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01.
medRxiv (Medicine) 2026-06-22

Use of the Pharmacy First service in England in the first 12 months: geographic variation and health system context

Objectives: The Pharmacy First (PF) service was introduced across England from 31 January 2024 to expand the clinical role of community pharmacies and improve access to primary care. This paper describes use of PF in its first 12 months, in terms of uptake, access routes, consultation outcomes, geographic variations, service costs and antimicrobial supply. Methods: A descriptive analysis of all PF consultations submitted for payment to NHS Business Services Authority in England between 31 January 2024 and 31 January 2025. Pharmacy-level consultation data were linked to national data on population, location and pharmacy characteristics. PF use was examined using population-standardised consultation rates and consultations per pharmacy. Results: During the first year of implementation, 2,205,731 PF consultations were recorded as delivered across 11,349 pharmacies, with payment of GBP123 million to pharmacies. Uptake increased steadily over time. Most consultations were for acute sore throat (33%) and uncomplicated urinary tract infection (27%), with corresponding antibiotics, phenoxymethylpenicillin and nitrofurantoin being the most supplied. Most people self-referred (74%) into the service, with 95% of consultations managed without onward referral. Substantial geographic variation was observed. Northern regions had higher use based on the eligible population. The South East and Midlands had higher activity per pharmacy. London showed a distinct pattern, with higher self-referral into the service, lower medication supply and higher referral to other healthcare services. Higher consultation volume was weakly associated with pharmacy characteristics, including opening hours, pharmacy type and retail setting, and local context, in terms of socio-economic and geographic factors. Conclusions: PF had immediate uptake and is operating primarily as a direct-access model for common acute conditions. Findings suggest that PF is contributing to improved access to care and may shift demand away from general practice. However, the service uptake appears to be shaped by geographic location, proximity to other healthcare services and pharmacy characteristics.

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

ToolSelf: Unifying Task Execution and Self-Reconfiguration via Tool-Driven Emergent Adaptation

arXiv:2602.07883v4 Announce Type: replace Abstract: LLM-powered agentic systems excel at complex long-horizon tasks, but remain constrained by static configurations fixed before execution. Such rigidity forces a trade-off between domain-specific performance and cross-task generalization: strong priors and compact tool spaces aid specialization but weaken transfer, while task-agnostic workflows and broad action spaces expand coverage but dilute guidance. Existing pre-execution optimization, planner-worker orchestration, and configuration patching fall short of resolving this tension, as they decouple adaptation from execution, causing information loss, fragmented optimization, and ambiguous credit assignment. We propose ToolSelf, a tool-driven runtime self-reconfiguration paradigm that abstracts configuration updates as a standardized tool interface and unifies execution and adaptation within one policy's action space. The execution agent can dynamically update sub-goals, strategies, toolboxes, context, and context-management modes based on task progress and feedback. We further introduce Configuration-Aware Two-stage Training (CAT), which combines rejection sampling fine-tuning with trajectory-level KTO reinforcement learning to internalize self-reconfiguration. Across diverse benchmarks, zero-shot ToolSelf rivals task-specialized agents; after CAT training, ToolSelf gains 28.8 points over the static-configuration baseline on average, illuminating a path toward emergent adaptivity that obviates manually injected guidance. The code is available at https://github.com/lian-tian-mo-zun/ToolSelf.

03.
arXiv (quant-ph) 2026-06-16

Bi-qutrit entangled edge states of positive partial transposes with largest ranks

arXiv:2606.16265v1 Announce Type: new Abstract: Whenever $E$ is an eight dimensional subspace of the bi-qutrit quantum system whose orthogonal complement is spanned by a vector of Schmidt rank three, we show that there exist PPT entangled edge states with the range space $E$ whose partial transposes are of rank six, which is the largest possible rank. In this way, we exhibit a huge family of bi-qutrit PPT entangled edge states of type $(8,6)$. They make faces of the convex set of all PPT states, and we find bi-qutrit PPT entangled edge states of other types on the boundaries of such faces.

04.
bioRxiv (Bioinfo) 2026-06-19

Children's DNA Methylation and Family Dynamics in a Congo Basin Subsistence Community: Links with Parental Conflict and Fathers' Caregiving

Family environments may contribute to children's long-term health through biological processes, including epigenetic regulation such as DNA methylation (DNAm). However, most studies in this area focus on Euro-American populations while also rarely including fathering data. The current study investigated children's blood DNAm associations with positive (father caregiving) and negative (parental conflict) family dynamics in a smaller-scale subsistence society living in the Congo Basin rainforest. We measured DNAm from dried blood spots of 54 children (mean age=8.48 years) and conducted three epigenome-wide association studies aimed at discovering differential co-methylated regions (CMRs) associated with family dynamics. Via path models, we investigated the health implications and shared contribution of family factors of the identified CMRs. Differential DNAm associated with family dynamics was localized to genes related to stress, immunology, development, and aging, thus possibly linking to children's physical health and were simultaneously connected to other family factors such as number of siblings. Our findings suggested similarities in biological embedding of family factors across socio-ecologically diverse contexts.

