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Jolijn R van Leeuwen,1 Luca Quartuccio,2 Juliana Bordignon Draibe,3 Iva Gunnarson,4 Ben Sprangers,5 Y K Onno Teng1 1Center of Expertise for Lupus-, Vasculitis- and Complement-Mediated Systemic Diseases (Luvacs), Department of Internal Medicine - Nephrology Section, Leiden University Medical Center, Leiden, the Netherlands; 2Division of Rheumatology, Department of Medicine, University of Udine, Udine, Italy; 3Department of Nephrology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain; 4Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden; 5Department of Nephrology, Ziekenhuis Oost Limburg Genk, Genk, BelgiumCorrespondence: Y K Onno Teng, Department of Nephrology, Leiden University Medical Center (LUMC), P.O. Box 9600, Leiden, 2300 RC, the Netherlands, Tel +31-71-5262148, Fax +31-71-5266868, Email Y.K.O.Teng@lumc.nlAbstract: Recently, avacopan has been approved for the treatment of ANCA-associated vasculitis (AAV). Avacopan is an inhibitor of the C5a-receptor, which plays an important role in chemotaxis and the amplification loop of inflammation in AAV. In the most recent, international guidelines avacopan is recommended as steroid-sparing agents for the management of AAV. Here, we review the clinical trials that have led to demonstrate that avacopan is an effective treatment option in the management of AAV, where it can significantly reduce the cumulative dosage of glucocorticoids (GC). Despite the new guideline recommendations, clear guidance on how to employ avacopan in real-world clinical practice is lacking. We therefore also address in this review the data and clinical experience with avacopan obtained from real-world evidence. Combining preclinical studies, clinical trials, and real-world evidence helps to provide a better position of avacopan for the management of AAV in routine clinical practice, taking advantage of the GC-sparing effects of avacopan as a possible solution for the current challenge of reducing GC-toxicity in AAV patients. Furthermore, we delineate current knowledge gaps and future research areas that need to be addressed.Keywords: antineutrophil cytoplasmic antibody, ANCA, pauci-immune glomerulonephritis, complement, C5a inhibition, glucocorticoid toxicity

Abstract Global climate models provide useful tools to forecast large‐scale anthropogenic trends and the impacts on ocean physics and marine biology and chemistry. Due to coarse spatial resolution, they typically lack the ability to represent important regional processes while underestimating mesoscale variability and vertical mixing. This means they provide limited value when it comes to regional climate projections. We developed a regional submesoscale‐permitting physical/biogeochemical model to dynamically downscale the output of a CMIP6 Earth System Model for three different Socioeconomic Pathways for the main Hawaiian Islands. We describe the methodology for downscaling the CMIP6 ocean physics and biogeochemistry along with atmospheric conditions in order to offline nest a regional model. We expect the large‐scale spatial and temporal features of the global model to be retained by the regional model, while adding representation of the regional processes that are crucial to understanding climate change on a local scale. We compare the regional model representation against both observed data and a regional reanalysis over the first two decades of the century. We show that the regional model maintains the large‐scale trends and interannual variability provided by the CMIP6 model while well‐representing the regional dynamics that drive the short‐term variability. To better illustrate the benefit of the downscaling, we present preliminary analysis of the downscaled results to examine climate impacts on the island corals that are not resolved by the global models. This analysis reveals that coastal corals are likely to experience unprecedented ocean acidification and substantial warming over the course of the century.

