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PurposeIntravenous paclitaxel (IVpac) is complicated by neuropathy and requires premedication to prevent hypersensitivity-type reactions. Paclitaxel is poorly absorbed orally; encequidar (E), a novel P-glycoprotein pump inhibitor, allows oral absorption.MethodsA phase III open-label study comparing oral paclitaxel plus E (oPac + E) 205 mg/m2 paclitaxel plus 15 mg E methanesulfonate monohydrate 3 consecutive days per week versus IVpac 175 mg/m2 once every 3 weeks was performed. Women with metastatic breast cancer and adequate organ function, at least 1 year from last taxane, were randomly assigned 2:1 to oPac + E versus IVpac. The primary end point was confirmed radiographic response using RECIST 1.1, assessed by blinded independent central review. Secondary end points included progression-free survival (PFS) and overall survival (OS).ResultsFour hundred two patients from Latin America were enrolled (265 oPac + E, 137 IVpac); demographics and prior therapies were balanced. The confirmed response (intent-to-treat) was 36% for oPac + E versus 23% for IVpac (P = .01). The PFS was 8.4 versus 7.4 months, respectively (hazard ratio, 0.768; 95.5% CI, 0.584 to 1.01; P = .046), and the OS was 22.7 versus 16.5 months, respectively (hazard ratio, 0.794; 95.5% CI, 0.607 to 1.037; P = .08). Grade 3-4 adverse reactions were 55% with oPac + E and 53% with IVpac. oPac + E had lower incidence and severity of neuropathy (2% v 15% > grade 2) and alopecia (49% v 62% all grades) than IVpac but more nausea, vomiting, diarrhea, and neutropenic complications, particularly in patients with elevated liver enzymes. On-study deaths (8% oPac + E v 9% IVpac) were treatment-related in 3% and 0%, respectively.ConclusionoPac + E increased the confirmed tumor response versus IVpac, with trends in PFS and OS. Neuropathy was less frequent and severe with oPac + E; neutropenic serious infections were increased. Elevated liver enzymes at baseline predispose oPac + E patients to early neutropenia and serious infections (funded by Athenex, Inc; ClinicalTrials.gov identifier: NCT02594371).

The Zwicky Transient Facility (ZTF), a public–private enterprise, is a new time-domain survey employing a dedicated camera on the Palomar 48-inch Schmidt telescope with a 47 deg2 field of view and an 8 second readout time. It is well positioned in the development of time-domain astronomy, offering operations at 10% of the scale and style of the Large Synoptic Survey Telescope (LSST) with a single 1-m class survey telescope. The public surveys will cover the observable northern sky every three nights in g and r filters and the visible Galactic plane every night in g and r. Alerts generated by these surveys are sent in real time to brokers. A consortium of universities that provided funding (“partnership”) are undertaking several boutique surveys. The combination of these surveys producing one million alerts per night allows for exploration of transient and variable astrophysical phenomena brighter than r∼20.5 on timescales of minutes to years. We describe the primary science objectives driving ZTF, including the physics of supernovae and relativistic explosions, multi-messenger astrophysics, supernova cosmology, active galactic nuclei, and tidal disruption events, stellar variability, and solar system objects.

The Zwicky Transient Facility (ZTF) is a new optical time-domain survey that uses the Palomar 48 inch Schmidt telescope. A custom-built wide-field camera provides a 47 deg 2 field of view and 8 s readout time, yielding more than an order of magnitude improvement in survey speed relative to its predecessor survey, the Palomar Transient Factory. We describe the design and implementation of the camera and observing system. The ZTF data system at the Infrared Processing and Analysis Center provides near-real-time reduction to identify moving and varying objects. We outline the analysis pipelines, data products, and associated archive. Finally, we present on-sky performance analysis and first scientific results from commissioning and the early survey. ZTF’s public alert stream will serve as a useful precursor for that of the Large Synoptic Survey Telescope.