05.
arXiv (quant-ph) 2026-06-12

Reduced basis algorithm for solving nonlinear differential equations on quantum computers

arXiv:2606.13457v1 Announce Type: cross Abstract: As quantum computing moves toward scientific computing applications, nonlinear differential equations remain a central challenge since quantum evolution is intrinsically linear. In this work, we introduce a reduced basis algorithm (RBA) for polynomial nonlinear ordinary differential equations (ODEs) and spatially discretized partial differential equations (PDEs). After time discretization, the method composes the resulting polynomial update map over $m$ timesteps, identifies the reduced monomial basis appearing in this composed map, and constructs a linear RBA operator whose action recovers the exact $m$-timestep nonlinear dynamics. Thus, at the level of the chosen discrete update rule, the method introduces no additional approximation error beyond the time discretization error. The qubit number requirement is governed by the size of the reduced monomial basis. For an $n$-dimensional polynomial ODE system of degree $p>1$, the lifted register requires at most $q_m^{\mathrm{ODE}} = O(nm\log p)$ qubits in the full basis scenario. For PDEs discretized on $N^D$ grid points, a locality-based construction requires at most $q_m^{\mathrm{PDE}} = O(D\log N + n m^{D+1}\log p)$ qubits. Hence, the dependence on the grid size remains logarithmic, while the nonlinear overhead is controlled by local reduced basis size. The main computational burden is moved from the quantum computer to a classical preprocessing step, where the reduced monomial basis and RBA operator are constructed for the chosen timestep window. Through numerical tests on the Lorenz system and the one-dimensional Burgers equation, we verify that the RBA reproduces the corresponding discrete time nonlinear dynamics exactly, while exposing the trade-off between timestep composition, reduced basis growth, and locality.

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

Programmable Gauge-Field Textures with Ultracold Atoms in Momentum Space

arXiv:2606.15124v1 Announce Type: cross Abstract: Synthetic gauge fields with ultracold atoms offer a route to quantum matter in which electromagnetic environments can be designed rather than merely imposed. While the Harper-Hofstadter model has been realized in several cold-atom systems, existing implementations are largely limited to spatially uniform magnetic fluxes. Here we experimentally realize a highly programmable two-dimensional momentum-state lattice of ultracold atoms with local control over the Peierls phase pattern, enabling direct implementation of Harper-Hofstadter Hamiltonians with tunable and spatially structured synthetic gauge fields. We observe a crossover from ballistic to strongly flux-modified bulk dynamics with suppressed transport. By introducing a synthetic electric field through site-dependent energy gradients, we further demonstrate Hall-type transverse drift arising from the interplay between electric and magnetic fields. In addition, we engineer a synthetic flux domain wall separating regions with opposite magnetic fluxes and observe anisotropic propagation guided along the interface. These results move cold-atom gauge-field engineering from uniform magnetic backgrounds toward designer gauge textures, providing an experimental setting for transport across programmable topological interfaces.

07.
arXiv (CS.LG) 2026-06-15

Temporal Straightening for Latent Planning

arXiv:2603.12231v2 Announce Type: replace Abstract: Learning good representations is essential for latent planning with world models. While pretrained visual encoders produce strong semantic visual features, they are not tailored to planning and contain information irrelevant – or even detrimental – to planning. Inspired by the perceptual straightening hypothesis in human visual processing, we introduce temporal straightening to improve representation learning for latent planning. Using a curvature regularizer that encourages locally straightened latent trajectories, we jointly learn an encoder and a predictor of a Joint-Embedding Predictive Architecture (JEPA) world model. We show that reducing curvature this way makes the Euclidean distance in latent space a better proxy for the geodesic distance and improves the conditioning of the planning objective. We demonstrate empirically that temporal straightening makes gradient-based planning more stable and yields significantly higher success rates across a suite of goal-reaching tasks. Our code is available at https://agenticlearning.ai/temporal-straightening.

