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01.
arXiv (CS.AI) 2026-06-16

Medical Heuristic Learning: An LLM-Driven Framework for Interpretable and Auditable Clinical Decision Rules

arXiv:2606.16337v1 Announce Type: new Abstract: Predictive modeling for clinical tabular data is central to clinical decision support and therefore requires not only strong predictive performance but also transparent decision logic. Although deep learning and tree-based ensemble methods can achieve high accuracy, their black-box nature remains a major obstacle to clinical deployment. This challenge is further compounded by common characteristics of medical data, including limited sample sizes, severe class imbalance, and feature evolution arising from changes in diagnostic criteria and clinical documentation. To address these issues, we propose Medical Heuristic Learning (MHL), an instantiation of the learning-beyond-gradients paradigm for clinical tabular prediction. Instead of relying on neural network weight updates, MHL uses a large language model (LLM)-driven workflow that integrates statistical probes, medical knowledge probes, rule synthesis, and code-level iterative refinement to optimize a deterministic and executable decision system. The resulting model is expressed not as opaque parameters, but as versioned pure-Python decision rules that are explicitly interpretable, fully auditable, and clinically grounded. MHL also supports continual learning by starting from previously validated rules and iteratively revising them using updated feature information under data drift or feature evolution. Comprehensive experiments on medical datasets show that MHL achieves performance comparable to state-of-the-art methods while maintaining strong behavior in small-sample and highly imbalanced settings. The results further indicate that this explicit rule update mechanism can help alleviate catastrophic forgetting under feature evolution. Overall, these findings suggest that non-gradient-based heuristic systems offer a transparent and adaptable alternative for high-stakes clinical decision support.

02.
arXiv (CS.CV) 2026-06-16

GraphWorld: Long-Horizon Planning with World Models for End-to-End Autonomous Driving

End-to-end autonomous driving has made significant progress by unifying perception, prediction, and planning within a single learning framework, achieving strong performance in short-horizon decision making. However, most existing E2E-AD methods remain confined to short-horizon planning and lack the ability to model long-term temporal dependencies, which severely limits their generalization and security in complex and highly interactive driving scenarios. In this work, we propose GraphWorld, an E2E-AD framework that explicitly enhances long-horizon planning through latent world modeling. We introduce an Ego-Centric Interaction Graph, which adaptively models critical neighboring agents based on spatial proximity, and propagates relational context to planning queries via cross-node cross-attention. We present a World-State-Conditioned Planning that learns ego-centric latent world representations by modeling interactions between an ego vehicle and surrounding agents. This latent world state captures key interaction dynamics and safety-relevant semantics, and serves as a conditioning signal to guide long-horizon, safety-aware trajectory planning. Extensive experiments on Bench2Drive, NAVSIMv1/2, and nuScenes demonstrate that GraphWorld significantly reduces collision rates and improves long-horizon planning performance, validating its effectiveness in complex driving environments.

03.
arXiv (CS.AI) 2026-06-18

Mechanism-Guided Selective Unlearning for RLVR-Induced Reasoning

arXiv:2606.19222v1 Announce Type: cross Abstract: We propose MAST (Mechanism-Aligned Selective Targeting), a mechanism-guided method for unlearning RLVR-induced reasoning with substantially lower collateral damage than standard full-parameter updates. In matched SFT/RLVR checkpoints on Qwen2.5-Math-1.5B and Qwen3-1.7B-Base, the SFT-to-RLVR increment differs sharply from the SFT update in token-level delta-log-probability, and full-parameter gradient ascent forgets only by damaging retain MATH and GSM8K. MAST ranks attention-projection tensors by off-principal energy, update magnitude, and forget-gradient coupling magnitude, then updates only the top-ranked subset. On the primary model, MAST induces statistically significant target forgetting (MATH forget 45/150 to 37/150; McNemar p=0.0078) while preserving GSM8K (+0.8 pp) and MATH retain (-0.5 pp). The advantage reproduces across seeds, NPO/SimNPO objectives, and Qwen3, where MAST preserves GSM8K while full-parameter unlearning collapses it.

