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01.
arXiv (CS.LG) 2026-06-25

Simplify to Amplify: Achieving Information-Theoretic Bounds with Fewer Steps in Spectral Community Detection

arXiv:2602.17104v2 Announce Type: replace-cross Abstract: We propose a streamlined spectral algorithm for community detection in the two-community stochastic block model (SBM) under constant edge density assumptions. By reducing algorithmic complexity through the elimination of non-essential preprocessing steps, our method directly leverages the spectral properties of the adjacency matrix. We demonstrate that our algorithm exploits specific characteristics of the second eigenvector to achieve improved error bounds that approach information-theoretic limits, representing a significant improvement over existing methods. Theoretical analysis establishes that our error rates are tighter than previously reported bounds in the literature. Comprehensive experimental validation confirms our theoretical findings and demonstrates the practical effectiveness of the simplified approach. Our results suggest that algorithmic simplification, rather than increasing complexity, can lead to both computational efficiency and enhanced performance in spectral community detection.

02.
arXiv (CS.LG) 2026-06-25

Extreme Meta-Classification for Large-Scale Zero-Shot Retrieval

arXiv:2606.25237v1 Announce Type: cross Abstract: We develop accurate and efficient solutions for large-scale retrieval tasks where novel (zero-shot) items can arrive continuously at a rapid pace. Conventional Siamese-style approaches embed both queries and items through a small encoder and retrieve the items lying closest to the query. While this approach allows efficient addition and retrieval of novel items, the small encoder lacks sufficient capacity for the necessary world knowledge in complex retrieval tasks. The extreme classification approaches have addressed this by learning a separate classifier for each item observed in the training set which significantly increases the representation capacity of the model. Such classifiers outperform Siamese approaches on observed items, but cannot be trained for novel items due to data and latency constraints. To bridge these gaps, this paper develops: (1) A new algorithmic framework, EMMETT, which efficiently synthesizes classifiers on-the-fly for novel items, by relying on the readily available classifiers for observed items; (2) A new algorithm, IRENE, which is a simple and effective instance of EMMETT that is specifically suited for large-scale deployments, and (3) A new theoretical framework for analyzing the generalization performance in large-scale zero-shot retrieval which guides our algorithm and training related design decisions. Comprehensive experiments are conducted on a wide range of retrieval tasks which demonstrate that IRENE improves the zero-shot retrieval accuracy by up to 15% points in Recall@10 when added on top of leading encoders. Additionally, on an online A/B test in a large-scale ad retrieval task in a major search engine, IRENE improved the ad click-through rate by 4.2%. Lastly, we validate our design choices through extensive ablative experiments. The source code for IRENE is available at https://aka.ms/irene.

03.
arXiv (math.PR) 2026-06-25

Degree-preserving conservative processes and a unified approach for their hydrodynamics

arXiv:2604.03548v2 Announce Type: replace Abstract: We investigate a broad class of large-scale one-dimensional interacting systems characterized by a single conservation law and satisfying the "degree-preserving property". Under mild and natural assumptions, we establish a unified framework for the analysis of both invariant measures and hydrodynamic limits. In particular, we prove that when the generator preserves the degree of polynomials of the state variables up to order two, the marginals of any product invariant measure must belong to a family of six specific distributions. This classification is shown to be consistent with a classical result on univariate natural exponential families due to C.N. Morris, which we apply here for the first time in the context of microscopic stochastic systems. As a consequence, we construct a new interacting particle system whose invariant measure is given by the generalized hyperbolic secant distribution. Furthermore, we prove that, despite the generality of the dynamics, the macroscopic behavior of all models in this class is governed by the classical heat equation, with a diffusion coefficient depending explicitly on the underlying microscopic interactions.

