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Changes in corticosteroid and non-steroidal immunosuppressive therapy with long-term zilucoplan treatment in generalized myasthenia gravis
Get PDFBackground
The efficacy and safety of complement component 5 inhibitor zilucoplan in patients with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG) were assessed in two double-blind studies (NCT03315130/NCT04115293 [RAISE]). During these studies and the first 12 weeks of the open-label extension study, RAISE-XT, corticosteroid and non-steroidal immunosuppressive therapy (NSIST) doses were kept stable; thereafter doses could be changed at the investigator’s discretion. We evaluated corticosteroid and NSIST dose changes in patients with gMG during zilucoplan treatment in RAISE-XT.
Methods
In RAISE-XT, patients who completed a qualifying double-blind study self-administered once-daily subcutaneous zilucoplan 0.3mg/kg. We assessed (post hoc) patients who changed their corticosteroid or NSIST dose relative to double-blind baseline at Week 120 (data cutoff: November 11, 2023).
Results
Overall, 200 patients enrolled. At Week 120, 61.1% (n = 33/54) of patients who were on corticosteroids at double-blind baseline had reduced or discontinued corticosteroids (mean 15.5mg dose reduction); mean change from baseline (CFB) in Myasthenia Gravis Activities of Daily Living (MG-ADL) score:−6.55 (standard deviation [SD] 3.65). Of patients on NSIST at double-blind baseline, 29.8% (n = 14/47) reduced or discontinued ≥ 1 NSIST; mean CFB in MG-ADL score:−7.57 (SD 4.69). Among all patients at Week 120, 9.3% (n = 8/86) had increased or started corticosteroids; 2.4% of patients (n = 2/85) had increased NSIST, including one who started a new NSIST. Zilucoplan was well tolerated.
Conclusions
Treatment with zilucoplan allowed for reduction or discontinuation of corticosteroids in the majority of patients and NSIST in about a third of patients, while maintaining efficacy.
Trial registration
NCT04225871; October 2, 2019
Overcoming cloud obstruction: Fast forest-damage assessment in post-tropical cyclone optical remote sensing
Get PDFTimely mapping of damaged forests is critical for disaster assessment. However, remote sensing data immediately after natural hazards is always scarce and susceptible to cloud contamination, hindering holistic assessment of damaged forests in a timely manner. Herein, we propose a novel method to map damaged forests obscured by clouds in post-hazard images by taking the September 2024 typhoon Yagi in Hainan Island, China as an example. Our approach uniquely integrates observed forest damage in cloud-free pixels with its influencing factors (the maximum wind speed and cumulative rainfall during the typhoon, terrain (elevation, slope and aspect), and canopy height) to interpolate the relationship into cloud-covered pixels by using three mainstream machine learning models (XGBoost, artificial neural networks and random forest). We found severe forest damage in the Northeast Hainan and the total area of the typhoon-damaged forests accounts for 12.8 %–15.5 % of the island's forest cover. This method can also be used for fast mapping of forest damage in partially available remote sensing images after other major natural hazards such as wildfires and landslides
Secondary electron hyperspectral imaging of carbons: new insights and good practice guide
Get PDFEnergy storage technologies such as lithium-ion batteries (LIBs) incorporate carbon components key to their function. Graphite and carbon binder components in LIB electrodes are engineered to deliver critical electrical and mechanical properties, as are the surface chemistry and morphology of carbon blacks (CBs) in LIBs and catalysts. The challenge of relating surface chemistry to morphology is complicated by the numerous forms of carbon bonding and potential for surface functional groups. Furthermore, materials processing can influence bonding and structure of carbon at multiple length scales, as seen in mechanochemical functionalization of CBs. To understand the nature of carbon surfaces, secondary electron hyperspectral imaging (SEHI) is introduced as a spatially resolved analysis bridging the nano to microscale. The ability to provide novel insights is demonstrated three example applications: observation of nanoscale “satellite” particles of amorphous hydrogenated carbon on graphitic CB particles, differentiation between graphitic and amorphous hydrogenated nano-thickness carbon coatings on particles of lithium iron phosphate, and differentiation between graphitic carbon active material and carbon binder domain in a LIB anode material. SEHI analysis using peak fitting models for graphitic and disordered carbons is developed based on reference materials and standard spectroscopic methods: Raman spectroscopy and X-ray photoelectron spectroscopy
