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Background: Eukaryotic RNA polymerase II contains a C-terminal repeated domain (CTD) consisting of 52 consensus heptad repeats of Y1S2P3T4S5P6S7 that mediate interactions with many cellular proteins to regulate transcription elongation, RNA processing and chromatin structure. A number of CTD-binding proteins have been identified and the crystal structures of several protein-CTD complexes have demonstrated considerable conformational flexibility of the heptad repeats in those interactions. Furthermore, phosphorylation of the CTD at tyrosine, serine and threonine residues can regulate the CTD-protein interactions. Although the interactions of CTD with specific proteins have been elucidated at the atomic level, the capacity and specificity of the CTD-interactome in mammalian cells is not yet determined. Results: A proteomic study was conducted to examine the mammalian CTD-interactome. We utilized six synthetic peptides each consisting of four consensus CTD-repeats with different combinations of serine and tyrosine phosphorylation as affinity-probes to pull-down nuclear proteins from HeLa cells. The pull-down fractions were then analyzed by MUDPIT mass spectrometry, which identified 100 proteins with the majority from the phospho-CTD pull-downs. Proteins pulled-down by serine-phosphorylated CTD-peptides included those containing the previously defined CTD-interacting domain (CID). Using SILAC mass spectrometry, we showed that the in vivo interaction of RNA polymerase II with the mammalian CID-containing RPRD1B is disrupted by CID mutation. We also showed that the CID from four mammalian proteins interacted with pS2-phosphorylated but not pY1pS2-doubly phosphorylated CTD-peptides. However, we also found proteins that were preferentially pulled-down by pY1pS2- or pY1pS5-doubly phosphorylated CTD-peptides. We prepared an antibody against tyrosine phosphorylated CTD and showed that ionizing radiation (IR) induced a transient increase in CTD tyrosine phosphorylation by immunoblotting. Combining SILAC and IMAC purification of phospho-peptides, we found that IR regulated the phosphorylation at four CTD tyrosine sites in different ways. Conclusion: Upon phosphorylation, the 52 repeats of the CTD have the capacity to generate a large number of binding sites for cellular proteins. This study confirms previous findings that serine phosphorylation stimulates whereas tyrosine phosphorylation inhibits the protein-binding activity of the CTD. However, tyrosine phosphorylation of the CTD can also stimulate other CTD-protein interactions. The CTD-peptide affinity pull-down method described here can be adopted to survey the mammalian CTD-interactome in various cell types and under different biological conditions.

Background: There is a remarkable variability in the frequency of HLA-B27 positivity in patients with spondyloarthritis (SpA), which may be associated with different clinical presentations worldwide. However, there is a lack of data considering ethnicity and sex on the evaluation of the main clinical and prognostic outcomes in mixed-race populations. The aim of this study was to evaluate the frequency of HLA-B27 and its correlation with disease parameters in a large population of patients from the Brazilian Registry of Spondyloarthritis (RBE)., Methods: The RBE is a multicenter, observational, prospective cohort that enrolled patients with SpA from 46 centers representing all five geographic regions of Brazil. The inclusion criteria were as follow: (1) diagnosis of axSpA by an expert rheumatologist; (2) age ≥18 years; (3) classification according to ASAS axial. The following data were collected via a standardized protocol: demographic data, disease parameters and treatment historical., Results: A total of 1096 patients were included, with 73.4% HLA-B27 positivity and a mean age of 44.4 (±13.2) years. Positive HLA-B27 was significantly associated with male sex, earlier age at disease onset and diagnosis, uveitis, and family history of SpA. Conversely, negative HLA-B27 was associated with psoriasis, higher peripheral involvement and disease activity, worse quality of life and mobility., Conclusions: Our data showed that HLA-B27 positivity was associated with a classic axSpA pattern quite similar to that of Caucasian axSpA patients around the world. Furthermore, its absence was associated with peripheral manifestations and worse outcomes, suggesting a relevant phenotypic difference in a highly miscegenated population., (© 2024. The Author(s).)

Background: Real-world, primary data on the treatment of psoriasis are scarce, especially concerning the role of soluble biomarkers as outcome predictors., Objective: The authors evaluated the utility of Th1/Th17 serum cytokines along with clinical characteristics as predictors of drug survival in the treatment of psoriasis., Methods: The authors consecutively included participants with moderate to severe psoriasis who were followed up for 6 years. Baseline interferon-α, tumor necrosis factor-α, and interleukin (IL)-2, IL-4, IL-6, IL-10, and IL-17A were measured using a cytometric bead array; clinical data were assessed. The authors calculated hazard ratios (HRs) for drug survival using a Cox proportional hazards model., Results: The authors included 262 patients, most of whom used systemic immunosuppressants or biologics. In the multivariate model, poor quality of life measured by the Dermatology Life Quality Index (HR = 1.04; 95% CI 1.01‒1.07; p = 0.012) and elevated baseline IL-6 (HR = 1.99; 95% CI 1.29‒3.08; p = 0.002) were associated with treatment interruption., Study Limitations: The main limitation of any cohort study is the presence of confounders that could not be detected in clinical evaluation., Conclusions: Poor quality of life and elevated baseline serum IL-6 level predicted treatment interruption in patients with moderate to severe psoriasis. Although IL-6 is not the most important mediator of the inflammatory pathway in the skin environment, it is an interesting biomarker candidate for predicting psoriasis treatment response., (Copyright © 2023 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. All rights reserved.)

Leprosy is an infectious and contagious disease of slow evolution, triggered by Mycobacterium leprae . Arthritis is its third most common manifestation, after cutaneous and peripheral nerve involvement. Since musculoskeletal symptoms may be the initial presentation of the disease, it is important for health professionals to recognize its rheumatic manifestations for early diagnosis and appropriate treatment, especially in endemic areas. In addition, cases of leprosy have increased globally, notably in patients undergoing treatment with TNF-α blockers and due to the increase in migration and travel of people from developing countries to developed countries. This review proposes to discuss the main scenarios of mimicry of different rheumatic diseases by leprosy, as well as the role of immunosuppressive drugs used in rheumatology practice in the treatment of reactional states and in the risk of developing the infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cruz, Albuquerque, Guimarães, Dionello, Ribeiro, Souza, Gomes and Mota.)

Background: SARS-CoV-2 infection and perinatal neurologic outcomes are still not fully understood. However, there is recent evidence of white matter disease and impaired neurodevelopment in newborns following maternal SARS-CoV-2 infection. These appear to occur as a consequence of both direct viral effects and a systemic inflammatory response, with glial cell/myelin involvement and regional hypoxia/microvascular dysfunction. We sought to characterize the consequences of maternal and fetal inflammatory states in the central nervous system of newborns following maternal SARS-CoV-2 infection., Methods: We conducted a longitudinal prospective cohort study from June 2020 to December 2021, with follow-up of newborns born to mothers exposed or not exposed to SARS-CoV-2 infection during pregnancy. Brain analysis included data from cranial ultrasound scans (CUS) with grayscale, Doppler studies (color and spectral), and ultrasound-based brain elastography (shear-wave mode) in specific regions of interest (ROIs): deep white matter, superficial white matter, corpus callosum, basal ganglia, and cortical gray matter. Brain elastography was used to estimate brain parenchymal stiffness, which is an indirect quantifier of cerebral myelin tissue content., Results: A total of 219 single-pregnancy children were enrolled, including 201 born to mothers exposed to SARS-CoV-2 infection and 18 from unexposed controls. A neuroimaging evaluation was performed at 6 months of adjusted chronological age and revealed 18 grayscale and 21 Doppler abnormalities. Predominant findings were hyperechogenicity of deep brain white matter and basal ganglia (caudate nuclei/thalamus) and a reduction in the resistance and pulsatility indices of intracranial arterial flow. The anterior brain circulation (middle cerebral and pericallosal arteries) displayed a wider range of flow variation than the posterior circulation (basilar artery). Shear-wave US elastography analysis showed a reduction in stiffness values in the SARS-CoV-2 exposed group in all analyzed regions of interest, especially in the deep white matter elasticity coefficients (3.98 ± 0.62) compared to the control group (7.76 ± 0.77); p -value < 0.001., Conclusion: This study further characterizes pediatric structural encephalic changes associated with SARS-CoV-2 infection during pregnancy. The maternal infection has been shown to be related to cerebral deep white matter predominant involvement, with regional hyperechogenicity and reduction of elasticity coefficients, suggesting zonal impairment of myelin content. Morphologic findings may be subtle, and functional studies such as Doppler and elastography may be valuable tools to more accurately identify infants at risk of neurologic damage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Alves de Araujo Junior, Motta, Fernandes, Castro, Sasaki, Luna, Rodrigues, Kurizky, Soares, Nobrega, Espindola, Zaconeta, Gomes, Martins-Filho, Albuquerque and Mota.)

