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Background: Systemic inflammation has a critical role in the development of symptomatic coronary artery disease (CAD). Identification of inflammatory pathways may provide a platform for novel therapeutic approaches. We sought to determine whether there are differences in circulating cytokine profiles between patients with CAD and disease-free controls as well as according to the severity of the disease. Methods: Case-control study's population consisted of 452 patients who underwent diagnostic invasive coronary angiography due to clinical indications. We measured the serum concentrations of 48 circulating cytokines. Extent of CAD was assessed using the SYNTAX Score in 116 patients. Cytokine differences between groups were tested using Mann-Whitney U test and associations with CAD were explored using a logistic regression model. Results: Overall, 310 patients had angiographically verified CAD whereas 142 had no angiographically-detected coronary atherosclerosis. In multivariable logistic regression models adjusted for age, sex, hypertension, atrial fibrillation, history of smoking and treatment for diabetes and hyperlipidemia, increased levels of interleukin 9 (OR 1.359, 95%CI 1.046-1.766, p = 0.022), IL-17 (1.491, 95%CI 1.115-1.994, p = 0.007) and tumor necrosis factor alpha (TNF-α) (OR 1.440, 95%CI 1.089-1.904, p = 0.011) were independently associated with CAD. Patients with SYNTAX Score>22 had increased levels of stromal cell-derived factor 1 alfa (SDF-1α), beta-nerve growth factor (ß-NGF), IL-3 and decreased level of IL-17 compared to those with score ≤22 when adjusted for smoking and use of beta-blockers. Conclusions: Patients with CAD have distinct circulating cytokine profiles compared to disease-free controls. Distinct cytokines may have pivotal roles at different stages of coronary atherosclerosis. ClinicalTrials.gov Identifier: NCT03444259 (https://clinicaltrials.gov/study/NCT03444259).
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Chronic inflammation plays a crucial role in coronary artery disease (CAD), but differences in specific cytokine profiles between acute coronary syndrome (ACS) and stable CAD remain unknown. We investigated cytokine differences between these two manifestations of CAD. The study included 308 patients with angiographically detected, hemodynamically significant CAD: 150 patients undergone angiography for ACS, 158 patients undergone angiography for stable CAD. To assess dynamic changes, 116 patients had index angiogram at least 3 months earlier. We measured the serum concentrations of 48 circulating cytokines. The ACS group had decreased interleukin (IL) 4 (p = 0.005), and increased IL-8 (p = 0.008), hepatocyte growth factor (HGF) (p < 0.001) and macrophage colony-stimulating factor (M-CSF) (p = 0.002) levels compared with the stable CAD group. Multivariable logistic regression revealed increased levels of HGF (OR 18.050 [95% CI 4.372-74.517], p < 0.001), M-CSF (OR 2.257 [1.375-3.705], p = 0.001) and IL-6 (OR 1.586 [1.131-2.224], p = 0.007), independently associated with ACS. In the post-angiography group, only diminished platelet-derived growth factor-BB levels in ACS-manifested patients were observed (OR 0.478, [0.279-0.818], p = 0.007). Cytokine profiles differ between ACS and stable CAD. Such differences seem to be mainly reversible within 3 months after ACS. Thus, targeting one or two cytokines only might not offer one-size fits all-therapeutic approach for CAD-associated inflammation.Trial registration: NCT03444259.
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Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Citocinas , Humanos , Masculino , Feminino , Síndrome Coronariana Aguda/sangue , Doença da Artéria Coronariana/sangue , Citocinas/sangue , Pessoa de Meia-Idade , Idoso , Angiografia Coronária , Biomarcadores/sangue , Fator de Crescimento de Hepatócito/sangueRESUMO
Cardiovascular disease plays a central role in the electrical and structural remodeling of the right atrium, predisposing to arrhythmias, heart failure, and sudden death. Here, we dissect with single-nuclei RNA sequencing (snRNA-seq) and spatial transcriptomics the gene expression changes in the human ex vivo right atrial tissue and pericardial fluid in ischemic heart disease, myocardial infarction, and ischemic and non-ischemic heart failure using asymptomatic patients with valvular disease who undergo preventive surgery as the control group. We reveal substantial differences in disease-associated gene expression in all cell types, collectively suggesting inflammatory microvascular dysfunction and changes in the right atrial tissue composition as the valvular and vascular diseases progress into heart failure. The data collectively suggest that investigation of human cardiovascular disease should expand to all functionally important parts of the heart, which may help us to identify mechanisms promoting more severe types of the disease.
