The definition of neuronopathic Gaucher disease.

Neuronopathic Gaucher disease (nGD) has a very wide clinical and genotypic spectrum. However, there is no consensus definition of nGD, including no description of how best to diagnostically separate the acute form-Gaucher type 2-from the subacute or chronic form-Gaucher type 3. In this article, we define the various forms of Gaucher disease with particular emphasis on the presence of gaze palsy in all patients with nGD. This consensus definition will help in both clinical diagnosis and appropriate patient recruitment to upcoming clinical trials.

Accuracy of serum procalcitonin for the diagnosis of sepsis in neonates and children with systemic inflammatory syndrome: a meta-analysis.

BACKGROUND: A number of biomarkers have been studied for the diagnosis of sepsis in paediatrics, but no gold standard has been identified. Procalcitonin (PCT) was demonstrated to be an accurate biomarker for the diagnosis of sepsis in adults and showed to be promising in paediatrics. Our study reviewed the diagnostic accuracy of PCT as an early biomarker of sepsis in neonates and children with suspected sepsis. METHODS: A comprehensive literature search was carried out in Medline/Pubmed, Embase, ISI Web of Science, CINAHL and Cochrane Library, for studies assessing PCT accuracy in the diagnosis of sepsis in children and neonates with suspected sepsis. Studies in which the presence of infection had been confirmed microbiologically or classified as "probable" by chart review were included. Studies comparing patients to healthy subjects were excluded. We analysed data on neonates and children separately. Our primary outcome was the diagnostic accuracy of PCT at the cut-off of 2-2.5 ng/ml, while as secondary outcomes we analysed PCT cut-offs <2 ng/ml and >2.5 ng/ml. Pooled sensitivities and specificities were calculated by a bivariate meta-analysis and heterogeneity was graphically evaluated. RESULTS: We included 17 studies, with a total of 1408 patients (1086 neonates and 322 children). Studies on neonates with early onset sepsis (EOS) and late onset sepsis (LOS) were grouped together. In the neonatal group, we calculated a sensitivity of 0.85, confidence interval (CI) (0.76; 0.90) and specificity of 0.54, CI (0.38; 0.70) at the PCT cut-off of 2.0-2.5 ng/ml. In the paediatric group it was not possible to undertake a pooled analysis at the PCT cut-off of 2.0-2.5 ng/ml, due to the paucity of the studies. CONCLUSIONS: PCT shows a moderate accuracy for the diagnosis of sepsis in neonates with suspected sepsis at the cut-off of 2.0-2.5 ng/ml. More studies with high methodological quality are warranted, particularly in neonates, studies considering EOS and LOS separately are needed to improve specificity. TRIAL REGISTRATION: PROSPERO Identifier: CRD42016033809 . Registered 30 Jan 2016.

Video-based assessments of activities of daily living: generating real-world evidence in pediatric rare diseases.

INTRODUCTION: Preserving function and independence to perform activities of daily living (ADL) is critical for patients and carers to manage the burden of care and improve quality of life. In children living with rare diseases, video recording ADLs offer the opportunity to collect the patients' experience in a real-life setting and accurately reflect treatment effectiveness on outcomes that matter to patients and families. AREAS COVERED: We reviewed the measurement of ADL in pediatric rare diseases and the use of video to develop at-home electronic clinical outcome assessments (eCOA) by leveraging smartphone apps and artificial intelligence-based analysis. We broadly searched PubMed using Boolean combinations of the following MeSH terms 'Rare Diseases,' 'Quality of Life,' 'Activities of Daily Living,' 'Child,' 'Video Recording,' 'Outcome Assessment, Healthcare,' 'Intellectual disability,' and 'Genetic Diseases, Inborn.' Non-controlled vocabulary was used to include human pose estimation in movement analysis. EXPERT OPINION: Broad uptake of video eCOA in drug development is linked to the generation of technical and clinical validation evidence to confidently assess a patient's functional abilities. Software platforms handling video data must align with quality regulations to ensure data integrity, security, and privacy. Regulatory flexibility and optimized validation processes should facilitate video eCOA to support benefit/risk drug assessment.

Key considerations for digital decentralised clinical trials from a feasibility study assessing pacing interventions for long COVID.

