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15 pages, 887 KiB

Open AccessArticle

Predictors of Progression and Mortality in Patients with Prevalent Rheumatoid Arthritis and Interstitial Lung Disease: A Prospective Cohort Study

by Natalia Mena-Vázquez, Marta Rojas-Gimenez, Carmen María Romero-Barco, Sara Manrique-Arija, Espildora Francisco, María Carmen Aguilar-Hurtado, Isabel Añón-Oñate, Lorena Pérez-Albaladejo, Rafaela Ortega-Castro, Francisco Javier Godoy-Navarrete, Inmaculada Ureña-Garnica, Maria Luisa Velloso-Feijoo, Rocio Redondo-Rodriguez, Francisco Gabriel Jimenez-Núñez, Blanca Panero Lamothe, María Isabel Padin-Martín and Antonio Fernández-Nebro

J. Clin. Med. 2021, 10(4), 874; https://doi.org/10.3390/jcm10040874 - 20 Feb 2021

Cited by 30 | Viewed by 3530

Abstract

Objectives: To describe a prospective cohort of patients with rheumatoid arthritis associated with interstitial lung disease (RA-ILD) and identify risk factors associated with disease progression and mortality in this cohort. Patients and methods: We performed a multicenter, prospective, observational study of patients with [...] Read more.

Objectives: To describe a prospective cohort of patients with rheumatoid arthritis associated with interstitial lung disease (RA-ILD) and identify risk factors associated with disease progression and mortality in this cohort. Patients and methods: We performed a multicenter, prospective, observational study of patients with RA-ILD receiving disease-modifying antirheumatic drugs (DMARDs) between 2015 and 2020. The patients were assessed using high-resolution computed tomography and pulmonary function tests at baseline and at 60 months. The main endpoint was “Progression to ILD at the end of follow-up” in terms of the following outcomes: (1) improvement (i.e., improvement in forced vital capacity (FVC) ≥10% or diffusing capacity of the lungs for carbon monoxide (DLCO) ≥15% and absence of radiological progression); (2) nonprogression (stabilization or improvement in FVC ≤10% or diffusing capacity of the lungs for carbon monoxide (DLCO) <15% and absence of radiological progression); (3) progression (worsening of FVC >10% or DLCO >15% and radiological progression); or (4) death. We recorded demographic and clinical characteristics, lung function, and the incidence of adverse events. A Cox regression analysis was performed to identify factors associated with the worsening of ILD. Results: After 60 months, lung disease had stabilized in 66 patients (56.9%), improved in 9 (7.8%), and worsened in 23 (19.8%). Eighteen patients (15.5%) died, with a mean survival of 71.8 (1.9) months after diagnosis of ILD. The Cox multivariate analysis revealed the independent predictors of worsening of RA-ILD to be usual interstitial pneumonia (hazard ratio (HR), 2.6 (95%CI, 1.0–6.7)), FVC <80% (HR, 3.8 (95%CI, 1.5–6.7)), anticitrullinated protein antibody titers (HR, 2.8 (95%CI, 1.1–6.8)), smoking (HR, 2.5 (95%CI, 1.1–6.2)), and treatment with abatacept, tocilizumab, or rituximab (HR, 0.4 (95%CI, 0.2–0.8)). During follow-up, 79 patients (68%) experienced an adverse event, mostly infection (61%). Infection was fatal in 10/18 patients (55.5%) during follow-up. Conclusions: Lung function is stable in most patients with RA-ILD receiving treatment with disease-modifying anti-rheumatic drugs (DMARDs), although one-third worsened or died. Identifying factors associated with worsening in RA-ILD is important for clinical management. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis and Other Inflammatory Diseases: From Pathogenesis through Therapeutic Targets to Personalized Medicine)

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8 pages, 835 KiB

Open AccessArticle

Renalase in Haemodialysis Patients with Chronic Kidney Disease

by Magda Wisniewska, Natalia Serwin, Violetta Dziedziejko, Małgorzata Marchelek-Mysliwiec, Barbara Dołegowska, Leszek Domanski, Kazimierz Ciechanowski, Krzysztof Safranow and Andrzej Pawlik

