454 research outputs found
Uncovering spatiotemporal patterns of atrophy in progressive supranuclear palsy using unsupervised machine learning
No full textData availability: Source data are not publicly available but non-commercial academic researcher requests may be made to the chief investigators of the seven source studies, subject to data access agreements and conditions that preserve participant anonymity. The underlying SuStaIn model code is publicly available at https://github.com/ucl-pond/pySuStaIn.68 .Supplementary data: available online at: https://academic.oup.com/braincomms/article/5/2/fcad048/7067775#398676040 .Copyright © The Author(s) 2023. To better understand the pathological and phenotypic heterogeneity of progressive supranuclear palsy and the links between the two, we applied a novel unsupervised machine learning algorithm (Subtype and Stage Inference) to the largest MRI data set to date of people with clinically diagnosed progressive supranuclear palsy (including progressive supranuclear palsy–Richardson and variant progressive supranuclear palsy syndromes).
Our cohort is comprised of 426 progressive supranuclear palsy cases, of which 367 had at least one follow-up scan, and 290 controls. Of the progressive supranuclear palsy cases, 357 were clinically diagnosed with progressive supranuclear palsy–Richardson, 52 with a progressive supranuclear palsy–cortical variant (progressive supranuclear palsy–frontal, progressive supranuclear palsy–speech/language, or progressive supranuclear palsy–corticobasal), and 17 with a progressive supranuclear palsy–subcortical variant (progressive supranuclear palsy–parkinsonism or progressive supranuclear palsy–progressive gait freezing). Subtype and Stage Inference was applied to volumetric MRI features extracted from baseline structural (T1-weighted) MRI scans and then used to subtype and stage follow-up scans. The subtypes and stages at follow-up were used to validate the longitudinal consistency of subtype and stage assignments. We further compared the clinical phenotypes of each subtype to gain insight into the relationship between progressive supranuclear palsy pathology, atrophy patterns, and clinical presentation.
The data supported two subtypes, each with a distinct progression of atrophy: a ‘subcortical’ subtype, in which early atrophy was most prominent in the brainstem, ventral diencephalon, superior cerebellar peduncles, and the dentate nucleus, and a ‘cortical’ subtype, in which there was early atrophy in the frontal lobes and the insula alongside brainstem atrophy. There was a strong association between clinical diagnosis and the Subtype and Stage Inference subtype with 82% of progressive supranuclear palsy–subcortical cases and 81% of progressive supranuclear palsy–Richardson cases assigned to the subcortical subtype and 82% of progressive supranuclear palsy–cortical cases assigned to the cortical subtype. The increasing stage was associated with worsening clinical scores, whilst the ‘subcortical’ subtype was associated with worse clinical severity scores compared to the ‘cortical subtype’ (progressive supranuclear palsy rating scale and Unified Parkinson’s Disease Rating Scale). Validation experiments showed that subtype assignment was longitudinally stable (95% of scans were assigned to the same subtype at follow-up) and individual staging was longitudinally consistent with 90% remaining at the same stage or progressing to a later stage at follow-up.
