A practical WSI experimental programme

At Brunel University, research has been underway for several years to assess the architectural, electrical and physical benefits and constraints of the WASP wafer-scale Associative String Processor (ASP). This is intended to implement a massively parallel processor entirely within the constraints of WSI. WASP 1 and WASP 2 were the technology demonstrators of the UK funded Alvey programme (starting 1984), researching fundamental design methodologies for WSI. They are both examples of the Associative String Processor (ASP) architecture, developed by Brunel University. Further demonstrators are currently funded by a 31/2-year US ONR IS&T programme (starting 1987), involving both further technology demonstration, applications research and fundamental packaging and manufacturing design issue

Allelic Origin of Protease-Sensitive and Protease-Resistant Prion Protein Isoforms in Gerstmann-Sträussler-Scheinker Disease with the P102L Mutation

Gerstmann-Sträussler-Scheinker (GSS) disease is a dominantly inherited prion disease associated with point mutations in the Prion Protein gene. The most frequent mutation associated with GSS involves a proline-to-leucine substitution at residue 102 of the prion protein, and is characterized by marked variability at clinical, pathological and molecular levels. Previous investigations of GSS P102L have shown that disease-associated pathological prion protein, or PrPSc, consists of two main conformers, which under exogenous proteolysis generates a core fragment of 21 kDa and an internal fragment of 8 kDa. Both conformers are detected in subjects with spongiform degeneration, whereas only the 8 kDa fragment is recovered in cases lacking spongiosis. Several studies have reported an exclusive derivation of protease-resistant PrPSc isoforms from the mutated allele; however, more recently, the propagation of protease-resistant wild-type PrPSc has been described. Here we analyze the molecular and pathological phenotype of six GSS P102L cases characterized by the presence of 21 and 8 kDa PrP fragments and two subjects with only the 8 kDa PrP fragment. Using sensitive protein separation techniques and Western blots with antibodies differentially recognizing wild-type and mutant PrP we observed a range of PrPSc allelic conformers, either resistant or sensitive to protease treatment in all investigated subjects. Additionally, tissue deposition of protease-sensitive wild-type PrPSc molecules was seen by conventional PrP immunohistochemistry and paraffin-embedded tissue blot. Our findings enlarge the spectrum of conformational allelic PrPSc quasispecies propagating in GSS P102L thus providing a molecular support to the spectrum of disease phenotypes, and, in addition, impact the diagnostic role of PrP immunohistochemistry in prion diseases

Physical activity assessment by accelerometry in people with heart failure

Background: International guidelines for physical activity recommend at least 150 min per week of moderate-to-vigorous physical activity (MVPA) for adults, including those with cardiac disease. There is yet to be consensus on the most appropriate way to categorise raw accelerometer data into behaviourally relevant metrics such as intensity, especially in chronic disease populations. Therefore the aim of this study was to estimate acceleration values corresponding to inactivity and MVPA during daily living activities of patients with heart failure (HF), via calibration with oxygen consumption (VO2) and to compare these values to previously published, commonly applied PA intensity thresholds which are based on healthy adults. Methods: Twenty-two adults with HF (mean age 71 ± 14 years) undertook a range of daily living activities (including laying down, sitting, standing and walking) whilst measuring PA via wrist- and hip-worn accelerometers and VO2 via indirect calorimetry. Raw accelerometer output was used to compute PA in units of milligravity (mg). Energy expenditure across each of the activities was converted into measured METs (VO2/resting metabolic rate) and standard METs (VO2/3.5 ml/kg/min). PA energy costs were also compared with predicted METs in the compendium of physical activities. Location specific activity intensity thresholds were established via multilevel mixed effects linear regression and receiver operator characteristic curve analysis. A leave-one-out method was used to cross-validate the thresholds. Results: Accelerometer values corresponding with intensity thresholds for inactivity ( 50% lower than previously published intensity thresholds for both wrists and waist accelerometers (inactivity: 16.7 to 18.6 mg versus 45.8 mg; MVPA: 43.1 to 49.0 mg versus 93.2 to 100 mg). Measured METs were higher than both standard METs (34-35%) and predicted METs (45-105%) across all standing and walking activities. Conclusion: HF specific accelerometer intensity thresholds for inactivity and MVPA are lower than previously published thresholds based on healthy adults, due to lower resting metabolic rate and greater energy expenditure during daily living activities for HF patients. Trial registration: Clinical trials.gov NCT03659877, retrospectively registered on September 6th 2018.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This study was undertaken as part of a PhD, which was funded by a University of Exeter Postgraduate Studentship Grant. The funders were not involved in design of the study, data collection, analysis, and interpretation of data, and in writing the manuscript.published version, accepted versio

Biochemical components of wild relatives of chickpea confer resistance to pod borer, Helicoverpa armigera

Efforts are being made to develop chickpea varieties with resistance to the pod borer, Helicoverpa armigera for reducing pesticide use and minimizing the extent of losses due to this pest. However, only low to moderate levels of resistance have been observed in the cultivated chickpea to this polyphagous pest. Hence, it is important to explore wild relatives as resistance sources to develop insect-resistant cultivars. Therefore, we studied different biochemical components that confer resistance to H. armigera in a diverse array of wild relatives of chickpea. Accessions belonging to wild relatives of chickpea exhibited high levels of resistance to H. armigera as compared to cultivated chickpea genotypes in terms of lower larval survival, pupation and adult emergence, decreased larval and pupal weights, prolonged larval and pupal developmental periods and reduced fecundity of the H. armigera when reared on artificial diet impregnated with lyophilized leaf powders. Amounts of proteins and phenols in different accessions of chickpea wild relatives were significantly and negatively correlated with larval weight, pupation and adult emergence. Phenols showed a negative correlation with pupal weight and fecundity, but positive correlation with pupal period. Total soluble sugars showed a negative correlation with larval period, but positive correlation with pupation and pupal weight, while tannins showed a positive correlation with larval weight, pupation and adult emergence. The flavonoid compounds such as chlorogenic acid, ferulic acid, naringin, 3,4-dihydroxy flavones, quercetin, naringenin, genistein, biochanin-A and formononetin that were identified through HPLC fingerprints, exhibited negative effects on survival and development of H. armigera reared on artificial diet impregnated with lyophilized leaf powders. The wild relatives with diverse mechanisms of resistance conferred by different biochemical components can be used as sources of resistance in chickpea breeding programs to develop cultivars with durable resistance to H. armigera for sustainable crop production

Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19

Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI 90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT0437258

A Human Factors Engineering Perspective to Aging and Work

This chapter examines aging and work from the perspectives of two interrelated scientific disciplines—human factors and ergonomics—which concern understanding the interactions among humans and various other elements of a system. These fields apply theories, principles, tools, and methods toward design solutions with the objective of optimizing human well-being and overall system performance while ensuring compatibility in the design of interactive systems involving people, devices, and environments. In this chapter, four broad topics related to the employability of older workers are examined: macroergonomics and sociotechnical system design; physical work demands; changes in work configuration and job selection; and technology, the future of work, and cognitive work demands