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Integration of Digital Therapeutics Into Occupational Rehabilitation in Germany: Multilevel Simulation Study

Background: Expenditures for physiotherapy and extended outpatient physiotherapy (EAP) are increasing within Germany’s statutory accident insurance system (Berufsgenossenschaften), placing growing pressure on rehabilitation capacity and timely access to care. Digital health applications (DiGAs) are reimbursable nationwide and represent a novel component of routine rehabilitation pathways. However, their real-world system-level and economic effects in occupational rehabilitation remain insufficiently understood. Objective: This study aimed to evaluate how the integration of DiGAs into occupational rehabilitation pathways may influence costs, service capacity, and waiting times within routine care delivered by 5 German statutory accident insurance funds that cover 25.9 million insured individuals. Methods: Aggregated administrative data from 5 Berufsgenossenschaften (fiscal years 2023‐2024) were analyzed using a multilevel simulation framework combining (1) probabilistic cost-consequence modeling with Monte Carlo simulation (10,000 iterations), (2) an adherence-based adoption funnel distinguishing long-term engaged users (15%) and short-term users (85%) based on German claims data, and (3) a calibrated M/M/1 queuing model validated through discrete event simulation to estimate the effects on waiting times and system capacity. Primary outcomes included net financial impact, break-even thresholds, and changes in access-related performance metrics. Results: Combined physiotherapy and EAP expenditures reached €404 million (€1=US $1.18) in 2024, increasing by 10.1% year-over-year. The primary simulation (N=10,000 iterations) indicated mean annual net savings of €18.4 million (median €17.9 million) with a 90.7% probability of cost savings (95% uncertainty range: net cost of €8 million to net savings of €47.7 million). After incorporating adherence dynamics, the projected mean net savings were €16.2 million (95% CI €5-€29.8 million), corresponding to a 100% probability of positive financial impact within the modeled parameter space. Cost neutrality was maintained for DiGA prices up to €617.8 per prescription, nearly 40% above the base-case assumption of €450, indicating substantial economic robustness. Queuing analyses demonstrated that modest reductions in therapeutic demand decreased mean waiting times from 17.3 to 12.8 days (−26%), equivalent to approximately 120,000 cumulative patient waiting days saved annually across 26,705 EAP patients. The validation of discrete event simulation confirmed the magnitude and direction of analytic estimates. Conclusions: Under conservative assumptions, integrating digital therapeutics into occupational rehabilitation pathways is likely to generate both economic benefits and substantial system-level capacity gains. The break-even threshold of €617.80 per prescription provides a wide margin for pricing policy. Beyond cost effects, DiGAs may function as scalable capacity tools that alleviate systemic bottlenecks and improve timely access to rehabilitation services in capacity-constrained systems.
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Large Language Model–Generated Patient Instructions for Prescriptions in Primary Health Care: Preclinical Algorithm Validation

