Safety and Efficacy of Adipose-Derived Mesenchymal Stem Cell Therapy for Ischemic Heart Disease: A Systematic Review. / Segurança e Eficácia da Terapia com Células-tronco Mesenquimais Derivadas do Tecido Adiposo para Cardiopatia Isquêmica: Revisão Sistemática.

BACKGROUND: Cell therapy using adipose-derived mesenchymal stem cells (ADSCs) shows great potential as a treatment for cardiovascular diseases. OBJECTIVE: We conducted a systematic review to describe the safety and efficacy of ADSCs in ischemic heart disease. METHODS: We searched PubMed/MEDLINE, EMBASE, Web of Science, CENTRAL, and LILACS (from inception to March 2024) for clinical studies involving ADSCs in patients with ischemic heart disease. We excluded studies involving patients with other types of heart disease, studies using mesenchymal stem cells derived from other tissues, as well as ongoing studies. Two independent reviewers screened the retrieved citations, extracted relevant data, and assessed the risk of bias in the included trials, using the Cochrane Collaboration criteria modified by McMaster University and Methodological Index for Non-Randomized Studies (MINORS). We used a narrative synthesis to present the results. RESULTS: Ten studies (comprising 29 publications) met our inclusion criteria, including 8 randomized controlled trials and 2 uncontrolled trials. No severe adverse events associated with ADSC therapy were reported. While most efficacy endpoints did not reach statistical significance, there were reports of improved ischemic area, functional capacity, symptoms, and contractility in patients treated with ADSCs. CONCLUSIONS: The findings from our review suggest that ADSC therapy is generally safe for patients with ischemic heart disease. However, further investigation is warranted to confirm its efficacy, particularly with larger clinical trials and in specific conditions where improvements in microcirculation may have a notable impact on clinical outcomes.

FUNDAMENTO: A terapia celular utilizando células-tronco mesenquimais derivadas do tecido adiposo (ADSC, sigla em inglês) apresenta grande potencial como tratamento para doenças cardiovasculares. OBJETIVO: Realizamos uma revisão sistemática para descrever a segurança e a eficácia das ADSC na cardiopatia isquêmica. MÉTODOS: Pesquisamos na PubMed/MEDLINE, EMBASE, Web of Science, CENTRAL e LILACS (desde o início até março de 2024) por estudos clínicos envolvendo ADSC em pacientes com cardiopatia isquêmica. Excluímos estudos envolvendo pacientes com outros tipos de doenças cardíacas, estudos utilizando células-tronco mesenquimais derivadas de outros tecidos, bem como estudos em andamento. Dois revisores independentes realizaram a triagem das citações recuperadas, extraíram dados relevantes e avaliaram o risco de viés nos ensaios incluídos, utilizando os critérios da Colaboração Cochrane modificados pela Universidade McMaster e o Índice Metodológico para Estudos Não-Randomizados (MINORS). Utilizamos uma síntese narrativa para apresentar os resultados. RESULTADOS: Dez estudos (compreendendo 29 publicações) preencheram nossos critérios de inclusão, incluindo 8 ensaios controlados randomizados e 2 ensaios não controlados. Não foram relatados eventos adversos graves associados à terapia com ADSC. Embora a maioria dos desfechos de eficácia não tenha alcançado significância estatística, houve relatos de melhora da área isquêmica, capacidade funcional, sintomas e contratilidade em pacientes tratados com ADSC. CONCLUSÕES: Os resultados da nossa revisão sugerem que a terapia com ADSC é geralmente segura para pacientes com cardiopatia isquêmica. Contudo, são necessárias mais investigações para confirmar a sua eficácia, particularmente em ensaios clínicos de maior escala e em condições específicas onde as melhorias na microcirculação podem ter um impacto notável nos desfechos clínicos.

Effect of nuts on lipid profile and inflammatory biomarkers in atherosclerotic cardiovascular disease: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Nut-enriched diets are related to improve lipid and inflammatory biomarkers in meta-analyses in the context of primary cardiovascular prevention. However, primary studies on secondary cardiovascular prevention are scarce and controversial. This systematic review and meta-analysis aimed to evaluate the effect of nut supplementation on lipid and inflammatory profiles in individuals with atherosclerotic cardiovascular disease, and the frequency of adverse events. METHODS: Six databases were used for research: PubMed, EMBASE, BVS, Cochrane Library, Web of Science, and ClinicalTrials.gov, until February 2023, with no language restrictions. We performed random-effects meta-analyses to compare nut-enriched diets vs. control diets for pre-post intervention changes. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system assessed the evidence's certainty. RESULTS: From the 5187 records identified, eight publications containing data referring to five randomized clinical trials involving 439 participants were included in the final analyses. The nuts evaluated were almonds, pecans, Brazil nuts, and mixed nuts, with doses ranging between 5 g and 85 g (median: 30 g/day). The intervention time varied between 6 and 12 weeks. Compared to nut-free diets, nut intake did not have a statistically significant effect on lipid profile biomarkers, except on the atherogenic index (MD: -0.32 [95% CI -0.58 to -0.06], I2 = 0% - moderate certainty of the evidence). Similarly, there was no effect of nuts on inflammatory profile biomarkers. It was not possible to aggregate data on adverse events. CONCLUSIONS: Nut supplementation did not change lipid and inflammatory profiles in the secondary cardiovascular prevention setting.

Methodological guidelines and publications of benefit-risk assessment for health technology assessment: a scoping review.

