Cell-free DNA analysis in current cancer clinical trials: a review

Cell-free DNA (cfDNA) analysis represents a promising method for the diagnosis, treatment selection and clinical follow-up of cancer patients. Although its general methodological feasibility and usefulness has been demonstrated, several issues related to standardisation and technical validation must be addressed for its routine clinical application in cancer. In this regard, most cfDNA clinical applications are still limited to clinical trials, proving its value in several settings. In this paper, we review the current clinical trials involving cfDNA/ctDNA analysis and highlight those where it has been useful for patient stratification, treatment follow-up or development of novel approaches for early diagnosis. Our query included clinical trials, including the terms ‘cfDNA’, ‘ctDNA’, ‘liquid biopsy’ AND ‘cancer OR neoplasm’ in the FDA and EMA public databases. We identified 1370 clinical trials (FDA = 1129, EMA = 241) involving liquid-biopsy analysis in cancer. These clinical trials show promising results for the early detection of cancer and confirm cfDNA as a tool for real-time monitoring of acquired therapy resistance, accurate disease-progression surveillance and improvement of treatment, situations that result in a better quality of life and extended overall survival for cancer patients.

Multicenter Technical Validation of 30 Rapid Antigen Tests for the Detection of SARS-CoV-2 (VALIDATE)

During COVID19 pandemic, SARS-CoV-2 rapid antigen tests (RATs) were marketed with minimal or no performance data. We aimed at closing this gap by determining technical sensitivities and specificities of 30 RATs prior to market release. We developed a standardized technical validation protocol and assessed 30 RATs across four diagnostic laboratories. RATs were tested in parallel using the Standard Q® (SD Biosensor/Roche) assay as internal reference. We used left-over universal transport/optimum media from nasopharyngeal swabs of 200 SARS-CoV-2 PCR-negative and 100 PCR-positive tested patients. Transport media was mixed with assay buffer and applied to RATs according to manufacturer instructions. Sensitivities were determined according to viral loads. Specificity of at least 99% and sensitivity of 95%, 90%, and 80% had to be reached for 107, 106, 105 virus copies/mL, respectively. Sensitivities ranged from 43.5% to 98.6%, 62.3% to 100%, and 66.7% to 100% at 105, 106, 107 copies/mL, respectively. Automated assay readers such as ExDia or LumiraDx showed higher performances. Specificities ranged from 88.8% to 100%. Only 15 of 30 (50%) RATs passed our technical validation. Due to the high failure rate of 50%, mainly caused by lack of sensitivity, we recommend a thorough validation of RATs prior to market release.

The Interpersonal Entrainment in Music Performance Data Collection

The Interpersonal Entrainment in Music Performance Data Collection (IEMPDC) comprises six related corpora of music research materials: Cuban Son & Salsa (CSS), European String Quartet (ESQ), Malian Jembe (MJ), North Indian Raga (NIR), Tunisian Stambeli (TS), and Uruguayan Candombe (UC). The core data for each corpus comprises media files and computationally extracted event onset timing data. Annotation of metrical structure and code used in the preparation of the collection is also shared. The collection is unprecedented in size and level of detail and represents a significant new resource for empirical and computational research in music. In this article we introduce the main features of the data collection and the methods used in its preparation. Details of technical validation procedures and notes on data visualization are available as Appendices. We also contextualize the collection in relation to developments in Open Science and Open Data, discussing important distinctions between the two related concepts.

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

IntroductionExisting 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 analysisThis 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 disseminationThe 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 numberISRCTN (12246987).

RLEP LAMP for the laboratory confirmation of leprosy: towards a point-of-care test

Background Nucleic acid-based amplification tests (NAAT), above all (q)PCR, have been applied for the detection of Mycobacterium leprae in leprosy cases and household contacts with subclinical infection. However, their application in the field poses a range of technical challenges. Loop-mediated isothermal amplification (LAMP), as a promising point-of-care NAAT does not require sophisticated laboratory equipment, is easy to perform, and is applicable for decentralized diagnosis at the primary health care level. Among a range of gene targets, the M. leprae specific repetitive element RLEP is regarded as highly sensitive and specific for diagnostic applications. Methods Our group developed and validated a dry-reagent-based (DRB) RLEP LAMP, provided product specifications for customization of a ready-to-use kit (intended for commercial production) and compared it against the in-house prototype. The assays were optimized for application on a Genie® III portable fluorometer. For technical validation, 40 “must not detect RLEP” samples derived from RLEP qPCR negative exposed and non-exposed individuals, as well as from patients with other conditions and a set of closely related mycobacterial cultures, were tested together with 25 “must detect RLEP” samples derived from qPCR confirmed leprosy patients. For clinical validation, 150 RLEP qPCR tested samples were analyzed, consisting of the following categories: high-positive samples of multibacillary (MB) leprosy patients (> 10.000 bacilli/extract), medium-positive samples of MB leprosy patients (1.001–10.000 bacilli/extract), low-positive samples of MB leprosy patients (1–1.000 bacilli/extract), endemic controls and healthy non-exposed controls; each n = 30. Results Technical validation: both LAMP formats had a limit of detection of 1.000 RLEP copies, i.e. 43–27 bacilli, a sensitivity of 92% (in-house protocol)/100% (ready-to-use protocol) and a specificity of 100%. Reagents were stable for at least 1 year at 22 °C. Clinical validation: Both formats showed a negativity rate of 100% and a positivity rate of 100% for high-positive samples and 93–100% for medium positive samples, together with a positive predictive value of 100% and semi-quantitative results. The positivity rate for low-positive samples was 77% (in-house protocol)/43% (ready-to-use protocol) and differed significantly between both formats. Conclusions The ready-to-use RLEP DRB LAMP assay constitutes an ASSURED test ready for field-based evaluation trials aiming for routine diagnosis of leprosy at the primary health care level.

