Automated and foundational verification of low-level programs

Formal verification is a promising technique to ensure the reliability of low-level programs like operating systems and hypervisors, since it can show the absence of whole classes of bugs and prevent critical vulnerabilities. However, to realize the full potential of formal verification for real-world low-level programs one has to overcome several challenges, including: (1) dealing with the complexities of realistic models of real-world programming languages; (2) ensuring the trustworthiness of the verification, ideally by providing foundational proofs (i.e., proofs that can be checked by a general-purpose proof assistant); and (3) minimizing the manual effort required for verification by providing a high degree of automation. This dissertation presents multiple projects that advance formal verification along these three axes: RefinedC provides the first approach for verifying C code that combines foundational proofs with a high degree of automation via a novel refinement and ownership type system. Islaris shows how to scale verification of assembly code to realistic models of modern instruction set architectures-in particular, Armv8-A and RISC-V. DimSum develops a decentralized approach for reasoning about programs that consist of components written in multiple different languages (e.g., assembly and C), as is common for low-level programs. RefinedC and Islaris rest on Lithium, a novel proof engine for separation logic that combines automation with foundational proofs.Formale Verifikation ist eine vielversprechende Technik, um die Verlässlichkeit von grundlegenden Programmen wie Betriebssystemen sicherzustellen. Um das volle Potenzial formaler Verifikation zu realisieren, müssen jedoch mehrere Herausforderungen gemeistert werden: Erstens muss die Komplexität von realistischen Modellen von Programmiersprachen wie C oder Assembler gehandhabt werden. Zweitens muss die Vertrauenswürdigkeit der Verifikation sichergestellt werden, idealerweise durch maschinenüberprüfbare Beweise. Drittens muss die Verifikation automatisiert werden, um den manuellen Aufwand zu minimieren. Diese Dissertation präsentiert mehrere Projekte, die formale Verifikation entlang dieser Achsen weiterentwickeln: RefinedC ist der erste Ansatz für die Verifikation von C Code, der maschinenüberprüfbare Beweise mit einem hohen Grad an Automatisierung vereint. Islaris zeigt, wie die Verifikation von Assembler zu realistischen Modellen von modernen Befehlssatzarchitekturen wie Armv8-A oder RISC-V skaliert werden kann. DimSum entwickelt einen neuen Ansatz für die Verifizierung von Programmen, die aus Komponenten in mehreren Programmiersprachen bestehen (z.B., C und Assembler), wie es oft bei grundlegenden Programmen wie Betriebssystemen der Fall ist. RefinedC und Islaris basieren auf Lithium, eine neue Automatisierungstechnik für Separationslogik, die maschinenüberprüfbare Beweise und Automatisierung verbindet.This research was supported in part by a Google PhD Fellowship, in part by awards from Android Security's ASPIRE program and from Google Research, and in part by a European Research Council (ERC) Consolidator Grant for the project "RustBelt", funded under the European Union’s Horizon 2020 Framework Programme (grant agreement no. 683289)

Outcome Measures for Disease-Modifying Trials in Parkinson's Disease:Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative

BACKGROUND: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach.OBJECTIVE: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials.METHODS: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory.RESULTS: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages.CONCLUSION: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges.</p

Towards a multi-arm multi-stage platform trial of disease modifying approaches in Parkinson’s disease

An increase in the efficiency of clinical trial conduct has been successfully demonstrated in the oncology field, by the use of multi-arm, multi-stage trials allowing the evaluation of multiple therapeutic candidates simultaneously, and seamless recruitment to phase 3 for those candidates passing an interim signal of efficacy. Replicating this complex innovative trial design in diseases such as Parkinson’s disease is appealing, but in addition to the challenges associated with any trial assessing a single potentially disease modifying intervention in Parkinson’s disease, a multiarm platform trial must also specifically consider the heterogeneous nature of the disease, alongside the desire to potentially test multiple treatments with different mechanisms of action. In a multi-arm trial, there is a need to appropriately stratify treatment arms to ensure each are comparable with a shared placebo/standard of care arm; however, in Parkinson’s disease there may be a preference to enrich an arm with a subgroup of patients that may be most likely to respond to a specific treatment approach. The solution to this conundrum lies in having clearly defined criteria for inclusion in each treatment arm as well as an analysis plan that takes account of predefined subgroups of interest, alongside evaluating the impact of each treatment on the broader population of Parkinson’s disease patients. Beyond this, there must be robust processes of treatment selection, and consensus derived measures to confirm target engagement and interim assessments of efficacy, as well as consideration of the infrastructure needed to support recruitment, and the long-term funding and sustainability of the platform. This has to incorporate the diverse priorities of clinicians, triallists, regulatory authorities and above all the views of people with Parkinson’s disease.</p