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Átrios do Coração , Microvasos , Isquemia Miocárdica , Transcriptoma , Humanos , Átrios do Coração/patologia , Átrios do Coração/metabolismo , Isquemia Miocárdica/genética , Isquemia Miocárdica/patologia , Isquemia Miocárdica/metabolismo , Transcriptoma/genética , Microvasos/patologia , Inflamação/patologia , Inflamação/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Regulação da Expressão GênicaRESUMO
Biotechnology and small pharma companies must recognize the opportunity presented by FDA Breakthrough Therapy Designation (BTD) to expedite drug development for serious conditions. This paper evaluates BTD economic and developmental impacts on such companies. Analysis of 29 BTD events from 2017 to 2022 revealed immediate share price boosts and improved drug approval rates, alongside faster development times. Yet, long-term share prices underperformed relative to the broader market, underscoring the persistent risks in pharma investments. Although offering new insights, the limited sample size calls for further investigation.
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Biotecnologia , Investimentos em Saúde , Estados Unidos , Aprovação de Drogas , United States Food and Drug AdministrationRESUMO
OBJECTIVES: Cardiac surgery induces systemic inflammatory response syndrome (SIRS), leading to higher morbidity and mortality. There are no individualized predictors for worse outcomes or biomarkers for the multifactorial, excessive inflammatory response. The interest of this study was to evaluate whether a systematic use of the SIRS criteria could be used to predict postoperative outcomes beyond infection and sepsis, and if the development of an exaggerated inflammation response could be observed preoperatively. DESIGN: The study was observational, with prospectively enrolled patients. SETTING: This was a single institution study in a hospital setting combined with laboratory findings. PARTICIPANTS: The study included a cohort of 261 volunteer patients. INTERVENTIONS: Patients underwent cardiac surgery with cardiopulmonary bypass, and were followed up to 90 days. Biomarker profiling was run preoperatively. MEASUREMENTS AND MAIN RESULTS: Altogether, 17 of 261 (6.4%) patients had prolonged SIRS, defined as fulfilling at least 2 criteria on 4 consecutive postoperative days. During hospitalization, postoperative atrial fibrillation (POAF) was found in 42.2% of patients, and stroke and transient ischemic attack in 3.8% of patients. Prolonged SIRS was a significant predictor of POAF (odds ratio [OR] 4.5, 95% CI 1.2-17.3), 90-day stroke (OR 4.5, 95% CI 1.1-18.0), and mortality (OR 10.7, 95% CI 1.7-68.8). Biomarker assays showed that preoperative nerve growth factor and interleukin 5 levels were associated with prolonged SIRS (OR 5.6, 95%, CI 1.4-23.2 and OR 0.7, 95%, CI 0.4-1.0, respectively). CONCLUSIONS: Nerve growth factor and interleukin 5 can be used to predict prolonged systemic inflammatory response, which is associated with POAF, stroke, and mortality.
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Fibrilação Atrial , Procedimentos Cirúrgicos Cardíacos , Acidente Vascular Cerebral , Humanos , Interleucina-5 , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica/epidemiologia , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Biomarcadores , Fatores de Crescimento Neural , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Fatores de RiscoRESUMO
Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n = 30) and no additional safety signals in part II (n = 108). Disease control (DC) rates of 25%-40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer.
