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

NanoQuant: Efficient Sub-1-Bit Quantization of Large Language Models

arXiv:2602.06694v3 Announce Type: replace Abstract: Weight-only quantization has become a standard approach for efficiently serving large language models (LLMs). However, existing methods fail to efficiently compress models to binary (1-bit) levels, as they either require large amounts of data and compute or incur additional storage. In this work, we propose NanoQuant, the first post-training quantization (PTQ) method to compress LLMs to both binary and sub-1-bit levels. NanoQuant formulates quantization as a low-rank binary factorization problem, and compresses full-precision weights to low-rank binary matrices and scales. Specifically, it utilizes an efficient alternating direction method of multipliers (ADMM) solver to precisely initialize latent binary matrices and scales, and then tunes the initialized parameters through a block and model reconstruction process. Consequently, NanoQuant establishes a new Pareto frontier in low-memory post-training quantization, and enables sub-1-bit compression. NanoQuant makes large-scale deployment feasible on consumer hardware. For example, it compresses Llama2-70B by 25.8$\times$ in just 13 hours on a single H100, enabling a 70B model to operate on a consumer 8 GB GPU. Code is available at https://github.com/SamsungLabs/NanoQuant.

02.
arXiv (CS.CV) 2026-06-12

Plug-and-Play image restoration with Stochastic deNOising REgularization

Plug-and-Play (PnP) algorithms are a class of iterative algorithms that address image inverse problems by combining a physical model and a deep neural network for regularization. Even if they produce impressive image restoration results, these algorithms rely on a non-standard use of a denoiser on images that are less and less noisy along the iterations, which contrasts with recent algorithms based on Diffusion Models (DM), where the denoiser is applied only on re-noised images. We propose a new PnP framework, called Stochastic deNOising REgularization (SNORE), which applies the denoiser only on images with noise of the adequate level. It is based on an explicit stochastic regularization, which leads to a stochastic gradient descent algorithm to solve ill-posed inverse problems. A convergence analysis of this algorithm and its annealing extension is provided. Experimentally, we prove that SNORE is competitive with respect to state-of-the-art methods on deblurring and inpainting tasks, both quantitatively and qualitatively.

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

Beyond Models: Reflections on Engineering AI-enabled Systems in a Project-Based Course

arXiv:2606.16842v1 Announce Type: cross Abstract: Teaching Software Engineering for AI-enabled systems entails addressing the integration of AI components within full-scale software architectures under realistic constraints. While machine learning courses emphasize model development, students often lack experience in architectural design, deployment, and monitoring of AI-enabled systems. Empirical evaluations of such system-oriented AI courses remain limited. This paper reflects on the design and implementation of a project-based master's-level course titled AI Algorithms: Theory and Engineering, at the University of Bremen, in which students developed a movie recommendation system while making architectural design decisions to address challenges related to scalability, deployment, and evolving requirements. We conducted a mixed-methods study combining analyses of student submissions and questionnaire responses to investigate integration challenges, learning outcomes, and opportunities for improvement. Our results indicate persistent difficulties in early architectural decisions, heterogeneous ML integration, evolving requirements, and data management, largely due to uneven ML and software engineering expertise. From the educator's perspective, the course fostered system-level reasoning and strengthened awareness of data-centric ML practices in AI-enabled systems.

04.
arXiv (quant-ph) 2026-06-17

Tungsten Germanide Superconducting Nanowire Single-Photon Detectors with Saturated Internal Detection Efficiency at Wavelengths up to 29 {\mu}m

arXiv:2511.20868v2 Announce Type: replace-cross Abstract: Superconducting nanowire single-photon detectors (SNSPDs) are among the most sensitive single-photon detectors available and have the potential to transform fields ranging from infrared astrophysics to molecular spectroscopy. However, extending their performance into the mid-infrared spectral region - crucial for applications such as exoplanet transit spectroscopy and vibrational fingerprinting of molecules - has remained a major challenge, primarily due to material limitations and scalability constraints. Here, we report on the development of SNSPDs based on tungsten germanide, a novel material system that combines high mid-infrared sensitivity with compatibility for large-scale fabrication. Our detectors exhibit saturated internal detection efficiency at wavelengths up to 29 {\mu}m, while using 2.7x thicker films (8 nm vs 3 nm) and up to 4.5x wider nanowires (360 nm vs 80 nm) compared to mid-infrared-optimized SNSPDs fabricated from tungsten silicide. This advance will enable scalable, high-performance single-photon detection in a spectral region that was previously inaccessible, opening new frontiers in remote sensing, thermal imaging, environmental monitoring, molecular physics, and astronomy.