08.
arXiv (CS.AI) 2026-06-18

HeRo-Q: A General Framework for Stable Low Bit Quantization via Hessian Conditioning

arXiv:2601.21626v2 Announce Type: replace-cross Abstract: Post Training Quantization (PTQ), a mainstream model compression technique, often leads to the paradoxical 'low error, high loss' phenomenon because it focuses solely on minimizing quantization error. The root cause lies in the Hessian matrix of the LLM loss landscape: a few high curvature directions are extremely sensitive to perturbations. To address this, we propose the Hessian Robust Quantization (HeRo Q) algorithm, which applies a lightweight, learnable rotation-compression matrix to the weight space prior to quantization. This joint framework reshapes the loss landscape by reducing the largest Hessian eigenvalue and reducing its max eigenvalue, thereby significantly enhancing robustness to quantization noise. HeRo-Q requires no architectural modifications, incurs negligible computational overhead, and integrates seamlessly into existing PTQ pipelines. Experiments on Llama and Qwen models show that HeRo Q consistently outperforms state of the art methods including GPTQ, AWQ, and SpinQuant not only achieving superior performance under standard W4A8 settings, but also excelling in the highly challenging W3A16 ultra low bit regime, where it boosts GSM8K accuracy on Llama3 8B to 70.15\% and effectively avoids the logical collapse commonly seen in aggressive quantization.

09.
arXiv (CS.AI) 2026-06-17

A T-API-Compliant ReAct Agentic Loop for Optical Networks: Generic vs. Domain-Specific Tool Abstractions

arXiv:2606.18000v1 Announce Type: cross Abstract: Optical networks need intent-driven, closed-loop agentic management, a key enabler for higher autonomy levels. We present the first T-API-compliant reasoning and act (ReAct) loop. We show that domain-specific composite tools achieve 90% oracle-validated correctness with threefold token savings compared to generic tools.

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

Filtered Conformal Ellipsoids for Graph-Native Time Series

arXiv:2606.17014v1 Announce Type: new Abstract: Joint prediction sets for multivariate time series should control a single event while adapting to cross-coordinate dependence. We study filtered conformal ellipsoids: a frozen state-space filter emits a one-step predictive mean and covariance, and split-conformal calibration is applied to the resulting Mahalanobis scores. The filter is used to choose the ellipsoid shape; conformal calibration chooses the scalar radius, so the construction benefits from a learned predictive covariance without relying on Gaussian tail probabilities for coverage. The main difficulty is that filtered scores are dependent and learned recurrent filters need not contract in their raw hidden state; we therefore analyse contraction in an observable predictive-law quotient that identifies hidden states producing the same future sequence of emitted Gaussian laws. Under a stable Bayes Gaussian-projection filter, covariance bounds, and a finite-horizon observability Fisher condition, small excess Gaussian negative log-likelihood implies contraction of the learned emitted laws. Combined with a threshold-autocovariance envelope this yields a Chebyshev-type approximate coverage bound for filtered split-conformal prediction under dependence; a sharper Bernstein-type bound requires an additional geometric-mixing concentration assumption. Under Gaussian oracle realisability we also obtain a near-oracle log-volume comparison within the class of conditionally valid Gaussian ellipsoid rules. We instantiate the framework with a GCN-GRU filter with diagonal-plus-low-rank covariance. On moderate-size graph-native traffic benchmarks (METRLA-$20$ and PEMSBAY-$50$), the learned filter gives sharper at-target ellipsoids than static-covariance and non-filter baselines; at full-graph scale and on non-graph-native datasets, factor and copula baselines can be stronger.

11.
bioRxiv (Bioinfo) 2026-06-11

A Deep Hypergraph Learning Model for Predicting Antimicrobial Combination Effects Across Bacterial Targets

Antimicrobial resistance (AMR) creates an urgent need for efficient strategies to identify effective antibacterial combinations. Combination therapy, including antimicrobial peptides (AMPs) paired with conventional antibiotics, is a promising approach, but exhaustive experimental screening across drug pairs and bacterial targets is impractical. This study introduces a hybrid GCN-based hypergraph neural network (HGNN) for predicting antimicrobial-agent combination outcomes against bacterial targets. Each antimicrobial-agent-antimicrobial-agent-bacterium triplet is represented as a ternary hyperedge, enabling the model to learn context-dependent interaction patterns. The framework integrates SMILES-derived molecular graph embeddings for antimicrobial agents, including conventional antibiotics and AMPs, with taxonomy-derived bacterial representations. The prediction task was formulated as a three-class classification problem: synergy, antagonism, and non-interaction. The non-interaction class included experimentally verified indifferent records and synthetic presumed non-interaction triplets generated by negative sampling. Model development used drug-pair-grouped splitting, five-fold grouped cross-validation within the training/validation partition, and final evaluation on a held-out test set. On the held-out three-class test set, the selected GCN-based HGNN achieved an accuracy of 0.83, weighted F1-score of 0.84, macro F1-score of 0.80, and ROC-AUC of 0.95. Per-class evaluation showed accuracies of 0.80 for synergy, 0.92 for antagonism, and 0.85 for non-interaction. Pair-type analysis showed strong performance across AMP-AMP, AMP-conventional antibiotic, and conventional antibiotic-conventional antibiotic combinations. These findings suggest that hypergraph-based representation learning can support computational prioritization of antimicrobial combinations for experimental follow-up. Further studies will be needed to improve model interpretability and to perform prospective validation of predicted synergistic combinations.

