Pan-American Guidelines for the treatment of SARS-CoV-2/COVID-19: a joint evidence-based guideline of the Brazilian Society of Infectious Diseases (SBI) and the Pan-American Association of Infectious Diseases (API).

BACKGROUND: Since the beginning of the COVID-19 pandemic, therapeutic options for treating COVID-19 have been investigated at different stages of clinical manifestations. Considering the particular impact of COVID-19 in the Americas, this document aims to present recommendations for the pharmacological treatment of COVID-19 specific to this population. METHODS: Fifteen experts, members of the Brazilian Society of Infectious Diseases (SBI) and the Pan-American Association of Infectious Diseases (API) make up the panel responsible for developing this guideline. Questions were formulated regarding prophylaxis and treatment of COVID-19 in outpatient and inpatient settings. The outcomes considered in decision-making were mortality, hospitalisation, need for mechanical ventilation, symptomatic COVID-19 episodes, and adverse events. In addition, a systematic review of randomised controlled trials was conducted. The quality of evidence assessment and guideline development process followed the GRADE system. RESULTS: Nine technologies were evaluated, and ten recommendations were made, including the use of tixagevimab + cilgavimab in the prophylaxis of COVID-19, tixagevimab + cilgavimab, molnupiravir, nirmatrelvir + ritonavir, and remdesivir in the treatment of outpatients, and remdesivir, baricitinib, and tocilizumab in the treatment of hospitalised patients with severe COVID-19. The use of hydroxychloroquine or chloroquine and ivermectin was discouraged. CONCLUSION: This guideline provides recommendations for treating patients in the Americas following the principles of evidence-based medicine. The recommendations present a set of drugs that have proven effective in the prophylaxis and treatment of COVID-19, emphasising the strong recommendation for the use of nirmatrelvir/ritonavir in outpatients as the lack of benefit from the use of hydroxychloroquine and ivermectin.

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.

Dual and Poly Use of Tobacco Products in a Sample of Pregnant Smokers: A Cross-sectional Study.

OBJECTIVES: Our aim was to assess the use of dual/poly tobacco in a sample of pregnant women. DESIGN: cross-sectional survey. METHODS: Twenty prenatal care units in Botucatu, Sao Paulo, Brazil. We evaluated 127 high-risk pregnant smokers during prenatal care. Those who were 12-38 weeks pregnant and were currently smoking conventional cigarettes. The study enrollment took place between January 2015 and December 2015. The dual/poly prevalence of tobacco products during pregnancy and the characteristics related to smoking in pregnant smokers through a specific questionnaire containing questions related to sociodemographic characteristics, comorbidities, gestational history, smoking history, secondhand smoke exposure, nicotine dependence, motivation stage and use of alternative forms of tobacco. RESULTS: Mean age was 26.9 ± 6.6 years, most had only elementary education and belonged to lower income economic groups. Twenty-five (19.7%) smoked conventional cigarettes only while 102 used conventional and alternative forms of tobacco products. Smoking pack-years was significantly lower in those only smoking conventional cigarettes than in dual/poly users. Proportion of patients with elevated degree of nicotine dependence was higher in conventional cigarettes users. On the other side, alcohol intake was higher in dual/poly smokers when compared to conventional cigarettes group. The alternative forms of smoking were associated with significantly higher occurrences of comorbidities as pulmonary, cardiovascular and cancer. CONCLUSIONS FOR PRACTICE: The prevalence of alternative forms users of smoking products is high during pregnancy. These data reinforce the importance of a family approach towards smoking in pregnant women and education about the risks of alternative forms of tobacco.

What is Already Known? Studies show that the prevalence of pregnant women who consume alternative forms of tobacco is high, and that these types of smoking are also harmful to pregnancy.What this Study Adds? Our study describes the characteristics related to smoking in pregnant smokers and identifies dual/poly use of tobacco products.

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.

Characterization of subclinical diastolic dysfunction by cardiac magnetic resonance feature-tracking in adult survivors of non-Hodgkin lymphoma treated with anthracyclines.

