Asthma in the Brazilian Unified Health Care System: an epidemiological analysis from 2008 to 2021.

OBJECTIVE: To analyze the number of hospitalizations, the length of hospital stay, and mortality due to asthma, as well as the costs to the Unified Health Care System in Brazil between 2008 and 2021. METHODS: This was a cross-sectional epidemiological study using data from the Information Technology Department of the Brazilian Unified Health Care System. Proportional hospitalization and death rates were estimated per 100,000 population by age, microregion, and year. RESULTS: The number of hospitalizations and deaths due to asthma decreased from 2008 to 2021 (205,392 vs. 55,009 and 822 vs. 327, respectively). In addition, a between-sex difference was observed in asthma-related hospitalizations in 2008, and more men were hospitalized in 2021 (51.8%). Asthma mortality rates were similar for both sexes (50.0% each) in 2008, and a slight increase was observed in women's deaths in 2021 (52.9%). Even so, approximately one death/day and more than 55,000 hospitalizations were observed yearly, with a mean length of hospital stay of three days. Additionally, the Southeast region allocated more financial resources to asthma-related hospitalizations. CONCLUSIONS: Our results showed that the number of deaths and hospitalizations due to asthma substantially declined during the study period.

Postural balance in COPD with obstructive sleep apnoea: a cross-sectional study.

Objective: The aim of this study was to assess the postural balance in COPD patients with obstructive sleep apnoea (OSA). Physical activity, anxiety and depression symptoms, mood, and falls were also assessed in this population. Methods: Moderate to severe COPD patients were assessed for laboratory and clinical postural balance (force platform and mini-balance evaluation systems test (Mini-BESTest)), physical activity (accelerometry), OSA (polysomnography), sleep quality (Pittsburgh Sleep Quality Index), sleepiness (Epworth Sleepiness Scale), anxiety and depression symptoms (Hospital Anxiety and Depression Scale), dyspnoea (modified Medical Research Council), clinical status (COPD Assessment Test) and mood (Brunel Mood Scale). Self-reported falls were recorded for 6 months via phone calls. Results: COPD patients (n=70) were divided according to the polysomnography findings into the no OSA (n=30), mild OSA (n=25), and moderate to severe OSA (n=15) groups. Compared to patients with no OSA, those with moderate to severe OSA (msOSA group) presented median (interquartile range) increased path length (30.5 (23.9-34.5) cm versus 39.0 (30.6-52.6) cm, anteroposterior displacement (1.89 (1.39-2.31) cm versus 2.54 (2.06-2.83) cm and postural adjustment velocity (1.02 (0.80-1.15) cm·s-1 versus 1.30 (1.02-1.76) cm·s-1) (p<0.05). No differences were observed in the Mini-BESTest scores among the groups. The msOSA group presented a greater number of recurrent fallers in the first follow-up trimester. No association was observed between postural balance and age and pulmonary function. Conclusion: Individuals with COPD and moderate to severe OSA present changes in postural balance, including broader oscillation, faster postural adjustments and a greater risk of falls than those with no OSA. Physical activity, anxiety and depression symptoms, and mood are similar between COPD patients with and without OSA.

Physical Activity and Sedentary Behavior as Treatable Traits for Clinical Control in Moderate-to-Severe Asthma.

BACKGROUND: Physical activity and sedentary behavior are treatable traits that may impact asthma control in distinct manners, but this impact remains poorly understood. OBJECTIVE: To evaluate the influence of physical activity and sedentary behavior on clinical control in adults with moderate-to-severe asthma. METHODS: This cross-sectional, multicentric study included 426 individuals with moderate-to-severe asthma. Assessments included physical activity and sedentary time (actigraphy), clinical asthma control (Asthma Control Questionnaire [ACQ]), quality of life (Asthma Quality of Life Questionnaire), anxiety and depression symptoms (Hospital Anxiety and Depression Scale), anthropometric data, and lung function. Participants were grouped according to physical activity levels and sedentary behavior. RESULTS: Participants who walked ≥7500 steps/day presented better ACQ scores than those who walked <7500 steps/day (P < .05), independent of sedentary status. The percentage of patients with controlled asthma was higher in the active/sedentary (43.9%) and active/nonsedentary (43.8%) groups than in the inactive/sedentary (25.4%) and inactive/nonsedentary (23.9%) groups (P < .02). The likelihood of having uncontrolled asthma according to the treatable traits of physical inactivity (odds ratio [95% confidence interval]: 2.36 [1.55-3.59]), higher anxiety (2.26 [1.49-3.42]), and depression symptoms (1.95 [1.28-2.95]) was significant (P ≤ .002). Obesity and sedentary time were not associated with asthma control. CONCLUSIONS: Our results show that ≥7500 steps/day is associated with better asthma control independent of sedentary time in adults with moderate-to-severe asthma. Physical inactivity, anxiety, and depression symptoms are associated with higher odds of uncontrolled asthma. These results suggest that interventions should mainly focus on increasing physical activity rather than reducing sedentary time.