04.
arXiv (math.PR) 2026-06-25

Exponential Rank Bounds for Random Matrices

arXiv:2606.25204v1 Announce Type: new Abstract: Fix $b\in(0,1)$, let $1\leq k\leq n$, and let $A=(A_{ij})$ be an $n\times n$ random matrix with independent real entries satisfying $$ \sup_{x\in\mathbb{R}}\mathbb{P}\{A_{ij}=x\}\leq b0$ such that $$ \mathbb{P}\{\operatorname{rank} A\leq n-k\}\leq \exp(-cnk), \qquad 1\leq k\leq n. $$

05.
arXiv (CS.CL) 2026-06-25

Adapting Self-Supervised Speech Representations for Cross-lingual Dysarthria Detection in Parkinson's Disease

The limited availability of dysarthric speech data makes cross-lingual detection an important but challenging problem. A key difficulty is that speech representations often encode language-dependent structure that can confound dysarthria detection. We propose a representation-level language shift (LS) that aligns source-language self-supervised speech representations with the target-language distribution using centroid-based vector adaptation estimated from healthy-control speech. We evaluate the approach on oral DDK recordings from Parkinson's disease speech datasets in Czech, German, and Spanish under both cross-lingual and multilingual settings. LS substantially improves sensitivity and F1 in cross-lingual settings, while yielding smaller but consistent gains in multilingual settings. Representation analysis further shows that LS reduces language identity in the embedding space, supporting the interpretation that LS removes language-dependent structure.

06.
arXiv (CS.CL) 2026-06-25

How Large Language Models Source Brand Reputation Across Languages and Markets

When a large language model (LLM) answers a question about a company, it grounds the answer in retrieved web sources, and those sources decide what the model says. Most analysis of AI brand visibility looks at the answer text. This study looks one step earlier, at the citations. We merge three Rankfor.AI datasets covering 128 brands across 12 home markets and 13 languages, and analyse 167,551 URL-grounded citations (189,974 total attribution rows). We classify each citation by domain and source type and measure where AI gets its brand information, by language and by market. Four patterns hold. First, AI grounds brand answers overwhelmingly in third-party sources: 85.7% of citations point to sites the brand does not own, against 14.3% owned. Second, the source base is concentrated and long-tailed: 80% of citations come from about 18% of domains, fitting a Zipf law (alpha = 0.86, R^2 = 0.983). Third, one reference site dominates almost everywhere: Wikipedia is the most-cited domain in 11 of 12 languages, the exception being Lithuanian, where the business daily vz.lt edges it (4.38%). Fourth, the source mix is market-specific at the margin: for 46 Polish national brands the most-cited domain is YouTube, and four HR and careers portals supply 637 citations against 297 for Polish Wikipedia, about twice as many.

07.
arXiv (CS.CL) 2026-06-25

SpeechEQ: Benchmarking Emotional Intelligence Quotient in Socially Aware Voice Conversational Models

As multimodal conversational systems increasingly engage in spoken interaction, their ability to navigate paralinguistic social cues has become a critical bottleneck for natural human-AI communication. However, existing evaluations of machine emotional intelligence assess reasoning exclusively through isolated text or passive acoustic perception, overlooking the complex cross-modal reasoning required for active, multi-turn dialogue. We introduce \textsc{SpeechEQ}, a comprehensive framework designed to evaluate the sociolinguistic reasoning of Speech-Language Models (SLMs). The framework includes a validated dataset of 2,265 dialogues across 15 Emotional Quotient (EQ) subscales grounded in EQ-i 2.0 theory, along with a multi-turn evaluation protocol measured by our proposed Spoken EQ (SEQ) score inspired by human EQ assessments. Experiments show limitations in how both existing Speech Emotion Recognition and end-to-end Speech-Language Models understand and apply paralinguistic cues through speech. While end-to-end architectures outperform cascaded systems, \textsc{SpeechEQ} reveals that current multimodal models remain bottlenecked by a text-reliant ``modality shortcut,'' an alignment-induced ``safety trap,'' and ``contextual amnesia,'' highlighting the barriers to truly emotionally aware AI. Our benchmark can be accessed at https://huggingface.co/datasets/SpeechEQ/SpeechEQ and demo page at https://binomial14.github.io/speecheq-demo/