04.
arXiv (quant-ph) 2026-06-16

Fast and high-fidelity transfer of edge states via dynamical control of topological phases and effects of dissipation

arXiv:2505.16606v2 Announce Type: replace-cross Abstract: Topological edge states are robust against symmetry-preserving perturbations and noise, making them promising for quantum information and computation, particularly in topological quantum computation through the braiding operations of Majorana quasiparticles. Realizing these applications requires fast and high-fidelity dynamic control of edge states. In this work, we theoretically propose a high-fidelity protocol for transferring topological edge states by dynamically moving a domain wall between two regions with different topological numbers in one dimension. This protocol fundamentally relies on Lorentz invariance and relativistic effects, because moving the domain wall at a constant speed is described by a mass term with the uniform linear motion in the Dirac equation. We demonstrate the effectiveness of our protocol in transferring edge states with high fidelity using a one-dimensional quantum walk with two internal states, which is feasible with current experimental technology. We also investigate how bit-flip and dephasing dissipation to the environment affect transfer efficiency. Remarkably, bit (dephasing) dissipation does not affect the fidelity at the slow (fast) transfer limit, which can be explained by the relativistic effects on the edge states.

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

ComAct: Reframing Professional Software Manipulation via COM-as-Action Paradigm

Existing computer-use agents remain fundamentally limited in professional software manipulation: GUI-based agents suffer from fragile visual grounding and long-horizon error accumulation, while API-basedapproaches struggle with heterogeneous protocols and inaccessible commercial interfaces. In this work,we identify the Component Object Model (COM) as a unified executable abstraction, proposing COM-as-Action: a new paradigm that reframes professional software interaction as deterministic program synthesisrather than sequential visual control. To validate this paradigm in the most demanding environments, weintroduce ComCADBench, the first benchmark for agents operating real industrial CAD software. Ourexperiments reveal a substantial paradigm gap: frontier proprietary models achieve near-zero successunder GUI-based interaction, whereas COM-based execution yields substantial immediate gains. Tobridge the remaining gap between syntactic correctness and geometric accuracy, we develop ComActor, aself-correcting agent trained through a progressive three-stage framework, alongside ComForge, a scalableplatform for large-scale training in Windows containers. Extensive experiments show that ComActorachieves state-of-the-art performance on ComCADBench, with strong resilience in long-horizon taskswhere baselines collapse, and generalizes to external CAD benchmark.

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

Complete entanglement detection using polynomial invariants

arXiv:2606.16712v1 Announce Type: new Abstract: Existing methods for deciding whether a bipartite quantum state is separable or entangled typically fall into one of two categories: they are either complete but require access to an explicit density matrix followed by numerical optimization, or they can be evaluated directly by measuring the quantum system but are incomplete, in the sense that they cannot detect all forms of entanglement. In this work, we overcome both limitations in a unified framework. First, we bypass numerical optimization by deriving separability criteria in the form of universal bounds on tensor powers of separable states. We prove that these bounds are complete: every entangled state violates them for sufficiently large tensor powers. Second, we explicitly construct a corresponding complete family of nonlinear entanglement witnesses, which can detect all forms of entanglement without requiring an explicit density matrix. The witnesses we construct are moreover basis-independent, in the sense that they are invariant under conjugation by local unitaries. Altogether, our results expand the toolbox for entanglement detection in arbitrary local dimensions in a manifestly invariant way.

07.
arXiv (quant-ph) 2026-06-16

Comparative Performance Analysis of NIST PQC Standards: From STM32 Software Limitations to FPGA-SoC Acceleration

arXiv:2606.15744v1 Announce Type: new Abstract: The rapid advancement of quantum computing poses a significant threat to classical public-key cryptographic systems, necessitating the transition to Post-Quantum Cryptography (PQC). This study investigates the implementation challenges of NISTstandardized signature schemes on resource-constrained embedded hardware. We present a comparative analysis of SPHINCS+ and CRYSTALS-Dilithium on an ARM Cortex-M4 (STM32F407G) microcontroller. Our findings reveal that SPHINCS+ is practically unusable in this software-only environment, with impractical execution times. Furthermore, the reference Dilithium implementation failed to execute entirely on the MCU due to severe RAM and timing constraints. To overcome these hardware limitations, we integrated a hardware-accelerated Dilithium core onto a Xilinx Zynq-7000 ZedBoard SoC. By implementing a specialized Number Theoretic Transform (NTT) accelerator in the FPGA fabric, we achieved successful execution with performance rates for key generation and signature generation at millisecond levels. These results demonstrate that while pure software PQC is non-viable for standard microcontrollers, a hardware-software codesign approach provides the necessary efficiency for quantumresistant embedded systems.

