Nephrologisches Zentrum Villingen-Schwenningen

Abstract Vaccines capable of eliciting broadly neutralising antibodies (bnAbs) are a major goal for pandemic preparedness. A persistent challenge across vaccine Wields is how to deliberately recruit the rare B cell clones that recognise conserved epitopes shared across diverse viral variants. BnAbs have been known to frequently emerge through extensive somatic hypermutation during afWinity maturation, here we describe an alternative, structure-driven mechanism for bnAb selection. We designed an mRNA vaccine in which two antigenically distinct SARS-CoV-2 variant’s (Omicron and Delta; O-Δ) receptor binding domains (RBDs) are physically fused on a single polypeptide. This design is predicted to favour B cell antigen receptors capable of engaging conserved epitopes on both RBDs with enhanced avidity. A matched non-divergent tandem RBD (Delta-Delta; Δ-Δ) served as a control. The divergent (O-Δ) immunogen was robustly expressed and retained high-afWinity ACE2 binding. In mice, immunisation elicited potent antibody responses and increased the frequency of antigen-speciWic cross-reactive B cells, recognising Delta, Omicron, and the 2002 pandemic strain SARS-CoV RBDs. Using multicolour RBD tetramers and single-cell B cell receptor sequencing, we show that breadth arises via two distinct pathways. The divergent vaccine preferentially enriches clonally distinct cross-reactive B cells (not present within non-cross-reactive B cell pools) with low levels of somatic hypermutation (SHM), consistent with selection of germline-biased precursors. In contrast, the matched control vaccine yields cross-reactivity primarily within existing clonal lineages (clonal overlap between cross-reactive and non-cross-reactive cells) and at higher mutational burdens, consistent with afWinity-maturation-driven acquisition of breadth. Together, these Windings demonstrate that antigen structure can bias B cell selection towards cross-reactive speciWicities without requiring extensive SHM. This work establishes a simple, modular antigen-design principle in which juxtaposing appropriately divergent antigens on a single scaffold promotes the enrichment of bnAb-prone B cells, providing a scalable strategy for vaccine development against rapidly evolving pathogens.

ABSTRACTBackgroundChronic pain significantly impacts health-related quality of life (HRQOL) in patients with non-dialysis chronic kidney disease (ND-CKD), yet the management of pain in this population is challenging. We hypothesized that analgesic prescription practices vary internationally, influencing the pain experience and HRQOL of patients with stage 3–5 ND-CKD.MethodsThis descriptive, observational, multinational cohort study utilized data from the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps), enrolling adult patients from nephrology practices in Brazil, France and the USA between 2013 and 2020. Analgesic prescriptions within 6 months before HRQOL assessment were categorized as non-steroidal anti-inflammatory drugs (NSAIDs), opioids or other analgesics. HRQOL was measured using the Kidney Disease Quality of Life Short Form, assessing multiple subdomains.ResultsAmong 3945 patients, analgesics were most frequently prescribed in the USA across all CKD stages, with opioids prescribed nearly twice as often compared with Brazil and France. NSAIDs are frequently prescribed in Brazil, including in advanced CKD stages, contrasting sharply with practices in France and the USA. Higher reported pain intensity consistently correlated with poorer outcomes across all HRQOL subdomains.ConclusionsThis study identifies considerable international variability in pain reporting and analgesic prescription patterns in patients with stage 3–5 ND-CKD. Randomized controlled trials evaluating the efficacy and safety of analgesics are warranted to improve key patient-reported outcomes such as pain in patients with ND-CKD.

