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The coronavirus disease 2019 (COVID-19) pandemic substantially impacted different age groups, with children and young people not exempted. Many have experienced enduring health consequences. Presently, there is no consensus on the health outcomes to assess in children and young people with post-COVID-19 condition. Furthermore, it is unclear which measurement instruments are appropriate for use in research and clinical management of children and young people with post-COVID-19. To address these unmet needs, we conducted a consensus study, aiming to develop a core outcome set (COS) and an associated core outcome measurement set (COMS) for evaluating post-COVID-19 condition in children and young people. Our methodology comprised of two phases. In phase 1 (to create a COS), we performed an extensive literature review and categorisation of outcomes, and prioritised those outcomes in a two-round online modified Delphi process followed by a consensus meeting. In phase 2 (to create the COMS), we performed another modified Delphi consensus process to evaluate measurement instruments for previously defined core outcomes from phase 1, followed by an online consensus workshop to finalise recommendations regarding the most appropriate instruments for each core outcome. In phase 1, 214 participants from 37 countries participated, with 154 (72%) contributing to both Delphi rounds. The subsequent online consensus meeting resulted in a final COS which encompassed seven critical outcomes: fatigue; post-exertion symptoms; work/occupational and study changes; as well as functional changes, symptoms, and conditions relating to cardiovascular, neuro-cognitive, gastrointestinal and physical outcomes. In phase 2, 11 international experts were involved in a modified Delphi process, selecting measurement instruments for a subsequent online consensus workshop where 30 voting participants discussed and independently scored the selected instruments. As a result of this consensus process, four instruments met a priori consensus criteria for inclusion: PedsQL multidimensional fatigue scale for "fatigue"; PedsQL gastrointestinal symptom scales for "gastrointestinal"; PedsQL cognitive functioning scale for "neurocognitive" and EQ-5D for "physical functioning". Despite proposing outcome measurement instruments for the remaining three core outcomes ("cardiovascular", "post-exertional malaise", "work/occupational and study changes"), a consensus was not achieved. Our international, consensus-based initiative presents a robust framework for evaluating post-COVID-19 condition in children and young people in research and clinical practice via a rigorously defined COS and associated COMS. It will aid in the uniform measurement and reporting of relevant health outcomes worldwide.
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COVID-19 , Síndrome de COVID-19 Pós-Aguda , Adolescente , Criança , Humanos , Técnica Delphi , Avaliação de Resultados em Cuidados de Saúde , Projetos de Pesquisa , Resultado do TratamentoRESUMO
BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an underdiagnosed cause of acute coronary syndrome, particularly in younger women. Due to limited information about SCAD, case reports and case series can provide valuable insights into its features and management. This study aimed to comprehensively evaluate the features of SCAD patients who experienced psychophysical stress before the SCAD event. METHODS: We conducted an electronic search of PubMed, Scopus, and Web of Science from inception until January 7, 2023. We included case reports or series that described patients with SCAD who had experienced psychophysical stress before SCAD. Patients with pregnancy-associated SCAD were excluded from our analysis. RESULTS: In total, we included 93 case reports or series describing 105 patients with SCAD. The average patient age was 44.29 ± 13.05 years and a total of 44 (41.9%) of patients were male. Among the included SCAD patients the most prevalent comorbidities were fibromuscular dysplasia (FMD) and hypertension with the prevalence of 36.4 and 21.9%, respectively. Preceding physical stress was more frequently reported in men than in women; 38 out of 44 (86.4%) men reported physical stress, while 36 out of 61 (59.1%) females reported physical stress (p value = 0.009). On the other hand, the opposite was true for emotional stress (men: 6 (13.6%)), women: 29 (47.6%), p value < 0.001). Coronary angiography was the main diagnostic tool. The most frequently involved artery was the left anterior descending (LAD) (62.9%). In our study, recurrence of SCAD due to either the progression of a previous lesion or new SCAD in another coronary location occurred more frequently in those treated conservatively, however the observed difference was not statistically significant (p value = 0.138). CONCLUSION: While physical stress seems to precede SCAD in most cases, emotional stress is implicated in females more than males.
