165 results on '"David A, Cabral"'
Search Results
2. Predictive utility of ANCA positivity and antigen specificity in the assessment of kidney disease in paediatric-onset small vessel vasculitis
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Dirk Foell, Adam Huber, Linda Wagner-Weiner, Susan Shenoi, Vidya Sivaraman, Sirirat Charuvanij, Jeffrey N Bone, David A Cabral, Paul Dancey, Susanne Benseler, Flora Mcerlane, Marek Böhm, Neil Martin, Phil Riley, Roberta Berard, Rae Yeung, Eslam Al-Abadi, Alan Rosenberg, Kamran Mahmood, Else S Bosman, Simranpreet K Mann, Kimberly A Morishita, Kelly L Brown, Melissa Elder, Stacey Tarvin, Kathryn Cook, and Karen James
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Medicine - Abstract
Objectives The objective of this study is to evaluate whether anti-neutrophil cytoplasmic antibody (ANCA) seropositivity and antigen specificity at diagnosis have predictive utility in paediatric-onset small vessel vasculitis.Methods Children and adolescents with small vessel vasculitis (n=406) stratified according to the absence (n=41) or presence of ANCA for myeloperoxidase (MPO) (n=129) and proteinase-3 (PR3) (n=236) were compared for overall and kidney-specific disease activity at diagnosis and outcomes between 1 and 2 years using retrospective clinical data from the ARChiVe/Paediatric Vasculitis Initiative registry to fit generalised linear models.Results Overall disease activity at diagnosis was higher in PR3-ANCA and MPO-ANCA-seropositive individuals compared with ANCA-negative vasculitis. By 1 year, there were no significant differences, based on ANCA positivity or specificity, in the likelihood of achieving inactive disease (~68%), experiencing improvement (≥87%) or acquiring damage (~58%). Similarly, and in contrast to adult-onset ANCA-associated vasculitis, there were no significant differences in the likelihood of having a relapse (~11%) between 1 and 2 years after diagnosis. Relative to PR3-ANCA, MPO-ANCA seropositivity was associated with a higher likelihood of kidney involvement (OR 2.4, 95% CI 1.3 to 4.7, p=0.008) and severe kidney dysfunction (Kidney Disease Improving Global Outcomes (KDIGO) stages 4–5; OR 6.04, 95% CI 2.77 to 13.57, p
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- 2024
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3. Anti-LAMP-2 Antibody Seropositivity in Children with Primary Systemic Vasculitis Affecting Medium- and Large-Sized Vessels
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Tayfun Hilmi Akbaba, Kirandeep K. Toor, Simranpreet K. Mann, Kristen M. Gibson, Gabriel Alejandro Alfaro, Banu Balci-Peynircioglu, David A. Cabral, Kimberly A. Morishita, and Kelly L. Brown
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lysosome-associated membrane protein-2 ,anti-neutrophil cytoplasmic antibodies ,childhood-onset primary vasculitis ,autoantibodies ,Takayasu’s arteritis ,polyarteritis nodosa ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Chronic primary systemic vasculitis (PSV) comprises a group of heterogeneous diseases that are broadly classified by affected blood vessel size, clinical traits and the presence (or absence) of anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3 (PR3) and myeloperoxidase (MPO). In small vessel vasculitis (SVV), ANCA are not present in all patients, and they are rarely detected in patients with vasculitis involving medium (MVV) and large (LVV) blood vessels. Some studies have demonstrated that lysosome-associated membrane protein-2 (LAMP-2/CD107b) is a target of ANCA in SVV, but its presence and prognostic value in childhood MVV and LVV is not known. This study utilized retrospective sera and clinical data obtained from 90 children and adolescents with chronic PSV affecting small (SVV, n = 53), medium (MVV, n = 16), and large (LVV, n = 21) blood vessels. LAMP-2-ANCA were measured in time-of-diagnosis sera using a custom electrochemiluminescence assay. The threshold for seropositivity was established in a comparator cohort of patients with systemic autoinflammatory disease. The proportion of LAMP-2-ANCA-seropositive individuals and sera concentrations of LAMP-2-ANCA were assessed for associations with overall and organ-specific disease activity at diagnosis and one-year follow up. This study demonstrated a greater time-of-diagnosis prevalence and sera concentration of LAMP-2-ANCA in MVV (52.9% seropositive) and LVV (76.2%) compared to SVV (45.3%). Further, LAMP-2-ANCA-seropositive individuals had significantly lower overall, but not organ-specific, disease activity at diagnosis. This did not, however, result in a greater reduction in disease activity or the likelihood of achieving inactive disease one-year after diagnosis. The results of this study demonstrate particularly high prevalence and concentration of LAMP-2-ANCA in chronic PSV that affects large blood vessels and is seronegative for traditional ANCA. Our findings invite reconsideration of roles for autoantigens other than MPO and PR3 in pediatric vasculitis, particularly in medium- and large-sized blood vessels.
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- 2024
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4. Photobiomodulation therapy on local effects induced by juvenile and adult venoms of Bothrops alternatus
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David, Amanda Cabral, Silva, Luciana Miato Gonçalves, Garcia Denegri, Maria Emília, Leiva, Laura Cristina Ana, Silva Junior, José Antônio, Zuliani, Juliana Pavan, and Zamuner, Stella Regina
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- 2022
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5. The use of ozone therapy and photobiomodulation therapy to treat local effects of Bothrops jararacussu snake venom
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dos Santos Fernandes, Jessia Oliveira, de Gouveia, Daniel Mussuri, David, Amanda Cabral, Nunez, Silvia Cristina, Zamuner, Stella Regina, Magalhães, Daniel Souza Ferreira, Navarro, Ricardo Scarparo, and Cogo, José Carlos
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- 2021
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6. Design of an Antipodal Vivaldi Antenna Focusing on Constructional Aspects
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David S. Cabral, Leandro Manera, Leonardo B. Zoccal, Daniel B. Ferreira, and Francesco Prudenzano
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AVA design ,Antipodal Vivaldi ,Full-wave simulations ,UWB Antenna ,Electrical engineering. Electronics. Nuclear engineering ,TK1-9971 - Abstract
Abstract This paper presents an Antipodal Vivaldi Antenna (AVA) design, focusing on its constructional aspects. The main features analysed are the connector attachment structure and the introduction of a polytetrafluoroethylene (PTFE) part that supports the antenna laminate. Issues related to dielectric penetration by milling tools are also addressed. The proposed AVA was manufactured through a low-cost prototyping process and tested, achieving an operational bandwidth from 5 to 18 GHz for a reflection coefficient less than −10 dB and an average gain of 6.23 dBi. The prototype meets all design requirements, which shows the viability of the developed radiator.
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- 2021
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7. A INCIDÊNCIA DO CONSUMO DO ÁLCOOL EM GESTANTES: E SEUS EFEITOS DELETÉRIOS; REVISÃO BIBLIOGRÁFICA
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Ocon, Carlos Alberto, primary, Miniaci, Renata, additional, Castro, Andressa Viveiros de, additional, Cabral, Dannielly Gomes, additional, Silva, José Almir Alves da, additional, Castro, Letícia Medeiros de, additional, David, Amanda Cabral, additional, Macedo, Rayssa Rayane Alves de, additional, and Marreira, Marcelo, additional
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- 2022
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8. Pathogenic variant c.1052T>A (p.Leu351Gln) in adenosine deaminase 2 impairs secretion and elevates type I IFN responsive gene expression
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Sarah M. Bowers, Martina Sundqvist, Paul Dancey, David A. Cabral, and Kelly L. Brown
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adenosine deaminase 2 (ADA2) ,type I Interferon (IFN) ,systemic vasculitis ,pediatric ,inflammation ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundAdenosine deaminase 2 (ADA2) is a homodimeric, extracellular enzyme and putative growth factor that is produced by cells of the myeloid lineage and, catalytically, deaminates extracellular adenosine to inosine. Loss-of-(catalytic)-function variants in the ADA2 gene are associated with Deficiency of ADA2 (DADA2), an autosomal recessive disease associated with an unusually broad range of inflammatory manifestations including vasculitis, hematological defects and cytopenia. Previous work by our group led to the identification of ADA2 variants of novel association with DADA2, among which was a unique c.1052T>A (p.Leu351Gln; herein referred to as L351Q) variant located in the catalytic domain of the protein.MethodsMammalian (Flp-IN CHO) cells were engineered to stably express wild-type ADA2 and ADA2 protein variants, including the pathogenic L351Q variant identified in DADA2 patients. An enzyme assay and immunoblotting were used to assess ADA2 catalytic activity and secretion, respectively, and the outcome of experimentally induced inhibition of protein processing (Golgi transport and N-linked glycosylation) was assessed. Reverse transcription quantitative real-time PCR (RT-qPCR) was applied to determine the relative expression of Type I Interferon stimulated genes (ISGs), IFIT3 and IRF7.ResultsIn addition to abrogating catalytic activity, the L351Q variant impaired secretion of L351Q ADA2 resulting in an intracellular accumulation of L351Q ADA2 protein that was not observed in cells expressing wild-type ADA2 or other ADA2 protein variants. Retention of L351Q ADA2 was not attributable to impaired glycosylation on neighboring asparagine residues and did not impact cell growth or integrity. Constitutive expression of Type I ISGs IFIT3 and IRF7 was observed in cells expressing L351Q ADA2.ConclusionsThe impaired secretion of L351Q ADA2 may be an important factor leading to the severe phenotype observed in patients with this variant further emphasizing the importance of assessing impacts beyond catalytic activity when evaluating genotype-phenotype relationships in DADA2.