Background: The COVID-19 pandemic put healthcare professionals, including residents (postgraduate trainees of health professions), under intense physical and psychological stress, hence at risk for mental disorders. We evaluated the prevalence of mental disorders among healthcare residents during the pandemic., Methods: From July to September 2020, residents in medicine and other healthcare specialties in Brazil were recruited. The participants completed electronic forms with validated questionnaires (DASS-21, PHQ-9, BRCS) to screen for depression, anxiety, and stress, and to evaluate resilience. Data on potential predisposing factors for mental disorders were also collected. Descriptive statistics, chi-squared, students t, correlation and logistic regression models were applied. The study received ethical approval, and all participants provided informed consent., Results: We included 1313 participants (51.3% medical; 48.7% nonmedical) from 135 Brazilian hospitals; mean (SD) age: 27.8 (4.4) years; 78.2% females; 59.3% white race. Of all participants, 51.3%, 53.4% and 52.6% presented symptoms consistent with depression, anxiety, and stress, respectively; 61.9% showed low resilience. Nonmedical residents exhibited higher anxiety compared to medical residents (DASS-21 anxiety score, mean difference: 2.26; 95% CI: 1.15-3.37; p < 0.001). In multivariate analyses, having any pre-existent, nonpsychiatric chronic disease was associated with higher prevalence of symptoms indicative of depression (odds ratio, OR: 2.05; 95% CI: 1.47-2.85, on DASS-21 | OR: 2.26; 95% CI: 1.59-3.20, on PHQ-9), anxiety (OR: 2.07; 95% CI: 1.51-2.83, on DASS-21), and stress (OR: 1.53; 95% CI: 1.12-2.09, on DASS-21); other predisposing factors were identified; by contrast, high resilience (BRCS score) was protective against symptoms of depression (OR 0.82; 95% CI: 0.79-0.85, on DASS-21 | OR 0.85; 95% CI: 0.82-0.88, on PHQ-9), anxiety (OR 0.90; 95% CI: 0.87-0.93, on DASS-21), and stress (OR 0.88; 95% CI: 0.85-0.91, on DASS-21); p < 0.05 for all outcomes., Conclusions: We found a high prevalence of mental disorder symptoms among healthcare residents during COVID-19 pandemic in Brazil. Nonmedical residents exhibited higher levels of anxiety than medical ones. Some predisposing factors for depression, anxiety and stress among residents were identified., (© 2023. The Author(s).)

Introduction: SARS-CoV-2 infection during pregnancy can induce changes in the maternal immune response, with effects on pregnancy outcome and offspring. This is a cross-sectional observational study designed to characterize the immunological status of pregnant women with convalescent COVID-19 at distinct pregnancy trimesters. The study focused on providing a clear snapshot of the interplay among serum soluble mediators., Methods: A sample of 141 pregnant women from all prenatal periods (1 st , 2 nd and 3 rd trimesters) comprised patients with convalescent SARS-CoV-2 infection at 3-20 weeks after symptoms onset (COVID, n=89) and a control group of pre-pandemic non-infected pregnant women (HC, n=52). Chemokine, pro-inflammatory/regulatory cytokine and growth factor levels were quantified by a high-throughput microbeads array., Results: In the HC group, most serum soluble mediators progressively decreased towards the 2 nd and 3 rd trimesters of pregnancy, while higher chemokine, cytokine and growth factor levels were observed in the COVID patient group. Serum soluble mediator signatures and heatmap analysis pointed out that the major increase observed in the COVID group related to pro-inflammatory cytokines (IL-6, TNF-α, IL-12, IFN-γ and IL-17). A larger set of biomarkers displayed an increased COVID/HC ratio towards the 2 nd (3x increase) and the 3 rd (3x to 15x increase) trimesters. Integrative network analysis demonstrated that HC pregnancy evolves with decreasing connectivity between pairs of serum soluble mediators towards the 3 rd trimester. Although the COVID group exhibited a similar profile, the number of connections was remarkably lower throughout the pregnancy. Meanwhile, IL-1Ra, IL-10 and GM-CSF presented a preserved number of correlations (≥5 strong correlations in HC and COVID), IL-17, FGF-basic and VEGF lost connectivity throughout the pregnancy. IL-6 and CXCL8 were included in a set of acquired attributes, named COVID-selective (≥5 strong correlations in COVID and <5 in HC) observed at the 3 rd pregnancy trimester., Discussion and Conclusion: From an overall perspective, a pronounced increase in serum levels of soluble mediators with decreased network interplay between them demonstrated an imbalanced immune response in convalescent COVID-19 infection during pregnancy that may contribute to the management of, or indeed recovery from, late complications in the post-symptomatic phase of the SARS-CoV-2 infection in pregnant women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fernandes, Sasaki, Jardim-Santos, Schulte, Motta, da Silva, de Carvalho, Pereira, Alves, de Araújo Júnior, Mendonça-Silva, Costa, de Castro, Lauand, Nery, Tristão, Kurizky, Nóbrega, Espindola, de Castro, Alpoim, Godoi, Dusse, Coelho-dos-Reis, Amaral, Gomes, Bertarini, Brito-de-Sousa, Costa-Rocha, Campi-Azevedo, Peruhype-Magalhães, Teixeira-Carvalho, Zaconeta, Soares, Valim, Gomes, de Albuquerque, Martins-Filho and da Mota.)

Background: Management delays imply worse outcomes in rheumatoid arthritis (RA) and, therefore, should be minimized. We evaluated changes in diagnostic and treatment delays regarding RA in the last decades in Brazil., Methods: Adults fulfilling the ACR/EULAR (2010) criteria for RA were assessed. Delays in diagnosis and treatment, and the frequencies of early management initiation within thresholds (windows of opportunity) of 3, 6, and 12 months from symptoms onset were evaluated. The Mann-Kendall trend test, chi-squared tests with Cramer's V effect sizes and analysis of variance were conducted., Results: We included 1116 patients: 89.4% female, 56.8% white, mean (SD) age 57.1 (11.5) years. A downward trend was found in diagnostic (tau = - 0.677, p < 0.001) and treatment (tau = - 0.695, p < 0.001) delays from 1990 to 2015. The frequency of early management increased throughout the period, with ascending effect sizes across the 3-, 6-, and 12-month windows (V = 0.120, 0.200 and 0.261, respectively). Despite all improvements, even in recent years (2011-2015) the diagnostic and treatment delays still remained unacceptably high [median (IQR): 8 (4-12) and 11 (5-17) months, respectively], with only 17.2% of the patients treated within the shortest, 3-month window., Conclusion: The delays in diagnosis and treatment of RA decreased during the last decades in Brazil. Improvements (effect sizes) were greater at eliminating extreme delays (≥ 12 months) than in attaining really short management windows (≤ 3 months). Very early treatment was still an unrealistic goal for most patients with RA., (© 2023. The Author(s).)

The present study applied distinct models of descriptive analysis to explore the integrative networks and the kinetic timeline of serum soluble mediators to select a set of systemic biomarkers applicable for the clinical management of COVID-19 patients. For this purpose, a total of 246 participants (82 COVID-19 and 164 healthy controls - HC) were enrolled in a prospective observational study. Serum soluble mediators were quantified by high-throughput microbeads array on hospital admission (D0) and at consecutive timepoints (D1-6 and D7-20). The results reinforce that the COVID-19 group exhibited a massive storm of serum soluble mediators. While increased levels of CCL3 and G-CSF were associated with the favorable prognosis of non-mechanical ventilation (nMV) or discharge, high levels of CXCL10 and IL-6 were observed in patients progressing to mechanical ventilation (MV) or death. At the time of admission, COVID-19 patients presented a complex and robust serum soluble mediator network, with a higher number of strong correlations involving IFN-γ, IL-1Ra and IL-9 observed in patients progressing to MV or death. Multivariate regression analysis demonstrates the ability of serum soluble mediators to cluster COVID-19 from HC. Ascendant fold change signatures and the kinetic timeline analysis further confirmed that the pairs "CCL3 and G-CSF" and "CXCL10 and IL-6" were associated with favorable or poor prognosis, respectively. A selected set of systemic mediators (IL-6, IFN-γ, IL-1Ra, IL-13, PDGF and IL-7) were identified as putative laboratory markers, applicable as complementary records for the clinical management of patients with severe COVID-19., Competing Interests: LM received personal or institutional support from Abbvie, Janssen, Pfizer, Boehringer-Ingelheim, Sandoz and Roche; has delivered speeches at events and sponsored by Abbvie, Boheringer- Ingelheim, Janssen, Pfizer, Roche, Sandoz, Lilly and UCB. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jardim-Santos, Schulte, Kurizky, Gomes, Nóbrega, de Gois, de Carvalho, Martins, Nicola, de Albuquerque, Espindola, Naves, Soares, Albuquerque, Fontes, Amaral, Gomes, Bertarini, Brito-de-Sousa, Campi-Azevedo, Peruhype-Magalhães, Teixeira-Carvalho, Valim, Martins-Filho and da Mota.)

