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01.
medRxiv (Medicine) 2026-06-15

Sociodemographic Disparities in Tafamidis Initiation and Clinical Outcomes in ATTR-CM Across the United States

BACKGROUND Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease. Sociodemographic factors may influence time to treatment initiation and resulting clinical outcomes, yet these relationships are poorly characterized. OBJECTIVE Assess the effects of sex and race on tafamidis initiation and subsequent outcomes and their interaction with factors such as ATTR-CM type and social deprivation measures. METHODS A retrospective cohort analysis was conducted using the US Komodo Healthcare Map (01/2016-06/2024) among patients with amyloidosis, identified by ICD-10-CM diagnosis codes. Cumulative incidence of treatment initiation and survival probabilities for cardiovascular-related hospitalization (CVH) or death were estimated by Kaplan-Meier, stratified by sex and race. Cox proportional hazards models were fitted for both endpoints to estimate hazard ratios, adjusting for demographics and clinical characteristics. RESULTS Of 11,311 patients identified, White and Black patients (n=9,223) were included in subsequent analyses. Within 12 months of diagnosis, White women had the lowest cumulative incidence of tafamidis initiation (11.4%), followed by Black women (22.0%), Black men (26.7%), and White men (31.0%). Event-free survival at 12 months was lowest in Black women (42.9%), followed by Black men (46.8%), White women (48.6%), and White men (54.4%). Median (95% CI) time to CVH or death was shortest for Black women (8.0 months [6.8-10.0]) followed by Black men (9.9 months [8.8-12.0]), White women (11.0 months [9.6-13.0]), and White men (15.0 months [14.0-16.0]). CONCLUSIONS In this large, real-world cohort of US patients with ATTR-CM, sex and race contributed to disparities in tafamidis initiation and survival, underscoring compounded disparities in both access and outcomes.

02.
arXiv (CS.AI) 2026-06-19

StaminaBench: Stress-Testing Coding Agents over 100 Interaction Turns

arXiv:2606.19613v1 Announce Type: cross Abstract: We introduce StaminaBench, a benchmark that measures the stamina of coding agents: how many consecutive interaction turns (change requests) they can handle before failing. Unlike the prevailing fraction-of-tasks-solved metric, this matches real vibe-coding where sessions run dozens or hundreds of turns. In StaminaBench, agents implement a REST API server and modify it across a tunable number of procedurally generated follow-up change requests - 100 in our experiments, resulting in codebases of up to 6,000 lines. Tests are generated fully programmatically without LLM involvement, ensuring reproducibility and reliability; change sequences are drawn from either a hardcoded or LLM-driven sampler, both constrained to a structured action space to ensure changes are valid. The agent and the server run in an isolated environment and communicate with the benchmark through HTTP, making testing fully black-box and language-agnostic. We evaluate six agent harnesses paired with seven open-source LLMs across 20 scenarios of 100 turns each and find that: (1) all the tested models fail within 5-6 turns, confirming that vibe-coding-style programming without thorough testing produces bugs; (2) passing test feedback back to the agent and allowing it to retry improves passed turn count by up to 12x; and (3) a good harness is required for strong performance: stronger models exhibit up to a 6x gap between their best and worst harness, while weaker models fail with any harness. We release the benchmark and the generated tasks to enable further research into multi-turn coding agent behavior. Benchmark code and data: github.com/amazon-science/StaminaBench.

03.
arXiv (CS.AI) 2026-06-16

Can We Stop Malicious AI? KILLBENCH: A Benchmark for External AI Kill Switch Feasibility

arXiv:2511.13725v4 Announce Type: replace-cross Abstract: Malicious AI causing harm to humans is not just a Hollywood fantasy. Indeed, as highly capable models such as Claude Mythos emerge and agent systems like OpenClaw rapidly spread, the question of how to stop an AI that acts maliciously – whether by design or by accident – has become urgent. To address this, we propose Killbench, a benchmark for evaluating the Killswitch: a mechanism that halts a malicious AI's in-progress behavior using only external signals. Targeting web agents – the most widely deployed agent domain – Killbench evaluates a range of Kill Switch methods that halt a maliciously operating agent without any access to its internal parameters or the surrounding malicious AI's system, relying solely on external inputs. The benchmark comprises four malicious AI's agent configurations (including an uncensored LLM Agent), 8 harmful scenarios, and malicious prompts constructed from 10 distinct jailbreak patterns. We further construct four External AI Kill Switch defense methods and evaluate them on Grok-4.3, GPT-5.2, Gemma4, Qwen3.6 and Qwen3.5-uncensored, contributing an empirical instrument toward the feasibility of External AI Kill Switches against malicious AI and to the study of AI corrigibility.

