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01.
arXiv (CS.LG) 2026-06-19

Environment-Adaptive Covariate Selection: Learning When to Use Spurious Correlations for Out-of-Distribution Prediction

arXiv:2601.02322v2 Announce Type: replace-cross Abstract: A common approach to out-of-distribution prediction restricts models to causal or invariant covariates to avoid spurious associations that may change across environments. Despite its theoretical appeal, this strategy can underperform empirical risk minimization when only a subset of the causal parents of the outcome is observed. In such settings, non-causal covariates can serve as proxies for unobserved causal parents and improve prediction when the proxy relationship is stable, but they can hurt when shifts disrupt that relationship. Thus, the optimal covariate set can depend on the specific shift encountered. Because different shifts leave signatures in the unlabeled covariate distribution, we propose an environment-adaptive covariate selection algorithm that maps environment-level summaries to environment-specific covariate sets. These summaries may be hand-crafted or learned from multi-environment data, and prior causal knowledge can be incorporated as constraints. Across simulations and applied datasets, the proposed method improves over static causal, invariant, and other non-adaptive rules under diverse shifts.

02.
medRxiv (Medicine) 2026-06-18

Cost analysis of overseas versus domestic vaccination of US-bound refugees

Context: To ensure healthy resettlement and protect US health security, the Vaccination Program for US-bound Refugees (VPR) offers some recommended vaccines to refugees overseas before resettlement to the United States. The selected vaccines and number of doses vary by country of departure. VPR was found to be cost-saving in 2018 but had since expanded to more sites. Objective: Assess VPR's current costs and impact on post-arrival domestic vaccination needs and costs. Setting and Participants: A model-based analysis of the Federal government costs for VPR and post-arrival (US) vaccination of resettled refugees separated across five regions: Africa, Asia, the Middle East and North Africa/Republic of Turkiye and Middle East, Europe, and the Americas using fiscal year 2024 data. Design: We quantified and compared full vaccination costs for refugees under two scenarios: (1) 'No VPR' and (2) 'VPR'. Refugees would receive no vaccines overseas and be fully vaccinated after US arrival under 'No VPR'. Under 'VPR', refugees receive one or two doses of selected vaccines overseas before completing vaccination schedules after arrival. Main Outcomes: Costs were reported in 2023 US dollars for 'VPR' and 'No VPR' scenarios and further subdivided by grouping countries/sites depending on whether the International Organization for Migration (IOM) provides vaccination services for refugees (IOM sites) versus non-IOM providers (non-IOM sites). Results: 'VPR' resulted in average net cost savings of $147 per person or $14.7 million per 100,000-refugee cohort compared to providing all vaccines after US arrival ('No VPR'). 'VPR' was cost-saving across most regions, except for IOM sites in Europe, where a net cost of $44 per person was observed. Net cost savings per person were highest for IOM sites in Africa ($333). Conclusions: VPR remains a cost-saving strategy, while protecting US-bound refugees' health and US health security by preventing disease outbreaks during resettlement.

03.
arXiv (CS.LG) 2026-06-15

Leave-One-Out-, Bootstrap- and Cross-Conformal Anomaly Detectors

arXiv:2402.16388v4 Announce Type: replace-cross Abstract: The need for uncertainty quantification in anomaly detection systems has become increasingly important. In this context, effectively controlling Type I error rates without inflating Type II error rates in these systems can build trust and reduce costs associated with false discoveries. The field of conformal anomaly detection emerges as a promising approach for providing respective statistical and finite-sample validity guarantees through model calibration. However, reliance on calibration data imposes practical limitations, especially in low-data regimes. In this work, we formally define and evaluate leave-one-out-, bootstrap-, and cross-conformal methods for conformal anomaly detection, building on methods from the field of conformal prediction. Looking beyond the classical split-conformal approach, we show that derived methods for calculating resampling-conformal $p$-values offer a practical compromise between the data efficiency of full-conformal (transductive) approaches and the computational efficiency of split-conformal (inductive) methods. We validate derived methods and quantify their improvements for a range of one-class classifiers and datasets.

