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Robson Prudente,1 Renata Ferrari,2 Carolina Mesquita,2 Luiz Machado,2 Estefânia Franco,1 Irma Godoy,2 Suzana Tanni2 1Clinical Hospital of Botucatu Medical School, Department of Internal Medicine, Pneumology Area, Botucatu School of Medicine, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil; 2Department of Internal Medicine, Pneumology Area, Botucatu School of Medicine, São Paulo State University (UNESP), Botucatu, São Paulo, BrazilCorrespondence: Robson PrudenteClinical Hospital of Botucatu Medical School, Department of Internal Medicine, Pneumology Area, Botucatu School of Medicine, São Paulo State University (UNESP), Botucatu, São Paulo, BrazilEmail robsonapp@gmail.comBackground: Systemic manifestations of chronic obstructive pulmonary disease (COPD) are related to increased systemic inflammatory process; however, it is not entirely clear how much they are related and how the systemic inflammation, in particular interleukin-6 (IL-6), is associated with exacerbation and mortality risk.Objective: To evaluate the role of IL-6 in COPD patients over nine years.Study Design and Methods: A total of 133 COPD patients were assessed at baseline between 2004 and 2006 and reassessed after three and nine years through clinical evaluation, comorbidities, hematological blood count and IL-6 analysis.Results: After nine years, 19 patients lost the follow-up and were not possible to identify the date of death of four patients; 12 refused to participate and 1 could not be involved due to recurrent exacerbations. Therefore, 33 patients were included in the reassessment after nine years of follow-up and 92 patients were included in the Cox mortality analysis with IL-6 as a time-dependent covariate. Regarding the inflammatory profile, in patients who survived after nine years, there was a significant increase in IL-6 [0.4 (0.2– 0.8) vs 5.7 (3.4– 11) pg/mL; p < 0.001] and reduction in lymphocyte count [2.1 (1.6– 2.4) vs 1.4 (1.2– 2.1)10^9/L; p < 0.01] with an increase in the neutrophil/lymphocyte ratio (2.0 ± 0.7 vs 2.7 ± 1.2; p = 0.003). The Cox mortality model did not show a statistical significance influence of IL-6 assessed during the follow-up.Conclusion: There was a progressive increase in IL-6 during the follow-up, however, without influence on mortality.Keywords: chronic obstructive pulmonary disease, inflammation, interleukin-6, severity of illness index, mortality

Abstract In a rapidly urbanizing world, heavy air pollution and increasing surface temperature pose significant threats to human health and lives, especially in densely populated cities. In this study, we took an information theory perspective to investigate the causal relationship between diel land surface temperature (LST) and transboundary air pollution (TAP) from 2003 to 2020 in the Bangkok Metropolitan Region (BMR), which includes Bangkok Metropolis and its five adjacent provinces. We found an overall increasing trend of LST over the study region, with the mean daytime LST rising faster than nighttime LST. Evident seasonal variations showed high aerosol optical depth (AOD) loadings during the dry period and low loadings at the beginning of the rainy season. Our study revealed that TAP affected diel surface temperature in Bangkok Metropolis significantly. Causality tests show that air pollutants of two adjacent provinces west of Bangkok, i.e., Nakhon Pathom and Samut Sakhon, have a greater influence on the LST of Bangkok than other provinces. Also, the bidirectional relationship indicates that air pollution has a greater impact on daytime LST than nighttime LST. While LST has an insignificant influence on AOD during the daytime, it influences AOD significantly at night. Our study offers a new approach to understanding the causal impact of TAP and can help policymakers to identify the most relevant locations that cause pollution, leading to appropriate planning and management.

Background: Appendiceal neuroendocrine tumors (NETs) rank as the third most frequent neoplasm affecting the appendix, originating from enterochromaffin cells. This study aims to evaluate the influence of various prognostic factors on the mortality rates of patients diagnosed with NETs of the appendix. Methods: Conducted retrospectively, the study involved 3346 patients, utilizing data sourced from the Surveillance, Epidemiology, and End Results (SEER) database. Our analysis centered on investigating demographic characteristics, clinical features, overall mortality (OM), and cancer-specific mortality (CSM) among the cohort. Variables showing a p-value < 0.1 in the univariate Cox regression were incorporated into the multivariate Cox regression analysis. A Hazard Ratio (HR) > 1 indicated an unfavorable prognosis. Results: In the multivariate analysis, higher OM and CSM were observed in males, older age groups, tumors with distant metastasis, poorly differentiated tumors, and those who underwent chemotherapy. Non-Hispanic Black individuals showed elevated mortality rates. Conclusion: Delayed diagnosis may contribute to the increased mortality in this community. Improved access to healthcare and treatment is crucial for addressing these disparities. Larger prospective studies are needed to pinpoint the underlying causes of elevated mortality in non-Hispanic Black populations, and randomized controlled trials (RCTs) are warranted to evaluate therapies for advanced-stage appendix NETs.

