Using illness trajectories to inform person-centred, advance care planning

What you need to know- Most patients with progressive illness follow characteristic trajectories of decline, previously identified as rapid, intermittent, or a gradual decline from a low baseline- Multimorbidity is increasingly common and follows a distinct fourth trajectory- An understanding of the dynamic multidimensional trajectories of patients with progressive illnesses helps clinicians consider individual holistic needs and have meaningful conversations with patients and families about advance care planning- In patients with an acute deterioration in health (such as from an infection), considering the main underlying illness trajectory helps guide shared decision making about realistic current and future treatment and care option

Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity

The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels correlate with poor clinical outcome. This work reveals a previously undescribed invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion

Integrating lived experiences of out-of-hours health services for people with palliative and end-of-life care needs with national datasets for people dying in Scotland in 2016:A mixed methods, multi-stage design

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Marie Curie and Chief Scientist Office Scotland, combined grant MCRGS-07-16-37.Peer reviewedPublisher PD

Compartment-specific immunity in the human gut: Properties and functions of dendritic cells in the colon versus the ileum

© 2015 The Authors. Published by BMJ. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: http://dx.doi.org/10.1136/gutjnl-2014-307916Objective Dendritic cells (DC) mediate intestinal immune tolerance. Despite striking differences between the colon and the ileum both in function and bacterial load, few studies distinguish between properties of immune cells in these compartments. Furthermore, information of gut DC in humans is scarce. We aimed to characterise human colonic versus ileal DC. Design Human DC from paired colonic and ileal samples were characterised by flow cytometry, electron microscopy or used to stimulate T cell responses in a mixed leucocyte reaction. Results A lower proportion of colonic DC produced pro-inflammatory cytokines (tumour necrosis factor-a and interleukin (IL)-1ß) compared with their ileal counterparts and exhibited an enhanced ability to generate CD4+FoxP3+IL-10+ (regulatory) T cells. There were enhanced proportions of CD103+Sirpa- DC in the colon, with increased proportions of CD103+Sirpa+ DC in the ileum. A greater proportion of colonic DC subsets analysed expressed the lymph-node-homing marker CCR7, alongside enhanced endocytic capacity, which was most striking in CD103+Sirpa+ DC. Expression of the inhibitory receptor ILT3 was enhanced on colonic DC. Interestingly, endocytic capacity was associated with CD103+ DC, in particular CD103+Sirpa+ DC. However, expression of ILT3 was associated with CD103- DC. Colonic and ileal DC differentially expressed skin-homing marker CCR4 and small-bowel-homing marker CCR9, respectively, and this corresponded to their ability to imprint these homing markers on T cells. Conclusions The regulatory properties of colonic DC may represent an evolutionary adaptation to the greater bacterial load in the colon. The colon and the ileum should be regarded as separate entities, each comprising DC with distinct roles in mucosal immunity and imprinting.This research was funded by St. Mark's Foundation (Harrow, UK), The Biotechnology and Biological Sciences Research Council (BBSRC; BB/J004529/1) and The National Institutes of Health (NIH; US) including The National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK; T32-DK07632 and P01-DK072084) and The National Institute of Allergy and Infectious Disease (NIH/NIAID; R21-AI094033). We also gratefully acknowledge funding support from The Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Centre at The Johns Hopkins Hospital, Baltimore, US.Published versio

The role of changing geodynamics in the progressive contamination of Late Cretaceous to Late Miocene arc magmas in the southern Central Andes

The tectonic and geodynamic setting of the southern Central Andean convergent margin changed significantly between the Late Cretaceous and the Late Miocene, influencing magmatic activity and its geochemical composition. Here we investigate how these changes, which include changing slab-dip angle and convergence angles and rates, have influenced the contamination of the arc magmas with crustal material. Whole rock geochemical data for a suite of Late Cretaceous to Late Miocene arc rocks from the Pampean flat-slab segment (29–31 °S) of the southern Central Andes is presented alongside petrographic observations and high resolution age dating. In-situ U–Pb dating of magmatic zircon, combined with Ar–Ar dating of plagioclase, has led to an improved regional stratigraphy and provides an accurate temporal constraint for the geochemical data. A generally higher content of incompatible trace elements (e.g. Nb/Zr ratios from 0.019 to 0.083 and Nb/Yb from 1.5 to 16.4) is observed between the Late Cretaceous (~ 72 Ma), when the southern Central Andean margin is suggested to have been in extension, and the Miocene when the thickness of the continental crust increased and the angle of the subducting Nazca plate shallowed. Trace and rare earth element compositions obtained for the Late Cretaceous to Late Eocene arc magmatic rocks from the Principal Cordillera of Chile, combined with a lack of zircon inheritance, suggest limited assimilation of the overlying continental crust by arc magmas derived from the mantle wedge. A general increase in incompatible, fluid-mobile/immobile (e.g., Ba/Nb) and fluid-immobile/immobile (e.g., Nb/Zr) trace element ratios is attributed to the influence of the subducting slab on the melt source region and/or the influx of asthenospheric mantle. The Late Oligocene (~ 26 Ma) to Early Miocene (~ 17 Ma), and Late Miocene (~ 6 Ma) arc magmatic rocks present in the Frontal Cordillera show evidence for the bulk assimilation of the Permian–Triassic (P–T) basement, both on the basis of their trace and rare earth element compositions and the presence of P–T inherited zircon cores. Crustal reworking is also identified in the Argentinean Precordillera; Late Miocene (12–9 Ma) arc magmatic rocks display distinct trace element signatures (specifically low Th, U and REE concentrations) and contain inherited zircon cores with Proterozoic and P–T ages, suggesting the assimilation of both the P–T basement and a Grenville-aged basement. We conclude that changing geodynamics play an important role in determining the geochemical evolution of magmatic rocks at convergent margins and should be given due consideration when evaluating the petrogenesis of arc magmas.</p

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Multi-messenger Observations of a Binary Neutron Star Merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ∼ 1.7 {{s}} with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of {40}-8+8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 {M}ȯ . An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ∼ 40 {{Mpc}}) less than 11 hours after the merger by the One-Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ∼10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ∼ 9 and ∼ 16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC 4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta.</p