04.
arXiv (CS.AI) 2026-06-17

Trust the Right Teacher: Quality-Aware Self-Distillation for GUI Grounding

arXiv:2606.18101v1 Announce Type: new Abstract: Graphical user interface (GUI) grounding requires vision-language models (VLMs) to identify small target elements in high-resolution screenshots and predict precise screen coordinates. On-policy self-distillation (OPSD) is a promising post-training approach for this coordinate-sensitive task, since it provides dense token-level teacher signals beyond hard coordinate labels. However, naive OPSD is not well suited to GUI grounding: OPSD evaluates the teacher on student-generated prefixes, the quality of coordinate-token teacher signals can degrade when the prefix has already deviated from the target coordinate, leading to unreliable teacher signal. To mitigate this, We propose quality-aware self-distillation for VLM-based GUI grounding, which improves coordinate-token teacher-signal quality through soft correctness-aware gating and teacher-probability scaling. The soft correctness-aware gate checks whether the teacher's current coordinate-token prediction can still be completed into the ground-truth box under the student-generated prefix. If not, the corresponding teacher signal is down-weighted. Teacher-probability scaling then uses the teacher's confidence as a lightweight factor to further calibrate the strength of the gated supervision. A key empirical finding is that neither component alone improves overall performance, whereas combining them consistently improves performance. This suggests that the two mechanisms play complementary roles: correctness-aware gating suppresses unreliable coordinate-token supervision, while teacher-probability scaling calibrates the strength of the remaining signals. Experiments across six GUI grounding benchmarks show that our method consistently improves the base model and outperforms strong baselines.

05.
arXiv (CS.CL) 2026-06-16

FraudSMSWalker: Benchmarking Agentic Large Language Models for SMS-to-Webpage Fraud Detection

SMS fraud is increasingly cross-channel: a message directs the user to a webpage, and the final risk depends on how the SMS claim aligns with the page content and requested user action. However, existing evaluations either focus on message-only smishing classification or expose URL and domain cues that allow models to rely on reputation shortcuts. To address this gap, we introduce FraudSMSWalker, a controlled benchmark for URL-masked SMS-to-webpage fraud judgment. FraudSMSWalker contains 699 bilingual chains, including 332 fraudulent and 367 benign cases, across ten service scenarios. The model-visible input consists of the SMS context and sanitized webpage evidence, while raw URLs, hosts, domains, IPs, redirects, and reputation metadata are withheld. The benchmark further includes hard benign cases whose pages contain login, payment, verification, or account-management elements that are plausible under the service context but also appear in scam flows. We evaluate nine web agents under masked browser-agent protocols and conduct URL-visibility ablations. The results show that current agents can detect suspicious cues, but struggle to preserve benign recall and often produce positive predictions that are weakly supported by the observed evidence. These findings position FraudSMSWalker as a benchmark for measuring whether web agents can make fraud judgments that remain both accurate and evidence-grounded when direct reputation shortcuts are suppressed. The associated code and dataset are accessible at the \href{https://anonymous.4open.science/w/FraudMessageWalker-Bench}{anonymous link}.

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

Human-on-the-Loop Orchestration for AI-Assisted Legal Discovery

arXiv:2606.19812v1 Announce Type: new Abstract: Autonomous Large Language Model (LLM) agents are increasingly deployed in electronic discovery (e-discovery), where compounding errors across multi-step reasoning chains can constitute legal malpractice. Unlike single-turn retrieval, agentic workflows operating over privileged document corpora exhibit a class of failure we term "trajectory collapse": an early misclassification silently propagates, rendering an entire privilege review invalid. This paper makes three contributions. First, we propose a structured taxonomy of agentic failures in legal information retrieval, organized by functional stage. Second, we introduce a four-layer verification architecture – spanning planning, reasoning, execution, and uncertainty quantification – designed to intercept these failures before they compound. Third, we present a preliminary simulation study on a synthetic e-discovery corpus that demonstrates how mandatory Human-on-the-Loop (HOTL) escalation thresholds reduce privilege-waiver risk relative to fully autonomous baselines. Our results suggest that calibrated uncertainty thresholds can reduce privilege-waiver risk by up to 61% versus fully autonomous deployment, while routing fewer than one quarter of documents to attorney review.

07.
arXiv (CS.LG) 2026-06-11

Open Materials Generation with Inference-Time Reinforcement Learning

arXiv:2602.00424v2 Announce Type: replace Abstract: Continuous-time generative models for crystalline materials enable inverse materials design by learning to predict stable crystal structures, but incorporating explicit target properties into the generative process remains challenging. Policy-gradient reinforcement learning (RL) provides a principled mechanism for aligning generative models with downstream objectives but typically requires access to the score, which has prevented its application to flow-based models that learn only velocity fields. We introduce Open Materials Generation with Inference-time Reinforcement Learning (OMatG-IRL), a policy-gradient RL framework that operates directly on the learned velocity fields and eliminates the need for the explicit computation of the score. OMatG-IRL leverages stochastic perturbations of the underlying generation dynamics preserving the baseline performance of the pretrained generative model while enabling exploration and policy-gradient estimation at inference time. Using OMatG-IRL, we present the first application of RL to crystal structure prediction (CSP). Our method enables effective reinforcement of an energy-based objective while preserving diversity through composition conditioning, and it achieves performance competitive with score-based RL approaches. Finally, we show that OMatG-IRL can learn time-dependent velocity-annealing schedules, enabling accurate CSP with order-of-magnitude improvements in sampling efficiency and, correspondingly, reduction in generation time. The OMatG-IRL code is included in a new release of the Open Materials Generation (OMatG) framework available at https://github.com/FERMat-ML/OMatG.

