Search

Background: Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update. Methods: Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations. Results: Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4-5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV. Conclusions: In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance. © Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.

Introduction: Patients with immune-mediated glomerular diseases are considered at high risk for severe COVID-19 outcomes. However, conclusive evidence for this patient population is scarce.Methods: We created a global registry and retrospectively collected clinical data of patients with COVID-19 and a previously diagnosed immune-mediated glomerular disease to characterize specific risk factors for severe COVID-19 outcomes.Results: Fifty-nine patients with a history of immune-mediated glomerular diseases were diagnosed with COVID-19 between 01.03.2020 and 31.08.2021. Over a mean follow-up period of 24.79 +/- 18.89 days, ten patients (16.9%) developed acute kidney injury. Overall, 44.1% of patients were managed in an outpatient setting and therefore considered as having "non-severe" COVID-19, while 55.9% of patients had severe COVID-19 requiring hospitalization including worse outcomes. Comparing both groups, patients with severe COVID-19 were significantly older (53.55 +/- 17.91 versus 39.77 +/- 14.95 years, p = .003), had lower serum albumin levels at presentation (3.00 +/- 0.80 g/dL versus 3.99 +/- 0.68 g/dL, p = .016) and had a higher risk of developing acute kidney injury (27% versus 4%, p = .018). Male sex (p <.001) and ongoing intake of corticosteroids at presentation (p = .047) were also significantly associated with severe COVID-19 outcomes, while the overall use of ongoing immunosuppressive agents and glomerular disease remission status showed no significant association with the severity of COVID-19 (p = .430 and p = .326, respectively).Conclusion: Older age, male sex, ongoing intake of corticosteroids and lower serum albumin levels at presentation were identified as risk factors for severe COVID-19 outcomes in patients with a history of various immune-mediated glomerular diseases., Funding Agencies|The authors thank Lalit Kaltenbach for his support with the creation and administration of the REDCap database.

Updated guidelines on the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were released in 2021 by the American College of Rheumatology jointly with the Vasculitis Foundation and, subsequently, in 2022 by the European Alliance of Associations for Rheumatology. In addition, in 2021, the Kidney Disease: Improving Global Outcomes had released updated recommendations on the treatment of AAV with glomerulonephritis (AAV-GN). Kidney involvement is particularly relevant in microscopic polyangiitis and granulomatosis with polyangiitis, but is less frequent in eosinophilic granulomatosis with polyangiitis. The management of AAV-GN has been a focus for drug development and change over the past 10 years. Avoidance of progression to end-stage kidney disease (ESKD) or kidney failure is one of the main unmet needs in the management of AAV, with ESKD having a major impact on morbidity, health costs and mortality risk. Relevant changes in AAV-GN management are related to remission-induction treatment of patients with severe kidney disease, the use of glucocorticoids and avacopan, and remission-maintenance treatment. All the documents provide guidance in accordance with the evidence-based standard of care available at the time of their release. With our work we aim to (i) show the progress made and identify the differences between guidelines and recommendations, (ii) discuss the supporting rationale for those, and (iii) identify gaps in knowledge that could benefit from additional research and should be revised in subsequent updates.

We present an implementation of a stage-parallel preconditioner for Radau IIA type fully implicit Runge–Kutta methods, which approximates the inverse of the Runge–Kutta matrix AQ from the Butcher tableau by the lower triangular matrix resulting from an LU decomposition and diagonalizes the system with as many blocks as stages. For the transformed system, we employ a block preconditioner where each block is distributed and solved by a subgroup of processes in parallel. For combination of partial results, we use either a communication pattern resembling Cannon’s algorithm or shared memory. A performance model and a large set of performance studies (including strong-scaling runs with up to 150k processes on 3k compute nodes) conducted for a time-dependent heat problem, using matrix-free finite element methods, indicate that the stage-parallel implementation can reach higher throughputs near the scaling limit. The achievable speedup increases linearly with the number of stages and is bounded by the number of stages. Furthermore, we show that the presented stage-parallel concepts are also applicable to the case that AQ is directly diagonalized, which requires either complex arithmetic or solutions of two-by-two blocks, both exposing about half the parallelism. Alternatively to distributing stages and assigning them to distinct processes, we discuss the possibility of batching operations from different stages together., eSSENCE - An eScience Collaboration