J. Clin. Med. 2021, 10(4), 680; https://doi.org/10.3390/jcm10040680 - 10 Feb 2021

Cited by 7 | Viewed by 1749

Abstract

Chronic kidney disease (CKD) is an inflammatory disease leading to kidney insufficiency and uremia. Renalase is a novel flavoprotein with enzymatic activities. Previous studies have shown that chronic kidney disease may influence renalase serum levels. Renalase metabolises catecholamines and therefore may be involved [...] Read more.

Chronic kidney disease (CKD) is an inflammatory disease leading to kidney insufficiency and uremia. Renalase is a novel flavoprotein with enzymatic activities. Previous studies have shown that chronic kidney disease may influence renalase serum levels. Renalase metabolises catecholamines and therefore may be involved in the pathogenesis of hypertension and other diseases of the circulatory system. In this study, we examined renalase levels in serum, erythrocytes and urine from haemodialysis CKD patients. The study enrolled 77 haemodialysis CKD patients and 30 healthy subjects with normal kidney function as the control group. Renalase serum and urine concentrations in CKD patients were significantly increased when compared with control subjects (185.5 ± 64.3 vs. 19.6 ± 5.0 ng/mL; p < 0.00001 and 207.1 ± 60.5 vs. 141.6 ± 41.3 ng/mL; p = 0.00040, respectively). In contrast, renalase levels in erythrocytes were significantly lower in CKD patients when compared with control subjects (176.5 ± 60.9 vs. 233.2 ± 83.1 ng/mL; p = 0.00096). Plasma levels of dopamine, adrenaline and noradrenaline were also significantly lower in CKD patients when compared with controls. Conclusions: Increased serum and urine concentrations of renalase in haemodialysis CKD patients are likely related to compensatory production in extrarenal organs as a result of changes in the cardiovascular system and hypertension. The decreased plasma concentrations of catecholamines may be due to their increased degradation by plasma renalase. Decreased renalase levels in erythrocytes may be probably due to lower renalase synthesis by the kidneys in CKD. The results indicate the presence of renalase in erythrocytes. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis and Other Inflammatory Diseases: From Pathogenesis through Therapeutic Targets to Personalized Medicine)

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11 pages, 215 KiB

Open AccessArticle

The Impact of Epstein-Barr Virus Infection on Juvenile Idiopathic Arthritis Activity and Patient’s Response to Treatment

by Violetta Opoka-Winiarska, Ewelina Grywalska, Aleksandra Sobiesiak and Jacek Roliński

J. Clin. Med. 2020, 9(11), 3453; https://doi.org/10.3390/jcm9113453 - 27 Oct 2020

Cited by 1 | Viewed by 1544

Abstract

This study aimed to investigate the relationship between Epstein-Barr virus (EBV) infection and the onset of juvenile idiopathic arthritis (JIA), disease activity, and response to treatment. The study included 44 children with JIA, 23 children with different types of arthritis, and 44 controls. [...] Read more.

This study aimed to investigate the relationship between Epstein-Barr virus (EBV) infection and the onset of juvenile idiopathic arthritis (JIA), disease activity, and response to treatment. The study included 44 children with JIA, 23 children with different types of arthritis, and 44 controls. We measured EBV infection markers, including the EBV DNA load and the concentration of antibodies to viral antigens, at disease onset, before treatment. Six months after JIA diagnosis and the initiation of treatment patients with anti-viral capsid antigen IgG had a higher disease activity and worse response to treatment than patients without previous infection. After six months of treatment, the probability of disease inactivity in children without a history of EBV infection was almost 6.5 times greater than in a child with a history of infection. Furthermore, the probability of a better response after six months of treatment in a child with a history of EBV infection was more than five times smaller than in a child without infection. A past EBV infection can have a negative effect on achieving disease remission and may be associated with a worse response to treatment. Our results do not indicate the need for routine assessment of EBV infection markers in patients with JIA. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis and Other Inflammatory Diseases: From Pathogenesis through Therapeutic Targets to Personalized Medicine)

