Evaluation of real-world mepolizumab use in severe asthma across Europe: the SHARP experience with privacy-preserving federated analysis.

Background: An objective of the Severe Heterogeneous Asthma Registry, Patient-centered (SHARP) is to produce real-world evidence on a pan-European scale by linking nonstandardised, patient-level registry data. Mepolizumab has shown clinical efficacy in randomised controlled trials and prospective real-world studies and could therefore serve as a proof of principle for this novel approach. The aim of the present study was to harmonise data from 10 national severe asthma registries and characterise patients receiving mepolizumab, assess its effectiveness on annual exacerbations and maintenance oral glucocorticoid (OCS) use, and evaluate treatment patterns. Methods: In this observational cohort study, registry data (5871 patients) were extracted for harmonisation. Where harmonisation was possible, patients who initiated mepolizumab between 1 January 2016 and 31 December 2021 were examined. Changes of a 12-month (range 11-18 months) period in frequent (two or more) exacerbations, maintenance OCS use and dose were analysed in a privacy-preserving manner using meta-analysis of generalised estimating equation parameters. Periods before and during the coronavirus disease 2019 pandemic were analysed separately. Results: In 912 patients who fulfilled selection criteria, mepolizumab significantly reduced frequent exacerbations (OR 0.18, 95% CI 0.13-0.25), maintenance OCS use (OR 0.75, 95% CI 0.61-0.92) and dose (mean -3.93 mg·day-1, 95% CI -5.24-2.62 mg·day-1) in the pre-pandemic group, with similar trends in the pandemic group. Marked heterogeneity was observed between registries in patient characteristics and mepolizumab treatment patterns. Conclusions: By harmonising patient-level registry data and applying federated analysis, SHARP demonstrated the real-world effectiveness of mepolizumab on asthma exacerbations and maintenance OCS use in severe asthma patients across Europe, consistent with previous evidence. This paves the way for future pan-European real-world severe asthma studies using patient-level data in a privacy-proof manner.

Chronic hyperglycemia impairs hippocampal neurogenesis and memory in an Alzheimer's disease mouse model.

During aging, lifestyle-related factors shape the brain's response to insults and modulate the progression of neurodegenerative pathologies such as Alzheimer's disease (AD). This is the case for chronic hyperglycemia associated with type 2 diabetes, which reduces the brain's ability to handle the neurodegenerative burden associated with AD. However, the mechanisms behind the effects of chronic hyperglycemia in the context of AD are not fully understood. Here, we show that newly generated neurons in the hippocampal dentate gyrus of triple transgenic AD (3xTg-AD) mice present increased dendritic arborization and a number of synaptic puncta, which may constitute a compensatory mechanism allowing the animals to cope with a lower neurogenesis rate. Contrariwise, chronic hyperglycemia decreases the complexity and differentiation of 3xTg-AD newborn neurons and reduces the levels of ß-catenin, a key intrinsic modulator of neuronal maturation. Moreover, synaptic facilitation is depressed in hyperglycemic 3xTg-AD mice, accompanying the defective hippocampal-dependent memory. Our data suggest that hyperglycemia evokes cellular and functional alterations that accelerate the onset of AD-related symptoms, namely memory impairment.