Approximately 75% of the raw material and 50% of the products in the chemical industry are granular materials. The discrete element method (DEM) provides detailed insights of phenomena at particle scale, and it is therefore often used for modeling granular materials. However, because DEM tracks the motion and contact of individual particles separately, its computational cost increases nonlinearly O (n(p) log(n(p))) - O (n(2)) (depending on the algorithm) with the number of particles (n(p)). In this article, we introduce a new open-source parallel DEM software with load balancing: Lethe-DEM. Lethe-DEM, a module of Lethe, consists of solvers for two-dimensional and three-dimensional DEM simulations. Load balancing allows LetheDEM to significantly increase the parallel efficiency by approximate to 25-70% depending on the granular simulation. We explain the fundamental modules of Lethe-DEM, its software architecture, and the governing equations. Furthermore, we verify LetheDEM with several tests including analytical solutions and comparison with other software. Comparisons with experiments in a flat-bottomed silo, wedge-shaped silo, and rotating drum validate Lethe-DEM. We investigate the strong and weak scaling of Lethe-DEM with 1 <= n(c) <= 192 and 32 <= n(c) <= 320 processes, respectively, with and without load balancing. The strong-scaling analysis is performed on the wedge-shaped silo and rotating drum simulations, while for the weak-scaling analysis, we use a dam-break simulation. The best scalability of Lethe-DEM is obtained in the range of 5000 <= n(p)/n(c) <= 15,000. Finally, we demonstrate that large-scale simulations can be carried out with Lethe-DEM using the simulation of a three-dimensional cylindrical silo with n(p) = 4.3 x 10(6) on 320 cores., eSSENCE - An eScience Collaboration

This work studies three multigrid variants for matrix-free finite-element computations on locally refined meshes: geometric local smoothing, geometric global coarsening (both h-multigrid), and polynomial global coarsening (a variant of p-multigrid). We have integrated the algorithms into the same framework-the open source finite-element library deal.II-, which allows us to make fair comparisons regarding their implementation complexity, computational efficiency, and parallel scalability as well as to compare the measurements with theoretically derived performance metrics. Serial simulations and parallel weak and strong scaling on up to 147,456 CPU cores on 3,072 compute nodes are presented. The results obtained indicate that global-coarsening algorithms show a better parallel behavior for comparable smoothers due to the better load balance, particularly on the expensive fine levels. In the serial case, the costs of applying hanging-node constraints might be significant, leading to advantages of local smoothing, even though the number of solver iterations needed is slightly higher. When using p- and h-multigrid in sequence (hp-multigrid), the results indicate that it makes sense to decrease the degree of the elements first from a performance point of view due to the cheaper transfer., eSSENCE - An eScience Collaboration

Lay Summary This review focuses on kidney survival of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Impaired kidney function is a major contributor to morbidity and mortality. In this review we discuss current knowledge about recovery potential of the kidney, influences thereof and how future modern approaches may help to improve prediction. This will eventually include kidney biopsies, markers measured in blood and urine and baseline characteristics of patients. Avoiding end-stage kidney disease in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has a high therapeutic priority. Although renal response is a crucial measure to capture clinically relevant changes, clinal trials have used various definitions and no well-studied key surrogate markers to predict renal outcome in AAV exist. Differences in clinical features and histopathologic and therapeutic approaches will influence the course of kidney function. Its assessment through traditional surrogates (i.e. serum creatinine, glomerular filtration rate, proteinuria, hematuria and disease activity scores) has limitations. Refinement of these markers and the incorporation of novel approaches such as the assessment of histopathological changes using cutting-edge molecular and machine learning mechanisms or new biomarkers could significantly improve prognostication. The timing is favourable since large datasets of trials conducted in AAV are available and provide a valuable resource to establish renal surrogate markers and, likely, aim to investigate optimized and tailored treatment approaches according to a renal response score. In this review we discuss important points missed in the assessment of kidney function in patients with AAV and point towards the importance of defining renal response and clinically important short- and long-term predictors of renal outcome., Funding Agencies|Austrian Science Fund [J 4664-B]; Wellcome Trust; Health Research Board [203930/B/16/Z]; Health Service Executive, National Doctors Training and Planning; Health and Social Care, Research and Development Division, Northern Ireland

We present an efficient solver for the simulation of many-particle solid-state-sintering processes. The microstructure evolution is described by a system of equations consisting of one Cahn–Hilliard equation and a set of Allen-Cahn equations to distinguish neighboring particles. The particle packing is discretized in space via multicomponent linear adaptive finite elements and implicitly in time with variable time-step sizes, resulting in a large nonlinear system of equations with strong coupling between all components to be solved. Since on average 10k degrees of freedom per particle are necessary to accurately capture the interface dynamics in 3D, we propose strategies to solve the resulting large and challenging systems. This includes the efficient evaluation of the Jacobian matrix as well as the implementation of Jacobian-free methods by applying state-of-the-art matrix-free algorithms for high and dynamic numbers of components, advances regarding preconditioning, and a fully distributed grain-tracking algorithm. We validate the obtained results, examine in detail the node-level performance and demonstrate the scalability up to 10k particles on modern supercomputers. Such numbers of particles are sufficient to simulate the sintering process in (statistically meaningful) representative volume elements. Our framework thus forms a valuable tool for the virtual design of solid-state-sintering processes for pure metals and their alloys.

