Real-world evidence from the Global aHUS Registry confirms the safety and effectiveness of switching to ravulizumab from eculizumab in patients with aHUS: a plain language summary

Registry; Atypical hemolytic uremic syndrome; RavulizumabRegistre; Síndrome hemolític urèmic atípic; RavulizumabRegistro; Síndrome hemolítico urémico atípico; RavulizumabWhat is aHUS? Atypical hemolytic uremic syndrome (aHUS) is a rare disease that is caused by tiny blood clots that can block small blood vessels in the body, especially in the kidneys. This happens when a part of the immune system, called the complement system, becomes overactive. What are ravulizumab and eculizumab? Ravulizumab and eculizumab are approved treatments that help to prevent overactivity of the complement system by blocking a protein called complement component C5. Ravulizumab is derived from eculizumab and works immediately to block C5. It also lasts longer than eculizumab so can be given less often (every 4–8 weeks compared with every 2 weeks with eculizumab). What is the current gap in knowledge in aHUS? There are limited data on how well ravulizumab works to treat aHUS based on real-life patient experiences. What did this study look at? This article describes a study on the real-world safety and effectiveness of ravulizumab in patients with aHUS who switched from eculizumab, using data from the Global aHUS Registry, which has been collecting information since April 2012. Who was involved in the study? The study included 60 patients (43 adults and 17 children) who switched to ravulizumab from eculizumab, including 15 who received a kidney transplant before starting ravulizumab treatment. What were the safety results? Overall, 13 patients experienced an unwanted reaction or side effect after ravulizumab treatment, but none of these were unexpected by their doctors. Three of these reactions (fatigue and headache in 1 patient and infusion reaction in another patient) were thought to be related to ravulizumab treatment. There were no cases of meningococcal infection (a serious bacterial infection that may be related to treatment with either ravulizumab, eculizumab or another treatment that affects the complement system) or deaths during treatment. What were the effectiveness results? A subset of patients (49 out of 60) was eligible for the effectiveness analyses. These were patients who were treated with ravulizumab long enough to assess how well it works and who had a short time gap between switching to ravulizumab from eculizumab. No patient required dialysis or kidney transplantation while receiving ravulizumab. Markers of disease measured by blood tests were stable after switching to ravulizumab from eculizumab. What do the results mean? The study provides real-world evidence that ravulizumab is safe and works in patients with aHUS after switching from eculizumab.The Global aHUS Registry is sponsored by Alexion, AstraZeneca Rare Disease. This plain language summary was sponsored by Alexion, AstraZeneca Rare Disease

An apoplastic peptide signal activates salicylic acid signalling in maize

Control of plant pathogen resistance or susceptibility largely depends on the promotion of either cell survival or cell death. In this context, papain-like cysteine proteases (PLCPs) regulate plant defence to drive cell death and protection against biotrophic pathogens. In maize (Zea mays), PLCPs are crucial in the orchestration of salicylic acid (SA)-dependent defence signalling. Despite this central role in immunity, it remains unknown how PLCPs are activated, and which downstream signals they induce to trigger plant immunity. Here, we present the discovery of an immune signalling peptide, Zea mays immune signalling peptide 1 (Zip1). A mass spectrometry approach identified the Zip1 peptide being produced after salicylic acid (SA) treatment. In vitro studies using recombinant proteins demonstrate that PLCPs are required to release bioactive Zip1 from its propeptide precursor (PROZIP1). Strikingly, Zip1 treatment strongly elicits SA accumulation in maize leaves. Moreover, RNAseq based transcriptome analyses revealed that Zip1 and SA treatments induce highly overlapping transcriptional changes. Consequently, Zip1 promotes the infection of the necrotrophic pathogen Botrytis cinerea in maize, while it reduces virulence of the biotrophic fungus Ustilago maydis. Together, Zip1 represents the previously missing signal that is released by PLCPs to activate SA defence signalling

