Genome-wide association study of behavioural and psychiatric features in human prion disease.

Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10(-5)) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves

The Quality of Life scale for Children (QoL-C)

This is the author's version of the article, which has been published in final form at http://dx.doi.org/10.1108/JCS-05-2013-0019Purpose – There is a lack of valid and reliable generic measures of Health-Related Quality of Life (HRQoL) for children under eight. The purpose of this paper is to assess the psychometric properties of the newly formulated Quality of Life Scale for Children (QoL-C), which uses a pictorial response format. Design/methodology/approach – In total, 335 primary school children completed the QoL-C on two occasions, two weeks apart. Children aged four to seven were interviewed one-to-one while children aged eight to nine completed the measure as a class activity. Test-re-test reliability, convergent validity and child-parent concordance were assessed. Findings – Only one child refused to complete the QoL-C, which suggests the measure is user-friendly. Test-re-test reliability was moderate for the measure's total score (intraclass correlation coefficient =0.48, 95 percent CI 0.39, 0.57) but low to fair for individual items (K from 0.13 to 0.37). Internal consistency was moderate (α=0.42 time one, 0.53 time two). A small significant correlation was found between the QoL-C and Child Health Meter in the expected direction (r=−0.32), suggesting convergent validity. There was low concordance between the children's QoL-C responses and parent's responses (r=0.19) to a parallel measure. Research limitations/implications – The results suggest that further development of this measure is needed. However, the findings indicate that one-to-one support increases the reliability of very young children's responses. The use of pictures, emoticons and minimal text used in the QoL-C should be investigated further. Originality/value – Low parent-child concordance underscores the importance of younger children getting the opportunity to share their views about their HRQoL

Start-to-end modelling of a mode-locked optical klystron free electron laser amplifier

A free electron laser (FEL) in a mode-locked optical klystron (MLOK) configuration is modelled using start-to-end simulations that simulate realistic electron beam acceleration and transport before input into a full three-dimensional FEL simulation code. These simulations demonstrate that the MLOK scheme is compatible with the present generation of radiofrequency accelerator designs. A train of few-optical cycle pulses is predicted with peak powers similar to those of the equivalent conventional FEL amplifier. The role of electron beam energy modulation in these results is explained and the limitations of some simulation codes discussed. It is shown how seeding the FEL interaction using a High Harmonic seed laser can improve the coherence properties of the output

Uncertainty assessment in river flow projections for Ethiopia’s Upper Awash Basin using multiple GCMs and hydrological models

Uncertainty in climate change impacts on river discharge in the Upper Awash Basin, Ethiopia, is assessed using five MIKE SHE hydrological models, six CMIP5 general circulation models (GCMs) and two representative concentration pathways (RCP) scenarios for the period 2071–2100. Hydrological models vary in their spatial distribution and process representations of unsaturated and saturated zones. Very good performance is achieved for 1975–1999 (NSE: 0.65–0.8; r: 0.79–0.93). GCM-related uncertainty dominates variability in projections of high and mean discharges (mean: –34% to +55% for RCP4.5,–2% to +195% for RCP8.5). Although GCMs dominate uncertainty in projected low flows, inter-hydrological model uncertainty is considerable (RCP4.5: –60% to +228%, RCP8.5: –86% to +337%). Analysis of variance uncertainty attribution reveals that GCM-related uncertainty occupies, on average, 68% of total uncertainty for median and high flows and hydrological models no more than 1%. For low flows, hydrological model uncertainty occupies, on average, 18% of total uncertainty; GCM-related uncertainty remains substantial (average: 28%)

Quantitative EEG parameters correlate with the progression of human prion diseases

BACKGROUND: Prion diseases are universally fatal and often rapidly progressive neurodegenerative diseases. EEG has long been used in the diagnosis of sporadic Creutzfeldt-Jakob disease; however, the characteristic waveforms do not occur in all types of prion diseases. Here, we re-evaluate the utility of EEG by focusing on the development of biomarkers. We test whether abnormal quantitative EEG parameters can be used to measure disease progression in prion diseases or predict disease onset in healthy individuals at risk of disease. METHODS: In the National Prion Monitoring Cohort study, we did quantitative encephalography on 301 occasions in 29 healthy controls and 67 patients with prion disease. The patients had either inherited prion disease or sporadic Creutzfeldt-Jakob disease. We computed the main background frequency, the α and θ power and the α/θ power ratio, then averaged these within 5 electrode groups. These measurements were then compared among participant groups and correlated with functional and cognitive scores cross-sectionally and longitudinally. RESULTS: We found lower main background frequency, α power and α/θ power ratio and higher θ power in patients compared to control participants. The main background frequency, the power in the α band and the α/θ power ratio also differed in a consistent way among the patient groups. Moreover, the main background frequency and the α/θ power ratio correlated significantly with functional and cognitive scores. Longitudinally, change in these parameters also showed significant correlation with the change in clinical and cognitive scores. CONCLUSIONS: Our findings support the use of quantitative EEG to follow the progression of prion disease, with potential to help evaluate the treatment effects in future clinical-trials