05.
arXiv (CS.LG) 2026-06-19

A deep learning framework for jointly solving transient Fokker-Planck equations with arbitrary parameters and initial distributions

arXiv:2604.06001v2 Announce Type: replace-cross Abstract: Efficiently solving the Fokker-Planck equation (FPE) is central to analyzing complex parameterized stochastic systems. However, current numerical methods lack parallel computation capabilities across varying conditions, severely limiting comprehensive parameter exploration and transient analysis. This paper introduces a deep learning-based pseudo-analytical probability solution (PAPS) that, via a single training process, simultaneously resolves transient FPE solutions for arbitrary multi-modal initial distributions, system parameters, and time points. The core idea is to unify initial, transient, and stationary distributions via Gaussian mixture distributions (GMDs) and develop a constraint-preserving autoencoder that bijectively maps constrained GMD parameters to unconstrained, low-dimensional latent representations. In this representation space, the panoramic transient dynamics across varying initial conditions and system parameters can be modeled by a single evolution network. Extensive experiments on paradigmatic systems demonstrate that the proposed PAPS maintains high accuracy while achieving inference speeds four orders of magnitude faster than GPU-accelerated Monte Carlo simulations. This efficiency leap enables previously intractable real-time parameter sweeps and systematic investigations of stochastic bifurcations. By decoupling representation learning from physics-informed transient dynamics, our work establishes a scalable paradigm for probabilistic modeling of multi-dimensional, parameterized stochastic systems.

06.
medRxiv (Medicine) 2026-06-11

Association between depressive symptoms and physical function among participants with heart disease in the Reasons for Geographic And Racial Differences in Stroke (REGARDS) study.

Background: Depression and heart disease frequently co-occur in the aging population and are associated with functional decline and poor health outcomes. Understanding how depressive symptoms relate to different aspects of physical function among adults with heart disease may help identify high-risk subgroups. Objective: To examine the association of depressive symptoms with self-reported and observed physical function measures among participants with heart disease in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study and assess whether associations differ by sex and race?sex groups. Methods: We conducted a cross-sectional analysis using data from REGARDS study second in-home visit (2013?2016). Depressive symptoms were measured with the 10-item Center for Epidemiologic Studies Depression scale (CES D 10), considering scores ?10 as clinically significant. Physical function measures were instrumental activities of daily living (IADL), activities of daily living (ADL), chair stand time (5 repetitions), and gait speed. Linear regression models estimated associations of depressive symptoms with function, adjusting for sociodemographic, health behavior, antidepressant medications, body mass index, and social support. Effect modification by sex and race?sex group was evaluated. Results: Among 3,055 participants, 11.7% had CES D 10 ?10. Compared to CES-D-10 scores

07.
arXiv (CS.LG) 2026-06-17

Memory-Efficient Meta-Reinforcement Learning for Adaptive Safety-Critical Control in Adversarial Spacecraft Proximity Operations