Robson Prudente, Renata Ferrari, Carolina B Mesquita, Luiz HS Machado, Estefânia AT Franco, Irma Godoy, Suzana E Tanni Department of Internal Medicine, Botucatu School of Medicine, São Paulo State University (UNESP), Botucatu, São Paulo, BrazilCorrespondence: Robson PrudenteDepartment of Internal Medicine, Botucatu Medical School, São Paulo State University (UNESP), Av. Prof. Montenegro, s/n, Distrito de Rubião Junior, Botucatu, São Paulo, 18618-970, BrazilTel +55 14 99734-9653Email robsonapp@gmail.comBackground: 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.Keywords: chronic airflow obstruction, inflammation, death rate

José William Zucchi,1 Estefânia Aparecida Thomé Franco,1 Thomas Schreck,2 Maria Helena Castro e Silva,3 Sandro Rogerio dos Santos Migliorini,3 Thaís Garcia,1 Gustavo Augusto Ferreira Mota,1 Bruna Evelyn Bueno de Morais,1 Luiz Henrique Soares Machado,1 Ana Natália Ribeiro Batista,1 Sergio Alberto Rupp de Paiva,1 Irma de Godoy,1 Suzana Erico Tanni1 1Pulmonology Division of Botucatu Medical School, São Paulo State University (UNESP), Botucatu, Brazil; 2Ostbayerische Technische Hochschule Regensburg (OTH Regensburg), Faculty of Business Studies, Regensburg, German; 3Pulmonology Division of Federal University of Triângulo Mineiro, Uberaba, BrazilCorrespondence: José William Zucchi Email jwzucchi@hotmail.comBackground: Chronic obstructive pulmonary disease (COPD) has a functional definition. However, differences in clinical characteristics and systemic manifestations make COPD a heterogeneous disease and some manifestations have been associated with different risks of acute exacerbations, hospitalizations, and death.Objective: Therefore, the objective of the study was to evaluate possible clinical clusters in COPD at two study centers in Brazil and identify the associated exacerbation and mortality rate during 1 year of follow-up.Methods: We included patients with COPD and all underwent an evaluation composed of the Charlson Index, body mass index (BMI), current pharmacological treatment, smoking history (packs-year), history of exacerbations/hospitalizations in the last year, spirometry, six-minute walking test (6MWT), quality of life questionnaires, dyspnea, and hospital anxiety and depression scale. Blood samples were also collected for measurements of C-reactive protein (CRP), blood gases, laboratory analysis, and blood count. For the construction of the clusters, 13 continuous variables of clinical importance were considered: hematocrit, CRP, triglycerides, low density lipoprotein, absolute number of peripheral eosinophils, age, pulse oximetry, BMI, forced expiratory volume in the first second, dyspnea, 6MWD, total score of the Saint George Respiratory Questionnaire and packs-year of smoking. We used the Ward and K-means methods and determined the best silhouette value to identify similarities of individuals within the cluster (cohesion) in relation to the other clusters (separation). The number of clusters was determined by the heterogeneity values of the cluster, which in this case was determined as four clusters.Results: We evaluated 301 COPD patients and identified four different groups of COPD patients. The first cluster (203 patients) was characterized by fewer symptoms and lower functional severity of the disease, the second cluster by higher values of peripheral eosinophils, the third cluster by more systemic inflammation and the fourth cluster by greater obstructive severity and worse gas exchange. Cluster 2 had an average of 959± 3 peripheral eosinophils, cluster 3 had a higher prevalence of nutritional depletion (46.1%), and cluster 4 had a higher BODE index. Regarding the associated comorbidities, we found that only obstructive sleep apnea syndrome and pulmonary thromboembolism were more prevalent in cluster 4. Almost 50% of all patients presented an exacerbation during 1 year of follow-up. However, it was higher in cluster 4, with 65% of all patients having at least one exacerbation. The mortality rate was statistically higher in cluster 4, with 26.9%, vs 9.6% in cluster 1.Conclusion: We could identify four clinical different clusters in these COPD populations, that were related to different clinical manifestations, comorbidities, exacerbation, and mortality rate. We also identified a specific cluster with higher values of peripheral eosinophils.Keywords: COPD, eosinophils, cluster analysis, COPD phenotype, lung function

