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01.
PLOS Computational Biology 2026-06-01

A statistical framework for comparing epidemic forests

Authors:

by Cyril Geismar, Peter J. White, Anne Cori, Thibaut Jombart Inferring who infected whom in an outbreak is essential for characterising transmission dynamics and guiding public health interventions. However, this task is challenging due to limited surveillance data and the complexity of immunological and social interactions. Instead of a single definitive transmission tree, epidemiologists often consider multiple plausible trees forming epidemic forests. Various inference methods and assumptions can yield different epidemic forests, yet no formal test exists to assess whether these differences are statistically significant. We propose such a framework using a chi-square test and permutational multivariate analysis of variance (PERMANOVA). We assessed each method’s ability to distinguish simulated epidemic forests generated under different offspring distributions. While both methods achieved perfect specificity for forests with 100+ trees, PERMANOVA consistently outperformed the chi-square test in sensitivity across all epidemic and forest sizes. Implemented in the R package mixtree, we provide the first statistical framework to robustly compare epidemic forests.

02.
arXiv (CS.AI) 2026-06-24

HOLMES: Evaluating Higher-Order Logical Reasoning in LLMs

arXiv:2606.23238v2 Announce Type: replace Abstract: Logical reasoning is essential for reliable AI, yet existing benchmarks are largely first-order-logic-centric, focusing on object-level deduction over fixed predicates. This misses many realistic scenarios where models must reason over rules, predicates, functions, constraints, and decision procedures themselves. We introduce HOLMES (Higher-Order Logic Meets real-world Explainable Symbolic reasoning), the first real-world benchmark for higher-order symbolic reasoning in LLMs, containing 1379 instances. Built on higher-order logic, HOLMES pairs natural-language problems with HOL formalizations, ground-truth answers, verifiable reasoning traces, and fine-grained controllable reasoning factors across law and finance. Experiments show that current LLMs still struggle on HOLMES, with an average accuracy of only 50.64% and the best model reaching 59.54%. Our analyses further reveal that high final-answer accuracy can mask shortcut reasoning in conflict-resolution settings, while performance drops sharply under scope-conditioned and compositional reasoning. These findings identify higher-order symbolic reasoning as a key bottleneck for building reliable and verifiable LLMs. The project code and dataset are publicly available at https://github.com/wuyucheng2002/HOLMES.

03.
bioRxiv (Bioinfo) 2026-06-11

Combinatorial docking and molecular generation to navigate over 100-billion molecules for prospective ligand discovery

Commercially available make-on-demand libraries now exceed 100 billion compounds, requiring over 50 years to screen on 2,000 CPU cores using conventional docking. We present two complementary approaches to address this challenge. CombiDOCK, a combinatorial docking framework, enables exhaustive screening at the 100-billion scale within 40 days. MINT-Dock, a generative framework, accelerates navigation of this space by integrating CombiDOCK with Monte Carlo Tree Search. Benchmarked on 46 diverse targets, CombiDOCK matched full-molecule docking accuracy, and MINT-Dock achieved a 4,800-fold enrichment over random selection. Compared with prior billion-scale brute-force campaigns against {sigma}2, VMAT2, and VAChT, prospective CombiDOCK screens of the 100-billion-molecule library yielded higher hit rates and more potent ligands, while MINT-Dock achieved comparable outcomes across single- and multi-target objectives with >20-fold computational cost reductions. Docking-predicted poses of the best VAChT-binding compounds were confirmed by cryo-EM structures. These methods provide exhaustive and generative paths for navigating the trillion-molecule frontier of drug discovery.