OBJECTIVES: To map the available methodological guidelines and documents for conducting and reporting benefit-risk assessment (BRA) during health technologies' life cycle; and to identify methodological guidelines for BRA that could serve as the basis for the development of a BRA guideline for the context of health technology assessment (HTA) in Brazil. DESIGN: Scoping review. METHODS: Searches were conducted in three main sources up to March 2023: (1) electronic databases; (2) grey literature (48 HTA and regulatory organisations) and (3) manual search and contacting experts. We included methodological guidelines or publications presenting methods for conducting or reporting BRA of any type of health technologies in any context of the technology's life cycle. Selection process and data charting were conducted by independent reviewers. We provided a structured narrative synthesis of the findings. RESULTS: From the 83 eligible documents, six were produced in the HTA context, 30 in the regulatory and 35 involved guidance for BRA throughout the technology's life cycle. We identified 129 methodological approaches for BRA in the documents. The most commonly referred to descriptive frameworks were the Problem, Objectives, Alternatives, Consequences, Trade-offs, Uncertainty, Risk and Linked decisions and the Benefit-Risk Action Team. Multicriteria decision analysis was the most commonly cited quantitative framework. We also identified the most cited metric indices, estimation and utility survey techniques that could be used for BRA. CONCLUSIONS: Methods for BRA in HTA are less established. The findings of this review, however, will support and inform the elaboration of the Brazilian methodological guideline on BRA for HTA. TRIAL REGISTRATION NUMBER: https://doi.org/10.17605/OSF.IO/69T3V.

Effect of Nuts on Anthropometric and Glycemic Indexes and Blood Pressure in Secondary Cardiovascular Prevention: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

CONTEXT: Nut-enriched diets have a positive impact on cardiovascular risk factors, such as body mass, blood pressure, and fasting blood glucose. However, studies in individuals undergoing secondary cardiovascular prevention show controversial results. OBJECTIVE: This systematic review with meta-analysis assessed the effect of nut supplementation on anthropometric, glycemic, and blood pressure indices in patients with atherosclerotic cardiovascular disease, as well as the frequency of adverse events. DATA SOURCES: Six databases were used for the search-PubMed, Cochrane Library, EMBASE, BVS (Biblioteca Virtual da Saude), Web of Science, and ClinicalTrials.gov-until February 2023, with no language restrictions. DATA EXTRACTION: The Cochrane Handbook for Systematic Reviews of Interventions methodology and the PICOS (Population, Intervention, Comparison, Outcome, Setting/design) strategy were used. Seven independent reviewers were involved in data extraction and resolution of disagreements. Certainty of the evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. DATA ANALYSIS: From 5187 records identified, 6 publications containing data referring to 5 randomized clinical trials (n = 436) were included in the final analyses. The nuts evaluated were almonds, pecans, Brazil nuts, and mixed nuts, with portions that varied between 5 g and 85 g (median: 30 g/day). The intervention period varied between 6 and 12 weeks. The nuts had no effect on fasting glucose and anthropometric indices, although the certainty of the evidence for most of these outcomes was low or very low. They also had no effect on systolic (mean difference [MD]: -1.16 mmHg [95% CI, -5.68 to 3.35], I2 = 0%-moderate certainty of evidence) or diastolic (MD: 0.10 mmHg [95% CI, -2.30 to 2.51], I2 = 0%-high certainty of evidence) blood pressure. It was not possible to aggregate data on adverse events. CONCLUSION: Nut supplementation had no effect on blood pressure, fasting glucose, or anthropometric profile in the context of atherosclerotic cardiovascular disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42020163456.

Methodological guidelines and publications of benefit-risk assessment for health technology assessment: a scoping review protocol.

BACKGROUND: Benefit-risk assessment (BRA) is used in multiple phases along the health technology's life-cycle to evaluate the balance between the benefits and risks, as it is fundamental to all stakeholders. BRA and its methodological approaches have been applied primarily in the context of regulatory agencies. However, BRA's application and extent in the context of health technology assessment (HTA) bodies remain less clear. Our goal is to perform a scoping review to identify and map methodological guidelines and publications on methods of BRA. This will be done considering the different phases of the life-cycle of health technologies to underline both the depth and extent of research concerning BRA, especially in the context of HTA. METHODS AND ANALYSIS: This scoping review protocol was developed following the framework proposed by Arksey and O'Malley, and the updated guidelines by the Joanna Briggs Institute. We will include methodological publications that provide recommendations or guidelines on methods for BRA. We will conduct electronic searches on Medline (PubMed) and EMBASE (Ovid) databases; manual searches on the main websites of HTA bodies and drug regulatory organisations; and contact experts in the field. Systematic extraction forms will be used to screen and assess the identified publications by independent assessors. We will provide a qualitative synthesis using descriptive statistics and visual tools. Results will be summarised in systematic evidence tables and comparative evidence scoping charts. ETHICS AND DISSEMINATION: This review will use data publicly available and does not require ethics approval. The results of this scoping review will contribute to scientific knowledge and act as a basis for methodologists, guideline developers and researchers for the development of BRA to inform regulatory decisions, reimbursement and coverage decision making. The results will be disseminated through peer-reviewed articles, conferences, policy briefs and workshops. TRIAL REGISTRATION NUMBER: Open Science Framework (https://doi.org/10.17605/OSF.IO/69T3V).

Values and Preferences of Patients and Caregivers Regarding Treatment of Atopic Dermatitis (Eczema): A Systematic Review.