BACKGROUND: The use of anthracycline-based chemotherapy is associated with the development of heart failure, even years after the end of treatment. Early detection of cardiac dysfunction could identify a high-risk subset of survivors who would eventually benefit from early intervention. Cardiac magnetic resonance feature-tracking (CMR-FT) analysis offers a practical and rapid method to calculate systolic and diastolic strains from routinely acquired cine images. While early changes in systolic function have been described, less data are available about late effects of chemotherapy in diastolic parameters by CMR-FT. The main goal of this study was to determine whether left ventricular (LV) early diastolic strain rates (GDSR-E) by CMR-FT are impaired in long-term adult survivors of non-Hodgkin lymphoma (NHL). Our secondary objective was to analyze associations between GDSR-E with cumulative anthracycline dose, systolic function parameters and myocardial tissue characteristics. METHODS: This is a single center cross-sectional observational study of asymptomatic patients in remission of NHL who previously received anthracycline therapy. All participants underwent their CMR examination on a 3.0-T scanner, including cines, T2 mapping, T1 mapping and late gadolinium enhancement imaging. Derived myocardial extracellular volume fraction was obtained from pre- and post-contrast T1 maps. CMR-FT analysis was performed using Trufi Strain software. The data obtained were compared between anthracycline group and volunteers without cardiovascular disease or neoplasia. RESULTS: A total of 18 adult survivors of NHL, 14 (77.8%) males, at mean age of 57.6 (± 14.7) years-old, were studied 88.2 (± 52.1) months after exposure to anthracycline therapy (median 400 mg/m2). Compared with controls, anthracycline group showed impaired LV global early diastolic circumferential strain rate (GCSR-E) [53.5%/s ± 19.3 vs 72.2%/s ± 26.7, p = 0.022], early diastolic longitudinal strain rate (GLSR-E) [40.4%/s ± 13.0 vs 55.9%/s ± 17.8, p = 0.006] and early diastolic radial strain rate (GRSR-E) [- 114.4%/s ± 37.1 vs - 170.5%/s ± 48.0, p < 0.001]. Impaired LV GCSR-E, GLSR-E and GRSR-E correlated with increased anthracycline dose and decreased systolic function. There were no correlations between GDSR-E and myocardial tissue characteristics. CONCLUSIONS: Left ventricular early diastolic strain rates by CMR-FT are impaired late after anthracycline chemotherapy in adult survivors of non-Hodgkin lymphoma.

Comparison of morphometry and ventricular function of healthy and smoking young people.

BACKGROUND: Tobacco smoke is one of the most significant risk factors for cardiovascular diseases and damages in the myocardial tissue directly. Cardiac magnetic resonance (CMR) has been used and is a promising tool to evaluate morphometry and cardiac function in humans. The objective of this study was to evaluate associations of smoking with morphometry and cardiac function by CMR technique in young adult smokers. METHODS: Altogether, 49 volunteers (22 smokers and 27 non-smokers) were included in the study. The comparisons between groups were performed by multiple linear regression adjusting for body mass index and gender. RESULTS: In the morphometric and functional evaluation of the left ventricle, we observed statistical significant lower values of end-diastolic volume (EDV) (p = 0.02), ejection volume (EV) (p = 0.001) and indexed ejection volume (IEV) (p = 0.007) in smokers when compared to no-smoker group. Right ventricle showed statistical significant lower values of EDV (p = < 0.001), end-systolic volume (p = 0.01), EV (p = < 0.001), IEV (p = 0.001), indexed end-diastolic volume (p = 0.001) and major axis (p = 0.01) in smokers when compared to non-smokers group. CONCLUSIONS: There is a strongly association of smoking in young adult and cardiac function decline, even adjusted by cofounders, which compromises the proper functioning of the heart. Evidence confirms that smoking can directly influence the cardiac function, even without atherosclerosis or other chronic comorbidities, associated with increased risk of cardiovascular diseases.

Peptidylarginine deiminase 4 concentration, but not PADI4 polymorphisms, is associated with ICU mortality in septic shock patients.

