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Objetivos: Relatar caso de anemia hemolítica autoimune (AHAI) por anticorpos frios associada a Leucemia Linfoblástica Aguda B (LLA-B). Resultados: Paciente feminina, 53 anos, com antecedente de câncer de mama curado, apresentou-se em setembro/2023 com equimoses espontâneas e sintomas gripais que haviam iniciado na semana anterior. Hemograma mostrou anemia (Hb 11,4 g/dL), leucocitose (26400/μL), linfocitose (16100/μL) e plaquetopenia (20000/mm3). O mielograma apresentou 57% de blastos, compatível com LLA-B comum. A pesquisa da translocação BCR::ABL foi negativa. Iniciada indução quimioterápica com prednisona, metotrexato, dexametasona, vincristina e daunorrubicina. Durante o tratamento, intercorreu com disfunção hepática após pegasparaginase em outubro/2023, pneumonia em novembro/2023 e neutropenia febril em dezembro/2023. Em fevereiro/2024, foi reinternada devido fadiga, vômitos, diarreia e febre. Exames evidenciaram anemia intensa (Hb 4,2 g/dL) e plaquetopenia moderada (82.000/mm3), em associação a coombs direto positivo (C3d positivo, eluato negativo) sugerindo doença da aglutinina a frio, embora houvesse reticulocitopenia. Estudo imunohematologico foi realizado em mais de uma ocasião e consistentemente mostrava anticorpos anti-IgM com especificidade anti-I em título maior que 1/64. Prosseguiu-se com investigação de diagnósticos diferenciais que evidenciou infecção pelo citomegalovírus, com carga viral de 682 cópias. Assim, apesar de sintomatologia gastrointestinal frustra e da ausência de anatomopatológico confirmatório, foi iniciado tratamento empírico com ganciclovir, mas não houve melhora da anemia. Exames medulares imediatamente antes e logo após o aparecimento da anemia evidenciaram doença residual mensurável negativa (DRM). Dessa forma, optou-se por realizar modalidades de tratamento focadas na AHAI (Prednisona, Azatioprina, Rituximabe e Bortezomibe), mas, sem resposta. A paciente manteve anemia intensa (hemoglobina abaixo de 6 g/dL), necessitando de transfusões sanguíneas com concentrados de hemácias aquecidos para melhor rendimento. Sendo assim, deu-se seguimento ao tratamento da LLA e a paciente foi encaminhada para o transplante de medula alogênico haplo-idêntico em maio/2024. Evoluiu com com síndrome veno oclusiva e faleceu no 8º dia após o transplante. Discussão: A doença da crioaglutinina caracteriza-se por AHAI causada por anticorpos monoclonais a frio com títulos iguais ou maiores que 1/64. Frequentemente apresenta-se em associação a Linfomas B, embora possa ser identificada em pacientes com evidência de população clonal de linfócitos, mas sem sinais radiológicos ou clínicos de malignidade. Sua identificação em concomitância à LLA é extremamente infrequente. Torna o caso ainda mais intrigante a ausência de doença detectável no momento do aparecimento da AHAI, vistos os estudos medulares mostrando DRM negativa. Realça-se ainda a gravidade da manifestação, visto a manutenção de anemia grave, durante 3 meses, apesar dos múltiplos tratamentos realizados. Apenas cerca de 27% dos casos de doença da crioaglutinina apresentam-se com hemoglobina abaixo de 8, embora o quadro possa ser exacerbado durante quadros inflamatórios/infecciosos agudos devido à ativação do complemento. Conclusão: O caso evidencia uma apresentação atípica da doença da aglutinina a frio associada, também de forma infrequente, a LLA-B, evidenciando a necessidade de avançarmos em nosso entendimento de ambas as doenças e etiopatogenias.

Objetivos: Descrever caso de paciente com diagnóstico de Doença de Rosai Dorfman (DRD) com antecedente de Linfoma de Hodgkin (LH) em resposta completa, com objetivo de reforçar esta entidade como diagnóstico diferencial de linfonodomegalia durante o seguimento clínico de pacientes com antecedente de neoplasia linfoproliferativa tratada, enfatizando a importância do estudo anatomopatológico. Materiais e métodos: Trata-se de um relato de caso, composto de dados clínicos vindos da revisão de prontuário somada a revisão da literatura. Resultados: paciente do sexo feminino, 30 anos de idade, com diagnóstico há 08 anos de linfoma de Hodgkin subtipo esclerose nodular, estadio de Ann Harbor IIB. O LH havia sido tratado com 06 ciclos de quimioterapia com esquema ABVD (doxorrubicina, bleomicina, vinblastina e dacarbazina) e radioterapia de campo envolvido de consolidação (21 sessões - 4 Gy) em região cervical e mediastino, apresentando resposta completa evidenciada por PET-CT. Após 07 anos do término do tratamento, apresentou linfonodomegalia inguinal, bilateralmente, o maior medindo aproximadamente 03 centímetros em seu maior eixo. A paciente não relatava sintomas B. Realizada biópsia excisional de linfonodo inguinal, com resultado de anatomopatológico evidenciando linfonodo com arquitetura extensamente alterada às custas de intensa histiocitose, com emperipolese e presença focal de células atípicas. O estudo imunohistoquímico demonstrou CD20 e PAX5 positivos nos folículos linfoides hiperplásicos, CD3 positivo em pequenos linfócitos, LMP1 e CD1a negativos, CD68 e S100 positivos em numerosos histiócitos, CD30 negativo, CD15 positivo em células mononucleadas sugestivas de linhagem histiocitária; negativo nas grandes células de interesse, IGG positivo em numerosos plasmócitos e IGG4 positivo em raros plasmócitos. Assim, concluiu-se tratar de um quadro de histiocitose sinusal maciça (DRD), com ausência de critérios para o diagnóstico de LH. Paciente permaneceu em seguimento clínico no ambulatório, em tratamento expectante, sem evidência de recaída do linfoma, e sem progressão de linfonodomegalias. Discussão: A DRD foi descrita como histiocitose sinusal com linfonodomegalias de grande monta pelos autores de mesmo nome em 1969. Entretanto, sua etiopatogenia continua pouco compreendida. A subclassificação da doença baseia-se na apresentação clínica, dividindo-a em doença cutânea, familiar ou esporádica (que por sua vez classifica-se em doença nodal, extranodal, relacionada à neoplasia ou a doença autoimune). Na literatura, encontram-se casos de DRD coexistentes com as mais diversas neoplasias sólidas e hematológicas. Em associação a LH, poucos casos foram relatados, alguns de diagnóstico concomitante ao aparecimento da doença linfoproliferativa (em ocasiões no mesmo linfonodo analisado para o diagnóstico) e outros vários anos após o término do tratamento do linfoma, similarmente ao aqui relatado. A DRD esporádica é de bom prognóstico e frequentemente auto-limitada, podendo ser indicada observação ativa, conforme optado neste caso, guardando excisão cirúrgica ou tratamentos sistêmicos para casos em que a linfonodomegalia ou lesões extranodais incorrem em sintomas. Conclusão: Embora infrequente, a DRD deve ser lembrada dentre os diagnósticos diferenciais de linfonodomegalia mesmo em pacientes com doença neoplasia atual ou anterior, o que corrobora a importância da avaliação anatomopatológica no seguimento de pacientes com doença linfoproliferativa.

Objetivos: Descrever o caso clínico de paciente que vive com HIV (PVHIV) cuja investigação de linfonodomegalias e bicitopenia, resultou nos diagnósticos de tuberculose ganglionar e leucemia mieloide aguda (LMA). Há o propósito de evidenciar a possibilidade de coexistência de tais patologias, sendo importante sua consideração. Materiais e métodos: Trata-se de um estudo do tipo relato de caso, cujos dados clínicos são provenientes da realização de revisão de prontuário e a discussão através de revisão da literatura. Descrição do caso: Paciente do sexo feminino de 54 anos, com diagnóstico de HIV desde 2005, com carga viral indetectável, e CD4 de 215. Iniciou em março de 2024, febre vespertina diária, tosse seca, perda de 6kg em 1 mês, linfonodomegalias, lesões cutâneas em membros inferiores, além de anemia normocrômica e normocítica, sem sangramentos. Em investigação, através da biópsia de linfonodo, realizado diagnóstico de tuberculose ganglionar, iniciado tratamento com esquema RIPE. Durante internação, identificada bicitopenia (anemia e neutropenia), sendo realizado um estudo medular com diagnóstico de leucemia mieloide aguda de risco desfavorável (presença de cariótipo complexo), e optado por iniciar indução com esquema 3+7 (citarabina e daunorrubicina), concomitante ao tratamento de tuberculose. Evoluiu com piora progressiva, com a presença de disfunção hepática e respiratória, sendo necessário aumento prosseguir com suporte intensivo. A despeito de medidas clínicas otimizadas, a paciente foi a óbito por choque séptico por Magnusiomyces capitatus (Geotrichum capitatum). Discussão: A infecção crônica pelo vírus do HIV, mesmo que com adequado tratamento e controle com as medicações anti-retrovirais (TARV), pode acarretar em aumento de neoplasias não definidoras da síndrome de imunodeficiência adquirida (SIDA); neste contexto, há de se considerar a possibilidade de desenvolvimento de leucemia mieloide aguda. Não há consenso na literatura se o risco é maior que a população em geral, no entanto, com o envelhecimento da PVHIV, principalmente associado a efetividade dos tratamentos, tem-se evidenciado maior número de casos de LMA nessa população. Além disso, é conhecido que o processo inflamatório proporcionado pela doença viral pode contribuir para a regulação e proliferação das células leucêmicas. Ademais, é importante ressaltar que durante o tratamento quimioterápico não há indicação de suspender terapia antirretroviral, sendo importante inclusive para favorecer reconstituição imune. Conclusão: Na população de PVHIV em que há a presença de citopenias e/ou linfonodomegalias, devemos considerar, entre os diagnósticos diferenciais, mesmo em pacientes com infecções oportunistas, a possibilidade de neoplasias não definidoras de SIDA, entre elas a LMA. Apesar dos tratamentos disponíveis para LMA serem viáveis e seguros para essa população, os resultados de sobrevida ainda são insatisfatórios e chamam a atenção sobre a necessidade de aperfeiçoar novos tratamentos.