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- 2022
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9. Clinical and psychosocial stress factors are associated with decline in physical activity over time in children with juvenile idiopathic arthritis
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Liane D. Heale, Kristin M. Houghton, Elham Rezaei, Adam D. G. Baxter-Jones, Susan M. Tupper, Nazeem Muhajarine, Susanne M. Benseler, Gilles Boire, David A. Cabral, Sarah Campillo, Gaëlle Chédeville, Anne-Laure Chetaille, Paul Dancey, Ciaran Duffy, Karen Watanabe Duffy, Janet Ellsworth, Jaime Guzman, Adam M. Huber, Roman Jurencak, Bianca Lang, Ronald M. Laxer, Kimberly Morishita, Kiem G. Oen, Ross E. Petty, Suzanne E. Ramsey, Johannes Roth, Rayfel Schneider, Rosie Scuccimarri, Lynn Spiegel, Elizabeth Stringer, Shirley M. L. Tse, Lori B. Tucker, Stuart E. Turvey, Rae S. M. Yeung, Alan M. Rosenberg, and for the BBOP Study Group
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Juvenile arthritis ,Physical activity ,Psychosocial stress ,Pediatrics ,RJ1-570 ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Background Physical activity (PA) patterns in children with juvenile idiopathic arthritis (JIA) over time are not well described. The aim of this study was to describe associations of physical activity (PA) with disease activity, function, pain, and psychosocial stress in the 2 years following diagnosis in an inception cohort of children with juvenile idiopathic arthritis (JIA). Methods In 82 children with newly diagnosed JIA, PA levels, prospectively determined at enrollment, 12 and 24 months using the Physical Activity Questionnaire for Children (PAQ-C) and Adolescents (PAQ-A) raw scores, were evaluated in relation to disease activity as reflected by arthritis activity (Juvenile Arthritis Disease Activity Score (JADAS-71)), function, pain, and psychosocial stresses using a linear mixed model approach. Results in the JIA cohort were compared to normative Pediatric Bone Mineral Accrual Study data derived from healthy children using z-scores. Results At enrollment, PA z-score levels of study participants were lower than those in the normative population (median z-score − 0.356; p = 0.005). At enrollment, PA raw scores were negatively associated with the psychosocial domain of the Juvenile Arthritis Quality of Life Questionnaire (r = − 0.251; p = 0.023). There was a significant decline in PAQ-C/A raw scores from baseline (median and IQR: 2.6, 1.4–3.1) to 24 months (median and IQR: 2.1, 1.4–2.7; p = 0.003). The linear mixed-effect model showed that PAQ-C/A raw scores in children with JIA decreased as age, disease duration, and ESR increased. The PAQ-C/A raw scores of the participants was also negatively influenced by an increase in disease activity as measured by the JADAS-71 (p
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- 2021
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10. Adenosine deaminase 2 activity negatively correlates with age during childhood
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Sarah M. Bowers, Kristen M. Gibson, David A. Cabral, and Kelly L. Brown
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Adenosine deaminase 2 ,Adenosine ,Pediatrics ,Inflammation ,RJ1-570 ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Background Human adenosine deaminase 2 (ADA2) is an extracellular enzyme that negatively regulates adenosine-mediated cell signaling by converting adenosine to inosine. Altered ADA2 enzyme activity has been associated with some viral infections and rheumatic diseases. The potential utility of ADA2 as a biomarker is, however, limited by the absence of established ranges of ADA2 concentration and enzyme activity in the healthy population. It is known that ADA2 enzyme activity is lower in adults, but when (and why) this decline happens is not known. The purpose of this study was to establish normative ranges of ADA2 enzyme activity and protein concentration in the healthy pediatric population. Methods We modified a commercially available ADA2 enzyme activity assay to enable higher throughput analysis of fresh, frozen and hemolyzed blood samples. With this assay and ADA2 protein immunoblotting, we analyzed ADA2 enzyme activity and protein concentration in blood plasma from a cohort of children and adolescents (n = 94) aged 5 months to 18 years. One-way ANOVA with subsequent Tukey multiple comparison test was used to analyze group differences. Reference intervals were generated using the central 95% of the population (2–97.5 percentiles). Results ADA2 enzyme activity was consistent in fresh, frozen, and hemolyzed sera and plasma as measured by our modified assay. Analysis of plasma samples from the healthy pediatric cohort revealed that ADA2 enzyme activity is significantly lower in older children than in younger children (p
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- 2020
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11. Complexity in unclassified auto-inflammatory disease: a case report illustrating the potential for disease arising from the allelic burden of multiple variants
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Lori B. Tucker, Lovro Lamot, Iwona Niemietz, Brian K. Chung, David A. Cabral, Kristin Houghton, Ross E. Petty, Kimberly A. Morishita, Gillian I. Rice, Stuart E. Turvey, William T. Gibson, and Kelly L. Brown
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Autoinflammatory disease ,Periodic fever syndrome ,Macrophage activation syndrome ,Type I interferon score ,NLRP12 ,MEFV ,Pediatrics ,RJ1-570 ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Background Despite recent advances in the diagnosis and understanding of many autoinflammatory diseases, there are still a great number of patients with phenotypes that do not fit any clinically- and/or genetically-defined disorders. Case presentation We describe a fourteen-year-old boy who presented at two and a half years of age with recurrent febrile episodes. Over the course of the disease, the episodes increased in frequency and severity, with new signs and symptoms continuing to appear. Most importantly, these included skin changes, splenomegaly and transaminitis. Only partial control of the disease was achieved with anti-IL-1 therapy. Extensive investigation showed generalized inflammation without immune deficiency, with increased levels of serum amyloid A and several pro-inflammatory cytokines including interferon-γ, as well as an increased type I interferon score. Exome sequence analysis identified P369S and R408Q variants in the MEFV innate immunity regulator, pyrin (MEFV) gene and T260 M and T320 M variants in the NLR family pyrin domain containing 12 (NLRP12) gene. Conclusion Patients with unclassified and/or unexplained autoinflammatory syndromes present diagnostic and therapeutic challenges and collectively form a substantial part of every cohort of patients with autoinflammatory diseases. Therefore, it is important to acquire their full genomic profile through whole exome and/or genome sequencing and present their cases to a broader audience, to facilitate characterization of similar patients. A critical mass of well-characterized cases will lead to improved diagnosis and informed treatment.
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- 2019
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12. Health-related quality of life in children with inflammatory brain disease
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Elina Liu, Marinka Twilt, Pascal N. Tyrrell, Anastasia Dropol, Shehla Sheikh, Mark Gorman, Susan Kim, David A. Cabral, Rob Forsyth, Heather Van Mater, Suzanne Li, Adam M. Huber, Elizabeth Stringer, Eyal Muscal, Dawn Wahezi, Mary Toth, Pavla Dolezalova, Katerina Kobrova, Goran Ristic, and Susanne M. Benseler
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Pediatrics ,Inflammatory brain disease ,CNS vasculitis ,Health-related quality of life ,Quality of life ,RJ1-570 ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Objective To quantify the impact of inflammatory brain diseases in the pediatric population on health-related quality of life, including the subdomains of physical, emotional, school and social functioning. Methods This was a multicenter, observational cohort study of children (
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- 2018
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13. Autoantibodies Against Lysosome Associated Membrane Protein-2 (LAMP-2) in Pediatric Chronic Primary Systemic Vasculitis
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Kristen M. Gibson, Renate Kain, Raashid A. Luqmani, Colin J. Ross, David A. Cabral, and Kelly L. Brown
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anti-neutrophil cytoplasmic antibody ,ANCA-associated vasculitis ,LAMP-2 ,lysosome-associated membrane protein-2 ,pediatric ,systemic vasculitis ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundAnti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis in adults and children that commonly affects the kidneys. Although the frequent antigenic, and presumed pathogenic, targets of ANCA in AAV are proteinase-3 (PR3) and myeloperoxidase (MPO), ANCA against lysosome associated membrane protein-2 (LAMP-2), a lesser known ANCA antigen that is expressed on the glomerular endothelium, are present in some adults with AAV-associated renal disease. LAMP-2-ANCA has not been assessed in children with chronic systemic vasculitis, and, if present, would be a potentially valuable biomarker given that treatment decisions for these pediatric patients at diagnosis are largely informed by kidney function.MethodsA custom ELISA, using commercially available reagents, was designed to detect autoantibodies to human LAMP-2 in serum. Sera obtained from 51 pediatric patients at the time of diagnosis of chronic primary systemic vasculitis (predominantly AAV) were screened. LAMP-2-ANCA titers were evaluated for correlation with clinical metrics of disease activity (pediatric vasculitis activity score [pVAS], C-reactive protein [CRP] concentration, and erythrocyte sedimentation rate [ESR]), MPO- and PR3-ANCA titers, and renal function (glomerular filtration rate [GFR], renal-specific pVAS, and serum creatinine concentration).ResultsLAMP-2-ANCA (>1,000 ng/ml) were detected in 35% (n = 18) of pediatric systemic vasculitis patients, of which, 10 (20% of all patients) were found to have high positive titers (>1,500 ng/ml). Undetectable or negative titres (1,500 ng/ml) of LAMP-2-ANCA. LAMP-2-ANCA titers did not correlate with measures of disease activity (pVAS, CRP, or ESR) at the time of diagnosis. In contrast, for patients with 12-month post diagnosis follow-up, a negative correlation was observed between the change in GFR (from diagnosis to 12-month follow-up) and LAMP-2-ANCA titer at diagnosis.ConclusionsModerate to high LAMP-2-ANCA titers were detected in 35% (18/51) of children with chronic systemic vasculitis affecting small-to-medium vessels. Although the highest concentrations of LAMP-2-ANCA in this population were observed in individuals positive for classic ANCA (MPO- or PR3-ANCA), similar to previous reports on adult patients, LAMP-2-ANCA titers do not correlate with classic ANCA titers or with overall disease activity at diagnosis. Renal disease is a common manifestation in systemic small-medium vessel vasculitis (both in adults and children, though more severe in children) and our preliminary data suggest LAMP-2-ANCA at diagnosis may be a risk factor for more severe renal disease.
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- 2021
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14. Different Disease Endotypes in Phenotypically Similar Vasculitides Affecting Small-to-Medium Sized Blood Vessels
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Erin E. Gill, Maren L. Smith, Kristen M. Gibson, Kimberly A. Morishita, Amy H. Y. Lee, Reza Falsafi, Jinko Graham, Dirk Foell, Susanne M. Benseler, Colin J. Ross, Raashid A. Luqmani, David A. Cabral, Robert E. W. Hancock, Kelly L. Brown, and The PedVas Initiative Investigators
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vasculitis ,neutrophils ,transcriptome ,inflammation ,ANCA ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Objectives: Chronic primary vasculitis describes a group of complex and rare diseases that are characterized by blood vessel inflammation. Classification of vasculitis subtypes is based predominantly on the size of the involved vessels and clinical phenotype. There is a recognized need to improve classification, especially for small-to-medium sized vessel vasculitides, that, ideally, is based on the underlying biology with a view to informing treatment.Methods: We performed RNA-Seq on blood samples from children (n = 41) and from adults (n = 11) with small-to-medium sized vessel vasculitis, and used unsupervised hierarchical clustering of gene expression patterns in combination with clinical metadata to define disease subtypes.Results: Differential gene expression at the time of diagnosis separated patients into two primary endotypes that differed in the expression of ~3,800 genes in children, and ~1,600 genes in adults. These endotypes were also present during disease flares, and both adult and pediatric endotypes could be discriminated based on the expression of just 20 differentially expressed genes. Endotypes were associated with distinct biological processes, namely neutrophil degranulation and T cell receptor signaling.Conclusions: Phenotypically similar subsets of small-to-medium sized vessel vasculitis may have different mechanistic drivers involving innate vs. adaptive immune processes. Discovery of these differentiating immune features provides a mechanistic-based alternative for subclassification of vasculitis.
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- 2021
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15. Design and application of a compact UWB Antipodal Vivaldi Antenna.
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David S. Cabral, Leandro Manera, and Leonardo Breseghello Zoccal
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- 2017
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16. Photobiomodulation therapy on bothrops snake venom-induced local pathological effects: A systematic review
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Silva, Luciana Miato Gonçalves, Zamuner, Luis Fernando, David, Amanda Cabral, dos Santos, Solange A., de Carvalho, Paulo de Tarso Camilo, and Zamuner, Stella Regina
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- 2018
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17. Surgical Limitations of the Microscopic Transciliary Supraorbital Keyhole Approach to the Anterior and Middle Skull Base
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Hamid Borghei-Razavi, Aldo Eguiluz-Melendez, Xiong Wenping, Huy Q. Truong, David Fernandes-Cabral, Edinson Najera, Tonya Stefko, Juan C. Fernandez-Miranda, and Paul A. Gardner
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Surgery ,Neurology (clinical) - Abstract
The microscopic transciliary SupraOrbital keyhole (mtSO) approach has been used for a wide variety of anterior and middle fossa pathologies, including aneurysms, meningiomas, craniopharyngiomas, and other skull-base tumors. Several clinical series have proven its efficacy and safety, but detailed anatomical demarcations of the anterior and middle cranial base exposure are lacking. Our aim was to define the surgical limitations of the mtSO approach to the ipsilateral and contralateral anterior and middle skull base.Five cadaveric specimens (10 sides) were studied with image guidance to illustrate the limits of the surgical exposure. In addition, 30 dry skulls were used to measure the working distances between the craniotomy and key bony landmarks of the mtSO approach.Surgical exposure at the anterior skull base covered the area between the medial half of the contra- and the medial two-thirds of the ipsilateral sphenoid wing including both optic nerves and interoptic space. The anterior limit at the midline was the sphenoethmoidal suture. Ipsilateral anterior clinoidectomy permitted exposure of the superior orbital fissure, which defined the anteromedial limit at the middle fossa, whereas the anterolateral limit was defined by the ophthalmic branch of the trigeminal nerve. Moreover, the posteromedial and posterolateral limits were the posterior clinoid process and the petrous ridge, respectively.Our findings define the surgical limitations of the mtSO approach for the treatment of anterior and middle cranial base pathologies. These limits can be reliably identified on imaging studies allowing assessment of exposure to guide preoperative case selection.
