MORE THAN TEA AND CAKE: A REALIST EVALUATION OF MEMORY CAFÉS IN CORNWALL

Background: Memory cafés are a growing community based response to supporting people living with dementia and their carers. They are now well established in the UK and elsewhere; with over forty cafés in Cornwall. Despite their growth, there has been little research into their structure, aims and impact. Aims: The aim of this research was to explore how and why memory cafés work for people living with dementia and their carers. Methodology: Realist methodology is a theory driven approach that seeks to explain why a programme works, for whom and in what circumstances. The research consisted of three stages. Firstly, the development of initial programme theories through a realist review. Secondly, the testing and refinement of those theories, and the development of new theories through a realist evaluation. Thirdly, the formulation of a conceptual platform from the programme theories of how and why memory cafés work. The realist evaluation used ethnographic approaches of observation and in-situ interviews in four memory cafés, to enable a greater understanding of the café structures, processes and reported benefits. Results: A conceptual platform comprising twelve core processes of how and why memory cafés work was developed from nine programme theories. Cafés generally adopted a volunteer-led, more structured approach or a guest-led, unstructured approach. Memory cafes are multi-faceted; providing a safe place where people with dementia and their carers can meet with others in a similar situation, and engage in a range of activities. Furthermore, they provide a place of continuity for a carer once their loved one has passed away. They create opportunities for humour and laughter, outside of normal routines and can be a source of information on other services. Most importantly they enable the development of relationships. Conclusions: Memory cafés provide a valuable community based service to people living with and affected by dementia.  The National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) South West Peninsula (PenCLAHRC

Inhibitors of diacylglycerol metabolism suppress CCR2 receptor signalling in human monocytes

Background and purpose CCL2 is an inflammatory chemokine that stimulates the recruitment of monocytes into tissue via activation of the GPCR CCR2. Experimental approach Freshly isolated human monocytes and THP‐1 cells are used; Fura‐2 loaded cells used to measure intracellular Ca2+ responses; transwell migration; siRNA‐mediated gene knockdown. Key results We observed that CCL2 evokes intracellular Ca2+ signals and stimulates migration in THP‐1 monocytic cells and human CD14+ monocytes in a CCR2‐dependent fashion. Attenuation of diacylglycerol (DAG) catabolism in monocytes by inhibiting DAG kinase (R59949) or DAG lipase (RHC80267) activity suppresses CCL2‐evoked Ca2+ signalling and transwell migration in monocytes. These effects were not due to a reduction in the number of cell surface CCR2 receptors. The effect of DAG kinase or DAG lipase inhibition could be mimicked by the addition of the DAG analogue 1‐oleoyl‐2‐acetyl‐glycerol (OAG) but was not rescued by application of exogenous phosphatidylinositol 4,5‐bisphosphate. Suppressive effects of R59949, RHC80267 and OAG could be partially or fully reversed by the Gö6983 (pan PKC isoenzyme inhibitor) but not by Gö6976 (PKCα and PKCβ inhibitor). RNAi‐mediated knock‐down of DAG kinase α isoenzyme modulated CCL2‐evoked Ca2+ responses in THP‐1 cells. Conclusions & Implications Taken together, these data suggest that DAG production resulting from CCR2 activation is metabolised by both DAG kinase and DAG lipase pathways in monocytes, and that pharmacological inhibition of DAG catabolism or application suppresses signalling on the CCL2‐CCR2 axis via a mechanism dependent upon a PKC isoenzymes(s) that are sensitive to Gö6983 but not Gö6976

Human Faces Are Slower than Chimpanzee Faces

BACKGROUND: While humans (like other primates) communicate with facial expressions, the evolution of speech added a new function to the facial muscles (facial expression muscles). The evolution of speech required the development of a coordinated action between visual (movement of the lips) and auditory signals in a rhythmic fashion to produce "visemes" (visual movements of the lips that correspond to specific sounds). Visemes depend upon facial muscles to regulate shape of the lips, which themselves act as speech articulators. This movement necessitates a more controlled, sustained muscle contraction than that produced during spontaneous facial expressions which occur rapidly and last only a short period of time. Recently, it was found that human tongue musculature contains a higher proportion of slow-twitch myosin fibers than in rhesus macaques, which is related to the slower, more controlled movements of the human tongue in the production of speech. Are there similar unique, evolutionary physiologic biases found in human facial musculature related to the evolution of speech?\ud \ud METHODOLOGY/PRINICIPAL FINDINGS: Using myosin immunohistochemistry, we tested the hypothesis that human facial musculature has a higher percentage of slow-twitch myosin fibers relative to chimpanzees (Pan troglodytes) and rhesus macaques (Macaca mulatta). We sampled the orbicularis oris and zygomaticus major muscles from three cadavers of each species and compared proportions of fiber-types. Results confirmed our hypothesis: humans had the highest proportion of slow-twitch myosin fibers while chimpanzees had the highest proportion of fast-twitch fibers.\ud \ud CONCLUSIONS/SIGNIFICANCE: These findings demonstrate that the human face is slower than that of rhesus macaques and our closest living relative, the chimpanzee. They also support the assertion that human facial musculature and speech co-evolved. Further, these results suggest a unique set of evolutionary selective pressures on human facial musculature to slow down while the function of this muscle group diverged from that of other primates.\ud \u

