IntroductionWalking speed is a key measure of health and mobility across a wide range of diseases. Traditional gait assessments in clinical settings may not accurately reflect real-world mobility patterns. Wearable sensors offer an ecologically valid alternative by capturing every movement in daily life, but there are few robust, validated reports. We aimed to identify evidence on real-world gait speed measurements that have received or are seeking regulatory approval from agencies such as the European Medicines Agency and the U.S. Food and Drug Administration.MethodWe conducted a systematic review following a comprehensive search strategy using the Ovid platform, guided by pre-defined selection criteria and in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We also manually searched the websites of key regulatory agencies and the ClinicalTrials.gov database.ResultsOur search identified 503 records, of which 10 met the inclusion criteria. Most studies were part of large-scale initiatives, including the qualification of the Stride Velocity 95th Centile and the MOBILISE-D project. No device or outcome measure that assesses walking speed in real-world conditions has been fully validated by the FDA. We found four letters of intent on the FDA website related to this concept. One outcome, the 95th centile of stride velocity, has been approved by the EMA as a primary endpoint for assessing ambulant patients with Duchenne Muscular Dystrophy.ConclusionDespite the potential of wearable devices to enhance drug development and clinical decision-making, real-world walking speed remains insufficiently validated across most conditions because data is missing. The widespread adoption of digital outcomes to assess ambulation will require extensive validation efforts, regulatory pathway adaptations, and improved standardization of devices, algorithms, and study methodologies.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD42025633578, PROSPERO CRD42025633578.

BACKGROUND:Primary progressive multiple sclerosis (PPMS) involves gradual disability accumulation driven by neurodegeneration. Standard outcomes, including the Expanded Disability Status Scale (EDSS) and timed 25-foot walk (T25FW), lack sensitivity to subtle functional changes. Real-life walking speed (RWS) measured with wearable sensors may offer a more responsive marker of progression. OBJECTIVES:In a prospective cohort (2012-2022) at the University Medical Center Hamburg-Eppendorf, adults with PPMS (18-65 years, EDSS ⩽7.0) underwent repeated EDSS, T25FW, Nine-Hole Peg Test (9HPT), and Symbol Digit Modalities Test (SDMT). RWS was recorded using an accelerometer. Disease progression was defined as ⩾20% worsening in T25FW/9HPT, ⩾8-point SDMT decline, EDSS increase (⩾1.0 or ⩾0.5 if >5), or RWS reduction >0.08 m/s. RESULTS:Among 110 participants (mean age: 52 years; baseline EDSS: 3.5) followed for a median of 3 years, RWS showed a symmetric distribution and declined steadily with increasing EDSS, unlike the skewed T25FW distribution. Annual progression was detected in >30% of participants using RWS, compared with <20% for EDSS/SDMT and <10% for T25FW/9HPT. Composite endpoints including RWS identified earlier and more frequent disease progression (p < 0.01). CONCLUSION:Continuous RWS monitoring is more sensitive than conventional metrics for detecting functional decline in PPMS and may strengthen progression endpoints.

Walking speed is a key measure of health and mobility across a wide range of diseases. Traditional gait assessments in clinical settings may not accurately reflect real-world mobility patterns. Wearable sensors offer an ecologically valid alternative by capturing every movement in daily life, but there are very few reports of robust, validated outcomes derived from these sensors. We aimed to identify evidence on real-world gait speed measurements that have received or are seeking regulatory approval from agencies such as the European Medicines Agency and the U.S. Food and Drug Administration. We conducted a systematic review following a comprehensive search strategy using the Ovid platform, guided by pre-defined selection criteria and in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We also manually searched the websites of key regulatory agencies and the ClinicalTrials.gov database. Our search identified 503 records, of which 10 met the inclusion criteria. Most studies were part of large-scale initiatives, including the qualification of the Stride Velocity 95th Centile and the MOBILISE-D project. No device or outcome measure that assess walking speed in real-world conditions has been fully validated by the FDA. We found four letters of intent on the FDA website related to this concept. One outcome, the 95th centile of stride velocity, has been approved by the EMA as a primary endpoint for assessing ambulant patients with Duchenne Muscular Dystrophy. Despite the potential of wearable devices to enhance drug development and clinical decision-making, real-world walking speed remains insufficiently validated across most conditions because data is missing. The widespread adoption of digital outcome to assess ambulation will require extensive validation efforts, regulatory pathway adaptations, and improved standardization of devices, algorithms, and study methodologies.