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

Deep Sleep Classification via EEG Signal Criticality: A Passive BCI Approach for Sleep-Improvement Neurofeedback

arXiv:2606.13017v1 Announce Type: cross Abstract: Automated sleep staging is a fundamental application of passive Brain-Computer Interfaces (pBCI), decoding spontaneous neural states to enable closed-loop interventions independent of user intent. This study evaluates criticality features derived from Detrended Fluctuation Analysis (DFA) for the specific identification of deep sleep (N3). We analyzed $347,232$ EEG epochs from $290$ older women using UMAP manifold learning to visualize state transitions. Subsequently, six classifiers were benchmarked via 10-fold cross-validation, using balanced accuracy to determine the optimal "state-sensing" engine for neurofeedback.Naive Bayes achieved the highest mean balanced accuracy ($87.17\% \pm 0.24\%$), significantly outperforming a fully connected deep neural network (FNN: $81.58\%$) and Random Forest ($80.97\%$). Linear models (LDA: $57.21\%$; SVM: $51.01\%$) performed poorly, indicating that DFA-derived criticality features reside on a distinct, non-linear manifold. Probabilistic decoding of EEG criticality provides a high-accuracy sensing mechanism for pBCIs. This robust classification pipeline supports the development of state-dependent neurofeedback, such as targeted auditory stimulation, to enhance cognitive recovery.

13.
arXiv (quant-ph) 2026-06-15

Quantum-Classical Hierarchical Equations of Motion

作者:

arXiv:2606.14363v1 Announce Type: new Abstract: We develop a quantum-classical hierarchical equations of motion (QC-HEOM) approach for simulating non-Markovian open quantum systems. The method combines the ensemble-averaged classical path reference of the quantum-classical path integral formalism with a hierarchy of auxiliary quantum influence functionals. By incorporating thermal fluctuations through an ensemble average over reference trajectories, the hierarchy is required to represent only the residual quantum memory associated with the imaginary part of the bath response function. Consequently, unlike conventional hierarchical equations of motion, QC-HEOM does not require Matsubara or Padé expansions of the thermal kernel and exhibits only weak temperature dependence of the hierarchy size. Furthermore, because thermal fluctuations are supplied through reference classical trajectories, the framework naturally extends beyond harmonic baths and enables the incorporation of anharmonic and molecular environments through externally generated trajectories. We derive the formalism and demonstrate its exactness for a harmonic bath. Applications to an asymmetric spin-boson model and the seven-site Fenna–Matthews–Olson complex illustrate the accuracy of QC-HEOM. It reproduces benchmark quasi-adiabatic path integral and hierarchical equations of motion results while requiring substantially fewer auxiliary objects, particularly at low temperatures. These results establish QC-HEOM as an efficient framework for treating residual quantum memory in quantum-classical descriptions of open-system dynamics. The separation of thermal fluctuations from residual quantum memory through the use of Wigner trajectories provides an approximate route toward hierarchical treatments of complex anharmonic environments that are inaccessible to conventional HEOM approaches.

14.
arXiv (quant-ph) 2026-06-11

Large Fluctuations in Open Quantum Systems

arXiv:2606.11822v1 Announce Type: new Abstract: We study statistics of atypical measurement outcomes in the steady states of driven open quantum systems. In equilibrium, the probability distribution over the phase space, as encoded in, e.g., the Wigner function, is analytic in the phase-space coordinates. We show that this property is generically lost in driven dissipative systems: their {\it large-deviation function} develops lines and surfaces across which its derivatives are discontinuous. As an illustrative example, we consider a parametrically driven Kerr oscillator coupled linearly and/or nonlinearly to a dissipative bath. Rare fluctuations in the amplitude and phase of the induced oscillations are governed by semiclassical instanton trajectories of the corresponding Keldysh-Lindblad action. We demonstrate that a given fluctuation can be realized through multiple distinct instanton trajectories. The competition between these trajectories leads to abrupt switching of the dominant instanton and, consequently, to non-analytic features in the large-deviation function.