Introduction: Rheumatoid arthritis (RA) composite disease activity indices have become handy tools in daily clinical practice and crucial in defining remission or low disease activity, the main target of the RA treatment. However, there is no definition of the best index to assess disease activity in clinical practice., Objectives: To compare the residual activity among the indices with the ACR/EULAR remission criteria (Boolean method) to identify the most feasible for assessing remission in daily practice, also considering correlation and concordance, sensibility, and specificity., Patients and Methods: We selected 1116 patients with established RA from the real-life rheumatoid arthritis study database-REAL. The composite disease activity indices-DAS28-ESR, DAS28-CRP, SDAI, and CDAI-and their components were compared to the Boolean method to identify residual activity using binomial regression. The indices were analyzed for correlation and agreement using the Spearman index and weighted kappa. The chi-square test evaluated sensibility and specificity for remission based on the Boolean method., Results: DAS28-CRP overestimated remission and confirmed higher residual activity than SDAI and CDAI. The indices showed good correlation and agreement, with a better relationship between SDAI and CDAI (k:0,88). CDAI and SDAI showed higher sensitivity and specificity for remission based on the Boolean method. CDAI was performed in 99% of patients, while DAS28 and SDAI were completed in approximately 85%., Conclusions: Although all composite indices of activity can be used in clinical practice and showed good agreement, CDAI and SDAI have better performance in evaluating remission based on the Boolean method, showing less residual activity and higher sensibility and specificity. In addition, CDAI seems to be more feasible for disease activity evaluation in daily clinical practice, especially in developing countries., Competing Interests: The authors have declared that no competing interests exist.

Purpose: COVID-19 infection has been associated with a high risk of complications and death among patients with acute coronary syndrome (ACS). However, there is little information on the simultaneous involvement in Latin American countries., Methods: In the period between May 2020 and February 2021, an observational, longitudinal, prospective cohort study with two parallel branches was conducted in private and public hospitals in Brasilia, Brazil, including patients with ACS with and without a positive SARS-CoV-2 test result during hospitalization., Results: A total of 149 patients with ACS were included (75 with COVID-19 and 74 controls). Patients with COVID-19 exhibited an average of 62 years of age, 57% men, 40% diabetics, 67% hypertensive, 48% had an ACS with ST-segment elevation, Killip I was predominant, a low Syntax Score in 72%, with an average Grace Score of 117, and a length of hospitalization of 43 days in average. The control branch was similar in clinical characteristics, except for a lower proportion of ST-segment elevation ACS (16%, p < 0.01) and a higher incidence of arrhythmias (8 vs. 20 %, p = 0.03). Using the Cox regression method of analysis of covariates collected in the study, it was identified that patients with COVID-19 had a risk of death 2.34 times higher than patients without COVID-19 ( p = 0.049)., Conclusion: In this study conducted in a Latin American capital, SARS-CoV-2 infection predicted a higher chance of death in patients admitted with ACS, which is a finding that reinforces the need for greater care when diseases develop in overlapping ways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Junior, Ferreia, Santos, Borges, Albuquerque, Espindola, Nóbrega, Gomes, Mota and Soares.)

Elective procedures were temporarily suspended several times over the course of the pandemic of COVID-19. Monthly data from the Unified Health System (SUS) were used for the period between January 2008 and December 2020 and the interrupted time series method was used to estimate the effect of the pandemic on the number of elective surgeries and elective procedures that were not performed. Considering a 9-month period, a reduction of 46% in the number of elective procedures carried out in the SUS could be attributed to COVID-19, corresponding to about 828,429 elective procedures cancelled, ranging from 549,921 to 1,106,936. To a full recovery of pre-pandemic performance, SUS would need to increase about 21,362 hospital beds, ranging from 12,370 to 36,392 hospital beds during a 6 month-period. This effort would represent an increase of 8.48% (ranging from 4.91 to 14.45%) in relation to the total number of SUS's hospital beds in 2019. As a result, the pandemic will leave a large number of elective procedures to be carried out, which will require efforts by health agencies to meet this demand., (© 2022. The Author(s).)

Background: Patients using immunosuppressive drugs may have unfavorable results after infections. However, there is a lack of information regarding COVID-19 in these patients, especially in patients with rheumatoid arthritis (RA). Therefore, the aim of this study was to evaluate the risk factors associated with COVID-19 hospitalizations in patients with RA., Methods: This multicenter, prospective cohort study is within the ReumaCoV Brazil registry and included 489 patients with RA. In this context, 269 patients who tested positive for COVID-19 were compared to 220 patients who tested negative for COVID-19 (control group). All patient data were collected from the Research Electronic Data Capture database., Results: The participants were predominantly female (90.6%) with a mean age of 53 ± 12 years. Of the patients with COVID-19, 54 (20.1%) required hospitalization. After multiple adjustments, the final regression model showed that heart disease (OR = 4.61, 95% CI 1.06-20.02. P < 0.001) and current use of glucocorticoids (OR = 20.66, 95% CI 3.09-138. P < 0.002) were the risk factors associated with hospitalization. In addition, anosmia was associated with a lower chance of hospitalization (OR = 0.26; 95% CI 0.10-0.67, P < 0.005)., Conclusion: Our results demonstrated that heart disease and the use of glucocorticoids were associated with a higher number of hospital admissions for COVID-19 in patients with RA., Trial Registration: Brazilian Registry of Clinical Trials - RBR-33YTQC., (© 2022. The Author(s).)

Rheumatoid arthritis (RA) is a chronic and autoimmune systemic inflammatory disease that can cause irreversible joint deformities, with increased morbidity and mortality and a significant impact on the quality of life of the affected individual. The main objective of RA treatment is to achieve sustained clinical remission or low disease activity. However, up to 40% of patients do not respond to available treatments, including bDMARDs. New therapeutic targets for RA are emerging, such as Janus kinases (JAKs). These are essential for intracellular signaling (via JAK-STAT) in response to many cytokines involved in RA immunopathogenesis. JAK inhibitors (JAKi) have established themselves as a highly effective treatment, gaining increasing space in the therapeutic arsenal for the treatment of RA. The current recommendations aim to present a review of the main aspects related to the efficacy and safety of JAKis in RA patients, and to update the recommendations and treatment algorithm proposed by the Brazilian Society of Rheumatology in 2017., (© 2021. The Author(s).)

Background: Since the novel coronavirus disease outbreak, over 179.7 million people have been infected by SARS-CoV-2 worldwide, including the population living in dengue-endemic regions, particularly Latin America and Southeast Asia, raising concern about the impact of possible co-infections., Methods: Thirteen SARS-CoV-2/DENV co-infection cases reported in Midwestern Brazil between April and September of 2020 are described. Information was gathered from hospital medical records regarding the most relevant clinical and laboratory findings, diagnostic process, therapeutic interventions, together with clinician-assessed outcomes and follow-up., Results: Of the 13 cases, seven patients presented Acute Undifferentiated Febrile Syndrome and six had pre-existing co-morbidities, such as diabetes, hypertension and hypopituitarism. Two patients were pregnant. The most common symptoms and clinical signs reported at first evaluation were myalgia, fever and dyspnea. In six cases, the initial diagnosis was dengue fever, which delayed the diagnosis of concomitant infections. The most frequently applied therapeutic interventions were antibiotics and analgesics. In total, four patients were hospitalized. None of them were transferred to the intensive care unit or died. Clinical improvement was verified in all patients after a maximum of 21 days., Conclusions: The cases reported here highlight the challenges in differential diagnosis and the importance of considering concomitant infections, especially to improve clinical management and possible prevention measures. Failure to consider a SARS-CoV-2/DENV co-infection may impact both individual and community levels, especially in endemic areas., (© 2021. The Author(s).)

Background: Rheumatoid arthritis (RA) is a common autoimmune systemic inflammatory disease. In addition to joint involvement, RA patients frequently have other comorbidities, such as cardiovascular diseases. Drugs used for RA treatment may increase or decrease the risk of a cardiovascular event. This study aims to analyze cardiovascular risk comorbidities in patients with RA and the correlation with the use of anti-rheumatic drugs., Methods: Cross-sectional study conducted based on the real-life rheumatoid arthritis study database - REAL, a prospective observational cohort study. Associations between the use of anti-rheumatic drugs and the presence of comorbidities were represented by their prevalence ratio and evaluated using the Chi-square or Fisher's Exact tests., Results: We assessed 1116 patients, 89.4% women, mean age of 55.15 years and predominance of seropositive disease. 63.3% had some cardiovascular comorbidity, predominantly hypertension (49.9%). The use of glucocorticoids was observed in 47.4% of patients and there was a significant tendency of lower use of these drugs in the presence of dyslipidemia (PR: 0.790; p = 0.007). We observed that the presence of cardiovascular comorbidities was associated with higher use of bDMARDs (PR:1.147; p = 0.003)., Conclusions: The presence of cardiovascular risk comorbidities was confirmed to be higher in RA patients. Different treatment strategies using less glucocorticoids in the presence of dyslipidemia and more common use of bDMARDs in patients with cardiovascular comorbidities suggest that rheumatologists are aware of the potential influence of the DMARDs in the risk of cardiovascular event. Reinforcing these results, we highlight the need for a better baseline assessment to guide the choice of anti-rheumatic drugs in RA patients who have comorbidities.

