arXiv:2605.25681v1 Announce Type: cross Abstract: Designing a single molecule that modulates two targets is a promising strategy for polypharmacology, but it remains substantially harder than standard single-target generation because one candidate must satisfy two binding requirements while preserving drug-likeness and synthesizability. Existing dual-target generative methods typically introduce dual-target capability by either retraining the generator or intervening in the diffusion process during sampling. The former can be costly and difficult to stabilize when dual-target supervision is sparse, while the latter may be sensitive to denoising-time target balancing and competing update directions. These limitations motivate a generator-preserving alternative that keeps the pretrained prior intact: can dual-target candidates instead be recovered from the input space of a frozen single-target diffusion model, without modifying its parameters or denoising dynamics? We formulate this task as a constrained multi-objective optimization problem and propose REUSE, a hierarchical evolutionary input-space search framework that combines pair-conditioned exploration with structured multi-stage selection to enforce dual-target affinity, chemical quality, and diversity. Experiments show that, compared with methods that modify the diffusion process, REUSE consistently improves dual-target affinity and balance, achieving a 20.9-percentage-point gain in Dual High Affinity over the strongest prior baseline while maintaining competitive molecular quality.

arXiv:2510.08350v3 Announce Type: replace-cross Abstract: Objective: Enteral nutrition (EN) delivery in the ICU remains suboptimal due to limited personalization and uncertainty regarding appropriate calorie, protein, and fluid targets under dynamic metabolic demands. We introduce DeepEN, a reinforcement learning (RL) framework for personalized EN optimization using electronic health record data. Methods: DeepEN was trained on over 11,000 ICU patients from MIMIC-IV to generate 4-hourly, patient-specific caloric, protein, and fluid targets. The state representation incorporated demographics, comorbidities, vital signs, laboratory values, and recent interventions. A physiologically aligned reward framework balanced biomarker stability with long-term survival. Policy learning employed a dueling double deep Q-network with Conservative Q-Learning regularization to enable safe offline training. Results: DeepEN achieved the highest estimated policy value ($V^\pi = 9.48$) and the lowest calibrated mortality (18.8 +/- 1.0%), representing a 4.0 percentage-point absolute reduction compared with clinician practice (22.8%). The policy also demonstrated superior metabolic stability, achieving the highest proportion of glucose, phosphate, and sodium values within target range. Furthermore, deviation from the DeepEN policy was independently associated with increased mortality and biomarker instability, whereas deviation from a random policy showed no such association. Interpretability analyses further indicated that recommendations were conditioned on physiologically relevant markers of organ function and metabolic status rather than static dosing heuristics. Conclusion: DeepEN demonstrates the feasibility of conservative offline RL for safe, individualized EN optimization, highlighting the potential of data-driven personalization to complement guideline-based approaches in critical care.