Virtual Integration of Satellite and In-situ Observation Networks (VISION) v1.0: In-Situ Observations Simulator (ISO_simulator)
Get PDFThis work presents the first step in the development of the VISION toolkit, a set of Python tools that allows easy, efficient, and more meaningful comparison between global atmospheric models and observational data. Whilst observational data and modelling capabilities are expanding in parallel, there are still barriers preventing these two data sources from being used in synergy. This arises from differences in spatial and temporal sampling between models and observational platforms: observational data from a research aircraft, for example, are sampled on specified flight trajectories at very high temporal resolution. Proper comparison with model data requires generating, storing, and handling a large number of highly temporally resolved model files, resulting in a process which is data-, labour-, and time-intensive. In this paper we focus on comparison between model data and in situ observations (from aircraft, ships, buoys, sondes, etc.). A standalone code, In-Situ Observations Simulator, or ISO_simulator for short, is described here: this software reads modelled variables and observational data files and outputs model data interpolated in space and time to match observations. These model data are then written to NetCDF files that can be efficiently archived due to their small sizes and directly compared to observations. This method achieves a large reduction in the size of model data being produced for comparison with flight and other in situ data. By interpolating global gridded hourly files onto observation locations, we reduce data output for a typical climate resolution run, from ∼3 Gb per model variable per month to ∼15 Mb per model variable per month (a 200-times reduction in data volume). The VISION toolkit is relatively fast to run and can be automated to process large volumes of data at once, allowing efficient data analysis over a large number of years. Although this code was initially tested within the Unified Model (UM) framework, which is shared by the UK Earth System Model (UKESM), it was written as a flexible tool and it can be extended to work with other models
Measurable Residual Disease-Guided Therapy for Chronic Lymphocytic Leukemia
No full textBackground
An interim analysis of progression-free survival in this trial showed that ibrutinib–venetoclax was superior to fludarabine–cyclophosphamide–rituximab (FCR) among patients with chronic lymphocytic leukemia (CLL). Whether ibrutinib–venetoclax is more effective than ibrutinib alone is unclear.
Methods
In this phase 3, multicenter, open-label trial, we randomly assigned patients with CLL to receive ibrutinib–venetoclax, ibrutinib alone, or FCR. The primary end points were undetectable measurable residual disease (MRD) in bone marrow within 2 years in the ibrutinib–venetoclax group as compared with the ibrutinib-alone group and progression-free survival in the ibrutinib–venetoclax group as compared with the FCR group. A powered secondary end point was progression-free survival in the ibrutinib–venetoclax group as compared with the ibrutinib-alone group. Other secondary end points included overall survival.
Results
A total of 172 of the 260 participants (66.2%) in the ibrutinib–venetoclax group had undetectable MRD in bone marrow within 2 years, as compared with none of the 263 participants in the ibrutinib-alone group (P<0.001) and 127 of the 263 participants (48.3%) in the FCR group. With a median follow-up of 62.2 months, disease progression or death occurred in 18 participants (6.9%) in the ibrutinib–venetoclax group, as compared with 59 (22.4%) in the ibrutinib-alone group (hazard ratio, 0.29; 95% confidence interval [CI], 0.17 to 0.49; P<0.001) and 112 (42.6%) in the FCR group (hazard ratio, 0.13; 95% CI, 0.08 to 0.21; P<0.001). Progression-free survival at 5 years was 93.9% with ibrutinib–venetoclax, 79.0% with ibrutinib alone, and 58.1% with FCR. Death occurred in 11 participants (4.2%) in the ibrutinib–venetoclax group, as compared with 26 (9.9%) in the ibrutinib-alone group (hazard ratio, 0.41; 95% CI, 0.20 to 0.83) and 39 (14.8%) in the FCR group (hazard ratio, 0.26; 95% CI, 0.13 to 0.50). Sudden death occurred in 3, 8, and 4 participants in the ibrutinib–venetoclax, ibrutinib-alone, and FCR groups, respectively.