Importance: Patient values and preferences can inform atopic dermatitis (AD) care. Systematic summaries of evidence addressing patient values and preferences have not previously been available. Objective: To inform American Academy of Allergy, Asthma & Immunology (AAAAI)/American College of Allergy, Asthma and Immunology (ACAAI) Joint Task Force on Practice Parameters AD guideline development, patient and caregiver values and preferences in the management of AD were systematically synthesized. Evidence Review: Paired reviewers independently screened MEDLINE, Embase, PsycINFO, and CINAHL databases from inception until March 20, 2022, for studies of patients with AD or their caregivers, eliciting values and preferences about treatment, rated risk of bias, and extracted data. Thematic and inductive content analysis to qualitatively synthesize the findings was used. Patients, caregivers, and clinical experts provided triangulation. The GRADE-CERQual (Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative Research) informed rating of the quality of evidence. Findings: A total of 7780 studies were identified, of which 62 proved eligible (n = 19 442; median age across studies [range], 15 years [3-44]; 59% female participants). High certainty evidence showed that patients and caregivers preferred to start with nonmedical treatments and to step up therapy with increasing AD severity. Moderate certainty evidence showed that adverse effects from treatment were a substantial concern. Low certainty evidence showed that patients and caregivers preferred odorless treatments that are not visible and have a minimal effect on daily life. Patients valued treatments capable of relieving itching and burning skin and preferred to apply topical corticosteroids sparingly. Patients valued a strong patient-clinician relationship. Some studies presented varied perspectives and 18 were at high risk for industry sponsorship bias. Conclusions and Relevance: In the first systematic review to address patient values and preferences in management of AD to our knowledge, 6 key themes that may inform optimal clinical care, practice guidelines, and future research have been identified.

Economic evaluation of wheelchairs interventions: a systematic review.

OBJECTIVE: The overall aim of this systematic review was to identify and synthesise the best available evidence on effectiveness, resource use and costs involved in wheelchair interventions of adults with mobility limitations. METHODOLOGY: This systematic review was undertaken in accordance with the Centre for Reviews and Dissemination Guidelines. The protocol for this systematic review was registered with PROSPERO International Prospective Register of Systematic reviews. The following PICOS eligibility criteria were considered: (P) Population was individuals with mobility limitations that live in their community (e.g., non-institutionalized), with aged 18 or older; (I) Intervention was mobility assistive technologies (MAT), such as manual and powered wheelchairs; (C) Comparators (Not Applied); (O) Outcome, the primary outcome of interest, was established as the cost-effectiveness of wheelchair interventions. Direct and indirect costs per unit of effect were expressed in terms of clinical outcome units, quality-adjusted life years gained, utility scores, quality of life measures and incremental cost-effectiveness ratios to inform the economic outcomes. (S) Study design was considered as a health economic evaluation (i.e., including cost-effectiveness analysis, cost-utility analysis and cost benefit analysis as well as partial economic evaluations). The Consolidated Health Economic Evaluation Reporting Standards - CHEERS, checklist was used for summarising and interpreting the results of economic evaluations. RESULTS: Sixteen studies were included, two were identified as full health economic evaluations and 14 were considered partial health economic evaluations. CONCLUSION: Only two full health economic analyses of wheelchair interventions have been conducted and both focussed on powered wheelchair provision. There are important gaps in current knowledge regarding wheelchair health economic methods and available outcome measures, which there is a great need for further research.Implication for RehabilitationSystematic reviews of health economic evaluation studies are useful for synthesising economic evidence about health interventions and provide insight in new research development.Organisations involved in the provision of wheelchairs should apply cost-effectiveness outcome measures to help raise the standard of provision, to support evidence-based practice, and to improve resource utilisation.

Multicriteria decision analysis in health care decision in oncology: a systematic review.

INTRODUCTION: Multicriteria decision analysis (MCDA) has been used to inform health decisions in health technology assessments (HTA) processes. This is particularly important to complex treatment decisions in oncology. AREAS COVERED: Five databases (PubMed, EMBASE, LILACS, Web of Science and CRD's NHS Economic Evaluation Database) were searched for studies comparing health technologies in oncology, involving the concept MCDA. The ISPOR MCDA Good Practices Guidelines were used to assess the reporting quality. Study selection, appraisal, and data extraction were performed by two reviewers. Fifteen studies were included. The main decision problem was related to health technology assessment of cancer treatments. Clinicians and public health experts were the most frequent stakeholders. The most frequently included criteria comprised therapeutic benefit, and socio-economic impact. Value measurement approach, direct rating techniques, and additive model for aggregation were used in most studies. Uncertainty analysis revealed the impact of posology and costs on the studies' results. All studies showed some level of overlapping decision criteria. EXPERT OPINION: There is considerable diversity of methods in MCDA for healthcare decision-making in oncology. The evidence presented can serve as a resource when considering which stakeholders, criteria, and techniques to include in future MCDA studies in oncology.

