Real-World Gait Detection Using a Wrist-Worn Inertial Sensor: Validation Study.

Background: Wrist-worn inertial sensors are used in digital health for evaluating mobility in real-world environments. Preceding the estimation of spatiotemporal gait parameters within long-term recordings, gait detection is an important step to identify regions of interest where gait occurs, which requires robust algorithms due to the complexity of arm movements. While algorithms exist for other sensor positions, a comparative validation of algorithms applied to the wrist position on real-world data sets across different disease populations is missing.

Laboratory and free-living gait performance in adults with COPD and healthy controls.

Background: Gait characteristics are important risk factors for falls, hospitalisations and mortality in older adults, but the impact of COPD on gait performance remains unclear. We aimed to identify differences in gait characteristics between adults with COPD and healthy age-matched controls during 1) laboratory tests that included complex movements and obstacles, 2) simulated daily-life activities (supervised) and 3) free-living daily-life activities (unsupervised).

Methods: This case-control study used a multi-sensor wearable system (INDIP) to obtain seven gait characteristics for each walking bout performed by adults with mild-to-severe COPD (n=17; forced expiratory volume in 1 s 57±19% predicted) and controls (n=20) during laboratory tests, and during simulated and free-living daily-life activities.

Assessing real-world gait with digital technology? Validation, insights and recommendations from the Mobilise-D consortium.

Background: Although digital mobility outcomes (DMOs) can be readily calculated from real-world data collected with wearable devices and ad-hoc algorithms, technical validation is still required. The aim of this paper is to comparatively assess and validate DMOs estimated using real-world gait data from six different cohorts, focusing on gait sequence detection, foot initial contact detection (ICD), cadence (CAD) and stride length (SL) estimates.

Methods: Twenty healthy older adults, 20 people with Parkinson's disease, 20 with multiple sclerosis, 19 with proximal femoral fracture, 17 with chronic obstructive pulmonary disease and 12 with congestive heart failure were monitored for 2.

A multi-sensor wearable system for the assessment of diseased gait in real-world conditions.

Accurately assessing people's gait, especially in real-world conditions and in case of impaired mobility, is still a challenge due to intrinsic and extrinsic factors resulting in gait complexity. To improve the estimation of gait-related digital mobility outcomes (DMOs) in real-world scenarios, this study presents a wearable multi-sensor system (INDIP), integrating complementary sensing approaches (two plantar pressure insoles, three inertial units and two distance sensors). The INDIP technical validity was assessed against stereophotogrammetry during a laboratory experimental protocol comprising structured tests (including continuous curvilinear and rectilinear walking and steps) and a simulation of daily-life activities (including intermittent gait and short walking bouts).

Reverse Engineering of Digital Measures: Inviting Patients to the Conversation.

Background: Digital measures offer an unparalleled opportunity to create a more holistic picture of how people who are patients behave in their real-world environments, thereby establishing a better connection between patients, caregivers, and the clinical evidence used to drive drug development and disease management. Reaching this vision will require achieving a new level of co-creation between the stakeholders who design, develop, use, and make decisions using evidence from digital measures.

Summary: In September 2022, the second in a series of meetings hosted by the Swiss Federal Institute of Technology in Zürich, the Foundation for the National Institutes of Health Biomarkers Consortium, and sponsored by Wellcome Trust, entitled "Reverse Engineering of Digital Measures," was held in Zurich, Switzerland, with a broad range of stakeholders sharing their experience across four case studies to examine how patient centricity is essential in shaping development and validation of digital evidence generation tools.

Design and validation of a multi-task, multi-context protocol for real-world gait simulation.

Background: Measuring mobility in daily life entails dealing with confounding factors arising from multiple sources, including pathological characteristics, patient specific walking strategies, environment/context, and purpose of the task. The primary aim of this study is to propose and validate a protocol for simulating real-world gait accounting for all these factors within a single set of observations, while ensuring minimisation of participant burden and safety.

Methods: The protocol included eight motor tasks at varying speed, incline/steps, surface, path shape, cognitive demand, and included postures that may abruptly alter the participants' strategy of walking.

Technical validation of real-world monitoring of gait: a multicentric observational study.

Introduction: Existing mobility endpoints based on functional performance, physical assessments and patient self-reporting are often affected by lack of sensitivity, limiting their utility in clinical practice. Wearable devices including inertial measurement units (IMUs) can overcome these limitations by quantifying digital mobility outcomes (DMOs) both during supervised structured assessments and in real-world conditions. The validity of IMU-based methods in the real-world, however, is still limited in patient populations.

Evaluation of two assays for tumorigenicity assessment of CRISPR-Cas9 genome-edited cells.

Off-target editing is one of the main safety concerns for the use of CRISPR-Cas9 genome editing in gene therapy. These unwanted modifications could lead to malignant transformation, which renders tumorigenicity assessment of gene therapy products indispensable. In this study, we established two transformation assays, the soft agar colony-forming assay (SACF) and the growth in low attachment assay (GILA) as alternative methods for tumorigenicity evaluation of genome-edited cells.

