Tumour-agnostic drugs in paediatric cancers.

The recognition that new cancer drugs can be truly tumour-agnostic based on mechanism-of-action is important for paediatric cancers, where access to novel targeted therapies developed for adult indications has sometimes been problematic. The recently approved drug larotrectinib is an excellent case study of the development of a tumour-agnostic drug relevant to children

Inner-shelf circulation and sediment dynamics on a series of shoreface-connected ridges offshore of Fire Island, NY

Locations along the inner-continental shelf offshore of Fire Island, NY, are characterized by a series of shoreface-connected ridges (SFCRs). These sand ridges have approximate dimensions of 10 km in length, 3 km spacing, and up to similar to 8 m ridge to trough relief and are oriented obliquely at approximately 30 degrees clockwise from the coastline. Stability analysis from previous studies explains how sand ridges such as these could be formed and maintained by storm-driven flows directed alongshore with a key maintenance mechanism of offshore deflected flows over ridge crests and onshore in the troughs. We examine these processes both with a limited set of idealized numerical simulations and analysis of observational data. Model results confirm that alongshore flows over the SFCRs exhibit offshore veering of currents over the ridge crests and onshore-directed flows in the troughs, and demonstrate the opposite circulation pattern for a reverse wind. To further investigate these maintenance processes, oceanographic instruments were deployed at seven sites on the SFCRs offshore of Fire Island to measure water levels, ocean currents, waves, suspended sediment concentrations, and bottom stresses from January to April 2012. Data analysis reveals that during storms with winds from the northeast, the processes of offshore deflection of currents over ridge crests and onshore in the troughs were observed, and during storm events with winds from the southwest, a reverse flow pattern over the ridges occurred. Computations of suspended sediment fluxes identify periods that are consistent with SFCR maintenance mechanisms. Alongshore winds from the northeast drove fluxes offshore on the ridge crest and onshore in the trough that would tend to promote ridge maintenance. However, alongshore winds from the southwest drove opposite circulations. The wind fields are related to different storm types that occur in the region (low-pressure systems, cold fronts, and warm fronts). From the limited data set, we identify that low-pressure systems drive sediment fluxes that tend to promote stability and maintain the SFCRs while cold front type storms appear to drive circulations that are in the opposite sense and may not be a supporting mechanism for ridge maintenance

Primary Progressive Aphasia: Toward a Pathophysiological Synthesis

PURPOSE OF REVIEW: The term primary progressive aphasia (PPA) refers to a diverse group of dementias that present with prominent and early problems with speech and language. They present considerable challenges to clinicians and researchers. RECENT FINDINGS: Here, we review critical issues around diagnosis of the three major PPA variants (semantic variant PPA, nonfluent/agrammatic variant PPA, logopenic variant PPA), as well as considering 'fragmentary' syndromes. We next consider issues around assessing disease stage, before discussing physiological phenotyping of proteinopathies across the PPA spectrum. We also review evidence for core central auditory impairments in PPA, outline critical challenges associated with treatment, discuss pathophysiological features of each major PPA variant, and conclude with thoughts on key challenges that remain to be addressed. New findings elucidating the pathophysiology of PPA represent a major step forward in our understanding of these diseases, with implications for diagnosis, care, management, and therapies

Parents’ experiences of health visiting for children with Down syndrome

© MA Healthcare Limited.Children with Down syndrome have an increased likelihoodof experiencing serious health conditions. Health visitors canhave an important role in monitoring and promoting healthand development for young children with Down syndrome.This study aimed to explore parents’ experiences of healthvisiting services for children with Down syndrome. Twentyfour parents of children with Down syndrome aged 0–5 yearscompleted a brief questionnaire about the number and natureof visits from health visitors in the previous 12 months andtheir support needs. Some parents commented that otherprofessionals met the needs of their child, whereas others saidthat they would like more advice and support from healthvisitors. A further exploration of broader health serviceprovision, including health visiting, for young children withDown syndrome is needed.Peer reviewedFinal Accepted Versio

Attachment styles and personal growth following romantic breakups: The mediating roles of distress, rumination, and tendency to rebound