08.
arXiv (CS.CL) 2026-06-25

What Intermediate Layers Know: Detecting Jailbreaks from Entropy Dynamics

Jailbreak attacks reveal a persistent weakness in aligned Large Language Models: carefully crafted prompts can elicit policy-violating responses despite safety training. While most defenses operate at the prompt or output level, it remains unclear how harmful intent is encoded within the model's internal representations. We investigate this question by analyzing token-level predictive entropy trajectories across layers of a frozen LLM using the logit lens. We find that static aggregate statistics of prompt-level entropy (e.g., mean, variance) carry little discriminative signal, whereas features capturing how entropy evolves across token positions, such as monotonic rank-based trend scores, are substantially more informative. Importantly, this signal is not uniform across model depth: it is concentrated in intermediate layers and degrades at the final layer, indicating that jailbreak-relevant structure is most pronounced in mid-network representations rather than at the output head. Across multiple models (Llama, Qwen, Gemma) and adversarial benchmarks, these entropy dynamics provide architecture-consistent separation without additional training. Together, our findings show that jailbreak behavior is reflected in structured intermediate uncertainty dynamics, clarifying both which entropy-derived features encode harmful intent and where in the network that signal is most pronounced.

09.
arXiv (CS.CV) 2026-06-25

SPARC: Separating Perception And Reasoning Circuits for Test-time Scaling of VLMs

Despite recent successes, test-time scaling – i.e., dynamically expanding the token budget during inference as needed – remains brittle for vision-language models (VLMs). Unstructured visual reasoning chains entangle perception and reasoning, leading to long, disorganized contexts where small perceptual mistakes may cascade into completely wrong answers. Reasoning also requires expensive reinforcement learning with hand-crafted rewards. Here, we introduce SPARC (Separating Perception And Reasoning Circuits), a modular framework that explicitly decouples visual perception from reasoning. Inspired by sequential sensory-to-cognitive processing in the brain, SPARC implements a two-stage pipeline where the model first performs explicit visual search to localize question-relevant regions, then conditions its reasoning on those regions to produce the final answer. This separation enables independent test-time scaling with asymmetric compute allocation (e.g., prioritizing perceptual processing under distribution shift), and supports selective optimization (e.g., improving the perceptual stage alone when it is the bottleneck for end-to-end performance). It also accommodates compressed contexts by running global search at lower image resolutions and allocating high-resolution processing only to selected regions, thereby reducing visual token count and compute. SPARC outperforms monolithic baselines and strong visual-grounding approaches across challenging visual reasoning tasks, such as improving Qwen3VL 4B on the $V^*$ VQA benchmark by 6.7 points and surpassing "thinking with images" by 4.6 points in an OOD setting with a $200\times$ lower token budget.

10.
arXiv (CS.CV) 2026-06-25

Beyond Visual Forensics: Auditing Multimodal Robustness for Synthetic Medical Image Detection

With the rapid adoption of generative AI, synthetic medical images pose growing risks, including diagnostic deception and insurance fraud. Although prior work has explored vision-language model (VLM)-based synthetic image detection, these evaluations typically consider images in isolation. In clinical practice, however, images are interpreted alongside structured records and metadata, and VLMs are increasingly deployed under joint image-record inputs. We uncover a previously underexamined multimodal vulnerability: when given both modalities, VLMs may overweight record context in authenticity judgments, such that the same image receives different predictions solely due to changes in its accompanying text. This raises concerns about robustness in real-world deployment. To systematically characterize this effect, we reformulate synthetic medical image detection as an audit of multimodal robustness at the image-record interface and introduce a paired benchmark that holds the image fixed while swapping controlled metadata variants. Across multiple imaging modalities, we evaluate diverse open-weight and frontier API VLMs and quantify how metadata alone shifts authenticity predictions. Our benchmark provides a standardized tool for assessing and improving multimodal robustness beyond image-only settings. The code is available at https://github.com/chiuhaohao/Beyond-Visual-Forensics.