Effects of constant-load exercise and high-intensity interval training on reliever medication consumption and peak expiratory flow in individuals with asthma: a randomised controlled trial.

Introduction: The effect of aerobic training on reliever medication consumption (short-acting ß2-agonist (SABA)) and peak expiratory flow (PEF) in participants with asthma is poorly known. The comparison between constant-load exercise (CLE) and high-intensity interval training (HIIT) in these outcomes has never been tested. The purpose of the present study was to compare the effects of CLE or HIIT in SABA consumption and PEF improvement during an exercise programme in subjects with asthma. Methods: Clinically stable participants were randomised into CLE (n=27; 70-85% of the maximal load (Wmax)) or HIIT (n=28; 80-140% Wmax). The programme lasted 12 weeks (two sessions per week, 40 min per session), and the intensity was based on cardiopulmonary exercise testing (CPET). PEF was assessed before and after each exercise session. SABA was used if PEF was <70%. Clinical control (Asthma Control Questionnaire (ACQ)-6), CPET and aerobic fitness were also assessed before and after the intervention. Results: Both groups were similar at baseline. CLE and HIIT reduced SABA consumption throughout the intervention (p<0.05). Before training, 14 patients required SABA before exercising, but only one needed it after the intervention. Changes in post-exercise PEF were lower in the CLE group than in the HIIT group (1.6±25.3 versus 10.3±13.7%). Both groups improved aerobic fitness (10.1±12.8% versus 5.7±15.6%) and clinical asthma control; however, only the HIIT group achieved a minimal clinically important difference in the ACQ-6 post-intervention (-0.23±1.06 versus -0.52±0.73 Δ score). Conclusion: CLE and HIIT reduced SABA consumption; however, only HIIT increased PEF and asthma clinical control after the intervention. These results reinforce the importance of exercise training in moderate-to-severe asthma.

Elastic tape reduces dyspnea and improves health status in the short term in nonobese COPD males: A randomized controlled trial.

INTRODUCTION AND OBJECTIVES: The elastic tape (ET) is a novel intervention that acutely improves exercise capacity in laboratory tests; however, its effect on a patient's daily life remains unknown. This randomized controlled trial evaluated the effects of ET on daily life physical activity (DLPA), dyspnea symptoms, health status, and health-related quality of life (HRQoL) in individuals with COPD. METHODS: Fifty males with moderate to very severe COPD were randomly assigned to an intervention group (ETG, n = 25), receiving ET on the chest wall and abdomen, or a control group (CG, n = 25). The intervention was for 14 days. DLPA (accelerometry; steps per day, and sedentary time), dyspnea symptoms (transition dyspnea index, TDI; and modified Medical Research Council, mMRC), health status (COPD assessment test, CAT), and health-related quality of life (HRQoL, CRQ) were evaluated at baseline and on Day 21 after the intervention. RESULTS: No change in the DLPA was observed in between-group comparison. CG presented a reduction in step counts after 21days (-707,p <0.05) while ETG. maintained (-114,p > 0.94). However, ET reduced dyspnea symptoms in all TDI domains (functional, task, and effort) and on the mMRC scale after 14 days compared with CG (p < 0.01). Also, the ETG improved CAT score compared to the CG, reaching minimal clinical important difference (MCID) (-4.4 score, p <0.01). The ETG also improved in most CRQ domains reaching MCID after 21 days. CONCLUSIONS: ET does not modify DLPA but reduces dyspnea and improves health status and HRQoL in nonobese males with moderate to very severe COPD in the short term. This novel and low-cost intervention improves COPD symptoms.

