ABSTRACT
Sickle cell disease is a hereditary multiorgan disease that is considered rare in the EU. In 2017, the Rare Diseases Plan was implemented within the EU and 24 European Reference Networks (ERNs) were created, including the ERN on Rare Haematological Diseases (ERN-EuroBloodNet), dedicated to rare haematological diseases. This EU initiative has made it possible to accentuate existing collaborations and create new ones. The project also made it possible to list all the needs of people with rare haematological diseases not yet covered health-care providers in the EU to allow optimised care of individuals with rare pathologies, including sickle cell disease. This Viewpoint is the result of joint work within 12 EU member states (ie, Belgium, Cyprus, Denmark, France, Germany, Greece, Ireland, Italy, Portugal, Spain, Sweden, and The Netherlands), all members of the ERN-EuroBloodNet. We describe the role of the ERN-EuroBloodNet to improve the overall approach to and the management of individuals with sickle cell disease in the EU through specific on the pooling of expertise, knowledge, and best practices; the development of training and education programmes; the strategy for systematic gathering and standardisation of clinical data; and its reuse in clinical research. Epidemiology and research strategies from ongoing implementation of the Rare Anaemia Disorders European Epidemiological Platform is depicted.
Subject(s)
Anemia, Sickle Cell , Rare Diseases , Humans , Netherlands , Germany , Greece , Italy , Rare Diseases/epidemiology , Rare Diseases/therapy , Anemia, Sickle Cell/epidemiology , Anemia, Sickle Cell/therapy , Europe/epidemiologyABSTRACT
INTRODUCTION: Rotavirus (RV) is the most common cause of childhood diarrhea. Argentina introduced RV vaccination in the National Immunization Program in January 2015. This study evaluates the impact of RV vaccine implementation on the burden of acute diarrheal disease (ADD) and RV positive cases, and hospitalizations among children in Argentina. METHODS: A counterfactual time-series analysis was performed. Data on ADD (2013-2018) and RV diarrhea (2012-2018) cases in children aged < 5 years were collected from the National Healthcare Surveillance System (clinical and laboratory data). Data on hospital discharges following ADD and RV diarrhea (2011-2017) were retrieved from the Health Statistics and Information Office. All data were classified by the age groups < 1 year, < 2 years, 2-5 years. Vaccine impact was defined as the difference between the predicted time trend (simulated using 2012-2014 data) and the actual post-vaccination data (2015-2018). RESULTS: A significant reduction of 22.1% of notified ADD cases and 15.4% of hospital discharges following ADD among children < 2 years was observed in the 3 years after RV vaccine implementation. Data also showed a significant decline of 54.0% and 59.4% of notified RV cases in children < 2 and < 1 years, respectively, and a reduction of 39.3% and 40.8% in RV hospital discharges for the same age groups. CONCLUSION: This study shows a significant reduction in notified ADD cases and RV cases and hospital discharges following ADD and RV cases in children < 2 years after RV vaccine introduction in Argentina in 2015.
ABSTRACT
OBJECTIVES: To determine the comparative efficacy and safety of a fixed dose of benznidazole (BZN) with an adjusted-dose for Trypanosoma cruzi-seropositive adults without cardiomyopathy. METHODS: We conducted a systematic review and individual participant data (IPD) meta-analysis following Cochrane methods, and the PRISMA-IPD statement for reporting. Randomised controlled trials (RCTs) allocating participants to fixed or adjusted doses of BZN for T. cruzi-seropositive adults without cardiomyopathy were included. We searched (December 2021) Cochrane, MEDLINE, EMBASE, LILACS and trial registries and contacted Chagas experts. Selection, data extraction, risk of bias assessment using the Cochrane tool, and a GRADE summary of finding tables were performed independently by pairs of reviewers. We conducted a random-effects IPD meta-analysis using the one-stage strategy, or, if that was impossible, the two-stage strategy. RESULTS: Five RCTs (1198 patients) were included, none directly comparing fixed with adjusted doses of BZN. Compared to placebo, BZN therapy was strongly associated with negative qPCR and sustainable parasitological clearance regardless of the type of dose and subgroup analysed. For negative qPCR, the fixed/adjusted rate of odds ratios (RORF/A ) was 8.83 (95% CI 1.02-76.48); for sustained parasitological clearance, it was 4.60 (95% CI 0.40-52.51), probably indicating at least non-inferior effect of fixed doses, with no statistically significant interactions by scheme for global and most subgroup estimations. The RORF/A for treatment interruption due to adverse events was 0.44 (95% CI 0.14-1.38), probably indicating no worse tolerance of fixed doses. CONCLUSIONS: We found no direct comparison between fixed and adjusted doses of BZN. However, fixed doses versus placebo are probably not inferior to weight-adjusted doses of BZN versus placebo in terms of parasitological efficacy and safety. Network IPD meta-analysis, through indirect comparisons, may well provide the best possible answers in the near future. REGISTRATION: The study protocol was registered in PROSPERO (CRD42019120905).
Subject(s)
Cardiomyopathies , Chagas Disease , Trypanosoma cruzi , Adult , Humans , Evidence Gaps , Chagas Disease/drug therapyABSTRACT
Multicellular tumor spheroids represent a 3D in vitro model that mimics solid tumor essential properties including assembly and development of extracellular matrix and nutrient, oxygen and proliferation gradients. In the present study, we analyze the impact of 3D spatial organization of HER2-overexpressing breast cancer cells on the response to Trastuzumab. We cultured human mammary adenocarcinoma cell lines as spheroids with the hanging drop method and we observed a gradient of proliferating, quiescent, hypoxic, apoptotic and autophagic cells towards the inner core. This 3D organization decreased Trastuzumab sensitivity of HER2 over-expressing cells compared to monolayer cell cultures. We did not observe apoptosis induced by Trastuzumab but found cell arrest in G0/G1 phase. Moreover, the treatment downregulated the basal apoptosis only found in tumor spheroids, by eliciting protective autophagy. We were able to increase sensitivity to Trastuzumab by autophagy inhibition, thus exposing the interaction between apoptosis and autophagy. We confirmed this result by developing a resistant cell line that was more sensitive to autophagy inhibition than the parental BT474 cells. In summary, the development of Trastuzumab resistance relies on the balance between death and survival mechanisms, characteristic of 3D cell organization. We propose the use of spheroids to further improve the understanding of Trastuzumab antitumor activity and overcome resistance.