstellung und Kalibrierung beschrieben. Das Normal ermöglicht die Prüfung von μCT-Messsystemen mit den Verfahren der klassischen Koordinatenmesstechnik nach ISO 10360 bzw. VDI/VDE 2617 sowie dem Verfahren des Soll-Ist-Vergleiches von Referenz- und μCT-Messdaten.

Gastrointestinal tract spasms are convulsive pain attacks projected to the abdomen. They are generated by stimulation of mechanoreceptors in the enteric nervous system with successive maximal increase of gastrointestinal mobility. The present article discusses three non-obstructive diseases of the gastrointestinal tract with spastic pain as an essential part of the clinical picture; these diseases are described with respect to their symptom pattern, their pathogenesis and their treatment. The underlying motility disorders are insufficiently determined in the very frequent irritable bowel syndrome, but very well characterized in the much rarer spastic diseases of the oesophagus or the biliary tract.

Randomized search heuristics, among them randomized local search and evolutionary algorithms, are applied to problems whose structure is not well understood, as well as to problems in combinatorial optimization. The analysis of these randomized search heuristics has been started for some well-known problems, and this approach is followed here for the minimum spanning tree problem. After motivating this line of research, it is shown that randomized search heuristics find minimum spanning trees in expected polynomial time without employing the global technique of greedy algorithms.

Evolutionary algorithms have been frequently used to deal with dynamic optimization problems, but their success is hard to understand from a theoretical perspective. With this paper, we contribute to the theoretical understanding of evolutionary algorithms for dynamic combinatorial optimization problems. We examine a dynamic version of the classical vertex cover problem and analyse evolutionary algorithms with respect to their ability to maintain a 2-approximation. Analysing the different evolutionary algorithms studied by Jansen et al. (2013), we point out where two previously studied approaches are not able to maintain a 2-approximation even if they start with a solution of that quality. Furthermore, we point out that the third approach is very effective in maintaining 2-approximations for the dynamic vertex cover problem.

In the above quote, Gil (2011) emphasizes the fundamentally changed characteristics of knowledge-rich systems through the emergence of the Web and of Semantic Web technologies. In contrast to earlier knowledge-based systems that were depending on a central knowledge base, today’s knowledge-based systems comprise a set of distributed knowledge bases usually with heterogeneous content. Likewise, the number of users providing content to the knowledge bases significantly increased from the very few users involved in earlier knowledge acquisition activities to the high number of users contributing their content in a Web-based setting. Altogether, the given description of today’s knowledge-rich systems matches well the characteristics encountered in MPD, where many users with distinct competences contribute different pieces of information and knowledge in a distributed manner. Accordingly, the chosen set of semantic technologies for the design support system in the previous chapter matches well the distributed and heterogeneous style of activities encountered in MPD.

In the quote above, Comerford (1994) tellingly depicts the situation which initiated the development of Mechatronics. Characterized by the cited blend of technologies, Mechatronic products have gradually emerged from electromechanical products through the addition of first electronics, later computer controls, and software. Ko Kikuchi, the former president of the Yasakawa Electric Company, introduced the term Mechatronics from “mecha” for mechanism and “tronics” for electronics in 1969, in order to use the term as trademark for such devices (Comerford 1994).