Asthma in the Brazilian Unified Health Care System: an epidemiological analysis from 2008 to 2021

ABSTRACT Objective: To analyze the number of hospitalizations, the length of hospital stay, and mortality due to asthma, as well as the costs to the Unified Health Care System in Brazil between 2008 and 2021. Methods: This was a cross-sectional epidemiological study using data from the Information Technology Department of the Brazilian Unified Health Care System. Proportional hospitalization and death rates were estimated per 100,000 population by age, microregion, and year. Results: The number of hospitalizations and deaths due to asthma decreased from 2008 to 2021 (205,392 vs. 55,009 and 822 vs. 327, respectively). In addition, a between-sex difference was observed in asthma-related hospitalizations in 2008, and more men were hospitalized in 2021 (51.8%). Asthma mortality rates were similar for both sexes (50.0% each) in 2008, and a slight increase was observed in women's deaths in 2021 (52.9%). Even so, approximately one death/day and more than 55,000 hospitalizations were observed yearly, with a mean length of hospital stay of three days. Additionally, the Southeast region allocated more financial resources to asthma-related hospitalizations. Conclusions: Our results showed that the number of deaths and hospitalizations due to asthma substantially declined during the study period.

Tobacco exposure, but not aging, shifts the frequency of peripheral blood B cell subpopulations.

Several disturbances in T-cell mediated immunity have been described during aging, but immunosenescence of the B-cell compartment is less well elucidated. The peripheral blood B-cell compartment (CD19+) can be split into six main subpopulations according to the cell surface markers IgD, CD27, CD24, and CD38: Transitional, naïve, unswitched, switched, double negative and plasmablasts. We thus aimed to verify whether shifts in these subsets occur during healthy and pathological aging. We recruited three groups of aged people (> 60 years old), healthy, COPD patients, and smokers without altered pulmonary function test, and a fourth group of individuals 18-40 years old (youngs). Total B-cells percentage and absolute number were similar among the healthy aged, COPD patients, and youngs, but the smokers showed significantly higher absolute numbers. While all six B-cell subset percentages were comparable among the healthy aged, COPD patients, and youngs, smokers showed significantly higher percentages of switched B-cells and reduced naïve B-cells than the other three groups, resulting in an inverted naive:switched ratio. Analysis of the cell subset absolute numbers showed a similar trend. Overall, our results suggest that aging drives milder alterations in the distribution of peripheral blood B-cell subpopulations than in the T-cell compartment. We suggest that it is the T-cell immunosenescence that most contributes to the poor humoral immune responses in the elderly, vaccine responses included. Surprisingly it was the smokers who showed significant alterations when compared with the youngs, healthy aged, and aged COPD patients, probably as a result of the chronic immune stimulation described in active smoking subjects.

Identifying the Characteristics of Responders and Nonresponders in a Behavioral Intervention to Increase Physical Activity Among Patients With Moderate to Severe Asthma: Protocol for a Prospective Pragmatic Study.

BACKGROUND: Previous research has suggested that most adults improve their asthma control after a short-term behavioral intervention program to increase physical activity in daily life (PADL). However, the characteristics of individuals who respond and do not respond to this intervention and the medium-term response remain unknown. OBJECTIVE: This study aims to (1) identify the characteristics of adult responders and nonresponders with asthma to a behavioral intervention to increase physical activity and (2) evaluate the functional and clinical benefits in the medium term. METHODS: This prospective pragmatic study will include adults with moderate to severe asthma who enroll in a behavioral intervention. All individuals will receive an educational program and an 8-week intervention to increase PADL (1 time/wk; up to 90 min/session). The educational program will be conducted in a class setting through group discussions and video presentations. Behavioral interventions will be based on the transtheoretical model using counseling, incentives, and individual feedback aiming to increase participation in physical activity. Motivational interviewing and guidelines for overcoming barriers will be used to stimulate individuals to reach their goals. Pre- and postintervention assessments will include the following: PADL (triaxial accelerometry), body composition (octopolar bioimpedance), barriers to PADL (questionnaire), clinical asthma control (Asthma Control Questionnaire), quality of life (Asthma Quality of Life Questionnaire), anxiety and depression levels (Hospital Anxiety and Depression Scale), and exacerbations. "Responders" to the intervention will be defined as those who demonstrate an increase in the number of daily steps (≥2500). RESULTS: In December 2021, the clinical trial registration was approved. Recruitment and data collection for the trial is ongoing, and the results of this study are likely to be published in late 2024. CONCLUSIONS: The intervention will likely promote different effects according to the clinical characteristics of the individuals, including asthma control, age, anxiety and depression levels, obesity, and several comorbidities. Identifying individuals who respond or do not respond to behavioral interventions to increase PADL will help clinicians prescribe specific interventions to adults with asthma. TRIAL REGISTRATION: ClinicalTrials.gov NCT05159076; https://clinicaltrials.gov/ct2/show/NCT05159076. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/49032.

