DElaying Disease Progression In COPD with Early Initiation of Dual Bronchodilator or Triple Inhaled PharmacoTherapy (DEPICT): A Predictive Modelling Approach.

INTRODUCTION: Clinical studies demonstrate an accelerated decline in lung function in patients with moderate chronic obstructive pulmonary disease (COPD) (Global Initiative for Chronic Obstructive Lung Disease [GOLD] grade 2) versus severe and very severe COPD (GOLD grades 3 and 4). This predictive modelling study assessed the impact of initiating pharmacotherapy earlier versus later on long-term disease progression in COPD. METHODS: The modelling approach used data on decline in forced expiratory volume in 1 s (FEV1) extracted from published studies to develop a longitudinal non-parametric superposition model of lung function decline with progressive impact of exacerbations from 0 per year to 3 per year and no ongoing pharmacotherapy. The model simulated decline in FEV1 and annual exacerbation rates from age 40 to 75 years in COPD with initiation of long-acting anti-muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA) (umeclidinium (UMEC)/vilanterol (VI)) or triple (inhaled corticosteroid (ICS)/LAMA/LABA; fluticasone furoate (FF)/UMEC/VI) therapy at 40, 55 or 65 years of age. RESULTS: Model-predicted decline in FEV1 showed that, compared with 'no ongoing' therapy, initiation of triple or LAMA/LABA therapy at age 40, 55 or 65 years preserved an additional 469.7 mL or 236.0 mL, 327.5 mL or 203.3 mL, or 213.5 mL or 137.5 mL of lung function, respectively, by the age of 75. The corresponding average annual exacerbation rates were reduced from 1.57 to 0.91, 1.06 or 1.23 with triple therapy or to 1.2, 1.26 and 1.4 with LAMA/LABA therapy when initiated at 40, 55 or 65 years of age, respectively. CONCLUSIONS: This modelling study suggests that earlier initiation of LAMA/LABA or triple therapy may have positive benefits in slowing disease progression in patients with COPD. Greater benefits were demonstrated with early initiation therapy with triple versus LAMA/LABA.

Exercise intolerance in post-coronavirus disease 2019 survivors after hospitalisation.

Rationale: Post-coronavirus disease 2019 (COVID-19) survivors frequently have dyspnoea that can lead to exercise intolerance and lower quality of life. Despite recent advances, the pathophysiological mechanisms of exercise intolerance in the post-COVID-19 patients remain incompletely characterised. The objectives of the present study were to clarify the mechanisms of exercise intolerance in post-COVID-19 survivors after hospitalisation. Methods: This prospective study evaluated consecutive patients previously hospitalised due to moderate-to-severe/critical COVID-19. Within mean±sd 90±10 days of onset of acute COVID-19 symptoms, patients underwent a comprehensive cardiopulmonary assessment, including cardiopulmonary exercise testing with earlobe arterialised capillary blood gas analysis. Measurements and main results: 87 patients were evaluated; mean±sd peak oxygen consumption was 19.5±5.0 mL·kg-1·min-1, and the tertiles were ≤17.0, 17.1-22.2 and ≥22.3 mL·kg-1·min-1. Hospitalisation severity was similar among the three groups; however, at the follow-up visit, patients with peak oxygen consumption ≤17.0 mL·kg-1·min-1 reported a greater sensation of dyspnoea, along with indices of impaired pulmonary function, and abnormal ventilatory, gas-exchange and metabolic responses during exercise compared to patients with peak oxygen consumption >17 mL·kg-1·min-1. By multivariate logistic regression analysis (receiver operating characteristic curve analysis) adjusted for age, sex and prior pulmonary embolism, a peak dead space fraction of tidal volume ≥29 and a resting forced vital capacity ≤80% predicted were independent predictors of reduced peak oxygen consumption. Conclusions: Exercise intolerance in the post-COVID-19 survivors was related to a high dead space fraction of tidal volume at peak exercise and a decreased resting forced vital capacity, suggesting that both pulmonary microcirculation injury and ventilatory impairment could influence aerobic capacity in this patient population.

Influence of CReatine supplementation on mUScle mass and strength after stroke (ICaRUS Stroke Trial): study protocol for a randomized controlled trial.