Background: The application of generative artificial intelligence to simplify medication use instructions has the potential to enhance people’s health by improving treatment adherence. Objective: We evaluated the performance of large language models (LLMs) in generating medication usage instructions to complement prescriptions in primary health care. Methods: This randomized, blinded experimental preclinical study used prescription-inducing scenarios, assigned to 62 health care professionals, to validate instructions generated by LLMs during electronic prescriptions. The instructions were generated by ChatGPT-4.0 (OpenAI), Llama3.1-8B (Meta), and Llama3.1-8B-RAG (Meta) using retrieval-augmented generation based on patient information leaflets. Performance metrics assessed adequacy, completeness, clarity, language simplification, usefulness, and errors in the generated instructions, with scores to analyze overall and individual metrics. Results: The 3 models yielded high overall scores for producing qualified instructions (ChatGPT-4.0: median 88.4, IQR 22.8; Llama3.1-8B: median 66.5, IQR 50.9; Llama3.1-8B-RAG: median 79.9, IQR 34.4; Kruskal-Wallis test P=.003). Llama3.1-8B-RAG received evaluations with similar overall scores to ChatGPT-4.0 (post hoc test, P=.05) and similar to Llama3.1-8B (post hoc test, P=.44). ChatGPT-4.0 outperformed Llama3.1-8B (Bonferroni test, P<.001). Regarding specific domains, Llama3.1-8B-RAG received scores equivalent to those of ChatGPT-4.0 for adequacy (mean 6.24, SD 2.3 vs mean 6.82, SD 2.1; post hoc test, P=.54); completeness (mean 5.94, SD 2.2 vs 6.55, SD 1.9; post hoc test P=.38), clarity (mean 5.77, SD 2.4 vs mean 6.68, SD 1.9; post hoc test P=.09), and usefulness (mean 5.42, SD 2.4 vs mean 5.96, SD 2.2; post hoc test P=.63). ChatGPT-4.0 received higher scores in the language simplification criterion than Llama3.1-8B-RAG (mean 7.05, SD 1.5 vs mean 5.44, SD 2.6; post hoc test P<.001). Interrater variability in assigning scores ranged from 4.2% (n=3) to 85.8% (n=6) among primary health care professionals. Instructions leading to incorrect use of the medication had similar frequency among the models(ChatGPT-4.0: n=15, 22.7%; Llama3.1-8B: n=19, 22.8%; Llama3.1-8B-RAG: n=19, 22.8%; chi-square test P=.71). The frequencies of hallucination were similar (ChatGPT-4.0: n=7, 10.6%; Llama3.1-8B: n=9, 13.6%; Llama3.1-8B-RAG: n=6, 9.1%; chi-square test P=.67). Conclusions: The open-source LLM enhanced with external information presented similar performance to the closed-source model, except for ChatGPT4.0, which was superior in language simplification of messages. LLM generation demonstrated potential for instructing patients on medication use. Nonetheless, the introduction of this innovation into the electronic prescribing workflow demands prescriber validation for human oversight of the technology and requires a strategy for LLM performance governance.
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Safety of Telemedicine Versus In-Person Care for Patients With Tracheal Devices: Propensity Score–Matched Cohort Study

Background: Patients with tracheal diseases often require long-term follow-up after tracheal device placement, with a risk of adverse events that may lead to emergency care and unplanned interventions. Telemedicine has been proposed as an alternative to in-person follow-up to improve access and continuity of care. Objective: The primary objective of this study was to compare the need for emergency department (ED) visits between telemedicine and in-person groups. Secondary objectives included comparing hospital readmissions, 30-day hospital readmissions, and unplanned interventions between groups. Methods: This retrospective, single-institution study included adult patients with tracheal devices who underwent telemedicine and in-person outpatient clinic visits between 2020 and 2024. To balance the groups, we used 1:1 propensity score matching. We collected demographic and clinical data and evaluated the need for ED visits, hospital readmissions, 30-day hospital readmissions, and unplanned interventions. Kaplan-Meier estimation of time to first ED visit was performed to assess outcomes after outpatient visits. Results: A total of 483 patients (n=277, 57% telemedicine and n=206, 43% in-person) underwent 2487 visits (1258 telemedicine and 1229 in-person). After propensity score matching, 336 patients remained (168 in each group). There were no significant differences in the need for ED visits, hospital readmissions, or unplanned interventions. The telemedicine group had significantly fewer 30-day hospital readmissions (odds ratio 0.38, 95% CI 0.16-0.87; =.02). Kaplan-Meier analysis indicated no statistically significant difference in ED-free visits. Conclusions: Telemedicine follow-up was associated with outcomes comparable to those of in-person follow-up in this cohort of adult patients with tracheal devices, with no evidence of an increased need for ED visits. In the matched analysis, telemedicine was associated with lower odds of 30-day hospital readmission.
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A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

Adv Sci (Weinh). 2026 May 26:e75839. doi: 10.1002/advs.75839. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

PMID:42189071 | DOI:10.1002/advs.75839

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Multi-Omics Identification of Biomarkers for High-Altitude Pulmonary Hypertension

J Cardiovasc Dev Dis. 2026 Apr 30;13(5):195. doi: 10.3390/jcdd13050195.