Military education is for most people an unknown process that takes place behind closed doors. Based on text analysis, eighteen months of ethnographic fieldwork, and interviews at the Netherlands Defence Academy, this article seeks to understand military education as a dynamic process between the cadets' experience and the institute. As such, this study can be understood as an institutional ethnography, intending to open the black-box of military education. This study shows that military education affects cadets in a powerful way. They quickly learn to navigate the 'underlife' of the institute by carefully avoiding confrontation with the official structures. In a final discussion, we identify two remarkable paradoxes -- "perfect imperfection" and "individual in the system" -- that we consider exemplary for the learning environment at the NLDA. We argue that the Defence Academy constitutes, in essence, a paradoxical learning environment that influences the character development of the cadets -- sometimes in unintended ways.

The Christian confession of who Jesus is must be made in the contested space of conflicting accounts of history. This article compares the shape of universal history set out by Yuval Noah Harari with that of Wolfhart Pannenberg by sketching their accounts of human beginnings, the middle of history, and their view to the future. Harari's secular account can be summarized as the rise and fall of homo sapiens, as historical developments lead to techno‐humanism and dataism. Jesus Christ holds no significant place in this narrative. Pannenberg's theological interpretation of history sees it originating in God's self‐giving love, climaxing in the Son's revelation, and leading to a new creation. This comparison leads to five propositions on how Christians may speak of who Jesus Christ is today. [ABSTRACT FROM AUTHOR]

Europeans are increasingly challenged by the multiplicity of languages that surround them. In this paper I offer a thought experiment on what our best answer regarding the phenomenon of language in the new creation might be, and I suggest that this might help Christians to engage positively with the multiple languages in their daily lives and local churches. I argue that we should expect the presence of a diversity of languages in the new creation. I do so on the basis of a biblical-theological analysis of key scriptural passages, support from the doctrine of the resurrection, and an appreciation of the significance of missions for language in the eschaton. These steps lead to a weighing of conceivable alternatives and a defence of my preferred solution. I conclude that these results encourage a generous and hospitable attitude towards speakers of other languages and provide a renewed incentive to make space for them in our churches and our lives. [ABSTRACT FROM AUTHOR]

Neutrophil extracellular traps contribute to lung injury in cystic fibrosis and asthma, but the mechanisms are poorly understood. We sought to understand the impact of human NETs on barrier function in primary human bronchial epithelial and a human airway epithelial cell line. We demonstrate that NETs disrupt airway epithelial barrier function by decreasing transepithelial electrical resistance and increasing paracellular flux, partially by NET-induced airway cell apoptosis. NETs selectively impact the expression of tight junction genes claudins 4, 8 and 11. Bronchial epithelia exposed to NETs demonstrate visible gaps in E-cadherin staining, a decrease in full-length E-cadherin protein and the appearance of cleaved E-cadherin peptides. Pretreatment of NETs with alpha-1 antitrypsin (A1AT) inhibits NET serine protease activity, limits E-cadherin cleavage, decreases bronchial cell apoptosis and preserves epithelial integrity. In conclusion, NETs disrupt human airway epithelial barrier function through bronchial cell death and degradation of E-cadherin, which are limited by exogenous A1AT. [ABSTRACT FROM AUTHOR]

In this paper a method for the prediction of the airfoil trailing-edge far-field noise is presented. The model employs the airfoil analysis code XFOIL to determine the initial and boundary conditions for a subsequent boundary-layer analysis using the finite-difference code EDDYBL featuring a Reynolds stress turbulence model that finally provides the input data for the noise prediction by a modified TNO Institute of Applied Physics model. The prediction scheme was applied in the European silent rotors by acoustic optimization project to design new, quieter airfoils for the outer blade region of three different wind turbines in the megawatt class. The objective was to reduce the airfoil self-noise without loss in aerodynamic performance. Wind-tunnel tests showed that a noticeable noise reduction could be achieved compared with the airfoils currently in use. Moreover, the aerodynamic performance could be improved in the design region as well. DOI: 10.2514/1.27658

Author(s): A. A. S. Gulbis (corresponding author) [1]; J. L. Elliot [1, 2, 3]; M. J. Person [1]; E. R. Adams [1]; B. A. Babcock [4, 6]; M. Emilio [7]; [...]