Conclusions
With extended follow-up and increased enrollment, our trial showed that undetectable MRD and extended progression-free survival were more common with ibrutinib–venetoclax than with ibrutinib alone or FCR. The results for overall survival were also consistent with a benefit of ibrutinib–venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.
Definitions of clinical study outcome measures for cardiovascular diseases:the European Unified Registries for Heart Care Evaluation and Randomized Trials (EuroHeart)
Get PDFBACKGROUND AND AIMS: Standardized definitions for outcome measures in randomized clinical trials and observational studies are essential for robust and valid evaluation of medical products, interventions, care, and outcomes. The European Unified Registries for Heart Care Evaluation and Randomised Trials (EuroHeart) project of the European Society of Cardiology aimed to create international data standards for cardiovascular clinical study outcome measures. METHODS: The EuroHeart methods for data standard development were used. From a Global Cardiovascular Outcomes Consortium of 82 experts, five Working Groups were formed to identify and define key outcome measures for: cardiovascular disease (generic outcomes), acute coronary syndrome and percutaneous coronary intervention (ACS/PCI), atrial fibrillation (AF), heart failure (HF) and transcatheter aortic valve implantation (TAVI). A systematic review of the literature informed a modified Delphi method to reach consensus on a final set of variables. For each variable, the Working Group provided a definition and categorized the variable as mandatory (Level 1) or optional (Level 2) based on its clinical importance and feasibility. RESULTS: Across the five domains, 24 Level 1 (generic: 5, ACS/PCI: 8, AF: 2; HF: 5, TAVI: 4) and 48 Level 2 (generic: 18, ACS-PCI: 7, AF: 6, HF: 2, TAVI: 15) outcome measures were defined. CONCLUSIONS: Internationally derived and endorsed definitions for outcome measures for a range of common cardiovascular diseases and interventions are presented. These may be used for data alignment to enable high-quality observational and randomized clinical research, audit, and quality improvement for patient benefit
A Decade of Mizer:A Systematic Review of Advancements and Applications of Size Spectrum Modeling in Aquatic Ecosystems
Get PDFThis systematic review examines the use of the mizer R package, a tool for multi-species size-spectrum modeling of marine ecosystems, over the past decade. We analyzed 43 publications, including peer-reviewed articles and academic theses, to highlight its contributions, strengths and limitations across various research domains. We grouped studies into five categories: fisheries management and policy, ecosystem dynamics and species interactions, methodological advances, climate change projections, and broad-scale ecological studies. Geographically, the majority of studies were concentrated in marine ecosystems, particularly in the North Sea and Haizhou Bay, China. Our visualizations, including maps, timelines, Sankey diagrams, and a scientific collaboration network, revealed strong international collaboration, with the UK, Australia, and the USA emerging as central hubs in the global research network. The mizer package has evolved through various extensions such as therMizer, MizerShelf and MizerEvo, broadening its application in studying climate impacts and eco-evolutionary dynamics. Overall, mizer has proven to be a valuable tool in advancing our understanding of aquatic ecosystems and informing sustainable management practices. Despite its widespread use in theoretical and exploratory studies, direct applications of mizer-derived strategies in real-world fisheries management remain limited, underscoring the challenges of integrating complex models into decision-making frameworks. We identify several opportunities to enhance mizer’s practical relevance, including the development of validation datasets and benchmarking protocols, comparative evaluation with other ecosystem models, structured sensitivity and uncertainty analyses, and incorporation of socio-environmental feedbacks. We also highlight key technical limitations, such as the absence of automated parameter optimization and the reliance on equilibrium-based model structure, which currently constrain its use in dynamic or data-limited contexts. Addressing these challenges will be critical for advancing the integration of size-spectrum modeling into ecosystem-based management and policy
Atomic-Scale Imaging of Transformation of Nickel Nanocrystals to Nickel Carbides in Real Time.