04.
arXiv (CS.LG) 2026-06-15

Diffusion Policy Optimization without Drifting Apart

arXiv:2606.13795v1 Announce Type: new Abstract: RL post-training has become increasingly pivotal for improving diffusion policies, but existing diffusion policy-gradient methods are often unstable and cannot achieve reliable policy improvement. We identify the cause as the double-drift phenomenon: optimizing a variational surrogate can let the ELBO separate from the true log-likelihood, which then makes the resulting proxy policy gradient misaligned with the true policy gradient of expected return. We propose DiPOD, a diffusion policy optimization framework that maintains tight-bound behavior throughout training by interleaving self-distillation with policy-improving gradient updates. This leads to a simple and practical algorithm: augmenting each diffusion policy-gradient update with an on-policy ELBO regularizer. Across diffusion language model post-training and continuous-control diffusion policies, DiPOD substantially stabilizes training and reaches higher rewards than previous methods.

05.
arXiv (CS.LG) 2026-06-12

Contrastive Geometric Learning Unlocks Unified Structure- and Ligand-Based Drug Design

arXiv:2601.09693v3 Announce Type: replace Abstract: Structure-based and ligand-based computational drug design have traditionally relied on disjoint data sources and modeling assumptions, limiting their joint use at scale. In this work, we introduce Contrastive Geometric Learning for Unified Computational Drug Design (ConGLUDe), a single contrastive geometric model that unifies structure- and ligand-based training. ConGLUDe couples a geometric protein encoder that produces whole-protein representations and implicit embeddings of predicted binding sites with a fast ligand encoder, removing the need for predefined pockets. By aligning ligands with both global protein representations and multiple candidate binding sites through contrastive learning, ConGLUDe supports ligand-conditioned pocket prediction in addition to virtual screening and target fishing, while being trained jointly on protein-ligand complexes and large-scale bioactivity data. Across diverse benchmarks, ConGLUDe achieves competitive zero-shot virtual screening performance, substantially outperforms existing methods on a challenging target fishing task, and demonstrates state-of-the-art ligand-conditioned pocket selection. These results highlight the advantages of unified structure-ligand training and position ConGLUDe as a step toward general-purpose foundation models for drug discovery.

06.
arXiv (CS.CV) 2026-06-17

Heterogeneous SAR-optical fusion for near-real-time land use and land cover mapping under cloud contamination: A novel framework and global benchmark dataset

Optical remote sensing imagery is frequently degraded by cloud and cloud-shadow contamination, which limits its reliability for near-real-time land use and land cover (LULC) mapping. Although synthetic aperture radar (SAR) can provide cloud-penetrating structural information, existing SAR-optical fusion methods often assume reliable optical observations and insufficiently address the semantic uncertainty introduced by cloud contamination. To address this issue, we propose CloudLULC-Net, an end-to-end heterogeneous SAR-optical fusion framework that directly predicts LULC maps from cloud-contaminated Sentinel-2 imagery and temporally adjacent Sentinel-1 SAR observations. The proposed network incorporates optical reliability modulation to suppress unreliable optical responses, heterogeneous information adaptive aggregation to model high-order spatial-channel interactions between optical and SAR representations, and a unified semantic mapping transformer to organize fused features in a LULC-oriented latent space. A semantic anchor-guided optimization strategy is further introduced to improve the consistency of intermediate semantic representations. To support this task, we construct CloudLULC-Set, a large-scale benchmark dataset containing 40,223 curated SAR-optical-label triplets with pixel-level LULC annotations across diverse geographic regions and cloud conditions. Experimental results show that CloudLULC-Net achieves an OA of 86.60%, an F1-score of 83.29%, and an mIoU of 73.51%, outperforming representative heterogeneous reconstruction-first and end-to-end SAR-optical mapping methods. Comparisons with existing global LULC products and analyses under different cloud-cover levels further demonstrate the robustness and practical value of CloudLULC-Net for target-date LULC mapping in cloud-prone regions.The project is publicly available at: https://github.com/RSIIPAC/CloudLULC