HUS and atypical HUS

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. HUS is usually categorized as typical, caused by Shiga toxin-producing Escherichia coli (STEC) infection, as atypical HUS (aHUS), usually caused by uncontrolled complement activation, or as secondary HUS with a coexisting disease. In recent years, a general understanding of the pathogenetic mechanisms driving HUS has increased. Typical HUS (ie, STEC-HUS) follows a gastrointestinal infection with STEC, whereas aHUS is associated primarily with mutations or autoantibodies leading to dysregulated complement activation. Among the 30% to 50% of patients with HUS who have no detectable complement defect, some have either impaired diacylglycerol kinase epsilon (DGK epsilon) activity, cobalamin C deficiency, or plasminogen deficiency. Some have secondary HUS with a coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs, or pregnancy. The common pathogenetic features in STEC-HUS, aHUS, and secondary HUS are simultaneous damage to endothelial cells, intravascular hemolysis, and activation of platelets leading to a procoagulative state, formation of microthrombi, and tissue damage. In this review, the differences and similarities in the pathogenesis of STEC-HUS, aHUS, and secondaryHUSare discussed. Commonfor the pathogenesis seems to be the vicious cycle of complement activation, endothelial cell damage, platelet activation, and thrombosis. This process can be stopped by therapeutic complement inhibition in most patients with aHUS, but usually not those with a DGK epsilon mutation, and some patients with STEC-HUS or secondary HUS. Therefore, understanding the pathogenesis of the different forms of HUS may prove helpful in clinical practice.Peer reviewe

Global aHUS Registry Analysis of Patients Switching to Ravulizumab From Eculizumab

Síndrome hemolítico urémico atípico; Eculizumab; ResultadosAtypical hemolytic uremic syndrome; Eculizumab; OutcomesSíndrome hemolític urèmica atípica; Eculizumab; ResultatsIntroduction Atypical hemolytic uremic syndrome (aHUS) is a progressive rare disease that, if untreated, can result in severe organ damage and death. Ravulizumab, a next-generation terminal complement inhibitor, provides immediate, complete, and sustained complement C5 inhibition. Real-world data in patients with aHUS who switched to ravulizumab from eculizumab are lacking. Methods The Global aHUS Registry is a multicenter study (NCT01522183) collecting data on adult or pediatric patients with an aHUS diagnosis, regardless of treatment. Patient characteristics, genetic data, hematological and renal parameters, clinical events (e.g., dialysis and kidney transplantation), and adverse events (AEs) were extracted from patients who switched to ravulizumab from eculizumab up to July 3, 2023. Results Overall, 60 patients switched to ravulizumab (adult: n = 43; pediatric: n = 17); 11 patients were excluded from effectiveness and genetic analyses (N = 49; adult: n = 40; pediatric: n = 9) because they received 1 month between eculizumab discontinuation and ravulizumab initiation. Pathogenic complement variants were identified in 11 of 49 patients (22%); the most common was a complement factor H variant (n = 5/49 [10%]). During ravulizumab treatment, 20 AEs occurred in 13 patients, with no unexpected AEs and only 3 treatment-related AEs (infusion reaction, headaches, and fatigue). No meningococcal infections or deaths were reported. No new events of dialysis, kidney transplantation, or thrombotic microangiopathy were reported. Renal and hematological parameters remained stable after switching to ravulizumab. Conclusion This is the first real-world cohort analysis of data from patients treated with ravulizumab and reinforces the real-world safety and effectiveness data of ravulizumab in patients with aHUS who switched from eculizumab

