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01.
arXiv (CS.AI) 2026-06-11

LaQual: An Automated Framework for LLM App Quality Evaluation

arXiv:2508.18636v2 Announce Type: replace-cross Abstract: Representing a new paradigm in software distribution, LLM app stores are rapidly emerging, offering users diverse choices for content generation, coding assistance, education, and more. However, current ranking and recommendation mechanisms in LLM app stores predominantly rely on static metrics, such as user interactions and favorites, making it challenging for users to efficiently identify high-quality apps. At the same time, current academic research focuses on specific vertical fields and lacks a general, automated evaluation framework applicable to the diverse LLM app ecosystem. To address the above challenges, we present LaQual, an automated framework for LLM app quality evaluation. LaQual integrates three key stages: (1) LLM app labeling and hierarchical classification for precise scenario mapping; (2) static indicator evaluation using time-weighted user engagement and functional capability indicators to filter low-quality apps; and (3) dynamic scenario-adapted evaluation, where an LLM generates scenario-specific evaluation metrics, scoring criteria, and tasks for comprehensive quality evaluation. Experiments on a mainstream LLM app store demonstrate the effectiveness of LaQual. Its automated scores show high consistency with human judgments. Through effective screening, LaQual can reduce the candidate LLM app pool by 66.7% to 81.3%. User studies further validate its significant outperformance over baseline systems, particularly in comparison efficiency (mean 5.45 vs. 3.30) and value of explanatory information (4.75 vs. 2.25). These results demonstrate that LaQual provides a scalable, objective, and user-centric solution for high-quality discovery and recommendation of LLM apps in real-world scenarios.

02.
PLOS Medicine 2026-06-09

Prediction of hospitalisation in young children with pneumonia in Malawi: A machine learning-based approach

by Patrick Staunton, Mohammad Adib Makrooni, Master Chisale, Billy Nyambolo, Joseph Wu, Damien McCarthy, Mark Ledwidge, Yasir Bin Nisar, Chris Watson, Balwani Mbakaya, Cathal Seoighe, Joe Gallagher Background Globally, pneumonia remains the single biggest cause of mortality in children under 5 years of age. This study sought to train and test a prediction model for hospitalisation within 7 days after initial presentation in 2- to 59-month-old Malawian children with WHO-defined pneumonia in primary care and compare its performance to existing risk prediction models. Methods and findings BIOTOPE is a cohort study of children with pneumonia in a primary healthcare setting in Malawi. The training cohort involved nine primary care centres and the testing cohort involved two primary care centres in Northern Malawi. The training cohort was recruited between December 2022 and April 2023 while the testing cohort was recruited in 2016. Participants were consecutive children aged 2–59 months presenting with cough and/or difficulty breathing and who were diagnosed as WHO-defined pneumonia in primary care of any severity. The training cohort was used to train and validate a machine learning model with a prespecified primary outcome defined as hospitalisation and/or death within 7 days as the outcome. This model was then further evaluated in the testing cohort.Median age was 15 months (interquartile range 8−27) in the training and 17 months (interquartile range 9−29) in the external testing cohort (52.1% and 54.4% male, respectively). Hospitalisation occurred in 14.3% (294) of the training cohort and 12.1% (55) of the testing cohort. There was one death in the training cohort only. WHO danger signs were present in 17.6% (360) and 15.9% (70) of children in the training and testing cohorts, respectively. The optimal machine learning model achieved an area under the receiver operating characteristic and precision recall curves of 0.87 and 0.57, respectively, in the testing cohort outperforming existing risk prediction models; furthermore, this model produced an expected calibration error of 0.16 (a logistic regression model using severity status as the response variable and the log odds of the machine learning model’s calibrated probabilities produced an intercept estimate of −0.32 and a slope estimate of 1.13). Key limitations include the use of hospitalisation and/or death as a severity outcome, which may reflect health system factors rather than true disease severity, that mortality-based comparisons were not possible due to low mortality in these primary care cohorts, and that comparator tools were developed for hospital populations rather than primary care populations. Conclusion This machine learning score outperformed traditional pneumonia risk scores in predicting hospitalisation within 7 days in Malawian children presenting to primary care. Traditional pneumonia risk scores diminish in performance when externally applied to new datasets suggesting they may not generalise well beyond their original derivation settings. Mortality-related findings are not applicable as there was only one death in this cohort. Overall these findings support the potential of machine learning to meaningfully improve early identification of children at risk of severe pneumonia in low-resource primary care settings. Further external validation and clinical impact studies are needed to confirm these results.