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Anticorpos Monoclonais Humanizados , Neoplasias , Humanos , Anticorpos Monoclonais Humanizados/farmacologia , Ativação de Macrófagos , Neoplasias/terapiaRESUMO
BACKGROUND: The use of glucocorticoids has given contradictory results for treating acute respiratory distress syndrome (ARDS). The use of intravenous Interferon beta (IFN ß) for the treatment of ARDS was recently tested in a phase III ARDS trial (INTEREST), in which more than half of the patients simultaneously received glucocorticoids. Trial results showed deleterious effects of glucocorticoids when administered together with IFN ß, and therefore, we aimed at finding the reason behind this. METHODS: We first sequenced the genes encoding the IFN α/ß receptor of the patients, who participated in the INTEREST study (ClinicalTrials.gov Identifier: NCT02622724 , November 24, 2015) in which the patients were randomized to receive an intravenous injection of IFN ß-1a (144 patients) or placebo (152 patients). Genetic background was analyzed against clinical outcome, concomitant medication, and pro-inflammatory cytokine levels. Thereafter, we tested the influence of the genetic background on IFN α/ß receptor expression in lung organ cultures and whether, it has any effect on transcription factors STAT1 and STAT2 involved in IFN signaling. RESULTS: We found a novel disease association of a SNP rs9984273, which is situated in the interferon α/ß receptor subunit 2 (IFNAR2) gene in an area corresponding to a binding motif of the glucocorticoid receptor (GR). The minor allele of SNP rs9984273 associates with higher IFNAR expression, more rapid decrease of IFN γ and interleukin-6 (IL-6) levels and better outcome in IFN ß treated patients with ARDS, while the major allele associates with a poor outcome especially under concomitant IFN ß and glucocorticoid treatment. Moreover, the minor allele of rs9984273 associates with a less severe form of coronavirus diseases (COVID-19) according to the COVID-19 Host Genetics Initiative database. CONCLUSIONS: The distribution of this SNP within clinical study arms may explain the contradictory results of multiple ARDS studies and outcomes in COVID-19 concerning type I IFN signaling and glucocorticoids.
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COVID-19 , Síndrome do Desconforto Respiratório , Humanos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , COVID-19/genética , Interferon beta/farmacologia , Interferon beta/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/genética , Interferon-alfaRESUMO
Many small pharmaceutical companies find that they lack the resources, knowledge and expertise of the regulatory landscape for adequate vendor management in clinical trials, making the organization vulnerable. Recent research suggests that some pharmaceutical companies have found themselves out of compliance with ICH, FDA or EMA guidelines. This paper aims to perform a comprehensive review of the regulatory landscape for vendor selection, oversight and ongoing evaluation in clinical trials. In addition, the case study performed studies the practices recently implemented at small pharmaceutical company Faron Pharmaceuticals to assess regulatory compliance and identify any potential best practices. Faron Pharmaceuticals conducted a process improvement activity at the beginning of 2022 to improve the vendor selection, oversight and evaluation of their clinical trial partners. The results of this case study indicate that Faron Pharmaceuticals' processes are regulatory compliant, suggesting that QTLs, KPIs, SOPs and communication plans are effective vendor oversight mechanisms for small pharmaceutical companies to utilize.
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Comunicação , Indústria Farmacêutica , Empresa de Pequeno Porte , Preparações FarmacêuticasRESUMO
Objective: Patients undergoing heart surgery are at high risk of postoperative fluid accumulation due to long procedures and cardiopulmonary bypass. In the present study, we sought to investigate the prevalence of postoperative fluid accumulation and its relation to adverse events in patients undergoing cardiac surgery. Methods: CAREBANK is prospective, single-center cohort study focusing on the adverse events after cardiac surgery. The study population was divided into 2 groups based on 5% postoperative weight gain. All the in-hospital adverse events are registered on the database. The end points of the present study were length of hospital stay, length of intensive care unit stay, occurrence of new-onset atrial fibrillation after hospital major bleeding episodes major cardiac events, cerebrovascular events, and death. Three-month and 1-year follow-up data also include all major adverse events. Results: Altogether 1001 adult cardiac surgery patients were enrolled. The most frequent operations were coronary artery bypass grafting (56.3%). Five hundred fifty-four out of 939 (59.0%) patients had ≥5% weight gain during index hospitalization. Patients with a weight gain ≥5% were more likely to be women, have lower body mass index, had heart failure, and more often had preoperative atrial fibrillation. In-hospital period fluid accumulation was associated with reoperation due bleeding and longer total hospital stay. At 3 months' follow-up, weight gain 5% or more was associated with increased occurrence of new-onset atrial fibrillation, this was not reflected in the occurrence of strokes, transient ischemic attacks, or myocardial infarctions. Conclusions: Postoperative fluid excess is associated with adverse outcomes in cardiac surgery. Women, low-weight patients, and patients with cardiac failure or atrial fibrillation are prone to perioperative fluid accumulation.