Digital endpoints for self-administered home-based functional assessment in pediatric Friedreich's ataxia.

Background: Friedreich's ataxia is an inherited, progressive, neurodegenerative disease that typically begins in childhood. Disease severity is commonly assessed with rating scales, such as the modified Friedreich's Ataxia Rating Scale, which are usually administered in the clinic by a neurology specialist.

Objective: This study evaluated the utility of home-based, self-administered digital endpoints in children with Friedreich's ataxia and unaffected controls and their relationship to standard clinical rating scales.

A Roadmap to Inform Development, Validation and Approval of Digital Mobility Outcomes: The Mobilise-D Approach.

Health care has had to adapt rapidly to COVID-19, and this in turn has highlighted a pressing need for tools to facilitate remote visits and monitoring. Digital health technology, including body-worn devices, offers a solution using digital outcomes to measure and monitor disease status and provide outcomes meaningful to both patients and health care professionals. Remote monitoring of physical mobility is a prime example, because mobility is among the most advanced modalities that can be assessed digitally and remotely.

Continuous Digital Monitoring of Walking Speed in Frail Elderly Patients: Noninterventional Validation Study and Longitudinal Clinical Trial.

Background: Digital technologies and advanced analytics have drastically improved our ability to capture and interpret health-relevant data from patients. However, only limited data and results have been published that demonstrate accuracy in target indications, real-world feasibility, or the validity and value of these novel approaches.

Objective: This study aimed to establish accuracy, feasibility, and validity of continuous digital monitoring of walking speed in frail, elderly patients with sarcopenia and to create an open source repository of raw, derived, and reference data as a resource for the community.

Drug-induced chromatin accessibility changes associate with sensitivity to liver tumor promotion.

Liver cancer susceptibility varies amongst humans and between experimental animal models because of multiple genetic and epigenetic factors. The molecular characterization of such susceptibilities has the potential to enhance cancer risk assessment of xenobiotic exposures and disease prevention strategies. Here, using DNase I hypersensitivity mapping coupled with transcriptomic profiling, we investigate perturbations in -acting gene regulatory elements associated with the early stages of phenobarbital (PB)-mediated liver tumor promotion in susceptible versus resistant mouse strains (B6C3F1 versus C57BL/6J).

Validity of accelerometry in step detection and gait speed measurement in orthogeriatric patients.

Background: Mobile accelerometry is a powerful and promising option to capture long-term changes in gait in both clinical and real-world scenarios. Increasingly, gait parameters have demonstrated their value as clinical outcome parameters, but validation of these parameters in elderly patients is still limited.

Objective: The aim of this study was to implement a validation framework appropriate for elderly patients and representative of real-world settings, and to use this framework to test and improve algorithms for mobile accelerometry data in an orthogeriatric population.

Continuous Monitoring of Patient Mobility for 18 Months Using Inertial Sensors following Traumatic Knee Injury: A Case Study.

Continuous patient activity monitoring during rehabilitation, enabled by digital technologies, will allow the objective capture of real-world mobility and aligning treatment to each individual's recovery trajectory in real time. To explore the feasibility and added value of such approaches, we present a case study of a 36-year-old male participant monitored continuously for activity levels and gait parameters using a waist-worn inertial sensor following a tibial plateau fracture on the right side, sustained as a result of a high-energy trauma during a sporting accident. During rehabilitation, data were collected for a period of 553 days, with > 80% daytime compliance, until the participant returned to near full mobility.

Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1.

High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1. Synthesis of the four separate stereoisomers identified the (,)-diastereomer (, ) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1.

Informed consent in a vulnerable population group: supporting individuals aging with intellectual disability to participate in developing their own health and support programs.

Objective The aim of the present study was to explore the use of complementary consent methodologies to support a potentially vulnerable group of people, namely those aging with intellectual disability, to provide personal input. It was premised on the view that processes to determine capacity for consent, appropriately modified to account for individual capabilities and current circumstances, could facilitate meaningful participation in the development of personal health care plans of people previously excluded from contributing. Methods The present descriptive case study research was undertaken in New South Wales, Australia.

Reciprocal changes in DNA methylation and hydroxymethylation and a broad repressive epigenetic switch characterize FMR1 transcriptional silencing in fragile X syndrome.

Background: Fragile X syndrome (FXS) is the most common form of inherited intellectual disability, resulting from the loss of function of the fragile X mental retardation 1 (FMR1) gene. The molecular pathways associated with FMR1 epigenetic silencing are still elusive, and their characterization may enhance the discovery of novel therapeutic targets as well as the development of novel clinical biomarkers for disease status.

Results: We have deployed customized epigenomic profiling assays to comprehensively map the FMR1 locus chromatin landscape in peripheral mononuclear blood cells (PBMCs) from eight FXS patients and in fibroblast cell lines derived from three FXS patient.