Robson Prudente,1 Estefânia Aparecida Thomé Franco,2 Carolina Bonfanti Mesquita,1 Renata Ferrari,1 Irma de Godoy,1 Suzana Erico Tanni1 1Department of Internal Medicine, São Paulo State University (UNESP), Medical School, Botucatu, São Paulo Brazil; 2University Hospital of São Paulo State University (UNESP), Medical School, Botucatu, São Paulo, Brazil Background: COPD is one of the leading causes of morbidity and mortality in the world; however, the most varied amounts of clinical and laboratory characteristics acts in different ways in the mortality among over time. Therefore, this study aimed to evaluate the predictors of mortality in patients with COPD after 9 years.Patients and methods: One hundred and thirty-three patients with COPD were assessed at baseline by spirometry, pulse oximetry (SpO2), body composition, intensity of dyspnea, distance walked in the 6-minute walk test (6MWT), and Charlson Comorbidity Index (CCI).Results: After 9 years, it was not possible to identify the lifetime of 4 patients who died and of 19 patients who stopped follow-up; thus, 110 patients were included in the analysis of predictors of mortality (67% male, 65±9 years old, and FEV1: 52.5 [40%–73%]). Male sex, age, SpO2, Body mass index, airway Obstruction, Dyspnea, and Exercise capacity (BODE) index, and frequency of exacerbations in the first 3 years of follow-up were considered in the model. Patients classified at baseline with BODE class 2 (HR: 2.62, 95% CI: 1.36–5.04; P=0.004), BODE class 3 (HR: 2.54, 95% CI: 1.15–5.61; P=0.02), and BODE class 4 (HR: 15.35, 95% CI: 3.11–75.75; P=0.001) showed increased risk of death compared to those with BODE class 1. The CCI (HR: 1.29, 95% CI: 1.00–1.68; P=0.04) and the number of exacerbations in the first 3 years (HR: 1.32, 95% CI: 1.00–1.76; P=0.04) also showed increased risk of death. By replacing the BODE index for the variables that compose it, those with body mass index ≤21 kg/m2 showed increased risk of death compared to those with body mass index (BMI)>21 kg/m2 (HR: 2.70, 95% CI: 1.38–5.25; P=0.003).Conclusion: After 9 years, we identified that those with high BODE index, greater CCI, greater frequency of exacerbations in the first 3 years, and BMI ≤21 kg/m2 showed increased risk of death. Keywords: COPD, disease severity index, mortality

Laura Miranda de Oliveira Caram,1 R Ferrari,1 DL Nogueira,1 MRM Oliveira,2 FV Francisqueti,2 SE Tanni,1 CR Corrêa,2 I Godoy1 1Department of Internal Medicine, 2Department of Pathology, Botucatu Medical School, UNESP – Univ Estadual Paulista, Botucatu Campus, Botucatu-São Paulo, Brazil Introduction: Oxidative stress and systemic inflammation are higher in smokers and patients with COPD; however, markers that may help differentiate between smokers and patients with COPD have not yet been identified. We hypothesized that tumor necrosis factor-alpha receptor (TNFR) and soluble form of the receptor for advanced glycation end products (sRAGE) can be indicators of COPD in asymptomatic patients.Patients and methods: We evaluated 32 smokers (smoking history >10 pack-years), 32 patients with mild/moderate COPD (smokers and ex-smokers), and 32 never smokers. Concentrations of C-reactive protein (CRP), interleukin (IL)-6, TNFR1 and TNFR2, advanced glycation end products (AGEs), and the sRAGE were measured in serum.Results: There were higher CRP and AGEs concentrations in smokers and in patients with COPD (P

