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Background In KEYNOTE-355 (NCT02819518), the addition of pembrolizumab to chemotherapy led to statistically significant improvements in progression-free survival and overall survival in patients with advanced triple-negative breast cancer with tumor programmed cell death ligand 1 (PD-L1) combined positive score of at least 10. We report patient-reported outcomes from KEYNOTE-355. Methods Patients were randomly assigned 2:1 to pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus investigator's choice chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30), Breast Cancer–Specific Quality of Life Questionnaire, and EuroQol 5-Dimension questionnaire visual analog scale were prespecified. Patient-reported outcomes were analyzed for patients who received at least 1 dose of study treatment and completed at least 1 patient-reported outcome assessment. Changes in patient-reported outcome scores from baseline were assessed at week 15 (latest time point at which completion and compliance rates were at least 60% and at least 80%, respectively). Time to deterioration in patient-reported outcomes was defined as time to first onset of at least a 10-point worsening in score from baseline. Results Patient-reported outcome analyses included 317 patients with tumor PD-L1 combined positive score of at least 10 (pembrolizumab plus chemotherapy: n = 217; placebo plus chemotherapy: n = 100). There were no between-group differences in change from baseline to week 15 in QLQ-C30 global health status/quality of life (QOL; least-squares mean difference = −1.81, 95% confidence interval [CI] = −6.92 to 3.30), emotional functioning (least-squares mean difference = −1.43, 95% CI = −7.03 to 4.16), physical functioning (least-squares mean difference = −1.05, 95% CI = −6.59 to 4.50), or EuroQol 5-Dimension questionnaire visual analog scale (least-squares mean difference = 0.18, 95% CI = −5.04 to 5.39) and no between-group difference in time to deterioration in QLQ-C30 global health status/QOL, emotional functioning, or physical functioning. Conclusions Together with the efficacy and safety findings, patient-reported outcome results from KEYNOTE-355 support pembrolizumab plus chemotherapy as a standard of care for patients with advanced triple-negative breast cancer with tumor PD-L1 expression (combined positive score ≥10). [ABSTRACT FROM AUTHOR]

Since its birth in the 1920s, quantum mechanics has motivated and advanced the analysis of linear operators. In this effort, it significantly contributed to the development of sophisticated mathematical tools in spectral theory. Many of these tools have also found their way into classical fluid mechanics and enabled elegant and effective solution strategies as well as physical insights into complex fluid behaviors. This review provides supportive evidence for synergistically adopting mathematical techniques beyond the classical repertoire, both for fluid research and for the training of future fluid dynamicists. Deeper understanding, compelling solution methods, and alternative interpretations of practical problems can be gained by an awareness of mathematical techniques and approaches from quantum mechanics. Techniques such as spectral analysis, series expansions, considerations on symmetries, and integral transforms are discussed, and applications from acoustics and incompressible flows are presented with a quantum mechanical perspective. [ABSTRACT FROM AUTHOR]

Dynamic mode decomposition (DMD) is a factorization and dimensionality reduction technique for data sequences. In its most common form, it processes high-dimensional sequential measurements, extracts coherent structures, isolates dynamic behavior, and reduces complex evolution processes to their dominant features and essential components. The decomposition is intimately related to Koopman analysis and, since its introduction, has spawned various extensions, generalizations, and improvements. It has been applied to numerical and experimental data sequences taken from simple to complex fluid systems and has also had an impact beyond fluid dynamics in, for example, video surveillance, epidemiology, neurobiology, and financial engineering. This review focuses on the practical aspects of DMD and its variants, as well as on its usage and characteristics as a quantitative tool for the analysis of complex fluid processes. [ABSTRACT FROM AUTHOR]

In KEYNOTE-119 (ClinicalTrials.gov, NCT02555657), overall survival (primary end-point) was similar between pembrolizumab and chemotherapy in patients with previously treated metastatic triple-negative breast cancer (TNBC), although the pembrolizumab treatment effect increased with tumour PD-L1 expression. We report results of prespecified health-related quality of life (HRQoL) analyses from KEYNOTE-119. Eligible patients were randomised 1:1 to pembrolizumab 200 mg Q3W intravenously for up to 35 cycles or treatment of physician's choice per local/country guidelines. Prespecified exploratory end-points were the change from baseline in HRQoL (EORTC QLQ-C30, QLQ-BR23) and to characterise utilities (EQ-5D-3L). Time to deterioration (TTD) was the time from start of treatment to first onset of a ≥10-point worsening from baseline. HRQoL analyses included 187 patients with tumour PD-L1 combined positive score (CPS) ≥10. Changes from baseline at 6 weeks (primary analysis time point) were directionally better with pembrolizumab versus chemotherapy for QLQ-C30 GHS/QoL (between-group difference in least-squares mean scores of 4.21 [95% CI, −1.38 to 9.80]), QLQ-C30 functional scales (physical, role, cognitive, social), QLQ-C30 symptom scales/items (fatigue, nausea/vomiting, dyspnoea, appetite loss), and QLQ-BR23 symptom scales/items (systemic therapy side-effects, upset by hair loss). Median TTD was directionally longer for pembrolizumab versus chemotherapy for QLQ-C30 QHS/QoL (4.3 versus 1.7 months), QLQ-C30 nausea/vomiting (7.7 versus 4.8 months), and QLQ-BR23 systemic therapy side-effects (6.1 versus 3.4 months). Minimal treatment differences were observed for other HRQoL end-points. HRQoL results were consistent with clinical outcomes and appeared to be driven by results for patients with tumour PD-L1 CPS ≥10. • We report health-related quality of life (HRQoL) analyses from KEYNOTE-119. • First HRQoL data on anti-PD1 versus chemo in metastatic triple-negative breast cancer. • Most HRQoL results favored pembrolizumab in combined positive score-enriched patients. • HRQoL was consistent with previously reported safety findings in overall patients. • HRQoL was consistent with efficacy data in combined positve score-enriched patients. [ABSTRACT FROM AUTHOR]

