NeuroBridge: A prototype platform for discovery of the long-tail neuroimaging data

INTRODUCTION: Open science initiatives have enabled sharing of large amounts of already collected data. However, significant gaps remain regarding how to find appropriate data, including underutilized data that exist in the long tail of science. We demonstrate the NeuroBridge prototype and its ability to search PubMed Central full-text papers for information relevant to neuroimaging data collected from schizophrenia and addiction studies. METHODS: The NeuroBridge architecture contained the following components: (1) Extensible ontology for modeling study metadata: subject population, imaging techniques, and relevant behavioral, cognitive, or clinical data. Details are described in the companion paper in this special issue; (2) A natural-language based document processor that leveraged pre-trained deep-learning models on a small-sample document corpus to establish efficient representations for each article as a collection of machine-recognized ontological terms; (3) Integrated search using ontology-driven similarity to query PubMed Central and NeuroQuery, which provides fMRI activation maps along with PubMed source articles. RESULTS: The NeuroBridge prototype contains a corpus of 356 papers from 2018 to 2021 describing schizophrenia and addiction neuroimaging studies, of which 186 were annotated with the NeuroBridge ontology. The search portal on the NeuroBridge website https://neurobridges.org/ provides an interactive Query Builder, where the user builds queries by selecting NeuroBridge ontology terms to preserve the ontology tree structure. For each return entry, links to the PubMed abstract as well as to the PMC full-text article, if available, are presented. For each of the returned articles, we provide a list of clinical assessments described in the Section Methods of the article. Articles returned from NeuroQuery based on the same search are also presented. CONCLUSION: The NeuroBridge prototype combines ontology-based search with natural-language text-mining approaches to demonstrate that papers relevant to a user\u27s research question can be identified. The NeuroBridge prototype takes a first step toward identifying potential neuroimaging data described in full-text papers. Toward the overall goal of discovering enough data of the right kind, ongoing work includes validating the document processor with a larger corpus, extending the ontology to include detailed imaging data, and extracting information regarding data availability from the returned publications and incorporating XNAT-based neuroimaging databases to enhance data accessibility

Clinical trial protocol: PRednisolone in early diffuse cutaneous Systemic Sclerosis (PRedSS)

Background: Many of the painful, disabling features of early diffuse cutaneous systemic sclerosis have an inflammatory component and are potentially treatable with corticosteroid therapy. These features include painful and itchy skin, fatigue and musculoskeletal involvement. Yet many clinicians are understandably reluctant to prescribe corticosteroids because of the concern that these are a risk factor for scleroderma renal crisis. The aim of PRedSS (PRednisolone in early diffuse cutaneous Systemic Sclerosis) is to evaluate the efficacy and safety of moderate dose prednisolone in patients with early diffuse cutaneous systemic sclerosis, specifically whether moderate dose prednisolone is (a) effective in terms of reducing pain and disability, and improving skin score and (b) safe, with particular reference to renal function. Methods: PRedSS is a Phase II, multicentre, double-blind randomised controlled trial which aims to recruit 72 patients with early diffuse cutaneous systemic sclerosis. Patients are randomised to receive either prednisolone (dosage approximately 0.3 mg/kg) or placebo therapy for 6 months. The two co-primary outcome measures are the difference in mean Health Assessment Questionnaire Disability Index at 3 months and the difference in modified Rodnan skin score at 3 months. Secondary outcome measures include patient reported outcome measures of itch, hand function, anxiety and depression, and helplessness. Results: Recruitment commenced in December 2017 and after a slow start (due to delays in opening centres) 25 patients have now been recruited. Conclusion: PRedSS should help to answer the question as to whether clinicians should or should not prescribe prednisolone in early diffuse cutaneous systemic sclerosis

Nailfold Videocapillaroscopic Features and Other Clinical Risk Factors for Digital Ulcers in Systemic Sclerosis: A Multicenter, Prospective Cohort Study