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Anomalias dos Vasos Coronários , Estresse Psicológico , Doenças Vasculares , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Relatos de Casos como Assunto , Comorbidade , Anomalias dos Vasos Coronários/epidemiologia , Anomalias dos Vasos Coronários/diagnóstico por imagem , Anomalias dos Vasos Coronários/complicações , Prevalência , Prognóstico , Medição de Risco , Fatores de Risco , Fatores Sexuais , Estresse Psicológico/epidemiologia , Estresse Psicológico/diagnóstico , Doenças Vasculares/congênito , Doenças Vasculares/epidemiologia , Doenças Vasculares/diagnóstico por imagem , Doenças Vasculares/psicologia , Doenças Vasculares/fisiopatologia , Doenças Vasculares/diagnósticoRESUMO
BACKGROUND: Shortly after the Coronavirus disease 2019 (COVID-19) pandemic, a considerable number of recovered patients reported persisting symptoms, especially neuropsychological manifestations, which were later named post-COVID syndrome (PCS). Immune dysregulation was suggested as one of the main mechanisms for PCS. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) that is mostly used to treat depression, anxiety disorders, and obsessive-compulsive disorder, has been suggested as an anti-COVID drug due to its anti-inflammatory effects, mainly through the sigma-1 receptor. Therefore, we aimed to evaluate fluvoxamine's effect on PCS neuropsychiatric symptoms. METHOD: In this double-blind randomized clinical trial, we included confirmed mild to moderate COVID-19 outpatients using polymerase chain reaction (PCR) by an infectious disease specialist. The presence of severe COVID-19 symptoms was evaluated by the infectious disease specialist and included dyspnea, SpO2 < 94% on room air, PaO2/FiO2 < 300 mm Hg, a respiratory rate > 30 breaths/min, and lung infiltrates > 50%. Then we performed permuted block randomization and assigned patients 1:1 into two groups to either receive fluvoxamine 100 mg tablet or a placebo daily for 10 days. Eligible patients were evaluated after 12 weeks for the presence of fatigue, as the primary, and other PCS symptoms as secondary outcomes. RESULTS: We screened a total of 486 patients from March to June 2022. After 12 weeks, 42 patients receiving fluvoxamine and 43 patients receiving Placebo were evaluated for PCS. Patients had a mean age of 38.5 ± 14.1 and 48% of them were women. Fatigue was significantly lower in the fluvoxamine group (p-value 0.026). No significant differences were observed in other symptoms. CONCLUSION: We concluded that taking fluvoxamine during active COVID-19 can reduce the chance of fatigue but the advantage of fluvoxamine was not observed for other symptoms. Further studies are necessary to confirm these preliminary results.
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COVID-19 , Doenças Transmissíveis , Humanos , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Masculino , Fluvoxamina/uso terapêutico , Fluvoxamina/farmacologia , Tratamento Farmacológico da COVID-19 , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Doenças Transmissíveis/tratamento farmacológico , Método Duplo-Cego , Resultado do TratamentoRESUMO
BACKGROUND: Preoperative coronary artery disease risk factors (CADRFs) distribution and pattern may also have an important role in determining major adverse cardiovascular events (MACEs). In this study, we aimed to evaluate the CADRFs distribution and trend over 10 years and also the long-term outcome of CABG in different age-sex categories. METHOD: In this registry-based serial cross-sectional study, we enrolled 24,328 patients who underwent isolated CABG and evaluated the prevalence of CADRFs according to sex and age. We used inverse probability weighting (IPW) to compare survival and MACE between the sexes. We also used Cox regression to determine each CADRFs effect on survival and MACEs. RESULTS: In general, DLP (56.00%), HTN (53.10%), DM (38.40%), and positive family history (38.30%) were the most frequent risk factors in all patients. Prevalence of HTN, DLP, DM, obesity, and positive family history were all higher in women, all statistically significant. The median follow-up duration was 78.1 months (76.31-79.87 months). After inverse probability weighting (to balance risk factors and comorbidities), men had lower MACEs during follow-up (HR 0.72; 95% CI 0.57-0.91; P value 0.006) and there was no significant difference in survival between sexes. DM and HTN were associated with higher mortality and MACEs in both sexes. CONCLUSION: Although DLP is still the most frequent CADRF among the CABG population, the level of LDL and TG is decreasing. Women experience higher MACE post CABG. Therefore, health care providers and legislators must pay greater attention to female population CADRFs and ways to prevent them at different levels.