Objetivo: Relatar caso de aspergilose disseminada em paciente com leucemia linfoide aguda B em tratamento quimioterápico de indução. Relato de caso: Paciente feminino, 37 anos, com diagnóstico de LLA-B comum em quimioterapia de indução (protocolo BRALLA20), evolui no 11°dia de internação, em período de neutropenia, com paresia em mão esquerda. Em 24 horas, evolui com paresia em todo o membro superior esquerdo e surgimento de lesões cutâneas dolorosas com halo necrótico no dorso; na ocasião realizada pesquisa de galactomanana sérica com resultado positivo e cultura das lesões cutâneas compatível com Aspergillus flavus. Realizada ressonância magnética de crânio compatível com aspergilose angioinvasiva, sendo iniciada anfotericina B empírica. Paciente evoluiu com piora progressiva do quadro neurológico, aumento das lesões intraparenquimatosas e hipertensão intracraniana, além de novas lesões cutâneas; neste contexto, necessitou de suporte intensivo sendo transferida à UTI. Foi submetida drenagem de abscesso fúngico em lobo frontal, com cultura positiva para Aspergillus no material. Após 13 dias de terapia antifúngica, fungigrama demonstrou resistência a Anfotericina sendo realizado escalonamento guiado para Voriconazol. No 29° dia de Voriconazol, evoluiu com sepse de foco pulmonar por Acinetobacter baumanii e Klebsiella pneumoniae ESBL+. Evoluiu a óbito por piora progressiva do quadro infeccioso. Discussão: As infecções fúngicas invasivas são uma importante causa de complicação em imunocomprometidos, principalmente em pacientes com neoplasias hematológicas. Dentre elas, a aspergilose invasiva (AI) é uma grande preocupação nos departamentos de hematologia devido à sua alta incidência e mortalidade associada. As espécies causadoras de AI mais comuns são Aspergillus fumigatus seguido por Aspergillus flavus. A AI ocorre principalmente em pacientes com neutropenia prolongada induzida por quimioterapia e/ou pacientes submetidos a transplante de células tronco hematopoiéticas. A neutropenia apresenta-se como o principal fator de risco para esta complicação, sendo a duração da neutropenia diretamente associada ao aumento do risco. Outros fatores de risco incluem linfopenia e infecções virais respiratórias. Casos de aspergilose disseminada, em especial com acometimento cerebral, são raros e apresentam prognóstico ruim, com mortalidade de aproximadamente 54%. Pacientes com leucemia mieloide aguda e leucemia linfoblástica aguda em terapia de indução a base de citarabina e daunorrubicina constituem as principais populações em risco de aspergilose cerebral (AC). Uso de corticoides am altas doses e por tempo prolongado, também apresenta-se como fator de risco para AC. O diagnóstico de aspergilose cerebral baseia-se em cultura e avaliação anátomo-patológica da lesão cerebral, podendo ser utilizados em conjunto métodos de detecção de material genético do fungo ou quantificação de galactomanana. O tratamento de AI baseia-se em uso de imidazólicos (voriconazol, itraconazol) ou Anfotericina B lipossomal, com boas taxas de resposta. Por outro lado, o tratamento de aspergilose cerebral não apresenta dados concretos na literatura, variando de combinação de imidazólicos, Anfotericina B, ou mesmo combinação de ambos. Conclusão: A aspergilose disseminada apresenta-se como uma patologia de difícil manejo e alta mortalidade, devendo ser suspeitada, diagnosticada e tratada com brevidade, visando maior chance de sucesso do tratamento antifúngico.

Objetivo: Relatar caso de paciente com LMC com gravidez durante tratamento com asciminibe. Relato de caso: Paciente do sexo feminino, 33 anos, com diagnóstico de leucemia mieloide crônica desde 2017, tratada em primeira linha com imatinibe 400 mg, segunda linha com dasatinibe 100 mg e em terceira linha com asciminibe 80 mg/dia, desde maio de 2023, acesso via programa de uso compassivo. A troca dos inibidores de tirosina quinase (ITQ) foi motivada por perda de resposta molecular e citogenética nos dois inibidores de tirosina quinase anteriores, sem mutação do BCR::ABL1. Apesar de orientada contracepção hormonal e método de barreira, paciente fazia uso apenas de contraceptivo oral combinado, e em agosto de 2023, foi diagnosticado gestação gemelar no primeiro trimestre, sendo orientada a suspender asciminibe imediatamente. Foi prescrito Interferon peguilado 180 mcg SC a cada 2 semanas. Após 15 dias da modificação do tratamento, houve perda de resposta molecular, porém sem perda de resposta hematológica. Durante a gestação, a paciente foi acompanhada pela equipe de ginecologia e obstetrícia. Na 32ª semana de gestação, a paciente foi internada por quadro de pré-eclâmpsia, mantendo-se internada até o final da 34ª semana de gestação (fevereiro de 2024), quando foi submetida a uma cesariana, com nascimento de RNPT sexo feminino, vivo, Apgar 8/10, e RNPT sexo masculino, vivo, Apgar 8/10. Apresentou hemorragia pós parto revertida com massagem uterina e ocitocina 20UI, transamin, misoprostol via retal. Evoluiu com pico pressórico e cefaleia pós parto, com indicação de sulfatação de 24 a 25/02/2024. Após 5 dias da alta, retornou para unidade de saúde com hipertensão, sendo internada para controle, com alta após 4 dias, sem mais intercorrências. Recebeu no total 9 doses de Interferon peguilado. Após alta da maternidade, foi suspensa a amamentação e reiniciado asciminibe 80 mg ao dia, com recuperação resposta molecular maior em 2 meses de reinício do tratamento. Discussão: Com a revolução do tratamento da LMC após o surgimento dos ITQ, a população tem alcançado sobrevida semelhante à população geral. O tratamento da LMC em gestantes é uma condição rara e muito desafiadora e por ser conhecido o risco teratogênico associado aos ITQ, principalmente no primeiro trimestre, indica-se suspensão de seu uso quando ocorre gestação, devendo manter-se o monitoramento para avaliar persistência ou perda da resposta, para que possa ser feito o tratamento adequado (seja com interferon alfa ou leucocitoaférese). O asciminibe é um ITQ de 3ª geração com um mecanismo de ação diferente dos demais, atuando no sítio do miristoil. São raros os relatos de gravidez após exposição ao asciminibe. Conclusão: Relatamos um caso de gestação gemelar bem-sucedido após exposição ao asciminibe, com rápida recuperação da resposta molecular após a reintrodução da medicação pós parto. Há necessidade de individualizar a terapêutica da LMC durante a gestação, baseando-se nos níveis dos transcritos BCR::ABL1, resposta hematológica, status da LMC e curso da gravidez. Deve-se manter monitorização molecular regular através do PCR quantitativo. Gestantes com resposta molecular estável e duradoura podem interromper de modo mais seguro o tratamento. No presente caso, a gravidez precoce em início de tratamento com asciminibe, em uma paciente resistente a dois ITQ prévios, sem atingir estabilidade da resposta molecular poderia ter colocado em risco a evolução da doença.

Objetivos: Descrever o caso clínico de paciente com diagnóstico de mieloma múltiplo (MM) tratado e com resposta parcial muito boa (VGPR), que apresentou durante o seguimento anemia refratária, sendo diagnosticado com neoplasia mielodisplásica (SMD) com deleção do braço longo do cromossomo 5 (del(5q)). Materiais e métodos: Trata-se de um estudo do tipo relato de caso, cujos dados clínicos são provenientes da realização de revisão de prontuário e a discussão através de revisão da literatura. Resultados: Paciente masculino de 71 anos, com diagnóstico de MM IgA/Kappa ISS 3. Considerado paciente idoso frágil, com múltiplas patologias prévias, foi considerado inelegível para transplante de medula óssea autólogo, sendo tratado com 6 ciclos de VTd (bortezomibe, talidomida e dexametasona) e ácido zoledrônico mensal. Evoluiu com progressão de doença, sendo optado por esquema de 2ª linha com 6 ciclos de VMP (Bortezomibe, Melfalano e Prednisona). Após o término do tratamento, atingiu VGPR. Ao longo do seguimento, apresentou piora da anemia, no mesmo mês de término do tratamento. Em avaliação laboratorial, evidenciou-se reticulocitopenia grave. Novo estudo medular demonstrou ausência de infiltração por neoplasia de plasmócitos, com presença de atipias de séries granulocítica e de megacariócitos. A avaliação de cariótipo evidenciou a presença de alteração cromossômica, 46, XY,del(5)(q13q31). Nesse contexto, paciente teve o diagnóstico de SMD com del(5q), sendo optado por iniciar tratamento com talidomida, além de inserção em programa de transfusão, havendo melhora sintomática significativa. Discussão: A presença SMD no contexto de neoplasias linfoproliferativas pode ocorrer como consequência do dano genômico cumulativo dos tratamentos prévios da neoplasia ou de novo. No caso em questão, o paciente teve o diagnóstico de MM sem evidência, na avaliação inicial, de alterações citogenéticas ou cito morfológicas relacionadas à SMD. O paciente foi tratado do MM com 2 linhas de tratamento, com exposição a alquilante (melfalano) na última. Entretanto, o intervalo entre a exposição e o diagnóstico de SMD não sugere que o melfalano esteja relacionado na fisiopatologia da SMD. Alguns estudos sugerem que 1 a cada 10 pacientes com o diagnóstico de MM apresentam displasia das linhagens hematopoiéticas ao diagnóstico, sendo atribuído a isso menor sobrevida. Além disso, pelo impacto no microambiente tumoral, há uma modificação na mielotoxicidade ao tratamento quimioterápico, havendo a necessidade de redução de dose, com consequente impacto em sua efetividade; há estudos que também sugerem um favorecimento na proliferação do plasmócito monoclonal. O diagnóstico de SMD com del(5q) é uma entidade importante a ser considerada no contexto de anemias refratárias, que impacta diretamente na qualidade de vida do paciente em virtude da alta necessidade de transfusão de hemocomponentes. Uma opção terapêutica a ser considerada é o uso de imunomoduladores (IMiD) (como a lenalidomida, talidomida), com boa resposta e diminuição da demanda transfusional. No caso em questão, o uso de um IMiD torna-se particularmente interessante pela concomitância do MM e da SMD com del(5q). Conclusão: A associação entre o MM e SMD é algo importante a ser considerado, reforçando a importância da sua pesquisa ao diagnóstico e durante o seguimento do paciente. A presença da SMD com del(5q) impacta significativamente o tratamento e deve ser aventada na presença de anemias graves e refratárias.

BACKGROUND: The liver is an important organ for its ability to transform xenobiotics, making the liver tissue a prime target for toxic substances. The carotenoid bixin present in annatto is an antioxidant that can protect cells and tissues against the deleterious effects of free radicals. In this study, we evaluated the protective effect of bixin on liver damage induced by carbon tetrachloride (CCl4) in rats. RESULTS: The animals were divided into four groups with six rats in each group. CCl4 (0.125 mL kg-1 body wt.) was injected intraperitoneally, and bixin (5.0 mg kg-1 body wt.) was given by gavage 7 days before the CCl4 injection. Bixin prevented the liver damage caused by CCl4, as noted by the significant decrease in serum aminotransferases release. Bixin protected the liver against the oxidizing effects of CCl4 by preventing a decrease in glutathione reductase activity and the levels of reduced glutathione and NADPH. The peroxidation of membrane lipids and histopathological damage of the liver was significantly prevented by bixin treatment. CONCLUSION: Therefore, we can conclude that the protective effect of bixin against hepatotoxicity induced by CCl4 is related to the antioxidant activity of the compound.

Objective: Several rehabilitation interventions have been proposed to support people with post-COVID-19 condition (PCC). However, the full spectrum of these interventions remains unclear, partly due to the complexity of PCC, which encompasses a broad range of symptoms affecting multiple organ systems and health domains. This scoping review aimed to identify the available rehabilitation interventions for PCC and the outcome measures used to evaluate them, to facilitate the development of multifaceted interventions and improve patient care., Methods: Following the Joanna Briggs Institute Framework, we searched CINAHL, EMBASE, MEDLINE, PsychINFO, CENTRAL and Scopus databases from inception to 22 January 2024 for experimental and observational studies investigating rehabilitation interventions for adults with PCC. Interventions and their corresponding outcome measures were synthesised based on targeted outcomes aligned with the most common manifestations of PCC. The quality of intervention reporting was assessed using the Template for Intervention Description and Replication (TIDieR) checklist., Results: We identified 74 studies; 28 randomised trials (37.8%) and 46 observational and quasi-experimental designs (62.2%). Most interventions consisted of different combinations of education, exercises and therapies to manage dyspnoea, fatigue and psychological symptoms, such as anxiety and depression. Few studies addressed postexertional malaise, cognitive function, memory, balance and coordination. At least half of the included studies required a confirmed SARS-CoV-2 infection for participant inclusion. Reporting on adherence rates was limited, and 65% of the studies did not report adverse events., Conclusion: There is a need for more comprehensive and inclusive approaches that address the full spectrum of PCC symptomatology to improve patient care and enhance the reproducibility of future studies., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. Published by BMJ Group.)