Background Rheumatoid arthritis is a chronic, autoimmune disease in which treatment has evolved with a variety of therapeutic classes. Biological disease-modifying antirheumatic drugs have improved therapy; however, the continued long-term use of these drugs with sustained safety and efficacy remains a challenge. ObjectiveThe objective of this study was to analyze time of use and reasons for discontinuation of biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.SettingIt is as part of REAL (Rheumatoid Arthritis in Real Life), a multicenter project that evaluated Brazilian patients with rheumatoid arthritis in a real-life setting. Eleven referral centers for the treatment in the public network participated in the study.MethodsWe conducted a cross-sectional analysis of data collected in the REAL study from August to October 2015 study. The patients were submitted to clinical evaluation and analysis of medical records.Results1125 patients were included (89.5% women; median age: 56.6 years; and disease time: 12.8 years). A total of 406 (36.09%) participants were on a biological disease-modifying antirheumatic drugs. Infliximab was the drug with the longest time of use (12 years). Most (64.4%) drug suspension episodes were due to inefficacy. Adalimumab and certolizumab had a greater number of suspensions due to primary inefficacy, while discontinuations for abatacept were due more to secondary inefficacy. Infliximab had fewer suspensions due to primary inefficacy and golimumab had fewer episodes of secondary inefficacy. Regarding side effects, infliximab was suspended a greater number of times because of clinical and laboratory side effects. Abatacept and adalimumab had fewer suspensions due to clinical side effects, and certolizumab, rituximab and tocilizumab had fewer laboratory adverse effects. Conclusion Among the biological disease-modifying antirheumatic drugs being used for long periods, infliximab had greater time of use. Most drug suspensions (64%) were due to primary or secondary inefficacy. Number of discontinuations due to clinical and laboratory adverse effects for each drug was analyzed, and these data should be confirmed by other real-life studies. Knowledge of what is happening in real life is essential to health professionals, who need to be aware of the most common adverse effects and to health managers, who aim for greater cost-effectiveness in the choice of medications.

Background: In Brazil, socioeconomic differences in the incidence of rheumatoid arthritis (RA) have been demonstrated, which are important in the formulation of hypotheses regarding the association between environmental factors, lifestyle and the risk of disease development. This study examines how the socioeconomic condition of the patient with RA in Brazil, assessed according to social class, educational level, employment situation and use of caregivers, affects the times between the beginning of symptoms and diagnosis and the beginning of the use of disease-modifying antirheumatic drugs, as well as the presence of erosive disease and functional status., Methods: This work is part of a multicentric study called REAL - Rheumatoid Arthritis in Real Life in Brazil, which is a prospective observational cohort study., Results: As described in the REAL study, we included a total of 1115 patients. It was noted that patients with an educational classification of up to second grade incomplete presented with erosion percentages above those with a higher grade complete. Patients with caregivers presented a higher percentage of erosion than patients without caregivers. We verified that patients from economic classes above B2 presented fewer occurrences of erosion than those from classes C2, D-E. We also analyzed the average time differences from the beginning of symptoms and diagnosis and the beginning of treatment, according to academic level, erosion and economic classification. Patients with first grade complete showed an HAQ-DI averages higher than those with second grade complete. The patients who had employment showed lower HAQ-DI averages than patients who were not employed. The patients with erosion showed an HAQ-DI value higher than those without erosion. Patients with caregivers showed an HAQ-DI average higher than that of without caregivers., Conclusion: This study showed that the therapeutic window of RA is not being reached, and therefore we should have a policy to expand and ensure access to public health for all patients, especially those with lower levels of education and income., Trial Registration: This study was approved by the National Commission of Ethics in Research.

Background: Last decades witnessed great technological advances in rheumatoid arthritis (RA) management, but their implementation in clinical practice might prove difficult. Despite the efficacy demonstrated in controlled trials this information needs to be confirmed by real life data. This study assessed real-life treatment among RA patients., Methods: REAL study included Brazilian RA patients from eleven centers. Interview and medical records were performed. Continuous variables were compared using Student's t or Mann-Whitney and categorical variables were assessed with chi-square or Fisher's exact tests., Results: 1115 patients were included, women 89.5%. Median age 56.6 years, disease duration 152.5 months; 78.7% were rheumatoid fator positive; 55.2% had erosive disease; DAS28 (disease activity index-28 joints) = 3.5, HAQ (health assessment questionnaire) =0.875. The median duration of symptoms until the start of first DMARD was 12 months. A total of 529 (47.2%) patients used corticosteroids; 1022 (90.8%) were on conventional synthetic (cs) DMARDs and 406 (36.1%) on biological (b) DMARDs. Methotrexate (MTX) was the most frequent csDMARD: 748 (66.5%) patients, followed by leflunomide (LFN), used by 381 (33.9%) of patients. MTX was associated to LFN in 142 (12.6%) patients. Only five (0.4%) patients used triple therapy (MTX + hydroxychloroquine + sulfasalazine) or sulfasalazine in monotherapy., Conclusions: Despite advances in therapeutic resources, roughly half RA patients failed achieve T2T goals and 55.2% developed erosive disease. The frequent use of corticosteroids and delay in initiating DMARDs were demonstrated. Issues concerning timely access to medical care are crucial for effective management.

The treatment of rheumatoid arthritis (RA) has evolved rapidly in recent years. Nonetheless, conventional synthetic disease-modifying drugs (csDMARDs) remain the gold standard for RA treatment. The treatment for RA is expensive and this has a negative impact on public health. Given the low cost of csDMARDs compared to those of other treatment strategies, it is important to manage this type of treatment properly. Information on the duration of use of each drug and the reasons for their discontinuation is relevant to medical practitioners as it could improve the information available regarding side effects and their proper management. Moreover, data from clinical practice in the population can provide health care managers with information for resource allocation and optimization of csDMARD use with a consequent cost reduction in the treatment of RA. In this cross-sectional study, we aimed to describe the use of csDMARDs in public health services in Brazil, emphasizing on the duration of use and reasons for discontinuation of each drug. This study is a part of the REAL, a multicenter project that evaluated Brazilian patients with RA from eleven rheumatology services from August to October 2015. Patients were examined clinically, and an analysis of complementary exams and medical records was performed. A total of 1125 patients were included. 98.5% were women with a median age of 55.6 years. 36% and 90.84% patients were using biological disease-modifying drugs (bDMARDs) and csDMARDs, respectively. The duration of use and doses of each medication and the causes of suspension were analyzed. Most of the patients analyzed in this study were using csDMARDs for prolonged periods and methotrexate showed the longest duration of use. Interruption indexes due to ineffectiveness and side effects were analyzed. The knowledge of common adverse effects may alert attending physicians to the proper management of effective and low-cost therapeutic groups., Competing Interests: Ana Paula Monteiro Gomides: Has received personal support and consulting fees from Pfizer. Cleandro Pires de Albuquerque: Has received personal fees and/or non-financial support from Pfizer, AbbVie, AstraZeneca, Janssen, Bristol-Myers Squibb, Roche, Novartis and UCB Ana Beatriz Vargas Santos: Has received supporting for international medical events from AbbVie and Janssen Rodrigo Balbino Chaves Amorim: No financial disclosures Manoel Barros Bértolo: Has participated in clinical and/or experimental studies related to this work and sponsored by Roche; has delivered speeches at events related to this work and sponsored by AbbVie and Pfizer Paulo Louzada Júnior: Has received supporting for internationals congresses from Bristol-Myers Squibb, UCB and consulting fees from Pfizer Isabela Araújo Santos: No financial disclosures Rina Dalva Neubarth Giorgi: Has received consulting fees, speaking fees and supporting for internationals congresses from Roche, Pfizer, Bristol-Myers Squibb, UCB, Eli-Lilly, AbbVie, Abbott and EMS Sebastião Cezar Radominski: Has received consulting and speaking fees from Abbvie, Janssen, Pfizer, Roche and UCB Fernanda Maria Borghi: No financial disclosures Maria Fernanda B. Resende Guimarães: No financial disclosures Karina Rossi Bonfiglioli: Has received speaking fees and supporting for international congresses from Roche, Pfizer, Bristol-Myers Squibb, Abbvie and Janssen. Henrique Carriço da Silva: No financial disclosures Maria de Fátima Lobato da Cunha Sauma: No financial disclosures Ivânio Alves Pereira: Has received consulting fees, speaking fees and supporting for internationals congresses from Roche, Pfizer, UCB Pharma, Eli-Lilly, Abbvie and Janssen Gláucio Ricardo Wernwer de Castro: No financial disclosures Claiton Viegas Brenol: Has participated in clinical and/or experimental studies related to this work and sponsored by AbbVie, BMS, Janssen, Pfizer and Roche; has received personal or institutional support from AbbVie, BMS, Janssen, Pfizer and Roche; has delivered speeches at events related to this work and sponsored by AbbVie, Janssen, Pfizer and Roche Ricardo Machado Xavier: Consultancies for Abbvie, BMS, GSK, Janssen, Lilly, Novartis, Pfizer, Roche, UCB. Clinical trials: Abbvie, UCB, Pfizer, GSK, Lilly. Licia Maria Henrique da Mota: Has received personal or institutional support from AbbVie, Janssen, Pfizer and Roche; has delivered speeches at events related to this work and sponsored by AbbVie, Janssen, Pfizer, Roche and UCB. Geraldo da Rocha Castelar Pinheiro: Has received consulting fees from AbbVie, Bristol-Myers Squibb, Eli Lilly, Glaxosmithkline, Janssen, Pfizer, Sanofi Genzyme and Roche. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Ulp1 and Ulp2, in the yeast Saccharomyces cerevisiae , are the founding members of deSUMOylating enzymes. These enzymes remove s mall u biquitin-like mo difier (SUMO) from proteins and are conserved in all eukaryotes. Previous studies have shown that Ulp1 deSUMOylates the bulk of intracellular SUMOylated proteins, whereas Ulp2 is a highly specific enzyme. However, the mechanism for Ulp2's substrate specificity has been insufficiently understood. Here we show that the C-terminal regulatory domain of Ulp2 contains three distinct, yet conserved, motifs that control its in vivo substrate specificity and cell growth. Among them, a SUMO-interacting motif (SIM) was found to coordinate with the domain of Ulp2 that binds to the nucleolar protein Csm1 to ensure maximal deSUMOylation of Ulp2's nucleolar substrates. We found that whereas the Csm1-binding domain of Ulp2 recruits this enzyme to the nucleolus, Ulp2's C-terminal SIM promotes its SUMO protease activity and plays a key role in mediating the in vivo specificity of Ulp2. Thus, the substrate specificity of Ulp2 is controlled by both its subcellular localization and the SUMOylation status of its substrates. These findings illustrate the highly coordinated and dynamic nature of the SUMO pathways in maintaining homeostasis of intracellular SUMOylation., (© 2018 Ponte de Albuquerque et al.)

