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1.
BMC Med Genomics ; 12(1): 144, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31651337

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease whose pathogenesis remains incompletely understood. Increasing evidence suggests that both genetic susceptibilities and changes in DNA methylation influence pivotal biological pathways and thereby contribute to the disease. The role of DNA methylation in SSc has not been fully elucidated, because existing investigations of DNA methylation predominantly focused on nucleotide CpGs within restricted genic regions, and were performed on samples containing mixed cell types. METHODS: We performed whole-genome bisulfite sequencing on purified CD4+ T lymphocytes from nine SSc patients and nine controls in a pilot study, and then profiled genome-wide cytosine methylation as well as genetic variations. We adopted robust statistical methods to identify differentially methylated genomic regions (DMRs). We then examined pathway enrichment associated with genes located in these DMRs. We also tested whether changes in CpG methylation were associated with adjacent genetic variation. RESULTS: We profiled DNA methylation at more than three million CpG dinucleotides genome-wide. We identified 599 DMRs associated with 340 genes, among which 54 genes exhibited further associations with adjacent genetic variation. We also found these genes were associated with pathways and functions that are known to be abnormal in SSc, including Wnt/ß-catenin signaling pathway, skin lesion formation and progression, and angiogenesis. CONCLUSION: The CD4+ T cell DNA cytosine methylation landscape in SSc involves crucial genes in disease pathogenesis. Some of the methylation patterns are also associated with genetic variation. These findings provide essential foundations for future studies of epigenetic regulation and genome-epigenome interaction in SSc.

2.
Nat Commun ; 10(1): 4712, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624262

RESUMO

Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B+, interferon (IFN)-γ+ CD8+ cytotoxic T cell and circulating regulatory T (Treg) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated Treg cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-γ+ CD4+ T cells and serum IFN-γ levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.

3.
Psychother Psychosom ; : 1-13, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31593971

RESUMO

BACKGROUND: Screening for major depression with the Patient Health Questionnaire-9 (PHQ-9) can be done using a cutoff or the PHQ-9 diagnostic algorithm. Many primary studies publish results for only one approach, and previous meta-analyses of the algorithm approach included only a subset of primary studies that collected data and could have published results. OBJECTIVE: To use an individual participant data meta-analysis to evaluate the accuracy of two PHQ-9 diagnostic algorithms for detecting major depression and compare accuracy between the algorithms and the standard PHQ-9 cutoff score of ≥10. METHODS: Medline, Medline In-Process and Other Non-Indexed Citations, PsycINFO, Web of Science (January 1, 2000, to February 7, 2015). Eligible studies that classified current major depression status using a validated diagnostic interview. RESULTS: Data were included for 54 of 72 identified eligible studies (n participants = 16,688, n cases = 2,091). Among studies that used a semi-structured interview, pooled sensitivity and specificity (95% confidence interval) were 0.57 (0.49, 0.64) and 0.95 (0.94, 0.97) for the original algorithm and 0.61 (0.54, 0.68) and 0.95 (0.93, 0.96) for a modified algorithm. Algorithm sensitivity was 0.22-0.24 lower compared to fully structured interviews and 0.06-0.07 lower compared to the Mini International Neuropsychiatric Interview. Specificity was similar across reference standards. For PHQ-9 cutoff of ≥10 compared to semi-structured interviews, sensitivity and specificity (95% confidence interval) were 0.88 (0.82-0.92) and 0.86 (0.82-0.88). CONCLUSIONS: The cutoff score approach appears to be a better option than a PHQ-9 algorithm for detecting major depression.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31504944

RESUMO

OBJECTIVES: In severe rapidly progressive SSc, autologous haematopoietic stem cell transplantation (AHSCT) allows significant improvements in overall and event-free survival. We undertook this study to identify, appraise and synthesize the evidence on health-related quality of life (HRQoL) before and after AHSCT for SSc. METHODS: We performed a systematic review of the literature, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, in PubMed and ScienceDirect from database inception to 1 February 2019. All articles with original HRQoL data were selected. RESULTS: The search identified 1080 articles, of which 8 were selected: 3 unblinded randomized controlled trials [American Scleroderma Stem Cell versus Immune Suppression Trial (ASSIST), Autologous Stem Cell Transplantation International Scleroderma, Scleroderma: Cyclophosphamide or Transplantation), 3 uncontrolled phase I or II trials and 2 cohort studies. HRQoL data from 289 SSc patients treated with AHSCT and 125 treated with intravenous CYC as a comparator with median 1.25-4.5 years follow-up were included. HRQoL was evaluated with the HAQ Disability Index (HAQ-DI; 275 patients), the 36-item Short Form Health Survey (SF-36; 249 patients) and the European Quality of Life 5-Dimensions questionnaire (EQ-5D; 138 patients). The quality of the studies was moderate to low. AHSCT was associated with significant improvement in the HAQ-DI (P = 0.02-<0.001), SF-36 Physical Component Summary score (P = 0.02-<0.0001) and EQ-5D index-based utility score (P < 0.001). The SF-36 Mental Component Summary score improved in the ASSIST (n = 19) and one small retrospective cohort (n = 30 patients, P = 0.005) but did not improve significantly in 2 randomized controlled trials (n = 200 patients, P = 0.1-0.91). CONCLUSION: AHSCT in severe SSc patients is associated with significant and durable improvement in physical HRQoL.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31504972

