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01.
medRxiv (Medicine) 2026-06-15

International Consensus Guideline on Management of Genitourinary Adverse Events Associated with Prostate Cancer Radiotherapy

Purpose/Objective: Genitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers. Materials/Methods: A systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study. Results: Consensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis. Conclusions: The consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.

02.
bioRxiv (Bioinfo) 2026-06-20

Seed variation impacts clustering stability in Single-Cell RNA-Seq and can be mitigated by StAbility-BasEd-Reassignment (SABER)

Single-cell RNA-seq clustering is commonly treated as reproducible once a random seed is fixed, yet the choice of seed itself may alter cell assignments and downstream interpretation. We systematically quantified seed-induced clustering variability by running Louvain and Leiden clustering across 100 seeds in Seurat and Scanpy on 28 single-cell RNA-seq datasets from the Human Cell Atlas and IMMUcan. Using Element-Centric Consistency, we found that seed choice affected a substantial fraction of cells, with Scanpy showing more unstable assignments than Seurat on average, 40.46% versus 26.78% unstable cells, respectively. This increased stability came at a marked computational cost: Seurat required approximately 19-fold higher median memory than Scanpy. Seed-dependent clustering variability also propagated to cell-type annotation, particularly among transcriptionally related populations including macrophage/monocyte, endothelial/epithelial and T/NK cell states. To mitigate this instability, we developed StAbility-BasEd Reassignment (SABER), a Scanpy-based framework that identifies seed-sensitive cells across repeated clusterings and reassigns them to stable cluster cores using cosine similarity. SABER improved clustering quality while preserving annotation concordance and reduced median memory usage 3.5-fold compared with Seurat-Louvain. Our results identify seed choice as an underappreciated source of variability in single-cell analysis and provide a scalable strategy to improve clustering robustness.

03.
arXiv (CS.CV) 2026-06-18

S3OD: Towards Generalizable Salient Object Detection with Synthetic Data

Salient object detection exemplifies data-bounded tasks where expensive pixel-precise annotations force separate model training for related subtasks like DIS and HR-SOD. We present a method that dramatically improves generalization through large-scale synthetic data generation and ambiguity-aware architecture. We introduce S3OD, a dataset of over 139,000 high-resolution images created through our multi-modal diffusion pipeline that extracts labels from diffusion and DINO-v3 features. The iterative generation framework prioritizes challenging categories based on model performance. We propose a streamlined multi-mask decoder that handles the inherent ambiguity in salient object detection by predicting multiple valid interpretations. Models trained only on synthetic data achieve 20-50% error reduction in cross-dataset generalization, while fine-tuned versions reach state-of-the-art performance across DIS and HR-SOD benchmarks.

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

Softmax as Linear Attention in the Large-Prompt Regime: a Measure-based Perspective

arXiv:2512.11784v2 Announce Type: replace Abstract: Softmax attention is a central component of transformer architectures, yet its nonlinear structure poses significant challenges for theoretical analysis. We develop a unified, measure-based framework for studying single-layer softmax attention under both finite and infinite prompts. For i.i.d. Gaussian inputs, we lean on the fact that the softmax operator converges in the infinite-prompt limit to a linear operator acting on the underlying input-token measure. Building on this insight, we establish non-asymptotic concentration bounds for the output and gradient of softmax attention, quantifying how rapidly the finite-prompt model approaches its infinite-prompt counterpart, and prove that this concentration remains stable along the entire training trajectory in general in-context learning settings with sub-Gaussian tokens. In the case of in-context linear regression, we use the tractable infinite-prompt dynamics to analyze training at finite prompt length. Our results allow optimization analyses developed for linear attention to transfer directly to softmax attention when prompts are sufficiently long, showing that large-prompt softmax attention inherits the analytical structure of its linear counterpart. This, in turn, provides a principled and broadly applicable toolkit for studying the training dynamics and statistical behavior of softmax attention layers in large prompt regimes.

