Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2.

BackgroundIn the BOLERO-2 trial, everolimus (EVE), an inhibitor of mammalian target of rapamycin, demonstrated significant clinical benefit with an acceptable safety profile when administered with exemestane (EXE) in postmenopausal women with hormone receptor-positive (HR(+)) advanced breast cancer. We report on the incidence, time course, severity, and resolution of treatment-emergent adverse events (AEs) as well as incidence of dose modifications during the extended follow-up of this study.Patients and methodsPatients were randomized (2:1) to receive EVE 10 mg/day or placebo (PBO), with open-label EXE 25 mg/day (n = 724). The primary end point was progression-free survival. Secondary end points included overall survival, objective response rate, and safety. Safety evaluations included recording of AEs, laboratory values, dose interruptions/adjustments, and study drug discontinuations.ResultsThe safety population comprised 720 patients (EVE + EXE, 482; PBO + EXE, 238). The median follow-up was 18 months. Class-effect toxicities, including stomatitis, pneumonitis, and hyperglycemia, were generally of mild or moderate severity and occurred relatively early after treatment initiation (except pneumonitis); incidence tapered off thereafter. EVE dose reduction and interruption (360 and 705 events, respectively) required for AE management were independent of patient age. The median duration of dose interruption was 7 days. Discontinuation of both study drugs because of AEs was higher with EVE + EXE (9%) versus PBO + EXE (3%).ConclusionsMost EVE-associated AEs occur soon after initiation of therapy, are typically of mild or moderate severity, and are generally manageable with dose reduction and interruption. Discontinuation due to toxicity was uncommon. Understanding the time course of class-effect AEs will help inform preventive and monitoring strategies as well as patient education.Trial registration numberNCT00863655

The spatial experiences of dwarfs in public spaces

Dwarfism is commonly defined as anyone 4ft 10″ (147.32 cm) or below and whose short stature involves a medical condition [Adelson, M. B. 2005. The Lives of Dwarfs, xv. NJ: Rutgers University Press]. Whilst it recognized that the built environment is unsuitable for dwarfs [see Kruse, R. 2002. “Social Spaces of Little People: The Experiences of the Jamisons.” Social and Cultural Geography 3 (2): 175–191, Kruse, R. 2010. “Placing Little People: Dwarfism and Geographies of Everyday Life.” In Towards Enabling Geographies, edited by V. Chouinard, E. Hall, and R. Wilton, 183–198. Surrey: Ashgate; Shakespeare, T., M. Wright, and S. Thompson. 2007. A Small Matter of Equality: Living with Restricted Growth. Newcastle: Newcastle University], this paper critically examines how spaces and facilities designed with other users in mind, including disabled people and children, can have unintended consequences for dwarfs. The data used in this paper are taken from semi-structured interviews and photo elicitation exercises conducted with 22 dwarfs living in the UK. Overall this paper shows the spatial experiences of dwarfs, which are a result of the unintended consequences of disabled child spaces and facilities, and suggests how Universal Design may be a more appropriate design concept

Glass ceilings and stone floors: an intersectional approach to challenges UK geographers face across the career lifecycle

While there has been a steady growth of women working in geography in UK universities since the mid-Twentieth Century, there are continuing challenges in gendered career progression and professional interactions within the contemporary discipline. These range from problems associated with employment precarity and inflexible work practices, life choices and obligations in the domestic arena, discrimination and bullying, to less tangible gendered norms and cultures in the workplace. This paper discusses these challenges and inequalities in the light of a brief overview of sector-wide statistical data on appointments by gender and career-stage and with the analysis of some 250 in-depth responses to a nationwide qualitative survey of gender and career experience in UK universities (Maddrell et al 2016). While the term ‘glass ceiling’ still has significant relevance, findings show a more complicated picture which also includes ‘stone floors’ and stumbling blocks. It also shows how career experience varies by institution and individual: challenges in career progression can be compounded by institutional protocols and intersectional factors, and vary with career stage. The intersection of early-career job precarity, reproductive decisions and associated family responsibilities were particularly highlighted in this study. These ‘pinch points’ in career development disproportionately affect, but are not limited to, female early career scholars. Early career progress may be stalled in mid-career in multi-staged promotional systems such as that in UK universities; some from minorities face compound barriers; men with caring responsibilities may face prejudice. The paper concludes with suggested strategies for change, highlighting the importance of individual university and department protocols and practices; line manager and other senior colleagues’ attitudes and leadership in creating workplaces with an equality-driven ethos and structures that allow individuals to flourish