BACKGROUND: Stroke is a leading cause of mortality and disability, and its sequelae are associated with inadequate food intake which can lead to sarcopenia. The aim of this study is to verify the effectiveness of creatine supplementation on functional capacity, strength, and changes in muscle mass during hospitalization for stroke compared to usual care. An exploratory subanalysis will be performed to assess the inflammatory profiles of all participants, in addition to a follow-up 90 days after stroke, to verify functional capacity, muscle strength, mortality, and quality of life. METHODS: Randomized, double-blind, unicenter, parallel-group trial including individuals with ischemic stroke in the acute phase. The duration of the trial for the individual subject will be approximately 90 days, and each subject will attend a maximum of three visits. Clinical, biochemical, anthropometric, body composition, muscle strength, functional capacity, degree of dependence, and quality of life assessments will be performed. Thirty participants will be divided into two groups: intervention (patients will intake one sachet containing 10g of creatine twice a day) and control (patients will intake one sachet containing 10g of placebo [maltodextrin] twice a day). Both groups will receive supplementation with powdered milk protein serum isolate to achieve the goal of 1.5g of protein/kg of body weight/day and daily physiotherapy according to the current rehabilitation guidelines for patients with stroke. Supplementation will be offered during the 7-day hospitalization. The primary outcomes will be functional capacity, strength, and changes in muscle mass after the intervention as assessed by the Modified Rankin Scale, Timed Up and Go test, handgrip strength, 30-s chair stand test, muscle ultrasonography, electrical bioimpedance, and identification of muscle degradation markers by D3-methylhistidine. Follow-up will be performed 90 days after stroke to verify functional capacity, muscle strength, mortality, and quality of life. DISCUSSION: The older population has specific nutrient needs, especially for muscle mass and function maintenance. Considering that stroke is a potentially disabling event that can lead the affected individual to present with numerous sequelae, it is crucial to study the mechanisms of muscle mass loss and understand how adequate supplementation can help these patients to better recover. TRIAL REGISTRATION: The Brazilian Clinical Trials Registry (ReBEC) RBR-9q7gg4 . Registered on 21 January 2019.

Serum Vitamin D Levels, Disease Activity Score-28 for Rheumatoid Arthritis with C-Reactive Protein (DAS28-CRP), and Cardiac Remodeling Determined by Ventricular Dimensions and Left Atrium Diameter in Patients with Rheumatoid Arthritis: A Prospective Observational Study.

BACKGROUND Rheumatoid arthritis (RA) can cause extra-articular manifestations, and the myocardium can be a target. This study aimed to describe structural and functional cardiac echocardiographic variables in RA patients and to evaluate whether vitamin D (VD) levels and inflammation markers, evaluated by Disease Activity Score-28 for Rheumatoid Arthritis with C-reactive protein (DAS28-CRP), are associated with cardiac remodeling (CR) in this population. MATERIAL AND METHODS This prospective observational study evaluated 90 patients with RA in Botucatu University Hospital wards from 2014 to 2017. Clinical data were recorded, including demographic information, comorbidities, length of disease, and treatment type. Serum VD and C-reactive protein levels were measured, and the DAS28-CRP was calculated. A transthoracic echocardiography study was performed. The outcome evaluated was CR. This parameter was assessed by left ventricular geometric patterns and left atrium diameter. RESULTS We evaluated 90 RA patients. The mean age was 52.9±10.8 years, and 17.8% were male. The length of the disease was 96 (60-180) months. Serum VD levels were 30.7±10.4 ng/mL and the DAS28 was 2.7±0.9. Regarding the CR parameters, 56.7% had altered left ventricular geometric patterns and 25.8% had enlargement of left atrium diameter. Even in multivariate analysis, the left ventricular geometric patterns were not associated with the VD levels and the inflammation marker used. However, sufficient VD levels protect from left atrium enlargement (OR: 0.905; IC 95%: 0.843-0.973; P=0.007). CONCLUSIONS Low serum vitamin D values, but not inflammation, are associated with CR in patients with RA.

Use of anticoagulants in patients with COVID-19: a living systematic review and meta-analysis.

OBJECTIVE: To answer questions related to the use of anticoagulants in the treatment of COVID-19 patients. METHODS: This was a systematic review and meta-analysis of phase 3 randomized controlled trials comparing the use of anticoagulants in non-hospitalized and hospitalized COVID-19 patients. We searched the following databases: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to January 22, 2022. The risk of bias was assessed by the Cochrane risk-of-bias tool, and the quality of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: A total of 401 studies were initially selected. Of those, 9 met the inclusion criteria and were therefore analyzed (a total of 6,004 patients being analyzed). In non-hospitalized COVID-19 patients, no significant difference was found between post-discharge prophylactic anticoagulation and no intervention regarding venous thromboembolism or bleeding at 30 days. In hospitalized COVID-19 patients, full anticoagulation resulted in a slight reduction in thrombotic events at 30 days (risk difference, -0.03; 95% CI, -0.06 to -0.00; p = 0.04; I2 = 78%), the quality of evidence being moderate. However, no significant difference was found between full anticoagulation and no intervention regarding the risk of major bleeding, the quality of evidence being very low. No significant difference was found between intermediate- and standard-dose prophylactic anticoagulation (risk difference, -0.01; 95% CI, -0.07 to 0.06; p = 0.81; I2 = 0%), the quality of evidence being very low. CONCLUSIONS: Therapeutic anticoagulation appears to have no effect on mortality in COVID-19 patients, resulting in a slight reduction in venous thromboembolism in hospitalized patients.