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- 2022
18. Stereotactic Radiosurgery for Meningiomas in Children and Adolescents: An International Multi-Institutional Study
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Yavuz Samanci, M. Orbay Askeroglu, Ahmed M. Nabeel, Wael A. Reda, Sameh R. Tawadros, Khaled Abdelkarim, Amr M. N. El-Shehaby, Reem M. Emad, Andrew Legarreta, David Fernandes Cabral, Sharath Anand, Ajay Niranjan, L. Dade Lunsford, Manjul Tripathi, Narendra Kumar, Roman Liščák, Jaromir May, Cheng-chia Lee, Huai-che Yang, Nuria Martínez Moreno, Roberto Martínez Álvarez, Keiss Douri, David Mathieu, Stylianos Pikis, Georgios Mantziaris, Jason P. Sheehan, Kenneth Bernstein, Douglas Kondziolka, and Selcuk Peker
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Surgery ,Neurology (clinical) - Published
- 2023
19. Clinical practice variation and need for pediatric-specific treatment guidelines among rheumatologists caring for children with ANCA-associated vasculitis: an international clinician survey
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Clara Westwell-Roper, Joanna M. Lubieniecka, Kelly L. Brown, Kimberly A. Morishita, Cherry Mammen, Linda Wagner-Weiner, Eric Yen, Suzanne C. Li, Kathleen M. O’Neil, Sivia K. Lapidus, Paul Brogan, Rolando Cimaz, David A. Cabral, and for ARChiVe Investigators Network within the PedVas initiative
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Pediatric rheumatology ,Anti-neutrophil cytoplasmic antibody-associated vasculitis ,Granulomatosis with polyangiitis ,Microscopic polyangiitis ,Physician practice patterns ,Clinical practice guidelines ,Pediatrics ,RJ1-570 ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Background Because pediatric antineutrophil cytoplasmic antibody-associated vasculitis is rare, management generally relies on adult data. We assessed treatment practices, uptake of existing clinical assessment tools, and interest in pediatric treatment protocols among rheumatologists caring for children with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Methods A needs-assessment survey developed by an international working group of pediatric rheumatologists and two nephrologists was circulated internationally. Data were summarized with descriptive statistics. Pearson’s chi-square tests were used in inferential univariate analyses. Results The 209 respondents from 36 countries had collectively seen ~1600 children with GPA/MPA; 144 had seen more than two in the preceding 5 years. Standardized and validated clinical assessment tools to score disease severity, activity, and damage were used by 59, 63, and 36%, respectively; barriers to use included lack of knowledge and limited perceived utility. Therapy varied significantly: use of rituximab rather than cyclophosphamide was more common among respondents from the USA (OR = 2.7 [1.3-5.5], p = 0.0190, n = 139), those with >5 years of independent practice experience (OR = 3.8 [1.3-12.5], p = 0.0279, n = 137), and those who had seen >10 children with GPA/MPA in their careers (OR = 4.39 [2.1-9.1], p = 0.0011, n = 133). Respondents who had treated >10 patients were also more likely to continue maintenance therapy for at least 24 months (OR = 3.0 [1.4-6.4], p = 0.0161, n = 127). Ninety six percent of respondents believed in a need for pediatric-specific treatment guidelines; 46% supported adaptation of adult guidelines while 69% favoured guidelines providing a limited range of treatment options to allow comparison of effectiveness through a registry. Conclusions These data provide a rationale for developing pediatric-specific consensus treatment guidelines for GPA/MPA. While pediatric rheumatologist uptake of existing clinical tools has been limited, guideline uptake may be enhanced if outcomes of consensus-derived treatment options are evaluated within the framework of an international registry.
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- 2017
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20. S100A12 Serum Levels and PMN Counts Are Elevated in Childhood Systemic Vasculitides Especially Involving Proteinase 3 Specific Anti-neutrophil Cytoplasmic Antibodies
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Kelly L. Brown, Joanna M. Lubieniecka, Giulia Armaroli, Katharina Kessel, Kristen M. Gibson, Jinko Graham, Dongmeng Liu, Robert E. W. Hancock, Colin J. Ross, Susanne M. Benseler, Raashid A. Luqmani, David A. Cabral, Dirk Foell, and Christoph Kessel
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chronic primary systemic vasculitis ,neutrophils ,proteinase 3 ,disease activity score ,S100A12 ,Pediatrics ,RJ1-570 - Abstract
Objectives: Chronic primary systemic vasculitidies (CPV) are a collection of rare diseases involving inflammation in blood vessels, often in multiple organs. CPV can affect adults and children and may be life- or organ-threatening. Treatments for adult CPV, although effective, have known severe potential toxicities; safety and efficacy of these drugs in pediatric patients is not fully understood. There is an unmet need for biologic measures to assess the level of disease activity and, in turn, inform treatment choices for stopping, starting, or modifying therapy. This observational study determines if S100 calcium-binding protein A12 (S100A12) and common inflammatory indicators are sensitive markers of disease activity in children and adolescents with CPV that could be used to inform a minimal effective dose of therapy.Methods: Clinical data and sera were collected from 56 participants with CPV at study visits from diagnosis to remission. Serum concentrations of S100A12, C-reactive protein (CRP) and hemoglobin (Hb) as well as whole blood cell counts and erythrocyte sedimentation rate (ESR) were measured. Disease activity was inferred by physician's global assessment (PGA) and the pediatric vasculitis activity score (PVAS).Results: Serum concentrations of standard markers of inflammation (ESR, CRP, Hb, absolute blood neutrophil count), and S100A12 track with clinically assessed disease activity. These measures—particularly neutrophil counts and sera concentrations of S100A12–had the most significant correlation with clinical scores of disease activity in those children with vasculitis that is associated with anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3.Conclusions: S100A12 and neutrophil counts should be considered in the assessment of disease activity in children with CPV particularly the most common forms of the disease that involve proteinase 3 ANCA.Key messages:- In children with chronic primary systemic vasculitis (CPV), classical measures of inflammation are not formally considered in scoring of disease activity.- Inflammatory markers—specifically S100A12 and neutrophil count—track preferentially with the most common forms of childhood CPV which affect small to medium sized vessels and involve anti neutrophil cytoplasmic antibodies (ANCA) against proteinase-3.
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- 2018
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21. CanVasc consensus recommendations for the use of avacopan in antineutrophil cytoplasm antibody-associated vasculitis: 2022 addendum
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David Turgeon, Volodko Bakowsky, Corisande Baldwin, David A Cabral, Marie Clements-Baker, Alison Clifford, Jan Willem Cohen Tervaert, Natasha Dehghan, Daniel Ennis, Leilani Famorca, Aurore Fifi-Mah, Louis-Philippe Girard, Frédéric Lefebvre, Patrick Liang, Jean-Paul Makhzoum, David Massicotte-Azarniouch, Arielle Mendel, Nataliya Milman, Heather N Reich, David B Robinson, Carolyn Ross, Dax G Rumsey, Medha Soowamber, Tanveer E Towheed, Judith Trudeau, Marinka Twilt, Elaine Yacyshyn, Gozde K Yardimci, Nader Khalidi, Lillian Barra, and Christian Pagnoux
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Rheumatology ,Pharmacology (medical) - Abstract
ObjectiveIn 2020, the Canadian Vasculitis Research Network (CanVasc) published their updated recommendations for the management of ANCA-associated vasculitides (AAV). The current addendum provides further recommendations regarding the use of avacopan in AAV based on a review of newly available evidence.MethodsAn updated systematic literature review on avacopan (formerly, CCX168) using Medline, Embase, and the Cochrane Library was performed for publications up to September 2022. New recommendations were developed and categorized according to the EULAR grading levels, as done for previous CanVasc recommendations. A modified Delphi procedure and videoconferences were used to reach ≥80% consensus on the inclusion, wording and grading of each recommendation.ResultsThree new recommendations were developed. They focus on avacopan therapy indication and duration, as well as timely glucocorticoid tapering.ConclusionThese 2022 addended recommendations provide rheumatologists, nephrologists and other specialists caring for patients with AAV with guidance for the use of avacopan, based on current evidence and consensus from Canadian experts.
- Published
- 2023
22. Juvenile Spondyloarthritis
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Dax G. Rumsey, David A. Cabral, and Shirley M. L. Tse
- Published
- 2023
23. HLA-DPB1 is associated with ANCA-associated vasculitis in children
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Kristen M, Gibson, Britt I, Drögemöller, Dirk, Foell, Susanne M, Benseler, Jinko, Graham, Robert E W, Hancock, Raashid A, Luqmani, David A, Cabral, Kelly L, Brown, Colin J, Ross, and Heidi, Stapp
- Abstract
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare, life-threatening inflammation of blood vessels that can affect both adults and children. Compared to adult-onset disease, AAV is especially rare in children with an annual prevalence of 0.5-6.4 cases per million children. The etiology of AAV remains largely unknown and both environmental and genetic factors are likely involved. Genetic susceptibility factors recently identified in adult patients, including HLA-DP and HLA-DQ, are explored in pediatric patients.We performed a genome-wide association study of pediatric AAV in patients of European ancestry (n = 63 AAV cases, n = 315 population matched controls).We identified a significant genetic association with the HLA-DPB1*04:01 allele (p = 1.5e-08, OR = 3.5), with a stronger association seen in PR3-ANCA+ children than MPO-ANCA+. The HLA-DPB1*04:01 allele was the most highly associated (though not significant) HLA allele in a follow-up adult AAV cohort (p = 2.6e-04, OR = 0.4). TCR and IFN signalling pathways were also found to be enriched in the pediatric AAV cohort.Similar to previous findings in adult AAV, we found that the HLA-DPB1 locus is associated with pediatric AAV. Despite the difference in the age of onset, these findings suggest that childhood- and adult-onset vasculitis share a common genetic predisposition. The identification of genetic variants contributing to AAV is an important step to improved classification tools and treatment strategies.