The coronavirus disease 2019 (COVID-19) pandemic revealed that our understanding of infectious complications and strategies to mitigate severe infections in patients with glomerular diseases is limited. Beyond COVID-19, there are several infections that specifically impact care of patients receiving immunosuppressive measures. This review will provide an overview of six different infectious complications frequently encountered in patients with glomerular diseases, and will focus on recent achievements in terms of vaccine developments and understanding of the use of specific antimicrobial prophylaxis. These include influenza virus, Streptococcus pneumoniae, reactivation of a chronic or past infection with hepatitis B virus in cases receiving B-cell depletion, reactivation of cytomegalovirus, and cases of Pneumocystis jirovecii pneumonia in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Varicella zoster virus infections are particularly frequent in patients with systemic lupus erythematosus and an inactivated vaccine is available to use as an alternative to the attenuated vaccine in patients receiving immunosuppressants. As with COVID-19 vaccines, vaccine responses are generally impaired in older patients, and after recent administration of B-cell depleting agents, and high doses of mycophenolate mofetil and other immunosuppressants. Strategies to curb infectious complications are manifold and will be outlined in this review., Funding Agencies|Marato TV3 [215/C/2021]

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic led to rapid vaccine development and large global vaccination schemes. However, patients with immune-mediated kidney disease, chronic kidney diseases and kidney transplant recipients show high non-response rates to vaccination despite more than three vaccinations and, consequently, reduced viral clearance capacity when infected while receiving certain immunosuppressants, carrying an elevated risk for coronavirus disease 2019 (COVID-19)-related morbidity and mortality. SARS-CoV-2 evolution has been characterized by the emergence of novel variants and spike mutations contributing to waning efficacy of neutralizing antibodies. To this end, the therapeutic field expands from vaccination towards a combined approach of immunization, pre-exposure prophylaxis and early post-exposure treatment using direct-acting antivirals and neutralizing monoclonal antibodies to treat early in the disease course and avoid hospitalization. This expert opinion paper from the Immunonephrology Working Group of the European Renal Association (ERA-IWG) summarizes available prophylactic and/or early treatment options (i.e. neutralizing monoclonal antibodies and direct-acting antivirals) of SARS-CoV-2-infected patients with immune-mediated kidney disease, chronic kidney disease and kidney transplant recipients.

This article proposes a novel high-performance computing approach for the prediction of the temperature field in powder bed fusion (PBF) additive manufacturing processes. In contrast to many existing approaches to part-scale simulations, the underlying computational model consistently resolves physical scan tracks without additional heat source scaling, agglomeration strategies or any other heuristic modeling assumptions. A growing, adaptively refined mesh accurately captures all details of the laser beam motion. Critically, the fine spatial resolution required for resolved scan tracks in combination with the high scan velocities underlying these processes mandates the use of comparatively small time steps to resolve the underlying physics. Explicit time integration schemes are well-suited for this setting, while unconditionally stable implicit time integration schemes are employed for the interlayer cool down phase governed by significantly larger time scales. These two schemes are combined and implemented in an efficient fast operator evaluation framework providing significant performance gains and optimization opportunities. The capabilities of the novel framework are demonstrated through realistic AM examples on the centimeter scale including the first scan-resolved simulation of the entire NIST AM Benchmark cantilever specimen, with a computation time of less than one day. Apart from physical insights gained through these simulation examples, also numerical aspects are thoroughly studied on basis of weak and strong parallel scaling tests. As potential applications, the proposed thermal PBF simulation framework can serve as a basis for microstructure and thermo-mechanical predictions on the part-scale, but also to assess the influence of scan pattern and part geometry on melt pool shape and temperature, which are important indicators for well-known process instabilities.

In 2019 and 2021, the European League for Rheumatism (EULAR) jointly with the European Renal Association (ERA) and the Kidney Disease: Improving Global Outcomes (KDIGO), respectively, released updated guidelines on the management of lupus nephritis (LN). The Immunology Working Group of the ERA reviewed and compared both updates. Recommendations were either consistent or differences were of negligible clinical relevance for: indication for kidney biopsy, kidney biopsy interpretation, treatment targets, hydroxychloroquine dosing, first-line initial immunosuppressive therapy for active class III, IV (+/- V) LN, pregnancy in LN, LN in paediatric patients and LN patients with kidney failure. Relevant differences in the recommended management relate to the recognition of lupus podocytopathies, uncertainties in steroid dosing, drug preferences in specific populations and maintenance therapy, treatment of pure class V LN, therapy of recurrent LN, evolving alternative drug options and diagnostic work-up of thrombotic microangiopathy. Altogether, both documents provide an excellent guidance to the growing complexity of LN management. This article endeavours to prevent confusion by identifying differences and clarifying discrepancies., Funding Agencies|Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [AN372/29-1, 30-1]