Use of remdesivir in patients with COVID-19: a systematic review and meta-analysis.

OBJECTIVE: Studies in the literature regarding the use of remdesivir to treat COVID-19 patients have shown conflicting results. This study sought to answer questions related to the use of remdesivir for the treatment of patients hospitalized with moderate to severe COVID-19. METHODS: This was a systematic review and meta-analysis including phase 3 randomized clinical trials (RCTs) and observational cohort studies selected from various databases, comparing patients hospitalized with moderate to severe COVID-19 receiving remdesivir and controls. RESULTS: A total of 207 studies were retrieved, 9 of which met the eligibility criteria and were included in the study. The meta-analysis using RCTs alone showed no statistically significant differences regarding mortality or use of mechanical ventilation/extracorporeal membrane oxygenation between remdesivir and control groups, and the quality of evidence was moderate and low, respectively. The use of remdesivir increased the recovery rate by 6% (95% CI, 3-9); p = 0.004) and the clinical improvement rate by 7% (95% CI, 1-14); p = 0.02). Additionally, no significant differences in mortality were found between remdesivir and control groups when the meta-analysis used observational cohort studies alone (risk difference = -0.01 (95% CI, -0.02 to 0.01; p = 0.32), the quality of evidence being moderate, and the risk of adverse events was 4% ([95% CI, -0.08 to 0.01]; p = 0.09). CONCLUSIONS: The use of remdesivir for the treatment of patients with moderate to severe COVID-19 had no significant impact on clinically important outcomes.

Use of remdesivir in patients with COVID-19: a systematic review and meta-analysis / Uso de remdesivir em pacientes com COVID-19: revisão sistemática e meta-análise

ABSTRACT Objective: Studies in the literature regarding the use of remdesivir to treat COVID-19 patients have shown conflicting results. This study sought to answer questions related to the use of remdesivir for the treatment of patients hospitalized with moderate to severe COVID-19. Methods: This was a systematic review and meta-analysis including phase 3 randomized clinical trials (RCTs) and observational cohort studies selected from various databases, comparing patients hospitalized with moderate to severe COVID-19 receiving remdesivir and controls. Results: A total of 207 studies were retrieved, 9 of which met the eligibility criteria and were included in the study. The meta-analysis using RCTs alone showed no statistically significant differences regarding mortality or use of mechanical ventilation/extracorporeal membrane oxygenation between remdesivir and control groups, and the quality of evidence was moderate and low, respectively. The use of remdesivir increased the recovery rate by 6% (95% CI, 3-9); p = 0.004) and the clinical improvement rate by 7% (95% CI, 1-14); p = 0.02). Additionally, no significant differences in mortality were found between remdesivir and control groups when the meta-analysis used observational cohort studies alone (risk difference = −0.01 (95% CI, −0.02 to 0.01; p = 0.32), the quality of evidence being moderate, and the risk of adverse events was 4% ([95% CI, −0.08 to 0.01]; p = 0.09). Conclusions: The use of remdesivir for the treatment of patients with moderate to severe COVID-19 had no significant impact on clinically important outcomes.

RESUMO Objetivo: Estudos na literatura sobre o uso de remdesivir no tratamento de pacientes com COVID-19 têm apresentado resultados divergentes. O objetivo deste estudo foi responder a perguntas a respeito do uso de remdesivir no tratamento de pacientes hospitalizados com COVID-19 moderada a grave. Métodos: Trata-se de uma revisão sistemática e meta-análise de ensaios clínicos controlados randomizados (ECR) de fase 3 e estudos observacionais de coorte recuperados de diversos bancos de dados, comparando pacientes hospitalizados com COVID-19 moderada a grave recebendo remdesivir a controles. Resultados: Foram recuperados 207 estudos, dos quais 9 preencheram os critérios de elegibilidade e foram incluídos no estudo. A meta-análise somente dos ECR não mostrou diferenças estatisticamente significativas entre os grupos remdesivir e controle quanto à mortalidade ou ao uso de ventilação mecânica/oxigenação por membrana extracorpórea, e a qualidade das evidências foi moderada e baixa, respectivamente. O uso de remdesivir aumentou a taxa de recuperação em 6% (IC95%: 3-9; p = 0,004) e a taxa de melhora clínica em 7% (IC95%: 1-14; p = 0,02). Além disso, não foram observadas diferenças significativas entre os grupos remdesivir e controle quanto à mortalidade quando a meta-análise concentrou-se apenas nos estudos observacionais de coorte [diferença de risco = −0,01 (IC95%: −0,02 a 0,01); p = 0,32; qualidade das evidências: moderada], e o risco de eventos adversos foi de 4% (IC95%: −0,08 a 0,01; p = 0,09). Conclusões: O uso de remdesivir no tratamento de pacientes com COVID-19 moderada a grave não teve impacto significativo em desfechos clinicamente importantes.