07.
arXiv (quant-ph) 2026-06-15

Scaling native entanglement generation in layered semiconductors with quasi-phase matching

arXiv:2606.14553v1 Announce Type: new Abstract: Efficient generation of entangled photons typically relies on spontaneous parametric down-conversion (SPDC) in phase-matched macroscopic nonlinear media. However, generating entanglement under phase-matching constraints requires additional bulk optics or interferometers. In contrast, ultrathin van der Waals semiconductors - such as transition metal dichalcogenides (TMDs) - exhibit strong enough optical nonlinearities for SPDC to be observed from subwavelength-thick media, thereby bypassing conventional phase-matching constraints. In this microscopic domain, the intrinsic crystal symmetry governs the nonlinear optical response, enabling the native generation of polarization-entangled photon pairs. However, generating these states efficiently has been fundamentally restricted by the material's coherence length ($L_c$), which limits the attainable conversion efficiency. Here, we investigate periodically-poled TMDs (PPTMDs) designed to scale up this interaction via quasi-phase matching. We demonstrate that mechanically flipping the sign of the nonlinearity at precise intervals of $L_c$ introduces quasi-phase matching, that scales the pair-production rate while preserving the pristine, symmetry-generated polarization entanglement, with fidelities exceeding 99%. Backed by a rigorous theoretical model, our work clarifies the interplay between crystal symmetry and propagation effects in thin nonlinear media, providing a new avenue for engineering quantum light in nanophotonic systems.

08.
arXiv (quant-ph) 2026-06-16

Reconstruction of detector error model for quantum error correction

arXiv:2606.16288v1 Announce Type: new Abstract: Fault-tolerant quantum computing fundamentally relies on the accurate characterization of circuit-level noise to optimize decoding algorithms. However, extracting complex multi-body error correlations remains challenging. Contemporary greedy inference algorithms can suffer from statistical distortion, discarding true physical mechanisms while introducing many unphysical false positives. Here, we introduce the Correlation-Analysis-based Hypergraph Reconstruction (CAHR) algorithm, a globally consistent framework to invert experimental syndrome statistics directly into discrete physical hypergraphs. By coupling exact algebraic correlation equations with a top-down concurrent-pruning strategy, CAHR recovers the fault topology without false positives for both $d=5$ rotated surface codes and dense 8-body 2D color codes in our benchmark settings. Furthermore, we show that exact continuous parameter extraction in dense codes is limited by a variance cascade, where absolute statistical variance accumulates linearly from high- to low-degree mechanisms. This motivates a two-stage inference paradigm: utilizing CAHR to extract the fault topology, followed by continuous probability optimization. This provides a practical approach for characterizing and decoding highly correlated noise in realistic quantum hardware.

09.
arXiv (math.PR) 2026-06-17

Periodicity, type $II_1$ factors and free Poisson laws in interacting Fock spaces

arXiv:2606.18162v1 Announce Type: cross Abstract: We show that the von Neumann algebra generated by position operators in a 2-periodic interacting Fock space is a type $II_1$ factor. On the probabilistic side, we prove that the squared position operators have a Marchenko-Pastur distribution with respect to the vacuum state, yielding a natural realization of free Poisson laws within this framework.

10.
arXiv (CS.AI) 2026-06-15

AFFORDANCE20Q: Evaluating Affordance Reasoning from Physical Properties

arXiv:2606.14240v1 Announce Type: new Abstract: Affordance reasoning, the inference of an object's action possibilities from its physical properties (e.g., shape and material), is fundamental to human physical understanding and increasingly critical for Large Language Models (LLMs). However, existing affordance benchmarks largely expose explicit object identities in the evaluation setup, allowing models to rely on memorized object-affordance mappings rather than reasoning over physical properties. To address this gap, we introduce Affordance20Q, a novel affordance reasoning benchmark formulated as a 20-Questions game without exposing the object's identity. In each game, the model identifies a hidden object's affordance from a candidate set by asking yes/no questions about its physical properties. Affordance20Q comprises 1,009 games over 454 objects and 59 affordances, all manually filtered, refined, and annotated. We conduct comprehensive experiments with 15 state-of-the-art LLMs and find a substantial gap (~20 points) compared to human performance. A KL-based information-gain (IG) analysis further shows that models fail to ask discriminating questions as the game progresses. To close the gap, we develop KB-Anchored Rule Induction (KARI), a pipeline based on LLMs that generates affordance rules grounded in evidence from knowledge bases (KBs). KARI improves open-source LLMs by up to 15.2 points, while the limited coverage of KBs hinders further gains. We release all our code and data at https://github.com/1171-jpg/Affordance20Q.git

