Publications by Year: 2026

Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). However, it is known that other pathways independent of APOE also play a role in AD. Disentangling APOE-dependent and independent effects is instrumental for understanding the biology of AD. We conducted an APOE-stratified multi-omic analysis in multiple large datasets to identify AD-associated plasma proteins and metabolites. More than 64% of the identified proteins were not found in non-APOE stratified studies, and 17% of the proteins showed APOE-specific trends. Mitochondrial dysfunction was associated in AD independently of APOE and was accompanied by disruptions in glucose and lipid metabolism and cell death and increased in inflammatory signaling activation. Lipid upregulation was found in AD cases when compared with controls with the same APOE genotype, indicating that additional factors beyond APOE affect lipid regulation and AD risk. These findings may be informative in guiding the development of effective medications for AD.

KEY POINTS: In a large longitudinal study of predialysis CKD, plasma fibroblast growth factor 23 was stable in most of the children when modeled as linear trajectories over time Children with rapidly rising fibroblast growth factor 23 trajectories exhibited lower eGFR, higher serum phosphorus, proteinuria, and anemia compared with those with stable levels Longitudinal fibroblast growth factor 23 monitoring provides a powerful, independent predictor of kidney disease progression in children with CKD.

BACKGROUND: In children and adults, plasma fibroblast growth factor 23 (FGF23) concentrations increase early in CKD and associate with disease progression and adverse cardiovascular outcomes. However, longitudinal changes in FGF23 in children with progressive CKD are not well characterized.

METHODS: We measured c -terminal FGF23 biannually and eGFR in 543 children with CKD stages 2-4 enrolled in the CKD in children study. All participants had 2-3 FGF23 measurements. We used a linear mixed model to estimate the average percent change in FGF23 and eGFR over time for the overall cohort and latent group-based trajectory modeling to identify populations with distinct patterns of change in FGF23 concentration, eGFR, and phosphorus z -score. We used Cox proportional hazards model to examine the risk of progression to kidney failure according to FGF23 trajectory group.

RESULTS: At study enrollment, the median age was 12 years and eGFR 52 ml/min per 1.73 m 2 . In univariate models with repeated measures, FGF23 increased by a mean of 3.7% annually, and eGFR decreased by 3.8% annually over a median observation period of 4 years. We identified three distinct FGF23 trajectories: stable in 64% of participants (FGF23 slope 0% per year); slowly rising in 30% (slope 6% per year) and rapidly rising in 6% (slope 39% per year). Membership in the faster-rising trajectory groups was associated with lower eGFR, higher serum phosphorus, greater proteinuria, and anemia. With subsequent median 4.9 years of follow-up, the risk of kidney failure was 1.7-fold higher (95% confidence interval, 1.09 to 2.67) in the slowly rising and 8-fold higher (95% confidence interval, 2.41 to 23.56) in the rapidly rising FGF23 trajectory group compared with the stable trajectory group, in fully adjusted analyses. Phosphorus z -score trajectories did not associate with progression to kidney failure in adjusted models.

CONCLUSION: By characterizing longitudinal changes in FGF23 in children with CKD, we find that FGF23 was stable in most children. Membership in the faster-rising FGF23 trajectory groups associates with increased risk of progression to kidney failure. Future studies are needed to investigate whether FGF23 is a modifiable cause or a consequence of CKD progression in children with CKD.