RESUMO

OBJECTIVES: Abatacept, a biologic DMARD, was associated with respiratory adverse events in a small subgroup of RA patients with chronic obstructive pulmonary disease (COPD) in a trial. Whether this potential risk is specific to abatacept or extends to all biologics and targeted synthetic DMARDs (tsDMARDs) is unclear. We assessed the risk of adverse respiratory events associated with biologic and tsDMARDs compared with conventional synthetic DMARDs (csDMARDs) among RA patients with concomitant COPD in a large, real-world cohort. METHODS: We used a prevalent new-user design to study RA patients with COPD in the US-based MarketScan databases. New users of biologic DMARDs and/or tsDMARDs were matched on time-conditional propensity scores to new users of csDMARDs. Adverse respiratory events were estimated using Cox models comparing current use of biologic/tsDMARDs with csDMARDs. RESULTS: The cohort included 7424 patients initiating biologic/tsDMARDs and 7424 matched patients initiating csDMARDs. The adjusted hazard ratio of hospitalized COPD exacerbation comparing biologic/tsDMARD vs csDMARD was 0.76 (95% CI: 0.55, 1.06), while it was 1.02 (95% CI: 0.82, 1.27) for bronchitis, 1.21 (95% CI: 0.92, 1.58) for hospitalized pneumonia or influenza and 0.99 (95% CI: 0.87, 1.12) for outpatient pneumonia or influenza. The hazard ratio of the combined end point of COPD exacerbation, bronchitis and hospitalized pneumonia or influenza was 1.04 (95% CI: 0.89, 1.21). CONCLUSION: In this large, real-world comparative safety study, biologic and tsDMARDs, including abatacept, were not associated with an increased risk of adverse respiratory events when compared with csDMARDs in patients with RA and COPD.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31535689

RESUMO

OBJECTIVE: Interstitial lung disease (ILD) is a leading cause of mortality in SSc. Little is known about the benefits of immunosuppressive drugs in mild ILD. Our aim was to determine whether use of CYC or MMF was associated with an improved ILD course in patients with normal or mildly impaired lung function. METHODS: A retrospective cohort of SSc subjects with ILD, disease duration below seven years and no exposure to CYC or MMF prior to the baseline visit was constructed from the Canadian Scleroderma Research Group registry. Subjects were categorized as having mild ILD if baseline forced vital capacity (FVC % predicted) was >85%. The primary exposure was any use of CYC or MMF at the baseline visit. FVC at one year was compared between exposed and unexposed subjects, using multivariate linear regression. RESULTS: Out of 294 eligible SSc-ILD subjects, 116 met criteria for mild ILD. In this subgroup, mean (s.d.) disease duration was 3.7 (2.0) years. Thirteen (11.2%) subjects were exposed to CYC or MMF at baseline. The one-year FVC was higher in exposed subjects compared with unexposed subjects, by a difference of 8.49% (95% CI: 0.01-16.98%). None of the exposed subjects experienced clinically meaningful progression over two years, whereas 24.6% of unexposed subjects did. CONCLUSION: In this real-world setting, CYC/MMF exposure at baseline was associated with higher FVC values and a lower risk of progression among subjects with mild ILD. These data suggest a window of opportunity to preserve lung function in SSc-ILD.