Mixing is an omnipresent process in a wide range of industrial applications, which supports scientific efforts to devise techniques for optimizing mixing processes under time and energy constraints. In this endeavour, we present a computational framework based on nonlinear direct-adjoint looping for the enhancement of mixing efficiency in a binary fluid system. The governing equations consist of the nonlinear Navier–Stokes equations, complemented by an evolution equation for a passive scalar. Immersed and moving stirrers are treated by a Brinkman penalization technique, and the full system of equations is solved using a Fourier-based pseudospectral approach. The adjoint equations provide gradient and sensitivity information which is in turn used to improve an initial mixing strategy, based on shape, rotational and path modifications. We utilize a Fourier-based approach for parameterizing and optimizing the embedded stirrers and consider a variety of geometries to achieve enhanced mixing efficiency. We consider a restricted optimization space by limiting the time for mixing and the rotational velocities of all stirrers. In all cases, non-intuitive shapes are found which produce significantly enhanced mixing efficiency. [ABSTRACT FROM AUTHOR]

Freshwater meiofauna occupies a central role in stream food webs, not always as intermediary but also as top consumers. Consequently, the meiofauna's transient dynamical patterns and turnover are vital to understand its contribution to the overall production and energy flow within benthic freshwater systems. Here, we revise the current methodological procedures used to estimate production in benthic meiofauna, and compare their biomass and production data (a) to other benthic taxa, (b) in different habitats and systems, and (c) at the species level. Given the phyla diversity and when including temporary meiofauna (i.e. small insect larvae), care must be taken in selecting a production method and/or relying on published generation times. A handful of studies demonstrate that meiofaunal production values are well within the range displayed by macrofauna. We show that temperature-adjusted production and biomass of meiofaunal species from lakes, wetlands, and streams display a positive linear relationship with an exponent around 0.9, whereby biomass explains 90% of the variation in production. Further studies on meiofauna production should test the validity of our proposed allometric model for stream ecosystems and, thus, its possible generality. [ABSTRACT FROM AUTHOR]

Let G be a finite transitive permutation group of degree n, with point stabilizer H ≠ 1 and permutation character π. For every positive integer t, we consider the generalized character ψt = ρG−t ⁢ (π−1G), where ρG is the regular character of G and 1G the 1-character. We give necessary and sufficient conditions on t (and G) which guarantee that ψt is a character of G. A necessary condition is that t ≤ min{n − 1, |H|}, and it turns out that ψt is a character of G for t = n − 1 resp. t = |H| precisely when G is 2-transitive resp. a Frobenius group. [ABSTRACT FROM AUTHOR]

Summary: During winter, timberline trees are exposed to drought and frost, factors known to induce embolism. Studies indicated that conifers cope with winter embolism by xylem refilling. We analysed the loss of hydraulic conductivity (LC) in Picea abies branch xylem over 10 years, and correlated winter embolism to climate parameters. LC was investigated by direct X‐ray micro‐computer tomography (micro‐CT) observations and potential cavitation fatigue by Cavitron measurements. Trees showed up to 100% winter embolism, whereby LC was highest, when climate variables indicated frost drought and likely freeze–thaw stress further increased LC. During summer, LC never exceeded 16%, due to hydraulic recovery. Micro‐CT revealed homogenous embolism during winter and that recovery was based on xylem refilling. Summer samples exhibited lower LC in outermost compared to older tree rings, although no cavitation fatigue was detected. Long‐term data and micro‐CT observations demonstrate that timberline trees can survive annual cycles of pronounced winter‐embolism followed by xylem refilling. Only a small portion of the xylem conductivity cannot be restored during the first year, while remaining conduits are refilled without fatigue during consecutive years. We identify important research topics to better understand the complex induction and repair of embolism at the timberline and its relevance to general plant hydraulics. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer.Methods: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method (block size of four) and an interactive voice-web response system. Randomisation was stratified by previous taxane use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received atezolizumab 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m2 of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891.Findings: Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18·5 months (IQR 9·6-22·8) in the atezolizumab group and 17·5 months (8·4-22·4) in the placebo group. Median overall survival in the intention-to-treat patients was 21·0 months (95% CI 19·0-22·6) with atezolizumab and 18·7 months (16·9-20·3) with placebo (stratified hazard ratio [HR] 0·86, 95% CI 0·72-1·02, p=0·078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25·0 months (95% CI 19·6-30·7) with atezolizumab versus 18·0 months (13·6-20·1) with placebo (stratified HR 0·71, 0·54-0·94]). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3-4 adverse events were neutropenia (38 [8%] of 453 patients in the atezolizumab group vs 36 [8%] of 437 patients in the placebo group), peripheral neuropathy (25 [6%] vs 12 [3%]), decreased neutrophil count (22 [5%] vs 16 [4%]), and fatigue (17 [4%] vs 15 [3%]). Treatment-related deaths occurred in two (<1%) patients in the atezolizumab group (autoimmune hepatitis related to atezolizumab [n=1] and septic shock related to nab-paclitaxel [n=1]) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been reported since the primary clinical data cutoff date (April 17, 2018).Interpretation: Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need.Funding: F Hoffmann-La Roche and Genentech. [ABSTRACT FROM AUTHOR]

Encounter is much more than a way of practicing psychotherapy or group work. These practices are just applications of a basic anthropological, epistemological and (socio-)ethical stance on how we humans find ourselves in the world and how we can choose to relate to other human beings, groups, communities, the society, givens in the world and the world as such. This paper tries to call to mind and revive the fundamental, provocative and thought-provoking notion of encounter as a way of being in relationship to persons, society and the world we live in. All concretizations of encounter must be critically measured by the challenge of its profound meaning. [ABSTRACT FROM AUTHOR]

