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Background: Chimeric antigen receptor T-cell (CAR-T) cell therapies have been claimed to be curative in responsive patients. Nonetheless, response rates can vary according to different characteristics, and these therapies are associated with important adverse events such as cytokine release syndrome, neurologic adverse events, and B-cell aplasia. Objectives: This living systematic review aims to provide a timely, rigorous, and continuously updated synthesis of the evidence available on the role of CAR-T therapy for the treatment of patients with hematologic malignancies. Design: A systematic review with meta-analysis of randomized controlled trials (RCTs) and comparative non-randomized studies of interventions (NRSI), evaluating the effect of CAR-T therapy versus other active treatments, hematopoietic stem cell transplantation, standard of care (SoC) or any other intervention, was performed in patients with hematologic malignancies. The primary outcome is overall survival (OS). Certainty of the evidence was determined using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Data sources and Methods: Searches were performed in the Epistemonikos database, which collates information from multiple sources to identify systematic reviews and their included primary studies, including Cochrane Database of Systematic Reviews, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, DARE, HTA Database, Campbell database, JBI Database of Systematic Reviews and Implementation Reports, EPPI-Centre Evidence Library. A manual search was also carried out. We included the evidence published up to 1 July 2022. Results: We included the evidence published up to 1 July 2022. We considered 139 RCTs and 1725 NRSI as potentially eligible. Two RCTs ( N = 681) comparing CAR-T therapy with SoC in patients with recurrent/relapsed (R/R) B-cell lymphoma were included. RCTs did not show statistical differences in OS, serious adverse events, or total adverse events with grade ⩾ 3. Higher complete response with substantial heterogeneity [risk ratio = 1.59; 95% confidence interval (CI) = (1.30–1.93); I 2 = 89%; 2 studies; 681 participants; very low certainty evidence] and higher progression-free survival [hazard ratio for progression or death = 0.49; 95% CI = (0.37–0.65); 1 study; 359 participants; moderate certainty evidence] were reported with CAR-T therapies. Nine NRSI ( N = 540) in patients with T or B-cell acute lymphoblastic leukemia or R/R B-cell lymphoma were also included, providing secondary data. In general, the GRADE certainty of the evidence for main outcomes was mostly low or very low. Conclusion: So far, assuming important limitations in the level of certainty due to scarce and heterogenous comparative studies, CAR-T therapies have shown some benefit in terms of progression-free survival, but no overall survival, in patients with R/R B-cell lymphoma. Despite one-arm trials have already facilitated approval of CAR-T cell treatments, additional evidence from large comparative studies is still needed to better characterize the benefit-harm ratio of the use of CAR-T in a variety of patient populations with hematological malignancies. Registration: https://doi.org/10.12688/openreseurope.14390.1 PROSPERO/OSF Preregistration: 10.17605/OSF.IO/V6HDX

Objective This living, systematic review aims to provide a timely, rigorous, and continuously updated summary of the evidence available on the role of macrolides for treating patients with COVID-19. Design A living, systematic review. Database We conducted searches in the centralized repository L·OVE (Living OVerview of Evidence). L·OVE is a platform that maps PICO questions to evidence from the Epistemonikos database. In response to the COVID-19 emergency, L·OVE was adapted to expand the range of evidence it covers and customized to group all COVID-19 evidence in one place. Today it is maintained through regular searches in 39 databases. Methods We included randomized trials evaluating the effect of macrolides — as monotherapy or in combination with other drugs — versus placebo or no treatment in patients with COVID-19. Randomized trials evaluating macrolides in infections caused by other coronaviruses, such as MERS-CoV and SARS-CoV, and non-randomized studies in COVID-19 were searched in case we found no direct evidence from randomized trials. Two reviewers independently screened each study for eligibility, extracted data, and assessed the risk of bias. Measures included all-cause mortality; the need for invasive mechanical ventilation; extracorporeal membrane oxygenation, length of hospital stay, respiratory failure, serious adverse events, time to SARS-CoV-2 RT-PCR negativity. We applied the GRADE approach to assess the certainty of the evidence for each outcome. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it every time the conclusions change or whenever there are substantial updates. Results The search in the L·OVE platform retrieved 424 references. We considered 260 as potentially eligible and were reviewed in full texts. We included one randomized clinical trial that evaluated the use of azithromycin in combination with hydroxychloroquine compared to hydroxychloroquine alone in hospitalized patients with COVID 19. The estimates for all outcomes evaluated resulted in insufficient power to draw conclusions. The quality of the evidence for the main outcomes was low to very low. Conclusions Macrolides in the management of patients with COVID 19 showed no beneficial effects compared to standard of care. The evidence for all outcomes is inconclusive. Larger trials are needed to determine the effects of macrolides on pulmonary and other outcomes in COVID-19 patients. Systematic review registration PROSPERO Registration number: CRD42020181032 Protocol preprint DOI: 10.31219/osf.io/rvp59