fMRI evidence of ‘mirror’ responses to geometric shapes

Mirror neurons may be a genetic adaptation for social interaction [1]. Alternatively, the associative hypothesis [2], [3] proposes that the development of mirror neurons is driven by sensorimotor learning, and that, given suitable experience, mirror neurons will respond to any stimulus. This hypothesis was tested using fMRI adaptation to index populations of cells with mirror properties. After sensorimotor training, where geometric shapes were paired with hand actions, BOLD response was measured while human participants experienced runs of events in which shape observation alternated with action execution or observation. Adaptation from shapes to action execution, and critically, observation, occurred in ventral premotor cortex (PMv) and inferior parietal lobule (IPL). Adaptation from shapes to execution indicates that neuronal populations responding to the shapes had motor properties, while adaptation to observation demonstrates that these populations had mirror properties. These results indicate that sensorimotor training induced populations of cells with mirror properties in PMv and IPL to respond to the observation of arbitrary shapes. They suggest that the mirror system has not been shaped by evolution to respond in a mirror fashion to biological actions; instead, its development is mediated by stimulus-general processes of learning within a system adapted for visuomotor control

Radon backgrounds in the DEAP-1 liquid-argon-based Dark Matter detector

The DEAP-1 \SI{7}{kg} single phase liquid argon scintillation detector was operated underground at SNOLAB in order to test the techniques and measure the backgrounds inherent to single phase detection, in support of the \mbox{DEAP-3600} Dark Matter detector. Backgrounds in DEAP are controlled through material selection, construction techniques, pulse shape discrimination and event reconstruction. This report details the analysis of background events observed in three iterations of the DEAP-1 detector, and the measures taken to reduce them. The $^{222}$Rn decay rate in the liquid argon was measured to be between 16 and \SI{26}{\micro\becquerel\per\kilogram}. We found that the background spectrum near the region of interest for Dark Matter detection in the DEAP-1 detector can be described considering events from three sources: radon daughters decaying on the surface of the active volume, the expected rate of electromagnetic events misidentified as nuclear recoils due to inefficiencies in the pulse shape discrimination, and leakage of events from outside the fiducial volume due to imperfect position reconstruction. These backgrounds statistically account for all observed events, and they will be strongly reduced in the DEAP-3600 detector due to its higher light yield and simpler geometry

Resourcing Scholar-Activism: Collaboration, Transformation, and the Production of Knowledge

In this article we offer a set of resources for scholar-activists to reflect on and guide their practice. We begin by suggesting that research questions should be triangulated to consider not only their scholarly merit but the intellectual and political projects the findings will advance and the research questions of interest to community and social movement collaborators

In-situ characterization of the Hamamatsu R5912-HQE photomultiplier tubes used in the DEAP-3600 experiment

The Hamamatsu R5912-HQE photomultiplier-tube (PMT) is a novel high-quantum efficiency PMT. It is currently used in the DEAP-3600 dark matter detector and is of significant interest for future dark matter and neutrino experiments where high signal yields are needed. We report on the methods developed for in-situ characterization and monitoring of DEAP's 255 R5912-HQE PMTs. This includes a detailed discussion of typical measured single-photoelectron charge distributions, correlated noise (afterpulsing), dark noise, double, and late pulsing characteristics. The characterization is performed during the detector commissioning phase using laser light injected through a light diffusing sphere and during normal detector operation using LED light injected through optical fibres