arXiv:2606.17414v1 Announce Type: new Abstract: Autonomous spacecraft rendezvous and proximity operations (RPO) require controllers that guarantee safety under thrust constraints while minimizing fuel expenditure. Input-constrained control barrier functions (ICCBFs) provide a control method for nonlinear systems with actuation constraints that construct a forward-invariant safe set. Previous work has shown that learning class-$\mathcal{K}$ functions defining the ICCBF recursion via meta reinforcement learning (meta-RL) yields a robust, non-greedy approach to safety-critical control in RPO. This paper extends that framework further by investigating the performance of three recurrent network architectures (Long Short Term Memory (LSTM), Gated Recurrent Unit (GRU), Selective State Space Model (Mamba)) and two training algorithms (Proximal Policy Optimization (PPO) and Soft Actor Critic (SAC)) to identify the best setup for tuning ICCBF class-K functions via meta-RL. In addition to cooperative test cases, performance is evaluated in the presence of adversarial behavior where the target spacecraft behaves in a way that worsens the safety of the chaser spacecraft. Results indicate that state space models such as Mamba when used with PPO achieve superior task completion, safety, and fuel-savings compared to other architectures, across all cooperative and uncooperative scenarios tested.

08.
arXiv (CS.CL) 2026-06-16

How Far Can Machine Translation Quality Take You? Extrinsic Discourse Evaluation in Goal-Oriented Setups

Existing machine translation (MT) metrics and discourse-focused evaluations primarily assess translation quality intrinsically, without measuring the downstream consequences of translation errors. In this work, we focus on extrinsic discourse evaluation of machine translation under two distinct regimes: static and interactive. Under the static regime, we propose an entity counting task as a probe of referential consistency in discourse. We show that high intrinsic MT quality does not reliably predict downstream discourse success and strong MT systems still produce referential inconsistencies. For the interactive regime, we study the goal-oriented multi-agent Welfare Diplomacy game as a probe of long-horizon communication and coordination. We find that interaction-specific translation failures impact downstream coordination. Our results highlight goal-oriented environments as a viable framework for discourse-sensitive extrinsic MT evaluation.

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

A Spatio-Temporal Expert Prefetching Framework for Efficient MoE-based LLM Inference

arXiv:2606.15453v1 Announce Type: cross Abstract: Mixture-of-Experts (MoE) based large language models (LLMs), such as Qwen and DeepSeek, have recently emerged as an effective approach to improving model capacity without proportionally increasing computational cost. By replacing the conventional feed-forward network in dense LLMs with a set of experts and activating only a subset of them for each input token, MoE models significantly increase the total number of parameters while keeping the per-token computation relatively manageable. However, this dynamic and irregular expert activation pattern also introduces substantial expert loading overhead during inference, since the required experts must be fetched on demand according to token-dependent routing results. As a result, expert loading latency becomes a major source of performance and energy inefficiency. To this end, we first perform a comprehensive analysis of expert selection behavior in various MoE-based LLMs and applications, including language understanding and code generation. Our analysis reveals that, within each application domain, expert requests exhibit strong correlation across both adjacent MoE layers and consecutive decoding tokens, making future expert activations predictable. Based on this insight, we propose ST-MoE, a spatio-temporal expert prefetching framework that proactively stages experts ahead of use to overlap expert loading with ongoing computation. ST-MoE combines a lightweight runtime prediction mechanism that preserves the original routing behavior with a reconfigurable hardware design that efficiently supports dynamic expert prefetching. The combined effect of the prediction mechanism with the supporting hardware significantly improves MoE inference performance and energy efficiency while preserving model inference accuracy.

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

UR-BERT: Scaling Text Encoders for Massively Multilingual TTS Through Universal Romanization and Speech Token Prediction

We propose UR-BERT, a Romanized transcription-based text-to-speech (TTS) encoder for massively multilingual TTS systems. Conventional grapheme-to-phoneme (G2P)-based approaches are limited to around 100 languages due to the availability of reliable G2P resources. In contrast, UR-BERT scales to 495 languages by unifying diverse writing systems into a shared Romanization representation. To further enhance phonetic fidelity and text-speech alignment, we introduce a speech token prediction objective during training, which encourages the encoder to learn speech-aware phonetic representations in a data-efficient manner. Experiments show that TTS systems built on UR-BERT consistently outperform recent text encoder baselines across a wide range of languages and resource conditions, and demonstrate strong generalization to unseen languages.