Use of anticoagulants in patients with COVID-19: a living systematic review and meta-analysis / Uso de anticoagulantes em pacientes com COVID-19: revisão sistemática "viva" e meta-análise

ABSTRACT Objective: To answer questions related to the use of anticoagulants in the treatment of COVID-19 patients. Methods: This was a systematic review and meta-analysis of phase 3 randomized controlled trials comparing the use of anticoagulants in non-hospitalized and hospitalized COVID-19 patients. We searched the following databases: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to January 22, 2022. The risk of bias was assessed by the Cochrane risk-of-bias tool, and the quality of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation system. Results: A total of 401 studies were initially selected. Of those, 9 met the inclusion criteria and were therefore analyzed (a total of 6,004 patients being analyzed). In non-hospitalized COVID-19 patients, no significant difference was found between post-discharge prophylactic anticoagulation and no intervention regarding venous thromboembolism or bleeding at 30 days. In hospitalized COVID-19 patients, full anticoagulation resulted in a slight reduction in thrombotic events at 30 days (risk difference, −0.03; 95% CI, −0.06 to −0.00; p = 0.04; I2 = 78%), the quality of evidence being moderate. However, no significant difference was found between full anticoagulation and no intervention regarding the risk of major bleeding, the quality of evidence being very low. No significant difference was found between intermediate- and standard-dose prophylactic anticoagulation (risk difference, −0.01; 95% CI, −0.07 to 0.06; p = 0.81; I2 = 0%), the quality of evidence being very low. Conclusions: Therapeutic anticoagulation appears to have no effect on mortality in COVID-19 patients, resulting in a slight reduction in venous thromboembolism in hospitalized patients.

RESUMO Objetivo: Responder a perguntas relacionadas ao uso de anticoagulantes no tratamento de pacientes com COVID-19. Métodos: Revisão sistemática e meta-análise de ensaios clínicos controlados randomizados de fase 3 comparando o uso de anticoagulantes em pacientes com COVID-19 não hospitalizados e hospitalizados. Os bancos de dados MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials e ClinicalTrials.gov foram investigados desde sua criação até 22 de janeiro de 2022. O risco de viés foi avaliado pela ferramenta de risco de viés da Cochrane, e a qualidade das evidências foi avaliada pelo sistema Grading of Recommendations Assessment, Development and Evaluation. Resultados: Inicialmente foram selecionados 401 estudos. Destes, 9 preencheram os critérios de inclusão e, portanto, foram analisados (num total de 6.004 pacientes analisados). Em pacientes com COVID-19 não hospitalizados, não se observou diferença significativa entre anticoagulação profilática pós-alta e nenhuma intervenção no que tange a tromboembolismo venoso ou sangramento em 30 dias. Em pacientes com COVID-19 hospitalizados, a anticoagulação plena resultou em ligeira redução de eventos trombóticos em 30 dias (diferença de risco: −0,03; IC95%: −0,06 a −0,00; p = 0,04; I2 = 78%); a qualidade das evidências foi moderada. No entanto, não se observou diferença significativa entre anticoagulação plena e nenhuma intervenção quanto ao risco de sangramento maior; a qualidade das evidências foi muito baixa. Não se observou diferença significativa entre anticoagulação profilática com dose intermediária e dose-padrão (diferença de risco: −0,01; IC95%: −0,07 a 0,06; p = 0,81; I2 = 0%); a qualidade das evidências foi muito baixa. Conclusões: A anticoagulação terapêutica parece não ter efeito na mortalidade em pacientes com COVID-19, resultando em ligeira redução do tromboembolismo venoso em pacientes hospitalizados.

Suplementação de Vitamina D Induz Remodelação Cardíaca em Ratos: Associação com a Proteína de Interação com a Tiorredoxina e a Tiorredoxina / Vitamin D Supplementation Induces Cardiac Remodeling in Rats: Association with Thioredoxin-Interacting Protein and Thioredoxin