08.
Nature Medicine 2026-06-15

Adaptive deep brain stimulation for dynamic gait control in Parkinson’s disease: a randomized feasibility trial

A randomized crossover study of five patients with Parkinson’s disease (PD) demonstrates that gait-synchronized adaptive deep brain stimulation is feasible and safe, and reduces falls compared with continuous stimulation. Gait dysfunction in PD is a major source of disability and is often insufficiently treated by continuous deep brain stimulation (cDBS). Although adaptive DBS (aDBS) has shown efficacy for other motor symptoms using β-based, state-driven neural signals, gait is a dynamic, cyclical behavior that may require temporally precise modulation. Here we evaluated a behavior-contingent aDBS approach that synchronizes stimulation to gait phase. We reported a single-center, blinded, randomized, crossover study evaluating the feasibility of identifying patient-specific biomarkers to drive aDBS. The primary outcome was feasibility of successful identification of gait-phase biomarkers to implement aDBS. Five participants with PD undergoing pallidal DBS and subdural electrode paddle implantation were enrolled. We successfully identified personalized gait-phase biomarkers from cortical or pallidal field potentials in all five patients and embedded them into a bidirectional neurostimulator. During acute in-clinic testing, aDBS improved step variability and step symmetry versus cDBS. Three participants subsequently completed a double-blinded, multi-day crossover phase. In this setting, aDBS maintained general motor symptom control, reduced falls and yielded patient-specific gait improvements. No adverse events occurred and aDBS was well tolerated. These findings establish the feasibility of biomarker-driven, movement-synchronized neuromodulation and support the development of a larger randomized trial to determine clinical efficacy. ClinicalTrial.gov registration: NCT04675398 . A randomized crossover study shows that gait-phase-synchronized adaptive deep brain stimulation is feasible and safe, and reduces falls compared to continuous stimulation in Parkinson’s disease.

09.
arXiv (CS.CL) 2026-06-19

Toten: Knowledge-Based Ontological Tokenization Of Physical Quantities And Technical Notation In Brazilian Portuguese

Byte-Pair Encoding tokenization is statistically efficient for vocabulary compression, but semantically blind to structured technical entities, fragmenting physical quantities, numbers, units, and symbolic expressions into lexically arbitrary subwords. We present TOTEN, a knowledge-based ontological tokenization framework that replaces statistical derivation with declarative classification grounded in a formal ontology of engineering entities (OEE). We formalize TOTEN as the triple : the ontology gathers types, structural principles, composition relations, and preservable invariants; the classification function maps raw text into typed regions; and the instantiator family yields a self-descriptive structured representation. Robustness derives from deterministic coupling with three external oracles: Pint (dimensional), Unicode Character Database (typographic), and RSLP (Portuguese morphology). Intrinsic evaluation covers four properties verifiable by construction – ontological atomicity, dimensional equivalence, typographic robustness, and numerical reconstruction – over an internal, physically validated benchmark (EngQuant, N=800) and four Brazilian Portuguese external corpora (N=1771 eligible cases). We also report detection recall, distinguishing coverage from conditional atomicity. Against eight state-of-the-art baselines, TOTEN achieves unit ontological atomicity in all contrasts and numerical reconstruction of 0.775-0.904 on external corpora, vs. 0.627-0.703 for the best baseline (Quantulum3); on EngQuant, 0.780 vs. 0.340. Differences are statistically significant (McNemar with Holm correction). Spearman correlation between internal and external rankings confirms concurrent validity of the control benchmark. Dimensional equivalence shows statistical parity with Pint, the oracle from which the system inherits dimensional authority.