Post COVID-19 condition or long COVID is highly prevalent and often debilitating, with key symptoms including fatigue, breathlessness, and brain fog. There is currently a lack of evidence-based treatments for this highly complex syndrome. There is a need for clinical trial platforms to rapidly evaluate nonpharmacological treatments to support affected individuals with symptom management. We co-produced a mixed methods feasibility study to evaluate a multi-arm digital decentralised clinical trial (DCT) platform to assess non-pharmacological interventions for Long COVID, using pacing interventions as an exemplar. The study demonstrated that the platform was able to successfully e-consent participants, randomise them into one of four intervention arms, capture baseline data, and capture outcomes relevant to a health economic evaluation. The study also highlighted several challenges, including difficulties with recruitment, imposter participants, and high attrition rates. We highlight how these challenges can potentially be mitigated to make a fully powered DCT more feasible.

Protocol for a mixed-methods study to develop and feasibility test a digital system for the capture of patient-reported outcomes (PROs) in patients receiving chimeric antigen receptor T-cell (CAR-T) therapies (the PRO-CAR-T study).

INTRODUCTION: Chimeric antigen receptor (CAR) T-cell therapies are novel, potentially curative therapies for haematological malignancies. CAR T-cell therapies are associated with severe toxicities, meaning patients require monitoring during acute and postacute treatment phases. Electronic patient-reported outcomes (ePROs), self-reports of health status provided via online questionnaires, can complement clinician observation with potential to improve patient outcomes. This study will develop and evaluate feasibility of a new ePRO system for CAR-T patients in routine care. METHODS AND ANALYSIS: Multiphase, mixed-methods study involving multiple stakeholder groups (patients, family members, carers, clinicians, academics/researchers and policy-makers). The intervention development phase comprises a Delphi study to select PRO measures for the digital system, a codesign workshop and consensus meetings to establish thresholds for notifications to the clinical team if a patient reports severe symptoms or side effects. Usability testing will evaluate how users interact with the digital system and, lastly, we will evaluate ePRO system feasibility with 30 CAR-T patients (adults aged 18+ years) when used in addition to usual care. Feasibility study participants will use the ePRO system to submit self-reports of symptoms, treatment tolerability and quality of life at specific time points. The CAR-T clinical team will respond to system notifications triggered by patients' submitted responses with actions in line with standard clinical practice. Feasibility measures will be collected at prespecified time points following CAR T-cell infusion. A qualitative substudy involving patients and clinical team members will explore acceptability of the ePRO system. ETHICS AND DISSEMINATION: Favourable ethical opinion was granted by the Health and Social Care Research Ethics Committee B(HSC REC B) (ref: 23/NI/0104) on 28 September 2023. Findings will be submitted for publication in high-quality, peer-reviewed journals. Summaries of results, codeveloped with the Blood and Transplant Research Unit Patient and Public Involvement and Engagement group, will be disseminated to all interested groups. TRIAL REGISTRATION NUMBER: ISCTRN11232653.

A patient-centred and multi-stakeholder co-designed observational prospective study protocol: Example of the adolescent experience of treatment for X-linked hypophosphataemia (XLH).

The importance of patient centricity and keeping the patient at the heart of research design is now well recognised within the healthcare community. The involvement of patient, caregiver and clinician representatives in the study design process may help researchers to achieve this goal and to ensure robust and meaningful data generation. Real-world data collection allows for a more flexible and patient-centred research approach for gaining important insights into the experience of disease and treatments, which is acutely relevant for rare diseases where knowledge about the disease is more likely to be limited. Here, we describe a practical example of a patient-centric, multi-stakeholder approach that led to the co-design of a prospective observational study investigating the lived experience of adolescents with the rare disease, X-linked hypophosphataemia. Specifically, we describe how the knowledge and expertise of a diverse research team, which included expert physicians, research and technology specialists, patients and caregivers, were applied in order to identify the relevant research questions and to ensure the robustness of the study design and its appropriateness to the population of interest within the context of the current clinical landscape. We also demonstrate how a structured patient engagement exercise was key to informing the selection of appropriate outcome measures, data sources, timing of data collection, and to assessing the feasibility and acceptability of the proposed data collection approach.

Recommendations to address respondent burden associated with patient-reported outcome assessment.