Background: There are few data on the epidemiology, clinical manifestations and management of RA in Brazil, even with the recognition of the high direct, indirect and societal costs of this disease. Herein, we report the formation of the REAL - Rheumatoid Arthritis in Real Life, the first nationally representative multicenter prospective observational study in Brazil., Methods: The REAL study was designed to include a total of 1300 evaluable patients from 13 tertiary care public health centers specialized in RA management and representative of 5 regions of Brazil. Each center was expected to enroll ~ 100 consecutively seen patients and follow them prospectively in a systematic protocol-driven fashion with scheduled visits at baseline, 6 and 12 months. Core clinical, laboratory and patient-reported outcomes measures were required to be collected at each visit., Results: A total of 1115 patients (89.4% female, mean age of 56.7 years and median disease duration of 12.7 years) were enrolled from 11 participating centers. Almost 80% of patients were of middle-low or low socioeconomic classes. The median educational time was 8 years, with 3.23% being below literacy level. The interval between symptoms and diagnosis varied from 1 to 457 months (median 12 months). Almost half of the patients were on glucocorticoids, 96.5% on DMARDs, with 35.7% on biologics. Median HAQ-DI was 0.875, ranging from 0 to 3. Median DAS28-ESR was 3.5, with 58.7% of patients presenting moderate or high disease activity., Conclusions: The first large cohort of Brazilian patients with RA in a real-life setting shows several striking differences from previously published cohorts from other countries. The long delay for diagnosis and start of DMARDs may partly explain the high frequency of erosive disease. An elevated percentage of patients on moderate or high disease activity was seen, despite of the high frequency of corticosteroid and biologics utilization. Data from this cohort may enable public health managers of developing countries better allocate the limited resources available for the care of RA patients.

The objective of this document is to provide a comprehensive update of the recommendations of Brazilian Society of Rheumatology on drug treatment of rheumatoid arthritis (RA), based on a systematic literature review and on the opinion of a panel of rheumatologists. Four general principles and eleven recommendations were approved. General principles: RA treatment should (1) preferably consist of a multidisciplinary approach coordinated by a rheumatologist, (2) include counseling on lifestyle habits, strict control of comorbidities, and updates of the vaccination record, (3) be based on decisions shared by the patient and the physician after clarification about the disease and the available therapeutic options; (4) the goal is sustained clinical remission or, when this is not feasible, low disease activity. Recommendations: (1) the first line of treatment should be a csDMARD, started as soon as the diagnosis of RA is established; (2) methotrexate (MTX) is the first-choice csDMARD; (3) the combination of two or more csDMARDs, including MTX, may be used as the first line of treatment; (4) after failure of first-line therapy with MTX, the therapeutic strategies include combining MTX with another csDMARD (leflunomide), with two csDMARDs (hydroxychloroquine and sulfasalazine), or switching MTX for another csDMARD (leflunomide or sulfasalazine) alone; (5) after failure of two schemes with csDMARDs, a bDMARD may be preferably used or, alternatively a tsDMARD, preferably combined, in both cases, with a csDMARD; (6) the different bDMARDs in combination with MTX have similar efficacy, and therefore, the therapeutic choice should take into account the peculiarities of each drug in terms of safety and cost; (7) the combination of a bDMARD and MTX is preferred over the use of a bDMARD alone; (8) in case of failure of an initial treatment scheme with a bDMARD, a scheme with another bDMARD can be used; in cases of failure with a TNFi, a second bDMARD of the same class or with another mechanism of action is effective and safe; (9) tofacitinib can be used to treat RA after failure of bDMARD; (10) corticosteroids, preferably at low doses for the shortest possible time, should be considered during periods of disease activity, and the risk-benefit ratio should also be considered; (11) reducing or spacing out bDMARD doses is possible in patients in sustained remission.

Background: The lack of a correlation between myocardial necrosis biomarkers and electrocardiographic abnormalities after revascularization procedures has resulted in a change in the myocardial infarction (MI) definition., Methods: Patients with stable multivessel disease who underwent percutaneous or surgical revascularization were included. Electrocardiograms and concentrations of high-sensitive cardiac troponin I (cTnI) and creatine kinase (CK)-MB were assessed before and after procedures. Cardiac magnetic resonance and late gadolinium enhancement were performed before and after procedures. MI was defined as more than five times the 99th percentile upper reference limit for cTnI and 10 times for CK-MB in percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG), respectively, and new late gadolinium enhancement for cardiac magnetic resonance., Results: Of the 202 patients studied, 69 (34.1%) underwent on-pump CABG, 67 (33.2%) off-pump CABG, and 66 (32.7%) PCI. The receiver operating characteristic curve showed the accuracy of cTnI for on-pump CABG, off-pump CABG, and PCI patients was 21.7%, 28.3%, and 52.4% and for CK-MB was 72.5%, 81.2%, and 90.5%, respectively. The specificity of cTnI was 3.6%, 9.4%, and 42.1% and of CK-MB was 73.2%, 86.8%, and 96.4%, respectively. Sensitivity of cTnI was 100%, 100%, and 100% and of CK-MB was 69.2%, 64.3%, and 44.4%, respectively. The best cutoff of cTnI for on-pump CABG, off-pump CABG, and PCI was 6.5 ng/mL, 4.5 ng/mL, and 4.5 ng/mL (162.5, 112.5, and 112.5 times the 99th percentile upper reference limit) and of CK-MB was 37.5 ng/mL, 22.5 ng/mL, and 11.5 ng/mL (8.5, 5.1, and 2.6 times the 99th percentile upper reference limit), respectively., Conclusions: Compared with cardiac magnetic resonance, CK-MB was more accurate than cTnI for diagnosing MI. These data suggest a higher troponin cutoff for the diagnosis of procedure-related MI., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Small ubiquitin-like modifier (SUMO) E3 ligases are known to have a major role in preventing gross chromosomal rearrangements (GCRs); however, relatively little is known about the role of SUMO isopeptidases in genome maintenance and their role in controlling intracellular sumoylation homeostasis. Here we show the SUMO isopeptidase Ulp2 in Saccharomyces cerevisiae does not prevent the accumulation of GCRs, and interestingly, its loss causes subunit-specific changes of sumoylated minichromosome maintenance (MCM) helicase in addition to drastic accumulation of sumoylated nucleolar RENT and inner kinetochore complexes. In contrast, loss of Ulp1 or its mis-localization from the nuclear periphery causes substantial accumulations of GCRs and elevated sumoylation of most proteins except for Ulp2 targets. Interestingly, the E3 ligase Mms21, which has a major role in genome maintenance, preferentially controls the sumoylation of Mcm3 during DNA replication. These findings reveal distinct roles for Ulp1 and Ulp2 in controlling homeostasis of intracellular sumoylation and show that sumoylation of MCM is controlled in a subunit-specific and cell cycle dependent manner., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

In 2014, tofacitinib, a target-specific, synthetic disease modifying anti rheumatic drug (DMARD) and a selective inhibitor of Janus kinase (JAK) was approved for use in Brazil. This position paper aims to update the recommendations of the Brazilian Society of Rheumatology (SBR) on the treatment of rheumatoid arthritis (RA) in Brazil, specifically regarding the use of target-specific synthetic DMARDs. The method of this recommendation consisted of a literature review of scientific papers held on the Medline database. After this review, a text was produced, answering questions in Pico structure, considering efficacy and safety issues of tofacitinib use for RA treatment in different scenarios (such as first-line treatment after failure with methotrexate [MTX] or other conventional synthetic DMARDs after failure with biological therapy). Based on existing evidence, and considering the available data on efficacy, safety and cost of medications available to treat the disease in Brazil, the RA Commission of SBR, after a process of discussion and voting on proposals, established the following position on the use of tofacitinib for treatment of RA in Brazil: "Tofacitinib, alone or in combination with MTX, is an alternative for RA patients with moderate or high activity after failure of at least two different synthetic DMARDs and one biological DMARD." The level of agreement with this recommendation was 7.5. This position may be reviewed in the coming years, in the face of a greater experience with the use of this medication., (Copyright © 2015 Elsevier Editora Ltda. All rights reserved.)