Resumo Fundamento: A vitamina D (VD) tem um importante papel na função cardíaca. No entanto, a vitamina exerce uma curva "dose-resposta" bifásica na fisiopatologia cardiovascular e pode causar efeitos deletérios, mesmo em doses não tóxicas. A VD exerce suas funções celulares ligando-se ao seu receptor. Ainda, a expressão da proteína de interação com a tiorredoxina (TXNIP) é positivamente regulada pela VD. A TXNIP modula diferentes visa de sinalização celular que podem ser importantes para a remodelação cardíaca. Objetivos: Avaliar se a suplementação com VD leva à remodelação cardíaca, e se a TXNIP e a tiorredoxina (Trx) estão associadas com esse processo. Métodos: Duzentos e cinquenta ratos Wistar machos foram alocados em três grupos: controle (C, n=21), sem suplementação com VD; VD3 (n = 22) e VD10 (n=21), suplementados com 3,000 e 10,000 UI de VD/ kg de ração, respectivamente, por dois meses. Os grupos foram comparados por análise de variância (ANOVA) com um fator e teste post hoc de Holm-Sidak (variáveis com distribuição normal), ou pelo teste de Kruskal-Wallis e análise post-hoc de Dunn. O nível de significância para todos os testes foi de 5%. Resultados: A expressão de TXNIP foi mais alta e a atividade do Trx foi mais baixa no grupo VD10. Os animais que receberam suplementação com VD apresentaram aumento de hidroperóxido lipídico e diminuição de superóxido dismutase e glutationa peroxidase. A proteína Bcl-2 foi mais baixa no grupo VD10. Observou-se uma diminuição na β-oxidação de ácidos graxos, no ciclo do ácido tricarboxílico, na cadeia transportadora de elétrons, e um aumento na via glicolítica. Conclusão: A suplementação com VD levou à remodelação cardíaca e esse processo pode ser modulado por TXNIP e Trx, e consequentemente por estresse oxidativo.

Abstract Background: Vitamin D (VD) has been shown to play an important role in cardiac function. However, this vitamin exerts a biphasic "dose response" curve in cardiovascular pathophysiology and may cause deleterious effects, even in non-toxic doses. VD exerts its cellular functions by binding to VD receptor. Additionally, it was identified that the thioredoxin-interacting protein (TXNIP) expression is positively regulated by VD. TXNIP modulate different cell signaling pathways that may be important for cardiac remodeling. Objective: To evaluate whether VD supplementation lead to cardiac remodeling and if TXNIP and thioredoxin (Trx) proteins are associated with the process. Methods: A total of 250 Male Wistar rats were allocated into three groups: control (C, n=21), with no VD supplementation; VD3 (n = 22) and VD10 (n=21), supplemented with 3,000 and 10,000 IU of VD/ kg of chow respectively, for two months. The groups were compared by one-way analysis of variance (ANOVA) and Holm-Sidak post hoc analysis, (variables with normal distribution), or by Kruskal-Wallis test and Dunn's test post hoc analysis. The significance level for all tests was 5%. Results: TXNIP protein expression was higher and Trx activity was lower in VD10. The animals supplemented with VD showed increased lipid hydroperoxide and decreased superoxide dismutase and glutathione peroxidase. The protein Bcl-2 was lower in VD10. There was a decrease in fatty acid β-oxidation, tricarboxylic acid cycle and electron transport chain with shift to increase in glycolytic pathway. Conclusion: VD supplementation led to cardiac remodeling and this process may be modulated by TXNIP and Trx proteins and consequently oxidative stress.

Use of hydroxychloroquine to prevent SARS-CoV-2 infection and treat mild COVID-19: a systematic review and meta-analysis.

OBJECTIVE: Chloroquine or hydroxychloroquine has demonstrated no effect on the treatment of hospitalized COVID-19 patients. This study aimed to answer questions related to the use of hydroxychloroquine for pre-exposure or post-exposure prophylaxis of SARS-CoV-2 infection and in the treatment of patients with mild COVID-19 in terms of hospitalization, adverse events, and mortality. METHODS: This was a systematic review and meta-analysis of phase 3 randomized clinical trials, selected from various databases, which compared patients who received hydroxychloroquine for SARS-CoV-2 prophylaxis or treatment of mild COVID-19 cases with controls. RESULTS: A total number of 1,376 studies were retrieved. Of those, 9 met the eligibility criteria and were included in the study. No statistically significant differences were found between the hydroxychloroquine and control groups in terms of pre- or post-exposure prophylaxis of SARS-CoV-2 infection. The use of hydroxychloroquine increased the risk of adverse events by 12% (95% CI, 6-18%; p < 0.001), and the number needed to harm was 9. In addition, no significant differences were found between the hydroxychloroquine and control groups regarding hospitalization (risk difference [RD] = -0.02; 95% CI, -0.04 to 0.00; p = 0.14) or mortality (RD = 0.00; 95% CI, -0.01 to 0.02; p = 0.98) in the treatment of mild COVID-19. CONCLUSIONS: The use of hydroxychloroquine for prophylaxis of SARS-CoV-2 infection or treatment of patients with mild COVID-19 is not recommended.

Vitamin D Supplementation Induces Cardiac Remodeling in Rats: Association with Thioredoxin-Interacting Protein and Thioredoxin. / Suplementação de Vitamina D Induz Remodelação Cardíaca em Ratos: Associação com a Proteína de Interação com a Tiorredoxina e a Tiorredoxina.