In summary, we applied Subtype and Stage Inference to structural MRI data and empirically identified two distinct subtypes of spatiotemporal atrophy in progressive supranuclear palsy. These image-based subtypes were differentially enriched for progressive supranuclear palsy clinical syndromes and showed different clinical characteristics. Being able to accurately subtype and stage progressive supranuclear palsy patients at baseline has important implications for screening patients on entry to clinical trials, as well as tracking disease progression.W.J.S. is supported by a Wellcome Trust Clinical PhD fellowship (220582/Z/20/Z). C.S. is supported by the UK Research and Innovation Medical Research Council (MR/S03546X/1). M.B. is supported by a fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517), and the UK Dementia Research Institute. D.M.C. is supported by the UK Dementia Research Institute, as well as Alzheimer’s Research UK (ARUK-PG2017-1946), and the University College London/University College London Hospitals, National Institute for Health and Care Research Biomedical Research Centre. H.H. is supported by the National Institutes of Health (R01AG038791, U19AG063911). A.L.Y. is supported by a Skills Development Fellowship from the Medical Research Council (MR/T027800/1). N.P.O. is a UK Research and Innovation Future Leaders Fellow (MR/S03546X/1). L.V.V. is supported by the National Institutes of Health (R01AG038791, K23AG073514) and the Alzheimer’s Association. D.C.A. is supported by the Engineering and Physical Sciences Research Council (EP/M020533/1), Medical Research Council (MR/T046422/1), and Wellcome Trust (UNS113739). J.B.R. is supported by the Wellcome Trust (220258), National Institute for Health and Care Research Cambridge Biomedical Research Centre (BRC-1215-20014), PSP Association, Evelyn Trust, and Medical Research Council (SUAG051 R101400). H.R.M. is supported by Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, CBD Solutions, Drake Foundation, Medical Research Council, and the Michael J Fox Foundation. A.L.B. is supported by the National Institutes of Health (U19AG063911, R01AG038791, R01AG073482, and U24AG057437), the Rainwater Charitable Foundation, the Bluefield Project to Cure FTD, and the Alzheimer’s Association and the Association for Frontotemporal Degeneration. J.D.R. is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from a Medical Research Council Clinician Scientist Fellowship (MR/M008525/1) and the National Institute for Health and Care Research Rare Disease Translational Research Collaboration (BRC149/NS/MH). P.A.W. is supported by a Medical Research Council Skills Development Fellowship (MR/T027770/1).
The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK. The PROSPECT study is funded by the PSP Association and CBD Solutions. The 4-Repeat Tauopathy Neuroimaging Initiative (4RTNI) and FTLDNI are funded by the National Institutes of Health Grant (R01 AG038791) and through generous contributions from the Tau Research Consortium. Both are coordinated through the University of California, San Francisco, Memory and Aging Center. 4RTNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California
Research on the evolutionary game of safety behavior of EPC consortium members based on prospect theory
No full textIn recent years, the consortium, composed of the design enterprise, construction enterprise, and supplier, has witnessed rapid development in implementing the EPC project model in China. However, there are conflicts of interest and ambiguous safety management among EPC consortium members, leading to accidents. This study aims to explore the decision-making process regarding different safety behavior strategies among EPC consortium members. Given the uncertainty of the EPC project environment, consortium members show risk preferences and perceptual biases. Prospect theory reveals the irrational elements in the decision-making process. Therefore, this study incorporates prospect theory, constructs a safety behavior perception payoff matrix and an evolutionary game model involving design enterprise, construction enterprise, and supplier as the primary stakeholders, analyzes the interactive mechanisms of safety behavior among the three parties, and uses MATLAB simulation to explain the evolutionary path of behavioral strategies under varying parameters. The consequence indicates that the optimal strategy’s stable state in the safety behavior evolution system of EPC consortium members is affected by the players’ cognitive biases and risk preferences, and the costs of safety input, punishment intensity, and accident losses. This study mainly provides theoretical evidence and decision support for safety control activities among EPC consortium members
Improving the effectiveness of active safety systems to significantly reduce accidents with vulnerable road users - the project PROSPECT (Proactive Safety for Pedestrians and Cyclists)
No full textAccidents involving Vulnerable Road Users (VRU) are still a very significant issue for road safety. ́PROactive Safety for PEdestrians and CyclisTs ́ is a collaborative research project funded by the European Commission. The objective of PROSPECT was to improve significantly the effectiveness of active VRU safety systems compared to those currently on the market by: (i) expanding the scope of urban scenarios addressed (ii) improving the overall Autonomous Emergency Braking (AEB) and Autonomous Emergency Steering (AES) system performance (iii) proposing extensive validation methodologies for consumer testing, simulation and acceptance studies with tools for testing. Concepts for sensors and control systems were shown in three vehicle demonstrators and a mobile driving simulator and tested with novel VRU dummy specimen. Those systems address the well-known barriers of current AEB systems such as limited sensors field-of-view, fuzzy path prediction, unreliable intent recognition and slow reaction times for the actuation. User acceptance tests with the participation of drivers were also crucial in PROSPECT for the success of all active safety systems. Driving simulator studies were then used in a controlled and repeatable environment for the collection of data regarding the interaction between the driver and the safety function. Finally, project consortium implemented a novel benefit estimation methodology that includes an assessment of the combined effect of active and passive safety measures of PROSPECT-like systems