- Published
- 2022
24. Higher concentrations of vitamin D in Canadian children with juvenile idiopathic arthritis compared to healthy controls are associated with more frequent use of vitamin D supplements and season of birth
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Elham Rezaei, Alan M. Rosenberg, Susan J. Whiting, Rae S. M. Yeung, Stuart E. Turvey, Hassan Vatanparast, Johannes Roth, Lori B. Tucker, Bianca Lang, Rayfel Schneider, Kimberly Morishita, Jaime Guzman, David A. Cabral, Michael Szafron, Shirley M. L. Tse, Adam D.G. Baxter-Jones, Rosie Scuccimarri, Sarah Campillo, Anne-Laure Chetaille, Anthony Kusalik, Roman Jurencak, Paul Dancey, Elizabeth Stringer, R. M. Laxer, Ross E. Petty, Adam M. Huber, Kristin Houghton, Susanne M. Benseler, Kiem Oen, Farhad Maleki, Karen Watanabe Duffy, Gilles Boire, Ciarán M. Duffy, Sarah L. Finch, Suzanne E. Ramsey, and Gaëlle Chédeville
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Male ,0301 basic medicine ,Canada ,Season of birth ,Childhood arthritis ,Endocrinology, Diabetes and Metabolism ,Physiology ,Arthritis ,030209 endocrinology & metabolism ,Autoimmune Diseases ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Immune system ,medicine ,Vitamin D and neurology ,Animals ,Humans ,Juvenile ,Vitamin D ,Child ,Inflammation ,Autoimmune disease ,030109 nutrition & dietetics ,Nutrition and Dietetics ,business.industry ,Infant, Newborn ,Parturition ,Vitamin D Deficiency ,medicine.disease ,Arthritis, Juvenile ,3. Good health ,C-Reactive Protein ,Milk ,Case-Control Studies ,Child, Preschool ,Dietary Supplements ,Cohort ,Female ,Seasons ,business - Abstract
A number of studies have demonstrated that patients with autoimmune disease have lower levels of vitamin D prompting speculation that vitamin D might suppress inflammation and immune responses in children with juvenile idiopathic arthritis (JIA). The objective of this study was to compare vitamin D levels in children with JIA at disease onset with healthy children. We hypothesized that children and adolescents with JIA have lower vitamin D levels than healthy children and adolescents. Data from a Canadian cohort of children with new-onset JIA (n= 164, data collection 2007-2012) were compared to Canadian Health Measures Survey (CHMS) data (n=4027, data collection 2007-2011). We compared 25-hydroxy vitamin D (25(OH)D) concentrations with measures of inflammation, vitamin D supplement use, milk intake, and season of birth. Mean 25(OH)D level was significantly higher in patients with JIA (79 ± 3.1 nmol/L) than in healthy controls (68 ± 1.8 nmol/L P.05). Patients with JIA more often used vitamin D containing supplements (50% vs. 7%; P.05). The prevalence of 25(OH)D deficiency (30 nmol/L) was 6% for both groups. Children with JIA with 25(OH)D deficiency or insufficiency (50 nmol/L) had higher C-reactive protein levels. Children with JIA were more often born in the fall and winter compared to healthy children. In contrast to earlier studies, we found vitamin D levels in Canadian children with JIA were higher compared to healthy children and associated with more frequent use of vitamin D supplements. Among children with JIA, low vitamin D levels were associated with indicators of greater inflammation.
- Published
- 2021
25. Elevated ADA2 Enzyme Activity at the Onset of Chronic Graft-versus-Host Disease in Children
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Sarah M. Bowers, Bernard Ng, Sayeh Abdossamadi, Amina Kariminia, David A. Cabral, Geoffrey D.E. Cuvelier, Kirk R. Schultz, and Kelly L. Brown
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
26. Anterior Thoracic Discectomy and Fusion for Symptomatic Ventral Bone Spur Associated Type I Cerebrospinal Fluid Leak: A Technical Report and Operative Video
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Joseph S. Hudson, David Fernandes-Cabral, Prateek Agarwal, Andrew Legarreta, Anthony Schulien, Hansen Deng, Vikas Agarwal, and David O Okonkwo
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Orthopedics and Sports Medicine ,Surgery ,Neurology (clinical) - Abstract
Study Design Technical Report Objective Cerebrospinal fluid (CSF) leak secondary to anterior osteophytes at the cervico-thoracic junction is a rare cause of intracranial hypotension. In this article we describe a technique for anterior repair of spontaneous ventral cerebrospinal fluid leaks in the upper thoracic spine. Methods In this technical report and operative video, we describe a 23-year-old male who presented with positional headaches and bilateral subdural hematoma. Dynamic CT myelography demonstrated a high flow ventral cerebrospinal fluid leak associated with a ventral osteophyte at the level of the T1-T2 disc space. Targeted blood patch provided only temporary improvement in symptoms. An anterior approach was chosen to remove the offending spur and micro-surgically repair the dural defect. Results The patient had complete resolution of his preoperative symptoms after primary repair. Conclusions In select cases, an anterior approach to the upper thoracic spine is effective to repair Type 1 cerebrospinal fluid leaks.
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- 2023
27. Streaming 2D-Endoscopic Video into an Augmented Reality Headset Display: A Feasibility Study
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Edward G. Andrews, Talha Khan, Arka Mallela, Joseph C. Maroon, Jacob Biehl, David Fernandes-Cabral, Zachary C. Gersey, Hussam Abou-Al-Shaar, Paul A. Gardner, and Georgios A. Zenonos
- Published
- 2022
28. CanVasc Consensus Recommendations for the Management of Antineutrophil Cytoplasm Antibody-associated Vasculitis: 2020 Update
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Gerard Cox, David B. Robinson, Maxime Rhéaume, Susanne M. Benseler, Jean-Paul Makhzoum, Heather N. Reich, Volodko Bakowsky, Ellen Go, Nader Khalidi, Christian Pagnoux, Marie Clements-Baker, David A. Cabral, Tanveer Towheed, Judith Trudeau, Alison H. Clifford, Louis-Philippe Girard, Dax G. Rumsey, Damien Noone, Leilani Famorca, Christian A. Pineau, Arielle Mendel, Corisande Baldwin, Stephanie Garner, Simon Carette, Elaine Yacyshyn, Aurore Fifi-Mah, Jan Willem Cohen Tervaert, Clode Lessard, Rae S. M. Yeung, Nataliya Milman, Lillian B. Barra, Daniel Ennis, Christine Dipchand, Patrick Liang, Marinka Twilt, Navjot Dhindsa, and Natasha Dehghan
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Canada ,Cytoplasm ,medicine.medical_specialty ,Consensus ,Immunology ,Supplementary appendix ,MEDLINE ,Modified delphi ,Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ,Antibodies, Antineutrophil Cytoplasmic ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Humans ,Immunology and Allergy ,Medicine ,030212 general & internal medicine ,030203 arthritis & rheumatology ,business.industry ,Evidence-based medicine ,medicine.disease ,Systematic review ,Family medicine ,Needs assessment ,business ,Vasculitis - Abstract
ObjectiveIn 2015, the Canadian Vasculitis Research Network (CanVasc) created recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. The current update aims to revise existing recommendations and create additional recommendations, as needed, based on a review of new available evidence.MethodsA needs assessment survey of CanVasc members informed questions for an updated systematic literature review (publications spanning May 2014 to September 2019) using Medline, Embase, and Cochrane. New and revised recommendations were developed and categorized according to the level of evidence and strength of each recommendation. The CanVasc working group used a 2-step modified Delphi procedure to reach > 80% consensus on the inclusion, wording, and grading of each new and revised recommendation.ResultsEleven new and 16 revised recommendations were created and 12 original (2015) recommendations were retained. New and revised recommendations are discussed in detail within this document. Five original recommendations were removed, of which 4 were incorporated into the explanatory text. The supplementary material for practical use was revised to reflect the updated recommendations.ConclusionThe 2020 updated recommendations provide rheumatologists, nephrologists, and other specialists caring for patients with AAV in Canada with new management guidance, based on current evidence and consensus from Canadian experts.
- Published
- 2020
29. Real‐World Effectiveness of Common Treatment Strategies for Juvenile Idiopathic Arthritis: Results From a Canadian Cohort
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Amieleena, Chhabra, Kiem, Oen, Adam M, Huber, Natalie J, Shiff, Gilles, Boire, Susanne M, Benseler, Roberta A, Berard, Rosie, Scuccimarri, Brian M, Feldman, Lily Siok Hoon, Lim, Julie, Barsalou, Alessandra, Bruns, David A, Cabral, Gaëlle, Chédeville, Janet, Ellsworth, Kristin, Houghton, Bianca, Lang, Kimberly, Morishita, Dax G, Rumsey, Alan M, Rosenberg, Shirley M, Tse, Karen, Watanabe Duffy, Ciaran M, Duffy, Jaime, Guzman, and Paul, Dancey
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Male ,Canada ,medicine.medical_specialty ,Intra-Articular ,Anti-Inflammatory Agents ,Juvenile ,Arthritis ,Logistic regression ,Pediatrics ,Injections ,Injections, Intra-Articular ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Joint injection ,Internal medicine ,Humans ,Medicine ,Child ,Preschool ,Glucocorticoids ,030203 arthritis & rheumatology ,business.industry ,Anti-Inflammatory Agents, Non-Steroidal ,Odds ratio ,medicine.disease ,Arthritis, Juvenile ,Confidence interval ,3. Good health ,Methotrexate ,Child, Preschool ,Cohort ,Female ,Non-Steroidal ,business ,Immunosuppressive Agents ,medicine.drug ,Cohort study - Abstract
OBJECTIVE Undervaluing the effectiveness of conventional treatments may lead to overtreatment with biologic medications in children with juvenile idiopathic arthritis (JIA). Using data from a nationwide inception cohort and strict methods to control bias, the aim of our study was to estimate the real-world effectiveness of simple JIA treatment strategies recommended in current guidelines. METHODS Children with JIA who were recruited at 16 Canadian centers from 2005 to 2010 were followed for up to 5 years. For each child, all observed treatment changes over time were assessed by independent physicians using prospectively collected data and published response criteria. Success was defined as attainment of inactive disease or maintenance of this state when stepping down treatment; minimally active disease was deemed acceptable for children with polyarticular JIA. Success rates were calculated for treatments tried ≥25 times, and logistic regression analysis identified features associated with success. RESULTS A total of 4,429 treatment episodes were observed in 1,352 children. Nonsteroidal antiinflammatory drug (NSAID) monotherapy was attempted 697 times, mostly as initial treatment when
- Published
- 2020
30. Long-term outcomes and disease course of children with juvenile idiopathic arthritis in the ReACCh-Out cohort: a two-centre experience
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Ross E. Petty, Maggie Larché, Kimberly Morishita, Jaime Guzman, Lori B. Tucker, Michelle Batthish, Cal Robinson, Kristin Houghton, David A. Cabral, and Amieleena Chhabra
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Joint replacement ,medicine.medical_treatment ,Arthritis ,Disease course ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,medicine ,Humans ,Juvenile ,Pharmacology (medical) ,030212 general & internal medicine ,Ontario ,030203 arthritis & rheumatology ,Oligoarthritis ,British Columbia ,business.industry ,Remission Induction ,Clinical Science ,medicine.disease ,Arthritis, Juvenile ,3. Good health ,Exact test ,Antirheumatic Agents ,Cohort ,Female ,Polyarthritis ,business - Abstract
Objective To assess long-term outcomes of children with JIA diagnosed in the biologic era. Methods Chart review of patients prospectively enrolled in the Research in Arthritis in Canadian Children Emphasizing Outcomes inception cohort at two Canadian centres. Inactive disease and remission were defined according to Wallace criteria. Results We included 247 of 254 (97%) eligible patients diagnosed 2005–10. At the last follow-up visit at a median age of 16.9 years, 47% were in remission off medications, 25% in remission on medications and 27% had active disease; 51% were on at least one anti-rheumatic medication (22% on biologics). Patients with systemic JIA had the highest frequency of remission off medications (70%) and patients with RF-positive polyarthritis had the lowest (18%) (P Conclusion Relative to historical cohorts, this study suggests a reduction in JIA permanent damage, a more favourable prognosis for systemic JIA and a lower progression to oligoarthritis extended category. However, in an era of biologic therapy, one in four patients with JIA still enter adulthood with active disease and one in two still on treatment.