03.
arXiv (CS.AI) 2026-06-19

Towards Engineering Scaling Laws with Pretraining Data Composition

arXiv:2606.19781v1 Announce Type: cross Abstract: Neural scaling laws describe how model performance improves as a power law in compute, model size, and dataset size. While well-established for large language models, these relationships are emerging for large models in particle physics. As with language, empirical studies show that the performance scales as a power law. However, unlike natural language or image domains, fundamental physics has high-fidelity simulators that produce synthetic data cheaply. This favors scaling regimes where additional data is cheaper than additional parameters, and allows the pretraining dataset itself to be engineered to influence the scaling. For the task of classifying hadronic jets produced in collisions of high-energy particle beams, we show that the scaling behavior can be engineered towards requiring more data rather than larger models by inclusion of pretraining data which is more diverse and better aligned with the downstream classification task.

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

Adaptive Model-Predictive Control of a Soft Continuum Robot Using a Physics-Informed Neural Network Based on Cosserat Rod Theory

arXiv:2508.12681v3 Announce Type: replace-cross Abstract: Dynamic control of soft continuum robots (SCRs) holds great potential for expanding their applications, but remains a challenging problem due to the high computational demands of accurate dynamic models. While data-driven approaches like Koopman-operator-based methods have been proposed, they typically lack adaptability and cannot reconstruct the full robot shape, limiting their applicability. This work introduces a real-time-capable nonlinear model-predictive control (MPC) framework for SCRs based on a domain-decoupled physics-informed neural network (DD-PINN) with adaptable bending stiffness. The DD-PINN serves as a surrogate for the dynamic Cosserat rod model with a speed-up factor of up to 44,000. It is also used within an unscented Kalman filter for estimating the model states and bending compliance from end-effector position measurements. We implement a nonlinear evolutionary MPC running at 70 Hz on the GPU. In simulation, it demonstrates accurate tracking of dynamic trajectories and setpoint control with end-effector position errors below 3 mm (2.3\% of the actuator's length). In real-world experiments, the controller achieves similar accuracy and accelerations up to 3.55 m/s2.

07.
arXiv (math.PR) 2026-06-16

Logarithmic Large Deviations for Heavy-Tailed Sums

arXiv:2606.16487v1 Announce Type: new Abstract: We establish logarithmic large-deviation bounds for sums of independent nonnegative random variables with regularly varying tails. The normalization is chosen at the extreme-value scale and the speed is $\log n$. In contrast with Cramér's theorem, the resulting rate function is determined only by the tail index. The proof transfers a maximum large-deviation principle to sums in the one-big-jump region.

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

Achieving High-Quality Portfolio Optimization with the Variational Quantum Eigensolver

arXiv:2508.18625v2 Announce Type: replace Abstract: Portfolio optimization lies at the core of quantitative finance and aims to determine how assets should be allocated to balance expected returns against risk. It can be formulated as a Quadratic Unconstrained Binary Optimization (QUBO) problem, which is NP-hard. Quantum computing offers the potential to solve such problems more efficiently than classical methods. In this work, we employ the Variational Quantum Eigensolver (VQE) to address the portfolio optimization problem. To increase the likelihood of converging to high-quality solutions, we propose using the Weighted Conditional Value-at-Risk (WCVaR) as the cost function and the Covariance Matrix Adaptation Evolution Strategy (CMA-ES) as the optimizer. Our experiments are conducted using both classical simulations and quantum hardware on the Wuyue QuantumAI platform. Together, these results demonstrate that the combination of WCVaR and CMA-ES improves the performance of VQE for portfolio optimization and provides a practical route for applications on NISQ devices.