Towards a multi-arm multi-stage platform trial of disease modifying approaches in Parkinson’s disease

An increase in the efficiency of clinical trial conduct has been successfully demonstrated in the oncology field, by the use of multi-arm, multi-stage trials allowing the evaluation of multiple therapeutic candidates simultaneously, and seamless recruitment to phase 3 for those candidates passing an interim signal of efficacy. Replicating this complex innovative trial design in diseases such as Parkinson’s disease is appealing, but in addition to the challenges associated with any trial assessing a single potentially disease modifying intervention in Parkinson’s disease, a multiarm platform trial must also specifically consider the heterogeneous nature of the disease, alongside the desire to potentially test multiple treatments with different mechanisms of action. In a multi-arm trial, there is a need to appropriately stratify treatment arms to ensure each are comparable with a shared placebo/standard of care arm; however, in Parkinson’s disease there may be a preference to enrich an arm with a subgroup of patients that may be most likely to respond to a specific treatment approach. The solution to this conundrum lies in having clearly defined criteria for inclusion in each treatment arm as well as an analysis plan that takes account of predefined subgroups of interest, alongside evaluating the impact of each treatment on the broader population of Parkinson’s disease patients. Beyond this, there must be robust processes of treatment selection, and consensus derived measures to confirm target engagement and interim assessments of efficacy, as well as consideration of the infrastructure needed to support recruitment, and the long-term funding and sustainability of the platform. This has to incorporate the diverse priorities of clinicians, triallists, regulatory authorities and above all the views of people with Parkinson’s disease.</p

Embracing monogenic Parkinson's disease: the MJFF Global Genetic PD Cohort

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Michael J. Fox Foundation for Parkinson's Research. Grant Number: ID 15015.02. NIHR Cambridge Biomedical Research Centre. Grant Number: BRC-1215-20014info:eu-repo/semantics/publishedVersio

Effects of auditory stimuli on electrical activity in the brain during cycle ergometry

© 2017 The Authors. The present study sought to further understanding of the brain mechanisms that underlie the effects of music on perceptual, affective, and visceral responses during whole-body modes of exercise. Eighteen participants were administered light-to-moderate intensity bouts of cycle ergometer exercise. Each exercise bout was of 12-min duration (warm-up [3 min], exercise [6 min], and warm-down [3 min]). Portable techniques were used to monitor the electrical activity in the brain, heart, and muscle during the administration of three conditions: music, audiobook, and control. Conditions were randomized and counterbalanced to prevent any influence of systematic order on the dependent variables. Oscillatory potentials at the Cz electrode site were used to further understanding of time–frequency changes influenced by voluntary control of movements. Spectral coherence analysis between Cz and frontal, frontal-central, central, central-parietal, and parietal electrode sites was also calculated. Perceptual and affective measures were taken at five timepoints during the exercise bout. Results indicated that music reallocated participants' attentional focus toward auditory pathways and reduced perceived exertion. The music also inhibited alpha resynchronization at the Cz electrode site and reduced the spectral coherence values at Cz–C4 and Cz–Fz. The reduced focal awareness induced by music led to a more autonomous control of cycle movements performed at light-to-moderate-intensities. Processing of interoceptive sensory cues appears to upmodulate fatigue-related sensations, increase the connectivity in the frontal and central regions of the brain, and is associated with neural resynchronization to sustain the imposed exercise intensity.Coordination for the Improvement of Higher Education Personnel (CAPES)

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.[Background] As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited.[Objective] The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.[Methods] We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed.[Results] We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published.[Conclusions] Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.This project was funded by The Michael J. Fox Foundation (ID 15015.02)Peer reviewe