Abstract Background Systematic reviews of Randomized Controlled Trials (RCTs) are considered high-level evidence to support a decision on therapeutic interventions, and their methodological quality is essential to provide reliable and applicable results. Objective This meta-epidemiological study aimed to map and critically appraise systematic reviews assessing treatments for vesiculobullous skin diseases. Methods We conducted a comprehensive search strategy on MEDLINE (via Pubmed) in December 2022 without restrictions to find systematic reviews evaluating pharmacological interventions for vesiculobullous skin diseases. The methodological quality was assessed using the AMSTAR-2 tool, and additional information was extracted. We identified nine systematic reviews published between 2002 and 2021, seven assessing pemphigus. Results According to the AMSTAR-2 tool, 55.6% were classified as critically low quality, 22.2% as moderate quality, 11.1% as low and 11.1% as high quality. No review assessed the certainty of the evidence (GRADE); 86% of pemphigus reviews had at least two overlapping RCTs. There were some limitations regarding methodological flaws and the AMSTAR-2 tool use Conclusions These findings reveal a frail methodological quality of systematic reviews about vesiculobullous diseases treatment that may impact the results. Therefore, methodological rigor is mandatory for future systematic reviews to avoid duplication of effort and increase the certainty of the evidence supporting decision-making. RCTs (RCTs highlevel level results metaepidemiological meta epidemiological via Pubmed 202 AMSTAR2 AMSTAR 2 AMSTAR- extracted 200 2021 556 55 6 55.6 222 22 22.2 111 11 1 11.1 GRADE (GRADE) 86 Therefore decisionmaking. decisionmaking making. making decision-making 20 5 55. 22. 11. (GRADE 8

RESUMO. O transtorno de pânico é uma condição de ansiedade caracterizada por ataques de pânico recorrentes e inesperados. A comparação entre tratamento ativo e placebo é essencial para analisar a eficácia e a segurança de uma intervenção. É importante identificar os estudos com maiores evidências para auxiliar os profissionais de saúde e gestores de políticas públicas nas decisões clínicas. Objetivo: Identificar e sumarizar todas as revisões sistemáticas (RS) publicadas na Cochrane que relatam a eficácia e a segurança de qualquer tratamento medicamentoso comparado ao placebo para pacientes com transtorno de pânico. Métodos: Foram selecionadas e analisadas todas as RS publicadas na base de dados Cochrane, sem restrição de data. A qualidade metodológica das RS foi avaliada utilizando a ferramenta AMSTAR-2. Resultados: Foram incluídas três RS Cochrane com alta qualidade metodológica que avaliaram os efeitos de antidepressivos, benzodiazepínicos e azapironas para transtorno de pânico. Todos os medicamentos mostraram benefícios na resposta ao tratamento, melhora dos sintomas e redução das crises de pânico. O número de desistências do tratamento foi baixo com antidepressivos tricíclicos e benzodiazepínicos e alto com azapironas. A ocorrência de eventos adversos foi elevada para os grupos das medicações analisadas Conclusões: Evidências de certeza muito baixa a moderada (pela Classificação de Recomendações, Avaliação, Desenvolvimento e Análises - GRADE) mostraram que antidepressivos e benzodiazepínicos parecem melhorar os sintomas clínicos em indivíduos com transtorno de pânico em menor prazo, em comparação ao placebo. Além disso, o uso de azapironas parece ter maior adesão por parte dos pacientes do que o placebo. No entanto, não há evidências suficientes para comprovar sua eficácia clínica.

ABSTRACT. Panic disorder is an anxiety condition characterized by recurrent and unexpected panic attacks. The comparison between active treatment and placebo is essential to analyze an intervention’s efficacy and safety. It is important to identify and summarize the studies with higher evidence to assist health professionals and public policy managers in clinical decision-making. Objective: The aim of this study was to identify and summarize all Cochrane systematic reviews (SRs) that compared the efficacy and safety of any drug treatment compared to placebo for panic disorder patients. Methods: SRs published in the Cochrane Library were included without date restriction. All outcomes presented were analyzed. The methodological quality of the SRs was evaluated using the AMSTAR-2 tool. Results: We included three Cochrane SRs of high methodological quality on the effects of antidepressants, benzodiazepines, and azapirones for panic disorder. All medications showed benefits in response to treatment, symptom improvement, and reduced panic attacks. Dropouts were lower with tricyclic antidepressants and benzodiazepines and higher with azapirones. The occurrence of adverse events was higher for drug groups. Conclusions: Very low to moderate certainty evidence (GRADE) showed that antidepressants and benzodiazepines seem to improve clinical symptoms in individuals with short-term panic disorder compared to placebo. In addition, the use of azapirones seems to have greater adherence by patients than placebo. However, there is insufficient evidence to support its clinical efficacy.