09.
arXiv (CS.LG) 2026-06-12

Evaluation of AutoML Frameworks for IDS under Imbalanced Data Conditions of the NSL-KDD Dataset

arXiv:2606.12611v1 Announce Type: new Abstract: This work investigates the impact of severe class imbalance on the performance of automated machine learning (AutoML) frameworks for multiclass network intrusion detection using the NSL-KDD dataset. Unlike previous studies that simplify the problem through binary classification or minority-class removal, we preserve the original five-class distribution, including highly underrepresented attacks such as R2L and U2R, enabling a realistic evaluation of imbalance-sensitive learning behavior. Nine open-source AutoML frameworks were analyzed under a unified and reproducible experimental protocol, considering differences in architectural design, ensemble strategies, validation procedures, hyperparameter optimization, and imbalance-handling mechanisms. The results demonstrate that frameworks incorporating ensemble learning and imbalance-aware optimization achieve better minority-class discrimination. PyCaret obtained the best overall performance, reaching 66\% macro-F1, followed by AutoGluon with 55\%, whereas frameworks lacking native balancing support exhibited significant degradation in minority-class detection capability. The analysis further shows that accuracy-oriented optimization alone is insufficient for highly imbalanced IDS scenarios, since high-weighted metrics may coexist with poor generalization on rare attack categories. As a contribution, this work establishes a standardized benchmark for AutoML-based intrusion detection under severe multiclass imbalance, highlighting current architectural limitations and the need for native integration of imbalance-aware optimization, resampling, and stratified evaluation strategies into automated learning pipelines. The source code is publicly available.

10.
arXiv (math.PR) 2026-06-12

Symmetric Cooperative Motion in Higher Dimensions

arXiv:2606.13459v1 Announce Type: new Abstract: We prove a distributional convergence result for a multidimensional version of symmetric cooperative motion which was introduced and studied in one dimension in [HRW, SCM1]. Our approach relies on framing the associated recursive distributional equation as a discretization of the porous medium equation. A major challenge is to analyze the behaviour of finite difference schemes which approximate weak solutions of the porous medium equation with unbounded initial data. In overcoming this difficulty, we perform a detailed analysis of the probability mass function of symmetric cooperative motion, in which we introduce several new comparison arguments for the discrete process. Consequently, along the way, we establish a novel multidimensional convergence result for a finite difference scheme approximating the ZKB/Barenblatt solution of the porous medium equation, which is of independent interest.

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

Empirical Study of Pop and Jazz Mix Ratios for Genre-Adaptive Chord Generation

作者:

arXiv:2605.04998v2 Announce Type: replace-cross Abstract: This revision updates a pop-to-jazz chord-generation rehearsal study. Best-epoch metrics still show that modest pop rehearsal preserves pop accuracy while improving jazz prediction, but v2 corrects released-checkpoint selection: the released F1 equals Phase 0, F2 had a transcription error, and ft-pop80-v2 restores a hash-distinct jazz-adapted F1 across 3 seeds.

13.
arXiv (CS.CV) 2026-06-11

From Content to Knowledge: Lightning Fast Long-Video Understanding with Neural Knowledge Representations

We propose a new paradigm for long video understanding by treating a long video as a Neural Knowledge Representation (NKR). NKR represents video contents neither as a stream of tokens nor pre-organized databases, but as an individual small portion of network weights attached to the VLM backbone. The NKR weights are optimized to encapsulate the video's semantic content via a novel Agentic Knowledge Distillation (AKD) process, where an agent automatically synthesizes dense descriptions and question-answer pairs to distill the video's knowledge into the NKR. While AKD serves as a comprehensive, one-time encoding phase, the resulting NKR transforms the video into a portable, reusable asset. At inference, the lightweight NKR is mounted onto a frozen Vision-Language Model (VLM), enabling direct, query-based understanding without reloading or re-encoding the original video. This approach decouples video length from inference cost, offering high amortized efficiency for multi-turn video understanding. Experiments on the LVBench benchmark show our method achieves performance comparable to state-of-the-art approaches while reducing end-to-end latency by over two orders of magnitude, opening new possibilities for interactive long-video understanding.

14.
arXiv (CS.LG) 2026-06-11

Calibrating Decision Robustness via Inverse Conformal Risk Control

arXiv:2510.07750v3 Announce Type: replace-cross Abstract: Robust optimization safeguards decisions against uncertainty by optimizing against worst-case scenarios, yet their effectiveness hinges on a prespecified robustness level that is often chosen ad hoc, leading to either insufficient protection or overly conservative and costly solutions. Recent approaches using conformal prediction construct data-driven uncertainty sets with finite-sample coverage guarantees, but they still fix coverage targets a priori and offer little guidance for selecting robustness levels. We propose a new framework that provides distribution-free, finite-sample guarantees on both miscoverage and regret for any family of robust predict-then-optimize policies. Our method constructs valid estimators that trace out the miscoverage–regret Pareto frontier, enabling decision-makers to reliably evaluate and calibrate robustness levels according to their cost–risk preferences. The framework is simple to implement, broadly applicable across classical optimization formulations, and achieves sharper finite-sample performance. This paper offers a principled data-driven methodology for guiding robustness selection and empowers practitioners to balance robustness and conservativeness in high-stakes decision-making.