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OBJECTIVE: The present study evaluates the association of aortic calcification with mortality and major adverse cardiovascular and leg events (MACEs and MALEs) in patients with peripheral artery disease (PAD). The risk for mortality and MACEs and MALEs is considered in clinical decision-making. METHODS: This cohort found in 2012-2013 consists of 226 patients with symptomatic PAD referred to Turku University Hospital for invasive treatment. Follow-up data about mortality and survival without MACEs and MALEs were collected up to 5 years from the inclusion date, and aortic calcification index (ACI) was measured from patients with available imaging studies (164 of 226). ACIs' association with events and mortality was evaluated in Cox regression, Kaplan-Meier, and classification and regression tree analysis. RESULTS: All-cause mortality at 1, 3, and 5 years was 13.7% (31), 26.1% (59), and 46.9% (106), respectively. In multivariable Cox regression analysis, ACI and ACI > 43 were independent risk factors for all-cause mortality (hazard ratio [HR]: 1.13 per 10 units, 95% confidence interval [CI]: 1.00-1.22 and HR: 1.83, 95% CI: 1.01-3.32, respectively) and for MACEs (HR: 1.10 per 10 units, 95% CI: 1.00-1.22 and HR: 3.14, 95% CI: 1.67-5.91, respectively), but not for MALEs. Classification and regression tree analysis showed that ACI = 43 best divides cohort in relation to mortality. Kaplan-Meier analyses showed that ACI > 43 is associated with greater mortality and occurrence of MACEs compared with those who have ACI ≤ 43 (log-rank P value .005 and .0012, respectively). CONCLUSIONS: Risk for mortality and MACEs is associated with high ACI. ACI can expose the risk in patients with PAD for further cardiovascular events and mortality.
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Doença Arterial Periférica , Masculino , Humanos , Seguimentos , Estudos Prospectivos , Prognóstico , Fatores de Risco , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/cirurgia , Medição de RiscoRESUMO
Mortality remains high after emergency open surgery for a ruptured abdominal aortic aneurysm (RAAA). The aim of the present study was to assess, if intravenous (IV) Interferon (IFN) beta-1a improve survival after surgery by up-regulating Cluster of differentiation (CD73). This is a multi-center phase II double-blind, 2:1 randomized, parallel group comparison of the efficacy and safety of IV IFN beta-1a vs. placebo for the prevention of death after open surgery for an infra-renal RAAA. All study patients presented a confirmed infra-renal RAAA, survived the primary emergency surgery and were treated with IFN beta-1a (10 µg) or matching placebo for 6 days after surgery. Major exclusion criteria included fatal hemorrhagic shock, chronic renal replacement therapy, diagnosed liver cirrhosis, severe congestive heart failure, advanced malignant disease, primary attempt of endovascular aortic repair (EVAR), and per-operative suprarenal clamping over 30 min. Main outcome measure was all-cause mortality at day 30 (D30) from initial emergency aortic reconstruction. The study was pre-maturely stopped due to a reported drug-drug interaction and was left under-powered. Out of 40 randomized patients 38 were included in the outcome analyses (27 IFN beta-1a and 11 placebo). There was no statistically significant difference between treatment groups at baseline except more open-abdomen and intestinal ischemia was present in the IFN beta-1a arm. D30 all-cause mortality was 22.2% (6/27) in the IFN beta-1a arm and 18.2% (2/11) in the placebo arm (OR 1.30; 95% CI 0.21-8.19). The most common adverse event relating to the IFN beta-1a was pyrexia (20.7% in the IFN beta-1a arm vs. 9.1% in the placebo arm). Patients with high level of serum CD73 associated with survival (P = 0.001) whereas the use of glucocorticoids and the presence of IFN beta-1a neutralizing antibodies associated with a poor CD73 response and survival. The initial aim of the trial, if postoperative INF beta-1a treatment results on better RAAA survival, could not be demonstrated. Nonetheless the anticipated target mechanism up-regulation of CD73 was associated with 100% survival. According to present results the INF beta-1a induced up-regulation of serum CD73 was blocked with both use of glucocorticoids and serum IFN beta-1a neutralizing antibodies. The study was pre-maturely stopped due to interim analysis after a study concerning the use if IV IFN beta-1a in ARDS suggested that the concomitant use of glucocorticoids and IFN beta-1a block the CD73 induction. Trial registration: ClinicalTrials.gov NCT03119701. Registered 19/04/2017 (retrospectively registered).