Identification of Conserved and HLA Promiscuous DENV3 T-Cell Epitopes

Anti-dengue T-cell responses have been implicated in both protection and immunopathology. However, most of the T-cell studies for dengue include few epitopes, with limited knowledge of their inter-serotype variation and the breadth of their human leukocyte antigen (HLA) affinity. In order to expand our knowledge of HLA-restricted dengue epitopes, we screened T-cell responses against 477 overlapping peptides derived from structural and non-structural proteins of the dengue virus serotype 3 (DENV3) by use of HLA class I and II transgenic mice (TgM): A2, A24, B7, DR2, DR3 and DR4. TgM were inoculated with peptides pools and the T-cell immunogenic peptides were identified by ELISPOT. Nine HLA class I and 97 HLA class II novel DENV3 epitopes were identified based on immunogenicity in TgM and their HLA affinity was further confirmed by binding assays analysis. A subset of these epitopes activated memory T-cells from DENV3 immune volunteers and was also capable of priming naïve T-cells, ex vivo, from dengue IgG negative individuals. Analysis of inter- and intra-serotype variation of such an epitope (A02-restricted) allowed us to identify altered peptide ligands not only in DENV3 but also in other DENV serotypes. These studies also characterized the HLA promiscuity of 23 HLA class II epitopes bearing highly conserved sequences, six of which could bind to more than 10 different HLA molecules representing a large percentage of the global population. These epitope data are invaluable to investigate the role of T-cells in dengue immunity/pathogenesis and vaccine design. © 2013 Nascimento et al

Whole-body tissue stabilization and selective extractions via tissue-hydrogel hybrids for high-resolution intact circuit mapping and phenotyping

To facilitate fine-scale phenotyping of whole specimens, we describe here a set of tissue fixation-embedding, detergent-clearing and staining protocols that can be used to transform excised organs and whole organisms into optically transparent samples within 1–2 weeks without compromising their cellular architecture or endogenous fluorescence. PACT (passive CLARITY technique) and PARS (perfusion-assisted agent release in situ) use tissue-hydrogel hybrids to stabilize tissue biomolecules during selective lipid extraction, resulting in enhanced clearing efficiency and sample integrity. Furthermore, the macromolecule permeability of PACT- and PARS-processed tissue hybrids supports the diffusion of immunolabels throughout intact tissue, whereas RIMS (refractive index matching solution) grants high-resolution imaging at depth by further reducing light scattering in cleared and uncleared samples alike. These methods are adaptable to difficult-to-image tissues, such as bone (PACT-deCAL), and to magnified single-cell visualization (ePACT). Together, these protocols and solutions enable phenotyping of subcellular components and tracing cellular connectivity in intact biological networks

Effectiveness and Safety of Switching to Ravulizumab From Eculizumab in Kidney Transplant Recipients With Atypical Hemolytic Uremic Syndrome:A Global aHUS Registry Analysis

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation that may lead to kidney failure. Ravulizumab and eculizumab are complement C5 inhibitors approved for the treatment of aHUS. This study assessed the real-world effectiveness and safety of switching to ravulizumab from eculizumab in kidney transplant recipients with aHUS. Methods: The Global aHUS Registry is a multicenter study enrolling patients with aHUS since 2012. Effectiveness and safety outcomes were assessed in kidney transplant recipients with aHUS who switched to ravulizumab from eculizumab up to September 2, 2024. Results: Overall, 38 patients received a kidney transplant before ravulizumab initiation; 27 patients with ≥3 months of ravulizumab treatment were included in the patient characteristics and effectiveness analyses. Median (range) time on eculizumab and ravulizumab treatment was 66.1 (3.7, 158.3) and 24.1 (4.2, 49.3) months, respectively (n = 27); time from last kidney transplantation to ravulizumab initiation was 65.9 (3.7, 184.0) months. Following ravulizumab initiation, laboratory parameters remained stable, and no kidney transplant rejections/graft failures were reported. In the safety analysis (n = 38), 23 adverse events were reported in 19 patients (50.0%) at or after ravulizumab initiation, and none were considered treatment-related. No new events of thrombotic microangiopathy or kidney impairment and no meningococcal infections or deaths were reported. Conclusion: This analysis from the Global aHUS Registry provides real-world evidence to demonstrate that the transition to ravulizumab from eculizumab in kidney transplant recipients with aHUS is successful, with stable graft function with no treatment-related safety concerns. Trial Registration: ClinicalTrials.gov identifier: NCT01522183.</p

Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy. European Society of Human Genetics and European Society of Human Reproduction and Embryology.

In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation - ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide an update of selected topics that have evolved since 2005