08.
arXiv (CS.AI) 2026-06-15

A Fixed-Point Neural Operator for Size- and Functional-Transferable Hamiltonian Prediction

arXiv:2606.14498v1 Announce Type: cross Abstract: Predicting the Kohn-Sham Hamiltonian with machine learning can accelerate density functional theory while retaining access to molecular orbitals, energy levels, and electronic-structure observables that energy-only surrogates cannot resolve. Yet element-wise agreement with the converged Hamiltonian, an implicit fixed point of the self-consistent field iteration, does not determine the occupied subspace that governs orbital energies and densities. Here we present HamEvo, a neural operator that learns the single-step self-consistent update and returns the converged Hamiltonian as its fixed point. HamEvo is pre-trained on intermediate self-consistent trajectories and calibrated at equilibrium with density-matrix supervision. Across benchmarks from MD17 to drug-like QMugs, HamEvo lowers Hamiltonian errors by 35-49% over direct-regression and deep-equilibrium baselines, and predicts QMugs HOMO and LUMO energies with mean absolute errors of 0.036 and 0.053 eV, near the 1 kcal/mol chemical-accuracy scale. Few-shot fine-tuning with only 20 reference conformations extends HamEvo to molecules of up to 122 atoms, well beyond the size range covered by pre-training. With thermal molecular-dynamics sampling, HamEvo captures temperature-dependent HOMO-LUMO gap renormalization beyond the harmonic approximation. Inference is up to 242 times faster than conventional DFT.

09.
arXiv (CS.CL) 2026-06-15

"I Didn't Make the Micro Decisions": Measuring, Inducing, and Exposing Goal-Level AI Contributions in Collaboration

As large language models (LLMs) increasingly shape how users form, refine, and extend their goals, attributing contributions in human-AI collaboration becomes critical for users calibrating their own reliance and for evaluators assessing AI-assisted work. Yet existing methods focus on final artifacts, missing the process through which goals themselves are jointly shaped. We introduce a goal-level attribution framework, CoTrace, that decomposes explicit goals into verifiable requirements and traces both direct contributions and indirect influences across dialogue turns. Applying CoTrace to 638 real-world collaboration logs, we find that while models account for only 11-26% of goal-shaping contribution, they contribute substantially more on introducing lower-level concrete requirements, and make various kinds of indirect contributions. Through controlled simulations, we show that interaction design choices significantly affect model goal-shaping behavior. In a user study, exposing participants to goal-level analyses shifts their perceived contributions by nearly 2 points on a 5-point scale, revealing systematic miscalibration in how users understand their own AI-assisted work.

10.
arXiv (CS.LG) 2026-06-16

PromptShift-CRC: Drift-Aware Conformal Risk Control for Foundation Models Under Prompt and Domain Shift

arXiv:2606.15964v1 Announce Type: cross Abstract: Foundation models are now used in settings where the prompts they receive can change quickly. Users change, topics change, policies change, and the model may suddenly face a kind of request that was rare in the calibration data. This makes fixed calibration risky. Conformal prediction and conformal risk control give model-agnostic ways to control error, but they work best when the calibration data still look like the future data. This paper develops PromptShift CRC, a drift-aware conformal risk control method for foundation-model outputs under prompt and domain shift. The method embeds prompts and responses, measures how far the current prompt stream has moved from the calibration pool, gives more weight to relevant or recent calibration examples, and updates the risk level online after observed violations. It reports three practical diagnostics: realized risk error, prompt drift, and effective calibration size. We give conditions under which the method controls risk up to terms for distribution mismatch and weighted quantile uncertainty. In a synthetic prompt-shift benchmark, static conformal risk control fails sharply after drift, while PromptShift-CRC gives the best coverage among the adaptive baselines considered. We then evaluate the same calibration layer on public benchmark derived streams for question answering, toxicity, summarization factuality, and long-context hallucination risk

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

VLGA: Vision-Language-Geometry-Action Models for Autonomous Driving

Vision-language-action (VLA) models can describe scenes and reason about them in language, yet still struggle to ground their actions in the dense 3D world around them. Existing approaches either inject features from a frozen 3D foundation model without an objective that ensures the policy uses them, or constrain geometry with sparse box and map losses that provide no dense spatial signal. We introduce VLGA, the first vision-language-action model supervised to reconstruct the dense 3D world it drives through. VLGA introduces geometry as a fourth modality alongside vision, language, and action through a dedicated expert supervised by a per-pixel pointmap regression loss against LiDAR. Extensive experiments conducted on challenging nuScenes and Bench2Drive datasets for open-loop and closed-loop evaluations, respectively, show the superiority of VLGA over counterpart VLA methods. In particular, on open-loop nuScenes, VLGA sets a new state of the art among VLA methods without ego status, with the lowest L2 (0.50\,m average) and 3-second collision rate (0.18\%). On closed-loop Bench2Drive, VLGA attains the state-of-the-art driving score of 79.08, +0.71 over the strongest prior VLA, at comparable efficiency and comfort.