Renata Ferrari,1 Laura MO Caram,1 Marcia M Faganello,2 Fernanda F Sanchez,3 Suzana E Tanni,1 Irma Godoy1 1Botucatu Medical School, Department of Internal Medicine, Pneumology Area, Botucatu, São Paulo, 2Paulista State University, Department of Physiotherapy and Occupational Therapy, Marilia, São Paulo, 3Federal University of Amazonas, Department of Physiotherapy, Manaus, Amazonas, Brazil Abstract: The aim of this study was to investigate the association between systemic inflammatory mediators and peripheral muscle mass and strength in COPD patients. Fifty-five patients (69% male; age: 64±9 years) with mild/very severe COPD (defined as forced expiratory volume in the first second [FEV1] =54%±23%) were evaluated. We evaluated serum concentrations of IL-8, CRP, and TNF-α. Peripheral muscle mass was evaluated by computerized tomography (CT); midthigh cross-sectional muscle area (MTCSA) and midarm cross-sectional muscle area (MACSA) were obtained. Quadriceps, triceps, and biceps strength were assessed through the determination of the one-repetition maximum. The multiple regression results, adjusted for age, sex, and FEV1%, showed positive significant association between MTCSA and leg extension (0.35 [0.16, 0.55]; P=0.001), between MACSA and triceps pulley (0.45 [0.31, 0.58]; P=0.001), and between MACSA and biceps curl (0.34 [0.22, 0.47]; P=0.001). Plasma TNF-α was negatively associated with leg extension (-3.09 [-5.99, -0.18]; P=0.04) and triceps pulley (-1.31 [-2.35, -0.28]; P=0.01), while plasma CRP presented negative association with biceps curl (-0.06 [-0.11, -0.01]; P=0.02). Our results showed negative association between peripheral muscle mass (evaluated by CT) and muscle strength and that systemic inflammation has a negative influence in the strength of specific groups of muscles in individuals with stable COPD. This is the first study showing association between systemic inflammatory markers and strength in upper limb muscles. Keywords: Inflammation, skeletal muscle, X-Ray Computed Tomography

Ilda Godoy,1 Suzana Erico Tanni,2 Carme Hernández,3 Irma Godoy21Department of Nursing, Botucatu School of Medicine, Universidade Estadual Paulista, Botucatu, São Paulo, Brazil; 2Department of Pulmonology, Botucatu School of Medicine, Universidade Estadual Paulista, São Paulo, Brazil; 3Integrated Care Unit, Hospital Clinic, Barcelona, SpainPurpose: Long-term oxygen therapy (LTOT) is one of the main treatments for patients with chronic obstructive pulmonary disease. Patients receiving LTOT may have less than optimal home conditions and this may interfere with treatment. The objective of this study was, through home visits, to identify the characteristics of patients receiving LTOT and to develop knowledge regarding the home environments of these patients.Methods: Ninety-seven patients with a mean age of 69 plus or minus 10.5 years were evaluated. This study was a cross-sectional descriptive analysis. Data were collected during an initial home visit, using a questionnaire standardized for the study. The results were analyzed retrospectively.Results: Seventy-five percent of the patients had chronic obstructive pulmonary disease, and 11% were active smokers. The patients’ mean pulse oximetry values were 85.9% plus or minus 4.7% on room air and 92% plus or minus 3.9% on the prescribed flow of oxygen. Most of the patients did not use the treatment as prescribed and most used a humidifier. The extension hose had a mean length of 5 plus or minus 3.9 m (range, 1.5–16 m). In the year prior to the visit, 26% of the patients received emergency medical care because of respiratory problems. Few patients reported engaging in leisure activities.Conclusion: The home visit allowed us to identify problems and interventions that could improve the way LTOT is used. The most common interventions related to smoking cessation, concentrator maintenance and cleaning, use of a humidifier, and adjustments of the length of the connector hose. Therefore, the home visit is a very important tool in providing comprehensive care to patients receiving LTOT, especially those who show lack of adequate progress and those who show uncertainty about the treatment method.Keywords: LTOT, home visits, chronic obstructive pulmonary disease (COPD), treatment compliance