Peer support is an effective strategy to promote self-management behaviors and improve well-being in those with cardiometabolic disease, including type 2 diabetes mellitus (T2DM). There is limited knowledge about stakeholder perceptions regarding peer support programs in low- and middle-income countries (LMICs). The study assessed stakeholders' awareness and understanding of peer support initiatives for T2DM, and explored their perceived barriers and readiness for implementation. A cross-sectional, self-administered online survey with branching logic was distributed to stakeholders across macro- (health policy), meso (tertiary hospital), and micro (community) levels of LMIC healthcare systems from June 1 to December 15, 2023. Quantitative data were analyzed descriptively; qualitative data underwent thematic content analysis. A total of 69 respondents from 25 LMICs participated in the survey. Due to branching logic and response attrition, 53 surveys (77%) had complete responses. Most respondents were medical doctors (n = 35, 50.7%) and a large proportion worked in tertiary hospitals (n = 27, 39.1%). Thirty-nine respondents (56.5%) were aware of peer support; among the 38 respondents with complete data, 29 (76%) reported active involvement in T2DM peer support initiatives. Of 15 responses to open-ended questionnaires regarding barriers to T2DM peer support, 9 (60%) cited concerns about limited resources and lack of funding. Local leadership (mean ± standard deviation: 3.4 ± 1.2), resource allocation (2.7 ± 1.4), and sustainability planning (2.7 ± 1.4) showed the highest perceived readiness on a 5-point Likert scale (1 = strongly disagree, 5 = strongly agree). Stakeholders in LMICs demonstrate awareness and active involvement in T2DM peer support programs. While limited resources and funding remain significant barriers, local leadership, resource allocation, and sustainability planning showed the highest perceived readiness, indicating promising foundations for implementation. Strengthening these areas through targeted support could facilitate the expansion and sustainability of peer support initiatives in resource-constrained settings.

Carotid sinus hypersensitivity (CSH) is commonly associated with elderly patients and underlying cardiovascular conditions. We present a rare case of cardiac arrest in a young, healthy female, occurring immediately after a jaw thrust maneuver during mask ventilation, due to carotid sinus compression and subsequent vagal stimulation. This case highlights the need to consider CSH as a cause of sudden intraoperative cardiac arrest, even in young patients without risk factors.

The treatment landscape of moderate-to-severe ulcerative colitis (UC) has diversified with the incorporation of Janus kinase inhibitors (JAKis) and interleukin (IL) antagonists. Upadacitinib, a selective JAK-1 inhibitor, and risankizumab, an inhibitor of the p19 subunit of IL-23, have demonstrated efficacy for UC in randomized trials.1,2 However, head-to-head comparisons of these therapies are needed to guide treatment positioning. We therefore compared the effectiveness and safety of upadacitinib and risankizumab in a real-world UC cohort.

Cardiac glycosides (CGs) such as ouabain exert positive inotropic effects by inhibiting the Na+-K+-ATPase. CGs' wide spread use is limited by CGs' narrow therapeutic window. Mis- or overdosing with CGs may cause cardiac arrhythmias, resulting from electrolyte disturbances. To study the ethically challenging topic of CG overdosing, we here optimized the in ovo platform to test whether treatment with the selective ouabain antagonist rostafuroxin prevents CG-mediated electrophysiological derangements and arrhythmia by restoring electrolyte homeostasis. We used incubated chicken eggs (iCEs), a 3 R-compliant model, for which we established electrocardiograms (ECGs). ECGs were recorded under 1) baseline conditions, 2) after treatment with ouabain, and 3) after cotreatment with rostafuroxin. Underlying mechanisms of ouabain and rostafuroxin effects were studied using blood gas analysis and fluorescence microscopy. Isolated murine and human cardiomyocytes served as an independent model to confirm in ovo results. Ouabain treatment resulted in increased heart rate variability (HRV), transient sinus arrest, and atrio-ventricular dyssynchrony, accompanied by plasma hyperkalemia and cardiomyocyte Na+ overload. Cotreatment of ouabain and rostafuroxin led to reduced HRV and ameliorated the frequency and duration of transient sinus arrest, whereas plasma K+ levels remained unchanged. In isolated cardiomyocytes, ouabain treatment induced intracellular Na+ overload, which was abolished by additional rostafuroxin treatment. Our work demonstrates the in ovo platform and corresponding readouts as a suitable tool to study cardiac electrophysiology in a 3 R-compliant manner. We found that rostafuroxin treatment ameliorated ouabain-induced electrophysiological disturbances, suggesting rostafuroxin as a potential therapeutic intervention for ouabain mis- or overdosing.NEW & NOTEWORTHY This study evaluates rostafuroxin, a selective ouabain inhibitor, for its potential to antagonize electrophysiological derangements in ouabain overdosing. Methodologically, the study uses the iCE model, previously introduced as a suitable 3 R-compliant cardiovascular research platform. We developed and validated a comprehensive electrophysiological workflow in iCEs to perform our investigations. Ouabain increased heart rate variability, induced arrhythmia and electrolyte imbalances in iCEs, whereas rostafuroxin largely protected them from these effects.

A hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. While repeat RNAs are implicated in disease pathogenesis, their mechanisms of action remain incompletely understood. Here, we show that GGGGCC repeat RNA engages chromatin genome-wide preferentially at promoter regions in patient cells. This interaction obstructs RNA polymerase II and transcription factors with GC-rich motifs, leading to broad transcriptional repression. Biochemical assays, single-molecule imaging, and native bisulfite sequencing analyses demonstrate that GGGGCC repeat RNA intrinsically forms DNA:RNA hybrid G-quadruplexes (HQs) with cognate DNA, providing a structural basis for transcriptional interference. Stabilization of these G-quadruplex structures exacerbates neuronal vulnerability to metabolic stress in patient-derived motor neurons and cortical organoids, whereas restoring key gene dysregulation improves resistance. These findings uncover a previously unrecognized trans-acting mechanism whereby repetitive RNAs form hybrid structures with genomic DNA, disrupt gene regulation, and contribute to neurodegeneration.

Human dermal sleeping nociceptors display ongoing activity in neuropathic pain, affecting 10% of the population. Despite advances in rodents, a molecular marker for these mechano-insensitive C-fibers (CMis) in human skin remains elusive, preventing targeted therapy. Using a Patch-seq approach, we combined single-cell transcriptomics, following electrophysiological characterization, with single-nucleus and spatial transcriptomics from pigs and integrated our findings with cross-species and human transcriptomic data. We functionally identified CMis in pig sensory neurons with patch clamp, using adapted protocols from human microneurography. We identified oncostatin M receptor (OSMR) and somatostatin (SST) as marker genes for CMis. Following dermal injection in healthy human volunteers, oncostatin M, the ligand of OSMR, exclusively modulates CMis. Our findings characterize the molecular architecture of human dermal sleeping nociceptors, providing a framework for mechanistic insight into neuropathic pain and potential therapeutic strategies.

INTRODUCTION: Catheter-based interventions (CBI) have yielded promising data in selected patients with acute pulmonary embolism (PE). Despite growing clinical use, high-quality comparative evidence on the efficacy and safety of CBI, especially in relation to standard anticoagulation or systemic thrombolysis, is limited. As new randomized controlled trials (RCTs) rapidly accumulate, this living evidence synthesis will aim to systematically and continuously evaluate the comparative efficacy and safety of reperfusion strategies vs standard of care in patients with high- and intermediate-risk acute PE.

METHODS: This living systematic review and meta-analysis will include RCTs comparing reperfusion strategies to standard of care in adult patients with high- or intermediate-risk PE. The primary analysis will pertain to trials that are powered and designed to assess hard clinical outcomes, such as death and hemodynamic deterioration. A secondary analysis will include additional studies reporting clinical outcomes, including those primarily evaluating hemodynamic or surrogate outcomes. Analyses will be stratified by PE severity (high- and intermediate-risk) and also conducted using a frequentist network meta-analysis framework. The review is ongoing, with new eligible trials added prospectively.

RESULTS: As of the initial search on 28 May 2025, 23 RCTs are included. Thirteen additional ongoing trials were identified for future inclusion, including trials with clinical outcomes such as PEITHO-3, HI-PEITHO, PEERLESS II, PE-TRACT, and PRAGUE-26 for intermediate-risk PE, and CATCH-PE II, PERSEVERE, and TORPEDONL for high-risk PE.

CONCLUSION: This living meta-analysis will offer continuously updated, comparative evidence on reperfusion strategies for acute PE, with a focus on informing the role of catheter-based interventions in clinical decision-making.

REGISTRATION: PROSPERO: CRD420251207053. Available from https://www.crd.york.ac.uk/PROSPERO/view/CRD420251207053.