Probiotics for the treatment of depression and anxiety: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND & AIM: Probiotics in the gut have been suggested to have a beneficial effect on anxiety response and depressive disorder. Hence we conducted a systematic review and meta-analysis to summarize the effects of probiotics associated with or without pharmacological or psychological therapies in patients with depressive and/or anxiety symptoms or disorders. METHODS: We conducted searches of MEDLINE, EMBASE, CENTRAL, PsycINFO, CINAHL, ProQuest, LILACS, and Web of Science up to February 2020 to identify randomized controlled trials (RCTs) investigating the efficacy of probiotics associated with or without pharmacological or psychological therapies for patient-important outcomes including relief of depressive, anxiety and stress symptoms, cognitive functions, adverse events and quality of life. We used the GRADE approach to rate the overall certainty of the evidence by outcome. The protocol of the systematic review was registered with PROPSERO and published under the number CRD4202016329. RESULTS: 16 RCTs including 1,125 patients proved eligible. Results suggested a significant improvement in using Beck Depression Index (MD, -3.20 [95% CI, -5.91 to -0.49], p = 0.02; I2 = 21%, p = 0.28) for depression symptoms and State-Trait Anxiety Inventory (STAI) (MD, -6.88 [95% CI, -12.35 to -1.41], p = 0.01; I2 = 24%, p = 0.25) for anxiety with overall certainty in evidence rated as moderate and low, respectively. However, Depression Scale (DASS-Depression) (MD, 2.01 [95% CI, -0.80 to 4.82], p = 0.16; I2 = 0%, p = 0.62), Montgomery-Asberg Depression Rating Scale (MADRAS) (MD, -2,41 [95% CI, -10,55 to 5,72], p = 0,56; I2 = 87%, p = 0,006), Anxiety scale (DASS-Anxiety) (MD, 0.49 [95% CI, -4.05 to 5.02], p = 0.83; I2 = 74%, p = 0.05), and Stress Scale (DASS-Stress) (MD, 0.84 [95% CI, -2.64 to 4.33], p = 0.64; I2 = 34%, p = 0.22) showed no significant decrease in the relief of depression, anxiety and stress symptoms of probiotics compared to placebo with overall certainty in evidence rated as very low for all outcomes. We also found no differences in the Beck Anxiety Index (BAI) (MD, -3.21 [95% CI, -6.50 to 0.08], p = 0.06; I2 = 0%, p = 0.88) with overall certainty in evidence rated as low. Results suggested a non-statistically significantly effect of probiotics in the adverse events outcomes. CONCLUSIONS: The current review suggests that probiotics may improve symptoms of depression and anxiety in clinical patients. However, given the limitations in the included studies, RCTs with long-term follow-up and large sample sizes are needed.

Effects of 3D image-guided brachytherapy compared to 2D conventional brachytherapy on clinical outcomes in patients with cervical cancer: A systematic review and meta-analyses.

PURPOSE: To assess the effects of three-dimensional image-guided brachytherapy (3D BT) compared to bi-dimensional BT (2D BT) on clinical outcomes in patients with cervical cancer. METHODS AND MATERIALS: We searched PubMed/MEDLINE, EMBASE, Scopus, CENTRAL, Web of Science, and LILACS for studies assessing the effects of 3D BT versus 2D BT on clinical outcomes. Two reviewers independently screened retrieved citations, extracted data and assessed risk of bias from eligible studies. Hazard ratios (HR) were calculated from Kaplan-Meier curves considering the number of events, their timing and the followup of censored patients. We conducted meta-analyses of HR using the inverse-variance random-effects method. Risk Difference (RD) for toxicities were pooled using the Mantel-Haenszel random-effects method. We used the GRADE system to rate the certainty of evidence. RESULTS: Twenty observational studies involving 4287 patients were included. The meta-analyses assessing the effect of 3D BT versus 2D BT on overall survival resulted in a HR of 0.78 (95%CI 0.62-0.98), HR of 0.75 (95%CI 0.62-0.90) for pelvic disease-free survival, HR of 0.93 (95%CI 0.81-1.06) for metastatic disease-free survival, and HR of 0.77 (95%CI 0.59-0.99) for local control. Grade 3-4 global and gastrointestinal toxicities were, respectively, 9% lower (95%CI 6% to 11%) and 5% lower (95%CI 2% to 8%) in patients receiving 3D BT versus 2D BT. Certainty of evidence was very low for all assessed outcomes. CONCLUSIONS: Our study may suggest a benefit of 3D BT over conventional 2D BT on important clinical outcomes.

Mindfulness Practice for Glycemic Control: Could it be a New Strategy for an Old Problem? A Systematic Review and Meta-Analysis.

BACKGROUND: The management of type 2 diabetes mellitus (T2DM) requires a complex and organized care that includes patient's lifestyle change. Additionally, emotional well-being is an important part of self-management, and it may impair the individual's adherence. Therefore, equipping the patients with the necessary coping and self-care techniques may be an important step in managing diabetes. OBJECTIVE: To evaluate the effect of interventions using established mindfulness-based protocols on glycemic control of individuals with T2DM. METHODS: Data sources: Two electronic databases (PubMed and EMBASE) were searched from inception to December 2019. We limited our search to published studies in English, Spanish and Portuguese languages. STUDY SELECTION: Randomized clinical trials that assessed the effects of mindfulness in individuals with T2DM were selected. DATA EXTRACTION: Two authors independently assessed the risk of bias and extracted data from the included trials. Data were pooled using inverse-variance random-effects meta-analyses. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Four randomized trials were included. There were no differences in blood glucose change (mean difference between groups (MD) -0.73mg/dl; 95% CI, -10.49; 9.02; I2 =0%; very low quality of evidence) or glycated hemoglobin (MD 0.05%; 95%CI -0.22 to 0.32; I2 =29%; very low quality of evidence). CONCLUSION: Although the quality of current evidence is very low, our findings suggest that established protocols involving mindfulness have no effect on blood glucose or glycated hemoglobin in individuals with T2DM. Indeed, large-scale trials are needed to evaluate the contribution of mindfulness to glycemic control in clinical practice. PROSPERO Registration ID: RD42020161940.