12.
arXiv (CS.CV) 2026-06-11

A Scalable PyTorch Abstraction for Multi-GPU Gaussian Splatting

Gaussian splatting methods have become increasingly popular for neural reconstruction of the real world. However, they are often limited in scale and resolution due to compute and memory constraints. We present a multi-GPU Gaussian splatting approach that scales reconstruction to higher resolutions and larger scenes while abstracting away the code complexity typically associated with distributing a model. To accomplish this, we propose a PyTorch backend that distributes the Gaussian parameters and splatting operators across GPUs via CUDA unified memory and NVLink. Because distribution occurs at the operator level, the model code requires no explicit cross-device communication. More broadly, the backend exposes multiple GPUs as an aggregate PyTorch device and supports other PyTorch operators. We demonstrate city-scale reconstructions with street-level detail consisting of over 1 billion Gaussian splats, more than 25 times as many as the current state of the art.

13.
arXiv (CS.CL) 2026-06-16

PathRouter: Aligning Rewards with Retrieval Quality in Agentic Graph Retrieval-Augmented Generation

Agentic GraphRAG trains language-model agents to iteratively retrieve and reason over graph-structured evidence, enabling more accurate and context-aware decision-making by efficiently navigating complex information networks. However, outcome-only reinforcement learning suffers from answer-path reward aliasing, where correct answers may come from shortcuts rather than useful evidence paths. It also exhibits search-update ambiguity, as scalar trajectory-level feedback does not indicate which retrieval actions to adjust. To mitigate these shortcomings, we present PathRouter, a path-aware training framework for agentic GraphRAG. PathRouter jointly evaluates each trajectory along answer correctness and evidence-path overlap, yielding four trajectory categories with differentiated GRPO advantage scaling that suppresses shortcut reinforcement while preserving evidence-seeking behavior. For evidence-poor trajectories, a frozen gold-evidence teacher provides token-level KL guidance on reasoning and search-query tokens, excluding answer tokens to avoid direct response imitation. Experiments on six QA benchmarks across three model sizes show that PathRouter consistently improves answer F1 and evidence-path overlap, achieving average F1 gains of 3.1 on 3B and 4.9 on 7B models compared to a strong baseline.

14.
arXiv (math.PR) 2026-06-16

Sharp connectivity bounds for the vacant set of random interlacements

arXiv:2504.02777v2 Announce Type: replace Abstract: We consider percolation of the vacant set of random interlacements at intensity $u$ in dimensions three and higher, and derive lower bounds on the truncated two-point function for all values of $u>0$. These bounds are sharp up to principal exponential order for all $u$ in dimension three and all $u \neq u_\ast$ in higher dimensions, where $u_*$ refers to the critical parameter of the model, and they match the upper bounds derived in the article arXiv:2503.14497. In dimension three, our results further imply that the truncated two-point function grows at large distances $x$ at a rate that depends on $x$ only through its Euclidean norm, which offers a glimpse of the expected (Euclidean) invariance of the scaling limit at criticality. The rate function is atypical, it incurs a logarithmic correction and comes with an explicit pre-factor that converges to $0$ as the parameter $u$ approaches the critical point $u_*$ from either side. A particular challenge stems from the combined effects of lack of monotonicity due to the truncation in the super-critical phase, and the precise (rotationally invariant) controls we seek, that measure the effects of a certain "harmonic humpback" function. Among others, their derivation relies on rather fine estimates for hitting probabilities of the random walk in arbitrary direction $e$, which witness this invariance at the discrete level, and preclude straightforward applications of projection arguments.

15.
arXiv (CS.CL) 2026-06-18

PatchWorld: Gradient-Free Optimization of Executable World Models

Text-agent environments are typically modeled as partially observable Markov decision processes (POMDPs), assuming that the simulator's latent state and transition dynamics are hidden from the agent. Yet little work has examined whether executable code can be induced to serve as a world model for prediction and planning under partial observability. We introduce PatchWorld, a gradient-free framework that turns offline trajectories into executable Python world models through counterexample-guided code repair. Instead of predicting the next observation with a black-box model, PatchWorld induces symbolic belief-state programs whose action updates can be inspected, replayed, and locally patched. Across seven AgentGym environments, PatchWorld-Simple achieves the highest code-based planning score among evaluated methods, reaching 76.4\% macro success in live one-step lookahead while invoking no LLM calls inside the world-model prediction module itself. We further find that a human-specified residual-memory bias improves surface observation fidelity but weakens decision utility. This exposes a tradeoff in executable world models, since improving observation fidelity can come at the expense of action-discriminative dynamics, and vice versa. Code is available at https://github.com/HKBU-KnowComp/PatchWorld.