No association between intravenous fluid volume and endothelial glycocalyx shedding in patients undergoing resuscitation for sepsis in the emergency department

Endothelial glycocalyx (EG) shedding is associated with septic shock and described following intravenous (IV) fluid administration. To investigate the possible impact of IV fluids on the pathobiology of septic shock we investigated associations between biomarkers of EG shedding and endothelial cell activation, and relationships with IV fluid volume. Serum samples were obtained on admission (T0) and at 24 h (T24) in patients undergoing haemodynamic resuscitation for suspected septic shock in the emergency department. Biomarkers of EG shedding—Syndecan-1 (Syn-1), Syndecan-4 (Syn-4), Hyaluronan, endothelial activation—Endothelin-1 (ET-1), Angiopoeitin-2 (Ang-2), Vascular Endothelial Growth Factor Receptor-1(VEGF-1) and leucocyte activation/inflammation—Resistin, Neutrophil Gelatinase Associated Lipocalin (NGAL) and a marker of cardiac stretch—Pro-Atrial Natriuretic Peptide (Pro-ANP) were compared to the total IV fluid volume administered using Tobit regression. Data on 86 patients (52 male) with a mean age of 60 (SD 18) years were included. The mean fluid volume administered to T24 was 4038 ml (SD 2507 ml). No significant association between fluid volume and Pro-ANP or any of the biomarkers were observed. Syn-1 and Syn-4 were significantly correlated with each other (Spearman Rho 0.43, p \u3c 0.001) but not with Hyaluronan. Syn-1 and Syn-4 both correlated with VEGFR-1 (Rho 0.56 and 0.57 respectively, p \u3c 0.001) whereas Hyaluronan correlated with ET-1 (Rho 0.43, p \u3c 0.001) and Ang-2 (Rho 0.43, p \u3c 0.001). There was no correlation between Pro-ANP and any of the EG biomarkers. Distinct patterns of association between biomarkers of EG shedding and endothelial cell activation were observed among patients undergoing resuscitation for sepsis. No relationship between IV fluid volume and Pro-ANP or any of the other biomarkers was observed

The potential for medicinal cannabis to help manage challenging behaviour in people with intellectual disability: A perspective review

Background: Around 2% of the population have intellectual disabilities. Over one-third people with intellectual disabilities (PwID) present with ‘challenging behaviour’, which nosologically and diagnostically is an abstract concept. Challenging behaviour is influenced by a range of bio-psycho-social factors in a population, which is unable to suitably comprehend and/or communicate concerns. This predisposes to poor health and social outcomes. There is no evidence-based treatments for managing challenging behaviour. Cannabidiol (CBD) and tetrahydrocannabinol (THC) are being trialled for a range of disorders, which are over-represented in PwID and provoke challenging behaviours, such as severe epilepsy, spasticity, post-traumatic stress disorder, social phobia, pain, etc.// Methods: This perspective review explores the different conditions, which benefit from medicinal CBD/THC preparations, by analysing recent literature from neurobiological, pre-clinical and clinical studies related to the topic. The evidence is synthesised to build an argument of the therapeutic benefits and challenges of medicinal cannabis to manage severe challenging behaviour in PwID.// Results: There is developing evidence of medicinal CBD/THC improving psychiatric and behavioural presentations in general. In particular, there is emergent proof in certain key areas of influence of medicinal CBD/THC positively supporting challenging behaviour, for example in children with neurodevelopmental disorders. However, there are significant challenges in employing such treatments in vulnerable populations such as PwID.// Conclusion: Further clinical research for the considered use of medicinal CBD/THC for challenging behaviour management in PwID is needed. Strong co-production with experts with lived experience is needed for further testing to be done in this exciting new area

Studies of the horizontal inhomogeneities in NO2 concentrations above a shipping lane using ground-based multi-axis differential optical absorption spectroscopy (MAX-DOAS) measurements and validation with airborne imaging DOAS measurements

This study describes a novel application of an “onion-peeling” approach to multi-axis differential optical absorption spectroscopy (MAX-DOAS) measurements of shipping emissions aiming at investigating the strong horizontal inhomogeneities in NO2 over a shipping lane. To monitor ship emissions on the main shipping route towards the port of Hamburg, a two-channel (UV and visible) MAX-DOAS instrument was deployed on the island Neuwerk in the German Bight, 6–7 km south of the main shipping lane. Utilizing the fact that the effective light path length in the atmosphere depends systematically on wavelength, simultaneous measurements and DOAS retrievals in the UV and visible spectral ranges are used to probe air masses at different horizontal distances to the instrument to estimate two-dimensional pollutant distributions. Two case studies have been selected to demonstrate the ability to derive the approximate plume positions in the observed area. A situation with northerly wind shows high NO2 concentrations close to the measurement site and low values in the north of the shipping lane. The opposite situation with southerly wind, unfavorable for the on-site in situ instrumentation, demonstrates the ability to detect enhanced NO2 concentrations several kilometers away from the instrument. Using a Gaussian plume model, in-plume NO2 volume mixing ratios can be derived from the MAX-DOAS measurements. For validation, a comparison to airborne imaging DOAS measurements during the NOSE campaign in July 2013 is performed, showing good agreement between the approximate plume position derived from the onion-peeling MAX-DOAS and the airborne measurements as well as between the derived in-plume NO2 volume mixing ratios (VMRs)