The aim of this work was to explore whether real-world walking speed (RWS) would change as a consequence of 60-day bed-rest. The main hypothesis was that daily RWS would decrease after the bed-rest, with a subsequent recovery during the first days of re-ambulation. Moreover, an exploratory analysis was done in order to understand whether there is an agreement between the loss in RWS after bed-rest and the loss in the maximum oxygen uptake capacity (VO 2max ), or the loss in maximal vertical jump power (JUMP) respectively. Twenty-four subjects were randomly assigned to one of three groups: a continuous artificial gravity group, an intermittent artificial gravity group, or a control group. The fitted linear mixed effects model showed a significant decrease ( p < 0.001) of RWS after the 60-day bed-rest and a subsequent increase ( p < 0.001) of RWS during the 14-day recovery period in the study facility. No or little agreement was found between the loss in RWS and the loss in VO 2max capacity or the loss in maximal vertical jumping power (RWS vs. VO 2max : p = 0.81, RWS vs. JUMP: p = 0.173). Decreased RWS after bed-rest, with a follow-up recovery was observed for all three groups, regardless of the training intervention. This suggests that RWS, also in these settings, was able to reflect a de-conditioning and follow-up recovery process.

Understanding differences between real-world walking speed (RWS) and laboratory-measured walking speed (LWS) is crucial for comprehensive mobility assessments, especially in context of prolonged immobilization. This study aimed to investigate disparities in walking speed following a 60-day bed-rest period.

Artificial intelligence (AI) and machine learning medical tools have the potential to be transformative in care delivery; however, this change will only be realized if accompanied by effective governance that ensures patient safety and public trust. Recent digital health initiatives have called for tighter governance of digital health. A correct balance must be found between ensuring product safety and performance while also enabling the innovation needed to deliver better approaches for patients and affordable efficient health care for society. This requires innovative, fit-for-purpose approaches to regulation. Digital health technologies, particularly AI-based tools, pose specific challenges to the development and implementation of functional regulation. The approaches of regulatory science and "better regulation" have a critical role in developing and evaluating solutions to these problems and ensuring effective implementation. We describe the divergent approaches of the European Union and the United States in the implementation of new regulatory approaches in digital health, and we consider the United Kingdom as a third example, which is in a unique position of developing a new post-Brexit regulatory framework.

Christian Lederer, Martin Daumer, Romain-Daniel Gosselin, Ijaz S. Jamall, and Björn L.D.M. Brücher 1 Sylvia Lawry Centre for Multiple Sclerosis Research e.V. – The Human Motion Institute, Munich, Germany Theodor-Billroth-Akademie , Germany, USA 3 INCORE, International Consortium of Research Excellence of the Theodor-Billroth-Academy , Germany, USA Precision Medicine Unit, Lausanne University Hospital, Chemin des Roches 1a/1b CH-1010 Lausanne, Switzerland Risk-Based Decisions Inc., Sacramento, CA, USA Department of Surgery, Carl-Thiem-Klinikum, Cottbus, Germany

Radioactivity and radiation-induced mutations are believed to be primary causal examples of cancer-initiating events (stimulus). The assumption that an increase in cancer risk develops from any amount of radiation gave rise to the linear no-threshold model. This also led to the assumption that cancer is caused by somatic mutations as described by the somatic mutation theory. Against this backdrop, in actuality only ~5%-10% of cancers result from somatic mutations or its various modifications, while ~80% of cancers are still termed as 'sporadic', meaning that their cause is unknown. Therefore, both the linear no-threshold model and the somatic mutation theory have resulted in an incongruity in thinking. Decades of molecular and clinical research since 2012 led to the development of the cancer paradigm, "Epistemology of the origin of cancer", which explains why the majority of cancers originate as a result of a sixstep sequence of events. An understanding of the essentials of physics helps to explain the interconnections between physics and the biology of cancer. This allows for a much-needed reconciliation of past errors and leads to a deeper understanding of carcinogenesis.