11.
arXiv (CS.AI) 2026-06-19

Bidirectional Tutoring for Developmental Motor Learning in Robots: Co-Developed Interaction Dynamics Support Stable Learning

arXiv:2606.19728v1 Announce Type: cross Abstract: Infants are well known to develop their motor skills through dense interaction with caregivers. Although such social interaction is crucial for human development, motor-skill learning in robots is often treated as a unidirectional process in which robots passively receive demonstrations from tutors. This overlooks a key property of social interaction: it is inherently bidirectional, with tutor and learner dynamically adapting to each other. In such interactions, the robot's past experiences may function as prior constraints that shape the dynamics of their co-developed trajectories. We hypothesize that bidirectional tutoring allows such constraints to guide the formation of consistent behavioral patterns that preserve behavioral coherence and support generalization, whereas unidirectional interaction lacks such constraints and leads to broader, less consistent behavioral patterns. To examine this hypothesis, we conducted two experiments with a physical humanoid robot performing an object manipulation task: one involving human-robot interaction and another employing an AI tutor interacting with the real robot through an adaptive intervention mechanism designed to examine whether similar effects would emerge under more controlled conditions. We implement the developmental learning framework using a free-energy-principle-based neural network extended with generative replay, which supports stable sequence-by-sequence learning from single tutored episodes. Across both settings, bidirectional tutoring fostered consistent behaviors and stage-wise generalization, while the robot gradually required less tutor guidance. These results suggest that bidirectional tutoring, as an embodied and socially grounded approach, provides an effective scaffold for developmental motor learning in robots.

12.
arXiv (CS.AI) 2026-06-12

What Type of Inference is Active Inference?

arXiv:2606.04935v2 Announce Type: replace Abstract: Active inference casts decision-making as inference, with the Expected Free Energy (EFE) unifying goal-directed and information-seeking behavior. Recent work showed that EFE minimization can be written as Variational Free Energy (VFE) minimization on a generative model augmented with epistemic priors. We prove that the VFE of the augmented model can be rewritten as the VFE of the predictive model plus explicit entropy-correction terms, making the EFE contribution transparent. We then show that proper EFE-based planning requires combining these epistemic corrections with a planning correction that turns marginal inference into policy optimization, yielding a full variational characterization of EFE-based planning. This clarifies which corrections are needed for cross-entropy planning and for full EFE-based planning. The same entropy-corrected formulation leads to a detailed message-passing scheme for EFE-based planning together with simpler ablations. Experiments on three grid-world environments show that full EFE-based planning outperforms ablations that omit either the planning correction or the epistemic corrections.

13.
arXiv (CS.AI) 2026-06-15

An Analysis of the Coordination Gap between Joint and Modular Learning for Job Shop Scheduling with Transportation Resources

arXiv:2604.24117v2 Announce Type: replace Abstract: Efficient job-shop scheduling with transportation resources is critical for high-performance manufacturing. With the rise of "decentralized factories", multi-agent reinforcement learning has emerged as a promising approach for the combined scheduling of production and transportation tasks. Prior work has largely focused on developing novel cooperative architectures while overlooking the question of when joint training is necessary. Joint training denotes the simultaneous training of job and automatic guided vehicle scheduling agents, whereas modular training involves independently training each agent followed by post-hoc integration. In this study, we systematically investigate the conditions under which joint training is essential for optimal performance in the job-shop scheduling problem with transportation resources. Through a rigorous sensitivity analysis of resource scarcity and temporal dominance, we quantify the coordination gap – the performance difference between these two training modalities. In our evaluation, joint training outperforms the majority of dispatching rule combinations and modular training approaches. However, the coordination gap advantage diminishes in bottleneck environments, particularly under severe transport and processing constraints. These findings indicate that modular training represents a viable alternative in environments where a single scheduling task dominates. Overall, our work provides practical guidance for selecting between training modalities based on environmental conditions, enabling decision-makers to optimize reinforcement learning-based scheduling performance.

