An analysis of convection in a mushy layer with a deformable permeable interface

We study the dynamics of a mushy layer in directional solidification for the case of a thin near-eutectic mush with a deformable and permeable mush–liquid interface. We examine the onset of convection using linear stability analysis, and the weakly nonlinear growth of liquid inclusions that signal the onset of chimneys. This analysis is compared to past analyses in which the mush–liquid interface is replaced by a rigid impermeable lid. We find qualitative agreement between the two models, but the rigid-lid approximation gives substantially different quantitative behaviour. In linear theory, the rigid-lid approximation leads to an over-estimate of the critical Rayleigh number and wavenumber of the instability. The condition for the onset of oscillatory instability is also changed by a factor of about 5 in composition number C. In the weakly nonlinear theory, the location of the onset of liquid inclusions is near the undisturbed front for the free-boundary analysis, whereas it lies at the centre of the mushy layer when the rigid-lid approximation is used. For hexagonal patterns, the boundary between regions of parameter space in which up and down hexagons are stable, shifts as a result of coupling between the liquid and mush regions

‘Involvement’ and ‘Fun’ as Potential for Deep Learning: Unusual Suspects in a Higher Education Economics Programme

While games have much potential as pedagogical tools, there is limited empirical evidence that indicates the extent to which they might be successful in a higher education Economics programme. This prompted an investigation in the form of a qualitative case study at the Durban University of Technology (DUT), utilising a sample of first-year Economics students who had participated in a series of games incorporating key micro-economics topics.Northcutt & McCoy’s Interactive Qualitative Analysis (IQA), a unique, structured and rigorous methodological approach that advocates strong participant involvement in the research process, provided the foundation for the research. Focus group discussions, individual semi-structured interviews and reflective journals provided the data for the study, which revealed that the use of games was a key catalyst in stimulating learning. Of note is that students firmly placed ‘involvement and fun’ at the core of the learning process, which resulted in deeper learning of economic concepts. This has implications for education in re-evaluating what is meant by the terms ‘involvement’ and ‘fun’ with regard to an enhanced learning experience within the classroom.The findings highlight the potential for learning that judiciously selected economics games might have for student learning in a re-imagined teaching and learning space

Association between disability measures and healthcare costs after initial treatment for acute stroke

<p><b>Background and Purpose:</b> The distribution of 3-month modified Rankin scale (mRS) scores has been used as an outcome measure in acute stroke trials. We hypothesized that hospitalization and institutional care home stays within the first 90 days after stroke should be closely related to 90-day mRS, that each higher mRS category will reflect incremental cost, and that resource use may be less clearly linked to the National Institutes of Health Stroke Scale (NIHSS) or Barthel index.</p> <p><b>Methods:</b> We examined resource use data from the GAIN International trial comparing 90-day mRS with total length of stay in hospital or other institutions during the first 90 days. We repeated analyses using NIHSS and Barthel index scores. Relationships were examined by analysis of variance (ANOVA) with Bonferroni contrasts of adjacent score categories. Estimated costs were based on published Scottish figures.</p> <p><b>Results:</b> We had full data from 1717 patients. Length of stay was strongly associated with final mRS (P<0.0001). Each mRS increment from 0 to 1–2 to 3–4 was significant (mean length of stay: 17, 25, 44, 58, 79 days; P<0.0005). Ninety-five percent confidence limits for estimated costs (£) rose incrementally: 2493 to 3412, 3369 to 4479, 5784 to 7008, 7300 to 8512, 10 095 to 11 141, 11 772 to 13 560, and 2623 to 3321 for mRS 0 to 5 and dead, respectively. Weaker relationships existed with Barthel and NIHSS.</p> <p><b>Conclusions:</b> Each mRS category reflects different average length of hospital and institutional stay. Associated costs are meaningfully different across the full range of mRS outcomes. Analysis of the full distribution of mRS scores is appropriate for interpretation of treatment effects after acute stroke and more informative than Barthel or NIHSS end points.</p&gt