7.
Clin Epigenetics ; 11(1): 110, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366403

RESUMO

OBJECTIVE: To compare DNA methylation in subjects positive vs negative for anti-citrullinated protein antibodies (ACPA), a key serological marker of rheumatoid arthritis (RA) risk. METHODS: With banked serum from a random subset (N = 3600) of a large general population cohort, we identified ACPA-positive samples and compared them to age- and sex-matched ACPA-negative controls. We used a custom-designed methylome panel to conduct targeted bisulfite sequencing of 5 million CpGs located in regulatory or hypomethylated regions of DNA from whole blood (red blood cell lysed). Using binomial regression models, we investigated the differentially methylated regions (DMRs) between ACPA-positive vs ACPA-negative subjects. An independent set of T cells from RA patients was used to "validate" the differentially methylated sites. RESULTS: We measured DNA methylation in 137 subjects, of whom 63 were ACPA-positive, 66 were ACPA-negative, and 8 had self-reported RA. We identified 1303 DMRs of relevance, of which one third (402) had underlying genetic effects. These DMRs were enriched in intergenic CpG islands (CGI) and CGI shore regions. Furthermore, the genes associated with these DMRs were enriched in pathways related to Epstein-Barr virus infection and immune response. In addition, 80 (38%) of 208 RA-specific DMRs were replicated in T cells from RA samples. CONCLUSIONS: Sequencing-based high-resolution methylome mapping revealed biologically relevant DNA methylation changes in asymptomatic individuals positive for ACPA that overlap with those seen in RA. Pathway analyses suggested roles for viral infections, which may represent the effect of environmental triggers upstream of disease onset.

9.
J Rheumatol ; 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308203

RESUMO

Immune checkpoint inhibitors have revolutionized cancer therapy by blocking inhibitory pathways of the immune system to fight cancer cells. Their use is often limited by the development of autoimmune toxicities, which can affect multiple organ systems and are referred to as immune-related adverse events (irAE). Amongst these are rheumatologic irAE, including inflammatory arthritis, myositis, vasculitis, and others. Rheumatologic irAE seem to be different from irAE in other organs and from traditional autoimmune diseases in that they can occur early or have delayed onset, and can persist chronically, even after cancer therapy is terminated. As immune checkpoint inhibitors are increasingly used for many types of cancer, it is important for oncologists and rheumatologists to recognize and manage toxicities early. In this review, we discuss currently approved immune checkpoint inhibitors, their mechanisms of action and systemic toxicities, with focus on rheumatic immune related adverse events, their management and impact on further cancer therapy.

10.
J Rheumatol ; 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308211

RESUMO

OBJECTIVE: To assess vaccination coverage and predictors of vaccination among a Canadian population of rheumatology patients in routine clinical care. METHODS: In this cross-sectional study, consecutive adult patients presenting to a tertiary rheumatology clinic at the McGill University Health Center between May and September 2015 were asked to fill a survey on vaccination. Patients self-identified as having rheumatoid arthritis (RA), systemic autoimmune rheumatic diseases (SARD), spondyloarthropathies (SpA), or other diseases (OD). Multivariate logistical regression analyses were performed to evaluate patient and physician factors associated with vaccination (influenza, pneumococcal, hepatitis B virus [HBV]). Published Quebec general population influenza and pneumococcal vaccination rates in those aged ≥ 65 were used as comparative baseline rates. RESULTS: 352 patients were included in the analysis (RA:136, SARD:113, SpA:47, OD:56). Vaccination rates were reported as: (1) influenza: RA:48.5%, SARD:42.0%, SpA:31.9%, OD:88.9%, Quebec general population:58.5%; (2) pneumococcal: RA:42.0%, SARD:37.8%, SpA:29.7%, OD:33.3%, Quebec general population:53.2%; (3) HBV: RA:33.6%, SARD:55.6%, SpA:73.5%, OD:36.8%; and (4) herpes zoster: RA:5.6%, SARD:28.6%, SpA:25.0%, OD:16.7%. Physician recommendation was the strongest independent predictor of vaccination across all vaccine types (influenza: OR 8.56, 95% CI 2.80-26.2, p<0.001; pneumococcal: OR 314, 95% CI 73.0-1353, p<0.001; HBV: OR 12.8, 95% CI 5.27-31.1, p<0.001). Disease group, disease duration, comorbidities, treatment type, and being followed by a primary care physician were not significantly associated with vaccination. CONCLUSION: There is suboptimal immunization coverage among ambulatory rheumatology patients. An important role for patient and physician education is highlighted from our study, especially as physician recommendation of vaccination was strongly predictive of vaccine uptake.

11.
Psychol Med ; : 1-13, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31298180

RESUMO

BACKGROUND: Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9. METHODS: We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy. RESULTS: 16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (-0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01). CONCLUSIONS: PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.