05.
arXiv (CS.CV) 2026-06-24

EgoSAT: A Comprehensive Benchmark of Egocentric Streaming Interaction Understanding

We introduce EgoSAT, the first comprehensive benchmark for egocentric video reasoning in streaming settings, designed to evaluate the capabilities of modern vision-language models (VLMs). The benchmark targets streaming interaction understanding, where video frames arrive sequentially and models must continuously interpret evolving visual context. EgoSAT unifies several previously distinct tasks within a single streaming framework. In this formulation, queries about completed events correspond to retrospective reasoning, queries about ongoing activities require online understanding, and queries about future actions involve prospective anticipation. This unified setting requires models to reason about the past, present, and future while operating under the constraint that only previously observed frames are available. EgoSAT contains 1,997 unique videos spanning 165 hours of egocentric footage and around 4,800 high-quality question-answer pairs, carefully designed to probe reasoning across varying temporal contexts. Using this benchmark, we evaluate a diverse set of both open-weight and closed-weight VLMs, providing a systematic assessment of their ability for streaming interaction understanding. By distinguishing answerability and conducting diagnostics on confidence of models, we find existing models not only struggle with prospective and retrospective modeling, but also exhibit severe mis-calibration: confidence often fails to track inherent answerability, leading to dangerous "confidently wrong" behaviors. Project page: https://leiyj23.github.io/EgoSAT/

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

SP$^3$: Spherical Priors for Plug-and-Play Restoration

In this paper, we introduce SP$^3$, a novel Plug-and-Play algorithm that accelerates maximum a posteriori image restoration by replacing denoisers with Spherical Encoders (SE) as generative priors. SP$^3$ approximates the intractable proximal prior step by utilizing the SE tightly structured latent space as a robust projection onto the natural image manifold. Alternating this projection with a closed-form data-consistency step, via Half-Quadratic Splitting, achieves stable convergence without requiring gradient computation during inference. This unique formulation unlocks "anytime" restoration capabilities, producing sharp, plausible images from the first iteration. Evaluations across a variety of image restoration tasks demonstrate that SP$^3$ achieves perceptual quality comparable to state-of-the-art zero-shot diffusion and flow methods while being $3$-$630\times$ faster.

07.
arXiv (CS.CL) 2026-06-19

Segment-Level Mandarin Chinese Speech-Based Cognitive Impairment Detection via an Autoencoder with Contrastive Learning

\noindentBackground and Objective: Speech has emerged as a low-cost and non-invasive digital biomarker with considerable potential for cognitive impairment detection. However, limited labeled data and cross-dataset variability remain major challenges for robust speech-based screening systems. \par\noindentMethods: We developed a segment-level representation learning framework for speech-based cognitive impairment detection. Speech recordings were divided into short segments and converted into spectrogram representations. To improve robustness under limited-data conditions, offline and online augmentation strategies were combined with autoencoder-based representation learning and contrastive objectives to enhance discriminative latent representations. \par\noindentResults: Experiments conducted on four independent Mandarin Chinese speech datasets demonstrated stable and competitive performance in both binary and three-class classification tasks, with particularly notable improvements in the clinically challenging three-class setting. Ablation studies further supported the effectiveness of the proposed framework. \par\noindentConclusions: The findings suggest that segment-level speech representation learning may provide a scalable and practical approach for cognitive impairment screening in resource-constrained clinical settings.

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

Towards Next-Generation Healthcare: A Survey of Medical Embodied AI for Perception, Decision-Making, and Action

Foundation models have demonstrated impressive performance in enhancing healthcare efficiency across a wide range of medical applications. Nevertheless, their limited ability to perceive, understand, and interact with the physical world significantly constrains their effectiveness in real-world clinical workflows, where safety-critical decision-making and physical execution are tightly coupled. Recently, embodied artificial intelligence (AI) has emerged as a promising physical-interactive paradigm for intelligent healthcare, enabling agents to operate in complex medical environments. As research in this area rapidly expands, understanding how intelligent agents function as integrated, end-to-end systems in clinical environments becomes increasingly critical. However, existing surveys on medical embodied AI largely emphasize individual aspects or functional components, lacking a unified system-level organization of the field. To support and consolidate recent advances, we systematically survey the core components of medical embodied AI, with a particular emphasis on the coordinated integration of perception, decision-making, and action. We further review representative medical applications and relevant datasets, and we analyze the major challenges encountered in real-world clinical practice. Finally, we discuss key directions for future research in this rapidly evolving field. The associated project can be found at https://github.com/VMVLab/Medical_Embodied_AI_Paper_List.