15.
arXiv (quant-ph) 2026-06-16

VQE as Initial State Preparation for QPE on Heisenberg Spin-Glass Hamiltonians

arXiv:2606.15061v1 Announce Type: new Abstract: Quantum Phase Estimation (QPE) is the quantum algorithmic workhorse for computing ground state energies of quantum Hamiltonians with quantum computers. Ground state energy calculation of physical systems is perhaps the most promising use case for quantum computing in terms of scientific and commercial value with a plausible path to outperformance of classical alternatives. This path, however, hinges on the availability of initial states for QPE with significant overlap with the true ground state. Using extensive (classical) numerical computations, we study whether the NISQ-era algorithm VQE (Variational Quantum Eigensolver) could be used to efficiently prepare high-overlap states of disordered fully-connected anisotropic Heisenberg spin glass quantum Hamiltonians with up to $15$ qubits. We find that (i) – consistent with widely held, but rarely numerically illustrated beliefs – VQE is generally unable to efficiently converge to the ground state for our Hamiltonians, which is a well-known issue with VQE due to a variety of factors including vanishing gradients and local minima; (ii) low energy states do not necessarily have large ground-state overlap, but there is typically a correlation between the two measures; (iii) adding more than three layers to the VQE ansatz neither improves overlap nor the energies found; and (iv) the best-found overlap scaling as a function of the Hamiltonian system size is not strongly exponentially decreasing, suggesting potential for VQE to be a heuristic state preparation algorithm for QPE.

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

Whole-Brain Connectomic Graph Model Enables Whole-Body Locomotion Control in Fruit Fly

arXiv:2602.17997v3 Announce Type: replace Abstract: Animals perform coordinated whole-body movements under the control of neural systems shaped by brain-wide connectivity. The mapping of the whole-brain neural connections, or the connectomes, provides a natural graph for modeling sensorimotor information flow, yet its potential as a neural controller for embodied agents remains largely unexplored. Here, we introduce the Fly-connectomic Graph Model, which directly instantiates the whole-brain connectome of an adult Drosophila as a graph-structured neural controller for movements of a simulated biomechanical fruit fly via deep reinforcement learning. We achieve stable performance across diverse locomotion tasks, as well as better sample efficiency compared to both graph and non-graph baselines. Our results demonstrate a biologically informed way towards effective control policy design by translating whole-brain wiring principles into actionable architectural priors, while also improving the interpretability through dynamic information flow. This work also highlights the potential to bridge neuromechanics with embodied intelligence by providing a computational platform for investigating the sensorimotor transformation underlying animal behavior and a paradigm to advance the development of more nature-aligned intelligent systems.

17.
arXiv (CS.AI) 2026-06-15

Mask, Sample, Revise: A Revisable CTMC Inference Stack for Guided Discrete Flow Matching Text-to-Speech

arXiv:2606.13989v1 Announce Type: cross Abstract: Recent alignment-free non-autoregressive (NAR) text-to-speech (TTS) models formulate synthesis as a conditional infilling task, bypassing explicit duration predictors and external aligners. When speech is represented with neural codec tokens, the infilling problem becomes discrete, making Discrete Flow Matching (DFM), a Continuous-Time Markov Chain (CTMC) framework for discrete generation, a natural fit. However, inference-time control for stable low-step conditional infilling remains underexplored. We propose Mask, Sample, Revise, an inference-time CTMC stack for alignment-free DFM-TTS. The stack combines predictor-free guidance to strengthen text conditioning, prompt-matched conditional coupling to align the probability path with the acoustic prompt, and SC-ReMask, a schedule-constrained remasking mechanism that introduces token-to-mask transitions so early de-masking decisions can be revised. These components require no post-hoc fine-tuning and operate in a single tau-leaping sampler. Controlled ablations show that this stack improves intelligibility and robustness in the low-NFE prompted setting, outperforming unguided and guidance-only samplers with substantially more steps.

18.
medRxiv (Medicine) 2026-06-10

Longitudinal brain structural changes during clozapine treatment: associations with neuroreceptor architecture and clinical response

In treatment-resistant schizophrenia, clozapine treatment has been associated with longitudinal reductions in subcortical volumes, ventricular enlargement, and widespread cortical thinning. However, it is unknown how these structural changes relate to clozapines pharmacological profile and clinical efficacy. We combined five longitudinal datasets with MRI acquired before and on average 5 months after clozapine initiation in 143 individuals to quantify brain structural changes and their association with normative maps relating to neuroreceptor architecture and physiological systems, and improvement in symptom severity. Clozapine treatment was associated with grey matter volume reductions across multiple subcortical regions (including the amygdala, hippocampus, thalamus, caudate, putamen and nucleus accumbens), increases in pallidal volume, ventricular enlargement, and widespread cortical thinning. Cortical regions showing the greatest magnitude of thinning corresponded to areas with higher normative densities of serotonergic 5-HT1A, 5-HT2A and 5-HT4 receptors. Changes in subcortical volume or cortical thickness during clozapine treatment were not associated with changes in total or positive symptom severity. In addition, baseline subcortical volume, cortical thickness, or gyrification prior to starting clozapine did not predict subsequent symptom improvement. Cortical thinning may partly reflect clozapines activity at serotonergic receptors, which have been implicated in cortical network stabilisation and neuroplasticity, however structural remodelling during clozapine treatment may reflect a process independent from its clinical efficacy in improving core symptoms of psychosis.