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

From Passive Generation to Investigation: A Proactive Scientific Peer Review Agent

Large language models (LLMs) have shown promise in automating scientific peer review. However, existing approaches often struggle to generate in-depth reviews supported by concrete evidence. We argue that a key limitation is the lack of flexibility to proactively investigate suspicious parts of a paper based on accumulated evidence, as human reviewers do. In this paper, we explore how to enable an LLM-based review agent to perform such proactive investigation. We find that this can be naturally formulated as a Markov Decision Process (MDP), and propose ProReviewer, a scientific peer review agent that proactively reviews a paper guided by a maintained, structured review log. The structured review log serves as a workspace for the agent to track evidence and intermediate findings collected during review. Experiments show that ProReviewer with an 8B backbone, trained by supervised fine-tuning and optimized by reinforcement learning, achieves the highest average score across five quality dimensions, outperforming prompt-based methods with much larger frontier LLMs by up to 39% and the strongest fine-tuned baseline by 16% relatively. It also attains the highest win rates against baselines in human evaluation.

13.
arXiv (CS.CV) 2026-06-19

Efficiently Linking Real Scenes with Synthetic Data Generation for AI-based Cognitive Robotics and Computer Vision Applications

AI vision models are a driving factor for the potential use case scenarios of cognitive robotics within in the industry and household applications. A large array of methods from semantic environment analysis towards 6D and grasping pose estimation have been proposed based on the latest AI achievements. However, such advancements require further strong and efficient methods w.r.t. training data and AI-architectures, which are capable in synergy to tackle current challenges, precision limits, and scalability beyond domain gaps. In this paper, we discuss these current limits and trends in the related state-of-the-art which are challenging those. Further we discuss our current work in progress on bridging the domain gap between simulations and real world applications by linking those in the training data generation.

14.
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.

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

Learning and Generating Mixed States Prepared by Shallow Channel Circuits

arXiv:2604.01197v4 Announce Type: replace-cross Abstract: Learning quantum states from measurement data is a central problem in quantum information and computational complexity. In this work, we study the problem of learning to generate mixed states on a finite-dimensional lattice. Motivated by recent developments in mixed state phases of matter, we focus on arbitrary states in the trivial phase. A state belongs to the trivial phase if there exists a shallow preparation channel circuit under which local reversibility is preserved throughout the preparation. We prove that any mixed state in this class can be efficiently learned from measurement access alone. Specifically, given copies of an unknown trivial phase mixed state, our algorithm outputs a shallow local channel circuit that approximately generates this state in trace distance. The sample complexity and runtime are polynomial (or quasi-polynomial) in the number of qubits, assuming constant (or polylogarithmic) circuit depth and gate locality. Importantly, the learner is not given the original preparation circuit and relies only on its existence. Our results provide a structural foundation for quantum generative models based on shallow channel circuits. In the classical limit, our framework also inspires an efficient algorithm for classical diffusion models using only a polynomial overhead of training and generation.

16.
bioRxiv (Bioinfo) 2026-06-13

Testing the reliability of AI-generated protein structures

Although AlphaFold2 and its competitors have demonstrated remarkable abilities to predict protein structure, more work is needed to explore the limitations of these methods. Here we investigated the reliability of AlphaFold2 and ColabFold by creating a set of realistic but false protein sequences, using ColabFold to predict their structure, and then asking how often the program produces a high-scoring structure for a sequence that does not represent a protein. We determined that AlphaFold2 has a very small but non-zero false positive rate, estimated here at approximately 1 in 435 if one uses a threshold pLDDT score of 70 to define positive predictions. We also discovered, serendipitously, that some high-scoring sequences in the human genome were not false positives, but instead were previously unknown and un-annotated pseudogenes. These latter findings indicate that some well-established human annotations of protein-coding genes may have incorrectly extended the 5-prime untranslated regions too far. They also suggest that the false positive rate of AlphaFold2 is low enough that almost any high-scoring structure, even in a noncoding region, is worthy of further investigation.