Objective: To assess the prevalence of PEM in people with PCC; and the change in prevalence of PEM following rehabilitation interventions in people with PCC., Data Sources: We searched MEDLINE, Embase, Central, CINAHL, PsychINFO and Clinical Trial Registries from inception until January 12 th , 2024., Study Selection: We included observational studies that measured the prevalence of PEM in adults with PCC and interventional studies that measured the change in prevalence of PEM following rehabilitation interventions in adults with PCC. Two independent researchers screened titles and abstracts. Any discrepancies underwent full text review. Two independent researchers screened the articles included at the full text level. Any discrepancies were resolved by consensus., Data Extraction: Two independent researchers extracted data from eligible studies. We extracted point-prevalence from the cross-sectional studies; and period-prevalence from the longitudinal studies. Two independent reviewers assessed the risk of bias (ROB). Discrepancies were resolved with a senior research team member. For the prevalence studies we used the Cochrane Risk Of Bias In Non-randomized Studies - of Exposure (ROBINS-E) tool. For randomised controlled trials we used the Cochrane Risk of Bias tool II - (RoB2). For non-randomised interventional studies we used the Cochrane Risk Of Bias In Non-Randomized Studies - of Interventions (ROBINS-I) 1 to assess the non-randomised studies. We applied the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach to grade the quality of the evidence DATA SYNTHESIS: We performed a single-arm proportional meta-analysis to synthesize prevalence estimates using logit transformation. We conducted a sensitivity analysis using multilevel-mixed-effects logistic regression. This study is registered with PROSPERO (CRD42024516682).The prevalence of PEM in community-dwelling adults living with PCC was 36% (95% CI: 0.19 to 0.57; 2,263 participants). Two of the included studies (61 patients) found a decrease in the frequency and intensity of PEM episodes in adults with PCC following a tailored rehabilitation program centered on integrating pacing approaches. None of the included studies reported an increase of PEM symptoms' frequency and intensity following an individually tailored rehabilitation program with a therapeutic exercise component (5 studies; 892 patients)., Conclusions: Our research confirms that there is a large burden of PEM in adults living with PCC, highlighting a critical challenge for healthcare systems and an urgent need for more inclusive and rigorous research, to offer safe and effective therapeutic solutions and meet the variable needs of people with PCC that experience PEM.There is a subgroup of patients with PCC that do not experience PEM; and there is limited evidence that supervised, individually tailored, symptom-titrated rehabilitation interventions with active exercise components may not trigger PEM in this subgroup of people with PCC. Our results are limited by the insufficient reporting of the percentage of PEM in the baseline before enrolling patients in the rehabilitation programs, and the large number of studies using non-validated, unstandardized tools to measure PEM in people with PCC, hence there is an urgent need to strengthen the methods of future trials., Competing Interests: Conflicts of interest declaration The authors declare no conflicts of interest, (Copyright © 2025. Published by Elsevier Inc.)

Objective: To quantify the effectiveness and safety of intra-articular interventions for knee and hip osteoarthritis (OA) through a systematic review and Bayesian random-effects network meta-analysis., Design: We searched CENTRAL and regulatory agency websites (inception-2023) for large, English-language, randomized controlled trials (RCTs) (≥100 patients/group) examining any intra-articular intervention., Primary Outcome: pain intensity., Secondary Outcomes: physical function and safety outcomes. Pain and function outcomes were analyzed at 2, 6, 12, 24, and 52 weeks post-randomization, and presented as standardized mean differences (SMDs) (95% credible intervals, 95% CrI). The prespecified minimal clinically important between-group difference (MID) was -0.37 SMD. Safety outcomes were presented as odds ratios (OR) (95% CrI)., Findings: Among 57 RCTs (22,795 participants) examining 18 intra-articular interventions, usual care or placebo, treatment effects were larger in 35 high-risk-of-bias trials than in 22 low/unclear-risk-of-bias trials. In the main analysis (excluding high-risk-of-bias trials), triamcinolone had the highest probabilities of reaching the MID at weeks 2 and 6 (75.3% and 90%, respectively) with corresponding SMDs of -0.48 (95% CrI,-0.85 to -0.10) and -0.53 (95% CrI,-0.79 to -0.27) compared to placebo (1 trial). The complex homeopathic products Tr14/Ze14 showed therapeutic potential at week 6 compared to placebo (SMD:-0.42, 95% CrI,-0.71 to -0.11, 63.5% probability of reaching the MID, 1 trial). Hyaluronic acid had no effect on pain (SMD:-0.04, 95% CrI,-0.19 to 0.11, 11 trials) but a higher risk of dropouts due to adverse events (OR: 2.01, 95% CrI,1.08 to 3.77) and serious adverse events (OR: 1.86, 95% CrI, 1.16 to 3.03) than placebo., Conclusion: Triamcinolone had the highest probabilities to have a treatment effect beyond the MID at weeks 2-6. Large RCTs with lower risk of bias indicate that the effects of 16 intra-articular interventions in knee or hip OA were smaller than the MID, and that most were consistent with placebo effects. Lack of evidence of long-term effectiveness underscores the need for further research beyond 24 weeks., Competing Interests: Declaration of Competing Interest Peter Tugwell is an advisory committee member of the Canadian Reformulary Group Inc., a company that reviews evidence for health insurance companies' employer drug plans. He is also the unpaid Chair of the Management Group of OMERACT, a registered non-profit independent medical research organization dedicated to improving health outcomes for patients with musculoskeletal conditions. OMERACT receives arms-length funding from 11 companies (AbbVie, AstraZeneca, Aurinia, BMS, Centrexion, GSK, Horizon Pharma Inc., Janssen, Novartis, Pfizer, and Sparrow). The remaining authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

BACKGROUND AND CONTEXT OF THE STUDY: Neck pain is a prevalent and globally burdensome problem. Clinical practice guidelines have recommended conservative treatments such as education, exercise therapy (ET), manual therapy (MT), and pharmacological therapy (i.e., medication) to manage all types of neck pain based on the chronicity of the disease (acute, subacute, and chronic pain). However, there is scarce evidence to determine which interventions constitute the most effective strategy for this condition. RESEARCH QUESTION: What are the best conservative treatment options (i.e., ET, MT, education, and/or medication) to relieve pain and disability-related outcomes in patients with neck pain? THE OVERALL PURPOSE OF THE STUDY: (1) To identify which type of conservative treatment (education, ET, MT, and/or medication) and their combinations have the greatest probability of being most effective for neck pain using a network meta-analysis (NMA) approach. (2) To rank these conservative treatments in terms of safety (when possible) and effectiveness for managing neck pain. METHODOLOGY: Systematic review (SR) with NMA of randomized controlled trials (RCTs). Studies should include adults (aged > 18) with neck pain who received any of the interventions of interest (education, ET, MT, and medication). The main outcome will be pain intensity. Searches will be conducted in Ovid Medline All®, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Scopus, and Cochrane Library Trials database. No language or publication date restrictions will be applied. The revised Cochrane Risk-of-Bias (RoB) tool for RCTs (RoB-2) will be used to evaluate RoB, and the certainty of evidence will be evaluated by Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). NMAs will be conducted to rank interventions according to their effectiveness and safety (when possible), allowing a comprehensive analysis of all available evidence, with different nodes specified for all conservative interventions of interest, placebo, sham therapy, and non-intervention control. This NMA will help clinicians and the scientific community choose the most effective strategy or combinations of strategies for treating neck pain. The information gathered in this project will inform decision-making and guide personalized care of individual patients in the future., Competing Interests: Declarations. Ethics approval and consent to participate: Not needed (systematic review). Consent for publication: The authors agree with the publication of this study. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Objective: To rank commonly used patient-reported outcome measures (PROMs) for assessing pain in osteoarthritis trials according to their assay sensitivity, defined as the ability of a PROM to distinguish an effective from a less effective intervention or placebo, proposing a hierarchy for PROM selection in trials and data-extraction in meta-analyses., Design: Analysis of trials with placebo, sham, or non-intervention control that included ≥100 patients per arm with knee/hip osteoarthritis, reporting treatment effects on ≥2 pain PROMs. Treatment effects from all PROMs were standardized on a 0-100 scale. Negative mean differences indicated a larger effect of the experimental treatment compared to control. We ranked PROMs by assay sensitivity using a Bayesian multi-outcome synthesis random-effects model., Results: 135 trials comprising 57,141 participants were included. The ranking of PROMs from highest to lowest assay sensitivity was as follows: pain overall, pain on stairs, pain at night, pain on walking, pain at rest, WOMAC pain, WOMAC global, Lequesne index. Pain overall, the highest-ranked PROM, had a pooled mean difference of -6.96 (95%CrI -7.94, -6.02), while WOMAC pain, the most reported PROM in our study, had a pooled mean difference of -4.90 (95%CrI -5.55, -4.26). The pooled ratio of mean differences between pain overall and WOMAC pain was 1.42 (95%CrI 1.30, 1.55), representing a 42% larger effect size with pain overall., Conclusions: Pain overall has better assay sensitivity than other pain PROMs. Investigators should consider the hierarchy proposed in this study to guide PROM selection in osteoarthritis clinical trials and data extraction in osteoarthritis meta-analyses., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Given the chronic immune activation and inflammatory milieu associated with Long COVID and HIV, we assessed the prevalence of Long COVID in adults living with HIV; and investigated whether adults living with HIV were associated with increased chance of developing Long COVID compared to adults living without HIV., Methods: In this systematic review and meta-analysis, we searched Medline, EMBASE, CINHAL, PubMed and CENTRAL from inception until June 14th, 2024, for observational studies that measured the prevalence of Long COVID in adults living with HIV and the odds of developing Long COVID following a SARS-CoV-2 infection in people living with HIV compared to people living without HIV. Reviews, case reports, randomised control trials and editorials were excluded. The search was conducted without language restrictions. We performed meta-analysis of proportions to synthesise prevalence estimates using logit transformation and a sensitivity analysis using mixed-effects logistic regression. We used random-effects meta-analyses to summarize the odds ratio (OR) of developing Long COVID in adults living with HIV compared to adults living without HIV and conducted a sensitivity analysis including only studies with covariate-adjusted estimates that was planned a-priori. We used ROBINS-E for the risk of bias assessment and GRADE to rate the certainty of evidence. We identified statistical heterogeneity using Cochran's Q test and quantified it using the I 2 statistic. For the Q test, a P  < 0.10 was considered statistically significant. PROSPERO registration: CRD42024577616., Findings: Our search returned 831 results, of which 8 studies (4489 participants) were deemed eligible for inclusion in the systematic review and meta-analysis. The prevalence of Long COVID in adults with HIV was 43% (95% CI: 32-54%, 8 studies; 1227 participants; low certainty, I 2  < 0.0001). The association of HIV status with Long COVID was inconclusive, with wide confidence intervals (OR: 1.16, 95% CI: 0.58-2.29; 4 studies; 3556 participants, low certainty, I 2  = 0.013). When the analysis was restricted to studies reporting covariate-adjusted estimates, adults living with HIV were associated with a higher odds of Long COVID than those not living with HIV (OR: 2.21, 95% CI: 1.12-4.36; 2 studies; 374 participants, low certainty, I 2  = 0.51)., Interpretation: Current evidence indicates that the prevalence of Long COVID in adults living with HIV may be high, suggesting the need for increased awareness and education of healthcare providers and policy makers. Evidence on whether HIV positivity increases the risk of Long COVID is limited and inconclusive, highlighting a need for further research to clarify this potential association., Funding: None., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

OBJECTIVE: To evaluate the effectiveness of remote rehabilitation interventions for people living with chronic musculoskeletal pain and depression. DESIGN: A systematic review with network meta-analysis (NMA) of randomized controlled trials. LITERATURE SEARCH: We searched the Cochrane Central Register of Controlled Trials, CINAHL, EMBASE, LILACS MEDLINE, PSYNDEX, and PsycINFO databases from inception to May 2023. STUDY SELECTION CRITERIA: Randomized controlled trials that evaluated the effectiveness of remote rehabilitation interventions in people with chronic musculoskeletal pain and depression. DATA SYNTHESIS: We used Bayesian random-effects models for the NMA. Effect estimates were comparisons between rehabilitation interventions and waitlist. We performed a sensitivity analysis based on bias in the randomization process, large trials (>100 patients per arm) and musculoskeletal condition. RESULTS: Fifty-eight randomized controlled trials involving 10 278 participants (median sample size: 137; interquartile range [IQR]: 77-236) were included. Interactive voice response cognitive behavioral therapy (CBT; standardized mean difference [SMD] -0.66, 95% credible interval [CrI] -1.17 to -0.16), CBT in person (SMD -0.50, 95% CrI -0.97 to -0.04), and mobile app CBT plus exercise (SMD -0.37, 95% CrI -0.69 to -0.02) were superior to waitlist at 12-week follow-up for reducing pain (> 98% probability of superiority). For depression outcomes, Internet-delivered CBT and telecare were superior to waitlist at 12-week follow-up (SMD -0.51, 95% CrI -0.87 to -0.13) (> 99% probability of superiority). For pain outcomes, the certainty of evidence ranged from low to moderate. For depression outcomes, the certainty of evidence ranged from very low to moderate. The proportion of dropouts attributed to adverse events was unclear. No intervention was associated with higher odds of dropout. CONCLUSION: Interactive voice response CBT and mobile app CBT plus exercise showed similar treatment effects with in-person CBT on pain reduction among people living with chronic musculoskeletal pain and depression had over 98% probability of superiority than waitlist control at 12-week follow-up. Internet-delivered CBT and telecare had over 99% probability of superiority than waitlist control for improving depression outcomes at 12-week follow-up. J Orthop Sports Phys Ther 2024;54(6):1-16. Epub 26 February 2024. doi:10.2519/jospt.2024.12216 .