- Published
- 2020
31. CanVasc Recommendations for the Management of Antineutrophil Cytoplasm Antibody (ANCA)-Associated Vasculitides – Executive Summary
- Author
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Lucy McGeoch, Marinka Twilt, Leilani Famorca, Volodko Bakowsky, Lillian Barra, Susan Benseler, David A. Cabral, Simon Carette, Gerald P. Cox, Navjot Dhindsa, Christine Dipchand, Aurore Fifi-Mah, Michele Goulet, Nader Khalidi, Majed M. Khraishi, Patrick Liang, Nataliya Milman, Christian A. Pineau, Heather Reich, Nooshin Samadi, Kam Shojania, Regina Taylor-Gjevre, Tanveer E. Towheed, Judith Trudeau, Michael Walsh, Elaine Yacyshyn, and Christian Pagnoux
- Subjects
Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
The Canadian Vasculitis research network (CanVasc) is composed of physicians from different medical specialties, including rheumatology and nephrology and researchers with expertise in vasculitis. One of its aims was to develop recommendations for the diagnosis and management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides in Canada. This executive summary features the 19 recommendations and 17 statements addressing general AAV diagnosis and management, developed by CanVasc group based on a synthesis of existing international guidelines, other published supporting evidence and expert consensus considering the Canadian healthcare context.
- Published
- 2015
- Full Text
- View/download PDF
32. Prevention of disease flares by risk-adapted stratification of therapy withdrawal in juvenile idiopathic arthritis: results from the PREVENT-JIA trial
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Joachim Gerss, Monika Tedy, Ariane Klein, Gerd Horneff, Maria Miranda-Garcia, Christoph Kessel, Dirk Holzinger, Valda Stanevica, Joost F Swart, David A Cabral, Hermine I Brunner, and Dirk Foell
- Subjects
Immunology ,S100A12 Protein ,Medizin ,Symptom Flare Up ,General Biochemistry, Genetics and Molecular Biology ,Arthritis, Juvenile ,C-Reactive Protein ,Treatment Outcome ,Rheumatology ,Antirheumatic Agents ,Immunology and Allergy ,Humans ,Child ,Biomarkers - Abstract
ObjectivesTo investigate the ability of high-sensitivity C-reactive protein (hsCRP) and S100A12 to serve as predictive biomarkers of successful drug withdrawal in children with clinical remission of juvenile idiopathic arthritis (JIA).MethodsThis multicentre trial (PREVENT-JIA) enrolled 119 patients with JIA in clinical remission, and 100 patients reached the intervention phase in which the decision whether to continue or stop treatment was based on S100A12 and hsCRP levels. Patients were monitored for 12 months after stopping medication for flares of disease. Results were compared with withdrawal of therapy without biomarker-based stratification in patients from the German Biologika in der Kinderrheumatologie (BiKeR) pharmacovigilance registry.ResultsIn the PREVENT-JIA group, 49 patients had a flare, and 45% of patients stopping medication showed flares within the following 12 months. All patients (n=8) continuing therapy due to permanently elevated S100A12/hsCRP at more than one visit flared during the observation phase. In the BiKeR control group, the total flare rate was 62%, with 60% flaring after stopping medication. The primary outcome, time from therapy withdrawal to first flare (cumulative flare rate after therapy withdrawal), showed a significant difference in favour of the PREVENT-JIA group (p=0.046; HR 0.62, 95% CI 0.38 to 0.99). As additional finding, patients in the PREVENT-JIA trial stopped therapy significantly earlier.ConclusionBiomarker-guided strategies of therapy withdrawal are feasible in clinical practice. This study demonstrates that using predictive markers of subclinical inflammation is a promising tool in the decision-making process of therapy withdrawal, which translates into direct benefit for patients.Trial registration numberISRCTN69963079.
- Published
- 2021
33. In vitro antitumor activity of dialkylamine-1,4-naphthoquinones toward human glioblastoma multiforme cells
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Clementino-Neto, José, primary, da Silva, João Kaycke Sarmento, additional, de Melo Bastos Cavalcante, Cibelle, additional, da Silva-Júnior, Paulo Fernando, additional, David, Cibelle Cabral, additional, de Araújo, Morgana Vital, additional, Mendes, Carmelita Bastos, additional, de Queiroz, Aline Cavalcanti, additional, da Silva, Elaine Cristina Oliveira, additional, de Souza, Samuel Teixeira, additional, da Silva Fonseca, Eduardo Jorge, additional, da Silva, Tânia Maria Sarmento, additional, de Amorim Camara, Celso, additional, Moura-Neto, Vivaldo, additional, de Araújo-Júnior, João Xavier, additional, da Silva-Júnior, Edeildo Ferreira, additional, da-Silva, Adriana Ximenes, additional, and Alexandre-Moreira, Magna Suzana, additional
- Published
- 2022
- Full Text
- View/download PDF
34. Efeito da fotobiomodulação na modulação da interleucina-10: revisão narrativa de estudos clínicos
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David, Amanda Cabral, primary and Zamuner, Stella Regina, additional
- Published
- 2021
- Full Text
- View/download PDF
35. Prospective Determination of the Incidence and Risk Factors of New‐Onset Uveitis in Juvenile Idiopathic Arthritis: The Research in Arthritis in Canadian Children Emphasizing Outcomes Cohort
- Author
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Lynn Spiegel, Elizabeth Stringer, Ciarán M. Duffy, Lori B. Tucker, Adam M. Huber, Brian M. Feldman, Jennifer J. Y. Lee, Alan M. Rosenberg, David A. Cabral, Bianca Lang, Kimberly Morishita, Gilles Boire, Jaime Guzman, Natalie J. Shiff, Rae S. M. Yeung, Deepti Reddy, Karen Watanabe Duffy, Kiem Oen, and Nick Barrowman
- Subjects
Male ,Canada ,medicine.medical_specialty ,Kaplan-Meier Estimate ,Uveitis ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Rheumatoid Factor ,Risk Factors ,Interquartile range ,Internal medicine ,Humans ,Medicine ,Prospective Studies ,Child ,10. No inequality ,Prospective cohort study ,Proportional Hazards Models ,030203 arthritis & rheumatology ,Oligoarthritis ,business.industry ,Incidence ,Incidence (epidemiology) ,Hazard ratio ,Age Factors ,medicine.disease ,Arthritis, Juvenile ,3. Good health ,Antibodies, Antinuclear ,Child, Preschool ,Cohort ,Female ,Polyarthritis ,business - Abstract
OBJECTIVE Identification of the incidence of juvenile idiopathic arthritis (JIA)-associated uveitis and its risk factors is essential to optimize early detection. Data from the Research in Arthritis in Canadian Children Emphasizing Outcomes inception cohort were used to estimate the annual incidence of new-onset uveitis following JIA diagnosis and to identify associated risk factors. METHODS Data were reported every 6 months for 2 years, then yearly to 5 years. Incidence was determined by Kaplan-Meier estimators with time of JIA diagnosis as the reference point. Univariate log-rank analysis identified risk factors and Cox regression determined independent predictors. RESULTS In total, 1,183 patients who enrolled within 6 months of JIA diagnosis met inclusion criteria, median age at diagnosis of 9.0 years (interquartile range [IQR] 3.8-12.9), median follow-up of 35.2 months (IQR 22.7-48.3). Of these patients, 87 developed uveitis after enrollment. The incidence of new-onset uveitis was 2.8% per year (95% confidence interval [95% CI] 2.0-3.5) in the first 5 years. The annual incidence decreased during follow-up but remained at 2.1% (95% CI 0-4.5) in the fifth year, although confidence intervals overlapped. Uveitis was associated with young age (
- Published
- 2019
36. Associations of clinical and inflammatory biomarker clusters with juvenile idiopathic arthritis categories
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Adam M. Huber, Anthony Kusalik, Roman Jurencak, Daniel J. Hogan, Susan Tupper, Shirley M. L. Tse, Lynn Spiegel, Ciarán M. Duffy, Rosie Scuccimarri, Stephen W. Scherer, Kimberly Morishita, Suzanne E. Ramsey, Jaime Guzman, Kristin Houghton, Regina M. Taylor-Gjevre, Elizabeth Stringer, John R. Gordon, Ronald M. Laxer, Bianca Lang, David A. Cabral, Richard F. Wintle, Paul Dancey, Alan M. Rosenberg, Brett Trost, Sarah Campillo, Gilles Boire, Simon W. M. Eng, Kiem Oen, Elham Rezaei, Stuart E. Turvey, Rae S. M. Yeung, Anne-Laure Chetaille, Ross E. Petty, Lori B. Tucker, Karen Watanabe Duffy, and Gaëlle Chédeville
- Subjects
Male ,0301 basic medicine ,Canada ,medicine.medical_specialty ,Adolescent ,Childhood arthritis ,Normal Distribution ,Arthritis ,Risk Assessment ,Severity of Illness Index ,Cohort Studies ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Rheumatology ,Internal medicine ,medicine ,Cluster Analysis ,Data Mining ,Humans ,Pharmacology (medical) ,In patient ,Prospective Studies ,Child ,030203 arthritis & rheumatology ,business.industry ,Incidence ,Age Factors ,Syndrome ,medicine.disease ,INCEPTION COHORT ,Inflammatory biomarkers ,Arthritis, Juvenile ,030104 developmental biology ,Homogeneous ,Principal component analysis ,Female ,Inflammation Mediators ,Inflammatory biomarker ,business ,Biomarkers - Abstract
Objective To identify discrete clusters comprising clinical features and inflammatory biomarkers in children with JIA and to determine cluster alignment with JIA categories. Methods A Canadian prospective inception cohort comprising 150 children with JIA was evaluated at baseline (visit 1) and after six months (visit 2). Data included clinical manifestations and inflammation-related biomarkers. Probabilistic principal component analysis identified sets of composite variables, or principal components, from 191 original variables. To discern new clinical-biomarker clusters (clusters), Gaussian mixture models were fit to the data. Newly-defined clusters and JIA categories were compared. Agreement between the two was assessed using Kruskal–Wallis analyses and contingency plots. Results Three principal components recovered 35% (three clusters) and 40% (five clusters) of the variance in patient profiles in visits 1 and 2, respectively. None of the clusters aligned precisely with any of the seven JIA categories but rather spanned multiple categories. Results demonstrated that the newly defined clinical-biomarker lustres are more homogeneous than JIA categories. Conclusion Applying unsupervised data mining to clinical and inflammatory biomarker data discerns discrete clusters that intersect multiple JIA categories. Results suggest that certain groups of patients within different JIA categories are more aligned pathobiologically than their separate clinical categorizations suggest. Applying data mining analyses to complex datasets can generate insights into JIA pathogenesis and could contribute to biologically based refinements in JIA classification.