RESUMO. O transtorno de pânico é uma condição de ansiedade caracterizada por ataques de pânico recorrentes e inesperados. A comparação entre tratamento ativo e placebo é essencial para analisar a eficácia e a segurança de uma intervenção. É importante identificar os estudos com maiores evidências para auxiliar os profissionais de saúde e gestores de políticas públicas nas decisões clínicas. Objetivo: Identificar e sumarizar todas as revisões sistemáticas (RS) publicadas na Cochrane que relatam a eficácia e a segurança de qualquer tratamento medicamentoso comparado ao placebo para pacientes com transtorno de pânico. Métodos: Foram selecionadas e analisadas todas as RS publicadas na base de dados Cochrane, sem restrição de data. A qualidade metodológica das RS foi avaliada utilizando a ferramenta AMSTAR-2. Resultados: Foram incluídas três RS Cochrane com alta qualidade metodológica que avaliaram os efeitos de antidepressivos, benzodiazepínicos e azapironas para transtorno de pânico. Todos os medicamentos mostraram benefícios na resposta ao tratamento, melhora dos sintomas e redução das crises de pânico. O número de desistências do tratamento foi baixo com antidepressivos tricíclicos e benzodiazepínicos e alto com azapironas. A ocorrência de eventos adversos foi elevada para os grupos das medicações analisadas Conclusões: Evidências de certeza muito baixa a moderada (pela Classificação de Recomendações, Avaliação, Desenvolvimento e Análises - GRADE) mostraram que antidepressivos e benzodiazepínicos parecem melhorar os sintomas clínicos em indivíduos com transtorno de pânico em menor prazo, em comparação ao placebo. Além disso, o uso de azapironas parece ter maior adesão por parte dos pacientes do que o placebo. No entanto, não há evidências suficientes para comprovar sua eficácia clínica.

ABSTRACT. Panic disorder is an anxiety condition characterized by recurrent and unexpected panic attacks. The comparison between active treatment and placebo is essential to analyze an intervention’s efficacy and safety. It is important to identify and summarize the studies with higher evidence to assist health professionals and public policy managers in clinical decision-making. Objective: The aim of this study was to identify and summarize all Cochrane systematic reviews (SRs) that compared the efficacy and safety of any drug treatment compared to placebo for panic disorder patients. Methods: SRs published in the Cochrane Library were included without date restriction. All outcomes presented were analyzed. The methodological quality of the SRs was evaluated using the AMSTAR-2 tool. Results: We included three Cochrane SRs of high methodological quality on the effects of antidepressants, benzodiazepines, and azapirones for panic disorder. All medications showed benefits in response to treatment, symptom improvement, and reduced panic attacks. Dropouts were lower with tricyclic antidepressants and benzodiazepines and higher with azapirones. The occurrence of adverse events was higher for drug groups. Conclusions: Very low to moderate certainty evidence (GRADE) showed that antidepressants and benzodiazepines seem to improve clinical symptoms in individuals with short-term panic disorder compared to placebo. In addition, the use of azapirones seems to have greater adherence by patients than placebo. However, there is insufficient evidence to support its clinical efficacy.