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5'-Nucleotidase/metabolismo , Adjuvantes Imunológicos/uso terapêutico , Aneurisma da Aorta Abdominal/terapia , Ruptura Aórtica/terapia , Interferon beta-1a/uso terapêutico , Procedimentos Cirúrgicos Vasculares , Adjuvantes Imunológicos/efeitos adversos , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/mortalidade , Ruptura Aórtica/diagnóstico , Ruptura Aórtica/imunologia , Ruptura Aórtica/mortalidade , Método Duplo-Cego , Interações Medicamentosas , Término Precoce de Ensaios Clínicos , Emergências , Feminino , Finlândia , Proteínas Ligadas por GPI/metabolismo , Glucocorticoides/efeitos adversos , Humanos , Interferon beta-1a/efeitos adversos , Interferon beta-1a/imunologia , Masculino , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Procedimentos Cirúrgicos Vasculares/mortalidadeRESUMO
Patients undergoing cardiac surgery develop a marked postoperative systemic inflammatory response. Blood transfusion may contribute to disruption of homeostasis in these patients. We sought to evaluate the impact of blood transfusion on serum interleukin-6 (IL-6), hypoxia induced factor-1 alpha (HIF-1α) levels as well as adverse outcomes in patients undergoing adult cardiac surgery. We prospectively enrolled 282 patients undergoing adult cardiac surgery. Serum IL-6 and HIF-1α levels were measured preoperatively and on the first postoperative day. Packed red blood cells were transfused in 26.3% of patients (mean 2.93 ± 3.05 units) by the time of postoperative sampling. Postoperative IL-6 levels increased over 30-fold and were similar in both groups (p = 0.115), whilst HIF-1α levels (0.377 pg/mL vs. 0.784 pg/mL, p = 0.002) decreased significantly in patients who received red blood cell transfusion. Moreover, greater decrease in HIF-1α levels predicted worse in-hospital and 3mo adverse outcome. Red blood cell transfusion was associated with higher risk of major adverse outcomes (stroke, pneumonia, all-cause mortality) during the index hospitalization. Red blood cell transfusion induces blunting of postoperative HIF-1 α response and is associated with higher risk of adverse thrombotic and pulmonary adverse events after cardiac surgery. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT03444259.
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Procedimentos Cirúrgicos Cardíacos , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/metabolismo , Transfusão de Eritrócitos/efeitos adversos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Complicações Pós-Operatórias , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cuidados Críticos , Síndrome da Liberação de Citocina/diagnóstico , Citocinas/sangue , Citocinas/metabolismo , Suscetibilidade a Doenças , Feminino , Hospitalização , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Masculino , Avaliação de Resultados da Assistência ao PacienteRESUMO
BACKGROUND: To investigate the potential of intravenously administered porcine recombinant interferon-ß1a (IFN-ß1a) for myocardial protection during acute ischemia-reperfusion (IR) injury in an experimental animal model. METHODS: Twenty-two piglets (mean ± standard deviation, 26.7 ± 1.65 kg) were assigned to either the IFN group (n = 12) or the control group (n = 10). IR injury was induced by occluding the distal left descending coronary artery for 30 minutes, with a reperfusion period of 6 h. In the IFN group, the animals received 12.5 µg IFN-ß1a intravenously repeatedly; the control group received saline solution. The levels of interleukin-6 (IL-6) and cardiac troponin I (TnI) were measured, and the amount of myocardial damage was quantified by analyzing myocardial apoptosis and the mean fluorescence intensity (MFI) of methylene blue-stained cardiac tissue. RESULTS: In the IFN group, significantly more premature deaths occurred compared with the control group (25% versus 17%, P = .013). Between the groups, the mean heart rate was higher in the IFN group (102 ± 22 versus 80 ± 20 beats per minute, P = .02). IL-6 and TnI levels were comparable between the groups, with no significant difference, and there was no difference between the study groups in myocardial apoptosis in the infarcted myocardium. The percentage of MFI differed significantly between the IFN and control groups (90.75% ± 4.90% versus 96.02% ± 2.73%, P = .01). CONCLUSION: In this acute IR injury animal model, IFN-ß1a did not protect the myocardium from IR injury, but rather increased some of the unfavorable outcomes studied.