04.
arXiv (CS.CV) 2026-06-17

FUSER: Feed-Forward MUltiview 3D Registration Transformer and SE(3)$^N$ Diffusion Refinement

Registration of multiview point clouds conventionally relies on extensive pairwise matching to build a pose graph for global synchronization, which is computationally expensive and inherently ill-posed without holistic geometric constraints. This paper proposes FUSER, the first feed-forward multiview registration transformer that jointly processes all scans in a unified, compact latent space to directly predict global poses without any pairwise estimation. To maintain tractability, FUSER encodes each scan into low-resolution superpoint features via a sparse 3D CNN that preserves absolute translation cues, and performs efficient intra- and inter-scan reasoning through a Geometric Alternating Attention module. Particularly, we transfer 2D attention priors from off-the-shelf foundation models to enhance 3D feature interaction and geometric consistency. Building upon FUSER, we further introduce FUSER-DF, an SE(3)$^N$ diffusion refinement framework to correct FUSER's estimates via denoising in the joint SE(3)$^N$ space. FUSER acts as a surrogate multiview registration model to construct the denoiser, and a prior-conditioned SE(3)$^N$ variational lower bound is derived for denoising supervision. Extensive experiments on 3DMatch, ScanNet and ArkitScenes demonstrate that our approach achieves the superior registration accuracy and outstanding computational efficiency.

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

CN-NewsTTS Bench: a target-level automatic benchmark for raw-input Chinese news TTS pronunciation

Authors:

Chinese news text contains dense written forms such as scores, hyphenated model names, ranges, unit symbols, percentages, English abbreviations, and mixed Chinese-Latin-digit names. These forms are frequent in real listening workflows, and a text-to-speech (TTS) system can preserve the written string while changing the spoken meaning. We introduce CN-NewsTTS Bench v0.1, an open target-level benchmark for evaluating whether Chinese news TTS products pronounce such targets correctly from raw text, without user-side rules, LLM rewriting, SSML hints, or manual edits. The release contains a 200-record development set, an 800-record public test set, 992 public auto-evaluable targets, fixed transcripts from a three-ASR ensemble, an automatic target scorer, and initial results for seven product TTS systems. We additionally report ASR-route diagnostics, ASR-subset ablations, category-level results, confidence intervals, and provider configuration metadata. The best system reaches 0.879 strict accuracy, while several systems remain below 0.60.

07.
arXiv (CS.CL) 2026-06-16

Fast When, Careful Who: Dual-Process Multiparty Turn-Taking with Diffusion Augmentation

Reliable turn-taking is essential for spoken dialogue systems. However, most existing methods are designed for two-speaker interaction and struggle with realistic multiparty audio containing overlap and rapid speaker changes. We study multiparty turn-taking on the VoxConverse dataset and propose an audio-only two-stage pipeline that separates when to trigger a turn boundary from whether the floor is actually transferring. A fast trigger scans the audio and proposes candidate end-of-turn times, while a lightweight verifier runs only at those times to decide \textsc{Hold} or \textsc{Shift} and support next-speaker prediction. We report results in the full multiparty setting and a controlled dyadic top-2 projection for comparability. We also investigate diffusion-based, label-preserving background-audio mixing as a data augmentation strategy. Results show improved shift detection over a baseline, with further improvements from diffusion augmentation.

08.
arXiv (quant-ph) 2026-06-11

Quantum iterative approach to the Traveling Salesman Problem

arXiv:2606.11843v1 Announce Type: new Abstract: The Traveling Salesman Problem (TSP) is a classical NP-hard problem in combinatorial optimization, where determining the shortest route among a set of cities becomes computationally prohibitive as the problem size increases. This work explores quantum computing as an alternative approach to address this complexity. Unlike existing methods that primarily rely on quantum annealing, we propose a quantum iterative framework integrating Quantum Phase Estimation (QPE) and Grover's search algorithm. Route costs are encoded as quantum phases, enabling QPE to efficiently evaluate them, while Amplitude Amplification, implemented via the Grover-Long algorithm, iteratively refines the solution space toward the optimal route. A proof-of-concept case study on a small-scale TSP instance demonstrates the feasibility of this approach and its potential for scaling to larger optimization problems. Furthermore, under an expectation-based analysis, the algorithm exhibits an expected computational complexity of $O(\frac{m^2\log_2(m)\log_2(1/\epsilon)}{\sqrt{\epsilon}})$ which depends on the error tolerance parameter $\epsilon$. This estimation omits the initialization term, which we expect future refinements to render subdominant to Phase Estimation.