Objective: To assess the distribution of rheumatologists in Brazil and their correlation with Medical Residency specialization offer, Gross Domestic Product (Gdp) And Municipal Human Development Index (HDI-M) of units of the federation (UFs)., Methods: Query to various official databases, data summarization by techniques for descriptive statistics and cross-referenced information. For correlation analysis, we used the Spearman correlation coefficient (r)., Results: There were 1229 rheumatologists regularly registered in the country. The Northern region had only 3.6% of the total (n = 44), while the Southeast had 42.2% (n = 519). The State capitals, added to the five largest municipalities in each UF, concentrated 75.8% of these specialists (n = 931). In total, 49.9% of rheumatologists offered treatment at SUS. A general ratio of 157,809 inhabitants per rheumatologist in Brazil was determined, but with wide variation among UFs with respect to this ratio. In the years 2000-2012, there were 593 Rheumatology Residency graduated physicians in Brazil. We observed a positive correlation among number of rheumatologists compared with GDP (r = 0.94), HDI-M of the State capitals (r = 0.77) and number of Rheumatology Residency graduated physicians (r = 0.79) in UFs., Conclusions: We noted a strong concentration of rheumatologists in State capitals and larger municipalities, with noticeable inequalities also between UFs and country regions. The distribution of these professionals accompanied GDP, HDI-M of the State capital and number of Rheumatology Residency graduated physicians, suggesting that factors related to income opportunities and human development and the place of speciality training may influence the geographical fixation of rheumatologists.

The objective of the present study was to estimate the frequency of infection by Cryptosporidium spp and other intestinal parasites in dehydrated children with gastroenteritis who were admitted to a pediatric hospital. Stool examinations from 218 children were performed. Cryptosporidium spp was identified in eighteen out of 193 stool samples (9.3%) subjected to safranin-methylene blue staining. Giardia lamblia was detected in ten out of 213 (4.7%) samples examined via the direct or Ritchie methods. Other parasites identified were Ascaris lumbricoides (4.2%), Blastocystis hominis (1.4%), Entamoeba coli (0.9%), Entamoeba histolytica/Entamoeba dispar (0.5%), Endolimax nana (0.5%), Trichuris trichiura (0.5%) and Enterobius vermicularis (0.5%).

Objectives: We tested whether acute hormone therapy reduces ambulatory electrocardiographic ischemia in postmenopausal (PMP) women with unstable angina (UA)., Background: Endothelial dysfunction contributes to the pathophysiology of UA. Acute estrogen administration improves endothelial function in PMP women with coronary artery disease and increases coronary artery blood flow., Methods: Two hundred ninety-three PMP women with UA (mean age 69.7 years), treated with standard anti-ischemic therapy, were enrolled within 24 h of symptom onset. In a double-blind fashion, subjects were randomized to receive intravenous followed by oral conjugated estrogen for 21 days, intravenous estrogen followed by oral conjugated estrogen plus medroxyprogesterone for 21 days or placebo. The primary end point was the number of ambulatory electrocardiographic ischemic events over the first 48 h. Clinical events were also determined over six months of follow-up., Results: Electrocardiographic ischemia did not differ among the three randomized groups. The mean number of ischemic events per patient over 48 h was 0.74 for estrogen, 0.86 for estrogen plus progesterone and 0.74 for the placebo groups (p = 0.87). The percentage of patients with ischemic events and the mean duration of ischemia did not differ between hormone- and placebo-treated patients. In-hospital and six-month rates of adverse clinical events were also similar among the three randomized groups., Conclusions: Acute hormone therapy does not reduce ischemia in PMP women with UA when added to standard anti-ischemic therapy.

The objective of this study was to assess quality of care for premature labor at public maternity facilities in Rio de Janeiro, Brazil, using referents, indicators, and standards of care derived from scientific evidence. The standard utilized in the process analysis for use of betamimetic tocolytics was 100%, considering the related referents. For outcome analysis, the standard applied was the occurrence of premature delivery in 11% of patients within 24 h and in 24% of patients (referent) within 48 h of hospital admission. Use of tocolytics was observed in 18.7% of patients admitted in premature labor. At gestational age from 28 weeks to 33 weeks and 6 days, especially critical for neonatal survival, tocolytics were used in 32.6% of patients. Premature birth occurred in 59% of patients within 24 h and in 64% within 48 h. These outcomes were consistent with the low rate of utilization of tocolytics. Effectiveness of care for preterm labor measured by rate of premature birth was low. Results of the corresponding process and outcomes analysis were consistent.

Objectives: We sought to investigate whether alterations in cardiac high energy phosphates occur in postischemic "stunned" human myocardium., Background: Transient postischemic myocardial dysfunction is a common phenomenon that occurs in a variety of clinical settings in the absence of necrosis, and its pathogenesis is still unclear. Cardiac high energy phosphates are reduced during ischemia, and persistently altered myocardial high energy phosphate metabolism has been suggested as a mechanism contributing to stunning., Methods: We studied 29 patients with a first anterior myocardial infarction (MI) who underwent successful reperfusion within 6 h of the onset of chest pain. These patients underwent 31P magnetic resonance spectroscopy (MRS) a mean of 4 days after MI for measurement of left ventricular contractility and relative high energy phosphate metabolites. Twenty-one patients underwent a second 31P MRS study a mean of 39 days after MI. Eight volunteers served as control subjects., Results: Global and infarct area wall motion scores improved significantly between the early and late studies. No difference was found between early cardiac phosphocreatine (PCr)/beta-adenosine triphosphate (beta-ATP) ratios in patients and control subjects ([mean +/- SD] 1.51 +/- 0.17 vs. 1.61 +/- 0.18, respectively, p = 0.17) or between early and late study results in patients (1.51 +/- 0.17 vs. 1.53 +/- 0.17, respectively, p = 0.6). For alpha of 0.05, the study had a 90% power to detect a 9% difference., Conclusions: The results of this study demonstrate normal myocardial PCr/ATP ratios in patients with myocardial stunning after reperfusion and suggest that relative cardiac high energy phosphates are not depleted in stunned human myocardium.

Background: Ischemic preconditioning (IPC) attenuates acidosis during prolonged ischemia and improves contractile and metabolic parameters during subsequent reperfusion. Glycogen depletion induced by IPC is proposed as a potential mechanism., Methods and Results: We studied the influence of manipulations of preischemic glycogen levels (Pre-G, micromol glucose/g wet wt) on contractile and metabolic (via 31P-nuclear magnetic resonance) parameters during 30 minutes of ischemia and recovery in four groups of isovolumic rat hearts: First, control (Con, n=18, mean Pre-G, 21.5+/-0.8); second, after two 5-minute IPC periods (IPC, n=12, Pre-G, 11.3+/-0.7); third, a control group in which Pre-G was depleted by glucose-free, acetate perfusion (Con-LowG, n=9, Pre-G, 7.9+/-1.2); and fourth, an IPC group in which Pre-G was raised by glucose and lactate perfusion such that Pre-G was similar to Con (IPC-HiG, n=11, Pre-G, 20+/-1.4). Manipulation of Pre-G significantly altered the pH fall during 30 minutes of ischemia (Con, 5.76+/-.03, Con-LowG, 6.26+/-.07; IPC-HiG, 5.91+/-.02, IPC, 6.05+/-.09). IPC-HiG hearts had significantly worse metabolic recovery (PCr, 70+/-7 versus 91+/-3% initial; IPC-HiG versus IPC, P<.05) and contractile recovery (end-diastolic pressure, 52+/-5 versus 29+/-5 mm Hg, P<.05) than IPC hearts but better recovery than Con (%PCr, 56+/-6% and end-diastolic pressure, 72+/-6 mm Hg). An ischemic rise in intracellular magnesium occurred and was atttenuated in preconditioned hearts., Conclusions: Pre-G levels before ischemia influence but are not the sole determinants of the extent of acidosis during prolonged ischemia and of metabolic and contractile recovery during reperfusion in control and preconditioned hearts.