15.
arXiv (quant-ph) 2026-06-17

On the entanglement induced by the deformation of phase-space

arXiv:2606.17587v1 Announce Type: new Abstract: Most quantum gravity theories propose that the fundamental concept of space-time is mostly compatible with quantum theory in noncommutative (NC) space. In the present paper, we revisit the notion of entanglement induced by NC deformations of phase space. The positive partial transpose (PPT) criterion for separability of bipartite Gaussian states is extended to a general class of Bopp's shift. In particular, we have considered both the position-position and momentum-momentum noncommutativity, with deformation parameters $\theta$ and $\eta$, respectively. It turns out that $\theta$ and $\eta$ induce the entanglement. We have directly applied the formalism for an anisotropic two-dimensional harmonic oscillator. Peres-Horodecki separability condition leads to a constraint equation for the parameter values of the oscillator in NC space. It turns out that the bipartite Gaussian state is almost always entangled in deformed space. To implement the theoretical idea, we provide an outline for a gedankenexperiment to identify the signature of phase-space noncommutativity, i.e., quantum gravity. In particular, the gedankenexperiment is devised to test the separability of supposedly separable Gaussian states in the usual commutative space, through the covariance matrix, which is constructed via measured output photocurrents after interaction of input Gaussian states and reference states. If the experiment shows that the supposedly separable states are actually entangled, then the entanglement is created through the intermediate background noncommutative space, which is a signature of the quantum nature of gravity.

16.
arXiv (math.PR) 2026-06-19

On creating convexity in high dimensions

arXiv:2502.10382v3 Announce Type: replace-cross Abstract: Given a subset $A$ of $\mathbb{R}^n$, we define \begin{align*} \mathrm{conv}_k(A) := \left\{ \lambda_1 s_1 + \cdots + \lambda_k s_k : \lambda_i \in [0,1], \sum_{i=1}^k \lambda_i = 1 , s_i \in A \right\} \end{align*} to be the set of vectors in $\mathbb{R}^n$ that can be written as a $k$-fold convex combination of vectors in $A$. Let $\gamma_n$ denote the standard Gaussian measure on $\mathbb{R}^n$. We show that for every $\varepsilon > 0$, there exists a subset $A$ of $\mathbb{R}^n$ with Gaussian measure $\gamma_n(A) \geq 1- \varepsilon$ such that for all $k = O_\varepsilon(\sqrt{\log \log(n)})$, $\mathrm{conv}_k(A)$ contains no convex set $K$ of Gaussian measure $\gamma_n(K) \geq \varepsilon$. This result acts as a complement to the recent affirmative resolution of Talagrand's convexity conjecture by Hua, Song, and Tudose, which states that a universal dilation of the threefold Minkowski sum $A+A+A$ of a large set $A$ guarantees a large convex subset. Our approach utilises concentration properties of random copulas and the application of optimal transport techniques to the empirical coordinate measures of vectors in high dimensions.

17.
arXiv (CS.LG) 2026-06-12

$\alpha$-fair heterogeneous agent reinforcement learning

arXiv:2606.13076v1 Announce Type: cross Abstract: Cooperation in multi-agent systems is typically optimized through utilitarian objectives that maximize overall efficiency but fail to account for reward distribution, often resulting in inequitable "leader-follower" dynamics. While fairness-based approaches encourage pro-social behaviors where every agent benefits from cooperation, many current algorithms - including those utilizing reward shaping - break the stationarity of Markov Games or lack rigorous theoretical guarantees. This creates a critical gap between fair objective methods and theoretically safe learning frameworks. We propose a novel framework that bridges $\alpha$-fairness with Heterogeneous-Agent Trust Region Learning (HATRL), ensuring monotonic improvement and convergence toward Nash Equilibria. Our approach leverages a fair advantage function that dynamically weights agent utilities based on their expected returns, allowing the global objective to transition from purely utilitarian efficiency to $\alpha$-fairness welfare based on the parameter $\alpha$. We introduce two practical algorithms, $\alpha$-fair HATRPO and $\alpha$-fair HAPPO, and demonstrate through experiments in sequential social dilemmas like CleanUp and CommonHarvest that they perform better than HATRL's algorithms from a utilitarian point of view while achieving socially higher outcomes.