09.
medRxiv (Medicine) 2026-06-22

Reform of the intermediate level of the health system in the Democratic Republic of the Congo: Adaptations and limits in the stabilization of the personnel of the Provincial Health Division: A cohort study.

Background: Human resources are one of the pillars of health systems. Since the World Health Organization's report on human resources issues, several countries have integrated this component into the various reforms aimed at strengthening their health systems. This study aims to explore the effects of reforming the intermediate level of a health system operating in a fragile state context. Methodology Our study was conducted in the Democratic Republic of Congo (DRC). It was a cohort study of the staff of the 14 Provincial Health Divisions (PHD) out of the 26 existing in the DRC. We established a database of the staff of these 14 PHD from 2016, just after the implementation of the intermediate level reform and the allocation of this staff by the Ministry of Health. We did a recall in 2021, in each of these PHD to survey this staff through a structured questionnaire and supplemented by the files of the agents available in each PHD. Sociodemographic, economic and academic variables were collected and analyzed. Data were entered into an Excel 2016 database and processed with SPSS software version 25. The chi-square test was used for comparison of proportions with a statistical significance level of p < 0.05. Risk ratios ratios (RR) and their 95% confidence intervals were calculated as measures of association. The error threshold was set at 5%. Results A total of 657 agents with an average age of 45.2 years had been identified in 2016 at the start of the survey and in 2021, 118 or 18% of them were no longer part of the PHD agents. Among the causes of absence noted: 48% of agents placed on leave, 16% promoted to other functions within the health system, 16% desertion and dismissal and 11% cases of death. 19.8% of absentees are executives, 19.5% men against 10.3% women; 22.3% of absentees in unstable provinces against 16.6% in stable ones. The factors associated with the absence of agents in the PHD remain the reaching of retirement age [RR (95% CI) = 5.5 (1.2-24.9) ]and male agents [RR (95% CI) = 3.2 (1.3-7.9)]. Among the agents who remained, 92% kept their initial position, 6% were subject to an internal permutation accompanied by a promotion. The factors associated with the stability of human resources at the level of the Provincial Health Division are: female gender, manager with experience or seniority > 5 years, Age > 35 years, Stable province, Presence of a partner bonus. Conclusion Even in a crisis and fragile context, health system reform is possible. It is possible to organize staff recruitment through a selection process independent of the political authorities of the Ministry of Health and supported by the technical services of the Ministry and partners . Experience and the presence of a financial bonus are motivating factors for staff stability. The involvement of Technical and Financial Support Partners in the recruitment process helped the Ministry of Health to minimize political influence in the recruitment of middle-level executives.

10.
arXiv (CS.CL) 2026-06-18

PEC-Home: Interpretation of Progressively Elliptical Commands in Smart Homes

Recent advancements in Large Language Models (LLMs) have empowered home assistants with natural language interaction capabilities. However, current assistants overlook the progressive omission that occurs in human dialogue as shared context accumulates, leading to more elliptical expressions for efficient communication. Thus, current assistants still struggle to interpret such elliptical expressions accurately, which limits their effectiveness in real-world applications. In practical smart home scenarios, assistants face two major challenges caused by elliptical commands: (1) referential ambiguity caused by different environmental expectations among multiple users; and (2) intention ambiguity resulting from user preferences that evolve over time or change with the environment. To address these challenges, we introduce PEC-Home, the first simulated home dataset specifically designed for interpreting progressively elliptical commands in smart homes. Extensive experiments on various LLMs, including GPT-4o, show that existing home assistants struggle to execute user-intended operations based solely on elliptical commands. Even when equipped with tools for storing and retrieving user dialogue history, execution accuracy remains below that achieved with complete commands.}.