This study investigated both the in-hospital and long-term prognostic significance of ST-segment depression in non-infarct-related leads in patients who received thrombolytic therapy after acute myocardial infarction (AMI). We evaluated 221 consecutive patients who were admitted with their first AMI and underwent thrombolysis. Patients were followed for an average of 31 months and were classified into 3 groups: group 1 included 51 patients with persistent ST-segment depression, group 2 had 97 patients with transient ST-segment depression, and group 3 consisted of 73 patients without ST-segment depression (absent). Group 1 had significantly worse long-term survival during follow up by Kaplan-Meier analysis (55%) versus group 2 (81%) and group 3 (94%) (p = 0.0004) and higher event rates. This prognostic significance seemed to be maintained in both the anterior and inferior wall AMI groups. Multivariate analysis, using the Cox model, showed that Killip class, in-hospital left ventricular ejection fraction, and the persistence of ST-segment depression on the predischarge electrocardiogram (group 1) were independent predictors of survival. ST-segment depression in non-infarct-related leads on the predischarge electrocardiogram is an independent risk factor for worse long-term survival after anterior as well as inferior AMI treated with thrombolytic therapy.

Prior transient episodes of ischemia ("ischemic preconditioning") reduce lactate accumulation and attenuate acidosis during a subsequent prolonged ischemic insult. The mechanisms responsible for attenuated glycolytic catabolite accumulation have not been established but may include earlier exhaustion of glycogen stores, slowed glycogenolysis before complete glycogen depletion, and/or inhibition of glycolysis. Simultaneous repeated measures of myocardial glycogen and the rates of glycolysis, glycogenolysis, glucose utilization, and glycolytic ATP production were obtained during total ischemia by 13C nuclear magnetic resonance spectroscopy in control and ischemia-preconditioned isolated rat hearts. Both [13C]glycolytic and [13C]glycogenolytic rates were significantly lower during total ischemia in preconditioned compared with control hearts (0.77 +/- 0.04 versus 1.06 +/- 0.06 mumol/min per gram wet weight [P < .01] for glycolysis and 0.15 +/- 0.07 versus 0.78 +/- 0.12 mumol/ min per gram wet weight [P < .001] for glycogenolysis, respectively, at 2.5 minutes of ischemia). Slowed glycolysis was present even during the early minutes of ischemia, when significant amounts of available [13C]glycogen were still present. Importantly, the reduction in the rate of glycogenolysis was larger and out of proportion to the reduction in glycolysis and occurred despite an increase in glucose utilization in preconditioned hearts (2.23 +/- 0.15 versus 1.5 +/- 0.10 mumol/min per gram wet weight at 1.25 minutes, P < .01). During early ischemia, conversion of glycogen phosphorylase to the a or "active" form was less in preconditioned than in control hearts (29.1 +/- 2.6% versus 41.2 +/- 9.8%, respectively; P < .05). Taken together, these findings demonstrate that ischemic preconditioning significantly depresses glycolytic catabolite accumulation during sustained ischemia not by more severe glycolytic inhibition or exhaustion of glycogen stores but by depressed glycogenolysis from the onset of ischemia.

Objectives: This study sought to evaluate, in a prospective and randomized trial, the relative efficacies of three possible therapeutic strategies for patients with a single severe proximal stenosis of the left anterior descending coronary artery and stable angina., Background: Although percutaneous transluminal coronary angioplasty and coronary artery bypass surgery are often performed in patients with a single proximal stenosis of the left anterior descending coronary artery, it is unclear whether revascularization offers greater clinical benefit than medical therapy alone., Methods: At a single center, 214 patients with stable angina, normal ventricular function and a proximal stenosis of the left anterior descending coronary artery > 80% were randomly assigned to undergo mammary bypass surgery (n = 70), balloon angioplasty (n = 72) or medical therapy alone (n = 72). Angioplasty had to be considered technically feasible in every case. The predefined primary study end point was the combined incidence of cardiac death, myocardial infarction or refractory angina requiring revascularization., Results: At an average follow-up period of 3 years, a primary end point had occurred in only 2 patients (3%) assigned to bypass surgery compared with 17 assigned to angioplasty (24%) and 12 assigned to medical therapy (17%) (p = 0.0002, angioplasty vs. bypass surgery; p = 0.006, bypass surgery vs. medical treatment; p = 0.28, angioplasty vs. medical treatment, all by log-rank test). There was no difference in mortality or infarction rates among the groups. However, no patient allocated to bypass surgery needed revascularization, compared with eight and seven patients assigned, respectively, to coronary angioplasty and medical treatment (p = 0.019). Both revascularization techniques resulted in greater symptomatic relief and a lower incidence of ischemia on the treadmill test; however, all three strategies eventually resulted in the abolition of limiting angina., Conclusions: The more aggressive therapeutic approach with initial bypass surgery for patients with a single severe proximal stenosis of the left anterior descending coronary artery is associated with a lower incidence of medium-term adverse events than coronary angioplasty or medical treatment. However, all three strategies resulted in a similar incidence of death and infarction during an average follow-up period of 3 years. This information should be taken into consideration when physicians and patients make therapeutic choices in this setting.

Purpose: To determine the patency and incidence rates of left circumflex coronary artery (LCX) as the infarct related artery (IRA) in Q-wave and non-Q wave acute myocardial infarction (AMI)., Methods: Two-hundreds and twenty one patients (172 men) with AMI were stratified in Q and non-Q waves groups. All patients were submitted to cinecoronary angiography 72 hours after the beginning of symptoms and the IRA and its patency were evaluated., Results: In non-Q wave AMI, the LCX was considered to be the IRA in 35% of the patients. In Q wave AMI, this incidence was 8% (p < 0.001). Occlusion of LCX was seen in all non-Q wave AMI patients when it was the IRA., Conclusion: The incidence of LCX as IRA was significantly higher in non-Q wave AMI patients. This group did not have the previously expected greater patency rates, what could result in different clinical and evolutive characteristics.

Purpose: To evaluate the importance of the right coronary artery (RCA) patency in patients with right ventricular infarction., Methods: Fifty-two patients with inferior wall myocardial infarction and right ventricular involvement were studied and divided in two groups: group A (GA) included 35 patients in whom the RCA was patent at coronary angiography, and group B (GB), 17 who had an occluded RCA. They were prospectively evaluated for electrical and hemodynamic complications, as well as in-hospital mortality., Results: The mortality in GA was 11% and 29% in GB, p = 0.13; electrical complications were 11% in GA and 35% in GB, p = 0.06; hemodynamic complications were 8% in GA and 41% in GB, p = 0.009., Conclusion: These findings suggest a trend towards reduction in mortality and electrical complications, and significant reduction of hemodynamic complications in patients with inferior wall myocardial infarction with involvement of the right ventricle who have the RCA patent. Thus, RCA patency appears to be important in determining in-hospital outcomes of these patients.

The appearance of 13C label in glutamate has been used to quantify cellular tricarboxylic acid (TCA) cycle activity using 13C-NMR spectroscopy. Glutamate is linked to the TCA cycle by the amino-transferase reactions, however the consequences of alterations in amino-transferase activity on glutamate labelling kinetics, at a constant total tricarboxylic acid cycle activity, have not been investigated. Aspartate amino-transferase activity in [2-13C]acetate-perfused beating rat hearts was found to be similar to total TCA cycle flux in the presence of normal perfusion conditions and was reduced by more than 50% with the subsequent administration of amino-oxyacetic acid (AOA). AOA did not reduce contractile or kinetic measures of total TCA cycle flux, but did slow the 13C labelling of glutamate, in accord with current mathematical predictions. The impact of similar reductions in amino-transferase activity on estimates of total TCA cycle flux derived from several previously reported methods was also evaluated. Because total TCA cycle and the amino-transferase activities both affect the kinetics of 13C-glutamate labelling and because the amino-transferase activities are often unknown under physiologic conditions and can be reduced under pathologic conditions, the calculation of total TCA cycle flux from 13C-NMR data in the future is probably best accomplished either with a sufficiently sophisticated mathematical model that assesses amino-transferase activity or with an empiric model that is relatively insensitive to variations in amino-transferase activity.

Purpose: To determine the value of magnetic resonance imaging (MRI) in the noninvasive detection of infarct related coronary artery patency after thrombolysis., Methods: We studied 26 patients with acute myocardial infarction submitted to thrombolysis underwent MRI studies before and after 0.1mmol/kg gadolinium-DTPA injection within the first 48 h of MI. Signal intensity was assessed by circumferential profile analysis techniques., Results: The average ratio of signal intensity of infarcted tissue over normal myocardium (I/N) was significantly higher in patients with patent arteries (1.3 +/- 0.13 vs 1.12 +/- 0.07, p < 0.02). Compared to coronariography MRI, sensitivity of 81% and specificity of 100% for the diagnosis of coronary patency., Conclusion: Gadolinium infusion increased infarcted and normal myocardium differentiation. The study of gadolinium kinetics at MRI is a promising technique for noninvasive diagnosis of coronary patency.

Many important aspects of Chagas' heart disease can be successfully assessed using magnetic resonance imaging of the heart. It is possible to obtain with great detail the anatomic characterization of the cardiac as well as important information of the functional or metabolic status of the heart. Magnetic resonance imaging after gadolinium infusion seems also a promising technique to obtain a better regional characterization of myocardial tissue, and may be important in the non-invasive diagnosis of active myocarditis in patients with Chagas' heart disease.