10.
arXiv (CS.AI) 2026-06-12

LLM-as-an-Investigator: Evidence-First Reasoning for Robust Interactive Problem Diagnosis

arXiv:2606.13220v1 Announce Type: new Abstract: Large language models (LLMs) are increasingly used as interactive assistants for technical problem solving. However, when users provide incomplete descriptions or plausible but unverified explanations, LLMs may prematurely align with these assumptions and propose solutions before collecting sufficient evidence. We refer to this behavior as user-driven sycophancy: the tendency of an LLM to reinforce a user-provided hypothesis instead of testing alternative explanations. This paper introduces LLM-as-an-Investigator, an evidence-first agentic AI methodology for robust problem diagnosis. The approach is implemented through a Solution Investigator Agent, which estimates the ambiguity of an initial problem description, generates candidate hypotheses, asks targeted clarification questions, and updates hypothesis probabilities after each answer. Rather than producing an immediate response, the agent continues the investigation until the evidence makes one candidate explanation stronger than the alternatives. To evaluate the approach, we build a benchmark from solved technical forum threads in mechanical, electrical, and hydraulic domains. We use a three-agent evaluation pipeline in which a Problem-Solution Extractor Agent converts solved threads into structured cases, a Ground-Truth Evaluator Agent simulates the user while hiding the known solution, and the tested assistant attempts to recover the solution through dialogue. The experiments compare standard assistants, reasoning-oriented LLMs, and the proposed investigator-based model across LLM backbones. In addition to diagnostic accuracy, we analyze how standard assistants follow misleading user hypotheses in diagnostic cases. The results show that the proposed approach identifies the problem more accurately than direct prompting and reasoning-only baselines, while its evidence-first protocol helps reduce user-induced conversational bias.

11.
arXiv (quant-ph) 2026-06-12

Experiment-compatible measurement–feedback quantum state preparation with reinforcement learning

arXiv:2606.13005v1 Announce Type: new Abstract: Ground-state preparation is a critical task in quantum simulation and quantum computing, as it enables the study of correlated phases and the generation of entangled resource states. While measurement–feedback control has emerged as a promising route to state preparation, existing schemes either rely on handcrafted, task-specific policies or are designed using full quantum-state information that is unavailable in real experiments and becomes impractical for large many-body systems. Here we develop an adaptive measurement–feedback protocol based on reinforcement learning under partial observability. The controller uses only the history of experimentally accessible measurement outcomes to choose both the measurement operator and the feedback action in real time. To make training compatible with experiments, we introduce a stochastic terminal reward built from one-shot measurements of randomly sampled Hamiltonian components, avoiding unphysical full-state reconstruction while remaining an unbiased estimator of the target energy. We demonstrate the method by preparing ground states of the Bose–Hubbard model and by generating GHZ states, establishing a scalable and hardware-compatible route to quantum state preparation.

12.
arXiv (CS.LG) 2026-06-16

Drivers, Receivers, and Dynamic Linkages: The Directed Structure of SDG Interdependence, 2000–2024

arXiv:2601.20875v2 Announce Type: replace-cross Abstract: Governments with limited fiscal and administrative capacity need to know which Sustainable Development Goals (SDGs) propagate progress through the goal system and how quickly. We map the directed interdependence structure of all seventeen goals using a balanced panel of 114 countries observed annually from 2000 to 2024. The goal series are persistent, trending, and cross-sectionally dependent, so we apply two estimators matched to this regime: a Dumitrescu-Hurlin panel Granger non-causality test, run on first-differenced series, to recover the directed interaction network, and panel local projections with Driscoll-Kraay standard errors to measure the dynamic magnitude of 31 theory-derived indicator linkages. Of 272 directed goal pairs, 84 linkages survive false-discovery control (40 synergies, 44 trade-offs; network density 0.31). Synergies and trade-offs occur at comparable strength, so no single goal behaves as a universal accelerator, and the goal-level hierarchy itself is fragile. Driver-receiver rankings correlate weakly across lag orders and centrality metrics, and under a country bootstrap only two roles are distinguishable from zero: peace and strong institutions as the clearest net receiver, and poverty reduction as the most probable effect-size-weighted driver. The supported linkages are dynamic, accruing over four to five years: sanitation and poverty improvements are the strongest predictors of lower child mortality, and the education-child-health association is corroborated in independent World Development Indicators data across 183 countries. These results caution against rankings-based accelerator policy and support adaptive portfolios built on supported, time-lagged linkages monitored through constituent indicators.