OBJECTIVE: To identify nailfold videocapillaroscopic and other clinical risk factors for new digital ulcers (DUs) in a 6-month period in patients with systemic sclerosis (SSc), the videoCAPillaroscopy (CAP) study. METHODS: Overall 623 patients with SSc from 59 centers (14 countries) were stratified into two groups: "DU History" and "No-DU History". At enrollment, patients underwent detailed nailfold videocapillaroscopic evaluation and an assessment of demographics, DU status, and clinical and SSc characteristics. Risk factors for developing new DUs were assessed using univariable and multivariable logistic regression analyses. RESULTS: Of the "DU History" group (n = 468), 79.5% were female, the mean age was 54.0 ± 13.7 years, 59.8% had limited cutaneous SSc, and 22% developed a new DU during follow-up. The strongest risk factors for new DUs identified by multivariable logistic regression (MLR) in the "DU History" group included: mean number of capillaries/mm in the middle finger of the dominant hand, number of DUs (0, 1, 2, ≥3), and presence of critical digital ischemia. The receiver operating characteristic area under the curve (ROC-AUC) (95% confidence interval [CI]) of the final MLR model was 0.738 (0.681-0.795). Internal validation through bootstrap generated a ROC-AUC (95% CI) of 0.633 (0.510-0.756). CONCLUSION: This international, prospective study including detailed nailfold videocapillaroscopic evaluation and extensive clinical characterization of patients with SSc identified the mean number of capillaries/mm in the middle finger of the dominant hand, number of DUs and presence of critical digital ischemia at enrollment as risk factors for the development of new DUs. This article is protected by copyright. All rights reserved

Clinical trajectories of hand function impairment in systemic sclerosis: an unmet clinical need across disease subsets

BACKGROUND: Hand involvement is an early manifestation of systemic sclerosis (SSc), culprit of diagnosis and classification, and recognised major driver of disability. Impairment of hand function burdens both limited and diffuse cutaneous subsets and therefore could be targeted as 'basket' endpoint in SSc. Nevertheless, its natural history in current standard of care is not well characterised, limiting the design of targeted trials. The aim of this study is to describe prevalence, natural history and clinical factors associated with hand function deterioration in a longitudinal, multicentre, observational SSc cohort. METHODS: Hand function was captured through the validated Cochin Hand Function Scale in patients consecutively enrolled in a multicentre observational study and observed over 24 months. Minimal clinically important differences and patient acceptable symptom state were analysed as previously described. RESULTS: Three hundred and ninety-six consecutive patients were enrolled from 10 centres; 201 with complete follow-up data were included in the analysis. Median (IQR) disease duration was 5 (2-11) years. One hundred and five (52.2%) patients reported clinically significant worsening. Accordingly, the proportion of patients reporting unacceptable hand function increased over 2 years from 27.8% to 35.8% (p<0.001). Least absolute shrinkage and selection operator analysis identified male gender, disease subset, Raynaud's Condition Score, tenosynovitis and pain, as some of the key factors associated with worsening hand involvement. CONCLUSIONS: Hand function deteriorates over time in more than 50% of SSc patients despite available therapies. The analysis of factors associated with hand function worsening supports the involvement of both inflammation, vascular and fibrotic processes in hand involvement, making it a hallmark clinical manifestation of SSc. Our data are poised to inform the design of intervention studies to target this major driver of disability in SSc

Primary Raynaud's phenomenon in an infant: a case report and review of literature

Raynaud's phenomenon (RP) is an extremely unusual finding in early infancy. In the present report we describe a one-month-old previously healthy male infant who presented with unilateral acrocyanosis. Although infantile acrocyanosis is known to be a benign and self-resolving condition, it is generally bilateral and symmetric. The unilateral nature of the acrocyanosis was an atypical finding in this infant. Consequently, he was closely monitored to evaluate the progression of his acrocyanosis. Based on his benign clinical course and failure to demonstrate other etiologies contributing to his acrocyanosis, he was diagnosed to have primary RP. Due to the rarity of RP in children, we review the progress in understanding the pathophysiology, epidemiology and management of RP and additionally discuss the differential diagnosis of unilateral and bilateral acrocyanosis in infants

Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes

Objective: The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes. Methods: 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA). Results: Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1∗11:04 and HLA-DPB1∗13:01, and revealed a novel association of HLA-B∗08:01. Stratified analyses showed specific associations of HLA-DQA1∗02:01 with lcSSc, and an exclusive association of HLA-DQA1∗05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1∗08:01 and confirmed the previously reported association of HLA-DRB1∗07:01 with ACA-positive patients, as opposed to the HLA-DPA1∗02:01 and HLA-DQB1∗03:01 alleles associated with ATA presentation. Conclusions: This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression

Evaluation of High Resolution Thermal Imaging to Determine the Effect of Vertebral Fractures on Associated Skin Surface Temperature in Children with Osteogenesis Imperfecta

Vertebral fractures are common in children with osteogenesis imperfecta (OI). Current imaging methods for fracture detection (X-ray and DXA) use ionising radiation. This pilot study explored whether the alteration in blood flow in vertebral fractures results in skin temperature changes that may be detected using high resolution thermal imaging (HRTI) and thus assist diagnosis and monitoring of fractures in OI patients. Eleven participants aged 5-18 years with OI and known vertebral fractures were enrolled. Small metal discs were placed on the skin surface alongside the vertebrae before participants had DXA and X-ray scans and thermal imaging of their backs. Visibility of the discs on the DXA and X-ray scans and thermal images allowed the temperatures of the skin surface above vertebrae without (healthy) and with fractures to be compared to their respective adjacent skin surface regions (Region of Reference, ROR) by calculating the temperature percentage change (TPC). The TPC between the skin temperature over the fractured thoracic vertebrae (n=11) and the ROR was significant (1.44%, p=0.002, 95% confidence). TPC between the skin temperature over healthy thoracic vertebrae and ROR was not (0.97%, p=0.15, 95% confidence). HRTI may provide a novel tool for assisting in detection of vertebral fractures in OI. Keywords: Computerised medical diagnosis, thermal imaging, vertebral fracture detection, osteogenesis imperfecta

Detection of human neutrophil elastase (HNE) on wound dressings as marker of inflammation

Chronic wound fluids have elevated concentration of human neutrophil elastase (HNE) which can be used as inflammation/infection marker. Our goal is to develop functional materials for fast diagnosis of wound inflammation/infection by using HNE as a specific marker. For that, fluorogenic peptides with a HNE-specific cleavage sequence were incorporated into traditional textile dressings, to allow real-time detection of the wound status. Two different fluorogenic approaches were studied in terms of intensity of the signal generated upon HNE addition: a fluorophore 7-amino-4-trifluormethylcoumarin (AFC) conjugated to a HNE-specific peptide and two fluorophore/quencher pairs (FAM/Dabcyl and EDANS/Dabcyl) coupled to a similar peptide as a Förster resonance energy transfer (FRET) strategy. Also, two immobilization methods were tested: sonochemistry immobilization onto a cotton bandage and glutaraldehyde (GTA)-assisted chemical crosslinking onto a polyamide dressing. The immobilized fluorogenic AFC peptide showed an intense fluorescence emission in the presence of HNE. HNE also induced an enhanced fluorescent signal with the EDANS/Dabcyl FRET peptide which showed to be a more sensitive and effective strategy than the AFC peptide. However, its chemical immobilization onto the polyamide dressing greatly decreased its detection, mainly due to the more difficult access of the enzyme to the cleavage sequence of the immobilized peptide. After optimization of the in situ immobilization, it will be possible to use these fluorescence-functionalized dressings for an effective and specific monitoring of chronic wounds by simply using a portable ultraviolet (UV) light source. We envision that the development of this point-of-care medical device for wound control will have a great impact on patients life quality and reduction of costs on health care system.This study was funded by the European project InFact-Functional materials for fast diagnosis of wound infection (FP7-NMP-2013-SME-7-grant agreement no. 604278). The work done at Centre of Biological Engineering (CEB) was also supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit, COMPETE 2020 (POCI-01-0145-FEDER-006684) and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by European Regional Development Fund under the scope of Norte 2020-Programa Operacional Regional do Norte