15 pages, 704 KiB

Open AccessArticle

Postprandial Apolipoprotein B48 is Associated with Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis

by Natalia Mena-Vázquez, Marta Rojas-Gimenez, Francisco Gabriel Jimenez Nuñez, Sara Manrique-Arija, José Rioja, Patricia Ruiz-Limón, Inmaculada Ureña, Manuel Castro-Cabezas, Pedro Valdivielso and Antonio Fernández-Nebro

J. Clin. Med. 2020, 9(8), 2483; https://doi.org/10.3390/jcm9082483 - 02 Aug 2020

Cited by 10 | Viewed by 1974

Abstract

Objective: To describe postprandial lipemia in patients with rheumatoid arthritis (RA) and to analyze its association with subclinical atherosclerosis measured as carotid intima-media thickness (cIMT). Methods: We performed an observational study of 40 patients with RA and 40 sex and age-matched controls. Patients [...] Read more.

Objective: To describe postprandial lipemia in patients with rheumatoid arthritis (RA) and to analyze its association with subclinical atherosclerosis measured as carotid intima-media thickness (cIMT). Methods: We performed an observational study of 40 patients with RA and 40 sex and age-matched controls. Patients with dyslipidemia were excluded. Pathologically increased cIMT was defined as a carotid thickness greater than the 90th percentile (>p90) for age and sex. Fasting and postprandial plasma lipids, cholesterol, triglycerides, apolipoprotein B48 (ApoB48), and total ApoB were evaluated. The other variables included were clinical and laboratory values, Framingham score, and the 28-joint Disease Activity Score (DAS28). Two multivariate models were constructed to identify factors associated with pathologic cIMT in patients with RA. Results: Fasting lipid values were similar in patients with RA and controls, although those of postprandial ApoB48 were higher (median (IQR), 14.4 (10.8–12.1) vs. 12.1 (2.3–9,8); p = 0.042). Pathologic cIMT was recorded in 10 patients with RA (25%) and nine controls (22.5%). In patients with RA, pathologic cIMT was associated with postprandial ApoB48 (OR (95% CI), 1.15 (1.0–1.3)) and total ApoB (OR [95% CI], 1.12 [1.1–1.2]). The second model revealed a mean increase of 0.256 mm for cIMT in patients with elevated anticitrullinated protein antibodies (ACPAs). Conclusion: Postprandial ApoB48 levels in patients with RA are higher than in controls. Postprandial ApoB48 and total ApoB levels and markers of severity, such as ACPAs, are associated with pathologic cIMT in patients with RA. Our findings could indicate that these atherogenic particles have a negative effect on the endothelium. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis and Other Inflammatory Diseases: From Pathogenesis through Therapeutic Targets to Personalized Medicine)

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12 pages, 1711 KiB

Open AccessArticle

Peptidyl Arginine Deiminase Type 4 Gene Promoter Hypo-Methylation in Rheumatoid Arthritis

by Bogdan Kolarz, Marek Ciesla, Magdalena Dryglewska and Maria Majdan

J. Clin. Med. 2020, 9(7), 2049; https://doi.org/10.3390/jcm9072049 - 30 Jun 2020

Cited by 10 | Viewed by 3214

Abstract

Protein citrullination is carried out by peptidylarginine deiminase type 4 (PAD4) enzyme. As a consequence of this process, post-translationally modified proteins are formed that become antigens for anti-citrullinated protein antibodies (ACPA). The study aimed at identifying whether the PADI4 gene is subject to [...] Read more.