The objective of our study was to evaluate the association between peptidylarginine deiminase 4 (PAD4) concentration and its polymorphisms with mortality in patients with septic shock. We prospectively evaluated 175 patients aged over 18 years with septic shock upon intensive care unit (ICU) admission. However, 48 patients were excluded. Thus, 127 patients were enrolled in the study. At the time of the patients' enrollment, demographic information was recorded. Blood samples were taken within the first 24 hours of the patient's admission to determine serum PAD4 concentrations and its polymorphism PADI4_89 [rs11203366], PADI4_94 [rs2240340] and PADI4_104 [rs1748033]. The mean age was 63.3 ± 15.2 years, 56.7% were male, PAD4 concentration was 4.62 (2.48-6.20) ng/mL and the ICU mortality rate was 67.7%. The patients who died in the ICU had higher APACHE II and Sequential Organ Failure Assessment (SOFA) scores. In addition, PAD4 concentration was higher in patients who died during ICU stay. However, there were no differences regarding PADI4 polymorphisms and ICU mortality. In the logistic regression models, PAD4 concentrations were associated with ICU mortality when adjusted for APACHE II score and lactate (OR: 1.477; CI 95%: 1.186-1.839; P < .001), and when adjusted for age, gender and APACHE II score (OR: 1.392; CI 95%: 1.145-1.692; P < .001). In conclusion, PAD4 concentration, but not PADI4_89, PADI4_94 and PADI4_104 polymorphisms, is associated with ICU mortality in septic shock patients.

Erythrocyte selenium concentration predicts intensive care unit and hospital mortality in patients with septic shock: a prospective observational study.

INTRODUCTION: Selenoenzymes can modulate the extent of oxidative stress, which is recognized as a key feature of septic shock. The pathophysiologic role of erythrocyte selenium concentration in patients with septic shock remains unknown. Therefore, the objective of this study was to evaluate the association of erythrocyte selenium concentration with glutathione peroxidase (GPx1) activity, GPx1 polymorphisms and with ICU and hospital mortality in septic shock patients. METHODS: This prospective study included all patients older than 18 years with septic shock on admission or during their ICU stay, admitted to one of the three ICUs of our institution, from January to August 2012. At the time of the patients' enrollment, demographic information was recorded. Blood samples were taken within the first 72 hours of the patients' admission or within 72 hours of the septic shock diagnosis for determination of selenium status, protein carbonyl concentration, GPx1 activity and GPx1 Pro198Leu polymorphism (rs 1050450) genotyping. RESULTS: A total of 110 consecutive patients were evaluated. The mean age was 57.6 ± 15.9 years, 63.6% were male. Regarding selenium status, only erythrocyte selenium concentration was lower in patients who died in the ICU. The frequencies for GPx1 Pro198Leu polymorphism were 55%, 38% and 7% for Pro/Pro, Pro/Leu and Leu/Leu, respectively. In the logistic regression models, erythrocyte selenium concentration was associated with ICU and hospital mortality in patients with septic shock even after adjustment for protein carbonyl concentration and acute physiology and chronic health evaluation II score (APACHE II) or sequential organ failure assessment (SOFA). CONCLUSIONS: Erythrocyte selenium concentration was a predictor of ICU and hospital mortality in patients with septic shock. However, this effect was not due to GPx1 activity or Pro198Leu polymorphism.

Metal in biological samples from electronic cigarette users and those exposed to their second-hand aerosol: a narrative review.

Introduction: Electronic nicotine delivery systems (ENDS) are gradually becoming more popular, particularly, among today's youth. Despite being marketed as safe by the tobacco industry, the notable absence of regulation in their composition is evident. Both the generated fluids and aerosol exhibit a wide variety of substances that are not yet fully identified. In addition to additives, the aerosol contains metals, the presence of which can be attributed to the excessive heating of metallic filaments used in vaporizing the liquid. Objective: This review aimed to identify and describe studies that have assessed metal levels in biological samples obtained from electronic cigarette users and those exposed to their second-hand aerosol. This involved detailing the types and concentrations of metals identified and the biological samples in which the metals were detected. Methods: Two independent researchers conducted searches in the MEDLINE and EMBASE databases to identify studies that measured the metal levels in human non-invasive biological samples from electronic cigarette users and second-hand exposure. Data were presented as a narrative review. Results: In total, 18 articles were included in this review. Overall active and passive exposure to ENDS was related to higher levels of many metals, including lead and cadmium, in biological samples. ENDS users, in general, have lower metal concentrations in biological samples compared to the users of combustible cigarettes. Conclusion: The exposure to primary and second-hand e-cigarette aerosol is related to higher metal concentrations in the biological samples. The adverse effects of this exposure on long-term users are yet to be determined.