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

Fusing Transferred Priors and Physics-based Decomposition for Underwater Image Enhancement

The underwater images are captured within diverse water-medium conditions, leading to complex degradation, including color bias, low contrast, and blur effect. Recently, learning-based methods have demonstrated their potential for underwater image enhancement (UIE). However, most of the previous work focus on the training strategy or network design to make the enhanced result aligned well with the labels in datasets, ignoring that the labels are selected from the enhanced results of previous UIE methods and these pseudo-labels are noisy. Consequently, the performance of their models is not satisfactory to a certain extent. However, collecting the true labels of the underwater images is challenging. In this work, we propose a transfer learning-based UIE that does not require underwater images to have paired noisy or true labels for learning. Instead, the UIE task is first divided into global color correction, haze removal, and background noise suppression following the underwater physics. Then multiple types of prior from other vision tasks are leveraged as cross-domain supervision in each step. In this way, a novel UIE is available via transfer learning, and the physics-aligned UIE decomposition provides theoretical soundness. Qualitative and quantitative experiments demonstrate that our proposal based on physics and priors fusion achieves SOTA performance in the UIE task and effectively boosts downstream vision tasks, significantly outperforming benchmark methods. Project repo: https://github.com/Haru2022/P2-UIE.

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

RoboPIN: Grounded Embodied Reasoning via Pinned Chain-of-Thought

arXiv:2606.15753v1 Announce Type: new Abstract: Embodied reasoning requires models to perceive task-relevant objects and spaces in physical environments and maintain consistent visual grounding throughout multi-step reasoning. However, current vision-language models rely on text-only or coordinate-augmented chain-of-thought, where entity references remain implicit and ambiguous. This may cause the reasoning process to decouple from visual evidence, entity references to drift across steps, and a causal disconnection between the reasoning trajectory and the final answer, with these problems further amplified in multi-view scenarios due to cross-view appearance changes. To address these issues, we propose Pinned Chain-of-Thought (\pincot{}), a structured reasoning paradigm that pins every reasoning step to visual evidence. \pincot{} introduces the concept of \reasoninganchor{}, which binds each task-relevant entity to a structured visual anchor with entity name, unique identity, view index, and spatial grounding, enabling consistent entity tracking across reasoning steps and views. We build a fully automated data generation pipeline to construct \dataset{}, a high-quality \pincot{}-formatted reasoning dataset. We then train \method{} through three-stage post-training that progressively injects embodied knowledge, structured reasoning ability, and process-supervised alignment, with rewards that directly constrain both anchor localization and identity consistency during reasoning. On 14 benchmarks covering embodied spatial reasoning, multi-view reasoning, and pointing, \method{} with only 4B parameters consistently outperforms 7B level open-source embodied models, achieving a 12\% average improvement over the strongest 7B baseline, Mimo-Embodied. Further analysis shows that \pincot{} improves grounding accuracy and cross-step identity consistency, validating the effectiveness of process supervision.

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

Bridging Distribution Shift and AI Safety: Conceptual and Methodological Synergies

arXiv:2505.22829v2 Announce Type: replace-cross Abstract: This paper bridges distribution shift and AI safety through a comprehensive analysis of their conceptual and methodological synergies. While prior discussions often focus on narrow cases or informal analogies, we establish two types connections between specific causes of distribution shift and fine-grained AI safety issues: (1) methods addressing a specific shift type can help achieve corresponding safety goals, or (2) certain shifts and safety issues can be formally reduced to each other, enabling mutual adaptation of their methods. Our findings provide a unified perspective that encourages deeper integration between distribution shift and AI safety research.

20.
arXiv (CS.CL) 2026-06-18

Improving Medical Communication using Rubric-Guided Counterfactual Recommendations

Text-based telemedicine increasingly relies on lightweight patient feedback, however, such feedback primarily reflects perceived communication quality rather than medical accuracy. We introduce an LM-guided counterfactual recommendation pipeline that discovers and refines interpretable communication features such as tone, personalization, actionability and completeness in addressing patient concerns, without interfering with the medical content. These features are used together with patient-doctor interaction metadata to estimate positive feedback. At inference time, the system searches over low-cost ordinal feature changes and recommends minimal communication changes predicted to increase the probability of positive feedback, while independent auditor models test whether these gains generalize beyond the selection model. Across interactions, recommendations yield a mean +6.41% gain in predicted positive feedback probability under independent auditors, and are non-negative for 93.31% of recommendations. These results suggest that small, interpretable communication changes can capture most predicted gains while preserving the doctor's control over medical reasoning and final wording.