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Ponte de Artéria Coronária , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/cirurgia , Fatores Etários , Idoso , Ponte de Artéria Coronária/efeitos adversos , Ponte de Artéria Coronária/mortalidade , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/mortalidade , Estudos Transversais , Feminino , Disparidades nos Níveis de Saúde , Fatores de Risco de Doenças Cardíacas , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Sistema de Registros , Medição de Risco , Fatores Sexuais , Fatores de Tempo , Resultado do TratamentoRESUMO
Injuries that result in the loss of limb functionality may be caused by the severing of the peripheral nerves within the affected limb. Several bioengineered peripheral nerve scaffolds have been developed in order to provide the physical support and topographical guidance necessary for the naturally disorganized axon outgrowth to reattach to distal nerve stumps as an alternative to other procedures, like nerve grafting. PDMS has been chosen for the base material of the scaffolds due to its biocompatibility, flexibility, transparency, and well-developed fabrication techniques. The process of observing the axon outgrowth across the nerve gaps with PDMS scaffolds has been challenging due to the limited number and fineness of longitudinal sections that can be extracted from harvested nerve tissue samples after implantation. To address this, multilayer microchannel scaffolds were developed with the object of providing more refined longitudinal observation of axon outgrowth by longitudinally 'sectioning' the device during fabrication, removing the need for much of the sample preparation process. This device was then implanted into the sciatic nerves of Lewis rats, and then harvested after two and four weeks to analyze the difference in nerve regeneration between two different time periods. The present layer by layer structure, which is separable after nerve regeneration and is treated as an individual layer during the histology process, provides the details of biological events during axonal regeneration. Confocal microscopic imaging showed the details of peripheral nerve regeneration including nerve branches and growth cones observable from within the microchannels of the multilayer PDMS microchannel scaffolds.
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Dimetilpolisiloxanos/química , Regeneração Nervosa , Nervo Isquiático/crescimento & desenvolvimento , Engenharia Tecidual/métodos , Alicerces Teciduais/química , Animais , Desenho de Equipamento , Tecido Nervoso/crescimento & desenvolvimento , Ratos , Ratos Endogâmicos LewRESUMO
Peanut allergy is a leading cause of severe food reactions. This meta-analysis evaluates the efficacy and safety of epicutaneous immunotherapy (EPIT) compared to placebo for peanut-allergic individuals. After prospectively registering on PROSPERO, we searched three databases (PubMed, Google Scholar, and Cochrane CENTRAL) and 2 trial registries till September 2023. Analysis was conducted via RevMan where data was computed using risk ratios (RR). The Cochrane Risk of Bias tool and GRADE criteria were used to appraise and evaluate the evidence. From 4927 records, six multicenter randomized placebo-controlled trials comprising 1453 participants were included. The 250 µg EPIT group had a significant increase in successful desensitization compared to placebo (RR: 2.13 (95% C.I: 1.72, 2.64), P < 0.01, I2 = 0%), while the 100 µg EPIT group did not (RR: 1.54 (95% C.I: 0.92, 2.58), P = 0.10, I2 = 0%) (moderate certainty evidence). Moreover, there was a significant increase in local (RR: 1.69 (95% C.I: 1.06, 2.68), P = 0.03, I2 = 89%) and systemic adverse events (RR: 1.75 (95% C.I: 1.14, 2.69), P = 0.01, I2 = 0%) with EPIT. Additionally, individuals administered EPIT have an increased probability of requiring rescue medications like epinephrine (RR: 1.91 (95% C.I: 1.12, 3.28), P = 0.02, I2 = 0%) and topical corticosteroids (RR: 1.49 (95% C.I: 1.29, 1.73), P < 0.01, I2 = 0%) to treat adverse events. The association of adverse events post-treatment including anaphylaxis (RR: 2.31 (95% C.I: 1.00, 5.33), P = 0.05, I2 = 36%), skin/subcutaneous disorders like erythema or vesicles (RR: 0.93 (95% C.I: 0.79, 1.08), P = 0.33, I2 = 0%), and respiratory disorders like dyspnea or wheezing (RR: 0.94 (95% C.I: 0.77, 1.15), P = 0.55, I2 = 0%) with EPIT is inconclusive. EPIT, although effective in desensitization, is linked to an increased risk of adverse events. PROSPERO registration: CRD42023466600.