13.
arXiv (CS.CL) 2026-06-17

Position: Coding Benchmarks Are Misaligned with Agentic Software Engineering

Coding agents have become a major mode of software engineering, but the benchmarks we use to compare them were designed in a pre-agent era: they collapse model, harness, and environment into a single end-to-end score, typically computed against one reference solution, with no component-level signal for iteration. We argue that current coding benchmarks are misaligned with agentic software engineering. A coding agent in practice is not a model: it is a system harness – a composite of models, harnesses, contexts, environments, and feedback signals, any one of which can move the benchmark score by margins comparable to those between adjacent model generations. We discuss three symptoms: (i) benchmark scores conflate the model with the rest of the harness; (ii) grading against a single reference solution penalises equally valid alternatives; and (iii) the absence of signal at the level of individual harness components makes the end-to-end system score difficult to iterate on.

14.
Science (Express) 2026-05-28

A Hormone Cell Atlas maps the human endocrine system at cellular resolution | Science

作者: 未知作者

Hormones act across tissues and organs to coordinate physiological functions. Drawing inspiration from the Human Cell Atlas, we analyzed expression of 379 hormone and receptor genes in a transcriptomic dataset comprising 14 million single cells and nuclei across 47 human tissues. Using hormone2cell, we mapped putative hormone-producing and hormone-receiving cell types, defining tissue-specific and cross-tissue endocrine signatures. We predicted non-classical sites of hormone expression, including secretin in plasmacytoid dendritic cells, inferred convergent hormone action and endocrine feedback loops, and implicated cell populations in monogenic endocrine disorders. In a cross-tissue integration of adipocyte datasets, we uncovered dynamic endocrine programs across depots, within adipocyte subtypes and through adipogenic differentiation. Cumulatively, the Hormone Cell Atlas ( hormonecellatlas.org.uk ) provides a comprehensive framework for dissecting hormonal impact on health and disease.

15.
arXiv (CS.AI) 2026-06-16

Beyond Case Law: Evaluating Structure-Aware Retrieval and Safety in Statute-Centric Legal QA

arXiv:2604.06173v2 Announce Type: replace-cross Abstract: Legal QA benchmarks have predominantly focused on case law, overlooking the unique challenges of statute-centric regulatory reasoning. In statutory domains, relevant evidence is distributed across hierarchically linked documents, creating a statutory retrieval gap where conventional retrievers fail and models often hallucinate under incomplete context. We introduce SearchFireSafety, a structure- and safety-aware benchmark for statute-centric legal QA. Instantiated on fire-safety regulations as a representative case, the benchmark evaluates whether models can retrieve hierarchically fragmented evidence and safely abstain when statutory context is insufficient. SearchFireSafety adopts a dual-source evaluation framework combining real-world questions that require citation-aware retrieval and synthetic partial-context scenarios that stress-test hallucination and refusal behavior. Experiments across multiple large language models show that graph-guided retrieval substantially improves performance, but also reveal a critical safety trade-off: domain-adapted models are more likely to hallucinate when key statutory evidence is missing. Our findings highlight the need for benchmarks that jointly evaluate hierarchical retrieval and model safety in statute-centric regulatory settings.

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

Light Interaction: Training-Free Inference Acceleration for Interactive Video World Models

arXiv:2605.31158v3 Announce Type: replace-cross Abstract: Interactive video world models generate video chunk by chunk in response to user-controlled camera movements, enabling applications such as real-time game simulation, virtual scene navigation, and embodied AI training. However, scaling to long interactive trajectories is prohibitively expensive due to growing context memory, quadratic attention complexity, and repeated denoising steps. We present Light Interaction, a training-free inference acceleration framework for interactive video world models. Our key insight is that interaction naturally enables trajectory-dependent adaptive computation: retrieved spatial memory can be discarded during novel exploration, temporal context can be adjusted according to local latent dynamics, and early-step model outputs can be reused when the camera revisits familiar regions. Based on this insight, Light Interaction combines adaptive context management, denoising cache acceleration, and hardware-software co-designed 3D block sparse attention with fused Triton kernels. Evaluated on HY-WorldPlay and Matrix-Game-3.0, Light Interaction achieves up to 2.59x speedup without model retraining while maintaining competitive visual quality.