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

Emyx: Fast and efficient all-atom protein generation

arXiv:2606.19377v1 Announce Type: cross Abstract: Computational enzyme design requires generating proteins that scaffold catalytic residues and ligands, a task that demands both geometric accuracy and structural diversity from the underlying generative model. Current all-atom generators inherit expensive architectures from structure prediction, leading to high training costs and limited sample diversity. We argue that much of this complexity is unnecessary for generators, which condition on sparse geometric constraints rather than rich co-evolutionary signals. Emyx is a 140M-parameter conditional flow matching model that concentrates capacity within standard transformer blocks, replacing heavy embedding stacks with lightweight conditional representations and sparse connectivity. We additionally derive an exact reparametrisation of the flow matching interpolant into the EDM noise-level framework, bridging flow matching training efficiency with state-of-the-art sampling methods designed for diffusion models without retraining. Despite being the smallest model, Emyx outperforms both Proteína-Complexa and RFdiffusion3 against the AME enzyme design benchmark across success rate under strict evaluation requiring both global fold recovery and catalytic geometry accuracy, structural novelty, scaffold diversity, and geometric validity, while training in just $682$ GPU-hours, roughly $4\times$ less than RFdiffusion3.

12.
medRxiv (Medicine) 2026-06-12

Immunologically Optimized Zmp1 Peptides Reveal a Translational Serological Biomarker Platform for Tuberculosis Diagnosis Across Disease Manifestations

Tuberculosis (TB) diagnosis remains challenging, particularly for extrapulmonary TB (EPTB), where invasive sampling, low bacillary burden, and suboptimal sensitivity of nucleic acid-based tests in peripheral specimens hinder timely detection. Here, we report an immunology-driven strategy for biomarker discovery and development of a peptide-based serological assay targeting Mycobacterium tuberculosis zinc metalloprotease-1 (Zmp1). Leveraging fundamental principles of adaptive immunity that antigenic regions containing overlapping B-cell and CD4 T-helper cell epitopes would preferentially generate high antibody titers through linked recognition and cognate T-cell help, we used an immunoinformatics pipeline to identify two nested immunodominant peptide regions within Zmp1 (Mtb-Zp-NT and Mtb-Zp-CT) enriched for overlapping B- and T-cell epitopes. The diagnostic potential of these peptides was evaluated through ELISA-based serological assays. A blinded pilot study (N=137) demonstrated a clear discrimination between active TB and TB-recovered individuals. The assay was subsequently validated in an expanded cohort (N=875) by screening 6,086 individuals, which identified 457 TB-positive cases. The cohort included pulmonary TB (PTB), EPTB, TB-recovered individuals, household contacts, non-specific infections, and healthy controls. Receiver operating characteristic analyses, supported by DeLong and bootstrap comparisons, revealed superior diagnostic performance of the peptide-based assays relative to full-length Zmp1. Mtb-Zp-CT exhibited the highest accuracy (AUC=0.93; specificity >90%), while Mtb-Zp-NT also demonstrated strong discriminatory power (AUC{approx}0.89). These findings establish that the immunologically optimized Zmp1 peptides are highly promising serological biomarkers for TB and EPTB. More broadly, they demonstrate how mechanistically informed epitope selection can accelerate translation of pathogen-specific immune signatures into sensitive, minimally invasive, and potentially point-of-care diagnostic platforms for resource-limited settings.

13.
arXiv (math.PR) 2026-06-17

Poisson approximation by coupling

arXiv:2605.01894v2 Announce Type: replace Abstract: It is well known that a binomial $(n,p)$ can be approximated by a Poisson distribution with parameter $np$. The typical approach in undergraduate probability texts is to show a convergence result for the distribution of the binomial as $n$ goes to infinity and $np$ converges to some $\lambda$. In this note we use instead the coupling technique to show a much more general result. Moreover, we only use elementary results from probability.

14.
arXiv (CS.CV) 2026-06-18

Fuzzy-Geometric Branch-Point Modeling for Structure-Aware Augmentation of Handwritten Chinese Characters