09.
arXiv (CS.AI) 2026-06-11

DiffCold: A Diffusion-based Generative Model for Cold-Start Item Recommendation

arXiv:2606.12245v1 Announce Type: cross Abstract: Cold-start item recommendation remains a persistent challenge in real-world systems due to the absence of interaction histories. While prior models attempt to bridge this gap using item content features, they universally suffer from the seesaw dilemma: enhancing performance for cold items inevitably degrades performance for warm items, and vice versa. We identify that this dilemma stems from a fundamental distributional disparity: warm item embeddings occupy a complex ``behavioral manifold" shaped by rich interaction signals, whereas cold item embeddings are constrained to a ``semantic manifold" derived solely from auxiliary content. Existing methods often force a rigid mapping between these inconsistent spaces, causing the model to sacrifice the precision of warm representations to accommodate cold ones. To address this, we propose DiffCold, a diffusion-based generative model that unifies warm and cold representations. Unlike GANs or VAEs, DiffCold leverages conditional diffusion to reconstruct warm item embeddings from content, preserving the underlying manifold structure without degradation. We further tailor this paradigm with two specific designs: a Retrieval-enhanced Aggregator that initializes generation using semantically similar warm items to bypass inefficient noise, and a Simulation-based Representation Alignment module that enforces distribution consistency between generated and real embeddings via contrastive learning. Experiments on three benchmarks confirm that DiffCold resolves the seesaw dilemma, consistently outperforming state-of-the-art methods across all metrics.

10.
arXiv (CS.LG) 2026-06-19

Influence-Guided Concolic Testing of Transformer Robustness

arXiv:2509.23806v2 Announce Type: replace-cross Abstract: Concolic testing for neural networks alternates concrete execution with constraint solving to search for inputs that flip model decisions. We present a concolic tester for Transformer classifiers that uses SHAP estimates to rank pending path predicates by their impact on the current prediction. To support self-attention with multiple heads in execution backed by SMT solving, we implement attention semantics in pure Python that are compatible with the solver and make the softmax boundary explicit by concretizing exponentiation arguments. We evaluate our method on CIFAR-10 across three compact Transformer classifiers, ResNet18, and VGG16 under a one-pixel budget and a 900s horizon. Across the 500 model–input pairs in this matched comparison, our method achieves 60% success, compared with 15% for a differential evolution baseline that treats the model as a black box. In the primary two-layer Transformer branch-ordering study, SHAP-based predicate prioritization raises success from 56% to 60% and reduces median attack time by 51%. These results show that influence-guided path exploration can make concolic testing a practical way to find adversarial examples in Transformer models.

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

Image Quality Assessment of Identity Cards Using Measures from Open Face Image Quality

This paper addresses the challenge of assessing image quality in ID cards in remote verification systems by applying capture-related quality measures from the Open Face Image Quality (OFIQ) standard to ID card images. Our preprocessing pipeline includes corner detection, perspective normalization, and comprehensive foreground masking to ensure accurate and unbiased quality measure computation. We evaluate the effectiveness of these measures by analyzing their correlation with the performance of three presentation attack detection (PAD) algorithms across four diverse ID card datasets, where two datasets contain bona fide, i.e. pristine, images and two contain printed mock ID cards. Our results suggest that quality assessment based on some OFIQ measures can significantly improve PAD performance.

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

CMIP-Forge: An Agentic System that Retrieves, Computes, and Self-Reviews Climate Science