ABSTRACT

(1) Aim: The incidence of high-altitude pulmonary hypertension (HAPH) has risen in recent years and is expected to continue increasing; however, its diagnosis remains challenging. In this study, we employed proteomics and metabolomics to identify the proteins and metabolic biomarkers that contribute to the development of HAPH. (2) Methods: We applied integrated proteomics and metabolomics to match blood samples from 40 HAPH patients and 40 healthy controls in Yunnan's high-altitude regions to characterize molecular profiles, identify biomarkers, and develop a predictive model. (3) Results: Proteomic analysis identified four proteins (A2IPH7, K1C14, PSME2, SERPINE2) commonly dysregulated in HAPH patients from two high-altitude regions. SERPINE2 was notably downregulated and showed a negative correlation with clinical severity, which was further validated in HAPH rat lung tissues and supported by UK Biobank data for idiopathic PAH. Concurrent metabolomics uncovered 11 shared metabolites, largely acyl fatty acids, enriched in pathways such as unsaturated fatty acid synthesis. Integration of these multi-omics data enabled the development of a robust predictive model. (4) Conclusion: Our study identified key protein and metabolic biomarkers involved in HAPH development, which were validated in animal models. Based on these findings, a predictive model was developed, highlighting SERPINE2 and 11 metabolites as promising targets for the prediction and prevention of HAPH.

PMID:42188081 | DOI:10.3390/jcdd13050195

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A visual analysis of the research dynamics of biomarkers for lung cancer screening

Clin Epigenetics. 2026 May 26;18(1):90. doi: 10.1186/s13148-026-02084-2.

ABSTRACT

BACKGROUND: Non-invasive biomarkers offer potential to improve risk stratification and early diagnosis of lung cancer, complementing low-dose computed tomography (LDCT) screening. This study employed bibliometric analysis to identify global research trends, collaborative networks, and future directions in lung cancer biomarker research. Publications on lung cancer biomarkers for screening were retrieved from the Web of Science Core Collection (WoSCC). Data processing and visualisation were performed using Citespace, VOSviewer, KH Coder, Latent Dirichlet Allocation (LDA) topic modelling, and the online bibliometric analysis platform. Burst detection analysis was performed to predict emerging research trends.

RESULTS: Analysis of 3636 publications revealed exponential growth in research output since 2014. International collaboration demonstrated a dual-core structure centred on China and the United States, with Chinese institutions showing high publication volumes and American institutions demonstrating greater citation influence. Journal citation mapping revealed three evolutionary phases: basic mechanisms-clinical translation-intelligent integration. LDA topic modelling identified 22 topics grouped into five core research directions: imaging and pathological diagnostic techniques; molecular and omics marker research; liquid biopsy and new detection technologies; clinical and translational medicine research; and tumour biology and treatment mechanisms. Burst detection analysis predicted future four priority areas: epigenetic studies centred on DNA methylation for risk prediction; treatment resistance and invasion mechanisms; liquid biopsy technology development; and targeted therapy clinical trials.

CONCLUSIONS: Lung cancer biomarker research has evolved towards multimodal, intelligent screening approaches. Future research priorities include DNA methylation-based markers, circulating microRNA signatures, and artificial intelligence-assisted diagnostic platforms to improve early detection accuracy and complement LDCT screening.

PMID:42185923 | DOI:10.1186/s13148-026-02084-2

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Mechanisms and reversal strategies of liver fibrosis: from regulation of cell fate to clinical translation

J Transl Med. 2026 May 25. doi: 10.1186/s12967-026-08312-w. Online ahead of print.