BACKGROUND: Vitamin D (VD) has been shown to play an important role in cardiac function. However, this vitamin exerts a biphasic "dose response" curve in cardiovascular pathophysiology and may cause deleterious effects, even in non-toxic doses. VD exerts its cellular functions by binding to VD receptor. Additionally, it was identified that the thioredoxin-interacting protein (TXNIP) expression is positively regulated by VD. TXNIP modulate different cell signaling pathways that may be important for cardiac remodeling. OBJECTIVE: To evaluate whether VD supplementation lead to cardiac remodeling and if TXNIP and thioredoxin (Trx) proteins are associated with the process. METHODS: A total of 250 Male Wistar rats were allocated into three groups: control (C, n=21), with no VD supplementation; VD3 (n = 22) and VD10 (n=21), supplemented with 3,000 and 10,000 IU of VD/ kg of chow respectively, for two months. The groups were compared by one-way analysis of variance (ANOVA) and Holm-Sidak post hoc analysis, (variables with normal distribution), or by Kruskal-Wallis test and Dunn's test post hoc analysis. The significance level for all tests was 5%. RESULTS: TXNIP protein expression was higher and Trx activity was lower in VD10. The animals supplemented with VD showed increased lipid hydroperoxide and decreased superoxide dismutase and glutathione peroxidase. The protein Bcl-2 was lower in VD10. There was a decrease in fatty acid ß-oxidation, tricarboxylic acid cycle and electron transport chain with shift to increase in glycolytic pathway. CONCLUSION: VD supplementation led to cardiac remodeling and this process may be modulated by TXNIP and Trx proteins and consequently oxidative stress.

FUNDAMENTO: A vitamina D (VD) tem um importante papel na função cardíaca. No entanto, a vitamina exerce uma curva "dose-resposta" bifásica na fisiopatologia cardiovascular e pode causar efeitos deletérios, mesmo em doses não tóxicas. A VD exerce suas funções celulares ligando-se ao seu receptor. Ainda, a expressão da proteína de interação com a tiorredoxina (TXNIP) é positivamente regulada pela VD. A TXNIP modula diferentes visa de sinalização celular que podem ser importantes para a remodelação cardíaca. OBJETIVOS: Avaliar se a suplementação com VD leva à remodelação cardíaca, e se a TXNIP e a tiorredoxina (Trx) estão associadas com esse processo. MÉTODOS: Duzentos e cinquenta ratos Wistar machos foram alocados em três grupos: controle (C, n=21), sem suplementação com VD; VD3 (n = 22) e VD10 (n=21), suplementados com 3,000 e 10,000 UI de VD/ kg de ração, respectivamente, por dois meses. Os grupos foram comparados por análise de variância (ANOVA) com um fator e teste post hoc de Holm-Sidak (variáveis com distribuição normal), ou pelo teste de Kruskal-Wallis e análise post-hoc de Dunn. O nível de significância para todos os testes foi de 5%. RESULTADOS: A expressão de TXNIP foi mais alta e a atividade do Trx foi mais baixa no grupo VD10. Os animais que receberam suplementação com VD apresentaram aumento de hidroperóxido lipídico e diminuição de superóxido dismutase e glutationa peroxidase. A proteína Bcl-2 foi mais baixa no grupo VD10. Observou-se uma diminuição na ß-oxidação de ácidos graxos, no ciclo do ácido tricarboxílico, na cadeia transportadora de elétrons, e um aumento na via glicolítica. CONCLUSÃO: A suplementação com VD levou à remodelação cardíaca e esse processo pode ser modulado por TXNIP e Trx, e consequentemente por estresse oxidativo.

Peripheral Blood Eosinophils and Nine Years Mortality in COPD Patients.

BACKGROUND: Eosinophil counts increase during chronic obstructive pulmonary disease (COPD) exacerbation and influence the response to different agents (such as inhaled and systemic corticosteroids), as well as increase the production of other inflammatory cytokines. However, few studies have evaluated the association between peripheral blood eosinophils with mortality rate. OBJECTIVE: To evaluate the association between peripheral blood eosinophils and mortality rate in COPD patients over a nine-year period. STUDY DESIGN AND METHODS: This cohort included 133 COPD patients assessed at baseline by spirometry, pulse oximetry (SpO2), complete blood count, body composition, dyspnea intensity [Modified Medical Research Council (mMRC)] and the six-minute distance test (6MWD). The Kaplan-Meier curve followed by a Log rank test was used to evaluate mortality rate related to eosinophil cutoff point categorization. Multivariate Cox regression analysis was performed to identify the association between eosinophils and mortality with all subjects evaluated at baseline, adjusted for age, gender, mMRC, 6MWT, forced expiratory volume in the first second (FEV1) and SpO2. RESULTS: Nineteen patients did not complete follow-up and it was not possible to identify the date of death in four others. Therefore, 110 patients were included in the analysis. At baseline, 81% presented ≥150 eosinophil cells and 72% presented ≥2%. We identified a three-fold higher risk of death in those with <2% eosinophils and <150 cells. We did not identify statistical differences when using other cutoff points. CONCLUSION: The decrease in number of peripheral eosinophils, with cutoff points at 2% and 150 cells, may be associated with a higher risk of death in COPD patients over nine years.