Abstract Background Smoking is known to be associated with oxidative stress; however, it has not been elucidated whether the oxidative response is influenced by the intensity of smoking exposure. Objectives Evaluate the effect of smoking exposure on the secretion of hydrogen peroxide (H2O2) by the peripheral blood monocytes of smokers. Methods A total of 25 smokers (50.3±8.8 years, 48% male) underwent the following evaluations: spirometry, pulse oximetry, body composition and total peripheral blood count. Peripheral blood monocyte (PBM) cultures were isolated and maintained, and IL-6 and TNF-α were measured in the plasma and in the supernatants of spontaneous and stimulated cultures. H2O2 was evaluated in the supernatants of the PBM cultures, and a subset of the PBM culture supernatants was stimulated with phorbol myristate acetate (PMA). We also evaluated 38 healthy controls (49.1±8.2 years, 42% male). Results The spontaneous and stimulated monocytes’ secretion of H2O2 were statistically higher in the smokers than in the healthy controls (p2O2 secretions were statistically significant higher after stimulation with PMA in both groups (p2O2 by PBM culture, adjusted for potential confounding variables. The association between PBM culture secretion of H2O2 and the production of TNF-α and IL-6 was not significant. Conclusion We identified a positive association between higher production of H2O2 in smokers and higher smoking exposure during life. The influence of pack-years smoking may be a key modifiable factor in oxidative stress associated to smoking.

Abstract Background The association between disease markers and health status (HS) overtime is unclear. The aim of this study was to verify the predictors of HS at baseline and after three years in Chronic Obstructive Pulmonary Disease (COPD) patients. Methods Ninety-five consecutive COPD patients (66% male, age = 67 ± 9 y, FEV1 = 58 ± 23%) underwent the following evaluations at baseline and after three years: body composition, pulse oximetry (SpO2), six-minute walk distance (6MWD), Modified edical Research Council dyspnea scale (MMRC) and Saint George's Respiratory Questionnaire (SGRQ). The Charlson comorbidity index and BODE index were calculated. COPD exacerbations during the follow-up were evaluated. At baseline, age, gender, smoking, SpO2, BODE index or its components (BMI, MMRC, FEV1 and 6MWD), and Charlson index were included in a multiple linear regression analysis with the baseline SGRQ total score as the dependent variable. After three years, we included the final values of the variables plus the number of exacerbations and the final SGRQ total score as the dependent variable. Results SGRQ total score (42 ± 19% vs 44 ± 19%; p = 0.041) and activity domain (52 ± 21% vs 60 ± 22%; p < 0.001) deteriorated during follow-up. At baseline, BODE index was selected as a predictor of SGRQ total score (R2 = 0.46; p < 0.001); after three years, BODE index and age were the predictors (R2 = 0.49; p < 0.001). When the BODE index was replaced by its variables, MMRC was selected as the only variable associated with the SGRQ total score (R2 = 0.58; p < 0.001). After three years, MMRC, FEV1 and number of exacerbations were selected as predictors of SGRQ total score (R2 = 0.63; p < 0.001). Conclusion HS deteriorated significantly over the three-year period and the predictors of HS do not change over time. BODE index and dyspnea were predictors at baseline and after three years. Exacerbation was also a predictor of HS after three years. Trial Registration ClinicalTrials.gov: NCT00605540

Abstract Background Smoking cause airway and systemic inflammation and COPD patients present low grade inflammation in peripheral blood. However, data on the influence of smoking itself on systemic inflammation in COPD patients are scarce. This study investigated the association between inflammation, smoking status, and disease. Methods A cross-sectional analysis comparing 53 COPD ex-smokers, 24 COPD current smokers, 24 current smoker controls and 34 never-smoker controls was performed. Assessments included medical history, body composition, spirometry, and plasma concentration of tumor necrosis factor-alpha (TNF-α), interleukins (IL)-6, IL-8, and C-reactive protein (CRP). Results Our exploratory analysis showed that serum TNF-α was higher in COPD current smokers [4.8(4.2-5.8)pg/mL] and in current smoker controls [4.8 (4.2-6.1) pg/mL] when compared to COPD ex-smokers [4.3 (3.9-4.9)pg/mL; p = 0.02] and to never-smoker controls [3.7 (3.4-4.0)pg/mL; p < 0.001]. Multiple regression results with and without adjustment for covariates were consistent with the hypothesis that TNF-α levels were associated with smoking status in both models (p < 0.001 and p < 0.001). IL-6 and CRP were significantly higher in COPD patients when compared to smoker and never-smoker controls and the multiple regression analysis confirmed the association of these mediators with disease, but not with smoking status (p < 0.001 and p < 0.001). IL-8 had only a borderline association with disease in both models (p = 0.069 and p = 0.053). No influence of disease severity, inhaled corticosteroid, fat-free mass (FFM) depletion and long term oxygen therapy (LTOT) use on systemic inflammation was found. Conclusion Smoking may influence TNF-α mediated systemic inflammation, which, in turn, may account for some of the benefits observed in patients with COPD who stop smoking.