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Administração Cutânea , Dessensibilização Imunológica , Hipersensibilidade a Amendoim , Hipersensibilidade a Amendoim/terapia , Hipersensibilidade a Amendoim/imunologia , Humanos , Dessensibilização Imunológica/métodos , Dessensibilização Imunológica/efeitos adversos , Alérgenos/imunologia , Alérgenos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Arachis/imunologiaRESUMO
BACKGROUND: Preoperative hemoglobin (Hb) level is a predictor of in-hospital and midterm mortality in patients undergoing coronary artery bypass grafting surgery (CABG). However, the debate about the different hazards across Hb levels and sex differences in outcome occurrence is still on the table. METHODS: This is a registry-based serial cross-sectional study at Tehran Heart Center. Nonanemic patients who underwent CABG with complete follow-up data were included. The Restricted Cubic Splines (RCS) in the Cox model was used to calculate the sex-specific correlation between in-hospital, 6-month, and 1-year mortalities and normal Hb levels using odds ratio for the in-hospital and hazard ratios for 6-month and 1-year mortality, adjusted for all possible confounders. RESULTS: From 2005 to 2016, a total of 13,557 patients were included, of which 134 had in-hospital mortality as our primary outcome. Preoperative Hb levels were significantly lower in the deceased. Moreover, dead patients had significantly higher rates of diabetes and hypertension, while lower ejection fraction. Cut-offs for reference Hb level were higher for males compared with females. The correlation between Hb level and in-hospital mortality was nearly U-shaped. Quantitatively, Hb of ≥15.62 and ≤13.25 g/dL for men and that of ≥14.92 and ≤13.4 g/dL for women tended to be associated with higher in-hospital mortality. CONCLUSIONS: The association between preoperative Hb level and in-hospital mortality differs in men and women and does not follow a linear correlation among nonanemic patients. Both low and high numbers in the Hb level spectrum are at greater risk.
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Ponte de Artéria Coronária , Hemoglobinas , Humanos , Masculino , Feminino , Estudos Transversais , Fatores de Risco , Irã (Geográfico)/epidemiologia , Ponte de Artéria Coronária/efeitos adversosRESUMO
BACKGROUND: Although low-density lipoprotein-cholesterol (LDL-C) level is considered one of the main prognostic factors in patients with coronary artery bypass grafting (CABG), the question about "the lower the better" is still unanswered. We aimed to evaluate and compare the outcomes of patients with CABG and low or very low baseline LDL-C, regardless of statin usage. METHODS: In this registry-based cohort study, 10,218 patients with low/very low (70-100 and ≤ 70 mg/dL) baseline LDL-C who underwent isolated and the first-time CABG without known previous history of cardio-cerebrovascular events, were included and compared. The median follow-up was 73.33 (72.15-74.51) months. Primary outcomes were all-cause mortality and major adverse cardio-cerebrovascular events (MACCE) (consisted of all-cause mortality, acute coronary syndrome, stroke or transient ischemic attack, and the need for repeat revascularization [percutaneous coronary intervention or redo-CABG]). Cox regression analyses before and after the propensity score matching (PSM) model were applied to evaluate and compare outcomes. RESULTS: The mean age of the study population was 66.17 ± 9.98 years old and 2506 (24.5%) were women. Diabetes mellitus and a history of cigarette smoking were significantly higher in the very low LDL group (P-value ≤ 0.001). In Cox regression analyses before applying PSM model, both all-cause mortality (14.2% vs. 11.9%, P-value = 0.004 and MACCE (26.0% vs. 23.6%, P-value = 0.006) were significantly higher in the very low LDL group compared to low LDL. However, these results were no longer significant after applying the PSM model (all-cause mortality HR: 1.115 [95% CI: 0.986-1.262], P = 0.083 and MACCE HR: 1.077 [95%CI: 0.984-1.177], P = 0.095). The sensitivity analysis to remove the statin effect demonstrated that very low LDL-C level was correlated to higher risk of all-cause mortality in both unmatched and PSM analyses. CONCLUSION: Very low serum LDL-C levels (≤ 70 mg/dl) could increase long-term all-cause mortality and cardiovascular events in patients who have undergone isolated CABG.
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Doença da Artéria Coronariana , Inibidores de Hidroximetilglutaril-CoA Redutases , Intervenção Coronária Percutânea , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Masculino , Doença da Artéria Coronariana/cirurgia , LDL-Colesterol , Prognóstico , Estudos de Coortes , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Resultado do Tratamento , Intervenção Coronária Percutânea/métodos , Sistema de Registros , Fatores de RiscoRESUMO
INTRODUCTION: Anomalous origin of the right coronary artery from the pulmonary artery (ARCAPA) is a rare coronary artery malformation with an incidence of 0.002% in patients undergoing coronary angiography. It can lead to an increased risk of myocardial infarction (MI) and sudden cardiac death, even in asymptomatic patients. METHODS: We conducted a review of published cases of ARCAPA using PubMed and Scopus databases and included patients over 18 years old with adequate echocardiographic data. RESULTS: We evaluated 28 patients with ARCAPA with a mean age of 42.8 from 1979 to 2021. Patients were diagnosed mostly by angiography and echocardiography, the most performed treatment was reimplantation (15, 53.6%) and the main echocardiographic findings were dilated coronary arteries (9, 32.1%), coronary collaterals (8, 28.6%), and retrograde flow from right coronary arteries to main pulmonary trunk (7, 25%). CONCLUSION: Although ARCAPA is rare and not as deadly as the anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) still there is a chance of serious outcomes, therefore surgical treatment should be performed upon diagnosis. Angiography is the gold standard for diagnosis, but echocardiography can be a convenient, non-invasive, and most reliable method as the primary step whenever ARCAPA is suspected.