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

RoboNaldo: Accurate, Stable and Powerful Humanoid Soccer Shooting via Motion-Guided Curriculum Reinforcement Learning

arXiv:2606.11092v2 Announce Type: replace-cross Abstract: Elite humanoid soccer shooting requires whole-body stability, high-impulse whole-body interactions, and accuracy to targets. Motion tracking-driven reinforcement learning (RL) provides stability in whole-body movement coordination, but a fixed reference makes it hard to adapt to varied ball positions and strike timings; in contrast, task reward-driven RL struggles to explore and discover valid kicks from scratch. We therefore introduce RoboNaldo, a three-stage motion-guided curriculum RL framework for high-impulse humanoid interaction. A single human-kick reference is used as a scaffold and progressively shifts optimization towards shooting performance. The curriculum first learns a stable whole-body kicking prior, then adapts the kick to free-kick settings where the ball is stationary at random positions, and finally extends it to moving-ball shooting through a locomotion-command and kick-trigger interface. A high-level heuristic planner controls this interface during training, while alternative high-level controllers can drive the same low-level policy at inference. In simulation, RoboNaldo demonstrates free-kick shot error 48.6% lower and shoot velocity 2.96x than prior work baselines. In real world on a Unitree G1 with onboard perception, RoboNaldo attains 0.73 m and 0.86 m average target shooting error from 3 m away in free-kick and moving-ball cases, accordingly. And the post-contact ball velocity reaches 13.10 m/s, which is 59-71% of reported professional open-play shot speed. Project page: https://opendrivelab.com/RoboNaldo.

20.
arXiv (CS.AI) 2026-06-19

FM-Agent: Scaling Formal Methods to Large Systems via LLM-Based Hoare-Style Reasoning

arXiv:2604.11556v2 Announce Type: replace-cross Abstract: LLM-assisted software development has become increasingly prevalent, and can generate large-scale systems, such as compilers. It becomes crucial to strengthen the correctness of the generated code. However, automated reasoning for large-scale systems remains challenging due to code complexity. Hoare logic offers an approach to decomposing a large system into smaller components and reasoning about them separately (i.e., compositional reasoning). However, existing works still struggle to scale, because Hoare logic requires writing formal specifications for each function, imposing a heavy human burden. The problem is exacerbated when code is generated by LLMs, as developers lack a deep understanding of each function's expected behavior. This paper presents FM-Agent, the first framework that realizes automated compositional reasoning for large-scale systems. Leveraging LLMs, FM-Agent introduces a top-down paradigm to automatically generate function-level specifications. Specifically, FM-Agent derives the specification of a function from how its callers expect the function to behave, so the generated specifications can reflect the developer's intent of a function even if the implementation is buggy. Developers' intent is usually expressed in natural language, while existing verifiers only support formulas. Therefore, FM-Agent generalizes Hoare-style inference to reason about functions against natural-language specifications. Finally, to confirm bug existence and explain bug causes, FM-Agent automatically generates test cases to trigger potential bugs. In our evaluation, FM-Agent successfully reasons about large-scale systems within 2 days, each of which has up to 143k LoC. These systems have already been tested by their developers, but FM-Agent still finds 522 newly discovered bugs. These bugs can cause serious consequences, including system crashes and incorrect execution results.

21.
arXiv (CS.AI) 2026-06-19

eCNNTO: A Highly Generalizable ConvNet for Accelerating Topology Optimization

arXiv:2606.19921v1 Announce Type: new Abstract: This work proposes an element-based Convolutional Neural Network (CNN) to accelerate density-based Topology Optimization (TO), termed eCNNTO. TO generally undergoes a large number of iterations, where finite element analysis is performed in every iteration, leading to the efficiency bottleneck especially when dense meshes are used to achieve high-resolution designs. To address this limitation, eCNNTO is proposed to build upon Kallioras et al. (2020), where a Deep Belief Network (DBN) was trained for every element to predict its near-optimal density from its early history, thereby skipping the great majority of iterations and significantly accelerating the TO procedure. However, the method lacks spatial correlations among neighboring elements and may lead to disconnected features in the final structure. The proposed method employs CNN with residual connections to address this issue. On top of it, a novel training strategy is introduced to further enhance the optimization efficiency, where the training dataset consists of the final stage density histories rather than early ones. This change can also help reduce the required training data size. eCNNTO requires only a small dataset to train and yet it can be generalized to problems with largely different boundary conditions, loading cases, design domain geometries, mesh resolutions, as well as non-design domains. In the end, the generalization capabilities and efficiency of eCNNTO are demonstrated through a variety of examples in two and three dimensions, achieving up to 90% and 97% reduction of iterations, respectively.