Rationale: The use of hydrocortisone in adult patients with septic shock is controversial, and the effectiveness of adding fludrocortisone to hydrocortisone remains uncertain. Objectives: To assess the comparative effectiveness and safety of fludrocortisone plus hydrocortisone, hydrocortisone alone, and placebo or usual care in adults with septic shock. Methods: A systematic review and a Bayesian network meta-analysis of peer-reviewed randomized trials were conducted. The primary outcome was all-cause mortality at last follow-up. Treatment effects are presented as relative risks (RRs) with 95% credible intervals (CrIs). Placebo or usual care was the reference treatment. Measurements and Main Results: Among 7,553 references, we included 17 trials (7,688 patients). All-cause mortality at last follow-up was lowest with fludrocortisone plus hydrocortisone (RR, 0.85; 95% CrI, 0.72-0.99; 98.3% probability of superiority, moderate-certainty evidence), followed by hydrocortisone alone (RR, 0.97; 95% CrI, 0.87-1.07; 73.1% probability of superiority, low-certainty evidence). The comparison of fludrocortisone plus hydrocortisone versus hydrocortisone alone was based primarily on indirect evidence (only two trials with direct evidence). Fludrocortisone plus hydrocortisone was associated with a 12% lower risk of all-cause mortality compared with hydrocortisone alone (RR, 0.88; 95% CrI, 0.74-1.03; 94.2% probability of superiority, moderate-certainty evidence). Conclusions: In adult patients with septic shock, fludrocortisone plus hydrocortisone was associated with lower risk of all-cause mortality at last follow-up than placebo and hydrocortisone alone. The scarcity of head-to-head trials comparing fludrocortisone plus hydrocortisone versus hydrocortisone alone led our network meta-analysis to rely primarily on indirect evidence for this comparison. Although we undertook several sensitivity analyses and assessments, these findings should be considered while also acknowledging the heterogeneity of included trials.

Importance: Central venous catheters (CVCs) are commonly used but are associated with complications. Quantifying complication rates is essential for guiding CVC utilization decisions., Objective: To summarize current rates of CVC-associated complications., Data Sources: MEDLINE, Embase, CINAHL, and CENTRAL databases were searched for observational studies and randomized clinical trials published between 2015 to 2023., Study Selection: This study included English-language observational studies and randomized clinical trials of adult patients that reported complication rates of short-term centrally inserted CVCs and data for 1 or more outcomes of interest. Studies that evaluated long-term intravascular devices, focused on dialysis catheters not typically used for medication administration, or studied catheters placed by radiologists were excluded., Data Extraction and Synthesis: Two reviewers independently extracted data and assessed risk of bias. Bayesian random-effects meta-analysis was applied to summarize event rates. Rates of placement complications (events/1000 catheters with 95% credible interval [CrI]) and use complications (events/1000 catheter-days with 95% CrI) were estimated., Main Outcomes and Measures: Ten prespecified complications associated with CVC placement (placement failure, arterial puncture, arterial cannulation, pneumothorax, bleeding events requiring action, nerve injury, arteriovenous fistula, cardiac tamponade, arrhythmia, and delay of ≥1 hour in vasopressor administration) and 5 prespecified complications associated with CVC use (malfunction, infection, deep vein thrombosis [DVT], thrombophlebitis, and venous stenosis) were assessed. The composite of 4 serious complications (arterial cannulation, pneumothorax, infection, or DVT) after CVC exposure for 3 days was also assessed., Results: Of 11 722 screened studies, 130 were included in the analyses. Seven of 15 prespecified complications were meta-analyzed. Placement failure occurred at 20.4 (95% CrI, 10.9-34.4) events per 1000 catheters placed. Other rates of CVC placement complications (per 1000 catheters) were arterial canulation (2.8; 95% CrI, 0.1-10), arterial puncture (16.2; 95% CrI, 11.5-22), and pneumothorax (4.4; 95% CrI, 2.7-6.5). Rates of CVC use complications (per 1000 catheter-days) were malfunction (5.5; 95% CrI, 0.6-38), infection (4.8; 95% CrI, 3.4-6.6), and DVT (2.7; 95% CrI, 1.0-6.2). It was estimated that 30.2 (95% CrI, 21.8-43.0) in 1000 patients with a CVC for 3 days would develop 1 or more serious complication (arterial cannulation, pneumothorax, infection, or DVT). Use of ultrasonography was associated with lower rates of arterial puncture (risk ratio [RR], 0.20; 95% CrI, 0.09-0.44; 13.5 events vs 68.8 events/1000 catheters) and pneumothorax (RR, 0.25; 95% CrI, 0.08-0.80; 2.4 events vs 9.9 events/1000 catheters)., Conclusions and Relevance: Approximately 3% of CVC placements were associated with major complications. Use of ultrasonography guidance may reduce specific risks including arterial puncture and pneumothorax.

Competing Interests: Dr. Bosch is supported by the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute, the NIH/National Center for Advancing Translational Sciences, and the Department of Defense. Dr. Teja is supported by the Canadian Institutes of Health Research and by a Merit Award from the Department of Anesthesiology and Pain Medicine, University of Toronto. Dr. Pereira has disclosed that he does not have any potential conflicts of interest.

Importance: Current rehabilitation guidelines for patients with post-COVID-19 condition (PCC) are primarily based on expert opinions and observational data, and there is an urgent need for evidence-based rehabilitation interventions to support patients with PCC., Objective: To synthesize the findings of existing studies that report on physical capacity (including functional exercise capacity, muscle function, dyspnea, and respiratory function) and quality of life outcomes following rehabilitation interventions in patients with PCC., Data Sources: A systematic electronic search was performed from January 2020 until February 2023, in MEDLINE, Scopus, CINAHL, and the Clinical Trials Registry. Key terms that were used to identify potentially relevant studies included long-covid, post-covid, sequelae, exercise therapy, rehabilitation, physical activity, physical therapy, and randomized controlled trial., Study Selection: This study included randomized clinical trials that compared respiratory training and exercise-based rehabilitation interventions with either placebo, usual care, waiting list, or control in patients with PCC., Data Extraction and Synthesis: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A pairwise bayesian random-effects meta-analysis was performed using vague prior distributions. Risk of bias was assessed using the Cochrane risk of bias tool version 2, and the certainty of evidence was evaluated using the GRADE system by 2 independent researchers., Main Outcomes and Measures: The primary outcome was functional exercise capacity, measured at the closest postintervention time point by the 6-minute walking test. Secondary outcomes were fatigue, lower limb muscle function, dyspnea, respiratory function, and quality of life. All outcomes were defined a priori. Continuous outcomes were reported as standardized mean differences (SMDs) with 95% credible intervals (CrIs) and binary outcomes were summarized as odds ratios with 95% CrIs. The between-trial heterogeneity was quantified using the between-study variance, τ2, and 95% CrIs., Results: Of 1834 identified records, 1193 were screened, and 14 trials (1244 patients; 45% female participants; median [IQR] age, 50 [47 to 56] years) were included in the analyses. Rehabilitation interventions were associated with improvements in functional exercise capacity (SMD, -0.56; 95% CrI, -0.87 to -0.22) with moderate certainty in 7 trials (389 participants). These improvements had a 99% posterior probability of superiority when compared with current standard care. The value of τ2 (0.04; 95% CrI, 0.00 to 0.60) indicated low statistical heterogeneity. However, there was significant uncertainty and imprecision regarding the probability of experiencing exercise-induced adverse events (odds ratio, 1.68; 95% CrI, 0.32 to 9.94)., Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that rehabilitation interventions are associated with improvements in functional exercise capacity, dyspnea, and quality of life, with a high probability of improvement compared with the current standard care; the certainty of evidence was moderate for functional exercise capacity and quality of life and low for other outcomes. Given the uncertainty surrounding the safety outcomes, additional trials with enhanced monitoring of adverse events are necessary.

Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I 2  = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Objective: To systematically assess the robustness of reported postacute SARS-CoV-2 infection health outcomes in children., Methods: A search on PubMed and Web of Science was conducted to identify studies published up to 22 January 2022 that reported on postacute SARS-CoV-2 infection health outcomes in children (<18 years) with follow-up of ≥2 months since detection of infection or ≥1 month since recovery from acute illness. We assessed the consideration of confounding bias and causality, as well as the risk of bias., Results: 21 studies including 81 896 children reported up to 97 symptoms with follow-up periods of 2.0-11.5 months. Fifteen studies had no control group. The reported proportion of children with post-COVID syndrome was between 0% and 66.5% in children with SARS-CoV-2 infection (n=16 986) and between 2.0% and 53.3% in children without SARS-CoV-2 infection (n=64 910). Only two studies made a clear causal interpretation of an association between SARS-CoV-2 infection and the main outcome of 'post-COVID syndrome' and provided recommendations regarding prevention measures. The robustness of all 21 studies was seriously limited due to an overall critical risk of bias., Conclusions: The robustness of reported postacute SARS-CoV-2 infection health outcomes in children is seriously limited, at least in all the published articles we could identify. None of the studies provided evidence with reasonable certainty on whether SARS-CoV-2 infection has an impact on postacute health outcomes, let alone to what extent. Children and their families urgently need much more reliable and methodologically robust evidence to address their concerns and improve care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: We compared the albuminuria-lowering effects of Roux-en-Y gastric bypass (RYGB) to best medical treatment in patients with diabetic kidney disease and obesity to determine which treatment is better., Methods: A 5 year, open-label, single-centre, randomised trial studied patients with diabetic kidney disease and class I obesity after 1:1 randomization to best medical treatment (n = 49) or RYGB (n = 51). The primary outcome was the proportion of patients achieving remission of microalbuminuria after 5 years. Secondary outcomes included improvements in diabetic kidney disease, glycemic control, quality of life, and safety. For efficacy outcomes, we performed an intention-to-treat (ITT) analysis. This study was registered with ClinicalTrials.gov, NCT01821508., Findings: 88% of patients (44 per arm) completed 5-year follow-up. Remission of albuminuria occurred in 59.6% (95% CI = 45.5-73.8) after best medical treatment and 69.7% (95% CI = 59.6-79.8) after RYGB (risk difference: 10%, 95% CI, -7 to 27, P = 0.25). Patients after RYGB were twice as likely to achieve an HbA1c ≤ 6.5% (60.2% versus 25.4%, risk difference, 34.9%; 95% CI = 15.8-53.9, P < 0.001). Quality of life after five years measured by the 36-Item Short Form Survey questionnaire (standardized to a 0-to-100 scale) was higher in the RYGB group than in the best medical treatment group for several domains. The mean differences were 13.5 (95% CI, 5.5-21.6, P = 0.001) for general health, 19.7 (95% CI, 9.1-30.3, P < 0.001) for pain, 6.1 (95% CI, -4.8 to 17.0, P = 0.27) for social functioning, 8.3 (95% CI, 0.23 to 16.3, P = 0.04) for emotional well-being, 12.2 (95% CI, 3.9-20.4, P = 0.004) for vitality, 16.8 (95% CI, -0.75 to 34.4, P = 0.06) for mental health, 21.8 (95% CI, 4.8-38.7, P = 0.01) for physical health and 11.1 (95% CI, 2.24-19.9, P = 0.01) for physical functioning. Serious adverse events were experienced in 7/46 (15.2%) after best medical treatment and 11/46 patients (24%) after RYGB (P = 0.80)., Interpretation: Albuminuria remission was not statistically different between best medical treatment and RYGB after 5 years in participants with diabetic kidney disease and class 1 obesity, with 6-7 in ten patients achieving remission of microalbuminuria (uACR <30 mg/g) in both groups. RYGB was superior in improving glycemia, diastolic blood pressure, lipids, body weight, and quality of life., Funding: The study was supported by research grants from Johnson & Johnson Brasil, Oswaldo Cruz German Hospital, and by grant 12/YI/B2480 from Science Foundation Ireland (Dr le Roux) and grant 2015-02733 from the Swedish Medical Research Council (Dr le Roux). Dr Pereira was funded by the Chevening Scholarship Programme (Foreign and Commonwealth Office, UK)., Competing Interests: During the study, Dr Cohen reported receiving grants from Johnson & Johnson Medical Brasil. Dr Petry reported receiving grants from Johnson &Johnson Medical Brasil during the study. Dr Schiavon reported receiving grants from 10.13039/100009933Ethicon and personal fees from Johnson & Johnson Brasil outside the submitted work. During the study, Dr Pompilio reported receiving grants from Johnson & Johnson Medical Brasil. Dr Sarian reported receiving grants from Johnson & Johnson Medical Brasil. Dr Nogueira Pechy reported receiving grants from Johnson & Johnson Medical Brasil and honoraria for lectures, Johnson&Johnson and Medtronic. Dr Porto da Silveira reported receiving grants from Johnson & Johnson Medical Brasil and honoraria for lectures, Johnson&Johnson and Medtronic. Dr Friedman reported partcipating on a Data. Safety Monitoring Board or Advisory Board for Gila Therapeutics and GI Dynamics, leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for the International Society of Renal Nutrition and Metabolism and Editorial board- Journal of Renal Nutrition Dr le Roux reported receiving grants from Science Foundation Ireland, Health Research Board, European Federation for Study of Diabetes, and the 10.13039/501100004359Swedish Research Council during the conduct of the study and receiving an honorarium for lectures and scientific advisory board from Novo Nordisk, GI Dynamics, Sanofi, Johnson & Johnson Brasil, Keyron, Herbalife, and Boehringer Ingelheim outside the submitted work. Dr. Pereira reported receiving consulting fees from 10.13039/100004336Novartis unrelated to the study. All other authors declare no competing interests., (© 2022 The Author(s).)

Objective: The aim of this study was to assess the accuracy of prenatal imaging for the diagnosis of congenital Zika syndrome., Data Sources: Medline (via Pubmed), PubMed, Scopus, Web of Science, and Google Scholar from inception to March 2022. Two researchers independently screened study titles and abstracts for eligibility., Study Eligibility Criteria: Observational studies with Zika virus-infected pregnant women were included. The index tests included ultrasound and/or magnetic resonance imaging. The reference standard included (1) Zika infection-related perinatal death, stillbirth, and neonatal death within the first 48 h of birth, (2) neonatal intensive care unit admission, and (3) clinically defined adverse perinatal outcomes., Synthesis Methods: We extracted 2 × 2 contingency tables. Pooled sensitivity and specificity were estimated using the random-effects bivariate model and assessed the summary receiver operating characteristic (ROC) curve. Risk of bias was assessed using QUADAS 2 tool. The certainty of the evidence was evaluated with grading of recommendations., Results: We screened 1,459 references and included 18 studies (2359 pregnant women, 347 fetuses with confirmed Zika virus infection). Twelve studies (67%) were prospective cohorts/case series, and six (37%) were retrospective cohort/case series investigations. Fourteen studies (78%) were performed in endemic regions. Ten studies (56%) used prenatal ultrasound only, six (33%) employed ultrasound and fetal MRI, and two studies (11%) used prenatal ultrasound and postnatal fetal MRI. A total of six studies (ultrasound only) encompassing 780 pregnant women (122 fetuses with confirmed Zika virus infection) reported relevant data for meta-analysis (gestation age at which ultrasound imagining was captured ranged from 16 to 34 weeks). There was large heterogeneity across studies regarding sensitivity (range: 12 to 100%) and specificity (range: 50 to 100%). Under a random-effects model, the summary sensitivity of ultrasound was 82% (95% CI, 19 to 99%), and the summary specificity was 97% (71 to 100%). The area under the ROC curve was 97% (95% CI, 72 to 100%), and the summary diagnostic odds ratio was 140 (95% CI, 3 to 7564, P < 0.001). The overall certainty of the evidence was "very low"., Conclusion: Ultrasound may be useful in improving the diagnostic accuracy of Zika virus infection in pregnancy. However, the evidence is still substantially uncertain due to the methodological limitations of the available studies. Larger, properly conducted diagnostic accuracy studies of prenatal imaging for the diagnosis of congenital Zika syndrome are warranted., Systematic Review Registration: Identifier [CRD42020162914]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Herrera, Cubilla-Batista, Goodridge and Pereira.)

Objective: To evaluate the effectiveness and safety of viscosupplementation for pain and function in patients with knee osteoarthritis., Design: Systematic review and meta-analysis of randomised trials., Data Sources: Searches were conducted of Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to 11 September 2021. Unpublished trials were identified from the grey literature and trial registries., Eligibility Criteria for Study Selection: Randomised trials comparing viscosupplementation with placebo or no intervention for knee osteoarthritis treatment., Main Outcome Measures: The prespecified primary outcome was pain intensity. Secondary outcomes were function and serious adverse events. Pain and function were analysed as standardised mean differences (SMDs). The prespecified minimal clinically important between group difference was -0.37 SMD. Serious adverse events were analysed as relative risks., Methods: Two reviewers independently extracted relevant data and assessed the risk of bias of trials using the Cochrane risk of bias tool. The predefined main analysis was based only on large, placebo controlled trials with ≥100 participants per group. Summary results were obtained through a random effects meta-analysis model. Cumulative meta-analysis and trial sequential analysis under a random effects model were also performed., Results: 169 trials provided data on 21 163 randomised participants. Evidence of small study effects and publication biases was observed for pain and function (Egger's tests with P<0.001 and asymmetric funnel plots). Twenty four large, placebo controlled trials (8997 randomised participants) included in the main analysis of pain indicated that viscosupplementation was associated with a small reduction in pain intensity compared with placebo (SMD -0.08, 95% confidence interval -0.15 to -0.02), with the lower bound of the 95% confidence interval excluding the minimal clinically important between group difference. This effect corresponds to a difference in pain scores of -2.0 mm (95% confidence interval -3.8 to -0.5 mm) on a 100 mm visual analogue scale. Trial sequential analysis for pain indicated that since 2009 there has been conclusive evidence of clinical equivalence between viscosupplementation and placebo. Similar conclusions were obtained for function. Based on 15 large, placebo controlled trials on 6462 randomised participants, viscosupplementation was associated with a statistically significant higher risk of serious adverse events than placebo (relative risk 1.49, 95% confidence interval 1.12 to 1.98)., Conclusion: Strong conclusive evidence indicates that viscosupplementation leads to a small reduction in knee osteoarthritis pain compared with placebo, but the difference is less than the minimal clinically important between group difference. Strong conclusive evidence indicates that viscosupplementation is also associated with an increased risk of serious adverse events compared with placebo. The findings do not support broad use of viscosupplementation for the treatment of knee osteoarthritis., Systematic Review Registration: PROSPERO CRD42021236894., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Arthritis Society, Canada Research Chairs Programme, National Institute for Health Research, Chevening Scholarship Program for the submitted work. PJ serves as unpaid member of the steering group of trials funded by Appili Therapeutics, Abbot Vascular, and Terumo; he has received research grants to the institution from Appili Therapeutics, and honorariums to the institution for participation in advisory boards or consulting from Amgen, Ava and Fresenius, but has not received personal payments by any pharmaceutical company or device manufacturer. All other authors report no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. All authors report no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Nanocrystalline silver dressings can reduce the number of changes, facilitating burn wound management. However, the evidence regarding their efficacy and cost-consequences compared to well-established treatments, such as 1% silver sulfadiazine, is still scarce., Objective: To determine the efficacy, safety, and costs of nanocrystalline silver dressings compared to 1% silver sulfadiazine dressings to treat adult patients with burns., Study Design and Setting: Randomized, single-center, single-blind trial conducted at a referral hospital in São Paulo, Brazil., Methods: 100 adult patients were randomized 1:1 to nanocrystalline silver (n = 50) or 1% silver sulfadiazine (n = 50). The primary outcome was the proportion of participants with complete re-epithelization at day 15 after randomization. Secondary outcomes included the number of dressing changes, direct medical costs (in international dollars, I$), pain intensity, the incidence of infections, number of patients undergoing surgery, and adverse events., Results: On day 15, the proportion of patients who reached the primary outcome did not differ significantly between participants treated with nanocrystalline silver dressings (24 [48%]) and those treated with 1% silver sulfadiazine dressings (26 [52%]); risk difference of -4.0 percentage points (95% confidence interval [CI], -17 to 9; P = 0.56). The number of patients undergoing surgical intervention was similar between groups (6% vs. 6%), and no local or serious adverse events were reported. The mean (standard deviation, SD) number of dressing changes in the nanocrystalline silver group was 4.1 (2.3), and the corresponding estimate in the 1% silver sulfadiazine group was 9.6 (6.7); mean difference of -5.56 (95% CI), -7.57 to -3.55, P < 0.001). Treatment with nanocrystalline silver dressing incurred significant cost reductions in medical materials, human resources, and administrative labor. However, the mean total cost with nanocrystalline silver dressing was higher compared to 1% silver sulfadiazine dressings: I$496.37 (445.90) vs. I$274.73 (182.76); mean difference = 221.63 (95% CI, 89.04 to 354.23, P = 0.001). The main driver of higher mean total costs among nanocrystalline silver-treated participants was the purchase cost of the dressings, representing 79.3% of the total cost in the nanocrystalline silver group but only 15.2% in the 1% silver sulfadiazine group., Conclusion: We found no evidence of a difference between nanocrystalline silver and 1% silver sulfadiazine dressings regarding efficacy and safety outcomes. Nanocrystalline silver dressings were associated with an increase in the total costs, but they could result in important savings for an institution (less changes of dressings, reducing human resources burden), especially if acquisition costs can be decreased. Additional cost-effectiveness studies are warranted., Trial Registration Number: NCT02108535., (Copyright © 2021 Elsevier Ltd and ISBI. All rights reserved.)

Olfactory dysfunction is reported frequently in patients with coronavirus disease 2019. However, an effective treatment for this dysfunction is unknown. The present study evaluated carbamazepine as a treatment option for olfactory dysfunction based on its use in cases of neuralgia, especially of the V cranial nerve. The study included 10 patients with coronavirus disease with olfactory complaints who were part of a cohort of 172 coronavirus disease patients monitored for late neurological manifestations. Carbamazepine was administered for 11 weeks. The adverse effects reported were drowsiness (9/10) and dizziness (2/10); 9 of the 10 patients reported improved olfactory function after carbamazepine treatment. While the role of carbamazepine in the control of post-coronavirus disease olfactory dysfunction could not be confirmed in this study, the satisfactory response observed in most patients in this series suggests that further studies are warranted., (© 2022. Journal of NeuroVirology, Inc.)