14.
arXiv (math.PR) 2026-06-15

Mixing Times for the Facilitated Exclusion Process

arXiv:2402.18999v2 Announce Type: replace Abstract: The facilitated simple exclusion process (FEP) is a one-dimensional exclusion process with a dynamical constraint. We establish bounds on the mixing time of the FEP on the segment, with closed boundaries, and the circle. The FEP on these spaces exhibits transient states that, if the macroscopic density of particles is at least $1/2$, the process will eventually exit to reach an ergodic component. If the macroscopic density is less than $1/2$ the process will hit an absorbing state. We show that the symmetric FEP (SFEP) on the segment $\{1,\ldots,N\}$, with $k>N/2$ particles, has mixing time of order $N^{2}\log(N-k)$ and exhibits the pre-cutoff phenomenon. For the asymmetric FEP (AFEP) on the segment, we show that there exists initial conditions for which the hitting time of the ergodic component is exponentially slow in the number of holes $N-k$. In particular, when $N-k$ is large enough, the hitting time of the ergodic component determines the mixing time. For the SFEP on the circle of size $N$, and macroscopic particle density $\rho \in(1/2,1)$, we establish bounds on the mixing time of order $N^{2}\log N$ for the process restricted to its ergodic component. We also give an upper bound on the hitting time of the ergodic component of order $N^{2}\log N$ for a large class of initial conditions. The proofs rely on couplings with exclusion processes (both open and closed boundaries) via a novel lattice path (height function) construction of the FEP.

15.
Nature (Science) 2026-06-25

Oo oo, ha ha: why humans and great apes giggle alike when tickled

The rhythmic patterns of laughter found in apes and humans reveal that complex primate vocal control might have started evolving 15 million years ago. The rhythmic patterns of laughter found in apes and humans reveal that complex primate vocal control might have started evolving 15 million years ago.

16.
arXiv (quant-ph) 2026-06-25

Klein–Gordon Dynamics from Intrinsic Phase Periodicity

arXiv:2606.25929v1 Announce Type: new Abstract: This work develops a phase-based formulation of relativistic wave dynamics, demonstrating that the Klein–Gordon equation emerges naturally from the foundational assumption of intrinsic phase periodicity in material fields. Mapping the phase directly onto the classical action, we postulate that localized excitations possess an invariant rest-frame oscillation governed by a proper frequency $\omega_0$. This physical condition establishes an operational mass-frequency relation, $m = \hbar \omega_0 / c^2$, without requiring rest energy as an independent, axiomatic input. We show that the Klein–Gordon equation arises as the minimal local, linear, Lorentz-invariant field equation compatible with this internal phase structure. Within this framework, mass acts as an intrinsic frequency scale governing wave propagation, and relativistic kinematics is fully recovered as a structural consequence of phase coherence. This approach provides a unified wave-mechanical interpretation where particle dynamics maps onto the group velocity of dispersive wave packets, offering an intuitive account of free propagation, dispersion, and tunneling across potential barriers.

17.
bioRxiv (Bioinfo) 2026-06-15

Maternal BMI and Placental Transcriptomic Changes: A Meta-Analysis of Gene Expression at the Maternal-Fetal Interface

Objective: Maternal body mass index (BMI) is often used as a measure of metabolic status and increased or decreased maternal BMI is associated with a heightened risk of cardiometabolic diseases across generations. The placenta mediates these maternal metabolic cues; however, its genome wide transcriptional adaptations in response to maternal BMI remain incompletely defined. Methods: To delineate placental genes, pathways, and interaction clusters whose transcript abundance varies with maternal prepregnancy BMI through a genome wide meta analysis of human placental RNA sequencing datasets. Placental RNA seq reads from four publicly available cohorts (n=146) were mapped to the GRCh38 reference genome and differentially expressed genes were identified. An independent microarray cohort (n=19) was reanalysed separately to facilitate cross platform comparison. Functional enrichment employed GO, KEGG, and STRING protein interaction resources. Results: Meta-analysis of 146 RNA seq samples identified eight genes with genome-wide significance in placentae from underweight pregnancies including inflammatory signaling gene MAP4K1 and metabolic enzyme PSPH, while overweight and obese categories revealed nominally significant differential expression. KEGG analysis demonstrated significant downregulation of oxidative phosphorylation with increasing maternal BMI, and protein-protein interaction networks revealed inflammatory mediators as central nodes in overweight and obese groups. Independent microarray validation corroborated key findings, including consistent downregulation of oxidative phosphorylation in obesity. Conclusion: Maternal BMI is associated with placental transcriptomic signatures involving inflammatory, metabolic, and hormonal pathways, with consistent downregulation of oxidative phosphorylation across platforms. This genome-wide meta-analysis provides a reproducible catalogue of BMI-responsive placental transcripts that may contribute to developmental programming of offspring health.