Data scarcity and structural distortion significantly limit handwriting recognition in high-security authentication. Existing augmentation methods often cause topological and morphological damage, particularly when processing complex Chinese characters where stroke intersections, ligatures, and sharp turns render traditional branch-point detection unreliable. To address this, this paper proposes a fuzzy geometry-driven structure-aware (FGSA) augmentation framework. We model branch points as fuzzy sets within the skeleton space, constructing a continuous branch-point membership field by integrating topological neighborhood evidence with direction field divergence. This membership field is adaptively optimized via an unsupervised surrogate objective, enabling robust stroke decoupling without manual annotation. Finally, kinematically-aligned samples are synthesized through parameterized cubic Bézier reconstruction and multi-strategy perturbations, ensuring a balance between structural fidelity and sample diversity. Moreover, we establish LZUSig, a large-scale, highly challenging dataset specifically dedicated to fine-grained structural degradation in Chinese handwritten signatures. Extensive experiments on CASIA-HWDB1.1, ChiSig, and LZUSig demonstrate that FGSA significantly reduces the word-level error rate ($\Delta$WER), achieving optimal recognition gains over the compared baselines. More importantly, it strikes a robust trade-off among task gain, structural fidelity, and discriminative feature preservation, offering a highly controllable solution for handwriting augmentation.

15.
arXiv (CS.CL) 2026-06-15

Graph-based Target Back-Propagation for Context Adaptation in Multi-LLM Agentic Systems

Context adaptation automates prompt engineering in LLM-based systems by iteratively revising tunable prompts from task feedback, without modifying model weights. Extending this paradigm to multi-LLM agentic systems is crucial: existing methods suffer from inaccurate credit assignment and lack convergence guarantees. We propose Graph-based Target Back-Propagation (GTBP), a context adaptation framework for agentic workflows modeled as directed acyclic graphs. GTBP propagates local target outputs backward through the workflow graph and uses target–output discrepancies to guide a stage-wise prompt update mechanism. Theoretically, we show that GTBP's stage-wise prompt updates become stable over iterations, and that a sufficiently capable LLM optimizer can decrease the overall objective. Empirically, GTBP consistently outperforms strong baselines across three benchmarks while maintaining comparable computational cost.

16.
arXiv (math.PR) 2026-06-16

Super-Arrhenius relaxation of the triangular plaquette model in any dimension

arXiv:2606.16259v1 Announce Type: new Abstract: Consider the following plaquette model from statistical physics: a lamp lies at every vertex of the triangular lattice and a switch lies at every even vertex of the (bipartite) dual hexagonal lattice. Each switch toggles the three lamps on its face. The energy of a configuration is the number of ON lamps. For the Glauber dynamics associated with the Gibbs measure defined by this Hamiltonian at any inverse temperature $\beta>0$, we show that, in any dimension $d\ge 2$, the infinite volume relaxation time satisfies \[e^{\beta^2/C}/C \le T_{\mathrm{rel}}\le Ce^{e^{C\beta}}\] for some $C>0$. Our result entails that the Gibbs measure is unique. The $e^{\beta^2}$ scaling was conjectured by Newman and Moore in 1999 and matches the behaviour of supercritical rooted kinetically constrained models such as the East model, thus recovering fragile glass phenomenology in the absence of kinetic constraints. More precisely, we show that, on a torus of side length $2^k$, when $\beta\to\infty$ and $k/\beta\to0$, we have $T_{\mathrm{rel}}=e^{2\beta k(1+o(1))}$. Quite surprisingly, however, we also prove that, on non-periodic finite domains of size $n\le e^{\beta/C}$ for large $C>0$, we have the much larger asymptotics $\ln T_{\mathrm{rel}}=\beta n^{\Theta(1)}$. The main ingredients of the proofs are new results in extremal and enumerative combinatorics and rely on renormalisation ideas for the dynamics and its groundstates also known as the Ledrappier subshift. We note consequences of our results to geometric group theory (more precisely to the complexity of the word problem for the Baumslag finitely presented group) and to ergodic theory.

17.
arXiv (CS.CV) 2026-06-16

Object Tokens as a Bridge Between Segmentation and Visual Question Answering in Robotic Surgery