Protein citrullination is carried out by peptidylarginine deiminase type 4 (PAD4) enzyme. As a consequence of this process, post-translationally modified proteins are formed that become antigens for anti-citrullinated protein antibodies (ACPA). The study aimed at identifying whether the PADI4 gene is subject to epigenetic regulation through methylation of its promoter region, whether the degree of methylation differs in healthy individuals vs. rheumatoid arthritis (RA) patients and changes in correlation with ACPA, anti-PAD4 and disease activity. A total of 125 RA patients and 30 healthy controls were enrolled. Quantitative real-time methylation-specific PCR was used to analyze the methylation status. ACPA and anti-PAD4 antibodies were determined in serum by enzyme-linked immunosorbent immunoassay. The differences were observed in the degree of PADI4 gene promoter methylation between RA patients and HC, along with an upward trend for the methylation in RA, which was inversely proportional to the disease activity. A weak or modest negative correlation between the degree of PADI4 gene methylation and anti-PAD4, disease activity score (DAS28) and ACPA level has been found. The elevated methylation is associated with lower disease activity, lower levels of ACPA and aPAD4. The methylation degree in this area is growing up during effective treatment and might play a role in the RA pathophysiology and therefore could be a future therapeutic target. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis and Other Inflammatory Diseases: From Pathogenesis through Therapeutic Targets to Personalized Medicine)

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11 pages, 1210 KiB

Open AccessArticle

Clinical, Radiological, and Laboratory Features of Spinal Cord Involvement in Primary Sjögren’s Syndrome

by Michaela Butryn, Jens Neumann, Leoni Rolfes, Claudius Bartels, Mike P. Wattjes, Nima Mahmoudi, Tabea Seeliger, Franz F. Konen, Thea Thiele, Torsten Witte, Sven G. Meuth, Thomas Skripuletz and Marc Pawlitzki

J. Clin. Med. 2020, 9(5), 1482; https://doi.org/10.3390/jcm9051482 - 14 May 2020

Cited by 13 | Viewed by 2839

Abstract

Objective: To identify radiological and laboratory hallmarks in patients with primary Sjögren’s syndrome (pSS) presenting with spinal cord involvement. Methods: Clinical and laboratory routine parameters were analyzed in a retrospective multicenter case series of four patients who developed myelitis associated with pSS. Serological [...] Read more.

Objective: To identify radiological and laboratory hallmarks in patients with primary Sjögren’s syndrome (pSS) presenting with spinal cord involvement. Methods: Clinical and laboratory routine parameters were analyzed in a retrospective multicenter case series of four patients who developed myelitis associated with pSS. Serological and cerebrospinal fluid (CSF) measurements of pSS associated anti-SSA(Ro)-antibodies were initiated, and CSF neurofilament light chain (NFL) levels were assessed. NFL values were compared with results from 15 sex- and age-matched healthy controls. Radiological assessment was performed using multi-sequence spinal cord magnetic resonance imaging. Results: Three of the four patients initially developed neurological signs suggestive of myelitis and were subsequently diagnosed with pSS. All patients presented a longitudinal spinal T2-hyperintense lesion in the cervical spinal cord, whereas only two patients showed pleocytosis and oligoclonal bands in the CSF. Median (range) CSF-NFL levels were significantly elevated in patients compared to controls (6672 pg/mL (621–50,000) vs. 585 pg/mL (357–729), p = 0.009). One patient showed sustained, highly increased NFL levels (50,000 pg/mL) in the initial assessment when radiological signs of axonal injury were still absent. Anti-SSA(Ro)-antibodies were found in the serum of three patients, while two patients additionally presented intrathecal anti-SSA(Ro)-antibody production. Elevated CSF-NFL levels and intrathecal synthesis of anti-SSA(Ro)-antibodies were associated with a relapsing and treatment-resistant disease course. Conclusion: Inflammatory spinal cord lesions associated with pSS are a rare but serious disease leading to severe disability. NFL and anti-SSA(Ro)-antibodies in CSF might serve as prognostic biomarkers and should be routinely assessed in patients with pSS. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis and Other Inflammatory Diseases: From Pathogenesis through Therapeutic Targets to Personalized Medicine)