Characteristics of individuals with moderate to severe asthma who better respond to aerobic training: a cluster analysis.

OBJECTIVE: To determine the characteristics of individuals with asthma who are responsive to aerobic training. METHODS: This post hoc analysis of pooled data from previous randomized controlled trials involved 101 individuals with moderate to severe asthma who underwent aerobic training. Participants underwent a maximal cardiopulmonary exercise test and completed the Asthma Control Questionnaire and the Asthma Quality of Life Questionnaire before and after a 24-session aerobic training program. Better and worse responders to aerobic training were identified by cluster analysis. RESULTS: Two clusters were identified according to the improvement in peak VO2 after aerobic training (better and worse responders). Characteristics of the better responder group were being older, being female, having higher BMI, and having higher cardiac reserve at baseline when compared with the worse responder group. Also, better responders had worse clinical control, worse quality of life, and lower physical capacity at baseline. After training, worse responders, in comparison with better responders, showed half the improvement in Δpeak VO2 (7.4% vs. 13.6%; 95% CI, -12.1 to -0.92%; p < 0.05) and worse asthma control. A weak, negative, but significant association (r = -0.35; p < 0.05) was observed between clinical control and aerobic fitness only in the better responder group. Both groups showed significant improvement in quality of life. CONCLUSIONS: Obese individuals with worse exercise capacity, clinical control, and quality of life showed improvement with aerobic training. Moreover, worse responders also improved with training, but to a lesser extent.

Increased physical activity reduces sleep disturbances in asthma: A randomized controlled trial.

BACKGROUND AND OBJECTIVE: Individuals with asthma are more likely to develop sleep-disordered breathing. Exercise training improves sleep; however, the effect of physical activity (PA) on improving sleep quality remains unknown. This study had two objectives: (i) to evaluate the effect of a behavioural intervention to increase physical activity in daily living (PADL) on sleep quality in adults with asthma; (ii) to verify the association between a change in sleep quality, quality of life, anxiety, depression and asthma symptoms. METHODS: This randomized controlled clinical trial included adults physically inactive with asthma. Participants were randomized into the control (CG; n = 25) and intervention groups (IG; n = 24). IG was submitted to a behavioural intervention to increase PADL, and CG received the usual care. Pre- and post-intervention assessments of sleep quality (by actigraphy and questionnaire), PADL level (by accelerometry), asthma control, health-related quality of life and anxiety and depression levels were conducted. RESULTS: Both groups were similar at baseline. After the intervention, IG increased daily steps and moderate to vigorous PA levels. IG also improved sleep efficiency and latency as well as increased asthma-symptom-free days compared to CG. In addition, a greater proportion of participants in the IG had improved sleep quality after the intervention. Lastly, IG presented clinical improvement in the asthma-related quality of life questionnaire and a reduction in anxiety symptoms. CONCLUSION: Our results demonstrate that a behavioural intervention can increase PA, enhance behavioural sleep quality, efficiency and quality of life and reduce asthma and anxiety symptoms.

Characteristics of individuals with moderate to severe asthma who better respond to aerobic training: a cluster analysis / Características de indivíduos com asma moderada a grave que melhor respondem a treinamento aeróbio: análise de conglomerados