21.
arXiv (CS.AI) 2026-06-11

Internet of Everything in the 6G Era: Paradigms, Enablers, Potentials and Future Directions

arXiv:2604.25018v2 Announce Type: replace-cross Abstract: The Internet of Everything (IoE) represents an evolution of the Internet of Things (IoT) by integrating people, data, processes, and things into a unified intelligent ecosystem. IoE aims to enhance automation, decision-making, and service efficiency across multiple application domains such as smart cities, healthcare, industry, and next-generation wireless networks. This paper provides a structured overview of the IoE concept, its core components, architectural foundations, enabling technologies, and major research challenges. Finally, open research directions toward 6G-enabled intelligent IoE systems are discussed, with emphasis on scalability, security, privacy, and energy efficiency.

22.
arXiv (CS.LG) 2026-06-12

CLARITree: Cholesky and Lookahead Accelerations for Regression with Interpretable Piecewise Linear Trees

arXiv:2606.12840v1 Announce Type: new Abstract: Regression trees are among the most interpretable yet expressive model classes in machine learning. Historically, greedy induction has been the dominant approach for constructing well-performing regression trees. While optimal methods based on dynamic programming and branch-and-bound exist, they are computationally prohibitive for general linear regression trees, despite often achieving substantially better performance than greedy approaches. Recent work has shown that specialized lookahead strategies can dramatically improve runtime while maintaining near-optimal performance, primarily in classification settings. In this work, we develop a novel algorithm for near-optimal, sparse, piecewise linear regression trees that combines a lookahead-style search strategy with efficient rank-one Cholesky updates of the Gram matrix. We demonstrate, both theoretically and empirically, that our method achieves a favorable trade-off between computational efficiency, predictive accuracy, and sparsity, and scales significantly better than the current state of the art.

23.
arXiv (CS.LG) 2026-06-16

PhysGuard: Fisher-Guided Gradient Projection for Sim-to-Real Neural PDE Surrogates

arXiv:2606.16602v1 Announce Type: new Abstract: Neural operator models trained on simulation data often lose accuracy when applied to experimental measurements due to the sim-to-real gap. Standard fine-tuning with limited real data can reduce this gap, but it may also damage the core physics-relevant representations learned during pretraining. Although knowledge-preserving adaptation has been widely investigated in vision or language tasks, it remains unclear whether these methods are suitable for neural operators whose architectures and protected knowledge are fundamentally different. Neural operators need to preserve core-scale physical structures rather than semantic or visual features. We propose PhysGuard, a physics-preserving framework for accurate sim-to-real adaptation of neural operators. Specifically, PhysGuard uses the empirical Fisher Information Matrix computed on simulation data to identify physics-critical parameter directions, then restricts fine-tuning updates to directions that do not interfere with them. A layer-wise Gram-matrix formulation makes this efficient for models with millions of parameters, while an adaptive threshold automatically determines the protected subspace size. A spectral probe experiment shows that the dominant Fisher directions are strongly associated with low-frequency output structures. Experiments on benchmark across four neural operator architectures and different physical systems show that PhysGuard performs strongly on most evaluation metrics compared to baselines. The benefits are most evident under severe domain shift, where it reduces low-frequency error by up to 32\% compared to standard fine-tuning while maintaining adaptability. Our code is available at https://github.com/ZhouChaunge/PhysGuard.

