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. It was deployed in a convenience sample of 108 participants recruited from six cohorts that included older healthy adults (HA) and participants with potentially altered mobility due to Parkinson’s disease (PD), multiple sclerosis (MS), proximal femoral fracture (PFF), chronic obstructive pulmonary disease (COPD) or congestive heart failure (CHF). A novelty introduced in the protocol was the tiered approach to increase difficulty both within the same task (e.g., by allowing use of aids or armrests) and across tasks. Results: The protocol proved to be safe and feasible (all participants could complete it and no adverse events were recorded) and the addition of the more complex tasks allowed a much greater spread in walking speeds to be achieved compared to standard straight walking trials. Furthermore, it allowed a representation of a variety of daily life relevant mobility aspects and can therefore be used for the validation of monitoring devices used in real life. Conclusions: The protocol allowed for measuring gait in a variety of pathological conditions suggests that it can also be used to detect changes in gait due to, for example, the onset or progression of a disease, or due to therapy. Trial registration: ISRCTN—12246987

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. Rigorous validation procedures should cover the device metrological verification, the validation of the algorithms for the DMOs computation specifically for the population of interest and in daily life situations, and the users’ perspective on the device. Methods and analysis: This protocol was designed to establish the technical validity and patient acceptability of the approach used to quantify digital mobility in the real world by Mobilise-D, a consortium funded by the European Union (EU) as part of the Innovative Medicine Initiative, aiming at fostering regulatory approval and clinical adoption of DMOs. After defining the procedures for the metrological verification of an IMU-based device, the experimental procedures for the validation of algorithms used to calculate the DMOs are presented. These include laboratory and real-world assessment in 120 participants from five groups: healthy older adults; chronic obstructive pulmonary disease, Parkinson’s disease, multiple sclerosis, proximal femoral fracture and congestive heart failure. DMOs extracted from the monitoring device will be compared with those from different reference systems, chosen according to the contexts of observation. Questionnaires and interviews will evaluate the users’ perspective on the deployed technology and relevance of the mobility assessment. Ethics and dissemination: The study has been granted ethics approval by the centre’s committees (London—Bloomsbury Research Ethics committee; Helsinki Committee, Tel Aviv Sourasky Medical Centre; Medical Faculties of The University of Tübingen and of the University of Kiel). Data and algorithms will be made publicly available

A validated liquid chromatography-tandem mass spectrometry method for the quantitative determination of 4 beta-hydroxycholesterol in human plasma

A novel liquid chromatography-tandem mass spectrometry method is described for the quantitative determination of the endogenous CYP 3A4/5 marker 4 beta-hydroxycholesterol in human K(2)-EDTA plasma. It is based on alkaline hydrolysis to convert esterified to free 4 beta-hydroxycholesterol, followed by analyte extraction from plasma by hexane and purification of the hexane extract by normal-phase solid-phase extraction. The analyte is chromatographically separated from endogenous isobaric plasma oxysterols and excess cholesterol by a 16-min reversed-phase gradient on a C18 column; detection is performed by atmospheric pressure photoionization tandem mass spectrometry in the positive ion mode, using toluene as a dopant. Using 400 mu l of plasma, 4 beta-hydroxycholesterol can be quantified in the concentration range 10.0-250 nM. Validation results show that the method is sufficiently selective towards endogenous plasma sterols and capable of quantifying the analyte with good precision and accuracy. The analyte is sufficiently stable in all relevant matrices and solvents; the addition of the anti-oxidant butylated hydroxytoluene to prevent in vitro formation of 4 beta-hydroxycholesterol from cholesterol during storage or analysis is not necessary, provided that long-term frozen storage of plasma occurs at -70 degrees C. (C) 2011 Elsevier B.V. All rights reserved

Wearable sensors to monitor physical activity in heart failure clinical trials: state-of-the-art review

Background: Estimation of the effects that drugs or other interventions have on patients’ symptoms and functions is crucial in heart failure trials. Traditional symptoms and functions clinical outcome assessments have important limitations. Actigraphy may help to overcome these limitations due to its objective nature and the potential for continuous recording of data. However, actigraphy is not currently accepted as clinically relevant by key stakeholders. Methods and Results: In this state-of-the-art study, the key aspects to consider when implementing actigraphy in heart failure trials are discussed. They include which actigraphy-derived measures should be considered, how to build endpoints using them, how to measure and analyze them, and how to handle the patients’ and sites’ logistics of integrating devices into trials. A comprehensive recommendation based on the current evidence is provided. Conclusion: Actigraphy is technically feasible in clinical trials involving heart failure, but successful implementation and use to demonstrate clinically important differences in physical functioning with drug or other interventions require careful consideration of many design choices

HPLC-MS/MS method for the determination of cytarabine in human plasma

Background: Cytarabine is an anti-tumor drug that is currently under investigation for treatment in combination with other anticancer drugs for the chemotherapy of leukemia. The quantitative determination of cytarabine in plasma is challenging due to the required sensitivity, its in vitro instability and the presence of an isobaric endogenous compound, cytidine. Owing to the polarity of cytarabine, conventional chromatography cannot provide adequate separation of the analyte and the interfering compounds. A few analytical methods have been reported for the determination of cytarabine in plasma, but their sensitivity was not sufficient since most of these methods apply spectrophotometric detection. Results: In this article, an LC-MS/MS method is described for the determination of cytarabine in human plasma down to the sub ng/ml level. To prevent conversion of cytarabine by cytidine deaminase, whole blood samples were stabilized with tetrahydrouridine directly after the collection of whole blood at the clinical site. Cation-exchange SPE was employed to extract cytarabine from 50 mu l human plasma. UHPLC on high strength silica T3 column (100 x 2.1 mm x 1.8 mu m) was applied to achieve adequate separation of cytarabine from cytidine within a reasonable run time of 5 min. A triple quad mass spectrometer equipped with an ESI source was used for detection. Conclusion: The method was linear over the concentration ranges of 0.500-500 ng/ml. The intra-and inter-day relative standard deviation (precision) as well as the bias (accuracy) were well below 15%. In the presence of tetrahydrouridine, cytarabine was sufficiently stable under all relevant conditions. The method was successfully applied to support a clinical pharmacokinetic study with a low dose of cytarabine

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. Rigorous validation procedures should cover the device metrological verification, the validation of the algorithms for the DMOs computation specifically for the population of interest and in daily life situations, and the users' perspective on the device. Methods and analysis: This protocol was designed to establish the technical validity and patient acceptability of the approach used to quantify digital mobility in the real world by Mobilise-D, a consortium funded by the European Union (EU) as part of the Innovative Medicine Initiative, aiming at fostering regulatory approval and clinical adoption of DMOs.After defining the procedures for the metrological verification of an IMU-based device, the experimental procedures for the validation of algorithms used to calculate the DMOs are presented. These include laboratory and real-world assessment in 120 participants from five groups: healthy older adults; chronic obstructive pulmonary disease, Parkinson's disease, multiple sclerosis, proximal femoral fracture and congestive heart failure. DMOs extracted from the monitoring device will be compared with those from different reference systems, chosen according to the contexts of observation. Questionnaires and interviews will evaluate the users' perspective on the deployed technology and relevance of the mobility assessment. Ethics and dissemination: The study has been granted ethics approval by the centre's committees (London-Bloomsbury Research Ethics committee; Helsinki Committee, Tel Aviv Sourasky Medical Centre; Medical Faculties of The University of Tübingen and of the University of Kiel). Data and algorithms will be made publicly available. Trial registration number: ISRCTN (12246987)