Patient-reported outcomes (PROs) are increasingly used in healthcare research to provide evidence of the benefits and risks of interventions from the patient perspective and to inform regulatory decisions and health policy. The use of PROs in clinical practice can facilitate symptom monitoring, tailor care to individual needs, aid clinical decision-making and inform value-based healthcare initiatives. Despite their benefits, there are concerns that the potential burden on respondents may reduce their willingness to complete PROs, with potential impact on the completeness and quality of the data for decision-making. We therefore conducted an initial literature review to generate a list of candidate recommendations aimed at reducing respondent burden. This was followed by a two-stage Delphi survey by an international multi-stakeholder group. A consensus meeting was held to finalize the recommendations. The final consensus statement includes 19 recommendations to address PRO respondent burden in healthcare research and clinical practice. If implemented, these recommendations may reduce PRO respondent burden.

So You Want to Build Your Disease's First Online Patient Registry: An Educational Guide for Patient Organizations Based on US and European Experience.

Patient registries fulfill a number of key roles for clinicians, researchers, non-profit organizations, payers, and policy makers. They can help the field understand the natural history of a condition, determine the effectiveness of interventions, measure safety, and audit the quality of care provided. Successful registries in cystic fibrosis, Duchenne's muscular dystrophy, and other rare diseases have become a model for accelerating progress. However, the complex tasks required to develop a modern registry can seem overwhelming, particularly for those who are not from a technical background. In this Education article, a team of co-authors from across patient advocacy, technology, privacy, and commercial perspectives who have worked on a number of such projects offer a "Registry 101" primer to help get started. We will outline the promise and potential of patient registries with worked case examples, identify some of the key technical considerations you will need to consider, describe the type of data you might want to collect, consider privacy risks to protect your users, sketch out some of the paths towards long-term financial sustainability we have observed, and conclude with plans to mitigate some of the challenges that can occur and signpost interested readers to further resources. While rapid growth in the digital health market has presented numerous opportunities to those at the beginning of their journey, it is important to start with the long-term goals in mind and to benefit from the learnings of those who have walked this path before.

Accelerometer-derived sleep measures in idiopathic dystonia: A UK Biobank cohort study.

BACKGROUND: Sleep disturbance is an increasingly recognized non-motor trait in dystonia, with varying findings reported to date. Here, we examine sleep in a UK Biobank derived dystonia cohort using subjective self-reported sleep symptoms and objective accelerometer-derived sleep measures, with comparison to a control population. METHODS: A total of 241 dystonia cases were compared to 964 matched controls in analysis of self-reported sleep symptoms and changes in sleep architecture using wrist-worn triaxial accelerometers. RESULTS: Dystonia participants had poorer self-reported sleep patterns compared to controls. Accelerometery measurements demonstrated later sleep times, reduced time in bed, and shifts in circadian rhythm. No association was observed with pain, and only limited relationships with psychiatric symptoms. DISCUSSION: This study demonstrates the utility of accelerometers in longer term evaluation of sleep in dystonia, for measurement of disturbance and response to treatment. Compared to controls, altered sleep and circadian rhythm were more common in dystonia patients which may contribute to the clinical phenotype.

Use of remote monitoring and integrated platform for the evaluation of sleep quality in adult-onset idiopathic cervical dystonia.

BACKGROUND: Up to 70% of individuals diagnosed with adult-onset idiopathic focal cervical dystonia (AOIFCD) report difficulties with sleep. Larger cohort studies using wrist-worn accelerometer devices have emerged as an alternative to smaller polysomnography studies, in order to evaluate sleep architecture. METHODS: To measure activity during the sleep/wake cycle, individuals wore a consumer-grade wrist device (Garmin vivosmart 4) continuously over 7 days on their non-dominant wrist, while completing a daily sleep diary and standardised sleep and non-motor questionnaires via a dedicated app. Sleep measures were derived from the captured raw triaxial acceleration and heart rate values using previously published validated algorithms. RESULTS: Data were collected from 50 individuals diagnosed with AOIFCD and 47 age- and sex-matched controls. Those with AOIFCD self-reported significantly higher levels of excessive daytime sleepiness (p = 0.04) and impaired sleep quality (p = 0.03), while accelerometer measurements found the AOIFCD cohort to have significantly longer total sleep times (p = 0.004) and time spent in NREM sleep (p = 0.009), compared to controls. Overall, there was limited agreement between wearable-derived sleep parameters, and self-reported sleep diary and visual analogue scale records. DISCUSSION: This study shows the potential feasibility of using consumer-grade wearable devices in estimating sleep measures at scale in dystonia cohorts. Those diagnosed with AOIFCD were observed to have altered sleep architecture, notably longer total sleep time and NREM sleep, compared to controls. These findings suggest that previously reported disruptions to brainstem circuitry and serotonin neurotransmission may contribute to both motor and sleep pathophysiology.

