Additional file 2: of Impaired function of endothelial progenitor cells in children with primary systemic vasculitis

Glossary and scoring for PVAS. (PDF 61 kb

Additional file 1: of Impaired function of endothelial progenitor cells in children with primary systemic vasculitis

Paediatric Vasculitis Activity Score. (PDF 51 kb

Additional file 2: of Screening assays for primary haemophagocytic lymphohistiocytosis in children presenting with suspected macrophage activation syndrome

Data set summary. Clinical information from 21 patients who underwent screening for suspected MAS clinical information. (DOCX 317 kb

Table_1_A rapid turnaround gene panel for severe autoinflammation: Genetic results within 48 hours.docx

There is an important unmet clinical need for fast turnaround next generation sequencing (NGS) to aid genetic diagnosis of patients with acute and sometimes catastrophic inflammatory presentations. This is imperative for patients who require precise and targeted treatment to prevent irreparable organ damage or even death. Acute and severe hyper- inflammation may be caused by primary immunodeficiency (PID) with immune dysregulation, or more typical autoinflammatory diseases in the absence of obvious immunodeficiency. Infectious triggers may be present in either immunodeficiency or autoinflammation. We compiled a list of 25 genes causing monogenetic immunological diseases that are notorious for their acute first presentation with fulminant inflammation and which may be amenable to specific treatment, including hemophagocytic lymphohistiocytosis (HLH); and autoinflammatory diseases that can present with early-onset stroke or other irreversible neurological inflammatory complications. We designed and validated a pipeline that enabled return of clinically actionable results in hours rather than weeks: the Rapid Autoinflammation Panel (RAP). We demonstrated accuracy of this new pipeline, with 100% sensitivity and 100% specificity. Return of results to clinicians was achieved within 48-hours from receiving the patient’s blood or saliva sample. This approach demonstrates the potential significant diagnostic impact of NGS in acute medicine to facilitate precision medicine and save “life or limb” in these critical situations.</p

Regions through time and space: Problem of regionalization

The thesis is rooted in the new regional geography paradigm that gained strength in geographical thought since the 1980s. This approach is characterized by emphasizing the socially constructed nature of regions; thus, regions are scrutinized as a historically contingent process. A region is formed, reproduced and eventually disappears in time. The thesis works with the assumption that a plurality of regions, that exists in changing time- space contexts of different mechanisms and meanings, can be experienced de facto in any particular area. In simpler terms, it can be understood as a plurality of regional images produced on the one side by regional actors to fulfil their particular goals and on the other regional images produced by inhabitants in and outside the region in order to understand the outside world and position themselves within it. Motivation for the production of images can vary, from a simple manifestation of one position in the regional system, through the attempt to attract attention towards the region to exploitation of the regional potential in order to fulfil particular power-oriented aims. The general idea of a region can be sought throughout the synthesis of the many regional images that can be understood as somewhat layers of a region. The thesis contributes to the discussion..

Additional file 5: of Mitochondrial and oxidative stress genes are differentially expressed in neutrophils of sJIA patients treated with tocilizumab: a pilot microarray study

File contains the enriched genes for KEGG_Oxidative Phosphorylation pathway obtained from GSEA. (XLS 13 kb

Additional file 1: of Clinical practice variation and need for pediatric-specific treatment guidelines among rheumatologists caring for children with ANCA-associated vasculitis: an international clinician survey

Copy of Needs-assessment Survey for Treatment of pediatric ANCA-associated vasculitis. (PDF 110 kb

Image_1_Curation and expansion of the Human Phenotype Ontology for systemic autoinflammatory diseases improves phenotype-driven disease-matching.pdf