Hope is not about the future. It denotes an existential human way of being and way of being within the present. 'Dum spiro, spero (As long as I breathe, I hope)' characterizes its fundamental aspect in life. Hope is not optimism towards the outlook, not an expectation of positive outcomes. Hope is a specific quality of being a person in the meaning of being fully oneself and being fully with others. It is more than human's capability to counterbalance fear and despair by envisioning something better and different from endurance. Rather, it is an active stance, the art of being fully present – with others. Thus, hope is a person-centered essential. It can be understood as the voice of the actualizing tendency, because it rests on the belief that potentiality is as important as actuality. Beyond the meaning of hope as a competence of the person, its importance in life and therapy the paper discusses how the present societal and political challenges can be met by a person-centered understanding of hope and trust: the task is not to raise hopes, but to facilitate hope; not to aim at solutions in order to change the world, but to encounter it. [ABSTRACT FROM AUTHOR]

Let G be a finite group, p a prime and c ∈ {0 , 1 , ... , p − 1}. Suppose that the degree of every nonlinear irreducible character of G is congruent to c modulo p. If here c = 0, then G has a normal p-complement by a well known theorem of Thompson. We prove that in the cases where c ≠ 0 the group G is solvable with a normal abelian Sylow p-subgroup. If p ≠ 3 then this is true provided these character degrees are congruent to c or to −c modulo p. [ABSTRACT FROM AUTHOR]

There are two living species of Old World camelids (Camelidae, Artiodactyla): the Bactrian camel (Camelus bactrianus) and the dromedary (Camelus dromedarius). Differences in osteology between them are poorly known, and this lack of knowledge hinders archaeological and paleontological research. Previous comparative studies have focused on subtle qualitative differences, which are subject to great intraspecific variation and interspecific overlap. In this study, we use simple morphometric methods and statistical analyses to compare the skeleton of Old World camels. Over the entire skeleton we were able to find several consistent differences, some univocal and highly diagnostic, others only slightly significant and noticeable only at a population level. Some of the distinctive traits are suggestive of previously unknown biological adaptations. In particular, the cranial anatomy of Bactrian camels shows characters correlated with increased grazing, while its limb muscle attachments may indicate additional need for lateral stability in a heavier animal. The presence and number of humps is reflected in the vertebral column, with several differences that will be helpful in the reconstruction of fossil species. [ABSTRACT FROM AUTHOR]

Finke wants to counterbalance what he regards as radical one-sidedness in person-centered therapy theory by promoting the need for diagnoses, interpretations, and techniques. And he tries to show that this is (at least implicitly) already implicated in Rogers’ own theory. In my rejoinder I try to show that Finke’s approach rests on an image of the human being, on an understanding of empathy and encounter different from Rogers’, which is, in fact, a step back to a theory before the Rogerian paradigm change. [ABSTRACT FROM AUTHOR]

It has been suggested that High-Antarctic waters, despite their remoteness from human activities, are impacted by anthropogenic pollution, and that the local biota are accumulating the contaminants. At present, no data exist on persistent organic pollutant (POP) body burdens for notothenioid fish inhabiting the High-Antarctic Weddell Sea. We determined the pollutant load in white muscle tissue of red- and white-blooded notothenoids from the Weddell Sea ( Trematomus loennbergii and Chionodraco hamatus , respectively), and compared them to our previous measurements of POPs in Low-Antarctic notothenioids. Analytes included various organochlorine pesticides (OCPs), polychlorinated biphenyls (indicator (i) PCBs, dioxine-like (dl) PCBs) and polybrominated diphenyl ethers (PBDEs). The analytical concentrations were converted into 2,3,7,8-TCDD toxic equivalents (TEQs). Compared to T. loennbergii, C. hamatus had lower levels of β-HCH (0.45 vs. 4.5 ng g −1 lipid weight), and Σ iPCBs (30 vs. 39 ng g −1 lipid weight), as well as lower levels of Σ PBDEs (131 vs. 261 ng g −1 fresh weight). POP body burdens and TEQs were mostly similar to those of Low-Antarctic notothenioids analysed previously, and not related to the trophic positions of the species. The variations in POP levels between and within High- and Low-Antarctic notothenioids only marginally corresponded to sampling site, ecological differences or trophic levels of the species, and might rather be related to metabolism or age effects. The present findings suggest that fishes of High-Antarctic waters, although this area is more remote and less influenced by local human activities, do not show lower POP body burdens than fishes from Low-Antarctic waters. [ABSTRACT FROM AUTHOR]

Compressible flow over a flat plate with two localised and well-separated roughness elements is analysed by global frequency-response analysis. This analysis reveals a sustained feedback loop consisting of a convectively unstable shear-layer instability, triggered at the upstream roughness, and an upstream-propagating acoustic wave, originating at the downstream roughness and regenerating the shear-layer instability at the upstream protrusion. A typical multi-peaked frequency response is recovered from the numerical simulations. In addition, the optimal forcing and response clearly extract the components of this feedback loop and isolate flow regions of pronounced sensitivity and amplification. An efficient parametric-sensitivity framework is introduced and applied to the reference case which shows that first-order increases in Reynolds number and roughness height act destabilising on the flow, while changes in Mach number or roughness separation cause corresponding shifts in the peak frequencies. This information is gained with negligible effort beyond the reference case and can easily be applied to more complex flows. [ABSTRACT FROM PUBLISHER]

Despite important advances in the ecology of river food webs, the strength and nature of the connection between the meio- and macrofaunal components of the web are still debated. Some unresolved issues are the effects of the inclusion of meiofaunal links and their temporal variations on the overall river food web properties, and the significance of autochthonous and allochthonous material for these components. In the present study, we conducted analyses of gut content of macro- and meiofauna and stable isotope analyses of meiofauna to examine seasonal food webs of a chalk stream. The results of the gut content analyses, confirmed by the δ13C signatures, revealed a seasonal shift from a dependence on autochthonous (biofilm) to allochthonous food sources. Here, we demonstrate that aggregating basal or meiofaunal species into single categories affects key web properties such as web size, links, linkage density, and predator-prey ratios. More importantly, seasonal variation in attributes characterized the entire web and these changes persist regardless of taxonomic resolution. Furthermore, our analyses evidenced discrete variations in δ15N across the meiofauna community with a trophic structure that confirms gut content analyses, placing the meiofauna high in the food web. We, therefore, conclude that small-body-sized taxa can occur high in dynamic river food webs, questioning assumptions that trophic position increases with body size and that webs are static. [ABSTRACT FROM AUTHOR]

