Viscossuplementation for the treatment of osteoarthritis of the knee: A protocol for an umbrella review of systematic reviews with meta-analyses of randomized controlled trials.

BACKGROUND: Knee osteoarthritis (KOA) is a common chronic disease with worldwide prevalence of 10% to 79%, with costs ranging from $560 to $635 billion for year in United States of America. The main guidelines recommend interventions with undesirable adverse events (AE) or highly dependent on the patient's persistence. Thus, intra-articular (IA) therapies appear to be attractive in patients with KOA, as well as a valid therapy by maximizing effects locally in the joint and limiting systemic AE. Presently, the main available IA therapies are corticosteroids and hyaluronic acid.As several meta-analyses about the efficacy of intra-articular hyaluronic acid (IAHA) for treatment of KOA with discordant results were published, we decided to conduct an umbrella review to summarize this efficacy METHODS:: We will search MEDLINE/PubMed, EMBASE, Cochrane Library, and Virtual Health Library (BVS) from inception to February 2020 for systematic reviews with meta-analyses of randomized clinical trials that investigate IAHA for therapy of KOA. Grey literature will be searched in Opengray platform, Research Gate, and Google Scholar. The reference lists of eligible studies will be screened. The search will be performed without language restriction.We will include any type of IAHA as experimental intervention and different types of oral or intra-articular placebo or medications as controls. The primary outcome will be measures of efficacy as the Western Ontario and McMaster Universities Osteoarthritis Index.A synthesis of the evidence will be conducted and data will be presented in tables.Two reviewers will independently appraise the quality of included meta-analyses using the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2) tool and will classify the included systematic reviews into high, moderate, low, or critically low levels of confidence. RESULTS: The results of this study will be published in a peer-reviewed journal. ETHICS AND DISSEMINATION: No ethical approval is required since this study data is based on published literature. PROTOCOL REGISTRATION NUMBER: PROSPERO CRD42019120269 (https://www.crd.york.ac.uk/PROSPERO/#joinuppage).

Polymorphisms in inflammasome genes and risk of asthma in Brazilian children.

Considering its role in inflammation and recently described "alternative" roles in epithelial homeostasis and Th1/Th2 balance, we hypothesize that inflammasome genetics could contribute to the development of asthma. Selected functional polymorphisms in inflammasome genes are evaluated in a cohort of asthmatic children and their families. Gain-of-function NLRP1 variants rs11651270, rs12150220 and rs2670660 resulted significantly associated to asthma in trios (TDT) analysis; and rs11651270 and rs2670660 also with asthma severity and total IgE level in asthmatic children. NLRP1 activators in humans are still unknown, however we hypothesized that individuals with gain-of-function SNPs in NLRP1 could be more prone in activating inflammasome in the presence of asthma-related cell stressors (i.e. ER stress or ROS), and this activation contribute to exacerbate inflammatory response and asthma development. Gain-of-function IL1A rs17561 resulted significantly associated with a reduced pulmonary capacity in asthmatic children. IL18 rs5744256 which lead to lower serum level of IL-18 appeared to be associated to a worse response to bronchodilators. Concluding, this work provides evidences about the contribution of inflammasome genetics in the development of paediatric asthma, both considering its inflammatory role in alveolar macrophages (i.e.: NLRP1) or its homeostatic role in lung epithelial cells (i.e.: IL1A, IL18).

Neonatal screening for severe combined immunodeficiency in Brazil / Triagem neonatal para imunodeficiência combinada grave no Brasil

