BackgroundCollection of real-world evidence (RWE) is important in achondroplasia. Development of a prospective, shared, international resource that follows the principles of findability,... Show moreBackgroundCollection of real-world evidence (RWE) is important in achondroplasia. Development of a prospective, shared, international resource that follows the principles of findability, accessibility, interoperability, and reuse of digital assets, and that captures long-term, high-quality data, would improve understanding of the natural history of achondroplasia, quality of life, and related outcomes.MethodsThe Europe, Middle East, and Africa (EMEA) Achondroplasia Steering Committee comprises a multidisciplinary team of 17 clinical experts and 3 advocacy organization representatives. The committee undertook an exercise to identify essential data elements for a standardized prospective registry to study the natural history of achondroplasia and related outcomes.ResultsA range of RWE on achondroplasia is being collected at EMEA centres. Whereas commonalities exist, the data elements, methods used to collect and store them, and frequency of collection vary. The topics considered most important for collection were auxological measures, sleep studies, quality of life, and neurological manifestations. Data considered essential for a prospective registry were grouped into six categories: demographics; diagnosis and patient measurements; medical issues; investigations and surgical events; medications; and outcomes possibly associated with achondroplasia treatments.ConclusionsLong-term, high-quality data are needed for this rare, multifaceted condition. Establishing registries that collect predefined data elements across age spans will provide contemporaneous prospective and longitudinal information and will be useful to improve clinical decision-making and management. It should be feasible to collect a minimum dataset with the flexibility to include country-specific criteria and pool data across countries to examine clinical outcomes associated with achondroplasia and different therapeutic approaches. Show less
Javaid, M.K.; Mordenti, M.; Boarini, M.; Sangiorgi, L.; Group, E.B.W.; Westerheim, I.; ... ; Grasemann, C. 2021
Background Understanding the natural history of rare bone and mineral conditions is essential for improving clinical practice and the development of new diagnostics and therapeutics. Recruitment... Show moreBackground Understanding the natural history of rare bone and mineral conditions is essential for improving clinical practice and the development of new diagnostics and therapeutics. Recruitment and long-term participation in registries are key challenges for researchers. Methods To understand the user needs, the European Reference Network on Rare Bone Diseases (ERN BOND) and European Patient Advocacy Groups developed and implemented a multinational survey about the patient's preferred database content and functionality through an iterative consensus process. The survey was disseminated by national and international patient groups and healthcare professionals. The findings were analysed using descriptive statistics and multivariate regression. Results There were 493 eligible responses from 378 adults, 15 children and 100 parents, guardians or carers (PGC) across 22 rare bone and mineral conditions. Osteogenesis imperfecta constituted 53.4% of responses. Contents related to improving treatment and medical services scored the highest and contents about anxiety and socializing scored less highly. Additional content was recommended by 205 respondents. Respondents preferred data entry by their Healthcare Provider (HCP). However, less than 50% of adults received followup from their specialist HCP at least annually and 29% were followed up as needed. Conclusions This survey of individuals, their family, guardians and carers has prioritised the key components for an EU-based rare bone and mineral condition research database. The survey highlights issues around collecting psychosocial impacts as well as measures of HCP trust. The survey demonstrated that using only specialist centre visits for data collection, while preferred by patients, will miss a substantial number of individuals, limiting generalisability. Combined HCP and patient platforms will be required to collect representative and complete natural history data for this patient group. Show less
Objective Changes in protein glycosylation are a hallmark of immune-mediated diseases. Glycans are master regulators of the inflammatory response and are important molecules in self-nonself... Show moreObjective Changes in protein glycosylation are a hallmark of immune-mediated diseases. Glycans are master regulators of the inflammatory response and are important molecules in self-nonself discrimination. This study was undertaken to investigate whether lupus nephritis (LN) exhibits altered cellular glycosylation to identify a unique glycosignature that characterizes LN pathogenesis. Methods A comprehensive tissue glycomics characterization was performed in kidney specimens from patients with systemic lupus erythematosus and biopsy-proven LN. A combination of advanced tissue mass spectrometry, in situ glyco-characterization, and ex vivo glycophenotyping was performed to structurally map the repertoire of N-glycans in LN tissue samples. Results LN exhibited a unique glycan signature characterized by increased abundance and spatial distribution of unusual mannose-enriched glycans that are typically found in lower microorganisms. This glycosignature was specific for LN, as it was not observed in other kidney diseases. Exposure of mannosylated glycans in LN was shown to occur at the cell surface of kidney cells, promoting increased recognition by specific glycan-recognizing receptors expressed by immune cells. This abnormal glycosignature of LN was shown to be due to a deficient complex N-glycosylation pathway and a proficient O-mannosylation pathway. Moreover, mannosylation levels detected in kidney biopsy samples from patients with LN at the time of diagnosis were demonstrated to predict the development of chronic kidney disease (CKD) with 93% specificity. Conclusion Cellular mannosylation is a marker of LN, predicting the development of CKD, and thus representing a potential glycobiomarker to be included in the diagnostic and prognostic algorithm of LN. Show less
Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans... Show moreTrait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.Analyses of expression profiles from whole blood of 31,684 individuals identify cis-expression quantitative trait loci (eQTL) effects for 88% of genes and trans-eQTL effects for 37% of trait-associated variants. Show less