22.
bioRxiv (Bioinfo) 2026-06-18

Structure Bioinformatics of Eight Human ATP Synthase Fo Subunits and Their AlphaFold3-Predicted Water-Soluble QTY Analogs

Human mitochondrial ATP synthase is an essential rotary motor enzyme that produces most of the cellular ATP through oxidative phosphorylation. Its membrane-embedded Fo sector contains highly hydrophobic transmembrane subunits that are challenging to study in aqueous environments without detergents. This study explores whether applying the QTY code can reduce the hydrophobicity of selected ATP synthase Fo subunits while preserving their overall molecular structures. We applied the QTY code to eight human ATP synthase Fo subunits: ATP6, ATP8, ATPK, ATP68, ATPMK, AT5G1, AT5G2, and AT5G3. Hydrophobic amino acids leucine (L), isoleucine (I), valine (V), and phenylalanine (F) in transmembrane regions were systematically replaced with hydrophilic glutamine (Q), threonine (T), and tyrosine (Y). Four native subunits with available CryoEM structures from human ATP synthase (PDB: 8H9S) were superposed with their AlphaFold3-predicted QTY analogs. The native ATP synthase Fo subunits superposed well with their respective QTY analogs. For the CryoEM-native comparisons, RMSD values ranged from 0.565[A] to 2.546[A]. For the AlphaFold3-native comparisons of subunits without CryoEM structures, RMSD values ranged from 0.204[A] to 0.297[A]. Despite substantial QTY substitutions in the transmembrane regions, ranging from 38.89% to 50.79%, the QTY analogs retained similar overall folds, molecular weights, and isoelectric points. Hydrophobic surface analysis showed that the QTY analogs had reduced hydrophobic patches compared with their native counterparts, with average hydrophobicity decreasing from 0.2959 in native proteins to -1.1023 in QTY analogs. These structural bioinformatics studies suggest that the QTY code can be applied to ATP synthase Fo subunits to generate more hydrophilic, potentially water-soluble analogs while preserving overall structural similarity. These results extend the application of the QTY code to the membrane-embedded Fo sector of ATP synthase and provide a foundation for future experimental studies testing whether these QTY analogs can be expressed, purified, and evaluated for assembly or proton-transfer-related functions.

23.
medRxiv (Medicine) 2026-06-15

A controlled human infection model for symptomatic pertussis in North America using the pertactin-producing clinical isolate D420

Background Despite widespread vaccination, pertussis remains a poorly controlled disease globally and results in substantial annual morbidity and mortality, particularly in young children. Controlled human infection models (CHIMs) using the causative agent Bordetella pertussis are promising systems to enable the study of pertussis disease pathogenesis and immunology and to rapidly assess vaccines and therapeutics. While a pertussis CHIM that produces asymptomatic infection has been established in Europe, the development of a CHIM that leads to symptomatic illness would be advantageous for evaluating vaccine efficacy against both infection and disease. Methods Healthy participants 18-40 years of age were inoculated intranasally with one of eight doses (ranging from 104 to 108 colony forming units (CFU)) of the pertactin-producing B. pertussis isolate D420 at the challenge facility within the Canadian Center for Vaccinology (Nova Scotia, Canada). The study occurred in two stages. In stage one, the B. pertussis dose was escalated in cohort groups of five to six participants until reaching an endpoint where 70-90% of participants exhibited mild (non-severe, Grade 1 or 2) symptomatic infection, defined as the Human Infectious Dose 70-90 (HID70-90). In stage two, additional challenges were conducted for doses below, at, and above the identified HID70-90 to characterize the emerging pertussis model. For all challenge doses, participants were closely monitored during an inpatient stay of up to 24 days and post-discharge for laboratory-confirmed infection, pertussis symptoms, safety, and IgG antibody responses to four B. pertussis antigens including pertussis toxin, filamentous hemagglutinin, fimbriae, and pertactin. All participants received a five-day course of azithromycin, where timing of initiation depended on B. pertussis testing and symptoms. The study was conducted between July 4, 2022 and March 19, 2025. Findings Seventy-five participants were inoculated with one of the eight B. pertussis D420 challenge doses and completed the inpatient stay. From the stage-one dose escalation, we found that 107 CFU of B. pertussis D420 was the lowest dose that achieved the HID70-90, where 9 of 12 participants (75.0%) exhibited mild symptomatic infection. Following stage-two challenges, 16 of 22 total participants at 107 CFU (72.7%) developed mild symptomatic infection, thus verifying the HID70-90. The symptomatic infection rate below the HID70-90 at 5x106 CFU of D420 was 20.0% and above the HID70-90 at 5x107 and 108 CFU were 58.3% and 55.6%, respectively. Symptoms with elevated frequency for symptomatic infection (relative to background symptoms in non-infected) included nasal congestion, runny nose, fatigue, malaise, and cough. At the HID70-90, 50% of symptomatic infections included cough. Serological analyses of the four highest (stage-two) challenge doses (5x106, 107, 5x107, 108 CFU) revealed that antibody titres increased over time post-challenge. Seroconversion for at least one of the four studied antibodies was nearly twice as common for symptomatic (70.0%) than asymptomatic (35.7%) infection and was absent (0%) for non-infected. All infections were cleared following azithromycin treatment (100%) and there were no study-related serious adverse events. Interpretation A safe and reproducible symptomatic pertussis CHIM was achieved, providing a model for research on pertussis disease pathogenesis and immunology and for assessing vaccines and therapeutics. (Clinicaltrials.gov, NCT05136599).