Introduction: Antiretroviral therapy (ART) for HIV/AIDS is associated with adverse events (AEs). However, little is known about the differences in the risk of AEs between women and men living with HIV/AIDS. This study aims to determine (1) whether there are sex differences in the risk of AEs in people with HIV/AIDS treated with ART and (2) the prevalence of AEs to the reproductive system and bone mineral density in women., Methods and Analysis: This systematic review (SR) will include randomised trials evaluating ART in people living with HIV/AIDS with at least 12 weeks of duration follow-up. Searches will be conducted in Medline, Embase, Cochrane Library, Epistemonikos, Lilacs, trial registries and grey literature databases, without restriction on publication status, year of publication and language. The primary outcome will be the risk of ART discontinuation or drop-outs/withdrawals of ART due to AEs and the number of any treatment-emergent AE. The secondary outcomes are the incidence of serious clinic or laboratory (grade 3 and/or 4) treatment-emergent AEs, hospitalisation, death and AEs specific to the reproductive system and bone mineral density (osteoporosis, osteopenia and fractures) of women. Selection, data extraction and quality assessment will be performed by pairs of reviewers. Cochrane collaboration tools will be used to assess the risk of bias. If appropriate, a meta-analysis will be conducted to synthesise results. The overall quality of the evidence for each outcome will be determined by the Grades of Recommendation, Assessment, Development and Evaluation., Ethics and Dissemination: The results of this SR will assist the formulation of public policies aimed at the management and monitoring of AEs of ART in people living with HIV/AIDS. A deliberative dialogue will be scheduled with the Department of Chronic Conditions and Sexually Transmitted Infections of Brazil's Ministry of Health to align the project with policymakers' interests., Prospero Registration Number: CRD42021251051., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To assess the feasibility and efficacy of interatrial shunt devices (IASD) for the treatment of chronic heart failure (CHF)., Methods and Results: MEDLINE and the Cochrane Central Register of Controlled Trials from inception until April 2021 were searched for prospective studies investigating dedicated transcatheter IASD for the treatment of CHF. Standardised mean differences were calculated for the within-group changes before and after implantation of the IASD. The pre-defined primary outcome was change in 6-min walking distance (6MWD) from baseline to 12 months. Other outcomes were change in New York Heart Association class, health-related quality of life (HRQoL), echocardiographic and haemodynamic data, device performance and safety. Subgroup analyses were crude univariable meta-regression analyses. Six studies (five single-arm open-label studies, one sham-controlled trial) were included. In these, 226 patients underwent IASD implantation using four different devices. From baseline to 12 months, 6MWD increased by 28.1 m [95% confidence interval (CI) 10.9-45.3] with no evidence for a difference between devices (P for interaction = 0.66) and patients with left ventricular ejection fraction (LVEF) >40% or ≤40% (P for interaction = 0.21). At 12 months, HRQoL improved by 17.7 points (95% CI 10.8-24.6) and pulmonary capillary wedge pressure (PCWP) decreased by 2.0 mmHg (95% CI -3.6 to -0.4). There were no changes in LVEF or N-terminal pro brain natriuretic peptide during follow-up. Shunt patency ranged from 50% for the first-generation v-Wave to 100% for the Corvia IASD II and the second-generation v-Wave system, respectively. The summary risk of serious adverse device-related effects was 8% (95% CI 1-20) at 12 months., Conclusions: Interatrial shunt device implantation in CHF is feasible and associates with improved submaximal exercise capacity (measured by 6MWD) and HRQoL, and reductions in PCWP., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Pompe disease (PD) is a glycogen storage disorder caused by deficient activity of acid alpha-glucosidase (GAA). We sought to review the latest available evidence on the safety and efficacy of recombinant human GAA enzyme replacement therapy (ERT) for late-onset PD (LOPD)., Methods: We systematically searched the MEDLINE (via PubMed), Embase, and Cochrane databases for prospective clinical studies evaluating ERT for LOPD on pre-specified outcomes. A meta-analysis was also performed., Results: Of 1601 articles identified, 22 were included. Studies were heterogeneous and with very low certainty of evidence for most outcomes. The following outcomes showed improvements associated with GAA ERT, over a mean follow-up of 32.5 months: distance walked in the 6-min walking test (6MWT) (mean change 35.7 m (95% confidence interval [CI] 7.78, 63.75)), physical domain of the SF-36 quality of life (QOL) questionnaire (mean change 1.96 (95% CI 0.33, 3.59)), and time on ventilation (TOV) (mean change -2.64 h (95% CI -5.28, 0.00)). There were no differences between the pre- and post-ERT period for functional vital capacity (FVC), Walton and Gardner-Medwin Scale score, upper-limb strength, or total SF-36 QOL score. Adverse events (AEs) after ERT were mild in most cases., Conclusion: Considering the limitations imposed by the rarity of PD, our data suggest that GAA ERT improves 6MWT, physical QOL, and TOV in LOPD patients. ERT was safe in the studied population. PROSPERO register: 135102.

Objective: To assess the effectiveness and safety of different preparations and doses of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and paracetamol for knee and hip osteoarthritis pain and physical function to enable effective and safe use of these drugs at their lowest possible dose., Design: Systematic review and network meta-analysis of randomised trials., Data Sources: Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, regulatory agency websites, and ClinicalTrials.gov from inception to 28 June 2021., Eligibility Criteria for Selecting Studies: Randomised trials published in English with ≥100 patients per group that evaluated NSAIDs, opioids, or paracetamol (acetaminophen) to treat osteoarthritis., Outcomes and Measures: The prespecified primary outcome was pain. Physical function and safety outcomes were also assessed., Review Methods: Two reviewers independently extracted outcomes data and evaluated the risk of bias of included trials. Bayesian random effects models were used for network meta-analysis of all analyses. Effect estimates are comparisons between active treatments and oral placebo., Results: 192 trials comprising 102 829 participants examined 90 different active preparations or doses (68 for NSAIDs, 19 for opioids, and three for paracetamol). Five oral preparations (diclofenac 150 mg/day, etoricoxib 60 and 90 mg/day, and rofecoxib 25 and 50 mg/day) had ≥99% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. Topical diclofenac (70-81 and 140-160 mg/day) had ≥92.3% probability, and all opioids had ≤53% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. 18.5%, 0%, and 83.3% of the oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of dropouts due to adverse events. 29.8%, 0%, and 89.5% of oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of any adverse event. Oxymorphone 80 mg/day had the highest risk of dropouts due to adverse events (51%) and any adverse event (88%)., Conclusions: Etoricoxib 60 mg/day and diclofenac 150 mg/day seem to be the most effective oral NSAIDs for pain and function in patients with osteoarthritis. However, these treatments are probably not appropriate for patients with comorbidities or for long term use because of the slight increase in the risk of adverse events. Additionally, an increased risk of dropping out due to adverse events was found for diclofenac 150 mg/day. Topical diclofenac 70-81 mg/day seems to be effective and generally safer because of reduced systemic exposure and lower dose, and should be considered as first line pharmacological treatment for knee osteoarthritis. The clinical benefit of opioid treatment, regardless of preparation or dose, does not outweigh the harm it might cause in patients with osteoarthritis., Systematic Review Registration: PROSPERO number CRD42020213656., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Arthritis Society, Canada Research Chairs Programme, National Institute for Health Research, Chevening Scholarship Program for the submitted work. PJ serves as unpaid member of the steering group of trials funded by Appili Therapeutics, Abbot Vascular, and Terumo; he has received research grants to the institution from Appili Therapeutics, and honorariums to the institution for participation in advisory boards or consulting from Amgen, Ava and Fresenius, but has not received personal payments by any pharmaceutical company or device manufacturer. AJS has been a paid consultant by Janssen-Cilag and GlaxoSmithKline. PT has received royalty payments as contributing author and editor for journals, textbooks and articles published by Elsevier, Little Brown, Wolters Kluwer, and John Wiley and Sons; PT has been an independent paid consultant to CHEOR Solutions (Canada), Innovative Science Solutions LLC and Reformulary Group; he serves as unpaid chair of the management subcommittee, of the executive committee of OMERACT; OMERACT receives unrestricted educational grants from the American College of Rheumatology, European League of Rheumatology, Amgen, Astra Zeneca, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Genzyme/Sanofi, Horizon Pharma, Merck, Novartis, Pfizer, PPD, Quintiles, Regeneron, Savient, Takeda Pharmaceutical, UCB Group, Vertex, Forest and Bioiberica; PT serves as an independent committee member in Data Safety Monitoring Boards of FDA approved trials being conducted by UCB Biopharma GmbH and SPRL, Parexel International and Prahealth Sciences. All other authors report no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. All authors report no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the effect of Pilates compared with circuit-based exercise in reducing arthralgia in women during hormone therapy for breast cancer., Design: Single-blind randomized controlled trial, parallel., Setting: University hospital of Brasilia and Brazilian Association for Assistance to People with Cancer., Participants: Sixty women with arthralgia were recruited. Eligibility criteria included women complaining of arthralgia during hormone therapy for breast cancer. The exclusion criteria were women with active cancer, lymphedema, limitations to physical exercise, or limitation to answer some questionnaires., Main Outcome Measures: Primary: Pain. Secondary: Function, flexibility, and sleep quality. Outcomes were assessed at baseline and the end of the intervention (8 weeks) by the same blinded evaluator., Intervention: Sixty participants were randomly assigned 20 to each of the three groups: Pilates, circuit-based exercise, and control groups. Exercise was performed twice per week for 75 min, over a period of 8 weeks. Participants in the control group were instructed to continue their usual activities. The Kolmogorov-Smirnov test was used to verify the normality of the outcomes. Intergroup differences were calculated using Kruskal-Wallis test with post hoc Mann Whitney U testing and the parametric data between the three groups with ANOVA of repeated measures with Bonferroni post hoc., Results: The Pilates group demonstrated a significant difference in pain reduction compared to the circuit group (mean difference: -1.95 points, p = 0.020)., Conclusion: Pilates was more effective than circuit-based exercise in reducing arthralgia in women during hormone therapy for breast cancer., Trial Registration: http://www.ensaiosclinicos.gov.br/rg/RBR-3wsdhs/ Registered on Octob 16th 2017., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background This study aimed to assess the effectiveness of sodium-glucose cotransporter 2 inhibitors in reducing the incidence of mortality and cardiovascular outcomes in adults with type 2 diabetes. Methods and Results We conducted a Bayesian meta-analysis of randomized controlled trials comparing sodium-glucose cotransporter 2 inhibitors with placebo. We used meta-regression to examine the association between treatment effects and control group event rates as measures of cardiovascular baseline risk. Fifty-three randomized controlled trials were included in our synthesis. Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause mortality (empagliflozin: rate ratio [RR], 0.79; 95% credibility interval [CrI], 0.63-0.97; canagliflozin: RR, 0.86; 95% CrI, 0.69-1.05; dapagliflozin: RR, 0.86; 95% CrI, 0.72-1.01) and cardiovascular mortality (empagliflozin: RR, 0.78; 95% CrI, 0.61-1.00; canagliflozin: RR, 0.83; 95% CrI, 0.63-1.05; dapagliflozin: RR, 0.88; 95% CrI, 0.71-1.08), with a 90.1% to 98.7% probability for the true RR to be <1.00 for both outcomes. There was little evidence for ertugliflozin and sotagliflozin versus placebo for reducing all-cause and cardiovascular mortality. There was no association between treatment effects for all-cause and cardiovascular mortality and the control group event rates. There was evidence for a reduction in the incidence of heart failure for empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin versus placebo (probability RR <1.00 of ≥99.3%) and weaker, albeit positive, evidence for acute myocardial infarction for the first 3 agents (probability RR <1.00 of 89.0%-95.2%). There was little evidence of any agent except canagliflozin for reducing the incidence of stroke. Conclusions Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause and cardiovascular mortality versus placebo. Treatment effects of sodium-glucose cotransporter 2 inhibitors versus placebo do not vary by baseline risk.