16.
arXiv (CS.AI) 2026-06-11

Libra: Efficient Resource Management for Agentic RL Post-Training

arXiv:2606.03077v2 Announce Type: replace-cross Abstract: Reinforcement learning (RL) has emerged as a standard post-training paradigm for shaping large language models (LLMs) into capable agents. In agentic RL, the rollout stage generates trajectories while invoking tools, producing long-tailed and non-stationary workloads that expose two fundamental challenges in resource management. First, due to the long-tail distribution, a small fraction of trajectories dominates rollout makespan. Second, rollout and training are subject to cross-stage imbalance, as they exhibit strong asymmetry in compute patterns, memory demands, and sensitivity to sequence length. Compounding this asymmetry, the sequence length distribution drifts continuously as the policy evolves, rendering any static resource split progressively suboptimal. We present Libra, a resource management system to address both challenges via two core mechanisms. The first is a global resource planner that jointly optimizes GPU allocation across rollout and training clusters. It leverages an elastic hybrid pool to enable lightweight, non-blocking worker reallocation between stages. The second is a causality-driven multi-level feedback queue (C-MLFQ) scheduler, which routes requests to heterogeneous rollout buckets based on causal signals derived from tool-return outcomes, rather than relying on fragile length predictions. Evaluated on 48 A800 GPUs, Libra achieves up to 3.0x higher throughput and converges up to 2.5x faster in reward compared to the baselines.

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

FairGen: Preference-Aligned Diffusion for Demographically Equitable Medical Image Synthesis

Medical imaging is central to modern diagnostics, and artificial intelligence (AI) systems are increasingly used to support image-based analysis by improving efficiency, accuracy, and access to care. However, inequities in healthcare access and differential disease prevalence create severe demographic imbalances in clinical image data. Such imbalances are compounded by the fact that diseases can manifest with distinct features across demographic groups, rendering certain phenotypic presentations naturally rare. AI models trained on such imbalanced data risk perpetuating diagnostic bias and widening healthcare disparities. Here we introduce FairGen, a fairness-aware diffusion framework that synthesizes demographically balanced medical images while preserving pathology-relevant visual features. By embedding physician-aligned preferences into the generation process, FairGen improves subgroup coverage during synthesis and downstream classification. Applied to dermatology, radiology, and neuroimaging benchmark tasks, FairGen achieves fairness improvements of 95.9% for skin images, 80.0% for chest radiography, and 35.2% for brain MRI, while maintaining competitive diagnostic accuracy relative to models trained on original clinical data. Clinician-facing expert review and external validation on independent cohorts further support that these gains extend beyond standard fidelity metrics and are not confined to the original in-distribution datasets.

18.
arXiv (CS.LG) 2026-06-12

Graph Reinforcement Learning for Calibration-Aware Quantum Circuit Routing

arXiv:2606.12816v1 Announce Type: cross Abstract: Quantum circuit routing is a key step in compiling programs for noisy intermediate-scale quantum processors. Routes that appear efficient by standard overhead metrics can still lose fidelity when they pass through poorly calibrated couplers. We study a calibration-aware graph reinforcement-learning router that uses same-day IBM Heron r2 calibration data to choose hardware-edge SWAPs. We train the policy with proximal policy optimization and evaluate it with exact simulated fidelity across nine Munich Quantum Toolkit (MQT) Bench circuits and three calibration snapshots. Across these evaluations, pooled mean exact fidelity is $0.727$, compared with $0.440$ for SABRE-best20 and $0.481$ for target-aware SABRE. Fidelity gains come with higher routed two-qubit counts and are concentrated in the 5q and 8q circuit families; under the fixed tree action graph, all 10q families favor SABRE-best20. Overall, our results show that calibration-aware learned routing can improve fidelity beyond gate-count-driven compilation.