A Unilateral Robotic Knee Exoskeleton to Assess the Role of Natural Gait Assistance in Hemiparetic Patients

Background: Hemiparetic gait is characterized by strong asymmetries that could severely affect the quality of life of stroke survivors. This asymmetry is due to motor deficits in the paretic leg and the resulting compensations in the non-paretic limb. In this study, we aim to evaluate the effect of actively promoting gait symmetry in hemiparetic patients by assessing the behavior of both paretic and non-paretic lower limbs. This paper introduces the design and validation of the REFLEX prototype, a unilateral active Knee-Ankle-Foot Orthosis able to naturally assist the paretic limb of hemiparetic patients during gait.Methods: REFLEX uses an Adaptive Frequency Oscillator to estimate the continuous gait phase of the non-paretic limb. Based on this estimation, the device synchronically assists the paretic leg following two different control strategies: (1) Replicating the movement of the sound leg or (2) Inducing a healthy gait pattern on the paretic leg. Technical validation of the system was implemented on three healthy subjects, while the effect of the generated assistance was assessed in three stroke patients. Results: Preliminary results proved the feasibility of the REFLEX prototype to assist gait by reinforcing symmetry. They also pointed out that the assistance of the paretic leg resulted in a decrease of the compensatory strategies developed by the non-paretic limb to achieve a functional gait. Notably, better results were attained when the assistance was provided according to a standard healthy pattern, which initially might suppose a lower symmetry but enabled a healthier evolution of the motion of the non-paretic limb.Conclusions: This work presents the preliminary validation of the REFLEX prototype, a unilateral knee exoskeleton for gait assistance in hemiparetic patients. The experimental results indicate that assisting the paretic leg of hemiparetic patients based on the movement of their non-paretic one is a valuable strategy for reducing the compensatory mechanisms developed by their sound limb.

Amacompri information system for postpartum nursing monitoring

Background: First-time mothers require greater nursing accompaniment in the postpartum period due to their lack of expertise and preparation for the new challenges of motherhood. Information and communication technologies (ICTCs) allow easy access to learning habits for the transition into motherhood; however, the lack of technological appropriation for postpartum monitoring becomes evident in developing countries and in the Western world. Methods: This study developed the Amacompri postpartum nursing tracking information system, which is based on Mercer's theory of becoming a mother and discusses the vital environment: First-time mother’s family and friends. The Amacompri software was designed using the SCRUM methodology, java web technologies and PostgreSQL database. Results: This information system features a web version and a mobile App. The technical validation involved 10 experts, and the validation by population 10 first-time mothers. This first group reviewed the quality of presentation and content in the early stages of the software. Finally, the Amacompri system was used for 4 months by 33 first-time mothers, who evaluated the application for design, usability, and applicability. Amacompri software was effective for non-face-to-face nursing accompaniment to first-time mothers. Conclusions: The Amacompri software was designed based on Mercer's theory of becoming a mother, and has been technically validated (experts) and validated by population (first mothers), demonstrating its quality in both presentation and content. Its evaluation demonstrated its effectiveness in meeting the development objective. In this context, the Amacompri software meets multimedia requirements in the functional, technical-esthetic, and pedagogical aspects.

A Sensor-Based mHealth Platform for Remote Monitoring and Intervention of Frailty Patients at Home

Frailty syndrome is an independent risk factor for serious health episodes, disability, hospitalization, falls, loss of mobility, and cardiovascular disease. Its high reversibility demands personalized interventions among which exercise programs are highly efficient to contribute to its delay. Information technology-based solutions to support frailty have been recently approached, but most of them are focused on assessment and not on intervention. This paper describes a sensor-based mHealth platform integrated in a service-based architecture inside the FRAIL project towards the remote monitoring and intervention of pre-frail and frail patients at home. The aim of this platform is constituting an efficient and scalable system for reducing both the impact of aging and the advance of frailty syndrome. Among the results of this work are: (1) the development of elderly-focused sensors and platform; (2) a technical validation process of the sensor devices and the mHealth platform with young adults; and (3) an assessment of usability and acceptability of the devices with a set of pre-frail and frail patients. After the promising results obtained, future steps of this work involve performing a clinical validation in order to quantify the impact of the platform on health outcomes of frail patients.

Update to the dataset of cerebral ischemia in juvenile pigs with evoked potentials

We expand from a spontaneous to an evoked potentials (EP) data set of brain electrical activities as electrocorticogram (ECoG) and electrothalamogram (EThG) in juvenile pig under various sedation, ischemia and recovery states. This EP data set includes three stimulation paradigms: auditory (AEP, 40 and 2000 Hz), sensory (SEP, left and right maxillary nerve) and high-frequency oscillations (HFO) SEP. This permits derivation of electroencephalogram (EEG) biomarkers of corticothalamic communication under these conditions. The data set is presented in full band sampled at 2000 Hz. We provide technical validation of the evoked responses for the states of sedation, ischemia and recovery. This extended data set now permits mutual inferences between spontaneous and evoked activities across the recorded modalities. Future studies on the dataset may contribute to the development of new brain monitoring technologies, which will facilitate the prevention of neurological injuries.