Abstract Objective To apply, in Brazil, the T-cell receptor excision circles (TRECs) quantification technique using real-time polymerase chain reaction in newborn screening for severe combined immunodeficiency and assess the feasibility of implementing it on a large scale in Brazil. Methods 8715 newborn blood samples were collected on filter paper and, after DNA elution, TRECs were quantified by real-time polymerase chain reaction. The cutoff value to determine whether a sample was abnormal was determined by ROC curve analysis, using SSPS. Results The concentration of TRECs in 8,682 samples ranged from 2 to 2,181 TRECs/µL of blood, with mean and median of 324 and 259 TRECs/µL, respectively. Forty-nine (0.56%) samples were below the cutoff (30 TRECs/µL) and were reanalyzed. Four (0.05%) samples had abnormal results (between 16 and 29 TRECs/µL). Samples from patients previously identified as having severe combined immunodeficiency or DiGeorge syndrome were used to validate the assay and all of them showed TRECs below the cutoff. Preterm infants had lower levels of TRECs than full-term neonates. The ROC curve showed a cutoff of 26 TRECs/µL, with 100% sensitivity for detecting severe combined immunodeficiency. Using this value, retest and referral rates were 0.43% (37 samples) and 0.03% (3 samples), respectively. Conclusion The technique is reliable and can be applied on a large scale after the training of technical teams throughout Brazil.

Resumo Objetivo Aplicar no Brasil a técnica de quantificação de T-cell Receptor Excision Circles (TRECs) por PCR em tempo real para triagem neonatal de imunodeficiência combinada grave (SCID) e avaliar se é possível fazê-la em grande escala em nosso país. Métodos Foram coletadas em papel filtro 8.715 amostras de sangue de recém-nascidos e, após eluição do DNA, os TRECs foram quantificados por PCR em tempo real. O valor de corte para determinar se uma amostra é anormal foi determinado pela análise de curva ROC com o programa SSPS. Resultados A concentração de TRECs em 8.682 amostras analisadas variou entre 2 e 2.181 TRECs/µL de sangue, com média e mediana de 324 e 259 TRECs/µL, respectivamente. Das amostras, 49 (0,56%) ficaram abaixo do valor de corte (30 TRECs/µL) e foram requantificadas. Quatro (0,05%) mantiveram resultados anormais (entre 16 e 29 TRECs/µL). Amostras de pacientes com diagnóstico clínico prévio de SCID e síndrome de DiGeorge foram usadas para validar o ensaio e todas apresentaram concentração de TRECs abaixo do valor de corte. Recém-nascidos prematuros apresentaram menores níveis de TRECs comparados com os nascidos a termo. Com o uso da curva ROC em nossos dados, chegamos ao valor de corte de 26 TRECs/µL, com sensibilidade de 100% para detecção de SCID. Com o uso desse valor, as taxas de repetição e encaminhamento ficaram em 0,43% (37 amostras) e 0,03% (3 amostras), respectivamente. Conclusão A técnica é factível e pode ser implantada em grande escala, após treinamento técnico das equipes envolvidas.

Análise de custo por resposta dos medicamentos biológicos no tratamento da psoríase moderada a grave sob as perspectivas dos sistemas de saúde público e privado, no Brasil / Cost per responder analysis of biologic drugs for the treatment of moderate to severe psoriasis under Brazilian public and private healthcare systems perspectives

Objetivo: Estimar o custo por resposta dos medicamentos biológicos no tratamento da psoríase moderada a grave sob as perspectivas do Sistema de Saúde Suplementar (SSS) e Sistema Único de Saúde (SUS), representado pela Secretaria de Estado da Saúde de São Paulo, no Brasil. Métodos: Quatro medicamentos biológicos foram considerados na análise: adalimumabe, etanercepte, infliximabe e ustequinumabe. Os dados de eficácia foram obtidos de uma metanálise publicada, que avaliou a resposta PASI 75 dos medicamentos na semana 24 de tratamento. O custo do tratamento foi obtido considerando o preço de aquisição dos medicamentos, conforme perspectiva analisada, e a posologia preconizada na bula de cada um deles. Análise de sensibilidade foi conduzida a fim de avaliar o impacto das incertezas nos resultados encontrados. Resultados: A análise mostrou que, sob a perspectiva do SSS, ustequinumabe apresentou o menor custo por resposta PASI 75 (R$ 66.371) por ano de tratamento, seguido por infliximabe (R$ 139.605), adalimumabe (R$ 152.501) e etanercepte (R$ 179.812). Resultado semelhante foi observado na perspectiva do SUS, no qual ustequinumabe apresentou custo por resposta PASI 75 de R$ 47.229, seguido por infliximabe (R$ 75.145), adalimumabe (R$ 90.292) e etanercepte (R$ 130.523). Ajuste de dose para ustequinumabe mostrou ser o parâmetro mais sensível na análise de sensibilidade. Conclusão: Avaliações econômicas são ferramentas importantes para auxiliar gestores de saúde no processo de tomada decisão. A presente análise mostrou que, dentre as alternativas comparadas, ustequinumabe é o medicamento biológico que apresenta o menor custo por resposta PASI 75 (mais custo-efetivo), independentemente da perspectiva analisada (público ou privado).