Perioperative Troponin Screening Identifies Patients at Higher Risk for Major Cardiovascular Events in Noncardiac Surgery.

Myocardial injury after noncardiac surgery (MINS) includes patients with traditional myocardial infarction and those with ischemic myocardial injury after surgery. This study evaluated the prognostic value of MINS on major cardiovascular events and 30-day mortality, and determined independent preoperative predictors of MINS in patients after noncardiac surgery. This multicenter prospective cohort study was part of the VISION Study. The sample consisted of 2504 patients who underwent noncardiac surgery at 2 tertiary hospitals in Brazil between September 2008 and July 2012. Troponin Ts were measured 6-12 hours, and on days 1-3 after surgery. Cox regression analyses were performed to identify independent variables of major outcomes. A total of 314 (13%) patients were diagnosed with MINS, of which 26 (8%) died. Length-of-hospital stay of MINS patients was 3 times higher (18 ± 22 days vs 5.8 ± 11 days). In multivariate analysis, 30-day mortality was significantly higher among patients with MINS (hazard ratio [HR] 3.17 (95% confidence interval [CI] 1.56-6.41)), and major bleeding (HR 5.76 (95% CI 2.75-12.05)), sepsis (HR 5.08 (95% CI 2.25-11.46)), active cancer (HR 4.22 (95% CI 1.98-8.98)), and general surgery (HR 3.11 (95% CI 1.51-6.41)). Multivariable analysis indicated a higher chance of MINS in patients ≥75 years of age, history of diabetes mellitus, hypertension, heart failure, coronary disease, and end-stage renal failure. The incidence of MINS within 30 days after noncardiac surgery is related to higher mortality. Postoperative troponin monitoring in elder patients and with risk factors for atherosclerotic disease may help reduce postoperative cardiovascular events.

Challenges for the development of alternative low-cost ventilators during COVID-19 pandemic in Brazil. / Desafios para o desenvolvimento de ventiladores alternativos de baixo custo durante a pandemia de COVID-19 no Brasil.

The COVID-19 pandemic has brought concerns to managers, healthcare professionals, and the general population related to the potential mechanical ventilators' shortage for severely ill patients. In Brazil, there are several initiatives aimed at producing alternative ventilators to cover this gap. To assist the teams that work in these initiatives, we provide a discussion of some basic concepts on physiology and respiratory mechanics, commonly used mechanical ventilation terms, the differences between triggering and cycling, the basic ventilation modes and other relevant aspects, such as mechanisms of ventilator-induced lung injury, respiratory drive, airway heating and humidification, cross-contamination risks, and aerosol dissemination. After the prototype development phase, preclinical bench-tests and animal model trials are needed to determine the safety and performance of the ventilator, following the minimum technical requirements. Next, it is mandatory going through the regulatory procedures as required by the Brazilian Health Regulatory Agency (Agência Nacional de Vigilância Sanitária - ANVISA). The manufacturing company should be appropriately registered by ANVISA, which also must be notified about the conduction of clinical trials, following the research protocol approval by the Research Ethics Committee. The registration requisition of the ventilator with ANVISA should include a dossier containing the information described in this paper, which is not intended to cover all related matters but to provide guidance on the required procedures.

A pandemia por COVID-19 tem deixado os gestores, os profissionais de saúde e a população preocupados com a potencial escassez de ventiladores pulmonares para suporte de pacientes graves. No Brasil, há diversas iniciativas com o intuito de produzir ventiladores alternativos para ajudar a suprir essa demanda. Para auxiliar as equipes que atuam nessas iniciativas, são expostos alguns conceitos básicos sobre fisiologia e mecânica respiratória, os termos comumente utilizados no contexto da ventilação mecânica, as fases do ciclo ventilatório, as diferenças entre disparo e ciclagem, os modos ventilatórios básicos e outros aspectos relevantes, como mecanismos de lesão pulmonar induzida pela ventilação mecânica, pacientes com drive respiratório, necessidade de umidificação de vias aéreas, risco de contaminação cruzada e disseminação de aerossóis. Após a fase de desenvolvimento de protótipo, são necessários testes pré-clínicos de bancada e em modelos animais, a fim de determinar a segurança e o desempenho dos equipamentos, seguindo requisitos técnicos mínimos exigidos. Então, é imprescindível passar pelo processo regulatório exigido pela Agência Nacional de Vigilância Sanitária (ANVISA). A empresa responsável pela fabricação do equipamento deve estar regularizada junto à ANVISA, que também deve ser notificada da condução dos testes clínicos em humanos, seguindo protocolo de pesquisa aprovado pelo Comitê de Ética em Pesquisa. O registro do ventilador junto à ANVISA deve ser acompanhado de um dossiê, composto por documentos e informações detalhadas neste artigo, que não tem o propósito de esgotar o assunto, mas de nortear os procedimentos necessários.