A global neuronopathic gaucher disease registry (GARDIAN): a patient-led initiative.

BACKGROUND: Gaucher disease (GD) is a rare autosomal recessive lysosomal storage disorder. GD types 2 and 3 are known as neuronopathic Gaucher disease (nGD) because they have brain involvement that progresses over time. Implementing a systematic approach to the collection of real-world clinical and patient-relevant outcomes data in nGD presents an opportunity to fill critical knowledge gaps and ultimately help healthcare providers in the management of this patient population. This paper summarizes the development of a patient-initiated Gaucher Registry for Development Innovation and Analysis of Neuronopathic Disease (GARDIAN). METHODS: The International Gaucher Alliance led the GARDIAN planning, including governance, scope, stakeholder involvement, platform, and reporting. Registry element input was determined in a series of meetings with clinical experts, patients, and caregivers, who identified key clinical variables and the draft content of nGD patient-reported outcomes (PRO) and observer-reported outcomes (ObsRO) focusing on symptoms, patient physical and emotional functioning. These were then tested in cognitive interviews with patients with nGD (> 12 years of age) and caregivers. RESULTS: Core registry data elements (n = 138) were identified by seven global clinical experts from Egypt, Germany, Israel, Japan, United Kingdom (UK), and United State (US) and reviewed via online Delphi method by 14 additional clinicians with experience of nGD from six countries and three pharmaceutical representatives. The elements were consistent with those identified via interviews with 10 patients/caregivers with nGD from Japan, Sweden, UK, and US. Key domains identified were demographics, diagnostic information, health status, clinical symptomatology, laboratory testing, treatment, healthcare resource utilization, aids/home improvements, and patient/caregiver burden and quality of life, specifically physical functioning, self-care, daily and social activities, emotional impacts, support services, and caregiver-specific impacts. Nine caregivers and six patients from the US, UK, China, Mexico, Egypt, and Japan participated in the cognitive interviews that informed revisions to ensure that all items are understandable and interpreted as intended. CONCLUSIONS: The comprehensive set of clinical and patient relevant outcomes data, developed collaboratively among all stakeholders, to be reported using GARDIAN will bridge the many gaps in the understanding of nGD and align with regulatory frameworks on real-world data needs.

Patient-reported, health economic and psychosocial outcomes in patients with Friedreich ataxia (PROFA): protocol of an observational study using momentary data assessments via mobile health app.

INTRODUCTION: Friedreich ataxia (FA) is the most common hereditary ataxia in Europe, characterised by progressively worsening movement and speech impairments with a typical onset before the age of 25 years. The symptoms affect the patients' health-related quality of life (HRQoL) and psychosocial health. FA leads to an increasing need for care, associated with an economic burden. Little is known about the impact of FA on daily lives and HRQoL. To fill that gap, we will assess patient-reported, psychosocial and economic outcomes using momentary data assessment via a mobile health application (app). METHODS AND ANALYSIS: The PROFA Study is a prospective observational study. Patients with FA (n=200) will be recruited at six European study centres (Germany, France and Austria). We will interview patients at baseline in the study centre and subsequently assess the patients' health at home via mobile health app. Patients will self-report ataxia severity, HRQoL, speech and hearing disabilities, coping strategies and well-being, health services usage, adverse health events and productivity losses due to informal care on a daily to monthly basis on the app for 6 months. Our study aims to (1) validate measurements of HRQoL and psychosocial health, (2) assess the usability of the mobile health app, and (3) use descriptive and multivariate statistics to analyse patient-reported and economic outcomes and the interaction effects between these outcomes. Insights into the app's usability could be used for future studies using momentary data assessments to measure outcomes of patients with FA. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of the University Medicine of Greifswald, (BB096/22a, 26 October 2022) and from all local ethics committees of the participating study sites. Findings of the study will be published in peer-reviewed journals, presented at relevant international/national congresses and disseminated to German and French Patient Advocacy Organizations. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05943002); Pre-results.

Co-production of a feasibility trial of pacing interventions for Long COVID.