Nonlinear model reduction for large-scale flows is an essential component in many fluid applications such as flow control, optimization, parameter space exploration and statistical analysis. In this article, we generalize the POD–DEIM method, introduced by Chaturantabut & Sorensen [1] , to address nonlocal nonlinearities in the equations without loss of performance or efficiency. The nonlinear terms are represented by nested DEIM-approximations using multiple expansion bases based on the Proper Orthogonal Decomposition. These extensions are imperative, for example, for applications of the POD–DEIM method to large-scale compressible flows. The efficient implementation of the presented model-reduction technique follows our earlier work [2] on linearized and adjoint analyses and takes advantage of the modular structure of our compressible flow solver. The efficacy of the nonlinear model-reduction technique is demonstrated to the flow around an airfoil and its acoustic footprint. We could obtain an accurate and robust low-dimensional model that captures the main features of the full flow. [ABSTRACT FROM AUTHOR]

The global occurrence of persistent organic pollutants (POPs) continuously contributes to their accumulation also in remote areas such as the Antarctic Ocean. Antarctic fish, which hold high trophic positions but appear to possess low endogenous elimination rates for chemicals, are expected to bioaccumulate POPs with rising anthropogenic pollution. Using a chemical-analytical method, we measured concentrations of PCBs, PBDEs, HCBs, HCH and DDTs and determined toxic equivalents (TEQs) and bioanalytical equivalents (BEQs) in muscle and ovaries of Antarctic icefish caught in the Southern Ocean around Elephant Island. We used two species with different feeding habits and trophic web positions: the planktivorous Champsocephalus gunnari and the piscivorous Chaenocephalus aceratus . Our results revealed higher contaminant levels in ovary than in muscle tissues of both species. Most analytes concentrations and the TEQs (0.2–0.5) and BEQs (0.2) were lower as in temperate species. Comparison with literature data points to higher PCB (20–22 ng g −1 lipid weight (lw)) and DDT (7–19.5 ng g −1 lw) concentrations than those measured in icefish in the 90's. For the other contaminants, we could not identify temporal trends. We found a higher bioaccumulation of contaminants, particularly HCB and DDTs, in C. aceratus (6.2 & 19.5 ng g −1 lw, respectively) than in C. gunnari (3.8 & 7.0 ng g −1 lw, respectively). However, there was no general species-specific accumulation pattern of the different toxicant classes between the two icefish. Thus, the expected link between contaminant burdens of C. aceratus and C. gunnari and their ecological traits was only weakly supported for these species. [ABSTRACT FROM AUTHOR]

Many fluid flows of engineering interest, though very complex in appearance, can be approximated by low-order models governed by a few modes, able to capture the dominant behavior (dynamics) of the system. This feature has fueled the development of various methodologies aimed at extracting dominant coherent structures from the flow. Some of the more general techniques are based on data-driven decompositions, most of which rely on performing a singular value decomposition (SVD) on a formulated snapshot (data) matrix. The amount of experimentally or numerically generated data expands as more detailed experimental measurements and increased computational resources become readily available. Consequently, the data matrix to be processed will consist of far more rows than columns, resulting in a so-called tall-and-skinny (TS) matrix. Ultimately, the SVD of such a TS data matrix can no longer be performed on a single processor, and parallel algorithms are necessary. The present study employs the parallel TSQR algorithm of (Demmel et al. in SIAM J Sci Comput 34(1):206-239, 2012), which is further used as a basis of the underlying parallel SVD. This algorithm is shown to scale well on machines with a large number of processors and, therefore, allows the decomposition of very large datasets. In addition, the simplicity of its implementation and the minimum required communication makes it suitable for integration in existing numerical solvers and data decomposition techniques. Examples that demonstrate the capabilities of highly parallel data decomposition algorithms include transitional processes in compressible boundary layers without and with induced flow separation. [ABSTRACT FROM AUTHOR]

This review article is concerned with the design of linear reduced-order models and control laws for closed-loop control of instabilities in transitional flows. For oscillator flows, such as open-cavity flows, we suggest the use of optimal control techniques with Galerkin models based on unstable global modes and balanced modes. Particular attention has to be paid to stability-robustness properties of the control law. Specifically, we show that large delays and strong amplification between the control input and the estimation sensor may be detrimental both to performance and robustness. For amplifier flows, such as backward-facing step flow, the requirement to account for the upstream disturbance environment rules out Galerkin models. In this case, an upstream sensor is introduced to detect incoming perturbations, and identification methods are used to fit a model structure to available input-output data. Control laws, obtained by direct inversion of the input-output relations, are found to be robust when applied to the large-scale numerical simulation. All the concepts are presented in a step-by-step manner, and numerical codes are provided for the interested reader. [ABSTRACT FROM AUTHOR]

The Middle East is apparently the most important passage for the dispersal of early hominins. Numerous archeological sites prove the existence of hominin populations in this region, but despite these rich cultural remains, hominin fossils are very rare. In 1996, a hominin left parietal was found in an Acheulean context. In addition, the faunal remains indicate a steppe environment. What does this single cranial fragment tell us? Based on new publications and in particular on recent finds, the value of isolated elements is discussed. [ABSTRACT FROM AUTHOR]

Psychotherapists concentrate on the experiencing of their clients and carefully separate their therapeutic work from direct interfering into the lives of their clients. This is essential because it fosters the clients’ empowerment and autonomy. However, external circumstances often ruin the clients’ and therapists’ hard therapeutic work. Particularly at a time when the world faces substantial challenges, the person-centered approach (PCA) provides also an approach to confront oneself with the societal realities, if we are ready not only to try to explain it and solve problems but to truly encounter these realities. Building on Rogers’ theories, a genuine understanding of the human person as an unavoidably interconnected being demands a fundamental rethinking of the role of psychotherapists in society and leads to a political self-understanding and engagement. It requires sociotherapy as a practice of social ethics, as therapy in and of society and its communities. The task is to realize the answers that are already there, even if we are not yet aware of them. The challenge is not to save the world but to encounter it. [ABSTRACT FROM PUBLISHER]