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BACKGROUND: Atrial septal defect (ASD) is one the most prevalent forms of congenital heart disease in adults. Closure of ASDs eliminates left-to-right shunt and reduces right heart volumes, but the effects of ASD closure, on the left ventricle (LV) and mitral valve competence are somewhat inconsistent. Therefore, we designed this study to evaluate the early effect of percutaneous closure of ASD on LV function and mitral regurgitation (MR) severity. METHODS: In this prospective study, we enrolled 32 patients with ASD secundum who underwent percutaneous device closure in Tehran Heart Center. We used transthoracic and transesophageal echocardiography (TEE) before the procedure and TTE 24 hours after the procedure, then compared obtained LV parameters before and after the procedure. RESULTS: LV end-diastolic diameter (LVEDD) increased significantly from 44.8 ± 2.4 to 45.8 ± 2.8 (P < 0.001). LV end-systolic diameter (LVESD) also increased but was statistically insignificant (P = 0.063) and LV ejection fraction (LVEF) remained nearly unchanged. Highest alteration was in right ventricular systolic pressure (12.4% decrease; P < 0.001) and mitral early Doppler/tissue Doppler velocity ratio (E/E') (9.7% increase; P = 0.010). The change in MR severity was insignificant using Wilcoxon signed-rank test (P = 0.157). CONCLUSIONS: We concluded that systolic functions do not change immediately. However, LVEDD and E/E' will increase immediately, resulting from the passage of all blood from the LA into the LV in the early diastole just after closure. We also observed the positive effect of device closure on reducing right ventricular systolic pressure, and at least it does not worsen MR early after the procedure.
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Comunicação Interatrial , Insuficiência da Valva Mitral , Adulto , Comunicação Interatrial/diagnóstico por imagem , Comunicação Interatrial/cirurgia , Humanos , Irã (Geográfico) , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/cirurgia , Estudos Prospectivos , Resultado do Tratamento , Função Ventricular EsquerdaRESUMO
BACKGROUND: Endocarditis is a potentially life-threatening infectious disease associated with significant morbidity and mortality and an escalating incidence in recent decades. In this study, as a part of the global burden of disease (GBD) 2019 study, we intend to report endocarditis burden in Iran at national and provincial levels from 1990 to 2019. METHOD: This study was conducted using GBD 2019 study data on endocarditis from 1990 to 2019. We gathered incidence, prevalence, disability-adjusted life years (DALYs), and mortality rates in Iran and its 31 provinces by sex and age groups as epidemiological indices for endocarditis burden. Further decomposition analysis was also performed to delineate the endocarditis new cases trend. RESULTS: On the country scale, age-standardized incidence rate (ASIR), age-standardized prevalence rate (ASPR), age-standardized mortality rate (ASMR), and age-standardized DALYs rate were (16.5 (95% uncertainty interval 13.7 to 19.8), 3.4 (2.9 to 4.1), 0.6 (0.5 to 0.9), and 14.4 (12.0 to 21.1) in 2019, respectively. Decomposition analysis showed that only 59.2% of the overall new cases increase (114.1%) was caused by the incidence rate change. All estimated age-standardized rates were higher in men in 1990 and 2019 with a ratio of 1.1-1.5. CONCLUSION: The ASIR and ASPR of endocarditis increased, and the ASMR and age-standardized DALYs rate declined over the past 30 years in Iran, nearly all the provinces followed the same pattern with North Khorasan having the Highest ASIR, ASPR, ASMR, and DALYs rates in both years. High systolic blood pressure (SBP) had the greatest attributed burden among risk factors.
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Endocardite , Carga Global da Doença , Adulto , Endocardite/diagnóstico , Endocardite/epidemiologia , Saúde Global , Humanos , Incidência , Irã (Geográfico)/epidemiologia , Masculino , Anos de Vida Ajustados por Qualidade de Vida , Fatores de RiscoRESUMO
Spinal epidural hematoma is a rare but devastating complication of iliac vein stenting. Radicular back pain during and after procedure is an alarming sign for this complication.