Get PDFTransition of metal-to-metal carbide plays a key role in heterogeneous catalysis. We confined nickel nanocrystals in single-walled carbon nanotubes, stimulated delivery of carbon atoms by the 80 keV electron beam, and imaged the entire carbonization process by time-resolved aberration-corrected transmission electron microscopy at the atomic scale. Metal nano crystal Ni₄₀ progressively capturing carbon atoms evolved from pure metal to Ni₄₀C₂₀ and then to Ni₄₀C₄₀. The carbonization is accompanied by changes in the structure of the crystal, including a two-dimensionalization process, at the Ni₄₀C₄₀ stage. This work provides valuable insights into the atomic mechanism of metal carbide formation, which may help to develop stable catalysts and provide a reliable route for synthesizing metal-based two-dimensional materials
Geotextile-encased cinder gravel columns: a coupled DEM-FDM analysis
Get PDFCinder gravel, a porous, lightweight, and durable volcanic byproduct, has the potential to be a sustainable and cost-effective alternative to conventional stone columns for ground improvement applications. Its use in soft soils, however, requires sufficient confining pressure to prevent bulging and thus performance degradation. Geotextile-encased cinder gravel (GECG) columns are an innovate method to overcome this, but studies on bearing response and pressure–deformation characteristics are limited. A comprehensive numerical analysis of GECG columns was conducted using a combination of the discrete-element method (DEM) and finite-difference method (FDM). The hybrid DEM–FDM framework enabled simulation of individual particle behavior while maintaining efficiency in modeling continuous, homogeneous materials. The key novelties were examining the macro and mesoscopic behavior of GECG columns under triaxial compression. The developed numerical model was validated and calibrated against triaxial test results. A parametric analysis of GECG columns investigated the influence of relative density and gradation on the compression behavior and load capacity. Upon triaxial compression, the results showed significant radial expansion near the column top, with stress and deformation fields aligning with the column's bearing capacity. The relative density had limited influence on the geotextile's radial deformation, while a higher content of coarse particles in the gradation enhanced the bearing capacity of the GECG columns
Controls on uranium isotope fractionation in the late Paleoproterozoic ocean
Get PDFUranium isotope data from Proterozoic carbonates (δ238Ucarb) and black shales (δ238Uauth) are enigmatic. Average Proterozoic δ238Ucarb (approximating Proterozoic seawater, δ238Usw) is similar to modern river/seawater δ238U, and Proterozoic black shales do not always record highly fractionated δ238Uauth compared to contemporaneous δ238Ucarb. However, very light δ238Ucarb and heavy δ238Uauth for the widely anoxic Proterozoic oceans was expected because large isotope fractionations accompany U reduction in anoxic environments. To address this enigma, we report black shale δ238Uauth through a well-characterised multi-core transect in the late Paleoproterozoic Animikie Basin, North America. There is a wide range of δ238Uauth, from –0.52‰ to 0.53‰, that generally correlates with organic carbon enrichments. Heavy δ238Uauth in organic-rich shallow shelf sediments within and near a euxinic wedge are attributed to enhanced productivity with vigorous sediment microbial activity, neutrally charged aqueous U species that slow reaction kinetics, and redoxcline fluctuations. In less organic-rich sediments of the anoxic-ferruginous deep shelf environment, characterized by lower productivity and plentiful reduced iron availability, light δ238Uauth may reflect rapid U reduction or adsorption to solid Fe/Mn species. Hence, for the widely anoxic Proterozoic oceans, we propose that large isotopic fractionations (0.4 to 1.2‰) were associated with highly productive areas on anoxic continental margins, and muted isotopic fractionations (–0.1 to 0.4‰) occurred in anoxic deep-ocean environments. Low-productivity Proterozoic oceans yielded sediments with δ238Ucarb and δ238Uauth close to modern river/seawater values, whereas higher-productivity basins (e.g., Animikie Basin) resulted in lower δ238Ucarb and more variable δ238Uauth
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