Objective To determine the efficacy and safety of CAR-T therapy in the treatment of patients with hematologic malignancies, in comparison with other current therapies. Design A living systematic review Methods We will include randomized trials evaluating the effect of CAR-T therapy versus other active treatments, hematopoietic stem cell transplantation, best supportive care or any other intervention in patients with hematologic malignancies. Non-randomized primary studies will be searched in case we found no direct evidence from randomized controlled trials. Two reviewers will independently screen each study for eligibility, extract data, and assess the risk of bias. Efficacy measures will include overall survival rate, overall response rate, complete response/remission (CR) rate, partial response/remission (PR) rate, relapse from CR, progression-free survival, and time from CAR-T infusion to transplantation. Safety measures will include serious adverse events, the incidence of cytokine release syndrome, graft-versus-host disease, neurotoxicity, and total adverse events. Quality of life will also be assessed. Meta-analyses will be carried out to summarize the results. We will apply the GRADE approach to assess the certainty of the evidence for each outcome. A living, web-based version of this review will be openly available until there is solid evidence to respond to the review objective. We will resubmit it for publication every time the conclusions change or whenever there are substantial updates.

Objective: To assess the effectiveness, safety, and cost-effectiveness of genicular artery embolization (GAE) for the treatment of mild or moderate knee osteoarthritis (KO) refractory to standard treatment, and/or severe KO in individuals not eligible for surgery. Method: We conducted a systematic review with meta-analysis, supplemented by a cost-analysis, comparing GAE and standard treatment, from the perspective of the Spanish National Health System (NHS) over a one-year time horizon. The health improvement required for GAE to be deemed cost-effective was quantified, considering a willingness-to-pay threshold of 25 000 €/quality-adjusted life year (QALY). Results: We included two randomized controlled trials in our analysis. Pain estimates showed inconsistent results, and no significant effects were observed for overall function, health-related quality of life, or changes in the need for pain management medication. No serious complications or major adverse events were observed. GRADE quality of evidence ranged from moderate to low. No economic evaluations were identified. Our cost-analysis revealed that GAE would result in an incremental cost of € 3432.37 per patient, requiring a health improvement of 0.137 QALY per patient to be deemed a cost-effective technology. Conclusions: In summary, based on moderate to low-certainty evidence, it remains inconclusive whether there is any difference between GAE and standard treatment for KO. However, the use of GAE would increase the costs. Larger randomized controlled trials are needed to determine the effects of using GAE for chronic pain secondary to KO and, consequently, to ascertain whether this technology could potentially become cost-effective from the NHS perspective. Resumen: Objetivo: Evaluar la efectividad, la seguridad y el coste-efectividad de la embolización de la arteria genicular (EAG) para el tratamiento de la artrosis de rodilla (AR) leve o moderada, refractaria al tratamiento habitual, o grave en personas no candidatas a cirugía. Método: Se llevó a cabo una revisión sistemática con metaanálisis y un análisis de costes para comparar la EAG y el tratamiento habitual, desde la perspectiva del Sistema Nacional de Salud (SNS) español, con un horizonte temporal de 1 año. Se estimó la mejora en salud necesaria para que la EAG se considere coste-efectiva, con un umbral de 25.000 €/año de vida ajustado por calidad (AVAC). Resultados: Se incluyeron dos ensayos controlados aleatorizados. Los resultados en dolor fueron inconsistentes y no se observaron efectos significativos en la función general, la calidad de vida ni la necesidad de medicación para el dolor. No se observaron complicaciones graves ni eventos adversos mayores. La calidad de la evidencia fue de moderada a baja. No se identificaron evaluaciones económicas previas. El coste incremental de la EAG sería de 3.432,37 €/paciente, requiriendo una mejora de 0,137 AVAC/paciente para ser coste-efectiva. Conclusiones: La evidencia de certeza moderada a baja no permite concluir si hay diferencias entre la EAG y el tratamiento habitual para la AR. Sin embargo, el uso de la EAG incrementaría los costes. Se necesitan ensayos controlados aleatorizados de mayor tamaño para determinar los efectos de la EAG en el dolor crónico secundario a la AR y establecer si podría ser coste-efectiva desde la perspectiva del SNS.

Background: Living evidence (LE) refers to the methodological processes that permit new research findings to be continually incorporated into evidence synthesis. This approach is of great value in the resolution of relevant and rapidly changing clinical questions. To date, the methods to carry out this type of synthesis are not completely defined, and great variability is observed in the approaches used by different groups of authors. Objective: To identify, evaluate and summarise the current methods used for living evidence synthesis Methods: We will conduct a methodological study based on a systematic literature search to identify any type of evidence synthesis such as systematic reviews, network metanalyses and overviews that used “living evidence synthesis” as part of their methods. The search will be conducted in Medline (via PubMed) and Epistemonikos databases. Additionally, we will search websites of the organisations publishing any living evidence synthesis retrieved in the two databases, in order to identify unpublished subsequent reports. Two reviewers will independently assess each article against the selection criteria, extract data on methods and procedures, and assess the methodological quality of each publication. Data will be analysed descriptively.