ABSTRACT Objective: To determine the characteristics of individuals with asthma who are responsive to aerobic training. Methods: This post hoc analysis of pooled data from previous randomized controlled trials involved 101 individuals with moderate to severe asthma who underwent aerobic training. Participants underwent a maximal cardiopulmonary exercise test and completed the Asthma Control Questionnaire and the Asthma Quality of Life Questionnaire before and after a 24-session aerobic training program. Better and worse responders to aerobic training were identified by cluster analysis. Results: Two clusters were identified according to the improvement in peak VO2 after aerobic training (better and worse responders). Characteristics of the better responder group were being older, being female, having higher BMI, and having higher cardiac reserve at baseline when compared with the worse responder group. Also, better responders had worse clinical control, worse quality of life, and lower physical capacity at baseline. After training, worse responders, in comparison with better responders, showed half the improvement in Δpeak VO2 (7.4% vs. 13.6%; 95% CI, −12.1 to −0.92%; p < 0.05) and worse asthma control. A weak, negative, but significant association (r = −0.35; p < 0.05) was observed between clinical control and aerobic fitness only in the better responder group. Both groups showed significant improvement in quality of life. Conclusions: Obese individuals with worse exercise capacity, clinical control, and quality of life showed improvement with aerobic training. Moreover, worse responders also improved with training, but to a lesser extent.

RESUMO Objetivo: Determinar as características de indivíduos com asma responsivos a treinamento aeróbio. Métodos: Esta análise post hoc de dados agrupados provenientes de ensaios clínicos controlados randomizados anteriores envolveu 101 indivíduos com asma moderada a grave submetidos a treinamento aeróbico. Os participantes foram submetidos a um teste de exercício cardiopulmonar máximo e responderam ao Asthma Control Questionnaire e ao Asthma Quality of Life Questionnaire antes e depois de um programa de treinamento aeróbio de 24 sessões. Melhores e piores respondedores ao treinamento aeróbio foram identificados por análise de conglomerados. Resultados: Foram identificados dois conglomerados de acordo com a melhora do VO2 de pico após o treinamento aeróbio (melhores e piores respondedores). As características do grupo melhor respondedor foram maior idade, sexo feminino, IMC mais elevado e maior reserva cardíaca basal em comparação com o grupo pior respondedor. Os melhores respondedores também apresentavam pior controle clínico, pior qualidade de vida e menor capacidade física basal. Após o treinamento, os piores respondedores, em comparação com os melhores respondedores, apresentaram metade da melhora no ΔVO2 de pico (7,4% vs. 13,6%; IC95%: -12,1 a -0,92%; p < 0,05) e pior controle da asma. Observou-se uma associação negativa fraca, mas significativa (r = −0,35; p < 0,05) entre controle clínico e aptidão aeróbia apenas no grupo melhor respondedor. Ambos os grupos apresentaram melhora significativa da qualidade de vida. Conclusões: Os indivíduos obesos com pior capacidade de exercício, controle clínico e qualidade de vida apresentaram melhora com o treinamento aeróbio. Além disso, os piores respondedores também melhoraram com o treinamento, mas em menor grau.

Tissue management in precision medicine: What the pathologist needs to know in the molecular era.

Precision medicine is "an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person." Among many medical specialists involved in precision medicine, the pathologists play an important and key role in the implementation and development of molecular tests that are in the center of decision of many therapeutic choices. Besides many laboratory procedures directly involved in the molecular tests, is fundamental to guarantee that tissues and cells collected for analysis be managed correctly before the DNA/RNA extraction. In this paper we explore the pivotal and interconnected points that can influence molecular studies, such as pre-analytical issues (fixation and decalcification); diagnosis and material selection, including the calculation of nuclei neoplastic fraction. The standardization of sample processing and morphological control ensures the accuracy of the diagnosis. Tissue or cytological samples constitutes the main foundation for the determination of biomarkers and development of druggable targets. Pathology and precision oncology still have a long way to go in terms of research and clinical practice: improving the accuracy and dissemination of molecular tests, learning in molecular tumor boards for advanced disease, and knowledge about early disease. Precision medicine needs pathology to be precise.

Searching for SARS-CoV-2 in Cancer Tissues: Results of an Extensive Methodologic Approach based on ACE2 and Furin Expression.