© 2013 Marshall et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.The purpose of this research was to examine the associations of attachment anxiety and avoidance with personal growth following relationship dissolution, and to test breakup distress, rumination, and tendency to rebound with new partners as mediators of these associations. Study 1 (N = 411) and Study 2 (N = 465) measured attachment style, breakup distress, and personal growth; Study 2 additionally measured ruminative reflection, brooding, and proclivity to rebound with new partners. Structural equation modelling revealed in both studies that anxiety was indirectly associated with greater personal growth through heightened breakup distress, whereas avoidance was indirectly associated with lower personal growth through inhibited breakup distress. Study 2 further showed that the positive association of breakup distress with personal growth was accounted for by enhanced reflection and brooding, and that anxious individuals’ greater personal growth was also explained by their proclivity to rebound. These findings suggest that anxious individuals’ hyperactivated breakup distress may act as a catalyst for personal growth by promoting the cognitive processing of breakup-related thoughts and emotions, whereas avoidant individuals’ deactivated distress may inhibit personal growth by suppressing this cognitive work

Radar Detectability Studies of Slow and Small Zodiacal Dust Cloud Particles. III. The Role of Sodium and the Head Echo Size on the Probability of Detection

We present a path forward on a long-standing issue concerning the flux of small and slow meteoroids, which are believed to be the dominant portion of the incoming meteoric mass flux into the Earth's atmosphere. Such a flux, which is predicted by dynamical dust models of the Zodiacal Cloud, is not evident in ground-based radar observations. For decades this was attributed to the fact that the radars used for meteor observations lack the sensitivity to detect this population, due to the small amount of ionization produced by slow-velocity meteors. Such a hypothesis has been challenged by the introduction of meteor head echo (HE) observations with High Power and Large Aperture radars, in particular the Arecibo 430 MHz radar. Janches et al. developed a probabilistic approach to estimate the detectability of meteors by these radars and initially showed that, with the current knowledge of ablation and ionization, such particles should dominate the detected rates by one to two orders of magnitude compared to the actual observations. In this paper, we include results in our model from recently published laboratory measurements, which showed that (1) the ablation of Na is less intense covering a wider altitude range; and (2) the ionization probability, βip for Na atoms in the air is up to two orders of magnitude smaller for low speeds than originally believed. By applying these results and using a somewhat smaller size of the HE radar target we offer a solution that reconciles these observations with model predictions

Mass spectrometry detection of inhaled drug in distal fibrotic lung

BACKGROUND: Currently the only available therapies for fibrotic Interstitial Lung Disease are administered systemically, often causing significant side effects. Inhaled therapy could avoid these but to date there is no evidence that drug can be effectively delivered to distal, fibrosed lung. We set out to combine mass spectrometry and histopathology with rapid sample acquisition using transbronchial cryobiopsy to determine whether an inhaled drug can be delivered to fibrotic, distal lung parenchyma in participants with Interstitial Lung Disease. METHODS: Patients with radiologically and multidisciplinary team confirmed fibrotic Interstitial Lung Disease were eligible for this study. Transbronchial cryobiopsies and endobronchial biopsies were taken from five participants, with Interstitial Lung Disease, within 70 min of administration of a single dose of nebulised ipratropium bromide. Thin tissue cryosections were analysed by Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging and correlated with histopathology. The remainder of the cryobiopsies were homogenised and analysed by Liquid Chromatography—tandem Mass Spectrometry. RESULTS: Drug was detected in proximal and distal lung samples from all participants. Fibrotic regions were identified in research samples of four of the five participants. Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging showed co-location of ipratropium with fibrotic regions in samples from three participants. CONCLUSIONS: In this proof of concept study, using mass spectrometry, we demonstrate for the first-time that an inhaled drug can deposit in distal fibrotic lung parenchyma in patients with Interstitial Lung Disease. This suggests that drugs to treat pulmonary fibrosis could potentially be administered by the inhaled route

Plasticity of the human visual system after retinal gene therapy in patients with Leber's congenital amaurosis.

Much of our knowledge of the mechanisms underlying plasticity in the visual cortex in response to visual impairment, vision restoration, and environmental interactions comes from animal studies. We evaluated human brain plasticity in a group of patients with Leber's congenital amaurosis (LCA), who regained vision through gene therapy. Using non-invasive multimodal neuroimaging methods, we demonstrated that reversing blindness with gene therapy promoted long-term structural plasticity in the visual pathways emanating from the treated retina of LCA patients. The data revealed improvements and normalization along the visual fibers corresponding to the site of retinal injection of the gene therapy vector carrying the therapeutic gene in the treated eye compared to the visual pathway for the untreated eye of LCA patients. After gene therapy, the primary visual pathways (for example, geniculostriate fibers) in the treated retina were similar to those of sighted control subjects, whereas the primary visual pathways of the untreated retina continued to deteriorate. Our results suggest that visual experience, enhanced by gene therapy, may be responsible for the reorganization and maturation of synaptic connectivity in the visual pathways of the treated eye in LCA patients. The interactions between the eye and the brain enabled improved and sustained long-term visual function in patients with LCA after gene therapy