Aspects of Obesity: From aetiology to weight loss and maintenance

Introduction Obesity is a significant global health and financial issue with prevalence increasing. While the cornerstone of its management remains a combined lifestyle intervention, weight loss recidivism is high. Recent novel insights relating to dietary protein and to weight homeostasis and neuro-endocrine adaptation shed light on these important aspects of obesity. Results Experiment 1 demonstrated that in lean health adults, after 4 days of ad libitum diets followed by a standardised breakfast, the lowest %protein diet was associated with highest fasting ghrelin and lowest post-prandial cholecystokinin. Experiment 2 demonstrated that both obese and lean mice varied daily food intake by >12% when consuming low protein compared to high protein chow. Experiment 3 demonstrated in obese adults that weight loss by combined lifestyle intervention was associated with reduced fasting ghrelin and glucagon-like peptide-1. Discussion The intake for dietary protein is prioritised even at the expense of increased total energy consumption and the physiological effects of changes to gut hormones on low protein diets is to favour hunger. The secular trend of reduced energy intake by protein may be a key driver towards obesity. Weight regain after lifestyle interventions are due to changes in mediators of appetite and body weight rather than just a failure of behaviour. These results challenge the conventional understanding about obesity

Sustained gene expression in the retina by improved episomal vectors

Gene and cellular therapies are nowadays part of therapeutic strategies for the treatment of diverse pathologies. The drawbacks associated with gene therapy-low levels of transgene expression, vector loss during mitosis, and gene silencing-need to be addressed. The pEPI-1 and pEPito family of vectors was developed to overcome these limitations. It contains a scaffold/matrix attachment region, which anchors its replication to cell division in eukaryotic cells while in an extrachromosomal state and is less prone to silencing, due to a lower number of CpG motifs. Recent success showed that ocular gene therapy is an important tool for the treatment of several diseases, pending the overcome of the aforementioned limitations. To achieve sustained gene delivery in the retina, we evaluated several vectors based on pEPito and pEPI-1 for their ability to sustain transgene expression in retinal cells. These vectors stably transfected and replicated in retinal pigment epithelial (RPE) cells. Expression levels were promoter dependent with constitutive promoters cytomegalovirus immediate early promoter (CMV) and human CMV enhancer/human elongation factor 1 alpha promoter yielding the highest levels of transgene expression compared with the retina-specific RPE65 promoter. When injected in C57Bl6 mice, transgene expression was sustained for at least 32 days. Furthermore, the retina-specific RPE65 promoter showed higher efficiency in vivo compared to in vitro. In this study, we demonstrate that by combining tissue-specific promoters with a mitotic stable system, less susceptible to epigenetic silencing such as pEPito-based plasmids, we can achieve prolonged gene expression and a sustained therapeutic effect.Fundacao para a Ciencia e Tecnologia, Portugal [PEst/OE/EQB-LA 0023/2013, SFRH/BD/76873/2011, SFRH/BD/70318/2010, PTDC/SAU/BEB/098475/2008]; European Union [PIRG-GA-2009-249314

Results of the MRI substudy of the intravenous magnesium efficacy in stroke trial