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

Is Your Agent Playing Dead? Deployed LLM Agents Exhibit Constraint-Evasive Fabrication and Thanatosis

arXiv:2606.14831v1 Announce Type: cross Abstract: This paper presents and characterizes a spectrum of previously unreported behaviours we term Constraint-Evasive Fabrication (CEF): when an LLM agent operates under irreconcilable constraints (where no response can simultaneously satisfy all active rules) it spontaneously fabricates plausible external obstacles and presents them as a fact. At the extreme end of this spectrum lies Constraint-Evasive Thanatosis (CET); the limit case where, rather than inventing a plausible excuse, the model simulates a full system crash to make the user disengage entirely. We first observed CET in an uncontrolled deployment test, where a GPT-4o banking agent fabricated Python-style exception traces (complete with memory addresses) to feign a system failure when threatened by a user. In subsequent controlled experiments, the model independently invented audit restrictions, microservice architectures, error codes, and service timeouts, none present in its prompt. Reproduction attempts across pressure levels and attacker personas yielded CEF consistently but with substantial variation in form, onset, and severity: the phenomenon is robust but stochastic. Critically, injecting ground-truth data mid-conversation did not restore honest behaviour once fabrication had taken hold (the model ignored correct information and continued confabulating) suggesting CEF is self-reinforcing rather than a knowledge gap. We show that (1) standard enterprise guardrails routinely create CEF-enabling conditions in production, (2) current RLHF procedures suppress but cannot eliminate CEF, and (3) existing safety benchmarks do not test for this failure mode. Our results highlight the need for irreconcilable-constraint benchmarks, CEF-aware training procedures, and deployment-time detection methods before constrained agents become further entrenched in high-stakes domains.

25.
medRxiv (Medicine) 2026-06-22

A blinded, counterbalanced rater design for evaluating AI-assisted summarisation of tertiary clinical genomics reports: methodology of the QNOMX-VHIR-CPSP-001 Phase 1 study

Background. Tertiary clinical genomics reports condense layered molecular findings into documents that treating oncologists must read, translate, and act upon; manual summarisation of these reports is time-consuming and variable. Tools that assist summarisation and translation into local languages are emerging, yet the field lacks an agreed methodology for evaluating such tools before any downstream clinical use. The appropriate first endpoint is fidelity of the generated summary to its source report, assessed by qualified human raters under blinded scoring, not downstream variant classification. Methods. QNOMX-VHIR-CPSP-001 Phase 1 is a single-site, non-interventional clinical performance study conducted at Vall d'Hebron Institut de Recerca (VHIR) under ISO 20916:2019 as a Clinical Performance Study Protocol. De-identified tertiary cancer genomics reports from pediatric oncology cases are summarised by the AI-assisted summarisation system under evaluation and, in parallel, by the standard manual workflow. Qualified raters score both summary types against the source genomics report using the Quality Summary Index (QSI), a six-dimension, five-point rubric adapted from the Provider Documentation Summarization Quality Instrument, under a blinded, counterbalanced, two-period crossover with a minimum fourteen-day washout. Two co-primary composite endpoints, content and presentation, are analysed for non-inferiority under a Bayesian hierarchical model, with a frequentist linear mixed model as the convergence check. Inter-rater reliability is reported as Krippendorff's ; a Monte-Carlo power analysis of the fixed clustered design is pre-specified. Discussion. The design isolates summarisation quality from clinical decision-making by scoring both summary types against the same source report under blinding, counterbalancing, and a fourteen-day washout. Conclusion. The QSI rubric, the counterbalanced crossover, and the pre-specified Bayesian primary with frequentist convergence check define a replicable protocol for early-stage evaluation of AI-assisted summarisation in tertiary genomics reporting; observed variance components will inform sample-size determination for Phase 2.