Addition of corticosteroids to local anaesthetics for chronic non-cancer pain injections: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Despite common use, the benefit of adding steroids to local anaesthetics (SLA) for chronic non-cancer pain (CNCP) injections is uncertain. We performed a systematic review and meta-analysis of English-language RCTs to assess the benefit and safety of adding steroids to local anaesthetics (LA) for CNCP. METHODS: We searched MEDLINE, EMBASE, and CENTRAL databases from inception to May 2019. Trial selection and data extraction were performed in duplicate. Outcomes were guided by the Initiative in Methods, Measurements, and Pain Assessment in Clinical Trials (IMMPACT) statement with pain improvement as the primary outcome and pooled using random effects model and reported as relative risks (RR) or mean differences (MD) with 95% confidence intervals (CIs). RESULTS: Among 5097 abstracts, 73 trials were eligible. Although SLA increased the rate of success (42 trials, 3592 patients; RR=1.14; 95% CI, 1.03-1.25; number needed to treat [NNT], 13), the effect size decreased by nearly 50% (NNT, 22) with the removal of two intrathecal injection studies. The differences in pain scores with SLA were not clinically meaningful (54 trials, 4416 patients, MD=0.44 units; 95% CI, 0.24-0.65). No differences were observed in other outcomes or adverse events. No subgroup effects were detected based on clinical categories. Meta-regression showed no significant association with steroid dose or length of follow-up and pain relief. CONCLUSIONS: Addition of cortico steroids to local anaesthetic has only small benefits and a potential for harm. Injection of local anaesthetic alone could be therapeutic, beyond being diagnostic. A shared decision based on patient preferences should be considered. If used, one must avoid high doses and series of steroid injections. CLINICAL TRIAL REGISTRATION: PROSPERO #: CRD42015020614.

Comparison of Biological and Mechanical Prostheses for Heart Valve Surgery: A Systematic Review of Randomized Controlled Trials.

BACKGROUND: The choice of a mechanical (MP) or biological prosthesis (BP) for patients with valvular heart disease undergoing replacement is still not a consensus. OBJECTIVE: We aimed to determine the clinical outcomes of MP or BP placement in those patients. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared biological prostheses and mechanical prostheses in patients with valvular heart diseases and assessed the outcomes. RCTs were searched in the MEDLINE, EMBASE, LILACS, CENTRAL, SCOPUS and Web of Science (from inception to November 2014) databases. Meta-analyses were performed using inverse variance with random effects models. The GRADE system was used to rate the quality of the evidence. A P-value lower than 0.05 was considered significant. RESULTS: A total of four RCTs were included in the meta-analyses (1,528 patients) with follow up ranging from 2 to 20 years. Three used old generation mechanical and biological prostheses, and one used contemporary prostheses. No significant difference in mortality was found between BP and MP patients (risk ratio (RR = 1.07; 95% CI 0.99-1.15). The risk of bleeding was significantly lower in BP patients than MP patients (RR = 0.64; 95% CI 0.52-0.78); however, reoperations were significantly more frequent in BP patients (RR = 3.60; 95% CI 2.44-5.32). There were no statistically significant differences between BP and MP patients with respect to systemic arterial embolisms and infective endocarditis (RR = 0.93; 95% CI 0.66-1.31, RR = 1.21; CI95% 0.78-1.88, respectively). Results in the trials with modern and old prostheses were similar. CONCLUSIONS: The mortality rate and the risk of thromboembolic events and endocarditis were similar between BP and MP patients. The risk of bleeding was approximately one third lower for BP patients than for MP patients, while the risk of reoperations was more than three times higher for BP patients.

Effects of oral supplementation with probiotics or synbiotics in overweight and obese adults: a systematic review and meta-analyses of randomized trials.

CONTEXT: Recent evidence suggests that modulation of the gut microbiota may contribute to body weight control. OBJECTIVE: This systematic review aimed to assess the effects of oral supplementation with probiotics or synbiotics on body weight, body mass index (BMI), and waist circumference in overweight and obese adults (BMI ≥ 25 kg/m2). DATA SOURCES: Five electronic databases-PubMed, Embase, Cochrane Library/CENTRAL, LILACS, and Web of Science-were searched from inception to August 2017. No language restrictions were applied. STUDY SELECTION: Randomized and quasi-randomized parallel trials that assessed the effects of oral supplementation with probiotics or synbiotics vs any other intervention but bariatric surgery or fecal transplantation in overweight or obese adults were selected. DATA EXTRACTION: Three teams of 2 authors independently assessed risk of bias and extracted data from the included trials. Data were pooled using inverse-variance random-effects meta-analyses. The quality of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. RESULTS: Nineteen randomized trials (28 publications, 1412 participants) were included. There were no differences in mean body weight change [mean difference (MD), -0.54 kg; 95%CI, -1.09 to 0.01; I2 = 0%; moderate quality of evidence) or mean BMI change (MD, -0.19 kg/m2; 95%CI, -0.43 to 0.04; I2 = 51%; low quality of evidence) between groups who received probiotics or synbiotics and control groups. Oral supplementation with probiotics or synbiotics reduced mean waist circumference compared with control (MD, -0.82 cm; 95%CI, -1.43 to -0.21; I2 = 46%; low quality of evidence). CONCLUSIONS: The findings suggest that oral supplementation with probiotics or synbiotics has a small effect to reduce waist circumference but no effect on body weight or BMI, although the quality of evidence is low to moderate. Therefore, the current evidence is not definitive. Large-scale trials are needed and may help to better inform clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42018075126.