11.
arXiv (CS.CV) 2026-06-24

Learning Ego-Centric BEV Representations from a Perspective-Privileged View: Cross-View Supervision for Online HD Map Construction

Bird's-eye-view (BEV) representations derived from multi-camera input have become a central interface for online high-definition (HD) map construction. However, most approaches rely solely on ego-centric supervision, requiring large-scale scene structure to be inferred from incomplete observations, occlusions, and diminishing information density at long range, where perspective effects and spatial sparsity hinder consistent structural reasoning. We introduce Cross-View Supervision (CVS), a representation learning paradigm that transfers geometric and topological priors from an ego-aligned overhead perspective into camera-based BEV encoders. Rather than adding auxiliary semantic losses, CVS aligns representations in a shared BEV feature space and distills globally consistent structural knowledge from a perspective-privileged teacher into the ego-centric backbone. This supervision enhances structural coherence without modifying the inference architecture or requiring overhead input at test time. Experiments on nuScenes using ego-aligned aerial imagery from the AID4AD cross-view extension demonstrate consistent improvements over StreamMapNet while maintaining identical camera-only inference. CVS yields +3.9mAP in the standard $60\times30\,\mathrm{m}$ region and +9.9mAP in the extended $100\times50\,\mathrm{m}$ setting, corresponding to a 44% relative gain at long range. These results highlight perspective-privileged structural supervision as a promising training principle for improving BEV representation learning in HD map construction.

12.
arXiv (CS.CV) 2026-06-24

AerialFusionMapNet: Online HD Map Construction with Aerial-Onboard BEV Fusion

High-resolution aerial imagery has recently emerged as a complementary modality for automated driving perception and has shown potential to improve birds-eye-view (BEV) scene understanding when fused with onboard sensors. Prior work demonstrated performance gains for online high-definition (HD) map construction through aerial-onboard fusion; however, conventional end-to-end fusion does not fully exploit the structural information contained in aerial representations. In this work, we introduce AerialFusionMapNet, a fusion-based mapping framework with a structured two-stage training strategy that explicitly enhances the contribution of aerial features within a unified pipeline. The proposed training scheme enables more effective integration of structural aerial priors. On the nuScenes geographic split, AerialFusionMapNet achieves up to 54.7 mAP, improving over prior aerial-onboard fusion baselines from 48.8 mAP by +5.9 absolute and +12.1% relative. The results suggest that structured training design, rather than increased architectural complexity, plays a more decisive role in unlocking the full potential of aerial imagery for online HD map construction. Code and trained models are available at https://github.com/DriverlessMobility/AerialFusionMapNet.

13.
arXiv (CS.CV) 2026-06-24

TrOCR for Medieval HTR: A Systematic Ablation Study with Cross-Dataset Validation

Fine-tuning transformer-based handwritten text recognition (HTR) models on medieval manuscripts is challenging because these models are pre-trained on modern text and must adapt to a very different visual domain. This paper studies how three controllable fine-tuning choices (contrast normalization, data augmentation, and layer freezing) affect recognition accuracy when adapting TrOCR to small historical datasets. We run controlled experiments on a 13th-century Italian manuscript (I-CT 91 "Cortonese") and replicate the same experimental grid on the public READ-16 benchmark as robustness evidence. On Cortonese, our best configuration achieves 8.03% character error rate (CER). Statistical comparisons across 13 configurations show that freezing up to three encoder layers or six decoder layers does not significantly harm accuracy, while deeper freezing becomes progressively detrimental. Removing contrast normalization (CLAHE) yields 7.84% CER, comparable to a domain-specialized baseline, suggesting strong optimization can reduce reliance on image preprocessing. Cross-dataset validation on READ-16 shows that decoder freezing thresholds transfer more robustly than encoder thresholds, and combined freezing strategies require dataset-specific re-validation. Finally, we use Grad-CAM gradient attributions and decoder cross-attention maps to diagnose error patterns and failure modes revealed by the ablations. Source code is available at https://github.com/LaudareProject/TrOCR-analysis

14.
arXiv (math.PR) 2026-06-24

REM universality and Poisson-Dirichlet Gibbs weights for linear random energy

arXiv:2606.07757v2 Announce Type: replace Abstract: We study the Hamiltonian $H_n(h,\sigma)=\sum_{i=1}^n h_i(\sigma_i-m), $ where $(h_i)$ are i.i.d.\ real random variables and $(\sigma_i)$ are i.i.d.\ Ising spins. We consider the energy levels obtained after an independent thinning that retains an exponential number of configurations ($e^{O(n)}$). We prove that, after an $(h_i)$-dependent centering, the resulting point process converges in distribution to a Poisson point process with exponential intensity. Thus, the energy levels asymptotically has the one of the Random Energy Model (REM). Our results extend previous ones, where REM universality for this model was established only either for energy fluctuations of order $e^{-O(n)}$ or for $e^{o(\sqrt n)}$ randomly selected configurations. We also identify the limiting Gibbs weights, which converge to a Poisson–Dirichlet law, and the quenched free energy, which exhibits a freezing transition at $\beta=\tilde\lambda$. The proofs are presented here in compressed form; full details are given in the companion preprint.

