The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders

Acord transformatiu CRUE-CSICThis work was supported by an NIHR Professorship (to M.A.K.). M.A.K. has received funding from the Sir Jules Thorn Award for Biomedical Research and Wellcome Trust. B.P.-D. was supported by Instituto de Salud Carlos III, PI 18/01319 and PI21/00248, and has received funding from Beca José Castillejos (CAS14/00328). K.J.P. was supported by an MRC Clinician-Scientist Fellowship (511015) and was supported by the Dystonia Medical Research Foundation and Fight for Sight. S.S.M. has received funding from the Winston Churchill Memorial trust and Cerebral Palsy Alliance.Background and Objective: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders. Methods: Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria. Results: One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders; and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P < 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia. Conclusions: This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

A Survey on Multithreading Alternatives for Soft Error Fault Tolerance

Smaller transistor sizes and reduction in voltage levels in modern microprocessors induce higher soft error rates. This trend makes reliability a primary design constraint for computer systems. Redundant multithreading (RMT) makes use of parallelism in modern systems by employing thread-level time redundancy for fault detection and recovery. RMT can detect faults by running identical copies of the program as separate threads in parallel execution units with identical inputs and comparing their outputs. In this article, we present a survey of RMT implementations at different architectural levels with several design considerations. We explain the implementations in seminal papers and their extensions and discuss the design choices employed by the techniques. We review both hardware and software approaches by presenting the main characteristics and analyze the studies with different design choices regarding their strengths and weaknesses. We also present a classification to help potential users find a suitable method for their requirement and to guide researchers planning to work on this area by providing insights into the future trend

Predicting the Soft Error Vulnerability of Parallel Applications Using Machine Learning

With the widespread use of the multicore systems having smaller transistor sizes, soft errors become an important issue for parallel program execution. Fault injection is a prevalent method to quantify the soft error rates of the applications. However, it is very time consuming to perform detailed fault injection experiments. Therefore, prediction-based techniques have been proposed to evaluate the soft error vulnerability in a faster way. In this work, we present a soft error vulnerability prediction approach for parallel applications using machine learning algorithms. We define a set of features including thread communication, data sharing, parallel programming, and performance characteristics; and train our models based on three ML algorithms. This study uses the parallel programming features, as well as the combination of all features for the first time in vulnerability prediction of parallel programs. We propose two models for the soft error vulnerability prediction: (1) A regression model with rigorous feature selection analysis that estimates correct execution rates, (2) A novel classification model that predicts the vulnerability level of the target programs. We get maximum prediction accuracy rate of 73.2% for the regression-based model, and achieve 89% F-score for our classification model

Efficient selective replication of critical code regions for SDC mitigation leveraging redundant multithreading

Redundant multithreading (RMT) is an effective reliability solution that provides thread-level replication; however, it imposes additional overheads in terms of performance loss or energy consumption. Partial-RMT is an alternative solution that provides partial redundancy of an executing thread to reduce such overheads while trading off full coverage from faults. In this study, we propose a software-level RMT approach that offers lightweight replication of partial code regions within the same application process. Our software-level RMT approach is particularly suitable for applications with varying code criticality, where we determine the critical code regions by performing a fault injection campaign in addition to execution time profile analysis. Using the results of the previous step, the application programmer annotates the source code to indicate the specific code regions that should be executed redundantly without re-implementing the application program from scratch. Our lightweight software-level RMT tool improves the average silent data corruption (SDC) rate of 30 applications of the PolyBench benchmark suite by around 7.6x with average performance and energy consumption overheads of 22 and 37%, respectively, compared to the original version of the program