ABSTRACT

BACKGROUND: Liver fibrosis is a dynamic and reversible pathological process underlying chronic liver diseases, characterized by excessive extracellular matrix deposition and progressive hepatic architectural distortion. It acts as a critical precursor to cirrhosis, hepatic decompensation, and hepatocellular carcinoma, imposing a substantial global disease burden.

MAIN BODY: Accumulating evidence indicates that liver fibrosis is a highly plastic process governed by multicellular crosstalk, immune microenvironment remodeling, epigenetic-metabolic coupling, and mechanotransduction. This review outlines core cellular effectors and their heterogeneity revealed by single-cell omics, and highlights key regulatory layers including circadian rhythm, epigenetic imprinting, metabolic reprogramming, and the gut-liver axis, as well as etiology-specific differences in fibrosis progression, reversibility, and therapeutic response. We also summarize advances in non-invasive diagnosis and clinical translation of anti-fibrotic therapies, and discuss key bottlenecks leading to clinical trial failures.

CONCLUSION: A deeper understanding of cell fate regulation and multicellular ecosystem remodeling will facilitate the development of precise strategies to achieve meaningful fibrosis regression and improve long-term clinical outcomes in chronic liver diseases.

PMID:42185911 | DOI:10.1186/s12967-026-08312-w

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A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

Adv Sci (Weinh). 2026 May 26:e75839. doi: 10.1002/advs.75839. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

PMID:42189071 | DOI:10.1002/advs.75839

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Multi-Omics Identification of Biomarkers for High-Altitude Pulmonary Hypertension

J Cardiovasc Dev Dis. 2026 Apr 30;13(5):195. doi: 10.3390/jcdd13050195.

ABSTRACT

(1) Aim: The incidence of high-altitude pulmonary hypertension (HAPH) has risen in recent years and is expected to continue increasing; however, its diagnosis remains challenging. In this study, we employed proteomics and metabolomics to identify the proteins and metabolic biomarkers that contribute to the development of HAPH. (2) Methods: We applied integrated proteomics and metabolomics to match blood samples from 40 HAPH patients and 40 healthy controls in Yunnan's high-altitude regions to characterize molecular profiles, identify biomarkers, and develop a predictive model. (3) Results: Proteomic analysis identified four proteins (A2IPH7, K1C14, PSME2, SERPINE2) commonly dysregulated in HAPH patients from two high-altitude regions. SERPINE2 was notably downregulated and showed a negative correlation with clinical severity, which was further validated in HAPH rat lung tissues and supported by UK Biobank data for idiopathic PAH. Concurrent metabolomics uncovered 11 shared metabolites, largely acyl fatty acids, enriched in pathways such as unsaturated fatty acid synthesis. Integration of these multi-omics data enabled the development of a robust predictive model. (4) Conclusion: Our study identified key protein and metabolic biomarkers involved in HAPH development, which were validated in animal models. Based on these findings, a predictive model was developed, highlighting SERPINE2 and 11 metabolites as promising targets for the prediction and prevention of HAPH.

PMID:42188081 | DOI:10.3390/jcdd13050195

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TamboUI Promises to Bring Better Capabilities to Build TUIs in Java

The call to action “to make 2026 the year of Java in the terminal” was quickly responded to by the launch of TamboUI. Inspired by Ratatui, the library used in Claude CLI, it promises support ranging from low-level terminal drawing to high-level APIs such as components and event handling. Currently at version 0.3.0, it has already been adopted by major projects such as Maven and Spring.

By Olimpiu Pop
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STAT+: How Kyle Diamantas defied expectations as he rose to lead the FDA

WASHINGTON — People in the food world didn’t know what to expect when the Trump administration appointed a little-known Florida attorney as the FDA’s top food official in 2025. 

They knew Kyle Diamantas worked at Jones Day representing food, beverage, and tobacco-industry clients. They saw the picture of him and Donald Trump Jr. holding giant, dead wild turkeys after a hunt. He had no experience in public health, in medicine or science, or in government.