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15 pages, 2840 KiB

Open AccessArticle

Peripheral Blood Lymphocyte Phenotype Differentiates Secondary Antibody Deficiency in Rheumatic Disease from Primary Antibody Deficiency

by Alexandra Jablonka, Haress Etemadi, Ignatius Ryan Adriawan, Diana Ernst, Roland Jacobs, Sabine Buyny, Torsten Witte, Reinhold Ernst Schmidt, Faranaz Atschekzei and Georgios Sogkas

J. Clin. Med. 2020, 9(4), 1049; https://doi.org/10.3390/jcm9041049 - 07 Apr 2020

Cited by 10 | Viewed by 2828

Abstract

The phenotype of primary immunodeficiency disorders (PID), and especially common variable immunodeficiency (CVID), may be dominated by symptoms of autoimmune disorders. Furthermore, autoimmunity may be the first manifestation of PID, frequently preceding infections and the diagnosis of hypogammaglobulinemia, which occurs later on. In [...] Read more.

The phenotype of primary immunodeficiency disorders (PID), and especially common variable immunodeficiency (CVID), may be dominated by symptoms of autoimmune disorders. Furthermore, autoimmunity may be the first manifestation of PID, frequently preceding infections and the diagnosis of hypogammaglobulinemia, which occurs later on. In this case, distinguishing PID from hypogammaglobulinemia secondary to anti-inflammatory treatment of autoimmunity may become challenging. The aim of this study was to evaluate the diagnostic accuracy of peripheral blood lymphocyte phenotyping in resolving the diagnostic dilemma between primary and secondary hypogammaglobulinemia. Comparison of B and T cell subsets from patients with PID and patients with rheumatic disease, who developed hypogammaglobulinemia as a consequence of anti-inflammatory regimes, revealed significant differences in proportion of naïve B cells, class-switched memory B cells and CD21^low B cells among B cells as well as in CD4⁺ memory T cells and CD4⁺ T follicular cells among CD4⁺ T cells. Identified differences in B cell and T cell subsets, and especially in the proportion of class-switched memory B cells and CD4⁺ T follicular cells, display a considerable diagnostic efficacy in distinguishing PID from secondary hypogammaglobulinemia due to anti-inflammatory regimens for rheumatic disease. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis and Other Inflammatory Diseases: From Pathogenesis through Therapeutic Targets to Personalized Medicine)

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13 pages, 1618 KiB

Open AccessArticle

Expansion of Rare and Harmful Lineages is Associated with Established Rheumatoid Arthritis

by Natalia Mena-Vázquez, Patricia Ruiz-Limón, Isabel Moreno-Indias, Sara Manrique-Arija, Francisco J. Tinahones and Antonio Fernández-Nebro

J. Clin. Med. 2020, 9(4), 1044; https://doi.org/10.3390/jcm9041044 - 07 Apr 2020

Cited by 27 | Viewed by 3516

Abstract

Objectives: To characterize the gut microbiota profile in rheumatoid arthritis (RA) patients and investigate its association with certain characteristics of RA. Patients and methods: A nested case–control cohort of 40 patients with RA and 40 sex-age matched controls was studied. Subjects with diabetes, [...] Read more.

Objectives: To characterize the gut microbiota profile in rheumatoid arthritis (RA) patients and investigate its association with certain characteristics of RA. Patients and methods: A nested case–control cohort of 40 patients with RA and 40 sex-age matched controls was studied. Subjects with diabetes, with any other inflammatory disease, practicing extreme diets, taking antibiotics, probiotics or under any new treatment for at least three months prior to sampling were excluded. The microbiota composition was determined by 16S rRNA pyrosequencing and bioinformatics analysis by Quantitative Insights Into Microbial Ecology (QIIME). Other variables included clinical-laboratory variables and average Disease Activity Score 28 points during the follow-up period. Multiple linear regression models were constructed to investigate the possible risk factors for the microbiota. Results: β-diversity data showed that patients tend to differ from healthy subjects according to their microbiota (p = 0.07). The analysis showed an increase in Collinsella aerofaciens, Sedimentibacter and Enterococcus genera in patients compared to controls, as well as a decrease in Dorea formicigenerans. Likewise, an increase in the activity of arginine deiminase was observed, which was found in approximately 90% of the RA genes of the genus Collinsela. The sequence number of Collinsella aerofaciens was independently associated with age (B (95%CI), −0.347 (−21.6, −2.1)), high ACPA (0.323 (27.4–390.0)) and smoking (0.300 (8.8–256.4)) in RA patients. In addition, we observed decreases in Sarcina, 02d06 and Porphyromonas bacterial lineages. Conclusion: Patients with RA present dysbiosis, resulting from an abundance of certain bacterial lineages and a decrease in others. These alterations could influence the maintenance of autoimmunity to this disease. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis and Other Inflammatory Diseases: From Pathogenesis through Therapeutic Targets to Personalized Medicine)