Micro- and nanorobots excel in navigating the intricate and often inaccessible areas of the human body, offering immense potential for applications such as disease diagnosis, precision drug delivery, detoxification, and minimally invasive surgery. Despite their promise, practical deployment faces hurdles, including achieving stable propulsion in complex in vivo biological environments, real-time imaging and localization through deep tissue, and precise remote control for targeted therapy and ensuring high therapeutic efficacy. To overcome these obstacles, we introduce a hydrogel-based, imaging-guided, bioresorbable acoustic microrobot (BAM) designed to navigate the human body with high stability. Constructed using two-photon polymerization, a BAM comprises magnetic nanoparticles and therapeutic agents integrated into its hydrogel matrix for precision control and drug delivery. The microrobot features an optimized surface chemistry with a hydrophobic inner layer to substantially enhance microbubble retention in biofluids with multiday functionality and a hydrophilic outer layer to minimize aggregation and promote timely degradation. The dual-opening bubble-trapping cavity design enables a BAM to maintain consistent and efficient acoustic propulsion across a range of biological fluids. Under focused ultrasound stimulation, the entrapped microbubbles oscillate and enhance the contrast for real-time ultrasound imaging, facilitating precise tracking and control of BAM movement through wireless magnetic navigation. Moreover, the hydrolysis-driven biodegradability of BAMs ensures its safe dissolution after treatment, posing no risk of long-term residual harm. Thorough in vitro and in vivo experimental evidence demonstrates the promising capabilities of BAMs in biomedical applications. This approach shows promise for advancing minimally invasive medical interventions and targeted therapeutic delivery. Editor's summary: Microrobots offer several opportunities in medicine for the diagnosis and treatment of various complications. However, there are several challenges related to their efficacy and ability to be detected in real time when deployed within the body. Han et al. have now developed bioresorbable acoustic microrobots that can be propelled acoustically and magnetically to tissues of interest and used for real-time ultrasound imaging and delivery of therapeutics. The gas-filled acoustic microrobots were used in vivo in a murine bladder tumor model and demonstrated the potential to support real-time imaging and delivery of anticancer drugs to the diseased tissue, resulting in the reduction in tumor size. —Amos Matsiko [ABSTRACT FROM AUTHOR]

Choosing a liquid chromatography (LC) column for a particular application can be a surprisingly challenging task. On one hand, column manufacturers give us many options to choose from, including particle types, pore sizes, particle sizes, and different lengths and diameters. On the other hand, we usually don't have time to experimentally evaluate many combinations of these parameters, and sometimes we end up picking something similar to the columns that are already in the drawer. The 'kinetic plot' is a powerful graphical tool that can help leverage the best available theory to help us understand how different combinations of parameters (that is, particle size and length) will perform in terms of the time needed to get to a particular column efficiency (and thus resolution), and therefore make well-informed decisions when choosing columns., In the last two installments of 'LC Troubleshooting,' we reviewed the basic idea of a 'kinetic plot' (1) and how to make the plots from experimental data or data from [...]

Abstract The copper‐catalyzed electrochemical CO2 reduction reaction represents an elegant pathway to reduce CO2 emissions while producing a wide range of valuable hydrocarbons. The selectivity for these products depends strongly on the structure and morphology of the copper catalyst. However, continued deactivation during catalysis alters the obtained product spectrum. In this work, we report on the stabilizing effect of three different carbon supports with unique pore structures. The influence of pore structure on stability and selectivity was examined by high‐angle annular dark field scanning transmission electron microscopy and gas chromatography measurements in a micro‐flow cell. Supporting particles into confined space was found to increase the barrier for particle agglomeration during 20 h of chronopotentiometry measurements at 100 mA cm−2 resembling long‐term CO2 reduction conditions. We propose a catalyst design preventing coalescence and agglomeration in harsh electrochemical reaction conditions, exemplarily demonstrated for the electrocatalytic CO2 reduction. With this work, we provide important insights into the design of stable CO2 electrocatalysts that can potentially be applied to a wide range of applications.

In micro-densitometry of wood it is standard procedure to extract resin and other soluble compounds before X-ray analysis to eliminate the influence of these extractives on wood-density. Dendrochemical studies using X-ray fluorescence analysis on the other hand are commonly conducted without previous extraction. However, it is well known that translocation processes of elements during heartwood formation in trees or (temporal) differences in sap content of wood samples can influence dendrochemical element profiles. This might bias environmental signals stored in time series of element concentrations in wood proxies. We hypothesize that metals tightly bound to cell walls show a more robust proxy potential for environmental conditions than easily translocated ones. To eliminate the noise of these soluble substances in wood elemental time series, their extraction prior to analysis might be necessary. In our study we tested the effect of different solvents (water, alcohol, and acetone) and different extraction times on elemental time series of three tree species with differing wood structure (Pinus sylvestris; Quercus robur and Populus tremula). Micro-XRF analysis was conducted on nine replicates per species using an ITRAX-Multiscanner. A set of elements commonly detected in wood (S, Cl, K, Ca, Ti, Mn, Fe, and Ni) was analysed at high resolution before and after several extraction runs. Besides lowering their levels, extraction did not significantly change the temporal trends for most elements. However, for some elements, e.g., Potassium, Chlorine or Manganese, especially the water extraction led to significant decreases in concentrations and altered temporal trends. Apparently the dipole effect of water produced the strongest extraction power of all three solvents. In addition we observed a dependency of extraction intensity from wood density which differed between wood types. Our results help in interpreting and evaluating element profiles and mark a step forward in establishing dendrochemistry as a robust proxy in dendro-environmental research.