Effectiveness of wearing masks during the COVID-19 outbreak in cohort and case-control studies: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy of wearing a mask to prevent COVID-19 infection. METHODS: This was a systematic review and meta-analysis of cohort and case-control studies, considering the best level of evidence available. Electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov) were searched to identify studies that evaluated the effectiveness of wearing masks compared with that of not wearing them during the COVID-19 pandemic. Risk of bias and quality of evidence were assessed using the Cochrane risk of bias tool and the Grading of Recommendations Assessment, Development, and Evaluation. RESULTS: Of the 1,028 studies identified, 9 met the inclusion criteria (2 cohort studies and 7 case-control studies) and were included in the analysis. The meta-analysis using cohort studies alone showed statistically significant differences, wearing a cloth mask decreased by 21% [RD = -0.21 (95% CI, -0.34 to -0.07); I2 = 0%; p = 0,002] the risk of COVID-19 infection, but the quality of evidence was low. Regarding case-control studies, wearing a surgical mask reduced the chance of COVID-19 infection [OR = 0.51 (95% CI, 0.37-0.70); I2 = 47%; p = 0.0001], as did wearing an N95 respirator mask [OR = 0.31 (95% CI, 0.20-0.49); I2 = 0%; p = 0.00001], both with low quality of evidence. CONCLUSIONS: In this systematic review with meta-analysis, we showed the effectiveness of wearing masks in the prevention of SARS-CoV-2 infection regardless of the type of mask (disposable surgical mask, common masks, including cloth masks, or N95 respirators), although the studies evaluated presented with low quality of evidence and important biases.

Use of elexacaftor+tezacaftor+ivacaftor in individuals with cystic fibrosis and at least one F508del allele: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of treatment with the combination of three cystic fibrosis transmembrane conductance regulator (CFTR) modulators-elexacaftor+tezacaftor+ivacaftor (ETI)-on important clinical endpoints in individuals with cystic fibrosis. METHODS: This was a systematic review and meta-analysis of randomized clinical trials that compared the use of ETI in individuals with CF and at least one F508del allele with that of placebo or with an active comparator such as other combinations of CFTR modulators, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) methodology. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to December 26th, 2022. The risk of bias was assessed using the Cochrane risk-of-bias tool, and the quality of evidence was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We retrieved 54 studies in the primary search. Of these, 6 met the inclusion criteria and were analyzed (1,127 patients; 577 and 550 in the intervention and control groups, respectively). The meta-analysis revealed that the use of ETI increased FEV1% [risk difference (RD), +10.47%; 95% CI, 6.88-14.06], reduced the number of acute pulmonary exacerbations (RD, -0.16; 95% CI, -0.28 to -0.04), and improved quality of life (RD, +14.93; 95% CI, 9.98-19.89) and BMI (RD, +1.07 kg/m2; 95% CI, 0.90-1.25). Adverse events did not differ between groups (RD, -0.03; 95% CI, -0.08 to 0.01), and none of the studies reported deaths. CONCLUSIONS: Our findings demonstrate that ETI treatment substantially improves clinically significant, patient-centered outcomes.

Methylene blue in sepsis and septic shock: a systematic review and meta-analysis.

Background: Methylene blue is an interesting approach in reducing fluid overload and vasoactive drug administration in vasodilatory shock. The inhibition of guanylate cyclase induced by methylene blue infusion reduces nitric oxide production and improves vasoconstriction. This systematic review and meta-analysis aimed to assess the effects of methylene blue administration compared to placebo on the hemodynamic status and clinical outcomes in patients with sepsis and septic shock. Methods: The authors specifically included randomized controlled trials that compared the use of methylene blue with placebo in adult patients with sepsis and septic shock. The outcomes were length of intensive care unit stay, hemodynamic parameters [vasopressor use], and days on mechanical ventilation. We also evaluated the abnormal levels of methemoglobinemia. This systematic review and meta-analysis were recorded in PROSPERO with the ID CRD42023423470. Results: During the initial search, a total of 1,014 records were identified, out of which 393 were duplicates. Fourteen citations were selected for detailed reading, and three were selected for inclusion. The studies enrolled 141 patients, with 70 of them in the methylene blue group and 71 of them in the control group. Methylene blue treatment was associated with a lower length of intensive care unit stay (MD -1.58; 95%CI -2.97, -0.20; I2 = 25%; p = 0.03), decreased days on mechanical ventilation (MD -0.72; 95%CI -1.26, -0.17; I2 = 0%; p = 0.010), and a shorter time to vasopressor discontinuation (MD -31.49; 95%CI -46.02, -16.96; I2 = 0%; p < 0.0001). No association was found with methemoglobinemia. Conclusion: Administering methylene blue to patients with sepsis and septic shock leads to reduced time to vasopressor discontinuation, length of intensive care unit stay, and days on mechanical ventilation. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023423470, CRD42023423470.