- Published
- 2019
37. Characterisation of graphene electrodes for microsystems and microfluidic devices
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Erica Pensini, Christopher M. Collier, C. Harrison Brodie, David M. Cabral, Ashutosh Singh, Michelle Del Rosso, and Saipriya Ramalingam
- Subjects
Fabrication ,Materials science ,Microfluidics ,lcsh:Medicine ,Graphite oxide ,Nanotechnology ,02 engineering and technology ,01 natural sciences ,Article ,law.invention ,Contact angle ,chemistry.chemical_compound ,law ,Microsystem ,0103 physical sciences ,lcsh:Science ,010302 applied physics ,Multidisciplinary ,Graphene ,lcsh:R ,021001 nanoscience & nanotechnology ,chemistry ,lcsh:Q ,Photolithography ,0210 nano-technology ,Optical disc - Abstract
Fabrication of microsystems is traditionally achieved with photolithography. However, this fabrication technique can be expensive and non-ideal for integration with microfluidic systems. As such, graphene fabrication is explored as an alternative. This graphene fabrication can be achieved with graphite oxide undergoing optical exposure, using optical disc drives, to impose specified patterns and convert to graphene. This work characterises such a graphene fabrication, and provides fabrication, electrical, microfluidic, and scanning electron microscopy (SEM) characterisations. In the fabrication characterisation, a comparison is performed between traditional photolithography fabrication and the new graphene fabrication. (Graphene fabrication details are also provided.) Here, the minimum achievable feature size is identified and graphene fabrication is found to compare favourably with traditional photolithography fabrication. In the electrical characterisation, the resistivity of graphene is measured as a function of fabrication dose in the optical disc drive and saturation effects are noted. In the microfluidic characterisation, the wetting properties of graphene are shown through an investigation of the contact angle of a microdroplet positioned on a surface that is treated with varying fabrication dose. In the SEM characterisation, the observed effects in the previous characterisations are attributed to chemical or physical effects through measurement of SEM energy dispersive X-ray spectra and SEM images, respectively. Overall, graphene fabrication is revealed to be a viable option for development of microsystems and microfluidics.
- Published
- 2019
38. Anesthesia Hacks
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John David Y. Cabral
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General Engineering ,General Earth and Planetary Sciences ,General Environmental Science - Published
- 2021
39. Wide variation in glucocorticoid dosing in paediatric ANCA-associated vasculitis with renal disease: a paediatric vasculitis initiative study
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Audrea Chen, Cherry Mammen, Jaime Guzman, Eslam Al-Abadi, Susanne M. Benseler, Roberta A. Berard, Dana Gerstbacher, Merav Heshin-Bekenstein, Susan Kim, Marisa Klein-Gitelman, Pallavi Pimpale Chavan, Karen E. James, Neil Martin, Flora McErlane, Charlotte Myrup, Damien G. Noone, Jyothi Raghuram, Susan Shenoi, Vidya Sivaraman, Tamara Tanner, Rae S.M. Yeung, David A. Cabral, and Kimberly A. Morishita
- Subjects
Adult ,Male ,Adolescent ,Immunology ,Remission Induction ,Microscopic Polyangiitis ,Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ,Antibodies, Antineutrophil Cytoplasmic ,Rheumatology ,Immunology and Allergy ,Humans ,Female ,Child ,Rituximab ,Glucocorticoids ,Immunosuppressive Agents - Abstract
High-dose glucocorticoids for remission-induction of ANCA-associated vasculitis are recommended and commonly used in adults, but recent studies suggest lower glucocorticoid doses can reduce toxicity without reducing efficacy. No paediatric-specific data exists to inform optimal glucocorticoid dosing in paediatric ANCA-associated vasculitis (pAAV). Our objectives were to describe glucocorticoid use in pAAV-related renal disease, and to explore associations between glucocorticoid dose, baseline patient characteristics and 12-month outcomes.Youth18 years with pAAV, biopsy-confirmed pauci-immune glomerulonephritis and 12-month follow-up data were included from an international paediatric vasculitis registry. Presenting features and 12-month outcomes (eGFR, glucocorticoid-related adverse effects), were compared between patients receiving no, low-moderate (≤90mg/kg) and high (90mg/kg) cumulative intravenous methylprednisolone (IVMP), and low (0.5mg/kg/day prednisone equivalent), moderate (0.5-1.5mg/kg/day) and high (1.5mg/kg/day) starting doses of oral glucocorticoids.Among 131 patients (101 granulomatosis with polyangiitis, 30 microscopic polyangiitis), 27 (21%) received no IVMP, 64 (49%) low-moderate and 29 (22%) high-dose IVMP, while 9 (7%) received low, 75 (57%) moderate and 47 (36%) high initial doses of oral glucocorticoids. Renal failure at diagnosis (p=0.022) and plasmapheresis use (p=0.0001) were associated with high-dose IVMP. Rates of glucocorticoid-related adverse effects ranged from 15-31% across dose levels, and glucocorticoid dosing did not associate with 12-month outcomes.Glucocorticoid dosing for pAAV-related renal disease was highly variable, and rates of adverse effects were high across all dosing groups. A significant proportion of patients received oral glucocorticoid or IVMP doses that were discordant with current adult guidelines. Higher glucocorticoid doses did not associate with improved outcomes.
- Published
- 2021
40. Osteoporotic Fractures and Vertebral Body Reshaping in Children With Glucocorticoid-treated Rheumatic Disorders
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Rosie Scuccimarri, Maya Scharke, Victor N. Konji, Leanne M Ward, Kristin Houghton, Robert Stein, Celia Rodd, Marie-Eve Robinson, Elizabeth Sykes, Brian C. Lentle, Anne Marie Sbrocchi, Nazih Shenouda, Frank Rauch, Julie Barsalou, Robert Couch, Kerry Siminoski, Mary Ann Matzinger, David A. Cabral, Paivi Miettunen, Johannes Roth, Adam M. Huber, Khaldoun Koujok, Elizabeth A. Cummings, Bianca Lang, Maggie Larché, Stephanie A. Atkinson, Jacob L. Jaremko, Claire LeBlanc, Nathalie Alos, Karen Watanabe Duffy, Josephine Ho, Roman Jurencak, and Jinhui Ma
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0301 basic medicine ,Male ,Pediatrics ,Vertebral Body ,Bone density ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Osteoporosis ,Biochemistry ,0302 clinical medicine ,Endocrinology ,Bone Density ,Risk Factors ,adolescents ,Longitudinal Studies ,Prospective Studies ,rheumatic disorders ,Child ,Bone mineral ,glucocorticoids ,Incidence (epidemiology) ,Incidence ,bone density ,Prognosis ,Child, Preschool ,Spinal Fractures ,Female ,Glucocorticoid ,medicine.drug ,medicine.medical_specialty ,Canada ,Adolescent ,030209 endocrinology & metabolism ,Context (language use) ,Standard score ,03 medical and health sciences ,children ,Internal medicine ,Rheumatic Diseases ,medicine ,Humans ,vertebral fractures ,Glucocorticoids ,business.industry ,Biochemistry (medical) ,Infant, Newborn ,Infant ,medicine.disease ,030101 anatomy & morphology ,business ,Body mass index ,Osteoporotic Fractures ,Follow-Up Studies - Abstract
Context Osteoporotic fractures are an important cause of morbidity in children with glucocorticoid-treated rheumatic disorders. Objective This work aims to evaluate the incidence and predictors of osteoporotic fractures and potential for recovery over six years following glucocorticoid (GC) initiation in children with rheumatic disorders. Methods Children with GC-treated rheumatic disorders were evaluated through a prospective inception cohort study led by the Canadian STeroid-induced Osteoporosis in the Pediatric Population (STOPP) Consortium. Clinical outcomes included lumbar spine bone mineral density (LS BMD), vertebral fractures (VF), non-VF, and vertebral body reshaping. Results A total of 136 children with GC-treated rheumatic disorders were enrolled (mean age 9.9 years, SD 4.4). The 6-year cumulative fracture incidence was 16.3% for VF, and 10.1% for non-VF. GC exposure was highest in the first 6 months, and 24 of 38 VF (63%) occurred in the first 2 years. Following VF, 16 of 19 children (84%) had complete vertebral body reshaping. Increases in disease activity and body mass index z scores in the first year and declines in LS BMD z scores in the first 6 months predicted incident VF over the 6 years, while higher average daily GC doses predicted both incident VF and non-VF. LS BMD z scores were lowest at 6 months (mean –0.9, SD 1.2) and remained low by 6 years even when adjusted for height z scores (–0.6, SD 0.9). Conclusion VF occurred early and were more common than non-VF in children with GC-treated rheumatic disorders. Eighty-four percent of children with VF underwent complete vertebral body reshaping, whereas vertebral deformity persisted in the remainder of children. On average, LS BMD z scores remained low at 6 years, consistent with incomplete recovery.
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- 2021
41. Consensus Treatment Plans for Severe Pediatric Antineutrophil Cytoplasmic Antibody-Associated Vasculitis
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Carra ANCA-Associated Vasculitis Workgroup, Linda Wagner-Weiner, David A. Cabral, Karen E. James, Kimberly Morishita, Dana Gerstbacher, Eric Y Yen, Ann M Szymanski, Kathleen M. O'Neil, and Vidya Sivaraman
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medicine.medical_specialty ,business.industry ,Childhood arthritis ,viruses ,Microscopic Polyangiitis ,Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ,medicine.disease ,Rheumatology ,Arthritis, Juvenile ,law.invention ,Antibodies, Antineutrophil Cytoplasmic ,Regimen ,Randomized controlled trial ,law ,Internal medicine ,Medicine ,Humans ,business ,Vasculitis ,Microscopic polyangiitis ,Granulomatosis with polyangiitis ,Child ,Anti-neutrophil cytoplasmic antibody - Abstract
There is no standardized approach to the treatment of pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Because of the rarity of pediatric AAV, randomized trials have not been feasible. The present study of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) was undertaken to establish consensus treatment plans (CTPs) for severe pediatric AAV to enable the future study of comparative effectiveness and safety.A workgroup of CARRA members (rheumatologists and nephrologists) formed the AAV Workgroup. This group performed a literature review on existing evidence-based treatments and guidelines for the management of AAV. They determined that the target population for CTP development was patients18 years of age with new-onset granulomatosis with polyangiitis (GPA), microscopic polyangiitis, or renal-limited AAV (eosinophilic GPA was excluded), with presentation confined to those with severe disease (i.e., organ- or life-threatening). Face-to-face consensus conferences employed nominal group techniques to identify treatment strategies for remission induction and remission maintenance, data elements to be systematically collected, and outcomes to be measured over time.The pediatric AAV Workgroup developed 2 CTPs for each of the remission induction and remission maintenance of severe AAV. A glucocorticoid-weaning regimen for induction and maintenance, a core data set, and outcome measures were also defined. A random sample of CARRA membership voted acceptance of the CTPs for remission induction and remission maintenance, with a 94% (75 of 80) and 98% (78 of 80) approval rate, respectively.Consensus methodology established standardized CTPs for treating severe pediatric AAV. These CTPs were in principle accepted by CARRA-wide membership for the evaluation of pragmatic comparative effectiveness in a long-term registry.