1 Theodor-Billroth-Academy , Germany, USA 2 INCORE, International Consortium of Research Excellence of the Theodor-Billroth-Academy , Germany, USA Department of Surgery, Carl-Thiem-Klinikum, Cottbus, Germany Neurogenetics, Institute of Zoology, University of Regensburg, Regensburg, Germany Department 4, Genetic Engineering and other Biotechnological Processes, Federal Office of Consumer Protection and Food Safety,

The SLCMSR was formed as an international Multiple Sclerosis Trials, Research and Resource Center to identify clinical MRI and other predictors of the course of multiple sclerosis (MS) based on a large database of natural history and clinical trial data. Using an elaborate validation concept several key findings were published, challenging established outcome parameters and their assessment in MS such as disability ratings with Expanded Disability Status Scale (EDSS), relapses and MRI endpoints. Sustained increase of EDSS appeared to be an invalid outcome for 2-3 year clinical trials at least in patients with relapsing-remitting MS. The number of gadolinium-enhancing lesions and T2-lesion load on MRI were shown not to have a meaningful additional predictive value for the disease course. These issues risen some 15 years ago had triggered controversial discussions which have also been noticed by regulatory authorities and they all have not been resolved. In addition the SLCMSR contributed to the development of new outcomes such as real-world walking speed as an attractive, ecologically valid tool based on a wearable device. A so-called evidence-based-decision-support tool was constructed to provide individual prognostic estimates based on a matching algorithm to a given database. This paper con-densates the findings of 20 years of critical MS research.

Accurate and robust tracking of natural human head motion in natural environments is important for a number of applications including virtual and augmented reality, clinical diagnostics, as well as basic scientific research. IMU provide a versatile solution for recording inertial data including linear acceleration and angular velocity, but reconstructing head position is difficult or impossible. This problem can be solved by incorporating visual data using a technique known as visual-inertial simultaneous localization and mapping (VI-SLAM). A recently released commercial solution, the Intel RealSense T265, uses a proprietary VI-SLAM algorithm to estimate linear and angular position and velocity, but the performance of this device for tracking of natural human head motion in natural environments has not yet been comprehensively evaluated against gold-standard methods. In this study, we used a wide range of metrics to evaluate the performance of the T265 with different walking speeds in different environments, both indoor and outdoor, against two gold-standard methods, an optical tracking system and a so-called perambulator. Overall, we find that performance of the T265 relative to these gold-standard methods is most accurate for slow to normal walking speeds in small- to medium-sized environments. The suitability of this device for future scientific studies depends on the application; data presented here can be useful in making that determination.