Dynamic mode decomposition (DMD) belongs to a class of data-driven decomposition techniques, which extracts spatial modes of a constant frequency from a given set of numerical or experimental data. Although the modal shapes and frequencies are a direct product of the decomposition technique, the determination of the respective modal amplitudes is non-unique. In this study, we introduce a new algorithm for defining these amplitudes, which is capable of capturing physical growth/decay rates of the modes within a transient signal and is otherwise not straightforward using the standard DMD algorithm. In addition, a parametric DMD algorithm is introduced for studying dynamical systems going through a bifurcation. The parametric DMD alleviates multiple applications of the DMD decomposition to the system with fixed parametric values by including the bifurcation parameter in the decomposition process. The parametric DMD with amplitude correction is applied to a numerical and experimental data sequence taken from thermo-acoustically unstable systems. Using DMD with amplitude correction, we are able to identify the dominant modes of the transient regime and their respective growth/decay rates leading to the final limitcycle. In addition, by applying parametrized DMD to images of an oscillating flame, we are able to identify the dominant modes of the bifurcation diagram. [ABSTRACT FROM AUTHOR]

This paper describes the learning program for person-centered therapists provided by the Institute for Person-Centered Studies in Austria (IPS of APG) and its theoretical background. The program essentially builds upon encounter groups. It even regards theory development and supervision processes as encounter-oriented parts of learning to become a psychotherapist. This learning in groups is set in relation to the development of the person-centered approach (PCA) as a social psychological approach. The underlying comprehension of the phenomena of encounter and encounter groups is evaluated from the viewpoint of learning programs. The experiences within this setting are discussed. [ABSTRACT FROM PUBLISHER]

In fireworks, organic additives with high chlorine content such as hexachlorobenzene (HCB) are used for the improvement of illumination effects. In the course of a monitoring campaign for the detection of HCB in fireworks, atmospheric concentrations of chlorobenzenes (CBs), chlorophenols (CPs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), were measured during the Swiss National holiday August 1, 2011 which is celebrated with fireworks nationwide. Samples were collected in the city of Zurich using high-volume air samplers equipped with quartz fiber filters and poly-urethane foam plugs. With one sampling period of 3h, a peak HCB concentration of 297pgm−3 was detected. Maximum total concentrations of pentachlorophenol and PCDD/Fs were 218pg m−3 and 61fg I-TEQ m−3, respectively. These levels are in the order of ten times above background concentrations measured one week before and two weeks after the event. Atmospheric emissions of HCB and CPs were quantified using a multimedia mass balance model to interpret the field measurements resulting in total emissions of HCB and CPs during the event of 23g and 25g, respectively. Based on per capita amounts this corresponds to total annual emissions from fireworks of 1.5kg for each of the two pollutants in Switzerland. Starting from an estimation of the total worldwide emissions of HCB, in Switzerland emissions from fireworks may represent about 2-14% of total HCB releases. [ABSTRACT FROM AUTHOR]

A putative involvement of the vasculature seems to play a critical role in the pathophysiology of graft-versus-host disease (GVHD). We aimed to characterize alterations of mesenteric resistance arteries in GVHD in a fully MHC-mismatched model of BALB/c mice conditioned with total body irradiation that underwent transplantation with bone marrow cells and splenocytes from syngeneic (BALB/c) or allogeneic (C57BL/6) donors. After 4 weeks, animals were sacrificed and mesenteric resistance arteries were studied in a pressurized myograph. The expression of endothelial (eNOS) and inducible nitric oxide (NO)–synthase (iNOS) was quantified and vessel wall ultrastructure was investigated with electron microscopy. The myograph study revealed an endothelial dysfunction in allogeneic-transplant recipients, whereas endothelium-independent vasodilation was similar to syngeneic-transplant recipients or untreated controls. The expression of eNOS was decreased and iNOS increased, possibly contributing to endothelial dysfunction. Additionally, arteries of allogeneic transplant recipients exhibited a geometry-independent increase in vessels strain. For both findings, electron microscopy provided a structural correlate by showing severe damage of the whole vessel wall in allogeneic-transplant recipient animals. Our study provides further data to prove, and is the first to characterize, functional and structural vascular alterations in the early course after allogeneic transplantation directly in an ex vivo setting and, therefore, strongly supports the hypothesis of a vascular form of GVHD. [ABSTRACT FROM AUTHOR]

PURPOSE: In the two-cohort phase II KEYNOTE-086 study (ClinicalTrials.gov identifier: NCT02447003), first-line and second-line or later pembrolizumab monotherapy demonstrated antitumor activity in metastatic triple-negative breast cancer (mTNBC; N = 254). This exploratory analysis evaluates the association between prespecified molecular biomarkers and clinical outcomes. METHODS: Cohort A enrolled patients with disease progression after one or more systemic therapies for metastatic disease irrespective of PD-L1 status; Cohort B enrolled patients with previously untreated PD-L1–positive (combined positive score [CPS] ≥ 1) metastatic disease. The association between the following biomarkers as continuous variables and clinical outcomes (objective response rate [ORR], progression-free survival [PFS], and overall survival [OS]) was evaluated: PD-L1 CPS (immunohistochemistry), cluster of differentiation 8 (CD8; immunohistochemistry), stromal tumor-infiltrating lymphocyte (sTIL; hematoxylin and eosin staining), tumor mutational burden (TMB; whole-exome sequencing [WES]), homologous recombination deficiency-loss of heterozygosity, mutational signature 3 (WES), mutational signature 2 (apolipoprotein B mRNA editing catalytic polypeptide–like; WES), T-cell–inflamed gene expression profile (TcellinfGEP; RNA sequencing), and 10 non-TcellinfGEP signatures (RNA sequencing); Wald test P values were calculated, and significance was prespecified at α = 0.05. RESULTS: In the combined cohorts (A and B), PD-L1 (P =.040), CD8 (P <.001), sTILs (P =.012), TMB (P =.007), and TcellinfGEP (P =.011) were significantly associated with ORR; CD8 (P <.001), TMB (P =.034), Signature 3 (P =.009), and TcellinfGEP (P =.002) with PFS; and CD8 (P <.001), sTILs (P =.004), TMB (P =.025), and TcellinfGEP (P =.001) with OS. None of the non-TcellinfGEP signatures were associated with outcomes of pembrolizumab after adjusting for the TcellinfGEP. CONCLUSION: In this exploratory biomarker analysis from KEYNOTE-086, baseline tumor PD-L1, CD8, sTILs, TMB, and TcellinfGEP were associated with improved clinical outcomes of pembrolizumab and may help identify patients with mTNBC who are most likely to respond to pembrolizumab monotherapy. [ABSTRACT FROM AUTHOR]