arXiv:2606.17076v1 Announce Type: cross Abstract: The Coupled Model Intercomparison Project Phase 6 (CMIP6) has generated thousands of peer-reviewed publications documenting model configurations, evaluation procedures, emergent constraints, and projection uncertainties. As the community transitions toward CMIP7, efficiently extracting and operationalizing this unstructured knowledge alongside live data analysis represents a critical bottleneck. Here we present CMIP-Forge, a hybrid retrieval-augmented generation (RAG) and autonomous analysis system that bridges the gap between scientific literature and Earth System Grid Federation (ESGF) data archives. The system pairs a curated corpus of 6,581 CMIP6-related open-access publications (101,828 indexed chunks) with an agentic pipeline in which a tool-augmented worker plans and executes Python workflows over live climate data, while a panel of independent reviewer models audits its methodology end to end. CMIP-Forge introduces a multi-layered Defense-in-Depth architecture that enforces physical and methodological invariants through executable mechanisms: Abstract Syntax Tree (AST) static analysis, audited scientific primitives, and an autonomous adversarial peer-review protocol. We demonstrate the system's capabilities through end-to-end autonomous research pipelines spanning atmospheric teleconnections, ocean dynamics, regional extremes, and global warming projections. An agentic analysis system grounded in peer-reviewed literature, constrained by automated code guardrails, and audited by an independent adversarial review loop can complete complex climate-research workflows autonomously. The same experiments expose concrete failure modes of the review loop (sycophantic regression, REVISE verdicts that are never resolved, and the submission of stub code for review), each diagnosable from the immutable telemetry and provenance record released with the article.

13.
medRxiv (Medicine) 2026-06-15

Pulmonary extracellular vesicles drive alveolar macrophage dysfunction via microRNA transfer in Acute Respiratory Distress Syndrome

Background: Alveolar macrophage (AM) dysfunction contributes to Acute Respiratory Distress Syndrome (ARDS) pathogenesis. We investigated the role of extracellular vesicles (EVs) in mediating this dysfunction. Methods: Pulmonary EVs were isolated from broncho-alveolar lavage and non-directed bronchial lavage samples of ventilated sepsis patients with and without ARDS, and post-operative control patients via ultracentrifugation. AMs were isolated from lung tissue resections of lobectomy patients. AMs were treated with pooled EVs for 24 hours prior to functional, metabolic and autophagy profiling. EV cargo was profiled via small RNA transcriptomics and proteomics. Mechanistic role of EV microRNAs was assessed via mimic / antagomir transfection. Results: Pulmonary EVs from sepsis patients with ARDS impaired AM efferocytosis, and control EVs had no effect. ARDS EV treatment enhanced AM mitochondrial-linked respiration, but not glycolysis. ARDS EV treatment impaired LC3B-II and LAMP1 expression, indicating dysregulated AM autophagy-lysosomal machinery. Proteomics revealed downregulation of innate immune pathways in ARDS EVs. Transcriptomics revealed enrichment of 24 microRNAs in ARDS EVs; miR-652-3p was the most enriched, validated by RT-qPCR. EV miR-652-3p was associated with 90-day mortality (9.20 vs 0.59 RQ, p=0.0295) and inversely correlated with oxygenation (PaO2/FiO2). AM transfection with miR-652-3p mimic induced similar dysregulation of function and autophagy as ARDS EVs. Transfection of ARDS EVs with antagomirs to miR-652-3p prior to AM treatment partially rescued efferocytosis and autophagy. Conclusions: Targeting EV miR-652-3p may restore alveolar macrophage function and reduce excessive inflammation, thus offering a novel therapeutic strategy for patients with ARDS.

14.
arXiv (CS.CV) 2026-06-18

Test-Time Adaptation in Optical Coherence Tomography Using Trajectory-Aligned Time-Independent Flow

Optical coherence tomography (OCT) is essential in ophthalmology, but inconsistent image quality especially in low-cost devices hinders automated analysis. To address this, we introduce a flow-matching-based test-time adaptation method that generates high-quality surrogate images from noisy inputs. Typically, domain gaps between test and training data cause pixel distribution mismatches during the denoising process. We overcome this by matching the test image's histogram to synthetic reference trajectories, successfully aligning the input with expected distributions. Additionally, we remove the network's time conditioning to account for slight deviations in real-world noise distributions. Our approach achieves state-of-the-art performance in segmenting critical biomarkers for two stages of Age-related Macular Degeneration (AMD). Code is available: https://github.com/Veit21/tta-flow.