18.
medRxiv (Medicine) 2026-06-15

Evaluation of AI-Generated Synthetic Data for Clinical Research in Secondary Cardiovascular Prevention among Dyslipidemia Patients

Background: Access to high-quality clinical data is essential for advancing medical research and developing effective medical statistical and Artificial Intelligence models. However, privacy regulations and logistical barriers often hinder timely access to real-world data. Synthetic data offer a promising solution, preserving the statistical characteristics of original datasets while protecting patient privacy. Objectives: This study investigates the use of synthetic data for secondary cardiovascular prevention in patients with dyslipidemia, using two real-world datasets from Centro Cardiologico Monzino. Methods: Given the high dimensionality and limited sample size of the datasets, we employed a custom generative framework based on Large Language Models (LLMs). Pre-trained LLMs were fine-tuned on original clinical records to synthesize tabular data replicating source-data distributions. Fine-tuning was performed within the Centro Cardiologico Monzino's secure infrastructure to ensure data sovereignty. We evaluate clinical utility and privacy using fidelity and privacy metrics, identifying the optimal generative model and benchmarking against traditional anonymization methods. Results: Synthetic data achieved a superior trade-off than classically anonymized datasets. Real and synthetic datasets showed strong agreement, with significant distributional differences limited to few variables. Models trained on synthetic data replicated key associations from the original dataset, including therapy modification and creatine phosphokinase as predictors of SAMS, and pharmacological intensity as the main driver of LDL-C reduction. Conclusions: Results support the feasibility of using synthetic data as a proxy for real-world datasets in exploratory analyses and model development. Despite slight attenuation of some effect sizes, preserved clinical relationships reinforce the validity of synthetic data in medical research.

19.
arXiv (CS.CL) 2026-06-16

Evaluating the Robustness of Proof Autoformalization in Lean 4

Proof autoformalization aims to translate a mathematical informal proof written in natural language into a formal proof in a formal language such as Lean~4. Several works have developed LLM-based models for proof autoformalization. However, existing evaluations have typically focused on translating well-formed informal proofs from curated datasets. We argue that a robust proof autoformalizer must remain faithful even for informal proofs that diverge from these idealized ones, and we present the first study on the robustness of proof autoformalization models. We formulate two categories of perturbations and evaluate robustness under each: a global perturbation paraphrases the informal proof in a different style, under which the formalization should remain consistent; a local perturbation alters a value, symbol, or proof step, possibly in a counterfactual way, and a robust formalization should faithfully reflect the perturbation rather than reverting to the original one or inferring a different one on its own. We build a benchmark with both perturbations on miniF2F and MATH-500, and automatically measure how stable a proof autoformalization's correctness is under global perturbations and how faithfully its output reflects local perturbations. We evaluate seven recent models, all of which are sensitive to global perturbations and mostly fail to remain faithful under local perturbations. Code and data are available via https://github.com/ucr-rai/robust-proof-autoformalization.

20.
Science (Express) 2026-05-06

A 481-meter-high landslide-tsunami in a cruise ship–frequented Alaska fjord | Science

作者: 未知作者

Early in the morning of 10 August 2025, a >64 × 10 6 m 3 landslide struck Tracy Arm fjord in Alaska. The landslide was preconditioned by glacial retreat caused by climate change. The resulting 481 m runup megatsunami followed an initial 100-m-high breaking wave traveling >70 m s −1 . The landslide was preceded by several days of microseismicity, which increased in rate and magnitude until ~1 hour before failure. The landslide produced globally observed long-period seismic waves equivalent in size to a M5.4 earthquake. A long-period (~66 s) global seismic signal, produced by a landslide-induced seiche trapped within the fjord, persisted for up to 36 hours, the second time a days-long seiche has been thus observed. With fjord regions increasingly visited by cruise ships, and climate change making similar events more likely, this unanticipated, near-miss event highlights the growing risk from landslides and tsunamis in coastal environments.