We present a highly time-resolved historical record of polychlorinated biphenyls (PCBs) from an Alpine ice core (Fiescherhorn glacier, Switzerland). Introduced in the 1940s, PCBs were widely used industrial chemicals. Because of their persistence they are still found in the environment, long after their production phase-out. The Fiescherhorn ice core record covers the entire time period of industrial use of PCBs, that is, 1940-2002. The total concentration of six PCBs varies from 0.5 to 5 ng L-1 and reveals a temporal trend, with an 8-fold increase from the early 1940s to the peak value in the 1970s. The level in 2002 is comparable to the concentration in the 1940s, when PCBs were introduced into the market. The time trend of PCBs associated with the particulate fraction closely follows the trend found in the dissolved fraction, but the absolute values are a factor of 10 lower. In addition to changing emissions, fluctuations in the PCB record were explained by variabilty in convective transport and postdepositional processes such as surface melting. Concentrations of PCBs are in agreement with data from seasonal snow samples in the Alps, but are a factor of 100 higher than concentrations measured in the Arctic. Contrasting time trends and congener patterns between the Alpine and Arctic region indicate the importance of atmospheric transport and postdepositional effects. [ABSTRACT FROM AUTHOR]

Highlights: [•] A novel method for analysis of hydrophobic compounds in aqueous samples. [•] PDMS coated open capillary trap for retention of the analytes. [•] Interference-free, small sample volumes, resource-saving, easy-handling. [•] Robust and widely applicable. [Copyright &y& Elsevier]

Xylem embolism is a limiting factor for woody species worldwide. Conifers at the alpine timberline are exposed to drought and freeze-thaw stress during winter, which induce potentially lethal embolism. Previous studies indicated that timberline trees survive by xylem refilling. In this study on Picea abies, refilling was monitored during winter and spring seasons and analyzed in the laboratory and in situ experiments, based on hydraulic, anatomical, and histochemical methods. Refilling started in late winter, when the soil was frozen and soil water not available for the trees. Xylem embolism caused up to 86.2% ± 3.1% loss of conductivity and was correlated with the ratio of closed pits. Refilling of xylem as well as recovery in shoot conductance started in February and corresponded with starch accumulation in secondary phloem and in the mesophyll of needles, where we also observed increasing aquaporin densities in the phloem and endodermis. This indicates that active, cellular processes play a role for refilling even under winter conditions. As demonstrated by our experiments, water for refilling was thereby taken up via the branches, likely by foliar water uptake. Our results suggest that refilling is based on water shifts to embolized tracheids via intact xylem, phloem, and parenchyma, whereby aquaporins reduce resistances along the symplastic pathway and aspirated pits facilitate isolation of refilling tracheids. Refilling must be taken into account as a key process in plant hydraulics and in estimating future effects of climate change on forests and alpine tree ecosystems. [ABSTRACT FROM AUTHOR]

Dynamic mode decomposition (DMD) represents an effective means for capturing the essential features of numerically or experimentally generated flow fields. In order to achieve a desirable tradeoff between the quality of approximation and the number of modes that are used to approximate the given fields, we develop a sparsity-promoting variant of the standard DMD algorithm. Sparsity is induced by regularizing the least-squares deviation between the matrix of snapshots and the linear combination of DMD modes with an additional term that penalizes the l1-norm of the vector of DMD amplitudes. The globally optimal solution of the resulting regularized convex optimization problem is computed using the alternating direction method of multipliers, an algorithm well-suited for large problems. Several examples of flow fields resulting from numerical simulations and physical experiments are used to illustrate the effectiveness of the developed method. [ABSTRACT FROM AUTHOR]

A data-driven hybrid numerical integrator is introduced to exploit, numerically, the formation of nonlinear coherent structures that often appear in nonlinear PDEs. Full simulations of the PDE allow model reduction algorithms such as the proper orthogonal decomposition and dynamic mode decomposition to generate reduced order models in an "online" manner. Criteria based on the comparison of these two independent reduction techniques, similar to model predictive control, determine whether the reduced model is accurate without direct evaluation of the underlying PDE. The method is implemented and explored for two prototypical PDE example models and significantly reduces the computational cost of solving those equations even when bifurcations occur. [ABSTRACT FROM AUTHOR]