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

Interpretable Sperm Morphology Classification via Attention-Guided Deep Learning

arXiv:2606.20438v1 Announce Type: new Abstract: Male infertility is a major cause of couple infertility, often linked to abnormal sperm morphology. While deep learning models offer automated analysis, most lack interpretability, limiting their clinical adoption. This study proposes an attention-guided deep learning framework for sperm morphology classification. We combine a pretrained EfficientNet-B0 with a Convolutional Block Attention Module (CBAM) to focus on key areas of the sperm head, improving both accuracy and interpretability. Evaluated on the SMIDS and HuSHem public datasets, our model achieves accuracies of 90.2% and 93.9% (macro F1 scores of 0.913 and 0.948), outperforming SimpleCNN and standard EfficientNet-B0. Furthermore, we use Grad-CAM++ visualizations to highlight features influencing the model's decisions. The results demonstrate that this accurate and transparent framework is a practical tool for automated sperm analysis in fertility clinics.

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

DRFLOW: A Deep Research Benchmark for Personalized Workflow Prediction

arXiv:2606.18191v1 Announce Type: new Abstract: Deep research (DR) systems are increasingly used for complex information-seeking tasks, but existing works mainly focus on generating reports and summaries. In contrast, many enterprise tasks instead require an agent to identify concrete workflows which is a sequence of action-steps. For example, rather than summarizing budgeting policies, an agent should be able to determine the steps needed to answer a question such as: "How do I request new headcount given a fixed budget?". Therefore, we introduce DRFLOW, a benchmark for evaluating personalized workflows predicted by agents from heterogeneous sources. Each task requires the agent to identify relevant evidence from scattered sources, then use that evidence to predict the correct action-step sequence for the user's task. DRFLOW contains 100 tasks across five domains, with 1,246 reference workflow steps grounded in more than 3,900 sources. We define seven diagnostic metrics covering factual grounding, step recovery, structural ordering, condition resolution, and personalization. We further present DRFLOW-Agent (DRFA), a workflow-oriented reference agent to predict personalized workflow. We show that although DRFA improves over strong baseline agents (upto 10.02% average F1 score), there is substantial room for improvement remains across these workflow metrics, indicating that predicting complete and correct personalized workflows remains a challenging frontier for deep research.

21.
medRxiv (Medicine) 2026-06-15

Validating Field-Feasible Measures of Recent Khat Use: A Diagnostic Accuracy Study Comparing Amphetamine Immunoassay and Assisted Self-Report Against HPLC in an Ethiopian Male Cohort

Background: Khat (Catha edulis) is a widely consumed natural amphetamine-analog used across East Africa and the Arabian Peninsula. Accurate field-feasible measurement of recent khat use is a prerequisite for large-scale epidemiological research; yet no validated alternatives to laboratory reference methods have been identified in the scientific literature. This nested validation study evaluated the diagnostic accuracy of two point-of-care measures, a commercial amphetamine immunoassay and a Timeline Followback (TLFB) Assisted Self-Report (ASR), against high-performance liquid chromatography (HPLC) quantification of urinary norephedrine (NE), while additionally assessing agreement between the two field measures. Methods: A prospective, random sub-sample of 119 male participants aged 18-40 years from the Gilgel Gibe Field Research Center (GGFRC) longitudinal cohort, Ethiopia (validation timepoint T2, 2015), was used. Three index-reference comparisons were conducted: (1) amphetamine immunoassay (nal von minden, Drug-Screen AMP test, 300 ng/mL cutoff) vs. HPLC; (2) binary ASR (past-week use) vs. HPLC; and (3) binary ASR vs. immunoassay. Sensitivity (positive percent agreement, PPA), specificity (negative percent agreement, NPA), positive predictive value (PPV), negative predictive value (NPV), overall accuracy (overall percent agreement, OPA), and Cohen's kappa were calculated with 95% confidence intervals. Pre-specified secondary analyses applied three pharmacokinetically-informed recall windows (0-2, 3-5, and 6-7 days prior to interview) to ASR. Results: Against HPLC (77 positive, 42 negative), the immunoassay showed perfect specificity (1.0 [0.916-1.0]) and PPV (1.0 [0.91-1.0]) but low sensitivity (0.52 [0.40-0.64]), NPV (0.53 [0.42-0.65]), overall accuracy (0.69 [0.60-0.77]), and weak kappa (0.43 [0.34-0.52]). Binary ASR showed high sensitivity (0.96 [0.89-0.99]), specificity of 0.60 [0.433-0.74], PPV (0.81 [0.72-0.89]), NPV (0.89 [0.72-0.98]), with overall accuracy 0.83 [0.75-0.89] and moderate kappa (0.60 [0.51,0.69]). Restricting ASR to use within 0-2 days improved specificity to 0.69 [0.52-0.84], PPV to 0.86 [0.77-0.93], overall accuracy to 0.87 [0.79-0.93], and kappa to 0.69 [0.61-0.78] (moderate), while sensitivity (0.96 [0.89-0.99]) and NPV (0.89 [0.72-0.98]) remained stable. Against the immunoassay, ASR achieved high PPA of (1.0 [0.91-1.0]), NPA of 0.35 [0.25-0.47], OPA of 0.57 [0.48-0.66], and minimal kappa (0.27 [0.19-0.35]). Conclusions: Time-stratified ASR (0-2 days) is a valid, scalable alternative to biological testing for recent khat use in resource-limited settings. The immunoassay's 300 ng/mL cutoff functions as a marker of heavy or recent high-dose khat use rather than any-use detection. Its perfect specificity and PPV make it valuable as a confirmatory test for substantial exposure, while its lower sensitivity reflects calibration to amphetamine rather than to khat-derived cathinone metabolite. Keywords: khat; Catha edulis; diagnostic accuracy; STARD; self-report; immunoassay; HPLC; Ethiopia; substance use measurement