Abstract Background and Aims Chronic kidney disease (CKD) is a widespread and progressive global health issue affecting over 850 million people worldwide. It can lead to kidney failure, severely diminishing patients’ quality of life and imposing a significant burden on caregivers. Although various treatment options are available, there remains limited insight into how patients and carers make treatment choices and prioritise treatment attributes. This study aimed to investigate treatment preferences through a discrete choice experiment (DCE) conducted across eight countries, reflecting diverse regional contexts. The goal was to provide evidence that supports more patient-centred decision-making in CKD management. Method This large, multi-country, non-interventional cross-sectional study included CKD patients and carers at all stages of the disease, with a total of 2,324 participants—1,511 patients and 813 carers—across 8 countries: Australia, Egypt, Germany, Italy, Mexico, Taiwan, the UK, and the US. Participants were identified via online research panels and patient advocacy groups and were required to have personal or informal caregiving experience with CKD for at least three months. A minimum of 30% of respondents in each country were receiving dialysis. Data was collected between 2022 to 2024. The experiment presented participants with 7 hypothetical scenarios, each offering two unlabelled treatment options (Treatment A and Treatment B) and an option to opt out or to choose “neither”. Five treatment attributes were assessed: (1) delay in the need for dialysis or transplant; (2) life extension; (3) reduced risk of heart failure hospitalisation; (4) risk of side effects; and (5) monthly out-of-pocket costs. Data were analysed using mixed multinomial logit (MMNL) models. Patient and carer models were estimated for each country, resulting in 16 models. To make comparisons between countries, relative attribute importance was estimated by taking the maximum difference in utility between the attribute's levels and expressed as a percentage of the sum of all maximum differences. Results The study revealed diverse treatment preferences among patients and carers: Model results can be used for scenario analysis (mapping real treatment attributes to the model parameters) through a dashboard, enabling country comparisons of preference shares and predicted treatment uptake (comparison of treatments based on patient values, otherwise referred to as patient value mapping). Conclusion This research represents the largest DCE conducted to date on CKD treatment preferences, both in sample size and geographic representation. It provides valuable insights into how patients and carers prioritise treatment attributes in CKD management across diverse settings. Differences in preferences (represented as preference heterogeneity) suggests that patients and carers should be included in the process of shared decision-making to pursue treatments that are in line with patients’ goals and values. By addressing regional and individual variations in preferences, this research advances the understanding of patient-centred CKD care and highlights the need for further exploration of caregiver priorities, which remain under-researched.

BackgroundOral semaglutide at a dose of 25 mg may provide an alternative treatment option to injectable semaglutide (2.4 mg) and higher-dose oral semaglutide (50 mg) for persons with overweight or obesity.MethodsIn a 71-week, double-blind, randomized, placebo-controlled trial conducted at 22 sites in four countries, we enrolled persons without diabetes who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or higher or a BMI of 27 or higher with at least one obesity-related complication. The participants were randomly assigned in a 2:1 ratio to receive oral semaglutide (25 mg) or placebo once daily, plus lifestyle interventions. The coprimary end points at week 64 were the percent change in body weight and a reduction of 5% or more in body weight; confirmatory secondary end points included reductions in body weight of 10% or more, 15% or more, and 20% or more and the change in the Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL-Lite-CT) Physical Function score.ResultsA total of 205 participants were randomly assigned to receive oral semaglutide, and 102 to receive placebo. The estimated mean change in body weight from baseline to week 64 was −13.6% in the oral semaglutide group and −2.2% in the placebo group (estimated difference, −11.4 percentage points; 95% confidence interval, −13.9 to −9.0; P<0.001). Participants in the oral semaglutide group were significantly more likely than those in the placebo group to have body-weight reductions of 5% or more, 10% or more, 15% or more, and 20% or more (P<0.001 for all comparisons) and to have an improved IWQOL-Lite-CT Physical Function score (P<0.001). Gastrointestinal adverse events were more common with oral semaglutide than with placebo (74.0% vs. 42.2%).ConclusionsOral semaglutide at a dose of 25 mg once daily resulted in a greater mean reduction in body weight than placebo in participants with overweight or obesity. (Funded by Novo Nordisk; OASIS 4 ClinicalTrials.gov number, NCT05564117.)