BACKGROUND: The high incidence of COVID-19 globally has led to a large prevalence of Long COVID but there is a lack of evidence-based treatments. There is a need to evaluate existing treatments for symptoms associated with Long COVID. However, there is first a need to evaluate the feasibility of undertaking randomised controlled trials of interventions for the condition. We aimed to co-produce a feasibility study of non-pharmacological interventions to support people with Long COVID. METHODS: A consensus workshop on research prioritisation was conducted with patients and other stakeholders. This was followed by the co-production of the feasibility trial with a group of patient partners, which included the design of the study, the selection of interventions, and the production of dissemination strategies. RESULTS: The consensus workshop was attended by 23 stakeholders, including six patients. The consensus from the workshop was to develop a clinical trial platform that focused on testing different pacing interventions and resources. For the co-production of the feasibility trial, patient partners selected three pacing resources to evaluate (video, mobile application, and book) and co-designed feasibility study processes, study materials and undertook usability testing of the digital trial platform. CONCLUSION: In conclusion, this paper reports the principles and process used to co-produce a feasibility study of pacing interventions for Long COVID. Co-production was effective and influenced important aspects of the study.

The World Health Organisation defines Long COVID as a condition which impacts people 3 months after they first had COVID-19. Some of the symptoms that characterise Long COVID symptoms include fatigue, breathlessness and brain fog. These symptoms have a major impact on people's health and quality of life. Today, over 2 million people in the United Kingdom suffer from Long COVID and there is a lack of drugs and non-drugs treatment. However, some non-drugs treatments which aim to manage fatigue in other conditions, such as pacing, could be used with people with Long COVID. In this paper, we report how we co-produced a study which tested whether or not it is feasible for people who have Long COVID to use a pacing resource and report their symptoms using an electronic platform. After a meeting to review existing non-drugs treatments, the research team and a group of patient partners agreed on co-developing a clinical trial platform to test different pacing resources. The research team then met with the patient partners twice a week to co-design the study during which people with Long COVID will use the pacing resources and report their symptoms. They also co-designed the study documents and how to report its results. Co-producing a study with patient partners was effective and influenced important aspects of the study.

Towards the international interoperability of clinical research networks for rare diseases: recommendations from the IRDiRC Task Force.

BACKGROUND: Many patients with rare diseases are still lacking a timely diagnosis and approved therapies for their condition despite the tremendous efforts of the research community, biopharmaceutical, medical device industries, and patient support groups. The development of clinical research networks for rare diseases offers a tremendous opportunity for patients and multi-disciplinary teams to collaborate, share expertise, gain better understanding on specific rare diseases, and accelerate clinical research and innovation. Clinical Research Networks have been developed at a national or continental level, but global collaborative efforts to connect them are still lacking. The International Rare Diseases Research Consortium set a Task Force on Clinical Research Networks for Rare Diseases with the objective to analyse the structure and attributes of these networks and to identify the barriers and needs preventing their international collaboration. The Task Force created a survey and sent it to pre-identified clinical research networks located worldwide. RESULTS: A total of 34 responses were received. The survey analysis demonstrated that clinical research networks are diverse in their membership composition and emphasize community partnerships including patient groups, health care providers and researchers. The sustainability of the networks is mostly supported by public funding. Activities and research carried out at the networks span the research continuum from basic to clinical to translational research studies. Key elements and infrastructures conducive to collaboration are well adopted by the networks, but barriers to international interoperability are clearly identified. These hurdles can be grouped into five categories: funding limitation; lack of harmonization in regulatory and contracting process; need for common tools and data standards; need for a governance framework and coordination structures; and lack of awareness and robust interactions between networks. CONCLUSIONS: Through this analysis, the Task Force identified key elements that should support both developing and established clinical research networks for rare diseases in implementing the appropriate structures to achieve international interoperability worldwide. A global roadmap of actions and a specific research agenda, as suggested by this group, provides a platform to identify common goals between these networks.

Considerations for patient and public involvement and engagement in health research.