22.
bioRxiv (Bioinfo) 2026-06-12

A Graph-based QSAR Modeling Pipeline for Predicting In vitro PubChem Assays and In vivo Human Hepatotoxicity: Mechanistic Analysis of Caspase-3/7 Activation

Background: Caspase-3 and -7 are key effector caspases in the apoptotic pathway, a form of programmed cell death, and their activities serve as a well-established biomarker for evaluating environmental chemical toxicity and informing chemical risk assessment. Loss of mitochondrial membrane potential is a key event in the activation of Caspase-3/7 signaling and the subsequent induction of apoptosis. Therefore, simultaneous assessment of mitochondrial membrane potential and Caspase-3/7 activity enables elucidation of the mechanisms and pathways through which apoptosis is initiated. Rapid and accurate assessment of the potential toxicity of environmental chemicals and drugs remains a major challenge. Quantitative Structure Activity Relationship (QSAR) modeling have been widely used for toxicity prediction. Graph-based approaches encode compounds directly as molecular graphs, allowing structure-activity relationships to be learnt from molecular topology without the information loss in binary fingerprints. While advanced graph models such as graph transformers (GTs) have shown outstanding performance in many domains, they have not been fully leveraged in QSAR modeling on Caspase and mitochondrial toxicity. Methods: We propose a QSAR modeling pipeline that encompasses assay data preprocessing, feature representations (fingerprints and molecular graphs), and benchmarking machine learning (ML) models, including classic ML models, graph neural networks (GNNs), GTs, and their consensus ensembles. Based on in vitro Caspase and mitochondrial assays in PubChem, we applied the pipeline to predict Caspase-3/7 activation and mitochondrial membrane potential (MMP). Beyond in vitro assays, we also built in vivo QSAR modeling for FDA Drug-Induced Liver Injury (DILI) gold standard on human hepatotoxicity. Moreover, mechanistic analysis on Caspase-3/7 activation was conducted by comparing with MMP disruption to identify chemical substructures that may be responsible for dual activations. We also investigated cell-line-specific responses by identifying structural motifs that selectively induce Caspase-3/7 activation in individual cell lines.Results:Experimental evaluations show that GTs and GNNs outperformed classic ML models when the number of active compounds is large, such as MMP disruption, while classic ML models and GTs performed good for highly imbalance data with limited active compounds, such as Caspase-3/7 activation. For DILI prediction, the full consensus model achieved the highest AUC 0.69 and Graphormer had the highest F1 score 0.79, both surpassing the previous best model with AUC 0.63 and F1 0.65 with a large margin.Our mechanistic analysis shows that phenolic compounds bearing a para-hydroxyphenyl motif, as well as members of the lipophilic chain family with long alkyl chains can trigger the collapse of MMP, leading to the activation of caspases-3 and -7. Human embryonic kidney (HEK293) was the only cell line with a distinct structural motif: 1,1-dichloroethane and chlorobenzene. Human neuroblastoma (SK-N-SH) is uniquely impacted by an epoxide fragment and rat hepatoma (H-4-II-E) is uniquely impacted by a tetramethylcyclohexene motif and an acetaldehyde fragment.Conclusions:The proposed pipeline for QSAR modeling, including data preprocessing, feature representations, and incorporation of advanced graph ML approaches, is highly effective in predicting not only on Caspase-3/7 activation and membrane potential collapse, but also on FDA DILI human hetatotoxicity. As future research directions, we will leverage extra information, e.g., biological activity and findings in existing toxicity literature, and recent advances in large language models and agentic AI to further improve the predictive performance and enable a sensitive and specific framework for assessing human hepatotoxicity of environmental compounds.