RESUMO CONTEXTO: A síndrome do intestino irritável (SII) é um distúrbio gastrointestinal complexo, cujo entendimento é relativamente incerto e a decisão de orientação do tratamento ainda representa um desafio. OBJETIVO: Identificar e avaliar criticamente as revisões sistemáticas (RSs) publicadas na base de dados de RSs Cochrane (CDSR) sobre os efeitos das intervenções (farmacológicas e não farmacológicas) para o tratamento da SII. MÉTODOS: A busca foi realizada na Biblioteca Cochrane em maio de 2020. A qualidade metodológica das RSs foi avaliada pela ferramenta AMSTAR-2. RESULTADOS: Foram incluídas oito RSs com qualidade moderada a alta, as quais abordaram os tratamentos: (a) farmacológico - agentes de volume, antiespasmódicos, antidepressivos e o tegaserod; e (b) não farmacológico - homeopatia, acupuntura, fitoterapia, biofeedback, intervenções psicológicas e hipnoterapia. Os resultados foram favoráveis aos medicamentos antiespasmódicos e antidepressivos em relação à melhora dos sintomas clínicos. Não houve diferença entre os agentes de volume ou tegaserod quando comparados ao placebo. Acupuntura e homeopatia apresentaram pequena melhora dos sintomas em comparação ao placebo, porém a qualidade da evidência foi considerada baixa a muito baixa. As intervenções psicológicas parecem melhorar a avaliação global do paciente e alívio de sintomas como dor abdominal. Contudo, não houve acompanhamento desses pacientes a longo prazo. Os resultados dos demais tratamentos foram considerados incertos devido ao alto risco de viés. CONCLUSÃO: Considerando a baixa qualidade dos estudos incluídos nas RSs, o tratamento farmacológico com antiespasmódicos e antidepressivos parece ser benéfico para os pacientes com SII. Entre os não-farmacológicos, as intervenções psicológicas parecem obter benefícios. Entretanto, novos ensaios clínicos são recomendados com maior rigor metodológico para comprovar estes achados.

ABSTRACT BACKGROUND: Irritable bowel syndrome (IBS) is a complex gastrointestinal disorder, whose understanding is relatively uncertain, and the treatment guidance decision still represents a challenge. OBJECTIVE: To identify and critically appraise systematic reviews (SRs) published in the Cochrane Database of SRs (CDSR) on the effects of interventions (pharmacological and non-pharmacological) for the treatment of IBS. METHODS: The search was conducted at the Cochrane Library in May 2020. The methodological quality of the SRs was evaluated by the AMSTAR-2 tool. RESULTS: Eight SRs with moderate to high quality were included, which addressed the treatments: (a) pharmacological: volume agents, antispasmodics, antidepressants and tegaserod; and (b) non-pharmacological: homeopathy, acupuncture, phytotherapy, biofeedback, psychological interventions and hypnotherapy. The results were favorable to antispasmodic drugs and antidepressants regarding the improvement of clinical symptoms. There was no difference between volume agents or tegaserod when compared to placebo. Acupuncture and homeopathy showed a little improvement in symptoms compared to placebo, but the certainty of this evidence was considered low to very low. Psychological interventions seem to improve the overall assessment of the patient and relief symptoms such as abdominal pain. However, there was no long-term follow-up of these patients. The results of the other treatments were considered uncertain due to the high risk of bias. CONCLUSION: Considering the low quality of the studies included in the SRs, pharmacological treatment with antispasmodics and antidepressants seems to be beneficial for patients with IBS. Among non-pharmacological interventions, psychological interventions seem to be beneficial. However, further clinical trials are recommended with greater methodological rigor to prove these findings.

Abstract Copy number variations (CNVs) constitute an important class of variation in the human genome and the interpretation of their pathogenicity considering different frequencies across populations is still a challenge for geneticists. Since the CNV databases are predominantly composed of European and non-admixed individuals, and Brazilian genetic constitution is admixed and ethnically diverse, diagnostic screenings on Brazilian variants are greatly difficulted by the lack of populational references. We analyzed a clinical sample of 268 Brazilian individuals, including patients with neurodevelopment disorders and/or congenital malformations. The pathogenicity of CNVs was classified according to their gene content and overlap with known benign and pathogenic variants. A total of 1,504 autosomal CNVs (1,207 gains and 297 losses) were classified as benign (92.9%), likely benign (1.6%), VUS (2.6%), likely pathogenic (0.2%) and pathogenic (2.7%). Some of the CNVs were recurrent and with frequency increased in our sample, when compared to populational open resources of structural variants: 14q32.33, 22q11.22, 1q21.1, and 1p36.32 gains. Thus, these highly recurrent CNVs classified as likely benign or VUS were considered non-pathogenic in our Brazilian sample. This study shows the relevance of introducing CNV data from diverse cohorts to improve on the interpretation of clinical impact of genomic variations.