15.
arXiv (quant-ph) 2026-06-24

Polynomial-time exact diagonalization via sparse guided eigenwalks

arXiv:2606.23967v1 Announce Type: new Abstract: Computing quantum ground states is generically difficult, but additional structure can sometimes allow diagonalization to be recast as a more feasible problem. For example, when the desired ground state is sparse in a given basis, diagonalization can be facilitated via graph search. We make this reformulation precise by introducing the eigenwalk problem, which seeks the support of a sparse eigenvector of a Hermitian matrix by exploring the graph induced by its nonzero entries. However, it is not obvious whether the relevant support vertices must always be efficiently reachable by a search on the graph. To resolve this question, we prove that for every sparse eigenvector, there exists a (possibly different) sparse eigenvector with the same eigenvalue whose support is tightly localized in the graph, with diameter scaling only linearly in the sparsity and independently of the total number of vertices. As a consequence, if a $2^n$-dimensional, $poly(n)$-sparse Hamiltonian has an $\mathcal{O}(1)$-sparse extremal eigenvector and one support element is known, then an exact eigenvector with the same eigenvalue can be computed classically in $poly(n)$ time. The same conclusion follows when the $\mathcal{O}(1)$-sparse eigenvector is non-extremal, provided that it is sparser than every eigenvector with a different eigenvalue. These results hold with no assumptions on the degeneracy, locality, spectral width, or spectral gap of the Hamiltonian, and the underlying support-localization principle also extends to problems beyond exact diagonalization, such as sparse principal component analysis.

16.
arXiv (CS.AI) 2026-06-24

A Benchmark for Hallucination Detection in VLMs for Gastrointestinal Endoscopy

arXiv:2606.24115v1 Announce Type: cross Abstract: Vision-language models (VLMs) are prone to hallucination, which remains a major barrier to their safe deployment in clinical practice. To date, most hallucination detection methods have been evaluated on radiology benchmarks such as MIMIC-CXR and VQA-RAD, while gastrointestinal (GI) endoscopy remains largely underexplored. In this paper, we benchmark nine hallucination detection methods on the Gut-VLM dataset, a GI diagnostic Visual Question Answering (VQA) dataset with 4,392 test VQA pairs, across five VLMs (MedGemma-4B, MedGemma-27B, LLaVA-Med-7B, LLaVA-v1.6-7B, and Lingshu-32B). The methods span three categories: black-box methods (RadFlag, SelfCheckGPT-NLI), gray-box methods (AvgProb, AvgEnt, MaxProb, MaxEnt, Semantic Entropy, and VASE), and a white-box method (ReXTrust). Our results show that ReXTrust, a white-box method, achieves the highest AUC across all five models, outperforming the strongest alternative method on each VLM by a statistically significant margin (paired permutation test, p < 0.001 in all cases), reaching a peak AUC of 93.0 on MedGemma-4B. White-box hidden-state access provides a consistent advantage of 19.5 AUC points on average (range: 9.5–33.5), with ReXTrust maintaining strong performance even on LLaVA-v1.6-7B (AUC 79.9), where black-box methods and clustering-based gray-box methods collapse to near-chance performance. Among non-white-box methods, token-level gray-box statistics (MaxEnt, MaxProb) are the strongest alternatives, outperforming both clustering-based gray-box methods (Semantic Entropy, VASE) and black-box approaches on average. We further identify confident confabulation, a failure mode in which models hallucinate with high inter-sample consistency or high token-level probability, as a systemic failure for both consistency and uncertainty-based methods.