Evolution of Diffusion-Weighted Magnetic Resonance Imaging Signal Abnormality in Sporadic Creutzfeldt-Jakob Disease, With Histopathological Correlation

IMPORTANCE: Prion diseases represent the archetype of brain diseases caused by protein misfolding, with the most common subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. Diffusion-weighted imaging (DWI) has emerged as the most sensitive magnetic resonance imaging (MRI) sequence for the diagnosis of sCJD, but few studies have assessed the evolution of MRI signal as the disease progresses. OBJECTIVES: To assess the natural history of the MRI signal abnormalities on DWI in sCJD to improve our understanding of the pathogenesis and to investigate the potential of DWI as a biomarker of disease progression, with histopathological correlation. DESIGN, SETTING, AND PARTICIPANTS: Gray matter involvement on DWI was assessed among 37 patients with sCJD in 26 cortical and 5 subcortical subdivisions per hemisphere using a semiquantitative scoring system of 0 to 2 at baseline and follow-up. A total brain score was calculated as the summed scores in the individual regions. In 7 patients, serial mean diffusivity measurements were obtained. Age at baseline MRI, disease duration, atrophy, codon 129 methionine valine polymorphism, Medical Research Council Rating Scale score, and histopathological findings were documented. The study setting was the National Prion Clinic, London, England. All participants had a probable or definite diagnosis of sCJD and had at least 2 MRI studies performed during the course of their illness. The study dates were October 1, 2008 to April 1, 2012. The dates of our analysis were January 19 to April 20, 2012. MAIN OUTCOMES AND MEASURES: Correlation of regional and total brain scores with disease duration. RESULTS: Among the 37 patients with sCJD in this study there was a significant increase in the number of regions demonstrating signal abnormality during the study period, with 59 of 62 regions showing increased signal intensity (SI) at follow-up, most substantially in the caudate and putamen (P < .001 for both). The increase in the mean (SD) total brain score from 30.2 (17.3) at baseline to 40.5 (20.6) at follow-up (P = .001) correlated with disease duration (r = 0.47, P = .003 at baseline and r = 0.35, P = .03 at follow-up), and the left frontal SI correlated with the degree of spongiosis (r = 0.64, P = .047). Decreased mean diffusivity in the left caudate at follow-up was seen (P < .001). Eight patients demonstrated decreased SI in cortical regions, including the left inferior temporal gyrus and the right lingual gyrus. CONCLUSIONS AND RELEVANCE: Magnetic resonance images in sCJD show increased extent and degree of SI on DWI that correlates with disease duration and the degree of spongiosis. Although cortical SI may fluctuate, increased basal ganglia SI is a consistent finding and is due to restricted diffusion. Diffusion-weighted imaging in the basal ganglia may provide a noninvasive biomarker in future therapeutic trials

Ion rocket engine development Quarterly report no. 3, 1 Apr. - 30 Jun. 1965

Integral focus cesium contact ion rocket engine and iridium and rhenium coated porous tungsten ionizer evaluation

Effect of time and day of admission on hospital care quality for patients with chronic obstructive pulmonary disease exacerbation in England and Wales: single cohort study

OBJECTIVE: To evaluate if observed increased weekend mortality was associated with poorer quality of care for patients admitted to hospital with chronic obstructive pulmonary disease (COPD) exacerbation. DESIGN: Prospective case ascertainment cohort study. SETTING: 199 acute hospitals in England and Wales, UK. PARTICIPANTS: Consecutive COPD admissions, excluding subsequent readmissions, from 1 February to 30 April 2014 of whom 13 414 cases were entered into the study. MAIN OUTCOMES: Process of care mapped to the National Institute for Health and Care Excellence clinical quality standards, access to specialist respiratory teams and facilities, mortality and length of stay, related to time and day of the week of admission. RESULTS: Mortality was higher for weekend admissions (unadjusted OR 1.20, 95% CI 1.00 to 1.43), and for case-mix adjusted weekend mortality when calculated for admissions Friday morning through to Monday night (adjusted OR 1.19, 95% CI 1.00 to 1.43). Median time to death was 6 days. Some clinical processes were poorer on Mondays and during normal working hours but not weekends or out of hours. Specialist respiratory care was less available and less prompt for Friday and Saturday admissions. Admission to a specialist ward or high dependency unit was less likely on a Saturday or Sunday. CONCLUSIONS: Increased mortality observed in weekend admissions is not easily explained by deficiencies in early clinical guideline care. Further study of out-of-hospital factors, specialty care and deaths later in the admission are required if effective interventions are to be made to reduce variation by day of the week of admission