The credentials didn’t scream qualified. And Diamantas was stepping into a center rocked by DOGE layoffs and a defiant resignation by former leader Jim Jones. 

Continue to STAT+ to read the full story…

© Camille MacMillin/STAT

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Opinion: The Ebola outbreak will lead to devastating violence against women and girls

The World Health Organization has declared a new public health emergency. Bundibugyo, an Ebola strain for which we have no vaccine and no treatment, is now spreading across the eastern Democratic Republic of Congo. So far, there have been more than 900 suspected cases and about 220 suspected deaths, according to the World Health Organization. Centered in a region with active conflict and fragile health systems, the outbreak has already crossed the borders into Uganda.

Public health advocates will spend the next several months talking about transmission, case fatality, contact tracing, and vaccine development. But one critical topic will go largely undiscussed: what this outbreak will do to women and girls.

Read the rest…

© ALEXIS HUGUET/AFP via Getty Images

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Opinion: 8 former CDC directors: Reform PEPFAR, don’t dismantle it

On Sunday, the World Health Organization (WHO) declared an Ebola outbreak in the Democratic Republic of the Congo and Uganda to be a public health emergency. This outbreak is deadly, with hundreds of cases across at least two countries, including, by report, one American who was working in the area.

At the same time, a cluster of hantavirus cases linked to a Dutch cruise ship in the South Atlantic has killed three and exposed hundreds more.

Read the rest…

© Hajarah Nalwadda/Getty Images

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In Search of the Ingredients of Open-Endedness: Replicating Picbreeder with Large Vision-Language Models

arXiv:2605.23908v1 Announce Type: new Abstract: We are in the midst of large-scale industrial and academic efforts to automate the processes of scientific, technological and creative production through AI-driven assistants. Historically, a fundamental property of these processes in their human form has been their open-endedness: their capacity for generating a seemingly endless supply of novel and meaningful new forms. Do artificial agents have any capacity for such fruitful unguided discovery? To answer this question, we turn to Picbreeder, the canonical exemplar of human-driven open-ended search, in which users collaboratively generated a diverse library of images through interactive evolution of small neural networks. We replicate Picbreeder, replacing human users with frontier Vision Language Models (VLMs). We observe clear qualitative differences between the output of our system and the historical human baseline, and attempt to characterize them using metrics of phylogenetic complexity and visual and semantic salience and novelty. In an effort to identify some of the causal factors contributing these differences, we study the addition of exploratory noise to the agents' selection process, of behavioral diversity between agents, and of narrative momentum in the form of memory of past actions. We make our code available at https://github.com/smearle/picbreeder-vlm.
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BODHI: Precise OS Kernel Specification Inference

arXiv:2605.23931v1 Announce Type: new Abstract: The formal verification of operating system kernels requires precise specifications that capture the intended behavior of system calls. Writing these specifications manually demands deep domain expertise, motivating the use of large language models (LLMs) to automate the process. However, in OSV-Bench, a benchmark of 245 specification generation tasks derived from the Hyperkernel OS kernel, the best reported Pass@1 is 55.10%. We propose a domain knowledge prompting method (BODHI), which augments the standard few-shot prompt with a structured C-to-Python translation guide covering 15 categories of domain-specific translation patterns. Inspired by Structured Chain-of-Thought (SCoT) prompting, the guide organizes translation by separation of concerns, addressing pre-condition extraction and post-condition generation as distinct categories. Evaluated on nine models from six providers (Anthropic, Mistral, Amazon, DeepSeek, Meta, Alibaba), covering dense, mixture-of-experts and reasoning architectures, BODHI improves every model tested, with gains ranging from +11% to +32%. The best configuration (Claude Opus 4.6 + BODHI) reaches 96.73% Pass@1. BODHI reduces both syntax and semantic errors, with the strongest effect on models that have sufficient instruction-following capability to utilize structured reference material. These results demonstrate that domain knowledge injection is a model-agnostic technique that substantially bridges the gap between general-purpose code generation and formal specification synthesis.
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BoxLitE: A Faithful Knowledge Base Embedding Based on Convex Optimization