Patient and public involvement and engagement (PPIE) can provide valuable insights into the experiences of those living with and affected by a disease or health condition. Inclusive collaboration between patients, the public and researchers can lead to productive relationships, ensuring that health research addresses patient needs. Guidelines are available to support effective PPIE; however, evaluation of the impact of PPIE strategies in health research is limited. In this Review, we evaluate the impact of PPIE in the 'Therapies for Long COVID in non-hospitalised individuals' (TLC) Study, using a combination of group discussions and interviews with patient partners and researchers. We identify areas of good practice and reflect on areas for improvement. Using these insights and the results of a survey, we synthesize two checklists of considerations for PPIE, and we propose that research teams use these checklists to optimize the impact of PPIE for both patients and researchers in future studies.

Development and usability testing of an electronic patient-reported outcome (ePRO) solution for patients with inflammatory diseases in an Advanced Therapy Medicinal Product (ATMP) basket trial.

BACKGROUND: Electronic patient-reported outcome (ePRO) systems are increasingly used in clinical trials to provide evidence of efficacy and tolerability of treatment from the patient perspective. The aim of this study is twofold: (1) to describe how we developed an electronic platform for patients to report their symptoms, and (2) to develop and undertake usability testing of an ePRO solution for use in a study of cell therapy seeking to provide early evidence of efficacy and tolerability of treatment and test the feasibility of the system for use in later phase studies. METHODS: An ePRO system was designed to be used in a single arm, multi-centre, phase II basket trial investigating the safety and activity of the use of ORBCEL-C™ in the treatment of patients with inflammatory conditions. ORBCEL-C™ is an enriched Mesenchymal Stromal Cells product isolated from human umbilical cord tissue using CD362+ cell selection. Usability testing sessions were conducted using cognitive interviews and the 'Think Aloud' method with patient advisory group members and Research Nurses to assess the usability of the system. RESULTS: Nine patient partners and seven research nurses took part in one usability testing session. Measures of fatigue and health-related quality of life, the PRO-CTCAE™ and FACT-GP5 global tolerability question were included in the ePRO system. Alert notifications to the clinical team were triggered by PRO-CTCAE™ and FACT-GP5 scores. Patient participants liked the simplicity and responsiveness of the patient-facing app. Two patients were unable to complete the testing session, due to technical issues. Research Nurses suggested minor modifications to improve functionality and the layout of the clinician dashboard and the training materials. CONCLUSION: By testing the effectiveness, efficiency, and satisfaction of our novel ePRO system (PROmicsR), we learnt that most people with an inflammatory condition found it easy to report their symptoms using an app on their own device. Their experiences using the PROmicsR ePRO system within a trial environment will be further explored in our upcoming feasibility testing. Research nurses were also positive and found the clinical dashboard easy-to-use. Using ePROs in early phase trials is important in order to provide evidence of therapeutic responses and tolerability, increase the evidence based, and inform methodology development. TRIAL REGISTRATION: ISRCTN, ISRCTN80103507. Registered 01 April 2022, https://www.isrctn.com/ISRCTN80103507.

More and more patients tell clinicians how they feel by completing questionnaires electronically. Therefore, it is important to assess how easy it is for patients to do this. In this study, we describe how we developed an electronic platform for patients to report their symptoms and how we tested the usability of this platform with patient partners and research nurses. Once the electronic platform was developed, quality of life and symptoms questionnaires were programmed onto it. Alerts were sent to the clinical team if specific scores were obtained on the symptoms questionnaires. Although two patient partners were not able to finish the testing session because of technical issues, the ones who completed the session liked its simplicity and responsiveness. The research nurses also liked the system and only suggested minor modifications. Following this testing, we refined the electronic platform to test it further in a larger study which investigates the safety and use of a drug. We hope that thanks to this electronic platform, we will obtain useful information on the safety and efficacy of treatment.