Aims: To assess children's acceptance to wear a 3D-accelerometer which is attached to the waist under real-world conditions, and also to compare gait speed during supervised testing with the non-supervised gait speed in every-day life.Methods: In a controlled observational, cross sectional study thirty subjects with cerebral palsy (CP), with level I&II of the Gross Motor Function Classification System (GMFCS) and 30 healthy control children (Ctrl), aged 3–12 years, were asked to perform a 1-min-walking test (1 mwt) under laboratory conditions, and to wear an accelerometric device for a 1-week wearing home measurement (1 WHM). Acceptance was measured via wearing time, and by a questionnaire in which subjects rated restrictions in their daily living and wearing comfort. In addition, validity of 3D-accelerometric gait speed was checked through gold standard assessment of gait speed with a mobile perambulator.Results: Wearing time amounted to 10.3 (SD 3.4) hours per day, which was comparable between groups (T = 1.10, P = 0.3). Mode for wearing comfort [CP 1, Range (1,4), Ctrl 1, Range (1,6)] and restriction of daily living [CP 1, Range (1,3), Ctrl 1, Range (1,4)] was comparable between groups. Under laboratory conditions, Ctrl walked faster in the 1 mwt than CP (Ctrl 1.72 ± 0.29 m/s, CP 1.48 ± 0.41 m/s, P = 0.018). Similarly, a statistically significant difference was found when comparing real-world walking speed and laboratory walking speed (CP: 1 mwt 1.48 ± 0.41 m/s, 1 WHM 0.89 ± 0.09 m/s, P = 0.012; Ctrl: 1mwt 1.72 ± 0.29, 1 WHM 0.97 ± 0.06, P < 0.001).Conclusion: 3D-accelerometry is well-enough accepted in a pediatric population of patients with CP and a Ctrl group to allow valid assessments. Assessment outside the laboratory environment yields information about real world activity that was not captured by routine clinical tests. This suggests that assessment of habitual activities by wearable devices reflects the functioning of children in their home environment. This novel information constitutes an important goal for rehabilitation medicine. The study is registered at the German Register of Clinical Trials with the title “Acceptance and Validity of 3D Accelerometric Gait Analysis in Pediatric Patients” (AVAPed; DRKS00011919).

PURPOSE:Skeletal muscle vascularization is important for tissue regeneration after injury and immobilization. We examined whether complete immobilization influences capillarization and oxygen delivery to the muscle and assessed the efficacy of rehabilitation by aerobic exercise training. METHODS:Young healthy males had one leg immobilized for 14 d and subsequently completed 4 wk of intense aerobic exercise training. Biopsies were obtained from musculus vastus lateralis, and arteriovenous blood sampling for assessment of oxygen extraction and leg blood flow during exercise was done before and after immobilization and training. Muscle capillarization, muscle and platelet content of vascular endothelial growth factor (VEGF), and muscle thrombospondin-1 were determined. RESULTS:Immobilization did not have a significant impact on capillary per fiber ratio or capillary density. The content of VEGF protein in muscle samples was reduced by 36% (P = 0.024), and VEGF to thrombospondin-1 ratio was 94% lower (P = 0.046). The subsequent 4-wk training period increased the muscle VEGF content and normalized the muscle VEGF to thrombospondin-1 ratio but did not influence capillarization. Platelet VEGF content followed the trend of muscle VEGF. At the functional level, oxygen extraction, blood flow, and oxygen delivery at rest and during submaximal exercise were not affected by immobilization or training. CONCLUSIONS:The results demonstrate that just 2 wk of leg immobilization leads to a strongly reduced angiogenic potential as evidenced by reduced muscle and platelet VEGF content and a reduced muscle VEGF to thrombospondin-1 ratio. Moreover, a subsequent period of intensive aerobic exercise training fails to increase capillarization in the previously immobilized leg, possibly because of the angiostatic condition caused by immobilization.

Background: Prognostic counselling is a sensitive issue in medicine and especially so in MS due to the highly heterogeneous disease course. However, people with MS (pwMS) seek prognostic information. The web-based 'Evidence-Based Decision Support Tool in Multiple Sclerosis' (EBDiMS) uses data of 717 patients from the London/Ontario cohort to calculate personalized long-term prognostic information. Objective: The aim of this study was to investigate the feasibility and effect of long-term prognostic counselling in pwMS using EBDiMS. Methods: Ninety consecutive pwMS were provided with personalized estimations of expected time to reach Expanded Disability Status Scale (EDSS) scores of 6 and 8 and time to conversion to secondary-progressive MS. Participants gave estimates on their own putative prognosis and rated the tool's acceptability on six-step Likert-type scales. Results: Participants rated EBDiMS as highly understandable, interesting and relevant for patient-physician encounters, coping and therapy decisions. Although it provoked a certain degree of worry in some participants, 95% would recommend using the tool. Participants' own prognosis estimates did not change significantly following EBDiMS. Conclusion: Long-term prognostic counselling using an online tool has been shown to be feasible in a clinical setting. EBDiMS provides pwMS with relevant, easy-to-understand, long-term prognostic information without causing relevant anxiety.