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BACKGROUND: Pre-operative ejection fraction (EF) and comorbidities affect post-op outcomes. We aimed to compare the mortality and adverse events of patients with different baseline EF and also to evaluate the distribution of comorbidities in each EF group. METHODS: A total of 20,937 patients who underwent isolated coronary artery bypass graft (CABG) surgery from January 2006 to December 2016 was included. Patients were divided into three groups based on their pre-operative left ventricular EF as follows; (1) Normal: EF ≥ 50%; (2) Mild to moderately reduced: 50% < EF ≤ 35%; and (3) Severely reduced: EF < 35%. The backward elimination method was considered for multivariate Cox-regression analysis to locate predictors of mortality and non-fatal cerebro-cardiovascular events (CCVEs). The median follow-up time was 5.61 [3.12-8.0] years. RESULTS: The mean age in the total population was 60.94 ± 9.51 years and 73.6% of the total population was male. Diabetes mellitus was the common risk factor of mortality and CCVE in all EF groups. Impaired renal function (GFR < 60 ml/min) was associated with a higher risk of mortality after CABG regardless of EF level. The median 5-year mortality rate in patients with normal EF, mild-moderately reduced EF and severely reduced EF were 9.5%, 12.8%, and 22.7% respectively (P < 0.001). Although the trend of CCVEs was higher in severe left ventricle (LV) dysfunction, it was not statistically significant (p = 0.071). CONCLUSION: Patients with severely reduced EF are at higher risk of mortality after CABG compared to those with higher EF levels; however, the rate of CCVEs may not be necessarily higher after adjustment for multiple pre-operative comorbidities.
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Disfunção Ventricular Esquerda , Função Ventricular Esquerda , Idoso , Ponte de Artéria Coronária , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Volume Sistólico , Resultado do TratamentoRESUMO
BACKGROUND: Abatacept was well tolerated by patients with early diffuse cutaneous systemic sclerosis in a phase 2, double-blind randomised trial, with potential efficacy at 12 months. We report here the results of an open-label extension for 6 months. METHODS: Patients (aged ≥18 years) with diffuse cutaneous systemic sclerosis of less than 3 years' duration from their first non-Raynaud's symptom were enrolled into the ASSET trial (A Study of Subcutaneous Abatacept to Treat DiffuseCutaneous Systemic Sclerosis), which is a double-blind trial at 22 sites in Canada, the UK, and the USA. Aftercompletion of 12 months of treatment with either abatacept or placebo, patients received a further 6 months ofabatacept (125 mg subcutaneous every week) in an open-label extension. The primary endpoint of the double-blind trial was modified Rodnan Skin Score (mRSS) at 12 months, which was reassessed at 18 months in the open-label extension. The primary analysis included all participants who completed the double-blind trial and received at least one dose of open-label treatment (modified intention to treat). This trial is registered with ClinicalTrials.gov, NCT02161406. FINDINGS: Between Sept 22, 2014, and March 15, 2017, 88 participants were randomly allocated in the double-blind trial either abatacept (n=44) or placebo (44); 32 patients from each treatment group completed the 6-month open-labelextension. Among patients assigned abatacept, a mean improvement from baseline in mRSS was noted at 12 months (-6·6 [SD 6·4]), with further improvement seen during the open-label extension period (-9·8 [8·1] at month 18). Participants assigned placebo had a mean improvement from baseline in mRSS at 12 months (-3·7 [SD 7·6]), with a further improvement at month 18 (-6·3 [9·3]). Infections during the open-label extension phase occurred in nine patients in the placebo-abatacept group (12 adverse events, one serious adverse event) and in 11 patients in theabatacept-abatacept group (14 adverse events, one serious adverse event). Two deaths occurred during the 12-month double-blind period in the abatacept group, which were related to scleroderma renal crisis; no deaths were recorded during the open-label extension. INTERPRETATION: During the 6-month open-label extension, no new safety signals for abatacept were identified in the treatment of diffuse cutaneous systemic sclerosis. Clinically meaningful improvements in mRSS and other outcome measures were observed in both the abatacept and placebo groups when patients transitioned to open-label treatment. These data support further studies of abatacept in diffuse cutaneous systemic sclerosis. FUNDING: Bristol-Myers Squibb and National Institutes of Health.
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OBJECTIVE: T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: In this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets. RESULTS: Among 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively. CONCLUSION: In this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.