Background: Biologic drugs such as adalimumab, etanercept, and infliximab represent major first-line and second-line treatments for rheumatoid arthritis (RA) patients. However, their high cost poses a massive burden on healthcare systems worldwide. The expiration of patents for these biologics has driven the production of biosimilar drugs, which are potentially less costly and remarkably similar, albeit not identical to the reference molecules. This paper aims to outline the protocol of a systematic review that will investigate the efficacy and safety profile of biosimilars compared to biologics (objective 1) and the impact of switching between biosimilar drugs and reference biologics on the management of RA patients (objective 2)., Methods: We will investigate the effects of any biosimilars of adalimumab, etanercept, and infliximab on RA patients. We will include randomized controlled trials (RCTs) or quasi-RCTs to assess efficacy and safety outcomes and RCTs with two- or multiple-part designs to evaluate the consequences of switching from reference biologics to biosimilar drugs (and vice-versa). Electronic searches will be performed through MEDLINE (via PubMed), EMBASE, LILACS, and CENTRAL (from inception to April 2021). Two independent reviewers will screen studies, extract data, and evaluate the risk of bias. The latter will be carried out considering specific domains from equivalence trials and switching studies. Random-effects models will be fitted to obtain summary estimates using either relative risk or standardized mean difference as a metric. The primary outcome will be the rate of treatment success according to the American College of Rheumatology 20 (ACR20), and the co-primary outcome will be the Health Assessment Questionnaire-Disability Index (HAQ-DI). Conclusions will be based on equivalence hypothesis testing using predefined margins of equivalence elicited from a group of experienced rheumatologists and prior studies. The overall certainty of the evidence will be assessed based on the GRADE system., Discussion: The present investigation proposes a comprehensive, clinician-oriented approach to assess the equivalence and the impact of switching between biosimilars and biologics on the management of patients with RA. Our results will elucidate the efficacy, safety, immunogenicity of biosimilars, and the clinical consequences of substituting biologics with biosimilars in the management of RA., Systematic Review Registration: PROSPERO CRD42019137152 and CRD42019137155., (© 2021. The Author(s).)

Introduction: Evidence suggests that brief interventions are effective in reducing alcohol consumption among older adults. However, the effectiveness of these interventions when delivered by community health workers (non-specialists) in a primary healthcare setting is unknown. To our knowledge, this will be the first randomised trial to examine this., Methods and Analysis: Two hundred and forty-two individuals considered at-risk drinkers (Alcohol Use Disorders Identification Test-Consumption, AUDIT-C score ≥4) will be recruited and randomly allocated to usual care (waiting-list) or usual care plus an intervention delivered by trained community health workers (non-specialists). Seven primary care units (PCUs) in Sao José dos Campos, Brazil. PCUs are part of the Brazilian public healthcare system (Sistema Único de Saúde). Follow-up 6 months. Outcomes The primary outcome will be the proportion of participants considered at-risk drinkers (AUDIT-C score ≥4). Secondary outcomes will include alcohol consumption in a typical week in the last 30 days (in units per week) assessed by the AUDIT, service use questionnaire, cognitive performance-assessed by The Health and Retirement Study Harmonised Cognitive Assessment, physical activity-assessed by the International Physical Activity Questionnaire, depression-assessed by the Geriatric Depression Scale and quality of life-assessed by the Control, Autonomy, Self-realisation and Pleasure-16 instrument. The analysis will be based on intention-to-treat principle., Ethics and Dissemination: This study has been approved by the Ethics Committee of the Universidade Federal de São Paulo, CEP/UNIFESP Project n: 0690/2018; CAAE: 91648618.0.0000.5505. All eligible participants will provide informed consent prior to randomisation. The results of this study will be published in relevant peer-reviewed journals and in conference presentations., Trial Registration Number: RBR-8rcxkk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To analyze the tuberculosis spatial pattern and its relationship with socioeconomic indicators, from 2008 to 2015, in a priority city for tuberculosis control by the National Tuberculosis Control Program, Juiz de Fora, Minas Gerais., Methods: Ecological study in which the units of analysis were 81 urban regions of Juiz de Fora. Secondary data from Notifiable Diseases Information System and 2010 Demographic Census were used. Georeferenced data from 1,854 notifications were used to elaborate thematic maps in order to verify the distribution pattern of average tuberculosis rates and socioeconomic indicators within the city. Global spatial autocorrelation (Moran's I) and local (Local Indicator of Spatial Association) and multiple linear regression model were estimated to analyze the relationship between the average tuberculosis incidence rate and socioeconomic indicators., Results: The average tuberculosis incidence rate was 48.3 cases/100,000 inhabitants/year. It was found that the urban regions corresponding to central regions of the city had lower rates with a progressive increase toward the urban regions representative of the most peripheral neighborhoods. All variables showed significant spatial autocorrelation. The regression model showed an association between the average tuberculosis incidence rate and the proportion of poor, household density, and aging index., Conclusion: The dynamics of tuberculosis transmission in Juiz de Fora may be explained by the maintenance of social inequality and urban space organization process.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 and quickly spread around the world, forcing global health authorities to develop protocols for its diagnosis. Here we report dimer formation in the N2 primers-probe set (CDC 2019-nCoV Real-Time RT-PCR) used in the diagnostic routine, and propose alternatives to reduce dimerization events. Late unspecific amplifications were visualized in 56.4% of negative samples and 57.1% of no-template control, but not in positive samples or positive control. In silico analysis and gel electrophoresis confirmed the dimer formation. The RT-qPCR parameters were optimized and the late unspecific amplifications decreased to 11.5% in negative samples and no-template control. The adjustment of PCR parameters was essential to reduce the risk of false-positives results and to avoid inclusive results requiring repeat testing, which increases the costs and generates delays in results or even unnecessary requests for new samples., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: Clinical trial evidence used to support drug approval is typically the only information on benefits and harms that patients and clinicians can use for decision-making when novel cancer therapies become available. Various evaluations have raised concern about the uncertainty surrounding these data, and a systematic investigation of the available information on treatment outcomes for cancer drugs approved by the US Food and Drug Administration (FDA) is warranted., Objective: To describe the clinical trial data available on treatment outcomes at the time of FDA approval of all novel cancer drugs approved for the first time between 2000 and 2016., Design, Setting, and Participants: This comparative effectiveness study analyzed randomized clinical trials and single-arm clinical trials of novel drugs approved for the first time to treat any type of cancer. Approval packages were obtained from drugs@FDA, a publicly available database containing information on drug and biologic products approved for human use in the US. Data from January 2000 to December 2016 were included in this study., Main Outcomes and Measures: Regulatory and clinical trial characteristics were described. For randomized clinical trials, summary treatment outcomes for overall survival, progression-free survival, and tumor response across all therapies were calculated, and median absolute survival increases were estimated. Tumor types and regulatory characteristics were assessed separately., Results: Between 2000 and 2016, 92 novel cancer drugs were approved by the FDA for 100 indications based on data from 127 clinical trials. The 127 clinical trials included a median of 191 participants (interquartile range [IQR], 106-448 participants). Overall, 65 clinical trials (51.2%) were randomized, and 95 clinical trials (74.8%) were open label. Of 100 indications, 44 indications underwent accelerated approval, 42 indications were for hematological cancers, and 58 indications were for solid tumors. Novel drugs had mean hazard ratios of 0.77 (95% CI, 0.73-0.81; I2 = 46%) for overall survival and 0.52 (95% CI, 0.47-0.57; I2 = 88%) for progression-free survival. The median tumor response, expressed as relative risk, was 2.37 (95% CI, 2.00-2.80; I2 = 91%). The median absolute survival benefit was 2.40 months (IQR, 1.25-3.89 months)., Conclusions and Relevance: In this study, data available at the time of FDA drug approval indicated that novel cancer therapies were associated with substantial tumor responses but with prolonging median overall survival by only 2.40 months. Approval data from 17 years of clinical trials suggested that patients and clinicians typically had limited information available regarding the benefits of novel cancer treatments at market entry.

Background: Due to the increasing popularity of bulk fill resins, there is a concern that their components can be leached; this is because these are inserted in a single 4-5 mm increment. This in vitro study evaluated the microhardness, sorption, solubility, and color stability of three restorative bulk fill resins, namely: Filtek Bulk Fill (FBF), Tetric N-Ceram Bulk Fill (TNC), and Opus Bulk Fill (OBF)., Material and Methods: Cylindrical samples were fabricated to be 15 mm in diameter and 1 mm thick (n = 10). For the microhardness test, three random indentations were formulated on the samples using a micro-durometer with a load of 300 gf for 15 s. Sorption and solubility were then evaluated (ISO 4049: 2009). Color stability was analyzed with a digital spectrophotometer three times (initially, after 24 h, and after 7 d) during immersion in coffee and distilled water (control). The Shapiro-Wilk test was applied to analyze normality. The Mann-Whitney and Kruskal-Wallis tests were used to compare the groups and the immersion solution, with a significance level of 5%., Results: There were a significant difference in microhardness ( p <0.001), with the FBF group showing a higher value compared to the other groups (56.38). The highest average of sorption scores was observed in the OBF group (16.9 µg / mm3), followed by FBF (16.8 µg / mm3) and TNC (11.3 µg / mm3). Solubility was lowest in the OBF group (-2.83 µg / mm3), with a significant difference ( p = 0.031). There was also a significant difference after 24 h in the mean ∆E score of all groups ( p <0.005). After one week of immersion, the group that pigmented most was OBF ( p = 0.008)., Conclusions: The three bulk fill resins had acceptable hardness, sorption, and solubility values. However, all groups showed a high pigmentation rate after 7 d of immersion in coffee. Key words: Bulk fill, color stability, composite resins, microhardness, solubility, sorption., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest., (Copyright: © 2020 Medicina Oral S.L.)

Importance: Early-stage chronic kidney disease (CKD) characterized by microalbuminuria is associated with future cardiovascular events, progression toward end-stage renal disease, and early mortality in patients with type 2 diabetes., Objective: To compare the albuminuria-lowering effects of Roux-en-Y gastric bypass (RYGB) surgery vs best medical treatment in patients with early-stage CKD, type 2 diabetes, and obesity., Design, Setting, and Participants: For this randomized clinical trial, patients with established type 2 diabetes and microalbuminuria were recruited from a single center from April 1, 2013, through March 31, 2016, with a 5-year follow-up, including prespecified intermediate analysis at 24-month follow-up., Intervention: A total of 100 patients with type 2 diabetes, obesity (body mass indexes of 30 to 35 [calculated as weight in kilograms divided by height in meters squared]), and stage G1 to G3 and A2 to A3 CKD (urinary albumin-creatinine ratio [uACR] >30 mg/g and estimated glomerular filtration rate >30 mL/min) were randomized 1:1 to receive best medical treatment (n = 49) or RYGB (n = 51)., Main Outcomes and Measures: The primary outcome was remission of albuminuria (uACR <30 mg/g). Secondary outcomes were CKD remission rate, absolute change in uACR, metabolic control, other microvascular complications, quality of life, and safety., Results: A total of 100 patients (mean [SD] age, 51.4 [7.6] years; 55 [55%] male) were randomized: 51 to RYGB and 49 to best medical care. Remission of albuminuria occurred in 55% of patients (95% CI, 39%-70%) after best medical treatment and 82% of patients (95% CI, 72%-93%) after RYGB (P = .006), resulting in CKD remission rates of 48% (95% CI, 32%-64%) after best medical treatment and 82% (95% CI, 72%-92%) after RYGB (P = .002). The geometric mean uACRs were 55% lower after RYGB (10.7 mg/g of creatinine) than after best medical treatment (23.6 mg/g of creatinine) (P < .001). No difference in the rate of serious adverse events was observed., Conclusions and Relevance: After 24 months, RYGB was more effective than best medical treatment for achieving remission of albuminuria and stage G1 to G3 and A2 to A3 CKD in patients with type 2 diabetes and obesity., Trial Registration: ClinicalTrials.gov Identifier: NCT01821508.