Long-term oxygen therapy to reduce length of hospital stay in COVID-19.

OBJECTIVE: The aim of this study was to evaluate the efficacy of long-term oxygen therapy as a strategy to reduce hospitalization time in patients affected by COVID-19. METHODS: Between April and December 2021, COVID-19 patients with stable clinical conditions needing supplementary oxygen therapy during hospitalization were oriented to have hospital discharge with long-term oxygen therapy and reassessment after 15 days. RESULTS: A total of 62 patients were evaluated and, 15 days after discharge, 69% of patients had suspended long-term oxygen therapy, with no difference between the groups admitted to the intensive care unit or the ward (p=0.319). Among the individuals who needed to maintain long-term oxygen therapy, in addition to worse P/F ratio (265±57 vs. 345±51; p<0.001) and lower partial pressure of oxygen (55±12 vs. 72±11 mmHg; p<0.001), were those more obese (37±8 vs. 30±6 kg/m2; p=0.032), needed more time for invasive mechanical ventilation (46±27 vs. 20±16 days; p=0.029), had greater persistence of symptoms (p<0.001), and shorter time between the onset of symptoms and the need for hospitalization (7 [2-9] vs. 10 [6-12] days; p=0.039). CONCLUSION: Long-term oxygen therapy is an effective strategy for reducing hospitalization time in COVID-19 patients, regardless of gravity. Additionally, more obese patients with persistence of respiratory symptoms, faster disease evolution, and more days of invasive mechanical ventilation needed to maintain the long-term oxygen therapy longer.

Clinical and Physiological Variables in Patients with Post-COVID-19 Condition and Persistent Fatigue.

Background/Objectives: Post-COVID-19 condition can manifest through various symptoms such as dyspnea, cognitive disturbances, and fatigue, with mechanisms related to these symptoms, particularly those related to fatigue, still requiring further clarification. Therefore, our aim was to assess the clinical and physiological variables in patients with post-COVID-19 condition and persistent fatigue. Methods: After one year post-COVID-19 infection, the patients underwent a comprehensive evaluation, including a complete blood count, a metabolic panel, complete spirometry, and assessments of dyspnea, quality of life, anxiety and depression, physical capacity, body composition, muscle strength, comorbidities, and medications. The participants were categorized into two groups: G1-fatigue and G2-non-fatigue. Results: Seventy-seven patients (53% female; 55 ± 11.8 years) were included, 37 in G1 and 40 in G2. As for clinical markers and symptoms of illness, in those with persistent fatigue symptoms, a greater sensation of dyspnea [BDI score: 7.5 (6-9) vs. 12 (9-12), p < 0.001; mMRC score: 1 (1-2) vs. 0 (0-1), p = 0.002], worse quality of life [SGRQ total score: 1404 (1007-1897) vs. 497 (274-985); p < 0.001], higher levels of anxiety [HADS-A score: 8 (5-9) vs. 3 (0.5-4); p < 0.001], and a reduction in peripheral and inspiratory muscle strength [handgrip strength: 34 (28-40) vs. 40 (30-46.5) kgf, p = 0.044; MIP: -81 ± 31 vs. -111 ± 33 mmHg, p < 0.001)] were observed. Conclusions: Those with persistent fatigue exhibited a greater sensation of dyspnea, higher levels of anxiety, reduced peripheral and inspiratory muscle strength, and a greater impairment of quality of life. The severity of fatigue was influenced by the worsening quality of life, heightened anxiety levels, and decreased peripheral muscle strength. Additionally, the worse quality of life was associated with a higher sensation of dyspnea, lower muscle strength, and reduced physical capacity.