Visual Question Answering (VQA) in robotic surgery, referred to as surgical VQA, requires high-level understanding of complex surgical scenes and the integration of visual perception with language reasoning, with the potential to support surgical training and intraoperative decision-making. Recent Vision-Language Models (VLMs) have shown promising performance through parameter-efficient fine-tuning; however, most existing approaches rely on coarse visual grounding, typically limited to bounding boxes, which fails to capture the fine-grained spatial structure of surgical objects. In this work, we propose a unified framework that jointly performs pixel-level segmentation and visual question answering within a single framework. Our approach integrates a VLM with a Segment Anything Model (SAM)-based decoder and represents scene elements as object tokens generated by the VLM. These object tokens guide answer prediction and are further projected to the SAM-based decoder to produce segmentation masks. By optimizing the object token embeddings through both segmentation and question answering objectives, the model learns spatially grounded representations that enhance visual reasoning while providing explicit pixel-level grounding. We evaluate the proposed method on the private RAMIE (Robot-Assisted Minimally Invasive Esophagectomy) dataset and the public EndoVis18 dataset, where it consistently outperforms baseline methods for surgical VQA. These results demonstrate that incorporating context-aware object tokens into vision-language models improves fine-grained surgical scene understanding.

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

RASST: Retrieval-Augmented Simultaneous Speech Translation

Simultaneous speech translation produces target text incrementally from partial speech input. Recent speech large language models have markedly improved SST quality but still struggle with rare and domain-specific terminology. Retrieval augmentation has helped in automatic speech recognition and neural machine translation, but extending it to SST is non-trivial: retrieval must be fast and accurate under partial speech, and the model must decide whether and when to apply retrieved terms during incremental generation. We propose Retrieval-Augmented Simultaneous Speech Translation (RASST), which addresses both challenges. For accurate cross-modal retrieval under partial input, RASST trains a lightweight speech-text retriever that produces chunkwise terminology hints for the Speech LLM via multi-scale retrieval. To use these hints correctly, we synthesize training data that teaches the Speech LLM to decide whether and when to apply each retrieved term. Experiments on ACL 60/60 dev set and the ESO test set show that RASST improves terminology accuracy by nearly 40% and overall translation quality by up to 3 BLEU points, with negligible computational overhead.

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

Reward-Centered ReST-MCTS: A Robust Decision-Making Framework for Robotic Manipulation in High Uncertainty Environments

Authors:

arXiv:2503.05226v2 Announce Type: replace-cross Abstract: Monte Carlo tree search is attractive for robotic manipulation because it can improve action selection through simulation without requiring a fully differentiable policy. In uncertain domains, however, sparse terminal rewards and noisy transitions can make shallow search brittle: many candidate branches remain indistinguishable until late rollouts, and small simulation budgets amplify this ambiguity. This paper presents Reward-Centered ReST-MCTS, a decision-making framework that decomposes intermediate feedback into rule, heuristic, optional neural, and value-estimation channels, centers the resulting process signal against matched task contexts, and uses it to bias or repair search while preserving terminal-task evaluation. The primary evidence is intentionally tiered. Local tasks and matched ManiSkill diagnostics isolate reward-center mechanisms and ablations; matched option-level ManiSkill sweeps test robustness under primitive failure, observation noise, and initial-pose shifts while not claiming standard benchmark superiority; and an official same-backbone OpenVLA-OFT/LIBERO bridge tests bounded VLA action repair. The OpenVLA-OFT clean reproduction reaches 10/10 LIBERO-Spatial successes both with and without RCRM-Guard. A single-suite same-backbone action-channel stress artifact over ten paired LIBERO-Spatial action-channel stress episodes records 0/10 unguarded successes and 9/10 guarded successes. Additional observation-noise, language-perturbation, and visual-distractor probes are reported as coverage and negative-result context rather than superiority evidence. The resulting claim is bounded: Reward-Centered ReST-MCTS is an inspectable test-time verifier for same-backbone high-uncertainty manipulation, not a replacement VLA policy or a broad standard-benchmark superiority claim.