24.
Nature Medicine 2026-06-08

Effects of SGLT2 inhibition on incident heart failure in carriers of cardiomyopathy-associated genetic variants

Although the beneficial effects of sodium–glucose cotransporter 2 (SGLT2) inhibition in heart failure (HF) have been well established, it is unknown whether SGLT2 inhibition confers benefit in carriers of rare variants in cardiomyopathy-associated genes. Here we evaluated whole-exome sequencing data from the randomized DECLARE-TIMI 58 trial, in which adults with type 2 diabetes and increased cardiovascular risk were randomized to dapagliflozin or placebo treatment. Pathogenic or likely pathogenic variants (P/LP) in high-confidence cardiomyopathy genes were identified, and treatment effects on hospitalization for HF (HHF) were compared between carriers of such variants and noncarriers. Among 12,685 patients for whom sequence data were obtained, 121 carried a cardiomyopathy variant (76 dilated cardiomyopathy, 25 hypertrophic cardiomyopathy and 25 arrhythmogenic cardiomyopathy). Over a median follow-up of 4.2 years, dapagliflozin lowered the risk of HHF more strongly in carriers (hazard ratio 0.18, 95% confidence interval 0.04–0.86) than in noncarriers (hazard ratio 0.70, 95% confidence interval 0.57–0.86; P interaction 0.03). Absolute risk reduction was 13.0% in carriers and 1.0% in noncarriers (P interaction 0.03). Most carriers (82%) had no prior HF, and in carriers without prior HF, treatment with dapagliflozin reduced the absolute risk of HHF by 12.8%, compared with a reduction of 0.6% in noncarriers (P interaction 0.01). The findings from this cohort of older and high-risk patients raise the possibility that SGLT2 inhibitor treatment should be started early to prevent HF in individuals who carry P/LP cardiomyopathy variants. These results need to be confirmed in a prospective, dedicated trial of preventive HF treatments in carriers of P/LP cardiomyopathy-associated variants. In a whole-exome sequencing analysis, the beneficial effects of the SGLT2 inhibitor dapagliflozin in reducing the risk of future heart failure hospitalization in individuals with type 2 diabetes were markedly greater in individuals who carried a cardiomyopathy-associated genetic variant compared with noncarriers, suggesting a personalized preventative therapy based on genetic information.

25.
medRxiv (Medicine) 2026-06-10

Developmental Associations Linking Childhood Trauma and Early Cannabis Use to Adolescent DNA Methylation and Psychotic-Like Experiences

Background. Psychotic-like experiences (PLEs) index early risk for psychotic disorders and are consistently associated with childhood trauma, yet underlying biological mechanisms remain poorly understood. DNA methylation (DNAm) may capture the biological embedding of early adversity, while adolescent exposures such as cannabis use may modify these processes. We examined epigenome-wide associations of childhood trauma and PLEs, tested the moderating role of early cannabis use, and evaluated DNAm as a potential mediator. Methods. We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort. Childhood trauma was assessed prospectively and retrospectively. Epigenome-wide DNAm was measured in peripheral blood at ~17 years using the Illumina 450K array, and PLEs were assessed at 18 using a structured interview. Epigenome-wide association studies were conducted for trauma-DNAm and DNAm-PLEs associations in the final sample (n = 1,457), adjusting for demographic, biological, and technical covariates. Differentially methylated regions (DMRs) were identified using DMRff, followed by functional enrichment analyses. Cannabis use at 15.5 was modelled as a moderator with multiple imputation for missing data. Mediation was tested using the Divide-Aggregate Composite-null Test (DACT). Results. Childhood trauma was associated with widespread DNAm differences, primarily at the regional level, with enrichment in pathways related to cellular stress responses. In contrast, DNAm associated with PLEs was more limited and implicated loci involved in epigenetic regulatory processes. These signatures were largely distinct, and there was no evidence supporting mediation after multiple testing correction. Incorporating cannabis use altered the pattern and extent of DNAm associations, with stronger and more significant signals observed at both CpG and regional levels, although these did not translate into evidence of mediation. Conclusion. Childhood trauma and PLEs show distinct DNAm signatures in adolescence, with trauma-related DNAm reflecting broad stress-related processes and PLE-associated DNAm implicating regulatory mechanisms. We found little evidence that DNAm mediates the trauma-PLE association. Instead, adolescent exposures, particularly cannabis use, may distinctly influence trauma-related epigenetic variation with limited detectable downstream effects on PLEs. These findings support a context-dependent model of epigenetic risk and highlight the need for larger longitudinal studies to clarify causal pathways linking early adversity to psychosis.