BackgroundMobile sensors offer enormous potential for the collection of informative clinical endpoints in clinical trials to support regulatory decision making and product labelling. There are currently no specific guidelines on the information needed to enable regulators to review and accept proposed endpoints derived from mobile sensors for use in drug development trials.ObjectiveThe purpose of this working group report is to recommend the structure and content of an evidence dossier intended to support whether a clinical endpoint derived from mobile sensor data is fit-for-purpose for use in regulatory submissions for drug approvals.Evidence dossierThe structure and content of a dossier to provide evidence supporting the use of a sensor-derived clinical endpoint is described. Sections include clinical endpoint definition and positioning, the concept of interest, the context of use, clinical validation and interpretation, study implementation, and analytical validity with sensor performance verification in support of the selected sensor.ConclusionsIn the absence of definitive regulatory guidance, this report provides a considered approach to compiling a comprehensive body of evidence to justify acceptance of mobile sensors for support of new drug applications.

Head stabilization is fundamental for balance during locomotion but can be impaired in elderly or diseased populations. Previous studies have identified several parameters of head stability with possible diagnostic value in a laboratory setting. Recently, the ecological validity of measures obtained in such controlled contexts has been called into question. The aim of this study was to investigate the ecological validity of previously described parameters of head stabilization in a real-world setting. Ten healthy subjects participated in the study. Head and trunk movements of each subject were recorded with inertial measurement units (IMUs) for a period of at least 10 h. Periods of locomotion were extracted from the measurements and predominant frequencies, root mean squares (RMSs) and bout lengths were estimated. As parameters of head stabilization, attenuation coefficients (ACs), harmonic ratios (HRs), coherences, and phase differences were computed. Predominant frequencies were distributed tightly around 2 Hz and ACs, HRs, and coherences exhibited the highest values in this frequency range. All head stability parameters exhibited characteristics consistent with previous reports, although higher variances were observed. These results suggest that head stabilization is tuned to the 2 Hz fundamental frequency of locomotion and that previously described measures of head stability could generalize to a real-world setting. This is the first study to address the ecological validity of these measures, highlighting the potential use of head stability parameters as diagnostic tools or outcome measures for clinical trials. The low cost and ease of use of the IMU technology used in this study could additionally be of benefit for a clinical application.

Background Walking ability is an important prerequisite for activity, social participation and independent living. While in most healthy adults, this ability can be assumed as given, limitations in walking ability occur with increasing age. Furthermore, slow walking speed is linked to several chronic conditions and overall morbidity. Measurements of gait parameters can be used as a proxy to detect functional decline and onset of chronic conditions. Up to now, gait characteristics used for this purpose are measured in standardized laboratory settings. There is some evidence, however, that long-term measurements of gait parameters in the living environment have some advantages over short-term laboratory measurements. Methods We evaluated cross-sectional data from an accelerometric sensor worn in a subgroup of 554 participants of the Berlin Aging Study II (BASE-II). Data from the two BASE-II age groups (age between 22-36 years and 60-79 years) were used for the current analysis of accelerometric data for a minimum of two days and a maximum of ten days were available. Real world walking speed, number of steps, maximum coherent distance and total distance were derived as average data per day. Linear regression analyses were performed on the different gait parameters in order to identify significant determinants. Additionally, Mann-Whitney-U-tests were performed to detect sex-specific differences. Results Age showed to be significantly associated with real world walking speed and with the total distance covered per day, while BMI contributed negatively to the number of walking steps, maximum coherent distance and total distance walked. Additionally, sex was associated with walking steps. However, R-2-values for all models were low. Overall, women had significantly more walking steps and a larger coherent distance per day when compared to men. When separated by age group, this difference was significant only in the older participants. Additionally, walking speed was significantly higher in women compared to men in the subgroup of older people. Conclusions Age- and sex-specific differences have to be considered when objective gait parameters are measured, e.g. in the context of clinical risk assessment. For this purpose normative data, differentiating for age and sex would have to be established to allow reliable classification of long-term measurements of gait.