13.
Artigo em Inglês | MEDLINE | ID: mdl-30979397

RESUMO

OBJECTIVE: The ASSURE randomized trial of abatacept safety in rheumatoid arthritis (RA) reported more frequent respiratory adverse events with abatacept among the subgroup of 54 patients with chronic obstructive pulmonary disease (COPD), leading to a label warning. We assessed the risk of adverse respiratory events associated with abatacept, compared with other biologic DMARDs (bDMARDs), among patients with RA and COPD in a real-world observational setting. METHODS: We formed a prevalent new-user cohort of patients with RA and COPD treated with bDMARDs within the US-based MarketScan databases from 2007 to 2014. Abatacept users were matched on time-conditional propensity scores to users of other bDMARDs. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of adverse respiratory events comparing abatacept with other bDMARDs were estimated using the Cox model. RESULTS: The cohort included 1807 patients initiating abatacept and 3547 matched patients initiating another bDMARD. The HR of the combined endpoint of hospitalized COPD exacerbation, bronchitis and hospitalized pneumonia or influenza with abatacept relative to other bDMARDs was 0.87 (95% CI: 0.68-1.12). For hospitalized COPD exacerbation it was 0.60 (95% CI: 0.32-1.11), 0.80 (95% CI: 0.56-1.14) for bronchitis, while for pneumonia or influenza it was 1.39 (95% CI: 0.91-2.13) if hospitalized and 1.05 (95% CI: 0.86-1.29) as outpatient. CONCLUSION: This large safety study from a real world setting finds no increased risk of adverse respiratory events with abatacept compared with other bDMARDs in patients with RA and COPD. This study does not substantiate the safety signal raised by the smaller ASSURE trial.

14.
Ann Rheum Dis ; 78(6): 807-816, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30928903

RESUMO

OBJECTIVE: We sought to develop the first Damage Index (DI) in systemic sclerosis (SSc). METHODS: The conceptual definition of 'damage' in SSc was determined through consensus by a working group of the Scleroderma Clinical Trials Consortium (SCTC). Systematic literature review and consultation with patient partners and non-rheumatologist experts produced a list of potential items for inclusion in the DI. These steps were used to reduce the items: (1) Expert members of the SCTC (n=331) were invited to rate the appropriateness of each item for inclusion, using a web-based survey. Items with >60% consensus were retained; (2) Using a prospectively acquired Australian cohort data set of 1568 patients, the univariable relationships between the remaining items and the endpoints of mortality and morbidity (Physical Component Summary score of the Short Form 36) were analysed, and items with p<0.10 were retained; (3) using multivariable regression analysis, coefficients were used to determine a weighted score for each item. The DI was externally validated in a Canadian cohort. RESULTS: Ninety-three (28.1%) complete survey responses were analysed; 58 of 83 items were retained. The univariable relationships with death and/or morbidity endpoints were statistically significant for 22 items, with one additional item forced into the multivariable model by experts due to clinical importance, to create a 23-item weighted SCTC DI (SCTC-DI). The SCTC-DI was predictive of morbidity and mortality in the external cohort. CONCLUSIONS: Through the combined use of consensus and data-driven methods, a 23-item SCTC-DI was developed and retrospectively validated.

15.
PLoS One ; 14(4): e0216075, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31022252

RESUMO

OBJECTIVE: To understand preferences for and estimate the likely uptake of preventive treatments currently being evaluated in randomized controlled trials with individuals at increased risk of developing rheumatoid arthritis (RA). METHODS: Focus groups were used to identify key attributes of potential preventive treatment for RA (reduction in risk of RA, how treatment is taken, chance of side effects, certainty in estimates, health care providers opinion). A web-based discrete choice experiment (DCE) was administered to people at-risk of developing RA, asking them to first choose their preferred of two hypothetical preventive RA treatments, and then between their preferred treatment and 'no treatment for now.' DCE data was analyzed using conditional logit regression to estimate the significance and relative importance of attributes in influencing preferences. RESULTS: Two-hundred and eighty-eight first-degree relatives (60% female; 66% aged 18-39 years) completed all tasks in the survey. Fourteen out of fifteen attribute levels significantly influenced preferences for treatments. How treatment is taken (oral vs. infusion ß0.983, p<0.001), increasing reduction in risk of RA (ß0.922, p<0.001), health care professional preference (ß0.900, p<0.001), and avoiding irreversible (ß0.839, p<0.001) or reversible serious side effects (ß0.799, p<0.001) were most influential. Predicted uptake was high for non-biologic drugs (e.g. 84% hydroxycholoroquine), but very low for atorvastatin (8%) and biologics (<6%). CONCLUSION: Decisions to take preventative treatments are complex, and uptake depends on how treatments can compromise on convenience, potential risks and benefits, and recommendations/preferences of health care professionals. This evidence contributes to understanding whether different preventative treatment strategies are likely to be acceptable to target populations.