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

Brep2Shape: Boundary and Shape Representation Alignment via Self-Supervised Transformers

arXiv:2602.07429v2 Announce Type: replace-cross Abstract: Boundary representation (B-rep) is the industry standard for computer-aided design (CAD). While deep learning shows promise in processing B-rep models, existing methods suffer from a representation gap: continuous approaches offer analytical precision but are visually abstract, whereas discrete methods provide intuitive clarity at the expense of geometric precision. To bridge this gap, we introduce Brep2Shape, a novel self-supervised pre-training method designed to align abstract boundary representations with intuitive shape representations. Our method employs a geometry-aware task where the model learns to predict dense spatial points from parametric Bézier control points, enabling the network to better understand physical manifolds derived from abstract coefficients. To enhance this alignment, we propose a Dual Transformer backbone with parallel streams that independently encode surface and curve tokens to capture their distinct geometric properties. Moreover, the topology attention is integrated to model the interdependencies between surfaces and curves, thereby maintaining topological consistency. Experimental results demonstrate that Brep2Shape offers significant scalability, achieving state-of-the-art accuracy and faster convergence across various downstream tasks.Code is available at this repository: https://github.com/thuml/Brep2Shape.

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

An alternative approach to well-posedness of McKean-Vlasov equations arising in Consensus-Based Optimization

arXiv:2512.19446v4 Announce Type: replace-cross Abstract: In this work we study the mean-field description of Consensus-Based Optimization (CBO), a derivative-free particle optimization method. Such a description is provided by a non-local SDE of McKean-Vlasov type, whose fields lack of global Lipschitz continuity. We propose a novel approach to prove the well-posedness of the mean-field CBO equation based on a truncation argument. The latter is performed through the introduction of a cut-off function, defined on the space of probability measures, acting on the fields. This procedure allows us to study the well-posedness problem in the classical framework of Sznitman. Through this argument, we recover the established result on the existence of strong solutions, and we extend the class of solutions for which pathwise uniqueness holds.

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

Graph Structured Combinatorial Semi-Bandit with Nonlinear Reward Associations through Separable Signals

arXiv:2606.14650v1 Announce Type: new Abstract: The identification of optimal structures within vast arrays of interconnected data necessitates significant sampling- and computational effort. Learning and leveraging underlying signal dependencies can improve efficiency and predictive capabilities considerably, but the ubiquity of nonlinear statistical relations amplifies the complexity of such undertakings. In this paper, we develop novel generic and adaptive strategies equipped with routines for graph-based causal reward modeling, analytic reproducing kernel methods, and Taylor approximation of functional processes. We establish theoretical performance guarantees sublinear in time and linear in data volume over time. Our analyses cover robustness to a multitude of uncertainties arising from noise interference, gradual model convergence, and solution space mismatch. The framework's general appeal is substantiated by a minimalistic set of conditions or reliance on prior estimates, while various outlined modifications address specific or extended settings. To demonstrate practical effectiveness, we conduct numerical experiments using both benchmarked synthetic and real-world transportation datasets.

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

Auditing Machine Unlearning: A Systematic Research on Whether Models Truly Forget

arXiv:2606.16110v1 Announce Type: new Abstract: Machine unlearning has been extensively studied in response to growing privacy concerns and regulatory requirements. However, auditing whether unlearning algorithms have truly erased the influence of specific data remains an open challenge. The lack of reliable and practical auditing mechanisms can lead to critical privacy risks, such as residual information leakage. This paper initiates a systematic investigation into whether existing unlearning algorithms can truly forget the designated data. We propose the first practical and general-purpose auditing framework for machine unlearning, inspired by the concept of proof of ignorance. Our framework addresses the key practicality limitations of existing methods by eliminating the need for retraining-from-scratch baselines, avoiding the training of large numbers of shadow models, and requiring no intrusive intervention in the original training process. To evaluate the effectiveness of our framework, we first conduct validation experiments to verify its soundness and completeness. We then perform comprehensive experiments across six datasets and ten representative unlearning methods. The results demonstrate that our framework reliably distinguishes between successful and failed unlearning. In particular, we observe that retraining-based and fine-tuning-based methods can achieve effective unlearning, even when the target data remain in the original dataset. In contrast, de-optimization-based methods fail to achieve true unlearning and instead degrade the model's performance. Fisher/Hessian-based methods also fail to unlearn requested data, even formal certification is provided. Moreover, we show that our framework is robust against fake unlearning attempts and generalizes well to large language models.