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Interferon beta-1a/administração & dosagem , Infarto do Miocárdio/complicações , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miocárdio/patologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Apoptose , Modelos Animais de Doenças , Injeções Intravenosas , Infarto do Miocárdio/diagnóstico , Traumatismo por Reperfusão Miocárdica/diagnóstico , Traumatismo por Reperfusão Miocárdica/etiologia , SuínosAssuntos
Antivirais/administração & dosagem , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Interferon beta-1a/administração & dosagem , Pneumonia Viral/tratamento farmacológico , COVID-19 , Relação Dose-Resposta a Droga , Humanos , Injeções Intramusculares , Injeções Intravenosas , Pandemias , SARS-CoV-2RESUMO
Importance: Acute respiratory distress syndrome (ARDS) is associated with high mortality. Interferon (IFN) ß-1a may prevent the underlying event of vascular leakage. Objective: To determine the efficacy and adverse events of IFN-ß-1a in patients with moderate to severe ARDS. Design, Setting, and Participants: Multicenter, randomized, double-blind, parallel-group trial conducted at 74 intensive care units in 8 European countries (December 2015-December 2017) that included 301 adults with moderate to severe ARDS according to the Berlin definition. The radiological and partial pressure of oxygen, arterial (Pao2)/fraction of inspired oxygen (Fio2) criteria for ARDS had to be met within a 24-hour period, and the administration of the first dose of the study drug had to occur within 48 hours of the diagnosis of ARDS. The last patient visit was on March 6, 2018. Interventions: Patients were randomized to receive an intravenous injection of 10 µg of IFN-ß-1a (144 patients) or placebo (152 patients) once daily for 6 days. Main Outcomes and Measures: The primary outcome was a score combining death and number of ventilator-free days at day 28 (score ranged from -1 for death to 27 if the patient was off ventilator on the first day). There were 16 secondary outcomes, including 28-day mortality, which were tested hierarchically to control type I error. Results: Among 301 patients who were randomized (mean age, 58 years; 103 women [34.2%]), 296 (98.3%) completed the trial and were included in the primary analysis. At 28 days, the median composite score of death and number of ventilator-free days at day 28 was 10 days (interquartile range, -1 to 20) in the IFN-ß-1a group and 8.5 days (interquartile range, 0 to 20) in the placebo group (P = .82). There was no significant difference in 28-day mortality between the IFN-ß-1a vs placebo groups (26.4% vs 23.0%; difference, 3.4% [95% CI, -8.1% to 14.8%]; P = .53). Seventy-four patients (25.0%) experienced adverse events considered to be related to treatment during the study (41 patients [28.5%] in the IFN-ß-1a group and 33 [21.7%] in the placebo group). Conclusions and Relevance: Among adults with moderate or severe ARDS, intravenous IFN-ß-1a administered for 6 days, compared with placebo, resulted in no significant difference in a composite score that included death and number of ventilator-free days over 28 days. These results do not support the use of IFN-ß-1a in the management of ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02622724.