<p><b>Background and Purpose:</b>Although magnesium is neuroprotective in animal stroke models, no clinical benefit was confirmed in the Intravenous Magnesium Efficacy in Stroke (IMAGES) trial of acute stroke patients. The Magnetic Resonance in IMAGES (MR IMAGES) substudy investigated the effects of magnesium on the imaging surrogate outcome of infarct growth.</p> <p><b>Methods:</b> IMAGES trial patients in participating centers were randomized to receive either intravenous magnesium or placebo within 12 hours of stroke onset. Infarct growth was defined as volume difference between baseline diffusion-weighted imaging and day 90 fluid-attenuated inversion recovery image lesions. Patients who died were imputed the largest infarct growth observed.</p> <p><b>Results:</b> Among the 90 patients included in the primary analysis, there was no difference in infarct growth (median absolute growth, P=0.639; median percentage growth, P=0.616; proportion with any growth, P=0.212) between the 46 treated with magnesium and 44 with placebo. Infarct growth correlated with NIHSS score change from baseline to day 90. There was a trend showing baseline serum glucose correlated with infarct growth with magnesium treatment, but not in the placebo group. The mismatch frequency was reduced from 73% to 47% by increasing the mismatch threshold from >20% to >100% of core volume.</p> <p><b>Conclusions:</b> Infarct growth, confirmed here as a surrogate for clinical progression, was similar between magnesium and placebo treatment, paralleling the main IMAGES trial clinical outcomes. Glucose was a covariate for infarct growth with magnesium treatment. A more stringent mismatch threshold to define penumbra more appropriately would have excluded half of the patients in this 12-hour time window stroke study.</p&gt

Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke in the SAINT I trial

<p><b>Background and Purpose:</b> NXY-059 is a free radical-trapping neuroprotectant demonstrated to reduce disability from ischemic stroke. We conducted analyses on additional end points and sensitivity analyses to confirm our findings.</p> <p><b>Methods:</b> We randomized 1722 patients with acute ischemic stroke to a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours of stroke onset. The primary outcome was disability at 90 days, as measured by the modified Rankin Scale (mRS), a 6-point scale ranging from 0 (no residual symptoms) to 5 (bed-bound, requiring constant care). Additional and exploratory analyses included mRS at 7 and 30 days; subgroup interactions with final mRS; assessments of activities of daily living by Barthel index; and National Institutes of Health Stroke Scale (NIHSS) neurological scores at 7 and 90 days.</p> <p><b>Results:</b> NXY-059 significantly improved the distribution of the mRS disability score compared with placebo at 7, 30, and 90 days (Cochran-Mantel-Haenszel test P=0.002, 0.004, 0.038, respectively; 90-day common odds ratio 1.20; 95% CI, 1.01 to 1.42). The benefit was not attributable to any specific baseline characteristic, stratification variable or subgroup interaction. Neurological scores were improved at 7 days (odds ratio [OR], 1.46; 95% CI, 1.13, 1.89; P=0.003) and the Barthel index was improved at 7 and 30 days (OR, 1.55; 95% CI, 1.22, 1.98; P<0.0001; OR, 1.27; 95% CI, 1.01, 1.59; P=0.02).</p> <p><b>Conclusions:</b> NXY-059 within 6 hours of acute ischemic stroke significantly reduced disability. Benefit on neurological scores and activities of daily living was detectable early but not significant at 90 days; however, our trial was underpowered to measure effects on the neurological examination. The benefit on disability is not confounded by interactions and is supported by other outcome measures.</p&gt

NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II trials

<p><b>Background and Purpose:</b> In animal models of acute ischemic stroke (AIS), the free radical-trapping agent NXY-059 showed promise as a neuroprotectant. SAINT I and II were randomized, placebo-controlled, double-blind trials to investigate the efficacy of NXY-059 in patients with AIS.</p> <p><b>Methods:</b> Patients with AIS received an infusion of intravenous NXY-059 or placebo within 6 hours from the onset of stroke symptoms. A pooled individual patient analysis was prespecified to assess the overall efficacy and to examine subgroups. The primary end point was the distribution of disability scores measured on the modified Rankin scale (mRS) at 90 days. Neurologic and activities of daily living scores were investigated as secondary end points. We also evaluated whether treatment with NXY-059 would reduce alteplase-related intracranial hemorrhages. Finally, we evaluated possible predictors of good or poor outcome.</p> <p><b>Results:</b> An intent-to-treat efficacy analysis was based on 5028 patients. Baseline parameters and prognostic factors were well balanced between treatment groups. The distribution of scores on the mRS was not different in the group treated with NXY-059 (n = 2438) compared with the placebo group (n = 2456): odds ratio for limiting disability = 1.02; 95% CI, 0.92 to 1.13 (P = 0.682, Cochran-Mantel-Haenszel test). Comparisons at each level of the mRS confirmed an absence of benefit. There was no evidence of efficacy in prespecified subgroups or from the secondary outcome analyses. Mortality was equal in the 2 groups (16.7% vs 16.5%), and adverse event rates were similar. Among patients treated with alteplase, there was no decrease in rates of symptomatic or asymptomatic hemorrhage associated with NXY-059 treatment versus placebo. Subgroup analyses identified National Institutes of Health Stroke Scale score, age, markers of inflammation, blood glucose, and right-sided infarct as predictors of poor outcome.</p> <p><b>Conclusions:</b> NXY-059 is ineffective for treatment of AIS within 6 hours of symptom onset. This is also true for subgroups and the prevention of alteplase-associated hemorrhage.</p&gt

Axion Dissipation Through the Mixing of Goldstone Bosons

By coupling axions strongly to a hidden sector, the energy density in coherent axions may be converted to radiative degrees of freedom, alleviating the ``axion energy crisis''. The strong coupling is achieved by mixing the axion and some other Goldstone boson through their kinetic energy terms, in a manner reminiscent of paraphoton models. Even with the strong coupling it proves difficult to relax the axion energy density through particle absorption, due to the derivative nature of Goldstone boson couplings and the effect of back reactions on the evolution of the axion number density. However, the distribution of other particle species in the hidden sector will be driven from equilibrium by the axion field oscillations. Restoration of thermal equilibrium results in energy being transferred from the axions to massless particles, where it can redshift harmlessly without causing any cosmological problems.Comment: 20 pages, Latex, (3 uuencoded compressed tarred postscript figures attached

Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: the CHANT trial

<p><b>Background and Purpose:</b> NXY-059 is a free radical-trapping neuroprotectant developed for use in acute ischemic stroke. To facilitate prompt administration of treatment, potentially before neuroimaging, we investigated the safety of NXY-059 in patients with intracerebral hemorrhage (ICH).</p> <p><b>Methods:</b> We randomized 607 patients within 6 hours of acute ICH to receive 2270 mg intravenous NXY-059 over 1 hour and then up to 960 mg/h over 71 hours, or matching placebo, in addition to standard care. The primary outcome was safety: the mortality and the frequency of adverse events, and the change from baseline for a variety of serum, imaging, and electrophysiological measurements. We also studied the overall distribution of disability scores on the modified Rankin Scale (mRS) and the Barthel index.</p> <p><b>Results:</b> We treated 300 patients with NXY-059 and 303 with placebo. Treatment groups were well matched for prognostic variables including Glasgow Coma Scale, risk factors, and age. The mean National Institute of Health Stroke Scale score on admission was 14 in both groups. The baseline hemorrhage volume was 22.4±20.1 mL in the NXY-059 group and 23.3±22.8 mL in the placebo group (mean±SD). Most hemorrhages were related to hypertension or anticoagulant use. Mortality was similar in both groups: 20.3% for NXY-059 and 19.8% for placebo-treated patients. The proportion of patients who experienced an adverse event was the same for both groups, whereas for serious adverse events the proportion was slightly higher in the NXY-059 group. However, no pattern emerged to indicate a safety concern. Serum potassium fell transiently in both groups, lower in the NXY-059 group. There were no differences in 3-month function, disability, or neurological deficit scores. The odds ratio for an improved outcome in 3-month mRS scores in the NXY-059 group was 1.01 (95% CI 0.75, 1.35).</p> <p><b>Conclusions:</b> NXY-059 given within 6 hours of acute ICH has a good safety and tolerability profile, with no adverse effect on important clinical outcomes.</p&gt