Background: Long COVID-19 has been characterized by the presence of symptoms lasting longer than 4 weeks after the acute infection. The pathophysiology of clinical manifestations still lacks knowledge. Objective: The objective of this paper was to evaluate metabolite abundance in the saliva of long COVID patients 60 days after hospital discharge. Methods: A convenience sample was composed of 30 post-discharge patients with long COVID and seven non-COVID-19 controls. All COVID-19 patients were evaluated by demographic characteristics, spirometry, 6 min walk test (6mWT), Saint George Respiratory Questionnaire (SGRQ), and body composition. Metabolomics was performed on saliva. Results: The long COVID-19 patients were 60.4 ± 14.3 years-old, and 66% male. Their lean body mass was 30.7 ± 7.3 kg and fat mass, 34.4 ± 13.7 kg. Spirometry evaluation showed forced vital capacity (FVC) of 3.84 ± 0.97 L with 96.0 ± 14.0% of the predicted value, and forced expiratory volume in the first second (FEV 1 ) of 3.11 ± 0.83 L with 98.0 ± 16.0 of the predicted value. The long COVID-19 patients had reduced maximal inspiratory (90.1 ± 31.6 cmH 2 O) and maximal expiratory (97.3 ± 31.0 cmH 2 O) pressures. SGRQ showed domain symptoms of 32.3 ± 15.2, domain activities of 41.9 ± 25.6, and domain impact 13.7 ± 11.4, with a mean of 24.3 ± 14.9%. Physical capacity measured by distance covered in the 6mWT was 418.2 ± 130 m with a 73.3% (22.3-98.1) predictive value. The control group consisted of 44.1 ± 10.7-year-old men with a body mass index of 26.5 ± 1.66 Kg/m 2 . Metabolomics revealed 19 differentially expressed metabolites; expression was lower in 16 metabolites, and 2 metabolites were absent in the COVID-19 patients compared to controls. Calenduloside G methyl ester ( p = 0.03), Gly Pro Lys ( p = 0.0001), and creatine ( p = 0.0001) expressions were lower in patients than controls. Conclusions: Long COVID-19 patients present less abundance of calenduloside G methyl ester, Gly Pro Lys, and creatine in saliva than healthy controls. Lower creatine abundance may be related to reduced physical capacity and 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., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of this study; in the collection, analyses, or interpretation of the data; in the writing of this manuscript; or in the decision to publish the results.

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.

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., Competing Interests: Biophytis declares that potential commercial interests had no impact on the scientific conduct of the study nor on the analysis/interpretation of data. Cendrine Tourette, Luis Esmeraldino, Pierre Jean Dilda, René Lafont, Serge Camelo, Sandrine Rabut, Waly Dioh, Rob van Maanen and Stanislas veillet are Biophytis company employees, Anait Azbekyan Samuel Agus and Mounia Chabane are former Biophytis company employees. Jean Mariani is emeritus professor at Sorbonne University and consultant for Biophytis, Richard Kay is a consultant for Biophytis. Alpesh Amin, MD declares that as principal investigator or co-investigator of clinical trials sponsored by NIH/NIAID, NeuroRx Pharma, Pulmotect, Blade Therapeutics, Novartis, Takeda, Humanigen, Eli Lilly, PTC Therapeutics, OctaPharma, Fulcrum Therapeutics, Alexion, BioPhysitis its institution received payments and that he personnally received consultant fees from BMS, Pfizer, BI, Portola, Sunovion, Mylan, Salix, Alexion, AstraZeneca, Novartis, Nabriva, Paratek, Bayer, Tetraphase, Achogen LaJolla, Ferring, Seres, Spero, Eli Lilly, Gilead, Millenium, HeartRite, Aseptiscope, and Sprightly; but that these relationships were unrelated to the current work. Shaheen Islam, MD declares that he received grants or was in contract as a principal or sub investigator from the following companies:–Pliant therapeutics: INTEGRIS-ARDS, drug (PLN74809) Covid -trial 2021 (PI).—CytoDyn, Inc.: CD12-COVID 19 Drug: Leronlimab COVID trial 2020 (PI). -Pluristem Ltd.: PLX-COV-01. Drug PLX-PAD, COVID Trial 2020 (Sub-I).—Edesa Biotech Inc.: EB05-04-2020. Drug: EB05 COVID Trial 2020 (Sub-I). Fabiano Ramos, MD declares that its institution: Hospital São Lucas da Pontíficia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil received financial resources to conduct the study from Biophytis. Brian Snyder, MD declares that he receives research funding from Biophytis as part of the present clinical trial. Moreover, he declares that he received grants or has contracts with Behring, and Rheonix as part of COVID research studies. None of the other investigators declare any relationship related to the current work., (© 2023 The Author(s).)