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Adjuvantes Imunológicos/administração & dosagem , Interferon beta-1a/administração & dosagem , Síndrome do Desconforto Respiratório/tratamento farmacológico , Adjuvantes Imunológicos/efeitos adversos , Corticosteroides/uso terapêutico , Adulto , Método Duplo-Cego , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Injeções Intravenosas , Interferon beta-1a/efeitos adversos , Masculino , Pessoa de Meia-Idade , Respiração Artificial , Síndrome do Desconforto Respiratório/mortalidade , Síndrome do Desconforto Respiratório/terapia , Tamanho da Amostra , Falha de Tratamento , Desmame do RespiradorRESUMO
AIM: Peripheral arterial disease is frequently associated with significant atherosclerosis of other vascular beds. The aim of the present study was to investigate a possible association between peripheral arterial disease segment-specific disease burden and cerebrovascular disease. METHODS: Two-hundred and twenty-six patients with clinically symptomatic peripheral arterial disease from the prospective PureASO registry were followed up after revascularization. The breadth of peripheral arterial disease was quantified at the time patients entered the study. The segment-specific peripheral arterial disease burden was correlated to cerebrovascular disease and imaging findings during a five-year follow-up. RESULTS: At five years, cerebrovascular disease-free survival after lower limb revascularization was 31%. Patients with peripheral arterial disease involving the crural arteries had significantly more ischemic degenerative changes at brain imaging (p = 0.031), whereas patients with aorto-iliac and femoropopliteal segment peripheral arterial disease had more significant (>50% uni- or bilaterally) internal carotid artery stenosis compared to patients with crural peripheral arterial disease (p = 0.006). According to Cox regression analyses, crural arteries burden was associated with a significantly increased risk of mortality (adjusted HR 2.07, CI 95% 1.12-3.28, p = 0.021) and cerebrovascular events (adjusted HR 1.97, CI 95% 1.19-3.26, p = 0.008). CONCLUSIONS: Present results suggest that atherosclerosis burden at different lower limb artery segments is associated with defined cerebrovascular disease. This further suggests that risk factors and pathophysiological mechanisms are congruent across particular vascular beds.
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Transtornos Cerebrovasculares/epidemiologia , Doença Arterial Periférica/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Angiografia Digital , Angiografia Cerebral , Transtornos Cerebrovasculares/diagnóstico por imagem , Transtornos Cerebrovasculares/mortalidade , Procedimentos Endovasculares , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/mortalidade , Doença Arterial Periférica/terapia , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Sistema de Registros , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with heart failure, stroke, and increased mortality. The myocardial substrate for AF is poorly understood because of limited access to primary human tissue and mechanistic questions around existing in vitro or in vivo models. METHODS: Using an MYH6:mCherry knock-in reporter line, we developed a protocol to generate and highly purify human pluripotent stem cell-derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells. We modeled human MYL4 mutants, one of the few definitive genetic causes of AF. To explore non-cell-autonomous components of AF substrate, we also created a zebrafish Myl4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations. RESULTS: There was evidence of increased retinoic acid signaling in both human embryonic stem cells and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins, and loss of intracellular nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide + hydrogen. To identify potentially druggable proximate mechanisms, we performed a chemical suppressor screen integrating multiple human cellular and zebrafish in vivo endpoints. This screen identified Cx43 (connexin 43) hemichannel blockade as a robust suppressor of the abnormal phenotypes in both models of MYL4 (myosin light chain 4)-related atrial cardiomyopathy. Immunofluorescence and coimmunoprecipitation studies revealed an interaction between MYL4 and Cx43 with altered localization of Cx43 hemichannels to the lateral membrane in MYL4 mutants, as well as in atrial biopsies from unselected forms of human AF. The membrane fraction from MYL4-/- human embryonic stem cell derived atrial cells demonstrated increased phospho-Cx43, which was further accentuated by retinoic acid treatment and by the presence of risk alleles at the Pitx2 locus. PKC (protein kinase C) was induced by retinoic acid, and PKC inhibition also rescued the abnormal phenotypes in the atrial cardiomyopathy models. CONCLUSIONS: These data establish a mechanistic link between the transcriptional, metabolic and electrical pathways previously implicated in AF substrate and suggest novel avenues for the prevention or therapy of this common arrhythmia.