20.
arXiv (CS.AI) 2026-06-17

Rethinking Multimodal Fusion for Time Series: Text Modalities Need Constrained Fusion

arXiv:2603.22372v2 Announce Type: replace-cross Abstract: Recent advances in multimodal learning have motivated the integration of auxiliary modalities such as text or vision into time series (TS) forecasting. However, most existing methods provide limited gains, often improving performance only in specific datasets or relying on architecture-specific designs that limit generalization. In this paper, we show that multimodal models with naive fusion strategies (e.g., simple addition or concatenation) often underperform unimodal TS models, which we attribute to the uncontrolled integration of auxiliary modalities which may introduce irrelevant information. Motivated by this observation, we explore various constrained fusion methods designed to control such integration and find that they consistently outperform naive fusion methods. Furthermore, we propose Controlled Fusion Adapter (CFA), a simple plug-in method that enables controlled cross-modal interactions without modifying the TS backbone, integrating only relevant textual information aligned with TS dynamics. CFA employs low rank adapters to filter irrelevant textual information before fusing it into temporal representations. We conduct over 20K experiments across various datasets and TS/text models, demonstrating the effectiveness of the constrained fusion methods. Code is available at: https://github.com/seunghan96/cfa.

21.
arXiv (CS.CL) 2026-06-16

Agentic Retrieval and Reinforcement Learned Equation Chains: A Controlled Generation Framework for Complex and Novel Physics Word Problems

Generating high-quality Physics Word Problems (PWPs) that are novel, complex, and solvable remains a challenging and underexplored problem in educational content generation. Existing approaches, many adapted from Math Word Problem (MWP) generation, often produce ambiguous, unsolvable, or structurally simple questions with limited linguistic diversity. We introduce ARVRE (Agentic Retrieval Value Reinforced Equation-chain), a two-stage framework for generating diverse and mathematically valid PWPs. In the first stage, a form of offline temporal-difference learning is used to construct valid chains of physics equations, while an agentic retrieval-augmented generation (RAG) framework dynamically selects topic-specific concepts and vocabulary. This design enables explicit control over problem structure and difficulty. In the second stage, a Large Language Model (LLM) converts the equation chain and retrieved concepts into a natural-language physics question. By grounding generation in valid equation chains, our method preserves mathematical correctness while promoting linguistic diversity and contextual richness. Human and automated evaluations demonstrate that ARVRE generates PWPs that are more complex, novel, and solvable than those produced by existing approaches. These results highlight the potential of combining reinforcement learning, retrieval, and LLMs for reliable generation of educational physics content.

22.
medRxiv (Medicine) 2026-06-12

An integrative multi-omics framework identifies epigenetic dysregulation of HAND2 as a potential primary driver of impaired enteric neural crest cell differentiation in Hirschsprung Disease

Hirschsprung disease (HSCR) is a congenital neurodevelopmental disorder characterized by segmental aganglionosis due to impaired developmental processes of enteric neural crest cells (NCCs). Despite being the leading genetic cause of functional intestinal obstruction in early childhood, HSCR represents a paradigmatic challenge in precision medicine: its multifactorial etiology, complex gene-environment interactions and limited resolution of single-modality analyses have long hindered mechanistic understanding and therapeutic translation. Here, we applied an integrative multi-omics approach combining genetic, phenotypic, epigenomic and transcriptomic analyses of matched ganglionic and aganglionic formalin-fixed paraffin-embedded (FFPE) patient tissues, complemented by patient-specific in vitro models. Beyond established genetic contributors, our integrative approach reveals novel regulatory pathways predominantly affecting enteric NCC differentiation, with convergent evidence pointing to epigenetic dysregulation as a primary disease mechanism. Notably, we identified over 1,300 differentially methylated positions between ganglionic and aganglionic FFPE samples, with HAND2 emerging as a key candidate due to multiple hypermethylated sites and consistently reduced expression levels in aganglionic tissues and in vitro models, suggesting a potential role in HSCR pathophysiology. We propose that our multi-omics approach offers a powerful and comprehensive framework for dissecting disease mechanisms. Beyond advancing biological understanding, this strategy holds promise for paving the way for molecularly informed patient stratification and supporting the development of personalized treatment and postoperative management strategies.