Objective: To estimate the cost per responder of biologic drugs in moderate to severe psoriasis treatment from the private and public (State Health Secretariat of São Paulo) perspectives in Brazil. Methods: Four biologic drugs were considered in the analysis: adalimumab, etanercept, infliximab and ustekinumab. Efficacy data was obtained from a published metanalysis, which evaluated PASI 75 response after treatment with biologic drugs after 24 weeks of treatment. The cost of treatment was obtained considering drug acquisition cost, according to the analyzed perspective, and dosage according to each drug information label. Sensitivity analysis was performed to evaluate the impact of uncertainty in the results. Results: The analysis demonstrated that, from the private perspective, ustekinumab presented lower cost per PASI 75 response (R$ 66,371), in one year of treatment, followed by infliximab (R$ 139,605), adalimumab (R$ 152,501), and etanercept (R$179,812). Similar results were found from public perspective, with ustekinumab presenting a cost per PASI 75 response of R$ 47,229 per year of treatment, followed by infliximab (R$ 75,145), adalimumab (R$ 90,292) and etanercept (R$ 130,523). Dose adjustment for ustekinumab was shown to be the most sensitive parameter in the sensitivity analysis. Conclusion: Economic evaluations are important tools to support payers during the decision making process. The current analysis demonstrated that, among compared options, ustekinumab is the biologic with the lowest cost per PASI 75 responder (more cost-effective), regardless the perspective considered (public or private).

Neonatal screening for severe combined immunodeficiency in Brazil.

OBJECTIVE: To apply, in Brazil, the T-cell receptor excision circles (TRECs) quantification technique using real-time polymerase chain reaction in newborn screening for severe combined immunodeficiency and assess the feasibility of implementing it on a large scale in Brazil. METHODS: 8715 newborn blood samples were collected on filter paper and, after DNA elution, TRECs were quantified by real-time polymerase chain reaction. The cutoff value to determine whether a sample was abnormal was determined by ROC curve analysis, using SSPS. RESULTS: The concentration of TRECs in 8,682 samples ranged from 2 to 2,181TRECs/µL of blood, with mean and median of 324 and 259TRECs/µL, respectively. Forty-nine (0.56%) samples were below the cutoff (30TRECs/µL) and were reanalyzed. Four (0.05%) samples had abnormal results (between 16 and 29TRECs/µL). Samples from patients previously identified as having severe combined immunodeficiency or DiGeorge syndrome were used to validate the assay and all of them showed TRECs below the cutoff. Preterm infants had lower levels of TRECs than full-term neonates. The ROC curve showed a cutoff of 26TRECs/µL, with 100% sensitivity for detecting severe combined immunodeficiency. Using this value, retest and referral rates were 0.43% (37 samples) and 0.03% (3 samples), respectively. CONCLUSION: The technique is reliable and can be applied on a large scale after the training of technical teams throughout Brazil.