No Correlation Between Host Galaxy Metallicity and Gamma-Ray Energy Release for Long-Duration Gamma-Ray Bursts

We compare the redshifts, host galaxy metallicities, and isotropic (E_gamma,iso) and beaming-corrected (E_gamma) gamma-ray energy release of 16 long-duration gamma-ray bursts (LGRBs) at z < 1. From this comparison, we find no statistically significant correlation between host metallicity and redshift, E_gamma,iso, or E_gamma. These results are at odds with previous theoretical and observational predictions of an inverse correlation between gamma-ray energy release and host metallicity, as well as the standard predictions of metallicity-driven wind effects in stellar evolutionary models. We consider the implications that these results have for LGRB progenitor scenarios, and discuss our current understanding of the role that metallicity plays in the production of LGRBs.Comment: 13 pages, 1 figure; accepted to Astrophysical Journa

Projected marine heatwaves in the 21st century and the potential for ecological impact

Marine heatwaves (MHWs) are extreme climatic events in oceanic systems that can have devastating impacts on ecosystems, causing abrupt ecological changes and socioeconomic consequences. Several prominent MHWs have attracted scientific and public interest, and recent assessments have documented global and regional increases in their frequency. However, for proactive marine management, it is critical to understand how patterns might change in the future. Here, we estimate future changes in MHWs to the end of the 21st century, as simulated by the CMIP5 global climate model projections. Significant increases in MHW intensity and count of annual MHW days are projected to accelerate, with many parts of the ocean reaching a near-permanent MHW state by the late 21st century. The two greenhouse gas (GHG) emission scenarios considered (Representative Concentration Pathway 4.5 and 8.5) strongly affect the projected intensity of MHW events, the proportion of the globe exposed to permanent MHW states, and the occurrence of the most extreme MHW events. Comparison with simulations of a natural world, without anthropogenic forcing, indicate that these trends have emerged from the expected range of natural variability within the first half of the 21st century. This discrepancy implies a degree of “anthropogenic emergence,” with a departure from the natural MHW conditions that have previously shaped marine ecosystems for centuries or even millennia. Based on these projections we expect impacts on marine ecosystems to be widespread, significant and persistent through the 21st century.This research was supported by the Australian Research Council grants CE170100023 and FT170100106, Natural Environment Research Council International Opportunity Fund NE/N00678X/1, National Sciences and Engineering Research Council of Canada Discovery Grant RGPIN-2018-05255, and Brian Mason (Impacts of an unprecedented marine heatwave). This project was partially supported through funding from the Earth Systems and Climate Change Hub of the Australian Government’s National Environmental Science Program.Peer ReviewedPostprint (published version

RTL551 Treatment of EAE Reduces CD226 and T-bet+ CD4 T Cells in Periphery and Prevents Infiltration of T-bet+ IL-17, IFN-γ Producing T Cells into CNS

Recombinant T cell receptor ligands (RTLs) that target encephalitogenic T-cells can reverse clinical and histological signs of EAE, and are currently in clinical trials for treatment of multiple sclerosis. To evaluate possible regulatory mechanisms, we tested effects of RTL therapy on expression of pathogenic and effector T-cell maturation markers, CD226, T-bet and CD44, by CD4+ Th1 cells early after treatment of MOG-35-55 peptide-induced EAE in C57BL/6 mice. We showed that 1–5 daily injections of RTL551 (two-domain I-Ab covalently linked to MOG-35-55 peptide), but not the control RTL550 (“empty” two-domain I-Ab without a bound peptide) or Vehicle, reduced clinical signs of EAE, prevented trafficking of cells outside the spleen, significantly reduced the frequency of CD226 and T-bet expressing CD4+ T-cells in blood and inhibited expansion of CD44 expressing CD4+ T-cells in blood and spleen. Concomitantly, RTL551 selectively reduced CNS inflammatory lesions, absolute numbers of CNS infiltrating T-bet expressing CD4+ T-cells and IL-17 and IFN-γ secretion by CNS derived MOG-35-55 reactive cells cultured ex vivo. These novel results demonstrate that a major effect of RTL therapy is to attenuate Th1 specific changes in CD4+ T-cells during EAE and prevent expansion of effector T-cells that mediate clinical signs and CNS inflammation in EAE