23.
arXiv (CS.AI) 2026-06-11

Preregistration for Experiments with AI Agents

arXiv:2606.11217v1 Announce Type: cross Abstract: The proliferation of large language models (LLMs) and autonomous AI agents has given rise to a rapidly growing methodological paradigm: "in silico" behavioral experiments. Originally conceived as a way to use AI agents as proxies for human participants in studies of cognition, decision-making, and social dynamics, this approach has taken on new significance – as AI agents increasingly negotiate, transact, and make consequential decisions on behalf of people and organizations, understanding their behavior has become a research priority in its own right. While these experiments with AI agents offer unprecedented advantages in terms of scalability, cost efficiency, and experimental control, they also inherit, and in some cases amplify, methodological vulnerabilities that have long plagued human subjects research. To address these issues, this paper argues that preregistration practices – central to improving the credibility of human subjects experiments – should now be extended to experiments with AI agents. We systematically catalog the researcher degrees of freedom that experiments with AI agents introduce – model selection, prompt wording, settings, and outcome-contingent redesign, for example – and show how the low cost of iteration and lack of reporting norms make these choices both easy to exploit and difficult to detect. We propose a preregistration template tailored to experiments with AI agents and call on conferences, journals, and funding agencies to make preregistration standard practice for this emerging research paradigm.

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

MetaPlate: Counterfactual-Guided RAG-LLM Tool for Personalized Food Recommendation and Hyperglycemia Prevention

arXiv:2606.10120v2 Announce Type: replace-cross Abstract: Postprandial hyperglycemia is a key risk factor for metabolic disorders; however, existing dietary guidance is often static, impractical, and insufficiently personalized, providing recommendations that are difficult to follow or not impactful. While recent advances leverage continuous glucose monitoring (CGM) and machine learning to predict glycemic responses, these approaches are largely predictive and lack actionable guidance. Moreover, recommendation systems are often misaligned with user goals and require extensive input. We present MetaPlate, a counterfactual explanation (CF) guided, context-aware decision-support framework that generates personalized meal recommendations to mitigate postprandial glucose excursions in healthy adults. MetaPlate integrates multimodal data, including CGM readings, wearable-derived physiological signals, and user-provided meal inputs from $25$ individuals to model pre-meal context. A machine learning model predicts glucose response, while a CF optimization module adjusts meal composition modifying macronutrient amounts to maintain glucose levels within a target range ($\leq 140$ mg/dL). An LLM-based retrieval-augmented generation (RAG) layer enhances interpretability by producing human-readable recommendations using constrained search of the USDA food database. We evaluate MetaPlate via a structured expert-in-the-loop assessment with registered dietitians (RDs), comparing performance before and after prompt refinement. Results show improvements in meal realism, portion suitability, and recommendation likelihood, with expert feedback indicating a shift from clinically implausible outputs to actionable, contextually appropriate recommendations. Our findings emphasize the importance of domain knowledge and structured constraints in LLM-driven systems and highlight the potential of MetaPlate as a real-time personalized dietary decision-support tool.

25.
medRxiv (Medicine) 2026-06-22

Accounting for uncertainty in the expected treatment effect substantially increases the sample size required for randomised trials: implications for the feasibility of clinical trials in anaesthesia and critical care

Background Multicentre trials in anaesthesia and critical care report low rates of statistically significant differences. This finding may partly reflect conventional sample size methods, which assume a fixed treatment effect. Assurance methods use a design prior to represent uncertainty in the expected treatment effect, which may provide a more realistic way of estimating sample sizes. Methods We calculated power curves across a range of effect sizes, design priors, and sample sizes using frequentist and Bayesian assurance methods and compared the sample sizes required to achieve 80% and 90% power to the conventional method. We standardised the design priors across effect sizes using the coefficient of variation. We derived a theoretical limit for achievable power. We validated a normal approximation to the Bayesian posterior distribution. Results Frequentist and Bayesian assurance methods produced similar power curves across all scenarios. At a coefficient of variation of 0.5 - reflecting realistic prior uncertainty in the expected effect size - both methods required sample sizes that were approximately 1.5 to 3.5 times larger than the conventional method. The theoretical power limit depends only on the coefficient of variation of the design prior and holds true across all effect sizes. The normal approximation to the Bayesian posterior distribution matched the results obtained from Markov chain Monte Carlo sampling. Conclusions Incorporating clinical uncertainty in the expected effect size substantially increases the sample size required to achieve adequate power, which has important implications for the feasibility of randomised trials in anaesthesia and critical care.