Precision Medicine for More Oxygen (P4O2)-Study Design and First Results of the Long COVID-19 Extension.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has led to the death of almost 7 million people, however, with a cumulative incidence of 0.76 billion, most people survive COVID-19. Several studies indicate that the acute phase of COVID-19 may be followed by persistent symptoms including fatigue, dyspnea, headache, musculoskeletal symptoms, and pulmonary functional-and radiological abnormalities. However, the impact of COVID-19 on long-term health outcomes remains to be elucidated. Aims: The Precision Medicine for more Oxygen (P4O2) consortium COVID-19 extension aims to identify long COVID patients that are at risk for developing chronic lung disease and furthermore, to identify treatable traits and innovative personalized therapeutic strategies for prevention and treatment. This study aims to describe the study design and first results of the P4O2 COVID-19 cohort. Methods: The P4O2 COVID-19 study is a prospective multicenter cohort study that includes nested personalized counseling intervention trial. Patients, aged 40-65 years, were recruited from outpatient post-COVID clinics from five hospitals in The Netherlands. During study visits at 3-6 and 12-18 months post-COVID-19, data from medical records, pulmonary function tests, chest computed tomography scans and biological samples were collected and questionnaires were administered. Furthermore, exposome data was collected at the patient's home and state-of-the-art imaging techniques as well as multi-omics analyses will be performed on collected data. Results: 95 long COVID patients were enrolled between May 2021 and September 2022. The current study showed persistence of clinical symptoms and signs of pulmonary function test/radiological abnormalities in post-COVID patients at 3-6 months post-COVID. The most commonly reported symptoms included respiratory symptoms (78.9%), neurological symptoms (68.4%) and fatigue (67.4%). Female sex and infection with the Delta, compared with the Beta, SARS-CoV-2 variant were significantly associated with more persisting symptom categories. Conclusions: The P4O2 COVID-19 study contributes to our understanding of the long-term health impacts of COVID-19. Furthermore, P4O2 COVID-19 can lead to the identification of different phenotypes of long COVID patients, for example those that are at risk for developing chronic lung disease. Understanding the mechanisms behind the different phenotypes and identifying these patients at an early stage can help to develop and optimize prevention and treatment strategies.

Time to See the Difference: Video Capture for Patient-Centered Clinical Trials.

Developing therapeutics for the treatment of rare diseases usually requires a strong understanding of the natural history of the disease. Often, it also requires the creation of novel assessment tools and clinical trial endpoints. In diseases where mobility is impacted, the use of video to capture the impact of the disease and the assessment of specific parameters, such as gait and stride length, can help design sensitive endpoints. Video as an assessment tool also allows the use of historical videos or videos filmed by non-experts outside of clinical settings. Given the increased use of telemedicine, the use of video may be a useful addition to clinical trial assessments. Two cases are presented: (1) the use of video in the development of asfotase alfa (Strensiq®) in hypophosphatasia is detailed as an example of the utility of this type of assessment in rare diseases; and (2) a home-setting video tool that was developed and validated (SARAhome) from a commonly used clinical scale (Scale for the Assessment and Rating of Ataxia [SARA]), allowing patients to record their own severity of ataxia. While there are certain limitations associated with video assessment, advancing technologies such as automated analysis and machine learning provide a tremendous opportunity for automated analysis of video recordings, reducing the bias associated with human assessment.

Patient-led development of digital endpoints and the use of computer vision analysis in assessment of motor function in rare diseases.

Digital health technologies are transforming the way health outcomes are captured and measured. Digital biomarkers may provide more objective measurements than traditional approaches as they encompass continuous and longitudinal data collection and use of automated analysis for data interpretation. In addition, the use of digital health technology allows for home-based disease assessments, which in addition to reducing patient burden from on-site hospital visits, provides a more holistic picture of how the patient feels and functions in the real world. Tools that can robustly capture drug efficacy based on disease-specific outcomes that are meaningful to patients, are going to be key to the successful development of new treatments. This is particularly important for people living with rare and chronic complex conditions, where therapeutic options are limited and need to be developed using a patient-focused approach to achieve the biggest impact. Working in partnership with patient Organisation Duchenne UK, we co-developed a video-based approach, delivered through a new mobile health platform (DMD Home), to assess motor function in patients with Duchenne muscular dystrophy (DMD), a genetic, rare, muscular disease characterized by the progressive loss of muscle function and strength. Motor function tasks were selected to reflect the "transfer stage" of the disease, when patients are no longer able to walk independently but can stand and weight-bear to transfer. This stage is important for patients and families as it represents a significant milestone in the progression of DMD but it is not routinely captured and/or scored by standard DMD clinical and physiotherapy assessments. A total of 62 videos were submitted by eight out of eleven participants who onboarded the app and were analysed with pose estimation software (OpenPose) that led to the extraction of objective, quantitative measures, including time, pattern of movement trajectory, and smoothness and symmetry of movement. Computer vision analysis of video tasks to identify voluntary or compensatory movements within the transfer stage merits further investigation. Longitudinal studies to validate DMD home as a new methodology to predict progression to the non-ambulant stage will be pursued.