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- 2021
42. Parent-Reported Medication Side Effects and Their Impact on Health-Related Quality of Life in Children With Juvenile Idiopathic Arthritis
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Gordon S Soon, Ciarán M. Duffy, Heinrike Schmeling, Jaime Guzman, David A. Cabral, Michelle Batthish, Alessandra Bruns, Natalie J. Shiff, Capri Registry Investigators, Lori B. Tucker, Dax G. Rumsey, Kerstin Gerhold, Tommy Gerschman, Jean-Philippe Proulx-Gauthier, Gaëlle Chédeville, Katherine McGuire, and Roberta A. Berard
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Health related quality of life ,Parents ,medicine.medical_specialty ,Canada ,Drug-Related Side Effects and Adverse Reactions ,business.industry ,Arthritis ,medicine.disease ,Arthritis, Juvenile ,Methotrexate ,Rheumatology ,Quality of life ,Prednisone ,Internal medicine ,medicine ,Mixed effects ,Quality of Life ,Juvenile ,Humans ,Cumulative incidence ,Adverse effect ,business ,Child ,medicine.drug - Abstract
To describe the frequency and severity of parent-reported medication side effects (SEs) in children with juvenile idiopathic arthritis (JIA) relative to physician-reported actionable adverse events (AEs), and to assess their impact on health-related quality of life (HRQoL).Newly diagnosed JIA patients recruited between 2017 and 2019 to the Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) Registry were included. Parents reported presence and severity (0 = no problem, 10 = very severe) of medication SEs at every clinic visit. Physicians were asked to report any actionable AE. HRQoL was assessed using the Quality of My Life (QoML) questionnaire (0 = the worst, 10 = the best) and parent's global assessment (0 = very well, 10 = very poor). Analyses included proportion of visits with SEs or actionable AEs, cumulative incidence by Kaplan-Meier methods, and HRQoL impact measured with longitudinal mixed-effects models.SEs were reported at 371 of 884 (42%) visits (95% confidence interval [95% CI] 39, 45%) in 249 patients, with a median of 2 SEs per visit (interquartile range [IQR] 1-3), and median severity of 3 (IQR 1.5-5). Most SEs were gastrointestinal (32.5% of visits) or behavioral/psychiatric (22.4%). SE frequency was lowest with nonsteroidal antiinflammatory drugs alone (34.7%) and highest with prednisone and methotrexate combinations (66%). SE cumulative incidence was 67% (95% CI 59, 75) within 1 year of diagnosis, and 36% (95% CI 28, 44) for actionable AEs. Parent global and QoML scores were worse with SEs present; the impact persisted after adjusting for pain and number of active joints.Parents report that two-thirds of children with JIA experience SEs impacting their HRQoL within 1 year of diagnosis. SE mitigation strategies are needed in managing JIA.
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- 2021
43. Zoledronic Acid vs Placebo in Pediatric Glucocorticoid-induced Osteoporosis: A Randomized, Double-blind, Phase 3 Trial
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Sarfaraz Sayyed, R. Paul Aftring, Nathalie Alos, Leanne M Ward, Mikhail Kostik, Ekaterina Alexeeva, Anne Marie Sbrocchi, Nazih Shenouda, Kebashni Thandrayen, Craig F Munns, Gangadhar Sunkara, Nick Shaw, Jacob L. Jaremko, David A. Cabral, Éva Hosszú, Shayne Taback, Celia Rodd, Raja Padidela, and Anup Choudhury
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Male ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Osteoporosis ,Context (language use) ,Placebo ,Biochemistry ,Zoledronic Acid ,Endocrinology ,Double-Blind Method ,Internal medicine ,Clinical endpoint ,medicine ,Humans ,Adverse effect ,Child ,Glucocorticoids ,Bone mineral ,Bone Density Conservation Agents ,business.industry ,Biochemistry (medical) ,medicine.disease ,Prognosis ,Confidence interval ,Zoledronic acid ,Child, Preschool ,Female ,business ,medicine.drug ,Follow-Up Studies - Abstract
Context Glucocorticoids (GCs) prescribed for chronic pediatric illnesses are associated with osteoporotic fractures. Objective This study aims to determine the efficacy and safety of intravenous (IV) zoledronic acid (ZA) compared with placebo to treat pediatric GC-induced osteoporosis (GIO). Methods Children aged 5 to 17 years with GIO were enrolled in this multinational, randomized, double-blind, placebo-controlled phase 3 trial (ClinicalTrials.gov NCT 00799266). Eligible children were randomly assigned 1:1 to 6 monthly IV ZA 0.05 mg/kg or IV placebo. The primary end point was the change in lumbar spine bone mineral density z score (LSBMDZ) from baseline to month 12. Incident fractures and safety were assessed. Results Thirty-four children were enrolled (mean age 12.6 ± 3.4 years [18 on ZA, 16 on placebo]), all with low-trauma vertebral fractures (VFs). LSBMDZ increased from −2.13 ± 0.79 to −1.49 ± 1.05 on ZA, compared with −2.38 ± 0.90 to −2.27 ± 1.03 on placebo (least squares means difference 0.41 [95% CI, 0.02-0.81; P = .04]); when corrected for height z score, the least squares means difference in LBMDZ was 0.75 [95% CI, 0.27-1.22; P = .004]. Two children on placebo had new low-trauma VF vs none on ZA. Adverse events (AEs) were reported in 15 of 18 children (83%) on ZA, and in 12 of 16 (75%) on placebo, most frequently within 10 days after the first infusion. There were no deaths or treatment discontinuations due to treatment-emergent AEs. Conclusion LSBMDZ increased significantly on ZA compared with placebo over 1 year in children with GIO. Most AEs occurred after the first infusion.
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- 2021
44. Autoantibodies Against Lysosome Associated Membrane Protein-2 (LAMP-2) in Pediatric Chronic Primary Systemic Vasculitis
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Kristen M. Gibson, Renate Kain, Raashid A. Luqmani, Colin J. Ross, David A. Cabral, and Kelly L. Brown
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0301 basic medicine ,Male ,urologic and male genital diseases ,Gastroenterology ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,Immunology and Allergy ,Medicine ,lysosome-associated membrane protein-2 ,skin and connective tissue diseases ,Child ,Original Research ,education.field_of_study ,medicine.diagnostic_test ,3. Good health ,Erythrocyte sedimentation rate ,Child, Preschool ,Female ,systemic vasculitis ,Vasculitis ,Systemic vasculitis ,lcsh:Immunologic diseases. Allergy ,medicine.medical_specialty ,Adolescent ,Population ,Immunology ,Renal function ,Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ,03 medical and health sciences ,Internal medicine ,Lysosomal-Associated Membrane Protein 2 ,Humans ,cardiovascular diseases ,education ,Anti-neutrophil cytoplasmic antibody ,Autoantibodies ,030203 arthritis & rheumatology ,Creatinine ,business.industry ,anti-neutrophil cytoplasmic antibody ,Autoantibody ,Infant ,medicine.disease ,respiratory tract diseases ,030104 developmental biology ,pediatric ,chemistry ,Chronic Disease ,LAMP-2 ,lcsh:RC581-607 ,business ,ANCA-associated vasculitis - Abstract
BackgroundAnti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis in adults and children that commonly affects the kidneys. Although the frequent antigenic, and presumed pathogenic, targets of ANCA in AAV are proteinase-3 (PR3) and myeloperoxidase (MPO), ANCA against lysosome associated membrane protein-2 (LAMP-2), a lesser known ANCA antigen that is expressed on the glomerular endothelium, are present in some adults with AAV-associated renal disease. LAMP-2-ANCA has not been assessed in children with chronic systemic vasculitis, and, if present, would be a potentially valuable biomarker given that treatment decisions for these pediatric patients at diagnosis are largely informed by kidney function.MethodsA custom ELISA, using commercially available reagents, was designed to detect autoantibodies to human LAMP-2 in serum. Sera obtained from 51 pediatric patients at the time of diagnosis of chronic primary systemic vasculitis (predominantly AAV) were screened. LAMP-2-ANCA titers were evaluated for correlation with clinical metrics of disease activity (pediatric vasculitis activity score [pVAS], C-reactive protein [CRP] concentration, and erythrocyte sedimentation rate [ESR]), MPO- and PR3-ANCA titers, and renal function (glomerular filtration rate [GFR], renal-specific pVAS, and serum creatinine concentration).ResultsLAMP-2-ANCA (>1,000 ng/ml) were detected in 35% (n = 18) of pediatric systemic vasculitis patients, of which, 10 (20% of all patients) were found to have high positive titers (>1,500 ng/ml). Undetectable or negative titres (1,500 ng/ml) of LAMP-2-ANCA. LAMP-2-ANCA titers did not correlate with measures of disease activity (pVAS, CRP, or ESR) at the time of diagnosis. In contrast, for patients with 12-month post diagnosis follow-up, a negative correlation was observed between the change in GFR (from diagnosis to 12-month follow-up) and LAMP-2-ANCA titer at diagnosis.ConclusionsModerate to high LAMP-2-ANCA titers were detected in 35% (18/51) of children with chronic systemic vasculitis affecting small-to-medium vessels. Although the highest concentrations of LAMP-2-ANCA in this population were observed in individuals positive for classic ANCA (MPO- or PR3-ANCA), similar to previous reports on adult patients, LAMP-2-ANCA titers do not correlate with classic ANCA titers or with overall disease activity at diagnosis. Renal disease is a common manifestation in systemic small-medium vessel vasculitis (both in adults and children, though more severe in children) and our preliminary data suggest LAMP-2-ANCA at diagnosis may be a risk factor for more severe renal disease.
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- 2020
45. Does Bilevel Noninvasive Ventilation Have a Bronchodilating Effect and Alter Respiratory Mechanics in Asthmatic Individuals After Bronchoprovocation? Randomized, Crossover Study
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Gomes, Evelim Leal de Freitas Dantas, primary, Cavassini, Carla Lima Feitosa, additional, David, Maisi Cabral Muniz, additional, Luiz, Josiane Germano, additional, Santos, Adriana do Carmo, additional, Capeletti, Aldenice Magalhães, additional, and Costa, Dirceu, additional
- Published
- 2021
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46. Soluble Low-density Lipoprotein Receptor-related Protein 1 in Juvenile Idiopathic Arthritis
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Stuart E. Turvey, Lori B. Tucker, Marianna M. Newkirk, Ciarán M. Duffy, David A. Cabral, Gaëlle Chédeville, Gilles Boire, Suzanne E. Ramsey, Ross E. Petty, Shirley M. L. Tse, Zhenhong Li, Sarah Campillo, Rosie Scuccimarri, Alan M. Rosenberg, Adam M. Huber, Johannes Roth, Elham Rezaei, Karen Watanabe Duffy, Rae S. M. Yeung, Lynn Spiegel, Rayfel Schneider, Kimberly Morishita, Paul Dancey, Elizabeth Stringer, Susanne M. Benseler, John R. Gordon, Roman Jurencak, Kristin Houghton, Anne-Laure Chetaille, Bianca Lang, and Kiem Oen
- Subjects
musculoskeletal diseases ,0301 basic medicine ,medicine.medical_specialty ,Canada ,Adolescent ,Immunology ,Arthritis ,Inflammation ,03 medical and health sciences ,Psoriatic arthritis ,0302 clinical medicine ,Rheumatology ,Internal medicine ,medicine ,Immunology and Allergy ,Juvenile ,Humans ,Child ,business.industry ,Arthritis, Psoriatic ,030224 pathology ,medicine.disease ,Arthritis, Juvenile ,Lipoproteins, LDL ,030104 developmental biology ,LDL receptor ,Cohort ,Biomarker (medicine) ,medicine.symptom ,business ,Low Density Lipoprotein Receptor-Related Protein-1 ,Lipoprotein - Abstract
ObjectivesThis study aimed to expand knowledge about soluble low-density lipoprotein receptor-related protein 1 (sLRP1) in juvenile idiopathic arthritis (JIA) by determining associations of sLRP1 levels in nonsystemic JIA patients with clinical and inflammatory biomarker indicators of disease activity.MethodsPlasma sLRP1 and 44 inflammation-related biomarkers were measured at enrollment and 6 months later in a cohort of 96 newly diagnosed Canadian patients with nonsystemic JIA. Relationships between sLRP1 levels and indicators of disease activity and biomarker levels were analyzed at both visits.ResultsAt enrollment, sLRP1 levels correlated negatively with age and active joint counts. Children showed significantly higher levels of sLRP1 than adolescents (mean ranks: 55.4 and 41.9, respectively; P = 0.02). Participants with 4 or fewer active joints, compared to those with 5 or more active joints, had significantly higher sLRP1 levels (mean ranks: 56.2 and 40.7, respectively; P = 0.006). At enrollment, considering the entire cohort, sLRP1 correlated negatively with the number of active joints (r = –0.235, P = 0.017). In the entire cohort, sLRP1 levels at enrollment and 6 months later correlated with 13 and 6 pro- and antiinflammatory biomarkers, respectively. In JIA categories, sLRP1 correlations with inflammatory markers were significant in rheumatoid factor–negative polyarticular JIA, oligoarticular JIA, enthesitis-related arthritis, and psoriatic arthritis at enrollment. Higher sLRP1 levels at enrollment increased the likelihood of absence of active joints 6 months later.ConclusionPlasma sLRP1 levels correlate with clinical and biomarker indicators of short-term improvement in JIA disease activity, supporting sLRP1 as an upstream biomarker of potential utility for assessing JIA disease activity and outcome prediction.