19.
arXiv (quant-ph) 2026-06-11

The quantum harmonic oscillator and the real Hilbert space

arXiv:2606.12060v1 Announce Type: new Abstract: The harmonic oscillator is considered within generalized frameworks using complex and quaternionic numbers. The classical oscillator is considered in terms of a complex position function, and quantum oscillators are examined in terms of complex wave functions, and in terms of quaternionic wave functions as well. Both of the quantum solutions are obtained within the real Hilbert space formalism. The results reveal the complex and quaternionic descriptions as suitable frameworks for non-stationary processes, including damped oscillations, forced oscillations, and additionally self-interacting processes that cannot be appropriately described otherwise.

20.
arXiv (quant-ph) 2026-06-19

Maximum entropy principle for quantum processes

arXiv:2506.24079v3 Announce Type: replace Abstract: The maximum entropy principle, as applied to quantum systems, is a fundamental prescript positing that for a quantum system for which we only have partial knowledge, the maximum entropy state consistent with the partial knowledge is a valuable choice as the system's state. An intriguing result is that in case the only prior knowledge is of a fixed energy, the maximum entropy state turns out to be the thermal state, a ubiquitous state in several arenas, especially in statistical mechanics. We extend the consequences of this principle from static quantum states to dynamic quantum processes. We establish that a quantum channel attains maximal output entropy under a fixed energy constraint if and only if it is an absolutely thermalizing channel, where the fixed output is the thermal state corresponding to that energy. Our results have potential implications for understanding the informational and thermodynamic utility of quantum channels under physical constraints. As an application, we examine the consequences for private randomness distillation from fixed energy constrained quantum processes.

21.
PLOS Computational Biology 2026-06-04

CIPHER: An end-to-end framework for designing optimized aggregated spatial transcriptomics experiments

by Zachary Hemminger, Haley De Ocampo, Fangming Xie, Zhiqian Zhai, Jingyi Jessica Li, Roy Wollman Motivation Most imaging-based spatial transcriptomics methods measure individual genes, which limits scalability and typically requires integration with scRNA-seq to recover full cellular states. Recent approaches such as CISI, FISHnCHIPs, and ATLAS address this limitation by measuring aggregate transcriptional signatures, where multiple genes are pooled into each channel to increase throughput. While aggregate measurements improve scalability, they shift the problem from gene selection to feature design. For effective integration with scRNA-seq, these signatures must be not only discriminative in transcriptional space but also straightforward to measure, with balanced signal, sufficient dynamic range, and robustness to experimental noise. By optimizing decoding accuracy in isolation, existing methods leave substantial performance on the table. Results We present CIPHER (Cell Identity Projection using Hybridization Encoding Rules), a neural-network framework that jointly optimizes the experimental encoding matrix, i.e., the way that genes are aggregated to signatures, and the downstream cell embedding. CIPHER integrates the physical limits of imaging assays directly into its loss function, shaping the latent space to maximize discriminability while maintaining robustness to measurement noise and signal constraints. Using a large-scale mouse brain scRNA-seq reference, we show that CIPHER-designed encodings yield latent spaces with improved cell-type separability, uniform signal utilization, and greater resilience to hybridization variability, resulting in higher decoding accuracy from both simulated and experimental data. Conclusion CIPHER formulates aggregate signature design as a joint optimization problem over decoding accuracy and experimental measurability. This enables systematic, scRNA-seq-aligned feature design for scalable spatial transcriptomics based on aggregate measurements. Availability Code and documentation are available at https://github.com/wollmanlab/Design/.

22.
medRxiv (Medicine) 2026-06-22

Reform of the intermediate level of the health system in the Democratic Republic of the Congo: Adaptations and limits in the stabilization of the personnel of the Provincial Health Division: A cohort study.