Efficacy of oral 20-hydroxyecdysone (BIO101), a MAS receptor activator, in adults with severe COVID-19 (COVA): a randomized, placebo-controlled, phase 2/3 trial.

Background: SARS-CoV-2 binding to ACE2 is potentially associated with severe pneumonia due to COVID-19. The aim of the study was to test whether Mas-receptor activation by 20-hydroxyecdysone (BIO101) could restore the Renin-Angiotensin System equilibrium and limit the frequency of respiratory failure and mortality in adults hospitalized with severe COVID-19. Methods: Double-blind, randomized, placebo-controlled phase 2/3 trial. Randomization: 1:1 oral BIO101 (350 mg BID) or placebo, up to 28 days or until an endpoint was reached. Primary endpoint: mortality or respiratory failure requiring high-flow oxygen, mechanical ventilation, or extra-corporeal membrane oxygenation. Key secondary endpoint: hospital discharge following recovery (ClinicalTrials.gov Number, NCT04472728). Findings: Due to low recruitment the planned sample size of 310 was not reached and 238 patients were randomized between August 26, 2020 and March 8, 2022. In the modified ITT population (233 patients; 126 BIO101 and 107 placebo), respiratory failure or early death by day 28 was 11.4% lower in the BIO101 (13.5%) than in the placebo (24.3%) group, (p = 0.0426). At day 28, proportions of patients discharged following recovery were 80.1%, and 70.9% in the BIO101 and placebo group respectively, (adjusted difference 11.0%, 95% CI [-0.4%, 22.4%], p = 0.0586). Hazard Ratio for time to death over 90 days: 0.554 (95% CI [0.285, 1.077]), a 44.6% mortality reduction in the BIO101 group (not statistically significant). Treatment emergent adverse events of respiratory failure were more frequent in the placebo group. Interpretation: BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19. Funding: Biophytis.

Three-year follow-up of Interleukin 6 and C-reactive protein in chronic obstructive pulmonary disease.

BACKGROUND: Past studies have shown that mean values of Interleukin-6 (IL-6) and C-reactive protein (CRP) do not change significantly in COPD patients over a one-year period. However, longer period follow-up studies are still lacking. Thus, the aim of this study is to evaluate plasma CRP and IL-6 concentration over three years in COPD patients and to test the association between these inflammatory mediators and disease outcome markers. METHODS: A cohort of 77 outpatients with stable COPD was evaluated at baseline, and 53 (mean FEV1, 56% predicted) were included in the prospective study. We evaluated Interleukin-6 (IL-6), C-reactive protein (CRP), six-minute walking distance (6MWD), and body mass index (BMI) at baseline and after three years. Plasma concentration of IL-6 was measured by high sensitivity ELISA, and CRP was obtained by high sensitivity particle-enhanced immunonephelometry. RESULTS: IL-6 increased significantly after 3 years compared to baseline measurements [0.8 (0.5-1.3) vs 2.4 (1.3-4.4) pg/ml; p < 0.001] and was associated with worse 6MWD performance. In the Cox regression, increased IL-6 at baseline was associated with mortality [Hazard Ratio (95% CI) = 2.68 (0.13, 1.84); p = 0.02]. CRP mean values did not change [5 (1.6-7.9) vs 4.7 (1.7-10) pg/L; p = 0.84], although eleven patients (21%) presented with changes >3 mg/L in CRP after 3 years. CONCLUSIONS: The systemic inflammatory process, evaluated by IL-6, seems to be persistent, progressive and associated with mortality and worse physical performance in COPD patients. TRIAL REGISTRATION: No.:NCT00605540.

Mini Nutritional Assessment predicts gait status and mortality 6 months after hip fracture.

