Global named patient use program of afatinib in advanced non-small-cell lung carcinoma patients who progressed following prior therapies.

AIM: A global afatinib named patient use program in non-small-cell lung carcinoma (NSCLC) commenced in 2010. MATERIALS & METHODS: Eligible NSCLC patients had progressed after clinical benefit on prior erlotinib/gefitinib and/or had activating EGFR/HER2 mutations, exhausted all other treatments, and were ineligible for afatinib trials. RESULTS: Data, as of January 2016, were reported on 3966 heavily pretreated NSCLC patients (41 countries; six continents). Among 2595/3966 (65.4%) patients with tumor EGFR status, 2407 (92.8%) were EGFR mutation positive. Median time to treatment failure (2862/3966 [72.2%] patients with available data) was 4.4 months. Among 1141/2862 (39.9%) patients with response reported, objective response rate was 23.4% (267/1141). Safety findings were as expected. CONCLUSION: Time to treatment failure durations and objective response rates were encouraging.

Lactation and neonatal nutrition: defining and refining the critical questions.

This paper resulted from a conference entitled "Lactation and Milk: Defining and refining the critical questions" held at the University of Colorado School of Medicine from January 18-20, 2012. The mission of the conference was to identify unresolved questions and set future goals for research into human milk composition, mammary development and lactation. We first outline the unanswered questions regarding the composition of human milk (Section I) and the mechanisms by which milk components affect neonatal development, growth and health and recommend models for future research. Emerging questions about how milk components affect cognitive development and behavioral phenotype of the offspring are presented in Section II. In Section III we outline the important unanswered questions about regulation of mammary gland development, the heritability of defects, the effects of maternal nutrition, disease, metabolic status, and therapeutic drugs upon the subsequent lactation. Questions surrounding breastfeeding practice are also highlighted. In Section IV we describe the specific nutritional challenges faced by three different populations, namely preterm infants, infants born to obese mothers who may or may not have gestational diabetes, and infants born to undernourished mothers. The recognition that multidisciplinary training is critical to advancing the field led us to formulate specific training recommendations in Section V. Our recommendations for research emphasis are summarized in Section VI. In sum, we present a roadmap for multidisciplinary research into all aspects of human lactation, milk and its role in infant nutrition for the next decade and beyond.

Never run a changing system: Action-effect contingency shapes prospective agency.

Human action control is highly sensitive to action-effect contingencies in the agent's environment. Here we show that the subjective sense of agency (SoA) contributes to this sensitivity as a subjective counterpart to instrumental action decisions. Participants (N = 556) experienced varying reward probabilities and were prompted to give summary evaluations of their SoA after a series of action-effect episodes. Results first revealed a quadratic relation of contingency and SoA, driven by a disproportionally strong impact of perfect action-effect contingencies. In addition to this strong situational determinant of SoA, we observed small but reliable interindividual differences as a function of gender, assertiveness, and neuroticism that applied especially at imperfect action-effect contingencies. Crucially, SoA not only reflected the reward structure of the environment but was also associated with the agent's future action decisions across situational and personal factors. These findings call for a paradigm shift in research on perceived agency, away from the retrospective assessment of single behavioral episodes and towards a prospective view that draws on statistical regularities of an agent's environment.

Generality of shear thickening in dense suspensions.

Suspensions are of wide interest and form the basis for many smart fluids. For most suspensions, the viscosity decreases with increasing shear rate, that is, they shear thin. Few are reported to do the opposite, that is, shear thicken, despite the longstanding expectation that shear thickening is a generic type of suspension behaviour. Here we resolve this apparent contradiction. We demonstrate that shear thickening can be masked by a yield stress and can be recovered when the yield stress is decreased below a threshold. We show the generality of this argument and quantify the threshold in rheology experiments where we control yield stresses arising from a variety of sources, such as attractions from particle surface interactions, induced dipoles from applied electric and magnetic fields, as well as confinement of hard particles at high packing fractions. These findings open up possibilities for the design of smart suspensions that combine shear thickening with electro- or magnetorheological response.

Shear thickening and jamming in densely packed suspensions of different particle shapes.

We investigated the effects of particle shape on shear thickening in densely packed suspensions. Rods of different aspect ratios and nonconvex hooked rods were fabricated. Viscosity curves and normal stresses were measured using a rheometer for a wide range of packing fractions for each shape. Suspensions of each shape exhibit qualitatively similar discontinuous shear thickening. The logarithmic slope of the stress vs shear rate increases dramatically with packing fraction and diverges at a critical packing fraction φ(c) which depends on particle shape. The packing fraction dependence of the viscosity curves for different convex shapes can be collapsed when the packing fraction is normalized by φ(c). Intriguingly, viscosity curves for nonconvex particles do not collapse on the same set as convex particles, showing strong shear thickening over a wider range of packing fraction. The value of φ(c) is found to coincide with the onset of a yield stress at the jamming transition, suggesting the jamming transition also controls shear thickening. The yield stress is found to correspond with trapped air in the suspensions, and the scale of the stress can be attributed to interfacial tension forces which dramatically increase above φ(c) due to the geometric constraints of jamming. Using this connection we show that the jamming transition can be identified by simply looking at the surface of suspensions. The relationship between shear and normal stresses is found to be linear in both the shear thickening and jammed regimes, indicating that the shear stresses come from friction. In the limit of zero shear rate, normal stresses pull the rheometer plates together due to the surface tension of the liquid below φ(c), but push the rheometer plates apart due to jamming above φ(c).