Background: Human resources are one of the pillars of health systems. Since the World Health Organization's report on human resources issues, several countries have integrated this component into the various reforms aimed at strengthening their health systems. This study aims to explore the effects of reforming the intermediate level of a health system operating in a fragile state context. Methodology Our study was conducted in the Democratic Republic of Congo (DRC). It was a cohort study of the staff of the 14 Provincial Health Divisions (PHD) out of the 26 existing in the DRC. We established a database of the staff of these 14 PHD from 2016, just after the implementation of the intermediate level reform and the allocation of this staff by the Ministry of Health. We did a recall in 2021, in each of these PHD to survey this staff through a structured questionnaire and supplemented by the files of the agents available in each PHD. Sociodemographic, economic and academic variables were collected and analyzed. Data were entered into an Excel 2016 database and processed with SPSS software version 25. The chi-square test was used for comparison of proportions with a statistical significance level of p < 0.05. Risk ratios ratios (RR) and their 95% confidence intervals were calculated as measures of association. The error threshold was set at 5%. Results A total of 657 agents with an average age of 45.2 years had been identified in 2016 at the start of the survey and in 2021, 118 or 18% of them were no longer part of the PHD agents. Among the causes of absence noted: 48% of agents placed on leave, 16% promoted to other functions within the health system, 16% desertion and dismissal and 11% cases of death. 19.8% of absentees are executives, 19.5% men against 10.3% women; 22.3% of absentees in unstable provinces against 16.6% in stable ones. The factors associated with the absence of agents in the PHD remain the reaching of retirement age [RR (95% CI) = 5.5 (1.2-24.9) ]and male agents [RR (95% CI) = 3.2 (1.3-7.9)]. Among the agents who remained, 92% kept their initial position, 6% were subject to an internal permutation accompanied by a promotion. The factors associated with the stability of human resources at the level of the Provincial Health Division are: female gender, manager with experience or seniority > 5 years, Age > 35 years, Stable province, Presence of a partner bonus. Conclusion Even in a crisis and fragile context, health system reform is possible. It is possible to organize staff recruitment through a selection process independent of the political authorities of the Ministry of Health and supported by the technical services of the Ministry and partners . Experience and the presence of a financial bonus are motivating factors for staff stability. The involvement of Technical and Financial Support Partners in the recruitment process helped the Ministry of Health to minimize political influence in the recruitment of middle-level executives.

23.
medRxiv (Medicine) 2026-06-15

Comparative Analysis of Machine Learning Models vs. Traditional Clinical Calculators for Cardiovascular Risk Prediction

Background: Cardiovascular diseases (CVD) remain the leading global cause of mortality, responsible for approximately 31% of all deaths worldwide in 2021. Traditional risk calculators, including Framingham, ASCVD, SCORE, and SCORE2, have long constituted the cornerstone of primary prevention strategies; however, they were derived predominantly from high-income European and North American populations, thereby limiting their predictive accuracy in diverse epidemiological contexts, particularly among Hispanic/Latino communities. Machine learning (ML) offers an alternative to capture the non-linear interactions inherent in biomedical data. Objective: The present study develops and validates ML-based models for cardiovascular mortality prediction using the National Health and Nutrition Examination Survey (NHANES) 1999-2018 dataset, and systematically compares their discriminative performance against eleven conventional clinical CVD risk calculators. Materials and Methods: A dedicated software platform, "CardioPrediQ," was designed to integrate multiple CVD calculators with ML-based risk assessment. A cohort of 12,847 participants with 16 predictor variables was derived from NHANES. Six algorithms (Logistic Regression, Cox Proportional Hazards, Gradient Boosting, AdaBoost, Random Forest, and Extra Trees) were trained in combination with six class-balancing strategies, yielding 36 model configurations. All models were trained on a stratified 70/30 split and calibrated using the Saerens prior probability adjustment method. Performance was evaluated using AUC-ROC, sensitivity, specificity, F1-score, and a weighted composite score. DeLong's test was employed to assess the statistical significance of AUC differences between the best-performing ML model and each conventional calculator. Results: Gradient Boosting with 2:1 oversampling and Saerens calibration achieved the best overall performance (AUC = 0.8934; composite score = 0.7904), outperforming all traditional calculators in composite ranking. The top six positions were occupied exclusively by ML and statistical models. The mean age of cardiovascular decedents was 67.43 years compared with 47.74 years among survivors. DeLong's test confirmed statistical superiority over six traditional CVD calculators (p < 0.05), whereas the difference against the top-performing calculators (ASCVD, HEARTS Caribbean, ASCVD Colombia, SCORE2, HEARTS North America) did not reach statistical significance. Age dominated feature importance at 41.2% relative weight, followed by systolic blood pressure (18.7%). Saerens calibration reduced the Brier score from 0.1286 to 0.1158, substantially improving probability calibration. Conclusions: ML models demonstrated superior composite performance over traditional calculators. The statistical equivalence with the highest-performing conventional calculators in the NHANES cohort is context-dependent and validates the methodological pipeline. The CardioPrediQ platform addresses the critical need for integrated, scalable CVD risk assessment tools, which is particularly relevant for Latin American populations where calculator validation remains limited. These findings support the integration of calibrated ML-based risk prediction into clinical practice while underscoring the importance of probability calibration for informed clinical decision-making.