arXiv:2605.23937v1 Announce Type: new Abstract: Knowledge base (KB) embeddings aim at combining the capability of classical knowledge graph embeddings to generalize the information present in facts, the ABox, with conceptual knowledge represented in an ontology language, the TBox. Several authors have recently explored the idea of mapping concepts to convex regions in a vector space. This is useful to represent hierarchies, typically present in TBoxes, since more general concepts can be mapped to larger regions, containing those regions associated with more specific concepts. However, the power of convexity is rarely leveraged during the actual learning tasks. Here, we introduce BoxLitE, a KB embedding model for DL-Lite$^{\mathcal{H}}$ that allows for convex optimization. We show that for any satisfiable DL-Lite$^{\mathcal{H}}$ KB, there is a BoxLitE embedding that is a weakly faithful model. As a proof of concept, we show how to formulate the KB embedding task as a convex optimization problem and how to obtain embeddings with such desirable faithfulness properties.
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DRIVE: Modeling Skills at the Reasoning and Interaction Levels for Web Agents under Continual Learning

arXiv:2605.23939v1 Announce Type: new Abstract: Web agents require both high-level reasoning (for task decomposition) and low-level interactions (for page elements manipulation) to conduct different tasks. However, these knowledge types differ fundamentally: reasoning knowledge (e.g., booking a flight requires first searching for routes) is abstract and transferable across websites, while interaction knowledge (e.g., clicking the Search button at a specific coordinate on Site A) depends heavily on page-specific contexts. Existing methods store experiences uniformly. This creates a dilemma: abstract representations lose executability on concrete pages, while concrete representations fail to generalize across domains. This entanglement limits capability accumulation: on new websites, agents either fail to recognize reusable task logic due to surface-level differences or attempt infeasible actions from outdated page structures. To disentangle them, we propose DRIVE, a dual-level skill modeling framework separating historical experience into natural language reasoning skills, which capture transferable task logic, and programmatic interaction skills, grounding abstract actions to executable operations. A scene-aware coordination mechanism adaptively retrieves and invokes these dual-level skills based on task semantics. DRIVE also uses skill-level reflection to identify hierarchy-specific failure modes, enabling targeted skill library expansion and refinement. Experiments across five WebArena domains show DRIVE attains an average task success rate of 52.8%, exceeding the skill-free baseline by 7.3 percentage points. Further ablations show reasoning and interaction skills provide distinct, complementary benefits, supporting separation of transferable task logic from executable page-level operations.
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MEMOR-E: In-Context and Fine-Tuned LLM Personalization for Alzheimer's Assistive Robotics

arXiv:2605.23941v1 Announce Type: new Abstract: Alzheimer's disease is a neurodegenerative disorder marked by progressive declines in memory and language that reduce independence in daily life, motivating socially assistive robotic support. This paper presents MEMOR-E, a mobile quadruped robot with an interactive tablet interface that assists patients and caregivers through medication reminders, routine guidance, memory oriented interactions, and companionship. We evaluated the feasibility of fine tuning large language models (LLMs) to emulate stage consistent cognitive behavior and interpret responses across standard neuropsychological language tasks, using audio transcriptions from 235 Alzheimer's patients and synthetically generated healthy controls. We also report findings on using in context learning (ICL) in LLMs, where a second LLM produced domain and severity level cognitive error summaries. Our results show that MEMOR-E can generate stage aware, non diagnostic cognitive summaries that support personalized assistive interactions, while explainable AI mechanisms translate model outputs into transparent, human readable evidence to enable caregiver oversight and trustworthy human robot interaction.
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