Comparison of Biological and Mechanical Prostheses for Heart Valve Surgery: A Systematic Review of Randomized Controlled Trials / Comparação de Próteses Biológicas e Mecânicas para Cirurgia de Válvula Cardíaca: Revisão Sistemática de Estudos Controlados Randomizados

Abstract Background: The choice of a mechanical (MP) or biological prosthesis (BP) for patients with valvular heart disease undergoing replacement is still not a consensus. Objective: We aimed to determine the clinical outcomes of MP or BP placement in those patients. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared biological prostheses and mechanical prostheses in patients with valvular heart diseases and assessed the outcomes. RCTs were searched in the MEDLINE, EMBASE, LILACS, CENTRAL, SCOPUS and Web of Science (from inception to November 2014) databases. Meta-analyses were performed using inverse variance with random effects models. The GRADE system was used to rate the quality of the evidence. A P-value lower than 0.05 was considered significant. Results: A total of four RCTs were included in the meta-analyses (1,528 patients) with follow up ranging from 2 to 20 years. Three used old generation mechanical and biological prostheses, and one used contemporary prostheses. No significant difference in mortality was found between BP and MP patients (risk ratio (RR = 1.07; 95% CI 0.99-1.15). The risk of bleeding was significantly lower in BP patients than MP patients (RR = 0.64; 95% CI 0.52-0.78); however, reoperations were significantly more frequent in BP patients (RR = 3.60; 95% CI 2.44-5.32). There were no statistically significant differences between BP and MP patients with respect to systemic arterial embolisms and infective endocarditis (RR = 0.93; 95% CI 0.66-1.31, RR = 1.21; CI95% 0.78-1.88, respectively). Results in the trials with modern and old prostheses were similar. Conclusions: The mortality rate and the risk of thromboembolic events and endocarditis were similar between BP and MP patients. The risk of bleeding was approximately one third lower for BP patients than for MP patients, while the risk of reoperations was more than three times higher for BP patients.

Resumo Fundamento: A escolha de próteses mecânicas ou biológicas para pacientes com doença de válvula cardíaca ainda não é um consenso. Objetivo: Determinar os desfechos clínicos de próteses mecânicas e biológicas nesses pacientes. Métodos: Conduzimos uma revisão sistemática e metanálise e estudos controlados randomizados (RCTs) que compararam próteses mecânicas e biológicas em pacientes com doenças de válvulas cardíaca, e avaliamos seus resultados. A busca por RCTs foi feita nas bases de dados MEDLINE, EMBASE, LILACS, CENTRAL, SCOPUS e Web of Science (do início a novembro de 2014). As metanálises foram realizadas usando variação inversa com modelos de efeitos aleatórios. Usamos o sistema GRADE para avaliar a qualidade da evidência. Um valor menor que 0,05 foi considerado significativo. Resultados: Um total de quatro RCTs foi incluído na metanálise (1528 pacientes) com acompanhamento de 2 a 20 anos. Em três estudos, foram utilizadas próteses mecânicas e biológicas mais antigas, e em um estudo próteses contemporâneas. Não foi observada diferença de mortalidade entre os pacientes que receberam próteses mecânicas e biológicas (risco relativo, RR = 1,07; IC95% 0,99-1,15). O risco de sangramento foi significativamente mais baixo nos pacientes que receberam próteses biológicas que naqueles com próteses mecânicas (RR = 0,64; IC95% 0,52-0,78). Contudo, as reoparações foram mais frequentes em pacientes com próteses biológicas (RR = 3,60; IC95% 2,44-5,32). Não houve diferenças estatisticamente significativas entre pacientes com próteses biológicas e mecânicas em relação à embolia arterial sistêmica e endocardite infecciosa (RR = 0,93; IC95% 0,66-1,31; RR = 1,21; IC95% 0,78-1,88, respectivamente). Resultados entre os estudos com próteses modernas e antigas foram similares. Conclusões: A taxa de mortalidade e o risco de eventos tromboembólicos e endocardite foram similares entre os pacientes que receberam próteses biológicas e mecânicas. O risco de sangramentos foi aproximadamente um terço menor nos pacientes com próteses biológicas que mecânicas, ao passo que o risco de reoperação foi mais que três vezes maior nos pacientes com próteses biológicas.

Noninvasive Brain Stimulations for Unilateral Spatial Neglect after Stroke: A Systematic Review and Meta-Analysis of Randomized and Nonrandomized Controlled Trials.

Background: Unilateral spatial neglect (USN) is the most frequent perceptual disorder after stroke. Noninvasive brain stimulation (NIBS) is a tool that has been used in the rehabilitation process to modify cortical excitability and improve perception and functional capacity. Objective: To assess the impact of NIBS on USN after stroke. Methods: An extensive search was conducted up to July 2016. Studies were selected if they were controlled and noncontrolled trials examining transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and theta burst stimulation (TBS) in USN after stroke, with outcomes measured by standardized USN and functional tests. Results: Twelve RCTs (273 participants) and 4 non-RCTs (94 participants) proved eligible. We observed a benefit in overall USN measured by the line bisection test with NIBS in comparison to sham (SMD -2.35, 95% CI -3.72, -0.98; p = 0.0001); the rTMS yielded results that were consistent with the overall meta-analysis (SMD -2.82, 95% CI -3.66, -1.98; p = 0.09). The rTMS compared with sham also suggested a benefit in overall USN measured by Motor-Free Visual Perception Test at both 1 Hz (SMD 1.46, 95% CI 0.73, 2.20; p < 0.0001) and 10 Hz (SMD 1.19, 95% CI 0.48, 1.89; p = 0.54). There was also a benefit in overall USN measured by Albert's test and the line crossing test with 1 Hz rTMS compared to sham (SMD 2.04, 95% CI 1.14, 2.95; p < 0.0001). Conclusions: The results suggest a benefit of NIBS on overall USN, and we conclude that rTMS is more efficacious compared to sham for USN after stroke.

Statistical analysis plan for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART). A randomized controlled trial. / Plano de análise estatística para o Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART). Ensaio controlado randomizado.