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

StereoFactory: A Unified Merging Framework for Robust Stereo Matching

Stereo matching has advanced through foundation models trained on large-scale datasets, yet this paradigm suffers from a scalability bottleneck: incorporating new data requires costly joint retraining. Model merging offers a scalable post-hoc alternative by integrating knowledge from specialized models after source checkpoints are available. However, existing merging methods typically retain all available models or rely on greedy inclusion, which can preserve harmful task-vector interference. We propose StereoFactory, a coarse-to-fine evolutionary framework for adaptive model merging. Stage~1 employs a genetic algorithm to search the combinatorial space of model subsets, determining which models should participate. Stage~2 addresses module-level knowledge specialization (different functional modules exhibit distinct preferences for knowledge sources) through CMA-ES optimization of architecture-adaptive routing over the selected task vectors, with optional module-level scaling. Experiments across two architectures and four benchmarks demonstrate that StereoFactory consistently achieves the best four-benchmark average under the same checkpoint pool, reducing the average error from 3.80 to 3.30 on NMRF and from 2.88 to 2.19 on FoundationStereo relative to the strongest controlled baseline. The post-hoc search requires only 2.7–3.7\% of the corresponding joint-retraining wall-clock time. Analysis reveals that knowledge contributions are inherently module-specific, and selected subsets can transfer across architectures with minimal degradation. Code will be publicly released upon acceptance at: https://github.com/XiandaGuo/StereoFactory.

18.
PLOS Medicine 2026-05-27

Sequential chemo-immunotherapy followed by standard versus reduced thoracic radiotherapy for older and/or frail stage III non-small-cell lung cancer: A randomized open-label cohort trial

作者:

by Wei-Xiang Qi, Shuyan Li, Mengdi Wang, Huan Li, Feifei Xu, Lei Yao, Biao Yu, Linlin Chen, Gang Cai, Cheng Xu, Xianwen Sun, Zhiyao Bao, Jiayi Chen, Yi Xiang, Shengguang Zhao Background The appropriateness of concurrent chemoradiotherapy (cCRT) for older or clinically vulnerable stage III unresectable non-small-cell lung cancer (NSCLC) patients remains contentious. Furthermore, the survival implications of de-escalating thoracic radiotherapy (RT) intensity in this population have not been conclusively elucidated. Methods and findings We conducted a phase II randomized, open-label, two-cohort (non-comparative) trial at a tertiary hospital in China (NCT05557552). Between September 30, 2022 and April 30, 2024, we enrolled 56 older and/or frail patients with stage III NSCLC who were ineligible for cCRT. The primary endpoint was the 1-year progression-free survival (PFS) rate estimated using the Kaplan–Meier method. Secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. In the intention-to-treat (ITT) set, which included all 56 randomized patients who received at least one dose of study treatment, the 1-year PFS was 84.3% (95% confidence interval [CI] [70.3%, 98.3%]) in the standard RT group and 70.7% (95% CI [54.3%, 87.1%]) in the reduced RT group. In the per-protocol set (53 patients), the 1-year PFS was 82.9% (95% CI [68.9%, 98.8%]) in the standard RT group and 73.4% (95% CI [58.3%, 92.4%]), with a median follow-up of 24 months. Among 56 patients in the safety analysis set, 71.4% of patients experienced grade 3/4 adverse events (AEs) in the standard RT group and 53.6% in the reduced RT group. One patient (3.6%) in the reduced RT and three patients (10.7%) in the standardized RT experienced grade 5 AEs. The main limitations are the non-comparative design, small sample size, and lack of power to establish non-inferiority or superiority. Conclusion The current study suggested that reduced RT combined with sequential chemo-immunotherapy might be feasible for older/frail patients intolerant to cCRT, showing numerically similar survival outcomes. These exploratory findings warrant confirmation in larger, adequately powered randomized trials. Trial registration The trial had been registered on ClinicalTrials.gov on Sep 30, 2022.ClinicalTrials.gov NCT05557552

19.
medRxiv (Medicine) 2026-06-15

Reaching out-of-school girls with HPV vaccination: A qualitative evaluation in six low- and middle-income countries using the RE-AIM framework

Background Infection with human papillomavirus (HPV), the primary cause of cervical cancer, disproportionately affects women in low- and middle-income countries (LMICs). While school-based vaccination of adolescent girls against HPV is highly effective, this strategy systematically excludes out-of-school (OOS) girls. Using the RE-AIM framework, we explored strategies to reach OOS girls with HPV vaccination across six African and Asian LMICs. Methods We conducted semi-structured key informant interviews with 32 vaccination program stakeholders from Cambodia, Cameroon, Kenya, Malawi, Mozambique, and Uganda between May and September 2024. Interviews explored countries implementation successes, challenges, and strategies to reach OOS girls with HPV vaccination and sustainability considerations. Data were analyzed using a hybrid team-based thematic analysis approach guided by the RE-AIM framework. Results Community outreach-based strategies, typically integrated into routine immunization outreach, were identified as the most effective approach to reach OOS girls with HPV vaccination. Targeted strategies, such as locating outreach clinics in community venues frequented by OOS girls (e.g., churches, markets) enhanced implementation. Perceived effectiveness of these strategies varied across participants, and formal assessment of effectiveness was constrained by the absence of disaggregated vaccination coverage data by school enrollment status. Some subpopulations of OOS girls (i.e., girls in nomadic or migrant communities, urban OOS girls) were not readily reached through standard outreach approaches, prompting implementation of adapted and tailored strategies for these subpopulations. Costs associated with conducting outreach in harder-to-reach areas were major barriers to reaching OOS girls, presenting challenges to the sustainability and cost-effectiveness of these approaches. Conclusions Routine community outreach platforms were widely perceived as most effective for reaching OOS girls. Strengthening disaggregated monitoring systems, adapting outreach for harder-to-reach subpopulations of OOS girls, and financing delivery models for tailored outreach strategies will be critical to improving equitable HPV vaccine coverage among OOS girls.