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

BadWorld: Adversarial Attacks on World Models

Visual world models (VWMs) synthesize interactive, action-conditioned rollouts from a single context image. However, it remains an open question how robust these models are to adversarial perturbations. Standard adversarial attacks fail to assess this vulnerability because attackers lack ground-truth future videos and cannot predict subsequent user controls. We introduce BadWorld, a label-free adversarial framework tailored for autoregressive VWMs that systematically overcomes both constraints. First, to bypass the need for future supervision, we propose a self-supervised velocity attack that directly disrupts the early denoising dynamics of the model. Second, to ensure the attack generalizes across unpredictable user actions, we formulate a trajectory-adaptive bi-level optimization that actively mines hard control sequences to forge control-agnostic perturbations. Evaluated on representative VWMs with continuous and discrete controls, BadWorld exposes severe structural fragility. Visually indistinguishable adversarial images reliably trigger catastrophic degradation in future rollouts, leading to incomplete denoising, structural collapse, and control inconsistency. These findings reveal critical risks for deploying VWMs in safety-critical systems while highlighting a practical mechanism for privacy protection.

22.
arXiv (CS.CV) 2026-06-18

DreamReg: Belief-Driven World Model for 2D-3D Ultrasound Registration

Ultrasound (US) is widely used for surgical navigation, yet real-time registration between intraoperative 2D slices and preoperative 3D volumes remains challenging due to partial observability, speckle noise, and the action-dependent US acquisition. Existing methods are one-shot or short-horizon, making it hard for them to gather evidence over time or capture how surgeons adjust probe motion based on on-screen feedback. We propose DreamReg, a belief-driven world-model framework that formulates 2D-3D registration as belief updating over rigid transformations. DreamReg maintains a latent belief state that summarizes past observations and poses information, and continuously refines the transformation through learned dynamics as new slices arrive. During training, DreamReg is exposed to probe-motion trajectories that mimic clinical scanning behavior and learns to update its belief by conditioning pose refinement on the current US observation. During inference, DreamReg refines registration via internal imagination: it rolls out the learned world model to simulate candidate probe motions and their predicted observations, and integrates these imagined outcomes to converge to an accurate rigid transformation. Experiments on CAMUS and u-RegPro datasets demonstrate improved robustness and competitive registration accuracy for real-time guidance compared with state-of-the-art methods.

23.
arXiv (CS.AI) 2026-06-17

Position: Modular Memory is the Key to Continual Learning Agents

arXiv:2603.01761v2 Announce Type: replace-cross Abstract: Foundation models have transformed machine learning through large-scale pretraining and increased test-time compute. Despite surpassing human performance in several domains, these models remain fundamentally limited in continuous operation, experience accumulation, and personalization, capabilities that are central to adaptive intelligence. While continual learning research has long targeted these goals, its historical focus on in-weight learning (IWL), i.e., updating a single model's parameters to absorb new knowledge, has rendered catastrophic forgetting a persistent challenge. Our position is that combining the strengths of In-Weight Learning (IWL) and the newly emerged capabilities of In-Context Learning (ICL) through the design of modular memory is the missing piece for continual adaptation at scale. We outline a conceptual framework for modular memory-centric architectures that leverage ICL for rapid adaptation and knowledge accumulation, and IWL for stable updates to model capabilities, charting a practical roadmap toward continually learning agents.

24.
medRxiv (Medicine) 2026-06-10

Towards the Virtual Amyotrophic Lateral Sclerosis Patient: Inferring Cortical Excitability through Whole-Brain Dynamical Modeling

Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a multisystem neurodegenerative disorder in which motor-neuron degeneration is accompanied by widespread alterations in cortical dynamics. Among its most reproducible neurophysiological signatures is cortical hyperexcitability, yet how this local excitability imbalance shapes distributed whole-brain activity remains poorly understood. Here, we combined source-reconstructed resting-state MEG data, tractography-informed whole-brain modeling, and simulation-based inference to investigate whether ALS-related alterations in large-scale brain dynamics can be mechanistically explained by changes in cortical excitability. First, we characterized empirical brain dynamics using complementary features spanning regional activity amplitude and variability, functional connectivity, and avalanche-based metrics. These analyses revealed significant alterations in ALS patients relative to healthy controls, as well as associations with clinical impairment and disease staging. To mechanistically interpret these changes, we employed a reduced Wong-Wang whole-brain model in which local recurrent excitation modulates emergent large-scale neural dynamics. Simulations showed that increasing excitability systematically reproduced the empirical dynamical signatures observed in ALS. We then applied a simulation-based inference framework to estimate latent excitability parameters directly from empirical observations. Whole-brain model inversion revealed increased excitability in ALS patients compared with controls. The recovered excitability parameter was associated with disease staging, supporting its clinical relevance as a model-derived descriptor of ALS progression. Finally, by extending the model to estimate frontal and non-frontal excitability separately, we found that ALS-related alterations were predominantly associated with increased frontal excitability, whereas non-frontal regions appeared comparatively less affected. The recovered parameters related to disease staging. Together, these findings provide a mechanistic framework linking altered large-scale brain dynamics in ALS to selective cortical hyperexcitability, explaining how local excitability changes can give rise to global network reorganization. More broadly, they show how computational model inversion can recover latent multiscale pathophysiological processes from empirical neural recordings, offering a non-perturbative alternative to complex experimental paradigms typically required to causally probe local-to-global mechanisms.