17.
arXiv (CS.AI) 2026-06-24

Engineering Reliable Autonomous Systems: Challenges and Solutions

arXiv:2606.23760v1 Announce Type: cross Abstract: Engineering reliable autonomous systems is an important and growing topic in computer science. As autonomous systems become more prevalent, easy-to-use techniques for building them reliably are increasingly important. This workshop report captures and expands on the discussions at the Lorentz Center Workshop "Engineering Reliable Autonomous Systems" (ERAS), held from 10 to 14 June 2024. The workshop was co-organised by the organisers of the Workshop on Formal Methods for Autonomous Systems (FMAS) and the Workshop on Agents and Robots for reliable Engineered Autonomy (AREA). It brought together members of the FMAS and AREA communities, industry practitioners, and representatives from sectors where autonomous systems pose distinctive engineering challenges. The workshop focused on three main research topics: techniques for verification and validation of autonomous systems; engineering real-world autonomous systems; and software architectures for safe autonomous systems. Its main outcome is a catalogue of challenges in these areas and, most importantly, a pathway to solutions. Some challenges can already be tackled by techniques that are well known in academia but have not yet become regularly used in practice. Other challenges remain unresolved and require further research. This roadmap is intended to support future research and industrial collaboration.

18.
arXiv (CS.AI) 2026-06-24

OpenThoughts-Agent: Data Recipes for Agentic Models

arXiv:2606.24855v1 Announce Type: new Abstract: Agentic language models dramatically expand the applications of AI yet little is publicly known about how to curate training data for broadly capable agents. Existing open efforts such as SWE-Smith, SERA, and Nemotron-Terminal typically target a single benchmark, leaving open the question of how to train models that generalize across diverse agentic tasks. The OpenThoughts-Agent (OT-Agent) project addresses this gap with a fully open data curation pipeline for training agentic models. We conduct more than 100 controlled ablation experiments to systematically investigate each stage of the pipeline, yielding insights on the importance of task sources and diversity. We then assemble a training set of 100K examples from our pipeline and fine-tune Qwen3-32B on this dataset, which yields an average accuracy of 44.8% across seven agentic benchmarks and a 3.9 percentage point improvement over the strongest existing open data agentic model (Nemotron-Terminal-32B, 40.9%). Moreover, our training data exhibits strong scaling properties, outperforming alternative open datasets at every training set size in compute-controlled comparisons. We publicly release our training sets, data pipeline, experimental data, and models at openthoughts.ai to support future open research on agentic model training.

19.
arXiv (CS.CL) 2026-06-24

Few shot chain-of-thought driven reasoning to prompt LLMs for open ended medical question answering

In this paper, we propose a modified version of the MedQA-USMLE dataset, named MEDQA-OPEN, which contains open-ended medical questions without options to mimic clinical scenarios, along with clinician-approved reasoned answers. Additionally, we implement a prompt driven by Chain of Thought (CoT) reasoning, CLINICR, to mirror the prospective process of incremental reasoning, reaching a correct response to medical questions. We empirically demonstrate how CLINICR outperforms the state-of-the-art 5-shot CoT-based prompt (Liévin et al., 2022). We also present an approach that mirrors real-life clinical practice by first exploring multiple differential diagnoses through MCQ-CLINICR and subsequently narrowing down to a final diagnosis using MCQ-ELIMINATIVE. Finally, emphasizing the importance of response verification in medical settings, we utilize a reward model mechanism, replacing the elimination process performed by MCQ-ELIMINATIVE.

20.
arXiv (CS.CL) 2026-06-24

Does My Embedding Reflect That $A = B$? Evaluating Mathematical Equivalence in Embedding Models

Because mathematics is highly abstract, a single statement can take very different forms depending on what subfield it is framed in. There are many examples where breakthroughs occurred after researchers discovered that a question had already been answered in a different field. At the same time, the growth of new resources related to formalization has increased the need for tools that enable efficient and reliable navigation between mathematical 'languages' (e.g., from Lean to natural language). In this paper, we investigate whether current embedding models capture mathematical equivalence. To do this, we introduce the Mathematically Equivalent but Lexically Different Pairs (MELD) Dataset, a collection of mathematically equivalent statements that are expressed in very different language. We show that current state-of-the-art embedding models tend to group statements by the terminology used to make them instead of the underlying math. Motivated by this, we propose a contrastive approach to learning embeddings of mathematical text that focuses on aligning informal statements with different formalizations. Our experiments demonstrate that this leads to improvements not only on informal-formal retrieval tasks but also on MELD, which only contains natural language statements.