Background: Adiponectin is able to induce NO-dependent vasodilation in Zucker lean (ZL) rats, but this effect is clearly alleviated in their diabetic littermates, the Zucker diabetic fatty (ZDF) rats. ZDF rats also exhibit hypoadiponectinemia and a suppressed expression of APPL1, an adaptor protein of the adiponectin receptors, in mesenteric resistance arteries. Whether an antidiabetic treatment can restore the vasodilatory effect of adiponectin and improve endothelial function in diabetes mellitus type 2 is not known. Methods: During our animal experiment from week 11 to 22 in each case seven ZDF rats received an antidiabetic treatment with either insulin (ZDF+I) or metformin (ZDF+M). Six normoglycemic ZL and six untreated ZDF rats served as controls. Blood glucose was measured at least weekly and serum adiponectin levels were quantified via ELISA in week 11 and 22. The direct vasodilatory response of their isolated mesenteric resistance arteries to adiponectin as well as the endothelium-dependent and -independent function was evaluated in a small vessel myograph. Additionally, the expression of different components of the adiponectin signaling pathway in the resistance arteries was quantified by real-time RT-PCR. Results: In ZDF rats a sufficient blood glucose control could only be reached by treatment with insulin, but both treatments restored the serum levels of adiponectin and the expression of APPL1 in small resistance arteries. Nevertheless, both therapies were not able to improve the vasodilatory response to adiponectin as well as endothelial function in ZDF rats. Concurrently, a downregulation of the adiponectin receptors 1 and 2 as well as endothelial NO-synthase expression was detected in insulin-treated ZDF rats. Metformin-treated ZDF rats showed a reduced expression of adiponectin receptor 2. Conclusions: An antidiabetic treatment with either insulin or metformin in ZDF rats inhibits the development of hypoadiponectinemia and downregulation of APPL1 in mesenteric resistance arteries, but is not able to improve adiponectin induced vasodilation and endothelial dysfunction. This is possibly due to alterations in the expression of adiponectin receptors and eNOS. [ABSTRACT FROM AUTHOR]

Let L|K be an extension of algebraic number fields. By a theorem of Hecke, the ideal class of the different L|K is a square in ClL. Whereas the class of the discriminant L|K=NL|K(L|K) is the square of the Steinitz class sL|K in ClK, which vanishes if and only if the ring RL of integers in L is a free module over RK, there is no distinguished square root for the different in general. In an attempt to give some interpretation for Hecke's theorem, we examine when there is r∈ClL such that r2=[L|K] and NL|K(r)=sL|K (‘Steinitz root’). In this case, every ideal of L in the class r−1 is a free RK-module. [ABSTRACT FROM PUBLISHER]

An experimental study has been conducted on a transitional water jet at a Reynolds number of Re = 5,000. Flow fields have been obtained by means of time-resolved tomographic particle image velocimetry capturing all relevant spatial and temporal scales. The measured three-dimensional flow fields have then been postprocessed by the dynamic mode decomposition which identifies coherent structures that contribute significantly to the dynamics of the jet. Both temporal and spatial analyses have been performed. Where the jet exhibits a primary axisymmetric instability followed by a pairing of the vortex rings, dominant dynamic modes have been extracted together with their amplitude distribution. These modes represent a basis for the low-dimensional description of the dominant flow features. [ABSTRACT FROM AUTHOR]

Let p be a rational prime. The k( GV) theorem states that, given a finite p′′-group G acting faithfully on a finite elementary abelian p-group V, the number of conjugacy classes of the semidirect product GV is bounded above by the order of V ( k( GV) ⩽⩽ | V|). In the present paper we examine when the upper bound k( GV) == | V| is attained. It is shown that for p > 5 this happens if and only if G/ CG( U) ≌≌ CG( V/ U) is cyclic of order | U| -- 1 for each nontrivial irreducible submodule U of V (Singer cycle). It remains open whether this is also true when p == 5. For p == 2, 3 there exist examples where equality holds but G is not abelian. [ABSTRACT FROM AUTHOR]

The dynamic mode decomposition (DMD) is a data-decomposition technique that allows the extraction of dynamically relevant flow features from time-resolved experimental (or numerical) data. It is based on a sequence of snapshots from measurements that are subsequently processed by an iterative Krylov technique. The eigenvalues and eigenvectors of a low-dimensional representation of an approximate inter-snapshot map then produce flow information that describes the dynamic processes contained in the data sequence. This decomposition technique applies equally to particle-image velocimetry data and image-based flow visualizations and is demonstrated on data from a numerical simulation of a flame based on a variable-density jet and on experimental data from a laminar axisymmetric water jet. In both cases, the dominant frequencies are detected and the associated spatial structures are identified. [ABSTRACT FROM AUTHOR]

After atmospheric deposition and storage in the ice, glaciers are temporary reservoirs of persistent organic pollutants (POPs). Recently, the hypothesis that melting glaciers represent secondary sources of these pollutants has been introduced by investigations of the historical trend of POPs in a dated sediment core from the proglacial Alpine Lake Oberaar. Here, the hypothesis is further confirmed by the comparison of sediment data gathered from two Alpine lakes with a glaciated and a nonglaciated hydrological catchment. The two lakes (Lake Engstlen and Lake Stein in the Bernese Alps in Switzerland) are situated only 8 km apart at similar altitude and in the same meteorological catchment. In the nonglacial lake sediment of Lake Engstlen, PCBs and DDT (polychlorinated biphenyls and dichlorodiphenyl trichloroethane) levels culminated with the historic usage of these chemicals some 30-50 years ago. In the glacial Lake Stein, this peak was followed by a reincrease in the 1990s, which goes along with the accelerated melting of the adjacent glacier. This study confirms the hypothesis of glaciers being a secondary source of these pollutants and is in accordance with the earlier findings in Lake Oberaar. [ABSTRACT FROM AUTHOR]

Let N be a normal subgroup of the finite group X and let G = X/ N. It is well known that the number k( X) = |Irr( X)| of conjugacy classes (irreducible characters) of X is bounded above by the product k( N) k( G). For more precise results one has to determine, for any θ ∈ Irr( N), the number of G-conjugates of θ and the number kθ( G) of irreducible characters of X lying above θ. Clifford theory reduces the computation of kθ( G) to the situation where N = Z is central in X, and then it only depends on the Clifford obstruction μ = μG( θ). The class number kμ( G) is defined for any μ ∈ H2( G, ℂ*), and behaves well when passing to isoclinic central extensions. Suppose that μ ≠ 1. There are examples where kμ( G) = 1, in which case X is a group of central type, and examples where kμ( G) = k( G) is as large as possible. In the first case G must be solvable (Howlett–Isaacs). The latter case can happen when G is perfect but not when G is a simple or, more generally, a quasisimple group. [ABSTRACT FROM AUTHOR]