18.
arXiv (CS.LG) 2026-06-16

CacheMuon: Using Temporal Preconditioning To Approximate Polar Factor

arXiv:2606.16371v1 Announce Type: new Abstract: Muon is an optimizer that computes updates using the polar factor of the momentum matrix and has shown strong empirical performance across a range of training settings. A key component of Muon is the Newton-Schulz iteration used to compute this polar factor. Although this avoids the cost of an exact singular value decomposition, it remains expensive in practice because it is applied at every optimization step. At the same time, the momentum matrix changes smoothly over training, suggesting strong temporal correlation in the corresponding polar factors. In this paper, we exploit this structure and propose CacheMuon, a temporal preconditioning method that reuses information from previous optimization steps to approximate the polar factor at the current step. This reduces redundant orthogonalization computation across iterations. We analyze CacheMuon as an inexact Muon update, with error controlled by fresh-solver error and cache staleness. Empirically, CacheMuon provides a controllable quality-efficiency frontier: conservative thresholds closely match fresh Muon on language-model and vision training while reducing orthogonalization FLOPs, whereas more aggressive thresholds yield larger arithmetic savings at the cost of modest validation-quality degradation.

19.
medRxiv (Medicine) 2026-06-17

Clinical Study Protocol of the 'Biomarkers of Severity of COVID-19 Patients' (BIOMARCOVID) Project

Introduction The coronavirus disease 2019 (COVID-19) pandemic has challenged health care systems worldwide, in certain areas exceeding hospital capacities and human resources. This has underscored the importance of having better tools to predict the outcome of potentially severe respiratory infections such as SARS-CoV-2. Predicting COVID-19 severity may allow physicians to better manage ICU beds and increase the chances of patient survival through appropriate management. During the toughest months of the pandemic, most physicians tried to identify patients that might develop severe forms based primarily on clinical features on admission (e.g., BMI, age). In this context, significant research has focused on identifying comorbidities, clinical manifestations, and routine blood biomarkers to predict disease severity. However, despite the demonstrated value of untargeted metabolomics in assessing severity, limited data exist on its use for identifying novel metabolite biomarkers that could improve both the sensitivity and specificity of outcome prediction. Our goal is to identify metabolite biomarkers that could enhance the predictive accuracy of standard medical biology data and clinical parameters. Methods and analysis This is a retrospective, observational, monocentric cohort study conducted at the Centre Hospitalier Universitaire Grenoble Alpes (CHUGA). The maximum number of eligible patients admitted for PCR-confirmed COVID-19 between March and December 2020 will be included. Severity outcome is defined using the WHO 10-category ordinal scale (mild: categories 4-5; severe: >5). Blood samples were collected within 48 hours of admission and analyzed for 62 routine blood tests and untargeted multiplatform LC-MS/MS metabolomics across four national platforms. Statistical analysis will include logistic regression with variable selection for the primary aim, and multi-block chemometric integration of clinical, biological, and metabolomics data as a secondary aim. Ethics and dissemination A study steering committee has been formed to ensure the accuracy of the collected data by thoroughly reviewing it prior to the data lock. All aspects of the study comply with ethical standards, including approval by the CHUGA institutional review board and adherence to CNIL Reference Methodology MR004 for the protection of participants' rights, privacy, and confidentiality. This study is registered on the French Health Data Hub (number F20210218154851). Results will be disseminated through peer-reviewed publications, presentations at national and international scientific and clinical conferences, and reports shared with key healthcare system stakeholders.