21.
medRxiv (Medicine) 2026-06-24

Atlas of glomerular disease-specific genetic effects on blood transcriptome

IgA nephropathy (IgAN), IgA vasculitis (IgAV), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and minimal change disease (MCD) account for the majority of idiopathic glomerulo-nephropathies (GN). These disorders involve immune system dysregulation and have a complex genetic architecture. Currently, there are no adequately powered blood transcriptomic datasets coupled to genetic data from patients with GN that can delineate disease-context specific genetic effects on blood immune cell transcriptome. We performed whole genome sequencing coupled with bulk blood transcriptome sequencing on 1,822 participants from the CureGN study, a prospective cohort of participants with a kidney biopsy diagnosis of primary GN. We generated disease-context specific transcriptome-wide maps of gene expression QTL (eQTL), splicing QTL (sQTL), and double strand RNA-editing QTL (edQTL) for FSGS (N=447), IgAN (N=403), IgAV (N=123), MCD (N=408), and MN (N=441), as well as cross-disease maps for all 1,822 participants. Our QTL mapping identified 16,068 eGenes, 4,644 sGenes and 4,611 edQTLs with an FDR

22.
medRxiv (Medicine) 2026-06-24

IgG2 Galactosylation is related to higher antibody dependent enhancement for dengue in cross-reactive antibodies from Sars-CoV-2

Cross-reactive antibodies against dengue virus are known to cause antibody-dependent enhancement (ADE) of infection or disease severity under specific conditions. In our previous study, we showed that primary immunization with the COVID-19 vaccine induces induces cross-reactive IgG causing ADE against dengue. In the present study, we investigated the influence of IgG Fc-glycosylation (analyzed by LC-MS/MS) on ADE mediated by cross-reactive IgG against dengue from IgG against SARS-CoV-2. We found a clear correlation between anti-DENV2 E IgG2 galactosylation and the ADE capacity of cross-reactive IgG against dengue in individuals vaccinated against COVID-19. IgG2 sialylation increased over time; however, it was not correlated with ADE capacity. This phenomenon was restricted to IgG2, whereas anti-DENV2 E IgG1 Fc-glycosylation remained stable after COVID-19 vaccination.

23.
medRxiv (Medicine) 2026-06-24

Cardiometabolic risk phenogroups from a data-driven classification with expanded risk factors

Background and Aims Current diagnostic criteria for metabolic syndrome (MetS) may inadequately capture underlying metabolic heterogeneity and associated cardiovascular risks. We aimed to use expanded cardiometabolic variables to identify new cardiometabolic phenogroups with relevance to prognosis and risk stratification. Methods Latent class analysis (LCA) was applied to a discovery cohort (RESET; n=1,034), using the six conventional MetS measures and eight additional variables. A decision tree model was constructed using the most important variables to enable practical phenogroup classification and facilitate external validation. External validation was conducted in three independent cohorts, PICMAN (n = 120), UK Biobank (n = 344,817), and CHARLS (n = 12,145), analysing for proteomic signatures and cardiovascular outcomes. Results Five latent phenogroups were identified in the discovery cohort: Metabolically Preserved with and without isolated hypertension (each n=244; 23.6%), Lean-Insulin Resistant (IR) (n=140; 13.5%), Obese-Insulin Sensitive (IS) (n=211; 20.4%), and Obese-IR (n=195; 18.9%). Lean-IR and Obese-IS showed discordant adiposity and insulin/glycemic status, and a low prevalence of MetS (21.4% and 31.3%, respectively), whereas MetS was high (75.9%) only in the Obese-IR group. A decision tree model using four binary indicators (visceral adiposity, IR, elevated SBP, and HbA1c) accurately classified individuals into the five latent phenogroups and was subsequently deployed for external validation. Validation in PICMAN showed significantly higher liver fat (Mean 9.0% [SD 6.3%]) in Lean-IR versus Metabolically Preserved (Mean 2.8% [SD 1.8%], P=0.002). Plasma proteomic analyses further reflected unique metabolic-inflammation signatures across the 5 groups. Validation in the UK Biobank showed significant association between the latent phenogroups with outcomes of myocardial infarction and stroke. Hazard ratios for the composite outcome after adjusting for age and sex were 1.52 (95% CI, 1.43-1.61) for isolated hypertension, 1.86 (1.75-1.98) for Lean-IR, 1.85 (1.75-1.97) for Obese-IS, and 2.75 (2.56-2.95) for Obese-IR, compared with the Metabolically Preserved group. Conclusion Expanded cardiometabolic risk factors reveal metabolic heterogeneity obscured by current MetS criteria. Incorporating visceral adiposity and IR into a novel classification system refines cardiovascular risk stratification for the management of cardiometabolic disease.