20.
Nature (Science) 2026-06-10

A first-in-class pulsatile FXR agonist for bile-acid-related liver diseases

作者:

Nuclear receptors are central regulators of metabolism1, yet therapeutic strategies that enforce continuous receptor activation frequently lead to reduced efficacy and unacceptable toxicity. Here we report a first-principles drug design strategy that aligns pharmacokinetics with physiological signalling cycles. We developed linafexor, a potent non-bile-acid agonist of the farnesoid X receptor (FXR)2; it is engineered for rapid systemic clearance, which enables pulsatile receptor activation that mirrors endogenous bile acid dynamics3–5. Linafexor has robust efficacy across multiple preclinical models of metabolic dysfunction-associated steatohepatitis6, liver fibrosis7, primary biliary cholangitis and primary sclerosing cholangitis8,9. Transcriptomic analyses reveal that, unlike long-acting FXR agonists10,11, linafexor preserves cyclic FXR signalling, avoids receptor downregulation and prevents broad transcriptional dysregulation. Direct manipulation of delivery patterns demonstrates that sustained FXR activation—independent of compound identity—induces severe toxicity, establishing activation duration as a determinant of therapeutic index. In phase 1 clinical studies (ClinicalTrials.gov; NCT05082779), linafexor administered once daily produces transient FXR pathway engagement, marked by (1) induction of FGF1912–14, a key endocrine mediator of bile acid feedback regulation; and (2) suppression of C415, an intermediate reflecting hepatic bile acid synthesis, with no treatment-related adverse events. Together, these findings identify pulsatile FXR activation as a mechanistically grounded and clinically translatable strategy, and establish linafexor as a first-in-class therapeutic for bile acid–related liver diseases. Linafexor is a rapidly cleared FXR agonist designed to mimic natural bile acid signalling, achieving transient receptor activation with strong efficacy and reduced toxicity in preclinical and early clinical studies.

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

Factions Within, Uncertain Across: Within-Document Reader Sub-Groups in Social Highlighting

When many people highlight the same document, is the crowd a single consensus, or is it internally structured into reader sub-groups that mark different things – and is that structure a stable property of a reader or of the document? Building on prior work showing an individual's within-document highlighting signal is a whisper while individuality lives in selection, we ask the group-level question on a co-readership platform using a margin-preserving curveball null. Experiment 1: within a document, readers form strong sub-groups – pairs agree far beyond what shared salience, mark density, and sentence popularity predict (nearest-neighbour agreement z=+6.3, significant in 88% of documents). Under an eight-block region-preserving null, shared engagement with the same coarse regions of the document accounts for about 40% of this excess; the majority survives as finer reader-specific agreement (z=+3.6, 77% significant). So the within-document crowd is, in a descriptive sense, factional. Experiment 2: is that grouping a stable reader trait? Here we are honest about power. The cross-document split-half reproducibility of a pair's agreement is near zero pooled (+0.078 and 0.000 in two separately drawn samples), and a power calibration shows the test is informative only for pairs that co-read many documents. In the only informative high-overlap subset (k>=4), point estimates are positive but small-sample, imprecise across the separately drawn samples, never significant, and attenuate under the region-preserving null. We therefore leave cross-document stability unresolved: the data is consistent with anything from situational grouping to a weak-to-moderate stable reader trait. The crowd is factional within a document; whether its factions follow the reader across documents is, honestly, beyond our reach.