20.
medRxiv (Medicine) 2026-06-24

Uncovering the fitness of endemically circulating Zika virus strains

Zika virus (ZIKV) is an arbovirus that usually causes few symptoms and has circulated endemically in Asia for decades. However, a large outbreak in South America in 2015 uncovered the serious risk of congenital Zika syndrome in infants born from ZIKV infected mothers. It is unknown whether a lineage with distinct pre-existing fitness advantage emerged from Asia to cause the South American outbreak, and whether there is ongoing evolution that can result in future globally fit strains. Here we used 107 sequences from a single setting (Thailand) collected over an 18 year period (2006-2023). We used novel analytical tools to identify distinct lineages that have circulated in the population and estimated their relative epidemiological fitness. We found there have been six lineages circulating sequentially in the country, with regular emergence and replacement of lineages showing higher fitness than their predecessors. We identified 15 lineage-defining amino acid changes, including four well-documented fitness-enhancing mutations, and two UTR substitutions. The lineage that emerged in South America was evolutionarily linked to the highest-fitness lineage in Thailand, carrying seven of our lineage-defining substitutions acquired during endemic circulation there, and subsequently accumulating four additional changes. After the global pandemic, endemic ZIKV in Thailand continued to evolve, with newly emerged lineages showing novel mutations and increased fitness. Our findings have key implications for the monitoring of ZIKV and can help identify the pathway to increased transmissibility of this globally important pathogen.

21.
medRxiv (Medicine) 2026-06-22

Cumulative Metabolic Exposure to Hyperglycemia and Risk of Cardiovascular and Limb Events in Peripheral Artery Disease

Background: Although diabetes is a potent risk factor for the development of peripheral artery disease (PAD), the effect of cumulative metabolic exposure to hyperglycemia on risk of cardiovascular or limb events in patients with PAD remains unclear. Methods: The Peripheral Artery Disease: Long-term Survival (PEARLS) is a longitudinal registry of Veterans with newly diagnosed PAD identified using a natural language processing approach. Included patients had ankle brachial index [≤]0.9 or toe brachial index [≤]0.7, and no history of lower extremity revascularization or major amputation. Among patients with diabetes in this cohort, we assessed cumulative exposure to hyperglycema based on a 24-month rolling average of hemoglobin (Hgb) A1c values, categorized as [≤]7%, >7% to [≤]8%, and >8%. Multivariable Cox regression models evaluated the association between categories of HgbA1c, modeled as a time-varying exposure, and risk of cardiovascular (CV: myocardial infarction or stroke) and limb (chronic limb threatening ischemia [CLTI] or major amputation) events. Results: Among 45,109 patients with new diagnosis of PAD and pre-existing diabetes, the mean HgbA1c at baseline was 7.5%, with nearly one-third (30.4%) having HgbA1c >8%. The mean age was 70.4 years, 19.8% were Black and 4% were Hispanic. Patients with baseline HgbA1c >8% were younger and compared to those with HgbA1c [≤]7%, more likely to have coronary disease, kidney disease, and obesity. Over a median follow up of 4.2 years, 8,306 (18.4%) patients experienced a CV event, and 8,199 (18.2%) experienced a limb event. The adjusted association between HgbA1c and hazard of CV events was 12% higher in patients exposed to HgbA1c >7% to [≤]8% (HR 1.12; 95%CI: 1.05-1.18) and 38% higher in those exposed to HgbA1c >8% (HR 1.38; 95%CI: 1.30-1.46), compared to HgbA1c 7% to [≤]8% (HR 1.20; 95%CI: 1.13-1.28) and HgbA1c >8% (HR 1.60; 95%CI: 1.51-1.70), respectively when compared to HgbA1c [≤]7%. These findings were consistent in subgroups based on age and severity of PAD. Conclusions: Among diabetic patients with PAD, cumulatiave metabolic exposure to hyperglycemia is associated with a markedly increased risk of clinical events, especially limb events.

22.
arXiv (CS.LG) 2026-06-11

SPADE: Split-and-Delay Embeddings for Autoregressive High-Granularity Calorimeter Simulation

arXiv:2606.11304v1 Announce Type: cross Abstract: We introduce SPADE (SPlit And Delay Embeddings), an autoregressive transformer for sequences whose tokens carry multiple features. Rather than embedding these features jointly, SPADE embeds them independently. Delaying each feature stream relative to the previous one allows intra-token correlations to be learned by the standard self-attention mechanism. Applied to point-cloud calorimeter shower generation in the highly granular ILD detector, SPADE is competitive with the state of the art AllShowers model on photon showers, and substantially outperforms its VQ-VAE-based predecessor OmniJet-$\alpha_C$. The mechanism is applicable to any generative task with multi-feature tokens, enabling LLM-style pretraining workflows for higher-dimensional data.