Orange Juice Attenuates Circulating miR-150-5p, miR-25-3p, and miR-451a in Healthy Smokers: A Randomized Crossover Study.

Introduction: Tobacco smoke is associated with oxidative and inflammatory pathways, increasing the risk of chronic-degenerative diseases. Our goal was to evaluate the effects of acute "Pera" and "Moro" orange juice consumption on inflammatory processes and oxidative stress in microRNA (miRNA) expression in plasma from healthy smokers. Methods: This was a randomized crossover study that included healthy smokers over 18 years old. Blood samples were collected before and 11 h after beverage ingestion. Participants were instructed to drink 400 mL of Pera orange juice (Citrus sinensis), Moro orange juice (Citrus sinensis L. Osbeck), or water. Each subject drank the beverages in a 3-way crossover study design. Inflammatory and oxidative stress biomarkers and circulating miRNA expression profiles were determined. The subjects maintained their usual tobacco exposure during the experiment. Results: We included 18 individuals (12 men and 6 women), with 37.0 ± 12.0 years old. All subjects received the 3 interventions. Increased expression of circulating miRNAs (miR-150-5p, miR-25-3p, and miR-451a) was verified after cigarette smoking, which were attenuated after intake of both types of orange juice. There was no difference regarding serum levels of TNF-α, IL-6, MMP-9, and C-reactive protein. Despite the increased activity of serum superoxide dismutase and glutathione peroxidase after "Pera" or "Moro" orange juice intake, respectively, no changes in lipid hydroperoxide levels were detected. Conclusion: Tobaccos smokers showed increased expression of miR-150-5p, miR-25-3p, and miR-451a was noted, and attenuated by orange juice intake. miRNAs were predicted to regulate 244 target genes with roles in oxidative stress, PI3K-Akt, and MAPK signaling, which are pathways frequently involved in smoking-related cardiovascular diseases and cancer.

The role of glucose metabolism and insulin resistance in cardiac remodelling induced by cigarette smoke exposure.

The aim of this study is to evaluate whether the alterations in glucose metabolism and insulin resistance are mechanisms presented in cardiac remodelling induced by the toxicity of cigarette smoke. Male Wistar rats were assigned to the control group (C; n = 12) and the cigarette smoke-exposed group (exposed to cigarette smoke over 2 months) (CS; n = 12). Transthoracic echocardiography, blood pressure assessment, serum biochemical analyses for catecholamines and cotinine, energy metabolism enzymes activities assay; HOMA index (homeostatic model assessment); immunohistochemistry; and Western blot for proteins involved in energy metabolism were performed. The CS group presented concentric hypertrophy, systolic and diastolic dysfunction, and higher oxidative stress. It was observed changes in energy metabolism, characterized by a higher HOMA index, lower concentration of GLUT4 (glucose transporter 4) and lower 3-hydroxyl-CoA dehydrogenase activity, suggesting the presence of insulin resistance. Yet, the cardiac glycogen was depleted, phosphofructokinase (PFK) and lactate dehydrogenase (LDH) increased, with normal pyruvate dehydrogenase (PDH) activity. The activity of citrate synthase, mitochondrial complexes and ATP synthase (adenosine triphosphate synthase) decreased and the expression of Sirtuin 1 (SIRT1) increased. In conclusion, exposure to cigarette smoke induces cardiac remodelling and dysfunction. The mitochondrial dysfunction and heart damage induced by cigarette smoke exposure are associated with insulin resistance and glucose metabolism changes.

Use of hydroxychloroquine to prevent SARS-CoV-2 infection and treat mild COVID-19: a systematic review and meta-analysis / Uso de hidroxicloroquina para prevenir a infecção por SARS-CoV-2 e tratar COVID-19 leve: revisão sistemática e meta-análise