Alérgenos recombinantes: papel no diagnóstico e na imunoterapia alérgeno-específica / Recombinant allergens: role in diagnosis and in allergen-specific immunotherapy

Nos últimos 30 anos tem havido um avanço notável na identificação, purificação e expressão recombinante de alérgenos relevantes das mais variadas fontes, incluindo ácaros, insetos, mamíferos, polens, alimentos, fungos, látex e outras fontes. Estes avanços resultaram na utilização crescente de alérgenos purificados, naturais ou recombinantes, para melhorar o diagnóstico de alergia pelos métodos que dispomos, incluindo os testes cutâneos de hipersensibilidade imediata, e os métodos in vitro para medida de anticorpos IgE específicos, como ImmunoCAP, ImmunoCAP-ISAC, ELISA e MARIA. Mais recentemente, o uso de alérgenos recombinantes de pólen de bétula (rBet v 1) e de gramas (coquetel de 5 alérgenos) em imunoterapia foi relatado como seguro e eficaz, com resultados comparáveis aos obtidos usando extratos naturais, em pacientes com rinoconjuntivite alérgicos a polens. No presente artigo, apresentamos revisão atualizada do uso de alérgenos recombinantes em diagnóstico de alergia e em imunoterapia alérgeno-específica, incluindo novas estratégias de imunoterapia. Focalizamos na avaliação crítica de estudos que investigaram sensibilidade, especificidade, reatividade cruzada e valor prognóstico de métodos diagnósticos com uso de alérgenos recombinantes versus extratos naturais; nas recomendações atuais para o uso destes novos métodos na prática clínica; e na revisão de estudos clínicos com imunoterapia usando alérgenos recombinantes realizados até o momento.

Over the past 30 years, a great deal of progress has been made in the identification, purification,and recombinant expression of relevant allergens from various sources, including mites, insects,mammals, pollens, foods, fungi, latex, and other sources. These new developments have resultedin an increasing use of purified allergens, either natural or recombinant, to improve the diagnosisof allergy via the methods currently available, including skin tests and in vitro tests for measuringspecific IgE antibodies, e.g., ImmunoCAP, ImmunoCAP-ISAC, ELISA, and MARIA. More recently,the use of recombinant allergens from birch pollen (rBet v 1) and from grass pollen (a cocktailof five allergens) in immunotherapy has been reported to be safe and effective, with resultscomparable to those obtained with natural extracts in patients with rhino-conjunctivitis due topollen allergy. In the present article, we present an up-to-date review on the use of recombinantallergens in the diagnosis of allergy and in allergen-specific immunotherapy, including newstrategies for immunotherapy. We focus on the critical analysis of studies that have investigatedsensitivity, specificity, cross-reactivity, and the prognostic value of diagnostic methods that includerecombinant allergens versus natural extracts; on current recommendations for the use of thesenew methods in clinical practice; and on the review of clinical studies using immunotherapy withrecombinant allergens performed to date.

Tropomiosinas e reatividade cruzada / Crossreactivity of tropomyosin

Objetivo: Apresentar e discutir a relevância da tropomiosina como panalérgeno e implicações clínicas de sua reatividade cruzada. Métodos: Revisão da literatura que aborda aspectos bioquímicos e moleculares da tropomiosina como alérgeno presente em ácaros, baratas, camarão, lagosta, caracol e helmintos, em particular Ascaris lumbricoides e Schistossoma mansoni. Buscou-se enfatizar a relevância desta família de proteínas como panalérgenos em estudos clínicos que analisaram as implicações da hipótese de reatividade cruzada desta proteína, levando à sensibilização do paciente infectado por helminto e ao reconhecimento e apresentação da tropomiosina, tornando-o igualmente sensibilizado a ácaros, baratas e outras fontes de tropomiosina de invertebrados, aumentando a chance de desenvolvimento de atopia e doenças alérgicas, particularmente asma. Resultados: A superfamília das tropomiosinas é considerada a mais prevalente fonte de alérgenos alimentares de origem animal. Existe alta homologia de sequência quando comparamos separadamente tropomiosinas de seres vertebrados e invertebrados, porém esta homologia torna-se baixa quando comparadas as sequências de grupos vertebrados versus invertebrados. Estudos apontam que existem diferentes desfechos para indivíduos parasitados quanto ao aumento da prevalência de doenças alérgicas. O mesmo para indivíduos sob imunoterapia específica para ácaros em indivíduos com alergia alimentar a tropomiosina. Conclusões: Tropomiosinas são proteínas altamente conservadas entre invertebrados e induzem resposta IgE mediada. Quanto maior a distância evolucionária dos seres vivos, menor a homologia de sequência de suas tropomiosinas (vertebrados versus invertebrados). Existe fundamento para a reatividade cruzada das tropomiosinas. Mais estudos são necessários para avaliar se a reatividade cruzada entre tropomiosinas de invertebrados é clinicamente relevante, de forma á permitir recomendações precisas aos pacientes.