Objective: To determine the occurrence of anti-tuberculosis drug resistance and its association with sociodemographic and clinical characteristics of patients in a referral hospital., Methods: This was a cross-sectional study based on data from patients who had mycobacterial culture identified and defined antimicrobials sensitivity profile (June 2014 to February 2016). The descriptive statistical analysis and Fisher's exact test were used to compare proportions., Results: The study included 104 patients who had positive results for Mycobacterium tuberculosis . Bacilloscopy had high positivity (93.3%). A total of 15 patients (14.4%) had resistant strains and six (5.6%) multidrug-resistant. The sociodemographic and clinical characteristics were not related with resistance., Conclusion: This study contributed to further the understandings about the tuberculosis patients' profile, the study also served as a tool for development of specific public policies. Patients diagnosed with resistant tuberculosis must be under greater supervision.

Background and Objective: Novel cancer therapies are often approved with evidence from a single pivotal trial alone. There are concerns about the credibility of this evidence. Higher validity may be indicated by five methodological and statistical characteristics of pivotal trial evidence that were described by the U.S. Food and Drug Administration (FDA), which may corroborate the reliance on a single trial alone for approval decisions., Study Design: We did a metaepidemiologic evaluation of all single pivotal trials supporting FDA approval of novel drugs and therapeutic biologicals for cancers between 2000 and 2016. For each trial, we determined the presence of these five characteristics, which we operationalized as (1) large and multicenter trial (≥200 patients; more than one center); consistent treatment benefits across (2) multiple patient subgroups (in view of FDA reviewers), (3) multiple endpoints (including overall survival, progression-free survival, response rate, health related quality of life), and (4) multiple treatment comparisons (e.g., multi-arm studies); and (5) "statistically very persuasive" results (P-values <0.00125)., Results: Thirty-five of 100 approvals were based on evidence from a single pivotal trial without any further supporting evidence on beneficial effects (20 randomized controlled trials and 15 single-arm trials). The number increased substantially from one approval before 2006 to 23 after 2011. Sixty-six percent (23/35) of the trials were large multicenter trials (median 301 patients and 63 centers). Consistent effects were demonstrated across subgroups in 66% (23/35), across endpoints in 43% (15/35), and across multiple comparisons in 3% (1/35). Very low P-values for the primary endpoint were seen in 34% (12/35). At least one of the corroborating characteristics was present in 94% (33/35) of all approvals, two or more were present in 54% (19/35), and none had all characteristics., Conclusions: Single pivotal trials typically have some of the corroborating characteristics, but often only one or two. These characteristics need to be better operationalized, defined, and reported and whether single trials with such characteristics provide similar evidence about benefits and harms of novel treatments as multiple trials would do needs to be shown., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: To determine whether a restrictive strategy of red blood cell (RBC) transfusion at lower haemoglobin concentrations is inferior to a liberal strategy of RBC transfusion at higher haemoglobin concentrations in patients undergoing cardiac surgery., Methods and Results: We conducted a systematic review, meta-analysis, and trial sequential analysis of randomized controlled trials of the effect of restrictive and liberal RBC transfusion strategies on mortality within 30 days of surgery as the primary outcome. Secondary outcomes were those potentially resulting from anaemia-induced tissue hypoxia and transfusion outcomes. We searched the electronic databases MEDLINE, EMBASE, and the Cochrane Library until 17 November 2017. Thirteen trials were included. The risk ratio (RR) of mortality derived from 4545 patients assigned to a restrictive strategy when compared with 4547 transfused according to a liberal strategy was 0.96 [95% confidence interval (CI) 0.76-1.21, I2 = 0]. A restrictive strategy did not have a statistically significant effect on the risk of myocardial infarction (RR 1.01, 95% CI 0.81-1.26; I2=0), stroke (RR 0.93, 95% CI 0.68-1.27, I2 = 0), renal failure (RR 0.96, 95% CI 0.76-1.20, I2 = 0), or infection (RR 1.12, 95% CI 0.98-1.29, I2 = 0). Subgroup analysis of adult and paediatric trials did not show a significant interaction. At approximately 70% of the critical information size, the meta-analysis of mortality crossed the futility boundary for inferiority of the restrictive strategy., Conclusion: The current evidence does not support the notion that restrictive RBC transfusion strategies are inferior to liberal RBC strategies in patients undergoing cardiac surgery., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Background: The available evidence on the benefits and harms of novel drugs and therapeutic biologics at the time of approval is reported in publicly available documents provided by the US Food and Drug Administration (FDA). We aimed to create a comprehensive database providing the relevant information required to systematically analyze and assess this early evidence in meta-epidemiological research., Methods: We designed a modular and flexible database of systematically collected data. We identified all novel cancer drugs and therapeutic biologics approved by the FDA between 2000 and 2016, recorded regulatory characteristics, acquired the corresponding FDA approval documents, identified all clinical trials reported therein, and extracted trial design characteristics and treatment effects. Herein, we describe the rationale and design of the data collection process, particularly the organization of the data capture, the identification and eligibility assessment of clinical trials, and the data extraction activities., Discussion: We established a comprehensive database on the comparative effects of drugs and therapeutic biologics approved by the FDA over a time period of 17 years for the treatment of cancer (solid tumors and hematological malignancies). The database provides information on the clinical trial evidence available at the time of approval of novel cancer treatments. The modular nature and structure of the database and the data collection processes allow updates, expansions, and adaption for a continuous meta-epidemiological analysis of novel drugs. The database allows us to systematically evaluate benefits and harms of novel drugs and therapeutic biologics. It provides a useful basis for meta-epidemiological research on the comparative effects of innovative cancer treatments and continuous evaluations of regulatory developments.

Background: The risk of thromboembolic events is increased in patients with heart failure (HF); however, few studies have reported thromboembolic findings in HF patients who have undergone autopsy., Methods and Results: We reviewed 1457 autopsies (January 2000/July 2006) and selected 595 patients with HF. We studied the occurrence of thromboembolic events in patients' autopsy reports. Mean age was 61.8±15.9 years; 376 (63.2%) were men and 219 (36.8%) women; left ventricular ejection fraction was 42.1±18.7%. HF etiologies were coronary artery disease in 235 (39.5%) patients, valvular disease in 121 (20.3%), and Chagas' disease in 81 (13.6%). The main cause of death was progressive HF in 253 (42.5%) patients, infections in 112 (18.8%), myocardial infarction in 86 (14.5%), and pulmonary embolism in 81 (13.6%). Altogether, 233 patients (39.2%) suffered 374 thromboembolic events. A thromboembolic event was considered the direct cause of death in 93 (24.9%) patients and related to death in 158 (42.2%). The most frequent thromboembolism was pulmonary embolism in 135 (36.1%) patients; in 81 events (60%), it was considered the cause of death. When we compared clinical characteristics of patients, sex (OR=1.511, CI 95% 1.066-2.143, P=.021) and Chagas disease (OR=2.362, CI 95% 1.424-3.918, P=.001) were independently associated with the occurrence of thromboembolisms., Conclusions: Thromboembolic events are frequent in patients with heart failure revealed at autopsy, and are frequently associated with the death process. Our findings warrant a high degree of suspicion for these occurrences, especially during the care of more susceptible populations, such as women and Chagas patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To compare the performance of the Ogawa-Kudoh method with the modified Petroff technique in diagnosis of pulmonary tuberculosis., Methods: A total of 205 sputum samples from 166 patients with clinical suspicion or under pulmonary tuberculosis follow-up, seen at a public tertiary care hospital, from July 2014 to July 2016 were used. All samples were simultaneously processed using the Ogawa-Kudoh and modified Petroff decontamination methods, according to the recommendations of the Ministry of Health. In the statistical analysis, the McNemar test and the Kappa index were used, respectively, to compare proportions and verify agreement between data., Results: The Ogawa-Kudoh and modified Petroff methods were efficient in mycobacteria detection, with no significant differences in results (p=0.549) and contamination rate of the cultures (p=0.065). The agreement between techniques was considered excellent (Kappa index of 0.877) and Ogawa-Kudoh, as compared to the modified Petroff technique, showed sensitivity of 90.4%, specificity of 96.6%, positive predictive value of 94.3% and negative predictive value of 94.2%., Conclusion: The Ogawa-Kudoh technique proved to be sufficiently sensitive and specific for diagnosis of pulmonary tuberculosis, and, therefore, suitable for routine laboratory application. Since it is simple, low-cost and has less technical requirements for biosafety and professional training, Ogawa-Kudoh is an alternative for managers and healthcare professionals to promote the expansion of bacteriological diagnostic coverage of pulmonary tuberculosis.

Aim: As little is known about alcohol and tobacco consumption concordance between older spouses in low- and middle-income countries, the present study aimed to estimate this in older couples from five Latin American countries., Methods: This study is a secondary analysis of data collected between 2003 and 2007 by the 10/66 Dementia Research Group, from 1451 couples aged over 65 years from Cuba, the Dominican Republic, Peru, Mexico and Puerto Rico. Kappa statistic was used to assess the agreement of the behavior beyond chance, and logistic regression models with meta-analyses were used to estimate the factors associated with concordance., Results: The mean age of the total sample was 74.8 years (SD 6.6). The results showed high levels of agreement rates in relation to drinking and smoking (75.9% and 85% of couples, respectively, did not drink or smoke), which were beyond the agreement expected by chance. Increased age was associated with concordance on both being non-drinkers (OR 1.03, 95% CI 1.01-1.05) and non-smokers (OR 1.05, 95% CI 1.02-1.07); and having a larger social network was associated with less likelihood of the couple being non-drinkers (OR 0.93, 95% CI 0.88-0.98). Attending religious meetings was associated with increased likelihood of the couple being non-smokers (OR 1.19, 95% CI 1.01-1.41). Socioeconomic circumstances were not associated with couples' concordance., Conclusions: Older Latin American couples have high levels of concordance in drinking and smoking habits, which increases with age, and were not associated with socioeconomic circumstances, but were with social network. This knowledge can assist the development of policies and interventions to promote health among this growing population. Geriatr Gerontol Int 2017; 17: 1849-1857., (© 2017 The Authors Geriatrics & Gerontology International published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society.)

Objective: To evaluate the efficacy and safety of IV laronidase for MPS I., Methods: A systematic literature review was performed by searching the ClinicalTrials.gov, MEDLINE/PubMed, EMBASE, LILACS, and Cochrane Library databases, limited to clinical trials published until December 31, 2016. The first inclusion criterion was being a randomized controlled trial (RCT). If < five RCTs were identified, open-label and nonrandomized trials, controlled or uncontrolled (quasi-experimental), including ≥ five patients, and evaluating relevant outcomes defined a priori, would also be included. For meta-analysis, primary inferences were based on random-effects models. Assessment of article quality was performed in accordance with the GRADE criteria. The Cochrane Risk of Bias tool was used to examine the risk of bias for RCTs., Results: The selection phase retrieved 632 articles. During the first phase of selection, 158 had the abstract or full text read for assessment of eligibility, of which nine (two RCTs) were included for qualitative synthesis. Four papers were included in the meta-analysis, which was performed for the following outcomes: occurrence of treatment-emergent or infusion-related adverse events (65%; 95%CI 53, 76), mild in most cases; development of IgG antibodies to laronidase (88%; 95%CI 67, 100); apnea-hypopnea index (not significant-NS), urinary glycosaminoglycans (GAGs) [mean change -65.5 μg/mg creatinine (95%CI -68.8, -62.3)], liver size [mean change -31.03% (95%CI -36.1, -25.9)], left ventricular mass index (LVMI) [mean change -1.8 (95%CI -2.32, -0.25)], and distance covered in the 6-minute walk test (NS). Among the outcomes not included in meta-analysis, we found evidence for benefit of laronidase only on shoulder flexion., Conclusions: Our findings suggest that IV laronidase effectively reduces urinary GAGs excretion, hepatomegaly and LVMI, and can improve shoulder flexion in MPS I patients. Laronidase appears to be safe in the studied population.