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- 2020
47. Clinical and associated inflammatory biomarker features predictive of short-term outcomes in non-systemic juvenile idiopathic arthritis
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Paul Dancey, Rayfel Schneider, Elham Rezaei, Kimberly Morishita, Jaime Guzman, Rae S. M. Yeung, Susanne M. Benseler, Nazeem Muhajarine, Susan Tupper, Shirley M. L. Tse, Johannes Roth, Karen Watanabe Duffy, Sarah Campillo, Ciarán M. Duffy, Kiem Oen, Brett Trost, Suzanne E. Ramsey, Janet Ellsworth, Chantal Guillet, Gilles Boire, Adam M. Huber, Anne-Laure Chetaille, Ross E. Petty, Kristin Houghton, Regina M. Taylor-Gjevre, Gaëlle Chédeville, Bianca Lang, Rosie Scuccimarri, Stuart E. Turvey, Lynn Spiegel, Elizabeth Stringer, John R. Gordon, Daniel J. Hogan, David A. Cabral, Anthony Kusalik, Roman Jurencak, Chandima Karananayake, Lori B. Tucker, and Alan M. Rosenberg
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musculoskeletal diseases ,Male ,Wrist Joint ,medicine.medical_specialty ,Canada ,Adolescent ,Knee Joint ,Childhood arthritis ,Arthritis ,Plasma biomarkers ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Predictive Value of Tests ,Internal medicine ,Vitamin D and neurology ,Medicine ,Humans ,Pharmacology (medical) ,Longitudinal Studies ,Prospective Studies ,Vitamin D ,Child ,030304 developmental biology ,030203 arthritis & rheumatology ,0303 health sciences ,business.industry ,Interleukins ,Interleukin-17 ,Area under the curve ,Clinical Science ,medicine.disease ,Interleukin-12 ,Arthritis, Juvenile ,Interleukin-10 ,medicine.anatomical_structure ,Area Under Curve ,Child, Preschool ,Female ,Ankle ,Inflammatory biomarker ,business ,Inactive disease ,Ankle Joint ,Biomarkers ,Low Density Lipoprotein Receptor-Related Protein-1 - Abstract
Objective To identify early predictors of disease activity at 18 months in JIA using clinical and biomarker profiling. Methods Clinical and biomarker data were collected at JIA diagnosis in a prospective longitudinal inception cohort of 82 children with non-systemic JIA, and their ability to predict an active joint count of 0, a physician global assessment of disease activity of ≤1 cm, and inactive disease by Wallace 2004 criteria 18 months later was assessed. Correlation-based feature selection and ReliefF were used to shortlist predictors and random forest models were trained to predict outcomes. Results From the original 112 features, 13 effectively predicted 18-month outcomes. They included age, number of active/effused joints, wrist, ankle and/or knee involvement, ESR, ANA positivity and plasma levels of five inflammatory biomarkers (IL-10, IL-17, IL-12p70, soluble low-density lipoprotein receptor-related protein 1 and vitamin D), at enrolment. The clinical plus biomarker panel predicted active joint count = 0, physician global assessment ≤ 1, and inactive disease after 18 months with 0.79, 0.80 and 0.83 accuracy and 0.84, 0.83, 0.88 area under the curve, respectively. Using clinical features alone resulted in 0.75, 0.72 and 0.80 accuracy, and area under the curve values of 0.81, 0.78 and 0.83, respectively. Conclusion A panel of five plasma biomarkers combined with clinical features at the time of diagnosis more accurately predicted short-term disease activity in JIA than clinical characteristics alone. If validated in external cohorts, such a panel may guide more rationally conceived, biologically based, personalized treatment strategies in early JIA.
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- 2020
48. Adenosine deaminase 2 activity negatively correlates with age during childhood
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Kelly L. Brown, Kristen M Gibson, David A. Cabral, and Sarah M. Bowers
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0301 basic medicine ,Male ,lcsh:Diseases of the musculoskeletal system ,Adenosine ,Adenosine Deaminase ,Pediatrics ,0302 clinical medicine ,Reference Values ,Blood plasma ,Immunology and Allergy ,Child ,Correlation of Data ,education.field_of_study ,biology ,lcsh:RJ1-570 ,Age Factors ,3. Good health ,Adenosine deaminase 2 ,Cohort ,Biomarker (medicine) ,Intercellular Signaling Peptides and Proteins ,Female ,Analysis of variance ,medicine.drug ,Signal Transduction ,Research Article ,medicine.medical_specialty ,Canada ,Adolescent ,Population ,03 medical and health sciences ,Rheumatology ,Internal medicine ,medicine ,Humans ,education ,Enzyme Assays ,030203 arthritis & rheumatology ,Inflammation ,business.industry ,Infant ,lcsh:Pediatrics ,Enzyme assay ,030104 developmental biology ,Endocrinology ,Pediatrics, Perinatology and Child Health ,biology.protein ,lcsh:RC925-935 ,business ,Biomarkers - Abstract
Background Human adenosine deaminase 2 (ADA2) is an extracellular enzyme that negatively regulates adenosine-mediated cell signaling by converting adenosine to inosine. Altered ADA2 enzyme activity has been associated with some viral infections and rheumatic diseases. The potential utility of ADA2 as a biomarker is, however, limited by the absence of established ranges of ADA2 concentration and enzyme activity in the healthy population. It is known that ADA2 enzyme activity is lower in adults, but when (and why) this decline happens is not known. The purpose of this study was to establish normative ranges of ADA2 enzyme activity and protein concentration in the healthy pediatric population. Methods We modified a commercially available ADA2 enzyme activity assay to enable higher throughput analysis of fresh, frozen and hemolyzed blood samples. With this assay and ADA2 protein immunoblotting, we analyzed ADA2 enzyme activity and protein concentration in blood plasma from a cohort of children and adolescents (n = 94) aged 5 months to 18 years. One-way ANOVA with subsequent Tukey multiple comparison test was used to analyze group differences. Reference intervals were generated using the central 95% of the population (2–97.5 percentiles). Results ADA2 enzyme activity was consistent in fresh, frozen, and hemolyzed sera and plasma as measured by our modified assay. Analysis of plasma samples from the healthy pediatric cohort revealed that ADA2 enzyme activity is significantly lower in older children than in younger children (p Conclusion We observed that ADA2 enzyme activity, but not ADA2 protein concentration, negatively correlates with age in a cohort of children and adolescents. Our findings stress the importance of appropriate age-matched controls for assessing ADA2 enzyme activity in the clinical setting.
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- 2019
49. Criação e validação de aplicativo para avaliação de dor infantil
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Aurimery Gomes Chermont, Valmor Arede Cordova Junior, Creusa Barbosa dos Santos Trindade, Silvestre Savino Neto, and David Santos Cabral
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Physics ,Mobile apps ,General Earth and Planetary Sciences ,Humanities ,Child health ,General Environmental Science - Abstract
O manejo da dor infantil é complexo devido as limitações de comunicação das crianças e tem seu ponto de partida em uma avaliação adequada da dor, contudo há uma gama de escalas de avaliação da dor e os profissionais em dificuldade em escolher a ferramenta adequada. Objetivo: construir e validar aplicativo de avaliação de dor em crianças a partir do estudo das escalas disponíveis. Metodologia: Trata-se de um estudo descritivo de desenvolvimento experimental. A pesquisa se desenvolveu nas seguintes etapas: desenvolvimento do aplicativo, validação por especialistas e análise de dados. Realizou-se a revisão exploratória sobre as escalas de avaliação de dor em crianças para fundamentar o aplicativo. O desenvolvimento do aplicativo foi realizado em parceria com profissional de computação a fim de fornecer uma interface amigável. A validação foi realizada por especialistas profissionais de saúde (médicos, enfermeiros e fisioterapeutas) através de um questionário pré-estabelecido contendo informações sobre a formação acadêmica e profissional dos validadores, e sobre os itens a serem validados. Resultados: Para análise de dados, utilizou-se o índice de validade de conteúdo (IVC), sendo considerado válido quando o quesito obtivesse IVC > 0.8. O aplicativo foi validado com IVC de 1.0 pelos especialistas. Conclusão: A avaliação positiva do aplicativo demonstra que é uma ferramenta válida e com boa aceitação pelos profissionais de saúde envolvidos nos cuidados da dor em crianças e que a incorporação de novas tecnologias pode otimizar e facilitar o uso de escalas na avaliação de dor em crianças.
- Published
- 2021
50. Therapeutic Management of Pediatric Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis
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Kimberly Morishita, David A. Cabral, and Georgina Tiller
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030203 arthritis & rheumatology ,medicine.medical_specialty ,business.industry ,Context (language use) ,ANCA-Associated Vasculitis ,General Medicine ,medicine.disease ,Optimal management ,Rheumatology ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,030212 general & internal medicine ,business ,Intensive care medicine ,Vasculitis ,Anti-neutrophil cytoplasmic antibody ,Systemic vasculitis - Abstract
Purpose of the Review To provide an overview of recent advances in the treatment of pediatric antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Recent Findings With advances in research, use of standardized clinical assessment tools, advent of biologic therapies, and use of patient registries, concepts relating to the optimal management of pediatric patients with chronic primary systemic vasculitis have evolved and newer treatments strategies and treatment guidelines continue to emerge. Conclusion Although most of what we have learned about pediatric AAV has come from adult data, the quality and breadth of pediatric data is accumulating because of multicenter, international collaborations. These efforts are critical given that optimal treatment strategies likely differ in the context of a developing immune system, and in a physically and emotionally developing child. Pragmatic clinical trials linked with international patient registries could help close the pediatric AAV evidence gap.
- Published
- 2017
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