Background: Left ventricular (LV) function is the most important determinant of outcome after a myocardial infarction. Global LV function after a myocardial infarction is affected not only by wall motion in the infarct zone but also by regional function in the contralateral territory. It was hypothesised that the presence of significant stenoses in coronary arteries supplying the contralateral territory might influence the ability of this region to compensate for damaged myocardium after a myocardial infarction., Methods and Results: 79 patients treated with thrombolysis for acute myocardial infarction had coronary and ventricular angiograms within 24 h and at a mean follow up of 12 months after myocardial infarction. Wall motion in the contralateral territory was analysed and scored by the centre line method and the change over time was correlated with the presence or absence of significant (> 70%) diameter stenoses in the non-infarct-related artery. Mean (SD) contralateral territory motion worsened, from 0.74 (1.78) to -1.55 (2.06) SD chord (p < 0.001) in 40 patients with stenoses, whereas contralateral territory motion improved from -0.02 (2.4) to 0.63 (2.21) SD chord (p < 0.05) in the 39 patients without coronary stenoses. The same pattern was present whether or not the infarct artery was patent. The global left ventricular ejection fraction at 12 months was also related to contralateral territory motion (r = 0.71, p < 0.001) and to the presence of coronary stenoses (54 (15)% in those with coronary stenoses and 62 (16)% in those without, p < 0.05)., Conclusion: The results demonstrate that significant stenoses in arteries supplying the non-infarct territory adversely affect global and regional left ventricular function after a transmural infarction. Non-infarct artery anatomy should be considered in intervention strategies to improve left ventricular function after acute myocardial infarction.

The pathophysiological mechanisms by which brief periods of flow interruption before a prolonged ischemic period, ischemic preconditioning (IPC), increase myocardial tolerance to ischemia and improve myocardial function during reperfusion are not completely understood. To test whether short periods of metabolic inhibition in the absence of a flow reduction induce similar protective effects, we studied cardiac function and metabolism using 31P nuclear magnetic resonance spectroscopy in isolated isovolumic rat hearts. Fifteen hearts underwent IPC, consisting of two 5-minute ischemia-reperfusion cycles (IPC group); 18 hearts underwent brief metabolic inhibition by exposure to two 5-minute infusions of 10 mmol/L sodium cyanide (CN group); and 15 hearts served as controls. Subsequently all hearts were subjected to 30 minutes of total global ischemia at 37 degrees C followed by reperfusion. At the end of the ischemic period, creatine phosphate and ATP levels did not differ among the groups. Cellular pH, however, plateaued at a higher level in the CN group (6.51 +/- 0.03) and IPC group (6.12 +/- 0.06) than in the control group (5.84 +/- 0.01, P < .001). IPC and CN hearts had better functional and metabolic recovery than the control hearts. Improved contractile recovery correlated with coronary flow rates at reperfusion (r = .7, P < .001) and with pHi values at 30 minutes of ischemia (r = .8, P < .001) but not with increased ATP levels during ischemia. Additional control hearts were reperfused at 15 mL/min so as to match the flow rates of IPC and CN groups, but this did not result in improved performance. To test the hypothesis that the preconditioning effect was related to pHi during ischemia, additional IPC and CN hearts underwent the same preconditioning protocol, except that the cellular pH at the end of the ischemic period was lowered by the use of hypercarbic superfusion during ischemia or by the use of bicarbonate-free perfusate just before sustained ischemia. Both of these interventions resulted in significantly lower contractile and metabolic recoveries than those observed in other IPC and CN hearts. Therefore, the preconditioning effect does not require reduced coronary flow but can be effectively elicited by metabolic inhibition per se in this model. The protective effect is not dependent on preservation of global myocardial energy stores but, rather, on reduced acidosis during the prolonged ischemic period.

Purpose: To evaluate if early interventions which increase flow in the non-infarct related arteries (NRA) could improve long-term ventricular function in the non-infarct (NI) area after an acute myocardial infarction (MI)., Methods: We studied regional wall motion analyzed by the center-line method in two groups of patients with significant stenoses (> or = 70%) in the NRA after successful coronary reperfusion (chemical or mechanical thrombolysis). Group I (GI) consisted of 21 patients that were submitted to early (mean 14 days) complete surgical revascularization of both NRA and infarct related artery (IRA); the 12 group II (GII) patients underwent successful revascularization of the IRA only, with percutaneous transluminal coronary angioplasty (mean 6 days). Paired ventriculograms were obtained within 48 hours of the infarction and a mean of 17 months later., Results: NI area contractility in GI patients improved from -0.35 +/- 2.16 to +0.62 +/- 1.6sd/chord (p < 0.05), whereas in GII decreased from +0.54 +/- 1.78 to -0.66 +/- 1.72 sd/chord (p < 0.05), p < 0.05 between the groups at follow-up. Mean infarct area wall motion did not differ between the two groups: from -3.04 +/- 2.43 to 2.61 +/- 2.49 sd/chord in GI (p = NS), and from -2.68 +/- 2.54 to -2.93 +/- 2.35 sd/chord in GII (p = NS). Mean global left ventricular (LV) ejection fraction did not change in GII patients (0.72 +/- 0.09 and 0.67 +/- 0.12, p = NS), but significantly increased from 0.63 +/- 0.12 to 0.72 +/- 0.11 in GI patients (p < 0.01)., Conclusion: These data suggest that early revascularization of NRA with significant stenoses can improve not only the NI area regional contractility, but also the global LV function in the long-term follow-up of post MI patients treated with thrombolytic therapy.

This study evaluates the association between the presence of diagonal earlobe creases (ELC) and coronary artery disease (CAD). One thousand four hundred twenty-four patients (760 men and 664 women, aged 30 to 80 years) were examined for the presence of ELC and classified into 2 groups: group I control--1,086 consecutive patients who denied symptoms of myocardial ischemia and were admitted to a general hospital for other reasons; group II CAD--338 patients with documented CAD (presence of > or = 70% coronary diameter stenosis at angiography). ELC was present in 304 patients (28%) in group I and 220 (65%) in group II (p < 0.0001). The patients were stratified in age groups to isolate the influence of age because the prevalence of ELC and CAD increased with advancing age (p < 0.0001 for both). This association remained statistically significant in all decades, except for patients aged > 70 years. To further remove the confounding effect of different age and sex distributions between the groups, a direct adjustment of the ELC prevalence was performed. When adjusted for age and sex, the prevalence of creases was still 58% higher in patients with CAD than in control subjects (p < 0.001). The presence of ELC was also related to the extent of CAD as measured by the number of major arteries narrowed (p = 0.015). The observed sensitivity of the sign for the diagnosis of CAD was 65%, the specificity 72%, the positive predictive value 42% and the negative predictive value 87%.

Purpose: To evaluate the feasibility of bedside Technetium99-methoxy-isobutyl-isonitrile (99mTc-MIBI) cardiac imaging to assess perfusion after thrombolytic therapy (TT) for myocardial infarction (MI)., Methods: We studied 9 patients (mean age 59 +/- 9 years) submitted to TT with 100 mg of rt-PA in 90 minutes within the 6 hours of the onset of MI with subsequent angiography. 99mTc-MIBI was injected intravenously in a doses of 740 MBq immediately before TT start. Imaging was performed in three moments: study 1--as soon as the TT finished, study 2--3-18 hours after TT; study 3--7-10 days after TT. A perfusion score was established in each study and then compared to determine the perfusion patterns after TT. We compared through linear regression, the perfusion score with left ventricle ejection fraction, and with CKMB enzymatic peak., Results: All patients had a patent infarct related artery. The perfusion score of study 1 varied from 12 to 22, mean 15.8 +/- 3.7, and correlated with ejection fraction (r = 0.9, p < 0.01) and peak CKMB (r = 0.78, p = 0.03). Four (44%) patients presented perfusion score improvement in study 2 (varied from 12 to 23, mean 16.8 +/- 4.3) and 8 (88%) in study 3 (varied from 12 to 28, mean 19.0 +/- 4.3)., Conclusion: Bedside 99mTc-MIBI cardiac imaging is useful to quantify myocardial area under risk before TT, and to identify the late (7 to 10 days) benefit of TT.

Purpose: To evaluate the influence of lipoprotein (a) (Lp (a)) levels in thrombolysis with rt-PA for myocardial infarction (MI)., Methods: Thirty-eight MI patients, 28 male, mean age 51 +/- 9 years, submitted to thrombolysis with rt-PA, divided in two groups according the result of the thrombolysis: A) Successful, B) Failure. Serum fibrinogen (SF) was assessed before and 90 minutes after treatment. Lp (a) levels were determined six months later. These parameters were analyzed in both groups., Results: Lp (a) levels were similar in groups A and B (p = 0.45). The SF levels were not different in the groups., Conclusion: Lp (a) seems to have no influence in thrombolysis with rt-PA for MI.