Objective: To present and discuss tropomyosin relevance as a pan allergen and the implication of its cross reactivity. Methods: Review of the literature from the biochemical and molecular aspects of tropomyosin as an allergen present in mite, cockroach, shrimp, lobster, snail and helminthes, particularly Ascaris lumbricoides and Schistossoma mansoni. Here we aimed to remark the relevance of this protein family as pan allergens in clinical trials which analyzed the implications of the cross reactivity hypothesis, where a patient infected by helminthes would be at risk to develop sensitivity to other tropomyosin sources, especially from mites and cockroaches, enhancing the odds of atopy and allergic diseases development, particularly asthma. Results: Tropomyosin superfamily is considered the most prevalent source of animal food allergen. There is a high homology sequence when tropomyosins are compared within the vertebrate group and invertebrate group, but there is a low sequence homology when vertebrate tropomyosin is compared to invertebrate tropomyosin. Clinical trials were inconsistent to confirm that helminthiasis would increase the prevalence of allergic diseases and there are different outcomes for tropomyosin food allergic patients that undergo immunotherapy. Conclusions: Tropomyosins are highly conserved proteins among invertebrates and induce IgE antibody responses. The higher tropomyosin evolutionary distance the lower the degree of sequence identity (vertebrates vs invertebrates). Tropomyosins provide support for IgE crossreactivity. Further studies are necessary to evaluate whether the immunologic crossreactivity among invertebrate tropomyosins is clinically relevant, and to allow precise recommendations to allergic patients.

Fator de necrose tumoral alfa (TNF- a) e asma: metanálise é a saída? / Tumor Necrosis Factor alpha (TNF-a) and Asthma: 15 Meta-ana/ysis the on/y way out?

O Fator de Necrose Tumoral Alfa (TNF-a) tem sido observado de perto nos últimos quinze anos e o emprego de ferramentas de biologia molecular tornou possível a descrição dos vários polimorfismos presentes em seu promotor. Acredita-se que a presença destes polimorfismos possa desempenhar papel crucial na regulação das funções do gene, propiciando em algumas situações a produção diferencial da citocina que por sua vez desempenha papéis centrais nos mecanismos inflamatórios, base do processo patológico que leva à asma. Nesta revisão procuramos explicar os critérios mais recentes adotados na realização de metanálise dos estudos de associação molecular, sem perder de vista a limitação deste método matemático quando aplicado à epidemiologia molecular

Asma Genes: conceitos prelilinares / Asthma and genes: preliminary concepts

Resumo: O conhecimento do genoma humano, decorrente do grande avanço obtido pela genética clínica tem possibilitado o estudo da identificaçâo dos possíveis genes envolvidos com o fenótipo de várias doenças, sobretudo as alérgicas. Entre elas destaca- se a asma. Neste trabalho so apresentados conceitos básicos sobre genética clínica que nos permitirão compreender de modo mais adequado esta nova área do conhecimento, sobretudo o estudo dos polimorfismos. Os conceitos aqui apresentados foram obtidos por busca ativa em tratados específicos e levantamento nos bancos de dados MEDLINE e EMBASE.

Otite média recorrente na infância / Recurrent otitis media in childhood

Os autores fazem revisäo sobre otite média recorrente, na infância, abordando aspectos clinicoepidemiógicos, seus principais agentes etiológicos, alterações imunológicas envolvidas e enfocam a necessidade de adequada propedêutica diagnóstica, propondo os principais exames complementares necessários