25.
PLOS Medicine 2026-06-18

Association between initial benzodiazepine prescribing patterns and time to benzodiazepine discontinuation: A population-based retrospective cohort study

by Nikki Bozinoff, Tanya S. Hauck, Robert A. Kleinman, Matthew E. Sloan, Beth A. Sproule, Simone N. Vigod, Jennifer Wyman, Priscila Pequeno, Tara Gomes Background Long-term benzodiazepine use has been associated with increased risk of morbidity and mortality. Preventing long-term use through safer prescribing practices has received little attention to date. We sought to better understand associations between initial prescription characteristics and duration of benzodiazepine use. Methods and findings This was a retrospective population-based cohort study of 1,820,808 adults in Ontario with incident benzodiazepine prescriptions between January 1, 2013 and December 31, 2020, with follow-up to December 31, 2021. The primary exposure was duration of the index prescription (≤7 days—referent group, 8–14 days, 15–30 days, or >30 days). Secondary exposures were: (a) duration of action of index benzodiazepine(s) prescription (short-acting, long-acting or both); (b) number of benzodiazepine dispensed on index (1 or 2+); and (c) mean daily dose of the index prescription in Diazepam Milligram Equivalents (DMEs). The primary outcome was time to benzodiazepine discontinuation in days. Multivariable models were adjusted for age, sex, anxiety, insomnia, and substance use disorders as well as other important comorbidities and socio-demographic characteristics. The median age at index was 53 years (Interquartile Range (IQR) 38–67), and 62.6% were women. The median time to discontinuation in women was 16 days (IQR: 6–29) while the median time to discontinuation in men was 19 days (IQR: 6–29). Lorazepam was the most commonly prescribed benzodiazepine on index (63.9%), followed by clonazepam (17.3%) and diazepam (5.8%). In multivariable Cox Proportional Hazards Models, longer index prescriptions were associated with a lower likelihood of benzodiazepine discontinuation (adjusted Hazard Ratio (aHR) 0.54 (95% Confidence Interval (CI) [0.54,0.54]) for 8–14 days; aHR 0.26 (95% CI [0.25,0.26] for 15–30 days and aHR 0.14 (95% CI [0.14,0.14]) for >30 days, compared to ≤7 days, respectively). Being prescribed two or more benzodiazepines versus 1 was also associated with a reduced likelihood of discontinuation (aHR 0.59 (95% CI [0.57,0.61])), as was being prescribed long-acting benzodiazepines (aHR 0.80 (95% CI [0.80,0.80])) or a combination of short and long acting benzodiazepine (aHR 0.84 (95% CI [0.80,0.88])) versus short-acting benzodiazepines alone. Mean daily doses of >5 to ≤10 DME and >10 to ≤20 DME were associated with an increased likelihood of discontinuation (aHR 1.03 (95% CI [1.03,1.03]); aHR: 1.03 (95% CI [1.03,1.04])), whereas doses >20 DME were associated with a reduced likelihood of discontinuation (aHR 0.98 (95% CI [0.97,0.98])) compared with ≤5 DME. Findings may be subject to bias from unmeasured confounding. Conclusion This large population-based cohort study found that prescribing shorter courses of benzodiazepines, use of a single benzodiazepine, use of a short-acting agent, were associated with reduced likelihood of long-term benzodiazepine use. Findings suggest that simple changes to prescribing practices could reduce prolonged benzodiazepine use and the morbidity and mortality associated with long-term use of these medications.