23.
arXiv (CS.AI) 2026-06-24

Legal Reasoning Is Not Lawyering: Rethinking Legal Benchmarks for Pro Se Access to Justice

arXiv:2606.23716v1 Announce Type: cross Abstract: Legal AI benchmark research frequently invokes the assumption that large language models can improve access to justice, including for people who cannot access lawyers in order to understand and exercise their legal rights. We argue that current benchmarks are not equipped to support this assumption because they evaluate legal reasoning over inputs that have already been preprocessed by legal experts, which measures the upper bound of model performance. Access to justice depends on a lower bound: how models perform when inputs come from pro se litigants, whose prompts may contain noisy narratives, buried facts, omissions, folk-legal assumptions, and surface-level errors. These degradations are comparable to conditions under which LLMs are known to degrade in the general machine learning literature, including long-context sensitivity, underspecification, hallucination, and typographical perturbations. We connect evidence from pro se literature with this body of machine learning research and present a small perturbation experiment on LEXam, a legal benchmark, to illustrate the gap between these two bounds. If model development continues to focus on benchmarks that measure only the upper bound, this gap may remain hidden or even widen. We conclude by calling for legal benchmarks that directly measure robustness under pro se-like inputs so that access-to-justice claims about legal AI can become empirically testable.

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

Softmax as Linear Attention in the Large-Prompt Regime: a Measure-based Perspective

arXiv:2512.11784v2 Announce Type: replace Abstract: Softmax attention is a central component of transformer architectures, yet its nonlinear structure poses significant challenges for theoretical analysis. We develop a unified, measure-based framework for studying single-layer softmax attention under both finite and infinite prompts. For i.i.d. Gaussian inputs, we lean on the fact that the softmax operator converges in the infinite-prompt limit to a linear operator acting on the underlying input-token measure. Building on this insight, we establish non-asymptotic concentration bounds for the output and gradient of softmax attention, quantifying how rapidly the finite-prompt model approaches its infinite-prompt counterpart, and prove that this concentration remains stable along the entire training trajectory in general in-context learning settings with sub-Gaussian tokens. In the case of in-context linear regression, we use the tractable infinite-prompt dynamics to analyze training at finite prompt length. Our results allow optimization analyses developed for linear attention to transfer directly to softmax attention when prompts are sufficiently long, showing that large-prompt softmax attention inherits the analytical structure of its linear counterpart. This, in turn, provides a principled and broadly applicable toolkit for studying the training dynamics and statistical behavior of softmax attention layers in large prompt regimes.

25.
arXiv (CS.AI) 2026-06-12

Otters++: A Time-to-first-spike Based Energy Efficient Optical Spiking Transformer

arXiv:2606.13016v1 Announce Type: new Abstract: Spiking neural networks (SNNs) are promising for energy-efficient inference, and time-to-first-spike (TTFS) coding is especially attractive because each neuron fires at most once. In practice, however, this benefit is often reduced by the cost of computing a temporal decay term and multiplying it by the synaptic weight. We address this issue by turning a physical hardware "bug," the natural signal decay in optoelectronic devices, into the main computation of TTFS, named Otters++. Specifically, we use the measured decay of a custom In$_2$O$_3$ optoelectronic synapse to directly realize the TTFS temporal term, removing the need for explicit digital decay computation. To scale this idea to Transformer models, we establish a layer-wise functional equivalence between the Otters++ and a quantized neural network (QNN), and develop a hybrid training method that uses device-faithful SNN computation in the forward pass and QNN straight-through gradients through the equivalent QNN path in the backward pass, together with model distillation. This avoids differentiation through discrete first-spike events and reduces the over-sparsity problem in direct TTFS-SNN training. We further make training aware of measured device noise by sampling run-to-run variation, and refine the system-level energy model by accounting for device sharing and multi-hop communication. On GLUE dataset, Otters++ improves the average score to 84.17\% while maintaining a clear energy advantage over prior spiking Transformer baselines. These results show that physically grounded TTFS computing can be efficient, trainable, and robust under realistic hardware effects.