24.
arXiv (CS.CV) 2026-06-17

A Quantitative Analysis of Multimodal Biomarkers in Alzheimer's Disease

Despite increasing adoption of multimodal approaches in Alzheimer's Disease (AD) research – aimed at integrating molecular, structural, clinical, and genetic biomarkers to enhance disease characterization – the relationships among these modalities remain poorly understood. A systematic analysis of their dynamic interaction is essential for improving disease modeling, identifying redundant assessments, and reducing patient burden and acquisition costs. In this paper, we present a quantitative analysis of multimodal AD biomarkers by integrating tau-PET, structural MRI, cognitive scores (MMSE and CDR), and APOE4 data from 789 subjects drawn from the ADNI dataset. In our analyses, we (A) quantify cross-modal mutual information and explained variance to assess redundancy and predictive dependencies; (B) examine associations between tau topologies and structural atrophy across brain regions to select informative ROIs; (C) perform a statistical decomposition of the tau-cognition association into atrophy-related and atrophy-independent components; (D) and identify a dominant neurodegenerative trajectory that aligns with cognitive decline. This study provides a systematic characterization of cross-modal relationships, improving the interpretability and selection of biomarkers in AD. Code is publicly available at: https://github.com/antonioscardace/Multimodal-AD.

25.
medRxiv (Medicine) 2026-06-15

Repurposing cardiovascular disease risk models to predict incident and co-occurring cardiovascular, cardiometabolic and neurocognitive outcomes.

Background: Cardiovascular disease (CVD), cardiometabolic and neurocognitive conditions share risk factors and frequently co-occur. We evaluated whether four established CVD risk prediction models (QRISK3, PCE, SCORE2, SCORE2-OP) can be repurposed to predict 10-year risk of these conditions and their co-occurrence with CVD. Methods: The models were recalibrated using 20% of the UK Biobank (UKB) and evaluated in the remaining 80%. We performed external validation using data from Clinical Practice Research Datalink (CPRD) Aurum, assessing model discrimination (c-statistics) and calibration (intercept and slope). We used permuted feature importance to determine the influence of each individual predictor in the models. Results: Depending on the model, the c-statistics for incident CVD ranged from 0.71 to 0.74 in the UKB test set (16,137 events). Discrimination was equal to or higher than CVD when evaluated against non-traditional CVD outcomes: 0.74 to 0.77 for heart failure (3,471 events), 0.72 to 0.73 for atrial fibrillation (9,213 events), 0.73 to 0.75 for peripheral arterial disease (1,927 events) and 0.80 to 0.82 for abdominal aortic aneurysm (595 events). For the multimorbidity endpoints, model discrimination ranged from 0.74 for the composite of CVD and T2DM (SCORE2-OP) to 0.83 for the composite of CVD and dementia or Parkinson's disease (QRISK3). When considering the onset of any cardiovascular, cardiometabolic, or neurocognitive outcome discrimination ranged from 0.71 to 0.72. The repurposed models slightly underestimated the predicted risk in the CPRD compared to the UKB: average difference in calibration intercept was at most -0.64. After age and sex, smoking status and systolic blood pressure contributed most to model predictions. Conclusions: Repurposed CVD models can be used to identify 10-year risk of many CVD-related conditions and their multimorbidity. These may be used to support risk-based approaches to prevention and screening. The repurposed models have been made available at: https://repurposed-cvd-risk-models.shinyapps.io/cvd_cmd_dementia_app/ Keywords: Risk prediction; cardiovascular disease; cardiometabolic disease; dementia; disease prevention.