Dowsett and colleagues used a genome-wide association approach to investigate the genetic influence on soluble urokinase-type plasminogen activator receptor presence in the plasma of humans. Their findings indicate a 60% heritability factor in British twins, and using a wide sample of Northern European genome samples they identify eleven genetic loci associated with an increase or decrease of this chronic inflammation marker.

Tree rings are a crucial archive for Common Era climate reconstructions, but the degree to which methodological decisions influence outcomes is not well known. Here, the authors show how different approaches taken by 15 different groups influence the ensemble temperature reconstruction from the same data.

Tree-ring records constitute excellent high-resolution data and provide valuable information for climate science and paleoclimatology. Tree-ring reconstructions of past temperature variations agree to show evidence for annual-to-centennial anomalies in past climate and place the industrial-era warming in the context of the late Holocene climate patterns and regimes. Despite their wide use in paleoclimate research, however, tree rings have also been deemed unsuitable as low-frequency indicators of past climate. The arising debate concerns whether the millennia-long tree-ring records show signals of orbital forcing due to the Milankovitch cycles. Here, we produce a summer-temperature reconstruction from tree-ring chronology running through mid- and late-Holocene times (since 5486 BCE) comprising minimum blue channel light intensity (BI). The BI reconstruction correlates with existing and new tree-ring chronologies built from maximum latewood density (MXD) and, unlike the MXD data, shows temperature trends on Milankovitch scales comparable to various types of sedimentary proxy across the circumpolar Arctic. Our results demonstrate an unrevealed potential of novel, unconventional tree-ring variables to contribute to geoscience and climate research by their capability to provide paleoclimate estimates from inter-annual scales up to those relevant to orbital forcing.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended for various conditions in cattle. Ibuprofen is an inexpensive short-acting NSAID and is readily available in liquid formulation for administration to bottle-fed calves. We compared the adverse effects of a 10-day course of ibuprofen and placebo in 16 five- to six-week-old Holstein bull calves that were being treated for experimentally induced bovine respiratory syncytial virus infection. Ibuprofen was administered as a liquid in milk replacer at 30 mg/kg divided three times daily. We found an increased prevalence of abomasal ulceration 5 of 8 in the ibuprofen compared to placebo group 2 of 6 (P = NS). There was one (1 of 8) case of mild interstitial nephritis in the ibuprofen and none (0 of 8) in the placebo group (P = NS). Renal function as measured by serum BUN and creatinine levels was not different between groups; no animal demonstrated an increase in creatinine.

Abstract The feeding behavior of the giant ambush-predator “Bobbit worm” (Eunice aphroditois) is spectacular. They hide in their burrows until they explode upwards grabbing unsuspecting prey with a snap of their powerful jaws. The still living prey are then pulled into the sediment for consumption. Although predatory polychaetes have existed since the early Paleozoic, their bodies comprise mainly soft tissue, resulting in a very incomplete fossil record, and virtually nothing is known about their burrows and behavior beneath the seafloor. Here we use morphological, sedimentological, and geochemical data from Miocene strata in northeast Taiwan to erect a new ichnogenus, Pennichnus. This trace fossil consists of an up to 2 m long, 2–3 cm in diameter, L-shaped burrow with distinct feather-like structures around the upper shaft. A comparison of Pennichnus to biological analogs strongly suggests that this new ichnogenus is associated with ambush-predatory worms that lived about 20 million years ago.

Glacial extent and mass balance are sensitive climate proxies providing solid information on past climatic conditions. However, series of annual mass-balance measurements of more than 60 years are scarce. To our knowledge, this is the first time the latewood density data (MXD) of the Swiss stone pine (Pinus cembra L.) have been used to reconstruct the summer mass balance (Bs) of an Alpine glacier. The MXD-based Bs well correlates with a Bs reconstruction based on the May to September temperature. Winter precipitation has been used as an independent proxy to infer the winter mass balance and to obtain an annual mass-balance (Bn) estimate dating back to the glaciological year 1811/12. The reconstructed MXD/precipitation-based Bn well correlates with the data both of the Careser and of other Alpine glaciers measured by the glaciological method. A number of critical issues should be considered in both proxies, including non-linear response of glacial mass balance to temperature, bedrock topography, ice thinning and fragmentation, MXD acquisition and standardization methods, and finally the ‘divergence problem’ responsible for the recently reduced sensitivity of the dendrochronological data. Nevertheless, our results highlight the possibility of performing MXD-based dendroglaciological reconstructions using this stable and reliable proxy.