The aim of the present study was to evaluate the Mini Nutritional Assessment (MNA), the Nutritional Risk Screening (NRS) 2002 and the American Society of Anesthesiologists Physical Status Score (ASA) as predictors of gait status and mortality 6 months after hip fracture. A total of eighty-eight consecutive patients over the age of 65 years with hip fracture admitted to an orthopaedic unit were prospectively evaluated. Within the first 72 h of admission, each patient's characteristics were recorded, and the MNA, the NRS 2002 and the ASA were performed. Gait status and mortality were evaluated 6 months after hip fracture. Of the total patients, two were excluded because of pathological fractures. The remaining eighty-six patients (aged 80·2 (sd 7·3) years) were studied. Among these patients 76·7 % were female, 69·8 % walked with or without support and 12·8 % died 6 months after the fracture. In a multivariate analysis, only the MNA was associated with gait status 6 months after hip fracture (OR 0·773, 95 % CI 0·663, 0·901; P= 0·001). In the Cox regression model, only the MNA was associated with mortality 6 months after hip fracture (hazard ratio 0·869, 95 % CI 0·757, 0·998; P= 0·04). In conclusion, the MNA best predicts gait status and mortality 6 months after hip fracture. These results suggest that the MNA should be included in the clinical stratification of patients with hip fracture to identify and treat malnutrition in order to improve the outcomes.

Organizing pneumonia and COVID-19.

Organizing pneumonia (OP) is an interstitial lung disease, and can be cryptogenic, if no cause is identified, or secondary to several conditions. COVID-19-induced persistent inflammation can be associated with interstitial lung disease. We present a review of literature of OP and COVID-19-induced OP with an illustrative case. A 38-year-old man was admitted with COVID-19 that required mechanical ventilation for 56 days. Initial chest computed tomography (CT) revealed diffuse bilateral ground-glass opacities in the lungs with consolidation areas involving 75 % of the parenchyma. After weaning from MV, the patient still required oxygen supplementation. A new chest CT scan also showed extensive diffuse areas of consolidation and ground-glass opacity. OP was hypothesized and 40 mg/day prednisone initiated and continued for six months with resolution of lung functional and image abnormalities. Organizing pneumonia should be included in the differential diagnosis of COVID-19 patients with respiratory symptoms after partial pulmonary recovery.

Cardiac function, myocardial fat deposition, and lipid profile in young smokers: a cross-sectional study.

Background: There is a possibility that cardiac morphometric characteristics are associated with the lipid profile, that is, the composition and concentration of triglycerides, total cholesterol, HDL, LDL, and others lipoproteins in young smokers without comorbidities. Thus, this study aimed to evaluate the association of cardiac morphometric characteristics, myocardial fat deposition, and smoking cessation with the lipid profile of young smokers. Methods: A clinical and laboratory evaluation of lipids and the smoking status was performed on 57 individuals, including both a smoker group and a control group. Cardiac magnetic resonance imaging (MRI) with proton spectroscopy was performed to identify cardiac changes and triglyceride (TG) deposition in myocardial tissue. Results: No differences were observed between the groups (control vs. smokers) in relation to the amount of myocardial TG deposition (p = 0.47); however, when TG deposition was correlated with cardiac MRI variables, a positive correlation was identified between smoking history and myocardial TG deposition [hazard ratio (95% CI), 0.07 (0.03-0.12); p = 0.002]. Furthermore, it was observed that the smoking group had lower high-density lipoprotein cholesterol [51 (45.5-59.5) mg/dl vs. 43 (36-49.5) mg/dl, p = 0.003] and higher TG [73 (58-110) mg/dl vs. 122 (73.5-133) mg/dl, p = 0.01] and very-low-density lipoprotein cholesterol [14.6 (11.6-22.2) mg/dl vs. 24.4 (14.7-26.6) mg/dl, p = 0.01] values. In the control and smoking groups, a negative correlation between TGs and the diameter of the aortic root lumen and positive correlation with the thickness of the interventricular septum and end-diastolic volume (EDV) of both the right ventricle (RV) and left ventricle (LV) were noted. Moreover, in the RV, positive correlations with the end-systolic volume (ESV) index (ESVI), stroke volume (SV), ESV, and EDV were observed. Regarding serum free fatty acids, we found a negative correlation between their values and the diameter of the lumen of the ascending aortic vessel. Lipoprotein lipase showed a positive correlation with the SV index of the RV and negative correlation with the diameter of the lumen of the ascending aortic vessel. Conclusion: Several associations were observed regarding cardiac morphometric characteristics, myocardial fat deposition, and smoking cessation with the lipid profile of young smokers.

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.