17.
Semin Arthritis Rheum ; 48(6): 1053-1058, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30772001

RESUMO

OBJECTIVE: To assess whether abatacept as initial biologic disease-modifying antirheumatic drug (DMARD) in the treatment of rheumatoid arthritis is associated with an increased risk of serious infections, including bone and joint, gastrointestinal, respiratory tract, skin and soft tissue, and urinary tract, when compared with other biologic DMARDs. METHODS: We performed a population-based cohort study among patients newly-treated with biologic DMARDs within the US-based Truven MarketScan® population and Supplemental US Medicare from 2007 to 2014. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of serious infections requiring hospitalisation associated with initiation of abatacept, compared with initiation of other bDMARDs, after controlling for age and deciles of the propensity score. RESULTS: The cohort included 5,752 patients who initiated abatacept and 78,556 who initiated another biologic DMARD, of whom 193 and 1531 had a serious infection during follow-up (crude incidence rate 4.45 per 100 person-years and 3.62 per 100 person-years, respectively). Compared with other biologic DMARDs, the use of abatacept was not associated with an increased incidence of serious infections overall (HR 1.04, 95% CI 0.89-1.21). The risk did not vary by duration of use (<1 year: HR 1.03, 95% CI 0.87-1.22; >1 year: HR 1.08, 95% CI 0.77-1.52). In addition, the risk was not increased for the site-specific infections. CONCLUSION: The use of abatacept as first biologic DMARD in the treatment of rheumatoid arthritis was not associated with different risks of serious infections compared with other biologic DMARDs.

18.
Artigo em Inglês | MEDLINE | ID: mdl-30805629

RESUMO

OBJECTIVE: Childhood-onset SLE (cSLE) manifests differently than adult-onset SLE (aSLE). This study determined whether ethnic differences contribute to the differences in clinical presentation between the two groups. METHODS: This cross-sectional study used data from a multi-centred registry from eight adult and four paediatric Canadian centres gathered at study entry. We compared the frequency of clinical manifestations and autoantibodies between aSLE and cSLE. For those with a significant difference, a multivariable logistic regression was performed, adjusting for ethnicity, SLE onset (cSLE vs aSLE), disease duration and centre. Disease activity and damage between aSLE and cSLE were compared after stratifying by disease duration. RESULTS: Of 552 aSLE subjects, 502 (90.9%) were female and 381 (69.0%) were Caucasian. Mean age at diagnosis was 37.0 ± 13.6 years and disease duration 10.9 ± 9.6 years. Of 276 cSLE subjects, 231 (83.7%) were female and 101 (36.6%) were Caucasian. Mean age at diagnosis was 12.7 ± 3.3 years and disease duration 5.6 ± 8.2 years. In multivariable regression analysis, aSLE was associated with decreased odds of having a neurologic disorder (odds ratio = 0.49) and increased odds of having aCL antibodies (odds ratio = 1.85). Disease activity and damage accrual scores were higher in aSLE than cSLE within the same disease duration strata, although the differences were not clinically significant. Ethnicity was not associated with any differences in clinical manifestations or autoantibody frequency between aSLE and cSLE. CONCLUSIONS: Although a crude comparison of aSLE and cSLE yielded several differences in clinical symptoms and autoantibodies, this difference was not attributable to ethnic differences between aSLE and cSLE.

20.
Arthritis Rheumatol ; 71(6): 964-971, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30614663

RESUMO

OBJECTIVE: To generate a core set of items to develop classification criteria for scleroderma renal crisis (SRC) using consensus methodology. METHODS: An international, multidisciplinary panel of experts was invited to participate in a 3-round Delphi exercise developed using a survey based on items identified by a scoping review. In round 1, participants were asked to identify omissions and clarify ambiguities regarding the items in the survey. In round 2, participants were asked to rate the validity and feasibility of the items using Likert-type scales ranging from 1 to 9 (where 1 = very invalid/unfeasible, 5 = uncertain, and 9 = very valid/feasible). In round 3, participants reviewed the results and comments from round 2 and were asked to provide final ratings. Items rated as highly valid and feasible (median scores ≥7 for each) in round 3 were selected as the provisional core set of items. A consensus meeting using a nominal group technique was conducted to further reduce the core set of items. RESULTS: Ninety-nine experts from 16 countries participated in the Delphi exercise. Of the 31 items in the survey, consensus was achieved on 13, in the categories hypertension, renal insufficiency, proteinuria, and hemolysis. Eleven experts took part in the nominal group technique discussion, where consensus was achieved in 5 domains: blood pressure, acute kidney injury, microangiopathic hemolytic anemia, target organ dysfunction, and renal histopathology. CONCLUSION: A core set of items that characterize SRC was identified using consensus methodology. This core set will be used in future data-driven phases of this project to develop classification criteria for SRC.

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