Treatment of Chorea in Childhood

WOS: 000509628500003PubMed: 31604647Chorea is a movement disorder characterized by ongoing random-appearing sequences of discrete involuntary movements or movement fragments. Chorea results from dysfunction of the complex neuronal networks that interconnect the basal ganglia, thalamus, and related frontal lobe cortical areas. the complexity of basal ganglia circuitry and vulnerability of those circuits to injury explains why chorea results from a wide variety of conditions. Because etiology-specific treatments or effective symptomatic treatments are available for causes of chorea, defining the underlying disease is important. the treatment of chorea can be considered in three main categories: (1) terminating or modifying exposure to the causative agent, (2) symptomatic treatment of chorea, and (3) treatment targeting the underlying etiology. Symptomatic treatment decision of chorea should be based on the functional impact on the child caused by chorea itself. There have been no reported randomized, placebo-controlled trials of symptomatic treatment for chorea in childhood. Thus the recommendations are based on clinical experience, case reports, expert opinions, and small comparative studies. Better knowledge of mechanisms underlying childhood chorea will provide more etiology-based treatments in the future. (C) 2019 Elsevier Inc. All rights reserved

A selective protection scheme of applications using asymmetrically reliable caches

Cache structures in a multicore system are highly vulnerable to soft errors. Enabling fault tolerance capabilities on all cache structures in a system is inefficient in terms of performance and power consumption. In this study, we propose an enhanced protection mechanism for code segments, which are critical in terms of reliability, by utilizing asymmetrically reliable cores under performance and power constraints. Our proposed system contains at least one high-reliability core, which has an ECC-protected L1 cache, and several low-reliability cores, which have no protection mechanisms. Reliability-based critical code regions are assumed to be high-priority functions, which are extracted by examining the execution time percentages and the program's call graph in our framework, statically. Software threads that invoke one of the high-priority functions are bound to the high-reliability cores dynamically during the execution, while the threads that execute the remaining functions are bound to the low-reliability cores. As part of the experimental analysis, our proposed framework is compared with traditional fully protected and unprotected configurations with respect to performance, power and reliability metrics for various applications of the benchmarks. Our framework exploits the benefits of providing the reliability-based critical regions of the applications exclusively by offering notable power and cost savings with close performance and reliability values for the set of functions reported in the experimental results. (C) 2016 Elsevier B.V. All rights reserved

Scheduling opportunities for asymmetrically reliable caches

Modern systems become more vulnerable to soft errors with technology scaling. Providing fault tolerance strategies on all structures in a system may lead to high energy consumption. Our framework with asymmetrically reliable caches with at least one protected core and several unprotected cores dynamically assigns the software threads executing critical code fragments to the protected core(s) with the FCFS-based algorithm. The framework can provide good reliability, performance, and power consumption trade-offs compared with the fully protected and unprotected systems. However, FCFS-based scheduling algorithm may degrade the system performance and unfairly slow down applications for some workloads. In this paper, a set of scheduling algorithms is proposed to improve both the system performance and fairness perspectives. Various static priority techniques that require preliminary information about the applications (such as their execution order, cache usage, number of requests sent to the protected core(s), and total burst time spent on the protected core(s)) are implemented and evaluated. On the other hand, dynamic priority techniques that target to equalize the total time spent of applications on the protected core(s) or the progress of the applications' requests are presented. Extensive evaluations using multi application workloads validate significant improvements of our static and dynamic priority scheduling techniques on system performance and fairness over the FCFS algorithm. (C) 2019 Elsevier Inc. All rights reserved

Protecting code regions on asymmetrically reliable caches

Cache structures in a multicore system are considerably susceptible to soft errors. Protecting all caches using fault tolerance techniques has notable overheads on performance and power consumption. In this paper, we propose an enhanced protection mechanism for reliabilitybased critical code regions of the applications on asymmetrically reliable cores which have different error-tolerant cache structures. In this system, software threads which execute reliability-based critical code regions are mapped onto the protected cores, whereas the threads which execute noncritical regions are mapped to the unprotected ones, dynamically during the execution. Our experimental evaluations indicate that the proposed system improves Silent Data Corruption (SDC) rate by 66% with 22% performance loss and 1.2% more power consumption for selected applications relative to the unprotected caches on average. © Springer International Publishing Switzerland 2016