24.
medRxiv (Medicine) 2026-06-24

Factors associated with the uptake of intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine: The experiences of postpartum women attending child welfare clinics in three rural districts in the Western Region of Ghana.

Background Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) is a key preventive strategy. However, optimal uptake remains inconsistent despite high antenatal care (ANC) attendance. This study assessed factors associated with IPTp-SP uptake and explored the experiences of postpartum women in rural Ghana. Methods A mixed-method study was conducted among 1,155 postpartum women attending child welfare clinics in Jomoro, Prestea-Huni Valley and Ellembelle districts of the Western Region of Ghana. Quantitative data were collected using structured questionnaires and analysed using descriptive statistics and chi-square tests. Qualitative data from in-depth interviews and focus group discussions were analysed thematically to explore womens experiences and perceptions. Results Overall, 73.5% (812/1105) of respondents received at least three doses of SP during pregnancy, in line with WHO recommendations. The most common number of doses received was three doses (31.5%, 348/1105), followed by four doses (26.4%, 292/1105), while a smaller proportion (8.1%, 90/1105) received only one dose. Knowledge of malaria in pregnancy was generally high: 92.7% (1027/1155) of respondents correctly identified its mode of transmission, while 75.1% (830/1155) and 83.5% (923/1155) were aware of the effects of malaria on pregnancy and the foetus, respectively. Uptake was not significantly associated with socio-demographic characteristics, including age, education, occupation, marital status, gravidity, and parity (p > 0.05). However, number of ANC visits was significantly associated with uptake (p = 0.006). Although not statistically significant, lower uptake was observed among peri-urban residents and uninsured women. Qualitative findings indicated that while women recognized the benefits of IPTp-SP, side effects such as nausea, dizziness, and discomfort, as well as challenges with tablet formulation and dosing negatively influenced adherence. Conclusions IPTp-SP uptake was high and largely independent of socio-demographic factors but strongly influenced by ANC attendance. Addressing experiential barriers and strengthening patient-centered counselling during ANC may further improve uptake and adherence.

25.
medRxiv (Medicine) 2026-06-22

Rare loss-of-function variants in POLD1, PMS1 and FAN1 modify age at onset of motor symptoms in Huntington's disease

Huntington's disease is a rare neurodegenerative disease whose primary risk factors are inherited expansions of a CAG repeat tract in the HTT gene. Somatic expansion of these tracts leads to neuronal toxicity, neuronal death and clinical disease progression. To identify genetic factors with a major impact on disease onset and progression, we genome sequenced 18,825 individuals for the ENROLL-HD study. Our results show rare inactivating mutations in three genes, all involved in DNA damage repair, are major determinants of age of onset for motor symptoms (n=10,610) and other clinical manifestations. Heterozygote carriers of predicted loss-of-function (pLoF) variants in POLD1 and PMS1 developed motor symptoms an average 20 years (n=3; P=1x10-5) and 7 years (n=6; P=2x10-3) later than non-carriers, respectively. Conversely, heterozygote carriers of pLoF variants in FAN1 (n=30) developed symptoms 10 years earlier (P=2x10-10). Our findings highlight therapeutic strategies and help predict age of onset for at-risk individuals.