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Review

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20 pages, 829 KiB

Open AccessReview

Application of NGS Technology in Understanding the Pathology of Autoimmune Diseases

by Anna Wajda, Larysa Sivitskaya and Agnieszka Paradowska-Gorycka

J. Clin. Med. 2021, 10(15), 3334; https://doi.org/10.3390/jcm10153334 - 28 Jul 2021

Cited by 3 | Viewed by 2614

Abstract

NGS technologies have transformed clinical diagnostics and broadly used from neonatal emergencies to adult conditions where the diagnosis cannot be made based on clinical symptoms. Autoimmune diseases reveal complicate molecular background and traditional methods could not fully capture them. Certainly, NGS technologies meet [...] Read more.

NGS technologies have transformed clinical diagnostics and broadly used from neonatal emergencies to adult conditions where the diagnosis cannot be made based on clinical symptoms. Autoimmune diseases reveal complicate molecular background and traditional methods could not fully capture them. Certainly, NGS technologies meet the needs of modern exploratory research, diagnostic and pharmacotherapy. Therefore, the main purpose of this review was to briefly present the application of NGS technology used in recent years in the understanding of autoimmune diseases paying particular attention to autoimmune connective tissue diseases. The main issues are presented in four parts: (a) panels, whole-genome and -exome sequencing (WGS and WES) in diagnostic, (b) Human leukocyte antigens (HLA) as a diagnostic tool, (c) RNAseq, (d) microRNA and (f) microbiome. Although all these areas of research are extensive, it seems that epigenetic impact on the development of systemic autoimmune diseases will set trends for future studies on this area. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis and Other Inflammatory Diseases: From Pathogenesis through Therapeutic Targets to Personalized Medicine)

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20 pages, 374 KiB

Open AccessReview

Cytokines and Their Genetic Polymorphisms Related to Periodontal Disease

by Małgorzata Kozak, Ewa Dabrowska-Zamojcin, Małgorzata Mazurek-Mochol and Andrzej Pawlik

J. Clin. Med. 2020, 9(12), 4045; https://doi.org/10.3390/jcm9124045 - 14 Dec 2020

Cited by 22 | Viewed by 2666

Abstract

Periodontal disease (PD) is a chronic inflammatory disease caused by the accumulation of bacterial plaque biofilm on the teeth and the host immune responses. PD pathogenesis is complex and includes genetic, environmental, and autoimmune factors. Numerous studies have suggested that the connection of [...] Read more.

Periodontal disease (PD) is a chronic inflammatory disease caused by the accumulation of bacterial plaque biofilm on the teeth and the host immune responses. PD pathogenesis is complex and includes genetic, environmental, and autoimmune factors. Numerous studies have suggested that the connection of genetic and environmental factors induces the disease process leading to a response by both T cells and B cells and the increased synthesis of pro-inflammatory mediators such as cytokines. Many studies have shown that pro-inflammatory cytokines play a significant role in the pathogenesis of PD. The studies have also indicated that single nucleotide polymorphisms (SNPs) in cytokine genes may be associated with risk and severity of PD. In this narrative review, we discuss the role of selected cytokines and their gene polymorphisms in the pathogenesis of periodontal disease. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis and Other Inflammatory Diseases: From Pathogenesis through Therapeutic Targets to Personalized Medicine)

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