Genome-wide association study identifies eight loci associated with blood pressure
No full textElevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and <i>in silico</i> comparison (CHARGE consortium, N= 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10<sup>−24</sup>), CYP1A2 (P = 1 × 10<sup>−23</sup>), FGF5 (P = 1 × 10<sup>−21</sup>), SH2B3 (P = 3 × 10<sup>−18</sup>), MTHFR (P = 2 × 10<sup>−13</sup>), c10orf107 (P = 1 × 10<sup>−9</sup>), ZNF652(P = 5 × 10<sup>−9</sup>) and PLCD3 (P = 1 × 10<sup>−8</sup>) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease
Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
No full textThe Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.Peer reviewe
Offering Role Mobility in a TINA Environment
No full textThis paper presents the concept of role mobility and the value of role mobility in an open service environment. We outline the aspects of role management and role mobility and we describe an open, reusable component for role management. Then, we show how this component can be deployed in a TINA environment with a minimum number of changes to the TINA service architecture
Understanding the Impact of TNC Pricing Strategies on the Prospect of Transit Agency-TNC Partnerships
No full text69A3551747110Transportation network company (TNC) trip prices have fluctuated significantly higher than they were two years ago, causing concerns about existing and planned partnerships between public transit agencies and private mobility service providers. This project explored three scenarios of future TNC price changes: (1) price trend extension based on forecasting models, (2) price increases in response to local policy changes, and (3) TNC/taxi price convergence due to increased competition. We then assessed the impacts of the price changes from each scenario on the prospect of transit agency-TNC partnerships, using a planned same-day-service (SDS) paratransit pilot project in the Seattle region as a case study. For the first scenario, we employed two time-series models, namely ARIMA and PROPHET, to forecast price changes within the next three years (October 2022- October 2025) based on publicly available TNC trip data from Chicago. The results showed that TNCs\u2019 daily average price would reach up to $3.23 per mile, increasing by 40 percent from 2019 average rates. For the second scenario, we tracked significant policies that directly affected TNC prices in Seattle and incorporated reported price increases
Making interactive TV easier to use : interface design for a second screen approach
No full textInteractive television (iTV) has the potential to revolutionize the way we consume broadcast media, but users still find both the notion of iTV and the services currently available problematic. This paper describes a project that investigates a representative group of users' aspirations, and barriers to iTV service engagement in the UK. This primary research informed the development of new User Interface (UI) and service solutions that addressed these barriers. Specifically, a second screen solution was developed to remove the need for iTV services to use on-screen graphics, dramatically improving the possibilities for effective interaction and navigation for iTV interfaces and services. The effectiveness of these solutions was evaluated through the testing of these new iTV services in a representative group of family homes
Characterization of sites of scientific interest for ESA's PROSPECT instrument
No full textMany upcoming lunar missions and payloads are targeting the south pole of the Moon, due to the volatiles potentially harboured in this region including ESA's PROSPECT instrument. PROSPECT is designed to sample the lunar regolith within the first meter of the surface and to analyse any volatiles found. Remote sensing methods and a range of datasets including thermal models, illumination models, LRO NAC images, LOLA DEMs and LRO NAC DEMs generated with shape-from-shading, were used to identify suitable areas for PROSPECT science within the south polar region (84–90°S). Sites identified were down selected using a science matrix and scoring sites of interest based on if and how well the point of interest met the science requirements of PROSPECT. The highest scoring sites are presented and proposed to be ideal candidate landing sites for missions targeting the lunar south polar region, especially for missions that are interested in sampling volatiles, micro cold traps and Permanently Shaded Regions (PSRs). Understanding and sampling these colder areas within the south polar region will advance the understanding of volatiles within the lunar surface and volatile transfer
A generic component for managing service roles
No full textThere are a number of architectures that describe how service providers can provide telecommunications services to their customers. Architectures like TINA address service control and service management issues for communication exchanges among human service users. n this paper we point out the importance of role-based exchanges in a telecommunications environment and we present a generic component that provides role management. We describe how this component was implemented and integrated in a TINA-like environment. We also describe why a role can be modelled as a mobile entity and how role mobility relates to role management. Finally, some conclusions are drawn
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