| 1. |
- Laurie, Steven, et al.
(författare)
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The RD-Connect Genome-Phenome Analysis Platform : Accelerating diagnosis, research, and gene discovery for rare diseases
- 2022
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Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 43:6, s. 717-733
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Tidskriftsartikel (refereegranskat)abstract
- Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes.
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| 2. |
- Poli, Sven, et al.
(författare)
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Penumbral Rescue by normobaric O?=?O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial
- 2024
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Ingår i: INTERNATIONAL JOURNAL OF STROKE. - 1747-4930 .- 1747-4949. ; 19:1, s. 120-126
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs.Aims: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion.Methods and design: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial.Study outcomes: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted.Sample size: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation.Discussion: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia.
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| 3. |
- Schoenmakers, Daphne H., et al.
(författare)
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Inventory of current practices regarding hematopoietic stem cell transplantation in metachromatic leukodystrophy in Europe and neighboring countries
- 2024
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Ingår i: Orphanet Journal of Rare Diseases. - 1750-1172. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: For decades, early allogeneic stem cell transplantation (HSCT) has been used to slow neurological decline in metachromatic leukodystrophy (MLD). There is lack of consensus regarding who may benefit, and guidelines are lacking. Clinical practice relies on limited literature and expert opinions. The European Reference Network for Rare Neurological Diseases (ERN-RND) and the MLD initiative facilitate expert panels for treatment advice, but some countries are underrepresented. This study explores organizational and clinical HSCT practices for MLD in Europe and neighboring countries to enhance optimization and harmonization of cross-border MLD care. Methods: A web-based EUSurvey was distributed through the ERN-RND and the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Personal invitations were sent to 89 physicians (43 countries) with neurological/metabolic/hematological expertise. The results were analyzed and visualized using Microsoft Excel and IBM SPSS statistics. Results: Of the 30 countries represented by 42 respondents, 23 countries offer HSCT for MLD. The treatment is usually available in 1–3 centers per country (18/23, 78%). Most countries have no or very few MLD patients transplanted during the past 1–5 years. The eligibility criteria regarding MLD subtype, motor function, IQ, and MRI largely differ across countries. Conclusion: HSCT for MLD is available in most European countries, but uncertainties exist in Eastern and South-Eastern Europe. Applied eligibility criteria and management vary and may not align with the latest scientific insights, indicating physicians’ struggle in providing evidence-based care. Interaction between local physicians and international experts is crucial for adequate treatment decision-making and cross-border care in the rapidly changing MLD field.
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