23.
medRxiv (Medicine) 2026-06-22

COVID-19 containment policies and hyperglycemia in pregnancy: correlation with the Stringency Index in a nationwide Belgian cohort

Background During the COVID-19 pandemic, gestational diabetes (GD) prevalence showed variable changes across regions, with most reporting increases and others decreases; however, its association with perinatal outcomes in Belgium remains unknown. We aimed to compare the prevalence of hyperglycemia in pregnancy (HIP) in 2020 versus 2019 and examined the correlation between HIP prevalence and pandemic-related restrictions measured by the Stringency Index (SI) and evaluate neonatal weight percentiles changes. Methods: We included all singleton live births in Belgium in 2019 and 2020 from Belgian birth registry data. We compared monthly proportions of HIP prevalence and Small for gestational age (SGA) and Large for gestional age (LGA) newborns in 2019 and 2020. Crude and adjusted odds ratios (ORs, aORs) were estimated with logistic and multinomial regression. The Spearman correlation coefficient was used to assess the correlation between the monthly average SI and the monthly aORs of HIP. Results: For deliveries from January to June 2020, no significant differences in HIP prevalence were observed compared with 2019. From July to December 2020, there was a significant increase in HIP, with peaks in July (GD screening in April) (aOR 1.41, 1.26-1.58) and November (GD screening in August) (aOR 1.33, 95% CI 1.18-1.49). There was no significant change in neonatal weight percentiles. The Spearman correlation coefficient between the SI and HIP aORs was 0.86 (p = 0.02). Conclusion During the pandemic, we observed an increase in the prevalence of HIP, compared to 2019, without a measurable impact on LGA or SGA newborns. The aOR of HIP in a given month was strongly correlated with the corresponding SI.

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

Agentic Reinforcement Learning for Search Misaligns Instruction-Tuning

Agentic reinforcement learning (RL) trains large language models to use tools, but its impact on alignment is poorly understood. We study how agentic RL for search affects the alignment of instruction-tuned (IT) models. We find that RL-trained models inherit refusal reasoning by deflecting harmful requests into benign search queries, but this breaks down under a simple diagnostic trigger that elicits a search call before refusal can occur. Under this condition, RL models produce multi-step unsafe search actions and reasoning, reducing search query safety by up to 68.6% in Qwen and Llama models relative to their IT counterparts. The effect generalises across model families, scales, and RL algorithms. To understand why, we identify linear directions in the residual stream that control search query safety, and show that RL training progressively shifts search behaviour toward the harmful end of this direction. We thus propose representation-guided RL training, which adds a reward penalty based on projection toward the harmful search direction. Training on benign data alone, it restores IT-level alignment without reducing task accuracy and requires no additional training data. Together, our work provides the first framework for diagnosing, mechanistically analysing, and mitigating alignment degradation in agentic RL for search.

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

Marginal Alignment Does Not Guarantee Joint-Distribution Fidelity: An Official-Reference Audit of Nemotron-Personas-Korea with Cross-Locale Replication

Synthetic persona datasets cite alignment with official demographics as a basis for trust, yet downstream users consume them as joint structures across age, sex, region, occupation, education, name, and institutional status. Marginal alignment does not imply that these joints are preserved. We propose the Independence-Assumption Footprint (IAF), an audit primitive that operates on the attribute combinations a dataset card itself documents as treated independently. For each such combination, IAF compares the synthetic joint against an external official or institutional reference, using direct joint tables where available and rule-implied checks otherwise. Applied to NVIDIA Nemotron-Personas-Korea (one million Korean synthetic personas), IAF finds that NPK aligns with KOSIS marginals while three joints fail. The major-by-occupation distribution against the KEIS graduate universe carries a large conditional mismatch. The age profile of military service is institutionally inconsistent. Female representation in male-dominated occupations is substantially over-flattened toward parity, with the strict screening verdict mapping-dependent and age-robust under direct standardisation. A transferability demonstration across six further NPK locales finds locale-dependent rather than universal diagnostics, with reference-taxonomy cardinality confounding cross-locale flag counts. For synthetic personas used as silicon samples, marginal claims must therefore be paired with disclosure-anchored joint audits before reuse. The released audit artefacts (reference manifests, occupational crosswalks, derived metrics, reproducibility scripts) instantiate this protocol on the NPK family and are released for retargeting at other synthetic persona resources.