Diesel exhaust contains several genotoxic compounds that may or may not penetrate diesel particulate filters (DPFs). Furthermore, the DPF-supported combustion of soot and adsorbed compounds may lead to the formation of additional pollutants. Herein, we compare the impact of 14 different DPFs on emissions of known genotoxic compounds. During a four year period, these DPFs were tested on a heavy duty diesel engine, operated in the ISO 8178/4 C1 cycle. Integral samples, including gas-phase and particle-bound matter were taken. All DPFs were efficient wall-flow filters with solid particulate number filtration efficiencies η > 98%. On the basis of their CO, NO, and NO2 emission characteristics, two different filter families were distinguished. DPFs with high oxidation potential (hox, n = 8) converted CO and NO besides hydrocarbons, whereas low oxidation potential DPFs (lox, n = 6) did not support CO and NO oxidation but still converted hydrocarbons. Lox-DPFs reduced NO2 from 1.0 ± 0.3 (engine-out) to 0.42 ± 0.11 g/kWh (η = 0.59), whereas hox-DPFs induced a NO2 formation up to 3.3 ± 0.7 g/kWh (η = -2.16). Emissions of genotoxic PAHs decreased for both filter families. Conversion efficiencies varied for individual PAHs and were lower for lox- (η = 0.31-0.87) than for hox-DPFs (η = 0.75-0.98). Certain nitro-PAHs were formed indicating that nitration is an important step along PAH oxidation. For example, 1-nitronaphthalene emissions increased from 11 to 17 to 21 μg/L without, with lox-, and hox-DPFs respectively, whereas 2-nitronaphthalene emissions decreased from 25 to 19 to 4.7 μg/L. In contrast to our expectations, the nitration potential of lox-DPFs was higher than the one of hox-DPFs, despite the intense NO2 formation of the latter. The filters converted most genotoxic PAHs and nitro-PAHs and most soot particles, acting as carriers for these compounds. Hox-DPF exhaust remains oxidizing and therefore is expected to support atmospheric oxidation reactions, whereas lox-DPF exhaust is reducing and consuming oxidants such as ozone, when mixed with ambient air. [ABSTRACT FROM AUTHOR]

Abstract: The combination of iterative Krylov-based eigenvalue algorithms and direct numerical simulations (DNS) has proven itself an effective and robust tool in solving complex global stability problems of compressible flows. A Cayley transformation is required to add flexibility to our stability solver and to allow access to specific parts of the full global spectrum which would be out of reach without such a transformation. In order to robustify the overall global stability solver an efficient ILU-based preconditioner has been implemented. With this Cayley-transformed DNS-based Krylov method two flow cases were successfully investigated: (i) a compressible mixing layer, a rather simple but well-known problem, which served as a test case and (ii) a supersonic flow about a swept parabolic body, a challenging large-scale flow configuration. [Copyright &y& Elsevier]

In this study, the hypothesis that melting Alpine glaciers may represent a secondary source of persistent organic chemicals is investigated. To this end, a dated sediment core from a glacier-fed lake (Lake Oberaar, Switzerland) was analyzed for a wide range of persistent organic pollutants, organochlorine pesticides, and synthetic musk fragrances. Input fluxes of all organochlorines increased in the 1950s, peaked in the 1960s-1970s, and decreased again to low levels in the 1980s-1990s. This observation reflects the emission history of these compounds and technical improvements and regulations leading to reduced emissions some decades ago. The input of synthetic musks remained at a high level in the 1950s-1990s, which is consistent with their relatively constant production throughout the second half of the 20th century. Since the late 1990s, input of all compound classes into the high-Alpine Lake Oberaar has increased sharply. Currently, input fluxes of organochlorines are similar to or even higher than in the 1960s-1970s. This second peak supports the hypothesis that there is a relevant release of persistent organic chemicals from melting Alpine glaciers. Considering ongoing global warming and accelerated massive glacier melting predicted for the future, our study indicates the potential for dire environmental impacts due to pollutants delivered into pristine mountainous areas. [ABSTRACT FROM AUTHOR]

The article discusses a study which assessed the long-term outcome of stage-adapted management by surgery, chemotherapy, or both for patients with placental-site trophoblastic tumours. The study involved 35,550 women who were registered with gestational trophoblastic disease in Great Britain from 1976 to 2006. It was found that the effectiveness of treatment for placental-site trophoblastic tumours could be improved with stage-adapted management with surgery for stage I disease, and combined surgery and chemotherapy for stage II, III and IV disease.

Non-pegylated liposomal doxorubicin (NPLD) has demonstrated equivalent antitumor activity to conventional doxorubicin and a significantly lower risk of cardiotoxicity when given as single agent or in combination with cyclophosphamide, but there is limited experience with the combination of NPLD and taxanes. This phase II study was performed to evaluate the efficacy and safety of the NPLD and docetaxel in patients with metastatic breast cancer. A total of 51 patients were treated with NPLD (60 mg/m2) and docetaxel (75 mg/m2) in 3-weeks intervals for up to eight cycles. The overall response rate was 50% and 78% of patients derived a clinical benefit. Median time to progression and overall survival were 10.0 months (95% CI, 6.9–13.1 months) and 25 months (95% CI, 22.1–29.8 months), respectively. Median duration of response was 12.0 months (95% CI 7.1–16.9). The treatment was generally well tolerated and associated with toxicities that were consistent with the known side-effects of the individual agents and of anthracycline/taxane combinations. There were no symptomatic cardiac averse events and mild asymptomatic LVEF changes were reported in five patients. The combination of NPLD and docetaxel is well tolerated and has high antitumour activity in MBC patients. [ABSTRACT FROM AUTHOR]

We give a new approach to the celebrated theorem of Frobenius (describing the structure of Frobenius groups). We also study the subgroup of a finite transitive permutation group generated by the fixed point free elements (derangements) and its relation to the Frobenius–Wielandt theorem. [ABSTRACT FROM AUTHOR]