BACKGROUND: The Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) is an international multicenter randomized pragmatic controlled trial with allocation concealment involving 120 intensive care units in Brazil, Argentina, Colombia, Italy, Poland, Portugal, Malaysia, Spain, and Uruguay. The primary objective of ART is to determine whether maximum stepwise alveolar recruitment associated with PEEP titration, adjusted according to the static compliance of the respiratory system (ART strategy), is able to increase 28-day survival in patients with acute respiratory distress syndrome compared to conventional treatment (ARDSNet strategy). OBJECTIVE: To describe the data management process and statistical analysis plan. METHODS: The statistical analysis plan was designed by the trial executive committee and reviewed and approved by the trial steering committee. We provide an overview of the trial design with a special focus on describing the primary (28-day survival) and secondary outcomes. We describe our data management process, data monitoring committee, interim analyses, and sample size calculation. We describe our planned statistical analyses for primary and secondary outcomes as well as pre-specified subgroup analyses. We also provide details for presenting results, including mock tables for baseline characteristics, adherence to the protocol and effect on clinical outcomes. CONCLUSION: According to best trial practice, we report our statistical analysis plan and data management plan prior to locking the database and beginning analyses. We anticipate that this document will prevent analysis bias and enhance the utility of the reported results. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01374022.

FUNDAMENTAÇÃO: O estudo Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) é um ensaio clínico internacional, multicêntrico, randomizado, pragmático e controlado com ocultação da alocação que envolve 120 unidades de terapia intensiva no Brasil, Argentina, Colômbia, Espanha, Itália, Polônia, Portugal, Malásia e Uruguai, com o objetivo primário de determinar se o recrutamento alveolar gradual máximo associado com titulação da pressão positiva expiratória final, ajustada segundo a complacência estática do sistema respiratório (estratégia ART), é capaz de aumentar, quando comparada aos resultados do tratamento convencional (estratégia ARDSNet), a sobrevivência em 28 dias de pacientes com síndrome do desconforto respiratório agudo. OBJETIVO: Descrever o processo de gerenciamento dos dados e o plano de análise estatística em um ensaio clínico internacional. MÉTODOS: O plano de análise estatística foi delineado pelo comitê executivo e revisado pelo comitê diretivo do ART. Foi oferecida uma visão geral do delineamento do estudo, com foco especial na descrição de desfechos primário (sobrevivência aos 28 dias) e secundários. Foram descritos o processo de gerenciamento dos dados, o comitê de monitoramento de dados, a análise interina e o cálculo do tamanho da amostra. Também foram registrados o plano de análise estatística para os desfechos primário e secundários, e os subgrupos de análise pré-especificados. Detalhes para apresentação dos resultados, inclusive modelos de tabelas para as características basais, adesão ao protocolo e efeito nos desfechos clínicos, foram fornecidos. CONCLUSÃO: Em acordo com as melhores práticas em ensaios clínicos, submetemos nossos planos de análise estatística e de gerenciamento de dados para publicação antes do fechamento da base de dados e início das análises. Antecipamos que este documento deve prevenir viés em análises e incrementar a utilidade dos resultados a serem relatados. REGISTRO DO ESTUDO: Número no registro ClinicalTrials.gov NCT01374022.

Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

Importance: The effects of recruitment maneuvers and positive end-expiratory pressure (PEEP) titration on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remain uncertain. Objective: To determine if lung recruitment associated with PEEP titration according to the best respiratory-system compliance decreases 28-day mortality of patients with moderate to severe ARDS compared with a conventional low-PEEP strategy. Design, Setting, and Participants: Multicenter, randomized trial conducted at 120 intensive care units (ICUs) from 9 countries from November 17, 2011, through April 25, 2017, enrolling adults with moderate to severe ARDS. Interventions: An experimental strategy with a lung recruitment maneuver and PEEP titration according to the best respiratory-system compliance (n = 501; experimental group) or a control strategy of low PEEP (n = 509). All patients received volume-assist control mode until weaning. Main Outcomes and Measures: The primary outcome was all-cause mortality until 28 days. Secondary outcomes were length of ICU and hospital stay; ventilator-free days through day 28; pneumothorax requiring drainage within 7 days; barotrauma within 7 days; and ICU, in-hospital, and 6-month mortality. Results: A total of 1010 patients (37.5% female; mean [SD] age, 50.9 [17.4] years) were enrolled and followed up. At 28 days, 277 of 501 patients (55.3%) in the experimental group and 251 of 509 patients (49.3%) in the control group had died (hazard ratio [HR], 1.20; 95% CI, 1.01 to 1.42; P = .041). Compared with the control group, the experimental group strategy increased 6-month mortality (65.3% vs 59.9%; HR, 1.18; 95% CI, 1.01 to 1.38; P = .04), decreased the number of mean ventilator-free days (5.3 vs 6.4; difference, -1.1; 95% CI, -2.1 to -0.1; P = .03), increased the risk of pneumothorax requiring drainage (3.2% vs 1.2%; difference, 2.0%; 95% CI, 0.0% to 4.0%; P = .03), and the risk of barotrauma (5.6% vs 1.6%; difference, 4.0%; 95% CI, 1.5% to 6.5%; P = .001). There were no significant differences in the length of ICU stay, length of hospital stay, ICU mortality, and in-hospital mortality. Conclusions and Relevance: In patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality. These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients. Trial Registration: clinicaltrials.gov Identifier: NCT01374022.