SARS-CoV-2 pandemics have been massively characterized on a global scale by the rapid generation of in-depth genomic information. The main entry gate of SARS-CoV-2 in human cells is the angiotensin-converting enzyme 2 (ACE2) receptor. The expression of this protein has been reported in several human tissues, suggesting a correlation between SARS-CoV-2 organotropism and ACE2 distribution. In this study, we selected (a series of) 90 patients who were submitted to surgery for tumor removal between the beginning of the SARS-CoV-2 pandemic and the closure of operating rooms (by the end of March 2020) in two different countries-Portugal and Brazil. We evaluated the expressions of ACE2 and furin (another important factor for virus internalization) in colon (n = 60), gastric (n = 19), and thyroid (n = 11) carcinomas. In a subseries of cases with PCR results for SARS-CoV-2 detection in the peri-operatory window (n = 18), we performed different methodological approaches for viral detections in patient tumor samples. Our results show that colon and gastric carcinomas display favorable microenvironments to SARS-CoV-2 tropism, presenting high expression levels of ACE2 and furin. From the subseries of 18 cases, 11 tested positive via PCR detection performed in tumor blocks; however, a direct association between the ACE2 expression and SARS-CoV-2 infection was not demonstrated in cancer cells using histology-based techniques, such as immunohistochemistry or in situ hybridization. This study raises the possibility of ACE2-mediated viral tropism in cancer tissues to be clarified in future studies.

Age-associated phenotypic imbalance in TCD4 and TCD8 cell subsets: comparison between healthy aged, smokers, COPD patients and young adults.

BACKGROUND: COPD is associated with an abnormal lung immune response that leads to tissue damage and remodeling of the lung, but also to systemic effects that compromise immune responses. Cigarette smoking also impacts on innate and adaptative immune responses, exerting dual, pro- and anti-inflammatory effects. Previously, we showed that COPD patients presented accelerated telomere shortening and decreased telomerase activity, while, paradoxically, cigarette-smokers exhibited preserved telomerase activity and slower rate of telomere shortening. RESULTS: Here, we evaluated the naive, CM, EM and TEMRA subsets of TCD4 and TCD8 cells according to the expression of CCR7/CD45RA. We compared age-matched COPD patients, cigarette-smokers without clinical-laboratory evidence of pulmonary compromise, and healthy individuals. They were additionally compared with a group of young adults. For each subset we analysed the expression of markers associated with late differentiation, senescence and exhaustion (CD27/CD28/CD57/KLRG1/PD1). We show that COPD patients presented a drastically reduced naive cells pool, and, paradoxically, increased fractions of naive cells expressing late differentiation, senescence or exhaustion markers, likely impacting on their immunocompetence. Pronounced phenotypic alterations were also evidenced in their three memory T-cell subsets compared with the other aged and young groups, suggesting an also dysfunctional memory pool. Surprisingly, our smokers showed a profile closer to the Healthy aged than COPD patients. They exhibited the usual age-associated shift of naive to EM TCD4 and TCD8 cells, but not to CM or TEMRA T-cells. Nonetheless, their naive T-cells phenotypes were in general similar to those of the Youngs and Healthy aged, suggesting a rather phenotypically preserved subset, while the memory T-cells exhibited increased proportions of cells with the late-differentiation or senescence/exhaustion markers as in the Healthy aged. CONCLUSION: Our study extends previous findings by showing that COPD patients have cells expressing a full range of late differentiated, senescent or exhausted phenotypes encompassing all TCD4 and TCD8 subsets, consistent with a premature immunosenescence phenotype. Surprisingly, the smokers group's results suggest that moderate to heavy chronic cigarette smoking did not accelerate the pace of immunosenescence as compared with the Healthy aged.

2021 Brazilian Thoracic Association recommendations for the management of severe asthma.

Advances in the understanding that severe asthma is a complex and heterogeneous disease and in the knowledge of the pathophysiology of asthma, with the identification of different phenotypes and endotypes, have allowed new approaches for the diagnosis and characterization of the disease and have resulted in relevant changes in pharmacological management. In this context, the definition of severe asthma has been established, being differentiated from difficult-to-control asthma. These recommendations address this topic and review advances in phenotyping, use of biomarkers, and new treatments for severe asthma. Emphasis is given to topics regarding personalized management of the patient and selection of biologicals, as well as the importance of evaluating the response to treatment. These recommendations apply to adults and children with severe asthma and are targeted at physicians involved in asthma treatment. A panel of 17 Brazilian pulmonologists was invited to review recent evidence on the diagnosis and management of severe asthma, adapting it to the Brazilian reality. Each of the experts was responsible for reviewing a topic or question relevant to the topic. In a second phase, four experts discussed and structured the texts produced, and, in the last phase, all experts reviewed and approved the present manuscript and its recommendations.