22.
arXiv (quant-ph) 2026-06-16

Sub-Poissonian Statistics and Quantum Non-Gaussianity from High-Harmonic Generation

arXiv:2602.10882v4 Announce Type: replace Abstract: Quantum technologies are powered by platforms to generate complex non-classical states of matter or light to realize applications. We investigate the non-classical properties of high-harmonic generation in semiconductors, an emerging photonic platform. Measuring the click statistics of three double-digit orders, we evaluate witness operators to certify the non-classicality of the generated states. We show that higher-order harmonics driven by a coherent laser are squeezed and entangled. The properties of the emission are well retrieved with an entangled Gaussian state model, obtained by numerical state optimization to multiple observables. Additionally, we perform inter-order heralded measurements to engineer the quantum state of the emission. The heralded states have distinct properties, showing sub-Poissonian photon statistics. Further, we witness the generation of a quantum non-Gaussian state, a resource highly relevant for quantum information. With this, we establish high-harmonic generation as a platform for generating quantum optical resources.

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

Audited Conformal Prediction for Classification under Unknown Distribution Shift

arXiv:2606.14909v1 Announce Type: cross Abstract: We consider the problem of uncertainty quantification for a pretrained classification model deployed under unknown distribution shift. We propose Audited Conformal Prediction (ACP), a method that leverages a small labeled dataset from the target population to train an auxiliary audit model identifying inputs where the legacy model is likely to fail. By integrating the audit model's outputs into the conformal prediction framework, ACP produces prediction sets that guarantee marginal coverage while achieving substantially higher conditional coverage in practice than existing approaches. We develop and analyze two complementary integration strategies – one targeting marginal coverage with improved conditional performance, the other providing explicit group-conditional coverage guarantees – and establish theoretical guarantees for both. Experiments on synthetic and real-world datasets validate the method and illustrate trade-offs between prediction set size and conditional coverage.

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

LiFT: Local Search via Linear Programming for Overfitting-Controlled Transformers

This paper proposes a Linear Programming (LP)-based local search framework for fine-tuning pretrained transformer models with explicit control against overfitting. The approach formulates transformer fine-tuning as a bilevel optimization-based regularization problem, in which model parameters and regularization hyperparameters are jointly updated. Information collected during initial warm-up iterations, including validation gradients and training Hessian information, is used to construct a local descent direction by solving an LP that minimizes a scaled directional derivative while preserving training optimality. This validation-aware descent direction enables focused local updates of both parameters and regularization hyperparameters, reducing overfitting without requiring repeated full retraining cycles. The resulting method, termed Linear Programming-based Fine-Tuning (LiFT) for transformers, differs from conventional fine-tuning by systematically identifying task-specific updates rather than relying on heuristic or grid-based hyperparameter selection. Experiments on GPT-2 Small fine-tuned on WikiText-2 demonstrate that LiFT enables effective adaptation through selective tuning of transformer blocks and regularization parameters, yielding consistent improvements in test perplexity across multiple layer configurations and regularization settings, with particularly pronounced gains in overfitting-prone scenarios. Beyond empirical performance, LiFT establishes a principled connection between transformer fine-tuning, bilevel optimization, local search, and regularization theory.

25.
Nature Medicine 2026-06-15

Long-term independent use of an intracortical brain–computer interface for speech and cursor control

Brain–computer interfaces (BCIs) can provide naturalistic communication and digital access to people with severe paralysis by decoding neural activity associated with attempted speech and movement. Recent work has demonstrated highly accurate intracortical BCIs for speech and cursor control, but two critical capabilities needed for practical viability were unmet: independent at-home operation without researcher assistance and reliable long-term performance supporting accurate speech and cursor decoding. Here we demonstrate the independent and near-daily use of a multimodal BCI with novel brain-to-text speech and computer cursor decoders by a man with paralysis and severe dysarthria due to amyotrophic lateral sclerosis. Over nearly 2 years, the participant used the BCI for more than 3,800 h at home with no researchers present to maintain rich interpersonal communication with his family and friends, independently control his personal computer and sustain full-time employment—despite being paralyzed. He communicated 183,060 sentences—totaling 1,960,163 words—at an average rate of 56 words per minute. He labeled 92% of sentences as being decoded at least mostly correctly. In formal quantifications of performance where he was asked to say words presented on a screen, attempted speech was consistently decoded with more than 99% word accuracy (125,000 word vocabulary). The participant also used the speech BCI as keyboard input and the cursor BCI as mouse input to control his personal computer, enabling him to send text messages and emails and to browse the internet. These results demonstrate that intracortical BCIs have the potential to support independent use in the home, marking a critical step toward practical assistive technology for people with severe motor impairment. An automated intracortical brain–computer interface, used at home with no researcher intervention, provides long-term and accurate restoration of speech-based communication and cursor-based computer usage in a person with severe dysarthria due to amyotrophic lateral sclerosis.