ABSTRACT Objective: Chloroquine or hydroxychloroquine has demonstrated no effect on the treatment of hospitalized COVID-19 patients. This study aimed to answer questions related to the use of hydroxychloroquine for pre-exposure or post-exposure prophylaxis of SARS-CoV-2 infection and in the treatment of patients with mild COVID-19 in terms of hospitalization, adverse events, and mortality. Methods: This was a systematic review and meta-analysis of phase 3 randomized clinical trials, selected from various databases, which compared patients who received hydroxychloroquine for SARS-CoV-2 prophylaxis or treatment of mild COVID-19 cases with controls. Results: A total number of 1,376 studies were retrieved. Of those, 9 met the eligibility criteria and were included in the study. No statistically significant differences were found between the hydroxychloroquine and control groups in terms of pre- or post-exposure prophylaxis of SARS-CoV-2 infection. The use of hydroxychloroquine increased the risk of adverse events by 12% (95% CI, 6-18%; p < 0.001), and the number needed to harm was 9. In addition, no significant differences were found between the hydroxychloroquine and control groups regarding hospitalization (risk difference [RD] = −0.02; 95% CI, −0.04 to 0.00; p = 0.14) or mortality (RD = 0.00; 95% CI, −0.01 to 0.02; p = 0.98) in the treatment of mild COVID-19. Conclusions: The use of hydroxychloroquine for prophylaxis of SARS-CoV-2 infection or treatment of patients with mild COVID-19 is not recommended.

RESUMO Objetivo: A cloroquina ou hidroxicloroquina não apresentou nenhum efeito no tratamento de pacientes hospitalizados com COVID-19. O objetivo deste estudo foi responder a questões a respeito do uso de hidroxicloroquina na profilaxia da infecção por SARS-CoV-2 pré ou pós-exposição e no tratamento de pacientes com COVID-19 leve no tocante à hospitalização, eventos adversos e mortalidade. Métodos: Trata-se de uma revisão sistemática e meta-análise de ensaios clínicos controlados aleatórios de fase 3 que foram selecionados por meio de buscas em diversos bancos de dados e que compararam controles e pacientes que receberam hidroxicloroquina para profilaxia de SARS-CoV-2 ou tratamento de COVID-19 leve. Resultados: Foram identificados 1.376 estudos. Destes, 9 preencheram os critérios de elegibilidade e foram incluídos no estudo. Não foram encontradas diferenças significativas entre os grupos hidroxicloroquina e controle quanto à profilaxia da infecção por SARS-CoV-2 pré ou pós-exposição. O uso de hidroxicloroquina aumentou o risco de eventos adversos em 12% (IC95%: 6-18%; p < 0,001), e o número necessário para prejudicar foi 9. Não foram encontradas diferenças significativas entre os grupos hidroxicloroquina e controle quanto à hospitalização [diferença de risco (DR) = −0,02; IC95%: −0,04 a 0,00; p = 0,14] e mortalidade (DR = 0,00; IC95%: −0,01 a 0,02; p = 0,98) no tratamento de COVID-19 leve. Conclusões: Não é recomendado o uso de hidroxicloroquina nem na profilaxia da infecção por SARS-CoV-2 nem no tratamento de pacientes com COVID-19 leve.

Evaluation of Inflammatory Markers in Patients Undergoing a Short-Term Aerobic Exercise Program while Hospitalized due to Acute Exacerbation of COPD.

INTRODUCTION: Acute exacerbation is an important factor for a worse prognosis in patients with chronic obstructive pulmonary disease (COPD). It promotes the increase of the inflammatory process and worsens quality of life, lung function, and muscle weakness. It is believed that physical exercise performed during the exacerbation breaks the vicious cycle of systemic manifestations without an increase in the inflammatory process. OBJECTIVE: To evaluate the influence of short-term aerobic physical exercise during hospitalization on inflammatory markers. Patients and Methods. 26 patients were evaluated (69.2% female, FEV 137.5 ± 12.9%, and age 68.4 ± 11.6 years) 24 hours after hospitalization for smoking history, Charlson index, quality of life, systemic inflammatory markers, and body composition. After 48 hours of hospitalization, all patients underwent a 6-minute walk test (6MWT) and a new spirometry test, and BODE index was calculated. After 72 hours of hospitalization, patients in the intervention group underwent aerobic exercise on a treadmill for 15 minutes twice daily; before and after the aerobic exercise, blood samples were collected for evaluation of inflammatory markers. Finally, a month after hospital discharge, all patients were reevaluated according to systemic inflammatory markers, quality of life, body composition, spirometry, 6MWT, and BODE index. RESULTS: Patients of both groups did not differ in severity of disease and general characteristics. The intervention group did not show worsening in the inflammatory process after aerobic activity: TNF-α from 1.19 (0 99-1.71) to 1.21 (0.77-1.53) (p = 0.58), IL-6 from 2.41 (2.02-0.58) to 2.66 (1.69-0.48) (p = 0.21), and CRP from 3.88 (2.26-8.04) to 4.07 (2.65-13.3) (p = 0.56). There was a negative correlation between the IL-6 marker and the 6MWT; that is, with the reduction in inflammatory levels, there was an improvement in exercise capacity one month after hospital discharge. CONCLUSION: The present study showed that the aerobic physical activity initiated during hospitalization in patients with exacerbated COPD did not worsen the inflammatory process.