IntroductionAccurate and standardized phenotypic descriptions are essential in diagnosing rare diseases and discovering new diseases, and the Human Phenotype Ontology (HPO) system was developed to provide a rich collection of hierarchical phenotypic descriptions. However, although the HPO terms for inborn errors of immunity have been improved and curated, it has not been investigated whether this curation improves the diagnosis of systemic autoinflammatory disease (SAID) patients. Here, we aimed to study if improved HPO annotation for SAIDs enhanced SAID identification and to demonstrate the potential of phenotype-driven genome diagnostics using curated HPO terms for SAIDs.MethodsWe collected HPO terms from 98 genetically confirmed SAID patients across eight different European SAID expertise centers and used the LIRICAL (Likelihood Ratio Interpretation of Clinical Abnormalities) computational algorithm to estimate the effect of HPO curation on the prioritization of the correct SAID for each patient.ResultsOur results show that the percentage of correct diagnoses increased from 66% to 86% and that the number of diagnoses with the highest ranking increased from 38 to 45. In a further pilot study, curation also improved HPO-based whole-exome sequencing (WES) analysis, diagnosing 10/12 patients before and 12/12 after curation. In addition, the average number of candidate diseases that needed to be interpreted decreased from 35 to 2.DiscussionThis study demonstrates that curation of HPO terms can increase identification of the correct diagnosis, emphasizing the high potential of HPO-based genome diagnostics for SAIDs.</p

Table_2_Curation and expansion of the Human Phenotype Ontology for systemic autoinflammatory diseases improves phenotype-driven disease-matching.xlsx

IntroductionAccurate and standardized phenotypic descriptions are essential in diagnosing rare diseases and discovering new diseases, and the Human Phenotype Ontology (HPO) system was developed to provide a rich collection of hierarchical phenotypic descriptions. However, although the HPO terms for inborn errors of immunity have been improved and curated, it has not been investigated whether this curation improves the diagnosis of systemic autoinflammatory disease (SAID) patients. Here, we aimed to study if improved HPO annotation for SAIDs enhanced SAID identification and to demonstrate the potential of phenotype-driven genome diagnostics using curated HPO terms for SAIDs.MethodsWe collected HPO terms from 98 genetically confirmed SAID patients across eight different European SAID expertise centers and used the LIRICAL (Likelihood Ratio Interpretation of Clinical Abnormalities) computational algorithm to estimate the effect of HPO curation on the prioritization of the correct SAID for each patient.ResultsOur results show that the percentage of correct diagnoses increased from 66% to 86% and that the number of diagnoses with the highest ranking increased from 38 to 45. In a further pilot study, curation also improved HPO-based whole-exome sequencing (WES) analysis, diagnosing 10/12 patients before and 12/12 after curation. In addition, the average number of candidate diseases that needed to be interpreted decreased from 35 to 2.DiscussionThis study demonstrates that curation of HPO terms can increase identification of the correct diagnosis, emphasizing the high potential of HPO-based genome diagnostics for SAIDs.</p

Table_1_Curation and expansion of the Human Phenotype Ontology for systemic autoinflammatory diseases improves phenotype-driven disease-matching.xlsx

IntroductionAccurate and standardized phenotypic descriptions are essential in diagnosing rare diseases and discovering new diseases, and the Human Phenotype Ontology (HPO) system was developed to provide a rich collection of hierarchical phenotypic descriptions. However, although the HPO terms for inborn errors of immunity have been improved and curated, it has not been investigated whether this curation improves the diagnosis of systemic autoinflammatory disease (SAID) patients. Here, we aimed to study if improved HPO annotation for SAIDs enhanced SAID identification and to demonstrate the potential of phenotype-driven genome diagnostics using curated HPO terms for SAIDs.MethodsWe collected HPO terms from 98 genetically confirmed SAID patients across eight different European SAID expertise centers and used the LIRICAL (Likelihood Ratio Interpretation of Clinical Abnormalities) computational algorithm to estimate the effect of HPO curation on the prioritization of the correct SAID for each patient.ResultsOur results show that the percentage of correct diagnoses increased from 66% to 86% and that the number of diagnoses with the highest ranking increased from 38 to 45. In a further pilot study, curation also improved HPO-based whole-exome sequencing (WES) analysis, diagnosing 10/12 patients before and 12/12 after curation. In addition, the average number of candidate diseases that needed to be interpreted decreased from 35 to 2.DiscussionThis study demonstrates that curation of HPO terms can increase identification of the correct diagnosis, emphasizing the high potential of HPO-based genome diagnostics for SAIDs.</p