(1) Background: A high concentration of sodium chloride on in vitro cell culture leads to reduced SARS-CoV-2 replication. Therefore, our aim was to evaluate the effects of inhaling hypertonic NaCl particles (BREATHOX ® ) on the duration of COVID-19-induced acute symptoms. (2) Methods: A prospective, open label, randomized, standard of care-controlled group (SOC) pilot trial compared inhaled oral and nasal administered BREATHOX ® (2.0 mg NaCl, particles size between 1-10 μm), with five or ten inhalations per day for ten days. The primary endpoint was the time to resolve COVID-19-related symptoms. Safety outcomes included adverse clinical and laboratory events. (3) Results: A total of 101 individuals were screened and 98 were randomly assigned to BREATHOX ® ten sessions per day (Group 1; 33 patients), BREATHOX ® five sessions per day (Group 2; 32 patients), or SOC (33 patients), and followed up for 28 days. There was an association with cough frequency after 10 days BREATHOX ® compared to SOC [Group 1: hazard ratio (HR) 2.01, 95% confidence interval (CI) 1.06-3.81; Group 2: HR 2.17, 95% CI 1.17-4.04]. No differences between the groups for the reported symptoms' resolution time were seen after 28 days. After combining both BREATHOX ® groups, the period to cough resolution 10 days after randomization was significantly lower than in SOC (HR 2.10, 95% CI 1.20-3.67). An adverse event occurred in 30% of Group 1, 36% of Group 2, and 9% in SOC individuals. One patient from SOC had a serious adverse event. Nasal burning, sore or itchy nose, and dry mouth were considered related to BREATHOX ® use and resolved after stopping inhalations. (4) Conclusion: BREATHOX ® inhalation is safe and may be effective in reducing the duration of COVID-19-induced coughing.

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., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: Clinical practice guidelines (CPGs) are often created through collaboration among organizations. The use of inconsistent terminology may cause poor communication and delays. This study aimed to develop a glossary of terms related to collaboration in guideline development., Study Design and Setting: A literature review of collaborative guidelines was performed to develop an initial list of terms related to guideline collaboration. The list of terms was presented to the members of the Guideline International Network Guidelines Collaboration Working Group, who provided presumptive definitions for each term and proposed additional terms to be included. The revised list was subsequently reviewed by an international, multidisciplinary panel of expert stakeholders. Recommendations received during this pre-Delphi review were implemented to augment an initial draft glossary. The glossary was then critically evaluated and refined through two rounds of Delphi surveys and a virtual consensus meeting with all panel members as Delphi participants., Results: Forty-nine experts participated in the pre-Delphi survey, and 44 participated in the two-round Delphi process. Consensus was reached for 37 terms and definitions., Conclusion: Uptake and utilization of this guideline collaboration glossary by key organizations and stakeholder groups may facilitate collaboration among guideline-producing organizations by improving communication, minimizing conflicts, and increasing guideline development efficiency., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The hippocampus occupies a central role in mammalian navigation and memory. Yet an understanding of the rules that govern the statistics and granularity of the spatial code, as well as its interactions with perceptual stimuli, is lacking. We analyzed CA1 place cell activity recorded while rats foraged in different large-scale environments. We found that place cell activity was subject to an unexpected but precise homeostasis-the distribution of activity in the population as a whole being constant at all locations within and between environments. Using a virtual reconstruction of the largest environment, we showed that the rate of transition through this statistically stable population matches the rate of change in the animals' visual scene. Thus, place fields near boundaries were small but numerous, while in the environment's interior, they were larger but more dispersed. These results indicate that hippocampal spatial activity is governed by a small number of simple laws and, in particular, suggest the presence of an information-theoretic bound imposed by perception on the fidelity of the spatial memory system., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)